GB1596510A - 16-hydroxyprostenoic acid derivatives and processes for their manufacture - Google Patents

16-hydroxyprostenoic acid derivatives and processes for their manufacture Download PDF

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GB1596510A
GB1596510A GB48955/77A GB4895577A GB1596510A GB 1596510 A GB1596510 A GB 1596510A GB 48955/77 A GB48955/77 A GB 48955/77A GB 4895577 A GB4895577 A GB 4895577A GB 1596510 A GB1596510 A GB 1596510A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4018—Esters of cycloaliphatic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/06—Five-membered rings having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl

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Description

(54) 16-HYDROXYPROSTENOIC ACID DERIVATIVES AND PROCESSES FOR THEIR MANUFACTURE (71) We, HOECHST AKTIENGESELLSCHAFT, a body corporate organised according to the laws of the Federal Republic of Germany, of 6230 Frankfurt/Main 80, Postfach 80 03 20, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The natural prostaglandins are a group of fatty acids which occur in numerous tissues and organs of humans and animals. The basic structure of the naturally occurring prostaglandins comprises 20 carbon atoms, which are arranged in the form of a five-membered ring and two adjacent linear side chains.
The pharmacological effects of the prostaglandins extend, inter alia, over the fields of reproduction, bronchial muscular tone, blood pressure and gastroenterology. These pharmacological properties are the subject of numerous review articles, for example N. H. Andersen and P. W. Ramwell in Arch. Internal Med. 133, 30 (1974); R. L. Jones in Pthobiology Ann. 1972, 359; J. Pike in Scient.
American 225, 84 (1971) or M. P. L. Caton in Progress in Med. Chem., volume 8, edition: Butterworth, London, 1971.
The syntheses of analogues of prostanoic acids, which analogues are not naturally occurring and in which the multiplicity of pharmacological actions of the naturally occurring prostaglandins are differentiated, are becoming increasingly important.
The present invention provides a cyclopentane derivative of the general formula
wherein: one of Rl and R2 represents a hydrogen atom and the other represents a hydroxyl group, or R1 and R2 together represent an oxygen atom; R3 represents a hydrogen atom; an aliphatic or cycloaliphatic hydrocarbon group having up to 8 carbon atoms; an alkoxyalkyl group having from 3 to 10 carbon atoms; an araliphatic hydrocarbon group having from 7 to 10 carbon atoms; a metal ion; an ammonium ion; or a substituted ammonium ion derived from a primary. secondary or tertiary amine; R4 represents an aliphatic hydrocarbon group having from 1 to 10 carbon atoms or a cycloaliphatic hydrocarbon group having from 3 to 7 carbon atoms, which aliphatic or cycloaliphatic group may be unsubstituted or substituted by one or more of the same or different substituents selected from: (a) aliphaticoxy or aliphaticthio groups having from 1 to 7 carbon atoms; (b) phenoxy groups which may be unsubstituted or substituted by one or two of the same or different substituents selected from alkyl groups having from 1 to 3 carbon atoms, which alkyl groups may be unsubstituted or substituted by one or more of the same or different halogen atoms; halogen atoms; phenoxy groups which may be unsubstituted or substituted by one or more of the same or different halogen atoms; and alkoxy groups having from 1 to 4 carbon atoms; (c) furyloxy, thienyloxy, benzyloxy, phenyl, thienyl or furyl groups, which may be unsubstituted or substituted by one or two of the same or different substituents selected from alkyl groups having from 1 to 3 carbon atoms which may be unsubstituted or substituted by one or more of the same or different halogen atoms; halogen atoms; and alkoxy groups having from 1 to 4 carbon atoms: (d) fluorine atoms, trifluoromethyl or pentafluoroethyl groups; and (e) cycloalkyl groups having from 3 to 7 carbon atoms; R5 represents an alkyl group having from 1 to 5 carbon atoms; an alkenyl or alkynyl group having from 2 to 5 carbon atoms; or a hydrogen atom; R6 represents a hydrogen atom or a group of the general formula R7CO, wherein R7 represents a hydrogen atom or an alkyl group having up to 10 carbon atoms; and A represents a trnns-CH=CH- group or a -CH2-CH2- group with the proviso that if A represents a -CH2-CH2- group, R5 may only represent a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms.
Preferably if R3 represents an ion, the ion is such that the resulting compound of the general formula I is physiologically tolerable. If the aliphatic or cycloaliphatic group represented by R4 is substituted, it is preferably monosubstituted by any one of the substituents listed or disubstituted by two fluorine atoms.
Amongst the substituents mentioned, the following are preferred: for R3: a hydrogen atom, an alkyl group having from 1 to 8 carbon atoms, an alkoxyalkyl group having a total of from 3 to 10 carbon atoms, an alkenyl group having from 2 to 4 carbon atoms, a cycloalkyl group having from 5 to 7 carbon atoms, an aralkyl group having 7 or 8 carbon atoms, an ammonium ion, a physiologically tolerable metal ion or substituted ammonium ion which is derived from a primary, secondary or tertiary amine; for R4: an aliphatic hydrocarbon group having from I to 8 carbon atoms or a cycloaliphatic hydrocarbon group having from 5 to 7 carbon atoms. which groups may be unsubstituted or substituted by: (a) an alkoxy, alkylthio, alkenyloxy or alkenylthio group having from 1 to 5 carbon atoms; (b) a phenoxy group which may be unsubstituted or substituted by one or two of the same or different substituents selected from alkyl groups having from 1 to 3 carbon atoms; trifluoromethyl groups; halogen atoms; phenoxy groups which may be unsubstituted or substituted by one or more of the same or different halogen atoms; and methoxy and ethoxy groups; (c) a thienyloxy, benzyloxy, phenyl or thienyl group which may be unsubstituted or substituted by one or two of the same or different substitutents selected from alkyl groups having from 1 to 3 carbon atoms; trifluoromethyl groups; halogen atoms; and methoxy and ethoxy groups; (d) one or two fluorine atoms or a trifluoromethyl groups; or (e) a cycloalkyl or cycloalkylidene group having from 5 to 7 carbon atoms.
for R5: an alkyl group having from 1 to 5 carbon atoms or an alkenyl or alkynyl group having from 2 to 4 carbon atoms; and for R6: a hydrogen atom or a group of the general formula R7CO, wherein R7 represents a hydrogen atom or an alkyl group having up to 4 carbon atoms.
The following substituents are especially preferred: for R3: a hydrogen atom; a straight chain alkyl group having from 1 to 6 carbon atoms; a branched alkyl group having from 3 to 5 carbon atoms; An alkoxyalkyl group; a straight chain alkenyl group having from 2 to 4 carbon atoms; a cyclopentyl, cyclohexyl or benzyl group; or a physiologically acceptable metal ion, ammonium ion or substituted ammonium ion which is derived from a primary, secondary or tertiary amine; and for R4: an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 3 to 5 carbon atoms or a cycloalkyl group having from 5 to 7 carbon atoms, which alkyl, alkenyl or cycloalkyl group may be unsubstituted or substituted by: (a) an alkoxy, alkylthio, alkenyloxy or alkenylthio group having from I to 4 carbon atoms; (b) a phenoxy group which may be unsubstituted or substituted by one or two of the same or different substituents selected from methyl, trifluoromethyl and methoxy groups; chlorine or fluorine atoms; and phenoxy groups which may be unsubstituted or substituted by one or more fluorine and/or chlorine atoms; (c) a thienyloxy, benzyloxy, phenyl or thienyl group which may be unsubstituted or substituted by one or two of the same or different substituents selected from methyl, trifluoromethyl and methoxy groups and chlorine and fluorine atoms; (d) one or two fluorine atoms or a trifluoromethyl group; or (e) a cycloalkyl group having from 5 to 7 carbon atoms.
R4 especially represents one of the groups listed in Table A.
TABLE A n - butyl, n - pentyl, n - hexyl, n - heptyl, 2,2 - dimethylhexyl, 3,3 dimethylhexyl, 4,4 - dimethylhexyl, 3 - ethylpentyl, 1,1 - dimethyl - 4 - pentenyl, 5 - methyl - 4 - hexenyl, 1 - methyl - 5 - cyclohexylpentyl, 4 cycloheptylidenebutyl, 4 - trifluoromethylbutyl, 5 - trifluoromethylheptyl, 1,1 dimethyl - 6 - trifluoromethylhexyl, 1 - methyl - 5 - trifluoromethylpentyl, 1,1 difluoro - 4,4 - dimethylpentyl, 4,4 - difluorocyclohexyl, 4 trifluoromethylcyclohexyl, 3 - trifluoromethylcyclohexyl, 2 trifluoromethylcycloheptyl, 3 - trifluoromethylcyclopentyl, 3,3 - dimethyl - 2 oxapentyl, 3 - methyl - 2 - oxahexyl, 4,4 - dimethyl - 2 - oxapentyl, 1,1,4 - trimethyl - 2 - oxapentyl, 3,4 - dimethyl - 2 - oxapentyl, 5 - methyl - 2 - oxa 4 - hexenyl, 2,2 - dimethyl - 3 - oxaheptyl, 1,1 - dimethyl - 3 - oxahexyl, 1,1 dimethyl - 3 - oxaoctyl, 1,1,5,5 - tetramethyl - 3 - oxahexyl, 1 - methyl - 3 oxahexyl, 1 - methyl - 3 - oxaoctyl, 1,1,6 - trimethyl - 3 - oxa - 5 - heptenyl, 1,1,6 - trimethyl - 3 - oxaheptyl, 7 - methyl - 4 - oxaoctyl, 1,1 - dimethyl - 4 oxa - 6 - heptenyl, 4- methoxycyclohexyl, 3 - butoxycyclohexyl, 2 ethoxycyclohexyl, 3 - ethoxycyclopentyl, 4 - methoxycycloheptyl, 2 - thiapentyl, 2 - thiahexyl, 2 - thiaheptyl, 4,4 - dimethyl - 2 - thiapentyl, 5 - methyl - 2 - thia 4 - hexenyl, 3 - thiapentyl, 3 - thiahexyl, 5,5 - dimethyl - 3 - thiahexyl, 1,1 dimethyl - 3 - thiapentyl, 1,1 - dimethyl - 4 - thiapentyl, 4 chlorophenoxymethyl, 3 - chlorophenoxymethyl, 2,3 - dichlorophenoxymethyl, 2,4 - dichlorophenoxymethyl, 2,5 - dichlorophenoxymethyl, 2,6 dichlorophenoxymethyl, 3,4 - dichlorophenoxymethyl, 3,5 dichlorophenoxymethyl, 2 - chloro - 6 - methylphenoxymethyl, 2 - chloro - 4 methylphenoxymethyl, 3 - chloro - 2 - methylphenoxymethyl, 4 - chloro - 2 methylphenoxymethyl, 5 - chloro - 2 - methylphenoxy, 4 trifluoromethylphenoxymethyl, 3 - trifluoromethylphenoxymethyl, 2 - methyl - 5 - trifluoromethylphenoxymethyl, 3 - methyl - 5 trifluoromethylphenoxymethyl, 3 - fluorophenoxymethyl, 2 fluorophenoxymethyl, 3 - (4 - fluorobenzyloxy)propyl, 4 - (3 chlorophenoxy)cyclohexyl, 4 - (3 - trifluoromethylphenoxy)cyclohexyl, 2 phenoxycyclohexyl, 4- (2 - chlorobenzyloxy)cyclohexyl, benzyl, 3 trifluoromethylbenzyl, 4 - methylbenzyl, 3 - chlorophenethyl, 4 - fluorophenethyl, 1,1 - dimethylphenethyl, 1,1 - dimethyl - 4 - phenylbutyl, 2 - methyl - 3 thienyloxymethyl, 2- chloro - 3 - thienyloxymethyl, 2- chloro - 4 thienyloxymethyl, 3 - chloro - 4 - thienyloxymethyl, 2,5 - dimethyl - 3 thienyloxymethyl, 2- chloro - 3 - methyl - 4- thienyloxymethyl, 2 thienyloxymethyl, 4- methyl - 2 - thienyloxymethyl, 5 - chloro - 2 thienyloxymethyl, 5 - chloro - 3 - methyl - 2 - thienyloxymethyl, 5 - chloro - 3 methyl - 2 - thienyloxymethyl, 3,5 - dimethyl - 2 - thienyloxymethyl, 2 - (3 thienyl) - 1,1 - dimethylethyl, 3 - (3 - thienyl) - 1 - methylpropyl, 3 - (2 methoxy - 4 - thienyl)propyl, 3 - thienyl, 2 - chloro - 4 - thenyl, 2 - methyl - 5 thenyl, (2- or 3 - thienyl)butyl, 3 - (1,1 - dimethyl - 3 - thienyl)propyl and 2 - (4 methoxy - 2 - thienyl)ethyl.
The invention also provides a process for the preparation of a compound of the general formula I into another compound of the general formula I by any general formula
wherein R3, R4, R5 and A have the meanings given for the general formula I, R'3 represents a hydrogen atom or a protecting group which can be eliminated by acid solvolysis; Y represents a single bond, a -CH2- group or an isopropylidene group, to give a compound of the general formula I wherein R' and R2 together represent an oxygen atom; and if desired, converting the resulting compound of the general formula I into another compound of the general formula I by any suitable method.
The compound of the general formula XXII may be prepared as described in the following reaction scheme. The present invention also provides a process for the preparation of a compound of the general formula I wherein there is used as starting material any one of the compounds of the general formula II, IV, V, VI, VII, VIII, X, XII, XIII, XV XVI, XVIII, XIX or XX, and the subsequent steps in the following reaction scheme are performed.
The reaction may begin by: (a) reacting a malonate of the general formula
wherein each R9, which may be the same or different, represents an alkyl group having from 1 to 5 carbon atoms or an aralkyl group having from 7 to 9 carbon atoms, with a cyclopentenone of the general formula
in which R8 represents a hydrogen atom or an aliphatic carboxylic acyl group having from 2 to 6 carbon atoms, to form a compound of the general formula
wherein a R8 and R9 have the meanings given above; (b) a compound of the general formula IV is converted by any suitable method into a compound of the general formula
wherein R8 has the meaning given for formula II; (c) (c) a compound of the general formula V is converted by any suitable method into a compound of the general formula
wherein R8 has the meaning given for formula II; (d) a compound of the general formula VI is converted, using an alkanol having from 1 to 5 carbon atoms in acid solution, into a compound of the general formula
wherein R10 represents an alkyl group having from 1 to 5 carbon atoms; (e) an alcohol of the general formula VII is oxidized to give an aldehyde of the general formula
wherein R'O has the meaning given for formula VII; (f) an aldehyde of the general formula VIII is selectively converted, using a dithiol of the general formula HS-CH2-X-CH2-SH IX wherein X represents a single bond, a -CH2- group or an isopropylidene group, in the presence of an acid catalyst, into a dithioacetal of the general formula
wherein R'O and X have the meanings given for formulae VII and IX respectively; (g) a dithioacetal of the general formula X is reacted with a diol of the general formula HOCH2-Y-CH2OH XI wherein Y represents a single bond, a -CH2- group or an isopropylidene group, in the presence of an acid catalyst, to give an acetal of the general formula
wherein X has the meaning given for formula IX, Y has the meaning given for formula XI and R'O has the meaning given for formula VII; (h) an ester of the general formula XII is reduced to give an aldehyde of the general formula
wherein X and Y have the meanings given for formulae IX and Xl respectively; (i) an aldehyde of the general formula XIII is reacted with a phosphonate of the general formula
wherein R4 has the meaning given for formula I and each R", which may be the same or different, represents an unbranched alkyl group having from 1 to 4 carbon atoms, to give an unsaturated ketone of the general formula
wherein X has the meaning given for formula IX and Y has the meaning given for formula XI; (1) an unsaturated ketone of the general formula XV is reduced to give a compound of the general formula
wherein R4 has the meaning given for formula I, X has the meaning given for formula IX, Y has the meaning given for formula XI; or if desired, (1') the unsaturated ketone of the general formula XV is reacted with an organometallic compound of the general formula RSbM XVII wherein R5b represents an alkyl group having from 1 to 5 carbon atoms or an alkenyl or alkynyl group having from 2 to 5 carbon atoms, and M represents an alkali metal or a group of the general formula HalMg, in which Hal represents a chlorine, bromine or iodine atom, to give a compound of the general formula
wherein R4 has the meaning given for formula I, R5b has the meaning given for formula XVII, X has the meaning given for formula IX and Y has the meaning given for formula XI.
(k) the hydroxyl group of a compound of the general formula XVI(b) or XVI(a) protected by means of a group which can be removed easily by acid solvolysis, give a compound of the general formula
wherein R4 and R5 have the meanings given for formula I, X has the meaning given for formula IX, Y has the meaning given for formula XI, and R'2 represents a protecting group which can be removed easily by acid solvolysis; (1) the thioacetal group in a compound of the general formula XVI(a) or (b) or XVIII is removed under mild conditions, for example in the presence of a heavy metal salt, HgCl2 or an alkyl halide in a mixture of an organic solvent and water, to form an aldehyde of the general formula
wherein R4 and R5 have the meanings given for formula I, Y has the meaning given for formula XI and R'3 represents a hydrogen atom or a protecting group which can be removed easily by acid solvolysis; (m) if desired, an aldehyde of the general formula XIX is hydrogenated in the presence of a suitable catalyst to form a compound of the general formula
wherein R4 has the meaning given for formula I, R'3 has the meaning given for formula XIX, Y has the meaning given for formula XI and Raa represents a hydrogen atom or an alkyl group having from one to five carbon atoms; (n) a compound of the general formula XIX or XX is reacted with an ylid of the general formula R4P=CH-CO2R3 XXI in which each R14, any two or three of which may be the same or different, represents a straight chain alkyl group having from 1 to 4 carbon atoms or a phenyl group, and R3 has the meaning given for formula I, to give a compound of the general formula
where R3, R4, Ra and A have the meanings given for formula I, R'3 has the meaning given for formula XIX and Y has the meaning given for formula XI; (o) if desired, a compound of the general formula XXII wherein R'3 represents a hydrogen atom is prepared by mild acid solvolysis of a compound of the general formula XXII in which R'3 represents a protecting group which can be removed easily: (p) the acetal protective group and also, if R13 does not denote a hydrogen atom, the protecting group Rug3, are removed from a compound of the general formula XXII by acid solvolysis, to give a compound of the general formula 1, wherein R1 and R2 together represent an oxygen atom, R6 represents a hydrogen atom, and R3, Rd, R5 and A have any one of the meanings given for formula l; and, if desired, one or more of the following reactions is carried out in any appropriate order: (q) a compound of the general formula I wherein R1 and R2 together represent an oxygen atom, R6 represents a hydrogen atom, R3 has any one of the meanings given for formula I except that it is not a hydrogen atom, R4, R5 and A have any one of the meanings given for formula I is converted by saponification into the corresponding free acid; (r) a compound of the general formula I wherein RX and R2 together represent an oxygen atom, R6 represents a hydrogen atom, R3 has any one of the meanings given for formula I except that it is not a hydrogen atom, and R4, R5 and A have any one of the meanings given for formula I is converted by transesterification into another ester of the general formula I; (s) a compound of the general formula I wherein R1 and R2 together represent an oxygen atom, R6 represents a hydrogen atom, R3 represents a hydrogen atom and R4, R5 and A have any one of the meanings given for formula I, is esterified to give a compound of the general formula I wherein R1 and R2 together represent an oxygen atom, R6 represents a hydrogen atom, R3 represents an aliphatic or cycloaliphatic hydrocarbon group having from 1 to 8 carbon atoms, an alkoxyalkyl group having from 3 to 10 carbon atoms or an araliphatic hydrocarbon group having from 7 to 9 carbon atoms, and R4, R5 and A have any one of the meanings given for formula I; (t) a compound of the general formula I, wherein R and R2 together represent an oxygen atom, R6 represents a hydrogen atom and R3, R4 and R5 have any one of the meanings given for formula I, is reacted with an acylating agent to give a compound of the general formula I in which R1 and R2 together represent an oxygen atom and R3 to R5 have any one of the meanings given for formula I and R6 represents a group of the general formula R7CO, wherein R7 is as hereinbefore defined; (u) a compound of the general formula I, wherein R and R2 together represent an oxygen atom and R3, R4, R5, R6 and A have any one of the meanings given for formula I, is reduced to give a compound of the general formula I wherein one of R1 and R2 represents a hydrogen atom and the other represents a hydroxyl group, and R3, R4, R5, R6 and A have any one of the meanings given for formula I; (v) a compound of the general formula I wherein R3 represents a hydrogen atom and Rr, R2, R4, R5, R6 and A have any one of the meanings given for formula I, is converted into a compound of the general formula I, wherein R3 represents a metal ion, an ammonium ion or a substituted ammonium ion derived from a primary, secondary or tertiary amine.
The 2 - (5 - acetoxypentyl)cyclopent - 2 - en - 1 - one of the general formula II (R8 represents an acetyl group), which may be used as a starting material in the process of the invention, may be prepared by various processes. A suitable route comprises reacting 2 - oxocyclopentancarboxylic acid ethyl ester of the formula
with a 5 - acetoxypentyl halide of the general formula XXIV
wherein Hal represents a chlorine, bromine or iodine atom, to give a 2 oxocyclopentancarboxylic acid ethyl ester which is substituted in the 1-position and of the general formula
saponifying and decarboxylating the compound of the general formula XXV with glacial acetic acid/H2O/H2SO4, to give the compound of the formula
and obtaining the compound of the general formula II via a compound of the general formula
wherein X represents a halogen atom, analogously to the process described in German Offenlegungsschrift No. 2,430,700.
The process of the invention may begin by adding a malonate of the general formula III to a cyclopentenone of the general formula II. This addition reaction is preferably carried out using an alcohol as solvent and a small amount of the corresponding alkoxide is preferably added as a basic catalyst. An alcohol which produces an alkoxide ion which, while it has good basicity, is only slightly nucleophilic, for example a tertiary alcohol, is preferred. The reaction temperature is suitably in the range of from +20 to +800 C.
A preferred process uses dibenzyl malonate as the compound of the general formula III in t - butanol as the solvent.
The malonate of the general formula IV which is thus obtained may then be converted into the corresponding substituted malonic acid of the general formula V. Alkaline saponification is especially suitable for this purpose. When R8 represents an aliphatic carboxylic acyl group, alkaline saponification leads to a acid of the general formula V in which the radical R8 represents a hydrogen atom.
A process which has proved especially useful for the manufacture of the free malonic acid of the general formula V is hydrogenolytic debenzylation of those malonates of the general formula IV in which each R9 represents a benzyl group.
Those malonic acids in which R8 represents an aliphatic carboxylic acyl radical are also preparable by this means.
For decarboxylation, the free malonic acid of the general formula V are preferably warmed in an aqueous lower carboxylic acid as the solvent, with the addition of a mineral acid, until the evolution of CO2 has ceased. If malonic acids in which R8 represents an aliphatic carboxylic acyl radical are used, it is advantageous to use the corresponding carboxylic acid as the solvent. A 3 oxocyclopentaneacetic acid of the general formula VI which can readily be purified by distillation is obtained.
The conversion of the compound of the general formula VI into the esteralcohol of the general formula VII is suitably effected by acid-catalysed alcoholysis in an alcohol of the general formula Rl OH as the solvent, at a temperature in the range of from +20 to +1000C. During this reaction both an esterification of the carboxy group and elimination of any aliphatic carboxylic acyl radical RB which may be present, take place.
In the next step of the process of the invention, an alcohol of the general formula VII is oxidised to give the corresponding aldehyde of the general formula VIII. Any suitable oxidising agent customarily used for the oxidation of aliphatic alcohols to aldehydes may be used.
Several methods are described for example, in Houben Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), volume 7/1, Georg Thieme Verlag, Stuttgart 1954, page 159 et seq.
Further suitable oxidizing agents include the complex formed from thioanisole and chlorine (J. Org. Chem. 38, 1233 (1973)), the chromium trioxide/pyridine complex (J. Org. Chem. 35, 4000 (1970) and J. Org. Chem. 26. 4814 (1961)), and dimethyl sulphoxide with various coreactants (J. Amer. Chem. Soc. 87, 5661 (1965), 88, 1762 (1966), 89, 5505 (1967), Chem. Rev. 67, 247 (1967) and J. Amer. Chem.
Soc. 94, 7586 (1972)).
An especially preferred process is an oxidation using the complex formed from dimethyl sulphoxide and chlorine. For this reaction the instructions of E. J.
Corey and C. K. Kim (Tetrahedron Letters 1973, 919) are suitably followed.
The aldehyde of the general formula VIII may be purified by distillation or by chromatography; however it is advantageous to react the crude aldehyde direct and selectively in the presence of an acid catalyst in an inert solvent with a dithiol of the general formula IX to give a dithioacetal of the general formula X.
The selective protection of the aldehyde group in the compound of the general formula VIII in preference to the oxo group which is also present, may be achieved by working with a stoichiometric amount of the dithiol of the general formula IX and carrying out the reaction at a temperature in the range of from -10"C to -300C.
A preferred embodiment of this process comprises allowing the crude aldehyde of the general formula VIII to react, at a temperature in the range of from -5 to + 100 C, with a slight excess of a dithiol of the general formula IX in the presence of boron trifluoride etherate and, if desired, a water-binding agent, for example magnesium sulphate, in benzene or methylene chloride.
The dithioacetal of the general formula X thus formed may be purified by distillation or chromatography or, alternatively, reacted directly with a diol of the general formula XI in the presence of an acid catalyst in an inert solvent, for example benzene or toluene, if desired in the presence of a water-binding agent, to give an acetal of the general formula XII. Preferably the dithioacetal of the general formula X is heated to boiling point with somewhat more than the stoichiometric amount of the diol of the general formula XI, in benzene or toluene, with an acid catalyst, for example p - toluenesulphonic acid, with a water separator and subsequently the reaction mixture is worked up in any suitable manner.
The acetal of the general formula XII may be purified by distillation under a high vacuum or by chromatography, and then reduced by any suitable method to give an aldehyde of the general formula XIII. Suitable reducing agents are reducing agents known for the reduction of esters to aldehydes, preferably complex metal hydrides, for example lithium triethoxyaluminium hydride. Diisobutylaluminium hydride in an inert solvent for example an aliphatic or aromatic hydrocarbon or an anhydrous ether, tetrahydrofuran or 1,2- dimethoxyethane, is especially preferred.
The reduction is suitably carried out at a temperature in the range of group to a hydroxyl group in the presence of an olefinic double bond. Preferred reducing agents are complex metal hydrides, especially the complex borohydrides, for example potassium borohydride, sodium borohydride, zinc borohydride or lithium perhydro - 9b - boraphenalkyl hydride (J. Amer. Chem. Soc. 92, 709 (1970)), or aluminium hydrides, for example sodium bis(2 methoxyethoxy)aluminium hydride or diisobutylamuminium hydride. The reduction is usually carried out at a temperature in the range of from -10" to 500C in a solvent which is inert towards the hydride, for example an ether, for example diethyl ether, 1,2 - dimethoxyethane, dioxane, tetrahydrofuran or diethylene glycol dimethyl ether, or a hydrocarbon, for example benzene, or in an alcohol/water mixture, for example ethanol/water.
In order to prepare an alkylated compound of the general formula XVI(b), a ketone of the general formula XV is reacted with an organometallic compound of the general formula XVII. Suitable organometallic compounds are, especially, organolithium or organomagnesium (Gridnard) compounds.
This reaction is carried out in a solvent which is inert under the reaction conditions, for example in a hydrocarbon or, preferably, an ether, for example diethyl ether, tetrahydrofuran or 1,2 - dimethoxyethane. The reaction may be carried out at a temperatures in the range of from -60 to +300C, preferably from -30 to -100C.
The isomeric a- and A - hydroxy compounds of the general formulae XVI(a) or XVI(b) which are formed during the reduction or the reaction with the organometallic compound may be separated into the two isomers using chromatographic methods, The subsequent reactions may, however, be carried out successfully with a mixture of two isomers, so that separation into cr- and p hydroxy compounds can be carried out at any desired stage in the process after the reduction.
In principle, the hydroxyl group in a compound of the general formula XVI(a) or XVI(b) may be protected by any protecting group which can be easily removed.
Protecting groups which are especially suitable for converting the compound of the general formula XVI(a) or XVI(b) into a compbund of the general formula XVIII are those which are introduced by acid catalysis, and usually by reaction with an enol-ether. Especially suitable enolethers are 2,3-dihydropyran, ethyl vinyl ether and methyl isopropenyl ether, and especially suitable acid catalysts, are, for example, p - toluenesulphonic acid and sulphuric acid. The reaction is suitably carried out in an aprotic solvent, for example diethyl ether, dioxane or benzene, and a temperature in the range of from -20"C to +400C is suitably maintained.
The liberation of an aldehyde of the general formula XIX from the dithioacetal of the general formula or XVIII, XVI(a), XVI(b) or XVIII, be effected in the presence of a heavy metal salt, HgCl2, or an alkyl halide, in a mixture of an organic solvent and water. Organic solvents which may be used are preferably water-miscible solvents, for example tetrahydrofuran or dioxane, and preferably dipolar aprotic solvents, for example acetonitrile, dimethylformamide or dimethyl sulphoxide. The elimination of the protecting group is advantageously carried out in the presence of an acid-binding agent. The reaction temperature is suitably in the range of from 0 to +100"C, preferably +10 to +600C.
Preferably the dithioacetal of the general frmu'a XVI(a), XVI(b) or XVIII is stirred in a dimethyl sulphoxide/water mixture with excess methyl iodide and calcium carbonate for 2 to 5 hours at 30 to 50 C. After removal of the inorganic salt and the solvent, the resulting aldehyde of the general formula XIX may be reacted further directly or purified by chromatography.
The unsaturated aldehyde of the general formula XIX may, if desired, be hydrogenated to give a saturated aldehyde of the general formula XX. Any process which will selectively reduce an isolated olefin is double bond without attacking an aldehyde group is suitable, Catalytic hydrogenation using nickel, palladium or platinum catalysts, if desired on a support material for example active charcoal or CaCO3, is especially suitable. Suitable solvents are the usual solvents for catalytic hydrogenation reactions, for example low-molecular weight alcohols, esters or ethers, for example methanol, ethyl acetate, tetrahydrofuran or 1,2 dimethoxyethane. Preferably the compound of the general formula XX is hydrogenated in an aprotic solvent, for example tetrahydrofuran, dioxane, 1,2 dimethoxyethane, ethyl acetate or acetone, using Raney nickel, or palladium on active charcoal, a temperature in the range of from 20 to 800C and a hydrogen pressure of from I to 20 atmospheres being maintained. If the group represented by R5 contains a multiple bond, this is also hydrogenated.
The aldehyde of the general formula XIX or XX is converted into a compound of the general formula XXII by reaction with a phosphonium ylid of the general formula XXI, in which R14 preferably represents a phenyl group, in a suitable solvent. The phosphonium ylid and the phosphonium salt from which it is derived.
may be prepared analogously to methods described in the literature (for example Organic Reactions, volume 14, (1965), page 270 et seq., edition John Wiley and Sons, New York, London, Sidney). Suitably, a solution of the resonance stabilized ylid of the general formula XXI is added in a slight excess to a solution of the aldehyde of the general formula XIX or XX and the reaction mixture is heated to a temperature in the range of from 40 to 100"C for between 2 and 12 hours. Examples of suitable solvents are ethers, for example diethyl ether, tetrahydrofuran and diethylene glycol dimethyl ether, di(lower alkyl)sulphoxides, for example dimethyl sulphoxide, amides of carboxylic acids, for example dimethylformamide and N,N dimethyl acetamide, hexamethylphosphoric acid triamide (HMPT) or hydrocarbons, especially benzene, toluene or xylene.
Preferably a solution of methoxycarbonylmethylenetriphenylphosphorane in toluene is added dropwise, in a slight excess, to a solution of the aldehyde of the general formula XIX or XX in toluene, and reaction mixture is heated to 40 to 80"C for between 4 and 6 hours in an inert gas atmosphere, for example argon; the end of the reaction may be determined using thin layer chromatography. In general, the resulting compound of the general formula XXII is purified by chromatography after working up. However, the compound may also be used further in the form of the crude product.
The protecting group for the hydroxyl group and the acetal protecting group may be removed either successively, or together in a one stage reaction. Under mild conditions, for example in an alcohol/water mixture which contains about 1",, by weight of oxalic acid, and preferably in ethylene glycol in the presence of an acid catalyst, for example dichloroacetic acid boron trifluoride etherate or oxalic acid, predominantly compounds of the general formula XXII wherein R11 represents a hydrogen atom are obtained, at temperatures between 0 and 30"C.
Under more vigorous hydrolysis conditions, the acetal protecting group in the compound of the general formula XXII is removed as well as the hydroxyl protecting group, and a compound of the general formula I wherein R1 and R2 together represent an oxygen atom, and Re represents a hydrogen atom, is obtained, If a lower alcohol which as a low water content and contains a small amount of a strong acid is chosen as the solvent, an ester of the general formula I is obtained, transesterification taking place in some cases.
The removal of the protecting group is suitable effected at a temperature in the range of from 20 to 500C with a reaction time of 3 to 24 hours. After evaporating off the solvent at low temperature, the keto-acid is suitably purified by a chromatographic method. However, it may also be directly reacted further after removing the acid catalyst, for example by partitioning the crude product between water or a saturated solution of sodium chloride and a non-polar solvent, for example benzene.
In general, the cr,-unsaturated esters of the general formula I wherein R1 and R2 together represents an oxygen atom, R3 does not represent a hydrogen atom and A, R4 and R5 have any of the given meanings, are not readily saponified under these conditions. In order to obtain compounds of the general formula I in which R3 represents a hydrogen atom, this reaction is suitably followed by alkaline saponification with an alkali metal hydroxide in aqueous alcoholic solution.
Starting from a compound of the general formula I in which R1 and R2 together represent an oxygen atom and R3 represents a hydrogen atom, it is possible to prepare the corresponding esters. This may be effected in a simple way by reacting the carboxylic acid with the diazoalkane in a solvent such as diethyl ether or THF.
Aromatic solvents, for example benzene, or a halogenated hydrocarbon, for example chloroform, are also suitable for this reaction.
The reaction of a salt of the carboxylic acid with an alkyl halide also provides a route to the corresponding esters. Suitable solvents for this reaction are, especially, dipolar, aprotic solvents, for example acetonitrile, dimethylformamide or dimethyl sulphoxide, and the reaction temperatures may be, for example between 100 and +100 C, preferably between +20 and +60"C.
in principle, any carboxylic acid of the general formula I (R3 represents a hydrogen atom) can be converted into one of the corresponding esters by these methods.
An ester obtained in this way may subsequently be reacted with a suitable acylating agent.
Acylating agents which may be used include free carboxylic acids and their reactive derivatives. When the free carboxylic acid is used, the reaction is preferably carried out using this acid as the solvent, at a temperature in the range of from 0 to 70". In some cases it is advantageous to buffer the reaction solution in order to avoid secondary reactions (compare J. E. Pike, F. H. Lincoln and W. P.
Schneider, H. Org. Chem. 34, 3553 (1969)).
The corresponding carboxylic acid halide or carboxylic acid anhydride may also be used for the acylation. The reaction is then preferably carried out in an aprotic solvent in the presence of a base at a temperature in the range of from 0 to 80". Furthermore, the reaction of the alcohol with the corresponding ketene can also be used for the acylation. This reaction is suitably carried out in an aprotic solvent at room temperature.
By reducing the carbonyl group in the compound of the general formula I wherein R1 and R2 together represent an oxygen atom, it is possible to prepare the corresponding alcohol of the general formula I wherein one of R1 and R2 represents a hydrogen atom and the other represents a hydroxyl group. Reducing agents which may be used are those which reduce a carbonyl group in preference to an ester or acid group and do not attack olefinic double bonds. Complex metal hydrides, for example sodium borohydride, zinc borohydride or lithium perhydro 9b - boraphenalkyl hydride, are preferred. However, reducing agents, for example lithium aluminum hydride, which are able to reduce a carboxyl group, can also be used for this reduction if they are not used in excess and if low temperatures are employed. The reaction conditions are suitably essentially those described for the manufacture of a compound of the general formula XVI from a compound of the general formula XV.
The reduction of the carbonyl group in the l-position of the cyclopentane range usually does not proceed stereospecifically. A mixture of a- and isomers relative to the position of the resulting hydroxyl group, is formed.
The same applies both for the reduction of the carbonyl group in the 3-position of the lower side chain (reaction of a compound of the general formula XV to give a compound of general formula XVI) and for the reaction thereof with an organometallic compound.
The stereoisomers may be separated directly after they are formed or after any of the subsequent reaction steps. This means that all of the reactions described can be carried out either with the pure a- or p-isomer, or with a mixture of the a- and pisomers, Compounds of the general formula I wherein R3 represents a hydrogen atom may be converted into the corresponding metal salts or ammonium salts by adding the equimolar amount of a base, for example an alkali, a carbonate or an amine.
Amines which are especially useful are physiologically tolerable primary, secondary or tertiary amines, tris(hydroxymethyl)aminomethane, piperidine or 4 ethylmorpholine. Suitable metal ions include those of the alkali metals and alkaline earth metals.
In the compounds of the general formulae IV to VII, X, XII, XIII, XV, XVI, XVIII to XX and XXII, the side chains in the 2- and 3-position of the cyclopentane ring may be cis or trans relative to one another. However, after the acetal protecting group in the 1-position of the cyclopentane ring has been removed, the two side chains generally assume the trans-configuration which is favoured thermodynamically. Therefore, if a compound of the general formula I wherein R1 and R2 together represent an oxygen atom is treated with a base, the compound obtained is generally one having the trans-configuration in respect of the linking of the side chains to the five-membered ring. The trans-configuration of the side chains is usually already obtained when these compounds are manufactured and purified.
The reactions for the introduction of double bonds do not proceed completely stereospecifically. In general, however, it can be assumed that, in the main, a translinkage is obtained from the Horner reaction and the corresponding cis-product is formed to only a slight extent; it may be removed by a chromatographic purification. Similarly, with the Witting reaction for the introduction of the carboxyl side chain, in the main the corresponding trans-olefin is formed. In this case also, the cis-olefin, which is formed to a slight extent as a by-product, may be separated off by purification operations.
If the individual reaction products are not obtained in a sufficiently pure form to be used directly in the subsequent reaction step, purification by means ot; tor example, column chromatography, thin layer chromatography or high pressure liquid chromatography, is advisable.
The compounds of the general formula I are usually obtained in the form of racemates. These may, if desired, be obtained in the form of the optically active antipodes by any suitable method of resolving the racemate.
Compounds which can be manufactured by the processes according to the invention are, in addition to those mentioned in the Examples, especially those listed in Table B.
TABLE B 9 - oxo - 165 - hydroxy - 20 - methylprosta - trans 2,,trans.14 - dienoic acid benzyl ester, 9 - oxo - 165 - hydroxyprosta - trans 2, trans 14 - dienoic acid benzyl ester, 9 - oxo - 165 - hydroxy - 20 - methylprosta - trans 2, trans 14 - dienoic acid phenethyl ester, 9 - oxo - 165 - hydroxyprosta - trans 2, trans 14 - dienoic acid phenethyl ester, 9 - oxo - 16g - hydroxy - 20 - methylprosta - trans 2, trans 14 dienoic acid butyl ester, 9 - oxo - 16t - hydroxyprosta - trans 2, trans 14 - dienoic acid butyl ester, 9 - oxo - 165 - hydroxy - 17,17.20 - trimethyl - 19 - oxoprosta trans 2, trans 14-dienoic acid propyl ester, 9 - oxo - 16N - hydroxy - 17,17 dimethyl - 19 - oxaprosta - trans 2, trans 14 - dienoic acid propyl ester, 9 - oxo 16,20 - dimethyl - 16g - hydroxyprosta - trans 2, trans 14 - dienoic acid hexvl ester, 9 - oxo - 16 - methyl - 16{ - hyxroxyprosta - trans 2, trans 14 - dienoic acid hexyl ester, 9 - oxo - 16 - hydroxy - 17 - (m - trifluoromethylphenyloxy) 18,19,20 - trinorprosta - trans 2, trans 14 - dienoic acid heptyl ester, 9g,16t - dihydroxy - 17 - (m - chlorophenoxy) - 18,19,20 - trinorprosta - trans 2, trans 14 dienoic acid ethyl ester, 9{,16t - dihydroxy - 17 - phenoxy - 18,19,20 trinorprosta - trans - 2, trans 14 - dienoic acid 2 - ethoxyethyl ester, 9g,16g - dihydroxy - 17 - (p - fluorophenoxy) - 18,19,20 - trinorprosta - trans 2, trans 14 dienoic acid 2 - n - butoxy - ethyl ester and 9g,16g - dihydroxy - 17 - phenoxy 18,19,20 - trinorprosta - trans 2, trans 14 - dienoic acid 4 - ethoxybutyl ester.
The compounds of the invention generally have spasmogenic, bronchodilating, gastric juice secretion-inhibiting, luteolytic and abortive and, especially, hypotensive, properties. The present invention therefore provides a pharmaceutical preparation which comprises a compound of the general formulu I in admixture or conjunction with a pharmaceutically suitable carrier. The pharmaceutical preparation contains a compound of the general formula I in the form of a free acid, physiologicallytolerabe salt, or an ester.
The pharmaceutical preparation may contain an acid, salt or ester in the form of an aqueous solution or suspension, or in the form of a solution or suspension in a pharmaceutically suitable organic solvent, for example a monohydric or polyhydric alcohol, for example ethanol, ethylene glycol or glycerol, an oil, for example sunflower oil or cod-liver oil, an ether, for example diethylene glycol dimethyl ether, or a polyether, for example a polyethylene glycol; pharmaceutically suitable polymeric excipients, for example polyvinylpyrrolidone, may be used.
The pharmaceutical preparation may have any suitable formulation; it may for example, be a galenic infusion solution, an injectable solution or oral dosage units, for example tablets; it may also be a formulation which can be applied locally, for example a cream, an emulsion or suppositories, and, especially, an aerosol.
The compound of the general formula I may be used in combination with other active ingredients, for example fertility-regulating hormones or releasing hormones, for example LH, FSH, oestradiol and LH-RH; diuretic agents, for example Furosemide; antidiabetic agents, for example Glycodiazine, Tolbutamide.
Glibenclamide, Phenformin, Buformin and Metformin; preparations for the treatment of diseases of the circulatory system in general for example agents which dilate the coronary vessels, for example Chromonar or Prenylamine; hypotensive agents, for example reserpine, ez-Methyldopa or Clonidine, or antiarrhythmic agents; agents which lower the lipid level; agents for use in geriatric medicine and other formulations which have an action on the metabolism; psychopharmacological agents, for example Chlordiazepoxide, Diazepam or Meprobamate; prostaglandins or prostaglandin-like compounds, prostaglandin antagonists or agents which inhibit prostaglandin biosynthesis, for example non steroid antiphlogistic agents.
The dosage unit is preferably in the range of from 0.05 to 150 mg, the daily dose suitably ranging from 0.1 to 750 mg.
The following Examples illustrate the invention. The proportions of solvents, mentioned with regard to chromatography hereinafter, are given on a volume basis: ether, when used hereinafter, is used to denote diethyl ether.
Example I 2-(5-acetoxypentyl)-3-carboxymethylcyclopentan- 1-one 200 g of dibenzyl malonate and 105 g of 2 - (5 - acetoxypentyl)cyclopent - 2 en - 1 - one were added successively to a solution of 0.1 mol of sodium tert butoxide in 250 ml of tert - butanol. The reaction solution is stirred for 72 hours at 50"C. It was then cooled, the solution was neutralised by adding glacial acetic acid and the bulk of the solvent was then evaporated off in vacuo. The crude residue was taken up in ether. The ether phase was washed with semi-saturated sodium chloride solution and NaHCO3 solution. The ether phase was dried and evaporated. The mixture of dibenzyl malonate and dibenzyl[2- (5 - acetoxypentyl)- 3oxocyclopent - 1 - yl]malonate, which was thus obtained, was hydrogenated, without further purification, in glacial acetic acid (1000 ml) using Pd/C as the catalyst, at room temperature and without excess pressure.
After the absorption of hydrogen had ceased, the catalyst was filtered off and the filtrate was heated for 12 hours under reflux in order to decarboxylate the [2 (5 - acetoxypentyl) - 3 - oxocyclopent - 1 - yl]malonic acid obtained. The solvent was then distilled off in vacuo. The residue was taken up in 11 of toluene and the solution was again evaporated in order to remove the excess glacial acetic acid.
The residue was again taken up in ether and the ether solution was extracted several times with 10% w/v ice-cold KHCO3 solution. The combined alkaline, aqueous extracts were immediately acidified with solid sodium bisulphate and extracted several times with ethyl acetate. The combined ethyl acetate extracts were dried and evaporated and the residue was distilled under a high vacuum.
94 g of the desired product were obtained at a boiling point005 of -190"C.
NMR (60 MHz CDCI3) 9.4 ppm IH singlet 4.1 ppm 2H triplet 2.8-1.0 ppm multiplet 2.0 ppm singlet.
Example 2 2-(5-hydroxypentyl)-3-ethoxycarbonylmethyl-cyclopentanone 7.0 g of 2 - (5 - acetoxypentyl) - 3 - carboxymethyl - cyclopentan - 1 - one were dissolved in 250 ml of absolute methanol and the solution, together with 1 ml of concentrated H2SO4, was boiled for one hour under reflux. The mixture was left to stand overnight and on the next day the product taken up in ether. The ether solution was washed with semi-saturated NaHCO3 solution and with semi-saturated NaCI solution, dried and evaporated. This gave 6.4 g of an end product which according to thin layer chromatography is a single compound.
Ref~0.18 (silica gel/cyclohexane, ethyl acetate, glacial acetic acid, 60/40/1).
NMR (60 MHz, CDCI3) 3.8 ppm singlet 3H 3.7 ppm triplet 2H 2.8-1.0 ppm multiplet 19H Singlet at 2.1 ppm.
Example 3 5-(5-oxo-2-methoxycarbonylmethylcyclopentyl)valeraldehyde A solution of 4.1 g of chlorine in 80 ml of absolute methylene chloride was prepared at OOC, with the exclusion of moisture. This solution was cooled to -45"C and a mixture of 20 g of absolute dimethyl sulphoxide and 22 ml of absolute methylene chloride was added dropwise, whilst stirring well. The temperature did not rise above -30"C during the addition. The mixture was stirred for a further 10 minutes and 5 g of 2 - (5 - hydroxypentyl) - 3 - methoxycarbonylmethylcyclopentanone in 7 ml of absolute methylene chloride were then added dropwise.
The mixture was stirred for a further one hour at -500C and for three hours at -300C. A solution of 12 g of freshly distilled triethylamine in 10 ml of absolute methylene chloride was then added dropwise to the reaction mixture. The mixture was stirred for a further 5 minutes and 200 ml of carbon tetrachloride were then added. The solution thus obtained was washed with 50 ml of saturated sodium chloride solution and 50 ml of semi-saturated sodium bicarbonate solution. The organic solution was then dried and concentrated to about 100 ml in vactlo at temperatures below 40"C. The solution of 5 - (5 - - oxo - 2 methoxycarbonylmethylcyclopentyl)valeraldehyde which was thus obtained was used, without further purification, for the preparation of the thioacetal described in Example 4. Thin layer chromatography (silica gel).
Ref~0.38 (cyclohexane/ethyl acetate/glacial acetic acid, 60/40/1), can be stained with 2,4 - dinitrophenyl - hydrazine.
Example 4 2-[4-( 1 ,3-dithiolan-2-yl)-butyl]-3-methoxycarbonylmethylcyclopentanone 15 g of anhydrous magnesium sulphate, 2.1 g of dithioglycol and 1 ml of boron trifluorode-etherate solution (45% by weight in ether) were added to the aldehyde solution obtained in Example 3. The mixture was stirred for 1 hour at room temperature and a further 1 ml of dithioglycol and 0.5 ml of boron trifluorideetherate were then added and the mixture left to stand overnight. The next morning the mixture was poured into 200 ml of ice water, the organic phase was separated off and the aqueous phase was washed with carbon tetrachloride. The combined organic extracts were washed, at -l00C, which 100 ml of 1N NaOH and then with twice 100 ml of water. The organic phase was dried and evaporated. The residue was chromatographed on silica gel using toluene/ethyl acetate, 10/1. 2.3 g of the desired thioacetal are obtained.
Ref~0.204 (toluene 10/ethyl acetate 1).
NMR (60 MH CDCI3) 4.5 ppm, 1H, triplet 3.6 ppm, 3H, singlet 3.2 ppm, 4H, singlet 2.61.0 ppm, 16H, multiplet.
Example 5 6-[4-( 1 ,3-dithiolon-2-yl)butyl]-7-methoxycarbonylmethyl- 1,4 dioxaspiro [4,4] nonane 7.5 g of 2 - [4 - (1,3 - ithiolon - 2 - yl)butyl] - 3 - methoxy carbonylmethylcyclopentanone were dissolved in 200 ml of toluene and, after adding 15 g of ethylene glycol and 2 ml of a 45% w/v solution of boron trifluoride etherate, the mixture was boiled for 4 hours with a water-separator. It was allowed to cool and 50 ml of water were added. The toluene phase was separated off.
washed with sodium bicarbonate solution and saturated sodium chloride solution, dried and evaporated. 7.2 g of crude product were obtained.
Thin layer chromatography (silica gel/cyclohexane, 60/ethyl acetate, 40/glacial acetic acid, 1).
Ref~0.51.
NMR (CDCI3/60 MHz) 63.9 ppm, 4H, multiplet.
Example 6 6-[4-(1,3-dithiolon-2-yl)butyl]-7-formylmethyl- 1,4 dioxaspiro[4,41nonane 7.2 g of6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - methoxycarbonylmethyl 1,4 - dioxaspiro[4,4]nonane were dissolved in 150 ml of absolute toluene. This solution is cooled to -70"C and 23 ml of a 200,, w/v solution of diisobutylaluminum hydride in toluene was added dropwise. After 3.5 hours, 10 g of glacial acetic acid in 40 ml of toluene were added at -700C. The temperature was allowed to rise to 0 C and 50 ml of water were then added to the mixture. The organic phase was separated off and the aqueous phase was extracted several times with toluene. The combined organic phases were washed once with semi-saturated sodium chloride solution and once with semi-saturated bicarbonate solution, dried over magnesium sulphate and evaporated to dryness. 6.9 g of the desired aldehyde were obtained.
Thin layer chromatography (silica gel/cyclohexane:ethyl acetate:giacial acetic acid, 60/40/1).
Rf~0.42.
NMR (60 MHz, CDCI3) S 9.85 ppm, 1H triplet 4.50 ppm, 1H triplet 3.95 ppm, 4H singlet 3.30 ppm, 4H singlet 2.4-1.1 ppm, 16H multiplet.
Example 7a 6-[4-(1,3-dithiolon-2-yl)butyl]-7-(4-oxonon-trans-2-enyl)- 1,4 dioxaspiro[4,4]nonane 420 mg of 80% by weight sodium hydride suspension (in mineral oil) were initially introduced into 45 ml of absolute 1,2 - dimethoxyethane and 2.66 g of dimethyl - 2 - oxo - heptylphosphonate in 60 ml of 1,2 - dimethoxyethane were added, under argon. The mixture was stirred for a further hour at room temperature and a solution of 3.2 g of the aldehyde from Example 6 then added.
The mixture was stirred for a further 3 hours at room temperature, neutralised with glacial acetic acid, clarified with a little animal charcoal and chromatographed on silica gel using toluene/ethyl acetate, 10/1, as the running agent.
Thin layer chromatography (silica gel/toluene/ethyl acetate, 1:1).
Rf~0.68.
NMR (CDClW60 MHz) s6.6--7.2 ppm, 1H multiplet 6.1 ppm, 1H doublet 4.5 ppm, 1H triplet 3.9 ppm, 4H singlet 3.2 ppm. 4H singlet 2.8-1.1 ppm, multiplet, other protons.
In an analogous manner, starting from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] 7 - formylmethyl - 1,4 - dioxaspiro[4,4]nonane, the following compounds were prepared: Example 7b 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - oxooct - trans - 2 - enyl) 1,4 - dioxaspiro[4,4]nonane.
NMR S 5.8-7.0 ppm, 2H multiplet by reaction with dimethyl 2 - oxohexylphosphonate, Example 7c 6 - [4 -(1,3 -dithiolon -2 -yl)butyl] -7 -(4 -oxoundec trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR S5.8--6.1 ppm, multiplet by reaction with dimethyl 1,2 - oxohexylphosphonate.
Example 7d 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - oxo - 4 - cyclohexylbut trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR S5.8--7.1 ppm, 2H multiplet by reaction with dimethyl - 2 - cyclohexyl - 2 - oxoethylphosphonate.
Example 7e 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - oxo - 5,5 - dimethyl - 7 oxanon - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR S5.87.1 ppm, 2H, multiplet 3.4 ppm, 2H, quartet 3.1 ppm, 2H, singlet 1.1 ppm, singlet for (CH3)2 by reaction with dimethyl - 2 - oxo - 3,3 - dimethyl - 5 - oxaheptylphosphonate.
Example 7f 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - oxo - 5,5 - dimethylnon traits - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR 5.8-7.2 ppm, 2H, by reaction with dimethyl - 2 - oxo - 3,3 - dimethylheptylphosphonate.
Example 7g 6 - [4- (1,3 - dithiolon - 2- yl)butyl] - 7 - (4- oxo - 5 - m chlorophenoxypent - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR Multiplet at 6.0-7.6 ppm (6H) by reaction with dimethyl - 2 - oxo - 3 - m - chlorophenoxypropylphosphonate.
Example 7h 6 - [4 - (1,3 - dithiolon - 2 - yl)butyll - 7 - (4 - oxo - 5 - phenoxypent trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR 5.8-7.6 ppm, multiplet, 7H by reaction with dimethyl - 2 - oxo - 3 - phenoxypropylphosphonate and Example 7i 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - oxo - 5 - (m trifluoromethylphenoxy)pent - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR 5.8-7.7 ppm, multiplet (6H) by reaction with dimethyl - 2 - oxo - 3 - (m trifluoromethylphenoxy)propylphosphonate.
Example 8a 6-[4-(1,3-dithiolon-2-yl)butyl]-7-(4-hydroxynon-trans-2-enyl)- 1,4 dioxaspiro[4,4] nonane 4.1 g of the a,-unsaturated ketone described in Example 7a were dissolved in 30 ml of tetrahydrofuran and 30 ml of methanol and the solution was added dropwise, at 0 to 50C, to a solution of 1.8 g of sodium borohydride in 20 ml of methanol and 2 ml of water, The mixture was stirred for a further one hour at 100 C, neutralised with glacial acetic acid and evaporated in vacuo. The residue was taken up in water and the aqueous solution was then extracted several times with ether.
The combined ether phases were washed with sodium bicarbonate solution, dried and evaporated. 4.1 g of the desired alcohol were obtained.
Thin layer chromatography (silica gel, toluene/ethyl acetate, 1:1).
Rf~0.60.
NMR (60 MH7, CDCI3) 85.55.7 ppm, 2H, multiplet IR P(OH)~3500- cm-t In a completely analogous manner the following compounds were prepared: Example 8b 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - hydroxyoct - trans - 2 enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR 5.5-5.9 ppm, 2H, multiplet IR v(OH)-3500 cm~' from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - oxooct - trans - 2 - enyl) 1,4 - dioxaspiro[4,4]nonane.
Example 8c 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - hydroxyundec - trans - 2 enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR 65.55.9 pm, 2H, multiplet IR r(OH)~3500 cm-' from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - oxoundec - trans - 2 enyl) - 1,4 - dioxaspiro[4,4]nonane.
Example 8d 6 - [4 -(1,3 -dithiolon -2 -yl)butyli -7 -(4 -hydroxy -4 -cyclohexylbut trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR 5.5-5.8 ppm, 2H, multiplet IR v(OH)-3500 cm' from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - oxo - 4 - cyclohexylbut trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
Example 8e 6 -[4 -(1,3 -dithiolon -2 -yl)butyl] -7 -(4 -hydroxy -5,5 - dimethyl - 7 oxanon - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4inonane.
NMR 5.5-5.9 ppm, 2H, multiplet IR #(OH)~3450 cm-' from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - oxo - 5,5 - dimethyl - 7 oxanon - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
Example 8f 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - hydroxy - 5,5 dimethylnon - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR a 5.4-5.8 ppm, 2H, multiplet IR v(OH)~3500 cm-1 from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - oxo - 5,5 - dimethylnon trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
Example 8g 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - hydroxy - 5 - m - chlorophenoxypent - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4inonane.
NMR 85.46.1 ppm, multiplet, 2H IR #(OH)~3500 cm-' from 6 - [4- (1,3 - dithiolon - 2- yl)butyl] - 7 - (4- oxo - 5 - m chlorophenoxypent - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
Eample 8h 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - hydroxy - 5 - phenoxypent trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR #5.4-6.0 ppm IR v(OH)-3500 cm-' from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - oxo - 5 - phenoxypent trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane, and Example 8i 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - hydroxy - 5 - (m trifluoromethylphenoxy)pent - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR 85.46.1 ppm IR #(OH)~3500 cm-' from 6 - [4 - (1,3 - dithiolon - 2- yl)butyl] - 7 - [4- oxo - 5 - (m - trifluoromethylphenoxy)pent - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
Example 9a 6-[4-(1 ,3-dithiolon-2-yl)butyl] -7- [4-(tetrahydropyran-2-yloxy)- non-trans-2-enyl]-l ,4-dioxaspiro[4,4]nonane 4.1 g of the alcohol obtained in Example 8a were dissolved in 120 ml of absolute ether, 7 ml of 2,3 - dihydropyran and 100 mg of p - toluenesulphonic acid were added and the mixture stirred for 5 hours at room temperature. For working up, the reaction solution was shaken with semi-saturated sodium chloride solution and semi-saturated sodium bicarbonate solution, dried with magnesium sulphate and evaporated. For purification, the residue was chromatographed on silica gel using toluene/ethyl acetate, 10/1.
3.8 g of the desired end product were obtained.
Thin layer chromatography (silica gel/toluene:ethyl acetate, 1:1), Rf~0.70.
NMR (60 MH,, CDCI3) b5.25.8 ppm, 2H, multiplet 4.34.8 ppm, 2H, multiplet and triplet 3.9 ppm, 4H, singlet 3.25 ppm, 4H, singlet In an analogous manner the following compounds were prepared: Example 9b 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - 14 - (tetrahydropyran - 2 - yloxy)oct - trans - 2 - enyl] - 1,4 - dioxaspiro[4,4]nonane NMR #4.3-4.8 ppm, 2H, multiplet with triplet from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - hydroxyoct - trans - 2 enyl) - 1,4 - dioxaspiro[4,4]nonane.
Example 9c 6 - [4 - (1,3 - dithiolon - 2 - yl)butyll - 7 - [4 - (tetrahydropyran - 2 yloxy)undec - trans - 2 - enyl] - 1,4 - dioxaspiro[4,4]nonane.
NMR #4.3-4.8 ppm 2H, multiplet with triplet from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - hydroxyundec - trans - 2 enyl) - 1,4 - dioxaspiro[4,4]nonane.
Example 9d 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - (tetrahydropyran - 2 yloxy) - 4 - cyclohexylbut - trans - 2 - enyl)] - 1,4 - dioxaspiro[4,4]nonane.
NMR s4.34.8 ppm, 2H, multiplet with triplet from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - hydroxy - 4 cyclohexylbut - trans - 2 - enyli - 1,4 - dioxaspiro[4,4]nonane.
Example 9e 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - (tetrahydropyran - 2 yloxy) - 5,5 - dimethyl - 7 - oxanon - trans - 2 - enyl] - 1,4 dioxaspiro[4,4]nonane.
NMR '34.3-4.8 ppm, 2H, multiplet with triplet from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - hydroxy - 5,5 - dimethyl 7 - oxanon - trans - 2 - enyl] - 1,4 - dioxaspiro[4,4]nonane.
Example 9f 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - (tetrahydropyran - 2 yloxy) - 5,5 - dimethylnon - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
NMR '34.3-4.8 ppm, 2H, multiplet with triplet from 6- [4- (1,3 - dithiolon - 2- yl)butyl] - 7 - (4- hydroxy - 5,5 dimethylnon - trans - 2 - enyl] - 1,4 - dioxaspiro[4,4]nonane.
Example 9g 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - (tetrahydropyran - 2 - yloxy) - 5 - m - chlorophenoxypent - trans - 2 - enyll - 14 - dioxaspiro[4,4]nonane.
NMR '34.3-4.8 ppm, 2H, multiplet with triplet from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - hydroxy - 5 - m chlorophenoxypent - trans - 2 - enyl] - 1,4 - dioxaspirn[4Alnonane.
Example 9h 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - (tetrahydropyran - 2 yloxy) - 5 - phenoxypent - trans - 2 - enyl] - 1,4 - dioxaspiro[4,4]nonane.
NMR #4.3-4.8 ppm, 2H, multiplet with triplet from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - (4 - hydroxy - 5 - phenoxypent trans - 2 - enyl] - 1,4 - dioxaspiro[4,4lnonane, and Example 9i 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - (tetrahydropyran - 2 yloxy)- 5 - (m - trifluoromethylphenoxy)pent - trans- 2 - enyli - 1,4 - dioxaspiro[4,4]nonane.
NMR '34.3-4.8 ppm, 2H, multiplet with triplet from 6 - [4- (1,3 - dithiolon - 2- yl)butyl] - 7- hydroxy - 5 - (m trifluoromethylphenoxy)pent - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4lnonane.
Example 10a 6-(4-formylbutyl)-7-[4-(tetrahydropyran-2-yloxy)non-trans-2-enyl]-1,4 dioxaspiro[4,4]nonane 2.3 g of 6 - [4 (1,3 - dithiolon - 2 -yl)butyl] - 7 - [4 - (tetrahydropyran - 2 yloxy)non - trans - 2 - enyl] - 1,4 - dioxaspiro[4,4]nonane were dissolved in 23 ml of dimethyl sulphoxide, 3.6 g of powdered calcium carbonate, 0.65 ml of water and 1.95 ml of methyl iodide were added and the mixture was stirred for 3 hours at 60"C.
After cooling, ether was added and the solids were filtered off. Ice water was added to the filtrate. The ether phase was separated off and the aqueous phase was extracted several times with ether. The combined either phases were washed with aqueous sodium thiosulphate solution and evaporated. The residue was purified by filtration through a short column containing silica gel, using ether. 1.7 g of the desired aldehyde are obtained, Thin layer chromatography (silica gel/toluene/ethyl acetate, 1/1).
Rf~0.32, can be stained with 2,4 - dinitrophenylhydrazine.
NMR (60 MHz, CDCI3) 89.85 ppm, 1H, triplet 5.4-5.8 ppm, 2H, multiplet.
In an analogous manner the following compounds were prepared: Example 10b 6 - (4 - formylbutyl) - 7 - [4 - (tetrahydropyran - 2 - yloxy)oct - trans - 2 enyl] - 1,4 - dioxaspiro[4,4]nonane.
Thin layer chromatography (silica gel//toluene/ethyl acetate, 1/1).
Rf-0.35, can be stained with 2,4 - dinitrophenylhydrazine.
NMR b9.8 ppm, 1H from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl - 7 - [4 - (tetrahydropyran - 2 yloxy)oct - trans - 2 - enyl] - 1,4 - dioxaspiro,[4,4]nonane.
Example 10c 6 - (4 - formylbutyl) - 7 - [4 - (tetrahydropyran - 2 - yloxy)undec - trans 2 - enyl] - 1,4 - dioxaspiro[4,4]nonane.
Thin layer chromatography (silica gelfitoluene/ethyl acetate, 1/1).
Rf~0.31, can be stained with 2,4 - dinitrophenylhydrazine.
NMR 89.8 ppm, 1H, triplet from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - (tetrahydropyran - 2 yloxy)undec - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
Example 10d 6 - (4 - formylbutyl) - 7 - [4 - (tetrahydropyran - 2 - yloxy) - 4cyclohexylbut - trans - 2 - enyl] - 1,4 - dioxaspiro[4,4]nonane.
Thin layer chromatography (toluene/ethyl acetate, 1/1).
Rf~0.35, can be stained with 2,4 - dinitrophenylhydrazine.
NMR 89.8 ppm, 1H, triplet from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - (tetrahydropyran - 2 yloxy) - 4 - cyclohexylbut - trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane.
Example 10e 6 - (4 - - formylbutyl) - 7 - [4 - (tetrahydropyran - 2 - yloxy) - 5,5 dimethyl - 7 oxanon - trans - 2 - enyl] - 1,4 - dioxaspiro[4,4]nonane.
Thin layer chromatography (toluene/ethyl acetate, 1/1).
Rf-0.35, can be stained with 2,4 - dinitrophenylhydrazine NMR b9.8 ppm, 1H, triplet from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - (tetrahydropyran - 2 yloxy) - 5,5 - dimethyl - 7 - oxanon - trans - 2 - enyl) - 1,4 dioxaspiro[4,4]nonane.
Example 10f 6-(4-formylbutyl)- 7 - [4 - (tetrahydropyran - 2 - yloxy) - 5,5 kvmethylnon - trans - 2 - enyl] - 1,4 - dioxaspiro[4,4]nonane.
Thin layer chromatography (toluene/ethyl acetate, 1/1).
Rf~0.35, can be stained with 2,4 - dinitrophenylhydrazine.
NMR 69.8 ppm, 1H, triplet from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - (tetrahydropyran - 2 yloxy) - 5,5 - dimethylnon - trans - 2 - enyl] - 1,4 - dioxaspirol4,4lnonane.
Example 10g 6-(4-formylbutyl)- 7 - [4 - (tetrahydropyran - 2 - yloxy) - 5 - m- chlorophenoxypent - trans - 2 - enyl] - 1,4 - dioxaspiro[4,4]nonane.
Thin layer chromatography (toluene/ethyl acetate, 1/1).
Rf~0.30, can be stained with 2,4 - dinitrophenylhydrazine.
NMR #~9.8 ppm, 1H, triplet from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - (tetrahydropyran - 2 yloxy) - 5 - m - chlorophenoxypent - trans - 2 - enyl] - 1,4 dioxaspiro[4,4]nonane.
Example 10h 6 - (4 - formylbutyl) - 7 - [4 - (tetrahydropyran - 2 - yloxy) - 5 phenoxypent - trans - 2 - enyl]1,4 - dioxaspiro[4,4]nonane.
Thin layer chromatography (toluene/ethyl acetate), Rf~0.3, can be stained with 2,4 - dinitrophenylhydrazine.
NMR #~9.8 ppm, 1H, triplet from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyl] - 7 - [4 - (tetrahydropyran - 2 yloxy) - 5 - phenoxypent - trans - 2 - enyl] - 1,41,4 - dioxaspiro[4,4]nonane, and Example 10i 6-(4-formylbutyl)- 7 - [4 - (tetrahydropyran - 2 - yloxy) - 5 - (m- trifluoromethylphenoxy)pent - trans - 2 - enyl] - 1,4 - dioxaspiro[4,4]nonane.
Thin layer chromatography (toluene/ethyl acetate, 1/1).
Rf~0.35, can be stained with 2,4 - dinitrophenylhydrazine.
* NMR 8~9.8 ppm from 6 - [4 - (1,3 - dithiolon - 2 - yl)butyll - 7 - [4 - (tetrahydropyran - 2 yloxy)- 5 - (m - trifluoromethylphenoxy)pent - trans - 2 - enyl] - 1,4 dioxaspiro[4,4]nonane.
Example lla 9,9-ethylenedioxy- 1 6-(tetrahydropyran-2-yloxy)-20-methylprosta- trans-2 trans- 1 4-dienoic Acid Methyl Ester 470 mg of 6 - (4 - formylbutyl) - 7 - [4 - (tetrahydropyran - 2 - yloxy)non trans - 2 - enyl) - 1,4 - dioxaspiro[4,4]nonane were dissolved in 25 ml of absolute toluene and the solution was boiled, together with 550 mg of methoxycarbonylmethylenetriphenylphosphorane, for 5 hours under reflux. The solution was evaporated in vacuo, the residue was taken up in ether and the solution was filtered through a column containing silica gel.
490 mg of 9,9 - ethylenedioxy - 16 - (tetrahydropyran - 2 - yloxy) - 20 methylprosta - trans - 2 - trans - 14 - dienoic acid methyl ester were obtained.
NMR 6.8-7.4 ppm, 1H, multiplet 5.4-6.2 ppm, 3H, multiplet 3.8 ppm, 3H, singlet In an analogous manner, the following compounds were obtained by reacting the aldehydes obtained in Examples 10b-10i with methoxycarbonylmethylenetriphenylphosphorane.
Example I lb 9,9 - ethylenedioxy - 16 - (tetrahydropyran - 2 - yloxy)prosta - trans - 2 trans - 14 - dienoic acid methyl ester.
NMR 6.8-7.4 ppm, 1H, multiplet 5.46.2 ppm, 3H, multiplet 3.8 ppm, 3H, singlet.
Example llc 9,9 - ethylenedioxy - 16 - (tetrahydropyran - 2 - yloxy) - 20 - propylprosta trans - 2 - trans - 14 - dienoic acid methyl ester.
NMR 6.8-7.5 ppm, 1H, multiplet 5.46.3 ppm, 3H, multiplet 3.8 ppm, 3H, singlet.
Example Ild 9,9 - ethylenedioxy - 16 - (tetrahydropyran - 2 - yloxy) - 16 - cyclohexyl 17,18,19,20 - tetranorprosta - trans - 2 - trans - 14 - dienoic acid methyl ester.
NMR 6.8-7.5 ppm, 1H, multiplet 5.4-6.3 ppm, 3H, multiplet 3.9 ppm, 3H, singlet.
Example lle 9,9 - ethylenedioxy - 16 - (tetrahydropyran - 2 - yloxy) - 17,17,20 - trimethyl - 19 - oxaprosta - trans - 2 - trans - 14 - dienoic acid methyl ester.
NMR 6.8-7.4 ppm, 1H, multiplet 5.46.4 ppm, 3H, multiplet 3.8 ppm, 3H, singlet.
Example lif 9,9 - ethylenedioxy - 16 - (tetrahydropyran - 2 - yloxy) - 17,17,20 - trimethylprosta - trans - 2 - trans - 14 - dienoic acid methyl ester.
NMR 6.8-7.4 ppm, 1H, multiplet 5.46.4 ppm, 3H, multiplet 3.8 ppm, 3H, singlet.
Example 1 lg 9,9 - ethylenedioxy - 16 - (tetrahydropyran - 2 - yloxy) - 17 - m chlorophenoxy - 18,19,20 - trinorprosta - trans - 2 - trans - 14 - dienoic acid methyl ester.
NMR 5.4-7.6 ppm, 8H, multiplet 3.8 ppm, 3H, singlet.
Example llh 9,9 - ethylenedioxy - 16 - (tetrahydropyran - 2 - yloxy) - 17 - phenoxy 18,19,20 - trinorprosta - trans - 2 - trans - 14 - dienoic acid methyl ester.
5.4-7.6 ppm, 9H, multiplet 3.8 ppm, 3H, singlet.
Example lli 9,9 - ethylenedioxy - 16 - (tetrahydropyran - 2 - yloxy) - 17 - (m trifluoromethylphenoxy) - 18,19,20 - trinorprosta - trans - 2 - trans - 14 - dienoic acid methyl ester.
5.4-7.6 ppm, 8H, multiplet 3.8 ppm, 3H, singlet.
Example 12a 9-oXo-16{-hydroxy-20-methylprosta-trans:2-trans-14-dienoic Acid Methyl Ester 258 mg of 9,9 - ethylenedioxy - 16 - (tetrahydropyran - 2 - yloxy) - 20 methylprosta - trans - 2 - trans - 14 - dienoic acid methyl ester were dissolved in 50 ml of absolute methanol and 2 ml of aqueous 10% w/v oxalic acid were added.
The reaction mixture was warmed to 500C for 3 hours and left to stand overnight at room temperature. The next morning, the mixture was substantially evaporated in vacuo, the residue was taken up in ether and the ether solution was washed once with semi-saturated. sodium bicarbonate solution. The reaction solution was dried with magnesium sulphate and then evaporated. The residue was chromatographed on silica gel using toluene/ethyl acetate, 60/40, as the running agent.
Thin layer chromatography (Merck ready-to-use plates//toluene/ethyl acetate/glacial acetic acid, 40/60/1).
Ref~0.37.
NMR: The signals at b=4.6 ppm and S=3.9 ppm, which were typical for the T11P group and the ketal bridge, had disappeared.
S3.7 ppm, singlet, 3H 3.7-4.0 ppm, multiplet, 1H 5.46.0 ppm, multiplet, 3H 6.6-7.4 ppm, multiplet, 1H.
The following compounds were obtained in an analogous manner from the compounds obtained in Example 1 lb to lli: Example 12b 9 - oxo - 16 - hydroxyprosta - trans - 2 - trans - 14 - dienoic acid methyl ester.
Thin layer chromatography Ref~0.36.
Example 12c 9 - oxo - 16 - hydroxy - 20 - propylprosta - trans - 2 - trans - 14 - dienoic acid methyl ester, Thin layer chromatography Ref4).38.
Example 12d 9 - oxo - 16 - hydroxy - 16 - cyclohexyl - 17,18,19,20 - tetranorprosta trans - 2 - trans - 14 - dienoic acid methyl ester.
Thin layer chromatography Rf~0.38.
Example 12e 9 - oxo - 16{ - hydroxy - 17,17,20 - trimethyl - 19 - oxaprosta - trans - 2 - trans - 14 - dienoic acid methyl ester.
Thin layer chromatography Rf-0.36.
Example 12f 9 - oxo - 16{ - hydroxy - 17,17,20 - trimethylprosta - trans - 2 - trans - 14 - dienoic acid methyl ester.
Thin layer chromatography Rf0.35.
Example 12g 9 - oxo - l6, - hydroxy - 17m - chlorophenoxy - 18,19,20 - trinorprosta trans - 2 - trans - 14 - dienoic acid methyl ester.
Thin layer chromatography Rf~0.35.
Example 12h 9 - oxo - 16{ - hydroxy - 17 - phenoxy - 18,19,20 - trinorprosta - trans - 2 trans - 14 - dienoic acid methyl ester.
Thin layer chromatography Rf~0.38, and Example 12i 9 - oxo - 16{ - hydroxy - 17 - (m - trifluoromethylphenoxy) - 18,19,20 trincrprosta - trans - 2 - trans - 14 - dienoic acid methyl ester.
Thin layer chromatography Rf~0.38.
The thin layer chromatography data given relates to Merck ready-to-use plates and the running agent toluene/ethyl acetate, 1/1.
Example 13a 9-oxo-16N-hydroxy-20-methylprosta-trans-2-trans-14-dienoic Acrid 480 g of 9 - oxo - 16J - hydroxy - 20 - methylprosta - trans - 2 - trans 14 - dienoic acid methyl ester were dissolved in 10 ml of methanol, 2 ml of 1N sodium hydroxide solution were added and the mixture was stirred at room temperature. After 3 hours the bulk of the methanol was removed in a rotary evaporator and the residue was taken up in 5 ml of water. The aqueous solution was extracted twice with ether.
The aqueous solution was then acidified with 10% w/v citric acid solution and extracted several times with ether, The combined acid ether extracts were dried and evaporated. The residue is purified by column chromatography on silica gel using ethyl acetate, 40/cyclohexane, 60/glacial acetic acid, 1 as the running agent.
Thin layer chromatography (silica gelfitoluene, 40/ethyl acetate, 60/glacial acetic acid, 1).
Rf~0.33.
NMR (60 MH,. CDCI3) '36.6-7.5 ppm, 1H, multiplet '34.8-5.0 ppm, 2H, multiplet '35.46.0 ppm 3H, multiplet '33.9-4.3 ppm, 1H, multiplet The acids indicated in Examples 13b to 13i were prepared in an analogous manner from the esters obtained in Examples 12b--12i. The thin layer chromatographic data relate to ethyl acetate/cyclohexane/glacial acetic acid, 60/40/1, as the running agent (Merck ready-to-use plates).
Example 13b 9 - oxo - 165 - hydroxyprosta - trans - 2 - trans - 14 - dienoic acid.
Thin layer chromatography Rf~0.35.
Example 13c 9 - oxo - 16{ - hydroxy - 20 - propylprosta - trans - 2 - trans - 14 - dienoic acid.
Thin layer chromatography Rf~0.32.
Example 13d 9 - oxo - 16g - hydroxy - 16 - cyclohexyl - 17,18,19,20 - tetranorprosta trans - 2 - trans - 14 - dienoic acid.
Thin layer chromatography Rf~0.32.
Example 13e 9 - oxo - 16g - hydroxy - 17,17,20 - trimethyl - 19 - oxaprosta - trans - 2 trans - 14 - dienoic acid.
Thin layer chromatography Rf~0.37.
Example 13f
Two isomeric products less polar product Rf~0.29 polar product Rf~0.22.
NMR (CDCl3) s6.5-7.5 ppm, 1H, multiplet 5.26.0 ppm, 3H, multiplet 4.8 ppm, 3H, broad singlet (3 acid H) 3.6-4.3 ppm, 2H, multiplet.
The 9g - hydroxyacids indicated in Examples 14b--14i which follow were preparated in an analogous manner from the compounds obtained in Example 13b--13i. The thin layer chromatography data given relate to Merck ready-to-use plates; running agent mixture:ethyl acetate/cyclohexane/glacial acetic acid, 60/40/1.
Example 14b 95,165 - dihydroxyprosta - trans - 2 - trans - 14 - dienoic acid.
Thin layer chromatography Rf~0.28 and 0.21.
Example 14c 95,165 - dihydroxy - 20 - propylprosta - trans - 2 - trans - 14 - dienoic acid Thin layer chromatography Rf~0.29 and 0.23.
Example 14d 95,165 - dihydroxy - 16 - cyclohexyl - 17,18,19,20 - tetranorprosta - trans 2 - trans - 14 - dienoic acid.
Thin layer chromatography Rf-0.27 and 0.21.
Example 14e 96,165- dihydroxy - 17,17,20 - trimethyl - 19 - oxaprosta - trans - 2 - trans 14 - dienoic acid.
Thin layer chromatography Rf~0.29/0.22.
Example 14f 95,165 - dihydroxy - 17,17,20 - trimethylprosta - trans - 2 - trans - 14 - dienoic acid.
Thin layer chromatography Rf~0.28/0.21.
Example 14g 95,165 - dihydroxy - 17 - m - chlorophenoxy - 18,19,20 - triprosta - trans 2 - trans - 14 - dienoic acid.
Thin layer chromatography Rf~0.29/0.23.
Example 14h . 9{,16g - dihydroxy - 17 - phenoxy - 18,19,20 - trinorprosta - trans - 2 - trans - 14 - dienoic acid.
Thin layer chromatography Rf~0.28/0.21.
Example 14i 9t,16 - dihydroxy - 17 - (m - trifluoromethylphenoxy) - 18,19,20 - trinorprosta - trans - 2 - trans - 14 - dienoic acid.
This layer chromatography Rf~0.29/0.22.
Example 15 9-oxo- 1 6,acetoxy- 17,17,20-tri'methyi- 19-oxaprosta-trans-2-trans- 14- dienoic Acid Methyl Ester 60 mg of 9 - oxo - 165 - hydroxy - 17,17,20 - trimethyl - 19 - oxaprosta trans - 2 - trans - 14 - dienoic acid methyl ester were dissolved in 2 ml of pyridine, 0.02 ml of acetic anhydride was added and the mixture was warmed to 650C for 8 hours. The reaction solution was then evaporated to dryness in vacuo and the residue was chromatographed through a silica gel column using cyclohexane/ethyl acetate, 8/2, as the running agent. 34 mg of the desired product were obtained.
Thin layer chromatography (Merck ready-to-use plates, cyclohexane/ethyl acetate/glacial acetic acid, 60/40/1).
Ref~0.57.
NMR (60 MHz, CDCI3) '37.2-6.6 ppm, 1H, multiplet 6.05.3 ppm, 3H, multiplet 5.3-5.0 ppm, 1H, multiplet 3.7 ppm, 3H, singlet 3.4 ppm, 2H, quartet 3.1 ppm, 2H, singlet 2.6-0.7 ppm, remaining protons with 2.0 ppm, singlet 1.1 ppm, triplet 0.8 and 0.9 ppm, singlet.
Example 16 9-oxo- 16D-formyloxy- 17,17,20-trimethyl- 19-oxaprosta-trans-2-trans- 14- dienoic Acid Methyl Ester 50 mg of 9 - oxo - 16.N - hydroxy - 17,17,20 - trimethyl - 19 - oxaprosta trans - 2 - trans - 14 - dienoic acid methyl ester were dissolved in 5 ml of 100% formic acid in which 130 mg of potassium carbonate had previously been dissolved.
This solution was left to stand overnight at OOC. The next morning the solution was evaporated to dryness in vacuo at room temperature. The residue was taken up in 10 ml of ether and 2 ml of water. The mixture was shaken round well and the ether phase was separated off. The aqueous phase was again extracted with ether. The combined ether phases were washed with semi-saturated sodium bicarbonate solution, dried and evaporated. 47 mg of the desired compound were obtained.
Thin layer chromatography (Merck ready-to-use plates, cyclohexane/ethyl acetate/glacial acetic acid, 60/40/1).
Rf=0.56.
NMR (60 MHz, CDCI3) 8.1 ppm, 1H, singlet 7.2-6.6 ppm, 1H, multiplet 6.Q--5.1 ppm, 4H, multiplet 3.7 ppm, 3H, singlet 3.4 ppm, 2H, quarter 3.1 ppm, 2H, singlet 2.8-0.7 ppm, remaining protons, including 1.1 ppm, triplet 0.9 and 0.95 ppm, singlet.
WHAT WE CLAIM IS: 1. A compound of the general formula
where one R' and R2 represents a hydrogen atom and the other represents a hydroxyl group, or R' and R2 together represent an oxygen atom; R3 represents a hydrogen atom; an aliphatic or cycloaliphatic hydrocarbon group having up to 8 carbon atoms; an alkoxyalkyl group having from 3 to 10 carbon atoms; an araliphatic hydrocarbon group having from 7 to 10 carbon atoms; a metal ion; an ammonium ion; or a substituted ammonium ion derived from a primary, secondary or tertiary amine; R4 represents an aliphatic hydrocarbon group having from 1 to 10 carbon atoms or a cycloaliphatic hydrocarbon group having from 3 to 7 carbon atoms, which aliphatic or cycloaliphatic group may be unsubstituted or substituted by one or more of the same or different substituents selected from: (a) aliphaticoxy or aliphaticthio groups having from 1 to 7 carbon atoms; (b) phenoxy groups which may be unsubstituted or substituted by one or two of the same or different substituents selected from alkyl groups having from 1 to 3 carbon atoms, which alkyl groups may be unsubstituted or substituted by one or
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (33)

**WARNING** start of CLMS field may overlap end of DESC **. Ref~0.57. NMR (60 MHz, CDCI3) '37.2-6.6 ppm, 1H, multiplet 6.05.3 ppm, 3H, multiplet 5.3-5.0 ppm, 1H, multiplet 3.7 ppm, 3H, singlet 3.4 ppm, 2H, quartet 3.1 ppm, 2H, singlet 2.6-0.7 ppm, remaining protons with 2.0 ppm, singlet 1.1 ppm, triplet 0.8 and 0.9 ppm, singlet. Example 16 9-oxo- 16D-formyloxy- 17,17,20-trimethyl- 19-oxaprosta-trans-2-trans- 14- dienoic Acid Methyl Ester 50 mg of 9 - oxo - 16.N - hydroxy - 17,17,20 - trimethyl - 19 - oxaprosta trans - 2 - trans - 14 - dienoic acid methyl ester were dissolved in 5 ml of 100% formic acid in which 130 mg of potassium carbonate had previously been dissolved. This solution was left to stand overnight at OOC. The next morning the solution was evaporated to dryness in vacuo at room temperature. The residue was taken up in 10 ml of ether and 2 ml of water. The mixture was shaken round well and the ether phase was separated off. The aqueous phase was again extracted with ether. The combined ether phases were washed with semi-saturated sodium bicarbonate solution, dried and evaporated. 47 mg of the desired compound were obtained. Thin layer chromatography (Merck ready-to-use plates, cyclohexane/ethyl acetate/glacial acetic acid, 60/40/1). Rf=0.56. NMR (60 MHz, CDCI3) 8.1 ppm, 1H, singlet 7.2-6.6 ppm, 1H, multiplet 6.Q--5.1 ppm, 4H, multiplet 3.7 ppm, 3H, singlet 3.4 ppm, 2H, quarter 3.1 ppm, 2H, singlet 2.8-0.7 ppm, remaining protons, including 1.1 ppm, triplet 0.9 and 0.95 ppm, singlet. WHAT WE CLAIM IS:
1. A compound of the general formula
where one R' and R2 represents a hydrogen atom and the other represents a hydroxyl group, or R' and R2 together represent an oxygen atom; R3 represents a hydrogen atom; an aliphatic or cycloaliphatic hydrocarbon group having up to 8 carbon atoms; an alkoxyalkyl group having from 3 to 10 carbon atoms; an araliphatic hydrocarbon group having from 7 to 10 carbon atoms; a metal ion; an ammonium ion; or a substituted ammonium ion derived from a primary, secondary or tertiary amine; R4 represents an aliphatic hydrocarbon group having from 1 to 10 carbon atoms or a cycloaliphatic hydrocarbon group having from 3 to 7 carbon atoms, which aliphatic or cycloaliphatic group may be unsubstituted or substituted by one or more of the same or different substituents selected from: (a) aliphaticoxy or aliphaticthio groups having from 1 to 7 carbon atoms; (b) phenoxy groups which may be unsubstituted or substituted by one or two of the same or different substituents selected from alkyl groups having from 1 to 3 carbon atoms, which alkyl groups may be unsubstituted or substituted by one or
more of the same or different halogen atoms; halogen atoms: phenoxy groups which may be unsubstituted or substituted by one or more of the same or different halogen atoms; and alkoxy groups having from I to 4 carbon atoms: (c) furyloxy, thienyloxy, benzyloxy, phenyl, thienyl or furyl groups, which may be unsubstituted or substituted by one or two of the same or different substituents selected from alkyl groups having from 1 to 3 carbon atoms which may be unsubstituted or substituted by one or more of the same or different halogen atoms: halogen atoms; and alkoxy groups having from I to 4 carbon atoms: (d) fluorine atoms, trifluoromethyl or pentafluoroethyl groups; and (e) cycloalkyl groups having from 3 to 7 carbon atoms; R5 represents an alkyl group having from 1 to 5 carbon atoms; an alkenyl or alkynyl group having from 2 to 5 carbon atoms; or a hydrogen atom; R6 represents a hydrogen atom or a group of the general formula R7CO, wherein R7 represents a hydrogen atom or an alkyl group having up to 10 carbon atoms; and A represents a trans- -CH=CH- group or a -CH2-C112- group with the proviso that if A represents a H2-CH2- group, R5 may only represent a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms,
2. A compound as claimed in Claim I, wherein R3 represents a hydrogen atom.
an alkyl group having from 1 to 8 carbon atoms, an alkoxyalkyl group having a totai of from 3 to 10 carbon atoms, an alkenyl group having from 2 to 4 carbon atoms, a cycloalkyl group having from 5 to 7 carbon atoms, an aralkyl group having 7 or 8 carbon atoms, an ammonium ion, a physiologically tolerable metal ion or substituted ammonium ion which is derived from a primary, secondary or tertiary amine.
3. A compound as claimed in Claim 2, wherein R3 represents a hydrogen atom; a straight-chain alkyl group having from 1 to 6 carbon atoms; a branched alkyl group having from 3 to 5 carbon atoms; an alkoxyalkyl group; a straight-chain alkenyl group having from 2 to
4 carbon atoms; a cyclopentyl, cyclohexyl or benzyl group; or a physiologically acceptable metal ion, ammonium ion or substituted ammonium ion which is derived from a primary, secondary or tertiary amine: 4. A compound as claimed in any one of Claims I to 3, wherein R4 represents an aliphatic hydrocarbon group having from 1 to 8 carbon atoms or a cycloaliphatic hydrocarbon group having from
5 to 7 carbon atoms, which groups may be unsubstituted or substituted by: (a) an alkoxy, alkylthio, alkenyloxy or alkenylthio group having from 1 to 5 carbon atoms; (b) a phenoxy group which may be unsubstituted or substituted by one or two of the same or different substituents selected from alkyl group having from 1 to 3 carbon atoms; trifluoromethyl groups; halogen atoms; phenoxy groups which may be unsubstituted or substituted by one or more of the same or different halogen atoms; and methoxy and ethoxy groups; (c) a thienyloxy, benyloxy, phenyl or thienyl group which may be unsubstituted or substituted by one or two of the same or different substituents selected from alkyl groups having from 1 to 3 carbon atoms; trifluoromethyl groups: halogen atoms; methoxy and ethoxy groups: (d) one or two fluorine atoms or a trifluoromethyl group; or (e) a cycloalkyl or cycloalkylidene group having from 5 to 7 carbon atoms.
s. A compound as claimed in Claim 4, wherein R4 represents an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 3 to 5 carbon atoms or a cycloalkyl group having from 5 to 7 carbon atoms, which alkyl, alkenyl or cycloalkyl group may be unsubstituted or substituted by: (a) an alkoxy, alkylthio, alkenyloxy or alkenylthio group having from I to 4 carbon atoms; (b) a phenoxy group which may be unsubstituted or substituted by one or two of the same or different substitutent selected from methyl, trifluoromethyl and methoxy groups; chlorine or fluorine atoms; and phenoxy groups which may be unsubstituted or substituted by one or more fluorine and/or chlorine atoms: (c) a thienyloxy, benzyloxy, phenyl or thienyl group which may be unsubstituted or substituted by one or two of the same or different substituents selected from methyl, trifluoromethyl and methoxy groups and chlorine and fluorine atoms; (d) one or two fluorine atoms or a trifluoromethyl group: or (e) a cycloalkyl group having from 5 to 7 carbon atoms,
6. A compound as claimed in Claim 5, whersin R4 represents any one of the groups listed in Table A herein,
7. A compound as claimed in any one of Claims 1 to 6, wherein R5 represents an alkyl group having from 1 to 5 carbon atoms or an alkenyl or alkynyl group having from 2 to 4 carbon atoms.
8. A compound as claimed in any one of Claims 1 to 7, wherein R6 represents a hydrogen atom or a group of the general formula R7CO, wherein R7 represents a hydrogen atom or an alkyl group having up to 4 carbon atoms.
9. A compound as claimed in Claim 1 and listed in Table B herein.
10. A compound as claimed in Claim 1 and named in any one of Examples 12 to 16 herein.
11. A process for the preparation of a compound as claimed in Claim 1, which comprises the acid solvolysis of a compound of the general formula
wherein R3, R4, R5 and A have the meanings given for the general formula I, with the proviso that if A represents a -C112-C112- group, R5 represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; R13 represents a hydrogen atom or a protective group which can be eliminated by acid solvolysis; and Y represents a single bond, a -C112- group or an isopropylidene group, to give a compound of the general formula I wherein R' and R2 together represent an oxygen atom, and Re represents a hydrogen atom; and if desired, converting the resulting compound of the general formula I into another compound of the general formula I by any suitable method.
12. A process as claimed in Claim 11, wherein the compound of the general formula XXII is prepared by reacting a compound of the general formula
wherein R4 and R5 have the meanings given in Claim 1, Y represents a single bond, a -C112- group or an isopropylidene group, R5" represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms, and R'3 represents a hydrogen atom or a protecting group which can be removed easily by acid solvolysis, with a compound of the general formula R34P=CHCO2R3 XXI wherein each R'4, any two or three of which may be the same or different, represents a straight-chain alkyl group having from 1 to 4 carbon atoms or a phenyl group, and R3 has the meaning given in Claim 1.
13. A process as claimed in Claim 12, wherein the compound of the general formula XX is prepared by hydrogenating a compound of the general formula XIX in the presence of a suitable catalyst.
14. A process as claimed in either Claim 12 or Claims 13, wherein the compound of the general formula XIX is prepared by removing the thioacetal group in a compound of the general formula
wherein R4 and R5 have the meanings given in Claim 1, X represents a single bond.
a -CIll2- group or an isopropylidene group, Y has the meaning given in Claim 12 and R12 represents a protecting group which can be removed easily by acid solvolysis, in the presence of a heavy metal salt, HgCI2 or an alkyl halide in a mixture of organic solvent and water.
15. A process as claimed in Claim 14, wherein the compound of the general formula XVIII is produced by protecting the hydroxyl group in a compound of the general formula
in which X has the meaning given in Claim 14, Y has the meaning given in Claim 12, R4 has the meaning given in Claim 1 and R5b represents an alkyl group having from 1 to 5 carbon atoms or an alkenyl or alkynyl group having from 2 to 5 carbon atoms.
16. A process as claimed in Claim 15, wherein the compound of the general formula XVI(b) is produced by reacting a compound of the general formula XV with an organometallic compound of the general formula R5bM XVII wherein R5b has the meaning given in Claim 15 and M represents an alkali metal or a group of the general formula HalMg, wherein Hal represents a chlorine, fluorine or bromine atom.
17. A process as claimed in either Claim 15 or Claim 16, wherein the compound of the general formula XVI(a) is produced by reducing a compound of the general formula
wherein R4 has the meaning given in claim 1, X has the meaning given in Claim 14 and Y has the meaning given in Claim 12.
18. A process as claimed in Claim 17, wherein the compound of the general formula XV is produced by reacting a compound of the general formula
wherein X has the meaning given in Claim 14 and Y has the meaning given in Claim 12, with a compound of the general formula
wherein R4 has the meaning given in Claim 1 and each R", which may be the same or different represents an unbranched alkyl group having from 1 to 4 carbon atoms.
19. A process as claimed in Claim 18, wherein the compound of the general formula XII is produced by reducing a compound of the general formula
wherein X has the meaning given in Claim 14, Y has the meaning given in Claim 12, and R'O represents an alkyl group having from 1 to 5 carbon atoms.
20. A process as claimed in Claim 19, wherein the compound of the general formula XII is produced reacting a compound of the general formula
wherein X has the meaning given in Claim 14 and R'O has the meaning given in Claim 19, with a compound of the general formula 11OC112-Y-CH2OH XI wherein Y has the meaning given in Claim 12.
21. A process as claimed in Claim 20, wherein the compound of the general formula X is produced by reacting a compound of the general formula
wherein R'O has the meaning given in Claim 19, with a compound of the general formula HS-C112-X-CH2-S11 IX wherein X has the meaning given in Claim 14.
22. A process as claimed in Claim 21, wherein the compound of the general formula VIII is produced by oxidizing a compound of the general formula
wherein R'O has the meaning given in Claim 19.
23. A process as claimed in Claim 22, wherein the compound of the general formula VII is produced by reacting a compound of the general formula
wherein R8 represents a hydrogen atom or an aliphatic acyl group having from 2 to 6 carbon atoms, in acid solution, with a alkanol having from 1 to 5 carbon atoms.
24. A process as claimed in Claim 23, wherein the compound of the general formula VI is prepared by any suitable method from a compound of the general formula
wherein R8 has the meaning given in Claim 23.
25. A process as claimed in Claim 24, wherein the compound of the general formula V is prepared by any suitable method from a compound of the general formula
wherein R8 has the meaning given in Claim 23 and each R9, which may be the same or different, represents an alkyl group having from 1 to 5 carbon atoms or an aralkyl group having from 7 to 9 carbon atoms,
26. A process as claimed in Claim 25, wherein the compound of the general formula IV is prepared by reacting a compound of the general formula
wherein R9 has the meaning given in Claim 25, with a compound of the general formula
wherein R8 has the meaning given in Claim 23.
27. A process as claimed in Claim 11, carried out substantially as described in Example 12 herein in combination, if desired, with a process substantially as described in Example 13, and if desired Example 14, and if desired Example 15, and if desired Example 16.
28. A process as claimed in Claim 27, carried out substantially as described in any one of Examples 1 to 11 herein in combination with all subsequent Examples up to Example 12.
29. A compound as claimed in Claim 1, whenever prepared by a process as claimed in one of Claims 11 to 28.
30. A pharmaceutical preparation which comprises a compound as claimed in any one of Claims I to 10 and 29, in admixture or conjunction with a pharmaceutically suitable carrier.
31. A pharmaceutical preparation as claimed in Claim 30, in dosage unit form, each unit containing in the range of from 0.1 to 750 mg of the compound of the general formula I.
32. A compound of the general formula
in which R1 and R2 together represent an oxygen atom or one represents a hydrogen atom and the other a hydroxyl group, R3 represents a hydrogen atom or a straight chain, branched chain, saturated or unsaturated, aliphatic or cycloaliphatic hydrocarbon radical having from 1 to 8 carbon atoms or a straight chain or branched chain alkoxyalkyl radical having from 3 to 10 carbon atoms, or an araliphatic hydrocarbon radical having from 7 to 9 carbon atoms, or a physiologically tolerable metal ion, ammonium ion or substituted ammonium ion which is derived from a primary, secondary or tertiary amine, and R4 represents a straight chain, branched chain, saturated or unsaturated aliphatic hydrocarbon radical having from I to 10 carbon atoms or a cycloaliphatic hydrocarbon radical having from 3 to 7 carbon atoms, it being possible for each of the said radicals to be substituted by a) a straight chain, branched chain, saturated or unsaturated alkoxy or alkylthio radical with I to 7 carbon atoms, b) a phenoxy radical which, itself, may be monosubstituted or disubstituted by an optionally halogensubstituted alkyl group having from 1 to 3 carbon atoms, by halogen atoms or by an optionally halogen-substituted phenoxy radical or an alkoxy radical having from 1 to 4 carbon atoms, it being possible in the case of disubstitution, for the substituents to be the same or different, c) a furyloxy, thienyloxy or benzyloxy radical, each of which may be monosubstituted or disubstituted by an alkyl group having from 1 to 3 carbon atoms, which, itself, may be halogen-substituted, by halogen atoms or by an alkoxy group having from I to 4 carbon atoms, it being possible in the case of -disubstitution, for the substituents to be the same or different, d) one or two fluorine atoms or a trifluoromethyl or pentafluoroethyl group, e) a cycloalkyl radical having from.3 to 7 carbon atoms or f) aphenyl, thienyl or furyl radical, each of which may be monosubstituted or disubstituted by an optionally halogensubstituted alkyl group having from 1 to 3 carbon atoms, by halogen atoms or by an alkoxy group having from 1 to 4 carbon atoms, it being possible, in the case of disubstitution, for the substituents to be the same or different, and R5 represents an alkyl radical having from 1 to 5 carbon atoms, an alkenyl or alkynyl group having from 2 to 5 carbon atoms or a hydrogen atom, R6 represents a hydrogen atom or a R7CO group, in which R7 may be a hydrogen atom or a straight chain or branched chain alkyl group having from 1 to 10 carbon atoms, and A represents a trans --CH=CHH- group or a -C112-C112- group with the provisio that if A represents a -C112-C112- group, R5 may only represent a hydrogen dom or an alkyl group having from 1 to 5 carbon atoms.
33. A process for the preparation of a compound as claimed in Claim 1, wherein a) the acetal protective group and also, if R'3 does not represent a hydrogen atom, the protective group R'3, are split off, by acid solvolysis, from a compound of the general formula
wherein R13 represents a hydrogen atom or a protective group which can be split off easily by acid solvolysis and Y represents a single bond, a -C112- group or an isopropylidene group and R3, R4, R5 and A have the meaning indicated under formula I to produce a compound of the general formula I, wherein R' and R2 together represent an oxygen atom, and R6 represents a hydrogen atom, and, if desired, one or more of the following reactions is carried out in any appropriate order: b) a compound of the general formula I, wherein R' and R2 together represent an oxygen atom, R6 represents a hydrogen atom and R3, R4, R5 and A have the meaning indicated under formula I in Claim 1, with the proviso that R3 does not represent a hydrogen atom, is converted, by saponification, into the free acid, c) a compound of the general formula I, wherein R' and R2 together represent an oxygen atom, R3, R4, R5 and A have the meaning indicated under formula I in Claim 1, R6 represents a hydrogen atom with the proviso that R3 does not represent a hydrogen atom is converted, by transesterification, into another ester of the general formula I, d) a compound of the general formula I, wherein R3 represents a hydrogen atom and R' and R2 together represent an oxygen atom. R4, R5 and A have the meaning indicated under formula I in Claim 1 and R6 represents a hydrogen atom.
is esterified, e) the compound of the general formula I, wherein R' and R2 together represent an oxygen atom, R3, R4, R5 and A have the meaning indicated under formula I in Claim 1, and R6 represents a hydrogen atom, is reacted with an acylating agent, f) a compound of the general formula 1, wherein R' and R2 together represent an oxygen atom and R3, R4, R5, R6 and A have the meaning indicated under formula I in Claim 1, is reduced to a compound of the general formula I wherein R' and R2 are different one representing a hydrogen atom and the other representing a hydroxyl group, and g) a compound of the general formula I, wherein R3 represents a hydrogen atom and R1, R2, R4, R5, R6 and A have the meaning indicated under formula I in Claim 1, is converted into a compound of the general formula I wherein R3 represents a metal ion, an ammonium ion or a substituted ammonium ion derived from a primary, secondary or tertiary amine.
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DE19772702369 DE2702369A1 (en) 1977-01-21 1977-01-21 2-Prostenoic and 2,14-prostadienoic acid derivs. - with prostaglandin-like activity, esp. hypotensive

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114349640A (en) * 2021-12-17 2022-04-15 山东新和成药业有限公司 Synthesis method of methyl dihydrojasmonate or intermediate thereof and catalyst used in synthesis method
CN114349640B (en) * 2021-12-17 2024-03-22 山东新和成药业有限公司 Synthesis method of methyl dihydrojasmonate or intermediate thereof and catalyst used in synthesis method

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