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Hydroxylated 15-deoxy derivatives of 9-hydroxyl-13-trans-prostenoic acid |
| RE29469 |
Hydroxylated 15-deoxy derivatives of 9-hydroxyl-13-trans-prostenoic acid
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| Patent Drawings: | |
| Inventor: |
Floyd, Jr., et al. |
| Date Issued: |
November 8, 1977 |
| Application: |
05/682,691 |
| Filed: |
May 3, 1976 |
| Inventors: |
Floyd, Jr.; Middleton Brawner (Suffern, NY)
McGahren; William James (Demarest, NJ)
Schaub; Robert Eugene (Upper Saddle River, NJ)
Weiss; Martin Joseph (Oradell, NJ)
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| Assignee: |
American Cyanamid Company (Stamford, CT) |
| Primary Examiner: |
Gerstl; Robert |
| Assistant Examiner: |
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| Attorney Or Agent: |
Polyn; Denis A. |
| U.S. Class: |
554/214; 560/121; 562/503 |
| Field Of Search: |
; 260/514D; 260/468D |
| International Class: |
C07C 405/00 |
| U.S Patent Documents: |
3770776 |
| Foreign Patent Documents: |
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| Other References: |
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| Abstract: |
This disclosure describes certain 15-deoxy prostanoic acid derivatives having a hydroxy group further along in the beta-chain, useful as bronchodilators; hypotensive agents, anti-ulcer agents, or as intermediates. |
| Claim: |
We claim:
1. An optically active compound of the formula: ##STR57## or a racemic compound of that formula and the mirror image thereof wherein R.sub.1 is selected from the group consisting ofhydroxy, .[.lower alkoxy, tetrahydropyranyloxy, lower alkanoyloxy,.]. .Iadd.methoxy, ethoxy and .Iaddend..omega.-hydroxy substituted .[.lower.]. alkoxy .[.and .omega.-tetrahydropyranyloxy substituted lower alkoxy.]. .Iadd.having from 2 to 4 carbonatoms; .Iaddend.R.sub.2 is a moiety selected from the group consisting of those of the formulae: ##STR58## wherein R' is selected from the group consisting of .[.a straight chain alkyl group having from 2 to 10 carbon atoms and a straight chain alkylgroup having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms.]. .Iadd.n-propyl, n-butyl and n-pentyl.Iaddend., and R" is .Iadd.a moiety .Iaddend.selected from the group consisting of .[.a straight chain alkylgroup having from 2 to 10 carbon atoms and substituted with an hydroxy group, a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with an hydroxy group, a straightchain alkenyl group having from 2 to 10 carbon atoms and substituted with an hydroxy group and a straight chain alkenyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with an hydroxygroup;.]. .Iadd.those of the formulae: .Iadd. ##STR59## .Iaddend. wherein m is an integer from 3 to 5, inclusive, p is an integer from 1 to 3, inclusive, q is zero, 1 or 2, and y is .Iadd. ##STR60## .Iaddend. R.sub.3 is selected from the groupconsisting of hydroxy .[.,.]. .Iadd.and .Iaddend.alkoxy having from 1 to .[.12.]. .Iadd.4 .Iaddend.carbon atoms .[.and tetrahydropyranyloxy.].; and Z is a divalent radical selected from the group consisting of those of the formulae: ##STR61## whereinn is an integer from .[.3.]. .Iadd.6 .Iaddend.to 8, inclusive .[., R.sub.4 is an alkyl group having up to 3 carbon atoms, and R.sub.5 is selected from the group consisting of an alkyl group having up to 3 carbon atoms, a fluorine atom and a phenylgroup.].; and the pharmacologically acceptable cationic salts thereof when R.sub.3 is hydroxy.
2. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR62## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,20-dihydroxy-13-trans-prostenoic acid.
3. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR63## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,20-dihydroxy-13-trans-prostenoic acid.
4. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR64## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(S)-dihydroxy-13-trans-prostenoic acid.
5. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR65## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16.Iadd.(S).Iaddend.-dihydroxy-13-trans-prostenoic acid.
6. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR66## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 9-oxo-11.alpha.,16-dihydroxy-13-trans-prostenoic acid.
7. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR67## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(R)-dihydroxy-13-trans-prostenoic acid.
8. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR68## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16.[.-epidihydroxy.]..Iadd.(R)-dihydroxy.Iaddend.-13-tr ans-prostenoic acid.
9. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR69## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 ; l-9-oxo-11.alpha.,16(S)-dihydroxy-20-methyl-13-trans-prostenoic acid.
10. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR70## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16.Iadd.(S).Iaddend.-dihydroxy-20-methyl-13-trans-prost enoic acid.
11. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR71## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 9-oxo-11.alpha.,16-dihydroxy-20-methyl-13-trans-prostenoic acid.
12. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR72## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(R)-dihydroxy-20-methyl-13-trans-prostenoic acid.
13. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR73## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16.Iadd.(R).Iaddend.-.[.epi-.].dihydroxy-20-methyl-13-t rans-prostenoic acid.
14. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR74## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(S)-dihydroxy-20-ethyl-13-trans-prostenoic acid.
15. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR75## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16.Iadd.(S).Iaddend.-dihydroxy-20-ethyl-13-trans-proste noic acid.
16. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR76## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 9-oxo-11.alpha.,16-dihydroxy-20-ethyl-13-trans-prostenoic acid.
17. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR77## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(R)-dihydroxy-20-ethyl-13-trans-prostenoic acid.
18. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR78## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16.[.-epidihydroxy.]..Iadd.(R)-dihydroxy.Iaddend.-20-ethyl-13-trans-prostenoic acid.
19. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR79## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(S)-dihydroxy-20-methyl-13-trans,17-trans-prostadienoi c acid. .[.
20. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR80## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16(S)-dihydroxy-20-methyl-13-trans,17-trans-prostadieno ic acid..].
21. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR81## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 9-oxo-11.alpha.,16-dihydroxy-20-methyl-13-trans,17-trans-prostadienoic acid. .[.
22. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR82## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(R)-dihydroxy-20-methyl-13-trans,17-trans-prostadienoi c acid..]. .[.
23. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR83## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16-epi-dihydroxy-20-methyl-13-trans,17-trans-prostadien oic acid..].
24. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR84## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,17(S)-dihydroxy-13-trans-prostenoic acid. .[.
25. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR85## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,17-dihydroxy-13-trans-prostenoic acid..]. .[.
26. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR86## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,17(R)-dihydroxy-13-trans-prostenoic acid..]. .[.
27. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR87## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,17-epi-dihydroxy-13-trans-prostenoic acid..].
28. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR88## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 9-oxo-11.alpha.,17-dihydroxy-13-trans-prostenoic acid.
29. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR89## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.-hydroxy-15(S)-hydroxymethyl-13-trans-prostenoic acid. .[.
30. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR90## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.-hydroxy-15-hydroxymethyl-13-trans-prostenoic acid..].
31. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR91## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 9-oxo-11.alpha.-hydroxy-15-hydroxymethyl-13-trans-prostenoic acid. .[.
32. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR92## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.-hydroxy-15(R)-hydroxymethyl-13-trans-prostenoic acid..]. .[.
33. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR93## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.-hydroxy-15-epi-hydroxymethyl-13-trans-prostenoic acid..]. .Iadd.
34. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR94## .Iaddend. R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.4 --O--CH.sub.2 --; l-9-oxo-11.alpha.,16(S)-dihydroxy-3-oxa-13-trans-prostenoicacid. .Iadd.
35. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR95## .Iaddend. R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.4 --O--CH.sub.2 --; dl-9-oxo-11.alpha.,16(S)-dihydroxy-3-oxa-13-trans-prostenoic acid. .Iadd.
36. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR96## .Iaddend. R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.4 --O--CH.sub.2 --; 9-oxo-11.alpha.,16-dihydroxy-3-oxa-13-trans-prostenoic acid. .Iadd.
37. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR97## .Iaddend. R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.4 --O--CH.sub.2 --; l-9-oxo-11.alpha.,16(R)-dihydroxy-3-oxa-13-trans-prostenoicacid. .Iadd.
38. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR98## .Iaddend. R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.4 --O--CH.sub.2 --; dl-9-oxo-11.alpha.,16(R)-dihydroxy-3-oxa-13-trans-prostenoic acid. .Iadd.
39. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is .Iadd. ##STR99## .Iaddend. R.sub.3 is ethoxy, and Z is --(CH.sub.2).sub.6 --; l-ethyl9-oxo-11.alpha.,16(S)-dihydroxy-20-methyl-13-trans,18-cis-prostadienoate. .Iadd.
40. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is .Iadd. ##STR100## .Iaddend. R.sub.3 is ethoxy, and Z is --(CH.sub.2).sub.6 --; ethyl9-oxo-11.alpha.,16-dihydroxy-20-methyl-13-trans,18-cis-prostadienoate. .Iadd.
41. The optically active compound ethyl l-9-oxo-11.alpha.,16-dihydroxy-17-methyl-13-transprostenoate. .Iaddend. .Iadd.42. The racemic compound ethyl dl-9-oxo-11.alpha.,16-dihydroxy-17-methyl-13-transprostenoate. .Iaddend. .Iadd.43. Theoptically active compound l-9-oxo-11.alpha.,16-dihydroxy-17-methyl-13-trans-prostenoic acid. .Iaddend. .Iadd.44. The racemic compound dl-9-oxo-11.alpha.,16-dihydroxy-17-methyl-13-trans-prostenoic acid. .Iaddend. .Iadd.45. The optically activecompound l-9-oxo-11.alpha.-hydroxy-16-hydroxy-17-methyl-19,20-dinor-13-trans-proste noic acid. .Iaddend. .Iadd.46. The racemic compound dl-9-oxo-11.alpha.-hydroxy-16-hydroxy-17-methyl-19,20-dinor-13-trans-prost enoic acid. .Iaddend. .Iadd.47. Theoptically active compound l-9-oxo-11.alpha.-hydroxy-16-hydroxy-17-ethyl-20-nor-13-trans-prostenoic
acid. .Iaddend. .Iadd.48. The racemic compound dl-9-oxo-11.alpha.-hydroxy-16-hydroxy-17-ethyl-20-nor-13-trans-prostenoic acid. |
| Description: |
BRIEF SUMMARY OF THE INVENTION
This invention relates to novel hydroxy substituted 15-deoxy prostanoic acids and derivatives as well as to intermediates and methods for their preparation. The novel compounds of this invention may be represented by the following generalformulae: wherein formula A has the absolute configuration of the naturally-occurring mammalian prostaglandins. ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen, hydroxy, lower alkoxy, tetrahydropyranyloxy, lower alkanoyloxy,.omega.-hydroxy substituted lower alkoxy and .omega.-tetrahydropyranyloxy substituted lower alkoxy; R.sub.2 is a moiety selected from the group consisting of those of the formulae: ##STR2## wherein P is an hydroxy or triphenylmethoxy group, R' is astraight chain alkyl group having from 2 to 10 carbon atoms, or a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms, and R" is a straight chain alkyl group having from 2 to 10carbon atoms and substituted with an hydroxy or triphenylmethoxy group, or a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with an hydroxy or triphenylmethoxygroup or a straight chain alkenyl group having from 2 to 10 carbon atoms and substituted with a hydroxy or triphenylmethoxy group, or a straight chain alkenyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbonatoms and substituted with a hydroxy or triphenylmethoxy group; R.sub.3 is selected from the group consisting of hydroxy, an alkoxy group having from 1 to 12 carbon atoms and tetrahydropranyloxy; R'" is a straight chain alkyl group having from 2 to 10carbon atoms and substituted with an hydroxy or triphenylmethoxy group, or a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with an hydroxy or triphenylmethoxygroup; Y is a divalent radical selected from the group consisting of those of the formulae: ##STR3## and Z is a divalent radical selected from the group consisting of those of the formulae: ##STR4## wherein n is an integer from 3 to 8 inclusive, R.sub.4is an alkyl group having up to 3 carbon atoms and R.sub.5 is an alkyl group having up to 3 carbon atoms, a fluorine atom or a phenyl group; and the moiety of the formula: ##STR5## may be the divalent radical of the formula: ##STR6## when R.sub.3 ishydroxy or an alkoxy group having from 1 to 12 carbon atoms; and the moiety of the formula: ##STR7## may be the divalent moiety of the formula: ##STR8## when R.sub.3 is hydroxy or an alkoxy group having from 1 to 12 carbon atoms. Suitable lower alkoxyand lower alkanoyl groups contemplated by the present invention are those having up to four carbon atoms such as, for example, methoxy, ethoxy, isopropoxy, sec-butoxy, formyl, acetyl, propionyl, isobutyryl, etc.
Also embraced within the scope of the present invention are the non-toxic, pharmaceutically acceptable salts of the novel compounds of the present invention when R.sub.3 is hydroxy. The cations comprised in these salts include, for example, thenon-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine cations such as the tri(lower alkyl)amine cations (e.g., triethylamine), procaine, and the like.
The novel compounds of the present invention are obtainable as yellow oils having characteristic absorption spectra. They are relatively insoluble in water but are relatively soluble in common organic solvents such as ethanol, ethyl acetate,dimethylformamide, and the like. The cationic salts of the compounds when R.sub.3 is hydrogen are, in general, white to yellow crystalline solids having characteristic melting points and absorption spectra. They are relatively soluble in water,methanol and ethanol but are relatively insoluble in benzene, diethyl ether, and petroleum ether.
DETAILED DESCRIPTION OF THE INVENTION
The prostaglandins are a family of closely related compounds which have been obtained from various animal tissues, and which stimulate smooth muscle, lower arterial blood pressure, antagonize epinephrine-induced mobilization of free fatty acids,and have other pharmacological and autopharmacological effects in mammals. See Bergstom et al., J. Biol. Chem. 238, 3555 (1963) and Horton, Experienta 21, 113 (1965) and references cited therein. All of the so-called natural prostaglandins arederivatives of prostanoic acid. ##STR9## The hydrogen atoms attached to C-8 and C-12 are in trans-configuration. The natural prostaglandins represent only one of the possible optical isomers. The compounds of this convention include all possibleoptical isomers.
The novel compounds of the present invention may be readily prepared from certain 4-substituted cyclopentenone intermediates which may be represented by the following general formulae: ##STR10## wherein R.sub.1 ' is hydrogen, lower alkoxy,tetrahydropyranyloxy, lower alkanoyloxy or .omega.-tetrahydropyranyloxy lower alkoxy; and R.sub.3 ' is tetrahydropyranyloxy or an alkoxy group having from 1 to 12 carbon atoms.
The 4-oxycyclopentenone intermediates may be readily prepared from 2-carbethoxycyclopentanone in accordance with the reaction schemes set forth in Flowsheets A through D. In particular, the requisite2-(.omega.-carbethoxyalkyl)cyclopent-2-en-1-one intermediates (VIII) may be prepared in accordance with the following reaction scheme: ##STR11## wherein n is as hereinabove defined .[.ans.]. .Iadd.and .Iaddend.X is iodo or bromo. In accordance withthis reaction scheme, the cyclopent-2-en-1-ones (VIII) are developed by first converting 2-carbethoxycyclopentanone (I) to the sodium enolate thereof by means of sodium hydride in dimethoxyethane and then treating the sodium enolate with an ethyl.omega.-haloalkanoate (II). There is thus obtained the corresponding 2-carbethoxy-2-(.omega.-carbethoxyalkyl)cyclopentanone (III) which is then hydrolyzed and decarboxylated to afford the 2-(.omega.-carboxyalkyl)cyclopentanone (IV). This acid is thenesterified with ethanol whereby the 2-(.omega.-carbethoxyalkyl)cyclopentanone (V) is obtained. The reaction conditions for carrying out the above sequence of reactions are well known in the art. The conversion of the cyclopentanone (V) to the enolacetate (VI) is effected by heating with acetic anhydride in the presence of p-toluenesulfonic acid. Preparation of the enol acetate (VI) usually requires heating for a period of from about 8 to 36 hours. During this period, it is preferable to allowby-product acetic acid to distill out in order to force the reaction to completion. The bromination of the enol acetates (VI) to the 2 -bromocyclopentanones (VII) is preferably carried out in a two phase system as follows. A solution of bromine inchloroform is added to a rapidly stirred mixture of a solution of the enol acetate (VI) in chloroform and an aqueous solution of an acid acceptor such as calcium carbonate or soda ash. This addition is carried out at 0.degree.-5.degree. C. over aperiod of about 90 minutes stirring is continued for an additional period of about half an hour to a few hours, and the product (VII) is then isolated by standard procedures. The dehydrobromination of the 2-bromocyclopentanones (VII) is preferablycarried out in dimethylformamide with a mixture of lithium bromide and lithium carbonate at the reflux temperature for a period of about 30 minutes to an hour or so. The so formed cyclopent-2-en-1-ones (VIII) are also isolated by standard procedureswell known in the art. Substitution of X--(CH.sub.2).sub.n --C(R.sub.4).sub.2 -- --CH.sub.2 --CO.sub.2 C.sub.2 H.sub.5 for (II) in Flowsheet A and carrying through the sequence of transformations illustrated therein is productive of the followingcyclopent-2-en-1-ones (VIIIa): ##STR12## wherein X, n, and R.sub.4 are as hereinabove defined.
The required cyclopent-2-en-1-one intermediates of general structure (XVI), wherein the side-chain has a lower alkyl group, fluorine atom or phenyl group alpha to the carbethoxy function, may be prepared in accordance with the following reactionscheme: ##STR13## wherein n and R.sub.5 are as hereinabove defined, and Y is a methyl or p-tolylradical. In accordance with this reaction scheme, the 2-(.omega.-carbethoxyalkyl)cyclopent-2-en-1-ones (IX), prepared as described in Flowsheet A for thepreparation of (VIII) where n is 2- 7, inclusive, are converted to the corresponding 1-methoximino-2-(.omega.-carbethoxyalkyl)-2-cyclopentenes (X) by treatment with methoxyamine. With the ring carbonyl function thus blocked it is possible to effect apreferential reduction of the ester group by treatment with diisobutylaluminum hydride. The resulting alcohol (XI) is converted to a mesylate or tosylate derivative (XII), which undergoes displacement on treatment with the sodium salt of a diethylsubstituted malonate (XIII) to provide the disubstituted malonate derivatives (XIV). Hydrolysis and decarboxylation as well as concomittant cleavage of the methoximino blocking group provides the desired 2-(.omega.-carboxy-.omega.-substitutedalkyl)cyclopent-2-en-1-ones (XV), which are readily converted to the corresponding ester (XVI) by the usual Fisher procedure.
The requisite 2-(.omega.-carbethoxy-3-oxa-alkyl)cyclopen-2-en-1-ones (XXII) may be prepared in the procedure the reaction scheme of Flowsheet C, wherein n is as hereinbefore defined. ##STR14##
In accordance with the reaction scheme shown in Flowsheet C, for the preparation of the oxa derivatives (XXII), an appropriate 2-(.omega.-carbethoxyalkyl)cyclopent-2-en-1-one (XVII) is converted to the corresponding methoxime (XVIII), the esterfunction of which is then preferentially reduced with diisobutylaluminum hydride to afford the methoxime alcohol (XIX). The alcohol (XIX) is converted on treatment with n-butyl lithium to the lithio alcoholate, which then is O-alkylated by reaction withethyl bromoacetate to provide (XX). Hydrolysis with acetone-aqueous hydrochloric acid furnishes the deblocked keto-acid (XXI), which is then re-esterified with ethanol in the presence of p-toluenesulfonic acid to give the required2-(.omega.-carbethoxy-3-oxa-alkyl)cyclopent-2-en-1-one (XXII). O-Alkylation can also be accomplished by treatment of the lithio alcoholate of (XIX) with sodium or other metal salt of bromoacetic acid, in which case the free carboxylic acid correspondingto ester (XX) is obtained. Hydrolysis as for (XX) provides the keto acid (XXI).
Some of the transformations involved in the preparation of the 4-oxycyclopentenone intermediates are set forth in the following reaction scheme: ##STR15## wherein R.sub.8 is hydrogen or lower alkyl, R.sub.9 is lower alkyl, and Z' is ashereinabove defined for Z except that it does not include the moiety: --(CH.sub.2).sub.n --S--CH.sub.2 --, and m is an integer from 2 to 5, inclusive. Introduction of the 4-oxy-function into the 4-unsubstituted cyclopentenones (XXIII) is accomplished byfirst halogenating the 4-position with an allylic halogenating reagent, preferably N-bromosuccinimide. The resulting 4-bromocyclopentenone (XXIV) is then solvolyzed for the introduction of the oxy function. This step is preferably carried out in thepresence of a silver salt to facilitate the displacement of the halide ion. The particular 4-oxy derivative that is formed is determined by the nature of the solvent system. Treatment of the 4-bromocyclopentenone with silver fluoroborate inwater-acetone (for solubility) provides the 4-hydroxycyclopentenone (XXV). When the cyclopentenone is a carboxylic acid (i.e. R.sub.8 = hydrogen), then this procedure provides (XXXI). When the solvent system is water-tetrahydrofuran, in addition to the4-hydroxy derivative there is also obtained the 4'-hydroxybutyloxy derivative (XXVI), formed by solvolysis with tetrahydrofuran. When the solvent is only tetrahydrofuran then only the latter compound is formed. Substitution of tetrahydrofuran withalcohols, e.g., methanol, ethanol, isopropyl, butanol and the like, provides the 4-alkoxycyclopentenones (XXVII). With ethylene glycol or propylene glycol etc. the corresponding 4-(.omega.-substituted hydroxy alkoxy) cyclopentenone (XXVIII) is obtained. In the latter three procedures it is preferable to add a proton acceptor which will not react with (XXIV), for example, sym. collidine. When solvolysis is carried out with a silver lower alkanoate in the corresponding lower alkanoic acid, such as thesilver acetateacetic acid system, the 4-acetoxy derivative (XXIX) is obtained. Careful alkaline hydrolysis of this product with potassium carbonate in aqueous methanol provides the free 4-hydroxy derivative (XXX); further hydrolysis with bariumhydroxide gives the free carboxylic acid (XXXI).
In general these procedures are operable with either the free carboxylic acid or alkyl carboxylate, as desired. A particular alkyl carboxylate not provided by formula (XXIII) can be obtained by hydrolysis to the acid and esterification in theusual way, for example with the appropriate alcohol, or for a t-butyl ester with isobutylene. However, for the subsequent alanate conjugate addition process it is necessary to utilize a cyclopentenone wherein the carboxylic acid as well as all freehydroxyl groups are blocked. A particularly useful blocking group for both functions is the tetrahydropyranyl group (see for example XXXI.fwdarw.XXXII) since this group can easily be cleaved with weak acid under conditions which do not disrupt thesubsequently-prepared, relativey-unstable 11-oxy-9-keto system (.beta.-hydroxy-ketone). Thus, it is not possible to effect a satisfactory chemical hydrolysis of an alkyl ester or of an 11-O-alkanoyl group in an 11-oxy-9-keto prostanoic acid derivativeunder conditions to which this system is stable (enzymatic hydrolysis, for example with baker's yeast is possible). Of course these stability considerations do not apply in the F (9-hydroxy) series.
The 9-keto-15-deoxy-13-trans-prostenoic acids and esters of this invention, as defined in the general formula on page 1 above may be prepared from cyclopentenone (XXXVII) and the triphenylmethoxy substituted 1-alkyne (XXXIII), as depicted inFlowsheet E. In Flowsheet E, R'.sub.1, R'.sub.3, and Z are as hereinabove defined and R.sub.6 is a moiety of the formulae: ##STR16## wherein R' is as hereinabove defined and R" is a straight chain alkyl group having from 2 to 10 carbon atoms andsubstituted with a triphenylmethoxy group, or a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with a triphenylmethoxy group, or a straight chain alkenyl grouphaving from 2 to 10 carbon atoms and substituted with a triphenylmethoxy group, or a straight chain alkenyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with a triphenylmethoxygroup; and R'.sub.6 has all the possibilities of R.sub.6 except that triphenylmethoxy is replaced by hydroxy. Also, R is a lower alkyl group of up to 4 carbon atoms, R".sub.1 is as defined above for R.sub.1 except that it is not tetrahydropyranyloxy or.omega.-tetrahydropyranyloxy substituted lower alkoxy, and R".sub. 3 is as defined above for R.sub.3 except that it is not tetrahydropyranloxy. ##STR17##
In accordance with the reaction scheme of Flowsheet E, the triphenylmethoxy substituted 1-alkyne (XXXIII) is treated with diisobutylaluminum hydride (XXXIV), This reaction of the 1-alkyne (XXXIII) with diisobutylaluminum hydride (XXIV) providesthe alane (XXXV) containing the trans-double bond and is carried out in an inert solvent such as benzene, toluene, and the like at temperatures in the range of 40.degree.-60.degree. C. for several hours. It can also be carried out in a solvent such astetrahydrofuran, usually in an approximate 2:1 mixture with benzene or hexane; in which case the reaction requires somewhat more vigorous conditions, usually treating at about 70.degree.-75.degree. C. for about eighteen hours. The subsequent reactionwith methyl or n-butyl lithium (R-Li) is preferably carried out in a mixture of the above solvents with an ether-type solvent such as diethyl ether, dibutyl ether, tetrahydrofuran, and the like. This reaction is rapid and is preferably carried out at0.degree.-10.degree. C. with cooling. The conjugate 1,4-addition of the resulting alanate salt (XXXVI) to the cyclopent-2-en-1-one (XXXVII) is preferably carried out at ambient temperatures for a period of 12 to 24 hours. This reaction is also bestcarried out in an ether-type solvent such as diethyl ether, dibutyl ether, and the like. The intermediate alanate-enolate adduct is then carefully hydrolyzed in situ with dilute hydrochloric acid with cooling, and the products (XXXVIII) are isolated inthe usual manner well known in the art. Removal of tetrahydropyranyl blocking groups and of the triphenylmethyl blocking group can then be accomplished by treating with weak acid. A preferred procedure involves heating at 45.degree. C. for 3.5 hoursin a solvent system consisting of acetic acid:tetrahydrofuran:water in the proportion of 4:2:1. If (XXXVIII) is a tetrahydropyranyl ester, there is then obtained the prostenoic acid (XXXIX, R".sub.3 =hydroxy).
All available evidence leads us to believe that the --CH=CH--R.sub.6 function introduced by the alanate process (see XXXVIII) occupies a position trans to the 11-oxy function (when R'.sub.1 is not hydrogen). Similarly, we are led to theconclusion that in the product (XXXIX) the two side-chains attached to C.sub.8 and C.sub.12 are trans to each other. However, we are not certain of this configurational relationship in product (XXXVIII) as it is obtained directly from the alanateprocess. These products may have the side-chains in a trans- or cis-relationships or they may be a mixture containing both the trans- and cis-isomers. This is indicated in the nomenclature of the compounds involved by the designation 8 .xi.. In orderto ensure a trans-relationship in both (XXXVIII) and XXIX) these products can be submitted to conditions known in the literature to equilibrate the cis-8-iso-PGE.sub.1 to a mixture containing about 90% of the trans product. These conditions involvetreatment with potassium acetate in aqueous methanol for 96 hours at room temperature.
An alternative procedure for the conversion of substituted 1-alkyne (XXXIII) to the 9-keto-15-deoxy-13-trans-prostenoic acids and esters of this invention entails reduction of 1-alkyne (XXXIII) with disiamylborane in an ether solvent, inaccordance with Flowsheet F. The intermediate dialkyl-alkenyl borane (XXXIXa) is not isolated but is sequentially treated with trimethylamine oxide, iodine, and aqueous sodium hydroxide solution in a manner known in the art [A. F. Kluge, K. G. Untch,and J. H. Fried, Journal Amer. Chem. Soc., 94, 7827 (1972)]. This treatment provides trans-vinyl iodide (XXXIXb), a novel and useful intermediate for preparation of certain of the compounds of this invention.
Submission of the substituted vinyl iodide (XXXIXb) to metal interchange with an alkyl lithium, e.g., n-butyl lithium, at very low temperatures, e.g. -78.degree. C., provides the vinyl lithium derivative (XXXIXc), the trans-configuration of thedouble bond being retained. After 1 to 4 hours, addition of a trialkyl aluminum, to the solution of the lithio derivative (XXXIXc) furnishes the lithio alanate intermediate (XXXIXd), also with retention of the trans-configuration of the double bond. The reaction of alanate (XXXIXd) with cyclopent-2-en-1-one (XXXVII) is carried out as described hereinabove (see Flowsheet E). ##STR18##
The triphenylmethoxy substituted 1-alkynes (A) and the alanes (B) derived from it are novel and useful intermediates for the synthesis of the compounds of this invention and are to be considered a part of this invention. In formulae (A) and (B),R.sub.6 and R are as hereinabove defined. ##STR19##
When the 11-oxy derivatives (XXXVIII or XXXIX, R'.sub.1 or R'.sub.1 is not hydrogen), preferably the 11-hydroxy derivative such as (XL), are treated with dilute acid it is possible to effect elimination and the formation of the corresponding.DELTA..sup.10 derivative (XLI, prostaglandins of the A type). A preferred procedure involves treatment in tetrahydrofuran: water (2:1) solvent 0.5N in hydrochloric acid for about seventy hours at ambient temperatures as set forth in the followingreaction scheme. Under these conditions a tetrahydropyranyl ester will undergo hydrolysis.
When the 11-oxy derivatives (XXXVIII) or (XXXIX) or (XL) or the .DELTA..sup.10 derivative (XLI) are treated with an aqueous base system, e.g., sodium carbonate in aqueous methanol, it is possible to prepare the corresponding .DELTA..sup.8(12)derivative (XLII), prostaglandins of the B type). The formation of the .DELTA..sup.8(12) compound (XLII) is conveniently observed by the appearance of the ultraviolet absorption maximum due to (XLII) at about 280 m.mu.. This is a procedure well-knownin the art. See Flowsheet G below, wherein Z, R.sub.2, R.sub.3 and R".sub.3 are as hereinabove defined. ##STR20##
Those compounds of this invention embodying the --CH.sub.2 --CH.sub.2 -- linkage at --C.sub.13 --C.sub.14 -- may be prepared from the corresponding .DELTA..sup.13 derivatives, obtained via the alanate process, by catalytic reduction, preferablyat low pressure with a noble metal catalyst in an inert solvent at ambient temperatures.
The 11 -oxy-9-keto derivatives of this invention can be converted to the corresponding 9-hydroxy derivatives. If this conversion is effected with sodium borohydride, the product is a mixture of 9.alpha.- and 9.beta.-hydroxy derivatives (XLIII)and (XLIV) as set forth in the following reaction scheme of Flowsheet H, wherein R.sub.1, R.sub.2, R.sub.3 and Z are as hereinabove defined. ##STR21## When the reaction is carried out with lithium perhydro-9b-boraphenylyl hydride [H. C. Brown and W. C.Dickason, Journ. Amer. Chem. Soc., 92,709 (1970)] or with lithium tri(sec-butyl)-borohydride [H. C. Brown and S. Krishnamerthy ibid. 94, 7159 (1972)], the product is at least predominantly the 9.alpha.-hydroxy derivative (XLIII), wherein the9-hydroxy group is cis to the side-chain attached to C.sub.8 and to the 11-oxy function. In accordance with accepted convention, an .alpha.-substituent at the 8-, 9-, 11- or 12-positions is behind the plane of the paper whereas a .beta.-substituent atthese positions is in front of the plane of the paper. This is usually represented by a - - - bond for an .alpha.-substituent, a -- bond for a .beta.-substituent, and a bond which both are indicated. Thus, the 9-hydroxy derivatives may be variouslyrepresented as follows: ##STR22##
The preparation of the thia intermediates (XLVIII) and (IL), proceeds from the intermediate (XLV) (XIX in Flowsheet C) which after conversion to the tosylate intermediate (XLVI) and reaction with the sodium salt of ethyl mercaptoacetate furnishesintermediate (XLVII). Deblocking of (XLVII) with acetone-aqueous hydrochloric acid provides the keto-acid (XLVIII), which on re-esterification with ethanol gives the required 2-(.omega.-carbethoxy-3-thia-alkyl)cycloalk-2-en-1-ones (IL). ##STR23##
When the compounds of this invention are prepared from racemic starting compounds two racemates are obtained. In appropriate instances these racemates can be separated from each other by careful application of the usual chromatographicprocedures. In the more difficult instances it may be necessary to apply high pressure liquid chromatography including recycling techniques. [See G. Fallick, American Laboratory, 19-27 (Aug., 1973) as well as references cited therein. Additionalinformation concerning high speed liquid chromatography and the instruments necessary for its application is available from Waters Associate, Inc. Maple St., Milford, Mass.]
It is also possible to prepare the individual enantiomers via the conjugate addition procedure discussed above by starting with a resolved 4-oxycyclopentenone (see XXXVII) and a resolved .beta.-chain precursor (see XXXIII or XXXIXb).
The 4-hydroxycyclopentenone racemates may be resolved into their component enantiomers (L) and (LI) by derivatizing the ketone function with a reagent having an optically active center. The resulting diastereoisomeric mixture can then beseparated by fractional crystallization, or by chromatography, or by hidh speed liquid chromatography involving, if necessary, recycling techniques. Among the useful optically active ketone derivatizing reagents are1-.alpha.-aminoxy-.gamma.-methylpentanoic acid hydrochloride (to give LII), (R)2-aminoxy-3,3-dimethylbutyric acid hydrochloride, and 4-.alpha.-methylbenzyl semicarbazide. After separation of the diastereomeric derivatives, reconstitution of the ketofunction provides the individual 4-hydroxycyclopentenone enantiomers (L) and (LI). A useful procedure for the resolution of a 4-hydroxycyclopentenone racemate via an oxime such as (LII) is described in the art [R. Pappo, P. Collins and C. Jung,Tetrahedron Letters, 973 (1973)]. ##STR24##
An alternative procedure for the preparation of the 4(R)-hydroxycyclopentenone enantiomers such as (L) involves as a key stop the selective microbiological or chemical reduction of trione (LIII) to the 4(R)-hydroxycyclopentanedione (LIV). A widevariety of microorganisms are capable of accomplishing this asymmetric reduction, one of the most useful being Dipodascus unincleatus. This step also can be achieved chemically by catalytic hydrogenation in the usual manner (for example, under about oneatmosphere of hydrogen in methanol) using a soluble rhodium catalyst with chiral phosphine ligands, such as (1,5-cyclooctadiene)-bis(o-anisylcyclohexylmethylphosphine)rhodium (I) tetrafluoroborate in the presence of one equivalent of organic base, suchas triethylamine.
Conversion of hydroxycyclopentanedione (LIV) to an enol ether or enol ester, (LV, E = alkyl, preferably isopropyl; aroyl such as benzoyl; or arylsulfonyl such as 2-mesitylenesulfonyl), is accomplished by treatment, for example, with isopropyliodide and a base such as potassium carbonate in refluxing acetone for from 15 to 20 hours, or with a base such as triethylamine and 0.95 equivalents of benzoyl chloride or a slight excess of 2-mesitylenesulfonyl chloride, in a non-prototropic solvent ata temperature of about -10.degree. to -15.degree. C. Reduction of (LV) with excess sodium bis(2-methoxyethoxy)aluminum hydride in a solvent such as tetrahydrofuran or toluene at low temperatures, such as -60.degree. to -78.degree. C., followed bymild acid hydrolysis (representative conditions: aqueous dilute hydrochloric acid, pH 2.5; or oxalic acid, sodium oxalate in chloroform) at ambient temperatures from 1 to 3 hours provides the 4(R)-hydroxycyclopentenone ester (LVI). The ester (LVI),after blocking the hydroxy function as described hereinabove, can be subjected to conjugate addition reactions also as described hereinabove. The conjugate addition product, after deblocking the 11- and 15-hydroxy groups, will then be a methyl esterwhich can be hydrolyzed to the corresponding carboxylic acid by enzymatic or microbiological procedures, for example with baker's yeast or by exposure to Rhizopus oryzae.
For a description of these procedures in the art see: C. J. Sih et al., Journ. Amer. Chem. Soc., 95 1676 (1973); J. B. Heather et al., Tetrahedron Letters, 2213 (1973); R. Pappo and P. W. Collins, Tetrahedron Letters, 2627 (1972) and R. Pappo,P. Collins and C. Jung, Ann. N.Y. Acad. Sci., 180, 64 (1971). For a descriptive of the baker's yeast procedure see C. J. Sih et al., Journ. Amer. Chem. Soc., 94 3643 (1972). ##STR25##
Procedures for the preparation of the requisite cyclopentanetriones (LII) are well-established in the art and generally involve the treatment of an .omega.-1 oxo long chain ester (LVII) with methyl or ethyl oxalate and a base such as sodiummethoxide in methanol, followed by treatment with dilute hydrochloric acid in aqueous methanol to effect the dealkoxalylation of the intermediate (LXVIII). See J. Kutsube and M. Matsui, Agr. Biol. Chem., 33, 1078 (1969); P. Collins, C. J. Jung and R.Pappo, Israel Journal of Chemistry, 6, 839 (1968); R. Pappo, P. Collins and C. Jung, Ann. N.Y. Acad. Sci. 180, 64 (1971); C. J. Sih et al., Journ. Amer. Chem. Soc., 95, 1676 (1973) (see reference 7); and J. B. Heather et al., Tetrahedron Letters,2313 (1973) for pertinent background literature. ##STR26##
The intermediate keto esters (LVII) may be prepared by a variety of methods known to the art. One useful procedure is outlined below and involves alkylation of ethyl acetoacetate sodium salt (LIX) in the usual manner with the appropriateside-chain precursor (LX, X=Cl, Br, I, preferably Br or I) followed by decarbethoxylation and reesterification, all in the usual manner. ##STR27##
The side-chain precursors (LX) are commercially available where Z is --(CH.sub.2).sub.n --, and can be prepared as described in Belgian Pat. No. 786,215 (granted and opened to inspection Jan. 15, 1973) where Z is ##STR28## precursor (LX) can beprepared as indicated below by mono-tetrahydropyranylation of the diol (LXIII) to (LXIV), followed by mesylation, treatment of the resulting mesylate (LXVI) with the appropriate substituted sodio malonate to give (LXV), decarbethoxylation andreesterification to (LXVII), mesylation of the second hydroxy function to (LXIX) and displacement with lithium bromide (or iodide) to (LXXI). Alternatively, the .omega.-bromo alcohol (LXX) after blocking as the tetrahydropyranyl derivative (LXVIII), ontreatment with the substitued sodio malonate provides (LXV). ##STR29##
Those precursors wherein Z is --(CH.sub.2).sub.n --O--CH.sub.2 -- can be prepared by the transformation shown directly below starting with the mono-tetrahydropyranyl derivative (LXIV). Thus, (LXIV) is converted to the lithium alcoholate bytreatment with butyl lithium, the alcoholate is then O-alkylated with ethyl bromoacetate to provide (LXXII), which on de-tetrahydropyranylation, mesylation and reaction with lithium bromide gives the required (LXXV). (These and all the above-describedtransformation can be effected in the usual manner, well-established in the art; pertinent examples for most of the reactions can be found in the above-cited Belgian Pat. No. 786,215.) ##STR30##
It is also possible to resolve the 4-hydroxycyclopentenone racemate (LXXVI) by microbiological means. Thus, treatment of the 4-O-alkanoyl or aroyl derivatives (LXXVII), R.sub.12 = aryl (or alkyl) of racemate (LXXVI) (preferably the 4-O-acetyland 4-O-propionyl derivatives) with an appropriate microorganism preferably a Saccharomyces species, e.g. 1375-143, affords preferential de-O-acylation of the 4(R)-enantiomer to give (LXXVIII), which is then separated from the unreacted 4(S)-O-acylenantiomer (LXXIX) by chromatographic procedures. After separation, mild hydrolysis of the 4(S) derivative (LXXIX) provides the 4(S)-hydroxycyclopentenone (LXXX) [See N.J. Marsheck and M. Miyano, Biochimica et Biophysica Acta, 316, 363 (1973) forrelated examples.] ##STR31##
It is also possible to prepare the individual 4-hydroxycyclopentenones (LXXVIII) and (LXXX) directly by selective microbial hydroxylations of the corresponding 4-unsubstituted cyclopentenone (LXXXI). For example, with Aspergillus niger ATCC9142; a selective 4(R)-hydroxylation of (LXXXI) [Z = (CH.sub.2).sub.6 ] has been reported; for a literature example, see S. Kurozumi, T. Tora and S. Ishimoto Tetrahedron Letters, 4959 (1973). Other organisms can also accomplish this hydroxylation. ##STR32##
An alternate resolution procedure involves derivatization of the alcohol function of the racemic hydroxycyclopentenone to give ester-acid derivatives such as (LXXXII) wherein R".sub.3 is hydrogen or an alkoxy group, n' is zero or two and Z is ashereinabove defined. ##STR33##
Such derivatives may be obtained from the corresponding free hydroxycyclopentenone by treatment in the usual manner with oxalyl chloride, succinyl chloride, succinic anhydride and the like. Treatment of the resulting acid or diacid (D".sub.3 =hydrogen) with optically active amines e.g., 1-(- )-.alpha.-methylbenzylamine, d-(+)-.alpha.-methylbenzylamine, brucine, dehydroabietylamine, strychnine, quinine, cinchonine, quinidine, ephedrine, (+)-.alpha.-amino-1-butanol and the like, and fractionalrecrystallization of the resulting diasteromeric mixtures, followed by cleavage of the 4-oxy ester function in each of the individually isolated diastereomers provides the individual 4(S)- and 4(R)-hydroxycyclopentenone enantiomers (L) and (LI) or theirrespective esters. Cleavage of the oxalate acid ester (LXXXII, n = 0) can be accomplished by treatment with lead tetraacetate in pyridine solution. For an example of a similar use of oxalate acid-esters see J. G. Molotkovsky and L. D. Bergelson,Tetrahedron Letters 4791 (No. 50, 1971); for an example of the use of the succinate acid-ester see B. Goffinet, Ger. Offen. No. 2,263,880; Chem. Abstracts, 79, 78215.sub.z (1973).
The racemic .beta.-chain precursors can be resolved at either the acetylenic alcohol stage (XXXIII, Flowsheet E) or the trans-vinyl iodide state (XXXIXb, Flowsheet F) by a variety of methods well-known in the art. These methods will beillustrated below with the acetylenic alcohol (LXXXIII), but they apply equally well to the trans-vinyl iodide (LXXXIV). Furthermore, the resolved acetylenic alcohols corresponding to (LXXXIII) can be converted to the trans-vinyl iodides correspondingto (LXXXIV) or its derivatives as described hereinabove without racemization [see for an example, A. F. Kluge, K. G. Untch and J. H. Fried, Journ. Amer. Chem. Soc., 94, 7827 (1972)]. ##STR34##
Racemates (LXXXIII) or (LXXXIV) can be resolved by reverse phase and absorption chromatography on an optically active support system or by selective transformation of one isomer by microbiological or enzymatic procedures.
A more generally applicable procedure involves conversion of the racemic alcohol to a mixture of diastereomers by derivatization of the hydroxy function with an optically active reagent, followed by separation of the diastereomers by fractionalcrystallization or chromatographic procedures, as discussed hereinabove. Regeneration of the alcohol function from the individual diasteromer then provides the individual enantiomeric alcohols, e.g. (LXXXV) and (LXXXVI). ##STR35##
Useful derivatives for resolution purposes include the salts of the phthalate half acid ester (LXXVII) with an optically active amine (e.g., 1-(-)-.alpha.-methylbenzylamine, d-(+)-.alpha.-methylbenzylamine, brucine, dehydroabietylamine,strychnine, quinine, cinchonine, cinchonidine, quinidine, ephedrine, deoxyephedrine amphetamine, (+)-2-amino-1-butanol, (-)-2-amino-1-butanol and the like). ##STR36##
For the resolution in the art of the related 3-hydroxy-1-octyne by this procedure see J. Fried et al., Annals of the N.Y. Acad. of Sci., 180, 38 (1971), and of the related 1-iodo-trans-1-octen-3-ol see A. F. Kluge, K. G. Untch and J. H. Fried,Jour. Amer. Chem. Soc., 94, 7827 (1972).
Other useful derivatives are the diastereomeric carbamates (LXXXVIII) obtained by treatment of racemate (LXXXIII) with an optically active isocyanate (e.g., (+)-1-phenylethylisocyanate and (-)-1-phenylethylisocyanate). ##STR37##
Various esters of racemate (LXXXIII) with optically active acids are also useful for resolution purposes. Among the optically active acids which can be used in this connection are .omega.-camphoric acid, methoxyacetic acid,3.alpha.-acetoxy-.DELTA..sup.5 -etianic acid, 3.alpha.-acetoxy-5,16-etiadienoic acid, (-)-.alpha.-methoxy-.alpha.-trifluoromethylphenylacetic acid (see LXXXIX), (+)-.alpha.-methoxy-.alpha.-trifluoromethylphenylacetic acid, and the like. ##STR38##
The resolution of the related 1-octyne-3-ol with 3.beta.-acetoxy-.DELTA..sup.5 -etianic acid and 3.beta.-acetoxy-5,16-etiadienoic acid has been described in the art [see R. Pappo, P. Collins, and C. Jung, Annals of the N.Y. Acad. of Sci., 180,64 (1971)].
The preparation of the enantiomeric acetylenic alcohols or 4-hydroxy-trans-vinyl iodides can also be accomplished by microbial techniques, involving a selective deesterification of 4-O-alkanoyl or aroyl derivatives (XL) followed bychromatographic separation to the individual enantiomers and hydrolysis of the non de-esterified ester. Useful microorganisms for this purpose are Rhizopus arrhizus and Rhizopus nigricans (ATCC 6227b). ##STR39##
Alternatively, it is possible to effect selective microbial reduction of the corresponding 4-keto derivatives (XCI) and (XCII) to a single enantiomer, useful microorganisms for this purpose are Penicillium decumbens and Aspergillus ustus. Ketones (XCI) and (XCII) are readily obtainable by oxidation under mild conditions of the corresponding alcohols. For pertinent literature examples see J. B. Heather et al., Tetrahedron Letters, 2313 (1973). It is also possible to effect opticallyselective reduction of ketones. ##STR40## (XCI) or (XCII) by the use of an optically active reducing agent such as tri(+S-2-methylbutyl)aluminum etherate, lithium aluminum hydride-3-O-benzyl-1,2-O-cyclohexylidene-.alpha.-glucofuranose complex, andlithium hydrodipinan-3.alpha.-ylborate. For pertinent references to this procedure see R. A. Kretchmer, Journ. Org. Chem. 37, 801 (1972); S. A. Landor et al., Journ. Chem. Soc. (C) 1822, 2280 (1966), ibid. 197 (1967); M. F. Grundon et al., ibid.,2557 (1971); and J. D. Morrison and H. S. Mosher, "Assymetric Organic Reactions", pp. 160-218, Prentice-Hall, Englewood Cliffs, N.J. (1971).
It is to be noted that use of only one resolved precursor, either the .beta.-chain or the 4-hydroxycyclopentenone, in the conjugate addition process will lead to the formation of two diastereomers, which, at least in appropriate instances, canthen be separated by chromatographic and other procedures (as described above for the corresponding racemate) into the individual component enantiomers.
For the particular case of the preparation of optically active acetylenic alcohols wherein the hydroxy group occupies the 4-position of the chain, advantage may be taken of a well-known and general microbiological reduction process, depicted inFlowsheet J. According to this process, a 1-hydroxy-2-oxoalkene (XCV) is added to the fermenting mixture obtained from sucrose and baker's yeast (see P. A. Levene and A. Walti, Org. Synthesis, Coll. Vol. II, p. 545 and J. P. Anette and N. Spassky, Bull. Soc. Chim. France, 1972, 4217, for appropriate examples). The reductase of this system stereospecifically provides the (R)-1,2 -dihydroxyalkanes (XCVII). The glycol thus prepared is converted stereospecifically to the (R)-1,2-epoxyalkane (XCVI) byone of several procedures known in the art (see B. T. Golding et al., Journal. Chim. Soc. Perkin I, 1973, 1214 and M. S. Newman and C. M. Chen, Journ. Amer. Chem. Soc. 95, 278 (1973), for appropriate examples). The stereospecific conversion ofthis epoxide to the (R)-4-hydroxy-1-alkyne (XCVIII) may be accomplished by displacement with lithium acetylide-ethylenediamine complex in dimethyl sulfoxide (see E. Casadevall, et al., Compt. Rind. C, 265, 839 for pertinent literature).
The (R)-1,2-dihydroxyalkane (XCVII) obtained from the yeast fermentation may also be used for the preparation of the (S)-4-hydroxy-1-alkyne (CII). Preferential triphenylmethylation of the primary alcohol group provides the monoether (IC) (see L.J. Stegerhoek and P. E. Verkade, Rec. Trav. Chim. 74, 143 (1955) for pertinent literature). The remaining alcohol group is esterified with a sulfonyl halide such p-toluenesulfonyl chloride to provide the sulfonate ester (CI). Catalytichydrogenolysis of the trityl group followed by treatment of the resulting free primary alcohol with a strong base, e.g. potassium hydroxide in methyl alcohol, provides the epoxide of the opposite configuration, a (S)-1,2-epoxyalkane (CIII) (see J. Fried,et al. Journ. Amer. Chem. Soc., 94, 4343 (1972) and J. W. Cornforth et al. Journ. Chem. Soc., 1959, 112, for pertinent literature). This substance is reacted with lithium acetylide-ethylenediamine complex to provide the (S)-4-hydroxy-1alkyne (CII).
Alternatively the (R)-4-hydroxy-1-alkyne (XCVIII) may be converted to a sulfonate ester (C), and the sulfonate function of the latter may be displaced by hydroxy to provide the (S)-4-hydroxy-1-alkyne (CII) (see R. Baker, et al., Journ. Chem.Soc. C. 1969, 1605 for pertinent literature).
The (R)- or (S)-4-hydroxy-1-alkynes are converted via either the vinyl iodide (XCIII) or the alane (XCIV) to 16-hydroxyprostaglandins of the (16R)- and (16S)-series respectively by the procedure outlined hereinabove. ##STR41##
The starting 1-hydroxy-2-oxoalkanes for this procedure may be prepared in a variety of ways well-known to the literature [see P. A. Levene and M. L. Maller, Journ. Biol. Chem., 79, 475 (1928) and I. Forgo and J. Buchi, Pharm. Acta Helv., 45,227 (1970)]. In Flowsheet J which follows Ra is an alkyl group.
______________________________________ FLOWSHEET J ______________________________________ ##STR42## ##STR43## ##STR44## ##STR45## ##STR46## ##STR47## ##STR48## ##STR49## ##STR50## ##STR51##
Utilization of only a resolved .beta.-chain or only a resolved hydroxycyclopentenone gives a mixture of diastereomers, which depending upon the circumstances, may or may not be separable by the usual procedures of crystallization andchromatography. If necessary, high speed liquid chromatography, including recycling techniques, can be applied. Additional procedures, well-understood in the literature, for effecting the resolution of diasteromeric prostenoic acids and esters (or oftwo racemates) of this invention are described below.
In these procedures 9-oxo-11.alpha. ,16(S)-dihydroxy-13-trans-prostenoic acid and its 9.alpha.-hydroxy derivative are used for illustrative purposes, it being understood, however, that the procedures are general and have applicability to theother products of this invention, particularly to those derivatives wherein the 11-position is not substituted with an oxy function.
Conversion of a 9.alpha.-hydroxy diasteromeric mixture (the component diastereomers are illustrated by CIV and CV below) wherein the C.sub.11 and C.sub.16 hydroxy functions have been preferentially blocked by tetrahydropyranyl or trialkylsilylgroups, to the corresponding phthalate half acid-ester, deblocking the C.sub.11 and C.sub.16 hydroxy functions and conversion of the diacid (e.g., CVI) to a bis salt (e.g., CVII) with an optically active amine (e.g., 1-(-)-.alpha.-methylbenzylamine,D-(+)-.alpha.-methylbenzylamine, brucine, dehydroaebietylamine, strychnine, quinine, cinchonine, cinchonindine, quindine, ephedrine, deoxyepedrine, amphetamine, (+)-2-amino-1-butanol, (-)-2-amino-1-butanol and the like). The resulting diastereomers arethen separated by fractional crystallization and the individual components are then converted by acidification and saponification to the individual optically active parent 9.alpha.-hydroxy diastereomers (CIV) and (CV), oxidation of which, afterpreferential blocking of the C.sub.11 and C.sub.16 hydroxy functions with tetrahydropyranyl or trialkylsilyl groups, provides the corresponding individual 9-oxo diastereomers (CVIII) and (CIX). (For an appropriate literature procedure see E. W. Yankee,C. H. Lin and J. Fried, Journ. Chem. Soc., 1972, 1120). ##STR52##
Another procedure involves conversion of the 9.alpha.-hydroxy diastereomeric mixtures (as the prostenoic acid ester and with the C.sub.11 and C.sub.16 alcohol functions preferentially blocked as tetrahydropyranyl or trialkylsilyl ethers) to thediastereomeric carbamates with an optically active isocyanate, e.g., (+)-1-phenylethylisocyanate or (-)-1-phenylethylisocyanate, followed by deblocking. Separation of the diastereomers, for example (CX) and (CXI) can be accomplished by fractionalcrystallization or by the usual chromatographic procedures, or if necessary by high speed liquid chromatography involving, if necessary, recycling techniques. Base-treatment of the individual diastereomeric carbamates affords the individualdiasteromeric alcohols, for example (CIV) and (CV). ##STR53##
It is also possible to effect resolution of the 9.alpha.-hydroxy derivative, preferably as the prostenoate esters, by esterification of the 9.alpha.-hydroxy function (prior preferential blocking of C.sub.11 and C.sub.16 hydroxy functions astetrahydropyranyl or trialkylsilyl ethers) with an optically active acid, via its acid chloride followed by deblocking the C.sub.11 and C.sub.16 alcohol groups. Suitable optically active acids include .omega.-camphoric acid, methoxyacetic acid,3.alpha.-acetoxy-.DELTA..sup.5 -etianic acid, (-)-.alpha.-methoxy-.alpha.-trifluoromethylphenylacetic acid and (+)-.alpha.-methoxy-.alpha.-trifluoromethylphenylacetic acid, and the like. The resulting diastereomeric esters, for example (CXII) and(CXIII), are then separated by fractional crystallization or by chromatographic techniques including, if necessary, the use of high speed liquid chromatography. Saponification of the individual diastereomers then provides the individual9.alpha.-hydroxyprostenoic acid diastereomers (CIV) and (CV). ##STR54##
Another resolution procedure, less useful than the methods described above based on the 9.alpha.-hydroxy derivative but particularly applicable to 11-unsubstituted compounds of this invention, involves derivatization of the keto function of thediastereomeric 9-oxo-prostenoic acid or ester illustrated by (CVIII and CIX) with the usual type of ketone derivatizing agents bearing an optically active center. The resulting mixture of diastereomeric derivatives can then be separated by fractionalcrystallization or by chromatography or, if necessary, by high speed liquid chromatography. The individual diastereomeric keto derivatives, for example (CXIV) and (CXV), are then convertable to the individual 9-oxo diastereomers (CVIII) and (CIX) by anyof the usual cleavage techniques, provided that they are sufficiently mild so as not to disturb the sensitive 11-hydroxy-9-keto system. (This latter point is not a problem with 11-unsubstituted derivatives.) Ketone reduction of the 9-oxo-enantiomer as.[.descried.]. .Iadd.described .Iaddend. hereinabove then provides the corresponding 9.alpha.-hydroxy or 9.beta.-hydroxy diastereomer (CIV) or (CV). Among the optically active reagents useful for ketone derivatization are 1-.alpha.-aminoxy-.alpha. -methylpentanoic acid hydrochloride [E. Testa et al., Helv. Chemica Acta, 47 (3), 766 (1973)], methylhydrazine, and 4-.alpha.-methylbenzylsemicarbazide. A useful procedure for the cleavage of oximes such as (CXIV) and (CXV) involves treatment of theoxime at about 60.degree. C. for about 4 hours in 1:2 aqueous-tetrahydrofuran buffered with ammonium acetate and containing titanium trichloride. ##STR55##
Other useful ketone derivatizing agents are optically active 1,2-glycols, e.g., D(-)-2,3-butanediol, or 1,2-dithiols, e.g., L(+)-2,3-butanedithiol. These are used to convert the 9-oxo derivative to 9,9-alkylenedioxa or 9,9-alkylenedithiaderivatives, separation of diastereomers by chromatographic procedures followed by regeneration of the individual 9-oxo diastereomer by ketal cleavage all by procedures well-known in the art. Both ketalization and deketalization would have to beaccomplished by procedures which would not disrupt the 11-oxo-9-keto system, which of course, is not a problem in the 11-unsubstituted series.
An alternative procedure for the conversion of substituted 1-alkyne (CXVI) to product (CXX) (formulae XXXIII and XXXVIII respectively of Flowsheet E) proceeds via vinyl lithium reagent (CXVII) (formula XXXIXc of Flowsheet F). ##STR56## In thisprocedure (CXVII) is reacted with the complex of cuprous iodide-tri-n-butylphosphine is an ether solvent at very low temperatures, e.g., -78.degree. C., to provide a divinyl lithio cuprate species (CXIX). This reagent (CXIX) is reacted withcyclopentenone (CXVIII) (XXXVII of Flowsheet E) in ether-hydrocarbon solvent at -78.degree. C. to 0.degree. C. to provide product (CXX), after workup with aqueous ammonium chloride.
The novel compounds of the present invention have potential utility as hypotensive agents, anti-ulcer agents, agents for the treatment of gastric hypersecretion and gastric erosion, agents to provide protection against the ulcerogenic and othergastric difficulties associated with the use of various non-sterodial antiinflammatory agents, e.g. indomethacin, aspirin, and phenylbutazone, bronchodilators, antimicrobial agents, anticonvulsants, abortifacients, agents for the induction of labor,agents for the induction of menses, fertility-controlling agents, central nervous system regulatory agents, salt and water-retention regulatory agents, diuretics, fat metabolic regulatory agents and as serum-cholesterol lowering agents. Certain of thenovel compounds of this invention possess utility as intermediates for the preparation of other of the novel compounds of this invention.
Anti-ulcerogenic Effect of Indomethacin
The compounds of this invention also provide protection against the ulcerogenic properties of indomethacin. This assay was carried out in the following manner.
Rats were starved for 48 hours (water was given ad libitum). Indomethacin (20 mg./kg. of body weight) was administered by the subcutaneous route and one-half the dose of the test compound was administered by gavage at the same time. After 3hours, the second half of the test compound was administered also by gavage. Five hours after the administration of indomethacin the animals were decapitated and the stomachs removed. The stomachs were washed with distilled water, blotted on gauze, cutalong the larger curvature, and the contents rinsed with distilled water. The stomachs were spread out, pinned on a cork and visualized under magnifying glass for ulcers. The criteria for scoring of .[.ulers.]. .Iadd.ulcers .Iaddend. was aspreviously reported. [Abdel-Galil et al. Brit. J. Pharmac. Chemotherapy 33:1-14 (1968)].
______________________________________ SCORE 0- Normal Stomach 1- Petechial hemorrhage or pin point ulcers 2- 1 or 2 small ulcers 3- Many ulcers, a few large 4- Many ulcers, mainly large ______________________________________
A difference of at least 0.7 unit between the scores for control animals (treated with indomethacin but not test compound) and animals treated with indomethacin and test compound is considered indicative of activity for the test compound. (Control animals treated with neither indomethacin nor test compound give scores of about 0.5-0.8.) The results obtained in this assay with typical compounds of the present invention are set forth in Table I below.
TABLE I ______________________________________ Total oral dose: mg./kg Score Compound of body weight treated control ______________________________________ 9-oxo-16-hydroxy- 13-trans-pro- stenoic acid 50 1.2 2.3 9-oxo-16-hydroxy- prostenoic acid 50 1.3 2.3 9-oxo-11.alpha.,16-di- 12.5 1.0 3.0 hydroxy-13-trans- 4.4 1.0 3.0 prostenoic acid 1.56 1.0 2.5 0.78 1.5 3.0 0.39 2.0 3.0 0.18 2.5 3.0 9-oxo-11.alpha.,17-di- hydroxy-13-trans- 25 1.3 2.7 prostenoic acid ______________________________________
The novel compounds of the present invention are also effective inhibitors of gastric acid secretion and of ulcer development in experimental animals, and thus are potentially valuable as agents for the control of gastric acid secretion and ofgastric erosion and as anti-ulcer agents. Gastric acid secretion inhibitory action is usually measure by the "Shay rat" procedure.sup.(1,2) with some modifications as follows.
The rats (male, CFE strain) were starved for 48 hours (water was given ad libitum) to permit evacuation of stomach contents. On the morning of the experiment, under ether anesthesia, the abdominal region was shaved and a midline incision (1-11/2inches) was made with a scapel. With the help of a closed curved hemostate the duodenum was picked up. Upon getting the duodenum into view, fingers were used to pull the stomach through the opening, the stomach was then gently manipulated with fingersto rid the stomach of air and residual matter which were pushed through the pylorus. Two-5 inch sutures were drawn under the pyloric-duodenal puncture. A ligature, at the juncture, was formed with one of the threads. The second ligature was alsoformed but not tightened.
The test compound and the vehicle, usually 1 ml./100 g. body weight, were injected into the duodenum as close as possible to the first ligature. After injection the second ligature was tightened below the injection site to minimize leakage. Thestomach was placed back through the opening into the abdominal cavity, the area of incision was washed with saline and the incision was closed with autoclips. (Occasionally, instead of an intraduodenal injection, animals were dosed by the oral orsubcutaneous route. In the latter case, dosing was done 30 to 60 minutes before the operation.)
Three hours later, the rats were decapitated and exanguinated, taking care that blood did not drain into the esophagus. The abdominal cavity was exposed by cutting with scissors and the esophagus close to the stomach was clamped off with ahemostat, the stomach was removed by cutting above the hemostat (the .[.espphagus.]. .Iadd.esophagus .Iaddend.was cut) and between the two sutures. Extraneous .[.tisue.]. .Iadd.tissue .Iaddend.was removed, the stomach washed with saline and blotted ongauze. A slit was carefully made in the stomach which was held over a funnel and the contents were collected in a centrifuge tube. The stomach was further cut along the outside edge and turned inside out. Two ml. H.sub.2 O were used to wash thestomach contents into the respective centrifuged tube. The combined stomach contents and wash were then centrifuged out for 10 min. in the International Size 2 Centrifuge (setting at 30). The supernatant was collected, volume measured and recorded, 2drops of a phenylphthalein indicator (1% in 95% ethanol) were added and the solution was titrated with 0.02N NaOH (or with 0.04N NaOH when large volumes of stomach contents were encountered to pH 8.4 (because of usual coloring of the stomach contents,phenolphthalein was only used to permit visual indication that the end point was near) and the amount of acid present was calculated.
Compounds inducing inhibition of gastric acid secretion of 20% or more were considered active. In a representative operation, and merely by way of illustration, the results obtained with this assay with typical compounds of the present inventionare given in Table II below.
Table II ______________________________________ Intraduodenal dose, mg./kg Percent Compound of body weight Inhibition ______________________________________ 9-oxo-16-hydroxy-13- trans-prostenoic acid 50 67 9-oxo-16-hydroxy prostanoicacid 50 58 9-oxo-20-hydroxy 13-trans-prostenoic acid 100 56 9-oxo-18/19-hydroxy- 13-trans-prostenoic acid 100 28 9-oxo-18-hydroxy-19, 20-dinor-13-trans- prostenoic acid 50 21 Ethyl 9-oxo-18-hy- droxy-19,20-dinor- 13-trans-prostenoate 100 49 9-oxo-11.alpha.,16-dihy- 1.6* 79 droxy-13-trans-pro- 0.8* 53 stenoic acid 0.4* 27 9-oxo-11.alpha.,17-dihy- droxy-13-trans-pro- stenoic acid 50 73 9-oxo-20-hydroxy-10, 13-trans-prosta- 50 91 dienoic acid ______________________________________
Bronchodilator activity was determined in guinea pigs against bronchospasms elicited by intravenous injections of 5-hydroxytryptamine, histamine or acetylcholine by the Konzett procedure, [See J. Lulling, P. Lievens, F. El Sayed and J. Prignot,Arzneimittel-Forschung, 18, 995 (1968).]
In the Table which follows bronchodilator activity for representative compounds of this invention against one or more of the three spasmogenic agents is expressed as an ED.sub.50 determined from the results obtained with three logarithemiccumulative intravenous dose.
TABLE III __________________________________________________________________________ Bronchodilator Activity (Konzett Assays) __________________________________________________________________________ ED.sub.50 mg./kg. Spasmorgenic Agent 5-hydroxy- Compound tryptamine histamine choline __________________________________________________________________________ 9-oxo-20-hydroxy-13- trans-prostenoic 117 .times. 10.sup.-3 30 .times. 10.sup.-3 2.16 acid 9-oxo-18-hydroxy- 19,20-dinor-13- 2.85 2.22 10.0 trans-prostenoic acid 9-oxo-16-hydroxy- 13-trans-prostenoic 277 .times. 10.sup.-a 34.6 .times. 10.sup.-3 455 .times. 10.sup.-3 acid 9-oxo-16-hydroxy- prostanoic acid 92.7 .times. 10.sup.-3 477 .times. 10.sup.-a 1.13 9-oxo-18/19-hydroxy- 13-trans-prostenoic 1.19 1.04 acid 9-oxo-11.alpha.,16-dihy- droxy-13-trans- .607 .times. 10.sup.-3 166 .times. 10.sup.-3 .420 .times. 10.sup.-3 prostenoic acid 9-oxo-11.alpha.,17-dihy- droxy-13-trans-pro- 0.235 0.450.518 stenoic acid 9-oxo-11.alpha.,20-dihy- droxy-13-trans- 0.377 0.077 2.34 prostenoic acid 9-oxo-20-hydroxy-10, 13-trans-prosta- 1.32 2.28 dienoic acid __________________________________________________________________________
This invention will be described in greater detail in conjunction with the following specific examples.
EXAMPLE 1
Preparation of 2-carbalkoxy(methyl/ethyl)-2-(4-carbethoxybutyl)cyclopentan-1-one
To a stirred solution of the sodium cyclopentanone carboxylate enolate in dimethoxyethane, prepared from 187 g. (1.248 moles) of 2-cyclopentanone carboxylate (mixed methyl and ethyl esters), 52.4 g. (1.248 moles) sodium hydride (57.2% in mineraloil) and 1.6 l. of dimethoxyethane, is added dropwise 309 g. (1.212 moles) of ethyl 5-iodovalerate. The reaction mixture is stirred and heated at reflux for 18 hours. The mixture is cooled and filtered. The solvent is removed from the filtrate byevaporation and the residue is poured into dilute hydrochloric acid and extracted with ether. The combined extracts are washed with water and saline, dried over magnesium sulfate and evaporated to give an oil. The oil is distilled under reducedpressure to give 274 g. of a light yellow oil, b.p. 140.degree.-143.degree. C. (0.17 mm).
EXAMPLE 2
Preparation of 2-(4-carboxybutyl)cyclopentan-1-one
A stirred mixture of 274 g. of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(4-carbethoxybutyl)cyclopentan-1-one (Example 1), 600 ml. of 20% hydrochloric acid and 325 ml. of acetic acid is heated at reflux for 20 hours. Solution occurs inapproximately one-half hour. The solution is cooled and diluted with water and extracted with ether. The combined extracts are washed with .[.salline.]. .Iadd.saline .Iaddend.and dried over magnesium sulfate and evaporated. The residue is evaporatedtwice with toluene to give 144 g. of an oil.
EXAMPLE 3
Preparation of 2-(4-carbethoxybutyl)cyclopentan-1-one
A stirred solution of 124 g. (0.673 mole) of 2-(4-carboxybutyl)cyclopentan-1-one (Example 2), 800 ml. of ethanol and 1 g. of p-toluenesulfonic acid monohydrate is heated at reflux for 18 hours. The solvent is evaporated and the residue isdissolved in ether. The ether solution is washed with saline, dilute sodium bicarbonate solution and again with saline, dried over magnesium sulfate and evaporated. The oil is distilled under reduced pressure to give 149 g. of a colorless oil, b.p. 106.degree.-109.degree. C. (0.23 mm).
EXAMPLE 4
Preparation of 2-carbalkoxy(methyl/ethyl)-2-(3-carbethoxypropyl)cyclopentan-1-one
In the manner described in Example 1, treatment of 2-cyclopentanone carboxylate (mixed methyl and ethyl esters) with sodium hydride in dimethoxyethane followed by ethyl 4-iodobutyrate gives a yellow oil, b.p. 136.degree.-137.degree. C. (0.16mm).
EXAMPLE 5
Preparation of 2-(3-carboxypropyl)cyclopentan-1-one
In the manner described in Example 2, treatment of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(3-carbethoxypropyl)cyclopentan-1-one (Example 4) with a 20% hydrochloric acid and acetic acid mixture gives a yellow oil.
EXAMPLE 6
Preparation of 2-(3-carbethoxypropyl)cyclopentan-1-one
In the manner described in Example 3, treatment of 2-(3-carboxypropyl)cyclopentan-1-one (Example 5) with p-toluenesulfonic acid monohydrate in ethanol gives a colorless oil, b.p. 93.degree. C. (0.10 mm).
EXAMPLE 7
Preparation of ethyl and methyl 2-(6-carbethoxyhexyl)-1-cyclopentanon-2-carboxylate
In the manner described in Example 1, ethyl and methyl 2-cyclopentanone carboxylate is reacted with ethyl 7-bromoheptanoate to furnish the subject product, b.p. 147.degree. C. (0.09 mm).
EXAMPLE 8
Preparation of 2-(6-carboxyhexyl)cyclopentan-1-one
In the manner described in Example 2, ethyl and methyl 2-(6-carbethoxyhexyl)-1-cyclopentanone-2-carboxylate (Example 7) is hydrolyzed to furnish the subject product, b.p. 143.degree. C. (0.05 mm).
EXAMPLE 9
Preparation of 2-(6-carbethoxyhexyl)cyclopentan-1-one
In the manner described in Example 3, 2-(6-carboxyhexyl)cyclopentan-1-one (Example 8) is esterified to furnish the subject product, b.p. 110.degree. C. (0.03 mm).
EXAMPLE 10
Preparation of 1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-ene
A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one (Example 9) in 250 ml. of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at118.degree. C. or less (i.e., acetic acid) to escape through a Vigreux column equipped with a condenser to collect the distillate. After 16 hours, during which period acetic anhydride is added in portions in order to keep the solvent level at at least100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodiumbicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g.(87%) of pale yellow oil, b.p. 118.degree. C. (0.07 mm).
EXAMPLE 11
Preparation of 1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-ene
In the manner described in Example 10, treatment of 2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 98.degree. -103.degree. C. (0.35 mm).
EXAMPLE 12
Preparation of 1-acetoxy-2-(4-carbethoxybutyl)cyclopent-1-ene
In the manner described in Example 10, treatment of 2-(4-carbethoxybutyl)cyclopentan-1-one (Example 3) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 109.degree.-110.degree. C. (0.37 mm).
EXAMPLE 13
Preparation of 2-(6-carbethoxyhexyl)cyclopent-2-en-1-one
To a rapidly stirred mixture of 50 g. of 1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-ene (Example 10) in 150 ml. of chloroform, 200 ml. of water and 18.8 g. of calcium carbonate, cooled in an ice bath, is added dropwise over a period of about 30minutes, a solution of 30 g. of bromine in 50 ml. of carbon tetrachloride. After stirring for an additional 45 minutes the chloroform layer is separated and washed successively with dilute sodium thiosulfate solution, saturated sodium chloridesolution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure.
The residual oil is dissolved in 50 ml. of N,N-dimethylformamide and added to a mixture of 33 g. of lithium bromide and 32 g. of lithium carbonate in 375 ml. of N,N-dimethylformamide, previously dried by refluxing with 375 ml. of benzene undera Dean-Stark apparatus followed by distillation of the benzene. The mixture is stirred at the reflux temperature for 30 minutes, then cooled and poured into 850 ml. of ice-cold water. The resulting mixture is acidified (cautiously) with 4Nhydrochloric acid and extracted with ether three times. The combined ether extracts are washed with saturated sodium chloride solution dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure to afford 41.5 g. of an amber oil. In order to convert any isomeric material to the desired product, 41.5 g. of the above material is treated with 0.500 g. of p-toluenesulfonic acid monohydrate in 450 ml. of absolute alcohol at the reflux temperature for 18 hours. The solution is takento dryness under reduced pressure. The resulting gum is dissolved in ether and washed with saturated sodium bicarbonate solution, saturatd sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure. Theresidual oil is distilled to give 30.2 g. of product; b.p. 118.degree. C. (0.05 mm); .lambda..sub.max.sup.MeOH 229 m.mu. (.epsilon.9950); .lambda..sub.max 5.75, 5.85, 6.15, 8.45 .mu.; vapor phase chromatography shows 99% product, containing 1%2-(6-carbethoxyhexyl)cyclopentan-1-one.
This product can be purified by the following procedure. A mixture of 120 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone, containing approximately 5% of the saturated analogue, and 7.67 g (10 mole percent) of p-carboxyphenylhydrazine in 400 ml. of absolute ethanol is stirred at ambient temperatures for 18 hours and is then refluxed for 1 hour. The mixture is cooled, the solvent is evaporated, and the residue is taken up into 150 ml. of chloroform and passed through a column of 450 g. ofaluminum oxide (Merck). The .[.fltrate.]. .Iadd.filtrate .Iaddend.is evaporated to yield a colorless oil containing <0.5% of the saturated impurity.
EXAMPLE 14
Preparation of 2-(3-carbethoxypropyl)cyclopent-2-en-1-one
In the manner described in Example 13, bromination of 1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-ene (Example 11) followed by dehydrobromination with lithium bromide and lithium carbonate is productive of the subject compound.
EXAMPLE 15
Preparation of 2-(4-carbethoxybutyl)cyclopent-2-en-1-one
In the manner described in Example 13, treatment of 1-acetoxy-2-(4-carbethoxybutyl)cyclopent-1-ene (Example 12) with bromine and subsequent treatment of the brominated product with a mixture of lithium bromide and lithium carbonate inN,N-dimethylformamide is productive of the subject compound. Treatment of this product with p-carboxyphenylhydrazine by the procedure of Example 13 furnishes a product which contains less than 0.5% of the corresponding saturated ketone.
EXAMPLE 16
Preparation of 1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene
To a mixture of 35.97 g. (0.151 mole) or of 2-(6-carbethoxyhexyl)-2-cycopentenone (Example 13) and 15.0 g. (0.180 mole) of methoxyamine hydrochloride in 300 ml. of absolute ethanol is added 25 ml. of pyridine and the resulting solution isstirred for 20 hours at ambient temperatures. The solvent is evaporated and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4), and the solvent is evaporatedto yeild an oil. Distillation yields 38.7 g. of a colorless oil, b.p. 115.degree.-118.degree. C. (0.075 mm). IR (film): 1740, 1627, 1053, 890 cm.sup.-1. .lambda..sub.max (MeOH) 243 (13,000). NMR.delta.(CDCl.sub.3): 3.89.
EXAMPLE 17
Preparation of 1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene
To an ice cooled solution of 34.10 g. (0.128 mole) of 1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene (Example 16) in 200 ml. of benzene under nitrogen is added dropwise 225 ml. of a 25% solution of diisobutyl aluminum hydride in hexane. The resulting solution is stirred for 2 hours at 0.degree.-5.degree. C., poured onto ice and dilute hydrochloric acid, and the aqueous phase is saturated with sodium chloride. The organic phase is separated, washed with saturated brine, dried (Na.sub.2SO.sub.4), and evaporated to yield an oil. The latter is dissolved in 100 ml. of hot hexane and cooled to yield 24.3 g. of crystals, m.p. 62.degree.-64.degree. C. IR (KBr) 3260, 1630, 1059, 893 cm.sup.-1. .lambda..sub.max 243 (14,200). NMR(CDCl.sub.3).delta.: 2.37.
EXAMPLE 18
Preparation of 1-methoximino-2-(7-p-toluenesulfonyloxyheptyl)-2-cyclopentene
To a solution of 5.00 g. (0.222 mole) of 1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene (Example 17) in 50 ml. of dry pyridine at 0.degree. C. is added 8.45 g. (0.0444 mole) of p-toluenesulfonyl chloride and the resulting solution is chilledat 5.degree. C. overnight. The mixture is partitioned between 300 ml. of ice water and diethyl ether. The organic phase is washed with 1:1 ice cold hydrochloric acid, cold water, and cold saturated brine, dried (NaSO.sub.4 /K.sub.2 CO.sub.3), andevaporated under reduced pressure at room temperature to yield an oil. The latter is dissolved in 600 ml. of hexane, treated with 0.5 g. of Darco, filtered and evaporated to yeild 7.7 g. of colorless oil. IR (film) 1600, 1192, 1182, 1053, 890cm.sup.-1. .lambda..sub.max (MeOH) 228 and 243.
EXAMPLE 19
Preparation of 1-methoximino-2-(8,8-dicarbethoxyoctyl)-2cyclopentene
To an alcoholic solution of sodiodiethyl malonate, prepared from 0.847 g. (0.0368 g. atoms) of sodium, 100 ml. of absolute ethanol, and 7.05 g. (0.0440 mole) of diethyl malonate is added 7.7 g. of the tosylate of Example 18 and the mixture isrefluxed for 2 hours under a nitrogen atmosphere. The mixture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4), and evaporated to yield anoil. The excess diethyl malonate is distilled off under reduced pressure to yield 6.45 g. of a yellowish oil. IR (film) 1755, 1728, 1625, 1054, 890 cm.sup.-1.
EXAMPLE 20
Preparation of 1-methoximino-2-(8,8-dicarboxyoctyl)-2-cyclopentene
A mixture of 6.45 g. of the diester of Example 19 and 6.72 g. of potassium hydroxide in 150 ml. of 1:1 aqueous methanol is refluxed for 1 hour, cooled, and is partitioned between water and diethyl ether. The aqueous phase is acidified withhydrochloric acid, extracted with ether, and the organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4) and evaporated to yield a solid. The solid is crystallized from benzene to yield 4.15 g. of tan crystals, m.p. 135.degree.-137.degree. C. (--CO.sub.2).
EXAMPLE 21
Preparation of 1-methoximino-2-(8-carboxyoctyl)-2-cyclopentene
A solution of 3.926 g. (0.0126 mole) of the diacid of Example 20 in 20 ml. of xylene is refluxed for 1.5 hours, cooled and evaporated to yield a tan solid. IR (KBr) 1720, 1618, 1179, .[.1050,,.]. .Iadd.1050, .Iaddend.986 cm.sup.-1.
EXAMPLE 22
Preparation of 2-(8-carboxyoctyl)cyclopent-2-en-1-one
The acid methoxime from Example 21 is refluxed for 5 hours with 55 ml. of acetone and 20 ml. of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated, and the residue is partitioned between water and diethyl ether. Theorganic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4), and evaporated to yield a tan solid. IR (KBr) 1745, 1665 cm.sup.-1. .lambda..sub.max (MeOH) 228 (12,600).
EXAMPLE 23
Preparation of 2-(8-carbethoxyoctyl)cyclopent-2-en-1-one
The acid ketone from Example 22 is Fisher esterfied with 100 ml. of absolute ethanol, 100 ml. of benzene, and 20 mg. of p-toluenesulfonic acid for 6 hours, cooled, and the solvent is evaporated. The resulting oil is dissolved in 3:1benzene-ether and the solution is passed through a column of 100 g. of Florisil. The filtrate is evaporated and the residue is distilled to yield 2.97 g. of a colorless oil, b.p. 137.degree.-139.degree. C. (0.05 Torr).
EXAMPLE 24
Preparation of 2-(4-carbethoxybutyl)-2-cyclopentenone methoxime
Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 15) with methoxyamine hydrochloride in the manner described in Example 16 gives an oil, b.p. 107.degree.-109.degree. C. (0.05 mm). IR (film): 1740, 1628, 1050, 885 cm.sup.-1. .lambda..sub.max (MeOH) 243 (13,600).
EXAMPLE 25
Preparation of 2-(5-hydroxypentyl)-2-cyclopentenone methoxime
Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenomethoxime (Example 24) with diisobutyl aluminum hydride in the manner described in Example 17 gives crystals, m.p. 33.degree.-35.degree. C. IR (KBr) 3420, 1630, 1050, 886 cm.sup.-1. .lambda..sub.max.sup.MeOH 243 (12,020).
EXAMPLE 26
Preparation of 2-(5-p-toluenesulfonyloxypentyl)-2-cyclopentenone methoxime
Treatment of 2-(5-hydroxypentyl)-2-cyclopentenone methoxime (Example 25) with p-toluenesulfonyl chloride in pyridine in the manner described in Example 18 gives a colorless oil. IR (film) 1600, 1190, 1180, 1050, 885 cm.sup.-1.
EXAMPLE 27
Preparation of 2-(6,6-dicarbethoxyoctyl)-2-cyclopentenone methoxime
To a solution of sodio diethyl ethylmalonate, prepared from 1.63 g. (0.0387 mole) of sodium hydride in mineral oil (57.2%), 100 ml. of ethylene glycol dimethyl ether and 8.5 g. (0.0452 mole) of ethyl diethyl malonate, is added 7.5 g. of tosylatefrom Example 26 in 20 ml. of ethylene glycol dimethyl ether and the mixture is refluxed for 3 hours and then allowed to stand at room temperature for 18 hours under nitrogen atmosphere. The reaction mixture is filtered and most of the solvent isremoved. The mixture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with water and saturated brine, dried (MgSO.sub.4), and evaporated to yield an oil. The excess ethyl diethyl malonate isdistilled off under reduced pressure to yield 6.7 g. of a yellow oil. IR (film) 1755, 1728, 1627, 1050, 885 cm.sup.-1.
EXAMPLE 28
Preparation of 2-(6,6-dicarboxyoctyl)-2-cyclopentenone methoxime
Treatment of 2-(6,6-dicarbethoxyoctyl)-2-cyclopentene methoxime (Example 26) with potassium hydroxide, and 1:1 aqueous methanol in the manner described in Example 20 gives a light yellow oil.
EXAMPLE 29
Preparation of 2-(6-carboxyoctyl)-2-cyclopentenone methoxime
In the manner described in Example 21, treatment of 2-(6,6-dicarboxyoctyl)-2-cyclopentenone methoxime (Example 28) with xylene at reflux for 18 hours gives a yellow oil.
EXAMPLE 30
Preparation of 2-(6-carboxyoctyl)-2-cyclopentenone
Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone methoxime (Example 29) with acetone and 2N hydrochloric acid in the manner described in Example 22 gives a light yellow oil.
EXAMPLE 31
Preparation of 2-(6-carbethoxyoctyl)-2-cyclopentenone
Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone (Example 30) with thionyl chloride and then treatment of the acid chloride with ethanol in the usual manner gives an amber oil. The oil is placed on a magnesia-silica gel column and eluted with3:1 benzene:ether. The solvent is removed and the residue is distilled, b.p. 122.degree. C. (0.06 mm).
EXAMPLE 32
Preparation of diethyl 1,1-dimethyl-5-tetrahydropyranylpentylmalonate
To 486 mg. (0.02 g.-atoms) of magnesium in 5 ml. of toluene containing one molar equivalent of tetrahydrofuran per equivalent of magnesium and one percent iodine (calculated in weight of magnesium) is added dropwise 3.86 g. (0.02 mole) of4-chloro-1-tetrahydropyranyloxybutane over a period of one hour with stirring, under nitrogen at 70.degree. C. The reaction mixture is stirred at 70.degree. C. for four hours. This reagent is then added dropwise to 3 g. (0.015 mole) of ethylisopropylidenemalonate in 40 ml. of tetrahydrofuran containing 392 mg. of tetrakis [iodo(tri-n-butylphosphine)copper (I)] and stirred at room temperature for 2 hours. The reaction mixture is poured into cold dilute hydrochloric acid and extracted withether. The ether extract is dried over magnesium sulfate and concentrated to give 5.92 g. of subject product as an oil.
EXAMPLE 33
Preparation of diethyl 1,1-dimethyl-5-hydroxypentylmalonate
A solution of 3.5 g. (0.01 mole) of diethyl 1,1-dimethyl-5-tetrahydrofuranyloxypentylamalonate in 70 ml. of ethanol containing 3 ml. of hydrochloric acid is allowed to stir at room temperature for 18 hours. The solution is concentrated,diluted with water and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and concentrated to give 3.262 g. of a light yellow oil. The oil is purified by distillation, b.p. 116.degree.- 117.degree. C. (0.05mm).
EXAMPLE 34
Preparation of 3,3-dimethyl-7-hydroxyheptanoic acid
A mixture of 32 g. (0.117 mole) of diethyl 1,1-dimethyl-5-hydroxypentylmalonate, 25 g. of potassium hydroxide and 600 ml. of methanol-water (1:1) is heated at reflux for 8 hours and then allowed to stand at room temperature for 18 hours. Themethanol is removed, diluted with water and the reaction mixture is acidified with concentrated hydrochloric acid. The mixture is extracted with ether. The extract is washed with water and saline, dried over anhydrous magnesium sulfate and concentratedto give 27 g. of 1,1-dimethyl-5-hydroxypentylmalonic acid. This crude oil is dissolved in 200 ml. of bis-(2-methoxyethyl)ether and is heated at reflux for 4 hours and then allowed to stand at room temperature overnight. The solvent is removed and thereaction mixture is diluted with water and extracted with ether. The organic solution is washed with saline, dried over magnesium sulfate and concentrated to give 18 g. of product as an oil.
EXAMPLE 35
Preparation of ethyl 3,3-dimethyl-7-chloroheptanoate
To a solution of 3.484 g. (0.02 mole) of 3,3-dimethyl-7-hydroxyheptanoic acid in 25 ml. of chloroform containing 3 drops of dimethylformamide is added 5.8 ml. (0.08 mole) of thionyl chloride and the solution is then heated at reflux for 3-4hours. The solution is concentated to give the intermediate 3,3-dimethyl-7-chloro-1-heptanoyl chloride. The acid chloride is dissolved in a minimum amount of benzene and added slowly to 20 ml. benzene, 10 ml. of ethanol and 2.65 ml. of collidine. The solution is heated at reflux for one hour and then concentrated. The residue is dissolved in ether, washed with water, dilute sodium bicarbonate solution and saline. The organic solution is dried over magnesium sulfate and concentrated to give 3.57g. of product as a yellow oil.
EXAMPLE 36
Preparation of ethyl 3,3-dimethyl-7-iodoheptanoate
To a solution of 3.57 g. (0.0162 mole) of ethyl 3,3-dimethyl-7-chloroheptanoate in 100 ml. of methyl ethyl ketone is added 4 g. of sodium iodide and the mixture heated at reflux for 18 hours. The reaction mixture is cooled, filtered andconcentrated. The residue is partitioned between ether and water. The aqueous phase is extracted several times with ether. The extract is washed with sodium bisulfite solution, water and saline. The organic solution is dried over magnesium sulfateand concentrated to give 4.182 g. of a yellow oil. The material is purified by distillation, b.p. 86.degree.-87.degree. C. (0.18 Torr).
EXAMPLE 37
Preparation of 2-carbalkoxy(methyl/ethyl)-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1 -one
This compound is prepared by treatment of sodiocyclopentanone carboxylate enolate with ethyl 3,3-dimethyl-7-iodoheptanoate by the procedure described in Example 1.
EXAMPLE 38
Preparation of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one
This compound is prepared by decarbalkoxylation of 2-carbalkoxy (mixed methyl and ethyl ester)-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one by the procedure described in Example 2.
EXAMPLE 39
Preparation of 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one
Esterification of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one with ethanol by the procedure described in Example 3 is productive of the subject compound.
EXAMPLE 40
Preparation of 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-one
This compound is prepared from 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one and acetic anhydride by the process described in Example 10.
EXAMPLE 41
Preparation of 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-2-en-1-one
This compound is prepared from 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene via bromination and dehydrobromination according to the procedure described in Example 13.
EXAMPLE 42
Preparation of 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene
In the manner described for the preparation of the compound of Example 16, 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene is prepared from 2-(3-carbethoxypropyl)-2-cyclopentenone (Example 14) and methoxyamine hydrochloride.
EXAMPLE 43
Preparation of 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene
In the manner described for the preparation of the compound of Example 17, 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene is prepared from 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene and diisobutylaluminum hydride.
EXAMPLE 44
Preparation of 2-(6-carbethoxy-5-oxahexyl)-1-methoximino-2-cyclopentene
To an ice cold solution of 4.833 g. (0.0266 mole) of 2-(4-hydroxypentane)-1-methoximino-2-cyclopentene in 50 ml. of dry tetrahydrofuran under nitrogen is added 16.7 ml. of 1.6 molar n-butyl lithium in hexane, dropwise. The reaction mixture isstirred for 0.5 hour and then 4.85 g. (0.029 mole) of ethyl bromoacetate is added dropwise. The reaction mixture is stirred overnight at room temperature and then refluxed for 1.5 hours. The reaction is cooled and poured into water and extractedseveral times with ether. The ether extracts are washed with saline, dried over magnesium sulfate, and concentrated. The residue is placed on an alumina column, chloroform being used as a wash solvent. The combined washings are concentrated to drynessto give 4.903 g. of product an a yellow oil.
EXAMPLE 45
Preparation of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone
In the manner described in Example 22, treatment of 2-(6-carbethoxy-5-oxahexyl)-1-methoximino-2-cyclopentene with acetone and 2N hydrochloric acid at reflux gives the subject compound as a yellow oil.
EXAMPLE 46
Preparation of 2-(6-carbethoxy-5-oxahexyl)-2-cyclopentenone
In the manner described in Example 23, treatment of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol produces the subject product as a light yellow oil.
EXAMPLE 47
Preparation of 2-(6-carboxy-5-oxahexyl)-1-methoximino-2-cyclopente
To an ice cold solution of 3.66 g. (0.02 mole) of 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene (Example 43) in 50 ml. of 1,2-dimethoxyethane under nitrogen is added dropwise 17 ml. of 1.6 M n-butyl lithium in hexane. The reaction mixture isstirred for half an hour and then the lithium salt of chloroacetic acid, prepared from 1.89 g. (0.02 mole) of chloroacetic acid and 16 ml. of 1.6M n-butyl lithium in 20 ml. of dimethoxyethane, is added and the reaction mixture is heated at reflux for48 hours. The solvent is evaporated and the residue is partitioned between ether and water. The aqueous phase is acidified with hydrochloric acid and extracted with ether. The organic phase is washed with water and saturated saline solution, dried(MgSO.sub.4), and evaporated to give 3.35 g. of a yellow oil.
EXAMPLE 48
Preparation of 2-(6-carboxy-5-oxahexyl)-2-cyclopenten-1-one
In the manner described in Example 22, treatment of 2-(6-carboxy-5-oxahexyl)-1-methoximino-2-cyclopentene (Example 47) with acetone and 2N hydrochloric acid at reflux gives the subject compound as a yellow oil.
EXAMPLE 49
Preparation of 1-methoximino-2-(4-methanesulfonyloxybutyl)-2-cyclopentene
To a solution of 1.83 g. (0.01 mole) of 1-methoximino-2-(4-hydroxybutyl)-2-cyclopentene (Example 43) in 10 ml. of methylene chloride containing 1.52 g. (0.015 mole) of triethylamine is added 1.265 g. (0.011 mole) of methanesulfonyl chloride overa period of 5-10 minutes at -10.degree.-0.degree. C. Stirring is continued for 15 minutes and the solution is then washed with cold water cold 10% hydrochloric acid, cold sodium bicarbonate solution, and cold saline solution. The organic phase is dried(MgSO.sub.4) and concentrated to give an oil which solidifies upon cooling. Crystallization from ether-petroleum ether (30.degree.-60.degree. C.) gives 1.797 g. of white crystals, m.p. 67.degree.-68.degree. C.
EXAMPLE 50
Preparation of 1-methoximino-2-(5-cyanopentyl)-2-cyclopentene
A mixture of 2.75 g. (0.01 mole) of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 60) and 1.47 g. (0.03 mole) of sodium cyanide in 20 ml. of dry N,N-dimethylformamide is heated at 65.degree.-70.degree. C. for 3 hours. The cooled reaction mixture is poured into water and extracted with diethyl ether. The organic phase is washed with water and saturated saline solution, dried (MgSO.sub.4), and evaporated to give 1.89 g. of a light yellow oil.
EXAMPLE 51
Preparation of 1-methoximino-2-(5-carboxypentyl)-2-cyclopentene
A mixture of 1.89 g. (0.0092 mole) of 1-methoximino-2-(5-cyanopentyl)-2-cyclopentene (Example 50) and 1 g. (0.025 mole) of sodium hydroxide in 50 ml. of 1:1 aqueous-ethanol is refluxed for 48 hours, coled, and partitioned between water anddiethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with diethyl ether, and the organic phase is washed with water and saturated saline solution, dried (MgSO.sub.4), and evaporated to give 1.86 g. of a yellow oil.
EXAMPLE 52
Preparation of 2-(5-carboxypentyl)-2-cyclopentenone
A solution of 1.86 g. (0.00825 mole) 1-methoximino-2-(5-carboxypentyl)-2-cyclopentene (Example 51) in 44 ml. of acetone and 13.1 ml. of 2N hydrochloric acid is refluxed for 5 hours. The solvent is partially evaporated and a solid precipitatesand is collected. The residue is extracted with diethyl ether and the organic phase is washed with saturated saline solution, dried (MgSO.sub.4), and evaporated to yield additional solid. The combined solid material is crystallized from ether/pet ether(30.degree.-60.degree. C) to yield crystalline material, m.p. 70.degree.-72.degree. C.
EXAMPLE 53
Preparation of 2-(5-carbethoxypentyl)-2-cyclopentenone
A solution of 1.309 g. (0.00668 mole) of 2-(5-carboxypentyl)-2-cyclopentenone (Example 52) and 90 mg. of p-toluenesulfonic acid in 150 ml. of ethanol is refluxed for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The organic phase is washed with water, sodium bicarbonate solution, and saturated saline solution, dried (MgSO.sub.4), and evaporated to give 1.371 g. of light yellow oil.
EXAMPLE 54
Preparation of 2-(5-acetoxypentyl-2-carbomethoxy/carbethoxy-cyclopentanone
A mixture of sodiocyclopentanone carboxylate, prepared from 1200 g. (8.0 moles) of cyclopentanone carboxylate (methyl and ethyl esters) and 200 g. (8.3 moles) of mineral oil free sodium hydride in 10 l. of 1,2-dimethoxyethane, 1320 g. (8.0 moles)of 5-chloro-1-amyl acetate [M.E. Synerholm, Journ. Amer. Chem. Soc., 69, 2681 (1947)], and 1200 g. (8.0 moles) of sodium iodide is refluxed under nitrogen for 18 hours. The mixture is cooled, connected to 4 l. and partitioned between dilutehydrochloric acid and diethyl ether. The organic phase is washed with water and saturated brine, dried (MgSO.sub.4), and evaporated to yield 1920 g. of an oil.
EXAMPLE 55
Preparation of 2-(5-hydroxypentyl)cyclopentanone/2-(5-acetoxypentyl)-cyclopentanone
A mixture of 4,500 g. (16.2 moles) of 2-(5-acetoxypentyl)-2-carbomethoxy/carboethoxy-cyclopentanone (Example 54), 2.2 l. of glacial acetic acid, 1 l. of concentrated hydrochloric acid, and 1 l. of water is refluxed for 18 hours, cooled, andpartitioned between saturated brine and benzene. The organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated in vacuo to yield 3155 g. of an oil.
EXAMPLE 56
Preparation of 1-acetoxy-2-(5-acetoxypentyl)-1-cyclopentene
A solution of 400 g. (2.04 moles) of a mixture of 2-(5-hydroxypentyl)cyclopentanone and 2-(5-acetoxypentyl)cyclopentanone (Example 55) and 4.0 g. of p-toluenesulfonic acid monohydrate in 11 l. of acetic anhydride is refluxed acetic a rate tomaintain a steady distillation of acetic acid from the reaction through a relix-packed fractionation column. The reaction is continued with the addition of acetic anhydride to maintain a constant volume until complete conversion of starting materials toproduct is evident. The mixture is cooled and partitioned between 2 l. of hexane and 3 l. of cold water containing solid sodium bicarbonate to maintain a neutral pH. The organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporatedto yield 452 g. of an oil.
EXAMPLE 57
Preparation of 2-(5-acetoxypentyl)-2-cyclopentenone
To a well stirred mixture of 405 g. (4.05 moles) of calcium carbonate, 3 l. of water, and 2.5 l. of chloroform cooled to 5.degree. C. is added simultaneously 1016 g. (4.0 moles) of 1-acetoxy-2-(5-acetoxy-pentyl)-1-cyclopentene (Example 56) and asolution of 648 g. (4.05 moles) of bromine in 500 ml. of carbon tetrachloride at a rate to maintain a temperature below 10.degree. C. The mixture is stirred for half an hour after addition of the reagents and the phases are then separated. The organicphase is washed with 2% sodium thiosulfate solution, water, and saturated brine, dried (MgSO.sub.4), and evaporated in vacuo to an oil. The oil is immediately added to a refluxing slurry of 500 g. (5.0 moles) of calcium carbonate in 2.5 l. ofN,N-dimethylacetamide under nitrogen and the mixture is then refluxed for 30 minutes. The mixture is cooled, filtered, and partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (MgSO.sub.4), andevaporated to yield 757 g. of an oil, b.p. 116.degree.-118.degree. C. (0.25 mm.).
EXAMPLE 58
Preparation of 1-methoximino-2-(5-acetoxypentyl)-2-cyclopentene
In the manner described for Example 16, 2-(5-acetoxypentyl)-2-cyclopentenone (Example 57) is treated with methoxyamine hydrochloride in pyridine and ethanol to yield the subject compound, b.p. 101.degree.-103.degree. C. (0.20 mm.).
EXAMPLE 59
Preparation of 1-methoximino-2-(5-hydroxypentyl)-2-cyclopentene
A mixture of 74 g. (0.22 mole) of 1-methoximino-2-(5-acetoxypentyl)-2-cyclopentene (Example 58) and 56 g. (1.0 mole) of potassium hydroxide in 300 ml. of 1:1 aqueous methanol is refluxed for 2 hours and then cooled. The solvent is partiallyremoved in vacuo and the residue is partitioned between saturated brine and diethyl ether. The organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated to yield an oil which crystallized, m.p. 35.degree.-36.degree. C.
EXAMPLE 60
Preparation of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene
To a cold solution of 9.85 g. (0.05 mole) of 1-methoximino-2-(5-hydroxypentyl)-2-cyclopentene (Example 59) and 7.6 g. (0.075 mole) of triethylamine in 100 ml. of methylene chloride at -10.degree. C. is added 6.3 g. (0.055 mole) ofmethanesulfonyl chloride at a rate to maintain a temperature of -10.degree. C. The mixture is then stirred for 15 minutes and then poured into ice water. The organic phase is washed with cold 10% hydrochloric acid, cold saturated sodium bicarbonatesolution, and cold saturated brine, dried (MgSO.sub.4), and evaporated to yield a solid, m.p. 78.degree.-80.degree. C.
EXAMPLE 61
Preparation of 1-methoximino-2-(6,6-dicarbethoxyhexyl)-2-cyclopentene
To a suspension of sodiodiethylmalonate in 1,2-dimethoxyethane, prepared from 248 g. (1.55 moles) of diethyl malonate and 17.2 g. (0.95 mole) of mineral oil free sodium hydride in 1 l. of 1,2-dimethoxyethane under nitrogen, is added 170 g. (0.62mole) of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 60) in 1.5 l. of 1,2-dimethoxyethane and the mixture is refluxed for 5 hours. The mixture is cooled, filtered, and the solvent is evaporated. The residue is partitionedbetween cold dilute hydrochloric acid and water, and the organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated to remove solvent and excess diethyl malonate to yield 209 g. of an oil.
EXAMPLE 62
Preparation of 1-methoximino-2-(6,6-dicarboxyhexyl)-2-cyclopentene
In the manner described in Example 20, 1-methoximino-2-(6,6-dicarbethoxyhexyl)-2-cyclopentene is treated with potassium hydroxide in 1:1 aqueous methanol and then hydrochloric acid to yield the desired compound as crystals from diethyl ether,m.p. 110.degree.-115.degree. C.
EXAMPLE 63
Preparation of 1-methoximino-2-(6-carboxyhexyl)-2-cyclopentene
A solution of 141 g. (0.50 mole) of 1-methoximino-2-(6,6-dicarboxyhexyl)-2-cyclopentene in 500 ml. of bis-(2-methoxyethyl) ether is refluxed for 2 hours, cooled, and evaporated to yeild an oil. The latter is crystallized from hexane to yield 92g. of solid, m.p. 70.degree.-72.degree. C.
EXAMPLE 64
Preparation of 2-(6-carboxyhexyl)-2-cyclopentenone
In the manner described in Example 22, treatment of 1-methoximino-2-(6-carboxyhexyl)-2-cyclopentene (Example 63) with acetone and 2N hydrochloric acid at reflux provides the subject compound.
EXAMPLE 65
Preparation of 2-(6-carbethoxyhexyl)-2-cyclopentenone
Fischer estification of 2-(6-carboxyhexyl)-2-cyclopentenone (Example 64) in the manner of Example 23 provides the subject compound.
EXAMPLE 66
Preparation of 1-methoximino-2-(6-fluoro-6,6-dicarbethoxyhexyl)-2-cyclopentene
To a solution of sodiodiethyl fluoromalonate, prepared from 2.062 g. (0.0491 mole) of sodium hydride in mineral oil (57.2%), 40 ml. of dry N,N-dimethylformamide and 8.174 g. (0.0458 mole) of diethyl fluoromalonate is added dropwise 11.32 g.(0.0413 mole) of 1-methoximino-2-(5-methylsulfonyloxypentyl)-2-cyclopentene (Example 60) in 60 ml. of N,N-dimethylformamide. The mixture is refluxed for 2 hours under a nitrogen atmosphere. The mixture is concentrated and partitioned between colddilute hydrochloric acid and diethyl ether, and the organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated to yield 13.631 g. (92%) of a yellow oil.
EXAMPLE 67
Preparation of 1-methoximino-2-(6fluoro,6,6-dicarboxyhexyl)-2-cyclopentene
A mixture of 13.631 g. of the diester of Example 66 and 16 g. of potassium hydroxide in 364 ml. of 1:1 aqueous methanol is refluxed for 5 hours, cooled, concentrated, and is partitioned between water and diethyl ether. The aqueous phase isacidified with hydrochloric acid, extracted with ether, and the organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated to yield a solid. The solid is crystallized free diethyl ether petroleum ether (30.degree.-60.degree. C.)to give 10 g. (90%) of white crystals, m.p. 143.degree.-145.degree. C. (--CO.sub.2).
EXAMPLE 68
Preparation of 1-methoximino-2-(6-fluoro-6-carboxyhexyl)-2-cyclopentene
A solution of 10 g. of the diacid of Example 67 in 60 ml. of 2-methoxyethyl ether is refluxed for 7 hours, cooled, and evaporated to yield 8.5 g. (95%) of a tan solid. A sample is crystallized from diethyl ether-petroleum ether(30.degree.-60.degree. C.) to give white crystals, m.p. 98.degree.-100.degree. C.
EXAMPLE 69
Preparation of 2-(6-fluoro-6-carboxyhexyl)cyclopent-2-en-1-one
The acid methoxime (8.5 g.) from Example 68 is refluxed for 5 hours with 180 ml. of acetone and 64 ml. of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated, and the residue is partitioned between water and diethyl ether. The organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated to yield 7.4 g. (98%) of a light yellow oil.
EXAMPLE 70
Preparation of 2-(6-fluoro-6-carbethoxyhexyl)cyclopent-2-en-1-one
The acid ketone (7.4 g.) from Example 69 is Fisher esterified with 300 ml. of absolute ethanol and 400 mg. of p-toluenesulfonic acid for 18 hours, cooled and the solvent is evaporated. The resulting oil is dissolved in ether, washed withdilute sodium bicarbonate solution, and saline, dried (MgSO.sub.4) and evaporated to give 7.306 g. (86%) of a light yellow oil.
EXAMPLE 71
Preparation of 2-(7-cyanoheptyl)-1-methoximino-2-cyclopentene
Treatment of 1-methoximino-2-(7-p-toluenesulfonyloxy)-2-cyclopentene (Example 18) with sodium cyanide in the manner of Example 50 is productive of the subject compound.
EXAMPLE 72
Preparation of 2-(7-carboxyheptyl)-1-methoximino-2-cyclopentene
Alkaline hydroylsis of 2-(7-cyanoheptyl)-1-methoximino-2-cyclopentene (Example 71) of th eprocedure of Example 51 is productive of the subject compound.
EXAMPLE 73
Preparation of
2-(7-carboxyheptyl)-2-cyclopenten-1-one
Hydrolysis of the methoxime of Example 72 with acetone-hydrochloric acid by the procedure of Example 52 is productive of the subject compound.
EXAMPLE 74
Preparation of 2-(7-carbethoxyheptyl)-2-cyclopenten-1-one
Fisher esterification of the carboxylic acid of Example 73 by the procedure of Example 53 is productive of the subject compound.
EXAMPLE 75
Preparation of 2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene
Treatment of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 60) with sodio diethyl phenylmalonate by the procedure of Example 61 is productive of the subject compound.
EXAMPLE 76
Preparation of 2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene
Alkaline hydrolysis of 2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 75) by the procedure of Example 20 is productive of the subject diacid.
EXAMPLE 77
Preparation of 2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene-dicarbethoxy
Decarboxylation of 2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 76) by the procedure of Example 63 is productive of the subject compound.
EXAMPLE 78
Preparation of 2-(6-carboxy-6-phenylhexyl)-2-cyclopentene-1-one
Methoxime cleavage of 2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 77) in the manner of Example 69 is productive of the subject ketone.
EXAMPLE 79
Preparation of 2-(6-carbethoxy-6-phenylhexyl)-2-cyclopentene-1-one
Fisher esterification of the carboxylic acid of Example 78 in the manner of Example 70 is productive of the subject keto-ester.
EXAMPLE 80
Preparation of 2-(6-fluoro-6,6-dicarbethoxyhexyl)-1-methoximino-2-cyclopentene
An ethanolic solution of sodium ethoxide, prepared from 0.389 g. of sodium and 40 ml. of absolute ethanol, is treated at ambient temperatures with 5.05 g. of 2-(6,6-dicarbethoxyhexyl)-1-methoximino-2-cyclopentene (Example 61). The resultingsolution is cooled to -20.degree. C. and then treated with a stream of perchloryl fluoride until the mixture becomes neutral. The excess perchloryl fluoride is removed with a stream of nitrogen and the mixture is retreated with 10 ml. of an ethanolsolution of sodium ethoxide (from 0.350 g. of sodium) and then with perchloryl fluoride until the mixture becomes neutral. The excess perchloryl fluoride is removed with a stream of nitrogen and the mixture is filtered an evaporated to an oil. Thelatter is partitioned between ether and water and the organic phase is washed with saturated saline, dried (Na.sub.2 SO.sub.4) and evaporated to afford the subject compound.
EXAMPLE 81
Preparation of 2-(6-carbo-n-butoxyhexyl)cyclopent-2-en-1-one
A solution of 50 g. of 2-(6-carboxyhexyl)cyclopent-2-en-1-one [Bagli et al., Tertrahedron Letters, No. 5, 465 (1966)] in 400 ml. of n-butanol containing 2.7 g. of p-toluenesulfonic acid monohydrate is allowed to stand at room temperature in astoppered flask for about 24 hours. The solution is taken to dryness. The residue is taken up in ether and the ethereal solution is washed several times with saline solution, dried with anhydrous magnesium sulfate, and taken to dryness to afford thesubject butyl ester.
EXAMPLES 82-84
Treatment of 2-(6-carboxyhexyl)cyclopent-2-en-1-one by the procedure of Example 81 with the appropriate alcohol affords the esters of the following table.
TABLE IV ______________________________________ Example Alcohol Product Ester ______________________________________ 82 isopropanol 2-(6-carboisopropoxyhexyl)cyclopent-2- en-1-one 83 methanol 2-(6-carbomethyoxyhexyl)cyclopent-2-en- 1-one 84 1-hydroxy- 2-(6-carbo-n-decyloxyhexyl)cyclopent-2- n-decane en-1-one ______________________________________
EXAMPLE 85
Preparation of diethyl (5-chloro-1,1-dimethylpentyl)malonate
To magnesium (71 g. 2.92 moles) under 1 l. of ether containing a few crystals of iodine is added dropwise 1-chloro-4-bromobutane (500 g., 2.92 moles) over a period of 30 minutes with stirring under nitrogen. The reaction is maintained at atemperature of 0.degree. C. to 5.degree. C. by immersing in an acetone-Dry Ice bath periodically. After stirring for 30 minutes at room temperature, the solution is chilled to below 0.degree. C. and is then transferred to a dropping funnel from whichit is added dropwise to diethyl isopropylidene malonate (440 g., 2.19 moles) [A.C. Cope and E. M. Hancock, J.A.C.S. 60, 2644 (1938)] dissolved in 1000 ml. of ether containing the tri(n-butyl)phosphine complex of copper (I) iodide (57 g.) [G. B.Kaufman and L. A. Teter, Inorganic Synthesis, 7, 9(1963)] at -10.degree. C. with stirring under nitrogen over a period of 2 hours. After stirring at room temperature for 4 hours, the reaction mixture is poured into cold dilute hydrochloric acid and isextracted with ether. The combined ether extracts are washed with saline solution, dried over magnesium sulfate, and concentrated in vacuo to give 700 g. of crude amber oil, which is distilled under vacuum to yield two fractions: 212.4 g. with b.p. at110.degree. - 135.degree. C. at 0.3 mm. and 100.0 g. with b.p. at 135.degree. -145.degree. C. at 0.3 mm. The total yield is 312.4 g. (49%).
EXAMPLE 86
Preparation of 3,3-dimethyl-7-chloroheptanoic acid
A mixture containing diethyl 5-(5-chloro-1,1-dimethylpentyl)malonate (648 g., 2.22 moles) potassium hydroxide (460 g. and eight liters of 1:1 isopropanol:water is stirred at room temperature overnight. Most of the isopropanol is distilled andthe residue is diluted with water, and then carefully acidified with conc. hydrochloric acid. The mixture is extracted with ether and the extracts are washed with water and saline, dried over magnesium sulfate and concentrated in vacuo to give 548 g. ofcrude oil. The oil is dissolved in three liters of diglyme which is heated under reflux for sixteen hours. About 2.7 l. of solvent is distilled, and the remainder is diluted with water and extracted with ether. The extracts are washed with saline,dried over magnesium sulfate and concentrated in vacuo to give 428 g. of crude oil (99%).
EXAMPLE 87
Preparation of ethyl 3,3-dimethyl-7-chloroheptanoate
To a solution of 3,3-dimethyl-7-chloroheptanoic acid (428 g., 2.21 moles) in 3 l. of chloroform containing 3 ml. of N,N-dimethylformamide is added 500 ml. of thionyl chloride and the resulting solution is tested under reflux for 3 hours. Thereaction solution then is concentrated in vacuo and the residual acid chloride is dissolved in a minimum amount of benzene and added slowly to a solution containing 1260 ml. of 95% ethanol and 2520 ml. of benzene and 390 ml. of collidine. Afterheating under reflux for one hour, the solution is concentrated and the residue is dissolved in ether washed with water, dilute sodium bicarbonate solution and saline solution, dried over magnesium sulfate and concentrated to give 415 g. of crude oil,which is distilled under vacuum to yield two fraction 46.6 g. boiling at 75.degree. C. (0.3 mm.) and 236.7 g. boiling at 75.degree. -80.degree. C. (0.3 mm). The total yield is 283.3 g. (60%) and the product is indicated to be 95% pure by g.l.c.
EXAMPLE 88
Preparation of methyl/ethyl 2-(6-carbethoxy-5,5-dimethylhexyl) cyclopentanone-2-carboxylate
Sodium hydride (67 g., 1.55 moles) is placed in a three l. round-bottom flask and to this is added 1.1 liters of glyme from a dropping funnel under nitrogen flow and with stirring. To the resulting grayish mixture is added the2-carbalkoxycyclopentanone (mixed methyl and ethyl esters) dropwise over a period of 45 minutes with nitrogen flow whilst the temperature is maintained in the range of 40.degree.-55.degree. . Ethyl 3,3-dimethyl-7-chloroheptanoate (283 g., 1.28 moles)and potassium iodide (195 g., 1.32 moles) are added and the mixture is heated at reflu | | | |
