CA1328113C - Process for the manufacture of novel unsaturated amino acid compounds - Google Patents

Abstract

A process for the manufacture of novel unsaturated amino acid compounds Abstract The invention relates to a process for the manufacture of unsaturated amino acid compounds of formula (I), in which R1 is hydrogen, alkyl or hydroxy, R2 is hydrogen, alkyl, halo-alkyl, hydroxyalkyl, lower alkoxyalkyl, aryl-lower alkyl, lower alkenyl, halogen or aryl, R3 is hydrogen, alkyl or aryl, R4 is hydrogen or alkyl, R5 is unsubstituted carboxy or esterified or amidated carboxy, R6 is an amino group that is unsubstituted or substituted by alkyl or by arylated alkyl, A is unsubstituted or alkyl-substituted .alpha.,.omega.-alkylene having from 1 to 3 carbon atoms (C-atoms) or is a direct bond, and B is methylene or a bond, with the proviso that A is unsubstituted or alkyl-substituted .alpha.,.omega.-alkylene having from 1 to 3 C-atoms when B is a direct bond, and the salts thereof, characterised in that in a compound of formula

Description

~ 8 ~ i 3 4-16618/+

_ ~rocess for the manufacture of novel unsaturated amino acid compounds The invention relates to a process for the manufacture of unsaturated amino acid compounds of formula ~3 ~4 HO~ A ~
~ 1 z in which R1 is hydrogen, C1-C8alkyl or hydroxy, Rz is hydrogen, C1-C8-alkyl, halo-C1-C4alkyl, mono- or dihydroxy-C1-C7alkyl, mono- or di-C1-C4-alkoxy-C1-C7alkyl, aryl-C1-C4alkyl, C2-C6alkenyl, halogen or aryl, R3 is hydrogen, C1-C8alkyl or aryl, R4 is hydrogen or C1-Cgalkyl, Rs is carboxy, C1-C8alkoxycarbonyl, phenyl-C1-C4alkoxycarbonyl which is unsub-stituted or substituted by C1-C4alkyl, C1-C4alkoxy and/or halogen, carbamoyl, mono- or di-C1-C4alkylcarbamoyl or 5- to 7-membered alkylen-carbamoyl, R~ is amino, mono- or di-C1-C4alkylamino or phenyl-C1-C4alkyl-i amino, A is unsubstituted or C1-C4alkyl-substituted ~,~-C1-C3alkylene or I a direct bond and B is methylene or a direct bont, with the proviso that ~` A is unsubstituted or alkyl-substituted ~,~-alkylene having from 1 to 3 C-atoms when B is a direct bond, and to the salts thereof.
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The compounds of formula I contain at least one chiral centre and may be in the form of enantiomers or enantiomeric mixtures, such as racemates, and if they contain more than one chiral centre, they may also be in the form of diastereoisomers or diastereoisomeric mixtures. The carbon-carbon double bond of the compounds according to the invention is in the trans-configuration in relation to R2 and R3, or in relation to A and B, that is to say the compounds of formula I are compounds of the E-series.

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132g~3 Compounds of formula I in which R1 is hydrogen are phosphonous acids, those in which R1 is alkyl are phosphinic acids, and thoss in which R1 is hydroxy are phosphonic acids. In the names of the compounds of formula I
that are to be regarded as substituted carboxylic acids, the prefixes "phosphino" (R1 is hydrogen), "phosphonyl" (R1 is alkyl) and "phosphono"
(R1 is hydroxy) are used.

Esterified carboxy is, for example, carboxy esterified by an aliphatic or araliphatic alcohol, such as an unsubstituted or substituted lower alkanol or phenyl-lower alkanol, such as corresponding lower alkoxy- or phenyl-lower alkoxy-carbonyl. Esterified carboxy is preferably pharma-ceutically acceptable esterified carboxy, such as, for example, esteri-fied carboxy that can be converted into carboxy under physiological conditions. These esters of formula I may also be called prodrug esters.

Carboxy esterified in a pharmaceutically acceptable manner is, for example, lower alkoxycarbonyl; lower alkoxycarbonyl substituted in a position higher than the ~-position by amino, by mono- or di-lower alkyl-amino or by hydroxy; lower alkoxycarbonyl substituted by carboxy, for example ~-carboxy-substituted lower alkoxycarbonyl; lower alkoxycarbonyl substituted by lower alkoxycarbonyl, for example ~-lower alkoxycarbonyl-substituted lower alkoxycarbonyl, aryl-lower alkoxycarbonyl, for example unsubstituted or substitutsd benzyloxycarbonyl, or pyridylmethoxycar-bonyl; lower alkanoyloxy-substituted methoxycarbonyl, for example pivaloyloxymethoxycarbonyl; lower alkoxymethoxycarbonyl substituted by lower alkanoyloxy or by lower alkoxy; bicyclo[2.2.1]heptyloxycarbonyl substituted methoxycarbonyl, such as bornyloxycarbonylmethoxycarbonyl;

3-phthalidoxycarbonyl; 3-phthalidoxycarbonyl substituted by lower alkyl, lower alkoxy or by halogen; or lower alkoxycarbonyloxy-lower alkoxycar-bonyl, for example 1-(methoxy- or ethoxy-carbonyloxy)-ethoxycarbonyl.

Especially preferred prodrug esters are, for example, lower alkyl esters having up to four carbon atoms, such as, for example, butyl or ethyl esters, lower alkanoyloxymethyl esters, such as, for example, pivaloyl-oxymethyl ester, lower alkyl esters that have from two to four carbon atoms in each lower alkyl group and are substituted in a position higher ~ i !:``

13~13 ~ 3 ~ 21489-7~96 than the ~-position by di-lower alkylamino, such as, for example, 2-di-ethylaminoethyl ester, and also pyridylmethyl esters, such as 3-pyridyl-methyl ester.

In amidated carboxy the amino group is, for example, amino that is un-substituted, monosubstituted by hydroxy, or mono-or di-substituted by aliphatic radicals, such as amino, hydroxyamino, mono- or di-lower alkyl-amino or lower alkyleneamino having from 5 to 7 ring members. Preferably, amidated carboxy is pharmaceutically acceptable amidated carboxy, such as, for example, amidated carboxy that can be converted into carboxy ~ under physiological conditions.
:' ; Preferred pharmaceutically acceptable amides are compounds of formula Iin which Rs is carbamoyl, lower alkylcarbamoyl, for example ethylcarba-moyl, di-lower alkylcarbamoyl, for example diethylcarbamoyl, or in the form of N-(di-lower alkylamino)-lower alkylcarbamoyl, for example N-(2-diethylaminoethyl)carbamoyl or (3-diethylaminopropyl)carbamoyl.

Within the scope of this invention, alkyl is a saturated aliphatic hydro-carbon radical having, for example, up to 12 carbon atoms, but especially having up to 8 carbon atoms, the latter range also being represented by the term lower alkyl.
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Alkylene having from 1 to 3 carbon atoms is methylene, 1,2-ethylene or 1,3-propylene. ~,~-Alkylene substituted by alkyl is substituted at any ; position. Thus, methylene substituted by alkyl is, for example, 1,1-ethylene, 1,1-butylene or 1,1-octylene, 1,2-ethylene substituted by alkyl is, for example, 1,2-propylene, 1,2-butylene, 2,3-butylene, 1,2-pentylene or 1,2-nonylene, and 1,3-propylene substituted by alkyl is, for example, 1,3-butylene, 1,3-pentylene or 1,3-decylene.

Aryl, also in definitions such as aroyl or aryl-lower alkoxycarbonyl, represents aromatic hydrocarbon radicals that are unsubstituted or sub-stituted by lower alkyl, hydroxy, protected hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl or by nitro, and is, for example, unsubstituted or correspondingly sub-, .

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``: 1328113 stituted 1- or 2-naphthyl, but preferably unsubstituted or corresponding-ly substituted phenyl, such as phenyl, lower alkylphenyl, for example methylphenyl, hydroxyphenyl, halophenyl, for example 4-halophenyl, such as 4-chlorophenyl, benzyloxyphenyl, lower alkoxyphenyl, for example methoxyphenyl, hydroxymethylphenyl, aminomethylphenyl or nitrophenyl.

The general terms used hereinbefore and hereinafter, unless defined otherwise, have the following meanings:

The term "lower" indicates that groups or compounds so defined contain up to and including 8, preferably up to and including 4, carbon atoms.

C1-C4Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl, but can also be Cs-C8alkyl, such as n-pentyl, n-hexyl, n-heptyl or n-octyl, and is preferably methyl.

Aryl-Cl-C4alkyl, also in definitions such as aryl-C1-C4alkylamino, is, for example, aryl-C1-C~,alkyl in which aryl has the meanings given above, and is especially, for example, unsubstituted phenyl-C1-C4alkyl, such as benzyl or 1- or 2-phenylethyl.

Cz-C4Alkenyl is preferably bonded by way of an sp3-hybridised carbon atom , and is, for example, 2-propenyl, 2- or 3-butenyl but can also be vinyl.

C1-C4Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy or tert.-butoxy.
:
Halogen preferably has an atomic number of up to 35 and is especially chlorine, or also fluorine or bromine, but can also be iodine.
:
Halo-Cl-C4alkyl is, for example, fluoromethyl, trifluoromethyl or 1- or ~ 2-chloroethyl.
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.

~3~113 - 5 - 214~9-7496 Mono- or di-hydroxy-Cl-C7alkyl, carries the hydroxy group(s) especially in a position higher than the ~-position and is, for example, hydroxy-methyl or especially mono- or di-hydroxy-C2-C7-alkyl, such as 2-hydroxy-ethyl, 3-hydroxy- or 2,3-dihydroxy-propyl, 4-hydroxy- or 2,4-dihydroxy-butyl, or 5-hydroxy-, 2,5-dihydroxy- or 3,5-dihydroxy-pentyl.

~ono- or di-Cl-C4alkoxy-C1-C7alkyl, carries the lower alkoxy group(s) especially in a position higher than the ~-position and is especially Cl-C4-alkoxy-C2-C4-alkyl, for example, 2-methoxy-, 2-ethoxy-, 2-propoxy-or 2-isopropoxy-ethyl, 3-methoxy- or 3-ethoxy-propyl or 3,3-dimethoxy-, 3,3-diethoxy-, 2,3-dimethoxy- or 2,3-diethoxy-propyl or 4,4-dimethoxy-butyl, but may also be methoxy-, ethoxy-, dimethoxy-, propoxy- or iso-propoxy-methyl.

Mono- or di-Cl-C4alkylamino is, for example, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino or butylamino.
';
Salts of compounds according to the invention are especially pharma-ceutically acceptable non-toxic salts of compounds of formula I. Such salts are formed, for example, from the carboxy group present in com-pounds of formula I, and are especially metal or ammonium salts, such as alkali metal and alkaline earth metal salts, Eor example sodium, potassium, magnesium or calcium salts, and also ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, for example methylamine, diethylamine or triethylamine, hydroxy-lower alkyl-amines, for example 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine, tris-(hydroxymethyl)-methylamine or tris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, for example l-ethyl-piperidine, lower alkylenediamines, for example ethylenediamine, cyclo-alkylamines, for example dicyclohexylamine, or benzylamines, for example N,N'-dibenzylethylenediamine, benzyltrimethylammonium hydroxide, dibenzylamine or N-benzyl-~-phenylethylamine. Compounds of formula I
having a primary or secondary amino group may also form acid addition salts, for example with preferably pharmaceutically acceptable inorganic acids, such as hydrohalic acids, for example hydrochloric acid or hydro-'~B

: ., ,............ :
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~ 3 ~ 3 - 6 - 21~89-7496 bromic acid, sulphuric acid, nitric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, for example acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, citric acid, pyruvic acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, pamoa acid, nicotinic acid, methanesulphonic acid, ethanesulphonic acid, hydroxy-ethanesulphonic acid, benzenesulphonic acid, 4-toluenesulphonic acid or naphthalenesulphonic acid.

It is also possible to use pharmaceutically unsuitable salts for isolation or purification. Only the pharmaceutically acceptable non-toxic salts are used therapeutically, and these are therefore preferred.

"
The compounds prepared in accordance with the invention have valuable pharmacological properties. They are, for example, active and selective antagonists of N-methyl-D-aspartic acid (NMDA)-sensitive excitatory amino acid receptors in mammals. They are therefore suitable for the treatment of diseases that respond to a blocking of NMDA-sensitive receptors, such as, for example, cerebral ischaemia, muscular spasms (spasticity), con-vulsions (epilepsy), conditions of anxiety, painful or manic conditions.
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These advantageous effects may be demonstrated in in vitro or in in vivo test arrangements. For these, preferably mammals are used, for example mice, rats or monkeys, or tissue or enzyme preparations from such , mammals. The compounds may be administered enterally or parentally, ; preferably orally; or subcutaneously, intravenously or intraperitoneally, for example in gelatin capsules or in the form of aqueous suspensions or A~ solutions. The dosage to be used in vivo may range from 0.1 to 600 mg/kg, preferably from 1 to 300 mg/kg. In vitro, the compounds may be used in the form of aqueous solutions, the concentrations ranging from 10 to 10 8 molar solutions.

The inhibiting action on the NMDA-sensitive excitatory amino acid receptors may be determined in vitro by measuring in accordance with G. Fagg and A. Matus, Proc. Nat. Acad. Sci., USA, 81, 6876-80 (1984) to what extent the bonding of L-3H-glutamic acid to NMDA-sensitive receptors j;
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~3281 13 .~

- 7 - 2148~-7496 is inhibited. In vivo, the inhibiting action on NMDA-sensitive excitatory amino acid receptors may be demonstrated by the inhibition of ~ NMDA-induced convulsions in mice.
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The anti-convulsive properties of the compounds according to the in-vention may furthermore be shown by their effectiveness in preventing audiogenically induced attacks in DBA/2 mice (Chapman et al., Arznei-mittel-Forsch. 34, 1261, 1984).
.
The anti-convulsive properties may furthermore be shown by the effective-ness of the compounds according to the invention as electric shock antagonists in mice or in rats.
: .
An indication of the anxiolytic activity of the compounds of the present invention is given by their pronounced effectiveness in the conflict model according to Cook/Davidson (Psychopharmacologia 15, 159-168 (1968)).
;

The pronounced effectiveness of the compounds of formula I depends to a surprisingly high extent on the configuration at the double bond. For example, the racemate of D-2-amino-5-phosphono-3-cis-pentenoic acid known from Agric. Biol. Chem. 41, 573-579 (1979), B. K. Park et al., proves, for example in its ability to bond to the NMDA-sensitive receptor 7 to be far inferior to the racemate of the 2-amino-5-phosphono-3-trans-pentenoic acid according to the invention (in the Examples these compounds are referred to as compounds of the "E-series"). Compounds of the formula I, whersin the carbon atom carrying the group R6 has R-configuration, have been found to be especially active.

The invention relates most especially to a process for the manufacture of compounds of formula I in which R1 is hydroxy, R2 is hydrogen or Cl-C4alkyl, R3 and R4 are hydrogen and Rs is C1-C4alkoxycarbonyl or carboxy, R6 is amino, A is methylene and B is a bond, especially the R-enantiomers thereof in respect of the atom carrying the amino group, and pharmaceutically acceptable salts thereof.

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The invention relates to the manufacture of the compounds mentioned specifically in the Examples and to the pharmaceutically acceptable salts theroof.

The process of the invention is characterised in that in a compound of Eormula Zl -~ - A ~ S (II), in which Z1 is free or protected hydroxy, Z2 is an R1 group or protected hydroxy, Z5 is an Rs group or protected carboxy, Z6 is a protected R6 group, and R1, R2, R3, R4, Rs, R&, A and B are as defined hereinbefore, the protected groups Z6 and, where applicable, Z1, Z2 and/or Zs are freed by reaction with a tri-lower alkylhalosilane and, if required a resulting compound of formula, wherein Rs denotes carboxy, is esterified with a Cl-Cgalkanol or phenyl-C1-C4alkanol which is unsubstituted or substituted by C1-C4alkyl, C1-C4alkoxy and/or halogen, or is aminated with ammonia or a mono-or di-C1-C4alkylamine or 5- to 7-membered alkylenamine, so as to produce the corresponding compound of formula I, wherein Rs denotes Cl-Cgalkoxycarbonyl, phenyl-Cl-C4alkoxycarbonyl which is unsubstituted or substituted by C1-C4alkyl, C1-C4alkoxy and/or halogen, carbamoyl, mono-or di-C1-C4alkylcarbamoyl or 5- to 7-membered alkylencarbamoyl, or a resulting compound of formula I, wherein Rs denotes Cl-C8alkoxycarbonyl, phenyl-C1-C4alkoxycarbonyl which is unsubstituted or substituted by C1-C4alkyl, C1-C4alkoxy and/or halogen, carbamoyl, mono- or di-C1-C4-alkylcarbamoyl or 5- to 7-membered alkylencarbamoyl, is hydrolysed so as to produce the corresponding compound of formula I, wherein Rl is carboxy, and, if required, in a resulting compound of formual I, wherein R6 denotes amino, the amino group is mono- or di-Cl-C4alkylated or phenyl-C1-C4alkylated so as to produce the corresponding compound of formula I, wherein R6 is mono- or di-C1 C4alkylamino or phenyl-Cl-C4-alkylamino, and, if required, a resulting mixture of optical isomers is ~' , .
;,. ;-. : ~ : ~, 2 83l~

- 9/10 - 2148g-7496 resolved into the components and the desired isomer is separated off, and/or a resulting free compound is converted into a salt or a resulting salt is converted into the free compound or into a different salt.

Protected hydroxy Zl and/or Z2 in intermediates of formula II is, for example, hydroxy etherified by an aliphatic alcohol, such as hydroxy etherifled by a lower alkanol, louer alkeDol or lo~r slky~l each oE

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1~28113 which is unsubstituted or substituted by halogen or, in a position higher than the ~-positlon, by hydroxy, oxo, lower alkoxy, lower alkanoyloxy and/or by mono- or di-lower alkylamino, and is, for example, lower alkoxy, halo-lower alkoxy, or corresponding hydroxy-, oxo-, lower alkoxy-, lower alkanoyloxy- or mono- or di-lower allcylamino-lower alkoxy.
Compounds of formula II in which Z1 and/or Z2 are etherified hydroxy are esters of the phosphorus-containing acid group and, depending on the meaning of R1, are phosphonous acid esters, phosphinic acid esters or phosphonic acid esters. Preferred esters are the respective lower al~yl esters and hydroxy-lower alkyl esters.

Groups Z6 in intermediates of formula II are, for example, R6 groups substituted by acyl, that is to ssy acylamino that is unsubstituted or N-substituted by lower alkyl or by aryl-lower alkyl in which acyl is the acyl radical of an organic acid having, for example, up to 18 carbon atoms, especially an alkanecarboxylic acid that is unsubstituted or sub-stituted, for example, by halogen, amino or by phenyl, or benzoic acid that is unsubstituted or substituted, for example, by halogen, lower alkoxy or by nitro, or of a carbonic acid semiester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or proplonyl, halo-lower alkanoyl, ~uch as 2-haloacetyl, especially ?-fluoro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, aroyl, such a3 unsubstituted or substituted benzoyl, for example benzoyl~
halobenzoyl, such as 4-chlorobenzoyl, lower alkoxybenzoyl, such as 4-methoxybenzoyl, or nitrobenzoyl, such as 4-nitrobenzoyl. The following are also especially suitable: lower alkenyloxycarbonyl, for example allyloxycarbonyl, or especially lower alkoxycarbonyl that i~ unsub-stituted or substituted in the 1- or 2-position, such as, especially, lower alkoxycarbonyl, for example tertlary butoxycarbonyl and also methoxy- or ethoxy-carbonyl, and also unsubstituted or substituted benzyloxycarbonyl, for example benzyloxycarbonyl or 4-nitrobenzyloxy-carbonyl, or aroylmathoxycarbonyl in which the aroyl group is benzoyl that i9 unsubstituted or substituted, for example, by halogen, such as bromine, for example phenacyloxycarbonyl or bromophenacyloxycarbonyl.

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132~13 Furthermore, in a corre3ponding acylamino group Z6, acyl may be alkanoyl-amino ~ubstituted by amlno and/or by phenyl, carbamoyl, carboxy, lmidaæolyl, lower alkylthio, tetrahydropyrrolyl, hydroxy, indolyl or by hydroxyphenyl, and thus includes, for e~ample, the acyl radicals of amino acids, for example naturally occurring amino acids, such as alanyl, asparaginyl, aspartyl, glycyl, histidyl, isoleucyl, leucyl, lysyl3 methionyl, phenylalanyl, prolyl, seryl, threonyl, tryptophyl, tyrosyl or valyl; al60 included are the acyl radicals of oligopeptides, for example di- or tri-peptides, such as oligopeptides of alanine, a3paragine or aspartic acid.

Furthermore, protected amino 26 may be a diacylamino group. In thi~ group diacyl is, for example, two acyl radicals of the definitions given hereinbefore, or diacyl is, for example, the acyl radical of an organic dicarboxylic acid having, for example, up to 12 carbon atoms, especially a corre#ponding aromatic dicarboxylic acid, such as phthalic acid. Such a group is especially phthalimido.

In addition, protected amino ~6 may also be amino substituted by sub-stituted lower alkoxycarbonyl, ~uch as amino substituted by 2-halo-lo~er alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-chloro-ethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or by 2-(tris-substituted silyl~-ethoxycarbonyl, such as 2-tri-lower alkyl-silylethoxycarbonyl, for example 2-trimethylsilylethoxycarbonyl or 2-(di n-butyl-methyl-silyl)-ethoxycarbonyl, or by 2-triarylsilylethoxy-carbonyl, such as 2-~riphenylsilylethoxycarbonyl, or etherified mercapto-amino or silylamino, or may be in the form of an enamino, nitro or azido group. An etherified mercaptoamino group i~ especially a phenylthioamino group that is unsubstituted or substituted by lower alkyl, such as methyl or tert.-butyl, lower alkoxy~ such as methoxy, halogen, such as chloine or bromine, and/or by nitro, or a pyridylthioamino group. Corresponding groups are, for example, 2- or 4-nitrophenylthloamlno or 2-pyridylthlo-amino. A silylamino group i~ especlally an organlc silylamino group. In such groups the silicon atom contalns as substituent(s) preferably lower alkyl, for example methyl, ethyl, n-butyl or tert.-butyl, al80 aryl, for example phenyl. Suitable silyl groups are especially tri-lower alkyl-. ~ , ~, .
~ - ,.; .

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13281~3 silyl, especially trimethylsllyl or dimethyl-tert.-butyl~ilyl. Enamino groups contain at the double bond in the 2-position an electron-attracting sub~tituent, for example a carbonyl group. Protectlng group~
of this kind are, for example, l-acyl-lower alk-l-en-2-yl radlcals in which acyl is, for example, the corresponding radical of a lower alkane-carboxylic acid, for example acetic acid, of a benzolc acid that i8 un-substituted or substituted, for example, by lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, or especially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester, for example methyl semiester or ethyl semiester, and lower alk-l-ane is especially l-propene.
Corresponding protecting groups are especially l-lo~er alkanoyl-prop-l-en-2-yl, for example 1-acetyl-prop-1-en-2-yl, or 1 lower alkoxycarbonyl-prop-l-en-2-yl, for example 1-ethoxycarbonyl~prop-1-en-2-yl.
~ . .
Protected carboxy ~5 is customarily protected in esterified form, it being possible for the ester group to be cleaved under reductive, such as hydrogenolytic, or solvolytic, such as acidolytic or hydrolytic, such as acid-hydrolytic, basic-hydrolytic or neutral-hydrolytic, conditions. A
protected carboxy group may furthermore be aD esterified carboxy group that can be cleaved under physiological conditions or that can readily be converted into a different functionally modified carboxy group~ such as into a dlfferent esterified carboxy group. Such esterified carboxy groups contain as esterifying groups especially silyl groups, especially tri-lower alkylsilyl groups, or lower alkyl groups that are suitably sub-stituted in the 1- or 2-position. Preferred carboxy groups in esterified form sre, inter alia, tri-lower alkylsllyloxycarbonyl, for example tri-methylsilyloxycarbonyl, ~hetero-)arylmethoxycarbonyl having ~rom 1 to 3 aryl radicals or having one monocyclic heteroaryl radical, these being unsubstituted or mono- or poly-substi~uted, for example, by lower alkyl, such as tert.-lower alkyl, for example tert.--butyl, halogen, for example chlorine, and/or by n~tro. Exsmples of such groups are benzyloxycarbonyl that ls unsubstituted or substi~uted, for example in the manner mentioned above, for example 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or triphenylmethoxycarbonyl that is unsubstituted or substituted, for example in the manner mentioned above, for example dlphenylmethoxycar-; 1 !
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bonyl, or picolyloxycarhonyl, for example 4-picolyloxycarbonyl, or fur-furyloxycarbonyl, such as 2-furfuryloxycarbonyl that is uns~bstituted or substituted, for example ln the manner mentioned above.

Protected hydroxy Z1 and/or Z2 iS especially lower alkoxy, such as methoxy, ethoxy or isopropoxy, protected carboxy is especially tri-lower alkylsilyloxycarbonyl, such as trimethylsilyloxycarbonyl, and protected amino Z6 unsubstitu~ed or substituted by lower alkyl or by aryl-lowPr alkyl is especially lower alkanoylamino, especially formylamino, N-lower alkanoyl-N-lower alkylamino, especially N-formyl-N-lower alkylamino, for example N-formyl-N-methylamino, or lower alkoxycarbonylamino, preferably tertiary bu~oxycarbonylamino.

Tri-lower alkylhalosilanas are, for example, tri-lower alkyliodosilanes or, especially, tri-lower alkylbromosilanes, preferably those in which the lower alkyl groups are identical Cl-C4alkyl radicals. Trimethyl-bromosilAne is preferred, with trimethyliodosilane as second choice.

Freelng the protected groups, thst is to say freeing hydroxy from protected hydroxy groups Zl and/or Z2, freeiDg carboxy from protected carboxy group~ Zs and/or freeing amino that i9 unsubstituted or sub-stituted by lower alkyl or by phenyl lower alkyl from protected amino groups Z6 by treat~ent with a tri-lower alkylhalosilane is effected, for example, in an inert solvent, such as a halogenated, preferably aliphatic hydrocarbon, for example dichloromethane or, less preferably, tri- or tetra-chloromethane, trichloroethane or tetrachloroethane, in a tempera-ture range of approximately from -25 to ~50C, pref~rably from approxi-mately 0C to approximately 30C, for example at tsmperatures in the region of room temperature, that is to say at from approximately 15C to approximately 25C, advantageously under substantially anhydrous conditions and under an inert gas, for exa~ple under argon or nitrogen.
. .
~;' Working up is carried out in a manner known per se, two purifying methods especially having proved advantageous. Either the crude product can be converted into a readily volatile derivative, for example by sllylation, ` ¦ and recovered as such by distillation and then desilylated, or the crude . ~
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product can be treated with an agent that reacts with excess acid, such as hydrohslic acid, thereby removing it. Suitable agents are, for example, compounds to which a corresponding acid can be added, for example lower alkylene oxides (epoxides), such as propylene oxide.

If compounds of formula I in which Rs is esterified or amidated carboxy, such as lower alkoxycarbonyl or carbamoyl, are desired as end products, the starting materials of formula II and the process conditions can be so selected that although in the last step Z1, Z2 and Z6 are freed, Zs, which represents the desired Rs group, remains unaffected.

An especislly preferred process variant is accordingly directed to the manufacture of compounds of formula I in which Rs is C1-C4alkoxycarbonyl and R6 is amino. In this process variant the starting materials used are preferably compound~ of formula II in which Z1 and Z2 are lower alkoxy or lower alkoxy substituted in a position higher than the ~-position by halogen, such as chlorine, Z5 i9 Cl-C4alkoxycarbonyl and Z6 i9 lower alkanoylamino, such as formylamino, or lower alkoxycarbonylamino, such as tert.-butoxycarbonylamino. Starting from such compounds of formula II the freeing of the protected groups can be so controlled by treatment in an inert solvent, such as a halogenated hydrocarbon, for example dichloro-methane, at temperatures in the region of room temperature, with a reagent such as trimethylbromosilane, and by subsequent treatment with a lower alkanol, such as ethanol, and a substance ab~orbing hydrogen halide, such as an aliphatic epo~ide, especially an epoxy-lower alkane, for example propylene oxide, that compounds of formula I in which R1 is hydroxy, Rs i8 C1-C4alkoxycarbonyl, R6 is amino and the variables Rz, R3 and R4 are as defined for formula I, are obtained directly.

This proce~s ia e~pecially preferred for the manufacture of compounds of formula I in whlch A i9 methylene or 1,3-propylene and B is a bond, R3 and R4 are hydrogen and Rz is alkyl having up to 4 carbon atoms, such as methyl.

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' ~' ' ' ~ ' ~ ' . - `

.

" 13~8~13 Another especially preferred process variant 1~ the m~nufacture of compounds of formula I in which Rs i8 carboxy. In thl~ ca3e the starting material3 used are preferably compounds of formula II in which Z1 and Z2 are lower alkoxy or lower alkoxy substituted in a position higher than the ~-position by halogen, such as chlorine, Zs i3 optionally protected carboxy and Z6 is lower alkoxycarbonylamino, especially ~-branched lower alkoxycarbonylamino, such as tert.-butoxycarbonylamlno. In this case, the carboxy group i9 preferably, but not neces~arily, intermediately protected, for exsmple by treatment with a 3ilylation agent, such as an N,0-silyl-lower alkanoic acid amide, for example with N,0-trimethylsllyl-` acetamide.

Intermediates of formula II are preferably manufactured by reacting acompound of formula ~ ~3 4 ~B~- - Zs ~III), X- A - ~ 6 ~' ~2 in which R2, R3, R4, A and B are as defined for formula I, Zs ha~ the meaning of Rs or is protected carboxy, Z6 ls a protec~ed R6 group and X
is reactive esterified hydro~y, with a compound of formula R
;
~ Zl - ' (IV), ``',.~1 2 in which Z1 is free or protected hydroxy, Z2 has the meaning of R1 or is ; protected hydroxy and R i8 an etherifying group, and ~an be used without ~` being isolated or ~peclally purified.

`~ Compound3 of formula III can be manufactured, for example, by r~actiDg anj N-protected aminomalonic acid e3ter of formula V
. . ~
:: ~',' Zg~ Z5 (V) :;1 6 '''`,' ' ~ ` .

:, . , :
,: , :

~32~13 in which Zs and Zg are identical or different esterified carboxy groups, for example lower alkoxycarbonyl groups, in a manner known per se with a compound of formula .
1~3 ~- B -X' (VI) ~l2 in which X and X', independently of one another, each represen~s reactive esterified hydroxy, such as halogen. The resulting compounds of formula Zs -B-¢-Zs (VII) X-A~ 6 can be conver~ed into compounds of formula III in which R4 i6 hydrogen by hydrolysis, for example under hydrolytic conditions, such as the con-ditions of an acidic hydrolysis, for example with hydrohalic acids, such as hydrochloric acid, preferably with heating, and by decarboxylation, or by dealkoxycarbonylation, without previous hydrolysis, by heat~ng in an aqueous aprotic solvent, ~uch as dimethyl sulphoxide, in the presence of an alkali metal halide, such as sodium chloride.

Thia varlant is accordingly e~pecially suitable for producing com-pounds III in which R4 is hydrogen, Zs is free or e~terified carboxy and Z6 iS protected amino, such as lower alkanoylamino.
~. ~

! Intermediates III in which A is methylene that is unsubstituted or sub-.l stituted by alkyl, B is a bond, X is halogen and ~6 i9 formylamino can furthermore be produced by reacting a compound of formula ~ 2 i; D~G\ (VIII), :~1 Ç

wherein D denotes optionally alkylatsd methylidene, such as a correspond-;`."i ing ~ unsaturated aldehyde, for example acrolein or methacrolsin, with an ~-isocyanoacetic acid derivative, such a~ an ~-isocyanoacetic acid ~ lower alkyl ester. With suitable catalysis, such as with low valency ~ :, ,,.,.~ , - :
.. '~
- :, 1~8:~3 ~ 18 - -metal salts, that is to say metal salts derived from metalq of groups I
and II of the Periodic Tab~e of Elements, for example correspondlng metal : oxides or metal halides, such as zinc chloride, cadmium chloride, silver oxide or, preferably, copper oxide or complexes of gold-I-tetrafluoro-borate wlth aliphatic or cycloaliphatic isocyanides, for sxample bis-; (cyclohexyli.socyanide)gold-I-tetrafluoroborate, there are thus obtained in a manner known per se 5-vinyl-2-oxazoline-4-carboxylic acid deriva-, tives, for example esters of formula : ~2 D=~\~3 /Zs (IX) ~,~
which can be converted into the open-chained compounds of formula ~H ~4 / ~ ZS (X) ~ 3 k6 j in which D is unsubstituted or alkyl-substituted methylidene. These com-:.~ pounds can in turn be converted by selective halogenation, such as 1 brominatlon or chlorination, preferably with cooling and with displace~
ment of the double bond in the manner of an allyl rearrangement, into compound~ of Pormula III.
``:!
:~ Another process for the manufacture of compounds II in which R4 is hydrogen, A is methylene or l,3-propylene and Rs is carboxy, i9 based on the principle that a compound of formula d ~ ~X1) , ;

132~13 ~ 19 -ln which RA and RB are hydrogen or preferably lower alkyl, such as methyl, and Rc is an ami.no-protecting group, is condensed with a 2-R2-: acetic acid ester or condensed first ~ith a l-R2-ethene-metal compound, for example with isopropenylmagnegium bromide, and subsequently with an acetic acid ester, in the resulting compound of formula 1~3 ~CM 2 CH 2--2 5 ~_~/ i2 ~ ~ (XIIa) or ~, ~ C

in which Zs is esterified carboxy, for example lower alkoxycarbonyl, this group is reduced to hydroxymethyl, for example by means of diiso-butylaluminium hydride, the hydroxymethyl group is halogenated, for example brominated by means of tetrabromomethane/triphenylphosphlne, the resulting compound of formula ~3 ~ (XI11)~

`~ in which A denotes methylene or 1,3-propylene and X is halogen, for , example bromine, is further reacted wi~h a compound of formula IV, the ~j oxazolidine ring is cleaved, for example, by means of an ion exchanger, .~l such as Amberlyst 15~, and, in the resulting compound of formuls Z~ A- ~ ~ (XIV), : z 2 ~ .
~' in whlch Z6 i5 a protected amino group of formula RC NH-(II'~, the l, hydroxymethyl group i9 oxidised to carboxy in customary manner.

.1 When carrying out the above described processe~ for the man~facture of -, intermediates III and the further reaction of the same to form inter-.. ~; mediates II it is not necessary to isolate all of the intermediate `: j .. ..

.

.

1~281~L3 stages. For example, especially the converslon of compounds X into com-pounds III and the further-reaction thereof with compounds IV to form intermediates II can advantageously be carried out in situ.

A preferred variant of the proces~ of the invention accordingly consist~
of the followlng: a compound of formula ~3 ~4 ~!_ B ~ - Zs (III), X - A - t ~6 ~2 in which R2, R3, R4, A and B are as defined for formula I, Zs ha~ the meaning of Rs or is protected carboxy, Z6 iS a protected R6 group, for example protected amino, and X is resctive esterifiad hydroxy, is reacted wlth a compound of formula R
I Z1~ (IV), ~ 2 in which Z1 is free or protected hydroxy, Z2 has the meanlng of Rl or is ~, protected hydroxy and R i~ an ethesifying group, the protected groups Z6 ~, and, where appllcable, Z1, Z2 andlor Zs are freed by treatment with atri-lower alkylhalosilane, for example wlth ~rimethylbromosilane, and, lf desired, a resulting compound of formula I i~ converted into a 3 different compound of formula I and/or, if desired, a resulting compound of formula I is converted lnto a salt or a resulting salt is converted into a dlfferent salt or into a free compound of formula I and/or, if ~o, desired, an optical i~omer 1~ isolated from a mixture of 3tereoisomeric : ~, forms of a resulting compound of formula I or of a salt thereof.

A reactive esterified hydroxy group, such as X, i8 8 hydroxy group esterifled by a strong organic acld, for example a hydroxy group esterified by an aliphatic or aromatic sulphonic acid (~uch as a lower alkanesulphonic acid, especially methanesulphonlc acld, trifluoromethane-sulphonic acid, ~specially benzenesulphon~c acid, p-toluenesulphon~c acid, p-bromobenzenesulphonlc acid and p-nitrobenzenesulphonic acid) or ' , - . ~ -.~: ' , . : - .

:-~ " - .

13281~l3 - 21 ~

by a strong inorganic acid, ~uch as ~ especially, sulphuric acid, or a hydrohalic acid, such as hydrochloric acid or, most preferably, hydriodic acid or hydrobromic acid.

Attention i8 drawn in this connection to the surprising finding that the manufacture of the intermediates II and their further reaction according to the invention to form the end products I can be carried out stereo-selectively. That is, neither in the reactlon sequence III + IV ~ II or IIa ~ I, nor in the reaction sequences X ~ III and XI ~ XII ~ XIII ~
XIV -> II is there reversal of configuration or significant racemisation.
The process of the invention is therefore excellently suitable for the direct manufacture of compounds of formula I with the preferred R-con-figuration at the carbon atom carrying the amino group R6. The invention also relates to the manufacture of sterically homogeneous compounds of formula I and sterically homogeneous intermediates of formulae II, III, X, XI, XII, XIII and/or XIV.

According to another preferred process variant, a compound of formula ~H 4 --Zs (X) '1 D=i 13 6 .
.,, g~

i~ sub~ected to selective halogenation, for example by means of thionyl chloride, to form the corresyonding intermediate III, and this is reacted ~-', in situ, that is to say without being isolated, ~ith component IV.
:1 As mentloned, compounds obtainable in accordance wi~h ~he inventlon can be converted into different compounds of formula I. In particular, a free a~ino group Rs may be substituted, for example converted into an unsub-stituted or phenylated alkylamino group, free carboxy Rs may be esteri-fied, or esterified or amidated carboxy Rs may be converted into free , carboxy, and/or free or esterified carboxy Rs may be converted into amidated carboxy.

.

- 22 - ~328113 To convert an amino group into an unsubstituted or phenylated alkylamino group the amino group may be alkylated by substitution, for example with a reactive esterified optionally phenylated alkanol, such as an alkyl halide, or by reduction, such as with an aldehyde or ketone, and also with catalytically activated hydrogen or, in the case of formaldehyde, sdvantageously with formic acid as reducing agent.

Free carboxylic acids of formula I or salts thereof may be converted according to known processes by suitable alcohols or corresponding derivstives thereof into the corresponding estars, that is to say into compounds of formula I that are, for example, in the form of lower alkyl esters, aryl-lower alkyl esters, lower alkanoyloxymethyl esters or lower alkoxycarbonyl-lower alkyl esters.

For the esterification, a carboxylic acid may be reacted directly with a diazoalkane, especlally diazomethane, or with a corresponding alcohol in the presence of a strongly acidic catalyst ~or example a hydrohalic acid, sulphuric acid or an organic sulphonic acid) and/or of a dehydratlng agent (for example dicyclohexylcarbodilmide). Alternatively, the carboxylic acid may be converted into a resctive derivative, such as into a reactive ester, or into a mixed anhydride, for example with an acid halide (for example, especially an acid chloride~, and this activated intermediate is reacted with the desired alcohol.

Compounds of formula I in which R5 is esterified carboxy, such as, especially, lower alkoxycarbonyl, for example ethoxycarbonyl, can be converted into compounds of formula I in which Rs is carboxy, for example by hydrolysis especially in the presence of inorganic acids, such as hydrohalic acids or sulphuric acid or, less preferably, aqueous alkalis, such as alkali metal hydroxides, for example lithium or sodium hydroxide.
In this connection attention is drawn to the fact that also carboxy can be freed from esterified carboxy in such a manner that no significan~
racemisation occurs. ~his can be achieved especially by ~reatment with from approximately 0.2N to approximately 4N, for example approximately lN, that is to say from approximately 0.5N to approximately 2N, aqueous mineral acid, if necessary while heating, for example at from approxi-' .

-.
:

-` 132~

mately 60C to approximately boiling temperature, that is to say approxi-mately 100C. Surprisingly, the hydrolysis, for example, of phosphonic acid carboxylic acid lower allcyl esters of formula I, proceeds with a high yield even without the addition of acidic or basic reagents. A
preferred process for the manufacture of carboxylic acids of formula I
from the corresponding lower alkyl esters, such as the re3pective ethyl esters, therefore consists in acidic hydrolysis by treatment with from approximately 0.2N to approximately 4N aqueous mineral acid, for example hydrochloric acid, sulphuric acld, phosphoric acid or the like, and also in the - possibly autocatalytic - hydrolysls in water, preferably at elevated temperatures, such as with heating under reflux.

The above reactions are carried out according to standard method6 in the absence or presence of diluents, preferably those that are inert towards the reagents and ara solvents therefor, in the presence of catalysts, condensation agents or the other agents and/or in an inert atmosphere, at low temperature, room temperature or elevated temperature, preferably at the boiling point of the solvents used, at atmospheric or superatmos-`I pheric pressure.

I The invention includ2s furthermore any varlant of the present processes in which an intermediate obtainable a~ any stage of that process is used j as starting material and the remaining steps are carried out, or the `~l process is discontinued at any stage, or in which the starting materials , are formed under the reaction conditions or in which the reactants are 'l, used in the form of their salts or optically pure antipode~ There should `~ especially be used in these reactions those starting materials that result in the formation of the compounds mentioned hereinbefore as being especially valuable.

The invention relates also to novel starting materials and processes fortheir manufacture.

Depending on the choice of startlng materials and methods, the novel compounds may be in the form of one of the possible optical isomers or in the form of mixtures thereof, for example depending on the number of , ' asymmetrlc carbon atoms they may be in the form of pure optical isomers, such as antipodes, or mixtures of optical isomers, such as racemates, or mixtures of diastereoisomers from which one ant~pode, if desired, may be lsolated.

Resulting mixtures of diastereoisomers and mixtures of racemates may be separated in known manner on the basis of the physico-chemical differen-ces between the canstituents into the pure isomers, diastereoisomers or racemates, for example by chromatography and/or fractional crystalll-sation.

The resulting racemates (racemic diastereolsomers) may furthermore be separated into the optical antipodes according to methods kno~n per se, for example by recrystallisation from an optically active solvent, with the aid of microorganisms or en~yme-catalyst in free or in an immobilised form or by reaction of an acidic end product with an optically active base that forms salts with the racemic acid, and separation of the salts obtained in this manner, for example on the basis of their different solubilities, into ~he diastereoisomers, from which the antipodes can be freed by the action of suitable agents. Basic racemic product3 can also be s~parated into the antipodes, for example by separation of ths dia-stareolsomeric salts thereof, for example by fractional crystallisation t of the d- or l-tartrates thereof. Any racemic intermediate or starting ~aterial can be separated in a similar manner.

Finally, the compounds according to the invention are ob~ained elther in free form or in the form of thelr salts. Any resulting base can be converted into a corresponding acld addition salt, preferably using a pharmaceutically acceptable acid or an anlon-exchange preparation, or resulting salts csn be converted into the corresponding free ba3es, for example using a stronger base, such a3 a metal or ammonium hydroxide or a basic sslt, for example an alkali metal hydroxide or carbonate, or a cation-exchange preparation. A compound of formula I can also be converted into the corresponding metal or ammonium ~alts. The~e or other salts, for example the picrates, can also be used for the purification of resultlng bases. The basQs are converted into salts, the salts are .

``` 1~28~13 separa~ed and the bases are freed from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is mentioned in this Application, a corresponding salt of that compound ls also included, provided that this is possible or appropriate under the given circumstances.

The compounds, including their salts, can also be obtained in the form of their hydrates or contain other solvents used for the crystalllsation.

The pharmaceutical preparations according to the invention are those that are suitable for enteral, such as oral or rectal, and parenteral administration to mammals, lncluding man, for the treatment or prevention of diseases that respond to the blocking of NMDA-receptors, such as, for example, cerebral ischaemia, muscular spasms (spasticity~, convulsions (epilepsy), conditions of anxiety or manic conditions. They comprise an effective amount of a pharmacologically active compound of formula I or a pharmaceutically acceptable salt thereof, on its own or in combination with one or more pharmaceutically acceptable carriers.
The pharmacologically active compounds of the inventlon can be used in the manufacture of pharmaceutical compositions that comprise an effective amount of the active compound on its own or in conjunction or admixture with excipients or carriera that are suitable for enteral or parenteral administration. Preferred are tablets and gelatin capsule~ that comprise i the active constltuent together ~ith a) diluents, for example lactose, dextrose, sucrose, mannitol7 sorbitol, cellulose and/or glycine, b) glidants, for example silicon dioxide, talo, stearic acid, the magnesium or calcium aalt thereoi and/or polyethylene glycol, for tablets also c) binders, for example magnesium aluminium sillcate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxgmethylcellulose and/or poly-vinylpyrrolldone, if desired d) dlspersing agents or disintegrstorq, for example starches~ agar, alginic acid or the sodlum salt thereof, or foaming mixtures and/or e) absorbents, colouring agents, flavourings and sweeteners. In~ectable preparation~ are preferably aqueou~ isotonic solutions or suspensions, and suppositories are advantageously produced from fatty emulsions or suspensions. These compositions may be sterilised ' ~ "
.. ~.
, ~.

and/or contain adjuvants, such as preservatives, stabilisers, wetting agents or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. In addition they may also contain other thera-peutically valuable substances. These preparations are manufactured according to conventional mixing, granulating or coating methods and contain approximately from 0.1 to 100 %, preferably approximately from 1 to S0 %, active cDnstituent. A unlt dose for a mammal weighing approxi-mately from 50 to 70 kg may contain approximately from 1 to S00 mg, preferably approximately from lO to 500 mg, of active constituent.

The following Examples are intended to illustrate the invention and do not represent limitations. The temperatures are in degrees Celsius and all parts are quoted in the form of parts by weight. Unless stated otherwise, all evaporation is carried out under reduced pressure, preferably approxima~ely from 2 to 13 Rilopascal (kPa).

Example l: E-2-amino-4-methyl-5-phDsphono-3-pentenoic acid ethyl ester ., t j a) $-~2-propenyl)-oxazoline-4-carboxylic acid ethyl ester (1) 1.6 g of red copper(I) oxide are introduced into 200 ml of benzene. A
~'1 solution of 140 g of isocyanoacetic acit ethyl ester and 105 g of fre~hly 1 distilled methacroleln in 200 ml of benzene i5 added dropwise to thissuspension within a period of lO minutes with vigorous stirring, during which time the reaction temperature is kept at between 30 and 32 by cooling with ice. When the addition is complete, the mixture is kept at 30-32 until the exothermic reaction subsides, aDd is then stirred st room temperature for one hour. After excess copper(I) oxide has been filtered off, the filtrate is concentrated by evaporation in vacuo at 30. 600 ml of ether are added to the residue, which is then filtered over Celite and concentrated to dryness by evaporatlon in vacuo. In this manner, 5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester is obtalned in the form of a colourless oil having a boiling polnt of 110-130 (5.3 Pa).
i rk .~

- 27 - ~ 32 8~3 b) E-2-formylamin~-3-hydroxy-4-methyl-4-pentenolc acid ethyl ester (2) 139 g of 5-(2-propenyl)-2-ox~zoline-4-carboxyllc acid ethyl ester are dissolved in 70 ml of tetrahydrofuran, and 27.4 g of water and 3.5 g of triethylamlne are added thereto. The reaction mixture is stirred at 65-70 for 62 hours and, after cooling, i9 taken up in 200 ml of di-chloromethane. The sollltion is dried over 200 g of magne3ium sulphate, filtered and concentrated by evaporation in vacuo. Purification of the viscous oil which remalns by column chromatography (silica gel; hexanel ethyl acetate 3:2~ ylelds 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in the form of a diastereoisomeric mixture having a meltlng point of 67~.

c) E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester (3) Under an argon atmosphere, 18.6 ml of thionyl bromide are added dropwise at 20, within a period of 5 minutes, to a solutlon of 40.20 g of crude 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in 600 ml of 1,2-dichloroethane (slight cooling). After stirring for two hours at room temperature, 400 ml of water are added, the first 50 ml being slowly added dropwise. The mixture is stirred thoroughly for a further 15 minutes to complete the reaction. The organic phase is separated off and washed three times witb ice-water and once with ice/saturated potasslum bicarbonate solution (pH approximately 7.5). Drying over sodium sulphste and removal of the 1,2-dichloroethane by distillation in vacuo at 35 yields the crude bromide as intermediate, to which 160 ml of triisopropyl phosphite are added at room temperature, and ~he mixture i8 then ~tirred at 75 (bath temperature) under a partial vacuum (approxi-mately 13 kPa) for 17 hours. The excess trii~opropyl phosphite and other volatile by-products are then dl~tilled off under a high vacuum (bath temperature 90). Chro~atography of the residue on ten ~imes the amount hy weigh~ of silica gel (particle size 0.04-0.06 mm) using ethyl acetate a~ eluant ylelds E-2 formylamino-4-methyl-5-dlisopropylphosphono-3-pentenoic acid ethyl ester in the form of a light-yellow honey, IR (CH2Cl2): 3410 (NH); 1740 (C0 e3ter); 1690 (C0 amide); 1235 (P~0);
980-lOI~ (~-0-C).

.
, .

~ - 28 - 1~2~13 d) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl e~ter (4) 56.7 ml of trimethylbromosilane are added dropwise within a period of 15 minutes at 20 to a solution of 25.42 g of E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester in 102 ml of dry di-chloromethane. After stirring at room temperature for 20 hours, 102 ml of ethanol are added dropwise within a period of 15 minutes, and the whole is stirred for a further 20 hour~. The clear reaction solutlon is then completely concentrated by evaporation in vacuo. The residue is concentrsted by evaporation a further three times in each case after the addition of 100 ml of toluene. The oily residue i9 dissolved in 102 ml of ethanol, and a solution of 102 ml of propylene oxide in 102 ml of ethanol i8 added dropwlse thereto. The product, obtained in crystalline form, is filtered off after 2 hours (room temperature) and washed with ethanol and ether. After drying (80, 4 hours) under a high vacuum, E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester i~ obtained in ana-lytically pure form, m.p. 212 (decomp.).

Example 2: E-2-a~ino-4-methyl-5-phosphono-3-pentenoic acid et~yl ester a) E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl ester (1~
100.5 g of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl e~ter are dis~olved in 1.5 litres of dichloroethane, and then 47 ml of thionyl bromide are added dropwise at 20-25 and the mixture is stirred at room te~perature for one hour, 750 ml of water are added to the reaction mixture, which ls then stirred vigorously for 10 minutes. The organic phase i8 ~eparated o~f, extracted with 1 litrs of ice-water, 1 litre of lN pota~sium hydrogen carbonate solution and a further 1 litre of ice-water, dried over magnesium sulphate and concentrated by evaporation.
S0 ml of trimethyl phosphite are added directly to the resultlng E 5-bromo-2-formylamino-4-methyl-3-pentenoic acld ethyl ester, a yellow oil, and the mixture i~ stirred at a bath temperature of 70 and approxi-mately 15 kPa for 15 hours. The reaction mixture is degs3sed for 30 minutes under a water-~et vacuum and for one hour under a high vacuum at 40-50. The resulting product i8 taken up ~n 600 ml of water and extracted three times with 500 ml of ethyl acetate each time. The :~

.
: .
: :

- ~

~L3281~3 combined organic phases are washerl twlce with 300 ml of water each time.
All the aqueous phases are combined, saturated with sodium chloride and extracted three times with 500 ml of dichloromethane each time. The combined organic phases are dried over magnesium sulphate and concen-trated by evaporation. The product is chromatographed over silica gel (ethyl acetate/isopropanol 7:2). In this manner, E-2-formylflmino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl ester is obtained in the form of a yellow oil, IH-NMR (DMS0): 1.82 (d, 3H, 4-CH3), 2.69 (d, 2H); 5.03 (m, lH); 5.32 (m, lH).

b) E-2-amino-4-methyl-5-phosphono-3-pentanoic acid ethyl ester (2) 16.9 g of E-2-formy1amino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl ester are dissolved in 80 ml of dichloromethane under a nitrogen atmosphere, and 30 ml of trimethylbromosilane are added dropwise at approximately 25 within a period of 30 minutes. The mixture is stirred at room temperature for 20 hours, and then 80 ml of ethanol are added dropwlse at approximately 25 within a period of 30 minutes. The mlxture i9 then again stirred at room temperature for 22 hours and is then concentrated by evaporation. The residue is dissolved in 80 ml of ethanol, and 80 ml of propylene oxide in 80 ml of 0thanol are added dropwise with slight cooling. The mixture is stirred at room temperature for one hour to complete the reaction, filtered and washed with ethanol and ether. In tbis manner there i8 obtained E-2-amino-4-mathyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 215-217 (decomp.).

Example 3-. E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester a,) E-2-formylamino-4-methyl-5-di~2-chloroethyl)phosphono 3- pentenoic acid ethyl ester (1) 8.2 g of E-5-bromo-2-formylamino-4-methyl-3-peDtenoic acid ethyl ester and 19 ml of tris-(2-chloroethyl)-phosphite are stirred at a bath tem-peraturs of 70 for 20 hours. The resulting mixture is chromatographed on silica gel using ethyl acetate and ethyl acetate/isopropanol (7:1) as eluant, and the product iB crystallised from ethyl acetate/diethyl ether.
In this manner there is obtalned E-2-formylamino-4-methyl-5-di(2-chloro-ethyl)phosphono-3-pentenoic acid ethyl ester, m.p. 47-49.

, .
,, : . . .

. .
:;:

; ~ 30 - 1328113 b) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (2) In a manner analogous to that described in Example 2, using 3 g of E-2-formylamino-4-methyl-5-di(chloroethyl)phosphono-3-pentenoic acid ethyl ester, there is also obtained E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 215 (decomp.).

:, .
Example 4: E-2-amino-4-phosphonomRthY1-3,6-heptadienoic acid ~1 .
I a) 2-methylene-4-pentenealdehyde (1) 24.5 g of a 37 % aqueous formaldehyde solution are added to a mixture of I 14.7 g of piperazine, 20.5 g of glacial acetic acid and 21.28 g of water, ', and the whole is stirred at room temperature for 10 minutes. While con-:~ tinuing stirring, 25.35 g of 4-pentenealdehyde are added, and the reaction mixture is heated at 75 Por 3 hours. After cooling to room temperature, the organic phase ls ~eparated off and the aqueous phase i3 extracted three times with 50 ml of diethyl ether each timc. The combined organic phases are washed three times with 50 ml of a saturated sodlum bicarbonate solution each time, dried over magnesium sulphate and concen-trated by evaporation in vacuo. Fractional distillation of the residue yields 2-methylene-4-pentenealdehyde in the form of a colourless oil, ~i b.p~ 65/6.6 kPa.
. ~
I b) 5~[2~(1,4-pentadienyl)]-2-oxazoline-4-carboxylic acid mathyl ester (2 By reaction of isocyanoacetic acid methyl ester with 2-methylene 4-;`~ pentenealdehyde in toluene in a manner analogous to that described in Example 1, and after subsequent purification by colu~n chroma~ography (silica gel, ethyl acetatelhexane 1:4), 5-(2~(1,4-pentadienyl))-2-oxa-~-j zoline-4-carboxylic acid methyl e~ter is obtained in the form of acolourless oil, lH-NMR (CDCl3): 2.80 (d, 2H, CH2); 4.45 (dd, lH, C(4)-H);
5.82 (m, lH, C~CH-); 7.00 (d, lH, C(2)-H).

8.1 g of 5-(2-(1,4-pentadienyl))-2-oxazoline-4-carboxylic acld methyl ester are di~solved in 20 ml oP tetrahydrofuran, and 10 ml of water ara added thereto. The reaction mixture is stirred at 75 for l.S hours and, l after cooling, is concentrated by evaporation in vacuo. Crystallisation : ` .
.`1 'I

:'`.: ' :
-, - 31 - ~3~8~13 of the resulti~g residue from isopropanol/hexane ylelds 2-formylamino-3-hydroxy-4-methylene-6-heptenoic acid methyl ester in the form of a diastereoi~omeric mixture, m.p. 75-77, , .
c) E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid methyl ester (3) 5.0 g of 2-formylamino-3-hydroxy-4-methylene-6-heptenoic acid methyl ester in 200 ml of dry tetrahydrofuran are cooled to -78, and 20 ml of 1,5 hexadiene are added thereto. 9 ml of thionyl bromide are added slowly dropwise in such a manner that the reaction temperature does not exceed -50. When the addition is complete, the reaction solution i3 heated to 0 within a period of approximately 3 hours and is stirred at that temperature for 3 hours. The solution i8 then poured onto 300 ml of a cold (5-10) saturatfld sodium bicarbonate solution and extracted with diethyl ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation in vacuo. Purification by column chromatography (silica gel, ethyl acetate/hexane 1:1) yields E-2-formylamino-4-bromomethyl-3,6-hepta-dienoic acid methyl e~ter in the form of a colourless oil, lH-NMR
(CDCl3): 3.20 (d, 2H, C(5)-H); 4.00 (s, 2H, CH2Br~.

d) E-2-formylamino-4 dlethylphosphonomethyl-3,6-heptadienoic acid methyl ester (4) 3.7 g of E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid methyl ester are dissolved in 37 ml of triethyl phosphite, and the mixture is heated at 75 for 8 hours. ExceQs triethyl phosphite is then distilled off under a high vacuum. Purification by column chromatography (silica gel, methanol/ethyl acetate 1:10) yields E-2-formyl~mino-4~diethylphosphono-methyl-3,6-heptadienoic acid methyl ester in the form of a colourless oil, lH-NMR (CDCl3): 2.54 (d, 2H, P-CH2) 3.10 (m, 2H, C(5)-H3 5.10 (m, 2H3 C(7)-H); 5.37 (d, lH, C(2)-H) 5.74 (m, lH, C(6)-H).

e) E-2-amino-4-phosphonomethyl-3,6-heptadieDoic acid (5) 0.74 g of E-2-formylamino-4-diethylphosphonomethyl-3,6-heptadienoic acid methyl ester i8 dissolved in 12 ml of dichloromethane, and 0.7 ml of trimethyliodosilane is added dropwise thereto. After stirring at room tflmperature for 4 hours, lN sodium thiosulphate solution is added until .
.

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.: . . ; ~:
' : ` . : ~ j - 32 - 1328~3 ths colour of the reaction solution hecomes lighter. 10 ml of a 4.5N
hydrochloric acid solution are then added to the reaction mixture, whlch is then stirrad at room temperaturs for 30 minutes. The aqueous phase i~
separated off, washed twice with 20 ml of dlchloromsthane each time, and concentrated by evaporation in vacuo. The residue i9 dissolved in 10 ml of 4.gN hydrochloric acid, stirred at room temperature for 16 hours, and t then concentrated by evaporatio~ in vacuo. The residue so obtained i8 taken up in 40 ml of ethanol and flltered until clear, and then 10 ml of prnpylene oxide~ethanol ~1:1) are added dropwise. The resulting white precipitate i8 filtsred off and purified by column chromatography (Dowex~
50 x 8/H~o3. Concentration yields E-2-amino-4-phosphonomsthyl-3,6-hepta-disnoic acid in the iorm of a white crystallisate, m.p. 154-lj7, IH-NMR
~D~0): 2.64 (d, 2H, P-CH~); 3.15 (m, 2H, C(5)-H); 5.20 (m, 2~, C(7)-H);
S.50 (dd, lH, C(3)-H~; 5.90 (~, lH, C(6)-H).

Example 5~ 2-amino-4-methyl-5-phosphono-3-pentenoic acid a) (L)-N-tert.butoxycarbonyl-s~rine-N-methoxy-N-methyl 541.6 ml of N-methylmorpholine are addsd within 27 minutes at -20 to --25 to ay solutlon of 1 kg of (L)-N-tert.butoxycarbonyl-~erine in 1 litre of tetrahydrofurane. The reaction mixture is stirred for 15 minutes at this temperature. Thsn 6g9.6 ml of chloroformic acid iso-butyl ester and subsequently 44S,8 ml of N-methoxy-N-~ethylamine are added within 42 and 40, resp. ~inutes. The reaction mixture iB allowed to warm to room te~perature and evaporated to dryness. The residue is dis-solved in 3 litres of ethyl acetate. The solution is extracted with 3.5 litres of 2n-hydrochloric acid and Yubsequently with 3 1 of sat~rated aqueous ~odium hydrogencarbonate solution. The water-layers are extrscted ~ith 3 l-lltre ethyl acetate. All organic extra~cts are combined, washed with 2 litres of ~aturated ~odium dichloride solution, drled o~er magns~ium sulfate an evaporated at 5~ to drynes3. ~he residue is triturated w~th 3.5 litre~ of hcxane with ice-cooling. The resulting white preclpitate is filt~ated off, washed with 1 1 of hexane and dried under reduced pressure to yield 781 g 2, ~.p. 116-117; cslculated for CllH~oN2os C 48.38 ~0, H 8.12 % N 11.28 %; found C 48.28 %, H 8.02 %, N 11.32 %.
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b) (L)-3-tert.butoxycarbonyl-2,2-dimethyl-oxazolldln2-4-carboxylic acid-; N-methoxy-N-methyl-amide (2) A mlxture of 781 g of 1, 3.3 lltres of acetone dimethylacetal and 42 g of pyridinium(toluol-4-sulfonate) are warmed to 72 and refluxed for l7 hours. Aftsr addition of additional 20 g of pyridinium(toluol-4-sulfonate) heating to boil is continued for additional 9 hours while gradually destilling of approximately 750 ml of solvent and adding 700 ml of acetone dimethylacetal. All volatila constituents we destilled off.
The residue is dessolved in 2 litres of diethyl ether and extracted twice with 1 litre and 0.5 litre of n-hydrochloric acid, once with 0.3 litre of saturated sodium hydrogencarbonate solution and once with 0.3 litre of saturated sodium chloride solution. The aqueous extracts we re~extracted twice with 0.5 litre either time of diethyl ether. All organic extracts are combined, dried over magnesium sulfate and evaporatad to dryness. The residue is dissolved hot in a 9:1-mixture of hexane and diethyl ether.
After addition of additional 600 ml of hexane and 50 ml of diethyl ether, the reaction mixture i9 cooled down while diluting a crystallisation with 1.1 lit~e of hexane. The precipitate formed is filtered off, washed with hexane and dried under reduced pressure at 40 yielding 640 g of 2 m.p. 67-68; calculated for Cl3H24N20s C 54.15 %, H 8.39 %, N 9.72 %;
found C 53.96 %, H 8.37 %, N 9.91 %.

c) (4S)-2,2-dimethyl-4-formyl-3-oxazolidine-carboxylic acid tert.butyl ester (3) 2.53 g of lithium aluminium hydride are added with cooling to malntain a temperature of 5 to 15 to 28.8 g of 2, dissolved in 350 ml of diethyl ether. After ~tlrring at 5 for 1.5 hours a solution of 5.77 g of sodium hydrogen sulfa~e i~ added 810wly to keep the reaction temperature at 15 (40 minut~s). The suspension~ formed i~ filtered clear and the solid portion is washed with ether. The filtrate is washed, with cooling, twice with 200 ml esch of n-hydrochloric acid, twice with 150 ml each of 5 %
odium hydrogencarbonate solution and dried with 100 ml of saturated sodium chloride solution. The aqueou~ extracts are re-extracted with ether and all organic extracts are combined, dried over sodium sulfate and evaporated. The residue i~ distllled at 0.4 ml yielding 17.78 g of 3;

.
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~ _ 34 _ 1 3 2 8~13 b.p. 85-90, 1~1D ~ -94 (c=1, CHCl3); calculated for Cl1HlgN04 C 57.63 %, ; H 8.35 % N 6.11 YO~ 0 27.91 %; found C 57.59 %, H 8.54 %, N 6.17 %, 0 27.74 %.
~ .
d) 3-((4'R)-N-tert.-butoxycarbonyl-2',2'-dimethyl-4'-oxazolidinyl)-2-methylpropenoic acid ethyl ester (4) A solutlon of 39.5 g of (4S)-2,2-dimethyl-4-formyl-3-oxazolidinecarbo-xylic acid tert.~butyl ester 3 in 200 ml of dichloromethane is added dropwise wlthin a period of 2 hours to a solution of 68.7 g of 1-ethoxy-carbonylethylidenetriphenylphosphorane in 900 ml of dichloromethane.
After stirring at room temperature for 6 hours, the mixture is cooled to 10 and there are then added dropwise within a period of 15 minute~
~ 530 ml of a 10 % aqueous sodium hydrogen phosphate solution. After `~ stirring at 15 for 30 minutes, the organic phase is separatad off and the aqueous phafie is extracted with 250 ml of dichloromethane. The organic phases are dried over magnesium sulphate and concentrated by evaporation. The residue is stirred with 70 ml of ether. The suspension is filtered and the filtration residue is wsshed with ether. The filtrate is concentrated by evaporation and the residue is separated by chromatography on silica gel. Elution with hexane/ethyl acetate 9:1 yields, in addition to 2.32 g of cis-isomer and 2.21 g of mixed fraction (cis/trans ~ 38:62), 45.4 g of 4. ~H-NMR (60 MHz, CDCl3, trans-isomer~: inter alia 4.7 ppm (m, H-C(4')); 6.7 ppm (d, J~9, H-C(3)).
lH-NMR (60 MH~, C~Cl3, Ci3 isomer): inter alia 5.2 ppm (m H-C~4'));
6.08 ppm (d, J-7, H-C(3)).

e) (4R)-2,2-dimethyl-4-~3'-hydroxy-2'-methylprop-1'-enyl)-oxazolidine-3-carboxylic acid tert.-butyl ester (5) 389 ml of a 1 molar ~olution of diisobutylaluminium hydride in hexane are added withln a period of 15 minutes to a solution, cooled to 3, of 48.7 g of 4 ln l litre of dry diethyl ether. The tempPrature of the mixture i8 allowed to ri~e to 11, and there are then added thereto, j while cooling with ice, 100 ml of ethyl acetate followed by 50 ml of 2N
;l sodium hydroxide solution. The temperature of the mixture is allowed to rise to approximately 28, without oooling~ and then a further 7 ml of 2N
¦ sodium hydroxide solution are added. The mix~ure is stirred at room . :~
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~328113 temperature for 15 hours, and then sodium sulphate is added and the whole i9 filtered. Concentration of the filtrate by evaporation yields 42.1 g of crude 2. A sample (0.97 g) is purified by chromatography on 40 g of silica gel. Elution with hexane/ethyl acetate 3:1 yields 0.74 g of 5.
H-NMR (300 MHz, DMSO-d6): inter alia 3.52 (dxd, J=9 and 3) and 4.02 (dxd, J-9 and 6) (2H-C(5)); 3.78 (m, 2H-C(3')); 4.54 (m, H-C(4)); 4.81 (t, J~6, OH); 5.33 (d, J~9, H-C(l')).

f) (4R)-2,2-dimethyl-4-(3'-bromo-2'-methylprop-1'-enyl)-o~azolidine-3-carboxylic acid tert.-butyl ester (6) 47.6 g of triphenylphosphine are addPd at 0 to a solution of 41.0 g of 5 and 60.2 g of tetrabromomethane in 1 litre of dry diethyl ether. After 30 minutes, the cooling bath is removed and the mi~tura is stirred at room temperature for 17 hours. 20 g of tetrabromomethane and 15.9 g of triphenylphosphine are added, and the mixture is stirred at room tem-perature for 2 hours. The white suspension is filtered and the filtration residue is wa~3hed with ether. The residue remaining after the filtrate ha~ been concentrsted by evaporation is chromatographed on 0.9 kg of silica gel. Elution with hexane/ethyl acetate 9:1 yields 30.59 g of 6, m.p. 62-65C. ~H-NMR (300 MHz, DMSO-d6): inter alia 3.55 (dxd, J~9 and 2) and 4.04 (dxd, J~9 and 6) (2H-C(5)); 4.15 (m~ 2H-C~3')); 4.49 (m, H-C(4)); 5.65 (d, J39, H-C(1')).
.
g) (4R)-2,2-dimethyl-4-(3'-dimethylphosphono-2'-methylprop-1'-enyl)-oxa-zolidine-3-carboxylic acid tert.-butyl ester (7) A solution of 13.4 g of 6 in 70 ml of trimethyl phosphite i9 stirred at 80 for 15 hours. The excess phosphite is e~aporated off at 24 mbar.
Drying of the residue under a high vacuum yields 14.3 g of crude 7.
H-NMR (300 MHz, DMSO d6): inter alia 2.63 (d, J=23, 2H-C(3')~; 3.59 (d, J-ll, (C~30)2PO).

h) N-((2R)-5-dimethylphosphono-1-hydroxy-4-methyl-3-penten- 2-yl)-carbamic acid tert.-butyl ester (8) 7 g of Amberly~t~ 15 (H~ form, 20-50 mesh) are added to a solution of 14.0 g of 7 ln 2~0 ml of methanol. The mixture is ~3tirred at room temperature for 17 hours and filtered, and the filt~ate is concentrated .

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~32~1~3 , by evaporation. Chromatography of the residue on 0.33 kg of silica gel ~sing ethyl acetate/methanol 10:1 as eluant yielcls 10.6 g of 8. lH-NMR
(300 MHz, DMSO-d6): inter alia 4.60 (t, J~6, OH) 6.67 ld, J-7, NH).

i) (2R)-2-tert.-butoxycarbonylamino-S-dimethylphosphono-4- methyl-3-pentenoic acid (9) i,a) Oxidation with chromosulphuric acid To a solutlon of 0.323 g of 8 in 10 ml of acetone there i9 added 0.77 ml of a solution that i8 3.25 ~olar in chremium trioxide and 5.29 molar in ~ulphuric acid. The mixture is stirred at room temperature for 40 minute~
and then there are added 2 ml of isopropanol followed by 50 ml of ethyl acetate. 0.1 g of actlve carbon i8 then added to the mixture. After 10 minutes, the mixture is filtered and wa~hed with SO ml of ethyl acetate. The filtrate i~ extracted three times with 50 ml of 10 ~0 sodium hydrogen carbonate solution each time. The aqueous phase is extracted twice with 40 ml of ethyl acetate each time, acidified to pH 1 using 2N
hydroehloric acld, and then extracted three times with 70 ml of ethyl acetate each time. The organic extracts are wa~hed with ~aturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. Chromatography on 8 g of sillca gel using chloroform/
methanol/acetic acid 18:1:1 a~ eluant yields 6S mg of 9. ~H-NMR
(300 MHz, DMSO-d6): 1.37 (s, (CH3)3CO) 1.82 (d, J~2, CH3-C(4)~ 2.63 (d, J~22, 2H-C~53~; 3.61 (d, J~ll, (CH~0)2PO); 4.62 (t, J~8, H-C(2)); 5.25 (m, H-C(3)); 7.18 (d, J~8, NH); 11.7-12.5 (CO2H).
' l,b~ Oxidation wlth oxygen/platinum To a solution of 0.66 g of 8 and 0.2 g of sodium hydrogen carbonate in 20 ml of water and 2 ml of dioxan th~re i9 added a suspension of platinum prepared by hydrogenation of 313 ~g of platinum oxide in 50 ml of water.
In a cyllndrical apparatu~, oxygen i8 passed through the mlxture from bottom to top at SS by means of a glas~ frit, with vigorous stirring.
The mixture is filtered and washed with ~ater, and the filtrate is extracted five times with 100-150 ml of ethyl acetate each ti~e. ~oncen-tratlon of the extracts by evaporation yields 220 mg of educt 5. 1 g of Amberly~t~ 15 (strongly acidic) is added to the aqueous phase, whlch i3 `I ~

,. ~ , `; ' `` ` ' ~ _ 37 _ ~ 3 ~ 8 ~3 then filtered and concentrated by evaporation in vacuo at 40. Purifi-cation as in ,a) yields 1-56 mg of 9. lH-NMR (300 MHz, CDC13): 1.43 (s, (CH3)3C); 1.96 (d, J~3 Hz, CH3-C(4)); 2.55 and 2.71 (2 dxd, J=22 and 15, 2H-C(5)) 3.75 and 3.76 (2 d, J511, 2 OCH3); 4.97 (m, H-C(2)); 5.25-5.45 (m, NH and H-C(3)).

;) (2R)-2-amino~4-methyl-5-phosphono-3-pentenoic acid (10) 0.71 ml of trimethylsilyl bromide is added at 0 to a solution of 123 mg of 9 in 3 ml of dichloromethane. After stirring at 0 for 4 hours, 20 ml of water are added. After 30 mlnutes, the dichloromethane phase is separated off and washed three times with 15 ml of water each time. The aqueous phases are extracted three times with 20 ml of dichloromethane each time and concentrated by evaporation in vacuo. The re~idue is dissolved in 10 ml of 5N hydrochloric acid and is then stirred for 48 hours, diluted with 20 ml of water and extracted three times with 20 ml of dichloromethane each time. The aqueous phase is concentrated by evaporatioD in vacuo, and the residue iB dried under a high vacuum and dissolved in 3 ml of ethanol, and then approximately 1 ml of propylene oxide ls added dropwise thereto. The suspension is filtered. Washing of the filtration residue with ethanol and drying under a high vacuum at room temperature yields 62 mg of 10, m.p. 165C (decomposition).

In order to analyse the purity o~ the enantiomer, a sample is derivatised to the amide with (R)-~+)-methoxytrifluoromethylphenylacetic acid chloride. lH-NMR analysis (300 MHz) by in~egration of the OCH3 signals gives 2 95 % (2R)-isomer (3.44 ppm) and < 5 % (2S)-isomer (3.37 ppm).
.~ .
E~a~ (2R)-2-amino-4-methyl-5-~os~hono-3-pentenoic acld ethyl ester ''`' a) (4R)-2,2-dimethyl-4-(3'-diisopropylphosphono-2'-methyl- prop-1'-enyl)--~ oxazolidins-3-carboxylic scid tert.-butyl ester (1) A solution of 6.68 g of bromlde according to Example 5f in 14.8 ml of dry triisopropyl phosphite is heated at 70C for 17 hours under a pressure of ,.,~
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- 38 - 1 3 28 ~3 100 mbar. The mixture is concentrated by evaporation at 0.4 mbar/70.
Chromatography on 350 g of-silica gel (eluant hexane/ethyl acetate 1:1) yields 8.28 g of 1, Rf value = 0.077.

b) N-((2R)-5-diisopropylphosphono-1 hydroxy-4-methyl-3-penten-2-yl)-carbamic acid tert.-butyl ester (2) 2.25 g of Amberlyst~ 15 (H form, 20-50 mesh) are added to a solution of 4.49 g of phosphonic acid ester 1 according to a) in 100 ml of methanol.
The mixture is stirred at room temperature for 2 days and is flltered, and the filtrate is concentrated by evaporation. Chromatography of the re~idue on 125 g of silica gel (eluant ethyl acetatelmethanol 20:1) yields 2.44 g of 2.
c) (2R)-2-tert.-butoxycarbonylamino-5-diisopropylphosphono-4-methyl-3-pentenoic acld (3) To a solution of 1.6 g of alcohol 2 according to b) in 60 ml of acetone there are added at 0-5 3.3 ml of a solution that i9 3.25 molar in chromium(VI) oxide and 5.29 molar in sulphuric acid. The mixture i9 stirred at 0 for 6 hours and at room temperature for 12 hours. After the addition of 5 ml of isopropanol and 40 ml of 20 % sodium chloride solution, the mixture is stirred for 10 minutes and is then extracted continuously with methyl acetate for 15 hours in a Kutscher-Steudel apparatus. The organic phase is dried over sodium sulphat~ and concen-trated by e~aporation, and the residue i9 chromatographed on 75 g of hexanelethyl acetate/acetic acid 16:10:1. This yields 0.92 g of 3, 1~]D
-94.5 (c = 1.2, CHCl3). 1H-NMR (300 MHz, C~Cl3): 1.2-1.3 (4d, (2-propO)z); 1.4 (s, ~CH3)3CO); 1.95 ~d, J=3, CH3-C(4)); 3.5 and 3.62 (2 dxd, Js23 and 15, 2H-C(5)); 4.66 (m, (2-propO)z); 4.92 (m, H-C(2)); 5.30 ~m, H-C(3)); 5.42 ~d, J~7, NH); 9.0-10.0 (broad~ COzH).
, `I d) (2R)-2-tert.-butoxycarbonylamino-5-diisopropylphosphono-4-methyl-3-pentenolc acid ethyl ester ~4) j 0.09 g of 1-amino-1-chloro-N,N,2-trimethylpropene ls added at 0-5 to a solution of 0.2 g of acld 3 according to c) in 15 ml of dry dichloro-methane. After stirring for 30 minutes at 0, 0.4 g of pyrldlne in S ml of ethanol 19 added. The mlxture ls stlrred further at 0 for 90 minutes .. :
. .
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:: : - ~ , - 39 - ~ 32 ~ i~3 and at room temperature for 15 hours, and is then diluted with 20 ml of dichloromethane and washed twice with 20 ml of water each time. The organic phase is dried using sodium sulphate, concentrated by evaporation and chromatographed on 25 g of silica gel. Elution with ethyl acetatel methanol 10:1 yields 0.12 g of 4. lH-NMR (300 MHz, CDC13): 1.2 1.4 (m, 2 (CH3)2CHO, CH3CH20); 1.45 (s, (CH3)3CO); 1.98 (d, J-3, CH3-C(4));
2.55 (d, Je23, 2H~C(5)); 4.2 (m, CH3~0) 4.69 (m, 2 (CH3)2CHO); 5.0 (m, H-C(2)); 5.16 (m, H-C(3), NH).

e) (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (_) 0.11 ml of trimethylsilyl bromide is added at 0 to a solution o 0.1 g of ester 4 according to d) in 10 ml of dichloromethane. The mixture is stirred at 0 for 4 hours and at room temperature for 15 hours. 20 ml of water are added, the mixture is stirred for 15 minutes, and then the aqueous phase is separated off and the water iB evaporated off under a high vacuum. The residue is dissolved twice in 5 ml of ethanol each time, concentrated by evaporation and again dissolved in 5 ml of ethanol.
0.5 ml of propylene oxide is added. The precipitate i8 filtered off, washed with ethanol and dried ~nder a high vacuum for 15 hours; 48 mg of 5' ~]D ~ ~75 (c=0.5, HzO).

In order to analyse the purity of the enantiomer, a sample ls derivatised to the amide dimethyl ester with ~R)-(+~-methoxytrifluoromethylphenyl-acetic acid chloride followed by diazomethane. lH-NMR analysis (300 MHz) hy integration of the OCH3 signals gives ~ 97 % (2R~-isomer (3.5 ppm) and 5 3 % (2S)-isomer (3.37 ppm).

Example 7: (2R)-2-amino-4-meth~1-7-phosphono-3-heptenoic acid (10) .
~` a) (4R)-2,2-dimethyl-4~ hydroxy-2'-methylprop-2'-enyl)-oxazolidine-3-carboxylic acid t~rt.-butyl ester (1) ~` 45 ml of a lol molar solution of isopropenylma~nesium bromlde are added dropwise at 0-5 within a period of 25 minutes to a solution of 6.9 g of (4S)-2,2-dlmethyl-4-formyloxaæolidine-3-carboxylic acid tert.-butyl ester (according to Example 5c)) in 60 ~1 of dry tetrahydrofuran. The mixture ls stirred at 0 for 45 minutes, allowed to warm up to room temperature !

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_ 40 - ~ 32 8 1~ 3 and cooled again to 10, and then 90 ml of buffer solution (1 molar, phosphate, pH 7) are added; The mlxture i~ filtered and the filtrate i9 extracted twice with 100 ml of ethyl acetate each time. The organic phase is washed twice with 50 ml of water each time and with ~aturated 60dium chloride solution, and 1~ dried with sodium sulphate. Removal of the solvent by evaporation yields 8 g of 1, a diastereoisomeric mixture.
Separation may be effected by chromatography on silica gel u~ing hexane/
ethyl acetate 4:1 and yield~ crystalline (l'S)-threo-epimer (Rf value:
0.2) and (l'R)-erythro-epimer (Rf value: 0.16) in a ratio of approxi-mately 1:2.

b) (4R)-4~ acetoxy-2'-methylprop-2'-enyl)-2,2-dlmethyl-oxazolidine-3-carboxylic acid tert.-butyl ester (2) 60 ml of acetlc anhydride are added dropwise at 0-5 within a period of 10 minutes to a solution of 15.6 g of the epimer mixture according to a) in 60 ml of pyridine. The mixture i9 stirred at room temperature for 15 hour6 and diluted with 0.5 litre of diethyl ether, and then 200 ml of 2~ hydrochloric acid are added while cooling with ice. The organic phase 18 washed with 250 ml of 2N hydrochloric acid and twice with 200 ml of 10 % sodium carbonate solution each time. Drying over sodium sulphate and remo~al of the solvent by evaporation yields 15.4 g of 2.
c) (4R~-4-¦4'-carboxy-2'-methylbutenyl~-2,2-dimethyl-oxazolidine-3-carboxylic acid tert.-butyl ester (3) 34.5 ml of a 1.6 molar solution of butyllithium in hexane are added at 0 to a solution of 5.25 g of dlisopropylamine in 200 ml of dry tetrahydro-furan. Ths mixture i8 cooled to -75C and a solution of 15 g of acetate 2 accordlng to b) in 100 ml of tetrahydrofuran i~ added dropwise within a period of 10 mi~ute~, and after 5 minutes a ~olution of 8 g of tert.-bu~yldimethylsilyl chlorida in 30 ml oP 1,3-dimethyl-3,4,5,6-tetrahydro-2-~lH)-pyrimidinone i8 added. The mixture i9 allowed to warm up to room temperature and i8 then heated under reflux for 2 hours and cooled to room temperature. 230 ml of 45 % ammonium fluoride solution are added, and the whole is stirred at room temperature for 20 hours and is then concentrated by evaporation. 150 ml of lN sodium hydroxide solution are added, while cooling with ice, to the olly re~ldue which i9 obtained .
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- 41 - ~ 32 ~ ~ ~ 3 after concentration of the organic phase by evaporatlon, and the mixture i8 extracted twice with 200 ml of dichloromethane each time. The aqueous phase is acidified with 300 ml o~ 20 % citric acid solution and is extracted three times with 300 ml of dichloromethane each time. The organic pha~es are washed with 20 % sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. Chromatography of the residue on 50 g of silica gel using hexane/ethyl acetate 1:1 as eluant yields 11 g of solid 3.

d) (4R)-4-(4'-carbaethoxy-2'-methylbutenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acld tert.-butyl ester (4) d,a) Startln~ from the acid 3 3.9 ml of 1-amino-1-chloro-N,N,2-trimethylpropene are added dropwise within a period of 10 minutes to an ice-cooled solution of 1.8 g of carboxylic acid 3 according to c) in 100 ml of dry dichloromethane. After 30 minute~ at 0, a solution of 2.2 g of pyridine in 80 ml of ethanol i8 added within a period of 20 minutes. After stirring at room temperature for 12 hours, the mixture i9 diluted with 100 ml of dichloromethane and washed twice with 100 ml of water each time. The organic phase 1~ dried over sodium sulphate and concentrated by evaporation. Chro~atography of the residue on silica gel using hexane/ethyl acetate 10:1 yields 6.5 g of ester 4~ [~]D 3 +6.17 (c-l, CHCl3~. Cl~H~1NOs, calculated: C 63.32 %, H 9.15 %, N 4.10 %; found: C 63.4 %, H 9.2 %, N 4.5 %.

d,b) Startin~ from the epimer mixture 1 A solution of 8 g of alcohol 1 according to a) and 0.05 ml of propionic acid in 10.5 ml of orthoacetlc acid triethyl ester i5 heated at 135-140 for 14 hours, with ethanol ~lowly being distilled off. The whole is concentrated by evaporation at 40 under a high vacuum~ Chromatography of the residue on silica gel using hexane/ethyl acetate 10:1 yields 8 g of ' .

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e) (4R~-2,2-dimethyl-4-(5'-hydroxy-2'-methylpent~ enyl)-oxazolidine-3-carboxylic acid tert.-butyl ester (5) 1.61 g of lithium aluminium hydride are added in portions at 0 to a solution of 14.5 g of 4 according to d) in 250 ml of absolute diethyl ether. The mixture i9 stirred at 0-2 for 18 hours, and a solution of S g of potassium hydrogen sulphate in 60 ml of water is added while cooling with scetone/dry ice. The mixture is filtered and washed four times with 200 ml of diethyl ether each time. The organic phase is washed three times with 80 ml of lN hydrochloric acid each time, three times with 80 ml of saturated sodium bicarbonate solution each time, and twice with 200 ml of saturated ~odium chloride solution each time, and is then dried over sodium sulphate and concentrated by evaporation. Chromatography on silica gel using hexane/ethyl acetate 1:1 yields 11.3 g of 5, C16H29N04, calculated: C 64.19 %, H 9.77 %, N 4.68 %; found: C 63.6 %, H 9.8 %, N 4.7 %.

~I f) (4R)-4-(5'-bromo-2'-methylpent-1'-enyl)-2,2-dimethyl-oxazolidine-3-;~, carboxylic acid tert.-butyl ester (6) 4.87 g of tetrab~omomethane, 3.85 g of triphenylphosphlne and 0.6 ml of pyridine are added at 0-2 to a solution of 4.4 g of alcohol 5 ac~ording to e) in 200 ml of dichloromethane. After 12 hours at 0-2~, a further 1 g of tetrabromomethane and 1 g of triphenylphosphine are added and the mixture is stirred at 0 for 6 hours. The mixture is concentratsd by evaporation, taken up in ethyl acetate, filtered and concentrated.
Chromatography on silica gel using hexane/ethyl acetate 10:1 yields 4.5 g of 6, Cl6H2aN03Br; calculated: C 53.04 %, ~ 7.79 %, N 3.87 %, Br 22.06 % found: C 53.1 %5 H 7.7 %, N 3.9 %, Br 21.6 %.
:~
g) ~4R)-2,2-dimethyl~4-(2'-methyl~5'-diisopropylphosphono-pent-1'-enyl)-oxazolidine-3-carboxylic acid tert.-butyl ester (7) A solution of 10.9 g of bromide 6 in 22 ml of triisopropyl phosphite is heated at 135-140 for 24 hours at 100 mbar. The excess reagent is evaporated off at 0.1 mbarl60. Chromatography of the residue on silica gel using hexanelethyl acetate 1:1 yields 10.7 g of 7.

.

`:
.

.

h) N-((2R)-l-hydroxy-4-methyl-7-diisopropylphosphonohept-3- en-2-yl)-carbamic acid tert.-butyl ester (8) 3 g of Amberlyst~ lS (H form) are sdded to a solution of 3 g of 7 according to g) in 100 ml of ethanol. The mixture is stirred a~ room temperature for 20 hours, filtered, concentrated by evaporation and chromatographed on 50 g of sil1ca gel. Elution with ethyl scetate/
methanol 10:1 yields 2.3 g of 8, 1a3D ~ ~5-9 (C31~ CHCl3). ClgH3gNO6P;
calculated: C 56.0 %, H 9.4 %, N 3.4~ %, P 7.6 % found: C 55.4 %, H 9.3 %, N 3.4 %, P 7.3 %.

i) (2R)-2-tert.-butoxycarbonylamino-4-methyl-7-dlisopropylphosphono-3--~ heptenoic acid (9) ;~ i,a) Oxidation with chromic acid 0.84 ml of a solution which i8 3.25 molar in chromium trioxlde and 5.29 molar in sulphuric acid is added dropwise at 0-5 to a solution of 0.5 g of alcohol 8 according to h) in 15 ml of acetone. The mixture i8 stirred at 0 for 30 mlnute~ and at room temperature for 35 minutes, and then 4 ml of isopropanol, 80 ml of ethyl acetate and 30 ml of 20 % sodium chloride solution are added th~reto, and the mixture is filtered. The aqueous phase i9 extracted three times with 20 ml of ethyl acetate each time. The organic phase i9 dried over sodium sulphate and concentrated by , evaporation. Chroma~ography on 20 g of silica gel using hexane/ethyl ;~l acetate/acetic acid 16:10:1 yields 0 34 g of 9~ [~]D ~ -35.25 (c-1.39, CHCl3), l3C-NMR ~75 MHz, CDCl3): 173.8 (CV2H~; 155.0 (OCON);
~l 140.4 (C(4)); 121.1 (C(3)); 79.5 ~OC(CH3)3); 70.3 (OCH~; 52.1 (C(2)~;
39.7 (d, J=18~ C(5)~; 28.3 ((CH~)3C); 25.7 (d, J=142~ C(7));
24.0 ((CH3)2CH); 20.2 (d, Ja5~ C(6))~

i,b) Oxidation with platinum/oxy~en To a solutlon of 3 g of alcohol 8 according to h) in 105 ml of dioxan there i5 added ~t 55 a ~uspension of platinum in 45 ml of water prepared by hydrogenation and degassing of 1 g of platinum oxide in 45 ml of water. Oxygen is passed through the mixture at 55~60 with vigorous stirring (approximately 1900 rpm). The mixture is filtered through Celite~ and washed twice with 80 ml of wa~er each time, and the filtrate .
:
::
. : ~ . : .

. . .
. - . :: : , : - ~, . . , -1 ~ L 3 is concentrated by evaporstion at 40 under a hlgh vacuum. The resulting product is dissolved in 200 ml of water, and 1 g of ~odium bicarbonate and 50 ml of 20 % sodlum chloride solution are added and the mixture is extracted three time3 with lOO ml of ethyl acetate each time. The organic phases are dried over sodium sulphate. Filtration and concentration by evaporation yleld 1.8 g of educt 8. The aqueous phase i8 acidified with approximately 20 ml of lN sulphuric acid and extrac~ed five times with l20 ml of ethyl acetate each time. Drying over sodium sulphate, concen-; tration by evaporation and chromatography of the re~idue according to i,a) yield 0.8 g of acid 9.
'J) (2R)-2-amino-4-methyl-7-phosphono-3-heptenoic acid (lO~
A 301ution of 3.3 g o~ acid 9 according to i) and 2.6 g of N,O-bis-tri methylsilylacetamide is stirred at room temperature for one hour under argon. After the addition of 4.4 g of trimethylbromo~3ilane, the mixtur~
i3 stirred for 24 hour~. The reaction mixture is added dropwise at 0 to 400 ml of ~ater, and the whole i8 stirred for 30 minutes. The organic phase is separated off and washed three times with 50 ml of water each time. The aqueou3 phases are extracted three times with 30 ml of di-chloromethane each time and concentrated to 10 ml at 40 under a high vacuum. Chromatography on 20 ml of Dowex~ 50 Wx8 using water as eluant, ~` and lyophilisation of the eluate yield 0.4 g of 10 in the form of an amorphous white powder having a melting point of 252 (decomposition);
1~]D ~ -86.5 (C~ 2); CaH16N05P.l ~2; calculated: C 37.05 %, 6.~ %, N 5.5 %; fo~nd: C 36.3 %, H 6.5 %, N 5.6 %.

In order to analys~ th~ purity of the enantiomer, a sample i~ derivatised ~o the amide ~lth ~R) (~)-methoxytrifluoromethylphenylacetic aoid chloride. IH-NMR anslysis (300 MHz) by integration of the OCH3 signsls gives 2 94 % (2R)-isomer (3.24 ppm) and S 6 % (2S)-iso~er (3.17 ppm~.

:, , :, Example 8: (2R)-2-amino-7-phosphono-3-heptenoic acid a) ~4R)-2,2-dimethyl-4-(1'-hydroxyprop-2'-enyl)~oxazol-idine-3-carboxylic acid tert.-butyl ester (1) 60 ml of a 2.4M solution of vinylmagnesium bromide in tetrahydrofuran are added at 0-5 within a period of 30 minutes to a solution of 25 g of (4S)-2,2-dimethyl-4-formyloxazolidine-3-carboxyllc acid tert.-butyl ester (according to Example 5c) in 300 ml of dry tetrahydrofuran. The mixture is ~tirred at 0 for one hour, allowed to warm up to room temperature and then stirred at room temperature for a further one hour. 300 ml of buffer solutio~ (1 molar, phosphate, pH 7) are added while cooling to 10. After 10 minutes, the mixture is filtered, extracted twice with 150 ml of ethyl acetate each time and washed twice with 100 ml of water each time. The aqueous phase is extracted twice with 100 ml of ethyl acetate each time.
The organic extracts are dried over 30dium sulphate and concentrated by evaporation. Chromstography of the rPsidue on silica gel using hexane/
ethyl acetate 4:1 yields 24.2 g of epimer mixture 1; C13H23N04; cal-culated: C 60.68 %, H 9.01 %, N 5.44 %; found: C 60.7 %, H 9.1 %, N 5.6 %.

., b) (4R)-4-(4'-ethoxycarbonylbutenyl)-2,2-dimethyloxazol-idine-3-carboxylic acid tert.-butyl ester (2) A solution of 22.5 g of alcohol 1 according to a) and 0.3 ml of propionic aci~ in 38.5 ml of orthoformic acid triethyl ester is heated at 135-140C
for 4 hour~, with ethanol slowly being distilled off. The mixture i9 concentrated by evaporation at 50 under a high vacuum and chromato-graphed on 300 g of silica gel. Elution with hexane/ethyl acetate 4:1 ylelds 23.9 g of 2, [~]D ~ -10.0 (c=1.5, CHCl3); C17H2gNOs; calculated:
C 62.36 %, H 8.93 %, N 4.28 %; found: C 62.2 %, H 8.9 %, N 4.4 %.

c) (4R)-2,2-dimethyl~4-(5'-hydroxypentenyl)-oxazolidine-3-carboxylic acid tert.-butyl ester (3) 2.7 g of llthium alumlnium hydride arc added in portions at 0-2 to a solution of 23.5 g of 2 according to b) in 550 ml of ab~olute diethyl ether. After stirring at 0-2 for 3 hours, a solution of 25 g of potas~ium hydrogen sulphate in 250 ml of water is added dropwi~e with .

,:
.
'..

- 46 - 13281~3 cooling. The mlxture is filtered through Celite~ and washed thoroughly with diethyl ethar. The organic phase i9 washed twice with 200 ml of lN
hydrochloric acid each time and twice with 250 ml of 10 % sodium bicarbonate solution each time. The aqu00us phases ars extracted twice with 100 ml of ether each time. The organic phases are wash~d with 20 %
sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. Chromatography on sllica gel using hexane/ethyl acetate as eluant yields 18.6 g of 3~ ~]D - -10.1 (c=1.4, CHCl3); ClsH27N0ll;
calculated: 63.13 %, H 9.54 %, N 4.91 %; found: C 63.0 %, H 9.5 %, N 5.0 %.
: I
.~
I
~l d) (4R)-4-(5'-bromopentenyl)-2,2-dimethyloxazolidine-3-carboxylic acid `~ tert.-butyl ester (4) 7 ml of pyridine ara added dropwise at 0 to a solution of 18.5 g of alcohol 3 according to c), 28.2 g of tetrabromomethane and 22.3 g of triphenylphosphine in 600 ml of dichloromethane. The mixture is stirred at 0-2 for 12 hours, concentrated by evaporation, taken up in 150 ml of ethyl acetate, filtered, concentrated to 50 ml and chromatographed on j 200 g of ~illca gel. Elution with hexane/ethyl acetate 10:1 yields 19.9 g i of bromide 4, [~lD ~ -18.9 (c=l, CHCl3); C1sH26N03Br; calculated:
C 51.73 %, H 7.53 %, N 4.02 %, Br 22.94 %; found: C 51.7 %, H 7.7 %, N 4.2 %, Br 23.0 %.

e) (4R)-2,2-dimethyl-4-(5'-di-2-propylphosphonopentenyl)-oxazolidine-3-carboxylic acid tert.-butyl e~ter (5) ~1 A ~olutioD of 19.S g of bromide 4 according to d) in 60 ml of triigo-propyl phosphite is heated at 130-135 for 20 hours at 100 ~bar. The excess reagent is distilled off at 60lO.1 mbar, and the residue i5 chromatographed on 250 g of silica gel. Elution with hexane/ethyl acetate 1:1 yield~ 20.6 g of pho~phonic acld ester 5~ [~3D - -8.6 (c~0.8, CHCl3); Czl~40N06P; calculated: C 58.18 %, H 9.30 %, N 3.23 %, P 7.15 %;
found: C 57.4 %, H 9.3 %, N 3.2 %, P 7.5 %.

~3~8~3 f) N-(~2R)-l~hydroxy-7-(diisopropylphosphonohept-3-en-2-yl)-carbamic acid tert.-butyl ester (6) A solution of 20.6 g of 5 accord~ng to e) in 800 ml of methanol is stirred at room temperature for 20 hours with 30 g of Amberlyst~ 15 (H+
form). The mixture i9 filtered, washed with methanol, concentrated by evaporation and chromatographed on 100 g of sllica gel. Elution with ethyl acetate yislds 14.8 g of 6, ~a~D ~ -3.6 (c-1.5, CHCl3~;
Cl8H36N06P calculated: C 54.95 %, H 9.22 %, N 3.56 %, P 7.87 % found:
C 53.6 %, H 9.0 %, N 3~4 %, P 9.0 %.

g) (2R)-2-tert.-butoxycarbonylamino-7-diisopropylphosphono- 3-heptenoic acid (7) To a solution of 7.4 g of alcohol 6 according to f) in 300 ml of acetone there are added dropwise at 0-2CI within a period of 20 minutes, 15 ml of a solution which i9 3.25 molar in chromium trioxide and 5.29 molar in ~j sulphuric acid. The mixture is stirred at 0-2 for 2 hours and at room temperature for 4 hours, and then 30 ml of isopropanol, 300 ml of ethyl acetate and 200 ml of 20 % sodium chloride solution are added. The aqueous pha~e i9 extracted three times with 250 ml of ethyl acetate each time, and the organic phase3 are dried over sodium ~ulphate and concen-~ trated by evaporation. Chromatography on 200 g of silica gel using ¦ hexane/ethyl acetate/acetic acid 16:10:1 yields 4.55 g of acid 7~ [~D
-24.9 (c~0.8, CHCl3).
j h) (2R)-2-amino-7-phosphono-3~heptenoic acid (8) A solution of 3.1 g of acid 7 and 3 ml of N,0-bis-trimethylsilylacetamide ; in 200 ml of dry dichloromethane is stirred at room temperature for one hour. 3.5 ml of trimethylbromosilane are added, and the mixture i~
stirred at room temperature for 30 hours. The volatile portions are evaporated off, the residue is taken up in 50 ml of dichloromethane, and ; 250 ~1 of water are added at 0-2. The aqueouu phase is separated off and concentrated ta 10 ml under a high vacuum. Chromatography an 20 ml of `I Dowex~ 50 Wx8 using water as eluant, and lyophilisation of the eluate .
:, . :,; .: ' ' ... . . .

yield 1.04 g of 8 in the form of an amorphous powder, ~1D = -65.2 (C-1, H20); 13C NMR (75 MHZ, D20): 172.8 ~CO2H); 140.3 (C(4)); 122.2 (C(3));
1 56.4 (C(2)) 33.3 (d, J~17, C(5)); 27.3 (d, J~134, C(7)) 22.6 (d, J~4,C~6)). In order to analyse the purity of the enantiomer, a sample i9 derivatlsed to the amide trimsthyl ester with (~)-(+~-methoxytrifluoro-methylphenylacetic acid chloride followed by diazomethane. lH-NMR
analysis (800 MHZ) by integration of the OCH~ signals gives 2 95 %
(2R)-isomer t3.54 ppm) and S 5 % (2S)-isomer (3.37 ppm).
.

Example 9: (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acld ethvl es~er a) (2R,3S) 2~formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester (1) aa) Starting from 1,1,3,3-tetramethyl-1,3-disilane~2-azolidine-N-acetic acid ethyl ester 7.6 ml of a 1.6 molar solution of butyllithium in hexane are added at -20 to a solution of 2.26 ml of N-cyclohexyl-N-isopropylamine in 60 ml of absolute tetrahydrofuran. After 20 mlnutes, the mixture is cooled to -78 and there i9 added dropwise a solution of 3 g of 1,1,3,3-tetra-methyl-1,3-di~ila-2-azolidine-N-acetic acid ethyl ester in 60 ml of ~i tetrahydrofuran. The mixture i8 stirred at -78 for one hour, and then 142 ml of an approximately 0.035 molar solution of cyclopentadienyl-bis-:'! 0-1,2:5,6-diisopropylidene-D-glucofuranosyltitanium(IV) chloride in e~her are added and the mixture is stirret at -78 for 17 hours. The reactlon j solution i3 tran~ferred via a small steel tubs, by argon pressure, into a vessel con~aining a solut~on, cooled to -78, of 1.1 ml of methacrolein in 15 ml of tetrahydrofuran. The whole is allowed to warm up 910wly to room temperature, and i~ then stirred for 2 hours. 1.5 ~1 of water are added, and the mixture is filtered. The filtrate is diluted with 250 ml of d~ethyl ether, and ls then washed three tlme~ with 250 ml of approxi-mately 10 % sodium chloride solution each time and with 250 ml of saturated 30dium chlor~de solution. The aqueous phases are extracted twice with 250 ml of diethyl ether each time. The organic phases are dried over sodium sulphate, concentrated by evaporat~on, and dissolved hot in 150 ml of cyclohexane. On cocling, 1,2:5,6-di-0-l~opropylidene-D-, :' ., ': . "
~, .
:: : .

- ~L3281~3 glucofuranose crystallises. The mother liquor is concentrated by evapora-tion, the regidue is taken up in 120 ml of tetrahydrofuran, 24 ml of water and 4.5 ml of acetic acid, and the mixture is stirred at room temperature for 2 hours. Concentration by evaporation at room temperature under a high vacuum yields 10.6 g of resldue, contamining (2R,3S)-2-amino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester. A sample (5 mg) is derivatised for 2 hours with 0.2 ml of trifluoroacetic acid anhydride in 0.3 ml of dichloromethane. Capillary gas chromatography (Chirasil~-L-Val, 90-180/2 per minute) yields 99.25 % (2R,3S)-enantiomer (retention time - Tret ~ 10.28 min~tes) and 0.75 % (2S,3R)-enantiomer (retention time Tret ~ 11.48 minutes). The main mixture is then heated under reflux for 5~ hours in 80 ml of formlc acid ethyl e~ter. Concentration by evapora-tion and chromatography on silica gel using hexanetethyl acetate 1:1 yield 1.64 g of formamid~ 1. Analysis of a sample (5 mg) in the form of the aceta~e by gas chromatography (Chirasil~-L-Val, 160-lS0, 1 per minute): 99.2 % (2R,3S)-enantiomer (T~et ~ 13.64 minutes), 0.8 %
(2S,3R)-enantiomer (T~et = 13.94 minutes).

a,b) Startlng from isocyanoacetic acid ethyl ester ;i 1.65 g of (S)-N-methyl-N-[2-~dim2thylamino)-ethyl]-l-[(R)-1',2-bis-(di-phenylpho~phino)-ferrocenyl]-ethylamine and 1.105 g of bis(cyclohexyl-isocyanide)gold~I) tetrafluoroborate are added at 50 to a solution of 24.88 g of isocyanoacetic acid e~hyl ester and 18.51 g of methacrolein in 220 ml of 1,2-dichloromethane. The mixture is stirred at 50 for 5 hours under argon, concentrated by evaporation, taken up in 400 ml of diethyl ether and filtered, and the filtrate is concentrated by evaporation.
~-~ Distillation of the residue under a high vacuum (0.04 mbar) yields 33.62 g of a ~tereoisomeric mixture of 5-(2-propenyl)-oxazoline-4-carboxylic acld ethyl ester ha~ing a boiling point of 42-52; MS.: m/e 183 (2 %, M ~), 110 (80 %), 85 (100 %). A solution of 33 g of this mixture in 74 ml of water and 33 ml of tetrahydrofuran i8 heated under ; reflux for 3 hours. Concentration by evaporation in vacuo yields 36.1 g of a mixture of stereoisomeric 2-formamino-3-hydroxy-4-me~hyl-4~pentenoic acid ethyl ester 2. A sample (35 mg) i3 derivatised in 2 ml of dichloro-methane with 0.05 ml of N,0-bi~-trimethylsilylacetamide and analysed by ~eans of capillary gas chromatography (Chirasil~-L-Val, 150): 39.1 %
:~ .
., ~
. :~
' ;

, : .:

~ 50 - ~ ~281~3 (2R,3S)~isomer (Tret ~ 22.1 minutes3, 5.8 % (2S,3R~-isomer ~Tret Y
23.1 minutes), 2.8 % (2R,3R)-isomer (T et - 24.3 minutes), 2.3 % (2S,3S)-isomer ~Tret ~ 25.4 minutes).

A solution of 11.42 ml of acetic anhydrlde in 50 ml of dichloromethane is added dropwise st 0-3 within a period of 25 minutes to a solutio~ of 20.2 g of 2, 16.83 ml of triethylamine and 0.62 g of 4-(dimethylamino)-pyridine in 300 ml of dichloromethane. After 30 minutes, the mixture is washed twice with ice-cold 2N hydrochloric acid and twice with 10 %
sodium chloride solution. The aqueous phases are extracted with 100 ml of dichloromethane. The organic phases are dried over sodium sulphate and concentrated by evaporation, and the residue is dissolved hot in hexanel ethyl acetate 4:1. On cooling slowly to approximately 30 there crystallise 1.82 g of racemic (2R*,2S*)-2-for~amino-3-acetoxy-4-methyl-4-yentenolc acid ethyl e~ter having a melting point of 98-106~. The mother liqour is slowly cooled to -12C and kept at that temperature for one hour. Filtration yields 15.04 g of acetate 3, m.p. 73~75~ ~]D ~ -75.6 (c-l, CHCl3~, analysis by ga~ chromatography (Chirasll~-L-Yal, 160-180, 1 per minute): (2R,3S)-isomer 93.5 % (Tr~t ~ 14.5 minutes), ~2S,3R)-isomer 2-2 % (Tret - 14~8 minutes), (2R,3R)-isomer 2.2 % (T t ~
16.8 minutes), (2S,3S)-isomer 2.1 % (Tret = 17.1 minutes).

20.64 g of anhydrous potasslum carbonate are added at -16 to a solution of (2R,3S)-2-formylamino-3-acetoxy-4-methyl-4-pentenoic acid ethyl ester (3) in 400 ml of absolute ethanol. After stirring at -18 to -11C for ~ 4 hours, 500 ml of buffer solution (1 molar, phosphate, pH=7) are added ; dropwise. The mlxture is stirred at room temperature for 30 minutes and extracted three times with 350 ml of dlchloromethane each time. The organic phases are dried over sodium sulphate and concentrated by evapo-ration, and the residue ls chromatographed on 1 kg of silica gel using hexane/~thyl acetate 1~2 a~ e1uant, yieldine 9.a g of alcohol i :; ~

,'"'`

. . ` .

.. .
.: ~ - , . ''':' - ~: : ' -` 13281~3 b) (2R)-2-formylamino-4-methyl~5-diisopropylphosphono-3~pentenoic acid ethyl ester (4) To a solution of 14.19 g of 1 according to a~ in 210 ml of 1,2-dichloro-ethane there are added at 18-20 6.57 ml of thionyl bromide and, after stirring for 2 hours, 135 ml of water. After 15 minutes, the organic pha9e i9 separated off and washed three times with 150 ml of ice-water each time and once wi~h 100 ml of ice-cooled saturated sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate and concentrated by evaporation, and the residue is dissolved in 60 ml of triisopropyl phosphlte and stirred at 75/100 mbar for 17 hours. The excess reagent is distilled off at 90 under a high vacuum. Chromato-graphy of th0 residue on 650 g of silica gel using ethyl acetate/methanol 20:1 yields 10.88 g of phosphonic acid ester 4~ [~]D ~ -123.5 (c=l, CHCl~ H-NMR analysi~ (300 MHz~ with the addition of (lR)-1-(9' anthra-cenyl)-2,2,2-trifluoroethanol shows an enantiomeric purity of > 90 %.

c) (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (5) 23 ml of trimethylbromosilane are added dropwise at room temperature within a period of lS minutes to a solution of 10.3 g of 4 according to b) in 42 ml of dichloromethane. After 21~ hours, 42 ml of ethanol are added while coollng with lce, and the mixture is stirred for 20 hours.
The whole is then concentrated by evaporation and the resldue is dissolved three times in 70 ml of toluene each time and in each ca~e is concentrated by ~vaporation again. The residue is dissolved in 42 ml of ethanol, and 42 ml of propylene oxide are added. After 1~ hour~, the mixture is filtered. Drying the filtration residue in a vacuum desicrato~
over P20slROH (3 hours/80) yields 6~17 g Of 5; 1a1D - -78 ~c=0.6, H203;
m.p. 194-197 (deco~p.~, CgH16NOsP; calculated: C 40.51 %, H 6.80 %, 5.91 %, P 13.06 %; found: C 39.4 %, H 7.09 %, N 5.73 %, P 12.98 %.

In order to analyse the purity of the enantiomer, a sample is derivatlsed to the amide dimethyl phosphonate with ~R)-(~)-methoxytrifluoromethyl-phenylacetic acid chloride and diazomethane and analysed by ~ MR
(300 MHz) using ths integration of the OCH3 signals: (2R)-isomer 2 93 %
(3. 51 ppm), (2S)-isomer ~ 7 % (3.37 ppm).
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- 52 - 1 328~

Example 10: (2R)-2-amino-4-methyl-5-pho3phono-3-pentenoic acid A solution of 100 mg of ( 2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester according to Example 6 in 3 ml of lN hydrochloric acid is heated in a bath at 100C for 4~ hour~. The solution i3 concentrated by evaporation and the residue i8 dried at 60 under a high vacuum for 30 minutes. The residue i9 dissolved in lS ml of ethanol, and 4 ml of propylene oxide are added thereto. Filtration and drying of the filtration residue in a vacuum desiccator over P2OslKOH yield 62 mg of acid.

In order to determine the purity of the enantiomer, a sample i~
derivatised to the amide with (R)-(~)-methoxytrifluoromethylphenyl scetic acid chloride and i9 analysed by lH-N~R (300 MH~), integration of the OCH3 signals: > 95 % (2R)-enantiomer (3.2S ppm) and ~ 5 % (2S)~enantiomer I (3.18 ppm~.
., Example 11: E-2-amino-4-methyl-5-Pho~Phono-3-Pentenoic acid 12 g of E-2-amino-4-methyl-5-phosphono-3~pentenoic acid ethyl ester are `~l stirred under reflux in 70 ml of wa~er for 19 hours. The reaction ~ixture ~! i9 slowly cooled to room temperature, stirred in an ice bath for one hour, filtared and washed wlth cold water. In this manner there is obtained E-2-amino-4-methyl-5-phosphono-3-pentenoic acid 1n the form of the monohydrate, m.p. 163 (decomp.).
:, Example 12: E-2-dimethylamino-4-methyl-5-pho~phono-3-pentenoic acid A mixture of 3.56 g of E~2-amino-4-methyl-S-phosphono-3-pentenolc ac~d ethyl e3ter, 45 ml of 98 % formic acid and 30 ml of 37 % aqueou~
formaldehyde ~olutlon is ~irred at a bath temperature of 105 for 30 minutes. The mixture i~ then concentrated to drynes~ by evaporation in vacuo. The re~idue is taken up in a little water and the whole i8 again concentrated by evaporation in vacuo. Thi~ procedure is repeated twice more. The solid re~idue i~ stirr~d with 80 ml of water. After one hour, the undissolved material i8 separated off over a hard filt~r and washed with water. The filtrate and the washing water are concentrated to dryness by ev~poration in vacuo. The residue is ~uspended in 100 ml of water and, after the addition of 30 ml of lN sodium hydroxide solution, ``'''`; "
~ ~ .

.
.
.: :

~32~3 19 left to stand at room temperature for 2 days. The reaction mlxture i9 concentrated to a re8idual-volume of approximately 25 ml by evaporation in vacuo and purlfied by ion exchanger chromatography (Dowex 50 W x 8 HzO). The fractions which contain the desired product are combined, concentrated by evaporation in vacuo and recrystallised from water/ ethanol. In this manner there i8 obtained E-2-dimethylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 239 (decomp.).
:
Example 13- E-2-dimethyla~lno-4-methyl-5-phosphono-3-pentenoic acid ` ethYl ester .
30 ml of 8N ethanolic hydrogen chloride solution are added to 1.19 g of E-2-dimethylamino-4-methyl-5-phosphono-3- pentenoic acid, and the mixture is stirred at 40 for 24 hours. The reaction mixture is concentrated to dryneæs by evaporation in vacuo. After the addition of 30 ml of pure ethanol, the mixture is again concentrated by evaporation, giving 1.90 g of reddish oil, whlch is dissolved in hot isopropanol. After cooling there i8 obtained cry~talllne E-2-di~ethylamino-4-msthyl-5-phosphono-3-pentenoic acid ethyl ester hydrochlor~de, m.p. 203 (decomp~).

Example 14: E-2-benzylamino-4-methyl-5-phosphono-3~pentenoic acid ethyl ester 16 ml of glacial scetic acid, 5.90 g of sodium acetate (anhydrous) and 12.2 ~1 of benzaldehyde are added to a solution of 5.69 g of E-2-amino-4-methyl-5-phosphono-3- pentenoic acid ethyl ester in 48 ~1 of water and 48 ml of ethanol. 15.70 g of sodium borohydride are added in approxi-mately 70 portions within a period of one hour with intensive coollng with icelsodium chloride, 4 ml of benzaldehyde being added after half the addition has taken place, after approximately 30 minutes. The tamperature of the reaction mixture is kept at from 0 to 10. When the addition is complete, the mixture 19 stirred at 0 for one hour to complete the reaction, and then lN hydrochloric acid is added dropwise until an acldlc reaction to Congo red takes place. The undissolved salts are flltered off and washed with water. The filtrate ls concentrated to dryness by evapo-ratlon in vacuo, and the residue is concentrated by evaporatlon twice .: .
'' ~

_ 54 _ ~ 3 2 8 1 1 3 more after the addition of ethanol. The re~idue is then stirred with 150 ml of ethanol, and the undissolved material is filtered off with suction and washed with ethanol. 2S ml of propylene oxide are added to the filtrate, and the mixture i8 ~hen stirred for 2 hours. The material which crystallises out (mainly educt) is filtered off. The mother liquor i9 concentrated to dryness by evaporation and stirred with 350 ml of ethyl acetate. The crystalline crude product obtained after filtration with suction is recrystallised from ethanol. In this manner there is obtained E-2-benzylamino-4-methyl-S-phosphono-3-pentenoic acid ethyl ester, m.p. 192 (decomp.).

Example 15: E-2-benzylamino-4-methyl-5-Phosphono-3-pentenoic acid ethyl .,, -; ester .~
A solution of 1.00 g of E-2-benzylamino-4-methyl-5-phoaphono-3-pentenoic acid ethyl ester in 6 ml of watsr is stirred under reflux for 20 hours.
The reaction mixture is concentrated to dryness by evaporation in vacuo.
Ethanol is added to the residue, and the ~ixture is again concentrated by evaporation. This proce3s 1~ repeated twice more. The residue is dissolved in boiling methanol. After cooling there is obtained crystalline E-2-ben~ylamino-4-m~thyl-5-phosphono-3-pentenoic acid, m r p. 150 (decomp.).

Examp]e 16: E-2-isopropYlamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 6.64 g o~ sodium aceta~e (anhydrous) and 18 ml of ace~one are added to a solutlon of 6.40 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester in 54 ml of water and 18 ml of glacial acetic acid. 17.67 g of sodium borohydride are added in approximately 70 portions within a period of 90 minutes with intensive cooling with ice/sodium chloride, 18 ml of acetone being added after 20 minutes and after 50 minutes. When the addition iB complete, the thick white suspenslon iB stirred at 0 for 30 minutes to complete the resction, and then lN hydrochloric acid i3 added dropwise until an acidic ~eaction to Congo red takes place. The resulting clesr solution i& concentrated by evaporation in vacuo, and the residue is concentrated by evaporation twice more after the addition of ethanol. The residue is then atirred with 200 ml of ethanol at room .

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temperature, snd the undissolved material is flltered off and washed with ethanol, The filtrate is concentrated by evaporation in vacuo, and the residue is recrystallised from isopropanol. In this manner there is obtained E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester hydrochloride, m.p. 203-20S (decomp.).

Example 17- E-2-isoProPylamino-4-methY1-5-Phosphono-3-pentenoic acid A solution of 1.20 g of E-2-isopropylamino-4-methyl-S-phosphono-3-pentenoic acid ethyl ester hydrochloride in 7 ml of water is stirred under reflux for 20 hours. The reaction mixture is concentrated to dryness by evaporation in vacuo. Ethanol is added to the residue, and the mixture i8 again concentrated by evaporation. This process is repeated twice more. The residue is dissolved in 25 ml of ethanol 9 a total of 5 ml of propylene oxide is added dropwise thereto with stirring, and the whole is concentrated to dryness by evaporation. The residue is dissolved in a little water, and ethanol is added until the solution becomes cloudy. The solution is stirred at room temperature for 4 hours to complete the reaction, during which time crystallisatlon slowly takes place. The product is filtered off, washed with ethanol and diethyl ether and dried at 100 under a high vacuum. In this manner there is obtained E-2-i~o-propylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 225-227 ~decomp.).

Example 18: E-2-meth~lamino-4-methyl-5-phosphono-3-pentenoic acid a~ 2-~N-methyl-N-formylamino)-3-hydroxy-4 methyl-4-pentenoic acid ethyl ester (1) 20.60 g of 5-(2-propenyl)-2-ox~zollne-4-carboxylic acid ethyl ester, prepared according to Example 1, are dissolved in 200 ml of dry dichloro-methane under argon. A suspension of 16.60 g of trimethyloxonium tetra-fluorobnrate in 200 ml of dry dichloromethane is then added dropwise at .:, ;~ 15. The reaction mixture is stirred a~ room temperature for 17 hours, and then 150 ml of water and 45 ml oF saturated potassium bicarbonate ~ solution are added slowly, so that a pH of 7 is produced. The organic ;, phase i~ separated off and washed twice with water and once with - saturated sodium chloride solution, and is then dried over sodium ,~
. t ~ j ..
`'; . , : : ' ~ ':: ~
, ' .: , : : `
: ' '': :: ' ' ' '~` ' ' `, ` !
' ' ' `' , ' ' "
. ' ' .- ~L328113 sulphate. After the dichloromethane has been dlstilled off, the oily residue is distilled in a bulb tube, b.p. 120-130~113 Pa. In this manner ~here is obtained 2-tN-methylformylamino)-3-hydroxy-4-methyl-4 pentenoic acid ethyl ester in the form of a light-yellow honey, IR (CH2C12): 3550 (H0); 1740 (C0 ester); 1675 (C0 amide).

b) E~2-(N-methyl-N-formylamino)~4-methyl-5-diisopropyl-phosphono-3-pentenoic acid ethyl ester (2) 7.70 ml of thionyl bromide are added dropwise at 20 under argon to a solution of 17.80 g of 2-(N-methylformylamino)-3-hydroxy-4-methyl-4-pentenoic acid ethyl estar in 248 ml of 1,2-dichloroethane. The mixture is stirred at room temperature for 2 hours. 150 ml of water are then added dropwlse wlth slight cooling (20). The two-phase mixture is stirred thoroughly for a further 20 minute~ to complete the reaction. The organic phase i~ ~eparated off and washed three time~ with water/ice, once with ice/saturated potassium bicarbonate solution and ~nce with saturated sodium chloride solution. To the intermediate obtained after drying over sodium sulphate and removal of the 1,2-dichloroethane by digtlllation at 35 in vacuo there are added at room temperature 66 ml of trii~opropyl phosphite, and the mixture i8 then stirred at 75 under reduced pressure (approximately 13 kPa) for 17 hourq. The excess tri-isopropyl phosphite and other vulatlle by-products are then di~tilled off under a high vacuum. Purification by column chromatography (9ilica gel~
ethyl acetate) yields E-2-(N-methylformylamino)-4-methyl-5-dii~opropyl-phosphono-3-pentenoic acid ethyl ester in the form of a yellowish honey;
IR (CH2Cl2): 1740 (C0 ester); 1670 ¦C0 am~de); 1235 ~pG0~; 980-1010 (P-O-C). According to the lH-NMR spectrum, the compound is in the form of a mixt~re Qf two rotamers~
,~, ~ c) E-2-methylamino-4-methyl-5-phosphono~3-pentenolc acid (3) `.I 20 ~1 of trimethylbromosilane are added dropwise at 20 within a period ~` of 10 minute~ under argon to a solution of 9.50 g of E-2-(N-methylformyl-`l amino~-4-methyl-5-diisopropylpho3phono 3-pen~enolc acid ethyl ester in ~ 40 ml of dry dichloromethane. After stirring at room temperat~re for :, ~

., .

., :

: :
,... . .. .
~ . , . : :-~ ~ 2. ~

20 hours, 37 ml of ethanol are added dropwise within a period of 15 minutes, and the whole is stirred for a further 20 hours. The clear reaction solution is then concentrated to dryness by evaporation in vacuo. The residue is concentrated by evaporation twice more in each case after the addition of 30 ml of toluene. 128 ml of 2N hydrochloric acid are added to the resulting oil, and the ~ixture i~ stirred at a bath temperature of 85 for 16 hours. The reaction mixture is concentrated by evaporation in vacuo. Concentration by evaporation twice after the addition of ethanol/toluene 1:1 yields an oily residue, which is dissolved ln 51 ml of ethanol and to which there is added dropwise a solution of Sl ml of propylene oxide in 51 ml of ethanol. The product obtained ln crystalline form is filtered off after 2 hours and re-crystallised from water/ethanol. In this manner there is obtained E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 239 (decomp.).

Example 19: The following can also be prepared in a manner analogous to that described in Examples 1-3 or 6 and 9:

E-2-amino-5-phosphino-3-pentenoic acid ethyl ester, m.p. 172-173;
E-2-amino-5-phosphino-3-pentenolc acid butyl sster, m.p. 160-161;
E-2-amino-S-phosphono-3-pentenoic acid ethyl ester, m.p. 167-168;
E-2-amlno-5-phosphono-3-pentenoic acid butyl ester, m.p. 160-161;
E-2-amino-5-phosphono-3-pentenoic acid octyl ester, m.p. 161-162;
E-2-amino-5-pho~phono-3~pentenoic acid propyl estsr, m.p. 161-162;
E-2-amino-5-phosphono-3-pentenoic acid pentyl ester, m.p. 160-161;
E-2-amino-5-phosphono-3-pentenoic acid isobutyl ester, m.p. 163-164;
E-2-amlno-5-phosphono-3-pentenoic acid sec.-butyl ester, m.p. 169-170;
E-2-amino-4-methyl-5-pho~phono-3-pentenoic acid methyl ester~
m.p. 193-194~ [water/acetone (9:1)];
E-2-amino-4-metbyl-5-phosphono-3-pentenoic acid n propyl ester, m.p. 184-185, (water);
E-2-amino-4-methyl--5-phosphono-3-pentenoic acid n-butyl ester, m.p. 186-187, [water/acetone (2:1)];
E-2-amino-4-methyl-5-phosphono-3-pentenoic acid isobutyl ester, m.p.
181-182, ~water/acetone (9:1)];

' ~'`'', ~, ' ` ' ' ':

- 58 - 1 32~1~3 E-2-amino-4-methyl-5-phosphono-3-pentenoic ac~d n-pentyl est~r, m.p. 207 208;
~-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-hexyl ester, m.p. 207-208;
E-2-amino-7-phosphono-4~heptenoic acid butyl ester, m.p. 186~;
E-2-amino-5-phosphono-4-pentenOic acid methyl ester, m.p. 219-220;
E-2-amino-s-phosphono-4-pent~noic acid ethyl ester, m.p. 234;
E-2-amino-S-phosphono-4-pentenoic acid butyl ester, m.p. 239;
E-2-amino-5-phosphono-4--pentenoio acid octyl ester, m.p. 236;
E-2-amino-5-phosphono-4-pentenoic acld 2-hydroxyethylester, m.p. 197.

Example 20: The following can also be prepared in a manner analogous to that described in Example~ 4, 11, 12, 17 and 18 or 5, 7, 8, 9 and 10:

E-2-amino-5-phosphono-4-pentenoic acid, m.p. 219-220;
E-2-amino-5-methylphosphonyl-4-pentenoic acid, m.p. 222 E-2-amino-5-butylphosphonyl-4-pentenoic acid~ m.p. 232-233;
E-2-amino-5-octylphosphonyl-4-pentenolc acid, m.p. 221-223;
E-2-amino-5-dodecylphosphonyl-4-pentenoic acid, m.p. 211;
E-2-amino-6-phosphono-4-hexenoic acid, m.p. 244-246;
E-2-amino-6-methylphosphonyl-4-hexenoic acid, m.p. 145-150 E-2-amino-6-butylphosphonyl-4-hexenoic acid, m.p. 216;
~, E-2-amino-6-octylphosphonyl-4-hexenoic acid, m.p. 209-210;
~ E-2-amlno-6-dodecylphogphonyl-4-hex~noic acid, m.p. 197-200 l E-2-amlno-7-phosphono-4-heptenoic acid, m.p. 125 ~decomposition);
^I (2R)-E-2-amino-4-fluo~o-5-phosphono-3-pentenoic acid, 1U]D ~ -44.8 (c~0.5; H2O~; 13C-NMR-spectrum (75 MHz, DzO): 172.7 ~CQOH); 161.5 ~dxd, J~263+12: C4); 100.9 (t, Jsll: C3); 49.5 (Cz); 33.5 (dxd, J~128~26: Cs);
-` E-2-amino-5-pho~phono-3-pentenoic acld, white a~orphous powder, lH-NMR
(DzO): 2.39 (dd, 2H, C(5)-H); 4.27 (d, 1~, C(2)-H); 5.53 (m, lH, C(3)-H~;
S.87 (m, lH, C(4)-H~; m.p. after recrystallisation from ethsnol/wat~r 191-192;
E-2-amino-4-methyl-5-phosphono-3-pentenoic acid, lH-NMR (D20): 1.73 ~s, 3H, CH3); 4.55 (8, lH, C(2)-H);
I
` 1 . ' , : :-: : : -.

_ 59 _ 1 3~8~13 E-2-amino-5-methylphosphonyl-3-pentenoic acid, amorphous white powder, lH-NMR (D20): 2.55 (dd, 2H, C(5)-H); 4.38 (d, lH, C(2)-H); 5.64 (m, lH, C(3)-H); 5.91 (m, lH, C(4)-H);
E-2-amino-5-phosphino-3-pentenoic acid, m.p. 139-140;
E-2-amino-4-methyl-5-pho~phino-3-pentenoic acid, m.p. 176-177 (2S)-E-2-amino-4-methyl-5-phosphono-3-pentenoiC acid, m.p. 196, [~120 - +97.1 ~ 1.9 (csO.5, w~ter);
(2R)-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 194V, [~]20 8 -9~.7 ~ 1.2 (c=0.8, water);
E-2-amlno-4-methyl-5-methylphosphonyl-3-pentenoic acid 9 lH-NMR (D20): 1.20 (d, 3H, CH3-P); 1.75 (d, 3H9 CH3); 2.45 (d, 2H, C(5~-H); 4.50 (d, lH, C(2)-H); 5.15 (m, lH, C(3)-H);
E-2-amino-2-methyl-5-phosphono-3-pentenoic acid, m.p. 225-226~ (from water);
E-2-amino-3-methyl-5-phosphono-3-pentenoic acid, white powder, m.p. 168, lH-NMR (D20): 1.50 (d, 3H, CH3); 2.4 (m, 2H, CH2); 4.30 (s, lH, C(2)-H);
5.60 (m, lH, C(4)-H);
E-2-amlno-5-methyl-5-phosphono-3-pentenoic acid, white amorphous solid, ~H-NMR (D20): 1.05 (dd, 3H, CHl); 2.45 (m, lH, C(5)-H); 4.33 (d, 2H, C(2)-H); 5.5 and 5.9 (2m, 2H, C(3)-H and C(4)-H);
:, E-2-amino-4-ethyl-5-phosphono-3 pentenoic acid, m.p. 176;
E-2-amino-4-propyl-5-phosphono-3-penteno~c acid, m.p. 193;
E-2-amino-4-butyl-5-phosphono-3-pentenoic acid, m.p. 186-187 E-2-amino-4-isopropyl-5-phosphono-3-pentenoic acid, m.p. 201;
E-2-amino-4-tert.-butyl-5-phosphono-3-pentenolc acid, m.p. 252-253, H-NMR (D203: 0.95 (s, 9H, (CH3)3C);
Z-2-amino-4-tert.-butyl-5-phosphono-3-pentenoic acid, lH-NMR (D20): 1.08 (S, 9H, (C~3)3C) 2.45 (m, 2H, CH2); 4.95 (d, lH, C(2)-H); 5.20 (m, lH, C(3)-H);
E-2-amino-4-benzyl-5-phosphono-3-pentenoic acid, colourless needles, m.p. 196 198;
E-2-amino-4-phenyl-5-phosphono-3-pentenoic acid, colourless needles, m.p. 230-233 E-2-amino-4-methyl-5-methylphosphono-3-pentenoic acid as by-product, m.p. 149~150.
''' , .

xample 21: E-2-methylamino-4-methyl-3-pentenoic acid ethyl ester 50 ml of 8N ethanolic hydrogen chlorlde solution are added to 1.20 g of E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid, and the mixture is stirred at 40D for 25 hours. The reaction mixture is concentrated to dryness by evaporation in vacuo. Concentration by evaporation twice after the addition of ethanol/toluene 1:1 yields an oily residue, which is dissolved in 5 ml of ethanol and to which there is added dropwise a solution of 5 ml of propylene oxide in 5 ml of ethanol. The product obtained in crystalline form is filtered off after 2 hours and washsd with ethanol and ether. After drying (80, 4 hours) under a high vacuum, there is obtained E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 235-240 ~with decomposition).

Example 22: Preparation of 1000 capsules each containing 10 mg of the active ingredient of Example 6 and having the following composition:
E-2-amino-6-phosphono-4-hexenoic acid 10.0 g lactose 207.0 g modified starch 80.0 g magnesium stearate 3.0 g Method: All the pulverulent coDstituent~ are sieved through a sieve .
, havlng a mesh width of 0.6 mm. The active ingredient i~ then placed in a sultable mixer and mixed first with the magnesium stearate and then with i the lactose and ~tarch, until a homogeneous mixture is obtained. No. 2 l gelatin cap~ule~ are each filled with 300 mg of tb~s mixture, a capsule-; filling machtne being used.
: .
: ::;,, Capsules tha~ contain from 10 to 200 mg of one of the other disclosed compounds ~entioned in Examples 1-20 are prepared ln analogous~manner.
'. ;'~
. I
;l Example 23: Preparatlon of 10,000 tablets each con~aining 10 mg of the active ingredlent of Example 6 and having the following composition:
, ~-2-amino-6-phosphono-4-hexenoic acid 100.00 g lactose 2535.00 g corn starch 125.00 g .

.

.

polyethylene glycol 6000 150.00 g magnesium stearate 40,00 g purified water q.s.

Method: All the pulverulent constituents are sieved through 8 sieve having a mesh width of 0.6 mm. The active ingredient is then mixed in a suitable mixer with the lactose, the magnesium stearate and half of the starch. The other half of the starch i8 suspended in 65 ml of water, and ; the suspension is added to a boiling solution of the polyethylene glycol in 260 ml of water. The resulting paste is added to the powders and the mixture is granulated, if necessary with the addition of more water. The granulate is dried overnight at 35, forced through a sieve having a mesh width of 1.2 mm, and compressed to form tablets which have a breaking groove.

Tablets that contain from 10 to 200 mg of one of the other disclosed h compounds mentioned in Examples 1-20 are prepared in analogous manner.

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Claims (22)

1. A process for the manufacture of an unsaturated amino acid compound of formula (I), in which R1 is hydrogen, C1-C8alkyl or hydroxy, R2 is hydrogen, C1-C8-alkyl, halo-C1-C4alkyl, mono- or dihydroxy-C1-C7alkyl, mono- or di-C1-C4-alkoxy-C1-C7alkyl, aryl-C1-C4alkyl, C2-C6alkenyl, halogen or aryl, R3 is hydrogen, C1-C8alkyl or aryl, R4 is hydrogen or C1-C8alkyl, R5 is carboxy, C1-C8alkoxycarbonyl, phenyl-C1-C4alkoxycarbonyl which is unsub-stituted or substituted by C1-C4alkyl, C1-C4alkoxy and/or halogen, carbamoyl, mono- or di-C1-C4alkylcarbamoyl or 5- to 7-membered alkylen-carbamoyl, R6 is amino, mono- or di-C1-C4alkylamino or phenyl-C1-C4alkyl-amino, A is unsubstituted or C1-C4alkyl-substituted .alpha.,.omega.-C1-C3alkylene or a direct bond and B is methylene or a direct bond, with the proviso that A is unsubstituted or alkyl-substituted .alpha.,.omega.-alkylene having from 1 to 3 C-atoms when B is a direct bond, or a salt therteof, characterised in that in a compound of formula (II), in which Z1 is free or protected hydroxy, Z2 is an R1 group or protected hydroxy, Z5 is an R5 group or protected carboxy, Z6 is a protected group R6, and R1, R2, R3, R4, R5, R6, A and B are as defined above, the pro-tected groups Z6 and, when applicable, Z1, Z2 or Z5 are freed by reaction with a tri-lower alkylhalosilane and, if required, a resulting compound of formula, wherein R5 denotes carboxy, is esterified with a C1-C8alkanol or phenyl-C1-C4alkanol which is unsubstituted or substituted by C1-C4-alkyl, C1-C4alkoxy and/or halogen, or is aminated with ammonia or a mono-or di-C1-C4alkylamine or 5- to 7-membered alkylenamine, so as to produce the corresponding compound of formula I, wherein R5 denotes C1-C8alkoxy-carbonyl, phenyl-C1-C4alkoxycarbonyl which is unsubstituted or substi-tuted by C1-C4alkyl, C1-C4alkoxy and/or halogen, carbamoyl, mono- or di-C1-C4alkylcarbamoyl or 5- to 7-membered alkylencarbamoyl, or a resulting compound of formula I, wherein R5 denotes C1-C8alkoxycarbonyl, phenyl-C1-C4alkoxycarbonyl which is unsubstituted or substituted by C1-C4alkyl, C1-C4alkoxy and/or halogen, carbamoyl, mono- or di-C1-C4-alkylcarbamoyl or 5- to 7-membered alkylencarbamoyl, is hydrolysed so as to produce the corresponding compound of formula I, wherein R1 is carboxy, and, if required, in a resulting compound of formual I, wherein R6 denotes amino, the amino group is mono- or di-C1-C4alkylated or phenyl-C1-C4alkylated so as to produce the corresponding compound of formula I, wherein R6 is mono- or di-C1-C4alkylamino or phenyl-C1-C4-alkylamino, and, if required, a resulting mixture of optical isomers is resolved into the components and the desired isomer is separated off, or resulting free compound is converted into a salt or a resulting salt is converted into the free compound or into a different salt.

2. A process according to claim 1 for the manufacture of a compound of formula I in which R1, R2, R3, R4, R6, A and B are as defined in claim 1 and R5 denotes C1-C8alkoxycarbonyl, phenyl-C1-C4alkoxycarbonyl which is unsubstituted or substituted by C1-C4alkyl, C1-C4alkoxy and/or halogen, carbamoyl, mono- or di-C1-C4alkylcarbamoyl or 5- to 7-membered alkylen-carbamoyl, or a salt thereof, characterised in that a compound of formula (III), in which R2, R3, R4, A and B are as defined for formula I, Z5 has the meaning of R5, Z6 is protected amino and X is reactive esterified hydroxy, is reacted with a compound of formula (IV), in which Z1 is free or protected hydroxy, Z2 has the meaning of R1 or is protected hydroxy and R is an etherifying group, in the resulting inter-mediate the protected groups Z6 and, when applicable, Z1 or Z2 are freed whilst R5 is retained, by reaction with trimethylbromosilane and, if required, a resulting compound of formula I is converted into a salt or a resulting salt is converted into a different salt or into a free compound of formula I or, if required, an optical isomer is isolated from a mixture of stereoisomeric forms of a resulting compound of formula I or of a salt thereof.

3. A process according to claim 1 for the manufacture of a compound of formula I in which R1, R2, R3, R4, R6, A and B are as defined in claim 1 and R5 is carboxy, and the salts thereof, characterised in that in a compound of formula II in which Z1 is free or protected hydroxy, Z2 is an R1 group or protected hydroxy, Z5 is free or protected carboxy and Z6 is protected group R6 and R1, R2, R3, R4, R6, A and B are as defined in claim 1, the protected groups Z6 and, when applicable Z1, Z2 or Z5 are freed by reaction with a tri-lower alkylhalosilane and, if required, a resulting compound of formula I, wherein R5 denotes C1-C8alkoxycarbonyl or phenyl-C1-C4alkoxycarbonyl which is unsubstituted or substituted by C1-C4alkyl, C1-C4alkoxy and/or halogen, is hydrolysed so as to produce the corresponding compound of formula I, wherein R1 is carboxy, or a resulting compound of formula I, wherein R5 denotes carboxy, is esteri-fied with a C1-C8alkanol or phenyl-C1-C4alkanol which is unsubstituted or substituted by C1-C4alkyl, C1-C4alkoxy and/or halogen so as to produce the corresponding compound of formula I, wherein R5 denotes C1-C8alkoxy-carbonyl or phenyl-C1-C4alkoxycarbonyl which is unsubstituted or substi-tuted by C1-C4alkyl, C1-C4alkoxy and/or halogen, or, if required, or if required, a resulting compound of formula I is converted into a salt or a resulting salt is converted into a different salt or into a free compound of formula I or, if required, an optical isomer is isolated from a mixture of stereoisomeric forms of a resulting compound of formula I or of a salt thereof.

4. A process according to claim 2, characterised in that the starting material used is a compound of formula IV in which protected hydroxy Z1 or Z2 is hydroxy etherified by an aliphatic alcohol.

5. A process according to claim 4, wherein Z1 or Z2 is hydroxy etherified by a lower alkanol, lower alkenol or lower alkynol each of which is unsubstituted or substituted by halogen or, in a position higher than the .alpha.-position, by hydroxy, oxo, lower alkoxy, lower alkanoyloxy or by mono-or di-lower alkylamino.

6. A process according to claim 5, wherein said lower alkanol, lower alkenol or lower alkynol is substituted in a position higher than the .alpha.-position by lower alkoxy.

7. A process according to any one of claims 1 to 6, characterised in that the starting material used is a compound of formulae II or III in which the protected group Z6 is an acylamino group or an acylamino group N-substituted by lower alkyl or phenyl-lower alkyl.

8. A process according to any one of claims 1 to 6, characterised in that the starting material used is a compound of formulae II or III in which the protected group Z6 is a lower alkoxycarbonylamino group that is unsubstituted or substituted in the 1- or 2-position.

9. A process according to claim 8, wherein Z6 is tert.-butoxycarbonyl-amino.

10. A process according to any one of claims 1 to 6, characterised in that the starting material used is a compound of formulae II or III in which the protected group Z6 is a lower alkanoylamino group or a lower alkanoylamino group N-substituted by lower alkyl or phenyl-lower alkyl.

11. A process according to claim 10, wherein Z6 is formylamino.

12. A process according to any one of claims 1 to 6, characterised in that the tri-lower alkylhalosilane used is a tri-lower alkylchlorosilano, tri-lower alkyliodosilane or tri-lower alkylbromosilane, especially trimethylbromosilane, and that the protected groups Z6 and, when applicable, Z1, Z2 or Z5 are freed in a halogenated hydrocarbon.

13. A process according to claim 12 wherein said halogenated hydrocarbon solvent or diluent comprises a halogenated aliphatic hydrocarbon and the substance absorbing hydrogen halide is an epoxy-lower alkane in admixture with a lower alkanol.

14. A process according to claim 13 wherein said halogenated hydrocarbon solvent or diluent comprises dichloromethane.

15. A process for the manufacture of an unsaturated amino acid compound of formula (Ia) in which R1 is hydrogen, C1-C8alkyl or hydroxy, R2 is hydrogen, C1-C8alkyl, halo-C1-C4alkyl, mono- or dihydroxy-C1-C4alkyl, mono- or di-C1-C4alkoxy-C1-C7alkyl, aryl-C1-C4alkyl, C2-C6alkenyl, halogen or aryl, R3 is hydrogen, C1-C8alkyl or aryl, R4 is hydrogen or C1-C8alkyl, R6 is amino, mono- or di-C1-C4alkylamino or phenyl-C1-C4alkylamino, A is unsubstituted or C1-C4alkyl-substituted .alpha.,.omega.-C1-C3alkylene or a direct bond, and B is methylene or a direct bond, with the proviso that A is unsubstituted or alkyl-substituted .alpha.,.omega.-alkylene having from 1 to 3 C-atoms when B is a direct bond, and the salts thereof, characterised in that a compound of formula (Ib), in which R? is an esterified carboxy group, especially a lower alkoxy-carbonyl group, is hydrolysed in water without the addition of acid or base.

16. A process according to any one of claims 1 to 6, wherein R1 is hydrogen, lower alkyl or hydroxy, R2 is hydrogen or lower alkyl, R3 and R4 are hydrogen, R5 is lower alkoxycarbonyl and R6 is amino, A represents .alpha.,.omega.-alkylene having from 1 to 3 carbon atoms and B represents a bond.

17. A process according to any one of claims 1 to 6, wherein R1 is hydroxy, R2 is hydrogen or lower alkyl, R3 and R4 are hydrogen R5 is lower alkoxycarbonyl or carboxy and R6 is amino, A is methylene and B is a bond.

18. A process according to any one of claims 1 to 6 wherein R1, R3 and R4 are hydrogen, R2 is methyl, R5 is carboxy or a pharmaceutically acceptable salt thereof, or carboxy ethyl ester, R6 is amino, A is methylene having 1 carbon atom and B is a direct bond.

19. A process according to any one of claims 1 to 6, wherein R1, R3 and R4 are hydrogen, R2 is methyl, R5 is carboxy or a pharmaceutically acceptable salt thereof or a carboxy methyl, ethyl, n-propyl, n-butyl, isobutyl, n-pentyl or n-hexyl ester, R6 is amino, A is methylene having 1 to 3 carbon atoms and B is a direct bond.

20. A process for preparing E-2-amino-4-phosphonomethyl-3,6-heptadienoic acid or a pharmaceutically acceptable salt thereof, which comprises reacting E-2-formylamino-4-diethylphosphonomethyl-3,6-heptadienoic acid methyl ester with trimethyliodosilane in dichloromethane and treating the primary product with hydrochloric acid.

21. A process according to any one of claims 1 to 6, characterised in that a compound of formula II or compounds of formulae III and IV, where-in A denotes methylene, B denotes a direct bond, R2 denotes methyl, R3 and R4 are hydrogen and Z1, Z2, R5, R6, X and R have the meanings given in any one of claims 1 to 6, are used as starting material(s) so as to produce E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester or E-2-amino-4-methyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof.

22. A process according to any one of claims 1 to 6, characterised in that a compound of formula II is or compounds of formulae III and IV, wherein A denotes methylene, B denotes a direct bond, R2 denotes methyl, R3 and R4 are hydrogen and Z1, Z2, R5, R6, X and R have the meanings given in any one of claims 1 to 6, are used as starting material(s) so as to produce (2R)-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid, (2R)-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, (2R)-2-amino-4-methyl-7-phosphono-3-heptenoic acid, (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, E-2-amino-4-methyl-5-phosphono-3-pentenoic acid methyl ester, E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-propyl ester, E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-butyl ester, E-2-amino-4-methyl-5-phosphono-3-pentenoic acid isobutyl ester, E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-pentyl ester, E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-hexyl ester, or in each case a pharmaceutically acceptable salt thereof.