CS229064B1 - Process for preparing prostaglandin f2 and analogs there e of - Google Patents

Description

This invention relates to prostaglandin F ^ ^and d ^our analog of formula I,

where

Y denotes alkyl or alkenyl of 1 to 6 carbon atoms, wherein the alkyl or alkenyl optionally contains 1 to 4 fluorine atoms or phenoxy optionally substituted with 1 to 3 fluorine, chlorine or trifluoromethyl or alkoxy groups containing 1 to 3 carbon atoms in the alkyl group X represents a hydroxyl group or an OR group wherein

R is alkyl having 1 to 3 carbon atoms,

A is a hydroxyl group or hydrogen,

V is hydrogen or a hydroxyl group, provided that when A is a hydroxyl group, V is hydrogen and if A is hydrogen, V is a hydroxyl group, n is 1 to 6.

In most known processes for the production of prostaglandins, a group of biologically active substances, especially in the F4 series, ^{and that in the} last stages of the multi-step synthesis utilizes a lactoldiol of formula a which has hydroxyl groups protected in ether, acetal or trialkylsilyl derivative, most commonly in tetrahydropyranoside.

(Z stands for ether, acetal, trialkylsilyl derivative, most commonly tetrahydropyranes1.)

The desired prostaglandin F ₂ * derivatives and an analog thereof are prepared from this compound by a Wittig reaction, i.e., by reaction with an ylide of formula (C HH)) - РR =НН (СН ₂ ) ^ COOH and subsequent removal of the Z protecting groups in acid The product of the formula b is isolated.

The disadvantage of these methods is that the removal of tetrahydropyranyl groups is carried out with dilute acetic acid at elevated temperature, lasting several hours, the desired product being contaminated with polycondensates resulting from the released protecting groups. Furthermore, the acetic acid used is relatively difficult to remove from the reaction mixture and causes difficulties in the subsequent chromatographic purification of the product.

These known processes are followed by a process according to the invention which eliminates the disadvantages of the hitherto known processes.

The essence of the process for the production of prostaglandin F ₂ ^ and its analogue utilizes, for the synthesis of easily and advantageously accessible M, the lactoldiol of formula II

wherein n and Ϊ are as defined above and

R ¹ ίηβϋί R ³ C ₆ H ₄ ² CHOR strike while ^nu ^ i, w ^e

R ^fc denotes C 1-4 alkyl and 1 to 4 carbon atoms α

R 'denotes hydrogen, alkyl or alkoxy of 1 to 2 carbon atoms, or its C-15 epimer (prostaglandin numbering).

Of the bisacetal of formula II with YLddmm * of formula III (C ₆ H ₅ ) ₃ P = CH (CH ₂ ) ₃ COX (III) wherein

X is as defined above, in the environment of polar aprotic solvents, a protected prostaglendine derivative of the general formula IV is obtained on hydroxyl groups

(IV) where

R ^1, X, Y, n maai with ^H ora defined above, or its C-15 epimer (prostaglandin numbering).

Chájiicí ^R1 groups are readily removed ^already has an s reakčSní decomposition ⁱⁿ the mixture for ^0, 4 ^and the second With a solution of oxalic acid or by shaking the reaction mixture with a strongly acidic catalyzed solution in a medium of 10 to 80% by weight of an alcohol having a carbon number of 1 to 4 at 20 to 80 ° C for several minutes.

This procedure substantially simplifies the isolation of the desired product of formula (I), with higher yields and purity of the product.

The examples are merely representative and do not limit the invention in any way.

Example 1 (lalfa (Z), 2beta (1E, 3S ⁺ ), 3alpha, Salpha-Ci-Y-4-U-4-chlorophenoxy-5-hydroxy-1-bute-4) -3,5- dihydroxycyclopentyl-5-heptenoic acid of general formula I, A = ОН, В = Η, X = OH, Y = OC ₆ H ₄ -mCl, n = 1

To a solution of 4.7 g of triphenyl- (4-kar0olbbulyl) fonnonium0nomidu of 20 m was during dimeeylsulfoxidu for 20 min, 12 ml of 1.77 M solution in dimeetlsulfoxidnatria dimeeylsulfoxidu and the resulting mixture was stirred for 15 minutes at room temperature then added with ^{g (3 ,} 5 millimolar. lektolu community Ы ^ he formula wherein ^{R 1} = C ^ = ^O COPD Y - ^CGH -mCC _4, n = 1, dissolved in 35 mL of dimeeylsulfoxidu and 7 ml of benzine. After three hours stirring at 25 ± 5 ° The reaction mixture was quenched with 35 ml of water and the pH was adjusted to 1.5-2 by the addition of a final oxalic acid solution. The acidic solution was stirred for 30 minutes, extracted with 4x 50 ml of ethyl acetate, the combined organic layers were free of 50 ml of saturated solution. sodium chloride, the solvents were evaporated and the distillation residue was dissolved in 100 ml of benzene, washed again with saturated sodium chloride solution, dried over magnesium sulphate and the solvent distilled off in vacuo. Residue (3.7 g) was obtained 0.9 g of product identical physico-chemical constants of the standard.

Example 2 ⁽¹ Al ^of a ^{(Z) b} eta 2 ⁽¹ E, 3 ^{S +} H and ^f 3 Al, and 5al ^f), l ⁽ⁱ⁾ 7 ^l - {2- ^(R - ^y y ^o OO) φ- 1ooktee ^l l) зЗ ^l -d ^ry ydroxlc klopentyl ^yl} -5-heptMiová acid of formula I, wherein A = · OH В = Η X = OH, Y = CH ^, n = 4

To a solution of 2.35 g of toiphenyl- (4-chloro-butylbutyl) fumoium oomide in 10 m dimethyl sulfoxide was added 4.8 ml over 25 minutes. A 1.77 M solution of dimeethysulfoxidnatrium in dimethylsulphide at room temperature. To the thus produced ylide solution was added 1.72 g (2.5 miimolu) of the lactol of general formula wherein ^{eh γ} = n ^ CCH, · ^R1 = n = ⁰ · 8 ^m in πο ^ ^ ^1! ^ ⁰ · oxide and 2 ml of benzene. After treatment in analogy to Example 1, 0.53 g of product was obtained. whose · spectral ^ ΐΜ * ί ^ βι? rsti ky _; they are in . · Present. . s. · Structure. '

Example 3,

Ο ^ Οι ^).,. 2 ^b eta ⁽¹ E, 3 ^{a +} b and 3a °, and 5al ^f) L ^(-) 7 ^1-21 - (7 _l 7- ^down ul31h- ^ld0 OO ^l l-8-meth ^y l ⁵ 10xa-. - 1,81eoeadieneУ) 13.5 ~ dli! ^y ydroxyc LTB У ^yl} -5-repteeoát meeylnatý general formula I, wherein A = OH, В = Η X = · OCH 3, Y = OlH2lF2l (lHз) ^β H 2, ' η = 1 '

To a solution of 2.40 g of triphenyl- (4-phenoxybolnylbutyl) foofouium bromide dissolved in 12 dimethylsulphoxide was added 4.8 ml of a 1.77 M solution of dimethylphosphonic acid. in dimethyl sulfoxide for 15 minutes and then stirred for 20 minutes at 22 ° C. Then 1.59 g (2.5 millimoles) of lactol of formula II, where Y = = OCH ₂ F ₂ L, were added to the reaction mixture. (1 H ^з ) = 1 H ^2, R ¹ = H ² OOC 4 CHOCH ³ , π 1, expanded in 8 ml of diaphthyl. Following an analogous procedure and work-up as in Example 1, 0.49 g of product as an oil was obtained. Spectral ^ γ-οΙ ^ Ο ethics are in t0Шr.ate with the proposed structure.

Example 4

The procedure is as in Example 1. After reaction with the ylide, the oxalic acid is acidified to pH 3-4 and the reaction mixture is worked up without further stirring and the resultant is a protected derivative of the formula I. The deprotection is carried out for 15 minutes 80% by volume of aqueous methanol in the presence of 2 g of Dowex 50 per cycle. After filtering off, the reaction mixture is evaporated to dryness and the product is purified by chromatography.

Claims (2)

The present invention relates to a process for the preparation of prostaglandin Fg4 ^and analogues thereof O.H (I) wherein Y represents alkyl or alkenyl of 1 to 6 carbon atoms, wherein alkyl or alkenyl optionally of 1 to 4 fluorine atoms or phenoxy optionally substituted with 1 to 6 carbon atoms; 3 atoms from the group of fluorine, chlorine or trifluoromethyl, or an alkoxy group; 1 to 3 carbon atoms in the chain, X represents a hydroxyl group or an OR group wherein R is alkyl having 1 to 3 carbon atoms, A is hydroxyl or hydrogen, B is hydrogen or a hydroxyl group, provided that when A is a hydroxyl group, B is hydrogen and when A is hydrogen, B is a hydroxyl group and n is 1 to 6, characterized in that the lactol of formula II (II) where Y and n have the above meanings a R ^{1 of} R ³ C ₆ H ₄ CHOR ² where p R is alkyl of 1 to 4 carbon atoms and ^R4 as hydrogen ⁱⁿ considerable ^alk yl or alkoxy having ^{1 and} 2 ^{carbon-Cart T u,} or ^h is about ^{- 15} C e ^{p p} Imer Úsobí ylide of formula III " (C ₆ H ₅ ) ₃ P = CH (CH ₂ ) ₃ COX (III) where X is as hereinbefore defined, in the environment of polar aprotic solvents, and the? Sacecl of the prostaglandin of formula IV is obtained ОН / \ '\ _ ЛЛ _С0Х отЧс ^{10 2} ' ” OR ¹ Н (IV) wherein, X, Y, n are as defined above, or a C-15 epimer thereof, from which the desired product of formula I is released without isolation with a 0.4 to 2 N Stavelic acid solution or after cation exchange isolation in the environment water with Ю to 80% w / w alcohol having a carbon number of 1 to 4 at 20 to 80 ° C. , Process according to claim 1, characterized in that dimethylsulfoxide is used as the polar aprotic solvent.