JPS6039260B2 - Cyclopentene derivatives and their production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to cyclobentene derivatives, more particularly IR4S
The present invention relates to 14-hydroxy-2-cyclobentenol ester and IS4R-14-hydroxy-2-cyclobentenol ester and a method for producing the same.

Therefore, an object of the present invention is to provide an important intermediate for the production of prostaglandins useful as pharmaceuticals.

The cyclobentene derivative of the present invention has the following general formula.

(In the formula, A represents a phenylene group) The compounds represented by the above formulas 1 and 2 are enantiomers of each other [Kyoritsu Shuppansha Publishing Co., Ltd., "Chemistry Dictionary" Vol. 5, pp. 576-57 and Vol. 3, p. 49, Published on August 5, 1969], and are related to IR book-4-hydroxy-2-cyclobentenol ester 1 and IS4R-4-hydroxy-2-, respectively.
It is called cyclobentenol ester, and both can be used as intermediates in the production of prostaglandins.

There are various synthetic versions of prostaglandin, and their steric configuration is closely related to their medicinal efficacy, so it is necessary to separate and isolate useful isomers at some stage of their synthesis. There is. In particular, it is known that useful prostaglandins can be stereospecifically obtained in a short process by using a compound represented by the formula a or a' as an intermediate raw material (Tetrahedron
lettersl970, 307).

Therefore, the present inventors conducted various studies to advantageously synthesize optical compounds a and a', and as a result, an industrial method for synthesizing a and a' via novel intermediates 1 and 0 was developed. completed. Therefore, the present invention aims to provide novel intermediates 1 and 2 and a method for producing them.
According to the present invention, compounds of formulas 1 and D are prepared according to the reaction scheme shown below. (In the formula, x represents a hydroxyl group-protecting group, and A has the above meaning.) That is, the compounds of formulas 1 and 0 are cis-2-cyclobentene-1,4-dio-
The product (W) is reacted with a dicarboxylic acid or a reactive derivative thereof, and then the resultant product (W) is salted with an optically active base (
V), separating it into an optically pure salt and then desalting it, or one of cis-2-cyclobentene-1,4-diol (m) The hydroxyl group of is protected to form a compound of the formula, which is then reacted with a dicarboxylic acid or a reactive derivative thereof to form a skin-type compound, and the protecting group is removed by acid treatment to obtain the d compound of m. This is manufactured by the second method, which is processed in the same manner as the first method.

Embodiments of the present invention will be described below.

To carry out this reaction, a dicarboxylic acid or a reactive derivative thereof is added in a solvent in the presence or absence of a base in an amount equal to or less than the equivalent of cis-2-cyclobentene-1.
, 4-diol m, and the compound of formula N produced by the reaction with m is isolated.

Examples of the base used at this time include tertiary amines such as ethylamine, dimethylaniline, and pyridine:
Alkali carbonates such as potassium hydrogen carbonate and sodium hydrogen carbonate; and other basic ion exchange resins. As the solvent, pyridine, tetrahydrofuran, acetone, ethyl acetate, methylene chloride, chloroform, dimethylformamide, dimethyl sulfoxide, acetonitrile, etc. are used. The reaction usually completes in 5 to 20 hours at room temperature, but the reaction can also be accelerated by heating. The reaction product is separated and purified by first separating the by-produced gester by a conventional method, such as column chromatography, to obtain a mixture of enantiomers 1 and 2. This separation of the enantiomers involves forming a salt with an optically active base, which is separated by fractional crystallization, column chromatography, etc., and then the salts of each diastereomer are separated by an appropriate method.
For example, this is carried out by desalting using ion exchange chromatography or the like, and in this case, pure isomers 1 and 2 are obtained. Examples of the optically active base used at this time include brucine, arginine, cinchonine, methylamine, morphine, and phenethylamine. Solvents used for fractional recrystallization include ethyl ether/tetrahydrofuran, ethyl acetate, alcohols, water, benzene, toluene, and chlorine. Examples include form, carbon tetrachloride, petroleum ether, hexane, acetone, etc.
Chromatography, preparative thin layer chromatography, etc. can be used. cis-2-cyclobentene-1,
As a method for producing a monoether compound by protecting one hydroxyl group of 4-diol m, a known method generally used for protecting a hydroxyl group is employed. Examples of the protecting group include a tetrahydropyranyl group, a trimethylsilyl group, a tri-n-butyltin group, and a 1-methoxy-4-tetrahydropyranyl group. For example, when protecting with a tetrahydropyranyl group, compound m and dihydropyran are used in approximately equal moles, and 30
The compound can be obtained by reacting for 2 minutes to 2 hours. This reaction product contains a small amount of ether compound, which can be removed, for example, by chromatography or distillation. However, this product can also be used as a raw material for the next reaction without being separated and purified. The same method as described above can be used for the reaction of the monoether with the hydrothermal carboxylic acid.

The protecting group of the dish-shaped compound thus obtained is easily removed under usual acidic conditions, for example by treatment with acetic acid. Moreover, the separation of compounds 1 and 0 obtained in this manner is carried out in the same manner as the above-mentioned method. Compounds 1 and 2 of the present invention obtained as described above can be converted into compound a or a', which is a useful intermediate for prostaglandins, according to the method shown in the following reaction formula.

As described above, a or a' can be obtained depending on the purpose using either Compound 1 of the present invention or Kawama, unlike conventional methods in which only one of the isomers can be used. , it has the advantage of being able to utilize 100% of both isomers.

In addition, the present invention uses meso form m, which has not been used as a raw material for synthesizing optically active compounds, as a raw material, and also uses inexpensive dicarboxylic acids such as phthalic acid and succinic acid, thereby producing prostaglandins. This is an extremely outstanding invention that succeeded in providing an important intermediate. Preferred embodiments of the method of the present invention are as follows.

'1} Claim 5 for producing W from compound m
The method described in section.

[The method according to claim 7, wherein 1 and m are produced from 2' compound m via N and V.

[3} The method according to claim 11, in which W is produced from compound m and via a plate. {4) Compound m
12. The method according to claim 11, wherein 1 and 2 are produced via wind, N and V.

Example 1 m→W cis-2-cyclobentene-1,4-diol 10 m→W cis-2-cyclobentene-1,4-diol (
0.10 mol) of pyridine was dissolved in 300 g of pyridine, and 14.8 mol of phthalic anhydride (0.10 mol) of tetrahydride was dissolved therein.

A solution of 80% of furan was added to the lamp for 1 hour, and the mixture was heated at room temperature for 1 hour.
Insect Time Light Azusa. After the reaction, the solvent is distilled off, and the residue is dissolved in ethyl acetate, washed with water, and dried. The operation of distilling off ethyl acetate under reduced pressure, adding toluene to the remaining vessel, and distilling it off is repeated twice. The resulting residue was applied to a column of silica gel (400 min) and eluted with chloroform containing 2.5% methanol. (2'-carboxy)-penzoyloxy-2-cyclobentenol 15.3 yen (yield 61.7%) NMR value 65 3 1.97 (d, t, J = 15, 3, IH) , 2.78 (
d, t, J = 15, 7, IH), 4.57-4.89 (
m, IH), 5.50-5.85 (m, IH), 5.9
5-6.27 (m, wide), 7.33-7.90 (m.4
H), 8.25 (s, 2H-〇H) IR value Kay-1 Back of the fin 3419, 3066, 2947, 1722,
1602, 1337, 1289, 1131, 1073,
1025, Shizui Yujime 3 3418, 2952, 1713
, 1603, 1337, 1286, 1129, 1076
Dicyclohexylamine salt (recrystallized from ethanol/ether) Colorless prism crystal Melting point 158-16000 Elemental analysis value C25 days Calculated value as 35NQ (%) 69.90 8.21 3.26 Actual value (%) 69.92 8.15 3.331R
Value, band cumulative - 13293, 2942, 2860, 1
731, 1620, 1553, 1374, 1265, 1
116 ■ Monoester body obtained on W → V → 1 and B (d) 20.1 (81
．． 0 mmol) and brucine dihydrate 34.9 mmol (8
When 1.1 mmol) is dissolved in acetone and left at room temperature, crystals precipitate.

When this crystal is recrystallized three times from acetone-methanol, optically pure brucine salt 12.5 is obtained. This brucine salt is dissolved in water and subjected to ion exchange chromatography using a strongly acidic ion exchange resin Amberlite IR-1 Gen B (manufactured by Rohm and Haas) with water as the eluent. is removed.
When the eluate was distilled off, 1IS4R-4- was obtained as a colorless liquid.
(2'-benzoyloxy)penzoyloxy 2-cyclobentenol The specific light intensity that yields 3.81 units [Q] Answer 14
7.40 (C; 2-0, CHC 3) NMR and IR values (d〆) were consistent with the body.

Furucin salt Melting point 118-120℃ (decomposition) Specific luminosity [Q] Keiichi 6.60 (C; 2.0, CHC so 3) Elemental analysis value: C39, 4N20.

(one molecule adduct of pursin and acetone) as C day
N Calculated value (%) 66.84 6.33 4.00 Actual value (%) 66.59 6.37 3.971R
Value obi bag - 12951, 1715, 1655, 150
2,1449,1283,1218,1200,111
5 Dicyclohexylamine salt (recrystallized from ethanol/ether) Colorless prism crystal Melting point 153-15400 Specific light intensity [Q] 轡19. (C=3. Yesterday C evening 3) Elemental analysis value C25th day 35NQ C day N Calculated value (%) 69.90 8.21 3.26 Actual value (%) 69.89 8.16 3.211R
The value (d) corresponded to the field.

When the solvent is distilled off from the recrystallized mother liquor of the brucine salt, colorless prism crystals are obtained.

When this is recrystallized five times from acetone, optically pure brucine salt 10.5 times is obtained. When this is treated in the same manner as above, -IR4S-4-(2
-carboxy)-benzoyloxy-2-cyclobentenol 3.199 is obtained. Specific luminosity [Q] Keiichi 47.
20 (C=2-Today C evening 3) NMR value and IR value (d evening) matched the body.

Furucin salt Melting point 120-12 is 0 Specific luminosity [Q] Keiichi 23.5o (C; 2. and HC so 3) Elemental analysis value C3 Rainbow 44N20.

Calculated value (%) 66.84 6.33 4.00 Actual value (%) 66.31 6.28 3.98 Dicyclohexylamine salt (recrystallized from ethanol/ether) Melting point 152.5-153. 500 Specific luminous intensity [Q] force -7.1o (C:3-0, CHC so3) Elemental analysis value C day N Calculated value (%) 69.90 8.21 3.26 Actual value (as C25 day 35 NQ) %) 69.94 8.22 3.26IR
The value (d) matched the field.

Example 2 5.0 m→ cis-2-cyclobesothene-1,4-diol (50 mmol) was dissolved in 300 methylene chloride,
Tetrahydride of p-toluenesulfonic acid.

Add 5 portions of furan solution (1 mmol/100 ships).
A solution of 4.2 g of dihydropyran (50 mmol) in 30 g of methylene chloride is added dropwise over 1 hour. After reacting overnight at room temperature, 3 drops of pyridine were added to stop the reaction, and methylene chloride was distilled off. Dissolve the residue in ethyl ether, wash with water,
After drying, the solvent is distilled off. When the residue is applied to a column of silica gel (200 mm) and eluted with chloroform, 6.6 mm of (d〆)-cis-4-tetrahydropyranyloxy-2-cyclobentenol flows out after the ether flows out. Colorless liquid boiling point 8400 (0.7 mmHg) NMR value 6 ≦ Yu 3 1.3-2.1 (n, 7H), 2.3-3.1 (m, I
H), 3.3-4.3 (m, ga), 4.4-4.9 (m
, coarse), 6,04 (s, 2H) IR value and silk robe-1 3400, 2940, 2870, 1352, 1200,
1134 ■ → W → W monoether body 5.2 evening (2
8.2 mmol) was dissolved in 40 mm of pyridine, and a solution of 5.0 mmol of phthalic anhydride (33.7 mmol) in 30 mm of tetrahydrofuran was added dropwise to the solution in 3 powders, and the mixture was reacted overnight at room temperature.

After the reaction, the solvent is distilled off, and the residue is dissolved in ethyl acetate, washed with dilute hydrochloric acid, water, dilute aqueous sodium bicarbonate solution, and water, dried, and the solvent is distilled off. The resulting oil was dissolved in 190' of acetic acid-water (7:3) mixture and heated at room temperature for 2.
React for 4 hours. After the reaction, the solvent is distilled off, the residue is extracted with ethyl acetate, washed with acid and alkali, dried, and the solvent is distilled off. The residue was applied to a column of silica gel (100%) and eluted with chloroform containing 2.5% methanol, yielding cy-4-(2'-carboxy)-penzoyloxy-2-cyclobentenol 5 as an oil (d).
．． You will get 3 evenings. The physicochemical properties of this product correspond to the (d) form obtained in Example 1. Example 3m → The solvent was distilled off from the reaction solution obtained by reacting in the same manner as in Example 2 (■), and the oily substance obtained by distilling off the solvent was purified by distillation. Boiling point 103-106℃
(lmmHg) of (d)-cis-4-tetrahydropyranyloxy-2-cyclobentenol is obtained in a yield of 45%.

This product has sufficient purity as a raw material for the next reaction.

Example 4 The reaction was carried out in the same manner as in Example 2 (2), and the solvent was removed from the resulting reaction solution to obtain 8.5 g of an oily substance.

Quantification of this oil by gas chromatography revealed that it contained 6.9 monoethers. ■W→Skin→W When treated in the same manner as in Example 2 (■) using 8.5% of this oily substance and 6.6% of phthalic anhydride, (d)-cis-(2'
-carboxy)-benzoyloxy-2-cyclobentenol 5.1 times are obtained.

Claims (1)

[Claims] 1. A cyclopentene free radical represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein A represents a phenylene group, and the hydroxyl group and ester group have a cis relationship with each other). 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A represents a phenylene group) 1R
The cyclopentene derivative according to claim 1, which is 4S-4-hydroxy-2-cyclopentenol ester. 3 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A represents a phenylene group) 1S
The cyclopentene derivative according to claim 1, which is 4R-4-hydroxy-2-cyclopentenol ester. 4. The cyclopentene derivative according to claims 1 to 3, wherein the carboxylic acid represented by the general formula HOOC-A-COOH is phthalic acid. 5 A general method characterized by reacting a dicarboxylic acid represented by the general formula HOOC-A-COOH (wherein A represents a phenylene group) or a reactive derivative thereof with cis-2-cyclopentene-1,4-diol. A method for producing a cyclopentene derivative represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. 6 Claim 5 in which the dicarboxylic acid is phthalic acid
The method described in section. 7. A dicarboxylic acid represented by the general formula HOOC-A-COOH (wherein A represents a phenylene group) or a reactive derivative thereof is reacted with cis-2-cyclopentene-1,4-diol, and then the resulting product is to form a salt by reacting with an optically active base,
The general formula, which is characterized by separating this salt into two types of diastereomers and further desalting them, is represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, A has the above meaning). 1R
4S-4-hydroxy-2-cyclopentenol ester and 1S4 represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (A in the formula has the meaning above)
Method for producing R-4-hydroxy-2-cyclobewatenol ester. 8 Claim 7 in which the dicarboxylic acid is phthalic acid
The method described in section. 9. The method according to claim 7, wherein the diastereomer separation method is a crystallization method or a chromatography method. 10. The method according to claim 7, wherein the desalting method is an ion exchange chromatography method. 11. Protecting one hydroxyl group of cis-2-cyclopentene-1,4-diol,
Next, this is reacted with a dicarboxylic acid represented by the general formula HOOC-A-COOH (wherein A represents a phenylene group) or a reactive derivative thereof, and the protecting group is further removed by a fermentation treatment. A method for producing a cyclopentene derivative represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. 12. The method according to claim 11, wherein the dicarboxylic acid is phthalic acid. 13. The method according to claim 11, wherein the hydroxyl protecting group is a tetrahydropyranyl group. 14 One hydroxyl group of cis-2-cyclopentene-1,4-diol is protected and then the general formula HOOC
A dicarboxylic acid represented by -A-COOH (in the formula, A represents a phenylene group) or a reactive derivative thereof is reacted, the protecting group is removed by acid treatment, and the resulting product is treated with an optically active base. A general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, A has the above meaning)
-Hydroxy-2-cyclopentenol ester and 1S represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A has the above meaning)
Method for producing 4R-4-hydroxy-2-cyclopentenol ester. 15. The method according to claim 14, wherein the dicarboxylic acid is phthalic acid. 16. The method according to claim 14, wherein the hydroxyl protecting group is a tetrahydropyranyl group. 17. The method according to claim 14, wherein the diastereomer separation method is a fractional recrystallization method or a chromatography method. 18. The method according to claim 14, wherein the desalting method is ion exchange chromatography.