DE2219601A1 - beta-lactams and processes for their preparation - Google Patents

Description

Dr. Hans-Heinrich Willrath

Dr. Dieter Weber Diploma in Phys. Klaus SeifFert

PATENT LAWYERS

D - 62 WIESBADENf April 20 PoMUd »1327 1972

»Μ«) 917 »XX / ga

i WUUPATEMI

AA 2991

Astra Läkemedel Aktiebolag Södertälje, Sweden

β-lactams and processes for their preparation

Priority; dated April 27, 1971, in

Sweden, registration no. 5405/71

The present invention relates to a new chemical process which enables the total synthesis of penicillins and penicillin-like compounds with a ß-lactam structure.

The isolation of 6-aminopenicillanic acid

H ₂ N-CH-CH

CO Ν—

CH - COOH

in 1959 made it possible to manufacture semi-synthetic penicillins, ie

209847/1230

ne side chain attached to the 6-aminopenicillanic acid residue. could be. A very large number of such semi-synthetic penicillins have been produced. Many of these semi-aesthetic penicillins have recently been found widely dispersed clinical use as they have better antibacterial properties than natural penicillins in several respects, such as benzylpenicillin or biosynthetic penicillins such as phenoxymethylpenicillin, which are produced by Fermentation of certain microorganisms can be produced.

Since the semisynthetic penicillins are produced by acylation of 6-aminopenicillanic acid, it was previously only possible to get modifications of the side chain. A method for the total synthesis of penicillins would mean that such a restriction would not be necessary, and a method for the total synthesis of penicillins would also make it possible to make compounds containing a modified penicillanic acid residue so that it would be possible to make new compounds with a penicillin-like structure. the In one aspect, the present invention provides such a method for the total synthesis of penicillins and penicillin analogs.

Attempts at a total synthesis of penicillins have already been made. Du Vigneaud et al., Science 104, p. 431 (1346) found benzylpenicillin after conversion of 2-benzyl-4-methoxyraethylene-5 (4) -oxazolone of the formula

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221Si

CH,

CHOCH ₅ '. ·.: »

with D-penicillaifiin hydrochloride of the formula

HS-

H ₂ N-

CH,

-CH COOH

* HCl

isolate. The yield of benzyl penicillin was 0.1%. Sneehan et al. _# J. Am.Soc. 78, page 3.677 (1956) phenoxymethylpenicillin and benzylpenicillin by cyclization of a compound of the formula ΐ

i RCONH - CH -CH

! "■■ 'COOH — NH-

N ;.

, CH ₁

> »CH ₃ ΪΗ — COO

- R-

produce, in which the radical R is a bensyl or radical and the radical R is a carboxyl protective group which can be split off by hydrogenation

and the yield of benzylpenicillin in the cyclization was 0.3%, see Sheehan et al., J. Am. Chexn. Soc. 81, p. 3089 (1959).

According to the present invention, it has surprisingly been found that compounds of the general formula

C COOH

wherein X is a halogen atom, the group N- or Η, Ν-, Α one of the divalent radicals -S-, -S-CH ₂ -, -O-, -0-CH ₂ -, -CH ₂ -, -CH ₂ -CH ₂ - or NH- and R ¹ , R and R are identical or different and are hydrogen atoms, alkyl groups with 1 to 6 carbon atoms or aryl groups, can be synthesized in good yields. If the radical X is a halogen atom, it is preferably Cl or Br, but the concept of the invention also includes the meaning of an iodine atom. Examples

12 3 of alkyl groups that explain the radicals R, R and R are Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl and hexyl. BeispMe of aryl groups that form the groups R,

2 3

R and R are monocarbocyclic groups, such as those in the formula

2QS347 / 1230

in which the substituents R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ 'are identical or different and are hydrogen atoms, alkyl groups with 1 to 4 carbon atoms, such as methyl, ethyl or propyl, alkoxy * groups with 1 to 3 carbon atoms such as methoxy, ethoxy and propoxy, or halogen atoms such as F, Cl, Br and I mean.

4 If in the present invention for R from an alkoxy group

4th
pe or an ester group for -CO-R is spoken of, these groups should also include those which. by halogen atoms, such as Cl or Br, are substituted. Illustrative examples of compounds of the formula I are as follows:

: H - COOH

Cl - CH - QH

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- COOH

g ^ OHM.

Br-CH -

^ 0: i

CH - COOH.

■ ·} ■ · ■

. - 'Br - CH - CE

■ ft-

H - COOH

CH - · CH

- cooH

-CH - CH.> CH ₂

■ Ν- CH - COOH

¹ ·. ■ ■. ·

Cl-

-CH

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H-COOH

-COOH

Cl-

CH-

! H ₃

Br-CH-CH

,NS

: H-COOH

Br-CH-CH

2098 4 7/123

N ₃ -CH-CH

-CH

CH-COOH

H ₂ N-CH-CH

-CH:

CHa

C — N—

J

: h-co-och ₃

Cl-CH-

) -CH ₂ Cl-CH-CH CII ₃

CH-COOH

Cl-CH-CH

H;

CH ₃ ⁽

CII-COOH

? 0 S 0 4 7/1 *; 3 0

■ "7" ~ "i

ORiGlNAL irvSf

Br-CH-CH

Cl-CH-CH

Cl-CH-CH 0-H-

-COOH

—CH-COOH

ι y

HaN-CH-CH

Ha -COOH '

209047/1230

According to the invention, the compounds of the formula I are prepared by reacting a compound of the general formula

H-C-C-

Λ '

II

12 3

wherein R, R, R and A have the above meaning; laben, the group

4 4

CO-R means an ester group, in which R is the alcohol part,

4th
which is removed with the conversion of the group CO-R into the group -COOH-

1 2

can be cleaved, and Y and Y, which may be the same or different, represent halogen atoms, with a compound the general formula

Hg-Y

III

wherein Y is a halogen atom, forming a compound of the general formula

- R

IV

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ORJQiNAL

wherein R ¹ , R ² , R ³ , R ⁴ , Y ¹ , Y ² and A have the above meaning , subsequent decomposition of the compound of the formula IV thus formed to form a compound of the formula ■. *

l _% i

-C - CO - R *

wherein R, R, R, R and Y ^{1 have} the above meaning, and optionally subsequent conversion of Y in a known manner into group N ₃ - or H ₃ N- and the radical R into a hydroxyl

group made,. Illustrative examples of the residues Y /

l 2
Y and Y are Cl, Br and I. Preferably Y is Cl or Br.

4th
Illustrative examples of the radical R are alkoxy groups with 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy and butoxy

groups. In a preferred embodiment of the process, the radical Y ^{1 is} Br, the radical Y ^{2 is} Cl and the radical Y is Cl.

The compound of formula IV can be decomposed by heating the compound, for example by refluxing in an organic solvent such as freshly distilled bromobenzene. The decomposition and cyclization can also be carried out by irradiation at wavelengths of 200 to 400 hm.

In another aspect, the invention relates to intermediates for the production of penicillins and "structurally penicillin-

OFHQSNAL m ^ fJ ^ u

similar connections. These intermediates have the

general formula

- R

VI

wherein X is Cl, Br, N. or H, N, A is one of the divalent groups -S-, -S-CH ₃ - / -0-, -0-CH ₂ -, -CH ₃ -, - ^ CH ₂ -CH ₂ - or

12 3
-NH- means? R, R and R are identical or different and are hydrogen atoms, alkyl groups with 1 to 6 carbon atoms

4th
or aryl groups and R is a hydroxyl group or a

1

Is alkoxy group of 1 to 6 carbon atoms, where R and R Are alkyl groups of 1 to 6 carbon atoms that can be converted to a hydroxyl group, but when A -S * - be

1 2
means, R and R are alkyl groups with 1 to 6 carbon atoms

1 2

and R and R together contain 3 to 12 carbon atoms. In other words, the group CO-R is a COOH group or an ester group which can be converted into the group COOH. The following combinations are suitable, where> A -S- means % methyl-ethyl, methyl-propyl , Methyl-isopropyl, methyl-η-butyl, methyl-isobutyl, ethyl-ethyl, ethyl-propyl, ethyl-isopropyl, ethyl-n-butyl, ethyl-isobutyl, n-propyl-n-propyl, n-propyl-isobutyl, Isopropyl-Ieopropyly leopropyl-n-Butyl _s

2098A7 / 1230 "

2,9601

Compounds VI include many of those compounds the above in general and specifically for the meaning of the connections I have been described as well as the connections.! with)

4 'i

the -CO-R group of the compounds II instead of the COOH group pe. Special compounds VI include the following _,

•NS

. ■ ···· ■ ■ ι

Cl-CH-CH

Ha .. ·

IH-CO-OCJi ₃ CCl ₃

CaHa · H-CO-OC (CHa) ₃

Cl-CH · -

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The preparation of compounds of the formula I can be carried out further

the following reaction scheme is explained, which the manu-

1 2

position of compounds of the formula I shows in which R, R and

3 4 *

R, denotes hydrogen atoms, R denotes a methoxy group Jet, A

-S- and Y ¹ Br- or Cl- mean. Y ¹ and Y ² in the reaction scheme can be the same or different and mean Cl or Br.

HgCl + H-C-rC-N

Level a

* ■ 1

- COOCK,

t-C ^ HgOK / Xetrahydrofuran

-25 ° C. .

CH - COOCH,

'Y ¹ CH-CH' CH,

.Level B P

• CH - COOCHj-

The condensation in stage Λ takes place in an organic solvent such as tetrahydrofuran or dimethoxyethane boi a temperature of about -10O ⁰ C to about + 10O ⁰ C, preferably at about -70 ⁰ C to about ^{0 0} C.

^E "proved to be particularly advantageous Aich _t condensation in

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ORiQiNAi. INSTECTCD

stage A in potassium tert-butoxide to be carried out. A particularly suitable potassium tert-butoxide is prepared by converting equimolar amounts of metallic potassium and dry tert-butanol in tetrahydrofuran and adjusting the reaction product to an approximately 1 m solution. When tert-butanol in; is present in excess, or if traces of water are present, the yield of the condensation product is low. The yield of the condensation product of step A _Λ is usually from about 30 "to 90%...

That. desired reaction products can be obtained from the reaction mixture by column chromatography at a low temperature

• from about -30 - to about O ⁰ C are isolated. For example, silica gel can be used to isolate the condensation product '

will. .

It is advantageous to use »starting materials» in which the radical Y ^{1 is} Br and the radical Y ^{2 is} Cl. If both radicals Y ¹ and Y ^{2 are} Cl or Br, the total yield of the end product is generally lower due to the decomposition of reactants and reaction products.

The riding Y in the connection of the general formula

I.

·; Y ¹ - CH - CH

209S41 / 123Ö

obtained in the process of the present invention after the decomposition and ring closure of the compound of formula IV is a halogen atom which is suitably converted to the H ₃ N- group for the preparation of penicillin and penicillin analogs. The amine compound obtained in this way can then easily be acylated to penicillins and penicillin analogs by acylation with a suitable acid, analogous to the acylation of 6-aminopenicillanic acid, as described, for example, by FP Doyle and JHC Nayler in Advances in Drug Research, Volume 1, Academic Press 1964 , is described ». Some possible reaction paths for replacing the halogen atom with an amino

1 4

group are listed below; The radicals R to R, A and Y are as defined above.

A. Conversion of the halogen atom Y into an amino group the corresponding acid:

Y '- CH

- Cii ^

.R

1 .

C- N-

■ + M

C - CO-R

-CO-R

M ^ HaI

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ORIGINAL etc.

catalytic

———. ^

Hydrogenation '

H ₂ N - CH - '

V R- ···

'Kr ² '' - C -. CO - R *

The rest

is a metal ion, such as K, Na, Li, or Zn

a transition metal ion, j such as Cu, Ni and Fe, and Hai is a

Halogen atom such as Cl or Br.

B. Exchange of the halogen atom Y «for an amino group corresponding metal amines or metal amides:

'yl - CH - CH j ~

■ N

· ... '■' Rf

R ⁴ '+

R:

10

CH - CH N

CO -

R ¹

ISn-Y

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The radicals R to R are identical or different alkyl groups with 1 to 6 carbon atoms. The reaction B can take very mild conditions. '

C. Replacement of the Halogenatoir.es Y by an amino group Substitution with Cu (II) or Ni (II) complexes

with triglycine:

Cu (II) and Ni (II) form easily ionizable complexes with triglycine. Such complexes can be used for substitution reactions can be used, such as:

Y ¹ - CH - CH

N-

2 ·

- CO -

¹¹

H ₂ lf

- C - NH - CH - CH

-If

The R «et R ¹¹ is a suitably selected monovalent radical.

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The invention is further illustrated by the following examples.

Example 1

Preparation of N- (O (^ , Φ -bromo, chloroacetyl) -3-L-methoxycarbonylthiazolidine

Bromochloroacetic acid (Jv Read and AM McMath, J. Chem. Soc. (1926), p. 2187.J- (1 mol) was added to freshly distilled thionyl chloride (2MoI) over one hour. The solution was heated under reflux conditions for an additional 3 hours. the thionyl chloride was removed and the product was distilled under reduced pressure to give bromochloroacetylchlorld, b.p. ₁₂ J _10n 45 to 47 ° C. (65%). The acid chloride (57 g) was de slowly to an ice-cold solution of 3-L-methoxycarbonylthiazolidine (S. Ratner and H.T. Clarke, J. Am. Chem. Soc. 59, Page 200 (1937) - (44 g) and triethylamine (30 g) in dry Ether (750 ml) added. The triethylamine hydrochloride which precipitated out was filtered off and washed with ether. The combined ether solutions were washed with water, dried over sodium sulfate, and the ether was evaporated. The residue was recrystallized from toluene to give N - (^, o ^ -Bromo, chlorine acetyl) -3-L-methoxycarbonylthiazolidine (45 g, 50%), mp 126-129 ° C, IR absorption at 1745, 1660 cm " ¹ 0

Il

209847 / 12.30.

Explanation of the reaction stages /

, CO ₂ H '"'. 1) Br ₂ 'Br CO ₂ H ν, 1) -CO ₂ (130 °)

CHBrCl-CO-Cl +:

: CHBrCl-CO · Ν ·

O ₂ CH ₃

CHBrCl-COCl

O ₂ H '2) SO ₂ Cl ₂ Cl. CO ₂ H. 2) SOCl ₂ .

CO ₂ CH ₃

(C ₂ H ₅ ) ₃ N / ether

Example 2

Manufacture. Of N- (oC-Phenylmercurio-o ^ 3-L-methoxycarbonylthlazolidine

-bromo, chloroacetyl) -

All tetrahydrofuran used was fresh over potassium metal been distilled. The potassium tert-butoxide was obtained by refluxing equimolar amounts of potassium metal and tert-butanol (freshly distilled over Natriuranetall) in tetrahydrofuran obtained under a nitrogen atmosphere. The potassium tert-butoxide concentration was about Im.

A mixture of N- ( cC, 6C'-bromochloroacetyl) -3-L-methoxycarbonylthiazolidine (15.1 g) and phenylmercuric chloride (15.6 g) in tetrahydrofuran (600 ml) was purified under an atmosphere of

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Nigtem nitrogen and cooled to -20 to -25 ° C. Select

A solution of potassium tert-butoxide was used for 15 minutes (7.5 g) in 70 ml of tetrahydrofuran was added. The solution was held at about -25 ° C for an additional 30 minutes and then left

'the temperature rise to 0 C over 30 minutes. The solution was evaporated on a rotary evaporator, whereby the temperature was kept at 20-25 ° C. The raw reaction scent was taken up in 1.5 1 toluene and 200 + 50 ml washed in distilled water. The water phase was washed with 250 ml of toluene. The combined toluene solutions were dried over magnesium sulfate and placed on a rotary evaporator Evaporated 40 to 45 ° C. The crude reaction mixture (18 g) was chromatographed on silica gel (Grace Chemical, Copenhagen, 0.15 to 0.30 mm). The column was maintained at about -15 ° C by circulating chilled ethanol in a jacket. This gave N- (δ ^ -phenylmercurio-C5 ^, oC-bromochloroacetyD-S-L-methoxycarbonylthiazolidine (4 g, 15%), mp 40-45 ° C., IR absorption at 1610, 1745 cm " ¹ (·?).

-C-

Explanation of the reaction stages:

f - ^ CO ₂ CH ^ PhHgCl + (CHJ ₃ CO ^ Κ® tetrahydrofuran

• C ₆ H ₅ -Hg-CBrCl-CO-N- 209847/1230

Example 3

Thermal decomposition of N - (^ - Phenylmercuria-O ^ ot / '- brom, chloroacetyl) -SL-methoxycarbonylthiazolidln',

The compound given in the title (600 mg) was refluxed in 300 ml of freshly distilled bromobenzene for 2 hours * The solvent was removed in vacuo / Xther was added and the insoluble mixture of phenyl mercury bromide and phenyl mercury chloride (270 g) , Mp 263 ° C, was filtered off. The other components of the product were then separated by chromatography at -15 ° C on 100 g of silica gel (Grace Chemical, Copenhagen, 0.15 to 0.30 mm), using increasing amounts of ether in light petroleum ether for elution and to obtain 2-methoxycarbonyl ~ 6-bromo-7-oxo-4-thia-1-azabicyclo 3.2.0 heptane (80 mg, 30%). This was further purified by sublimation. IR absorption at 1795,

1745 cm

-1

(-C-X

Explanation of the reaction: '

"C ₆ H ₅ -Hg-CBrCl-CO-N

Reflux

'C ₆ H ₅ -Hg-Br + C ₆ H ₅ -Hg-Cl

O ₂ CH ₅

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Example 4

Production of N- (oC, ^ - B "ort, chloracetyl) -4-DL-carbomethoxy" 5,5-dimethylthiazolidin '

Bromochloroetic acid (J. Read and A.M. McMath, J. Chem. Soc. 1926, p. 2187) - (1 mole) became too fresh during one hour distilled thionyl chloride (2 moles) was added. The solution was refluxed for a further 3 hours, the thionyl chloride was removed and the product was distilled under reduced pressure and gave bromochloroacetyl chloride, bp.

40 to 47 ° C (65%). The acid chloride (19 x, x 2 g) was slowly added to an ice cold solution of DL-4-carbomethoxy-5,5-dimethylthiazolidine (17.6 g), which was obtained by esterifying DL-4-carboxy-5,5- dixnethylthiazolidine (HT Clarke, JR Johnson, R. Robinson, The Chemistry of Penicillin, page 958, Princeton University Press, .1949) with diazomethane in ether and triethylamine (10.1 g) in dry ether (400 ml) obtained wax; The precipitated triethylamine hydrochloride was filtered off and washed with ether. The combined ethereal solutions were washed with sodium hydrogen carbonate, 0.5 η hydrochloric acid and water, dried over sodium sulfate, and the ether was evaporated. Purification with the aid of a silica gel column gave the residue N- (C &, CC-bromochloroacetyl) -4-DL-raethoxycarbonyl-5,5-dimethylthiazolidine) (19.8 g, 60%), P. 78 to 80 ° C, IR absorption: Co (KBr) 1750, 1660 cm " ¹ .

N- (GC, "2i" -Brora, chloroacetyl) -4-D-methoxycarbonyl-S ^ -dimethylthiazolidine was synthesized in the same way, mp 72 to 73 ° C, IR absorption: Co (KBr) 1750, 1660 cm ** ^1. -.

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Example 5

Production of N - (<? ^ - Phenylmercurio-ö ^, öi / -brom _f chloroacetyl) 4-DL-methoxycarbnnyl-5,5-dimethylthiazolidine

All of the tetrahydrofuran used was over potassium metal freshly distilled. The potassium tert-butoxide was obtained by refluxing equixolar amounts of potassium metal and tert-butanol (freshly distilled over sodium metal) in tetrahydrofuran produced under a nitrogen atmosphere · The potassium tert-butoxide concentration was about I'm.

Potassium tert-butoxide (1.69 g) in tetrahydrofuran (225 ml) was cooled to -75 ° C under an atmosphere of purified nitrogen. N- ( c ^ td ^ -Bromo ^ chloroacetyl) -4-DL-methoxycarbonyl-5,5-dimethylthiazolidine (4.95 g) in tetrahydrofuran (75 ml) was added over 10 minutes. Phenylmercuric chloride (4.68 g) in tetrahydrofuran (75 ml) was then added immediately over 10 minutes. The solution was held at -75 ° C for an additional 20 minutes, after which it was heated to room temperature. The solution was evaporated on a rotary evaporator, maintaining the temperature at 20-25 ° C. The crude reaction mixture was taken up in benzene (500 ml) and washed with distilled water (75 ml). The water phase was washed with benzene (100 ml). The combined benzene solutions were dried over magnesium sulfate and evaporated on a rotary evaporator at 30 to 35 ° C. In this special case, the crude reaction mixture (9.1 g) could be recrystallized from dry diethyl ether and gave N- (cl-phenyl-

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mercurio- ⁰ '', ⁰ ^ bromo, chloro acetyl) - ^ - DX.-carbomethoky-SiS-di-

• '■ _n i methylthiazolidine (7.5 g, 83%), P. 125 to 126 ° C |, XR absorption

tion: CO (KBr) 1750, 1660 cm " ¹ .

Other similar Phenylmercuriohalogenacety amide obtained in lower yields, it must be purified by chromatography on a silica gel column, to the -IQ ⁰ C is held by circulating in a jacket-cooled ethanol to -30, clean!. . ■ · .'...

Example 6

Thermal decomposition of N- (c ^ -phenylmercurio- (^, ol-bromo, chloroacetyl) -4-DL-carbomethoxy-5,5-dimethylthiazolidine

The title compound (2.00 g) was refluxed in freshly distilled bromobenzene (400 ml) for 3 hours heated. The solvent was removed in vacuo, ether was added, and the insoluble mixture of phenyl mercury bromide and phenyl mercury chloride (0.95 g) was filtered off. The other components of the products were then separated by chromatography at -25 ° C on 200 g of aluminum oxide (neutral, activity 1, Schuchardt), with increasing amounts of diethyl ether in light petroleum ether as the eluent were used. When silica gel was used in place of alumina, there was also unreacted mercury compound first by bubbling hydrogen sulfide through an ethereal solution of the crude reaction mixture during decomposed for a few minutes to make the separation easier «.

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This gave DL-methyl-6-bromopenicillinate as an optically active compound (see E. Evrard, M. Claesen and H. Vanderhaeghe, Nature, 201 (1964), page 1124) - (0.20 g, 20%), that through
Sublimation was further purified, P. 87 to 90 ° C, IR absorption: CO (KBr) 1785, 1730 cm " ¹ *

Example 7 '

The compounds listed in the table below have the structure according to that for the compounds of the formula
VI above formula. They can be prepared according to the methods described in the preceding examples by modifying the reactants accordingly to the
to get the connections you want. If necessary, can

in these compounds, the group X, the group H ₀ N and the

4 ²

Group R be converted into the OH group. The converted compounds can be acylated to form compounds
have the appropriate antibacterial activity and other therapeutic effects.

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° 27-

Tabel

.: ./ ■ £ ^: _ / A -. Sl Si "■■ '* /' ■ ^: si /; 7'v ... Rl _Λ . ^. · .Λί ..- / Br V / '/.S H; ■ '- H Λ '· ■ /, H · ■ ·;. · ,; . ■ '.'. ■ OCH ₃ ■ -. '; ·· ■ · ".... Br '' / S CH ₃ . - : CH ₃ -, ■ ";', .'V. η ■; '/ ;, OCHa- '.; '.; ■ "·, '. Cl / S-CHa H ■. · '- ¹ H "^; ■ ,,: ^V -.H · 'Z ¹ -' / ) .oh ;; ·; ■■ · ■ ·>: ■ "·" ■ ..: • Cl .. /. S-CH ₂ ' H ■ ■ -.κ.; V "CH ₃ Vv- .. '■ oh ■'"·. · _ ■■ ■■; . 'Br' - '.;. ./ S-CH ₂ CH ₃ . ■ CH ₃ - ..: / '■ - Λ
..H. .- ν- ■ - · OH. '/'/■-"■./ . -N ₃ , - ■ 'S-CHa •H • H '; '; ': .oh ■: - ■; ■■ ..
' ■ * -''* '/ HaN ".,; .'S-CHs •H ■ η "..y." ,; HV / ', VOCHaVv - /: ' ! ' ^: ci / "" · ■■ S-CHa ' CH ₃ . CH ₃ ■■■ ;. ^; - / ^H .//V/ OS · * - · ** ■ 'Br'. "... ';, S-CH _a ' · '• Η H.; ". ■■ _: ^ oh;: v //; ^: ^ / ci · v / ° CH ₃ :. .; ch _s ' ■' · ■ '·. h / vv- . Cl. ■ ";. 0-CH ₃ η. ; . HV. ; η- ./; '.; OH-. .. ·; ■ ·, "- ■; : .ci ··, '.. . ' CH ₂ '', H H ' ^: ' / Γ Η .-: ν // Λ ■■ '[.QE' . '// - ■ "/; VV ^Br '.: " ■■ " CH ₂ CHa • CH ₃ ; ■ ·. ■ '^;' ^: CH _e -.S // η. / "ν / : ■;. ■■ ^cl V . ■ NH, - ^: •H :- ■ • "■ 'h -οηΪ - ■■ /> . ci ^: ' ■ "NH ^! ' . CH ₃ . ■ "CH ₃ ■ ';'. η. - / / OH . Cl. ·, ■
t _§ O -CH ₃ approx . ₍ B. . OH Cl • s' .- ■ CHa CA ϊϊ ■ ' ■, OCH _a CCl _a ■ 'NH ₃ . 's CH ₃ approx. . ; η '. OC (CHa) a
r - · · ■ '

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Claims (1)

Claim ever , IA Process for the preparation of ß-lactams of the general v ■ ... formula x- ch.- css. ■■ V , 1 ■ ·· ■ i C - COOH wrin X is a halogen atom, the group N ^ - or H ₂ N-, A is one of the divalent groups -S-, -S-CH ₂ ", -0- ,, -O-CHj", -CH ₂ -, - CH ₂ -CH ₂ -OdCr-NH-, and R ¹ , R ² and R ^{3 are the} same or different and represent hydrogen atoms, alkyl groups with 1 to 6 carbon atoms or aryl groups , characterized in that a compound of the general formula 3 CH ₂ C \ ₂ H-C-C- N C-COR ^ 2 3 4 ξ liUä 2 dia ö & ige meanings, -CO-R one Hydroxyl group are different and mean halogen atoms, with Ölner Ver. binding the general formula Hg - Y ' , III where Y is a halogen atom, forming a ver * binding the general formula C - COR ⁴ --ν ..: wherein R ¹ , R ² , R ³ , -CO-R ⁴ , Y ¹ and Y ² and A are as defined above, converts the compound of the formula IV thus formed to form a compound of the general formula Y ¹ - C - COR * wherein R ¹ , Ri, -. R, R and Y ^{1 have} the above meanings, decomposed and then optionally Y in more well-known the a Weis «in group H ₃ - oä @ r HjH- nnü ümi U®et U 209847/1230 lsi aa sisfo converted into a hydroxyl group in a known manner. 2. The method according to claim 1, characterized in that one Starting materials used in which X is Cl or Br « 3. The method according to claim 1 and 2, characterized in that 1 2 starting materials are used in which Y is Bt and Y is Cl. 4. The method according to claim 1 to 3, characterized in that the reaction between the compounds of formulas II and III in an organic solvent. 5. The method according to claim 1 to 4, characterized in that the compounds of formulas II and III in a solution of potassium tert-butoxide in tetrahydrofuran with one another. 6. Method according to Claims 1 to 5, characterized in that the compound II is a compound of the general formula I ■■■■. " _Y 1 A f ^H 2? ^H 2 H - C - Ö - N -OH - COOCH ₃ 209847/1 2'30 original above i A 12th
wherein Y and Y are Cl or Br , and as of the formula III the compound ■ Hg - Cl used. 7. The method according to claim 1 to 6, characterized man _t converts the group Y into the group H ₃ N- by reacting the compound of formula V with a Metallaeid my formula N. where M ^{v =} ^ means a metal ion, and the N-- in the compound thus formed is converted ₅ -CH - CH \ j ¹ C-CO- 'R' 4 '! J ■ '& · ■■■' ■■■■ reduced to the NH ₂ 'group, 8. Method according to ÄRaprueh I ₉ thereby g © k © rßSi2 @ l © Mi (it _p (äai sa die ^ group dxsmh k & tSilftlmihQ Wfüskosm ^ r? Giä? AsiGS "feo 1Q9847 / 123Q ÖFMÖINAL INSfEGTBD 9 «Method according to claim 1 to 6, characterized in that that the group Y ₂ N- converted into the group H, by reacting the compound of formula V with a compound of general formula Sn - N: • R 10 in which the radicals R to R are identical or different and denote alkyl groups with 1 to 6 carbon atoms, 9 10 converts and then the radicals Ri ^- and R of the compound of the general formula obtained in this way t ι · R- - CO - R ' replaced by hydrogen in a manner known per se. 10. The method according to claim 1 to 6, characterized in that that Y is converted into the H ^ N group by the compound of formula V with a complex compound of Cu (II) and glycine or Ni (II) and glycine converts and O finally the group "in the R ^ ^X - CH -C- 0 9 8 4 7/1230 iNAL ι ta * £ GT £ D binding the general formula R ¹¹ '- CH NH, '0 r C " NH - CH ^ - CO - K * j wherein R denotes a monovalent radical «optionally splits off in a manner known per se. 11. ß-lactam of the general formula X-CH-CH - co - 43 wherein X is a halogen atom, the group N ₃ - or H ₂ N-, A is one of the divalent radicals -S-, -S-CH-- t -O- , -0-CHj ^- 1 -C, H ₂ -, -CH ₂ -CH ₂ - or -NH- denotes, R ¹ , R ² and R ^{3 are} identical or different and are hydrogen atoms, alkyl groups with 1 to 6 carbon atoms or aryl groups. and the group -CO-R denotes the group -COOH or an ester group which can be converted into the group -COOH when A -S- is 1 2
indicates, but R and R are alkyl groups with 1 to 6 carbon 1 2 mean material atoms and the groups R and R together 3 contain up to 12 carbon atoms. 209847/1230 12. β-lactam of the formula Cl.- CH - CH CH, -CH - COQH 13. ß-lactam of the formula CH- 6h NS, OH, - COOH 14. ß-lactam of the formula ) ■. ■ ', S-CH, -. Br-CH-CH ^ C • ι -CH - COOH '■. 15. β-lactam of the formula 2098A7 / 123 0 -CH -CH - CH CH, CH - COOH 16. O-lactam of the formula H ₂ N - CH ^ S-CH, CH, CH -COO-CH _x ' 17. β-lactam of the formula 31 - CH - CH τ — Ν · ' H • CH COOH 18. ß-LaCtam of the formula S-CH ₂ . sr-.CH - CH c. Kj CH - COOH 2098-7 / 1230 19. ß-lactam of the formula Cl-CH-CH N- CH - COOH 20 »flrLactam of the formula Cl-CH- ■ 0-CH « CH. CH, Jh -f cooH 21. β-lactam of the formula Cl - CH -. .CH ₂ CH CH ₂ . CH - COOH 22. ß-lactam of the general formula 2Θ88Α7 / 1230 Br-CH-CH CH ₅ "* ' "CH, N- cooH: 23. ß-lactam of the general formula r Cl - CH - CH, CH - COOH ί 24. ß-Lactam c ^ er general formula Cl-CH-CH CH - COOH '■ 209847/1230