CS229944B2 - Processing method of cyclopentane derivative - Google Patents

Description

The invention relates to a process for the production 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 Czechoslovak patent no. 229 917.

Said novel chiral compounds are cyclopentane derivatives and can be represented by formula (I)

in which

R represents a hydroxyl protecting group of the formula -CH ² R ¹ , wherein R ¹ represents a phenyl group optionally substituted by a methyl group, or a benzyl radical optionally substituted in the aromatic ring by a methyl group.

As a substituent R, benzyl groups are preferably used.

A preferred compound included within the scope of Formula I is 2-formylpropyleneacetal-4 (R 1 -benzyloxy-2-cyclopentenol, hereinafter referred to as synthon).

The preparation of the cyclopentane derivatives of the general formula (I) by the process according to the invention consists in that the compound of the general formula II is

in which

R is as defined above, treated with diisobutylaluminum hydride in a suitable anhydrous solvent at a temperature in the range of -10 ° C to room temperature to provide the desired cyclopentane derivatives of formula I.

Preferably benzene or toluene is used as solvent.

The process for the preparation of synthon comprises a number of original synthetic steps using (3R, 4S, 5R; β 3,4,4-O-cyclohexylidene-3,4,5-trihydroxycyclohexanone as starting material). Cleophax, Leboul, Gero, Akhtar, Barnett, and Pearce in J. Amer. Cheri). SOC. 98, 7110 (1976).

The process for the preparation of the chiral intermediate compounds of the formula I according to the invention can be summarized as follows:

A. Synthon Preparation

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

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

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

OH

b] Reaction of the 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 w from an aprotic solvent such as N, N -dimethylformamide yields C (3R, 4S, 5R) } -3,4-O-Cyclohexylidene-3,4,5-trihydroxycyclohexanone

in which

R ¹ has the abovementioned meaning; 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 affords the (3R, 4S, 5R) -3,4,5 derivative a trihydroxycyclohexanone ethylenedithioacetal of formula VI

in which

R ¹ has the abovementioned meaning,

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 4-oxoethylenedithioacetalhexanediol derivatives of formula VII

in which

R ¹ has the meaning given above, f) cyclizing the acyclic dialdehyde of Formula VII in situ, in an inert atmosphere or by treatment pyrrolidineacetate of piperidine in a suitable solvent such as benzene or toluene at a temperature ranging from -10 ° C to room temperature, preferably at 0 ° C, 2-formyl-2-cyclopentanone ethylenedithioacetal derivatives of formula VIII are obtained

in which

R ¹ is as defined above, g) Treatment of an aldehyde with 1,3-propanediol at room temperature in the presence of p-toluenesulfonic acid in an anhydrous solvent such as benzene or toluene affords 2-formylpropylene acetal-2-cyclopentanone ethylenedithioacetal derivatives of the general formula IX

in which

R ¹ has the above meaning.

hj Reaction of an ethylenedithioacetal derivative with neutral diphenylsulfonic dioxide at room temperature and in a suitable solvent, for example dichloromethane, affords 2-formylpropyleneacetal-2-cyclopentanone derivatives of formula X

in which

R ¹ has a constant T yynam.

i) Reaction of a compound of formula X with diisobutylaluminum hydride in a suitable anhydrous solvent, for example benzene or toluene, at a temperature ranging from -10 ° C to room temperature, preferably 0 ° C, yields 2-formylpropylene acetal-2-cyclopentanol derivatives of formula XI

OH

OCH ^ (XI) in which

R ¹ has the above meaning.

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

Example 1

Preparation of 2-f ormylpropylenacetal-4 (R) -benzyloxy-2-cyclopentanol or synthon (compound of formula XI, in which R ¹ represents a phenyl group).

a) (3R, 4S, 5R) -3,4,5-trihydroxycyclohexanone ethylenedioacetal (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 ethanedithiol

1.6 ml of freshly distilled boron trifluoride etherate. After stirring at room temperature for one hour, the starting material was no longer present in the reaction mixture (as determined by thin layer chromatography) in a 3: 1 chloroform-ethyl ether system). The desired compound of formula III, which is eliminated from the reaction medium, is dissolved by the addition of methanol, the solution is basified with sodium bicarbonate, filtered and the solvents are distilled off. The solid residue obtained is redissolved in hot acetone and the insoluble salts are filtered off. In this way, after recrystallization from acetone, the compound of formula III is obtained in a yield of 95%. 129 DEG-130 DEG C., optical rotation [.alpha.] _D = -41 DEG (in methanol, c = 1.4.

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

8 ml of 1,1-dimethoxycyclohexane and 0.5 ml of concentrated sulfuric acid are added to a solution of 7 g of the compound of formula III obtained above in 30 ml of N, N-dimethylformamide and the mixture is allowed to stand at room temperature with occasional distillation in the reaction. the evolving methanol in the water pump vacuum to facilitate the equilibrium shift; leading to the desired compound of formula IX. Progress; the reaction was monitored by thin layer chromatography in 3: 1 chloroform-ethyl ester solvent system. After 2 days, the reaction is complete, the solution is diluted with dichloromethane, and the mixture is 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, m.p. 138-140 ° C, [α] _D equals -44 ° (in chloroform, c = 1.02% him / v). .

¹³ C NMR Spectrum: no. CA (ppm) - 62.97

- 46.46, - 73.76, - 79.67,

- 71.55 - 41.59, ^- 40.16,

- 25.02, - 23.72, - 34.04,

- 35.35, - 110.09, - 38.01, - 38.21.

c) (3R, 4S, 5R) -3,4-O-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 nitrogen. 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 in a chloroform-ethyl ether 3: 1 solvent system. After 3 hours, the reaction is 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, and the solvents were distilled off to give a yellow oil which was recrystallized from aqueous ethanol to give the desired compound of formula V. Yield 95%. Mp 68-69 ° C, [α] _D = -50 ° (in chloroform, c = 1.06% w / v);

Elementary analysis:

for C21H28O3H2 (392.587) calculated:

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

% C, 64.15;% H, 6.96;% S, 16.52.

d) (3R, 4Sj5R) -5-O-benzyl-3,4,5-Trihydroxy-lohexanonethylendithioacetal (compound of formula VI wherein R ¹ represents a phenyl group), and

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 matter was 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. [α] _D equals —72 ”(in chloroform, c = 1.03 w / v).

Elementary analysis:

Calcd for C15H20O3S2 (mol% 312.457):

% C, 47.66;% H, 6.45;% S 20.53.

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

¹³ C NMR Spectrum: no. C - (ppm) - 65.4

- 40.2, - 69.2, - 72.3, - 79.3, - 46.4, - 38.2, - 39.5, - 71.4.

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

1.33 g (3 mmol) of lead acetate are added to the colored flask and dried to a residue of acetic acid. At the end of this operation, 100 ml of anhydrous toluene and 0.624 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 is 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 rotation [ _.alpha. ] _D = -11 DEG (in chloroform, ca. 2.4% w / v);

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

Elemental analysis of the diol for C 15 H 22 O 3 S 2 (mel. Wt. 314.473): calculated:

57.29% C, 7.05% H, 20.39% S, found:

% H, 6.47;% S, 20.18.

Optical rotation of the diol [[alpha]] _D = -20 [deg.] (In chloroform, c = 1.4 w / v).

f) 2-formyl-4 (R) -benzyloxy-2-cyclopentenone ethylenedithioacetal (compound of formula VIII wherein R ¹ is phenyl)

In 20 ml of dry toluene at 0 ^DEG C. under an atmosphere of nitrogen, dissolve 0.620 g of crude compound of formula VII prepared as described above and treated with 0.5 ml of 1N flowable pyrrolidineacetate in anhydrous benzene. The reaction mixture was allowed to stand for 18 hours at 0 ^° C under nitrogen, after which time the starting compound disappeared completely (as shown by TLC in 3: 1 chloroform-ethyl ether). 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.

In this way, the desired compound of formula VIII is obtained in the form of a light yellow colored gummy liquid, which is conveniently stored at 0 ° C in a color vial. Yield 95%.

1 H NMR Spectrum (60 MHz):

<S (ppm) - position H

2.7-2H (5) (A-B octuplet system)

3.45 - 2 H (7) + H (7 '> (multiplet)

4.4 - CH2 - (phenyl) (singlet)

4.7 - H ₍ 4) (sextupletj

6.65 - H ₃₎ (doublet)

7,2-phenyl

9.5 - H, ₆₎ (singlet).

IR (in chloroform):

1685 to 1705 cm ^-1 (unsaturated α, β-aldehyde).

Mass spectrum (electron impact: M @ ⁺ = 292 (201, 186, 91, 77, 65)).

g) 2-formylpropyleneacetal-4 (R) -benzyloxy-2-cyclopentenone ethylenedithioacetal (a compound of formula IX wherein R ¹ is phenyl)

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 is allowed to react for 24 hours and then 3/4 of the volume is rotary evaporated. 1.5 ml of 1,3-propanediol and 50 ml of anhydrous toluene are then added again to balance the favor of the desired compound. 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 (as determined by thin layer chromatography in a 3: 7 ethyl acetate-petroleum ether solvent system) leaving some starting aldehyde (5-10%) 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 sušidia solvent was distilled and the product obtained is separated by preparative thin layer chromatography in a solvent system petroleum ether-ethyl acetate 3: 7, strip material of the lower _Rf value 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 in a yield of 80%. Mp 70-71 ° C, [α] D = + 86 ° (chloroform, c = 1.12 w / v).

¹³ C NMR Spectrum: no. C - (ppm) - 146.3, - 131.6, - 80.3, - 53.8, - 41.3, - 40.5, - 97.3, - *) in the 8 'spectrum - unidentified - (quaternary 10-carbon).

Elemental analysis for C 18 H 22 O 3 S 2 (mol. Wt. 350.506): calculated:

% C, 61.68;% H, 8.32;% _S 18.29 ₎

% 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 ₍₃₁ J (H, _{3) -} H ₍₄₎ ) = 2 Hz 5.25 - H ₍₇₎

4.65 - H ₍₄₎

4.55 - CH ₂ - (phenyl)

4.22 - H _(8a) + H ( ₈ ' _a )

3.9 - H (g _e ) + H (g ' _e )

3.4-2H ₍₆₎ + 2H ₍₆ ', 1 (H, _5b) -H _(5a) ) = 13.5 Hz

J (H _(5b) -H ₍₄₎ ) = 6.5Hz J (H _(5b) -H _(5a) ) = 13.5Hz J (H _(5a ) - H ₍₄₎ j = 5Hz ^x (5b)

2.6 - H (5a)

H (9 _a )

H (9e).

2.2

1.4

f) 2-formylpropyleneacetal-4 (R) -benzyloxy-2-cyclopentenone (compound of formula X wherein R ¹ is phenyl)

To a solution of 0.180 g of the compound of formula IX, prepared as described above in 5 ml of anhydrous dichloromethane, was added 0.203 g (1.1 equivalents) of traces of nitric acid-free diphenylphosphoric oxide (PhzSezCb). Then one drop of propylene oxide is added for each 50 mg of starting compound to remove any likely nitric acid residues. The reaction mixture was allowed to stand for 20 hours and the reaction is monitored by thin layer chromatography (ethyl acetate-petroleum ether solvent system of 3: 7) at the times indicated the starting material disappeared and the resulting compound is a lower value of R _t.

The reaction mixture was diluted with a little dichloromethane, the solution is neutralized with sodium bicarbonate, filtered and the mixture is separated by thin layer preparative chromatography using a solvent system petroleum ether-EtOAc 3: 7. A strip containing material of lower Rf _{(UV detection at Lighten scraped, the substance was eluted ethyl acetate and the solvent was distilled off from the filtrate.

In this way the desired compound of formula X is obtained in the form of a colorless oil which crystallizes from petroleum ether. Yield 68%. Mp 42-43 ° C, [α] _D equals + 42 ° (in chloroform, c = 1% ham./vol.).

Elemental analysis for C 16 H 18 O 4 (mol. Wt. 274.316): calculated:

70.05% C, 6.61 «/ o H, found:

% C, 70.14;% H, 6.60.

¹ H NMR spectrum (at 250 MHz, in CHCl 3): δ (ppm) - position H

7.7 - H _"3)

7.3 - phenyl

5.3 - H ₍₆₎

4.7 - H ₍₃₎

4.6 - CH2- (phenyl) 4.18 - H <7 (a) + H ( ₇ 'a) 3.9 - H (7e) + H (7 > _e) J (H, _5b , - H (5a) = 18.5 Hz 2.75 - H _(5b) · J (H _(5b &gt;) -h ₍₃ ) = 6 Hz J (H (5b &gt;) ^- H ( _4a ) = 18.5 Hz 2.43 ~ H ₍₅ ?) 1j (H (5a)) -H ₍₃ ) = 2.5 Hz 2.5 H (8a) 1.35 - H (ge) · 2-formylpropyleneacetal-4 (R) -benzyl- oxy-2-cyclopentenol or synthon

(a compound of formula XI wherein R ¹ is a phenyl group)

To a solution of 2.44 g of the compound of formula (X) obtained above in 53 ml of anhydrous toluene was added dropwise at 0 ° C under nitrogen atmosphere 13.1 ml of dlisobutylaluminium hydride (commercial 1M solution in hexane). The progress of the reaction was monitored by thin layer chromatography in a 3: 1 chloroform / ethyl ether solvent system, after 30 minutes no starting material was present. The reaction was quenched by the slow addition of methanol at 0 ^° C, then the solution was poured into ice saturated aqueous sodium chloride and the product was taken up in dichloromethane. The organic portion was dried over anhydrous sodium sulfate and the solvents were distilled off. The oily residue is dissolved in a 3: 1 mixture of chloroform and ethyl ether, filtered through Celite (a trademark for commercially available diatomaceous earth) and the solvents are evaporated to dryness. The desired product is obtained from the residue by crystallization from a mixture of dichloromethane and petroleum ether. In the mother's meadow13

229344 ous with ^X H NMR spectra proved the presence of other substances, an isomer of the title compound.

In this way the desired compound of formula XI or synthon is obtained in a yield of 89%. Mp 88-90 ° C.

Elemental analysis for C 16 H 20 O 4 (mol. Wt. 276.336):

calculated:

69.54 «C, 7.2% H, found:

69.36% C, 7.30 ° C. Mass spectrum: M ⁺ = 276.

Claims (3)

PftEDMĚT OF THE INVENTION A process for the preparation of cyclopentene derivatives of the general 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 by a methyl group, or a benzyl radical optionally substituted in the aromatic ring by a methyl group, characterized in that R is as hereinbefore defined, acts in an anhydrous solvent at a temperature in the range of -10 ° C to room temperature to provide the desired cyclopentene derivatives of formula (I). 2. A process according to claim 1 wherein the solvent is benzene or toluene. 3. The method as under 1, characterized in that a compound of the formula II wherein R represents a group of formula -CH 2 R ¹ wherein R ¹ is phenyl, treated with diisobutyl aluminum hydride to give a compound of formula I wherein R is --CH2 R @ ¹ , wherein R @ ¹ is phenyl.