CS229926B2 - Production method of cyclopenthane derivative - Google Patents

Description

The invention relates to a process for the preparation of novel chiral compounds which can be used, in particular, as intermediates for the preparation of prostaglandin derivatives and in particular for the preparation of the 11-hydroxy-13-oxaprostaglandin derivatives described in Patent No. 229 917.

Said novel chiral compounds are cyclopentene derivatives of formula (I)

in which

R is a hydroxyl protecting group of the formula -CH ² R ¹ , wherein R ¹ is a phenyl group optionally substituted with methyl, or a benzyl group optionally substituted in the aromatic moiety with methyl;

A is CH 2 / or a

\ ^s ~ l

Benzyl groups are preferably used as substituents.

In particular, the following compounds are preferred within the scope of Formula I:

2-formylpropyleneacetal 4 (R) -benzyloxy-2-cyclopentenone ethylenedithioacetal, hereinafter referred to as "Synthon A" and 1-formylpropyleneacetal-3 (R) -benzyloxy-1-cyclopentene, hereinafter referred to as "Synthon B".

The process for preparing synthons A and B involves a number of original synthetic steps using (3R, RS, 5R) -3,4,0-cyclohexylidene-3,4,5-trihydroxycyclohexanone as starting material. The latter compound can be obtained from quinic acid by the method described by Cleofax, Leboul, Gero, Akhar, Barnett, and Pearce in J. Amer. Chem. Soc. 98, 7110 (1976).

The preparation of the cyclopentenone reductants of general formula (I) by the process according to the invention is characterized in that the cyclopentenone derivative of general formula (II)

229928

RO (II) wherein A and R are as defined above, is treated with 1,3-propanediol at room temperature to 40 ° C in the presence of p-toluenesulfonic acid, the reaction being carried out in an anhydrous solvent.

Benzene or toluene is preferably used as the anhydrous solvent.

The process for preparing the chiral intermediate compounds of formula I is summarized in the following detailed description.

Preparation of synthon

a] Reaction of (3R, 4S, 5R) -3,4-O-cyclohexylidene-3,4,5-trihydroxycyclohexanone of formula II

with ethanedithiol in the presence of boron trifluoride etherate at room temperature, in an aprotic solvent such as benzene, toluene, chloroform or dichloromethane, gives (3R, 4S, 5R) -3,4,5-trihydroxycyclohexanoneethylenedithioacetal of formula III

a solvent, for example N, N-dimethylformamide, yields the (3R, 4S, 5R) -3,4,0-cyclohexylidene-3,4,5-trihydroxycyclohexanone ethylenedithioacetal of formula IV

c) The free hydroxyl group of the latter compound is protected by reacting a compound of formula IV with a bromide of the formula R-Br, in which R is as defined above and preferably denotes a benzyl group, in the presence of an alkali metal hydride e.g. sodium hydride, preferably at 0 ° C and in an aprotic solvent such as N, N-dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide, to give the (3R, 4S, 5R) -3,4-O-cyclohexelidene-3 derivative, 4,5-trihydroxycyclohexanone-

wherein R ¹ is as defined above; said compound can be used in the next reaction step either after isolation from the reaction mixture or without isolation.

d) Treatment of a strong inorganic acid such as hydrochloric acid with the latter ether of formula V in an alcohol such as methanol, ethanol or isopropyl alcohol at the boiling point of the solvent used yields the (3R, 4S, 5R) -3,4,5 derivative - trihydroxycyclohexanone ethylenedithloacetal of formula VI (III)

b) Condensation of dithioacetal of formula III with 1,1-dimethoxycyclohexane in the presence of an acid catalyst such as sulfuric acid or p-toluenesulfonic acid at room temperature and in an aprotic environment

wherein R ¹ is as defined above.

e) Oxidation of the diol of formula VI with neutral lead acetate or triphenyl isismic carbonate in a suitable solvent, for example toluene, at room temperature yields a 4-oxoethylenedithioacetalhexanediol derivative of formula VII

§

B. Preparation of synthon B

(a) Treatment of the above diols of the formula VI with boiling in a suitable solvent, for example ethanol, by treatment of Raney nickel (finely divided nickel catalyst obtained by dissolving the aluminum contained in a nickel-aluminum alloy in a solution of an alkali metal hydroxide) affords derivatives (1R, 2S, 3R, -1,2,3-trihydroxycyclohexane of formula X

wherein R ¹ is as defined above.

f) Cyclization of an acyclic dialdehyde of formula VII in situ, under an inert atmosphere, by treatment with pyrrolidine acetate or piperidine acetate in a suitable solvent such as benzene or toluene, at a temperature ranging from -10 ° C to room temperature, preferably 0 ° C a 2-formyl-2-cyclopentenone-ethylenedithioacetal derivative of the general Formula VIII

O

ΡιΓΐ ^CH0 (VIU) wherein R ¹ is as defined above.

Reaction of an aldehyde of formula VIII with 1,3-propanediol at room temperature and in the presence of p-toluenesulfonic acid in an anhydrous solvent such as benzene or toluene affords a 2-formylpropylene acetal-2-cyclopentenone ethylenedithioacetal derivative of formula IX

wherein R ¹ is as defined above, or synthon A.

wherein R ¹ is as defined above, bj Oxidation of the diols of formula X with neutral lead acetate or triphenylvismuth carbonate in a suitable anhydrous solvent, for example chloroform, at room temperature yields the hexanediol derivatives of formula XI

wherein R ¹ is as defined above.

The cyclization of the acyclic dialdehydes of formula XI in situ, under an inert gas atmosphere, by treatment with pyrrolidine acetate or piperidine acetate in a suitable solvent, for example toluene, at a temperature ranging from -10 ° C to room temperature, preferably 0 ° C, yields 1-formyl-1-cyclopentene derivative of general formula XII

... Qt ^{cho 0Cw} txiu I ^R wherein R ¹ is as defined above.

d) Reaction of an aldehyde of formula XII with 1,3-propahdiol at room temperature ranging from room temperature to +40 ° C, for example at 30 ° C, in the presence of p-toluenesulfonic acid and in an anhydrous solvent such as benzene or toluene, yielding a 1-formylpropyleneacetyl-1-cyclonentene derivative of general formula XIII

wherein R ¹ is as defined above, or synthon B.

The process according to the invention is illustrated in more detail by the following non-limiting examples.

Example 1

2-Formylpropyleneacetal-4 (R) -benzyloxy-2-cyclopentanone-ethylenedithioacetal or synthon A [compound of formula IX wherein R ¹ is phenyl] and (3R, 4S, 5R) -3,4,5-Trihydroxycyclohexanone-ethylenedithioacetal (compound of formula III)

To a solution of 8 g of (3R, 4S, 5R) -3,4-O-cyclohexylidene-3,4,5-trihydroxycyclohexanone [compound of formula II] in 40 ml of anhydrous chloroform is added 16 ml of ethanediol and

1.6 ml of freshly distilled boron trifluoride etherate. After stirring at room temperature for one hour, the starting material is no longer present in the reaction mixture (as determined by thin-layer chromatography in chloroform-ethyl ether 3: 1). The desired compound of formula III which is eliminated from the reaction medium is dissolved by adding methanol. The solid residue is dissolved in hot acetone and the insoluble salts are filtered off to give a compound of the formula after recrystallization from acetone.

III in 95% yield. Melting point 129-130 ° C, optical rotation [α] _D = -41 ° (in methanol, c = 1.4% w / v).

b j (3R, 4S, 5R) -3,4-O-Cyclohexylidene-3,4,5-trihydroxycyclohexanone ethylenedioacetal (compound of formula IV)

To a solution of 7 g of the compound of formula (III) obtained above in 30 ml of N, N-dimethylformamide was added 8 ml of 1,1-dimethoxycyclohexane and 0.5 ml of concentrated sulfuric acid, and the mixture was allowed to stand at room temperature with occasional distillation. methanol in a water pump vacuum to facilitate the equilibrium shift leading to the desired compound of formula IX. The progress of the reaction was monitored by thin layer chromatography in a 3: 1 chloroform-ethyl ether solvent system. After 2 days the reaction was complete; the solution was diluted with dichloromethane and the mixture was neutralized with sodium bicarbonate. Insoluble materials are filtered off, the organic phase is washed with water, dried over sodium sulphate and the solvents are distilled off under reduced pressure. Recrystallization of the residue from petroleum ether gave the compound of formula

IV in 95% yield; mp 138-140 ° C, t "] _D = -44 ° (chloroform, c = 1.02% wt./vol.).

¹³ C NMR Spectrum:

no. C 1 2

4 5

7 8

S (ppm) 62.97 46.46 73.76 79.67 71.55 41.59 40.16 25.02 no. C 9 10 11 12 13 14 S (ppm) 23.72 34.04 35.35 110.09 38.01 38.21

(c) (3R, 4S, 5R, -3,4,0-Cyclohexylidene-5-O-benzyl-3,4,5-trihydroxycyclohexanone ethylenedioacetal (compound of formula V wherein R ¹ is phenyl))

0.845 g of sodium hydride and 47 ml of Ν, Ν-dimethylformamide are added to a three-necked flask at 0 ° C under a nitrogen atmosphere. 9 g of the compound of formula IV are then added and after dissolution of 3.6 ml (1.3 equivalents) of benzyl bromide. The reaction mixture turned orange-yellow. The progress of the reaction was monitored by thin-layer chromatography (chloroform-ethyl ether 3: 1). After 3 hours the reaction was complete; the excess hydride is quenched by the addition of methanol, then the reaction mixture is poured into ice water and the product is taken up in dichloromethane. The organic extract was washed with water and dried over sodium sulfate; distillation of the solvents gave a yellow oily residue which, after recrystallization from aqueous ethanol, gave no compound of formula V. Yield 95%; mp 68-69 ° C, [α] D = -50 ° (in chloroform, c = 1.06% w / v).

Elementary analysis:

For C21H23O3S2 (392.587) calculated:

64.25% C, 7.19% H, 16.34% S;

found *

H, 6.96; H, 16.52.

229920

d) (3R, 4S, 5Rj-5-O-Benzy 1-3,4,5-trihydroxycyclohexanone ethylenedio-thioacetal (compound of formula VI wherein R ¹ is phenyl))

The following reaction is carried out directly with the crude compound of formula V (yellow oil) obtained as described above.

12 g of crude compound of formula V are dissolved in 120 ml of methanol, 10 ml of 12N hydrochloric acid are added to the solution and the mixture is heated to 70 ° C; the progress of the reaction was monitored by thin layer chromatography (chloroform-ethyl ether 3: 1 solvent system). After complete hydrolysis, the reaction mixture was diluted with dichloromethane and neutralized with sodium bicarbonate. Insoluble ¹³ C NMR spectrum:

no. C 12 3 4

Δ (ppmj 65.4 40.2 69.2 72.3

e) 2 (R) -Benzyloxy-4-oxoethylenedithioacetalhexanedial (a compound of formula VII wherein R ¹ is phenyl).

1.33 g (3 mmol) of lead acetate are added to the colored flask and the substance is dried on an oil rotary pump until it is free of any acetic acid residue. At the end of this operation, 100 ml of anhydrous toluene and 0.642 g (2 mmol) of the compound of formula VI, prepared as described above, were added. The reaction mixture was stirred at room temperature and monitored by thin layer chromatography (3: 1 chloroform-ethyl ether). After one and a half hours, the reaction is complete and 3 ml of ethylene glycol are added to the mixture to remove excess lead acetate. When the excess reagent is decomposed, the solution becomes clear. The reaction mixture is diluted with dichloromethane, the organic portion is washed once with water, then with saturated sodium bicarbonate solution and then with water until neutral. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. In this way, the desired compound of formula (VII) is obtained in quantitative yield as a colorless oil which turns yellow in time, so that it must be worked up immediately after preparation. Optical [α] _D = -11 ° (in chloroform, c = 2.4% w / v).

Since this compound is particularly unstable, it was reduced to 2 (R 1 -benzyloxy-4-oxoethylenedithioacetalhexanediol for characterization purposes).

the aliquots were filtered off and the solvents were distilled off. The residue was taken up in dichloromethane, the organic portion was washed with water, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated. Recrystallization of the residue from ethanol or ethyl acetate gave the desired compound of formula VI. Yield 88%; mp 135-136 ° C, [a] _D = -72 ³ (in choloroformu, c = 1.03% lim. obj.j.

Elementary analysis:

For C 15 H 20 O 3 S 2 (mol. Wt. 312.457) calculated:

C 47.66, H 6.45, S 20.53;

. found:

% C, 57.65;% H, 6.53;% S, 20.23.

6 7 8 9

79.3 46.4 38.2 39.5 71.4

Elemental analysis of diol:

For C 15 H 22 O 3 S 2 (mol. Wt. 314.473) calculated:

H, 7.05; S, 20.39;

found:

% H, 6.47;% S, 20.18.

Optical rotation of the diol [α] _D - 20 ° (in chloroform, c = 1.4% w / v).

fj 2-Formyl-4 (R) -benzyloxy-2-cyclopentenone-ethylenedithioacetal (a compound of formula VIII wherein R ¹ is a phenyl group)

0.620 g of crude compound of formula VI is dissolved in 20 ml of anhydrous toluene at 0 ° C under a nitrogen atmosphere. prepared as above and 0.5 ml of a 1 N solution of pyrrolidine acetate in anhydrous benzene are added to the solution. The reaction mixture was allowed to stand for 18 hours at 0 ° C under nitrogen atmosphere; after this time, the starting compound disappears completely (as shown by thin layer chromatography in chloroform-ethyl ether 3: 1). The reaction mixture is diluted with dichloromethane, the organic phase is washed with water until neutral, dried over anhydrous sodium sulfate, filtered and the solvent is distilled off.

Above procedure yields the desired compound of formula VIII as a light yellow oil which is kept at a temperature appropriate to 0 C in ^three colored bottle. Yield 95%.

¹ H NMR spectrum (60 MHz):

5 (ppm) position H 2.7 2 H (5) (A-B octuplet system) 3.45 2H ( ₇₎ + 2H (7-) (multiplet) 4.4 CH2- (phenyl) (singlet) 4.7 H (5) (sextuplet) 6.65 H (3) (doublet) 7.2 phenyl 9.5 H ( ₆ , (singlet)).

IR spectrum in chloroform:

1685-1705 cm ^{@ -1} (unsaturated .alpha.) - (aldehyde).

Mass spectrum (electron impact):

M @ ⁺ = 292 (201, 186, 91, 77, 65).

g) 2-Formylpropyleneacetal-4 (R) -benzyloxy-2-cyclopentenone-ethylenedithioacetal or synthon A (a compound of formula IX wherein R ¹ is a phenyl group)

The reaction is carried out directly with the unsaturated α, β-aldehyde obtained by the foregoing process.

In 50 ml of anhydrous toluene, 0.550 g of the compound of formula VIII obtained as described above was dissolved, and 1.5 ml of 1,3-propanediol was added along with a trace of p-toluenesulfonic acid. The mixture was allowed to react for 24 hours and then volume was rotary evaporated. In order to shift the equilibrium in favor of the desired compound, 1.5 ml of 1.3 ¹³ C NMR spectrum are then added again:

no. C: 1 2 3 4 5 δ (ppm): *) 146.3 131.6 80.3 53.8

*) not identified in the spectrum (quaternary carbon)

Elementary analysis:

For C18H22O5S2 (mol. Wt. 350,506)

propanediol and 50 ml of anhydrous toluene. The reaction mixture is allowed to stand for 24 hours and then the operation is repeated. After a total of 72 hours, the reaction is almost complete (determined by thin layer chromatography in an ethyl acetate-petroleum ether 3: 7 solvent system), with some starting aldehyde (5-10%) remaining in the reaction mixture. The solution was diluted with dichloromethane, neutralized with sodium bicarbonate, the precipitated salts were filtered off and the organic portion was washed with water and dried over sodium sulfate. After filtration, the solvent was distilled and the product obtained is separated by preparative thin layer chromatography in the system rozpoušíědlové acetate-petroleum ether 3: 7. A strip material of a lower value of R _F was eluted with ethyl acetate to the filtrate, after evaporation of the solvent gives the product as colorless oil. Recrystallization of the crude material from petroleum ether gave the desired compound of formula IX or synthon A in 80% yield; mp 70-71 ° C, [α] _D = + 86 ° (chloroform, c = 1.12% w / v);

6 ‘7 8 8‘ 9 10

41.3 40.5 97.3 calculated:

% C, 61.68;% H, 6.32;

found:

% C, 61.44;% H, 6.28;% S, 18.37.

1 H NMR spectrum (at 250 MHz, in CHCl 3):

(PPm) position H 7.34 phenyl 6.34 H (3) J (H, _{3) -} (H) = 2 Hz 5.25 H, 7) 4.65 H (4) 4.55 CH2- (phenyl) 4.22 H (8a) 4 “H ( _8aJ ') 3.9 H (ge) + H (ge ') 3.4 2H ₍₆₎ -4- 2H ₍₆ ), (J, 5b ₎ -H (5a ₎ ) = 13.5 Hz 2.95 H, _5b , { 1j (H _<5b) —H ₍₄₎ ) = 6.5 Hz J (H (5b) - H (5a)) = 13.5Hz 2.6 H (5a) J (H (5a) - H (4)) = 5Hz 2.2 H (9a) 1.4 H (9e) ·

Example 2 1-Formylpropyleneacetal-3 (R) -benzyloxy-1-cyclopentenone or synthon B (compound of formula XIII wherein R ¹ is phenyl)

(a) (1R, 2S, 3R) -3-O-Benzyl-1,2,3-trihydroxycyclohexane (compound of formula X wherein R ¹ is phenyl)

1.3 g of the compound of formula VI obtained in the manner described in Example 1d are dissolved in 80 ml of 95% ethanol. After complete dissolution of the substance, a sufficient excess of Raney nickel is added to the solution and the mixture is refluxed for 12 hours. The reaction mixture was filtered through Celite and the Raney nickel was washed thoroughly with ethanol. The solvent was evaporated from the filtrate, the oily residue was taken up in chloroform and the solution was filtered through Whatmann filter paper. After distilling off the chloroform, the product is recrystallized from petroleum ether.

59-60 ° C (from petroleum ether), [α] D = + 83 ° (in chloroform, c = 1.3% w / v).

Elementary analysis:

For C 13 H 18 O 3 (mol. Wt. 222.289) calculated:

% C, 70.24;% H, 8.16;

found:

% C, 70.12;% H, 8.11.

Mass Spectrum: M ⁺ - 222.

b) 2 (R) -Benzyloxyhexanedial (a compound of formula XI wherein R ¹ is a phenyl group)

To a solution of 2.34 g of the compound of formula (X) obtained above in 120 ml of anhydrous chloroform was added 5.7 g of lead acetate in small portions. The reaction mixture was allowed to stand under exclusion of light and the progress of the reaction was monitored by thin layer chromatography in the ethyl acetate-petroleum ether solvent system. After ninety minutes the reaction was stopped and the excess lead acetate was quenched by addition of ethylene glycol. When the solution becomes clear, it is diluted with dichloromethane and washed with water, sodium bicarbonate solution and again with water, the organic portion is dried over sodium sulfate and the solvents are distilled off.

In this way the desired compound of formula XI is obtained, which is used directly in the next step without further purification.

³ H NMR spectrum of two aldehyde protons at 60 MHz:

9.6 ppm.

IR spectrum:

CHO group at 1720 cm ^-1 .

c) 1-Formyl-3 (R) -benzyloxy-1-cyclopentene (a compound of formula XII wherein R ¹ is phenyl)

The compound of formula XI obtained above is dissolved in 100 ml of dry toluene and 1 ml of a 2 N solution of pyrrolidineacetate in benzene is added at 0 ° C under nitrogen. The reaction mixture was allowed to stand for about 8 hours at 0 ° C and then poured into ice water. The product was taken up in dichloromethane, the organic difference was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The .alpha.,. Beta.-unsaturated aldehyde obtained in this way forms a clear yellow colored oily liquid, which is relatively unstable and which is used directly, without further purification, in the next reaction step.

There was thus obtained the desired compound of formula XII.

1 H NMR (at 60 MHz):

(ppm) position H

9.8 aldehyde group

7.3 phenyl

6.8 —CH.

IR spectrum:

α, β-unsaturated CHO 1680 to 1710 cm ^-1 .

d) 1-Formylpropyleneacetal-3 (R) -benzyloxy-1-cyclopentene or synthon B (a compound of formula XIII wherein R ¹ is a phenyl group)

To a solution of the compound of formula XI obtained previously as described in 100 ml of anhydrous toluene is added 10 ml of 1,3-propanediol and a trace of p-toluenesulfonic acid. The mixture was stirred for one hour at 30 ° C on a rotary evaporator and then for another 24 hours with a mechanical stirrer. After completion of the reaction, the reaction mixture was diluted with dichloromethane and neutralized with sodium bicarbonate.

The mixture was stirred at room temperature for 30 minutes, then filtered and washed with dichloromethane. The organic filtrate was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained dark colored oily residue was purified by preparative thin layer chromatography using 1: 2 ethyl acetate-petroleum ether solvent system.

In this way the desired compound of formula XIII or synthon B is obtained in the form of a colorless oil.

Yield 55% (calculated from compound X). Optical rotation [α] _D = + 74 ° (in chloroform, c - 1.4% w / v).

Elementary analysis:

For C 16 H 20 O 3 (mol. Wt. 260.333) calculated:

% C, 73.81;% H, 7.74; found:

% C, 73.81;% H, 7.71.

Mass Spectrum: M @ ⁺ = 260.

Claims (3)

Process for the preparation of cyclopentenone derivatives of the general formula I, characterized in that the cyclopentenone derivative of the general formula II RO in which R is a hydroxyl protecting group of the formula -CH ² R ¹ , wherein R ¹ is a phenyl group optionally substituted by methyl, or a benzyl group optionally substituted in the aromatic moiety by methyl, and A stands for \ CH2 Z or wherein A and R are as defined above, is treated with 1,3-propanediol at room temperature to 40 ° C in the presence of p-toluenesulfonic acid, the reaction being carried out in an anhydrous solvent. 2. A process according to claim 1 wherein the anhydrous solvent is benzene or toluene. 3. The method according to claim 1 for the production of the cyclopentene derivative of the above formula I wherein R represents a group of formula -CH 2 R ¹ wherein R ¹ is a phenyl group and A is as defined above, characterized in that the cyclopentenone derivative of the above wherein R is --CH2 R @ ¹ , wherein R @ ¹ is phenyl and A is as defined above with 1,3-propanediol.