JPS5944340A - Optical active crystalline amine salt of methanoprostacyclin derivative and its preparation - Google Patents

Abstract

PURPOSE:To separate an isomer having improved pharmaceutical action efficiently, by treating an isomer mixture of a methanoprostacyclin derivative with l-threo-2-amino-3-paranitrophenyl-1,3-propanediol in an inert solvent. CONSTITUTION:A mixture of a compound(A1) shown by the formula I [R1 is H, or CH3; R2 is alkyl, alkenyl, -A, -XA (X is CH2, NH, O, etc.; A is cycloalkyl which may be optionally replaced with alkyl); n is 1-5] and a Z-isomer(A2) of A1, a mixture of A1 and an antipode compound(A3) of A1, or a mixture of A1, A2, A3 and an antipode compound(A4) of A2 is treated with l-threo-2-amino-3- paranitrophenyl-1,3-propanediol(B) in an inert solvent, to form a novel crystalline salt of the compound A1 and the compound B, which, if necessary, recrystallized to give a salt, from which a compound shown by the formula useful as a remedy for thrombosis, etc. is obtained.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is useful for the separation and purification of optical and stereoisomers and has a novel general formula of mechnoprosuccicline derivatives and t-threo-2-amino-3-paranitroisomers. The present invention relates to a salt with phenyl-1,3-furopanediol (Ila) and a method for producing the same.

In the above formula, R1 represents a hydrogen atom or a methyl group, and R2
is an alkyl group having 1 to 12 carbon atoms; an alkenyl group having 2 to 12 carbon atoms; represents an alkyl group), formula -X-A
group (in the formula, A t'j represents the above-mentioned and Nissin Rabbit,
X is methylene, ethylene group, -NH- group, wiring Jim
', f or 詑 Huang atoms. )Mabukoke style-〇H2
-X-O group (in the formula, X is the same as the above l-46
: represents Y (a halogen also represents a trifluoromethyl group), and n represents 111 of 1 to 5.

Examples of alkyl groups having 1 to 12 carbon atoms in R2 include methyl, ethyl, 0-propyl,
Inflovir, n-butyl, isobutyl, n-pentyl, impentyl, 1-ethylpentyl, 2-methylpendel, 11-' xyl, n-hegutyl, 1.1-dimethylpentyl, 2-ethylpentyl, n- octyl,
2-methyloctyl, n-nonyl, 2-mernonyl, 2-ethyloctyl, n-decyl, 2-meglutecyl or 2-ethyldecyl 4y can be mentioned, preferably 4 to 10 carbon atoms. -4'alkyl^,
Examples are lobutyl, isobutyl, n-pentyl, inhentyl, 1-methylpendel, 2-ethylpentyl, n
-hexyl, n-hentyl, 1゜1-dimethylpentyl, 2-ethylpentyl, n-octyl, 2-methyloctyl or 2-ethyloctyl groups,
More preferably Ω-pentyl, 1-methylpentyl, n
-Can you name the hexyl or 2-methylhexyl group?

Examples of the alkenyl group having 2 to 12 carbon atoms in R2 include vinyl, allyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 2-methyl-3-pentenyl, 4-methyl-3-pentenyl. , 1-methyl-4-pentenyl, 4-hexenyl, 5-hexenyl, 1,4-sifnal-3-pentenyl, 5-heftynyl, -6-)f
Leu-5-hepteconyl, 2,6-dimethyl-5-hene.

tenyl, 1.1.6-drimethyl-5-heptenyl.

6-methyl-5-octenyl, 2,6-cymethyl-5-
Can include octenyl, 6-conityl-s-ocynyl, 2-methyl-6-ethyl-5-ocyanyl or 2,6-diethyl-5-octenyl group, preferably having 4 to 12 carbon atoms. An alkenyl group having, e.g.
, 2-butenyl, 2-pentenyl, 3-pentenyl, 2
-Methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-)if-benzonyl, 4-hexenyl,
5-hexenyl, 1,4-dimethyl-3-pentenyl,
5-hectynyl, 6-methyl-5-hectenyl, 2.6
-Sime1-5-hebutenyl, 1.1.6-trimethyl-5-hegetenyl, 6-methyl-5*-cutinyl,
2.6-dimethyl=5-octenyl, 6-nityl-5-
Octenyl, 2-7'thyl-6-ethyl-5- -hexenyl, 6-methyl-5-hebutenyl or 2,6-cymethyl-5-heptenyl groups may be mentioned.

The lower alkyl groups which are substituents of the formula-A group and the formula-X-A group in R2 include, for example, methyl, ethyl,
Mention may be made of n-propyl, n-butyl or isobutyl groups, preferably methyl or ethyl groups.

The number of carbon atoms in the formula-A group and the formula-X-A group in R2 is 3
Examples of the cycloalkyl group having 8 to 8 atoms include cyclopropyl, citalogtyl, cyclopentyl, cyclohexyl, cyclohenonal, and (ecycloocnal), and preferably cyclopentyl or cyclohexyl.

R2nioshij' 7-, formula -X-A basis ks formula -cH
X in the 2-x-CyY group is preferably a methylene group, an oxygen atom or a sulfur atom.

Y included in the formula -CH2-x-Cy group in R2
The halogen atom is a fluorine, chlorine, bromine or iodine atom, and in excess is a fluorine or chlorine atom.

n is preferably an integer of 3 to 5, more preferably 3
is an integer.

Or in compound (Ia), Hl is preferably a water purple atom or a methyl group, and R2 is the above-mentioned alkyl group having 4 to 10 carbon atoms; the above-mentioned alkenyl group having 4 to 12 carbon atoms; methyl Or IK with ethyl group
Cyclopentyl radical which may be substituted with cyclohexyl group; cyclopentylmethyl, cyclohexylmethyl, cyclohentyl-amino, cyclohexylamino, cyclopenaloxy, cyclohexyloxy, cyclopentylthio or cyclo which may be substituted with 1 or more methyl or ethyl groups; Hexylthio group; 2-phenylethyl, anilinomethyl, phenoxymethyl or) modified phenylthiomethyl group in which phenyl group may be substituted with a fluorine atom, chlorine atom or trifluoromethyl group, n
It is possible to have a chemical compound where is an integer from 3 to 5.

In compound (1a), further v, J suitably! 1 is hydrogen or a methyl group, and R2 is n-pentyl, 1-pentyl, rhohexyl, 2-methylhegycyl, 2-benzonyl, 4-hexenyl, 5-hexenyl, 6-methyl Leu 5-Hecteninope 2.6-Shif1 Nar-5-hectynyl, cyclohentyl, 3-ethylcyclobentyl, cyclohexyl, 3-methyldiclohexyl, cyclopentylmethyl, 3-methylshif[1pentylmethyl, cyclohexylmethyl, 3 -ethylcyclohexylmethyl, cyclopentylxy, 3-methylcyclopentyloxy, cyclohexyloxy, cyclopentylthio, cyclohexylthio% 3-methylcyclohexylthio, 2-phenylethyl, 2-(m-fluorophenyl)ethyl, 2-(p -fluorophenyl)
Ethyl, 2(o-chlorophenyl)ethyl, 2-(p-
chlorophenyl)ethyl, 2- (fn-) IJ fluoromethylphenyl)ethyl, 2-(ph'J fluoromethylphenyl)ethyl, phenoxymethyl, +n
-Fluorophenoginomemethyl p-chlorophenoxymethyl, p-1-lifluorophenoxymethyl, phenylthiomethyl, 0-fluorophenylthiomethyl, m-chlorophenyldiomethyl or p-1 rifluthromethylnoenylthiomethyl Are there any compounds in which the mediyl group is present and n is an integer of 3?

Methanoprostaliculin transfer derivatives are chemically stable7.
Glostacycline is currently being developed as an excellent therapeutic agent for thrombosis, etc., with a 4% incidence rate. Because this compound has a large number of asymmetric carbon atoms and three-pronged bonds,
Divine optical isomers and stereoisomers exist and exist, and the target compound can be synthesized as described above! Contamination with tetramers is unavoidable. Regarding the separation of isomers of methanoprostacyclin derivatives, the general formula (wherein 1 and 5 represent a trityloxymethyl group, 3-trityloxy-trans-1-propenyl group, etc.) is used.

) and its 5z-isomer (]IIt+) using dicyclohegycylamine, the compound Cl1la)'! It is known that ll=separation is possible (Japanese Unexamined Patent Publication No. 122328/1983).

The present inventors have conducted nine studies over many years regarding the separation of external forms of methanoprostacyclin derivatives, and have found that they are based on square bonds (E, Z-isomers can be separated more efficiently than known techniques≠). , 1. The present invention was created by discovering an off-1-order carbonated amine salt useful for separation of optical isomers based on asymmetric carbon atoms.

The salt of compound (Ia) and compound (Ila) according to the present invention can be produced according to the following method.

A mixture of compound (Ia) and the 2-isomer of compound (Ia) having the general formula (wherein R,, R2 and Ω have the same meanings as described above), a compound (IaJ and its antipode) mixture with compound (Ic) or compound (Ia), compound (lb), adduct (IC) and compound (1h) with its enantiomer compound (ld). In a liquid solvent, a chemical compound (][a) is applied to produce a crystalline VF base, and as required,
It is possible to do this by recrystallization.4)

4) Small ftj 19-: As a solvent, water, such as r]-pentane, n-hexano, n-octane 7. Cl1i-r aliphatic hydrocarbons, aromatics such as benzene, toluene, gysolene: hydrocarbon pto, dichlorofuran, ethers such as dioxane, methyl acetate, LIT't? , esters such as ethyl, nitrides such as acetonitrile, benzonitrile 11/l.

ketones, such as acetone, methyl ethyl ketone,
Methanol, ethanol, n-7' lovanol, ingropanol, ■]-butanol, isobuknol, 84-butanol, t-butanol, +1-amyl alcohol, sect-J mil alcohol, c-1 mil alcohol, isoamyl alcohol, Nada-isoamino alcohol,
Alcohols such as activated amyl alcohol or mixtures of these bath agents can be mentioned, but esters or mixtures of esters and the above-mentioned solvents are particularly preferred, and esters or alcohols are particularly preferred. and esters.

The amount of compound (l[a) used is 0.1 to 1.5 equivalents, preferably 0.9 to 1.5 equivalents, based on the carboxylic acid.
1. It's a matter of concern.

Compound (Ia) % (Ib), (IC) and (1d,
) and compound (Ila) are usually produced at a temperature close to room temperature, and recrystallization of the above salt is preferably carried out at i'! Heat to 50°C to 100°C to form a C1 supersaturated liquid, then
This is carried out by precipitating crystals at 0°C to 50°C.

In addition, according to the same method as above, compound (IC) and d
-threo-2-amino-3-paranitrophenyl-1,
3-Propanediol (lb) (7) salts can also be prepared.

Compound (Ia) and compound (Il) produced as above
a) Salt with compound (IC) and compound (Ilb)
The salt is prepared according to the conventional method, and the compound (
1a) or compound (IC). For example, add a small amount of the corresponding salt to water, add a dilute alkaline bath solution, remove the amine compound (Ila) or (I[b) produced in 4!1, and then add 1 g of the diluted salt. It can be obtained by making the bath liquid acidic, extracting with a water-immiscible bath agent, and eliminating the bath agent from the extract.

Compound (Ia) used as a raw material in this method.

(Ib), (Ic) and (Id) can be easily produced according to known methods (JP-A Iff (54)).
-95552, lh 54-130543 or JP-A-11-55-28945).

Next, the invention will be explained in more detail with reference to Examples.

Example 1 Monomethyl-20-imbropylidene gloss-(BB
, 9R, 11R, 12R, 158, 17R) -6゜9-methylene-It, 15-dihydroxy-11-
Methyl-20-inglobylidenebrost = 5(E)
, 13 (El-dienoic acid and its (7J 5 (composition of Zl-isomer with 'l'l! I (about 6.5 vs. 3.5) 0
．． 38 # /, J t -Threo-2-amino-3-valanitrophenyl-1,3-propanediol was dissolved in ethyl acetate containing 10% isopropanol and reconstituted at room temperature. Objective 5(E) by crystallization
- 0.26 g of the salt of the isomer was obtained.

Melting point 68-70℃ Engineering R spectrum ('Nujot) cm ・1350
, 1375 , 14B0 , 1520 , 335ON
MR spectrum (OD50D) δppm: Example 2 Method using g, z- mixture (88, 9R, IIR, 12R, 158) -6,9-
Methylene-11,15-dihydroxydigulost-5 (E
l, 13F;)-dienoic acid and its 5(Z)-isopari triad (approximately 65:3.5) 0.10, ?
An equivalent amount of t-threo-2-amino-3-valanitrophenyl-1°3-propanediol was heated at θ4 in ethyl acetate containing ethanol, and then recrystallized at room temperature to obtain the desired 5(E). -Isomer salt% = 0.07 y baby.

Melting point 55-65℃ Engineering R spectrum (liquid film) cm-1040, 13
50, 1405, 1530, 32500, 88 (3H,
t, 7VaH3)■ Method using enantiomer mixture (88,9R,IIR,12R,15S)-6,9α-
Methylene-11α, 15α-dihydroxydibrost-5
(K), 63 mg of a mixture (1:1) of 13(E)-dienoic acid and the heptadole enantiomer and L-threo-2 of 3Brn9.
-Amino-3-valanitrophenyl-1,3-furopanediol was treated in the same manner as in (1) to obtain the desired salt 40 (2).

Example 3 -1,3-propanediol salt (88, 9R, jIR, 12F, 15fJ
) ~ 6.9-methylene-11,15-D hydroxy-15-Schiff [Goventyl-16, 17, 18
, 19,20-pentatulprost-5 (H;l,
13 (E)-Jibun 1:1'! 1. Toso'J,)
5 (2) - Different t', f: body tono mixture (approximately 8:2
) 63 mg and the kick of T-Threo-2-1 Ryo Mino-
3-・Paranitrophenol-1,3-propanediol Kaoru 10・Voice isopropa,'-le? The mixture was heated and melted in ethyl acetate and reconstituted at room temperature.

Li’! i point 90-92℃ Engineering Spect # (Nujot) cm.

1350, 1460, 1520, 2600, 2
85G.

330 Patent applicant: Sankyotai Company

Claims (1)

[Claims] 1) General formula [wherein R1 is a hydrogen atom or methyl, Ji! -, R2 is an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, a group of the formula -A (wherein A is a carbon atom which may be substituted with a lower alkyl group) represents a number of 3 to 8 cycloalkyl groups), formula -
X-AM (in the formula, 8 has the same meaning as above,
represents a methylene group, an ethylene group, an -NH- group, an oxygen atom or a sulfur atom. ) or formula -〇H2-X-Q”
Group (wherein, X has the same meaning as above, and Y is)
・Indicates a rogen atom or a trifluoromethyl group. ), and n represents an integer from 1 to 5. ] and t-threo-2-amino-3
-Paranitrophenyl-1゜3-propanediol (I
Salt with [a). 2) General formula [wherein R7 represents a hydrogen atom or a methyl group, R2
is an alkyl group having 1 to 12 carbon atoms; an alkenyl group having 2 to 12 carbon atoms; represents a cycloalkyl group of formula 1.
- represents a group, an acid radical f or a sulfur atom. ) or formula-C
H2-X-cf group (in the formula, X has the same meaning as described above, Yμ), does not represent a rogen atom or a trifluoromethyl group. ) ke small, Ω is 1
Indicates an integer from 5 to 5. [In the formula, R1, R2 and Lorae 111 have the same meanings as described above. A mixture with Ic) or a mixture of compound (Ia), compound (Ib), compound (IC) and the enantiomer compound (Id, ) of compound (Ib)7)
t-threo-2-amino-3-valanitrophenyl-1,3-furopanediol (Ila
, )' to produce a crystalline salt, (X must be
Compound (I) characterized by recrystallization depending on vc
Method for producing a salt of a) and compound (■a).