JPS6141352B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to prostaglandin-like compounds. That is, the present invention is based on the general formula [] [In the formula, R ₁ represents a hydrogen atom or a lower alkyl group, and R ₂ represents a lower alkyl group having 4 to 8 carbon atoms. ] This relates to a novel cyclopentane derivative represented by:

Since its discovery, prostaglandin has attracted attention as a pharmaceutical product due to its diverse pharmacological actions, and has been extensively researched. Particularly in recent years, attempts have been made to synthesize new analogous compounds and to isolate and select the various pharmacological actions possessed by prostaglandins. The prostaglandin-like compound of the present invention represented by the general formula [] exhibits valuable pharmacological effects, such as suppressing gastric acid secretion stimulated by secretagogues such as histamine and pentagastrin, and , which has the surprising advantage of lacking the unpleasant side effects seen with related compounds.

The novel cyclopentane derivative represented by the general formula [] of the present invention was synthesized for the first time by the present inventors, for example, by the method shown below.

[In the figure, Ts represents a tosyl group, R ₃ represents a lower alkyl group, Ac represents an acetyl group, THP represents a tetrahydropyranyl group, and R ₁ and R ₂ have the same meanings as above. ] That is, compound (1) (tetrahedron
Tetrahedron, 22 , 95 (1966)) was tosylated with tosyl chloride in pyridine to give compound (2), and compound (2) was reacted with sodium cyanide in dimethyl sulfoxide to give compound (3). ) was hydrolyzed to give compound (4). Compound
After esterifying (4) to form compound (5), the double bond is oxidatively cleaved to form compound (6), and the carboxylic acid of compound (6) is converted into an acid chloride, which is reacted with diazomethane to form a diazoketone form and 50% hydroiodic acid to obtain the methyl ketone body (7). Compound (7) was subjected to Baeyer Billiger reaction to form diacetate compound (8). When compound (8) is heated under acidic conditions, lactone (9) is obtained. When this is treated with acetic anhydride, the acetate (10) is obtained. The carboxylic acid group of compound (10) was reduced with diborane to form an alcohol form (11), which was then subjected to Collins oxidation to form an aldehyde form (12), which was then reacted with a Witzte conversion reagent to form an enone. body (13) can be obtained. After reducing the carbonyl group of enone compound (13) to alcohol group (14), compound (14) was subjected to alkaline hydrolysis, and after deacetylation, the generated hydroxyl group was reacted with dihydropyran to dilute After obtaining the tetrahydropyranyl compound (15), the lactone group is reduced with diisobutylaluminum hydride to obtain the hemiacetal compound (16), which is then reacted with Wittstein's reagent to obtain compound (17). After oxidizing the hydroxyl group of compound (17), the tetrahydropyranyl group is eliminated with a weak acid to obtain the compound represented by the above general formula [].

In addition, the lower alkyl group represented by R ₁ and R ₃ in the present invention includes methyl, ethyl, propyl, etc., and the lower alkyl group having 4 to 8 carbon atoms includes butyl, pentyl, hexyl, α-methyl, etc. -pentyl, α-α-dimethyl-pentyl, and the like.

According to the present invention, for example, the following compounds can be obtained.

9-oxo-11α-16-dihydroxy-20-methyl-5-cis-14-trans-prostadienoic acid methyl ester 9-oxo-11α-16-dihydroxy-17・20
-dimethyl-5-cis-14-trans-prostadienoic acid methyl ester 9-oxo-11α-16-dihydroxy-17.
17・20-trimethyl-5-cis-14-trans-
Prostadienoic acid methyl ester 9-oxo-11α・16-dihydroxy-17-ethyl-20-methyl-5-cis-14-trans-Prostadienic acid methyl ester 9-oxo-11α・16-dihydroxy-5-cis- 14-trans-prostadienoic acid methyl ester The present invention will be specifically illustrated with reference to Examples and Reference Examples below, but the present invention is not limited thereto.

Reference example 1 2-exo-cyanomethyl-3-endo-cyanomethyl-bicyclo[2.2.1]hept-5
-ene 2-exo-hydroxymethyl-3-endo-
Hydroxymethyl-bicyclo[2.2.1]hept-5-ene (3.08 g) was dissolved in pyridine (10 ml), and p-toluenesulfonic acid chloride (7.7 g) was added to this solution under cooling in anhydrous benzene (10 ml). )
It was dissolved in and added. After stirring overnight at room temperature, benzene (100 ml) was added, the benzene layer was washed with water, and then
% hydrochloric acid solution, sodium bicarbonate solution, and water, and dried. The benzene layer was distilled off to obtain ditosylate (9 g) as crystals. The above ditosylate (9 g) was dissolved in anhydrous dimethyl sulfoxide, and sodium cyanide (4 g) was dissolved in anhydrous dimethyl sulfoxide.
g) was added and heated at 100°C for 1.5 hours. Benzene and water were added, and the benzene layer was separated, washed with water, and then dried. Benzene was distilled off to obtain the desired oily dicyano compound (3.1 g).

IRν ^film _nax cm ^-1 : 2950, 2250, 1420, 1340 NMR (CCl ₄ ) δ: 6.0 to 6.5 (2H, m, olefinic
Reference example 2 2-exo-3-endo-biscarbomethoxymethyl-bicyclo[2.2.1]hept-5-
Dicyano compound obtained by the method of Reference Example 1 (10g)
After heating under reflux for 5 hours in a 20% caustic potassium aqueous solution,
After extracting the neutral part with benzene, the aqueous layer was made acidic with 10% hydrochloric acid water, and then the acid part was extracted with ethyl acetate. After washing with water, it was dried and the solvent was distilled off to obtain a crystalline carboxylic acid with a melting point of 162°C. The crystals were dissolved in dry methanol, a small amount of concentrated sulfuric acid was added, and the mixture was stirred overnight. After neutralizing the sulfuric acid by adding aqueous sodium bicarbonate, the methanol was distilled off, and the desired diester was extracted with benzene.

Distillation yields 9.5g of target material (bp106~110℃/
0.2mmHg).

IRν ^film _nax cm ^-1 : 1740, 1440, 1150 NMR (CCl ₄ ) δ: 5.8 to 6.4 (2H, m), 3.65
(6H, s) Reference example 3 1-α-acetyl-4-α-acetyl-2-α
-Carbomethoxymethyl-3-β-carbomethoxymethyl-cyclopentane Bicycloheptene obtained by the method of Reference Example 2-
Diester (10 g) was dissolved in anhydrous benzene (200 ml) and Crownether (500 g) was dissolved in anhydrous benzene (200 ml).
mg) and potassium permanganate (22 g) and stirred overnight at room temperature. After adding water (50 ml) and stirring for 30 minutes, the precipitate was removed, the benzene layer of the mother liquor obtained was separated, and the aqueous layer was concentrated. After adjusting the pH to 1 with hydrochloric acid, the desired dicarboxylic acid was extracted with ethyl acetate. Yield 9.6
g The above dicarboxylic acid (9.6 g) was suspended in anhydrous benzene (150 ml), anhydrous dimethylformamide (1 ml) was added, 20% phosgene solution (30 ml) was added under cooling, and the reaction mixture was stirred at room temperature. The benzene layer was separated and concentrated to obtain carboxylic acid chloride. This material was dissolved in ether and added dropwise to an ether solution of diazomethane, and the mixture was stirred at room temperature for 3 hours. The ether was distilled off to obtain a bis-diazoketone body. Add this to chloroform (70ml)
50% hydroiodic acid (10 ml) was added dropwise. The chloroform layer was washed with water and then dried, and the obtained crude oil was subjected to silica gel column chromatography to obtain the desired diacetyl compound (3.2 g).

IRν ^film _nax cm ^-1 : 1740, 1710, 1440, 1360, 12
60 NMR (CCl ₄ ) δ: 3.6 (6H, s), 2.13 (6H,
s) Reference example 4 1-α-acetoxy-4-α-acetoxy-2
-α-Carbomethoxymethyl-3-β-carbomethoxymethyl-cyclopentane Diacetyl-cyclopentane derivative (1.5 g) obtained by the method of Reference Example 3 was mixed with dichloromethane (60 g).
ml) and sodium monohydrogen phosphate (6.7 g)
and to this suspension 90% hydrogen peroxide (1.28
ml) and trifluoroacetic anhydride (9.8 g) in dichloromethane (20 ml) were added at a rate of gentle reflux. After the reaction solution was added dropwise and stirred at room temperature for 2 hours, the precipitated crystals were separated and washed with chloroform, and the organic layer was washed with aqueous sodium bicarbonate and water, and then dried. The solvent was distilled off and the desired diacetoxy compound (1.48
g) was obtained as an oil.

IRν ^film _nax cm ^-1 : 1740, 1440, 1370, 1240, 11
60,
1070, 1020 NMR (CCl ₄ ) δ: 4.7-5.3 (2H, m), 3.6 (6H,
s), 2.0 (6H, s) Reference example 5 2,4-α・α-dihydroxy-5-β-carboxymethyl-cyclopentanyl-α-acetic acid
γ-Lactone 1,4-α,α-diacetoxy-2-carbomethoxymethyl-3-β obtained by the method of Reference Example 4
-carbomethoxymethyl-cyclopentane (300
mg) in concentrated hydrochloric acid (2.0 ml) for 2 hours, then
The water was distilled off under reduced pressure, and the resulting residue was extracted with ether to obtain the crystalline target product (160 mg).

IRν ^nujol _nax cm ^-1 : 1780, 1710, 1420, 1200,
1080,
1040 Reference example 6 α-α-hydroxy-4-α-acetoxy-5
-β-carboxymethyl-cyclopentanyl-
α-acetic acid γ-lactone 2,4-α,α-dihydroxy-5-β-carboxymethyl-cyclopentanyl-α-acetic acid γ-lactone obtained by the method of Reference Example 5 (100 mg)
After stirring the mixture with acetic anhydride overnight, excess acetic anhydride and the acetic acid produced were distilled off under reduced pressure, and the desired carboxylic acid (105 mg) was obtained as crystals with a temperature of 108 to 110°C from the resulting residue.

IRν ^nujol _nax (cm ^-1 ): 1770, 1740, 1710, 14
40,
1340, 1230, 1180, 1040 Reference example 7 2-α-hydroxy-4-α-acetoxy-5
-β-(2'-hydroxy-ethyl)-cyclopentanyl-α-acetic acid γ-lactone 2-α-hydroxy-4-α-acetoxy-5-β-carboxymethyl-cyclo obtained by the method of Reference Example 6 After stirring pentanyl-α-acetic acid γ-lactone (50 mg) in tetrahydrofuran containing excess diborane at 0 to -10°C for 1 hour, the excess diborane was consumed with acetone, and the solvent was distilled off under reduced pressure. Chloroform and saturated ammonium chloride water were added to the residue to extract the target product. By distilling off the solvent,
The desired alcohol (45 mg) was obtained as an oil.

IRν ^film _nax cm ^-1 : 3450, 1770, 1730, 1360, 12
40,
1160, 1020 NMR ( _CDl3 ) δ: 4.8-5.2 (2H, m), 3.7 (2H,
t), 2.0 (3H, s) Reference example 8 2-α-hydroxy-4-α-acetoxy-5
-β-(4-oxo-2-trans-nonenyl)-cyclopentanyl-α-acetic acid γ-lactone The alcohol derivative (50 mg) obtained by the method of Reference Example 7 was diluted with chromic acid-pyridine in dichloromethane (10 ml). After oxidation, ether is added to remove the precipitated crystals, and the resulting liquid is concentrated to obtain the desired 2-α
-Hydroxy-4-α-acetoxy-5-β-formylmethyl-cyclopentanyl-α-acetic acid γ
- The lactone was obtained as an oil. Dimethyl separately
The above aldehyde compound was added at room temperature to a dimethoxyethane solution containing a reagent prepared from 2-oxoheptyl phosphonate and 50% sodium hydride, and the mixture was stirred for 2 hours. After neutralizing by adding a small amount of acetic acid, the solvent was distilled off, the desired enone was extracted with ether, and the oil obtained after distilling off the ether solvent was subjected to silica gel chromatography to obtain the desired product (65 mg).

IRν ^film _nax cm ^-1 : 1770, 1730, 1700, 1660, 16
20,
1460, 1360, 1220, 1040 Reference example 9 2-α-hydroxy-4-α-acetoxy-5
-β-(4-hydroxy-2-trans-nonenyl)-cyclopentanyl-α-acetic acid γ-lactone The enone form (50 mg) obtained by the method of Reference Example 8 was added to sodium borohydride in anhydrous methanol under ice cooling. After consuming the excess reagent with acetone, the solvent was distilled off, ether and saturated ammonium chloride water were added to the resulting residue, and the target product was extracted with ether. The ether layer was washed with water, dried, and the solvent was distilled off.
The desired alcohol (45 mg) was obtained as an oil.

IRν ^film _nax cm ^-1 : 3500, 1770, 1730, 1190, 11
30,
1080 Reference example 10 2-α-hydroxy-4-α-hydroxy-5
-β-(4-hydroxy-2-trans-nonenyl)-cyclopentanyl-α-acetic acid γ-lactone The 4-α-acetoxy compound (150 mg) obtained by the method of Reference Example 9 was dissolved in methanol (3 ml). Potassium carbonate (50 mg) was added and stirred at room temperature for 1 hour.

The reaction mixture was neutralized with 1N hydrochloric acid, methanol was distilled off under reduced pressure, and the desired product was extracted with ethyl acetate.
The extract was washed with brine and then dried. The oily substance obtained by distilling off the solvent was subjected to silica gel column chromatography, and benzene-ethyl acetate (1:
The target diol lactone (112 mg) was obtained as an oil from the elution portion of 3).

IRν ^film _nax (cm ^-1 ): 3400, 3060, 2950, 2850
,
1770, 1460, 1380, 1340, 1260, 1180 Reference example 11 2-α-hydroxy-4-α-tetrahydropyranyloxy-5-β-(4-tetrahydropyranyloxy-2-trans-nonenyl)-cyclopenta Nyl-α-acetic acid γ-lactone Diol compound obtained by the method of Reference Example 10 (110
mg) was dissolved in dichloromethane (2 ml), and the solution was reacted with dihydropyran (50 mg) and p-toluenesulfonic acid (10 mg) at room temperature for 30 minutes.

The reaction mixture was neutralized with an aqueous sodium bicarbonate solution, diluted with ethyl acetate, washed with water and an aqueous sodium chloride solution, and concentrated under reduced pressure to obtain the desired tetrahydropyranyl compound (113 mg).

IRν ^film _nax (cm ^-1 ): 2950, 1775, 1490 Reference example 12 9α-hydroxy-11α-16-bis(tetrahydropyranyloxy)-20-methyl-5-cis-14-trans-prostodienoic acid methyl ester The tetrahydropyranyl compound (100 mg) obtained by the method of Reference Example 11 was dissolved in anhydrous toluene (5 ml), and 15% diisobutylaluminum hydride (3 ml of toluene solution) was added dropwise at -70°C. After stirring at the same temperature for 30 minutes, methanol was slowly added dropwise until no gas was generated. The temperature of the reaction mixture was raised to 0°C, water (1 ml) was added, and the mixture was stirred for 30 minutes. The mixture was filtered to remove precipitated aluminum hydroxide, the solution was separated into layers, and the organic layer was washed with brine and dried over magnesium sulfate.
The solvent was distilled off to obtain oily hemiacetal (93 mg).

Sodium hydroxide (50%, 96 mg) was added to dimethyl sulfoxide (10 ml) and heated at 70-75°C for 1 hour to prepare sodium methylsulfinyl methylide. -n
-A solution of butyl triphenylphosphonium bromide (443 mg) in dimethyl sulfoxide (5 ml) was added. After stirring for 5 minutes, a solution of hemiacetal in dimethyl sulfoxide (2 ml) obtained above was added, and the mixture was stirred at room temperature for 3 hours.

Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, the resulting aqueous layer was adjusted to pH 1 with diluted hydrochloric acid, and the desired product was extracted with ethyl acetate.

The oil obtained by distilling off the solvent was dissolved in a small amount of tetrahydrofuran, and an ether solution containing diazomethane was added to methyl esterify it. The oil obtained after evaporating the solvent was subjected to silica gel column chromatography to obtain the desired title compound (98 mg).

IRν ^film _nax (cm ^-1 ): 3350, 2930, 1735, 1280 Example 1 9-oxo-11α-16-dihydroxy-20-
Methyl-5-cis-14-trans-prostodienoic acid methyl ester 9α-hydroxy obtained by the method of Reference Example 12
11α-16-bis(tetrahydropyranyloxy)
-20-Methyl-5-cis-14-trans-prostodienoic acid methyl ester (95 mg) was dissolved in dichloromethane, added to a dichloromethane solution containing two equivalents of Collins reagent, and stirred at room temperature for 10 minutes. After adding anhydrous ether and removing the precipitated chromic acid using diatomaceous earth, the crude 9-oxo-11α-16-bis-
(tetrahydropyranyloxy)-20-methyl-5
-cis-14-tetrans-prostadienoic acid methyl ester (88 mg) was obtained.

IRν ^film _nax (cm ^-1 ): 3450, 2950, 1740, 1280 The above compound was dissolved in a mixture (10 ml) of acetic acid:tetrahydrofuran:water (65:10:35) and stirred at 45°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. After washing with brine and evaporating the solvent, the obtained oil was subjected to silica gel column chromatography to obtain the desired title compound.

IRν ^film _nax (cm ^-1 ): 3450, 2995, 2950, 1740
,
1730, 1480, 1380, 1250

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ represents a hydrogen atom or a lower alkyl group, and R ₂ represents a lower alkyl group having 4 to 8 carbon atoms. ] A novel cyclopentane derivative represented by