CA1071642A - Intermediates for 5-unsaturated prostanoic acid derivatives - Google Patents
Intermediates for 5-unsaturated prostanoic acid derivativesInfo
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- CA1071642A CA1071642A CA301,207A CA301207A CA1071642A CA 1071642 A CA1071642 A CA 1071642A CA 301207 A CA301207 A CA 301207A CA 1071642 A CA1071642 A CA 1071642A
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Abstract
Abstract of the Disclosure Intermediates of the formula
Description
~ l0~:16~2 Background of the Invention a) ~ield of` I _ ention_ This invention relates to prostaglandin derivatives.
More specifically this invention relates -to 9,15-dioxygenated derivatives of prost-5-enoic and prosta-5,13-dienoic acid having optional alkyl substituents, to lower alkyl esters thereof and to ho~ologs thereof. Also encompassed within this invention are processes for preparing these compounds and intermediates used therein.
b) Descr ption of the Prior Art .
The chemistry and pharmacological effects of the prostaglandins have been the subject of several recent reviews; for example see E.W. Horton, Physiol. Rev., 49, 122 (1969), J.F`. Bagli in "Annual Reports in Medicinal Chemistry, 1969", C.K. Cain, Ed., Academic Press, New York and l.ondon, 1979, p. 170, and J.E. Pike in "Progress in the Chemistry of Organic Natural Products", Vol. 28, W. Herz, et al. Eds., Springer Verlag, New York, 1970, p. 313.
Due to the increasing interest in these natural products a rather extensive effort has been given recently to the synthesis of prostaglandins and their analogs.
Included among -these syntheses are several synthetic methods for the preparation of 9,15-dioxygenated derivatives of prostanoic or prost-13-enoic acid. For example, the synthesis of the first pharmacologically active 9,15-dioxy-genated prostanoic acid derivative, 9~,15~-dihydroxyprost-13-enoic acid (ll-desoxyprostaglandin Fl~) was reported in detail by J.F. Bagli, T. Bogri and R. Deghenghi, Tetrahedron Letters, 455 (1966). A significant simplification and modification of that process was described by Bagli and Bo$ri in U.S. Patent No. 3,~55~992, issued July 15, 1969, whereby ~............. ~ .
~ ' i ~. , . ' ' . :
~`" Jl07~6~;~
9~,15~dihydroxyprost-13-enoic ac:id as well as homologs thereof were obtained, see also Bagli and Bogri, Ie-tra-hedron Letters, 5 (1967).
Further improvements in the synthesis of 9,15-dioxy-S genated derivatives of prostanoic acid have been described by Bagli and Bogri in Te-trahedron Letters, 1639 (1969) and German Offenlegungsschrift No. 1,953,232, published April 30, 1970, and in British Patent Specification No. 1,097,S33, published January 3, 1968.
More recently, Bagli and Bogri have extended the scope of their processes for preparing 9,15-dioxygenated derivatives of prostanoic acid to include the preparation of 9-oxo-lS-hydroxy prostanoic acid deriV~tives having an alkyl substituent at position lS, U.S. Pa-tent No. 3,671,S70, issued June 20, 1972. These lS-alkyl derivatives possess hypotensive, antihypertensive, bronchospasmolytic and gastric acid secretion inhibiting properties, as well as inhibiting the aggregation of platelets and promoting the disaggregation of aggregated platelets.
Still further improvements in the synthesis of such 9,15-dioxygenated derivatives are described in U.S. Patent No.
3,773,795, issued November 20, 1973, U.S. Patent No. 3,917,668, issued November 4, 1975 and the publication by N.A. Abraham, Tetrahedron Letters, 451 (1973).
Other recent syntheses of 9,15-dioxygenated derivatives are reported in Belgian Pat. No. 766,521, published November 3 9 1971, P. Crabbé and A. Guzman, Tetrahedron Letters, 115 (1972), M.P.L. Caton, et al., Tetrahedron Letters, 773 ~1972), C.J. Sih, et al., Tetrahedron Letters, 2435 (1972), F.S. Alverezt et al., J. Amer. Chern. Soc., 94.
7823 (1972), A.F. Kluge, et al. and J. Amer. Chem. Soc., 94, 9256 (1972).
t AHP-6~4 It Ts noteworthy that the synthetic 9,15-dioxy-senated prostanoic acid derivatives described above possess a number of the biological activities o$ the natural compounds although they lack the ll-hydroxyl of the latter~ -- 5 In addition tt should be noted that the natural PGEI,PG~ ~ PGFI~ and PGFa~ do have the disad~antage of being relatively unstable, see T.O. Oesterling, et al., J. eharm.
Sci., 61, 1861 (1972~. For example, it is well known that the il-hydroxy group of PGEI and PGE2 participates readily in dehydration reactions under both basic and acidic conditions, see S. Bergstrom et at., J. Biol. Chem. 238, 3555 (Ig63)> E.J. Corey et al., J. Amer. Ohem~ Soc., 90, 3245 (1968), J.E. Pike et al., J. Org. ~hem. 34, 3552 (196g) and "The Prostaglandins, Progress in Research", S.M.M. Karim, Ed., Wiley-lnterscience, New York, i972, p. 100 As realized by those skilled in the art th;s Inherenf disadvantage of the natural compounds must ~ ai~ays be ~aken into account when considering the practical aspects of prèparation, formulation or storage of these compounds. In contrast, the compounds of the present Invention are free from this disadvantage.
It is the purpose of the present disclosure to describe certain 9,15-dioxygenated prostanoic acid derivatives possessing useful pharmacologic properties coupled with a relatively low order of toxicity. Furthermore, there is disclosed a process for preparing the derivatives which starts from readity available starting materialsj avoids noxious agents, ts executed facilely and is adaptable to large scale prepara-tion of the derivatives.
-~ 10~ 2 For example, the present process u-tilizes as one of i-ts starting materials a dialkyl 2-(carboalkoxymethyl)malonate (formula 3, see below), which is readily prepared by condensing a dialkyl malonate with the appropriate readily available lower alkyl halo-acetic acid. The ready availability of this star-ting ma-terial re-presents an improvement over our earlier process of U.S. Patent 3,849,474, issued November 19, 1974 (see also corresponding Wes-t German Offenlegungsschrift 2,313,868, published October 4, 1973).
The earlier process utilizes a substituted malonate derivative which in some cases takes a seven or eight step synthesis to prepare.
Other advantages of the present process are tha-t it yields directly prostaglandin derivatives having the hydroxy group of the cyclopentane ring in the most desirable configuration. In other words -the more active epimer with respect to the confirguration of the cyclo-pentane hydroxy group is obtained. Furthermore, this desirable result can be achieved with simple and non-hazardous reagents, for example by reducing the appropriate precursor ke-tone with sodium borohydride, thereby eliminating the necessity of using noxious or expensive re-agents; cf. E.J. Corey, et al., J. Amer. Chem. Soc., 93, 1491 (1971).
Still another advantage of the present process features the preparation of an entirely new class of prostaglandin derivatives in which the acid side chain is unsaturated and the side chain bearing the hydroxy group is fully saturated.
The foregoing advantages render the prostaglandin derivatives of this invention par-ticularly desirable as pharmacologic agents.
Summary of the Invention:
One aspect of this invention is a process for -the preparation of the key intermediates, the hydroxylactone 6 and the ketolactone of formula 7. The process is represented by the following flow diagram:
, :, . .
.. . .
R IOOC COOR
More specifically this invention relates -to 9,15-dioxygenated derivatives of prost-5-enoic and prosta-5,13-dienoic acid having optional alkyl substituents, to lower alkyl esters thereof and to ho~ologs thereof. Also encompassed within this invention are processes for preparing these compounds and intermediates used therein.
b) Descr ption of the Prior Art .
The chemistry and pharmacological effects of the prostaglandins have been the subject of several recent reviews; for example see E.W. Horton, Physiol. Rev., 49, 122 (1969), J.F`. Bagli in "Annual Reports in Medicinal Chemistry, 1969", C.K. Cain, Ed., Academic Press, New York and l.ondon, 1979, p. 170, and J.E. Pike in "Progress in the Chemistry of Organic Natural Products", Vol. 28, W. Herz, et al. Eds., Springer Verlag, New York, 1970, p. 313.
Due to the increasing interest in these natural products a rather extensive effort has been given recently to the synthesis of prostaglandins and their analogs.
Included among -these syntheses are several synthetic methods for the preparation of 9,15-dioxygenated derivatives of prostanoic or prost-13-enoic acid. For example, the synthesis of the first pharmacologically active 9,15-dioxy-genated prostanoic acid derivative, 9~,15~-dihydroxyprost-13-enoic acid (ll-desoxyprostaglandin Fl~) was reported in detail by J.F. Bagli, T. Bogri and R. Deghenghi, Tetrahedron Letters, 455 (1966). A significant simplification and modification of that process was described by Bagli and Bo$ri in U.S. Patent No. 3,~55~992, issued July 15, 1969, whereby ~............. ~ .
~ ' i ~. , . ' ' . :
~`" Jl07~6~;~
9~,15~dihydroxyprost-13-enoic ac:id as well as homologs thereof were obtained, see also Bagli and Bogri, Ie-tra-hedron Letters, 5 (1967).
Further improvements in the synthesis of 9,15-dioxy-S genated derivatives of prostanoic acid have been described by Bagli and Bogri in Te-trahedron Letters, 1639 (1969) and German Offenlegungsschrift No. 1,953,232, published April 30, 1970, and in British Patent Specification No. 1,097,S33, published January 3, 1968.
More recently, Bagli and Bogri have extended the scope of their processes for preparing 9,15-dioxygenated derivatives of prostanoic acid to include the preparation of 9-oxo-lS-hydroxy prostanoic acid deriV~tives having an alkyl substituent at position lS, U.S. Pa-tent No. 3,671,S70, issued June 20, 1972. These lS-alkyl derivatives possess hypotensive, antihypertensive, bronchospasmolytic and gastric acid secretion inhibiting properties, as well as inhibiting the aggregation of platelets and promoting the disaggregation of aggregated platelets.
Still further improvements in the synthesis of such 9,15-dioxygenated derivatives are described in U.S. Patent No.
3,773,795, issued November 20, 1973, U.S. Patent No. 3,917,668, issued November 4, 1975 and the publication by N.A. Abraham, Tetrahedron Letters, 451 (1973).
Other recent syntheses of 9,15-dioxygenated derivatives are reported in Belgian Pat. No. 766,521, published November 3 9 1971, P. Crabbé and A. Guzman, Tetrahedron Letters, 115 (1972), M.P.L. Caton, et al., Tetrahedron Letters, 773 ~1972), C.J. Sih, et al., Tetrahedron Letters, 2435 (1972), F.S. Alverezt et al., J. Amer. Chern. Soc., 94.
7823 (1972), A.F. Kluge, et al. and J. Amer. Chem. Soc., 94, 9256 (1972).
t AHP-6~4 It Ts noteworthy that the synthetic 9,15-dioxy-senated prostanoic acid derivatives described above possess a number of the biological activities o$ the natural compounds although they lack the ll-hydroxyl of the latter~ -- 5 In addition tt should be noted that the natural PGEI,PG~ ~ PGFI~ and PGFa~ do have the disad~antage of being relatively unstable, see T.O. Oesterling, et al., J. eharm.
Sci., 61, 1861 (1972~. For example, it is well known that the il-hydroxy group of PGEI and PGE2 participates readily in dehydration reactions under both basic and acidic conditions, see S. Bergstrom et at., J. Biol. Chem. 238, 3555 (Ig63)> E.J. Corey et al., J. Amer. Ohem~ Soc., 90, 3245 (1968), J.E. Pike et al., J. Org. ~hem. 34, 3552 (196g) and "The Prostaglandins, Progress in Research", S.M.M. Karim, Ed., Wiley-lnterscience, New York, i972, p. 100 As realized by those skilled in the art th;s Inherenf disadvantage of the natural compounds must ~ ai~ays be ~aken into account when considering the practical aspects of prèparation, formulation or storage of these compounds. In contrast, the compounds of the present Invention are free from this disadvantage.
It is the purpose of the present disclosure to describe certain 9,15-dioxygenated prostanoic acid derivatives possessing useful pharmacologic properties coupled with a relatively low order of toxicity. Furthermore, there is disclosed a process for preparing the derivatives which starts from readity available starting materialsj avoids noxious agents, ts executed facilely and is adaptable to large scale prepara-tion of the derivatives.
-~ 10~ 2 For example, the present process u-tilizes as one of i-ts starting materials a dialkyl 2-(carboalkoxymethyl)malonate (formula 3, see below), which is readily prepared by condensing a dialkyl malonate with the appropriate readily available lower alkyl halo-acetic acid. The ready availability of this star-ting ma-terial re-presents an improvement over our earlier process of U.S. Patent 3,849,474, issued November 19, 1974 (see also corresponding Wes-t German Offenlegungsschrift 2,313,868, published October 4, 1973).
The earlier process utilizes a substituted malonate derivative which in some cases takes a seven or eight step synthesis to prepare.
Other advantages of the present process are tha-t it yields directly prostaglandin derivatives having the hydroxy group of the cyclopentane ring in the most desirable configuration. In other words -the more active epimer with respect to the confirguration of the cyclo-pentane hydroxy group is obtained. Furthermore, this desirable result can be achieved with simple and non-hazardous reagents, for example by reducing the appropriate precursor ke-tone with sodium borohydride, thereby eliminating the necessity of using noxious or expensive re-agents; cf. E.J. Corey, et al., J. Amer. Chem. Soc., 93, 1491 (1971).
Still another advantage of the present process features the preparation of an entirely new class of prostaglandin derivatives in which the acid side chain is unsaturated and the side chain bearing the hydroxy group is fully saturated.
The foregoing advantages render the prostaglandin derivatives of this invention par-ticularly desirable as pharmacologic agents.
Summary of the Invention:
One aspect of this invention is a process for -the preparation of the key intermediates, the hydroxylactone 6 and the ketolactone of formula 7. The process is represented by the following flow diagram:
, :, . .
.. . .
R IOOC COOR
2~ ~CR4R5 (CH ~ CH + CHCH2cooR3 _;~
O CoOR3 0 J~,~CH2COOR3 ~ CH COOH
- K I OOC--~ ~ ,~,~ 2 ~
~C CR4R5 (CH ) CH\_~6~C~CR R -(CH2) CH3
O CoOR3 0 J~,~CH2COOR3 ~ CH COOH
- K I OOC--~ ~ ,~,~ 2 ~
~C CR4R5 (CH ) CH\_~6~C~CR R -(CH2) CH3
3 . 4 O
OH ~P--" CH2COOH
~C-CR R - ( CH ) CH C~ 4 5 R6~oR2 2 n 3 C-CR R - ( CH2 ) CH3 ~ 6 ~/ R6 H
~
C-CR4R5- ( CH2 ) CH3 ~ O
i4~
I
in which Rl and R3 each are lower alkyi, R2 is hydrogen or a hydroxy protecting radical, R4,R5 and R6 each are hydrogen or lower alkyl, and n is an integer from two to fiYe with the provisos that at least one of R , R or R is hydrogen and that R is hydrogen when R is lowsr alkyl.
With reference to the above flow diagram a lower alkyl cyclopropanedicarboxylate of formuia I in Which R , R , R4, R5, R6 and n are as defined herein is condensed with a triester of formula 2 in which R3 is loweraIkylin the presence of a base to give the ` corresponding cyclopentanonetriester of formula 3. When : R of the latter compound is a hydroxy protecting radical, the radical is removed by treating the cyclopentanonetriester with a deprotecting agent to give the corresponding cyclo-pentanonetriester of formula 3 in which R is hydrogen~ The 1$ instant compound of formula 3 in which R2 is hydrogen is now subjected to base treatment in the presencé of water, followed by acidification of the basic reaction mixture to give the corresponding ~ketoacid of formula 4. In the case where R is hydrogen the latter compound is transformed to its corresponding ~1 hydroxy protected derivative (4, R = hydroxy protecting radical). ~.
Ths compound of formula 4 in which R is hydrogen or lower alkyl is ~i raduced with a complex borohydride to give a mixture of the corresponding acid of formula 5 and the corresponding hydroxylactone 6. Transformation of the acid 5 to the hydroxylactone 6,~thereby ~5 increasing the yield of the hydroxylactone 6, is effected by sub-jecting the acid 5, or the mixture of the acid 5 and the hydroxy-lactone 6, obtained as above, to treatment with methanesulfonyl or ~-toluenesulfonyl chloride or bromide in the presence of a suitable proton acceptor. In the case where the hydroxylactone of .
,_ , . .. . ~ .
- A~IP-6304 formula 6 is obtained in the form of its corresponding hydroxy protected derivative (6, R hydroxy protecting group and R l-l), the protected derivative is convcrted readily to its corresponding free hydroxy dcrivative (6, R2 = 11~ by treatment with a deprotecting agent.
On subjecting the latter free hydroxy derivatives of formula 6, in which R6 is hydrogen to oxidation with an agent known to be effective for oxidizing allylic alcohols to y,~-unsaturated ketones, the corresponding desired ketolactone of formula 7 in which R4 and R5 each are hydrogen or lower alkyl and n is an integer from two to five is obtained. One of these keto-lactones has been reported previously; i.e., the compound of forrnula 7 in whlch R4 and R5 each are hydrogen and n ~ 3, see E.J. Corey and X. Ilavindranathan, Tetrahedron Letters, 4755 (1971).
The ketolactone of fo~nula 7 is transformed to 15 pros~-5-eno:ic and prosta-5913-dienoic acid derivatives and related homologs according to one of the following three methods A, B, or C:
In rnethod A the ketolactone of forrnula 7 is reduced catalytically to give the corresponding dihydroketolactone of 20 forrnula 8 ~ ~'~
C-CR R -~CH2)n-C~13 ~ CR4RS (CH ) CH
25 0 oR2 in which R4, R5 and n are as defined herein. Subsequent reduction of the latter compound with a metal borohydride yields the corresponding dihydrohydroxylactone of formula g in ~hich ;~ ~
.. ..
R2 and R are hydrogen and R , R5 and n are as defIned herein.
Thereafter, +he latter dihydrohydroxylactone of formula 9, or preferably its hydroxy protected derivative, is reduced with . a mono- or dialkyl aluminum hydride to give the corresponding . hemiacetal of formula 10 OH
~
~ C CR4R5 (CH2) CH3 - . R6 ~ oR2 ,, 10 in which R2 Is hydrogen or a hydroxy protecting group, R is hydrogen, and R, R and n are as defined herein. Condensation of the latter compound with a Wittig reagent of the formula ( ~ P - CH2(CH2)mCOOR Hal in ~hich Hal is bromine, chlorine or iodine, m is an integer from one to three and R7 is hydrogen or lower alkyl yields the corresponding novel prostaglandin derivative . of formula 11 r ( CH2 ) mCR
X~
Z-C-CR4R5-(CH ) CH
R ~ ~oR2 2 n 3 ~ 11 .
. _ 9 _ 1~17~6~Z
in which R2 is hydrogen or a hydroxy protec-ting group, R6 is hydrogen, X is hydroxy, Y is hydrogen, z is CH2CH2 an~ R , R , R7, m and n are as defined herein; and when R of the latter compound is a hydroxy protecting group, subsequent reaction of the latter compound with a deprotecting agent for removing the protecting group yields the corresponding compound of formula 11 in which R is hydrogen.
In method B the ketolac-tone of formula 7 in which R is hydrogen and R5 and n are as defined herein is reduced cataly-tically in the same manner as described in the method A and the resulting corresponding dihydroketolactone of formula 8 (R = H and R = H or lower alkyl) is reacted with substantially one equivalent of a lower alkyl magnesium halide (i.e. a Grignard type reaction) -to yield the corresponding dihydrohydroxylactone of formula 9 in which lS R is hydrogen, R is lower alkyl, R is hydrogen and R
and n are as defined herein. Subsequent reduction of the latter compound with a mono- or dialkyl aluminum hydride gives the corresponding hemiacetal of formula 10 in which R is hydrogen, R6 is lower alkyl and R is hydrogen and R5 and n ~20 are as defined herein which is condehsed in a like manner with the appropria-te Wittig reagent as described in the first method to yield the corresponding novel prostaglandin derivative of formula 11 in which R and R each are hydrogen, R is lower alkyl, X is hydrogen, Y is hydrogen, Z is CH2CH2 and R , R7, m and n are as defined herein.
--10~
1~16~
In method C the ketolac-tone of formula 7 in which R4 is hydrogen and R5 and n are as defined herein is reacted with a lower alkyl magnesium halide to produce -the corresponding hydroxylactone of formula 12 S ~
C-CR R -(CH2)nCH3 R OR
in which R is hydrogen, R is hydrogen, R is lower alkyl, and R
and n are as defined herein. The latter compound is reduced with a monoalkyl or dialkyl aluminum hydride to give the corresponding hemi-acetal of formula 13 R ~ -(CH2)~CH3 /
in which R is hydrogen, R is hydrogen, R is lower alkyl, and R
and n are as defined herein. Subsequen-t condensation of the hemi-acetal of formula 13 with the appropriate Wittig reagen-t as described in the first method gives the prostaglandin derivatives of formula 11 in which R and R each are hydrogen, R is lower alkyl, X is hydroxy, Y is hydrogen, Z is trans CH-CH, and R , R , m and n are as defined herein.
These prostaglandin derivatives, prepared by a differ-ent process, are part of the sub,ject matter of our U.S. Patent No.
3,773,795, issued November 20, 1973 and U.S. Patent No. 3,917,668, issued November 4, 1975~
.. . .
P-630~
In ano-ther aspect of this invention the hydroxylactone of formula 6 in which R2, R4, R5 and n are as defined in khe first instance is utilized ~o prepare prostaglandin derivatives by one of the following two methods, D or E:
In method D the hydroxylactone of formula 6 in which R6 is hydrogen, preferably in its protected hydroxyl form (i.e., R2 is a hydroxy protecting group), is reduced catalytically to give the corresponding dihydrohydroxylactone of formula 9 in which R2 is hydrogen or hydroxy protecting group, R is hydrogen and R , R
and n are as defined in the first instance. Thereafter, the ]atter dihydrohydroxylactone, preferably in its protected hydroxyl form, is transformed to the corresponding novel prostaglandin derivative of formula 11, through the hemiacetal (10; R2 being hydrogen or a hydroxy protecting group, R6 being hydrogen and R~, R5 and n being as defined in the first instance) by reduction with a mono- or dialkylaluminum hydride to the corresponding hemiacetal followed by condensation with the appropriate Wittig reagent in the manner described previously.
In this manner the same prostaglandin derivatives are ob~ained as those obtained by transforming the ketolactone of formula 7 according to the method A described hereinbefore, i.e~, the deriva~ives of formula 11 in which R2 is hydrogen or a hydroxy protecting group, R6 is hydrogen, X is hydroxy, Y is hydrogen, Z is CH2CH2 and R4, R5, R7, m and n are as defined in the first instance.
In method E for transforming the hydroxylactone of formula 6 in which R2, R~, R5, R6 and n are as defined in the first instance to prostaglandin derivatives, the hydroxylactone of formula 6, preferably in its protected hydroxyl form when R6 is hydrogen, is reduced to its corresponding hemiacetal of formula 13 in which R , R , R , R and n are as defined in the first instance by treatment with a monoalkyl or dialkyl aluminum hydride. Thereafter, the latter hemiacetal, prefcrably iTI its 107:16a~
protected hydroxyl form when R2 is hydrogen, is condensed wi-th a Wittig reagent in the manner described above to yield the corres-ponding prostaglandin derivatives of formula 11 in which R2 is hydrogen or a hydroxy protecting group and R6 is hydrogen or R
is hydrogen and R is lower alkyl, X is hydroxy, Y is hydrogen, Z is trans CH=CH, and R4, R5, R7, m and n are as defined in the first ins-tance; and when R of the latter compound is a hydroxy protecting radical, treating said latter compound with a deprotecting agent for removing the radical to obtain the corresponding compound of formula 11 in which R is hydrogen. These latter prostaglandin derivatives, prepared by another process, are part of the subject matter of U.S.
Patent No. 3,917,668, issued November 4, 1975.
Thereafter, if desired, the aforementioned compounds of formula 11 in which R is a hydroxy protecting group, R is hydrogen or lower alkyl and R is hydrogen, or R and R each are hydrogen and R is a lower alkyl; R is hydrogen, X is hydroxy, Y is hydrogen and Z is CH2CH2 or trans CH=CH and R , m and n are as defined in the first instance, are treated with an agent capable of oxidizing the hydroxy function to its corresponding keto function to obtain the correspond-ing compound of formula 11 in which X and Y together are oxo, followed,when R of the latter compound is a hydroxy protecting group, by re-acting the latter compound with a deprotecting agent to obtain the corresponding compound of formula 11 in which R is hydrogen.
Furthermore, if desired, the aforementioned compound of formula 11 in which R and R are hydrogen, X is hydroxy and Y is hydrogen or X and Y together are oxo and Z is CH2CH2 or CH=CH and R , R , R , m and n are as defined in the first instance, are treated with a lower alkanol containing one to three carbons in the presence of an acid catalyst to obtain its corresponding ester derivative of formula 11 in which R7 is lower alkyl.
:10'^~16~Z
Details o-~ the Invention ____ _ ______ rlhe numbering sys-tem applied to -the compounds of this invention, as used hereinafter, refers to -the ~Lcyclopentyl(lower)alkanoic acid nucleus.
A feature of this invention is that the process described herein leads to the compounds of formula 11 in which the two side chains are in the trans configuration characteristic for the natural prostaglandins. Also, like the natural prostaglandins a double bond in -the acid side chain of the compounds of this invention has the cis configuration and the double bond in the side chain bearing the hydroxy group has the trans configuration.
Notwithstanding the preceding considerations the compounds of this invention having one or more asymmetric carbon atoms can exist in the form of various stereochemical isomers. More specifically, the compounds are produced as a mixture of racemates. These mixtures result from the asymmetric centers, for example the carbon bearing a hydroxyl group, and can be separated into pure racemates at appropriate stages by methods well known in the art, for example, see below. If desired, the racemates can be resolved into enantiomorphs also by known methods. It is to be understood that such racemates and enantiomorphs are included within the scope of this invention.
~i AHP-6304 .
- Furthermor~, it is to be understood that the pictorial representations used herein illustrating the compounds of this invention, are to be construed as including such racemates and enantiomorphs. For example, in for~ulall the dotted line joining the acid side chain to the cyclopentane ring and the solid line joining the side chain bearing the hydroxy group are used for the purpose of illustrating the trans relationship of these two side chains and shouid not be construed as limiting thc compounds to one enantiomorph but rather as including all possible enantiomorphs having this trans relationship.
Also included within this invention are the pharmaceutically acceptable salts of the acids of formula 11 in which R is hydrogen. The latter compounds are transformed in excellent yield into the correspond-ing pharmaceutically acceptable salts by nautrallzation of said latter compounds with the appropriate inorganic or organic base. The relativa stability of the acid ~acilitates this transformation. The salts possess the - same activities as the parent acid compounds when administered to animals and may be utilized in the same manner. Suitable inorganic bases to form these salts include, for example, ~he hydroxides, carbonates, bicarbonates or alkoxides of m e alka!i metals or alkaline ear~h metals, for example, sodium, potassium,magnesium,calcium and the like. Suitable ~rganic bases includa the following amines: lower mono-, di-ond r i a lky lami nes, the a l hy l radi ca l s of wh i ch contai n up .
,:
. -15-.. ? ~ ~.b~
.
: to 3 carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, di- and ~riathylamine, methyl-ethyla~ine, and the like; mono-, di-and trialkanolamines, - the alkanol radicals of which contain up to 3 carbon atoms, 5 . such as mono-, di- and triethanolamine alkylene-diamines : . which contain up to 6 carbon atoms, such as hexamethylene-diamine; cyclic saturated or unsaturated bases containing up to 6 carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and N-hydroxyalkyl 10 . derivattves, such as N-methyl-morphoiine and N-~2-hydroxy-athyl)-piperidine~ as well as pyridine. Furthermore, there may be mentioned the corresponding quaternary salts, such . as the tetraalkyl (for example tetramethyl), alkyl-alkanol - t~or example methyl-triethanol and trimethyl-moncethanol) and cyclic ammonium salts, for example the N-methyl-pyridinium, N-methyl-N-(2-hydroxyethyl)-pyrrolidinium, N,N-dimethyImorpholinium, N-methyl-N-(2-hydroxyethyl)-. morpholinium, N,N-dimethyl-pieeridinium and N-methyl-- N-(2-hydroxyethyl)piperidinium salts, which are characterized by an especially good water-solubility. In principle~ -however, there can be used àll ammonium salts which are physiologically compatible~
The transformations to the salts can be carried ou~ by a variety of methods known in the art. For example, in the case of tha inorganic salts, it is preferred to dlssolve the selected acid in water containing a- least an equtval~nt amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic sal-t desired. Advantageously, the reaction is performed in an iner-t organic solvent, for example, methanol, ethanol, dioxane, and the like.
Eor example, such use of sodium hydroxide, sodium carbonate or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the water or addition of a water-miscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone gives the solid inorganic salt if that form is desired. -To produce an amine salt, the selected acid is dissolved in a suitable solvent of either modera-te or lower polarity, for example, ethanol, acetone, ethyl acetate, diethyl ether and benzene. At least an equivalent amount of the amine corresponding to the desired cation 1~ is then added to that solution. If the resulting salt does not precipitate, it can usually be obtained in solid form by addition of a miscible diluent of lowe polarity, for example, benzene or diethyl ether or by evaporation.
If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use equivalen-t amounts of the less volatile amines.
Salts wherein the cation is quaternary ammonium are produced by mixing the selected acid with an equivalent amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.
The term "lower alkyl" as used herein con-templates straigh-t chain alkyl groups containing from one to three carbon atoms and includes methy], ethyl and propyl.
` - AHF'-6304 - The term "complex borohydride" as used herein contemplates the metal borohydrides, including sodium borohydride, potassium borohydride, lithium borohydride, 7inc borohydride and the like, and metal trihydrocarbyl-borohydrides including lithium 9-alkyl-9-borabicyclo[3,3,1]-ronylhydride, in which the alkyl contains one to seven carbon atom* preferably lithium 9~tert-butyl-9-borabicyclo-- ~3,3,13nonylhydride, prepared according to the procedure described in German Offenlegungsschrift 2,207,987, 1~ - published August 31, 1972, lithium diisopinocamphenyl-tert-butylborohydride and lithium 2-thexyl-4,8 dimethyl-2-boro-blcyclo[3,3,1]nonylhydride, described by E.J. Corey et al., J. Amer. Chem. Soc., 93, 1491 (1971), tithium perhydro-9b-borophenalylhydride, described by H.C. Brown and - ~5 W.C. Dickason, J. Amer. Chem. Soc., 92, 709 (1970) and - the like.
The compounds offormula llpossess interesting pharmacological properties when tested in standard pharma-cological tests. In particular, they have been found to possess hypotensive, antihypertensive, bronchospasmolytic, gastric acid secretion inhibiting, abortifacient and estrus synchronizing and ovulation regulating properties, which mzke them useful in the treatmen~ of condltions associated with high blood pressure, in the treatment of asthmatic conditions, in the treatment of pathological conditions associated with excessi~e secretion of gastric acid such as, for example, peptic ulcer, in population control, and in animal husbandry. In addition, the eompounds of this invention inhibit the aggregation of platelets and promote the disaggregation of aggregated platelets, and are useful as agents for the prevention and treatment of thrombosis.
More particularly, these compounds, when tested in a modification of the tests for determining hypo-tensive activities described in "Screening Methods in Pharmacology", Academic Press, New York and London 1965, page 146, using the cat in urethane-chloralose anaesthesia as the test animal and maasuring mean arterial blood pressure before and after intravenous administration of the cornpounds, have exhibited utility as hypotensive agents. When tested in the renalhypertensive rat, prepared by the method of A. GrolIman describad in Proc. Soc. Exp. Biol. Med., 7, 102 (1954), and neasuring blood pressure by the method described by H. Kersten, J. Lab. Clin. Med., 32, 1090 tl947), they have axhibited utility as antihypertensive agents.
- Moreover, the compounds of this invention, when tested in a modification of the test method described by A.K. Armitage, et al. , 8rit. J. Pharmacol., 16, 59 (1961), have been found to alleviate bronchospasrns, and are useful as bronchospasmolytic agents.
, " .
~ 64Z
Furthermore, -the compoun~s of -this lnven-tion, when administered to rats in the -tes-t method described by H. Shay, et al., Gastroenterol., 26, 906 (195~), have been found to inhibit the secretion of gastric acid, and are useful as agents inhibiting the secretion o~ gastric acid.
In addition, the compounds of this invention, when tested in a modification of the test method described by G.V.R. Born, Nature,194, 927 (1962), using the aggregometer manufactured by Bryston Manufacturing Limited, Rexdale, Ontario, Canada, have been shown to inhibit the aggregation of platelets and to promote the disaggregation of aggregated platelets, and are useful as agents for the prevention and treatment of -thrombosis.
When the compounds of this invention are employed as hypotensive or anti-hypertensive agents, as agents inhibit-ing gastric acid secretion in warm-blooded animals, for example, in cats or rats, as agents for the prevention or treatment of thrombosis, or as bronchospasmolytic agents, alone or in combination with pharmacologically acceptable carriers, their proportions are determined by their solubilities, by the chosen route of administration, and by standard biological practice. The compounds of this invention may be administered orally in solid form containing such excipients as starch, lactose, sucrose, certain types of clay, and flavouring and coating agents.
However, they are preferably administered parenterally in AHP-6~0~t .
~ .
- the form of steri1e solutions thereof which may also contain other solutes, for example, sufficient sodium chloride or glucose to make the solution isotonic. For use as bronchospasmolytic agents, the compounds of this invention are preferably administered as aerosols.
` The dosage of the present hypotensive, anti-hypertensive, gastric acid secretion inhibiting, or bronchospasmolytic agents, or agents for the prevention and treatment of thrombosis will vary with the forms of administration and the particular hosts under treatment.
Generally, treatments are initiated with small dosages substantially less than the optimum doses of the compounds.
Thereafter, the dosages are increased by smalt increments ~untTl the optimum effects under the circumstances are ~ reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side,effects and preferably at a level that is in a range of from about 0.1 mg to about 10.0 mg per kilo, although as aforementioned variations will occur. However, a dosaae level that is in the range of from about 0.5 mg to about 5 mg per kilo is most desirably smployed in order to achieve effective results. When adm1nistering the compounds of this invention as aerosols the liquid to be nebulized, for example, water, ethyl alcohol, O
. 10~16~
dichloro-tetrafluoroe-thane and dichlorodifluoromethane, contains preferably from 0.005 - 0.05 per cent of the acid, or a non-toxid alkali metal, ammonium or amine salt thereof, or ester of formula 11.
Furthermore, when the compounds of this inven-tion are tested by the method of A.P. Labhsetwar, Nature, 230, 528 (1971) whereby the compound is given subcutaneously on a daily basis to mated hamsters on days 4, 5 and 6 of pregnancy, thereafter the animals being sacrificed on day 7 of pregnancy and the number of abortions counted, the compounds are shown to have abortifacient properties.
For example, complete abortion resulted in all animals when the following compounds of formula 11 were tested according to this method at doses noted below:
15 trans,cis-7- ~ ~hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclo-penty~ -5-heptenoic acid (Example 175), 0.5 mg/kg/day, cis-7-~2~-hydroxy-5-(3-hydroxyoctyl)cyclopent ~ -5-heptenoic acid (Example 175), 2.5 mg/kg/day, and cis-7- ~ ~-hydroxy-5-(3-hydroxy-3-methyloctyl)cyclo-20 penty~ -5-heptenoic acid (Example 175), 5.0 mg/kg/day.
The potency of the above unsaturated compounds is especially noteworthy in light of -the fact that the completely saturated 15-methyl analog, 2-(3-hydroxy-3-methyl-octyl)-5-oxocyclopentaneheptanoic acid, described in 25 U.S. Patent 3,671,570, cited above, does not cause complete :: :. ... .. .
~ AHP-630~
~ ~7 ~ 3 ,~ .
.~
.
abor~ion in the above test at doses less than 30 mg/kg/day.
Furthermore, the compounds of this invention are useful for inducing labor in pregnant animals at or near term. When the compounds of this invention are employed as agents for abortion or for inducing labor, the compounds are infused intravenously at a dose of 0.01 to 100 mg/kg per - - minute untii the deslred effect is obtained.
Sttll furthermore, the compounds of formula 11 are useful for the synchronization of estrus and the regulation of ovulation in animals.
It is often desirabie to synchronize estrus in domestic animals, for example, horses, cattle, sheep, swine or dogs, in order to be able to perform artificial ----- Insemination or mating with a male of the deslred genetic- quality under optimum cond7tions. In the past, this has ~
- been done by administering to the animals a`n ovulation-inhibiting agent, withdrawing administration of said -a~ent shortly before the date chosen for mating or artificial insemination, and relying either upon the natural production of LH and FSH to induce ovulation and to produce estrus or by administering gonadotrophins.
However, this procedure was not entirely satisfactory because ovulation at a predetermined time occured only in a certain - proportion of the animals when gonadotrophins were not ~ used. On the other hand, the high cost of gonadotrophins ~, . .
--2 ~5--l AHP-6304 ,...... ..
.
and side effects encountered in their administration made this method impractical. !t is now possible to obtain - substantially complete synchronization of ovulation and of es~rus, by treating the animals in a given group ~ith the compound of formula 11 before the predetermined - 5 period of time for mating or artificial insemination, so as to obta;n ovuiation and estrus within that time interval. The delay in the onset of ovulation and estrus following administration of the compound of this invention Yar7es with the species of animal- For example~ in rodents such as rats or hamsters ovulation takes place withini8hours following administration of the compound and in the horse ovulation usually takes place within one week after the compound is given.
- More specifically, synchronization of estrus and regulation of ovulation in the horse is achieved by giving the compound of formulall either randomly to a group of horses during the life of the corpus luteum (usually day 5 to day 1~ of the cycle) or two to three days prior to the expected onset of estrus. The compound for example, trans, c~s-7-~2a-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]-5-heptenoic acid, is given by intrauterine infusion, subcutaneously or intramuscuiarly In sterile solutions. A dosage which is in the ranseof from about I to 100 mg/1000 1~, preferably 5 to 25 mg/1000 Ib i5 employed and is administered as a single dose or spread over ~ period of 72 hours. Practically speaking it is 64;z preferable to give one-half -the -total dose on two consecutive days for the latter form of administration. For example, in a group of horses receiving this medication on the second and -third day before expected estrus, estrus follows wi-thin 24 to 48 hours which in turn is rollowed by ovulation occuring in the majority of animals, from the fourth to the sixth day thereafter as determined by rectal pal-pation of the ovaries.
In a control group receiving no medication the occurance of ovulation was spread rather unevenly over the third to eighth day after the onset of estrus.
Process The starting materials of formula 1 are described in U.S.
: Patent No. 3,773,795 and U.S. Patent No. 3,917,668, issued November
OH ~P--" CH2COOH
~C-CR R - ( CH ) CH C~ 4 5 R6~oR2 2 n 3 C-CR R - ( CH2 ) CH3 ~ 6 ~/ R6 H
~
C-CR4R5- ( CH2 ) CH3 ~ O
i4~
I
in which Rl and R3 each are lower alkyi, R2 is hydrogen or a hydroxy protecting radical, R4,R5 and R6 each are hydrogen or lower alkyl, and n is an integer from two to fiYe with the provisos that at least one of R , R or R is hydrogen and that R is hydrogen when R is lowsr alkyl.
With reference to the above flow diagram a lower alkyl cyclopropanedicarboxylate of formuia I in Which R , R , R4, R5, R6 and n are as defined herein is condensed with a triester of formula 2 in which R3 is loweraIkylin the presence of a base to give the ` corresponding cyclopentanonetriester of formula 3. When : R of the latter compound is a hydroxy protecting radical, the radical is removed by treating the cyclopentanonetriester with a deprotecting agent to give the corresponding cyclo-pentanonetriester of formula 3 in which R is hydrogen~ The 1$ instant compound of formula 3 in which R2 is hydrogen is now subjected to base treatment in the presencé of water, followed by acidification of the basic reaction mixture to give the corresponding ~ketoacid of formula 4. In the case where R is hydrogen the latter compound is transformed to its corresponding ~1 hydroxy protected derivative (4, R = hydroxy protecting radical). ~.
Ths compound of formula 4 in which R is hydrogen or lower alkyl is ~i raduced with a complex borohydride to give a mixture of the corresponding acid of formula 5 and the corresponding hydroxylactone 6. Transformation of the acid 5 to the hydroxylactone 6,~thereby ~5 increasing the yield of the hydroxylactone 6, is effected by sub-jecting the acid 5, or the mixture of the acid 5 and the hydroxy-lactone 6, obtained as above, to treatment with methanesulfonyl or ~-toluenesulfonyl chloride or bromide in the presence of a suitable proton acceptor. In the case where the hydroxylactone of .
,_ , . .. . ~ .
- A~IP-6304 formula 6 is obtained in the form of its corresponding hydroxy protected derivative (6, R hydroxy protecting group and R l-l), the protected derivative is convcrted readily to its corresponding free hydroxy dcrivative (6, R2 = 11~ by treatment with a deprotecting agent.
On subjecting the latter free hydroxy derivatives of formula 6, in which R6 is hydrogen to oxidation with an agent known to be effective for oxidizing allylic alcohols to y,~-unsaturated ketones, the corresponding desired ketolactone of formula 7 in which R4 and R5 each are hydrogen or lower alkyl and n is an integer from two to five is obtained. One of these keto-lactones has been reported previously; i.e., the compound of forrnula 7 in whlch R4 and R5 each are hydrogen and n ~ 3, see E.J. Corey and X. Ilavindranathan, Tetrahedron Letters, 4755 (1971).
The ketolactone of fo~nula 7 is transformed to 15 pros~-5-eno:ic and prosta-5913-dienoic acid derivatives and related homologs according to one of the following three methods A, B, or C:
In rnethod A the ketolactone of forrnula 7 is reduced catalytically to give the corresponding dihydroketolactone of 20 forrnula 8 ~ ~'~
C-CR R -~CH2)n-C~13 ~ CR4RS (CH ) CH
25 0 oR2 in which R4, R5 and n are as defined herein. Subsequent reduction of the latter compound with a metal borohydride yields the corresponding dihydrohydroxylactone of formula g in ~hich ;~ ~
.. ..
R2 and R are hydrogen and R , R5 and n are as defIned herein.
Thereafter, +he latter dihydrohydroxylactone of formula 9, or preferably its hydroxy protected derivative, is reduced with . a mono- or dialkyl aluminum hydride to give the corresponding . hemiacetal of formula 10 OH
~
~ C CR4R5 (CH2) CH3 - . R6 ~ oR2 ,, 10 in which R2 Is hydrogen or a hydroxy protecting group, R is hydrogen, and R, R and n are as defined herein. Condensation of the latter compound with a Wittig reagent of the formula ( ~ P - CH2(CH2)mCOOR Hal in ~hich Hal is bromine, chlorine or iodine, m is an integer from one to three and R7 is hydrogen or lower alkyl yields the corresponding novel prostaglandin derivative . of formula 11 r ( CH2 ) mCR
X~
Z-C-CR4R5-(CH ) CH
R ~ ~oR2 2 n 3 ~ 11 .
. _ 9 _ 1~17~6~Z
in which R2 is hydrogen or a hydroxy protec-ting group, R6 is hydrogen, X is hydroxy, Y is hydrogen, z is CH2CH2 an~ R , R , R7, m and n are as defined herein; and when R of the latter compound is a hydroxy protecting group, subsequent reaction of the latter compound with a deprotecting agent for removing the protecting group yields the corresponding compound of formula 11 in which R is hydrogen.
In method B the ketolac-tone of formula 7 in which R is hydrogen and R5 and n are as defined herein is reduced cataly-tically in the same manner as described in the method A and the resulting corresponding dihydroketolactone of formula 8 (R = H and R = H or lower alkyl) is reacted with substantially one equivalent of a lower alkyl magnesium halide (i.e. a Grignard type reaction) -to yield the corresponding dihydrohydroxylactone of formula 9 in which lS R is hydrogen, R is lower alkyl, R is hydrogen and R
and n are as defined herein. Subsequent reduction of the latter compound with a mono- or dialkyl aluminum hydride gives the corresponding hemiacetal of formula 10 in which R is hydrogen, R6 is lower alkyl and R is hydrogen and R5 and n ~20 are as defined herein which is condehsed in a like manner with the appropria-te Wittig reagent as described in the first method to yield the corresponding novel prostaglandin derivative of formula 11 in which R and R each are hydrogen, R is lower alkyl, X is hydrogen, Y is hydrogen, Z is CH2CH2 and R , R7, m and n are as defined herein.
--10~
1~16~
In method C the ketolac-tone of formula 7 in which R4 is hydrogen and R5 and n are as defined herein is reacted with a lower alkyl magnesium halide to produce -the corresponding hydroxylactone of formula 12 S ~
C-CR R -(CH2)nCH3 R OR
in which R is hydrogen, R is hydrogen, R is lower alkyl, and R
and n are as defined herein. The latter compound is reduced with a monoalkyl or dialkyl aluminum hydride to give the corresponding hemi-acetal of formula 13 R ~ -(CH2)~CH3 /
in which R is hydrogen, R is hydrogen, R is lower alkyl, and R
and n are as defined herein. Subsequen-t condensation of the hemi-acetal of formula 13 with the appropriate Wittig reagen-t as described in the first method gives the prostaglandin derivatives of formula 11 in which R and R each are hydrogen, R is lower alkyl, X is hydroxy, Y is hydrogen, Z is trans CH-CH, and R , R , m and n are as defined herein.
These prostaglandin derivatives, prepared by a differ-ent process, are part of the sub,ject matter of our U.S. Patent No.
3,773,795, issued November 20, 1973 and U.S. Patent No. 3,917,668, issued November 4, 1975~
.. . .
P-630~
In ano-ther aspect of this invention the hydroxylactone of formula 6 in which R2, R4, R5 and n are as defined in khe first instance is utilized ~o prepare prostaglandin derivatives by one of the following two methods, D or E:
In method D the hydroxylactone of formula 6 in which R6 is hydrogen, preferably in its protected hydroxyl form (i.e., R2 is a hydroxy protecting group), is reduced catalytically to give the corresponding dihydrohydroxylactone of formula 9 in which R2 is hydrogen or hydroxy protecting group, R is hydrogen and R , R
and n are as defined in the first instance. Thereafter, the ]atter dihydrohydroxylactone, preferably in its protected hydroxyl form, is transformed to the corresponding novel prostaglandin derivative of formula 11, through the hemiacetal (10; R2 being hydrogen or a hydroxy protecting group, R6 being hydrogen and R~, R5 and n being as defined in the first instance) by reduction with a mono- or dialkylaluminum hydride to the corresponding hemiacetal followed by condensation with the appropriate Wittig reagent in the manner described previously.
In this manner the same prostaglandin derivatives are ob~ained as those obtained by transforming the ketolactone of formula 7 according to the method A described hereinbefore, i.e~, the deriva~ives of formula 11 in which R2 is hydrogen or a hydroxy protecting group, R6 is hydrogen, X is hydroxy, Y is hydrogen, Z is CH2CH2 and R4, R5, R7, m and n are as defined in the first instance.
In method E for transforming the hydroxylactone of formula 6 in which R2, R~, R5, R6 and n are as defined in the first instance to prostaglandin derivatives, the hydroxylactone of formula 6, preferably in its protected hydroxyl form when R6 is hydrogen, is reduced to its corresponding hemiacetal of formula 13 in which R , R , R , R and n are as defined in the first instance by treatment with a monoalkyl or dialkyl aluminum hydride. Thereafter, the latter hemiacetal, prefcrably iTI its 107:16a~
protected hydroxyl form when R2 is hydrogen, is condensed wi-th a Wittig reagent in the manner described above to yield the corres-ponding prostaglandin derivatives of formula 11 in which R2 is hydrogen or a hydroxy protecting group and R6 is hydrogen or R
is hydrogen and R is lower alkyl, X is hydroxy, Y is hydrogen, Z is trans CH=CH, and R4, R5, R7, m and n are as defined in the first ins-tance; and when R of the latter compound is a hydroxy protecting radical, treating said latter compound with a deprotecting agent for removing the radical to obtain the corresponding compound of formula 11 in which R is hydrogen. These latter prostaglandin derivatives, prepared by another process, are part of the subject matter of U.S.
Patent No. 3,917,668, issued November 4, 1975.
Thereafter, if desired, the aforementioned compounds of formula 11 in which R is a hydroxy protecting group, R is hydrogen or lower alkyl and R is hydrogen, or R and R each are hydrogen and R is a lower alkyl; R is hydrogen, X is hydroxy, Y is hydrogen and Z is CH2CH2 or trans CH=CH and R , m and n are as defined in the first instance, are treated with an agent capable of oxidizing the hydroxy function to its corresponding keto function to obtain the correspond-ing compound of formula 11 in which X and Y together are oxo, followed,when R of the latter compound is a hydroxy protecting group, by re-acting the latter compound with a deprotecting agent to obtain the corresponding compound of formula 11 in which R is hydrogen.
Furthermore, if desired, the aforementioned compound of formula 11 in which R and R are hydrogen, X is hydroxy and Y is hydrogen or X and Y together are oxo and Z is CH2CH2 or CH=CH and R , R , R , m and n are as defined in the first instance, are treated with a lower alkanol containing one to three carbons in the presence of an acid catalyst to obtain its corresponding ester derivative of formula 11 in which R7 is lower alkyl.
:10'^~16~Z
Details o-~ the Invention ____ _ ______ rlhe numbering sys-tem applied to -the compounds of this invention, as used hereinafter, refers to -the ~Lcyclopentyl(lower)alkanoic acid nucleus.
A feature of this invention is that the process described herein leads to the compounds of formula 11 in which the two side chains are in the trans configuration characteristic for the natural prostaglandins. Also, like the natural prostaglandins a double bond in -the acid side chain of the compounds of this invention has the cis configuration and the double bond in the side chain bearing the hydroxy group has the trans configuration.
Notwithstanding the preceding considerations the compounds of this invention having one or more asymmetric carbon atoms can exist in the form of various stereochemical isomers. More specifically, the compounds are produced as a mixture of racemates. These mixtures result from the asymmetric centers, for example the carbon bearing a hydroxyl group, and can be separated into pure racemates at appropriate stages by methods well known in the art, for example, see below. If desired, the racemates can be resolved into enantiomorphs also by known methods. It is to be understood that such racemates and enantiomorphs are included within the scope of this invention.
~i AHP-6304 .
- Furthermor~, it is to be understood that the pictorial representations used herein illustrating the compounds of this invention, are to be construed as including such racemates and enantiomorphs. For example, in for~ulall the dotted line joining the acid side chain to the cyclopentane ring and the solid line joining the side chain bearing the hydroxy group are used for the purpose of illustrating the trans relationship of these two side chains and shouid not be construed as limiting thc compounds to one enantiomorph but rather as including all possible enantiomorphs having this trans relationship.
Also included within this invention are the pharmaceutically acceptable salts of the acids of formula 11 in which R is hydrogen. The latter compounds are transformed in excellent yield into the correspond-ing pharmaceutically acceptable salts by nautrallzation of said latter compounds with the appropriate inorganic or organic base. The relativa stability of the acid ~acilitates this transformation. The salts possess the - same activities as the parent acid compounds when administered to animals and may be utilized in the same manner. Suitable inorganic bases to form these salts include, for example, ~he hydroxides, carbonates, bicarbonates or alkoxides of m e alka!i metals or alkaline ear~h metals, for example, sodium, potassium,magnesium,calcium and the like. Suitable ~rganic bases includa the following amines: lower mono-, di-ond r i a lky lami nes, the a l hy l radi ca l s of wh i ch contai n up .
,:
. -15-.. ? ~ ~.b~
.
: to 3 carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, di- and ~riathylamine, methyl-ethyla~ine, and the like; mono-, di-and trialkanolamines, - the alkanol radicals of which contain up to 3 carbon atoms, 5 . such as mono-, di- and triethanolamine alkylene-diamines : . which contain up to 6 carbon atoms, such as hexamethylene-diamine; cyclic saturated or unsaturated bases containing up to 6 carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and N-hydroxyalkyl 10 . derivattves, such as N-methyl-morphoiine and N-~2-hydroxy-athyl)-piperidine~ as well as pyridine. Furthermore, there may be mentioned the corresponding quaternary salts, such . as the tetraalkyl (for example tetramethyl), alkyl-alkanol - t~or example methyl-triethanol and trimethyl-moncethanol) and cyclic ammonium salts, for example the N-methyl-pyridinium, N-methyl-N-(2-hydroxyethyl)-pyrrolidinium, N,N-dimethyImorpholinium, N-methyl-N-(2-hydroxyethyl)-. morpholinium, N,N-dimethyl-pieeridinium and N-methyl-- N-(2-hydroxyethyl)piperidinium salts, which are characterized by an especially good water-solubility. In principle~ -however, there can be used àll ammonium salts which are physiologically compatible~
The transformations to the salts can be carried ou~ by a variety of methods known in the art. For example, in the case of tha inorganic salts, it is preferred to dlssolve the selected acid in water containing a- least an equtval~nt amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic sal-t desired. Advantageously, the reaction is performed in an iner-t organic solvent, for example, methanol, ethanol, dioxane, and the like.
Eor example, such use of sodium hydroxide, sodium carbonate or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the water or addition of a water-miscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone gives the solid inorganic salt if that form is desired. -To produce an amine salt, the selected acid is dissolved in a suitable solvent of either modera-te or lower polarity, for example, ethanol, acetone, ethyl acetate, diethyl ether and benzene. At least an equivalent amount of the amine corresponding to the desired cation 1~ is then added to that solution. If the resulting salt does not precipitate, it can usually be obtained in solid form by addition of a miscible diluent of lowe polarity, for example, benzene or diethyl ether or by evaporation.
If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use equivalen-t amounts of the less volatile amines.
Salts wherein the cation is quaternary ammonium are produced by mixing the selected acid with an equivalent amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.
The term "lower alkyl" as used herein con-templates straigh-t chain alkyl groups containing from one to three carbon atoms and includes methy], ethyl and propyl.
` - AHF'-6304 - The term "complex borohydride" as used herein contemplates the metal borohydrides, including sodium borohydride, potassium borohydride, lithium borohydride, 7inc borohydride and the like, and metal trihydrocarbyl-borohydrides including lithium 9-alkyl-9-borabicyclo[3,3,1]-ronylhydride, in which the alkyl contains one to seven carbon atom* preferably lithium 9~tert-butyl-9-borabicyclo-- ~3,3,13nonylhydride, prepared according to the procedure described in German Offenlegungsschrift 2,207,987, 1~ - published August 31, 1972, lithium diisopinocamphenyl-tert-butylborohydride and lithium 2-thexyl-4,8 dimethyl-2-boro-blcyclo[3,3,1]nonylhydride, described by E.J. Corey et al., J. Amer. Chem. Soc., 93, 1491 (1971), tithium perhydro-9b-borophenalylhydride, described by H.C. Brown and - ~5 W.C. Dickason, J. Amer. Chem. Soc., 92, 709 (1970) and - the like.
The compounds offormula llpossess interesting pharmacological properties when tested in standard pharma-cological tests. In particular, they have been found to possess hypotensive, antihypertensive, bronchospasmolytic, gastric acid secretion inhibiting, abortifacient and estrus synchronizing and ovulation regulating properties, which mzke them useful in the treatmen~ of condltions associated with high blood pressure, in the treatment of asthmatic conditions, in the treatment of pathological conditions associated with excessi~e secretion of gastric acid such as, for example, peptic ulcer, in population control, and in animal husbandry. In addition, the eompounds of this invention inhibit the aggregation of platelets and promote the disaggregation of aggregated platelets, and are useful as agents for the prevention and treatment of thrombosis.
More particularly, these compounds, when tested in a modification of the tests for determining hypo-tensive activities described in "Screening Methods in Pharmacology", Academic Press, New York and London 1965, page 146, using the cat in urethane-chloralose anaesthesia as the test animal and maasuring mean arterial blood pressure before and after intravenous administration of the cornpounds, have exhibited utility as hypotensive agents. When tested in the renalhypertensive rat, prepared by the method of A. GrolIman describad in Proc. Soc. Exp. Biol. Med., 7, 102 (1954), and neasuring blood pressure by the method described by H. Kersten, J. Lab. Clin. Med., 32, 1090 tl947), they have axhibited utility as antihypertensive agents.
- Moreover, the compounds of this invention, when tested in a modification of the test method described by A.K. Armitage, et al. , 8rit. J. Pharmacol., 16, 59 (1961), have been found to alleviate bronchospasrns, and are useful as bronchospasmolytic agents.
, " .
~ 64Z
Furthermore, -the compoun~s of -this lnven-tion, when administered to rats in the -tes-t method described by H. Shay, et al., Gastroenterol., 26, 906 (195~), have been found to inhibit the secretion of gastric acid, and are useful as agents inhibiting the secretion o~ gastric acid.
In addition, the compounds of this invention, when tested in a modification of the test method described by G.V.R. Born, Nature,194, 927 (1962), using the aggregometer manufactured by Bryston Manufacturing Limited, Rexdale, Ontario, Canada, have been shown to inhibit the aggregation of platelets and to promote the disaggregation of aggregated platelets, and are useful as agents for the prevention and treatment of -thrombosis.
When the compounds of this invention are employed as hypotensive or anti-hypertensive agents, as agents inhibit-ing gastric acid secretion in warm-blooded animals, for example, in cats or rats, as agents for the prevention or treatment of thrombosis, or as bronchospasmolytic agents, alone or in combination with pharmacologically acceptable carriers, their proportions are determined by their solubilities, by the chosen route of administration, and by standard biological practice. The compounds of this invention may be administered orally in solid form containing such excipients as starch, lactose, sucrose, certain types of clay, and flavouring and coating agents.
However, they are preferably administered parenterally in AHP-6~0~t .
~ .
- the form of steri1e solutions thereof which may also contain other solutes, for example, sufficient sodium chloride or glucose to make the solution isotonic. For use as bronchospasmolytic agents, the compounds of this invention are preferably administered as aerosols.
` The dosage of the present hypotensive, anti-hypertensive, gastric acid secretion inhibiting, or bronchospasmolytic agents, or agents for the prevention and treatment of thrombosis will vary with the forms of administration and the particular hosts under treatment.
Generally, treatments are initiated with small dosages substantially less than the optimum doses of the compounds.
Thereafter, the dosages are increased by smalt increments ~untTl the optimum effects under the circumstances are ~ reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side,effects and preferably at a level that is in a range of from about 0.1 mg to about 10.0 mg per kilo, although as aforementioned variations will occur. However, a dosaae level that is in the range of from about 0.5 mg to about 5 mg per kilo is most desirably smployed in order to achieve effective results. When adm1nistering the compounds of this invention as aerosols the liquid to be nebulized, for example, water, ethyl alcohol, O
. 10~16~
dichloro-tetrafluoroe-thane and dichlorodifluoromethane, contains preferably from 0.005 - 0.05 per cent of the acid, or a non-toxid alkali metal, ammonium or amine salt thereof, or ester of formula 11.
Furthermore, when the compounds of this inven-tion are tested by the method of A.P. Labhsetwar, Nature, 230, 528 (1971) whereby the compound is given subcutaneously on a daily basis to mated hamsters on days 4, 5 and 6 of pregnancy, thereafter the animals being sacrificed on day 7 of pregnancy and the number of abortions counted, the compounds are shown to have abortifacient properties.
For example, complete abortion resulted in all animals when the following compounds of formula 11 were tested according to this method at doses noted below:
15 trans,cis-7- ~ ~hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclo-penty~ -5-heptenoic acid (Example 175), 0.5 mg/kg/day, cis-7-~2~-hydroxy-5-(3-hydroxyoctyl)cyclopent ~ -5-heptenoic acid (Example 175), 2.5 mg/kg/day, and cis-7- ~ ~-hydroxy-5-(3-hydroxy-3-methyloctyl)cyclo-20 penty~ -5-heptenoic acid (Example 175), 5.0 mg/kg/day.
The potency of the above unsaturated compounds is especially noteworthy in light of -the fact that the completely saturated 15-methyl analog, 2-(3-hydroxy-3-methyl-octyl)-5-oxocyclopentaneheptanoic acid, described in 25 U.S. Patent 3,671,570, cited above, does not cause complete :: :. ... .. .
~ AHP-630~
~ ~7 ~ 3 ,~ .
.~
.
abor~ion in the above test at doses less than 30 mg/kg/day.
Furthermore, the compounds of this invention are useful for inducing labor in pregnant animals at or near term. When the compounds of this invention are employed as agents for abortion or for inducing labor, the compounds are infused intravenously at a dose of 0.01 to 100 mg/kg per - - minute untii the deslred effect is obtained.
Sttll furthermore, the compounds of formula 11 are useful for the synchronization of estrus and the regulation of ovulation in animals.
It is often desirabie to synchronize estrus in domestic animals, for example, horses, cattle, sheep, swine or dogs, in order to be able to perform artificial ----- Insemination or mating with a male of the deslred genetic- quality under optimum cond7tions. In the past, this has ~
- been done by administering to the animals a`n ovulation-inhibiting agent, withdrawing administration of said -a~ent shortly before the date chosen for mating or artificial insemination, and relying either upon the natural production of LH and FSH to induce ovulation and to produce estrus or by administering gonadotrophins.
However, this procedure was not entirely satisfactory because ovulation at a predetermined time occured only in a certain - proportion of the animals when gonadotrophins were not ~ used. On the other hand, the high cost of gonadotrophins ~, . .
--2 ~5--l AHP-6304 ,...... ..
.
and side effects encountered in their administration made this method impractical. !t is now possible to obtain - substantially complete synchronization of ovulation and of es~rus, by treating the animals in a given group ~ith the compound of formula 11 before the predetermined - 5 period of time for mating or artificial insemination, so as to obta;n ovuiation and estrus within that time interval. The delay in the onset of ovulation and estrus following administration of the compound of this invention Yar7es with the species of animal- For example~ in rodents such as rats or hamsters ovulation takes place withini8hours following administration of the compound and in the horse ovulation usually takes place within one week after the compound is given.
- More specifically, synchronization of estrus and regulation of ovulation in the horse is achieved by giving the compound of formulall either randomly to a group of horses during the life of the corpus luteum (usually day 5 to day 1~ of the cycle) or two to three days prior to the expected onset of estrus. The compound for example, trans, c~s-7-~2a-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]-5-heptenoic acid, is given by intrauterine infusion, subcutaneously or intramuscuiarly In sterile solutions. A dosage which is in the ranseof from about I to 100 mg/1000 1~, preferably 5 to 25 mg/1000 Ib i5 employed and is administered as a single dose or spread over ~ period of 72 hours. Practically speaking it is 64;z preferable to give one-half -the -total dose on two consecutive days for the latter form of administration. For example, in a group of horses receiving this medication on the second and -third day before expected estrus, estrus follows wi-thin 24 to 48 hours which in turn is rollowed by ovulation occuring in the majority of animals, from the fourth to the sixth day thereafter as determined by rectal pal-pation of the ovaries.
In a control group receiving no medication the occurance of ovulation was spread rather unevenly over the third to eighth day after the onset of estrus.
Process The starting materials of formula 1 are described in U.S.
: Patent No. 3,773,795 and U.S. Patent No. 3,917,668, issued November
4, 1975, cited above; see also West German Offenlegungsschrift, 15 2,313,868 published October 4, 1973 and the publication by N.A.
Abraham, cited above.
Briefly the starting materials are prepared readily by treating an aldehyde of formula 14 RlOOC COORl RlOOC COOR
~ CHO ~ Cl-CR ~ -(CH2)~
14 - .
in which Rl is lower alkyl with a Wittig reagent of formula (ALKO)2POCH2COCR R -(CH2)nCH3 in which Alk is lower alkyl and R , R5 and n are as defined herein to obtain the corresponding ketodi-25 carboxylic acid of formula 15 in which R , R , R and n are de~ined herein; followed by reduction of the latter compound with a metal borohydride, preferably sodium borohydride, -to obtain the corres-ponding starting material of formula ] in which R is hydrogen, 25_ 10~6a~2 which in turn is readily transformed to its corresponding hydroxy protected derivative. The starting material of formula 1 in which R is lower alkyl is obtained by reac-ting the ketodicarboxylic acid o~ formula 15 with substantially one molar equivalent of a lower alkyl magnesium halide in the manner described herein.
The aldehyde of formula 14 in which R is ethyl, required for the preceding preparation, has been described by D.T. Warner, J. Org. Chem., 24, 1536 (1959). By following the process described therein for the preparation of that aldehyde and using the appropriate -~
di(lower)alkylbromomalonate, the aldehydes of formula 14 in whichRl is a lower alkyl other than ethyl are obtained.
The requisite Wittig reagents are prepared by the method of E.J. Corey and G.T. Kwiatkowsky, J. Amer. Chem. Soc., 88, 5654 (1966) using the appropriate lower alkyl alkanoate and di(lower) alkyl ~ -lithiomethanephosphonate.
The triester of formula 2, the other starting material of this process, is readily prepared by condensing a di(lower)alkyl malonate with a lower alkyl bromoacetic acid ester in the presence of a base. ~or example, the preparation of the triester of formula 2 in which R is ethyl has been described by A. Horeau, Bull. Soc.
Chim. Fr., 1959 (1943) and by T.R. Kasturi, Indian Inst. Scio, Golden .Jubilee Research Vol., 1909 - 59, 40 (Publ. 1959); see Chem Abstr., 55, 23371 h (1961).
The preferred hydroxy protecting groups for use in the process of this invention are tetrahydropyran-2-yl (THP), trimethyl-silyl (TMS), dimethylisopropylsilyl (DMIS), dimethyl-tert-butylsilyl and tert-butyl. The transformation of hs fres hydr-oxy derivative to the hydroxy protected derivative is effected by treating th0 hydroxy derivative with a reagent known to be effective for converting a hydroxy group of a known compound to a protected hydroxy group. Such reagents include an excess of dihydropyran and an acid catalyst for example, ~-toluenesulfonic acid, hydrogen chloride or sulfuric acid for the THP group, trimethylchlorosilane with hexamethyldisilazane for the TMS group, dimethylisopropylchlorosilane and diisopropyItetramethyl-disilazane for the DMIS group, dimethyl-tert-butylchlorosil~ne and Tmidazole for the dimethyl-tert-butylsilyl group or isobutylene for tho t -butyl group.
For removal of the hydroxy protecting groups various agents known to be effective for this purpose are available~ These agents are called deprotecting agents. For example, t~e THP group is removed by treating the derivative having a THP group as the hydroxy protecting group with an acid, for example, hydrochlor;c acid, aqueous - acetic acid or preferably p-toluenesulfonic acid, in an inert solvent in the presence of water, preferably methanol-water (9:1). The TMS
radical is removed by treatment with an excess of water-methanol (10:1) for 24 hours or with tetrahydrofuran-acetic acid at room temperature for one to two hours. Likewise, the DMIS and dimethyl-ter~-butylsilyl group are removed by the same conditions used for the removal of the TMS radical.
in practising the process of this invention the starting material of formula 1, preferable in the form of its THP derivative, and the triester of formula~, preferably, the triethyl ester, are subjected to a base catalyzed condensation to give the corresponding 0~iL69~
cyclopentanone-triester of formula 3. This condensation is perform-ed in -the presence of a suitable base, preferably an alkali metal alkoxide, for example, sodium methoxide. Other suitable bases in-clude sodium ethoxide, potassium tert-butoxide, and sodium hydride.
More specifically, this condensation is conveniently effected by heating a mixture of about equimolar amounts of the compound of formula 1 and the triester 2 at 80 to 150C, pre-ferably 100 - 140 C, for 30 minutes to six hours, preferably one to three hours. The reaction mixture is then cooled, neutralized with an acid, for example, acetic acid, and extracted with a water-immiscible solvent, for example, diethyl ether. Evaporation of theextract and purification of the residue by chromatography on silica gel yields the cyclopentanonetriester of formula 3.
Thereafter, in the case where the hydroxy group has been protected by a suitable protecting group, said group is now removed by a deprotecting agent. The compound of formula 3 in its free hydroxy form is now treated with an alkali metal hydroxide in the presence of water to give the corresponding y -ketoacid of formula 4 in which P. , R , R5, R and n are defined in the first instance.
Preferably this reaction is done by heating a mixture of the cyclo-pentanonetries-ter with an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide, in the presence of water at reflux temperature of the mixture for a period of 15 minutes to six hours, preferably about one to three hours. Neutralization of the reaction mixture with acid, for example, 2N HCl, extraction with a wa-ter-immiscible solvent, for example, diethyl ether, and subsequent workup of the extract yields the desired ~-ketoacid of formula 4 as a mixture of stereoisomers, i.e., a mixture of trans and cis isomers with respect to the side chains of the cyclopentanone ring. The - -trans isomers, as shown in formula 4, is the preponderate isomer of the mixture.
A~IP-6~04 Thereafter, the latter compound is converted to its corresponding hydroxy protected derivative, which is treated with a complex borohydride to give 3 mixture of the corresponding acid 5 and hydroxylactone 6.
This reduction is carried out preferably by treating the ~ketoacid with sodium borohydride in an inert solvent, for example, mathanol, ethanol or tetrahydrofuran at -20 to 30C from 30 minutes to two hours. It is desirable to effect this reduction in the presence of about one equivalent of a base, for example, sodium methoxide, or potassium _-butoxide, so that effectively the reduction is performed on the salt of the ~ketoacid, for example, the sodium or potassium salt, and complex-formation between the acid and the reducing agent, and hence the need for an excess of the latter, is eliminated.
The reduction mixture of compounds 5 and 6 may be separated by conventional techniques, such as ex~raction or chromato-graphy. However, it has been found practical to treat the mîxture accordingto a procedure for converting tho acid 5 to the hydroxylactone 6.
The procedure for this latter conversion involves reacting the acid 5 or the mixture of compound 5 and 6 with methanesulfonyl or p-toluenesulfonyl chloride or bromide, in the presence of a proton acceptor, preferably tri-methylamine, N-methylmorpholine or pyridine. The reaction is conveniently performed in an inert organic solvent, for example, methylene chloride or tetrahydrofuran~ A reaction time of 30 to 180 minutes and a reaction temperature of -30 to 20C have been found to be practical and effective for this conversion. Under these conditions the preceding conversion apparently involves the transformation of the ring hydroxyl to a mesylate or D-toluenesulfonate, as the case may be, ~followed by a Sn2 displacement of the iatter by the carboxyl to g7ve 1~ 16~Z
the desired hydroxylactone. Ihereafter, i~ desired, the hydroxy-lactone of formula 6 in which R2 is a hydroxy protecting group is reacted with a deprotecting agent to give the corresponding hydroxy-lactone of formula 6 in which R is hydrogen.
From the latter key intermedia-te of formula 6, the key intermediate of formula 7 is obtained. More precisely, the compound of formula 6 in which R and R are both hydrogen (i.e., a compound of formula 6 in which the side chain alcohol is a secondary alcohol) is oxidized with an agent known to be effective for oxidizing allylic alcohols to ~,~ unsaturated ketones. Suitable agents for this purpose include manganese dioxide, selenium dioxide, chloranil and 2,3-dichloro-5,7-dicyano-1,4-benzoquinone. Manganese dioxide is a preferred reagent for this purpose. Treatment of -the compound of formula 6 with manganese dioxide at 20 to 70C for abou-t one to three hours in an inert organic solvent, for example, chloroform, benzene or carbon tetrachloride, readily gives the desired keto-lactone intermediate.
As noted above the key intermediates of formula 6 and 7 are used subsequently to prepare the prostaglandin derivatives of formula 11. Also as noted hereinbefore these subsequent trans-formations involve some or all of the following -types of reaction:
catalytic reduction, reduction with a monoalkyl or dialkyl aluminum hydride, treatment with a Wittig reagent, treatment with a lower alkyl magnesium ha]ide and reduction with a metal borohydride.
Convenient and effective conditions for effecting these reactions are generalized in the following manner.
The catalytic reduction is accomplished by treating the compound to be hydrogenated with hydrogen in -the presence of a hydro-genation catalyst in a nonreac-tive solvent medium. Suitable catalysts . . .
10~6~2 for this purpose include palladium or pla-tinum on a suitable inert carrier or Raney nickel in dioxane. The latter catalyst is prefer-red for catalytic reduction of the hydroxylactone of formula 6.
Suitable non-reactive solvents include ethyl acetate and ethanol.
The reduction with a monoalkyl or dialkyl aluminum hydride ; is accomplished by subjecting the compound to be reduced to -the action of the aluminum hydride reducing agent, for example, ethyl aluminum hydride, isopropyl aluminum hydride or preferably diisol-butyl aluminum hydride, in an inert organic solvent, -~or example, benzene, ether, hexane or toluene. Although the reaction can be practised over a wide range of temperatures from about -~0 C to the reflux temperature of the solvent, preferred temperatures are from -75 to O C. Also the reaction is preferably carried out in an atmosphere of an inert gas, for example, nitrogen or argon. Under these conditions this reduction is usually completed within 0.25 to five hours.
The Wittig reaction on the hemiacetals of this invention involves the use of a triphenylphosphonium halide of formula ( ~ P - CHz(CH2) COOR Ha]
in which R7 is hydrogen or lower alkyl, m is an integer from one to three, and Hal is bromine, chlorine or iodine. The preferred tri-phenylphosphonium halide is the triphenylphosphonium bromide, i.e.
Hal is bromine. The latter reagent is prepared readily by treating the appropriate -bromoacid or -bromoester of formula Br-CH2-(CH2) COOR in which m and R are as defined hereinbefore with triphenyl-phosphine in an inert solvent, for example, benzene, or acetonitrile, at 20 - 100 C for 12 to 24 hours and collecting -the precip:itate.
Similarly the corresponding triphenylphosphon:Lum chloride or iodide salts are prepared from appropriate haloacids or haloes-ters.
,-' ' :'' 10~
The Wittig reaction is carried out by -treating the appropriate hemiacetal with about two to ten molar equivalents o~ the above triphenylphosphonium halide in the presence of four to 20 molar equivalen-ts of a base. For a detailed discussion of the wittig reaction, see A. Maercker in Organic Reactions, Vol. 14, A.C. Cope, et al, Eds. John Wiley and Sons, Inc. New York, 1965, page 3. More particularly, the triphenylphosphonium halide is treated with an excess of a hydrogen halide-binding base,for example, sodium hydride in an inert organic solvent, for example, dimethoxyethane or dimethylformamide, or preferably sodium methyl-sulfinyl carbanide, prepared from sodium hydride and dimethylsulfoxide (see R. Greenwald, e-t al., J. Org. Chem., 28, 1128 (1963)). In this manner the corresponding ylide of the triphenylphosphonium halide is obtained. Subsequent reaction of ylide with the appropriate hemiacetal readily gives the correspond-ing compound of formula 11. The preparation of the ylide is accomplished readily at 20 - 100C at 10 to 60 minutes, preferably at 20 to 40C for about 1 to 2 hours when using sodium hydride is used as the hydrogen halide-binding base, and at 60 to 90C for about one to two hours when sodio methylsulfinyl carbanide is used at the base. Thereafter the solution of the resulting ylide is reacted with the appropriate hemiacetal at 20 to 60 C, con-veniently room temperature, for a period of time of from 2 to 24 hours. Preferably the reaction is performed in nitrogen atmos-phe~e.
The treatment with a lower alkyl magnesium halide, forexample, methyl magnesium bromide, ethyl magnesium chloride, propyl magnesium iodide and the like, is accomp~ished according to the conditions of the Grignard reaction. Conventient and practical conditions for this addition include ether or tetra-hydrofuran as the solvents for the reaction and a -32~
~ AHP-6304 , reaction temperature of from -80 to 25C, preferably -10 to 10C.
The aforementioned treatment of the compounds of formula 11 wTth an agent capable of oxidizing a hydroxy function to its corresponding keto function i~ effectively and conveniently accomplished by treating the appropriate compound of formula 11 7n which X is hydroxy - and Y is hydrogen with one of the agents chromium trioxide-pyridine complex or chromium trioxide-sulfuric acid in acetone, with the latter being preferred.
Finally, reductions with matal borohydride, preferably sodtum borohydride, are conveniently performed in a lower alkanol solvent, preferably methanol or ethanol, at 0 to 40C for five to 60 minutes.
- The following examples illustrate further this invention, In the examples the temperatures are noted in the Centigrade scale.
. ~
.
' .
.
EXAMPLE ]
D1methyl 3,3-dime-thyl-2-oxohep-tyl phosphonate ((AlkO)2POCH2COCR R -(CH2)nCH3 in which ~lk is CH3, R and R = CH3 and n = 3 ?
The title compound is prepared by treating 2,2-dimethyl-hexanoic acid methyl ester, S. M. McElvain, et al., J. Amer.
Chem Soc., 75, 3987 (1953), with dimethyl methyl phosphonate according to the procedure of E. J. Corey and G. T. Kwiatkowski, J. Amer. Chem. Soc., 88, 5654 (1966). An exemplification of this procedure is as follows:
Dimethyl methylphosphonate (14.88 g) is dissolved in dry tetrahydrofuran (THF, 34 ml) under a nitrogen atmosphere.
The solution is cooled to -78. Butyllithium (7.68 g, 52 ml of 2.3 molar solution, 3 equiv.) is added very slowly during one hour. The mixture is stirred at -78 for 15 minutes.
A solution of 2,2-dimethylhexanoic acid methyl ester (6.32 g) in dry THF (16 ml) is added to the cold solution over a period of one hour. The mixture is stirred for 30 minutes and then allowed to warm up -to room temperature.
The reaction mixture is diluted with ether. Dilute (10%) hydrochloric acid (30 ml) is added and the reaction mixture shaken well. The organic phase is separated and washed several times with water, dried (MgSO~) and the solvent removed. The residue is distilled under reduced pressure to give the title compound, b.p. 110 - 120/O.lmm,~falm 1700, 1250, 1020 cm 1 .
i A~IP-6304 ,;, . . . . .
o Similarly other Wittig reagents of the formula (AlkO)2POCH2COCR R (CU2)nCH3 in which Alk is an alkyl~containing one.to three carbon atoms, R4 and R5 are hydrogen or lower aIkyl and n is an integer from two to five are prepared by using the appropriate lower alkyl alkanoate and di(lower)alkyl mothanephosphonate. For instance, treatment of 2,2-d;-propylpentanoic acid methyl ester with dimethyl methylphospho-nate gives 2-oxo-3,3-dipropylhexyl phosphonate and treatment of 2,2-diethyloctanoic acid ethyl ester with diethyl methyl-phosphonate gives 2-oxo-3,3-diethylnonyl phosphonate.
-' - .
~i 1 hHP-630 - Dimethvl 2-formvlcyclopropane-~l-dicarboxylate (14: Rl = CH~
By following the procedure of D. T. Warner, cited above, used for preparing diethyl 2-formylcyclopropane-I,l-dicarboxylate from acrolein but using equivalent amounts of dimethylbromomalonate and methanol instead of diethyl-. bromomalonate and ethanol, respectiveiy, the title compound, nmr ~CDC13) ~ 1.98 (m, 2H), 2.80 (m, IH), 3.79 ts, 6H), 8082 (d, J = 4 cps, iH), is obtained.
Likewise the use of dipropylbromomalonate and pro-panol gives dipropyl 2-formylcyclopropane~ dicarboxylate.
~5 .
. . . . -36-~ f~lP-6304 '.
r Diethvl trans-2 (4.4-d im~th~ 3-oxo 1-octen~I )cyclo-Propane-l.l-dicarboxYlate (15 R4 and R5 = CH n - 3 R = C~
To a suspension of 50g sodium hydride (0~46 9, washed with hexane) in dimethylformamide ~DMF) is added a solution of dime+hyl 3,3-dimethyl 2-oxoheptyl phosphonate (2.75 9), dèscribed in Example 1, in DMF (15 ml) over a period of 30 min. The mixture is stirred and cooled in ice water during la tho addition and for an additional period of 45 min. A
solution of diethyl 2-formylcyclopropane-1,1-dicarboxylate t2.14 g) in DMF (15 ml) is added over 20 min. The reaction mixture is heated at 55 to 60 and stirred for ~5 min. The mixture is now cooled in an ice bath and acetic acid is added ~o render the mixture substantially neutral. The reaction mixture is poured into water (4 x the volume) and the resulting oily precipitate extracted with ether. The extract is ~ashed with water, dried tNa2S04) and concentrated~ The r~sidue is dissolved in ethyl acetate-benzene (1:9) and the solution poured through a coiumn of sil iC3 gel ( 148 9). The eluate is concentrated to yield the title compound,v faxm 1725, 1680, 1620 cm I, nmr (CDC13) ~ 0.88 tt, 3H), 4.27 (4H), 6.5, 6.68 and 7.39 (m, 2H), ~EaxH 242 nm (e = 7500~.
!n the same manner but replacing diethyl 2-formyl-cyclopropane-l,l-dicarboxylate with dimethyl 2-formylcyclo-propane~ dicarboxylate, dimethyl trans-t4,4-dimethyl-3-oxo-i-octenyl)cyclopropane-l,l-dicarboxylate,v;fixm 1728, 1682 cm 1, is obtained.
.
.
~ A~P-6304 - . , s~ . -In the same manner but repiacing dimethyl 3,3-dimethyl-2-oxoheptyl phosphonate with an equivalent amount of dimethyl 3-methyl-2-oxohep~yl phosphonate, b.p. 112 - 115/ 0.2 mm, prepared from 2-methylhexanoic acid methyl ester or the 2-methyl-S hexanoic acid chloride according to the procedure of Exampls 1, diethyl trans-2-(4-methyl-3-oxo-1-octenyl)cyclopropan~-1,1-dicarboxylate, ~max 1725, 1680, 1665, 1620 cm 1, nmr (COC13) ~ 4.19 (q, J - 7, 4H), 6.32 ~d, J = 5, 2H), i5 obtained.
In the same manner but replacing dimethyl 3,3-dimethyl-2-oxohep*yl phosphonate with an equivalent amount of dimethyl ~-oxoheptyl phosphonate, described by E. J. Corey, et al., J. Amer. Chem. Soc., 90, 3247 (1968), diethyl trans-2-(3-oxo-I-octenyl)cyclopropane-i,l-dicarboxylate, b.p. 153 - 154/ 0.7 mm, Ts obtained.
~ In the same manner but replacing dimethyl 3,3-dimethyl~2-oxoheptylphosphonate with an equivalent amount of dimethyi 3-ethyl-2-oxohexyl phosphonate, dimethyl 3-propyl-2-oxooctyl phos-phonate, or dlmethyl 3-ethy1-2-oxononyl phosphonate, dimethyl trans-2;~4-erhyl-3-oxo-1-heptenyl)cyclopropane-1,1-dicarboxylate, dimethyl trans-2-(3-oxo-4-propyl-1-nonenyl)cyclopropane-i,l-dicarboxyiate and dimethyl ~I~n~-2-(4-ethyl-3-oxo-1-decenyl)cyclopropane~ dicar-boxylate are obtained, respectively.
By following the procedure of Example 3 and utilizing ~he appropriate Wittig reagent and the aldehyde of formula 14 then o~her compounds of formula 15 are obtained. Examples of such compounds of formula 15 are listed in Table I
together wiTh the appropriate Wittig reagent ~nd aldehyde of form~la 14 utilized for Their preparation.
. .
, .
~,' ' .
~ .. ... .. .. _ _ _ ~ittig Reagent Product: (Prefix Listed 4 5 ALDEHYDE 14 below)-cyclopropane .EX. (AlkO2)POCH2COCR R -(CH2) CH3 --- !J!-diçarboxylate , _............. . w. ~
= A~h ~4 ... _ ~_ n R : _ _ 4 CH3 H H 2 CH3 dimethyl trans-2-~3-oxo-. I-heptenyl) CH3 H H 4 C2H5 diethyl trans-2-(3-oxo-I-nonenyl) 6 CH3 H H 5 CH3 dimethyl trans-2-(3-oxo-I-decenyl) 7 CH3 CH3 H 2 C2H5 diethyl trans-2-(4-.
methyl-3-oxo-1-heptenyl) 8 CH3 CH3 H 4 CH3 dimethyl trans-2-(4-. methyl,3-oxo-1-nonenyl) 9 CH3 C2H5 H 3 C~H5 diethyl trans-2-t4-ethyl-3-oxo-1-octenyl) CH3 C2H5 H 5 CH3 dimethyl trans-2-(4-. . . methy~3-oxo-1-decenyl) CH3 3H7 H 2 C2H5 diethyl trans-2-(3-oxo-. 4 propyl-l-heptenyl) 12 CH3 3 7 H 4 C~H3 dimethyl trans-2-(3-oxo-. 4-ethyl-1-nonenyl) 13 C2H5 CH3 CH3 5n~C3H7 , dipropyl trans-2-(4,4-. dimethy1-3-oxo-1-decenyl) 14 C2H5 C2H5 CH3 5 3 7 dipropyl trans-2-(4-ethyH
. . 4-methy1-3-oxo-1-decenyl) C2H5 n~C3H7 CH3 2 CH3 dimethyl trans-2-(4-methy1-3-oxo-4-propyl-.1-. . heptenyl) 16 C2H5 3 7 3 7 4 C2H5 diethyl trans-2-(3 oxo-4, . . . 4 dipropyl-l-nonenyl) . . .
_ _ .. .. _ _ ~.
, ., .
AH~-o304 . - , , : EXAMPLE 17 ~.
DiethYl trans-2-(3-hydroxy-4~4-dimethy~ octen - Cvc~proDane-l.l-djcarboxylafe (l; R = C,H5, R
and R6 = H.
.
Sodium borohydride (0.19 9) is added to a solution of diethyl tra~s-2-(4,4-dimethyl^3-oxo-1-octenyl)cyclopropane-l~l-dicarboxylate 11.62 9), described in Example 3, in ethanol (2.5 ml) at 0 to 5.
After the addition the mixture is rendered neu-~ral by the add;tion of acetic acid) diluted with ether and washed wi~h water. ~he ether phase is dried (Na2504) and concentrated. The residue is dissolved in ethyl acetate-benzene (1:9) and the solution poured through a column of silica gel (50 9). The eluate is concentrated to give ~he titie compound, vmaxm 3500, 1706 cm , nmr (COC13) ~ 2.6 (m, IH), 3.78 (m, IH), 4.21 (q, 4H), 5.28 (q, IH), 5.9 Sq, IH~.
In the same manner but replacing diethyl trans-2-(4,4-~imethyl-3-oxo-1-octenyl)cyclopropane-1 1-dicarboxylate with an equivalent amount of diethyl trans-2-(4 methyl-3-oxo-1-octenyl) cyclopropane-l,l-dicarboxylate, described in Example 3, diethyl trans-2-(3-hydroxy-4-methyl-1-octenyljcyclopropane-1,1-dicarboxylate, vfTIm 3500 cm 1, is obtained.
By folJowing the procedure of Example 17 and utilizing the appropriate compound of formula 15 then other compounds of formula I (R = H) are prepared. Examples of such compounds of formula I are listed in Table ~I. In each case the compound of formula 15 used as starting material is noted by the Example in which it is prepared.
.
~ AHP-6304 ., .~ ., ; . . .. . ... . .......... .
.... .
' ;[~ ' . .
~ . . .
. PRODUCT: (PREFIX LISTED .
. .NQ OF EXAMPLE IN WHICH STARTING 8ELOW)-CYCLO-. EXAMPLE MATERIAI OF FORMULA 1515 PREPARED PROPANE~ DICARBOXYLATE
.
18 . ~ dimethyl trans-2-~4-ethyl-. . . 3-hydroxy-1-heptenyl) 19 . 3 diethyl t~rans-2-(3-hydroxy-.. ~ . 4-propyl -I-nonenyl) 3 dimethyl trans 2-( 4-ethyl-. . 3-hydroxy-1-decenyl) 21 7 diethyl trans-2-(3-hydroxy-. 4-methyl-1-heptenyl) 22 8 dimethyl trans-2-(3-hydroxy-. 4-methyl-1-nonenyl) .
23 9 diethyl trans-2-(4-ethyl-3-. . hydroxy-l-octenyl~
24 . ~10 dTmethyl trans-2-(4-~ethyl-3-. . . hydroxy-l-decenyl) 25. . Il . diethyl trans-2-t3-hydroxy-4-. : propyl-l-heptenyl) 26 12 dimethyl trans-2-(3-hydroxy-- . 4-ethyl-1-nonenyl 27 . di,propyl trans-2 (3-hydroxy-. ~ 4,4-dlmethyl-1-decenyl) 28 ~ 14 dipropyl trans-2-(4-ethyl-. ~ 3-hydroxy-4-methyl-1-decenyl~
29 15 dimethyl trans-2-(3-hydroxy-. . ~-methy1-4-propyl-1-heptenyl) 16 diethyl trans-2-(3-hydroxy-4, . 4-dipropyl-1-nonenyl) .
.~
.. _ _ .. .......
: .
' EXAMPLE 3_ Dieth~l trans-2-(3-hydrox~-3-methyl-1-octen~l)cyclo~opane-l,l-dic~rboxyla-te (1; R = C H ; R , R and R = H, _ _ -- -2-5 R = CH3 and n = 3) A solution of the lower alkyl magnesium halide, methyl magnesium iodide, prepared from 24.31 g of magnesium turnings and 157 g of methyl iodide in 1000 ml of ether, is cooled to -70 .
Diethyl trans-2-(3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate (124.2 g); described in Example 3, in 600 ml ether is added slowly taking care that reaction mixture temperature does not exceed -45 . The mixture is stirred 75 min. at the temperature range -50 to -45 . Aqueous saturated NH4Cl solution is added slowly keeping the temperature of the reaction mixture below -55 . The mixture is diluted with water and extracted with 1500 ml ether. The ether layer is washed with saturated NaCl solution twice, then with 10% sodium thiosulfate solution twice, again with saturated NaCl solution, dried (Na2S04) and con-centrated to give a greenish yellow oil. The oil is dissolved in ethyl acetate-benzene (3:17) and poured through a column of silica gel. The eluate is concentrated to yield the title compound, nmr (CDCI3) ~ 0.88 (+, J = 5, 3H), 2.45 (q, 2H), 4.13 (q, 2H), 5.14 (2xd, J = 16.8, lH), 5.72 (d, J = 16, lH).
In the same manner but replacing methyl magnesium iodide with an equivalent amount of ethyl magnesium chloride, or propyl magnesium bromide, diethyl trans-2-(3-ethyl-3-hydroxy-1-octenyl)-cyclopropane-l,l-dicarboxylate and diethyl trans-2-(3-hydroxy-3-propyl-l-octenyl)cyclopropane-l,l-dicarboxylate, are obtained, respectively.
:' " .
j, -- , ., ., ~ , . , ....... , - .
.
- . ~ . .
.
. In the same manner but replacing diethyl trans-2-(3-oxo-1-octanyl)cyclopropane-l,l-dicarboxylate with an equival~nt amount of diethyl trans-2-(4-methyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate, described in Example 3 and using methyl magnesium iodide, ethyi magnesium chloride or propyl magnesium bromide as the lower alkyl magnesium halide, diethyl trans-2 (3-hydroxy-3,4-dimethyl-l-octenyl)cyclopropane~ dicarboxylate, diethyl trans-2~3-e~hyl-3-hydroxy-4-methyl-1-octenyl)cyclopropane-1,1-dicarboxy-Iate and diethyl trans-2-(3-hydroxy-4-methyl-3-propyl-1-octenyl)-10 cyclopropane-l,l-dicarboxylate, are obtained, respectively.
.. By following the procedure of Example 31 and utilizing the appropriate lower alkyl magnesium halide and compound of ~ormula 15., for examplo those described in Examples 4 to 12, then other compoundsof formula I in which R is lower alkyl are obtained.
15 Examples of such compounds of formula .I.are. Iisted in Table III
~ogether with the requisite Iower a!kyl magnesium halide and the compound of formula 15.
1.
,, ' :
-~13 O
TABLE III
__ . PRODUCT -NO. OF EXAMPLE (PREFIX LISTED
. IN ~HICH STARTING MATE~-TAL LOWER ALKYL BELO~ CYCLOPROPANE-EXAMPLE -OF FORMULA ~515 PREPARED MAGNESIUM HALIDE. !,I-DICARBOXYLATE
32 4 CH3MgI dimethyl ~L3~5-2-(3-. hydroxy-3-methyl-1-. heptenyl) 33 5 . C2H5MgBr diethyl trans-2-(3-. ethyl-3-hydroxy-1-. nonenyl) 34 6 n-C3H7MgCI dimethyi ~ 2-(3-. . . . decenyl) . .
7 CH3MgBr diethyl trans-2-(3-. . hydroxy-3,4-dimethyl-. I-heptenyl) 36 . 8 2 5 9 dimethyl trans-2-(3-. . ethy1-3-hydroxy 4--15 . . mathyl-l-nonenyl) . 37 9 . , n-C3H7MgCI diethyl trans-2-(4 . . ethy1-3-hydroxy-3-. . propyl-l-octenyl) }B IO CH3M9I . dimethyl trans-2-~3-. . . . hydroxy-3,4-dimethyl . . I-decenyl) 39 11 C2H5MgCI ! diethyl trans-2-(3-. . ~ ethy1-3-hydroxy 4-. . propyl-l-heptenyl) 12 n-C3H7MgCI dimethyl trans 2-(4-ethy1-3 hydroxy-3-. . . propyl-l-noncnyl~
.
~ .
.
. .. , .
.. _ . _~ . . - _ __ ~
s . 4~
-~ AllP-6~0l .
: EXAMPLE 41 Diethyl trans-2-~3-~(tetrahydrop~Jran-2-yl )Gxvl-3-rr.ethvl-octeny1~cycIoDro~ane-I .I-dicarboxyIate (I; R = C2H5 R = ttetrahydro~yran-2-yl~oxy, R and R - H R - CH3_ and n = 3) A solution of diethyl trans-2-(3-hydroxy-3-methyl-1-oc~enyl)cyclopropane-l,l-dicarboxylate (22 4 9~, described in Example 31, dihydropyran (80 ml, distilled over sodium) and D-toluenesulfonic acid monohydrate (300 m~g) is allowed to stand a~ room te~perature for 30 min. After adding a few ml of 10%
Na2003 sol~tion the mixture is extracted with ether. The ether ~xtract is washed with water, dried (Na2504) and evaporated.
Purification of the residue by chromatography on silica gel - gT~es the ~itle compound, nmr (~DC13) ~ 0.87 (t, 3H), 2.48 ~m, IH~, 4.6 (IH), 5.5 (m, 2H)~
In the same manner but using an equivalent amount ot one of the compounds of formula 1 (~ = H), for example, ~he compounds listed in Examples ~7 to 409 instead of diethyl trans-2-(3-hydroxy-3-methyl-1-octenyl)cyclopropane-1,1 dicarboxy-late, ~hen the corresponding tetrahydropyranyl ether compound of formula 1 (R2 = tetrahydropyranyl) i5 obtained, for example, th~ corresponding tetrahydropyranyl ether compounds of Examples 17 to 40, respectively. More specifically exemplified, in the same manner diethyl trans-2-(3-hydroxy-4-methyl-1-octenyl)-cyclopropane-lJI-dicarboxylate, described in Example 17 gives diethyl trans-2- !3- ~ttetrahydropyran-2-yl)oxy]-4-methyl--1-octenyl~-cyclopropane-l,l-dicarboxylate, ~m~lm 1035, 1140, 1220 cm 1, , ' ~ . AHP-6304 .. . . . . . .
and dimethyl trans-2-t4-ethyl-3-hydroxy-1-decenyl~cyclopropane-I,l-dicarboxylate, described in Example 24, gives dime~hyl trans-2-{4-ethyl-3-t(tetrahydropyran-2-yl)oxy]-1-decenyl~-- cyclopropane-l,l-dirarboxylate.
.
~' .
..
. . '. ~ , , .
.
- -' 10~16~2 Dimethyl trans-l-(Carbomethoxymethyl)-5-(3-hydroxy-l-octenyl)-2-oxo-1,3-cycl~eentanedicQrboxylate __~_ _ ______ (3; R and R = CH3, R , ~ R and R = H and n = 3) A solution of sodium methoxide (5 g of sodium dissolved in 150 ml of methanol) is added at room temperature to a solution of tiethyl l,1,2-e-thanetricarboxylate. The mix-ture is hea-ted to 80 and a solution of the compound of formula 1, dimethyl trans-2-f3 ~tetrahydropyran-2-yl)ox~ -l-octeny~ cyclopropane-l,l-dicar-boxylate, described by Abraham, cited above, is added slowly. The mixture is stirred for 1 hr. The methanol is removed under re-duced pressure and the residue heated at 110 for 1.5 hr. After cooling the mixture is acidified with ace-tic acid-water (25 ml, 1:1) and extracted with ether. The ether extract is washed with water, dried (MgS04) and concentrated to give dimethyl trans-l-(carbomethoxymethyl)-5-~3- ~tetrahydropyran-2-yl)oxy~ -l-octeny ~-2-oxo-1,3-cyclopentanedicarboxylate,~ a 290 nm (~ = 13,500) in the presence of a base. Note: Transesterification of the ester groups has occurred during the preceding condensation. If desired this can be avoided by the substitution of ethanol for me-thanol.
A mixture of the latter hydroxy protected derivative (95.1 g) in 375 ml of methanol-water (9:1) and ~-toluenesulfonic acid monohydrate (2.85 g) is stirred for 1 hr at room temperature.
The mixture is rendered neutral by the addition of 10% Na2C03.
The methanol is removed by distillation. The residue is extracted with ether. The organic extract is washed with water until neutral, dried (MgS04) and concentrated. The residue is . A~IP-6304 - . subjected to chromatography on SiO2 using 20% ethyl acetate as e!uant. Evaporation of the eluate gives the title compound 289 nm (14,500) in the presence of base.
.
- ~ .
., .
10'~ 4Z
LXAMPLL ~3 Dimethyl trans-l-(Carboethoxymethyl)-5-(3-hydroxy-3-m _l-l-octenyl)-2-oxo-1,3-c ~ pentanedicarboxylate_ _ (3 R , R and R6 = CH , R , R , and R = H and n = 3) S To a solution of triethyl 1,1,2-ethanetricarboxylate (1.36 g) in 3 ml of methanol7 a freshly prepared solution of sodium methoxide (from 0.126 g of sodium and 6 ml of absolute methanol) is added. The mixture is heated to 80 . A solution of dimethyl trans-2-(3-methyl-3-hydroxy-1-octenyl)cyclopropane-1,-l-dicarboxylate (1.7 g) is gradually added and the resulting mixture stirred for an additional 15 min. The methanol is removed by distillation a-t reduced pressure. The residue is then heated at 100 for 45 min. Thereafter the mixture is cooled in an ice bath and rendered neutral with acetic acid. The mixture is extracted with ether. The extract is drie- (Na2S04) and concentrated. Chromatography of the residue on silica gel using ethyl acetate-benzene (1:4) as eluant gives the title compound, ~~mfa m 3350, 1727 cm 1.
By following the procedures of Examples 42 and 43 and using the appropriate compounds of formulae 1 and formula 2 as starting materials, other cyclopentanonetriesters of formula 3 are obtained.
For example, the use of the compound of formula 1, diethyl trans-2- ~-((tetrahydropyran-2-yl)oxy)-3-methyl-l-octeny~ -cyclopropane-l,l-dicarboxylate, described in Example 41, and the compound of formula 2, triethyl ethane-1,1,2-tricarboxylate, in the procedure of Example 42 gives dimethyl trans-l-(carboethoxy-.
.
AH?-6304 ~3~
. .
: methyl)-5-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentane-dicarboxylate, identical to the product of Example 43, via the intermediate dimethyl trans-l-~carboethoxymethyl)-5-{3-~(tetra-hydropyran-2-yl)oxy]-3-methyl-1-octenyl}-2-oxo-1,3-cyclopentarle-dicarboxylate, ~maxm 1730 cm Likewise, the use of diethyl trans-2-{3-[(tetra-hydropyran-2-yl)oxy]-4,4-dimethyl-1-octenyl}cyclopropane-1,1-dicarboxylate and triethyl ethane-1,1,2-tricarboxylate gives dimethyl trans-l-tcarbomethoxymethyl)-5-(3-hydroxy-4,4-dimethyl-l-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate9 ~max 3500 cm ~EtOH 291 nm (~ = 13,600) in the presence of base (NaOH).
- Additional examples of compounds of formula 3 are listed in Table 111 together with the requisite starting materials. It is to be noted that when the procedure of Example 42 is used the requisite starting material of formula I is the corresponding tetrahydropyran-2-yl ether derivative o-~ the compound of formula 4 - noted therein; the tetrahydropyran-2-yl ether being prepared by following the procedure described~in Example 41.
- .
. .
-r Ll~ ].11 . _ _ NO. OF TIIE EXAMPLE
IN Wl-lICH STARTING STAlRTING PRODUCl': (PREFIX LISTED
MATERIAL OF FORMULA 1 MATERIAL OF BELO~-2--OXO-1~3-CYCLO-
Abraham, cited above.
Briefly the starting materials are prepared readily by treating an aldehyde of formula 14 RlOOC COORl RlOOC COOR
~ CHO ~ Cl-CR ~ -(CH2)~
14 - .
in which Rl is lower alkyl with a Wittig reagent of formula (ALKO)2POCH2COCR R -(CH2)nCH3 in which Alk is lower alkyl and R , R5 and n are as defined herein to obtain the corresponding ketodi-25 carboxylic acid of formula 15 in which R , R , R and n are de~ined herein; followed by reduction of the latter compound with a metal borohydride, preferably sodium borohydride, -to obtain the corres-ponding starting material of formula ] in which R is hydrogen, 25_ 10~6a~2 which in turn is readily transformed to its corresponding hydroxy protected derivative. The starting material of formula 1 in which R is lower alkyl is obtained by reac-ting the ketodicarboxylic acid o~ formula 15 with substantially one molar equivalent of a lower alkyl magnesium halide in the manner described herein.
The aldehyde of formula 14 in which R is ethyl, required for the preceding preparation, has been described by D.T. Warner, J. Org. Chem., 24, 1536 (1959). By following the process described therein for the preparation of that aldehyde and using the appropriate -~
di(lower)alkylbromomalonate, the aldehydes of formula 14 in whichRl is a lower alkyl other than ethyl are obtained.
The requisite Wittig reagents are prepared by the method of E.J. Corey and G.T. Kwiatkowsky, J. Amer. Chem. Soc., 88, 5654 (1966) using the appropriate lower alkyl alkanoate and di(lower) alkyl ~ -lithiomethanephosphonate.
The triester of formula 2, the other starting material of this process, is readily prepared by condensing a di(lower)alkyl malonate with a lower alkyl bromoacetic acid ester in the presence of a base. ~or example, the preparation of the triester of formula 2 in which R is ethyl has been described by A. Horeau, Bull. Soc.
Chim. Fr., 1959 (1943) and by T.R. Kasturi, Indian Inst. Scio, Golden .Jubilee Research Vol., 1909 - 59, 40 (Publ. 1959); see Chem Abstr., 55, 23371 h (1961).
The preferred hydroxy protecting groups for use in the process of this invention are tetrahydropyran-2-yl (THP), trimethyl-silyl (TMS), dimethylisopropylsilyl (DMIS), dimethyl-tert-butylsilyl and tert-butyl. The transformation of hs fres hydr-oxy derivative to the hydroxy protected derivative is effected by treating th0 hydroxy derivative with a reagent known to be effective for converting a hydroxy group of a known compound to a protected hydroxy group. Such reagents include an excess of dihydropyran and an acid catalyst for example, ~-toluenesulfonic acid, hydrogen chloride or sulfuric acid for the THP group, trimethylchlorosilane with hexamethyldisilazane for the TMS group, dimethylisopropylchlorosilane and diisopropyItetramethyl-disilazane for the DMIS group, dimethyl-tert-butylchlorosil~ne and Tmidazole for the dimethyl-tert-butylsilyl group or isobutylene for tho t -butyl group.
For removal of the hydroxy protecting groups various agents known to be effective for this purpose are available~ These agents are called deprotecting agents. For example, t~e THP group is removed by treating the derivative having a THP group as the hydroxy protecting group with an acid, for example, hydrochlor;c acid, aqueous - acetic acid or preferably p-toluenesulfonic acid, in an inert solvent in the presence of water, preferably methanol-water (9:1). The TMS
radical is removed by treatment with an excess of water-methanol (10:1) for 24 hours or with tetrahydrofuran-acetic acid at room temperature for one to two hours. Likewise, the DMIS and dimethyl-ter~-butylsilyl group are removed by the same conditions used for the removal of the TMS radical.
in practising the process of this invention the starting material of formula 1, preferable in the form of its THP derivative, and the triester of formula~, preferably, the triethyl ester, are subjected to a base catalyzed condensation to give the corresponding 0~iL69~
cyclopentanone-triester of formula 3. This condensation is perform-ed in -the presence of a suitable base, preferably an alkali metal alkoxide, for example, sodium methoxide. Other suitable bases in-clude sodium ethoxide, potassium tert-butoxide, and sodium hydride.
More specifically, this condensation is conveniently effected by heating a mixture of about equimolar amounts of the compound of formula 1 and the triester 2 at 80 to 150C, pre-ferably 100 - 140 C, for 30 minutes to six hours, preferably one to three hours. The reaction mixture is then cooled, neutralized with an acid, for example, acetic acid, and extracted with a water-immiscible solvent, for example, diethyl ether. Evaporation of theextract and purification of the residue by chromatography on silica gel yields the cyclopentanonetriester of formula 3.
Thereafter, in the case where the hydroxy group has been protected by a suitable protecting group, said group is now removed by a deprotecting agent. The compound of formula 3 in its free hydroxy form is now treated with an alkali metal hydroxide in the presence of water to give the corresponding y -ketoacid of formula 4 in which P. , R , R5, R and n are defined in the first instance.
Preferably this reaction is done by heating a mixture of the cyclo-pentanonetries-ter with an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide, in the presence of water at reflux temperature of the mixture for a period of 15 minutes to six hours, preferably about one to three hours. Neutralization of the reaction mixture with acid, for example, 2N HCl, extraction with a wa-ter-immiscible solvent, for example, diethyl ether, and subsequent workup of the extract yields the desired ~-ketoacid of formula 4 as a mixture of stereoisomers, i.e., a mixture of trans and cis isomers with respect to the side chains of the cyclopentanone ring. The - -trans isomers, as shown in formula 4, is the preponderate isomer of the mixture.
A~IP-6~04 Thereafter, the latter compound is converted to its corresponding hydroxy protected derivative, which is treated with a complex borohydride to give 3 mixture of the corresponding acid 5 and hydroxylactone 6.
This reduction is carried out preferably by treating the ~ketoacid with sodium borohydride in an inert solvent, for example, mathanol, ethanol or tetrahydrofuran at -20 to 30C from 30 minutes to two hours. It is desirable to effect this reduction in the presence of about one equivalent of a base, for example, sodium methoxide, or potassium _-butoxide, so that effectively the reduction is performed on the salt of the ~ketoacid, for example, the sodium or potassium salt, and complex-formation between the acid and the reducing agent, and hence the need for an excess of the latter, is eliminated.
The reduction mixture of compounds 5 and 6 may be separated by conventional techniques, such as ex~raction or chromato-graphy. However, it has been found practical to treat the mîxture accordingto a procedure for converting tho acid 5 to the hydroxylactone 6.
The procedure for this latter conversion involves reacting the acid 5 or the mixture of compound 5 and 6 with methanesulfonyl or p-toluenesulfonyl chloride or bromide, in the presence of a proton acceptor, preferably tri-methylamine, N-methylmorpholine or pyridine. The reaction is conveniently performed in an inert organic solvent, for example, methylene chloride or tetrahydrofuran~ A reaction time of 30 to 180 minutes and a reaction temperature of -30 to 20C have been found to be practical and effective for this conversion. Under these conditions the preceding conversion apparently involves the transformation of the ring hydroxyl to a mesylate or D-toluenesulfonate, as the case may be, ~followed by a Sn2 displacement of the iatter by the carboxyl to g7ve 1~ 16~Z
the desired hydroxylactone. Ihereafter, i~ desired, the hydroxy-lactone of formula 6 in which R2 is a hydroxy protecting group is reacted with a deprotecting agent to give the corresponding hydroxy-lactone of formula 6 in which R is hydrogen.
From the latter key intermedia-te of formula 6, the key intermediate of formula 7 is obtained. More precisely, the compound of formula 6 in which R and R are both hydrogen (i.e., a compound of formula 6 in which the side chain alcohol is a secondary alcohol) is oxidized with an agent known to be effective for oxidizing allylic alcohols to ~,~ unsaturated ketones. Suitable agents for this purpose include manganese dioxide, selenium dioxide, chloranil and 2,3-dichloro-5,7-dicyano-1,4-benzoquinone. Manganese dioxide is a preferred reagent for this purpose. Treatment of -the compound of formula 6 with manganese dioxide at 20 to 70C for abou-t one to three hours in an inert organic solvent, for example, chloroform, benzene or carbon tetrachloride, readily gives the desired keto-lactone intermediate.
As noted above the key intermediates of formula 6 and 7 are used subsequently to prepare the prostaglandin derivatives of formula 11. Also as noted hereinbefore these subsequent trans-formations involve some or all of the following -types of reaction:
catalytic reduction, reduction with a monoalkyl or dialkyl aluminum hydride, treatment with a Wittig reagent, treatment with a lower alkyl magnesium ha]ide and reduction with a metal borohydride.
Convenient and effective conditions for effecting these reactions are generalized in the following manner.
The catalytic reduction is accomplished by treating the compound to be hydrogenated with hydrogen in -the presence of a hydro-genation catalyst in a nonreac-tive solvent medium. Suitable catalysts . . .
10~6~2 for this purpose include palladium or pla-tinum on a suitable inert carrier or Raney nickel in dioxane. The latter catalyst is prefer-red for catalytic reduction of the hydroxylactone of formula 6.
Suitable non-reactive solvents include ethyl acetate and ethanol.
The reduction with a monoalkyl or dialkyl aluminum hydride ; is accomplished by subjecting the compound to be reduced to -the action of the aluminum hydride reducing agent, for example, ethyl aluminum hydride, isopropyl aluminum hydride or preferably diisol-butyl aluminum hydride, in an inert organic solvent, -~or example, benzene, ether, hexane or toluene. Although the reaction can be practised over a wide range of temperatures from about -~0 C to the reflux temperature of the solvent, preferred temperatures are from -75 to O C. Also the reaction is preferably carried out in an atmosphere of an inert gas, for example, nitrogen or argon. Under these conditions this reduction is usually completed within 0.25 to five hours.
The Wittig reaction on the hemiacetals of this invention involves the use of a triphenylphosphonium halide of formula ( ~ P - CHz(CH2) COOR Ha]
in which R7 is hydrogen or lower alkyl, m is an integer from one to three, and Hal is bromine, chlorine or iodine. The preferred tri-phenylphosphonium halide is the triphenylphosphonium bromide, i.e.
Hal is bromine. The latter reagent is prepared readily by treating the appropriate -bromoacid or -bromoester of formula Br-CH2-(CH2) COOR in which m and R are as defined hereinbefore with triphenyl-phosphine in an inert solvent, for example, benzene, or acetonitrile, at 20 - 100 C for 12 to 24 hours and collecting -the precip:itate.
Similarly the corresponding triphenylphosphon:Lum chloride or iodide salts are prepared from appropriate haloacids or haloes-ters.
,-' ' :'' 10~
The Wittig reaction is carried out by -treating the appropriate hemiacetal with about two to ten molar equivalents o~ the above triphenylphosphonium halide in the presence of four to 20 molar equivalen-ts of a base. For a detailed discussion of the wittig reaction, see A. Maercker in Organic Reactions, Vol. 14, A.C. Cope, et al, Eds. John Wiley and Sons, Inc. New York, 1965, page 3. More particularly, the triphenylphosphonium halide is treated with an excess of a hydrogen halide-binding base,for example, sodium hydride in an inert organic solvent, for example, dimethoxyethane or dimethylformamide, or preferably sodium methyl-sulfinyl carbanide, prepared from sodium hydride and dimethylsulfoxide (see R. Greenwald, e-t al., J. Org. Chem., 28, 1128 (1963)). In this manner the corresponding ylide of the triphenylphosphonium halide is obtained. Subsequent reaction of ylide with the appropriate hemiacetal readily gives the correspond-ing compound of formula 11. The preparation of the ylide is accomplished readily at 20 - 100C at 10 to 60 minutes, preferably at 20 to 40C for about 1 to 2 hours when using sodium hydride is used as the hydrogen halide-binding base, and at 60 to 90C for about one to two hours when sodio methylsulfinyl carbanide is used at the base. Thereafter the solution of the resulting ylide is reacted with the appropriate hemiacetal at 20 to 60 C, con-veniently room temperature, for a period of time of from 2 to 24 hours. Preferably the reaction is performed in nitrogen atmos-phe~e.
The treatment with a lower alkyl magnesium halide, forexample, methyl magnesium bromide, ethyl magnesium chloride, propyl magnesium iodide and the like, is accomp~ished according to the conditions of the Grignard reaction. Conventient and practical conditions for this addition include ether or tetra-hydrofuran as the solvents for the reaction and a -32~
~ AHP-6304 , reaction temperature of from -80 to 25C, preferably -10 to 10C.
The aforementioned treatment of the compounds of formula 11 wTth an agent capable of oxidizing a hydroxy function to its corresponding keto function i~ effectively and conveniently accomplished by treating the appropriate compound of formula 11 7n which X is hydroxy - and Y is hydrogen with one of the agents chromium trioxide-pyridine complex or chromium trioxide-sulfuric acid in acetone, with the latter being preferred.
Finally, reductions with matal borohydride, preferably sodtum borohydride, are conveniently performed in a lower alkanol solvent, preferably methanol or ethanol, at 0 to 40C for five to 60 minutes.
- The following examples illustrate further this invention, In the examples the temperatures are noted in the Centigrade scale.
. ~
.
' .
.
EXAMPLE ]
D1methyl 3,3-dime-thyl-2-oxohep-tyl phosphonate ((AlkO)2POCH2COCR R -(CH2)nCH3 in which ~lk is CH3, R and R = CH3 and n = 3 ?
The title compound is prepared by treating 2,2-dimethyl-hexanoic acid methyl ester, S. M. McElvain, et al., J. Amer.
Chem Soc., 75, 3987 (1953), with dimethyl methyl phosphonate according to the procedure of E. J. Corey and G. T. Kwiatkowski, J. Amer. Chem. Soc., 88, 5654 (1966). An exemplification of this procedure is as follows:
Dimethyl methylphosphonate (14.88 g) is dissolved in dry tetrahydrofuran (THF, 34 ml) under a nitrogen atmosphere.
The solution is cooled to -78. Butyllithium (7.68 g, 52 ml of 2.3 molar solution, 3 equiv.) is added very slowly during one hour. The mixture is stirred at -78 for 15 minutes.
A solution of 2,2-dimethylhexanoic acid methyl ester (6.32 g) in dry THF (16 ml) is added to the cold solution over a period of one hour. The mixture is stirred for 30 minutes and then allowed to warm up -to room temperature.
The reaction mixture is diluted with ether. Dilute (10%) hydrochloric acid (30 ml) is added and the reaction mixture shaken well. The organic phase is separated and washed several times with water, dried (MgSO~) and the solvent removed. The residue is distilled under reduced pressure to give the title compound, b.p. 110 - 120/O.lmm,~falm 1700, 1250, 1020 cm 1 .
i A~IP-6304 ,;, . . . . .
o Similarly other Wittig reagents of the formula (AlkO)2POCH2COCR R (CU2)nCH3 in which Alk is an alkyl~containing one.to three carbon atoms, R4 and R5 are hydrogen or lower aIkyl and n is an integer from two to five are prepared by using the appropriate lower alkyl alkanoate and di(lower)alkyl mothanephosphonate. For instance, treatment of 2,2-d;-propylpentanoic acid methyl ester with dimethyl methylphospho-nate gives 2-oxo-3,3-dipropylhexyl phosphonate and treatment of 2,2-diethyloctanoic acid ethyl ester with diethyl methyl-phosphonate gives 2-oxo-3,3-diethylnonyl phosphonate.
-' - .
~i 1 hHP-630 - Dimethvl 2-formvlcyclopropane-~l-dicarboxylate (14: Rl = CH~
By following the procedure of D. T. Warner, cited above, used for preparing diethyl 2-formylcyclopropane-I,l-dicarboxylate from acrolein but using equivalent amounts of dimethylbromomalonate and methanol instead of diethyl-. bromomalonate and ethanol, respectiveiy, the title compound, nmr ~CDC13) ~ 1.98 (m, 2H), 2.80 (m, IH), 3.79 ts, 6H), 8082 (d, J = 4 cps, iH), is obtained.
Likewise the use of dipropylbromomalonate and pro-panol gives dipropyl 2-formylcyclopropane~ dicarboxylate.
~5 .
. . . . -36-~ f~lP-6304 '.
r Diethvl trans-2 (4.4-d im~th~ 3-oxo 1-octen~I )cyclo-Propane-l.l-dicarboxYlate (15 R4 and R5 = CH n - 3 R = C~
To a suspension of 50g sodium hydride (0~46 9, washed with hexane) in dimethylformamide ~DMF) is added a solution of dime+hyl 3,3-dimethyl 2-oxoheptyl phosphonate (2.75 9), dèscribed in Example 1, in DMF (15 ml) over a period of 30 min. The mixture is stirred and cooled in ice water during la tho addition and for an additional period of 45 min. A
solution of diethyl 2-formylcyclopropane-1,1-dicarboxylate t2.14 g) in DMF (15 ml) is added over 20 min. The reaction mixture is heated at 55 to 60 and stirred for ~5 min. The mixture is now cooled in an ice bath and acetic acid is added ~o render the mixture substantially neutral. The reaction mixture is poured into water (4 x the volume) and the resulting oily precipitate extracted with ether. The extract is ~ashed with water, dried tNa2S04) and concentrated~ The r~sidue is dissolved in ethyl acetate-benzene (1:9) and the solution poured through a coiumn of sil iC3 gel ( 148 9). The eluate is concentrated to yield the title compound,v faxm 1725, 1680, 1620 cm I, nmr (CDC13) ~ 0.88 tt, 3H), 4.27 (4H), 6.5, 6.68 and 7.39 (m, 2H), ~EaxH 242 nm (e = 7500~.
!n the same manner but replacing diethyl 2-formyl-cyclopropane-l,l-dicarboxylate with dimethyl 2-formylcyclo-propane~ dicarboxylate, dimethyl trans-t4,4-dimethyl-3-oxo-i-octenyl)cyclopropane-l,l-dicarboxylate,v;fixm 1728, 1682 cm 1, is obtained.
.
.
~ A~P-6304 - . , s~ . -In the same manner but repiacing dimethyl 3,3-dimethyl-2-oxoheptyl phosphonate with an equivalent amount of dimethyl 3-methyl-2-oxohep~yl phosphonate, b.p. 112 - 115/ 0.2 mm, prepared from 2-methylhexanoic acid methyl ester or the 2-methyl-S hexanoic acid chloride according to the procedure of Exampls 1, diethyl trans-2-(4-methyl-3-oxo-1-octenyl)cyclopropan~-1,1-dicarboxylate, ~max 1725, 1680, 1665, 1620 cm 1, nmr (COC13) ~ 4.19 (q, J - 7, 4H), 6.32 ~d, J = 5, 2H), i5 obtained.
In the same manner but replacing dimethyl 3,3-dimethyl-2-oxohep*yl phosphonate with an equivalent amount of dimethyl ~-oxoheptyl phosphonate, described by E. J. Corey, et al., J. Amer. Chem. Soc., 90, 3247 (1968), diethyl trans-2-(3-oxo-I-octenyl)cyclopropane-i,l-dicarboxylate, b.p. 153 - 154/ 0.7 mm, Ts obtained.
~ In the same manner but replacing dimethyl 3,3-dimethyl~2-oxoheptylphosphonate with an equivalent amount of dimethyi 3-ethyl-2-oxohexyl phosphonate, dimethyl 3-propyl-2-oxooctyl phos-phonate, or dlmethyl 3-ethy1-2-oxononyl phosphonate, dimethyl trans-2;~4-erhyl-3-oxo-1-heptenyl)cyclopropane-1,1-dicarboxylate, dimethyl trans-2-(3-oxo-4-propyl-1-nonenyl)cyclopropane-i,l-dicarboxyiate and dimethyl ~I~n~-2-(4-ethyl-3-oxo-1-decenyl)cyclopropane~ dicar-boxylate are obtained, respectively.
By following the procedure of Example 3 and utilizing ~he appropriate Wittig reagent and the aldehyde of formula 14 then o~her compounds of formula 15 are obtained. Examples of such compounds of formula 15 are listed in Table I
together wiTh the appropriate Wittig reagent ~nd aldehyde of form~la 14 utilized for Their preparation.
. .
, .
~,' ' .
~ .. ... .. .. _ _ _ ~ittig Reagent Product: (Prefix Listed 4 5 ALDEHYDE 14 below)-cyclopropane .EX. (AlkO2)POCH2COCR R -(CH2) CH3 --- !J!-diçarboxylate , _............. . w. ~
= A~h ~4 ... _ ~_ n R : _ _ 4 CH3 H H 2 CH3 dimethyl trans-2-~3-oxo-. I-heptenyl) CH3 H H 4 C2H5 diethyl trans-2-(3-oxo-I-nonenyl) 6 CH3 H H 5 CH3 dimethyl trans-2-(3-oxo-I-decenyl) 7 CH3 CH3 H 2 C2H5 diethyl trans-2-(4-.
methyl-3-oxo-1-heptenyl) 8 CH3 CH3 H 4 CH3 dimethyl trans-2-(4-. methyl,3-oxo-1-nonenyl) 9 CH3 C2H5 H 3 C~H5 diethyl trans-2-t4-ethyl-3-oxo-1-octenyl) CH3 C2H5 H 5 CH3 dimethyl trans-2-(4-. . . methy~3-oxo-1-decenyl) CH3 3H7 H 2 C2H5 diethyl trans-2-(3-oxo-. 4 propyl-l-heptenyl) 12 CH3 3 7 H 4 C~H3 dimethyl trans-2-(3-oxo-. 4-ethyl-1-nonenyl) 13 C2H5 CH3 CH3 5n~C3H7 , dipropyl trans-2-(4,4-. dimethy1-3-oxo-1-decenyl) 14 C2H5 C2H5 CH3 5 3 7 dipropyl trans-2-(4-ethyH
. . 4-methy1-3-oxo-1-decenyl) C2H5 n~C3H7 CH3 2 CH3 dimethyl trans-2-(4-methy1-3-oxo-4-propyl-.1-. . heptenyl) 16 C2H5 3 7 3 7 4 C2H5 diethyl trans-2-(3 oxo-4, . . . 4 dipropyl-l-nonenyl) . . .
_ _ .. .. _ _ ~.
, ., .
AH~-o304 . - , , : EXAMPLE 17 ~.
DiethYl trans-2-(3-hydroxy-4~4-dimethy~ octen - Cvc~proDane-l.l-djcarboxylafe (l; R = C,H5, R
and R6 = H.
.
Sodium borohydride (0.19 9) is added to a solution of diethyl tra~s-2-(4,4-dimethyl^3-oxo-1-octenyl)cyclopropane-l~l-dicarboxylate 11.62 9), described in Example 3, in ethanol (2.5 ml) at 0 to 5.
After the addition the mixture is rendered neu-~ral by the add;tion of acetic acid) diluted with ether and washed wi~h water. ~he ether phase is dried (Na2504) and concentrated. The residue is dissolved in ethyl acetate-benzene (1:9) and the solution poured through a column of silica gel (50 9). The eluate is concentrated to give ~he titie compound, vmaxm 3500, 1706 cm , nmr (COC13) ~ 2.6 (m, IH), 3.78 (m, IH), 4.21 (q, 4H), 5.28 (q, IH), 5.9 Sq, IH~.
In the same manner but replacing diethyl trans-2-(4,4-~imethyl-3-oxo-1-octenyl)cyclopropane-1 1-dicarboxylate with an equivalent amount of diethyl trans-2-(4 methyl-3-oxo-1-octenyl) cyclopropane-l,l-dicarboxylate, described in Example 3, diethyl trans-2-(3-hydroxy-4-methyl-1-octenyljcyclopropane-1,1-dicarboxylate, vfTIm 3500 cm 1, is obtained.
By folJowing the procedure of Example 17 and utilizing the appropriate compound of formula 15 then other compounds of formula I (R = H) are prepared. Examples of such compounds of formula I are listed in Table ~I. In each case the compound of formula 15 used as starting material is noted by the Example in which it is prepared.
.
~ AHP-6304 ., .~ ., ; . . .. . ... . .......... .
.... .
' ;[~ ' . .
~ . . .
. PRODUCT: (PREFIX LISTED .
. .NQ OF EXAMPLE IN WHICH STARTING 8ELOW)-CYCLO-. EXAMPLE MATERIAI OF FORMULA 1515 PREPARED PROPANE~ DICARBOXYLATE
.
18 . ~ dimethyl trans-2-~4-ethyl-. . . 3-hydroxy-1-heptenyl) 19 . 3 diethyl t~rans-2-(3-hydroxy-.. ~ . 4-propyl -I-nonenyl) 3 dimethyl trans 2-( 4-ethyl-. . 3-hydroxy-1-decenyl) 21 7 diethyl trans-2-(3-hydroxy-. 4-methyl-1-heptenyl) 22 8 dimethyl trans-2-(3-hydroxy-. 4-methyl-1-nonenyl) .
23 9 diethyl trans-2-(4-ethyl-3-. . hydroxy-l-octenyl~
24 . ~10 dTmethyl trans-2-(4-~ethyl-3-. . . hydroxy-l-decenyl) 25. . Il . diethyl trans-2-t3-hydroxy-4-. : propyl-l-heptenyl) 26 12 dimethyl trans-2-(3-hydroxy-- . 4-ethyl-1-nonenyl 27 . di,propyl trans-2 (3-hydroxy-. ~ 4,4-dlmethyl-1-decenyl) 28 ~ 14 dipropyl trans-2-(4-ethyl-. ~ 3-hydroxy-4-methyl-1-decenyl~
29 15 dimethyl trans-2-(3-hydroxy-. . ~-methy1-4-propyl-1-heptenyl) 16 diethyl trans-2-(3-hydroxy-4, . 4-dipropyl-1-nonenyl) .
.~
.. _ _ .. .......
: .
' EXAMPLE 3_ Dieth~l trans-2-(3-hydrox~-3-methyl-1-octen~l)cyclo~opane-l,l-dic~rboxyla-te (1; R = C H ; R , R and R = H, _ _ -- -2-5 R = CH3 and n = 3) A solution of the lower alkyl magnesium halide, methyl magnesium iodide, prepared from 24.31 g of magnesium turnings and 157 g of methyl iodide in 1000 ml of ether, is cooled to -70 .
Diethyl trans-2-(3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate (124.2 g); described in Example 3, in 600 ml ether is added slowly taking care that reaction mixture temperature does not exceed -45 . The mixture is stirred 75 min. at the temperature range -50 to -45 . Aqueous saturated NH4Cl solution is added slowly keeping the temperature of the reaction mixture below -55 . The mixture is diluted with water and extracted with 1500 ml ether. The ether layer is washed with saturated NaCl solution twice, then with 10% sodium thiosulfate solution twice, again with saturated NaCl solution, dried (Na2S04) and con-centrated to give a greenish yellow oil. The oil is dissolved in ethyl acetate-benzene (3:17) and poured through a column of silica gel. The eluate is concentrated to yield the title compound, nmr (CDCI3) ~ 0.88 (+, J = 5, 3H), 2.45 (q, 2H), 4.13 (q, 2H), 5.14 (2xd, J = 16.8, lH), 5.72 (d, J = 16, lH).
In the same manner but replacing methyl magnesium iodide with an equivalent amount of ethyl magnesium chloride, or propyl magnesium bromide, diethyl trans-2-(3-ethyl-3-hydroxy-1-octenyl)-cyclopropane-l,l-dicarboxylate and diethyl trans-2-(3-hydroxy-3-propyl-l-octenyl)cyclopropane-l,l-dicarboxylate, are obtained, respectively.
:' " .
j, -- , ., ., ~ , . , ....... , - .
.
- . ~ . .
.
. In the same manner but replacing diethyl trans-2-(3-oxo-1-octanyl)cyclopropane-l,l-dicarboxylate with an equival~nt amount of diethyl trans-2-(4-methyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate, described in Example 3 and using methyl magnesium iodide, ethyi magnesium chloride or propyl magnesium bromide as the lower alkyl magnesium halide, diethyl trans-2 (3-hydroxy-3,4-dimethyl-l-octenyl)cyclopropane~ dicarboxylate, diethyl trans-2~3-e~hyl-3-hydroxy-4-methyl-1-octenyl)cyclopropane-1,1-dicarboxy-Iate and diethyl trans-2-(3-hydroxy-4-methyl-3-propyl-1-octenyl)-10 cyclopropane-l,l-dicarboxylate, are obtained, respectively.
.. By following the procedure of Example 31 and utilizing the appropriate lower alkyl magnesium halide and compound of ~ormula 15., for examplo those described in Examples 4 to 12, then other compoundsof formula I in which R is lower alkyl are obtained.
15 Examples of such compounds of formula .I.are. Iisted in Table III
~ogether with the requisite Iower a!kyl magnesium halide and the compound of formula 15.
1.
,, ' :
-~13 O
TABLE III
__ . PRODUCT -NO. OF EXAMPLE (PREFIX LISTED
. IN ~HICH STARTING MATE~-TAL LOWER ALKYL BELO~ CYCLOPROPANE-EXAMPLE -OF FORMULA ~515 PREPARED MAGNESIUM HALIDE. !,I-DICARBOXYLATE
32 4 CH3MgI dimethyl ~L3~5-2-(3-. hydroxy-3-methyl-1-. heptenyl) 33 5 . C2H5MgBr diethyl trans-2-(3-. ethyl-3-hydroxy-1-. nonenyl) 34 6 n-C3H7MgCI dimethyi ~ 2-(3-. . . . decenyl) . .
7 CH3MgBr diethyl trans-2-(3-. . hydroxy-3,4-dimethyl-. I-heptenyl) 36 . 8 2 5 9 dimethyl trans-2-(3-. . ethy1-3-hydroxy 4--15 . . mathyl-l-nonenyl) . 37 9 . , n-C3H7MgCI diethyl trans-2-(4 . . ethy1-3-hydroxy-3-. . propyl-l-octenyl) }B IO CH3M9I . dimethyl trans-2-~3-. . . . hydroxy-3,4-dimethyl . . I-decenyl) 39 11 C2H5MgCI ! diethyl trans-2-(3-. . ~ ethy1-3-hydroxy 4-. . propyl-l-heptenyl) 12 n-C3H7MgCI dimethyl trans 2-(4-ethy1-3 hydroxy-3-. . . propyl-l-noncnyl~
.
~ .
.
. .. , .
.. _ . _~ . . - _ __ ~
s . 4~
-~ AllP-6~0l .
: EXAMPLE 41 Diethyl trans-2-~3-~(tetrahydrop~Jran-2-yl )Gxvl-3-rr.ethvl-octeny1~cycIoDro~ane-I .I-dicarboxyIate (I; R = C2H5 R = ttetrahydro~yran-2-yl~oxy, R and R - H R - CH3_ and n = 3) A solution of diethyl trans-2-(3-hydroxy-3-methyl-1-oc~enyl)cyclopropane-l,l-dicarboxylate (22 4 9~, described in Example 31, dihydropyran (80 ml, distilled over sodium) and D-toluenesulfonic acid monohydrate (300 m~g) is allowed to stand a~ room te~perature for 30 min. After adding a few ml of 10%
Na2003 sol~tion the mixture is extracted with ether. The ether ~xtract is washed with water, dried (Na2504) and evaporated.
Purification of the residue by chromatography on silica gel - gT~es the ~itle compound, nmr (~DC13) ~ 0.87 (t, 3H), 2.48 ~m, IH~, 4.6 (IH), 5.5 (m, 2H)~
In the same manner but using an equivalent amount ot one of the compounds of formula 1 (~ = H), for example, ~he compounds listed in Examples ~7 to 409 instead of diethyl trans-2-(3-hydroxy-3-methyl-1-octenyl)cyclopropane-1,1 dicarboxy-late, ~hen the corresponding tetrahydropyranyl ether compound of formula 1 (R2 = tetrahydropyranyl) i5 obtained, for example, th~ corresponding tetrahydropyranyl ether compounds of Examples 17 to 40, respectively. More specifically exemplified, in the same manner diethyl trans-2-(3-hydroxy-4-methyl-1-octenyl)-cyclopropane-lJI-dicarboxylate, described in Example 17 gives diethyl trans-2- !3- ~ttetrahydropyran-2-yl)oxy]-4-methyl--1-octenyl~-cyclopropane-l,l-dicarboxylate, ~m~lm 1035, 1140, 1220 cm 1, , ' ~ . AHP-6304 .. . . . . . .
and dimethyl trans-2-t4-ethyl-3-hydroxy-1-decenyl~cyclopropane-I,l-dicarboxylate, described in Example 24, gives dime~hyl trans-2-{4-ethyl-3-t(tetrahydropyran-2-yl)oxy]-1-decenyl~-- cyclopropane-l,l-dirarboxylate.
.
~' .
..
. . '. ~ , , .
.
- -' 10~16~2 Dimethyl trans-l-(Carbomethoxymethyl)-5-(3-hydroxy-l-octenyl)-2-oxo-1,3-cycl~eentanedicQrboxylate __~_ _ ______ (3; R and R = CH3, R , ~ R and R = H and n = 3) A solution of sodium methoxide (5 g of sodium dissolved in 150 ml of methanol) is added at room temperature to a solution of tiethyl l,1,2-e-thanetricarboxylate. The mix-ture is hea-ted to 80 and a solution of the compound of formula 1, dimethyl trans-2-f3 ~tetrahydropyran-2-yl)ox~ -l-octeny~ cyclopropane-l,l-dicar-boxylate, described by Abraham, cited above, is added slowly. The mixture is stirred for 1 hr. The methanol is removed under re-duced pressure and the residue heated at 110 for 1.5 hr. After cooling the mixture is acidified with ace-tic acid-water (25 ml, 1:1) and extracted with ether. The ether extract is washed with water, dried (MgS04) and concentrated to give dimethyl trans-l-(carbomethoxymethyl)-5-~3- ~tetrahydropyran-2-yl)oxy~ -l-octeny ~-2-oxo-1,3-cyclopentanedicarboxylate,~ a 290 nm (~ = 13,500) in the presence of a base. Note: Transesterification of the ester groups has occurred during the preceding condensation. If desired this can be avoided by the substitution of ethanol for me-thanol.
A mixture of the latter hydroxy protected derivative (95.1 g) in 375 ml of methanol-water (9:1) and ~-toluenesulfonic acid monohydrate (2.85 g) is stirred for 1 hr at room temperature.
The mixture is rendered neutral by the addition of 10% Na2C03.
The methanol is removed by distillation. The residue is extracted with ether. The organic extract is washed with water until neutral, dried (MgS04) and concentrated. The residue is . A~IP-6304 - . subjected to chromatography on SiO2 using 20% ethyl acetate as e!uant. Evaporation of the eluate gives the title compound 289 nm (14,500) in the presence of base.
.
- ~ .
., .
10'~ 4Z
LXAMPLL ~3 Dimethyl trans-l-(Carboethoxymethyl)-5-(3-hydroxy-3-m _l-l-octenyl)-2-oxo-1,3-c ~ pentanedicarboxylate_ _ (3 R , R and R6 = CH , R , R , and R = H and n = 3) S To a solution of triethyl 1,1,2-ethanetricarboxylate (1.36 g) in 3 ml of methanol7 a freshly prepared solution of sodium methoxide (from 0.126 g of sodium and 6 ml of absolute methanol) is added. The mixture is heated to 80 . A solution of dimethyl trans-2-(3-methyl-3-hydroxy-1-octenyl)cyclopropane-1,-l-dicarboxylate (1.7 g) is gradually added and the resulting mixture stirred for an additional 15 min. The methanol is removed by distillation a-t reduced pressure. The residue is then heated at 100 for 45 min. Thereafter the mixture is cooled in an ice bath and rendered neutral with acetic acid. The mixture is extracted with ether. The extract is drie- (Na2S04) and concentrated. Chromatography of the residue on silica gel using ethyl acetate-benzene (1:4) as eluant gives the title compound, ~~mfa m 3350, 1727 cm 1.
By following the procedures of Examples 42 and 43 and using the appropriate compounds of formulae 1 and formula 2 as starting materials, other cyclopentanonetriesters of formula 3 are obtained.
For example, the use of the compound of formula 1, diethyl trans-2- ~-((tetrahydropyran-2-yl)oxy)-3-methyl-l-octeny~ -cyclopropane-l,l-dicarboxylate, described in Example 41, and the compound of formula 2, triethyl ethane-1,1,2-tricarboxylate, in the procedure of Example 42 gives dimethyl trans-l-(carboethoxy-.
.
AH?-6304 ~3~
. .
: methyl)-5-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentane-dicarboxylate, identical to the product of Example 43, via the intermediate dimethyl trans-l-~carboethoxymethyl)-5-{3-~(tetra-hydropyran-2-yl)oxy]-3-methyl-1-octenyl}-2-oxo-1,3-cyclopentarle-dicarboxylate, ~maxm 1730 cm Likewise, the use of diethyl trans-2-{3-[(tetra-hydropyran-2-yl)oxy]-4,4-dimethyl-1-octenyl}cyclopropane-1,1-dicarboxylate and triethyl ethane-1,1,2-tricarboxylate gives dimethyl trans-l-tcarbomethoxymethyl)-5-(3-hydroxy-4,4-dimethyl-l-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate9 ~max 3500 cm ~EtOH 291 nm (~ = 13,600) in the presence of base (NaOH).
- Additional examples of compounds of formula 3 are listed in Table 111 together with the requisite starting materials. It is to be noted that when the procedure of Example 42 is used the requisite starting material of formula I is the corresponding tetrahydropyran-2-yl ether derivative o-~ the compound of formula 4 - noted therein; the tetrahydropyran-2-yl ether being prepared by following the procedure described~in Example 41.
- .
. .
-r Ll~ ].11 . _ _ NO. OF TIIE EXAMPLE
IN Wl-lICH STARTING STAlRTING PRODUCl': (PREFIX LISTED
MATERIAL OF FORMULA 1 MATERIAL OF BELO~-2--OXO-1~3-CYCLO-
5 EX. IS DESCRIBED FORMULA 2 PENTANEDICARBOXYI,ATE
R _ _ 44 18 CH3 dimethyl trans-l-(carbo-methoxymethyl)-5-(4-ethyl-3-hydroxy-1-heptenyl) lg C21-15 diethyl trans-l-(carbo-ethoxymethyl)-5-(3-hydroxy-4-propyl-1-nonenyl) 46 20 C113 dimethyl trans-l-~carbo-methoxymethyl)-5-(4-ethyl-3-hydroxy-1-decenyl) 47 21 C2H5 diethyl trans-l-(carbo-ethoxymethyl)-5-(3-hydroxy-. 4-methyl-1-heptenyl) 15 48 22 C11~ dime~hyl trans-l-(carbo-methoxymethyl)-5-(3-hydroxy-4-methyl-1-nonenyl) 49 23 C2H5 diethyl trans-l-(carbo-ethoxymethyl)-5-(4-ethyl-3-hydroxy-1-octenyl) 24 CH3 dimethyl trans-l-(carbo-methoxymethyl)-5-(4-methyl-3-hydroxy-1-decenyl) 51 25 C2H5 diethyl ~rans-l-(carbo-ethoxymethyl)-5-(3-hydroxy-4-propyl-1-heptenyl) 52 26 CH3 dimethyl trans-l-(carbo-methoxymethyl)-5-(3-hydroxy-4-ethyl-1-nonenyl) .
53 27 n~C3~l7 dipropyl trans-l-(carbo-propoxymethyl)-5-(3-hydroxy-4~4-dime~hyl-1-decenyl) _ __ _~___ , .. _ ________ ~ A~IP-63()~
TABLE~ 111 _ ________. _ ~
_ NO. OF EXAMPLE
:[N WHlC~I Sl'ARTING STAR'I'ING
MATERIAL 01: ~TERlAL OF PRODUCT: (PREFIX LISI`ED
FORMULA 1 ~ORMULA 2 ~LQ~)-2-oxo-l~3-cycL()~
Ex. IS DESCRIB~D - R3 ~ - PENTANEDICARBOXYLATE
.. ____ _ 54 28 n C3 ~17 dipropyl trans-l-(carbo-propoxymethyl)-5-(4-ethyl-3-hydroxy-4-methyl-. l-decenyl) 29 CH dimethyl ~rans-l-(carbo-3 methoxymethyl)-5-(3-hydroxy 4-methyl-4-propyl-1 hyptenyl) 56 30 C 11 diethyl trans-l-(carbo-2 5 ethoxymethyl)-5-(3-hydroxy-4,4-dipropyl-1-nonenyl) 57 ' 32 CH dimethyl trans-l-(carbo-3 methoxymethyl)-5-(3-hydroxy-3-methyl-1-heptenyl) 58 33 C2~15 diethyl trans~l-(carbo~-ethoxymethy1)-5-(3-ethyl-3-hydroxy-l-nonenyl) 59 34 CH3 dimethyl trans-l-(carbo-methoxymethyl)-5-(3-hydroxy-3-propyl-1-decenyl) C2~15 diethyl trans-l-(carbo-ethoxymethyl)-5-(3-hydrocy-3,4-dimethyl-1-heptenyl) 61 36 CH3 dimethyl trans-l-~carbo-methoxymethyl)-5-(3-ethyl--3-hydroxy-4-methyl-1-nonenyl) 62 37 C }I diethyl ~rans-l-(carbo-2 5 athoxymethyl)-5-(4-ethyl-3-hydroxy-3-propyl-1-octenyl) 63 38 CH3 dimethyl trans-l-(carbo-methoxymethyl)-5-~3-hydroxy 3,4-dimethyl-1-~ecenyl) 64 39 C }I diethyl trans-l-(carbo-2 5 ethoxymethyl)-5-(3-e~hyl-3-hydroxy-4-propyl-1-heptenyl) C113 ~imethyl t_ ns-l-(carbo-metlloxymetllyi) _ 5-(4-ethyl-3-hy(lroxy-3-propyl-1-noneny:L) _ _ _ AhP-6304 trans-2-(3-HYdroxY-I-octenYI)-5-oxocYclopentan~acetic acid (4:-R , R . R and R6 = H and n = 3) - A suspension of dimethyl trans-l-(carbomethoxymethyl)-5-(3 hydroxy-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate (26.24 9), described in Example 42, in a solution of sodium hydroxide (12 9) in 70 ml of water and 80 ml of methanol is heated at reflux for 2 hr.
The reaction mixture is cooled, acidified to pH 6 with 2N HCI. The resulting oil is extracted with ether. The ether extract i5 washed with water, dried (MgS04) and the solvent removed. The residue is subjected to chromatography on silica gel (850 9). Elution with methanol-chloroform (1:9) yields the title compound, vmax 3350, 1727 cm . The corresponding methyl ester of the title compound, prepared by treatmenf with diazomethane,has vmaxm 3412, 1737 cm 1.
~y following the procedure of Example 66 and using the appropriate cyclopentanonetriester of formula 3, for example those described in Examp~es 43 to 65, other compounds of formula 4 are obtained.
For example, the use of the cyclopentanonetriester of formula 3, dimethyl trans-1-(carboethoxymethyl)-5-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate, described in Example 43, in the procedure of Example 66, gives trans-2-(3-hydroxy-3-methyl-1-octenyl)~5-oxocyclo-pentaneacetic acid, vmaxm 3350, 1727 cm 1, Likewise, the use of dimethyl trans-1-(2-carbomethoxymethyl)-5-(3-hydroxy-4,4-dimethyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate, described in Example 43, gives trans-2-(3-hydroxy-4,4-djmethyl-1-octenyl)-Y oxocyclop~ntaneocetic ecid, ~mex 3355, 1729 cm , ~ i AHP-o304 ....... .
. - , q, Further examples of such compounds of formula 4 are .
Iisted in Table IY to~ether with the requisite cyclopentanonetri-esters starting material, the latter compound being noted by the example describing its preparation.
~ AHP-6304 - TABLE IV
_ , .. ~ ...... __... ~
. NO. OF EXAMPLE IN WHICH
. CYCLOPENTANONETRIESTER
EX~PLEOF FORMULA 3 IS PREPARED PRODUCT:
67 44 trans-2-(4-ethy1-3-hydroxy-1-heptenyl)-5-oxocyclopentaneacetic . . acid 58 45 trans-2-(3-hydroxy-4-propyl-1-. . . nonenyl)-5-oxocyclopentaneacetic acid 10 . 69 46 trans-2-(4-ethyl-3-hydroxy-1-decen-. . yl)-5-oxocyclopentaneacetic acid 47 trans-2-(3-hydroxy-4-methyl-1-hepten-yl?-5-oxocyclopentaneacetic acid 71 48 trans-2-(3-hydroxy-4-methyl-1-nonen-~ yl)-5-oxocyclopentaneacetic acid .
72 49 trans-2-(4-ethyl-3-hydroxy-1-octen-: . yl)-5-oxocyclopentaneacetic acid 73 50 trans-2-(4-methy1-3-hydroxy-1-decen-. . yl)-5-oxocyclopentaneacetic acid 74 51 trans-2-(3-hydroxy-4-propyl-1-hepten-. yl)-5-oxocyclopentaneacetic acid . 75 , 52 trans-2-(3-hydroxy-4-ethyl-1-nonen-. yl)-5-oxocyclopentaneacetic acid 76 53 trans-2-(4,4-dimethyl-3-hydroxy-1-. decenyl)-5-oxocyclopentaneacetic acid 77 54 trans-2-(4-ethyl-4 methyl-3-hydroxy-I-decenyl)-5-oxocyclopentaneacetic ; acid . 78 55 trans-2-(4-methy1-3-hydroxy-4-propyl)-. . 1-heptenyl)-5-oxocyclopentaneacetic 79 56 trans-2-(3-hydroxy-4,4-dipropyl-1-nonenyl)-5-oxocyclopentaneacetic acid ~0 57 trans-2-(3-hydroxy-3-methyl-1-.. _ ~.__' .'.. ' : -55-.
~ AHP-6304 ,................ .
TABLE IV
NO. OF EXAMPLE I N WHICH ~ ~........... _ ._ CYCLOPENTANONETRIESTER
EXAMPLE OF FCR~`1ULA 4 !S_PREPARED- -- P~ODUCT: _ 81 58 trans-2-(3-ethy1-3-hydroxy-1-nonenyl)-5-oxocyclopentaneacetic acid 82 59 trans-2-(3-hydroxy-3-propyl~l-decenyl)-. 5-oxocyclopentaneacetic acid 83 60 trans-2-(3-hydroxy-3,4-dimethyl-1-. . . he.ptenyl)-5-oxocyclopentaneacetic acid 84 61 trans-2-(3-ethy1-3-hydroxy-4-methyl-1-. . nonenyl~-5-oxocyclopentaneacetic acid 62 trans-2-(4-ethy1-3-hydroxy-3-propyl-1-octenyl)-5-oxocyclopentaneacetic acid 86 63 trans-2-<3-hydroxy-3,4-dimethyl-1- .
. decenyl)-5-oxocyclopentaneacetic acid 87 64 trans-2-(3-ethyl-3-hydroxy-4-propyl-1-. : heptenyl)-5-oxocyclopentaneacetic acid a8 65 trans-2-(4-ethyl-3-hydroxy-3-propyl-i-. I nonenyl)-5-oxocyclopentaneacetic aci~
~ .~ -.' . ' ~ ' ~, .
. . .
. .
. .. .... ... . . . ..
_ ~ ~ -, AHf'-6304 -. . .
, trans-2-r3-r(Tetrahydro~yran-2-yl~oxyl-1-octenyll-5-oxo-cyclopen-taneacetic acid (4 R2 = tetrah~dropYran-2-YloxY.
R4 R5 and R6 = H and n - 3) To a solution of trans-2-(3-hydroxy-1-octenyl)-5-oxocyclopentane-acetic acid (4.7 9), described in Example 66, in methylene chloride (20 ml) at -20 i5 added dihydropyran (1.61 9? and p-toluenesulfonic acid (0.04 9). The mixture is stirred at that tem~erature for 30 ~ minutes. A further qunatity of P-toluenesulfonic acid (0107 g) is 10 added and the mixture maintained at the same temperature for I hr.
- The reaction mixture is diluted with ether, washed with water, dried (M9504) and the solvent removed. The residue is passad through a co!umn of silica gel (300 9) in a solution of 5~ methanol-chloroform.
The eluate is concentrated to give the title compound, vmaxm 1727 cm 1, 15 nmr (CDC13) ~ 0.88 (t, 3H), 4.69 (m, IH), 5.5 tm, 2H).
-~ ~ In the same manner but using an equivalent amount of one of the other compounds of formula 4 (R2 = H), for example the compound listed in Examples 67 to 81~ instead of trans-2-(3-hydroxy-1-octenyl)-5-oxocyclopentaneacetic acid, then the corresponding tetrahydropyranyl ether compound of formula 4 (R2 = tetrahydropyran-2~yl) is obtained;
for example, the use of trans-2-(3-hydroxy-4,4 dimethyl-1-octenyl)-5-- oxocyclopentaneacetic acid, described in Example 66, gives trans-2-{4,4 di~ethyl-3-[(tetrahydropyran-2-yl)oxy]-1-octenyl}-5-oxocyclopentane-acetic acid, ~max 1727 cm 1.
, ' , .
,.,, : . . : . . .
:~ AHP-6304 , tran~-2 ~ Hydroxy-5-r3-r(tetrahyd~opvr~n-2-yl~oxv~ octenyl~,cyclo-pentaneacetic acid t5:-~ - tetrahYdroDYran-2-Yloxv. R ! R _and R = H and n = 3)_and trans-2~-hydroxy-5-~3-r(tetrahydropyran-2-y!)oxyl-l-octenyi~cyclopentaneacetic acid ~lactone (6: R = __ - tetrahydroDyran-2-yloxy R R5 and R = H and n_~ 3) _ To a solution of trans-2-{3-~(tetrahydropyran-2-yl)oxy]-1-octenyl~-5-oxocyclopentaneacetic acid (5.1 9), described in Example 89, in methanol (10 ml), cooled to -10, is added a solution of sodium (0.354 9) in methanol (5 ml). Thereafter, sodium borohydride (0.152 9) is added to the mixture. The mixture is stirred for I hr,-diluted with ether and rendered acidic wick cone. HCI to pH 4.5. The ether layer is separated.
Tha aqueous phase is extracted with fresh ether. The combined ether layers arc washed quickly with water, dried (MgS04) and concentrated to yield a mixture of the title compounds in about a 7:3 ratio by weight.
The two compounds can be separated by dissolving the preceding mixture in methylene chloride extracting the acid 5 into an aqueous alkaline solution, for example, 5~ Na2C03, and subsequent acidification thereof gives the title compound of formula 5~ ~malm 3200, 1700 cm nmr ~CDC13) ~ 0.88 (t, 3H), 4.7 (m, IH), 5.6 (m, 2H). The corresponding ~lactone _ is described below.
The preceding mixture of the title compounds (4.0 9) in methylene dTchloride (35 ml) and triethylamine (2.339 9) is cooled to -5 to -10.
A 501ution of methanesulfonyl chloride (i.44 9), in methylene chloride (i5 ml) is added dropwise. The mixture is stirred at that temperature for 45 mi~nutes. The mixturé is diluted with methylene chloride, washer with water (5X), dried (MgS04) and the solvent removed to yield a crude .
-5~-. . .
product which is poured through on a column of silica gel (250 9) in ethylacetate-benzene. Evaporation of the eluate gives the title compound of formula 6, v~fnaxm 1762, 1030, 1012 cm 1, nmr (CDC13) 4.68 (s, IH), 5001 (s, IH), 5.5 (m, 211).
8y following the procedure of Example 90 and using the ~ppropriate compound of formula 4, for example those described in Examples 66 to 89, other compounds of formulae 5 and 6 are obtained.
For example, the use of the compound of formula 4, tran -2-~3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentaneacetic acîd, described in Example 66, gives trans-2Cl-hydroxy-5-t3-hydroxy-3-methyl-1-octenyl)-cyclopentaneacetic acid, and its corresponding ~lactone, vmax 3400, 1765 cm . Likewise, the use of trans 2-(3-hydroxy-4,4-dimethyl-1-octenyl)-5-oxocyclopentaneacetic acid, described in Example 66, gives trans-2~-hydroxy-5- (3-hydroxy-4,4-dimethyl-1-octenyl)cyclopentaneacetic acid, and its corresponding ~lactone, ~max 3450, 1765 cm 1.
Further examples of the compounds of formula 5 and their corresponding ~lactones of formula 6, which may be prepared by the procedure of Example 90, are listed in Table V~ In each case the requisite starting material of formula 4 are noted by the example describing its preparation also in each case the corresponding tetrahydropyranyl ether of the starting material of formula 4 may replace the designated starting rnaterial.
, ~ ~ AHP-6304 . .. ~ , .. . . . . .
.
TABLE V
., NO. OF EXAMPLE IN WHICH PRODUCT: (PREFIX LISTED BELO
STARTING MATERIAL OF CYCLOPENTANEACETIC ACI~, 5 EXAMPLE FORMULA 4 IS PREPARED (AND CORRESPONDIN~ Y~LACTONE, 6)-91 67 trans-2~-hydroxy-5-(4-ethyl-3-hydroxy-1-heptenyl) 92 68 trans-2~-hydroxy-5-(3-hydroxy-4-propyl-1-. nonenyl) 93 69 trans-2~-hydroxy- 4 (4-ethy1-3-hydroxy-1-. . decenyl) 94 70 trans-Za-hydroxy-5-(3-hydroxy-4~methyl-1-heptenyl) 71 trans-2~-hydroxy-5-(3-hydroxy-4-methyl-1-. nonenyl) .
96 72 trans-2a-hydroxy-5-(4-ethyl-3-hydroxy-1-. octenyl) 97 73 trans-2~-hydroxy-5-(4-methy1-3-hydroxy-1-. decenyl) .
. 98 74 trans-2~-hydroxy-5-(3-hydroxy-4-propyi-1-. . he~ptenyl) 99 75 ~ trans-2~-hydroxy-5-(3-hydroxy-4-ethyl-1-nonenyl) iOO 76 trans-2a-hydroxy-5-(4,4-dimethyl-3-hydroxy-. I-decenyl~
101 77 trans-2~-hydroxy-5-(4-ethy1-4-methyl-3-hydroxy-l-decenyl) 102 78 trans-2~-hydroxy-5-(4-methy1-3-hydroxy-4 . propyl-l-heptenyl) 103 79 trans-2a-hydroxy-5-(3-hydroxy-4,4-dipropyl-I-nonenyl) - 104 80 t!ans-2~-hydroxy-5-(3-hydroxy-3-methyl-1- .
. heptenyl) 105 81 trans-2~-hydroxy-5-(3-ethy1-3-hydroxy-1-. .~ nonenyl) , . .
TABLE V
_ . NO. OF EXAMPLE IN WHICH PRODUCT: (PREFIX-L!STED BELOW)-. STARTINC MATERIAL OF CYCLOPENTANEACETIC ACID, ~, EXAMPLE FORMULA 4 IS PREPARED _ (AND CORRESPONDING ~-LACTONE. 6~
106 82 trans-2~-hydroxy-5-(3-hydroxy-3 propyl-I-decenyl) 107 83 trans-2~-hydroxy-5-(3-hydroxy-3,4-. dimethyl-l-heptenyl~
108 84 trans-2a-hydroxy-5-(3-ethy1-3-hydroxy-4-methyl-1-nonenyl) . 109 85 trans-2~-hydroxy-5-t4~ethyl-3-hydroxy-.10 3-propyl-1-octenyl) . 86 trans-2a-hydroxy-5 (3-hydroxy-3,4-di-methyl-l-decenyl) 87 trans-2~-hydroxy-5-(3-ethyl-3-hydroxy- .
4-propyl l-heptenyl) 112 88 trans-2~-hydroxy-5-(4-ethyl-3-hydroxy-3- .
propyl-l-nonenyl) 1 , ..
'~
. , .
" ~ ,' .
. - . =_ ~ .
-~ , trans-2a-Hydroxy-5-(3-hvdroxy-l-octenyl)cyclopentaneacetic acid y~__ctone (6; R2 R4, R5 and R6 = H and n = 3) trans-20~-Hydroxy-5-'3-~tetrahvdro~yran-2-vloxv~ octen cyclopentaneacetic acid ~lactone (2.0 g),describedin Example 90,isdis-solved in methanol (10 ml):and water(3.5 ml) containingp-toluenesulfonic acid (0.4 9). The mixture isstirred at room temperature for 30 minutes.
The soivent is removed under reduced pressure. The residue is shaken between water and ether. The ether layer is dried ~MgS04) and evaporated . to glve the title compound, ~max 3450, 1765 cm 1, The corresponding DMIS ether of the titla compound has vma;x 1765 cm 1.
, . .
.-_ ' . , ' trans-2a-Hydroxy-5-(3-oxo-1-octenyl)cyclopentaneacetic acid ~iactone (7: R and R5 = H and n =_3) A solution of trans-2a-hydroxy-5-(3-hydroxy-1-octenyl)-cyclopentaneacetic acid ~lactone (I.9 9), described in Example 113;
in chloroform in (60 ml) is stirred with activated magnanise dioxide ~14.9 9) at 40 (bath temperature ) for 15 hr~ The reaction mixture ;s filtered and the precipitate washed with hot chloroform. The combined chloroform solutions are evaporated. The residue is subjected to chromatography on silica gel using ethyl acetate-benzene (3:7) as eluantO Evaporation of the eluant gives the title compound, mp 36 -36.5C, ~CmaHXCl3 1755, 1635, 1625 cm 1.
- By following the procedure of Example 114 and using - the appropriate hydroxylactone of formula ~; for example, those of Examples 91 to 103, other compounds of formula 7 are obtained.
- For example, the use of tne compound of formula 6, trans-2a-hydroxy-5-(3-hydroxy-4,4-dimethyl-I-octenyl)cyclopentaneacetic acid lflactone, described in Example,90, gives trans-2a-hydroxy-5 t4~4-dimethyl-3-oxo-1-octanyl)cyclopentaneacetic acid ~-Iactoner ~f~im 1/65, 1680, 1620 cm Further examples of the compounds of formula 7 are listed in Table Vl. In each case the requisite starting material of formula 6 is noted by the example describing its preparation.
' .
' .
.
~ .
TABLE Vl _ _ . NO. OF EXAMPLE IN
. WHICH STARTING MATERIAL PRODUCT: (PREFIX LISTED 8ELOW)-. EXAMPLE. OF FORMULA 6 IS PREPARED CYCLOPENTANEACETIC ACID l~LACTONE
. . .. ,.. ~ .
115 91 trans 2~-hydroxy-5-(4-ethyl-3-oxo-1-heptenyl) 116 . 92 trans-2a-hydroxy-5-t3-oxo-4-propyl-1-. nonenyl) . 117 93 trans-2~-hydroxy-5-(4-ethyl-3-oxo-1-decenyl) . 118 94 trans-2~-hydroxy-5-(4-methyl-3-oxo-1-. . heptenyl) 119 95 trans-2~-hydroxy-5-(3-oxo-4-methyl-1-. . nonenyl) 120 96 trans-2a-hydroxy-5-(4-ethyl-3-oxo-1-. octenyl) 121 97 trans-2~-hydroxy-5-(4 methy1-3-oxo-1-. . decenyl) .
122. 98 , trans 2~-hydroxy-5 (3-oxo-4-propyl-1-. . heptenyl) 123 99- trans-2~-hydroxy-5-(4-ethy1-3-oxo-1-nonenyl~
124 100 trans-2~-hydroxy-5-(4,4-diemthyl-3-. oxo-l-decenyl) 125 iOI trans-2a-hydroxy-5-(4-ethyl-4-methyl-ZO 3-oxo-1-decenyl) . 12.6 102 t _ -2a-hydroxy-5-t4-methyl-3-oxo-. . . 4-propyl-1-heptenyl) 127 103 trans-2~-hydroxy-5-(3-oxo-4,4-dipropyl-. I-nonenyl) .
. ~
._ _- . ' ''.~ .
. AHP-6304 2 ydroxy-5-(3-oxooctyl)cyclopentaneacetic acid-~t~lactone (8: R4-and R5 = H and n = 3) A solution of trans-2a-hydroxy-5-(3-oxo-1-octenyl)cyclo-pentaneacetic acid l~lactone (5.0 9), described in Example 114, in methanol (100 ml) is hydrogenated in the presence of 10% palladium-charcoal (1.0 9) at 25. After the uptake of the theoretical amount of hydrogen, the catalyst is collected on a filter and the fiItrate is concentrated to yield the title compound, vmalm 1765, 1710 cm 1 By following the procedure of Example 128 and using the appropriate hydroxylactone of formula 7; other compounds of formula 8 are obtained.
For example the use of the compound of formula 7, trans-2a-hydroxy-5-(4,4-dimethyl-3-oxo-1-octenyl)cyclopentaneacetic acid 15 ~lactone, described in Example ! 14, gives 2a-hydroxy-5-(4,4 dimethyl-3-oxooctyl)cyclopentaneacetic acid l-lactone, ~maxm 1770, 1700 cm 1.
Further examples of the compound of formula a are listed in Table Vlll. In each case the requisite starting material of formula 7 is noted by the example in which is is prepared.
.~i A~P-6304 ,TABLE V I I .,,, .. .. ' .. ..... _ NO. OF EXAMPLE IN
. WHICH STARTiNG MATERIAL OF PRODUCT: (PREFIX-LISTED-BELOW)-._EXAMPLE FORMULA 7 IS PREPARED CYCLOPENTANEACETIC ACID ~LACTONE_ .
12~ 115 2a-hydroxy-5-(4-elhyl-3 . . oxoheptyl) 130 116 2~-hydroxy-5-(3-oxo-4-. . propylnonyl) 131 . 117 2a-hydroxy-5-(4-ethyl-3-. oxodecyl) 132 118 2a-hydroxy-5-(4-methyl-3 . . oxoheptyl) 133 119 2a-hydroxy-5-(4 methyl-3-oxononyl) 134 120 2a-hydroxy-5-(4-ethyl-3-. . . oxooctyl) 135. 121 2~-hydroxy-5-(4-methyl-3-. oxodecyl) . 136 122 2a-hydroxy-5-(3-oxo-4-: . propylheptyl) 137 123 2a-hydroxy-5-t4-ethyl-3-. oxononyl) 138 124 2~-hydroxy-5-(4,4-dimethyl- .
. .. 3-oxo-1-decyl) 13~ 125 . 2a-hydroxy-5-(4-ethyl-4 . . . me.thy1-3-oxodecyl) .- I~Q 126 2a-hydroxy-5-(4-methyl-3- . oxo-4-propylheptyl) 141 . 127 2~-hydroxy-5-(3-oxo-4,4-dipropylnonyl) .
v 2a-~ydroxy-5-(3-hydroxyoct~l)cycloDentaneacetic acid lactone (9: R2, R4. R5 and R6 = H and n - 3) By following the procedure of Example 17 but replacing ~iethyl trans-2-(4,4-dimethyl-3-oxo-1-octenyl~cyclopropane-1,1-dicarboxy-late with an equivalent amount of 2a-hydroxy-5-~-oxooctyl)cyclopentane acetic acid ~lactone, described in Example 128, the latter compound is reduced to give the title compound, ~maxm 3400, 1770 cm 1~
. The title compound is also obtained by -the procedure of 10. Example 165.
By follo~ing the procedure of Example 142 and using the appropriate compound of formula 8, for example those 7n Examples 129.
to 141, other compounds of formula 9 in w~ich R~ is hydrogen~ are ~ obtained.
For exampleithe use of the compound of formula 8, 2a-hydroxy-5-~4,4-dimethyl-3-oxooctyl)cyclopentaneacetic acid ~-lactone, described - in Example 128, gives 2a-hydroxy-5-~3-hydroxy-4~4-dimethyloctyl) pentaneacetic acid ~-lactone.
Further examples of the compound of formula 9 in which R
is hydrogen are listed in Table Vlll. In each case the requisite `- starting material of formula is noted by the example in which it is prepared, 'I .
~ -67-.
. .
, . ' ! , .
.
. TABLE Vlll . ... .,.___ . . I
NO. OF EXAMPLE IN WHICH PRODUCT: (PREFIX LISTED 8ELOW)-STARTING MATERIAL OF CYCLOPENTANEACETIC ACID, 5 . EXAMPLE _ FORMULA 4 IS PREPARED (AND CORRESPONDING ~LACTONE~ 6) 143 136 2a-hydroxy-5-(3-hydroxy-4-pr . heptyl) 144 137 2a-hydroxy-5-( 4ethyl-3-hydroxy-. nonyl) 145 138 2~-hydroxy-5-(4,4-dimethy1-3-hydroxy-l-decyl) 146 139 ~ 2a-hydroxy-5-(4-ethy1-3-hydroxy-4-methyldecyl) 147 1~0 2a-hydroxy-5-(3 hydroxy-4-methyl-. 4-propylheptyl) 148 141 2a-hydroxy~5-(3-hydroxy-4~4 ¦ . ~ ' dipropy nonyl) . , .' :
. .
_... .. _ .. ___ ... ' _ i ., : ' .. . .
- 2X-Hydroxy-5-(3-hydroxy-3-methyloctyl)cycloDentaneaceticacid ~-lactone (9: R R _and R = H~ R = CH~ and n - 3) . A solution of 2a-hydroxy-5-(3-oxooctyl)cyclopentaneacetic acid l-lactone (6.66 9), described in Example 128, in ether (100 ml) is treated dropwise with the lower alkyl magnesium halide, methyl - magnesium iodide ~1.5 molar in ether, 33 ml) while keeping the reaction temperature at 0. The Grignard complex is then decomposed with 10% ammonium chloride solution. The reaction mixture i-s extracted with ether, washed with brine, dried (Na2S04) and concentratad.
The residue in ethyl acetate-benzene (2:8) is poured through a column of silica gel. Evaporation of the eluate gives the title compound, nmr (CDC13) ~ 0.9 (t, J = 5, 3H), 1.13 (s, 3H1, 1.67 - (b, IH), 2.33 and 2.71 ~m, 2H~, 500 (m, IH).
By following the procedure of Example 149 and using the appropriate compound of formula 8, for example, those described in Examples 129 to 137, together with the appropriate lower alkyl magnesium halide, other-compounds of formula 9 are obtained.
Furtber ex:mples of the compound of formula _ are listed in Table IX. In each case the requisite starting material of formula a is notFd by the examp!e in which it is prepared.
. ~ .
A~IP- 6304 TABLE IX
. . _ ...... _ , PRODUCT: (PREFIX LISTE~
. NO. OF EXAMPLE IN '~IHICH ~ELO'.l)-CYCLOPENTA~EACETIC
STARTING MATERIAL OF LOWER ALKYL ACID, 5 (AND CORRESPONDING
. EXAMPLE FORMULA 8 IS PREP.:RED MAGNESIUM HALIDE yrLAcToNE~ 6 150 129 CH3Mgl 2~-hydroxy-5-(4-ethyt-3-hydroxy-3-methylheptyl) 151 130 C2H5M93r 2~-hydroxy-5-(3-ethyl-3-. hydroxy-4-propylnonyl1 15Z 131 n-C3H7MgCI 2~-hydroxy-5-(4-ethyl-3-hydroxy~3~propyldecyl) . . .
O 153 132 2 5 9 2~-hydroxy-5-(3-ethy1-3-hydroxy-4-methylheptyl) . 154 133 CH3Mgl 2a-hydroxy-5-(3-hydr : 3,4-dimethylnonyl) 155 134 2 5 9 2a~hydroxy-5-(3J4-. diethy1-3-hydroxyoctyl) : 156 135 n-C3H7Mgl 2a-hydroxy-5-(3-hydr ¦ ~ ¦ 4-methyldecyl~
I' '. . .
~:' .
, ' ...... . ,, ., ....... ..... ,....... ... ....
.. _ . _ .
7~
, : EXAMPLE 157 . trans-2a-Hvdroxv-5-(3-hYdroxv-3-methyl-1-octenYl)cycloPentane-acetic acid ~lactone (12: R _L R and R = H, R = CH ~ 3) By fol lowing the procedure of Example 1499 but replacing 2~-hydroxy-5-(3-oxooctyl)cyclopentaneacetic acid ~!actone, with an equivalent amount of trans-2~-hydroxy-5-(3-oxo-1-octenyl)cyclopentane-acetic acid ~lactone, described in Example 114, ~he titie compound is obtainedJ ~ma~xm 3420, 1770 cm 1, nmr (CDC13) ~ 0.3 (t, J ~ 5, 3H), 1.26 (3H), 1.7 (IH), 5.05 (m, IH~, 5.65 (m, 2H).
By following the procedure of Example 157 and using the appropriate compound of formula 7, for example, those described in Examples 115 - 123, together with the appropriate lower alkyl magnesium halide, other compounds of formula 12 are obtained.
Further examples of the compound of formula 12 are listed in Table X- In each case the ~quisite starting material of formula is noted by the example in which it is prepared.
.
a .
TABLE X
.... . ... . .. .... ..
PRODUCT: (PREFIX LISTED
. NO. OF EXAMPLE IN WHICH BELOW)-CYCLOPENTANEACE-rlC
. . STARTING MATERIAL OF LOWER MAGNESIUM ACID,.5 (AND CORRESPONDING
EXAMPLE FORMULA 7 IS PREPAREDHALIDE ~LACTONE. 6-158 115 CH3MgBr trans-2a-hydroxy-5-(4-. ethyl-3-hydroxy-4-propyl-1-. nonenyl) 159 116 C2H MgBr trans-2a-hydroxy-5-(3-. . 5 ethy1-3-hydroxy-4- .
. propyl-l-nonenyl) : 160 117 n-C3H7MgCI trans-2a-hydroxy-5-(4-. ethyl-3-hydroxy-3-. propyl-l-decPnyl) i61 118 C2H5M9CI trans-~-hydroxy-5-(3-. ethy1-3-hydroxy-4-. . . methyl-l-heptenyl) 162 119 CH3 9 trans-2~-hydroxy-5-(3-. hydroxy-3,4-dimethyl-1-. . -. nonenyl) 163 120 C2H5M91 trans-2a-hydroxy-5-(3,4-diethyl-3-hydroxy-1-. . . ~ l octenyl) -. 164 - 121 3 9 trans-2a-hydroxy 5-(3-. hydroxy-3,4-dimethyl-1 j ~ decenyl~
.~', ~ ' : ~ ~, . . :..
" ' . ~
.
;' '., _____ ~_ '_' ' .
. ;' .
2~-Hy _oxy-5-(3-hydr_~y~tyl)cyclopen-taneace-tic acid ~-lact n _(g, R , _ ~ and R = H and n = 3 The ti-tle compound is obtained, in addition to the procedure of Example 142, by hydrogenation of the compound of formula 6 (R = H), trans-2~-hydroxy-5-(3-hydroxy-1-octenyl)cyclo-pentaneacetic acid ~-lactone, described in Example 113, by the procedure of R. D. Hoffsommer, et al, Te-trahydron Le-tters, 4085 (1971), using Raney nickel in dioxane.
By following the procedure of Example 165 and using the appropriate compound of formula 6 (R6 = H), for Example -those described in Examples 90 to 112, other corresponding compounds of formula 9 (R = H) are obtained.
Further examples of the compounds of formula 9 are listed in Table XI. In each case -the requisite star-ting material of iormula 6 is noted by the example in which it is prepared.
;
' ~ -73-~ HP-6304 .~ . . ..
. TABLE Xl , . , ~
NO. OF EXAMPLE IN WHICH PRODUCT: (PREFIX LISTED BELOW)-STARTING MATERIAL OF CYCLOPENTANEACETIC ACID, 5 -EXAh1PLE FORMULA 4 IS-PREPARED - (AND_CORRESPONDING ~LACTO~IE. 6~
166 99 2a-hydroxy-5-(3-hydroxy-4-ethylnonyl) 167 100 2~-hydroxy-5-(4,4-dimethyl-3-hydroxydecyl) 168 101 2a-hydroxy-5-(4-ethy1-4-~ethyl-3-. hydroxydecyl) 169 102 2a-hydroxy-5-(4-methyl-3-hydroxy-4 . propylheptyl) 170 103 2~-hydroxy-5-(3-hydroxy-4,4-dipropyl-nonyl~
171 104 2~-hydroxy-5-(3-hydroxy-3-methyIheptyl) 172 108 2x-hydroxy-5-(3-ethyl-3-hydroxy-4- . . methylnonyl) 173 109 2a-hydroxy-5-(4-ethy1-3-hydroxy-3-15 ¦ ,ropylcctyl~ .
. ~- , . `
-~- . . .
~ - ' : ; .
;
.
:
' ~ AHP-6304 , , ., ~ . - . " ~ . . . .. .
'~3~
.
Hexahydro-2-hydroxy-4-E3-(dimethyl-terf-butylsiIyloxy)-l-octenyll-2H-cyclopentarblfuran (13 _R?. R , R and R = H
and n = 3) - A solution of the compound of formula _, trans-2~-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentaneacetic acid ~-lactone, in the form of its dimethyl-tert-butylsilyl ether, (6.66 9), described in Example 113, in dry toluene t40 mll is cooled to -75C. As solution of diisobutyl aluminum hydride (3.9 9 in 10.8 ml. of hexane) is added by syr7nge under a nitrogen atmosphere. The mixture is stirred afor 15 minutes at that temperature and then diluted with ether, washed with water. The gelantinous aluminum salts are removed by fiItration. The fiItrate is washed with water (2X), dried (MgS04) and the solvent is removed to give the title compound, ~ 3360 cm , nmr (CDC13) ~ 4.02 (m, IH)J 4.63 (m, IH~, 5.42 (m, 2H).
: .
, .
' ` ' .
..
.
~7:~L6~Z
trans, cls-7-(2~-H droxy 5-(3-hydroxy-1-oc-tenyl)cyclopentyl)-5-he~tenoic acid (11; R2, R4, R5, R6 and R7 = H
X = OH, Y = H, Z = trans CH = CH, m __3 and n 3) __ To a suspension of sodium hydride (7.42 g, 57% in oil) washed with hexane, is added dry dimethyl sulfoxide (45 ml). The mixture is heated to 75 - 80 (bath temperature) for one hour. sy this all the sodium hydride has reacted. The mixture is cooled. A solution of the phosphonium bromide, (39.0 g) derived from triphenylphosphine and ~ -bromo pentanoic acid, in dry DMSO (90 ml) is added gradually to the solution of sodio methylsulfinyl carbanide; followed by the addition of a solution of the hemiacetal of formula 13, hexahydro-2 ¢hydroxy-4-(3-(dimethyl-tert-butylsilyloxy)-1-octenyl)-2H-cyclo-penta(b)furan (5.42 g), described in Example 174, in dry dimethyl-sulfoxide (15 ml). The mixture is stirred overnight at roomtemperature. The reaction mixture is diluted with water, acidified with acetic aid (5 ml), and extracted with ether. The ether extract is washed with water, dried (Na2S04) and the solvent is removed. The residu is passed through a column of silica gel (40Q g) using ether-hexane (1:1) as eluant. Evaporation of the eluate gives the corresponding dimethyl-tert-butylsilyl ether of the title compound,~malm 3470, 1710 cm lo Removal of the hydroxy protecting group:
The latter compound (4.1) g is dissolved in methanol (20 ml) and water (7 ml) containing p-toluene sulfonic acid (0.4 g). The reaction mixture is stirred for 30 minutes, the solvent is removed under reduced pressure. The residue is extractèd with ether. The extract is washed with water, dried (MgS04) the solvent is evaporated.
Purification by ~ Al-IP-6304 chromatography o~ the resi~u~ (SiO2, benzene-ethyl ace-tate ~9:1)) gives the title compound as a mix~ure of stereochemical isomers with respect to the asymmetric carbon atom in the side chain -to which the hydroxyl is attached. The mixture has vfilm 3480, 1700 cm nmr (CDC13) ~ 0.87 (m, 3H), ~.18 (m, 2H), 5.45 (m, 4fl), identical to the mixture of the s~me name described in U.S. Patent No. 3,849,474, issued November 19, 1974.
By following sequentically the procedure of Example 174 and 175, and using the appropriate compound of formula G or 9, for example, those of Examples 90 to 112 other prostaglandin derivatives of form~lla 11 are obtained.
For example the use of the compound of forn~ula 6, trans-2~-hydroxy-5-l3-hydroxy-3-methyl-1-octenyl)cyclopentaneacetic acid y-lactone, described in Example 9O, gives trans,cis-7-(2~-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl)-5-heptenoic acid, described in U.S. Patent No. 3,917,668, issued November 4, 1975, via the intermediate hemiacetal of formula 13, hexahydro-2-hydroxy-4-{3-((tetrahydropyran-2-yl)oxy)-1-octenyl}-2H-cyclopentan~b)furan, vnf~axn' 3350 cm~l.
Likewise, the use of 2~-hydroxy-5-~3-hydroxyoctyl)-cyclopentaneacetic acid ~-lactone, described in Example 142, gives cis-7-~2~-hydroxy-5-~3-hydroxyoctyl)cyclopentyl)-5-heptenoic acid, nmr ~CDC13) 6 9.O ~t, J = 5, 3H), 3.65 ~m, 1H)J 4.25 (m, lH), 4.9 (s, 3H), 5.5 (m, 2H), via the intermediate hemiacetal of formula 10, hexahydro-2-hydroxy-4-(3-(dimethyl-tert-butylsilyloxy)octyl)-2H-cyclo-penta~b)furan, vmiaxm 3360 cm 1.
Al-lP-6~04 I,ikewise, the use of 2~-hydroxy-5-(3-hydroxy-3-methyloctyl)-cyclopentaneace-tic acid y-lactone, ~escribed in Fxample 149, gives ClS-7- (2~-hydroxy-5-t3-hydroxy-3-methyloctyl)cyclopentyl)-5-heptenoic acidJ nmr (CDC13) ~ 0.9 (t, J ~ 5, 3fl), 1-2 (S, 3H), 1.5 ~s, 2H)~ 4-2 ~ (m, 11l), 5.5 (m, 2H), via the intermediate hemiacetal of formula 10, hexahydro-2-hydroxy-4-(3-hydroxy-3-methyloctyl)-2H-cyclopenta(b)furan, Vfilm 3355 Cm-l max Likewise, the use of 2~-hydroxy-5-(3-hydroxy-4,4-dimethyl-octyl)cyclopentaneacetic acid ~-lactone, described in Example 142, gives ClS-7- (Z~ hydroxy-5-(3-hydroxy-4,4-dimethyloctyl)cyclopen-tyl)-5-heptenoic acid, via the intermediate hemiacetal of formula 109 hexahydro-2-hydroxy-4-~3-(dimethyl-tert-butylsilyloxy)-4,4-dimethyloctyl}-2H-cyclopenta-(b)furan, vfixm 3350 cm 1 and the corresponding dimethyl tert-butylsilyl ether of ClS-7- (2G~-hydroxy-5-(3-hydroxy-4,4-dimethyloc-tyl)cyclopen~yl)-5-heptenoic acid has vfaxn~ 3350, 3260 cm 1.
Further examples of the compound of formula 11 are listed in Table Xll. In each case the requisite starting material of formula 9 is noted by the example in which it is prepared.
~IP-6304 TABLE X]l , . ... I
NO. OF FOI~ULA
EX~MPLE lN
WHICH STARTIN~ ( ~ )3-P C~l- PRODUCT:
EX. IS PREPARED (C112)mC ~ Br m R
_ _ _ _ 176 143 3 H ClS-7- (2~-hydroxy-5-(3-hydroxy-4-propylheptyl)cyclopentyl)-5-heptenoic acid 177 144 2 H cis-6-(2~-hydroxy-5-(4-ethyl-3-hydroxynonyl)cyclopentyl)-4-hexenoic acid 178 145 111 cis-5-(2~-hydroxy-5-(4,4-di-methyl-3-hydroxy-1-decyl)cyclo-pentyl)-3-pentenoic acid 179 146 2C}13 cis-6- (2~-hydroxy-5-(4-ethyl-3-hydroxy-4-Dlethyldecyl)cyclo-pentyl)-4-hexenoic acicl methyl ester 180 147 3ll cis-7-(2~-hydroxy-5-(3-hydroxy-4-methyl-4-propylheptyl)cyclo-pentyl)-5-heptenoic acid 181 148 2C2H5 cis-6-(2~-hydroxy-5-(3-hydroxy-4,4-dipropylnonyl)cyclopentyl)-4-hexenoic acid ethyl ester 182 150 3 H ClS-7- (2~-hydroxy-5-(4-ethyl-3-hydroxy 3-methylheptyl)-cyclopentyl)-5-heptenoic acid 183 151 2n C3H7 ci.s-6- (2~-hydroxy-5-(3-e~hyl-3-hydroxy-4-propylnonyl)cyclopent~
yl)-4-hexenoic acid propyl este~
184 152 1 H cis-5-(2~-hydroxy-5-(4-ethyl-3-hydroxy-3-propyldecyl)cyclo-pentyl)-3-pentenoic ~cid _ __._.__ .. __ ~
~IIP-~J30 TABLL Xll __ ....
EXAMPLE IN l ORMULA
WHICH STARTING
MATERIAL OF ( ~ ~-P -CH- PRODUCT:
FORMULA 9 ~
EX. IS PREPARED (Cll2)mCOOR7 Br m - R7 _ 185 153 2 CH3 cis-6- (2~-hydroxy-5-~3-ethyl-3-hydroxy-4-methylheptyl~-cyclopentyl)-4-hexenoic acid methyl es~er 0 186 154 3 H cis-7-(2~-hydroxy-5-(3-hydroxy-3,4-dimethylnonyl)cyclopentyl)-5-hexenoic acid 187 155 2 H cis-6- (2~-hydroxy-5-(3,4-di-ethyl-3-hydroxyoctyl)-cyclo-pentyl)-4-hexenoic acid 188 156 1 CH3 cis-5-(2~-hydroxy-5-(3-hydroxy-4-methyldecyl)cyclopentyl)-3-pentenoic acid methyl ester - ~0-~ AHP 6304 .
cis-7-~2-(3-hYdrox~ imethylocty ! )-5-oxocyclopentyll-5-heptenoic ac7d (II; R I R6 and R7 - H, R and R5 = CH~L_X
and Y = O; Z = CH~CH_ m = 3 and n = 3) To a solu+ion of cis-7-~2a-hydroxy-5-~3-(dimethy~+ert-butyl-- silyloxy)-4,4-dimethyloctyl]cyclopentyl}-5-heptenoic acid (0.817 9), described in-Example 175, in acetone (10 ml), cooled to -10, 0075 ml of Jones' reagent [chromic acid in acetone containing a trace of sulphuric acid, see E. R. H. Jones, et al., J. Chem. SocO, 2548 (1953)] is ~dded. After stirring for 10 minutes the excess reagent is destroyed wiTh methanol. The reaction mixture is diluted with water and extracted with etherO The extract is washed with water, dried (Na2S04) and the solvent removed to yield cls-7-{2-[3-(dimethyl-tert-butyl-silyloxy)-4~4-dimethyloctyl]~5-oxocyclopentyl~-5-heptenoic acid, ~ 15 vmax 1730, 1710 cm 1.
~ . The latter compound is deprotected by treatment with æ-toluene-sulfonic acid in aqueous methanol according to the procedure of Example 175 to.give the title compound vmax 3470, 1730, 1710 cm 0 In the same manner but replacing cls-7-r2~-hydroxy-5-[3-(dimethyl isopropylsi Iyloxy)-4,4-dimethyloctyl]cyclopentyl}-5- heptenoic.acid by the appropriate compound of formula 11 in which X and Y are hydroxy and hydrogen, respectively, other corresponding compounds of formula It in which X and Y are oxo are obtained. Note protection of the hydroxyl on the side chain is not required when it is a tertiary alcohol (iOeO, R
lower alkyl).
,j .
, . . .- . . _ ~ A~IP-630~
For example, in the same mann~r, but replacing cls-7-~2~ hydroxy-5-(3-~dimethyl-t~rt-butylsilyloxy)-4,4-climethyloctyl~cyclopentyl}-5-heptenoic acid, with cis-7-f2~-hydroxy-5-(3-(dimethyl-tert-butylsilyloxy)octyl)cyclo-pentyl~-5-heptenoic acid, described in Example 175, cis-7-~2-(3-hydroxy-octyl)-5-oxocyclopentyl)-5-heptenoic acid, nmr (CDC13) ~ 0.9 (t, J - 5, 3H), 3.7 (m, lH), 5.42 (m, 2H), 6.6 (s, 2H), is obtained.
Likewise, replacement with cis-7-(2~-hyd~oxy-5-(3-hydroxy-3-me~hyloctyl)cyclopentyl)-5-heptenoic acid, described in Example 175 gives cis-7- t2-~3-hydroxy-3-methyloctyl)-5-oxocyclopentyl)-5-heptenoic acid, nmr (CDC13) ~ 0.9 (t, J = 5, 3}1), 5.42 (mJ 2H), 6.5 (s, 2H).
Furthermore if desired a compound of formula 11 (R6 = H) may be separated into its two epimers with respect to the asymmetric carbon atom bearing the hydroxy group. This separation is effected preerably by converting the aforementioned compound to its corresponding methyl ester using methanol in the presence of a acid catalyst, for example, 2% perchloric acid, and subjecting the ester to chromatography on S.02 use benzene-ethyl acetate (9:1) as eluant. In this manner the epimers are separated. These isomers are arbitrarily designated as isomers A
(least polar isomer~ and isomer B (more polar isomer); ~he polarity being determined by the order in which they are eluted. Thereafter the epimers may be hydrolyzed with 5~ sodium hydroxide in aqueous methanol for 15 minutes at 30 to 40 to give the corresponding acid.
For example, by the preceding method the epimers of the ~itle compound are obtained, Isomer A has Vmfalm broad hydroxyl, 1725 - 1730 cm 1, and Isomer B has vfalm broad hydroxyl, 1725 - 1730 cm 1.
~ AHP-6304 ,, ~j~;, The corresponding methyl esters of the preceding Isomers A
and B have the following characteristics:
Isomer A, a racemate of methyl cis-7-~2-(3-hydroxy-4,4-dimethyioctyl)-5-oxocyclopentyl]-5-heptenoate, has RT of about 0.47 on thin layer plates of silica gel when using ethyl acetate-benzene (1:4) as the mobile phase~
Isomer 8, a second racemate of methyl cis-7-~2-t3-hydroxy-4J4-dimethyloctyl)-5-oxocyclopentyl]-5-heptenoate, has Rf of about 0.37 on thin layer plates of silica gel when using ethyl acetate-benzene tl;4) as the mobile phase.
.
,; ~ . .......................................................... .
.~ -
R _ _ 44 18 CH3 dimethyl trans-l-(carbo-methoxymethyl)-5-(4-ethyl-3-hydroxy-1-heptenyl) lg C21-15 diethyl trans-l-(carbo-ethoxymethyl)-5-(3-hydroxy-4-propyl-1-nonenyl) 46 20 C113 dimethyl trans-l-~carbo-methoxymethyl)-5-(4-ethyl-3-hydroxy-1-decenyl) 47 21 C2H5 diethyl trans-l-(carbo-ethoxymethyl)-5-(3-hydroxy-. 4-methyl-1-heptenyl) 15 48 22 C11~ dime~hyl trans-l-(carbo-methoxymethyl)-5-(3-hydroxy-4-methyl-1-nonenyl) 49 23 C2H5 diethyl trans-l-(carbo-ethoxymethyl)-5-(4-ethyl-3-hydroxy-1-octenyl) 24 CH3 dimethyl trans-l-(carbo-methoxymethyl)-5-(4-methyl-3-hydroxy-1-decenyl) 51 25 C2H5 diethyl ~rans-l-(carbo-ethoxymethyl)-5-(3-hydroxy-4-propyl-1-heptenyl) 52 26 CH3 dimethyl trans-l-(carbo-methoxymethyl)-5-(3-hydroxy-4-ethyl-1-nonenyl) .
53 27 n~C3~l7 dipropyl trans-l-(carbo-propoxymethyl)-5-(3-hydroxy-4~4-dime~hyl-1-decenyl) _ __ _~___ , .. _ ________ ~ A~IP-63()~
TABLE~ 111 _ ________. _ ~
_ NO. OF EXAMPLE
:[N WHlC~I Sl'ARTING STAR'I'ING
MATERIAL 01: ~TERlAL OF PRODUCT: (PREFIX LISI`ED
FORMULA 1 ~ORMULA 2 ~LQ~)-2-oxo-l~3-cycL()~
Ex. IS DESCRIB~D - R3 ~ - PENTANEDICARBOXYLATE
.. ____ _ 54 28 n C3 ~17 dipropyl trans-l-(carbo-propoxymethyl)-5-(4-ethyl-3-hydroxy-4-methyl-. l-decenyl) 29 CH dimethyl ~rans-l-(carbo-3 methoxymethyl)-5-(3-hydroxy 4-methyl-4-propyl-1 hyptenyl) 56 30 C 11 diethyl trans-l-(carbo-2 5 ethoxymethyl)-5-(3-hydroxy-4,4-dipropyl-1-nonenyl) 57 ' 32 CH dimethyl trans-l-(carbo-3 methoxymethyl)-5-(3-hydroxy-3-methyl-1-heptenyl) 58 33 C2~15 diethyl trans~l-(carbo~-ethoxymethy1)-5-(3-ethyl-3-hydroxy-l-nonenyl) 59 34 CH3 dimethyl trans-l-(carbo-methoxymethyl)-5-(3-hydroxy-3-propyl-1-decenyl) C2~15 diethyl trans-l-(carbo-ethoxymethyl)-5-(3-hydrocy-3,4-dimethyl-1-heptenyl) 61 36 CH3 dimethyl trans-l-~carbo-methoxymethyl)-5-(3-ethyl--3-hydroxy-4-methyl-1-nonenyl) 62 37 C }I diethyl ~rans-l-(carbo-2 5 athoxymethyl)-5-(4-ethyl-3-hydroxy-3-propyl-1-octenyl) 63 38 CH3 dimethyl trans-l-(carbo-methoxymethyl)-5-~3-hydroxy 3,4-dimethyl-1-~ecenyl) 64 39 C }I diethyl trans-l-(carbo-2 5 ethoxymethyl)-5-(3-e~hyl-3-hydroxy-4-propyl-1-heptenyl) C113 ~imethyl t_ ns-l-(carbo-metlloxymetllyi) _ 5-(4-ethyl-3-hy(lroxy-3-propyl-1-noneny:L) _ _ _ AhP-6304 trans-2-(3-HYdroxY-I-octenYI)-5-oxocYclopentan~acetic acid (4:-R , R . R and R6 = H and n = 3) - A suspension of dimethyl trans-l-(carbomethoxymethyl)-5-(3 hydroxy-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate (26.24 9), described in Example 42, in a solution of sodium hydroxide (12 9) in 70 ml of water and 80 ml of methanol is heated at reflux for 2 hr.
The reaction mixture is cooled, acidified to pH 6 with 2N HCI. The resulting oil is extracted with ether. The ether extract i5 washed with water, dried (MgS04) and the solvent removed. The residue is subjected to chromatography on silica gel (850 9). Elution with methanol-chloroform (1:9) yields the title compound, vmax 3350, 1727 cm . The corresponding methyl ester of the title compound, prepared by treatmenf with diazomethane,has vmaxm 3412, 1737 cm 1.
~y following the procedure of Example 66 and using the appropriate cyclopentanonetriester of formula 3, for example those described in Examp~es 43 to 65, other compounds of formula 4 are obtained.
For example, the use of the cyclopentanonetriester of formula 3, dimethyl trans-1-(carboethoxymethyl)-5-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate, described in Example 43, in the procedure of Example 66, gives trans-2-(3-hydroxy-3-methyl-1-octenyl)~5-oxocyclo-pentaneacetic acid, vmaxm 3350, 1727 cm 1, Likewise, the use of dimethyl trans-1-(2-carbomethoxymethyl)-5-(3-hydroxy-4,4-dimethyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate, described in Example 43, gives trans-2-(3-hydroxy-4,4-djmethyl-1-octenyl)-Y oxocyclop~ntaneocetic ecid, ~mex 3355, 1729 cm , ~ i AHP-o304 ....... .
. - , q, Further examples of such compounds of formula 4 are .
Iisted in Table IY to~ether with the requisite cyclopentanonetri-esters starting material, the latter compound being noted by the example describing its preparation.
~ AHP-6304 - TABLE IV
_ , .. ~ ...... __... ~
. NO. OF EXAMPLE IN WHICH
. CYCLOPENTANONETRIESTER
EX~PLEOF FORMULA 3 IS PREPARED PRODUCT:
67 44 trans-2-(4-ethy1-3-hydroxy-1-heptenyl)-5-oxocyclopentaneacetic . . acid 58 45 trans-2-(3-hydroxy-4-propyl-1-. . . nonenyl)-5-oxocyclopentaneacetic acid 10 . 69 46 trans-2-(4-ethyl-3-hydroxy-1-decen-. . yl)-5-oxocyclopentaneacetic acid 47 trans-2-(3-hydroxy-4-methyl-1-hepten-yl?-5-oxocyclopentaneacetic acid 71 48 trans-2-(3-hydroxy-4-methyl-1-nonen-~ yl)-5-oxocyclopentaneacetic acid .
72 49 trans-2-(4-ethyl-3-hydroxy-1-octen-: . yl)-5-oxocyclopentaneacetic acid 73 50 trans-2-(4-methy1-3-hydroxy-1-decen-. . yl)-5-oxocyclopentaneacetic acid 74 51 trans-2-(3-hydroxy-4-propyl-1-hepten-. yl)-5-oxocyclopentaneacetic acid . 75 , 52 trans-2-(3-hydroxy-4-ethyl-1-nonen-. yl)-5-oxocyclopentaneacetic acid 76 53 trans-2-(4,4-dimethyl-3-hydroxy-1-. decenyl)-5-oxocyclopentaneacetic acid 77 54 trans-2-(4-ethyl-4 methyl-3-hydroxy-I-decenyl)-5-oxocyclopentaneacetic ; acid . 78 55 trans-2-(4-methy1-3-hydroxy-4-propyl)-. . 1-heptenyl)-5-oxocyclopentaneacetic 79 56 trans-2-(3-hydroxy-4,4-dipropyl-1-nonenyl)-5-oxocyclopentaneacetic acid ~0 57 trans-2-(3-hydroxy-3-methyl-1-.. _ ~.__' .'.. ' : -55-.
~ AHP-6304 ,................ .
TABLE IV
NO. OF EXAMPLE I N WHICH ~ ~........... _ ._ CYCLOPENTANONETRIESTER
EXAMPLE OF FCR~`1ULA 4 !S_PREPARED- -- P~ODUCT: _ 81 58 trans-2-(3-ethy1-3-hydroxy-1-nonenyl)-5-oxocyclopentaneacetic acid 82 59 trans-2-(3-hydroxy-3-propyl~l-decenyl)-. 5-oxocyclopentaneacetic acid 83 60 trans-2-(3-hydroxy-3,4-dimethyl-1-. . . he.ptenyl)-5-oxocyclopentaneacetic acid 84 61 trans-2-(3-ethy1-3-hydroxy-4-methyl-1-. . nonenyl~-5-oxocyclopentaneacetic acid 62 trans-2-(4-ethy1-3-hydroxy-3-propyl-1-octenyl)-5-oxocyclopentaneacetic acid 86 63 trans-2-<3-hydroxy-3,4-dimethyl-1- .
. decenyl)-5-oxocyclopentaneacetic acid 87 64 trans-2-(3-ethyl-3-hydroxy-4-propyl-1-. : heptenyl)-5-oxocyclopentaneacetic acid a8 65 trans-2-(4-ethyl-3-hydroxy-3-propyl-i-. I nonenyl)-5-oxocyclopentaneacetic aci~
~ .~ -.' . ' ~ ' ~, .
. . .
. .
. .. .... ... . . . ..
_ ~ ~ -, AHf'-6304 -. . .
, trans-2-r3-r(Tetrahydro~yran-2-yl~oxyl-1-octenyll-5-oxo-cyclopen-taneacetic acid (4 R2 = tetrah~dropYran-2-YloxY.
R4 R5 and R6 = H and n - 3) To a solution of trans-2-(3-hydroxy-1-octenyl)-5-oxocyclopentane-acetic acid (4.7 9), described in Example 66, in methylene chloride (20 ml) at -20 i5 added dihydropyran (1.61 9? and p-toluenesulfonic acid (0.04 9). The mixture is stirred at that tem~erature for 30 ~ minutes. A further qunatity of P-toluenesulfonic acid (0107 g) is 10 added and the mixture maintained at the same temperature for I hr.
- The reaction mixture is diluted with ether, washed with water, dried (M9504) and the solvent removed. The residue is passad through a co!umn of silica gel (300 9) in a solution of 5~ methanol-chloroform.
The eluate is concentrated to give the title compound, vmaxm 1727 cm 1, 15 nmr (CDC13) ~ 0.88 (t, 3H), 4.69 (m, IH), 5.5 tm, 2H).
-~ ~ In the same manner but using an equivalent amount of one of the other compounds of formula 4 (R2 = H), for example the compound listed in Examples 67 to 81~ instead of trans-2-(3-hydroxy-1-octenyl)-5-oxocyclopentaneacetic acid, then the corresponding tetrahydropyranyl ether compound of formula 4 (R2 = tetrahydropyran-2~yl) is obtained;
for example, the use of trans-2-(3-hydroxy-4,4 dimethyl-1-octenyl)-5-- oxocyclopentaneacetic acid, described in Example 66, gives trans-2-{4,4 di~ethyl-3-[(tetrahydropyran-2-yl)oxy]-1-octenyl}-5-oxocyclopentane-acetic acid, ~max 1727 cm 1.
, ' , .
,.,, : . . : . . .
:~ AHP-6304 , tran~-2 ~ Hydroxy-5-r3-r(tetrahyd~opvr~n-2-yl~oxv~ octenyl~,cyclo-pentaneacetic acid t5:-~ - tetrahYdroDYran-2-Yloxv. R ! R _and R = H and n = 3)_and trans-2~-hydroxy-5-~3-r(tetrahydropyran-2-y!)oxyl-l-octenyi~cyclopentaneacetic acid ~lactone (6: R = __ - tetrahydroDyran-2-yloxy R R5 and R = H and n_~ 3) _ To a solution of trans-2-{3-~(tetrahydropyran-2-yl)oxy]-1-octenyl~-5-oxocyclopentaneacetic acid (5.1 9), described in Example 89, in methanol (10 ml), cooled to -10, is added a solution of sodium (0.354 9) in methanol (5 ml). Thereafter, sodium borohydride (0.152 9) is added to the mixture. The mixture is stirred for I hr,-diluted with ether and rendered acidic wick cone. HCI to pH 4.5. The ether layer is separated.
Tha aqueous phase is extracted with fresh ether. The combined ether layers arc washed quickly with water, dried (MgS04) and concentrated to yield a mixture of the title compounds in about a 7:3 ratio by weight.
The two compounds can be separated by dissolving the preceding mixture in methylene chloride extracting the acid 5 into an aqueous alkaline solution, for example, 5~ Na2C03, and subsequent acidification thereof gives the title compound of formula 5~ ~malm 3200, 1700 cm nmr ~CDC13) ~ 0.88 (t, 3H), 4.7 (m, IH), 5.6 (m, 2H). The corresponding ~lactone _ is described below.
The preceding mixture of the title compounds (4.0 9) in methylene dTchloride (35 ml) and triethylamine (2.339 9) is cooled to -5 to -10.
A 501ution of methanesulfonyl chloride (i.44 9), in methylene chloride (i5 ml) is added dropwise. The mixture is stirred at that temperature for 45 mi~nutes. The mixturé is diluted with methylene chloride, washer with water (5X), dried (MgS04) and the solvent removed to yield a crude .
-5~-. . .
product which is poured through on a column of silica gel (250 9) in ethylacetate-benzene. Evaporation of the eluate gives the title compound of formula 6, v~fnaxm 1762, 1030, 1012 cm 1, nmr (CDC13) 4.68 (s, IH), 5001 (s, IH), 5.5 (m, 211).
8y following the procedure of Example 90 and using the ~ppropriate compound of formula 4, for example those described in Examples 66 to 89, other compounds of formulae 5 and 6 are obtained.
For example, the use of the compound of formula 4, tran -2-~3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentaneacetic acîd, described in Example 66, gives trans-2Cl-hydroxy-5-t3-hydroxy-3-methyl-1-octenyl)-cyclopentaneacetic acid, and its corresponding ~lactone, vmax 3400, 1765 cm . Likewise, the use of trans 2-(3-hydroxy-4,4-dimethyl-1-octenyl)-5-oxocyclopentaneacetic acid, described in Example 66, gives trans-2~-hydroxy-5- (3-hydroxy-4,4-dimethyl-1-octenyl)cyclopentaneacetic acid, and its corresponding ~lactone, ~max 3450, 1765 cm 1.
Further examples of the compounds of formula 5 and their corresponding ~lactones of formula 6, which may be prepared by the procedure of Example 90, are listed in Table V~ In each case the requisite starting material of formula 4 are noted by the example describing its preparation also in each case the corresponding tetrahydropyranyl ether of the starting material of formula 4 may replace the designated starting rnaterial.
, ~ ~ AHP-6304 . .. ~ , .. . . . . .
.
TABLE V
., NO. OF EXAMPLE IN WHICH PRODUCT: (PREFIX LISTED BELO
STARTING MATERIAL OF CYCLOPENTANEACETIC ACI~, 5 EXAMPLE FORMULA 4 IS PREPARED (AND CORRESPONDIN~ Y~LACTONE, 6)-91 67 trans-2~-hydroxy-5-(4-ethyl-3-hydroxy-1-heptenyl) 92 68 trans-2~-hydroxy-5-(3-hydroxy-4-propyl-1-. nonenyl) 93 69 trans-2~-hydroxy- 4 (4-ethy1-3-hydroxy-1-. . decenyl) 94 70 trans-Za-hydroxy-5-(3-hydroxy-4~methyl-1-heptenyl) 71 trans-2~-hydroxy-5-(3-hydroxy-4-methyl-1-. nonenyl) .
96 72 trans-2a-hydroxy-5-(4-ethyl-3-hydroxy-1-. octenyl) 97 73 trans-2~-hydroxy-5-(4-methy1-3-hydroxy-1-. decenyl) .
. 98 74 trans-2~-hydroxy-5-(3-hydroxy-4-propyi-1-. . he~ptenyl) 99 75 ~ trans-2~-hydroxy-5-(3-hydroxy-4-ethyl-1-nonenyl) iOO 76 trans-2a-hydroxy-5-(4,4-dimethyl-3-hydroxy-. I-decenyl~
101 77 trans-2~-hydroxy-5-(4-ethy1-4-methyl-3-hydroxy-l-decenyl) 102 78 trans-2~-hydroxy-5-(4-methy1-3-hydroxy-4 . propyl-l-heptenyl) 103 79 trans-2a-hydroxy-5-(3-hydroxy-4,4-dipropyl-I-nonenyl) - 104 80 t!ans-2~-hydroxy-5-(3-hydroxy-3-methyl-1- .
. heptenyl) 105 81 trans-2~-hydroxy-5-(3-ethy1-3-hydroxy-1-. .~ nonenyl) , . .
TABLE V
_ . NO. OF EXAMPLE IN WHICH PRODUCT: (PREFIX-L!STED BELOW)-. STARTINC MATERIAL OF CYCLOPENTANEACETIC ACID, ~, EXAMPLE FORMULA 4 IS PREPARED _ (AND CORRESPONDING ~-LACTONE. 6~
106 82 trans-2~-hydroxy-5-(3-hydroxy-3 propyl-I-decenyl) 107 83 trans-2~-hydroxy-5-(3-hydroxy-3,4-. dimethyl-l-heptenyl~
108 84 trans-2a-hydroxy-5-(3-ethy1-3-hydroxy-4-methyl-1-nonenyl) . 109 85 trans-2~-hydroxy-5-t4~ethyl-3-hydroxy-.10 3-propyl-1-octenyl) . 86 trans-2a-hydroxy-5 (3-hydroxy-3,4-di-methyl-l-decenyl) 87 trans-2~-hydroxy-5-(3-ethyl-3-hydroxy- .
4-propyl l-heptenyl) 112 88 trans-2~-hydroxy-5-(4-ethyl-3-hydroxy-3- .
propyl-l-nonenyl) 1 , ..
'~
. , .
" ~ ,' .
. - . =_ ~ .
-~ , trans-2a-Hydroxy-5-(3-hvdroxy-l-octenyl)cyclopentaneacetic acid y~__ctone (6; R2 R4, R5 and R6 = H and n = 3) trans-20~-Hydroxy-5-'3-~tetrahvdro~yran-2-vloxv~ octen cyclopentaneacetic acid ~lactone (2.0 g),describedin Example 90,isdis-solved in methanol (10 ml):and water(3.5 ml) containingp-toluenesulfonic acid (0.4 9). The mixture isstirred at room temperature for 30 minutes.
The soivent is removed under reduced pressure. The residue is shaken between water and ether. The ether layer is dried ~MgS04) and evaporated . to glve the title compound, ~max 3450, 1765 cm 1, The corresponding DMIS ether of the titla compound has vma;x 1765 cm 1.
, . .
.-_ ' . , ' trans-2a-Hydroxy-5-(3-oxo-1-octenyl)cyclopentaneacetic acid ~iactone (7: R and R5 = H and n =_3) A solution of trans-2a-hydroxy-5-(3-hydroxy-1-octenyl)-cyclopentaneacetic acid ~lactone (I.9 9), described in Example 113;
in chloroform in (60 ml) is stirred with activated magnanise dioxide ~14.9 9) at 40 (bath temperature ) for 15 hr~ The reaction mixture ;s filtered and the precipitate washed with hot chloroform. The combined chloroform solutions are evaporated. The residue is subjected to chromatography on silica gel using ethyl acetate-benzene (3:7) as eluantO Evaporation of the eluant gives the title compound, mp 36 -36.5C, ~CmaHXCl3 1755, 1635, 1625 cm 1.
- By following the procedure of Example 114 and using - the appropriate hydroxylactone of formula ~; for example, those of Examples 91 to 103, other compounds of formula 7 are obtained.
- For example, the use of tne compound of formula 6, trans-2a-hydroxy-5-(3-hydroxy-4,4-dimethyl-I-octenyl)cyclopentaneacetic acid lflactone, described in Example,90, gives trans-2a-hydroxy-5 t4~4-dimethyl-3-oxo-1-octanyl)cyclopentaneacetic acid ~-Iactoner ~f~im 1/65, 1680, 1620 cm Further examples of the compounds of formula 7 are listed in Table Vl. In each case the requisite starting material of formula 6 is noted by the example describing its preparation.
' .
' .
.
~ .
TABLE Vl _ _ . NO. OF EXAMPLE IN
. WHICH STARTING MATERIAL PRODUCT: (PREFIX LISTED 8ELOW)-. EXAMPLE. OF FORMULA 6 IS PREPARED CYCLOPENTANEACETIC ACID l~LACTONE
. . .. ,.. ~ .
115 91 trans 2~-hydroxy-5-(4-ethyl-3-oxo-1-heptenyl) 116 . 92 trans-2a-hydroxy-5-t3-oxo-4-propyl-1-. nonenyl) . 117 93 trans-2~-hydroxy-5-(4-ethyl-3-oxo-1-decenyl) . 118 94 trans-2~-hydroxy-5-(4-methyl-3-oxo-1-. . heptenyl) 119 95 trans-2~-hydroxy-5-(3-oxo-4-methyl-1-. . nonenyl) 120 96 trans-2a-hydroxy-5-(4-ethyl-3-oxo-1-. octenyl) 121 97 trans-2~-hydroxy-5-(4 methy1-3-oxo-1-. . decenyl) .
122. 98 , trans 2~-hydroxy-5 (3-oxo-4-propyl-1-. . heptenyl) 123 99- trans-2~-hydroxy-5-(4-ethy1-3-oxo-1-nonenyl~
124 100 trans-2~-hydroxy-5-(4,4-diemthyl-3-. oxo-l-decenyl) 125 iOI trans-2a-hydroxy-5-(4-ethyl-4-methyl-ZO 3-oxo-1-decenyl) . 12.6 102 t _ -2a-hydroxy-5-t4-methyl-3-oxo-. . . 4-propyl-1-heptenyl) 127 103 trans-2~-hydroxy-5-(3-oxo-4,4-dipropyl-. I-nonenyl) .
. ~
._ _- . ' ''.~ .
. AHP-6304 2 ydroxy-5-(3-oxooctyl)cyclopentaneacetic acid-~t~lactone (8: R4-and R5 = H and n = 3) A solution of trans-2a-hydroxy-5-(3-oxo-1-octenyl)cyclo-pentaneacetic acid l~lactone (5.0 9), described in Example 114, in methanol (100 ml) is hydrogenated in the presence of 10% palladium-charcoal (1.0 9) at 25. After the uptake of the theoretical amount of hydrogen, the catalyst is collected on a filter and the fiItrate is concentrated to yield the title compound, vmalm 1765, 1710 cm 1 By following the procedure of Example 128 and using the appropriate hydroxylactone of formula 7; other compounds of formula 8 are obtained.
For example the use of the compound of formula 7, trans-2a-hydroxy-5-(4,4-dimethyl-3-oxo-1-octenyl)cyclopentaneacetic acid 15 ~lactone, described in Example ! 14, gives 2a-hydroxy-5-(4,4 dimethyl-3-oxooctyl)cyclopentaneacetic acid l-lactone, ~maxm 1770, 1700 cm 1.
Further examples of the compound of formula a are listed in Table Vlll. In each case the requisite starting material of formula 7 is noted by the example in which is is prepared.
.~i A~P-6304 ,TABLE V I I .,,, .. .. ' .. ..... _ NO. OF EXAMPLE IN
. WHICH STARTiNG MATERIAL OF PRODUCT: (PREFIX-LISTED-BELOW)-._EXAMPLE FORMULA 7 IS PREPARED CYCLOPENTANEACETIC ACID ~LACTONE_ .
12~ 115 2a-hydroxy-5-(4-elhyl-3 . . oxoheptyl) 130 116 2~-hydroxy-5-(3-oxo-4-. . propylnonyl) 131 . 117 2a-hydroxy-5-(4-ethyl-3-. oxodecyl) 132 118 2a-hydroxy-5-(4-methyl-3 . . oxoheptyl) 133 119 2a-hydroxy-5-(4 methyl-3-oxononyl) 134 120 2a-hydroxy-5-(4-ethyl-3-. . . oxooctyl) 135. 121 2~-hydroxy-5-(4-methyl-3-. oxodecyl) . 136 122 2a-hydroxy-5-(3-oxo-4-: . propylheptyl) 137 123 2a-hydroxy-5-t4-ethyl-3-. oxononyl) 138 124 2~-hydroxy-5-(4,4-dimethyl- .
. .. 3-oxo-1-decyl) 13~ 125 . 2a-hydroxy-5-(4-ethyl-4 . . . me.thy1-3-oxodecyl) .- I~Q 126 2a-hydroxy-5-(4-methyl-3- . oxo-4-propylheptyl) 141 . 127 2~-hydroxy-5-(3-oxo-4,4-dipropylnonyl) .
v 2a-~ydroxy-5-(3-hydroxyoct~l)cycloDentaneacetic acid lactone (9: R2, R4. R5 and R6 = H and n - 3) By following the procedure of Example 17 but replacing ~iethyl trans-2-(4,4-dimethyl-3-oxo-1-octenyl~cyclopropane-1,1-dicarboxy-late with an equivalent amount of 2a-hydroxy-5-~-oxooctyl)cyclopentane acetic acid ~lactone, described in Example 128, the latter compound is reduced to give the title compound, ~maxm 3400, 1770 cm 1~
. The title compound is also obtained by -the procedure of 10. Example 165.
By follo~ing the procedure of Example 142 and using the appropriate compound of formula 8, for example those 7n Examples 129.
to 141, other compounds of formula 9 in w~ich R~ is hydrogen~ are ~ obtained.
For exampleithe use of the compound of formula 8, 2a-hydroxy-5-~4,4-dimethyl-3-oxooctyl)cyclopentaneacetic acid ~-lactone, described - in Example 128, gives 2a-hydroxy-5-~3-hydroxy-4~4-dimethyloctyl) pentaneacetic acid ~-lactone.
Further examples of the compound of formula 9 in which R
is hydrogen are listed in Table Vlll. In each case the requisite `- starting material of formula is noted by the example in which it is prepared, 'I .
~ -67-.
. .
, . ' ! , .
.
. TABLE Vlll . ... .,.___ . . I
NO. OF EXAMPLE IN WHICH PRODUCT: (PREFIX LISTED 8ELOW)-STARTING MATERIAL OF CYCLOPENTANEACETIC ACID, 5 . EXAMPLE _ FORMULA 4 IS PREPARED (AND CORRESPONDING ~LACTONE~ 6) 143 136 2a-hydroxy-5-(3-hydroxy-4-pr . heptyl) 144 137 2a-hydroxy-5-( 4ethyl-3-hydroxy-. nonyl) 145 138 2~-hydroxy-5-(4,4-dimethy1-3-hydroxy-l-decyl) 146 139 ~ 2a-hydroxy-5-(4-ethy1-3-hydroxy-4-methyldecyl) 147 1~0 2a-hydroxy-5-(3 hydroxy-4-methyl-. 4-propylheptyl) 148 141 2a-hydroxy~5-(3-hydroxy-4~4 ¦ . ~ ' dipropy nonyl) . , .' :
. .
_... .. _ .. ___ ... ' _ i ., : ' .. . .
- 2X-Hydroxy-5-(3-hydroxy-3-methyloctyl)cycloDentaneaceticacid ~-lactone (9: R R _and R = H~ R = CH~ and n - 3) . A solution of 2a-hydroxy-5-(3-oxooctyl)cyclopentaneacetic acid l-lactone (6.66 9), described in Example 128, in ether (100 ml) is treated dropwise with the lower alkyl magnesium halide, methyl - magnesium iodide ~1.5 molar in ether, 33 ml) while keeping the reaction temperature at 0. The Grignard complex is then decomposed with 10% ammonium chloride solution. The reaction mixture i-s extracted with ether, washed with brine, dried (Na2S04) and concentratad.
The residue in ethyl acetate-benzene (2:8) is poured through a column of silica gel. Evaporation of the eluate gives the title compound, nmr (CDC13) ~ 0.9 (t, J = 5, 3H), 1.13 (s, 3H1, 1.67 - (b, IH), 2.33 and 2.71 ~m, 2H~, 500 (m, IH).
By following the procedure of Example 149 and using the appropriate compound of formula 8, for example, those described in Examples 129 to 137, together with the appropriate lower alkyl magnesium halide, other-compounds of formula 9 are obtained.
Furtber ex:mples of the compound of formula _ are listed in Table IX. In each case the requisite starting material of formula a is notFd by the examp!e in which it is prepared.
. ~ .
A~IP- 6304 TABLE IX
. . _ ...... _ , PRODUCT: (PREFIX LISTE~
. NO. OF EXAMPLE IN '~IHICH ~ELO'.l)-CYCLOPENTA~EACETIC
STARTING MATERIAL OF LOWER ALKYL ACID, 5 (AND CORRESPONDING
. EXAMPLE FORMULA 8 IS PREP.:RED MAGNESIUM HALIDE yrLAcToNE~ 6 150 129 CH3Mgl 2~-hydroxy-5-(4-ethyt-3-hydroxy-3-methylheptyl) 151 130 C2H5M93r 2~-hydroxy-5-(3-ethyl-3-. hydroxy-4-propylnonyl1 15Z 131 n-C3H7MgCI 2~-hydroxy-5-(4-ethyl-3-hydroxy~3~propyldecyl) . . .
O 153 132 2 5 9 2~-hydroxy-5-(3-ethy1-3-hydroxy-4-methylheptyl) . 154 133 CH3Mgl 2a-hydroxy-5-(3-hydr : 3,4-dimethylnonyl) 155 134 2 5 9 2a~hydroxy-5-(3J4-. diethy1-3-hydroxyoctyl) : 156 135 n-C3H7Mgl 2a-hydroxy-5-(3-hydr ¦ ~ ¦ 4-methyldecyl~
I' '. . .
~:' .
, ' ...... . ,, ., ....... ..... ,....... ... ....
.. _ . _ .
7~
, : EXAMPLE 157 . trans-2a-Hvdroxv-5-(3-hYdroxv-3-methyl-1-octenYl)cycloPentane-acetic acid ~lactone (12: R _L R and R = H, R = CH ~ 3) By fol lowing the procedure of Example 1499 but replacing 2~-hydroxy-5-(3-oxooctyl)cyclopentaneacetic acid ~!actone, with an equivalent amount of trans-2~-hydroxy-5-(3-oxo-1-octenyl)cyclopentane-acetic acid ~lactone, described in Example 114, ~he titie compound is obtainedJ ~ma~xm 3420, 1770 cm 1, nmr (CDC13) ~ 0.3 (t, J ~ 5, 3H), 1.26 (3H), 1.7 (IH), 5.05 (m, IH~, 5.65 (m, 2H).
By following the procedure of Example 157 and using the appropriate compound of formula 7, for example, those described in Examples 115 - 123, together with the appropriate lower alkyl magnesium halide, other compounds of formula 12 are obtained.
Further examples of the compound of formula 12 are listed in Table X- In each case the ~quisite starting material of formula is noted by the example in which it is prepared.
.
a .
TABLE X
.... . ... . .. .... ..
PRODUCT: (PREFIX LISTED
. NO. OF EXAMPLE IN WHICH BELOW)-CYCLOPENTANEACE-rlC
. . STARTING MATERIAL OF LOWER MAGNESIUM ACID,.5 (AND CORRESPONDING
EXAMPLE FORMULA 7 IS PREPAREDHALIDE ~LACTONE. 6-158 115 CH3MgBr trans-2a-hydroxy-5-(4-. ethyl-3-hydroxy-4-propyl-1-. nonenyl) 159 116 C2H MgBr trans-2a-hydroxy-5-(3-. . 5 ethy1-3-hydroxy-4- .
. propyl-l-nonenyl) : 160 117 n-C3H7MgCI trans-2a-hydroxy-5-(4-. ethyl-3-hydroxy-3-. propyl-l-decPnyl) i61 118 C2H5M9CI trans-~-hydroxy-5-(3-. ethy1-3-hydroxy-4-. . . methyl-l-heptenyl) 162 119 CH3 9 trans-2~-hydroxy-5-(3-. hydroxy-3,4-dimethyl-1-. . -. nonenyl) 163 120 C2H5M91 trans-2a-hydroxy-5-(3,4-diethyl-3-hydroxy-1-. . . ~ l octenyl) -. 164 - 121 3 9 trans-2a-hydroxy 5-(3-. hydroxy-3,4-dimethyl-1 j ~ decenyl~
.~', ~ ' : ~ ~, . . :..
" ' . ~
.
;' '., _____ ~_ '_' ' .
. ;' .
2~-Hy _oxy-5-(3-hydr_~y~tyl)cyclopen-taneace-tic acid ~-lact n _(g, R , _ ~ and R = H and n = 3 The ti-tle compound is obtained, in addition to the procedure of Example 142, by hydrogenation of the compound of formula 6 (R = H), trans-2~-hydroxy-5-(3-hydroxy-1-octenyl)cyclo-pentaneacetic acid ~-lactone, described in Example 113, by the procedure of R. D. Hoffsommer, et al, Te-trahydron Le-tters, 4085 (1971), using Raney nickel in dioxane.
By following the procedure of Example 165 and using the appropriate compound of formula 6 (R6 = H), for Example -those described in Examples 90 to 112, other corresponding compounds of formula 9 (R = H) are obtained.
Further examples of the compounds of formula 9 are listed in Table XI. In each case -the requisite star-ting material of iormula 6 is noted by the example in which it is prepared.
;
' ~ -73-~ HP-6304 .~ . . ..
. TABLE Xl , . , ~
NO. OF EXAMPLE IN WHICH PRODUCT: (PREFIX LISTED BELOW)-STARTING MATERIAL OF CYCLOPENTANEACETIC ACID, 5 -EXAh1PLE FORMULA 4 IS-PREPARED - (AND_CORRESPONDING ~LACTO~IE. 6~
166 99 2a-hydroxy-5-(3-hydroxy-4-ethylnonyl) 167 100 2~-hydroxy-5-(4,4-dimethyl-3-hydroxydecyl) 168 101 2a-hydroxy-5-(4-ethy1-4-~ethyl-3-. hydroxydecyl) 169 102 2a-hydroxy-5-(4-methyl-3-hydroxy-4 . propylheptyl) 170 103 2~-hydroxy-5-(3-hydroxy-4,4-dipropyl-nonyl~
171 104 2~-hydroxy-5-(3-hydroxy-3-methyIheptyl) 172 108 2x-hydroxy-5-(3-ethyl-3-hydroxy-4- . . methylnonyl) 173 109 2a-hydroxy-5-(4-ethy1-3-hydroxy-3-15 ¦ ,ropylcctyl~ .
. ~- , . `
-~- . . .
~ - ' : ; .
;
.
:
' ~ AHP-6304 , , ., ~ . - . " ~ . . . .. .
'~3~
.
Hexahydro-2-hydroxy-4-E3-(dimethyl-terf-butylsiIyloxy)-l-octenyll-2H-cyclopentarblfuran (13 _R?. R , R and R = H
and n = 3) - A solution of the compound of formula _, trans-2~-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentaneacetic acid ~-lactone, in the form of its dimethyl-tert-butylsilyl ether, (6.66 9), described in Example 113, in dry toluene t40 mll is cooled to -75C. As solution of diisobutyl aluminum hydride (3.9 9 in 10.8 ml. of hexane) is added by syr7nge under a nitrogen atmosphere. The mixture is stirred afor 15 minutes at that temperature and then diluted with ether, washed with water. The gelantinous aluminum salts are removed by fiItration. The fiItrate is washed with water (2X), dried (MgS04) and the solvent is removed to give the title compound, ~ 3360 cm , nmr (CDC13) ~ 4.02 (m, IH)J 4.63 (m, IH~, 5.42 (m, 2H).
: .
, .
' ` ' .
..
.
~7:~L6~Z
trans, cls-7-(2~-H droxy 5-(3-hydroxy-1-oc-tenyl)cyclopentyl)-5-he~tenoic acid (11; R2, R4, R5, R6 and R7 = H
X = OH, Y = H, Z = trans CH = CH, m __3 and n 3) __ To a suspension of sodium hydride (7.42 g, 57% in oil) washed with hexane, is added dry dimethyl sulfoxide (45 ml). The mixture is heated to 75 - 80 (bath temperature) for one hour. sy this all the sodium hydride has reacted. The mixture is cooled. A solution of the phosphonium bromide, (39.0 g) derived from triphenylphosphine and ~ -bromo pentanoic acid, in dry DMSO (90 ml) is added gradually to the solution of sodio methylsulfinyl carbanide; followed by the addition of a solution of the hemiacetal of formula 13, hexahydro-2 ¢hydroxy-4-(3-(dimethyl-tert-butylsilyloxy)-1-octenyl)-2H-cyclo-penta(b)furan (5.42 g), described in Example 174, in dry dimethyl-sulfoxide (15 ml). The mixture is stirred overnight at roomtemperature. The reaction mixture is diluted with water, acidified with acetic aid (5 ml), and extracted with ether. The ether extract is washed with water, dried (Na2S04) and the solvent is removed. The residu is passed through a column of silica gel (40Q g) using ether-hexane (1:1) as eluant. Evaporation of the eluate gives the corresponding dimethyl-tert-butylsilyl ether of the title compound,~malm 3470, 1710 cm lo Removal of the hydroxy protecting group:
The latter compound (4.1) g is dissolved in methanol (20 ml) and water (7 ml) containing p-toluene sulfonic acid (0.4 g). The reaction mixture is stirred for 30 minutes, the solvent is removed under reduced pressure. The residue is extractèd with ether. The extract is washed with water, dried (MgS04) the solvent is evaporated.
Purification by ~ Al-IP-6304 chromatography o~ the resi~u~ (SiO2, benzene-ethyl ace-tate ~9:1)) gives the title compound as a mix~ure of stereochemical isomers with respect to the asymmetric carbon atom in the side chain -to which the hydroxyl is attached. The mixture has vfilm 3480, 1700 cm nmr (CDC13) ~ 0.87 (m, 3H), ~.18 (m, 2H), 5.45 (m, 4fl), identical to the mixture of the s~me name described in U.S. Patent No. 3,849,474, issued November 19, 1974.
By following sequentically the procedure of Example 174 and 175, and using the appropriate compound of formula G or 9, for example, those of Examples 90 to 112 other prostaglandin derivatives of form~lla 11 are obtained.
For example the use of the compound of forn~ula 6, trans-2~-hydroxy-5-l3-hydroxy-3-methyl-1-octenyl)cyclopentaneacetic acid y-lactone, described in Example 9O, gives trans,cis-7-(2~-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl)-5-heptenoic acid, described in U.S. Patent No. 3,917,668, issued November 4, 1975, via the intermediate hemiacetal of formula 13, hexahydro-2-hydroxy-4-{3-((tetrahydropyran-2-yl)oxy)-1-octenyl}-2H-cyclopentan~b)furan, vnf~axn' 3350 cm~l.
Likewise, the use of 2~-hydroxy-5-~3-hydroxyoctyl)-cyclopentaneacetic acid ~-lactone, described in Example 142, gives cis-7-~2~-hydroxy-5-~3-hydroxyoctyl)cyclopentyl)-5-heptenoic acid, nmr ~CDC13) 6 9.O ~t, J = 5, 3H), 3.65 ~m, 1H)J 4.25 (m, lH), 4.9 (s, 3H), 5.5 (m, 2H), via the intermediate hemiacetal of formula 10, hexahydro-2-hydroxy-4-(3-(dimethyl-tert-butylsilyloxy)octyl)-2H-cyclo-penta~b)furan, vmiaxm 3360 cm 1.
Al-lP-6~04 I,ikewise, the use of 2~-hydroxy-5-(3-hydroxy-3-methyloctyl)-cyclopentaneace-tic acid y-lactone, ~escribed in Fxample 149, gives ClS-7- (2~-hydroxy-5-t3-hydroxy-3-methyloctyl)cyclopentyl)-5-heptenoic acidJ nmr (CDC13) ~ 0.9 (t, J ~ 5, 3fl), 1-2 (S, 3H), 1.5 ~s, 2H)~ 4-2 ~ (m, 11l), 5.5 (m, 2H), via the intermediate hemiacetal of formula 10, hexahydro-2-hydroxy-4-(3-hydroxy-3-methyloctyl)-2H-cyclopenta(b)furan, Vfilm 3355 Cm-l max Likewise, the use of 2~-hydroxy-5-(3-hydroxy-4,4-dimethyl-octyl)cyclopentaneacetic acid ~-lactone, described in Example 142, gives ClS-7- (Z~ hydroxy-5-(3-hydroxy-4,4-dimethyloctyl)cyclopen-tyl)-5-heptenoic acid, via the intermediate hemiacetal of formula 109 hexahydro-2-hydroxy-4-~3-(dimethyl-tert-butylsilyloxy)-4,4-dimethyloctyl}-2H-cyclopenta-(b)furan, vfixm 3350 cm 1 and the corresponding dimethyl tert-butylsilyl ether of ClS-7- (2G~-hydroxy-5-(3-hydroxy-4,4-dimethyloc-tyl)cyclopen~yl)-5-heptenoic acid has vfaxn~ 3350, 3260 cm 1.
Further examples of the compound of formula 11 are listed in Table Xll. In each case the requisite starting material of formula 9 is noted by the example in which it is prepared.
~IP-6304 TABLE X]l , . ... I
NO. OF FOI~ULA
EX~MPLE lN
WHICH STARTIN~ ( ~ )3-P C~l- PRODUCT:
EX. IS PREPARED (C112)mC ~ Br m R
_ _ _ _ 176 143 3 H ClS-7- (2~-hydroxy-5-(3-hydroxy-4-propylheptyl)cyclopentyl)-5-heptenoic acid 177 144 2 H cis-6-(2~-hydroxy-5-(4-ethyl-3-hydroxynonyl)cyclopentyl)-4-hexenoic acid 178 145 111 cis-5-(2~-hydroxy-5-(4,4-di-methyl-3-hydroxy-1-decyl)cyclo-pentyl)-3-pentenoic acid 179 146 2C}13 cis-6- (2~-hydroxy-5-(4-ethyl-3-hydroxy-4-Dlethyldecyl)cyclo-pentyl)-4-hexenoic acicl methyl ester 180 147 3ll cis-7-(2~-hydroxy-5-(3-hydroxy-4-methyl-4-propylheptyl)cyclo-pentyl)-5-heptenoic acid 181 148 2C2H5 cis-6-(2~-hydroxy-5-(3-hydroxy-4,4-dipropylnonyl)cyclopentyl)-4-hexenoic acid ethyl ester 182 150 3 H ClS-7- (2~-hydroxy-5-(4-ethyl-3-hydroxy 3-methylheptyl)-cyclopentyl)-5-heptenoic acid 183 151 2n C3H7 ci.s-6- (2~-hydroxy-5-(3-e~hyl-3-hydroxy-4-propylnonyl)cyclopent~
yl)-4-hexenoic acid propyl este~
184 152 1 H cis-5-(2~-hydroxy-5-(4-ethyl-3-hydroxy-3-propyldecyl)cyclo-pentyl)-3-pentenoic ~cid _ __._.__ .. __ ~
~IIP-~J30 TABLL Xll __ ....
EXAMPLE IN l ORMULA
WHICH STARTING
MATERIAL OF ( ~ ~-P -CH- PRODUCT:
FORMULA 9 ~
EX. IS PREPARED (Cll2)mCOOR7 Br m - R7 _ 185 153 2 CH3 cis-6- (2~-hydroxy-5-~3-ethyl-3-hydroxy-4-methylheptyl~-cyclopentyl)-4-hexenoic acid methyl es~er 0 186 154 3 H cis-7-(2~-hydroxy-5-(3-hydroxy-3,4-dimethylnonyl)cyclopentyl)-5-hexenoic acid 187 155 2 H cis-6- (2~-hydroxy-5-(3,4-di-ethyl-3-hydroxyoctyl)-cyclo-pentyl)-4-hexenoic acid 188 156 1 CH3 cis-5-(2~-hydroxy-5-(3-hydroxy-4-methyldecyl)cyclopentyl)-3-pentenoic acid methyl ester - ~0-~ AHP 6304 .
cis-7-~2-(3-hYdrox~ imethylocty ! )-5-oxocyclopentyll-5-heptenoic ac7d (II; R I R6 and R7 - H, R and R5 = CH~L_X
and Y = O; Z = CH~CH_ m = 3 and n = 3) To a solu+ion of cis-7-~2a-hydroxy-5-~3-(dimethy~+ert-butyl-- silyloxy)-4,4-dimethyloctyl]cyclopentyl}-5-heptenoic acid (0.817 9), described in-Example 175, in acetone (10 ml), cooled to -10, 0075 ml of Jones' reagent [chromic acid in acetone containing a trace of sulphuric acid, see E. R. H. Jones, et al., J. Chem. SocO, 2548 (1953)] is ~dded. After stirring for 10 minutes the excess reagent is destroyed wiTh methanol. The reaction mixture is diluted with water and extracted with etherO The extract is washed with water, dried (Na2S04) and the solvent removed to yield cls-7-{2-[3-(dimethyl-tert-butyl-silyloxy)-4~4-dimethyloctyl]~5-oxocyclopentyl~-5-heptenoic acid, ~ 15 vmax 1730, 1710 cm 1.
~ . The latter compound is deprotected by treatment with æ-toluene-sulfonic acid in aqueous methanol according to the procedure of Example 175 to.give the title compound vmax 3470, 1730, 1710 cm 0 In the same manner but replacing cls-7-r2~-hydroxy-5-[3-(dimethyl isopropylsi Iyloxy)-4,4-dimethyloctyl]cyclopentyl}-5- heptenoic.acid by the appropriate compound of formula 11 in which X and Y are hydroxy and hydrogen, respectively, other corresponding compounds of formula It in which X and Y are oxo are obtained. Note protection of the hydroxyl on the side chain is not required when it is a tertiary alcohol (iOeO, R
lower alkyl).
,j .
, . . .- . . _ ~ A~IP-630~
For example, in the same mann~r, but replacing cls-7-~2~ hydroxy-5-(3-~dimethyl-t~rt-butylsilyloxy)-4,4-climethyloctyl~cyclopentyl}-5-heptenoic acid, with cis-7-f2~-hydroxy-5-(3-(dimethyl-tert-butylsilyloxy)octyl)cyclo-pentyl~-5-heptenoic acid, described in Example 175, cis-7-~2-(3-hydroxy-octyl)-5-oxocyclopentyl)-5-heptenoic acid, nmr (CDC13) ~ 0.9 (t, J - 5, 3H), 3.7 (m, lH), 5.42 (m, 2H), 6.6 (s, 2H), is obtained.
Likewise, replacement with cis-7-(2~-hyd~oxy-5-(3-hydroxy-3-me~hyloctyl)cyclopentyl)-5-heptenoic acid, described in Example 175 gives cis-7- t2-~3-hydroxy-3-methyloctyl)-5-oxocyclopentyl)-5-heptenoic acid, nmr (CDC13) ~ 0.9 (t, J = 5, 3}1), 5.42 (mJ 2H), 6.5 (s, 2H).
Furthermore if desired a compound of formula 11 (R6 = H) may be separated into its two epimers with respect to the asymmetric carbon atom bearing the hydroxy group. This separation is effected preerably by converting the aforementioned compound to its corresponding methyl ester using methanol in the presence of a acid catalyst, for example, 2% perchloric acid, and subjecting the ester to chromatography on S.02 use benzene-ethyl acetate (9:1) as eluant. In this manner the epimers are separated. These isomers are arbitrarily designated as isomers A
(least polar isomer~ and isomer B (more polar isomer); ~he polarity being determined by the order in which they are eluted. Thereafter the epimers may be hydrolyzed with 5~ sodium hydroxide in aqueous methanol for 15 minutes at 30 to 40 to give the corresponding acid.
For example, by the preceding method the epimers of the ~itle compound are obtained, Isomer A has Vmfalm broad hydroxyl, 1725 - 1730 cm 1, and Isomer B has vfalm broad hydroxyl, 1725 - 1730 cm 1.
~ AHP-6304 ,, ~j~;, The corresponding methyl esters of the preceding Isomers A
and B have the following characteristics:
Isomer A, a racemate of methyl cis-7-~2-(3-hydroxy-4,4-dimethyioctyl)-5-oxocyclopentyl]-5-heptenoate, has RT of about 0.47 on thin layer plates of silica gel when using ethyl acetate-benzene (1:4) as the mobile phase~
Isomer 8, a second racemate of methyl cis-7-~2-t3-hydroxy-4J4-dimethyloctyl)-5-oxocyclopentyl]-5-heptenoate, has Rf of about 0.37 on thin layer plates of silica gel when using ethyl acetate-benzene tl;4) as the mobile phase.
.
,; ~ . .......................................................... .
.~ -
Claims (10)
1. A process for preparing a compound of formula 4 4 in which R2 is hydrogen or a hydroxy protecting radical, R4, R5 and R6 each are hydrogen or lower alkyl and n is an integer from two to five, with the provisos that at least one of R4, R5 or R6 is hydrogen and that R2 is hydrogen when R6 is lower alkyl, which comprises:
subjecting the cyclopentanone of formula 3 3 in which R1 and R3 each is lower alkyl, R2 is hydrogen and R4, R5, R6 and n are as defined herein to base treatment in the presence of water, followed by acidification of the basic reaction mixture to obtain the corresponding -ketoacid of formula 4 4 in which R2 is hydrogen and R4, R5, R6 and n are as defined herein, and if desired, followed by converting the .gamma.-ke-toacid 4 in which both R2 and R6 are hydrogen to its corresponding hydroxy protected derivatives of formula 4 in which R2 is a hydroxy protecting radical and R6 is hydrogen.
subjecting the cyclopentanone of formula 3 3 in which R1 and R3 each is lower alkyl, R2 is hydrogen and R4, R5, R6 and n are as defined herein to base treatment in the presence of water, followed by acidification of the basic reaction mixture to obtain the corresponding -ketoacid of formula 4 4 in which R2 is hydrogen and R4, R5, R6 and n are as defined herein, and if desired, followed by converting the .gamma.-ke-toacid 4 in which both R2 and R6 are hydrogen to its corresponding hydroxy protected derivatives of formula 4 in which R2 is a hydroxy protecting radical and R6 is hydrogen.
2. The process of Claim 1 for preparing trans-2-(3-hydroxy-1-octenyl)-5-oxocyclopentaneacetic acid, which comprises subjecting dimethyl trans-1-(carbomethoxymethyl)-5-(3-hydroxy-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate to base treatment in the presence of water, followed by acidification of the basic reaction mixture.
3. The process of Claim 1 for preparing trans-2-{3-((tetra-hydropyran-2-yl)oxy)-1-octeny}-5-oxocyclopentaneacetic acid, which comprises:
subjecting dimethyl trans-1-(carbomethoxymethyl)-5-(3-hydroxy-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate to base treatment in the presence of water, followed by acidification of the basic reaction mixture to obtain trans-2-(3-hydroxy-1-octenyl)-5-oxocyclopentaneacetic acid, followed by converting that latter compound to its corresponding hydroxy protected derivative by reaction with dihydropyran in the presence of p-toluenesulfonic acid.
subjecting dimethyl trans-1-(carbomethoxymethyl)-5-(3-hydroxy-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate to base treatment in the presence of water, followed by acidification of the basic reaction mixture to obtain trans-2-(3-hydroxy-1-octenyl)-5-oxocyclopentaneacetic acid, followed by converting that latter compound to its corresponding hydroxy protected derivative by reaction with dihydropyran in the presence of p-toluenesulfonic acid.
4. The process of Claim 1 for preparing trans-2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentaneacetic acid, which comprises:
subjecting dimethyl trans-1-(carboethoxymethyl)-5-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate to base treat-ment in the presence of water, followed by acidification of the basic reaction mixture.
subjecting dimethyl trans-1-(carboethoxymethyl)-5-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate to base treat-ment in the presence of water, followed by acidification of the basic reaction mixture.
5. The process of Claim 1 for preparing trans-2-(3-hydroxy-4,4-dimethyl-1-octenyl)-5-oxocyclopentaneacetic acid, which comprises:
subjecting dimethyl trans-1-(carbomethoxymethyl)-5-(3-hydroxy-4,4-dimethyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate to base treatment in the presence of water, followed by acidification of the basic reaction mixture.
subjecting dimethyl trans-1-(carbomethoxymethyl)-5-(3-hydroxy-4,4-dimethyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate to base treatment in the presence of water, followed by acidification of the basic reaction mixture.
6. The compound of formula 4, as defined in Claim 1, when prepared by the process of Claim 1 or an obvious chemical equivalent thereof.
7. trans-2-(3-Hydroxy-1-octenyl)-5-oxocyclopentaneacetic acid, when prepared by the process of Claim 2 or an obvious chemical equivalent thereof.
8. trans-2- {3-((Tetrahydropyran-2-yl)oxy)-1-octeny}-5-oxocyclo-pentaneacetic acid, when prepared by the process of Claim 3 or an obvious chemical equivalent thereof.
9. trans-2-(3-Hydroxy-3-methyl-1-octenyl)-5-oxocyclopentaneacetic acid, when prepared by the process of Claim 4 or an obvious chemical equivalent thereof.
10. trans-2-(3-Hydroxy-4,4-dimethyl-1-octenyl)-5-oxocyclopentane-acetic acid, when prepared by the process of Claim 5 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA301,207A CA1071642A (en) | 1974-06-19 | 1978-04-17 | Intermediates for 5-unsaturated prostanoic acid derivatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/480,788 US3959263A (en) | 1974-06-19 | 1974-06-19 | Prostaglandin intermediate |
| CA229,452A CA1034123A (en) | 1974-06-19 | 1975-06-16 | 5-unsaturated prostanoic acid derivatives and preparation thereof |
| CA301,207A CA1071642A (en) | 1974-06-19 | 1978-04-17 | Intermediates for 5-unsaturated prostanoic acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1071642A true CA1071642A (en) | 1980-02-12 |
Family
ID=27164010
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA301,207A Expired CA1071642A (en) | 1974-06-19 | 1978-04-17 | Intermediates for 5-unsaturated prostanoic acid derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1071642A (en) |
-
1978
- 1978-04-17 CA CA301,207A patent/CA1071642A/en not_active Expired
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