CS218287B1 - Method of making the analogue of the prostaglandine f2 alpha - Google Patents

Description

The invention relates to a process for the preparation of analogs of prostaglandin F ₂ and formula I

where

X is a hydroxyl group or OR ¹ , wherein R ¹ is alkyl of 1 to 6 carbon atoms, n is 0 to 6,

Y is hydrogen or (C 1 -C 6) alkyl or OR ² , wherein R ² is (C 1 -C 4) alkyl, or (C 6 -C 10) aryl optionally substituted with 1 to 3 halogen atoms,

A is a hydroxyl group or hydrogen,

B is hydrogen or a hydroxyl group, provided that when A is a hydroxyl group, B is hydrogen, or when A is a hydrogen is B a hydroxyl group.

Prostaglandins are groups of biologically active substances with characteristic activity. They regulate vital processes such as reproductive, nervous, digestive, respiratory, cardiovascular and renal. An analogue of prostaglandin F ₂ and found use in controlling the reproductive cycle of livestock and as an abortive.

The processes known to date for the production of prostaglandin F ₂ analogues are characterized by the following sequence of reactions in the last stages of multistep synthesis:

Reduction of the lactondiol of formula (a)

OT ^ ^(c m

OT (&) where T is hydrogen, or a protecting group, for example a tetrahydropyran-2-yl residue, to the lactoldiol of formula (b)

wherein T is hydrogen or a protecting group for example a tetrahydropyran-2-yl radical.

In the next step, the lactoidiol of formula (a) is converted to prostaglandin F _{2 by} formula (d) by treatment with an ylide of formula (c) (C ₆ H ₅ ) ₃ P = CH (CH ₂ ) ₃ COOH (c).

or, in the case where T is a protecting group, a derivative thereof from which the hydroxyl group on carbons 11 and 15 is released by treatment with acidic reagents.

Methods in which the hydroxyl group on carbons 11 and 15 is protected in the form of a THP (tetrahydropyran) derivative (NSR Patents Nos. 2,709,804, 2,736,110, 2,234,709, 2,345,695, U.S. Patent No. 3,933,892 and British Patent No. 1438,093) have the disadvantage that other asymmetric centers are formed in the molecule and thus a mixture of isomeric compounds is obtained. The obtained products then have a generally syrupy consistency, which makes their isolation difficult to purify and characterize.

Methods (J. Chem. Soc. Perkin I 1973, 2796), wherein the hydroxyl groups on carbons 11 and 15 are not protected prior to further processing, mainly have the disadvantage of significant consumption of costly reagents, while the desired products contaminated with ballasts are difficult to isolate from excess reagents. .

This process is followed in a positive way by the process according to the invention, which removes the disadvantages of the hitherto known methods.

According to the invention, the process for the preparation of prostaglandin F ₂ analogues and the above-mentioned general formula I is characterized in that the compound of the general formula II

wherein η, Y, A, B are as defined above, in the form of an alcoholate prepared by treatment with an alkali metal hydride, after reduction of the modified complex hydride lactone moiety to a lactoldiol moiety of formula III wherein η, Y, A, B are as defined above, is converted by treatment with an ylide of formula (C ₆ H ₅ ) ₃ P = CH (CH ₂ ) ₃ COX, where X is as defined above, to the desired prostaglandin F ₂ analogue of formula I.

When X is OR ¹ in the compound of formula (I), these are also prepared by treating the reaction product with a C 1 -C 4 diazoalkane or converting the product into a silver salt treated with an appropriate salt. an alkylating agent having 1 to 6 carbon atoms.

In the process of the invention, the lactondiol moiety of formula II is converted to the lactoldiol moiety of formula III, preferably at -40 +45 ° C, with a modified complex hydride, preferably readily available and inexpensive sodium bis- (2-methoxyethoxy jethoxyaluminium hydride) to the desired product of formula I (see Synthesis 1976, 526) or dilsobutylaluminum hydride For the next reaction step, the lacto-diol of formula III can be used without isolation, it is sufficient to evaporate most of the solvent under reduced pressure. The residue is converted to the corresponding alcoholate again by treatment with a calculated amount of dimethylsulfoxide of sodium in dimethylsulfoxide before further treatment, i.e. by reaction with the ylide.

Ylid of the formula (C ₆ H _{5) 3} P = CH _{(CH2) 3} COX according to the invention is preferably prepared from a phosphonium salt of the general formula · (CEH _{5) 3} P "+"(CHakCOXHlg'-'wherein Hlg represents halogen in anhydrous DMSO (dimethylsulfoxide) by treatment with salt bases, preferably alkali metal hydrides or alkyllithium.

These modifications, i.e. the use of compounds of formula II and formula III in the above reactions in the form of alcoholates or carrying out the reaction sequence II - III - I without isolating the compound of formula III, in the reaction sequence of the invention reduce the consumption of complex to protect hydroixyl groups. By reducing the amount of the above reagents in each reaction trace, the isolation of the desired products, their purity and the yields are substantially improved. From this, it is clear that the savings in reagents, easier product isolation and better yields also bring about a corresponding economic effect.

The invention and its effects are illustrated in more detail by the following examples of true events, which are illustrative only and in no way limit the scope of the invention.

Example 1

To a solution of 101.6 mg (0.3 millimoles) of the lactondiol of formula II, wherein n = 1, Y = OC ₆ H ₄ Cl-m, A = OH, B = H, in 20 ml toluene and 6 ml dimethoxyethane at of the reaction mixture at -78 + 2 ° C was added 1.2 millimoles of freshly prepared sodium bis- (methoxyethoxy) (ethoxy) aluminum hydride in toluene over 5 minutes (nitrogen atmosphere).

After stirring at this temperature for 20 minutes, the reaction mixture was quenched with 0.6 ml of methanol, the cooling bath was removed, and after 15 minutes 17 ml of a 1: 1 saturated solution of sodium chloride and water were added at 25 + 5 ° C, organic phase separated and aqueous extracted with ethyl acetate (3 x 25 mL). The combined organics were washed with saturated sodium chloride solution and dried over magnesium sulfate, the solvents evaporated in vacuo, and the distillation residue evaporated with 2 x 5 ml benzene.

To obtain 106 mg of oily laktoldiolu formula III wherein η, Y, A, B have the above meanings, _(Rf = 0.1 on silica; eluent of 4% methanol in chloroform), whose structure was confirmed by spectral methods. The lactoldiol thus obtained was dissolved in 2.5 ml of dimethylsulfoxide and added to a solution (nitrogen atmosphere) of the ylide prepared from 665 mg (1.5 millimoles) of 4-carboxybutyltriphenylphosphonium bromide and 3 millimoles of dimethylsulfoxidenium in dimethylsulfoxide at 25 + 5 °. C with vigorous stirring.

After stirring at this temperature for 2 hours, the reaction mixture was quenched with 7 mL of water, acidified with a solution of oxalic acid to pH 3-4 and extracted with 5 x 35 mL of ethyl acetate. The combined organics were washed with saturated sodium chloride solution, shaken with 2 g of sodium chloride, the solvents evaporated in vacuo, the distillation residue dissolved in benzene and chromatographed on a silica gel column which was successively washed with 10 ml of benzene, 10 ml of benzene-methanol (95: 5) and finally the product was eluted with benzene-methanol-acetic acid (16: 1: 1). After acidification of the solution with acetic acid, the solvents were evaporated under high vacuum to give 65 mg of the product of formula I, where n = 1, Y = OC ₆ H ₄ Cl-m, A = OH, B = H, X = -OH whose spectral the characteristics and the elution part of the high-pressure chromatography are in accordance with the proposed structure.

Example 2

To 677 mg (2 millimoles) of the lactondiol of formula II wherein n = 1, Y = OC ₆ H ₄ Cl-m, A = Η, B = OH in 80 mL of a 1: 1 mixture of toluene-dimethoxyethane in nitrogen; 192 mg of sodium hydride (4 mils, 50% suspension in oil) was added at -78 + 2 ° C and after stirring for 10 minutes, 3.2 ml of diisobutylaluminum hydride (4 millimoles) in toluene was added over 5 minutes. After the reaction mixture was worked up analogously to Example 1, 669 mg of crude oily lactoldiol of the formula III were obtained, where η, Y, A, B are as defined above, to which, after dissolution in 15 ml of dimethylsulfoxide, 2 millimoles of dimethylsulfoxidnatrium in dimethylsulfoxide were added. the solution was added at 22-25 ° C to a solution of an ylide prepared from 6 millimoles of 4-ethoxycarbonylbutyltriphenylphosphonium bromide and 6 millimoles of dimethylsulfoxidium in dimethylsulfoxide (nitrogen atmosphere). Following an analogous treatment to Example 1, 489 mg of an oily product of formula (I) are obtained, wherein η, Y, A, B are as defined above and X represents a C ₂ H ₈ O group whose spectral characteristics are in accordance with the proposed structure.

Example 3

To a solution of 268 mg (1 mmol) of lactondiol of formula (II). where n == 4, Y = GH3, A == OH, B-H; 98-99 ° C, more polar by thin-layer chromatography and dissolved in 50 ml toluene and 15 ml dimethoxyethane (nitrogen atmosphere), was added at -78 +2 ° C 4 ml (4 millimoles). of a toluene solution of sodium bis (2-methoxyethoxy) (ethoxy) alminium hydride over 5 minutes After stirring at this temperature for 30 minutes, 5 ml of a toluene solution of ethanol (containing 1 millimole of ethanol) was added to the reaction mixture; heated to 0 + 15 ° C, at which temperature a substantial part of the solvents was evaporated under high vacuum.

The distillation residue was dissolved in 10 ml of dimethylsulfoxide (nitrogen atmosphere) and added to a solution of an ylide prepared from 1330 mg (3 millimoles) of 4-carboxybutyltriphenylphosphonium bromide at 20 + 5 ° C with vigorous stirring. After 4 hours, the reaction mixture was worked up as in Example 1. 126 mg of an oily product of formula I were obtained, where η, Y, A, B are as defined above and X is OH, whose spectral characteristics are consistent with those in the literature.

Example 4

To an aqueous ethanolic solution (1: 1) of the compound of formula I (1 millimol), where n - 1, Y = OC ₆ H ₄ Cl-m, A = OH, B = Η, X = OH, was added silver nitrate solution ( After 20 minutes, the silver salt was filtered off with suction, washed with ethanol and, after drying, suspended in a mixture of dry ether and absolute ethanol. To this mixture was added 456 mg of ethyl y218287 didu and the mixture was heated to reflux with ether and absolute ethanol. din. The precipitated silver salts were then aspirated, washed with ethanol and the filtrate evaporated to dryness on a vacuum rotary evaporator. Column chromatography of the residue on silica gel (eluent chloroform-ethyl alcohol) yielded 82% of the product of formula I wherein n, Y, A, B are as defined above and X = - C ₂ H ₅ O-group whose structure is consistent with the interpretation spectra.

Claims (1)

A process for the production of prostaglandin F ₂ analogues of formula I wherein X is hydroxyl or OR ¹ , wherein R ¹ is alkyl of 1 to 6 carbon atoms, n is 0 to 6, Y is hydrogen or an alkyl group having 1 to 6 carbon atoms or an OR ² group wherein R ² is an alkyl having 1 to 4 carbon atoms, or an aryl group having 6 to 10 carbon atoms optionally substituted with 1 to 3 halogen atoms, A is hydroxyl or hydrogen, B is hydrogen or hydroxyl, provided that if A is hydroxyl, B is hydrogen, or when A is hydrogen, B is hydroxyl by reducing the lactondiol of formula II (II) yn Alzez wherein ^J , Y, A, B are as defined above, with OH-protected groups on the lactoldiol of formula III wherein ^J , Y, A, B are as defined above, and reacted with an ylide of formula ( C ₆ H ₅ ) P = CH (CH ₂ ) ₃ COX, where X is as defined above, to give the desired product of formula I, characterized in that the lactondiol moiety of formula II is reduced with a preferably modified complex hydride, for example riatrium bis- (methoxyethoxy) aluminum hydride or diisobutylaluminium hydride, at -40 +45 ° C, to the lactoldiol of formula III and the resulting reaction mixture is treated with ylld of the above formula to give the desired product of formula I, wherein: in the compounds of formulas II and III present, the OH groups present are protected in the form of their alkali metal alcoholate.