JPS5940832B2 - Epi conversion method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an epimerization process for the epilation of intermediates for producing 155 prostaglandin analogues into corresponding intermediates for producing the corresponding 15R prostaglandin analogues. Regarding.

Known 16-aryloxy-17, 18, 19,
In known syntheses of 20=tetranorprostaglandin analogues, the more fertility-blockingly active 15R epimer is synthesized from a solid crystalline precursor, e.g. The mixed C-15 epimer of 1-trans-enyl)-2,3,3aβ,6aβ-tetrahydro-2-oxo-5α-(4phenylbenzoyloxy)cyclopenteno[b]furan was fractionally crystallized or column chromatographed. Do 1 and continue the bow (1
) to the required prostaglandin analog by converting a suitable single epimer of the compound to the required prostaglandin analog by the same methods known for converting mixed epimers to prostaglandin analogs.

When the aryl group is 3-chlorophenyl or 3-trifluoromethylphenyl, the (3R)-4-aryloxy-3-hydroxybut-1-enyl epimer (which gives the 15R prostaglandin congener) is Obtained by fractional crystallization or by column chromatography, the 3S epimer is retained in the mother liquor or column liquid. Up to now it has been necessary to discard the undesired 3S epimer or to subsequently oxidize it to the corresponding compound, which is then reduced to a mixture of 50% 3S epimer and 50% 3R epimer ( 1), and then this mixture can be further subjected to fractional crystallization or column chromatography to further recover the desired 3R epimer. The aim of the present invention is to obtain an epimerization process which allows epimers of S configuration to be completely epimerized directly into the corresponding R epimers which are more useful. That is, according to the invention, a compound of the formula [wherein R1 represents a phenyl or naphthyl group, which is unsubstituted or a halogen atom, a hydroxy, nitro or phenyl group, an alkyl, halogenoalkyl group having 1 to 4 carbon atoms each] , substituted with an alkoxy, alkenyl or alkenyloxy group or a dialkylamino group, each alkyl having 1 to 3 carbon atoms. represents the above, and R2 represents an aroyloxy group having up to 12 carbon atoms or an alkanoyloxy group having up to 6 carbon atoms, such as a 4-phenylbenzoyloxy group], triphenylphosphine, azodicarbonyl Acid di(lower alkyl of 1 to 6 carbon atoms)
esters, such as diethyl esters, and carboxylic acids, such as aromatic acids of up to 8 carbon atoms, such as benzoic acid, or alkanonic acids of up to 6 carbon atoms, such as formic acid, in an inert solvent, such as an ether, such as tetrahydrofuran, and then The ester thus obtained is characterized in that it is hydrolyzed, for example with a base, for example potassium carbonate.

A suitable halogen atom substituent for R1 is, for example, a chlorine, bromine or fluorine atom.

Suitable alkyl, alkoxy, alkenyl or alkenyloxy substituents of 1 to 4 carbon atoms for R1 are, for example, methyl, t-butyl, allyl, methoxy or allyloxy groups. Suitable halogenoalkyl substituents for R1 are, for example, chloroalkyl or fluoroalkyl groups, such as trifluoromethyl groups. A suitable dialkylamino group (each alkyl having 1 to 3 carbon atoms) which may be a substituent for R1 is, for example, a dialkylamino group in which the two alkyl groups are the same, such as a dimethylamino group. Suitable substituted aryl groups are, for example:
Chlorphenyl, chlornaphthyl, promphenyl, fluorophenyl, tolyl, xylyl, methylnaphthyl,
t-butylphenyl, methylchlorophenyl, trifluoromethylphenyl, hydroxyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, dimethylaminophenyl and tetrahydronaphthyl groups.

Preferred aryl groups have up to two substituents as described above.

Therefore, the special ones for R1 are: phenyl,
1-naphthyl, 2-naphthyl, 2-3- and 4-chlorophenyl, 4-promphenyl, 2-3- and 4-fluorophenyl, 2.3-, 2.4-, 2.5-, 2.
63.4- and 3.5-dichlorophenyl, 2,3- and 4-tolyl, 2.3-, 3.4- and 3.5-xylyl, 4-t-butylphenyl, 3-allylphenyl, 3
-trifluoromethylphenyl, 4-hydroxyphenyl, 2-, 3- and 4-methoxyphenyl, 4-biphenylyl, 3-dimethylaminophenyl, 2-chloro-4-
Methylphenyl, 1-chloro-2-naphthyl, 4-chloro-2-naphthyl, 6-methyl-2-naphthyl, 6-methoxy-2-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl groups. Particularly preferred compounds of the formula which can be produced by the process of the invention are those in which R1 is a trifluoromethylphenyl or chlorophenyl group, especially racemic
(3aR・4R・5R・6aS)-2
・3 ・3a・6a-tetrahydro-5-hydroxy-4[(3R)~3-hydroxy-4-(3-trifluoromethyl-phenoxy)but-1-trans-enyl]~2-oxocyclopenteno[ b] Furan and racemic (3aR・4R・5R・6aS)-4-[(3R)-
4-(3-chlorophenoxy)3-hydroxybut-1
-trans-enyl]2,3,3a,6a-tetrahydro5-hydroxy-2-oxocyclopenteno[b]
It's a franc.

The feedstock for the process may contain 0-10% R epimer when obtained from crystallization or column liquids;
Moreover, in the process of the invention, this epimer is epimerized, so that the final product has, for example, 90 to 100 R epimers.
% and S epimers from 0 to 10%.

Thus, the overall result of the method of the invention in this context is that 90-100% of the less fertilization-blockingly active S epimer precursor
to obtain a product containing 90-100% of the corresponding precursor of the more antifertility-active R epimer. Furthermore, the epimerization method according to the present invention can also be used for compounds of the formula in which the aryloxymethyl group -CH2ORl has one or more substituents other than the above-mentioned substituents or is substituted with another group, It is clear that the products thus obtained are useful intermediates of known prostaglandin analogs and can be separated by conventional methods into epimers and selective groups such as -CH2ORl. .

Suitable selective groups for the group CH2ORl are, for example, aralkyl groups, such as phenethyl or α-methylphenethyl groups, optionally substituted on the phenyl group; heterocyclyloxymethyl groups, such as indolyloxymethyl, pyridyloxymethyl or benz[b]furyloxymethyl group, e.g. 5-indolyloxy, 5
-Chlorpyrid-13-yloxymethyl or benz[b
] a blue 2-yloxymethyl group; or a benz-cycloalkenyloxymethyl group, such as an indanyloxymethyl group, such as a 2-indanyloxymethyl group.

The invention will now be explained with reference to examples.

Example 1 Racemic (3aR, .4R・5R・6aS)-41 [(3
S)-4-(3-chlorophenoxy)-3hydroxybut-1-trans-enyl]-23,3a,6a-tetrahythro-2-oxo-5(4-phenylbenzoyloxy)cyclopenteno[b]furan (corresponding Containing approximately 5% of the 3R epimer (518 q), triphenylphosphine (524 q) and benzoic acid (244 w) were dissolved in dry tetrahydrofuran (10 ml) by stirring under a nitrogen atmosphere.

A solution of diethyl azodicarboxylate (348 ml) in tetrahydrofuran (2.0 ml) was added over a period of 2 minutes via a water funnel, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and the yellow residual syrup was purified using Kieselgel (607) using a mixture of 20% ethyl acetate and 80% toluene as eluent.
The product was purified by column chromatography, and 25 ml of fraction was collected. Fractions 5-10 were combined and the solvent was evaporated to give a gummy product. The gummy product (620m9) was dissolved in a mixture of methylene dichloride (3m0) and methanol (15m1).

Powdered anhydrous potassium carbonate (152 w) was added and the mixture was stirred at room temperature for 3.5 hours. The mixture was diluted with 1N monohydrochloric acid (2.
2 ml) and evaporated to dryness. The residue was diluted with saturated brine (5 ml) and diluted with ethyl acetate (10 ml and 5 ml).
), the extracts were combined, washed with brine, dried and the solvent was evaporated to give a white paste. This paste was dissolved in methylene dichloride and applied to an ether formulated FlOrisil column. The column was eluted with ether (total 150ml);
These fractions were discarded. Furthermore, ethyl acetate (total 475ml
) to give a colorless gum after evaporation of the solvent, which was dissolved in ethyl acetate (2a).
Add petroleum ether (boiling point 60~8'C, 1.5 m
By adding 1), the necessary racemic (3aR・4
R.5R.6aS)-4[(3R)-4-(3-chlorophenyl)-3hydroxybut-1-trans-enyl]-2.3.3a.6a-tetrahydro-5-hydroxy2-oxocyclopenteno [b] Furan (melting point 124
At ~126°C, rapid crystallization of RF-0,27 (silica gel thin-layer chromatography using a mixture of 60% methylene dichloride and 40% acetone) occurs, which is similar to the conventionally prepared authentic It is the same as the crystal of the substance and different from the crystal of 3S-epimer (RFO.3l, the same type).

Example 2 Racemic (3aR, 4R, 5R, 6aS)-2, 3, 3a
・6a-tetrahydro-4-[(3S)-3-hydroxy-4-(3-trifluoromethylphenoxy)but-1-trans-enyl]2-oxo-5-(4-phenylbenzoyloxy)cyclopenteno [b] Franc (1
4.50y), triphenylphosphine (10.327
) and benzoic acid (4.317) were dissolved in dry tetrahydrofuran (300 ml) by stirring under an atmosphere of argon.

A solution of diethyl azodicarboxylate (6.867) in dry tetrahydrofuran (40ml) was added over 35 minutes. The reaction was found to be fully complete after a further 30 minutes by thin layer chromatography. Evaporation of the solvent under reduced pressure gave a gummy semi-crystalline solid, from which trituration with ether and toluene gave a white crystalline product. The product was transferred to Kiesel gel (K
The product was purified by column chromatography on 60% ethyl acetate and eluted with a mixture of 15% ethyl acetate and 85% toluene, collecting 250 ml of fractions. Distillate 1~
4 was discarded and fractions 5-12 were combined and evaporated to dryness to give the crude ester product. Crude ester product (1
Potassium carbonate (6,98y) was dissolved in a mixture of dry methanol (200ml) and methylene dichloride (50ml washed with alumina and potassium carbonate).
was added and the mixture was stirred for 2 hours.

Claims (1)

[Claims] 1 Formula II: ▲Mathematical formulas, chemical formulas, tables, etc.▼II [In the formula, R^1 represents a phenyl or naphthyl group, which is unsubstituted or a halogen atom, hydroxy,
a nitro or phenyl group, each substituted with an alkyl, halogenalkyl, alkoxy, alkenyl or alkenyloxy group of 1 to 4 carbon atoms or a dialkylamino group (each alkyl being an alkyl of 1 to 3 carbon atoms); In the method for producing a compound, Formula III: ▲ Numerical formula, chemical formula, table, etc.▼III represents triphenylphosphine, azodicarboxylic acid di-(representing up to 1 to 1 carbon atoms)
A process for producing the compound of formula II, which comprises reacting six (low alkyl) esters and a carboxylic acid in an inert solvent, and then hydrolyzing the ester thus obtained.