CS244710B1 - Production method of (5z,13e) -prostadiene acid derivatives - Google Patents

Abstract

Process for the production of (5Z, 13E) -propadiene derivatives acids of formula I wherein R is hydrogen or tetrahydrofuryl- or tetrahydropyranol- or alpha- -methoxybenzyl, A represents hydrogen when B is RO, wherein R is as defined above, B is hydrogen, when A is RO or A + B together is OCH 2 CH 2 O R 1 represents n-butyl or phenoxy, optionally substituted by general lactol reaction of formula Π, wherein R, R 1, A and B are as defined above meaning with the ylide of formula m (C6H5> 3P = CHCH2CH2CH2COOK UH) consists in using an ylide of formula m, prepared in tetrahydrofuran by treatment with 0.02 to 0.2 excess of the theoretical amount of tert-butanol of potassium in tetrahydrofuran solution at temperature 5 to 30 ° C, reacted in an inert atmosphere with lactol of formula H in tetrahydrofuran at a molar ratio of 2 to 3: 1 at temperature -20 to +10 ° C for 0.2 to 2 hours, followed by stirring the reaction is terminated by sequential addition of saturated solution sodium chloride, water and after acidification with hydrogen sulfate alkali metal to pH 2.1 to 2.5 is organic the layer separated and after extraction of the aqueous phase with tetrahydrofuran from the combined organic fractions after evaporation of the solvent, the product is obtained in general of formula I. These substances are used in both human and veterinary applications medicine.

Description

The present invention relates to a process for the preparation of (5Z, 13E) -propadienoic acid derivatives of the general formula I, wherein R is hydrogen, tetrahydrofuryl, tetrahydropyranol or alpha-methoxybenzyl, n-butyl or phenoxy optionally substituted by chlorine or trifluoromethyl; hydrogen, when B is RO, where R is as defined above, B is hydrogen, when A is RO or A + B together is OCl 2 CH 2 O.

A number of functional derivatives of prostadienoic acid known under the collective name prostanoids find increasingly widespread use as pharmaceuticals in human and veterinary medicine. Total synthesis of these substances has been devoted to tremendous effort, which has resulted in the elaboration of several dozen completely original methods for their preparation (JS Bindra, R. Bindra in: Prostaglandin Synthesis, Academic Press, Inc., New York 1977; SMRoberts, RF Newton in: Prostaglandin and Thromboxanes, Butterworths, London, 1982).

However, only some of these processes are currently in place on an industrial scale. One of them is the so-called norbornadien route, used mainly for easy feasibility, unpretentiousness and flexibility, allowing the preparation of all basic prostaglandins and their analogs. The final step of this synthesis is the construction of the upper chain (alpha chain, prostaglandin marking) reacting a lactol of formula II wherein R, R₁, A and B are as defined above with an ylide of Formula III (ie. Wittig reaction) (C _g H ₅ ) ₃ p = chch ₂ ch ₂ ch ₂ coom (III) wherein M represents lithium, sodium or potassium, which is generated from triphenyl, 4-carboxybutyl) phosphonium bromide by treatment with a maximum of 2 moles of strong base relative to 1 mol of phosphonium salt. In this embodiment, a high amount of (5E) -isomer 1 is formed which is very difficult to remove from the reaction mixture. The prior art discloses a wide variety of potentially useful basic agents for this reaction in combination with various solvents (see, for example: AW Johnson, Ylid Chemistry, Academic Press, 1966).

The most commonly used base is dimethylsulfoxide sodium in dimethylsulfoxide prepared by the reaction of dimethylsulfoxide with sodium hydrin (see, for example: J. S. Bindra, R. Bindra in the book: Prostaglandin Synthesis, Academic Press, New York, 1977).

In rare instances, an alkali metal tert-butanoate tert-butoxide generation in benzene and tetrahydrofuran was used to generate the ylide (R.F. Newton et al., J. Chem. Soc. Perkin I, 1979,

789). Both of the above processes provide products in very good yields, but have some disadvantages, the most serious of which is the formation of relatively high (above 5%) c

undesired -trans-isomer. Since it is a contaminant structurally close to the desired product I (5-cis-isomer), its separation is virtually insoluble under technological conditions.

The use of dimethylsulfoxide as a solvent and sodium hydride as a basic reagent complicates the isolation of the product from the reaction mixture considerably and further requires costly measures in terms of occupational safety, fire protection and waste water purity. Thus, it is disadvantageous both from a technological and economic point of view.

These known processes are followed in a positive manner by the process according to the invention, which partially or completely removes the above mentioned deficiencies.

The process according to the invention is characterized in that the ylide of formula III (M is potassium) is prepared from triphenyl (4-carboxybutyl) phosphonium bromide by treatment with 0.02-0.2 molar excess of the theoretical amount of potassium terebutanolate in tetrahydrofuran at reaction temperature. mixtures of 5 to 30 ° C in an inert atmosphere. The ylide suspension of formula (III) prepared in this manner is reacted in an inert atmosphere with the lactol of formula (II) at a temperature of the reaction mixture of -20 to + 10 ° C, preferably -10 to + 5 ° C, for 0.2 to 2 hours, it is preferred to use a 2 to 3 molar excess of the ylide of formula III.

After this olefination reaction (monitored by thin-layer chromatography on silica gel), the excess ylide of formula III is decomposed successively with a saturated aqueous solution of sodium chloride, water and acidified to pH 2.1 to 2.5 with an aqueous solution of alkali metal hydrogen sulphate, preferably hydrogen sulphate. sodium or potassium. After separation of the organic layer, the aqueous phase is extracted with an organic solvent, preferably tetrahydrofuran, and the combined organic fractions are washed with an aqueous sodium chloride solution until the mineral acidity is removed. Then the solvents are evaporated in vacuo and the crude product is isolated by column chromatography.

In order to remove the protecting groups from the hydroxyl functions representing the transformation of a product of formula I wherein R is tetrahydrofuryl-, tetrahydropyranol-, or alpha-methoxybenzyl to a product of formula I where R is H, the organic portion containing the product is concentrated. to about 1/2 of the original volume, diluted with 0.2 to 1 volume of water and heated to boiling for 0.2 to 3 hours after addition of a catalytic amount of a strongly acidic ion exchanger (Dowex 50, Amberlite IR-120) reactions can be monitored by silica gel thin layer chromatography). After filtration of the ion exchanger and evaporation of the solvents, the product of formula I wherein R = H is isolated by column chromatography.

The advantage of the psotup according to the invention is that it is simple to carry out the reaction and easy to isolate the product which is practically free of the undesired trans-isomer. Another advantage is the use of readily available and inexpensive and safe chemicals. From this is evident its technological and economic advantage.

The effects of the invention are set forth in the following examples, which are illustrative only and in no way limit the scope and subject matter of the invention.

Example 1

To a suspension of 3.05 g of triphenyl (4-carboxybutyl) phosphonium bromide in 30 ml of anhydrous tetrahydrofuran (argon atmosphere), 13 ml of a 1.12 M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise with vigorous stirring until the temperature of the reaction mixture exceeded 25. Deň: 32 ° C. After 15 minutes the orange suspension of the ylide of formula III was cooled to +2 ° C and a solution of 1484 mg (3 millimoles) of lactol of formula II wherein R is tetrahydropyranyl, A is hydrogen, B is OR, R ¹ is 3-chlorophenoxy group, in 12 mL of tetrahydrofuran. After stirring at 0 ° C to + 5 ° C for 1 hour, 15 mL of saturated sodium chloride solution, 5 mL of water and 1.7 mL of 4M aqueous sodium hydrogen sulfate were added, the organic layer was separated and the aqueous phase extracted with 5 mL of the same solvent.

The combined organic extracts were washed with 2 x 5 mL saturated brine and evaporated to about half volume. To the distillation residue, 10 ml of water and 3 g of ion exchanger were added (dowex 50) and after 2 hours of boiling, the ion exchanger was filtered off, washed with 2 x 5 ml of tetrahydrofuran and the solvents were distilled off under vacuum.

The oily residue was chromatographed on a silica gel column (25 g), eluting with chloroform-methanol-acetic acid. The combined prostaglandin fractions were obtained

1.1 g of pure product of formula I wherein A is hydrogen, B = OR, R = H, R ¹ = 3-ClC H, O-, 4 which in this HPLC contains less than 1.8% of undesired trans -isomer. The identity of the product was confirmed by comparing the chromatographic and NMR and IR spectra to a standard preparation.

Example 2

To a suspension of the ylide of formula III, prepared from 0.89 g of triphenyl (4-carboxybutyl) phosphonium bromide and 3.1 ml of a 1.39 M solution of potassium tert-butoxide in tetrahydrofuran at 20-25 ° C, was added all at once. a solution of 0.26 g of a lactol of formula II wherein R = Η, A + B together form an OCH 3 CH 2 O group and R 1 = 3-ClC 8 H 4 O in 3.1 ml of the same solvent.

After stirring the mixture for 2 hours (nitrogen atmosphere), 1.5 ml of water and 4.3 ml of saturated sodium chloride solution were added, and finally 0.47 ml of 4M potassium hydrogen sulphate solution. After separation of the organic phase, the aqueous layer was extracted with 2 x 3 ml of tetraheddrofuran, the combined organics were dried over magnesium sulfate, and the solvents were evaporated in vacuo to give 0.88 g of an oily distillation residue. yielded 0.18 g of the product of formula X, where R = Η, a + B together form an OCH? CH? O group and 3-ClC = _fi it according to HPLC contains less than 2 J + Ϊ undesirable -trans.isomeru. The mass spectrum is in accordance with the proposed structure, optical rotation (alpha) β = + 18.6 ° (0.5-ethanol).

Example 3

To the suspension of the ylide prepared as in Example 1 was added at -15 ° C 1.9 g of the lactol of formula II, wherein R = -methoxybenzyl, A = Η, B = OR, R R = 3-CF CFCgH ^O, dissolved in 20 ml of tetrahydrofuran (inert atmosphere) and stirred at this temperature for 2 hours, quenched with 5 ml of water, 15 ml of saturated sodium chloride solution and worked up as in example 1. The ion exchange exchanger (Amberlite IR-120) was used to remove the protecting group.

Column chromatography gave 1.25 g of a compound of formula I wherein R = A = H,

R ¹ = 3-CF 3 C 8 H 4 O containing less than 2% of the undesired N -trans-isomer according to HPLC. The NMR and IR spectral characteristics of the product are identical to the authentic preparation.

Example 4

To the suspension of the ylide prepared as in Example 1 was added at -20 ° C 17 g of lactol of formula II wherein R = tetrahydrofuryl, A = Η, B = OR, R R = n-butyl dissolved in 15 ml of tetrahydrofuran . The mixture was stirred at this temperature for 2 hours, quenched with 5 mL of saturated sodium chloride solution and acidified with 1.7 mL of 4M potassium hydrogen sulfate solution and further processed as in Example 1.

The protecting group was removed by treatment with an ion exchanger (Dowex 50) in an H ⁺ cycle. Column chromatography yielded 1.1 g of a compound of formula I wherein R = A = H, R, = nC ^Hg- contaminated with less than 1.8 nežádoucí of the undesired β -trans isomer by HPLC analysis.

Claims (1)

A process for the preparation of (5Z, 13E) -propadienoic acid derivatives of formula I wherein R is hydrogen or tetrahydrofuryl or tetrahydropyranol- or alpha-methoxybenzyl, A is hydrogen when B is RO, wherein R is as defined above, B is hydrogen when A is RO or A + B together represents an OCH ₂ CH ₂ O group, R ² represents an n-butyl or phenoxy group optionally substituted by a chlorine atom or a trifluoromethyl group, by reacting a lactol of formula II wherein R, R 2 A and B are as defined above, with an ylide of formula III (CgHg) ₃ p = chch ₂ ch ₂ ch ₂ cook (III) prepared from triphenyl (4-carboxybutyl) phosphonium bromide in an organic solvent by treatment with potassium tert-butanols, characterized by 2. A method according to claim 1, wherein the ylide of formula III is prepared by treating with a 0.02 to 0.2 molar excess of the theoretical amount of potassium tert-butoxide in a tetrahydrofuran solution at a temperature of 5 to 30 ° C. reacted in an inert atmosphere with the lactol of formula (II) in tetrahydrofuran in a molar ratio of 2 to 3: 1 at -20 to + 10 ° C for 0.2 to 2 hours, then quenched by the sequential addition of saturated sodium chloride solution, The organic layer is separated and, after extraction of the aqueous phase with tetrahydrofuran, the product of formula (I) is obtained from the combined organic fractions after evaporation of the solvent, optionally from concentrated organic fractions containing compounds of the formula: I wherein R represents a protecting group of tetrahydrofuranyl, tetrahydropyranyl or a-methoxybenzyl, and a, B and R ¹ are as defined above, these protecting groups are removed to give compounds of formula I wherein R represents hydrogen and a, B and R ^ are as defined above.