CA1221963A - Prostaglandin analogues and process for making same - Google Patents
Prostaglandin analogues and process for making sameInfo
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- CA1221963A CA1221963A CA000492580A CA492580A CA1221963A CA 1221963 A CA1221963 A CA 1221963A CA 000492580 A CA000492580 A CA 000492580A CA 492580 A CA492580 A CA 492580A CA 1221963 A CA1221963 A CA 1221963A
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Abstract
NOVEL PROSTAGLANDIN ANALOGUES AND PROCESS FOR
MAKING SAME
Edward David Mihelich ABSTRACT OF THE DISCLOSURE
A novel process for the oxidation of olefins to the corresponding alpha-epoxy alcohols which can be incorporated in the total synthesis of members of a novel class of prostaglandin analogues.
Olefins are reacted with singlet oxygen in the 1.DELTA.g state in the presence of a group IVB, VB or VIB
transition metal catalyst, excluding chromium. The reaction is fast and highly selective to the alpha-epoxy alcohol. When cyclopentene is oxidized in the process of the invention, high yields of cis 2,3-epoxy-cyclopentan-1-ol are obtained. The latter compound is used as a starting material in the synthesis of prostaglandin analogues. The prostanoids of the invention are characterized by an oxa group replacing the methylene group at the 7-position, and the absence of a hydroxyl or other substituent at the 11-position.
Members of this class of prostanoids show important cytoprotective properties in animal tests.
MAKING SAME
Edward David Mihelich ABSTRACT OF THE DISCLOSURE
A novel process for the oxidation of olefins to the corresponding alpha-epoxy alcohols which can be incorporated in the total synthesis of members of a novel class of prostaglandin analogues.
Olefins are reacted with singlet oxygen in the 1.DELTA.g state in the presence of a group IVB, VB or VIB
transition metal catalyst, excluding chromium. The reaction is fast and highly selective to the alpha-epoxy alcohol. When cyclopentene is oxidized in the process of the invention, high yields of cis 2,3-epoxy-cyclopentan-1-ol are obtained. The latter compound is used as a starting material in the synthesis of prostaglandin analogues. The prostanoids of the invention are characterized by an oxa group replacing the methylene group at the 7-position, and the absence of a hydroxyl or other substituent at the 11-position.
Members of this class of prostanoids show important cytoprotective properties in animal tests.
Description
NOVEL PROSTAG3.ANDIN ANALOGUES hND PROCESS
FC)R MAKI ~I G SA ~IE
Edward David Mihelich .
Technical Field This invention relates to a process of making a novel class of prostaglandin-like compounds.
Since the discovery of the naturally occurring prostaglandins and their important biological properties1 a tremendous research effor~ has been 5 devoted to the synthesis of these compounds. Although much progress has been made in the deve!opment of synthesis rou~es for the natural prosta~landins, a major stumbling block remains - the requirement of stereospecific substitution at the positions 8, 9, 11 and 12 (c.f. prostanoic cid, compound (l).
5 ~ ~C O O H
W~, 2C
One solution to ;his problem is the art-disclosed synthesis of the 7-oxa prostaglandin analogues (1ll) which uses all cis 3~5-dihydroxy-l~2-epoxycyclopentanetII) as a starting material.
OH OH
~ ~O ~
OH OH III
A key feature of this synthesis is the trans opening of the oxirane by nucleophilic attack. Althou~h this synthesis solves the problem of the trans substitution at the 12-position, it creates the new problem of isomer selective synthesis of all c~s 3,5-dihydroxy-1,2-epoxycyclopentane. In an atternpt to 5 avoid the latter problem, prostaglandin-type compounds (V) have been synthesized from 1,2-epoxycyclopentane (IV). However, this further deviation from - ¢~ ~R~
IV V
the natural prostaglandin structure (elimination of the hydroxyl ~roups at the 9and 11 positions) results in an erratic biological activity of the compounds thus 10 obtained; some of ~hem act as prostaglandin agonists in one tes~, and as antagonists in another.
No attempt has been rnade thus far to use cis-2,3-epoxycyclopentan-1-ol (VI) OH
,;~
~o VI
, . ~
9~ i as a starting material in the synthesis o prostaglandin analogues. This is not surprising, as no attractive synthesis route for (~rI) has been available thus far.
~ ormally, (VI) is synthesized by reacting cyclopenten-3-ol, a relatively expensive startin~ material9 with t-butyl hydroperoxide in the 5 presence of a vanadium catalyst. Typically a 45% isolated yield is obtained after 2 days. The reaction time is less (about l day) if the t-butyl hydroperoxide is replaced with a peracid, but then a si~nificant amount of the trans isomer is formed (cls:trans ratio about 41)o Even if cis-2,3-epoxycyclopentan-l-ol were readily available, it 10 would not be expected to be a suitable starting material for th~ synthesls ofprostaglandin-like materials. Because of the asymmetry of the molecule, the oxirane bond opening would be expected to result in two regi~isomers, of which only one would be suitable for further synthesis; and ~he resulting prostanoid would lack the hydroxyl group at the l l-position which would make 15 it, in view of the state of the art, doubtful whether biological activity of any significance wouid be possessed by this class of prostanoids.
By the present invention it has been discovered that olefins can quite readily be converted to the corresponding alpha-epoxy alcohols when they are reacted with singlet oxygen in the presence of a suitable oxidation 20 catalyst. The reaction is fast, gives high yields, has a high selectivity towards the epoxy alcohol, and uses an inexpensive starting material.
It has further been discovered that when cyclopentene is subjected to the process of this invention, c~s-2,3-epoxycyclopentan-l-ol is obtained in hi8h yield. It has surprisingly been found that when this compound is, after 25 suitable protection of the hydroxyl group, subjected to a m~cleophilic attack on the oxirane, the trans opening of the epoxide is regio-selective. This makes this compound particularly suitable for the synthesis of a novel class of prostanoids. I~lembers of this class unexpectedly show important cytoprotective activity.
6~3 ~ackground Art Different syntheses of prostaglandins are reviewed by Corey, Ann.
~l.Y. Acad. Sci., 180 (1971) 24. The 7-oxa-prostaglandins are discussed by Fried, et al., Ann. N.Y. Acad. Sci., 180 (1971) 38. Other publications related 5 to the synthesis of 7-oxa-prostaglandins include: Fried, et al., ~. Am. ~hem, Soc, 93 (1971) 5594; Fried, et al., Chem~ Comm. (1968) 634. The 7-thia pros~anoids are disclosed in U.S. Patent No. 4,175,201 granted November 20, 1979 to Fried, and U.S. Patent No. 4,180,672 gran~ed December 25, 1979 to Kurozumi, et al.
The effect of a free hydroxyl group on the regio-specificity of the epoxide opening is discussed in Fried, et al., J Am. Chem. Soc.~ 94 (1972) 4343.The catalytic oxidation of olefins to alpha-epoxy alcohols is dealt with by Kaneda, et al., J. OrR. Chem. 45 (1980) 3004; Allison, et al., Ind. and ~. tProd. Res. and Dev.) 5 (1966) 166; Lyons, Tetrahedron Lett. 32 15 (1974) 2737; U.S. Patent No. 3,259,638, granted July 5, 1966 to Allison. A
bimetallic catalyst for this reaction is disclosed in U~SO Patent No. 4,021,369,granted May 3, 1977 to Lyons.
The preparation of alpha-epox~ alcohols via catalytic rearrangement of hydroperoxides is discussed by Mercier, et al., Chem. Phys.
20 Li~ids 12 (1974) 232. The use of singlet oxygen in the reaction of olefins tohydroperoxides is disclosed by Kopecky, et al., Can. J. Chem., 43 (1965) 2265.
Although much effort has been made to improve the process of catalytic oxidation of olefins to alpha-epoxy alcohols, ~he processes reported in the art suffer from low reaction rates, low yields, and poor selecti~ities.
25 The rearrangement of hydroperoxides is fast, but requires separate preparation of these peroxides and their isolation. The process of this invention is fast, gives hi8h yields and is highly selective. Moreover, the process herein is especially adaptable to a ~ot~l synthesis of prostaglandin analogues, using cyclopentene as a starting material.
. . .
P~ Ci3 Summary of the Invention In one of its aspects, the present invention is a process for the photo-oxidative conversion of olefins to alpha-epoxy alcohols using a vanadium catalyst The present invention also encompasses a process for makin8 prostaglandin analogues usin~ cyclopentene as a relatively inexpensive starting material. The first step in this process is the conversion of cyclopentene to cis-Z,3-epoxycyclopentan-i-ol by reacting cycloperi~ene with singlet oxygen in the presence of a catalytic amoun~ of a catalyst containing a transition rnetal 10 of group IV B, V B, or VI B of the Periodic Table, excluding chromium.
Application of this process to the conversion of other olefins to ~he corresponding alpha-epoxy alcohols is also within the scope of this invention.
The next step is a nucleophilic attack on the oxirane bond with an alkynylalane reagent, resulting in a regio-selective trans opening. Prior to 15 this reaction9 the hydroxyl group is protected against nucleophilic attack with a suitable protecting group. In the next step, ~he substituent at the 8-positionis attached via a W'illiamson synthesis. Deprotection and tailoring of the oxidation states at the 9-position and in the substituent chains leads to ~he desired pros~a~landin analogues, as described more fully hereinafter.
Finally, the present invention encompasses a new class of prostaglandin analogues which are characterized by an oxygen atom replacing the methylene group at the 7-position, and the absence of a hydroxyl subs~ituent at the 1 l-position~ Members of this class have been found to possess cytoprotective properties which make them useful for the prevention 25 and treatment of ~astric ulcers.
Detailed DescriPtion of the Invention By "olefin" herein is meant an aliphatic hydrocarbon having at least one double bond and at least one allylic hydrogen. By "mono-olefin" herein is meant an olefin with one double bond.
~y "corresponding alpha epoxy alcohol" herein is meant that when the olefin startin~ material has its double bond between the carbon atoms m and mf 1, the alpha-epoxy alcohol formed is the m-hydroxy-(m+l), tm+2)-epo~y compound or the (m+l~hydroxy~m-l), m epoxy compound.
&i3 By "heterogeneous catalyst" hereln is meant a catalyst which is in the solid state and is not soluble in the reaction mixture.
By "homo~eneous catalys~' herein is meant a catalyst which is soluble in the reaction mixture.
By "acac" hereln is meant acetylacetonate.
By "singlet oxygen" herein is meant oxygen molecules in the lowest excited electronic state that has spin multiplicity of one, generally denoted asthe ~g state.
l~y "photo-sensi~ize~' herein is meant an organic compound which 10 can be exci~ed to the triplet state by adsorption of visible light.
By "catalytic amount" herein is meant an amount significantly less than a stoichiometric amount which is sufficient to act as a catalyst in the reaction.
By "prostaglandin analogue" herein is meant a compound which is 15 structurally similar to the naturally occurring prostaglandins.
By "7-oxa~ deoxy prostaglandin analogue" herein is meant a compound struc~urally similar to the natural prostaglandins of the E-series or F-series, characterized by an oxa group replacing the methylene group at the 7-position, and by the absence of a hydroxyl substituent at the 1 l-position.
~y "suitable protecting group" herein is meant any base s~able protec~ing group for alcohols. ~xamples thereof are ethers, in particular methoxymethyl, t-butyl, ben~yl, dimethyl-t-butylsilyl and methylthiomethyl ether. Protection of alcoholic hydroxyl groups is discussed by Reese, in "Protective Groups in Organic Chemistry", McOmie, editor, Plenum Press ~5 (1973) p.95 et seq. In case one of the hydroxyl groups is protected with a dimethyl-t-butylsilyl grGup~ the hydroxyl group can be deprotected selectively by reaction with tetrabu1yl -ammonium fluoride. The procedure is described by E.J. Corey, et al., J. Am.
Chem. Soc., 94, 6190 (1972~.
By 'lalkynylalanereagentll herein is meant the dialkylalkynylaluminum compound formed by reaction of dialkylaluminum chloride with a lithi~l-alkyne.
Percenta~es herein are mole percentages, unless otherwise indicated.
The firs~ aspect of this inven~ion is a pr~cess for converting olefins to the corresponding alpha-epoxy alcohols comprising reacting an olefin with singlet oxygen in the ~g state and converting the reaction product to an alpha-epoxy alcohol by in situ rearrangement in the presence of a catalytic amou~t of a heterogeneous or homogeneo~s catalyst containing a transition metal of group IVB, VB or VIB of the Periodic Table, excluding chromium. When cyclopentene is subjected to this oxidation reaction, the major product is cls 2,3-epoxycyclopentan-1-ol.
This aspect of the invention is also described, and is claimed, in Canadian Patent Application No. 397,348, filed March 1, 1982, cf which the present application is a divisional.
The present oxidation pr~cess has general applicabili~y ~o all olefins capable of reaction with singlet oxygen, that is, alkyl substituted olefins having at least one allylic hydrogen. Preferred herein are dialkyl subs~ituted olefins. The double bond may be acyclic, as in alkenes, or semi-cyclic, as in sabinene and beta-pinene, or endocyclic, as in the cycloalkenes. Olefins 20 having functional substituents9 such as halogens, carboxyl radicals7 etc., at the alpha-position with respect to the double bond are less suitable for the oxidation reaction disclosed herein, and fall outside the scope of this invention.
A detailed discussion of olefin reactions with singlet oxygen is given by Gollnick, et al., in "Singlet Oxy~en", Wasserman and Murray, editors, 25 Academic Press ~1979).
Singlet oxygen from any source may be used in the olefin oxidation reaction. Thus, singlet oxygen can be ~enerated by contacting ground-state oxygen with a photo-sensitizer ~hich has been excited by irradiation with visible light, by the reaction of sodium hypochlorite with hydrogen peroxide; by30 reaction of hydro~en peroxide with bromine in an alkalirle medium; by decomposition of the 1:1 adduct of triphenyl phosphite and ozone generated by passage of ozone in~o a solution of triphenyl phosphite in methylene chloride;
by thermal decomposition of epidioxides; or by microwave discharge in a stream of gaseous oxygen. The different methods of generating singlet oxygen 3~ are discussed in more detail by Denny, et al., in 'IOrganic Reac~ions", vol. 20 ~Z,~ 3S3 (W.G. Dauben - edi~or-in-chief),published by John Wiley ~ Sons, pp. 133-136.
For purposes of the present invention, singlet oxygen is preferably generated by contacting ground-state molecular oxygen with a suitable photosensitizer which is activated by irradiation with 5 visible light.
Suitable sensitizers are those organic compounds which have a large molar absorptivity in the visible part of the electromagnetic spectrum, a high quantum yield of triplet formation, a long triplet lifetime, a low tendency toward hydrogen abstraction and self-oxidation, and a triplet çnergy not far 10 above ~he ene~gy of singlet oxygen to permit efficient energy transfer to oxygen. Many common dyes meet these requirements adequately. Typical classes of dyes that can advantageously be used in the olefin oxidation process of this invention are the xanthenes (rose bengal, erythrosin, eosin, fluorescein), the thiazines (methylene blue), the porphyrins (chlorophyll a and b, 15 hematoporphyrin), ehe porphins and the phthalocyanines and mLxtures thereof.
These and other dyes~such as rubene, are disclosed in the - Denny reference, cited supra.
Preferred photo-sensitizers for the present invention are the phthalocyanines and tetraphenylporphin, and most preferred is 20 tetraphenylporphin.
For optimum efficiency, the amount of photosensitizer should neither be very low nor very high. At very low concentrations the sensitizer may not absorb all the available useful light. At too high a concentration, it absorbs all the useful li~ht within a shor~ distance from its entrance to the 25 solution and depletes oxygen in that region of the reaction vessel. Preferredamounts of sensitizer range from about 0.01% to about 2.5~, more preferably amounts range from about 0.05% to about 1.3~.
Any source of visible light is suitable for the activation of the sensitizer. However, for maximum efficiency, the source should strongly emit 30 light of the wavelength corresponding with the absorptivity maximum of ~he sensitizer. Thus, a sodium vapor discharge tube is particularly suitable for usein combination with tetraphenylporphin.
g Any catalyst capable of converting the reaction product of the olefin wsth sin~let oxygen9 presumably a hydroperoxide, to an alpha-epoxy alcohol is suitable for use in the olefin oxidation reaction of the presen~
invention. 5uitable catalysts are those which contain a transition metal of the 5 groups IVB, VB, or YIB of the Periodic Table. Although both heterogene~us and homogeneous catalyst sys~ems can be used, homogeneous catalysts are preferred for their superior selectivity. Suitable homogeneous catalysts are soluble salts and metallo-organic eornplexes o~ transition metals of group IVB, yB, or VIB of the Periodic Table, excluding chromium. Preferred herein are 10 the soluble salts and metalio orgar~ic complexes of vanadium ancl molybdenurn.
Examples are vanadyl acetyl cetonate, molybdenyl acetylacetonate, molybdenum hexacarbonyl, tungsten hexacarbonyl, and vanadium carbonyl~
Other examples of suitable catalysts are disclosed by Allison, et al., Ind. Sc EnR. Chem. (Prod. Res. and Dev.) 5 (1966) l66.
Preferred catalysts are those containing vanadium or molybdenun~;
more preferred are ~hose con~ainin~ vanadium (IV), and most preferred is vanadyl acetylacetonate.
The amount of catalyst should be suf~icient to ensure instantaneous 20 conversion of the hydroperoxides. Much hi8her levels of catalyst may adversely affect the efficiency of the photo-sensitization reac~ion, as most catalyst systems absorb visible light.
Suitable levels of catalyst range from about 0.1% to about 2.5~6.
Preferred levels range from 0.7% to 1.3%.
Without limitation by theory, the superior yields of alpha epoxy alcohol obtained with the process of the present invention in comparison with art disclosed processes is belie~ed to be1 at least in part, due to the presenceof the catalyst at the time the reaction intermediate, the hydroperoxide, is formed. The hydroperoxide is instantaneously converted to the epoxy alcohol 30 by the action of the catalyst. Hence, the concentration of hydroperoxide remains low throughout the reaction period, and side reactions resulting in ketones and alkenols are suppressed.
~2~9~i3 Al~hough the olefin oxidation reaction of this invention does not require a solven~, better yields are obtained when a solvent is present. Any organic solvent which is miscible with the olefin, and readily dissolves ~he photo-sensitizer and the catalys~, ls suitable. The reaction mixture rnay S contain from about 5% to about 9~% of the solvent. Alcohols should not be used, however~ as they tend to interact too strongly with the active sites of the ca~alyst and make it inactive. The reaction mixture should be substantially water-free, as water interacts with the catalyst as well.
Examples of suitable solvents are methylene dichloride and ~oluene.
The olefin oxidation process of this invention can be u~sed for the conversion of any olefin capable of reactlon with singlet oxygen to the corresponding alpha-epoxy alcohol. Examples of suitable olefins are cyclopentene, cis-9-octadecenoic acid esters, c -4-octene,
FC)R MAKI ~I G SA ~IE
Edward David Mihelich .
Technical Field This invention relates to a process of making a novel class of prostaglandin-like compounds.
Since the discovery of the naturally occurring prostaglandins and their important biological properties1 a tremendous research effor~ has been 5 devoted to the synthesis of these compounds. Although much progress has been made in the deve!opment of synthesis rou~es for the natural prosta~landins, a major stumbling block remains - the requirement of stereospecific substitution at the positions 8, 9, 11 and 12 (c.f. prostanoic cid, compound (l).
5 ~ ~C O O H
W~, 2C
One solution to ;his problem is the art-disclosed synthesis of the 7-oxa prostaglandin analogues (1ll) which uses all cis 3~5-dihydroxy-l~2-epoxycyclopentanetII) as a starting material.
OH OH
~ ~O ~
OH OH III
A key feature of this synthesis is the trans opening of the oxirane by nucleophilic attack. Althou~h this synthesis solves the problem of the trans substitution at the 12-position, it creates the new problem of isomer selective synthesis of all c~s 3,5-dihydroxy-1,2-epoxycyclopentane. In an atternpt to 5 avoid the latter problem, prostaglandin-type compounds (V) have been synthesized from 1,2-epoxycyclopentane (IV). However, this further deviation from - ¢~ ~R~
IV V
the natural prostaglandin structure (elimination of the hydroxyl ~roups at the 9and 11 positions) results in an erratic biological activity of the compounds thus 10 obtained; some of ~hem act as prostaglandin agonists in one tes~, and as antagonists in another.
No attempt has been rnade thus far to use cis-2,3-epoxycyclopentan-1-ol (VI) OH
,;~
~o VI
, . ~
9~ i as a starting material in the synthesis o prostaglandin analogues. This is not surprising, as no attractive synthesis route for (~rI) has been available thus far.
~ ormally, (VI) is synthesized by reacting cyclopenten-3-ol, a relatively expensive startin~ material9 with t-butyl hydroperoxide in the 5 presence of a vanadium catalyst. Typically a 45% isolated yield is obtained after 2 days. The reaction time is less (about l day) if the t-butyl hydroperoxide is replaced with a peracid, but then a si~nificant amount of the trans isomer is formed (cls:trans ratio about 41)o Even if cis-2,3-epoxycyclopentan-l-ol were readily available, it 10 would not be expected to be a suitable starting material for th~ synthesls ofprostaglandin-like materials. Because of the asymmetry of the molecule, the oxirane bond opening would be expected to result in two regi~isomers, of which only one would be suitable for further synthesis; and ~he resulting prostanoid would lack the hydroxyl group at the l l-position which would make 15 it, in view of the state of the art, doubtful whether biological activity of any significance wouid be possessed by this class of prostanoids.
By the present invention it has been discovered that olefins can quite readily be converted to the corresponding alpha-epoxy alcohols when they are reacted with singlet oxygen in the presence of a suitable oxidation 20 catalyst. The reaction is fast, gives high yields, has a high selectivity towards the epoxy alcohol, and uses an inexpensive starting material.
It has further been discovered that when cyclopentene is subjected to the process of this invention, c~s-2,3-epoxycyclopentan-l-ol is obtained in hi8h yield. It has surprisingly been found that when this compound is, after 25 suitable protection of the hydroxyl group, subjected to a m~cleophilic attack on the oxirane, the trans opening of the epoxide is regio-selective. This makes this compound particularly suitable for the synthesis of a novel class of prostanoids. I~lembers of this class unexpectedly show important cytoprotective activity.
6~3 ~ackground Art Different syntheses of prostaglandins are reviewed by Corey, Ann.
~l.Y. Acad. Sci., 180 (1971) 24. The 7-oxa-prostaglandins are discussed by Fried, et al., Ann. N.Y. Acad. Sci., 180 (1971) 38. Other publications related 5 to the synthesis of 7-oxa-prostaglandins include: Fried, et al., ~. Am. ~hem, Soc, 93 (1971) 5594; Fried, et al., Chem~ Comm. (1968) 634. The 7-thia pros~anoids are disclosed in U.S. Patent No. 4,175,201 granted November 20, 1979 to Fried, and U.S. Patent No. 4,180,672 gran~ed December 25, 1979 to Kurozumi, et al.
The effect of a free hydroxyl group on the regio-specificity of the epoxide opening is discussed in Fried, et al., J Am. Chem. Soc.~ 94 (1972) 4343.The catalytic oxidation of olefins to alpha-epoxy alcohols is dealt with by Kaneda, et al., J. OrR. Chem. 45 (1980) 3004; Allison, et al., Ind. and ~. tProd. Res. and Dev.) 5 (1966) 166; Lyons, Tetrahedron Lett. 32 15 (1974) 2737; U.S. Patent No. 3,259,638, granted July 5, 1966 to Allison. A
bimetallic catalyst for this reaction is disclosed in U~SO Patent No. 4,021,369,granted May 3, 1977 to Lyons.
The preparation of alpha-epox~ alcohols via catalytic rearrangement of hydroperoxides is discussed by Mercier, et al., Chem. Phys.
20 Li~ids 12 (1974) 232. The use of singlet oxygen in the reaction of olefins tohydroperoxides is disclosed by Kopecky, et al., Can. J. Chem., 43 (1965) 2265.
Although much effort has been made to improve the process of catalytic oxidation of olefins to alpha-epoxy alcohols, ~he processes reported in the art suffer from low reaction rates, low yields, and poor selecti~ities.
25 The rearrangement of hydroperoxides is fast, but requires separate preparation of these peroxides and their isolation. The process of this invention is fast, gives hi8h yields and is highly selective. Moreover, the process herein is especially adaptable to a ~ot~l synthesis of prostaglandin analogues, using cyclopentene as a starting material.
. . .
P~ Ci3 Summary of the Invention In one of its aspects, the present invention is a process for the photo-oxidative conversion of olefins to alpha-epoxy alcohols using a vanadium catalyst The present invention also encompasses a process for makin8 prostaglandin analogues usin~ cyclopentene as a relatively inexpensive starting material. The first step in this process is the conversion of cyclopentene to cis-Z,3-epoxycyclopentan-i-ol by reacting cycloperi~ene with singlet oxygen in the presence of a catalytic amoun~ of a catalyst containing a transition rnetal 10 of group IV B, V B, or VI B of the Periodic Table, excluding chromium.
Application of this process to the conversion of other olefins to ~he corresponding alpha-epoxy alcohols is also within the scope of this invention.
The next step is a nucleophilic attack on the oxirane bond with an alkynylalane reagent, resulting in a regio-selective trans opening. Prior to 15 this reaction9 the hydroxyl group is protected against nucleophilic attack with a suitable protecting group. In the next step, ~he substituent at the 8-positionis attached via a W'illiamson synthesis. Deprotection and tailoring of the oxidation states at the 9-position and in the substituent chains leads to ~he desired pros~a~landin analogues, as described more fully hereinafter.
Finally, the present invention encompasses a new class of prostaglandin analogues which are characterized by an oxygen atom replacing the methylene group at the 7-position, and the absence of a hydroxyl subs~ituent at the 1 l-position~ Members of this class have been found to possess cytoprotective properties which make them useful for the prevention 25 and treatment of ~astric ulcers.
Detailed DescriPtion of the Invention By "olefin" herein is meant an aliphatic hydrocarbon having at least one double bond and at least one allylic hydrogen. By "mono-olefin" herein is meant an olefin with one double bond.
~y "corresponding alpha epoxy alcohol" herein is meant that when the olefin startin~ material has its double bond between the carbon atoms m and mf 1, the alpha-epoxy alcohol formed is the m-hydroxy-(m+l), tm+2)-epo~y compound or the (m+l~hydroxy~m-l), m epoxy compound.
&i3 By "heterogeneous catalyst" hereln is meant a catalyst which is in the solid state and is not soluble in the reaction mixture.
By "homo~eneous catalys~' herein is meant a catalyst which is soluble in the reaction mixture.
By "acac" hereln is meant acetylacetonate.
By "singlet oxygen" herein is meant oxygen molecules in the lowest excited electronic state that has spin multiplicity of one, generally denoted asthe ~g state.
l~y "photo-sensi~ize~' herein is meant an organic compound which 10 can be exci~ed to the triplet state by adsorption of visible light.
By "catalytic amount" herein is meant an amount significantly less than a stoichiometric amount which is sufficient to act as a catalyst in the reaction.
By "prostaglandin analogue" herein is meant a compound which is 15 structurally similar to the naturally occurring prostaglandins.
By "7-oxa~ deoxy prostaglandin analogue" herein is meant a compound struc~urally similar to the natural prostaglandins of the E-series or F-series, characterized by an oxa group replacing the methylene group at the 7-position, and by the absence of a hydroxyl substituent at the 1 l-position.
~y "suitable protecting group" herein is meant any base s~able protec~ing group for alcohols. ~xamples thereof are ethers, in particular methoxymethyl, t-butyl, ben~yl, dimethyl-t-butylsilyl and methylthiomethyl ether. Protection of alcoholic hydroxyl groups is discussed by Reese, in "Protective Groups in Organic Chemistry", McOmie, editor, Plenum Press ~5 (1973) p.95 et seq. In case one of the hydroxyl groups is protected with a dimethyl-t-butylsilyl grGup~ the hydroxyl group can be deprotected selectively by reaction with tetrabu1yl -ammonium fluoride. The procedure is described by E.J. Corey, et al., J. Am.
Chem. Soc., 94, 6190 (1972~.
By 'lalkynylalanereagentll herein is meant the dialkylalkynylaluminum compound formed by reaction of dialkylaluminum chloride with a lithi~l-alkyne.
Percenta~es herein are mole percentages, unless otherwise indicated.
The firs~ aspect of this inven~ion is a pr~cess for converting olefins to the corresponding alpha-epoxy alcohols comprising reacting an olefin with singlet oxygen in the ~g state and converting the reaction product to an alpha-epoxy alcohol by in situ rearrangement in the presence of a catalytic amou~t of a heterogeneous or homogeneo~s catalyst containing a transition metal of group IVB, VB or VIB of the Periodic Table, excluding chromium. When cyclopentene is subjected to this oxidation reaction, the major product is cls 2,3-epoxycyclopentan-1-ol.
This aspect of the invention is also described, and is claimed, in Canadian Patent Application No. 397,348, filed March 1, 1982, cf which the present application is a divisional.
The present oxidation pr~cess has general applicabili~y ~o all olefins capable of reaction with singlet oxygen, that is, alkyl substituted olefins having at least one allylic hydrogen. Preferred herein are dialkyl subs~ituted olefins. The double bond may be acyclic, as in alkenes, or semi-cyclic, as in sabinene and beta-pinene, or endocyclic, as in the cycloalkenes. Olefins 20 having functional substituents9 such as halogens, carboxyl radicals7 etc., at the alpha-position with respect to the double bond are less suitable for the oxidation reaction disclosed herein, and fall outside the scope of this invention.
A detailed discussion of olefin reactions with singlet oxygen is given by Gollnick, et al., in "Singlet Oxy~en", Wasserman and Murray, editors, 25 Academic Press ~1979).
Singlet oxygen from any source may be used in the olefin oxidation reaction. Thus, singlet oxygen can be ~enerated by contacting ground-state oxygen with a photo-sensitizer ~hich has been excited by irradiation with visible light, by the reaction of sodium hypochlorite with hydrogen peroxide; by30 reaction of hydro~en peroxide with bromine in an alkalirle medium; by decomposition of the 1:1 adduct of triphenyl phosphite and ozone generated by passage of ozone in~o a solution of triphenyl phosphite in methylene chloride;
by thermal decomposition of epidioxides; or by microwave discharge in a stream of gaseous oxygen. The different methods of generating singlet oxygen 3~ are discussed in more detail by Denny, et al., in 'IOrganic Reac~ions", vol. 20 ~Z,~ 3S3 (W.G. Dauben - edi~or-in-chief),published by John Wiley ~ Sons, pp. 133-136.
For purposes of the present invention, singlet oxygen is preferably generated by contacting ground-state molecular oxygen with a suitable photosensitizer which is activated by irradiation with 5 visible light.
Suitable sensitizers are those organic compounds which have a large molar absorptivity in the visible part of the electromagnetic spectrum, a high quantum yield of triplet formation, a long triplet lifetime, a low tendency toward hydrogen abstraction and self-oxidation, and a triplet çnergy not far 10 above ~he ene~gy of singlet oxygen to permit efficient energy transfer to oxygen. Many common dyes meet these requirements adequately. Typical classes of dyes that can advantageously be used in the olefin oxidation process of this invention are the xanthenes (rose bengal, erythrosin, eosin, fluorescein), the thiazines (methylene blue), the porphyrins (chlorophyll a and b, 15 hematoporphyrin), ehe porphins and the phthalocyanines and mLxtures thereof.
These and other dyes~such as rubene, are disclosed in the - Denny reference, cited supra.
Preferred photo-sensitizers for the present invention are the phthalocyanines and tetraphenylporphin, and most preferred is 20 tetraphenylporphin.
For optimum efficiency, the amount of photosensitizer should neither be very low nor very high. At very low concentrations the sensitizer may not absorb all the available useful light. At too high a concentration, it absorbs all the useful li~ht within a shor~ distance from its entrance to the 25 solution and depletes oxygen in that region of the reaction vessel. Preferredamounts of sensitizer range from about 0.01% to about 2.5~, more preferably amounts range from about 0.05% to about 1.3~.
Any source of visible light is suitable for the activation of the sensitizer. However, for maximum efficiency, the source should strongly emit 30 light of the wavelength corresponding with the absorptivity maximum of ~he sensitizer. Thus, a sodium vapor discharge tube is particularly suitable for usein combination with tetraphenylporphin.
g Any catalyst capable of converting the reaction product of the olefin wsth sin~let oxygen9 presumably a hydroperoxide, to an alpha-epoxy alcohol is suitable for use in the olefin oxidation reaction of the presen~
invention. 5uitable catalysts are those which contain a transition metal of the 5 groups IVB, VB, or YIB of the Periodic Table. Although both heterogene~us and homogeneous catalyst sys~ems can be used, homogeneous catalysts are preferred for their superior selectivity. Suitable homogeneous catalysts are soluble salts and metallo-organic eornplexes o~ transition metals of group IVB, yB, or VIB of the Periodic Table, excluding chromium. Preferred herein are 10 the soluble salts and metalio orgar~ic complexes of vanadium ancl molybdenurn.
Examples are vanadyl acetyl cetonate, molybdenyl acetylacetonate, molybdenum hexacarbonyl, tungsten hexacarbonyl, and vanadium carbonyl~
Other examples of suitable catalysts are disclosed by Allison, et al., Ind. Sc EnR. Chem. (Prod. Res. and Dev.) 5 (1966) l66.
Preferred catalysts are those containing vanadium or molybdenun~;
more preferred are ~hose con~ainin~ vanadium (IV), and most preferred is vanadyl acetylacetonate.
The amount of catalyst should be suf~icient to ensure instantaneous 20 conversion of the hydroperoxides. Much hi8her levels of catalyst may adversely affect the efficiency of the photo-sensitization reac~ion, as most catalyst systems absorb visible light.
Suitable levels of catalyst range from about 0.1% to about 2.5~6.
Preferred levels range from 0.7% to 1.3%.
Without limitation by theory, the superior yields of alpha epoxy alcohol obtained with the process of the present invention in comparison with art disclosed processes is belie~ed to be1 at least in part, due to the presenceof the catalyst at the time the reaction intermediate, the hydroperoxide, is formed. The hydroperoxide is instantaneously converted to the epoxy alcohol 30 by the action of the catalyst. Hence, the concentration of hydroperoxide remains low throughout the reaction period, and side reactions resulting in ketones and alkenols are suppressed.
~2~9~i3 Al~hough the olefin oxidation reaction of this invention does not require a solven~, better yields are obtained when a solvent is present. Any organic solvent which is miscible with the olefin, and readily dissolves ~he photo-sensitizer and the catalys~, ls suitable. The reaction mixture rnay S contain from about 5% to about 9~% of the solvent. Alcohols should not be used, however~ as they tend to interact too strongly with the active sites of the ca~alyst and make it inactive. The reaction mixture should be substantially water-free, as water interacts with the catalyst as well.
Examples of suitable solvents are methylene dichloride and ~oluene.
The olefin oxidation process of this invention can be u~sed for the conversion of any olefin capable of reactlon with singlet oxygen to the corresponding alpha-epoxy alcohol. Examples of suitable olefins are cyclopentene, cis-9-octadecenoic acid esters, c -4-octene,
2,3-dimethyl-2-butene, alpha-pinene and beta pinene. If the olefin is a cyclic 15 alkene, the reaction is highly selective to the cis epoxy alcohol. Thus, oxidation of cyclopentene yields cis 2,3~epoxycyclopentan-l-ol.
The high reaction rate, the high yield and the selectiYity towards the cls configuration make this reaction useful in a total synthesis of prostaglandin analogues.
The following examples illustrate that with the olefin oxidation process of this invention, alpha epoxy alcohols are obtained in high yields after a reaction time of only several hours.
Cyclopentene was converted to cls-2,3-epoxycyclopentan-1-ol in the following manner:
A solution of cyclopentene (27.25g, 0.4m), tetraphenylporphin (O.IS~, 0.061 mole %), vanadium tlV) oxide bis (2,4-pentanedionate) (0.33g, 0.31mole %) in 380 ml dry toluene was irradiated with a 400 watt sodium lamp 5 (General Electric LU 400) in an immersion well configuration while cooling with circulating water and continuously purging with oxygen. The solu tion temperature was maintained at 24C and vaporized materials returned to the reaction well by trapping with a cold water condenser. The reaction could be monitored by gas chroma~ography (gc) or thin layer chromatography on 10 silica gel. After 3 hours, gas phase chromatographic analysis showed > 90 conversion and ~10% each of cyclopentene oxide, 2-cyclopentenone, and 2-cyclopenten-1-ol by-products. The reaction mix~ure was stirred for 15 minutes with lg triphenylphosphine to destroy any excess hydroperoxide, concentrated, diluted with 200 ml ether, the solid precipitate filtered off and 15 concentrated again. Distillation through a 10 cm Vigreux column gave, after asmall forerun, 20.24g of colorless oil ~P59C (0.65mm Hg) which was 99.8%
pure by gc analysis and contained O.Z% trans-isomer. The yield as analyzed by ~c was 72 mole % of the starting olefin. The isolated yield after distillation was 50.5%. The difference was caused by distillation losses.
This example shows that high yields of cis-2,3-epoxycyclopentan-1 ol can be obtained with the process of this invention after an unusually short reaction time. It also shows the hi~h selectivity to the cis isomer.
, Table I
Conversion of a number of olefins. The ca~alyst was vanadyl acetylacetonate. The solvent was toluene, except where otherwise indicated.
OLEFIN TIMF YIELD ) CONV~RSION (%) (hrs) (%) Methyl oleate 3.5 97 52) > 99 cis-4-octene 5 83.43) > 9~
2,3-dimethyl ) 1.5 - 72 S) > 99 2-butene cyclopentene 3 50.56) ~ 90 10 alpha-pinene 3 54 ~ 90 beta-pinene 6 52 8) ~ 9~
1) Isolated yield~ defined as mole percentage of olefin starting material 2) Mixture of methyl-9-hydroxy-10, 1 l-epoxyoctadecanoate and methyl-8,9-epoxy-10-hydroxyoctadecanoate
The high reaction rate, the high yield and the selectiYity towards the cls configuration make this reaction useful in a total synthesis of prostaglandin analogues.
The following examples illustrate that with the olefin oxidation process of this invention, alpha epoxy alcohols are obtained in high yields after a reaction time of only several hours.
Cyclopentene was converted to cls-2,3-epoxycyclopentan-1-ol in the following manner:
A solution of cyclopentene (27.25g, 0.4m), tetraphenylporphin (O.IS~, 0.061 mole %), vanadium tlV) oxide bis (2,4-pentanedionate) (0.33g, 0.31mole %) in 380 ml dry toluene was irradiated with a 400 watt sodium lamp 5 (General Electric LU 400) in an immersion well configuration while cooling with circulating water and continuously purging with oxygen. The solu tion temperature was maintained at 24C and vaporized materials returned to the reaction well by trapping with a cold water condenser. The reaction could be monitored by gas chroma~ography (gc) or thin layer chromatography on 10 silica gel. After 3 hours, gas phase chromatographic analysis showed > 90 conversion and ~10% each of cyclopentene oxide, 2-cyclopentenone, and 2-cyclopenten-1-ol by-products. The reaction mix~ure was stirred for 15 minutes with lg triphenylphosphine to destroy any excess hydroperoxide, concentrated, diluted with 200 ml ether, the solid precipitate filtered off and 15 concentrated again. Distillation through a 10 cm Vigreux column gave, after asmall forerun, 20.24g of colorless oil ~P59C (0.65mm Hg) which was 99.8%
pure by gc analysis and contained O.Z% trans-isomer. The yield as analyzed by ~c was 72 mole % of the starting olefin. The isolated yield after distillation was 50.5%. The difference was caused by distillation losses.
This example shows that high yields of cis-2,3-epoxycyclopentan-1 ol can be obtained with the process of this invention after an unusually short reaction time. It also shows the hi~h selectivity to the cis isomer.
, Table I
Conversion of a number of olefins. The ca~alyst was vanadyl acetylacetonate. The solvent was toluene, except where otherwise indicated.
OLEFIN TIMF YIELD ) CONV~RSION (%) (hrs) (%) Methyl oleate 3.5 97 52) > 99 cis-4-octene 5 83.43) > 9~
2,3-dimethyl ) 1.5 - 72 S) > 99 2-butene cyclopentene 3 50.56) ~ 90 10 alpha-pinene 3 54 ~ 90 beta-pinene 6 52 8) ~ 9~
1) Isolated yield~ defined as mole percentage of olefin starting material 2) Mixture of methyl-9-hydroxy-10, 1 l-epoxyoctadecanoate and methyl-8,9-epoxy-10-hydroxyoctadecanoate
3) 5,6-epoxyoctan~4-ol
4) Solvent is dichloromethane
5) 2,3-dimethyl-3,4-epoxybutan-2-ol
6) 2,3-epoxycyclopentan-1-ol, 99.8% cis
7) 6,10-epoxypinan-5-ol
8) S,6-epoxypinan-10-ol , . _ :
:~2~
Example II
The process of this invention can be used for the conversion of a broad spectrum of olefins ~o the corresponding alpha epoxy alcohols. All conversion reactions are characterized by a high conversion, a short reaction time and a high yield of the epoxy alcohol.
Methyl oleate (14.83g, 0.05 mol) was photooxidized in the manner described in Example I (0.l5~ te~raphenylporphin, 0.132g VO(acac32). The reaction mixture was concentrated, diluted with 0.2L ether, and washed with water (2 x 0.ll) and brine (2 x 0.ll). After-drying with magnesiu~ sulfate and concentrating, the crude product was chromato~raphed on silica gel to give 10 the pure epoxy alcohol as a mixture of diastereomers. Isolated yields and reaction conditions are given in Table I.
Alpha and beta pinene were oxidized and purified in the same way.
Conditions and results are given in Table I.
Cis-4-octene and 2,3-dirnethyl 2-butene were oxidized in the manner 15 descri~ed in Example I, and the distilled yields determined. The results are given in Table I. Other olefins capable of reaction with singlet oxygen are oxidized in the same manner. Similar results are obtained.
Example III
The cyclopentene oxida~ion of Example I was repeated with 20 Mo(CO)6, Titi - PrO)4 and VO(acac)2 as oxidation catalysts. The reactions were run on 0.4 mole of cyclopentene using methylene dichloride as solvent. The conversions after three hours and the product distributions obtained with the different catalys~s are given in Table II.
The best yield of 2,3-e~oxycyclopentan-1-ol was obtained with the vanadium catalyst. Both the molybdenum and the titaniurn catalyzed reactions produced some 2,3-epoxycyclopentan-1-one, whereas very little if any was formed in the vanadium catalyzed reaction. The re ctions with V and 5 Mo gave selectively the cis-epoxy alcohol, whereas the Ti catalyst ga~e a 3:1 ~/trans mixture.
:~2~ $~
Table Il Comparison of Oxidation Reaction with Various Metal Catalysts CATALYST REACTION COMPONENTS AFTER 3 Hours (a~O by gc) . (MOLE %) . I~ II. III. IV7 V. OTHER
Mo(CO)6 53 l 4 .5 l 6 3 .4 9 4 (0.3 I) Ti~i-PrO)4 2 ~.6 28.7 39.5 21.4 some (1.0) VO(acac)2 6.4 6 9.6 6 72 none (0.25) I: Cyclopentene II: Epoxycyclopentane III: 2-cyclopenten- l -ol 15 IV: 2-cyclopenten- l -one V: 2,3-epoxycyclopenean-l-ol The second aspect of this invention is a process for synthesizing 7-oxa-1 l-deoxy prostaglandin analogues comprising the steps of - a) reacting protected cis-2,3-epoxycyclopentan-1-ol with an alkynylalane reagent;
b) reacting the product of step a) with an ester of an omega-iodo alkanoic acid, containing from 3 to 12 carbon a~oms.
The synthesis of prostaglandin analogues from all cis 1,2-epoxycyclopentane-3,5-diol has been disclosed by ~ried, et al., Ann. NY
Acad. Sci.., 180 tl971? 38. - . ~, The key 10 step in this synthesis is the attachment of ~he substituent in the beta-position by reaction of the protected epoxy diol with an alkynylalane rea~ent.
Reaction of C~5 2,3-epoxycyclopentan-1-ol with an alkynylalane reagent would be expecte~ to result in a mixture of 2-trans substituted and 3-trans substituted products, of which only the 3-trans substituted one is 15 suitable for further synthesis. It has now surprisingly been found that the alkynylalane reaction yields almost exclusively the desired 3-substituted product. The regio-selectivity of this substitution contributes importan~ly to the suitability of c~s-2,3-epoxycyclopentan-1-ol for the synthesis of prostaglandin analogues. The present invention thus provides a total synthesis 20 for a novel class of prostaglandin analogues, starting from the relatively inexpensive cyclopentene.
Cyclopentene (VII) is oxidized with singlet oxygen to cis-2,3-epoxycyclopentan-1-ol (VI) in the manner described above. Then, the hydroxyl group is protected with a suitable protecting group, e.g.
methoxymethyl. The protected cyclopentane compound ~s reacted with the 5 alkynylalane reagent.
The alkynylalane reagent is formed in situ by reaction of dimethyl-aluminum chloride with a lithlated l-alkyne. Any l-alkyne is suitable ~or the purpose OI the present invention. Preferred l-alkynes are l-hexyne and l-octyne, and derivatives thereof. The most preferred are the l-octynes. The 10 l-octyne may have substi~uents at the 3 and/or 4 positions. Examples oE
substituted l-octynes suitable for use in prostanoid synthesis are (R,S)-l-octyn3-ol, (R)-l-octyn-3-ol, (S)-l-octyn-3-ol, 3-methyl (S)-l-octyn-3-ol, 4-methyl(R ,S)- l -octyn-~-ol9 4-methyl(R)- l -octyn-3-ol, 4-methyl(S)-l-octyn-3-ol, 4,4 dimethyl(R,S)-l-octyn-3-ol, 4,4 15 dimethyl-(R)-l-octyn-3-ol, 4,4 dimethyl-(S)-l-octyn-3-ol, (R,S)-l-octyn-4-ol, (R)-l-octyn-4-ol, (S)-l-octyn-4-ol and 4-methyl-l-octyn-4-ol.
OH d~~o.~e C~ ~ 3 <~
VII VI\~
0~
/~
OH o OMe L
o. ~/ COOCH3 ao ~ COO
O
OE~ I
X IX
Highly preferred alkynylalane reagents herein are those derived from l-octyne, (R,S)-l-octyn-3-ol; (S)-l~octyn-3-ol, and 3-methyl (S)-l-octyn-3-ol. Most highly preferred are the alkynylalane reagents derived from (R,S)-lOoctyn-3-ol and (S)-l-octyn-3-ol.
In case the l-octyne contains an alcoholic hydroxyl ~roup, this group has to be protected prior to the reaction with dimethylaluminum chl~ride, by e.g. reaction to an e~her in a manner similar to She protection reaction for thealcoholic hydroxyl in cornpound I. The t-butyl ether generally is a suitable protective group for the !-octynol hydroxyl group.
- The alkynylalane reagent thus formed is reacted with compound (VI) to give the corresponding 3 beta-octynyl-alpha-l-methoxymethoxy alpha cyclopentan-2-ol (VIII). Compound (VIII) is cont~erted to compc~und (IX) by a Williamson synthesis. The carboxylic hydroxyl group needs to be protected prior to the exposure of the molecule to sodium hydride. The t-butyl ester is a 15 suitable protecting group. Any omega-iodo substituted carboxylic acid is suitable for this reaction. Preferred carboxylic acids are carboxylic acids csntaining from 3 ~o l2 carbon atoms. Particularly suitable are ~he omega-iodo alkanoic acid derivatives of the formula~
1- C - Rl - COO t-Bu wherein Rl is R2 l2 -C-C-C-C-; -C-C=C-C-; or - C = C - C - C ~ and R2 and R3 are each H, ÇH3~ C2Hs ~r C3H ~
The omega-iodo derivatives of hexanoic acid and 4-h~xenoic acid 30 are preferred herein. Most preferred is the hexanoic acid derivative.
~Z~$~
The hydroxyl groups in (IX) are deprotected by acid catalyzed de-etherification. Thus, reaction with trifluoroace~ic acid (TFA) followed by reaction with BF3 etherate gives methyl-9-alpha-hydroxy-15-hydroxy-7-oxa-prost-13,14-ynoate ~X), which is a 5 member of the novel class of prostanoids of this invention. Other members of this class can be derived herefrom by:
- reacting one or more of the hydroxy groups of ~he prostaglandin analogue with chromium trioxide;
- reacting the prostaglandin analogues with hydrogen in the presence of a l indlar catalyst9 - - -- reacting the prostaglandin analogue with hydrogen in the presence of a coal-supported palladium catalyst;
- reacting the prostaglandin analogue with diphenyl disulphide, followed by irradiation with u.v. light.
15 or by any combination of these steps.
Thus, hydrogenation of (X) over a Lindlar catalyst gives methyl-9-alpha-hydroxy-15-hydroxy-7-oxa-us prost-13,14-enoate (Xl). The latter compound can be oxidized in a Collins reaction to methyl-9 ,1 5-dioxo-7-oxa-cis-proct- 13 ,1 4-enoate (XII).
C~etails of the synthesis of 7-oxa-prostaglandin in accordance wi~h the process of the present invention will become apparent from the following examples.
OH
o ~ ~, COOCH3 OH
XI
o 1~ ~o ~ COOC~3 ~=,/~
XII
Example IV
2,3-Epoxymethoxymethoxycyclopentane (I) was prepared in accordance with the invention as follows.
A dried flask wi~h a magne~ic stirring bar was charged with 180 ml freshly distilled THF and cooled to 0-5C under argon. Potassium hydride (10 5 ml of a 22% dispersion in mineral oil) was then added, followed by 4.6g (46 mmol) 2,3-epo:cycyclopentan-1-ol as a solution in 12 ml THF, dropwise with stirring. ~.fter stirrin~ 5-10 min. more7 8.9g iodomethyl methyl ether was added, slowly wi~h stirring. ~ter 15 min., the reaction was quenched by careful, slow addition of 45 ml IN NaHCO3. After removing the THF under lOvacuum~ 100 ml H2O was added and the reaction mixture was extracted with three 75 ml po~tions of CH2C12. The combined organic portions were filtered and concentrated under vacuum to give the crude product. This material was purified by fractional distillation to give 4.15g pure product (bp 44-5C at 0.15mm), a 63% yield.
lS lH hlME~ (60 MHz): delta 4.65(s,2H) 4.1(m,1H), 3.55-3.3(m,2H), 3.35(s,3H), 2.45-1.15(m,4H).
C N~IR (20 MHz): 96.19, 78.69, 57.08, 55.26, 55.10, 25.42, 24.07 ppm.
3L~ r~ 3 - 21 ~-Example V
2-Alpha-hydroxy- l~alpha-methoxymethoxy-3-beta-(3-t-butoxy- 1 -octyn -yl)-cyclopentane (2) was prepared from compound (1) by reaction with n-butyllithium in the following manner To a solution of 3.16~ (17.36 mmol, 2.5 equiv.) 3-t-butoxy-1-oc~yne 5 in 20 ml dry ~oluene at 0C under argon was added 10.85 ml n-butylli~hium (1.6M, 2.5 equiv.). After stirring 15 min9 6.8 ml dimethylaluminum chloride (2M, 2 equiv.) was addedS dropwise via syrin~e. After 50 min. mo~e, lg epoxi~e (I) (6.94 mmol) was added dropwise, as a solution in 5 m~toluene. The cooling bath was removed, and the stirring was continued for 4 hrs. ~he 10 reaction was then quenched by careful addition of saturated aqueous Na2S04, and the mixture was partitioned between 200 ml H20 and 100 ml ether. The aqueous layer was extracted twice more with 150 ml portions of ether, then the combined etheral portions were dried (molecular sieves), filtered, and concentrated under vacuum to gi~/e the crude product, which was 15 purified ~y flash chromatography with 4:1 hexane:ethyl acetate to gi-ve 1.66g pure adduct (73% yield).
IR (Neat): 3480, 2200(w) crn H NMR (60 MHz~: delta 4.6(s,2H), 4.2-3.8(m,3H), 3.35(s,3H), 1.25(s,9H) C NMR(22.5MHz): 96.15(0-C~2-Ok 85.38, 84.40(C13,14);
79.18, 78.33(CB,9k 74.28(C-Me3);
62.14(C15); 55.55(0Me)~ 37.86, 35.77(C12,16); 31.S9(C18);
28.39(C-Me3); 28.00, 27.81, 25.33(Cl0,11917);22.65(C19); 14.03(C20) ppm.
Example V (Cont.) In the same manner epoxide 1 was reac~ed with l-hexyne, l-octyne, 3(S)t-butoxy- 1 -octyne, 3-~R)t-butoxy- I-octyne, 3-methyl-3(R,S)t-butoxy~l-octyne, 4,4-dimethyl-3(R,S)~ butoxy-l-octyne, and the corresponding 3-beta substituted 2-alpha hydroxy~l-alpha-S methoxymethoxy cyclopentane compounds were secured.
Similar compounds are secured when epoxide I is reacted with 4-methy1-3-t-butoxy-1-octyne, 4-methyl-3(S)t-butoxy-l-octyne, 4~t-butoxy-1-octyne, 4(S)t-butoxy-l-octyne, and 3(S)t-butoxy-4(S)t-butoxy- I -octyne.
. _ 23 - -E~
Compound (2) was converted to t-butyl-9-alpha-methoxymethoxy-7-oxa-15-t-butoxy-prost-13,14-ynoate(3) by William~on syn~hesis as follow~
A suspension of 0.44g sodium hydride (50~6 dispersion in mineral oil, 3 equiv.) in 22 rnl dry DMSO was heated in a 70C oil bath under argon for 5 50-60 min., at which time hydrogen eYolution stopped. The solution was cooled to 20C tunder argon) and a solution of lg alcohol t2) (3.06 mmol) in 3 ml DMSO was added dropwise via syringe. After 5 min. 4.57g 6-iodo-t-butyl hexanoate (15.33 mmol9 5 eq~iv.) was added in a slow stream, vi~ syringe.
After stirring 3 hrs., this mixture was added to a separatory funnel containing 10 50 ml H20 and 50 mlsaturated aqueous NaCI. The mixture was extracted with 3 50 ml portions of ether; the organic layers were combined, dried (molecular sieves), filtered, and concentrated under vacuum to Five the crude product. Upon purification by flash chromatography (4:1 hexane:ethyl acetate) two fractions were isolated: the first (R~ 0.5 with 3:1 hexane.ethyl 15 acetate) was product 3, 0.85g (56% yield), the second was recovered alcohol (2),0.43g(43%).
IR ( ~I eat): 1 730(s) cm H NMR (60 MHz): delta 4.6(s,2H), 4.2-3~85(m,2H), 3.7-3.3(m,3H),3.25(s,3H), 2.9-2.55(m-lH~,1.4(s,9H),1.2(s,9H) C N M R(22.5M Hz):172.98,95.63,86.56,86.36,83.88, 79.83y 76.6~, 74.22,70.37,62.14,55.29, 37.~6,35.51,32.90,31.59,29~70, 2~.39(3C),28.13(3C),27.94,27.74, 25.72,25.34,25.00,22.58,14.03 ppm.
~L 2 fr .!~ 3 In the same manner alcohol (2) is reacted with t-butyl-6-iodo-3-hexenoate, t-b~tyl-6-iodo-4-hexenoate, t-butyl-6-iodo-2,2 dimethyl-hexanoate, t butyl 6-iodo-2,2 diethyl-hexanoate, t-butyl-6-iodo-2 methoxymethoxy-hexanoate, and the corresponding prost-13,14-ynoates are 5 obtained.
Example Vll methyl-9-alpha-hydroxy-15-hydroxy-7-oxa-Prost-13,14-ynoate (4) was obtained from (3) by removal of the protecting groups To a solution of 1.85g (3.73 mmol) 3 in 8 ml CH2C12, stirred at - -10C under argon, was added 8 ml trifluoroacetic acid (which had been cooled 5 to 0C) in one portion. After 10 min. the cooling bath was removed and the reaction was stirred 60-90 min. lon~er. A vacuum pump was attached, and all volatiles were thus removed. The brown residue was taken up in 75 ml methanol ~anhydrous), and 7.5 ml BF3 etherate was added; this mixture was refluxed 10 min on a steam cone, and then concentrated under vacuum to 10 remove most of the methanol. The remainder was partitioned between 10~ ml NaHC03 and 75 ml CH2C12. After extracting the aqueous layer twice more, the organic layers were combined, filtered, and concentrated under vacuum to give the crude product. Purification by flash chromatography with 1.2:1 hexane.ethyl acetate ~ave 1.16g pure prostanoid (88% yield).
lS IR (Neat): 3480, 2250(w), 1745(s) H ~`IMR (60 MHz): delta 4.5-4.0(m,2H), 3.9-3.5(m,3H), 3.65(s,3H) C N~1R(22.5MHz): 174.09(CI); 87.01(C8), 82.84~C14);
77.03(C13); 71.54, 70.30(C9,6);
62.40(C 15); 51.50(-O-CH3);
38.12(C12); 33.88, 3~.96, 31.53, 30.09, 29.44, 28.26, 25.65, ~4.937 24.61, 22.58, 13.97(CH2CH3) ppm~
Compound (4) belongs to the novel class of 7-oxa-prostanoic acid 25 derivatives of this invention. The keto-analogues of (4~ can be prepared therefrom by oxidation with chromium trioxide (Example VIII). lf the 15_hydroxy is protected with TFA prior to the reaction with chromium trioxide ~Example IX), the 9-hydroxy is oxidized selectively (Example X).
Example VIII
Compound (4) was converted to methyl-9,15-dioxo-7-oxa-prost-13,14-ynoate (5) by oxidation with chromium trioxide as follows.
A mixture of 2.56~ chromium trioxide, 4.13 ml dry pyridine, and 65 ml CH2C12 was stirred 15 min a~ room temperature. A solution of 500 5 mg diol (4) (1.41 mmol) in 2 ml CH2C12 was added via pipe~e, and the resulting heterogeneous mixture was sti~red another 15-20 min. After adding 100 ml ether, the mixture was filtered through a short silica ~el column to remove the chromium salts (~he column was then washed uli~h 1~0 ml ethyl acetate). The combined effluent was concentrated under vacuum~ and the 10 residue was puri~ied by flash chromatography with 3:1 hexane ethyl acetate to get 440 mg pure diketone (89% yield).
IR (Neat): 2230(s), 1760ts), 1730(s), 16B0(s) cm H NMR (60 MHz): delta 3.85-3.45(m,3H), 3.61(s,3H) C NMR(22.5MHzk211.82(C9); lB7.40(C15k 173.64(CI);
:~2~
Example II
The process of this invention can be used for the conversion of a broad spectrum of olefins ~o the corresponding alpha epoxy alcohols. All conversion reactions are characterized by a high conversion, a short reaction time and a high yield of the epoxy alcohol.
Methyl oleate (14.83g, 0.05 mol) was photooxidized in the manner described in Example I (0.l5~ te~raphenylporphin, 0.132g VO(acac32). The reaction mixture was concentrated, diluted with 0.2L ether, and washed with water (2 x 0.ll) and brine (2 x 0.ll). After-drying with magnesiu~ sulfate and concentrating, the crude product was chromato~raphed on silica gel to give 10 the pure epoxy alcohol as a mixture of diastereomers. Isolated yields and reaction conditions are given in Table I.
Alpha and beta pinene were oxidized and purified in the same way.
Conditions and results are given in Table I.
Cis-4-octene and 2,3-dirnethyl 2-butene were oxidized in the manner 15 descri~ed in Example I, and the distilled yields determined. The results are given in Table I. Other olefins capable of reaction with singlet oxygen are oxidized in the same manner. Similar results are obtained.
Example III
The cyclopentene oxida~ion of Example I was repeated with 20 Mo(CO)6, Titi - PrO)4 and VO(acac)2 as oxidation catalysts. The reactions were run on 0.4 mole of cyclopentene using methylene dichloride as solvent. The conversions after three hours and the product distributions obtained with the different catalys~s are given in Table II.
The best yield of 2,3-e~oxycyclopentan-1-ol was obtained with the vanadium catalyst. Both the molybdenum and the titaniurn catalyzed reactions produced some 2,3-epoxycyclopentan-1-one, whereas very little if any was formed in the vanadium catalyzed reaction. The re ctions with V and 5 Mo gave selectively the cis-epoxy alcohol, whereas the Ti catalyst ga~e a 3:1 ~/trans mixture.
:~2~ $~
Table Il Comparison of Oxidation Reaction with Various Metal Catalysts CATALYST REACTION COMPONENTS AFTER 3 Hours (a~O by gc) . (MOLE %) . I~ II. III. IV7 V. OTHER
Mo(CO)6 53 l 4 .5 l 6 3 .4 9 4 (0.3 I) Ti~i-PrO)4 2 ~.6 28.7 39.5 21.4 some (1.0) VO(acac)2 6.4 6 9.6 6 72 none (0.25) I: Cyclopentene II: Epoxycyclopentane III: 2-cyclopenten- l -ol 15 IV: 2-cyclopenten- l -one V: 2,3-epoxycyclopenean-l-ol The second aspect of this invention is a process for synthesizing 7-oxa-1 l-deoxy prostaglandin analogues comprising the steps of - a) reacting protected cis-2,3-epoxycyclopentan-1-ol with an alkynylalane reagent;
b) reacting the product of step a) with an ester of an omega-iodo alkanoic acid, containing from 3 to 12 carbon a~oms.
The synthesis of prostaglandin analogues from all cis 1,2-epoxycyclopentane-3,5-diol has been disclosed by ~ried, et al., Ann. NY
Acad. Sci.., 180 tl971? 38. - . ~, The key 10 step in this synthesis is the attachment of ~he substituent in the beta-position by reaction of the protected epoxy diol with an alkynylalane rea~ent.
Reaction of C~5 2,3-epoxycyclopentan-1-ol with an alkynylalane reagent would be expecte~ to result in a mixture of 2-trans substituted and 3-trans substituted products, of which only the 3-trans substituted one is 15 suitable for further synthesis. It has now surprisingly been found that the alkynylalane reaction yields almost exclusively the desired 3-substituted product. The regio-selectivity of this substitution contributes importan~ly to the suitability of c~s-2,3-epoxycyclopentan-1-ol for the synthesis of prostaglandin analogues. The present invention thus provides a total synthesis 20 for a novel class of prostaglandin analogues, starting from the relatively inexpensive cyclopentene.
Cyclopentene (VII) is oxidized with singlet oxygen to cis-2,3-epoxycyclopentan-1-ol (VI) in the manner described above. Then, the hydroxyl group is protected with a suitable protecting group, e.g.
methoxymethyl. The protected cyclopentane compound ~s reacted with the 5 alkynylalane reagent.
The alkynylalane reagent is formed in situ by reaction of dimethyl-aluminum chloride with a lithlated l-alkyne. Any l-alkyne is suitable ~or the purpose OI the present invention. Preferred l-alkynes are l-hexyne and l-octyne, and derivatives thereof. The most preferred are the l-octynes. The 10 l-octyne may have substi~uents at the 3 and/or 4 positions. Examples oE
substituted l-octynes suitable for use in prostanoid synthesis are (R,S)-l-octyn3-ol, (R)-l-octyn-3-ol, (S)-l-octyn-3-ol, 3-methyl (S)-l-octyn-3-ol, 4-methyl(R ,S)- l -octyn-~-ol9 4-methyl(R)- l -octyn-3-ol, 4-methyl(S)-l-octyn-3-ol, 4,4 dimethyl(R,S)-l-octyn-3-ol, 4,4 15 dimethyl-(R)-l-octyn-3-ol, 4,4 dimethyl-(S)-l-octyn-3-ol, (R,S)-l-octyn-4-ol, (R)-l-octyn-4-ol, (S)-l-octyn-4-ol and 4-methyl-l-octyn-4-ol.
OH d~~o.~e C~ ~ 3 <~
VII VI\~
0~
/~
OH o OMe L
o. ~/ COOCH3 ao ~ COO
O
OE~ I
X IX
Highly preferred alkynylalane reagents herein are those derived from l-octyne, (R,S)-l-octyn-3-ol; (S)-l~octyn-3-ol, and 3-methyl (S)-l-octyn-3-ol. Most highly preferred are the alkynylalane reagents derived from (R,S)-lOoctyn-3-ol and (S)-l-octyn-3-ol.
In case the l-octyne contains an alcoholic hydroxyl ~roup, this group has to be protected prior to the reaction with dimethylaluminum chl~ride, by e.g. reaction to an e~her in a manner similar to She protection reaction for thealcoholic hydroxyl in cornpound I. The t-butyl ether generally is a suitable protective group for the !-octynol hydroxyl group.
- The alkynylalane reagent thus formed is reacted with compound (VI) to give the corresponding 3 beta-octynyl-alpha-l-methoxymethoxy alpha cyclopentan-2-ol (VIII). Compound (VIII) is cont~erted to compc~und (IX) by a Williamson synthesis. The carboxylic hydroxyl group needs to be protected prior to the exposure of the molecule to sodium hydride. The t-butyl ester is a 15 suitable protecting group. Any omega-iodo substituted carboxylic acid is suitable for this reaction. Preferred carboxylic acids are carboxylic acids csntaining from 3 ~o l2 carbon atoms. Particularly suitable are ~he omega-iodo alkanoic acid derivatives of the formula~
1- C - Rl - COO t-Bu wherein Rl is R2 l2 -C-C-C-C-; -C-C=C-C-; or - C = C - C - C ~ and R2 and R3 are each H, ÇH3~ C2Hs ~r C3H ~
The omega-iodo derivatives of hexanoic acid and 4-h~xenoic acid 30 are preferred herein. Most preferred is the hexanoic acid derivative.
~Z~$~
The hydroxyl groups in (IX) are deprotected by acid catalyzed de-etherification. Thus, reaction with trifluoroace~ic acid (TFA) followed by reaction with BF3 etherate gives methyl-9-alpha-hydroxy-15-hydroxy-7-oxa-prost-13,14-ynoate ~X), which is a 5 member of the novel class of prostanoids of this invention. Other members of this class can be derived herefrom by:
- reacting one or more of the hydroxy groups of ~he prostaglandin analogue with chromium trioxide;
- reacting the prostaglandin analogues with hydrogen in the presence of a l indlar catalyst9 - - -- reacting the prostaglandin analogue with hydrogen in the presence of a coal-supported palladium catalyst;
- reacting the prostaglandin analogue with diphenyl disulphide, followed by irradiation with u.v. light.
15 or by any combination of these steps.
Thus, hydrogenation of (X) over a Lindlar catalyst gives methyl-9-alpha-hydroxy-15-hydroxy-7-oxa-us prost-13,14-enoate (Xl). The latter compound can be oxidized in a Collins reaction to methyl-9 ,1 5-dioxo-7-oxa-cis-proct- 13 ,1 4-enoate (XII).
C~etails of the synthesis of 7-oxa-prostaglandin in accordance wi~h the process of the present invention will become apparent from the following examples.
OH
o ~ ~, COOCH3 OH
XI
o 1~ ~o ~ COOC~3 ~=,/~
XII
Example IV
2,3-Epoxymethoxymethoxycyclopentane (I) was prepared in accordance with the invention as follows.
A dried flask wi~h a magne~ic stirring bar was charged with 180 ml freshly distilled THF and cooled to 0-5C under argon. Potassium hydride (10 5 ml of a 22% dispersion in mineral oil) was then added, followed by 4.6g (46 mmol) 2,3-epo:cycyclopentan-1-ol as a solution in 12 ml THF, dropwise with stirring. ~.fter stirrin~ 5-10 min. more7 8.9g iodomethyl methyl ether was added, slowly wi~h stirring. ~ter 15 min., the reaction was quenched by careful, slow addition of 45 ml IN NaHCO3. After removing the THF under lOvacuum~ 100 ml H2O was added and the reaction mixture was extracted with three 75 ml po~tions of CH2C12. The combined organic portions were filtered and concentrated under vacuum to give the crude product. This material was purified by fractional distillation to give 4.15g pure product (bp 44-5C at 0.15mm), a 63% yield.
lS lH hlME~ (60 MHz): delta 4.65(s,2H) 4.1(m,1H), 3.55-3.3(m,2H), 3.35(s,3H), 2.45-1.15(m,4H).
C N~IR (20 MHz): 96.19, 78.69, 57.08, 55.26, 55.10, 25.42, 24.07 ppm.
3L~ r~ 3 - 21 ~-Example V
2-Alpha-hydroxy- l~alpha-methoxymethoxy-3-beta-(3-t-butoxy- 1 -octyn -yl)-cyclopentane (2) was prepared from compound (1) by reaction with n-butyllithium in the following manner To a solution of 3.16~ (17.36 mmol, 2.5 equiv.) 3-t-butoxy-1-oc~yne 5 in 20 ml dry ~oluene at 0C under argon was added 10.85 ml n-butylli~hium (1.6M, 2.5 equiv.). After stirring 15 min9 6.8 ml dimethylaluminum chloride (2M, 2 equiv.) was addedS dropwise via syrin~e. After 50 min. mo~e, lg epoxi~e (I) (6.94 mmol) was added dropwise, as a solution in 5 m~toluene. The cooling bath was removed, and the stirring was continued for 4 hrs. ~he 10 reaction was then quenched by careful addition of saturated aqueous Na2S04, and the mixture was partitioned between 200 ml H20 and 100 ml ether. The aqueous layer was extracted twice more with 150 ml portions of ether, then the combined etheral portions were dried (molecular sieves), filtered, and concentrated under vacuum to gi~/e the crude product, which was 15 purified ~y flash chromatography with 4:1 hexane:ethyl acetate to gi-ve 1.66g pure adduct (73% yield).
IR (Neat): 3480, 2200(w) crn H NMR (60 MHz~: delta 4.6(s,2H), 4.2-3.8(m,3H), 3.35(s,3H), 1.25(s,9H) C NMR(22.5MHz): 96.15(0-C~2-Ok 85.38, 84.40(C13,14);
79.18, 78.33(CB,9k 74.28(C-Me3);
62.14(C15); 55.55(0Me)~ 37.86, 35.77(C12,16); 31.S9(C18);
28.39(C-Me3); 28.00, 27.81, 25.33(Cl0,11917);22.65(C19); 14.03(C20) ppm.
Example V (Cont.) In the same manner epoxide 1 was reac~ed with l-hexyne, l-octyne, 3(S)t-butoxy- 1 -octyne, 3-~R)t-butoxy- I-octyne, 3-methyl-3(R,S)t-butoxy~l-octyne, 4,4-dimethyl-3(R,S)~ butoxy-l-octyne, and the corresponding 3-beta substituted 2-alpha hydroxy~l-alpha-S methoxymethoxy cyclopentane compounds were secured.
Similar compounds are secured when epoxide I is reacted with 4-methy1-3-t-butoxy-1-octyne, 4-methyl-3(S)t-butoxy-l-octyne, 4~t-butoxy-1-octyne, 4(S)t-butoxy-l-octyne, and 3(S)t-butoxy-4(S)t-butoxy- I -octyne.
. _ 23 - -E~
Compound (2) was converted to t-butyl-9-alpha-methoxymethoxy-7-oxa-15-t-butoxy-prost-13,14-ynoate(3) by William~on syn~hesis as follow~
A suspension of 0.44g sodium hydride (50~6 dispersion in mineral oil, 3 equiv.) in 22 rnl dry DMSO was heated in a 70C oil bath under argon for 5 50-60 min., at which time hydrogen eYolution stopped. The solution was cooled to 20C tunder argon) and a solution of lg alcohol t2) (3.06 mmol) in 3 ml DMSO was added dropwise via syringe. After 5 min. 4.57g 6-iodo-t-butyl hexanoate (15.33 mmol9 5 eq~iv.) was added in a slow stream, vi~ syringe.
After stirring 3 hrs., this mixture was added to a separatory funnel containing 10 50 ml H20 and 50 mlsaturated aqueous NaCI. The mixture was extracted with 3 50 ml portions of ether; the organic layers were combined, dried (molecular sieves), filtered, and concentrated under vacuum to Five the crude product. Upon purification by flash chromatography (4:1 hexane:ethyl acetate) two fractions were isolated: the first (R~ 0.5 with 3:1 hexane.ethyl 15 acetate) was product 3, 0.85g (56% yield), the second was recovered alcohol (2),0.43g(43%).
IR ( ~I eat): 1 730(s) cm H NMR (60 MHz): delta 4.6(s,2H), 4.2-3~85(m,2H), 3.7-3.3(m,3H),3.25(s,3H), 2.9-2.55(m-lH~,1.4(s,9H),1.2(s,9H) C N M R(22.5M Hz):172.98,95.63,86.56,86.36,83.88, 79.83y 76.6~, 74.22,70.37,62.14,55.29, 37.~6,35.51,32.90,31.59,29~70, 2~.39(3C),28.13(3C),27.94,27.74, 25.72,25.34,25.00,22.58,14.03 ppm.
~L 2 fr .!~ 3 In the same manner alcohol (2) is reacted with t-butyl-6-iodo-3-hexenoate, t-b~tyl-6-iodo-4-hexenoate, t-butyl-6-iodo-2,2 dimethyl-hexanoate, t butyl 6-iodo-2,2 diethyl-hexanoate, t-butyl-6-iodo-2 methoxymethoxy-hexanoate, and the corresponding prost-13,14-ynoates are 5 obtained.
Example Vll methyl-9-alpha-hydroxy-15-hydroxy-7-oxa-Prost-13,14-ynoate (4) was obtained from (3) by removal of the protecting groups To a solution of 1.85g (3.73 mmol) 3 in 8 ml CH2C12, stirred at - -10C under argon, was added 8 ml trifluoroacetic acid (which had been cooled 5 to 0C) in one portion. After 10 min. the cooling bath was removed and the reaction was stirred 60-90 min. lon~er. A vacuum pump was attached, and all volatiles were thus removed. The brown residue was taken up in 75 ml methanol ~anhydrous), and 7.5 ml BF3 etherate was added; this mixture was refluxed 10 min on a steam cone, and then concentrated under vacuum to 10 remove most of the methanol. The remainder was partitioned between 10~ ml NaHC03 and 75 ml CH2C12. After extracting the aqueous layer twice more, the organic layers were combined, filtered, and concentrated under vacuum to give the crude product. Purification by flash chromatography with 1.2:1 hexane.ethyl acetate ~ave 1.16g pure prostanoid (88% yield).
lS IR (Neat): 3480, 2250(w), 1745(s) H ~`IMR (60 MHz): delta 4.5-4.0(m,2H), 3.9-3.5(m,3H), 3.65(s,3H) C N~1R(22.5MHz): 174.09(CI); 87.01(C8), 82.84~C14);
77.03(C13); 71.54, 70.30(C9,6);
62.40(C 15); 51.50(-O-CH3);
38.12(C12); 33.88, 3~.96, 31.53, 30.09, 29.44, 28.26, 25.65, ~4.937 24.61, 22.58, 13.97(CH2CH3) ppm~
Compound (4) belongs to the novel class of 7-oxa-prostanoic acid 25 derivatives of this invention. The keto-analogues of (4~ can be prepared therefrom by oxidation with chromium trioxide (Example VIII). lf the 15_hydroxy is protected with TFA prior to the reaction with chromium trioxide ~Example IX), the 9-hydroxy is oxidized selectively (Example X).
Example VIII
Compound (4) was converted to methyl-9,15-dioxo-7-oxa-prost-13,14-ynoate (5) by oxidation with chromium trioxide as follows.
A mixture of 2.56~ chromium trioxide, 4.13 ml dry pyridine, and 65 ml CH2C12 was stirred 15 min a~ room temperature. A solution of 500 5 mg diol (4) (1.41 mmol) in 2 ml CH2C12 was added via pipe~e, and the resulting heterogeneous mixture was sti~red another 15-20 min. After adding 100 ml ether, the mixture was filtered through a short silica ~el column to remove the chromium salts (~he column was then washed uli~h 1~0 ml ethyl acetate). The combined effluent was concentrated under vacuum~ and the 10 residue was puri~ied by flash chromatography with 3:1 hexane ethyl acetate to get 440 mg pure diketone (89% yield).
IR (Neat): 2230(s), 1760ts), 1730(s), 16B0(s) cm H NMR (60 MHz): delta 3.85-3.45(m,3H), 3.61(s,3H) C NMR(22.5MHzk211.82(C9); lB7.40(C15k 173.64(CI);
9 1.84(C 13); 84.99~C~); 8 1.92(C 14);
71.35(C6); 51.11tO-CH3); 45.24(C12);
34.14, 33.68(2C), 30.~8, 29.18, 25.26, 24.419 23.76, 23.50, 22.13, 13 64(CH2CH3) ppm-` - 27 -E~
Compound (4~ was reac~ed with TFA ~o forrn methyl 9-alpha-hydroxy-7-oxa-15-trifluoroacetoxy-prost 13,14-ynoate (6) in the following manner:
To a solution of 0.1988~ diol t4) in 8 ml C~12C12, stirred at -78C under argon, was added 0.0S4 ml dry pyridine (1.5 equiv.), then 0.083 ml trifluoroacetic anhydride (1.05 equiv.), slowly via syringe. After stirring 2 hrs, the reaction mixture was concentrated under vacuum and purified by flash .
chromatography; 2:1 hexare:ethyl acetate eluted a diacetate fra~tion (Rf =
0.70, 0.103g, 34% yield), and a monoacetate fraction (Rf = 0.41, 0.0855g, 34~6 yield); 1:1 hexane:ethyl acetate eiuted recovered starting material (Rf -0.17 with 2:1 hexane:ethyl acetate, 0.056g, 28% yield). Starting material was regenerated from the diacetate fraction by stirring the latter in 2:1 ~SeOHdN
NaHCO3 for 1-2 hrs. Spectral analysis showed that the monoacetate fraction consis~ed of one, pure isomer (the title compound).
-IR (Neatk 3450, 2~20(w), 1785, 1740(br) cm H NMR (60 MHz): delta 5.5~5.1(m,1H), 4.3-3.9(m,2H), 3.7-3.3(rn,3H), 3.6(s,3H) C N MR(22.5~Hz): 174.02(C 1); 90.93(C 14); 87.01(C8);
76.50(C13); 71.54, 70.56, 69.32(C6,9,15);
51.50(0-CH3); 34.60, 33O94, 32.90, 31.14, 30.03, 29.50,.28.00, 25.65, 24.67, 24.48, 22045, 13.90 ppm.
(Diacetate) IR (Neat): 2250(w), 1785(s), 1740(br) cm lH NMR (60 MHz) delta 5.5-5.1(m,2H), 4.4-3.3(m,3H), 3.6(s,3H) i3 _ 28 -Exarnple X
Compound (6) was selectively oxidized at the 9 position; then the hydroxyl group at the 15 position was deprotected and methyl 15-hydroxy-7-oxa-9-oxo-prost-13914-ynoate (7) was isola~ed. The reaction scheme was as follows:
A solution of chromium trioxide (0.18g), pyridine (0.28 ml), and CH2C12 (3.9 ml) was stirred at room temperature for 15 min. A solution of monoacetate (6) (0.0855g, 0.19 mmol) in 1 ml CH2C12 was added in one portion, and t~e stirring was continued for 15 min. Ether (10 ml~ was added and the rnixture was passed through a short silica gel colurnn. The effluent
71.35(C6); 51.11tO-CH3); 45.24(C12);
34.14, 33.68(2C), 30.~8, 29.18, 25.26, 24.419 23.76, 23.50, 22.13, 13 64(CH2CH3) ppm-` - 27 -E~
Compound (4~ was reac~ed with TFA ~o forrn methyl 9-alpha-hydroxy-7-oxa-15-trifluoroacetoxy-prost 13,14-ynoate (6) in the following manner:
To a solution of 0.1988~ diol t4) in 8 ml C~12C12, stirred at -78C under argon, was added 0.0S4 ml dry pyridine (1.5 equiv.), then 0.083 ml trifluoroacetic anhydride (1.05 equiv.), slowly via syringe. After stirring 2 hrs, the reaction mixture was concentrated under vacuum and purified by flash .
chromatography; 2:1 hexare:ethyl acetate eluted a diacetate fra~tion (Rf =
0.70, 0.103g, 34% yield), and a monoacetate fraction (Rf = 0.41, 0.0855g, 34~6 yield); 1:1 hexane:ethyl acetate eiuted recovered starting material (Rf -0.17 with 2:1 hexane:ethyl acetate, 0.056g, 28% yield). Starting material was regenerated from the diacetate fraction by stirring the latter in 2:1 ~SeOHdN
NaHCO3 for 1-2 hrs. Spectral analysis showed that the monoacetate fraction consis~ed of one, pure isomer (the title compound).
-IR (Neatk 3450, 2~20(w), 1785, 1740(br) cm H NMR (60 MHz): delta 5.5~5.1(m,1H), 4.3-3.9(m,2H), 3.7-3.3(rn,3H), 3.6(s,3H) C N MR(22.5~Hz): 174.02(C 1); 90.93(C 14); 87.01(C8);
76.50(C13); 71.54, 70.56, 69.32(C6,9,15);
51.50(0-CH3); 34.60, 33O94, 32.90, 31.14, 30.03, 29.50,.28.00, 25.65, 24.67, 24.48, 22045, 13.90 ppm.
(Diacetate) IR (Neat): 2250(w), 1785(s), 1740(br) cm lH NMR (60 MHz) delta 5.5-5.1(m,2H), 4.4-3.3(m,3H), 3.6(s,3H) i3 _ 28 -Exarnple X
Compound (6) was selectively oxidized at the 9 position; then the hydroxyl group at the 15 position was deprotected and methyl 15-hydroxy-7-oxa-9-oxo-prost-13914-ynoate (7) was isola~ed. The reaction scheme was as follows:
A solution of chromium trioxide (0.18g), pyridine (0.28 ml), and CH2C12 (3.9 ml) was stirred at room temperature for 15 min. A solution of monoacetate (6) (0.0855g, 0.19 mmol) in 1 ml CH2C12 was added in one portion, and t~e stirring was continued for 15 min. Ether (10 ml~ was added and the rnixture was passed through a short silica gel colurnn. The effluent
10 was concentrated under vacuum, then dissolved in 5 rnl methanol; 2 ml IN
NaHCO3 was added, with stirring. After 45 min., the mixture was transferred to a separatory funnel with 100 ml H2O, and extracted with three 50 ml portions of ethyl acetate. The organic layers were combined, dried (molecular sieves), filtered, and concentrated to give the crude product, 15 purified by f3ash chromatography (1:1 hexane:ethyl acetate) ~o give keto alcohol (7) (0.0603g, 90% yield).
IR (Neat): 3450, 2190(w), 1730(br) cm H ~IMR (60 MHz): delta 4.S-4.15(m,1H), 4.2-3.4(rn,3H), 3.6(s,3H) C NMR(22.5MHz): 213.59(C9); 174.35(Cl); 85.90(C8); 84.53, 84.21(C13,14); 71.28(C6); 62.47(C15);
51.57(O-CH3h 37.99, 34.~7, 34.01(~C), 31.53, 29.37, 25.52, 24.93, 24.67, 22.65, 14.03 pprn.
3~ 3 Example XI
By varying the l-alkyne reagent in the re2ction of Example V, different prostanoid precursors could be synthesized. Thus, 2-alpha-hydroxy-1-alpha-methoxymethoxy-3-beta-(3 dimethyl-t-butyl silyloxy)-l-octynylcyclopentane (8) was prepared from epoxy ether (13 by 5 reaction with an alane rea~ent derived from 3-(dimethyl-t-butyl silyloxy)-l-octyne, exactly following the experimental procedure previously.
described for the synthesis of compound (2) (Example V). Thus, 1.26g (8.75 mmole) epoxide (1), upon treatment with 2 equivalents of the above, gave a crude product (Rf 0.37 using 3:1 hexane:ethyl acetate on silica gel), which 10 was purified by flash chromatography with 4.5:1 hexane:ethyl acetate to ~ive 1.45~ pure product (43% yield).
IR (Neat): 3490, 1460, 222û, 1250, 835 cm H NMR(60 MHz): delta 4.6 (s, 2H), 3.7-4.3(m,3H), 3.3(S~3H), 1.8(s,9H), O.l(s,6H) 13C NMR (22.5 MHz) 96.09, 85.45, 83.62, 79.12, 78.27, 63.12, S5.55, 38.84, 35.58, 31.40, 27.94, 27.68, 25.78, 25.00, 22.52, 18.21, 13~979 4.44, 4.96 ppm.
- 3~ -E
.
ay the Williamson synthesis of Example VI, Compound (8) was converted to t-bu~yl 9-alpha-methoxymethoxy~7-oxa-lS-dime~hyl-t-butyl-silyloxy-prost-13,14-ynoate (9).
The latter compound was prepared from alcohol (8) by a Williarnson 5 ether synthesis exactly as described for compound t3) (Example VI). From 1.7g (4.42 mmol) of alcohol (8) was obtained l.l4~ of 9 (46% yield) and 0.85g recorered (8) (S0~ recoveryk the Rf values on silica gel using 5:1 hexane:ethyl acetate were Q.46 and 0.31, respecti~rely. The separasion was effected by flash chromatography with 7:i hexane:ethyl acetate.
~ IR (Neat): 173û cm H NMR (60 MHz): delta4.S(s,2H), 3.8~.35(m,2H), 3.2-3.75(m,3H), 3.2(s,3H), 2.7(m71H), 1.3S(s,9H), 0.8(s,9H), 0.05(s76H~
13C NM~ (22.5 N!Hz): 172.S9(CI)~, 9s.38(O-c:H2-O);
8~.36~C8,C13), 82.90(C14); 79.44tO-C
Me3k 76.18(c9k 70.17(C7k 62.99(C15); 55.03 (OCH3); 38.71, 3S.25, 32.57, 31.27, 29.~4, 27.87(3C), 27.55, 25.65(3-4C), ~4.74, 22.39, 18.0Z, 13.77, 4.57, S.09 ppm (~ ~,J
E~
Due to ~he choice of me protection group of ~e hydroxyl at the 15 position, this hytroxyl was deprotected selectively to give t-butyl-15-hydroxy-9-alpha-methoxymethoxy-7-oxa-pr~st-13,14-ynoate (10), as follows:
410mg (0.74 rnmol) silyl ether (9) was dissolved in 4.4rnl d~y THF and - cooled to 0C under argon. Tetrabutylammonium fluoride (IM in THF, 1048ml, 2 equiv.~ was added dropwise via syringe. After 5 mir~. the solution was allowed to warm up to 25C, and stirring was continued for 40 min. llle reaction mixture was then added to a separatory funnel with lOOml Ir~l - 10 NaHC03. and was extracted with 3 40ml portions of ethyl acetate. The organic layers were combined, drled (molecular sieves), filtered, and concentrated under vacuum. This crude extract was puri~ied by flash chromatography (3:1 hexane.ethyl acetate) to ~ive 335mg pure alcohol (100%
; yield).
H N MR (60 MHz): delta 4.6(s,2H), 3 .8-4 .5(m,2H), 3.3-3.7(m,3H), 3.25(s,3H), 2.5-3.0(m,2H), 1.4(s,9H).
3C NMR (22.5 MHzk 173.18(Cl); 9S.56(0-CH2-53);
87.21(C13~; 8~.69(C8); 82.77(C14);
- 20 79.96(0-C Me3); 76.37(C9), 70.37(C7);
62.40(~15); 55.29(OC}13); 38.19, 3S.51, 32.77, 31.59, ~9.57, 28.13(3C), 27.94, 27.81, 25.65, 24.94, 22.65~ 14.03 ppm .. .. .. ..
(- ~
After t~e selective deprotection of the hydroxyl at the 15 position, (10) was oxidized to ~he ketone t-butyl ,9-alpha-methoxy~nethoxy-7-oxa-15-oxo-prost 13,14-ynoa~e(ll).
A solution of 0.67g C:rO3, 1.07ml pyridine, and 17ml CHiC12 was stirred 15 min. at 2SC. A solution of 17ml C~52C12 was added, and the resultin~ mixture was stirred 15 min. more. After adding lOOml Et20, the mixture was filtered through a shori silica gel column, starting with 50ml ethyl acetate. The combined effluent was concentrated ~mder vacuurn, and - purified by prep tlc (4 x 500u, 20 x 20cm silica gel plates with 4:1 hexane:ethyl acetate) to give 260mg pure ketone (80% yield).
, IR (Neat): 2200(s), 1725(s); 1670~s) cm . l H NMR (60 MHz): delta 4.6(s,2H), 4.1(m,1H), : ~ 3.4-3.9(mq3H), 3.3(s,3H), l.4(s,9H) 13C NMR (22.5 MHz3: 188.06(C15); 172.85(Cl);
95.83(C 13);95.56(0~CH2-O);
- 86.43(t::8~; 81.40(C14); 79.83(0-C
Me3k 76.05(C9)9 70.63(C7);
S5.35(0CH3); 45.50, 35.44, 32.83, 31.14, 29.579 ~.07(3-4C), 27.15, 25.59, 24.87, 23.83, 22.39, 13.84 ppm (~ ~f, , .
Example XV
Compound (I l) was converted to methyl ~-alpha-hydroxy-7-oxa-lS-oxo-prost-13914-ynoate(12) as follows.
Ketone(11)(220mg,0.5m mol) was dissolved ~ 1.4 ml C H2Cl~
and cooled ~o -lSC under argor~ trifluoroace~ic acid (1.4ml, cooled to 0C) 5 was added, with stirrlng. Af~er 10 min.the cooling bath was removed, alld the reaction stirred for 90 min. more. The reaction mixture was concentrated under vacuum and passed through a silica gel column (elution with 94:3:3 CHC13:methanol:acetic acid). llle 147mg crude acid thus obtain~d was esterified with CH2N2 by the usual method to give crude methyl ester, 10 which was purified by preparative tlc (3 x 500~ silica gel plates, developed with l.W hexan~.ethyl ace~ate) to give 90m~ pure ester (65% overall yield).
H NMR (60 MHz): delta 4.0-4.3(m,1H), 3.5-3.9(m-3~1)7 3.7(s,3H), 2.8-3.1(m,1H) C NMR (22.S MHz): 188.12(C15); 173.90(Cl); 95.63(C13);
86.88(C8); 8l.53(Cl~k 71.48, - ~0.63(C7,9k 51.~4(0CH3), 45.50, 33.88, 32.96, 31.14, 29.90, 2g.44, 27;6~, 25.59, 24.61, 23.83, 22.39, 13.84 ppm ( ` ~.t~' Example XVI
The prostynoate prepared acccrding to example VII (Compoun~ (4)) was hydrogenated to the corresponding as pro6tenoate, ~ethyl 9-alpha hydroxy-15-hydroxy 7 oxa-c s-prost-13,1~enoate (13) ~ ~ follows.
A solution of 410m~ (1.16mmol3 diol (4) in 20ml absolute ~thanol was 5 hydrogena~ed over SOmg Lindlar ca~alyst at 760mm. After I equivalent of hydrogen was consumed, ~he mixture was filtered, concentra~ed, and purified (flash chromatography, 1:1 hexan#ethyl acetate) to give 410mg c~s-olefin (99æ
yield). Spec~ral data (below) ir!dicate a 1:1 mix~ure of diastereorn~rs.
H NMR (90 MHz): delta 5.1-5.9(rn,2H), 3.7~s,3H) C NMR (22.5 MHz): 173.96, 135.78, 134.73~ 134.34, 133.36(C13,14); 87.60, 87.21(C8b 70.69, -- 70.43, 70O30~ 69.91, 67.95, 66.45(C7,9,15); 51.44t~CH3); 40.21, .; 15 39.88, 37.799 36.75, 33.~8, 32~0~, 31.92, - 3~.16, 29.83, 29.63, 29.1~, 27.68, 26.96, 25.65, 25.46, 2S.26, 25.13, 24.67, 24.54, 22.65, 14.03 ppm :~ .
In the same manner, compound ~7) (Example X) was converted to the 20 corresponding keto prostenoate: methyl-lS-hydroxy-7-oxa-9-oxo-cis-prost- 13-14-enoate (14).
.
J~I
' ' ! : ! rr Example XVII
The 9,1S-dihydroxy prostynoate of Example VII (Compound (4)) was hydro~enated to the corresponding pros~anoate (ISt, (15) was subsequently oxidized to ~e 9,1S dioxo analogue (16).
A solution of 30Smg (0.86mmol) diol (4) in 25ml abs. ethanol was hydrogenated over 30mg catalyst (50%Pd/C) at 760mm. After 2 equivalen~s of . hydrogen uptake, the mixture was filtered and concentrated under vacuum to give crude olefin, which could be purified (flash chromatography using 1:1 hexane-.ethyl acetate) or used directly in the next step.
A mixture of i.S4g chromium trioxide, 2.48ml pyridine, and 35ml methylene chloride was stirred 15 min. at 2SC. The crude diol ~15) was added as a solution in 2ml methylene chloride~ A~ter lS min., ~e crude diketone was isolated by the usual method and purified by flash chromatography (25:1 hexane:ethyl aceta~e) to give 250mg pure diketone (82~6 overall yield~.
For Diol (15)~
lS 13C NMR (22.5 MHz~: 174.02, 87.60, 71.93, 71.74, 70.83, 69.91, Sl.44, 41.32, 41.06, 37.60, 37.~0, 35.77, 33.88, 31.~2, 30.35, 29.57, ~6.57, 26.37, 25.72, 25.33, 2~.61, 22.S8, 13.97 ppm For Diketone ( 16): -C NMR ~22.5 MHz): 216.58(ClS)o, 210.26(C9); 173.70(Cl);
87.08(C8h 70.56(C6); 31.18(0CH33;
42.56, 41.19, 39.9S, 34~79, 33.75, 3 1.20, 29.50, 27.5~, ~S.46, ~4.~4, ~3.30(2C);
22.26,13.71 ppm .
, -~ ' . ,.
: Example xvm Cornpound (14) (Example XVI~ was converted ~o ~he ~rans isomer ~: methyl-15_hydroxy-7-oxa-9-oxo trans-prost-13,14-enoate (17) as described below. This cis-trans isomeriza~ion reaction is described in more detail by C-Moussebois and J. Dale9 ~ ~ 206 (1966).
` 5 To a solution of S8mg ke~o ~Icohol (1~) 30.16mmol, Lsorner "r') in 4.Sml cyclohexane was added 36mg dipihenyl disulfide. Aftç~r p~i~g with argon, the :stirred solution WZIS ~rradiat~d ( 3SOnm) for 90 min. wirlg a Rayonet photochemical reactorA The reac~ion mixture was then concentrated and 10 purified by flash chromatography (using 1 A hexane:ethyl aceta~e) to giYe some recoveret starting material (ca. 25mg, impure) and product (14.Smg, 25%
yield) with Rf values of 0.52 and 0.28, respec~ively (silica gel, 1:1 hexane:ethyl acetate).
IR (Nea~): 3490, 1740(br), 970(m) cm AH NMR (60 MHz): del~a 5.3~.0(m,211), 3.7(s,3H), 3.5(d,1H;
3-11 Hz) C NMR (22.5 MHz): 215.74, 174.22, 134A92, 131.14, 86.43, 72.65, 71.09, Sl.50, 44.98, 37,4~, 34.79, 34.01, 31.79, 29.57, 25.599 25.13, 24.74, 23.63, 22.~5, 14.03 ppm Exarnple XDC
-By its nature, the synthesis described in Examples IV through XVIII
produces racemic mixtures of the 7 oxa prostanoic acicl deri~atives. Optically pure compounds were prepared as follows~
dl-l-Octyn-3-o1 was resolved to (S)-l-octyn-3-o1 using 5 l(-)-alpha-methyl benzylamine. ~S)-l-Octyn-3-ol was used in the synthesis of methyl-(S)-lS-hydroxy-7-oxa-9-oxo-prost-13,14-ynoate (18) in the manner described in Examples V throu~h VII and IX-X. Similarly, me~hyl-(R)-15-hydroxy-7-oxa-9-oxo-~rost-13,14^ynoate (19) was prepared from l-octyn-3-ol, ` ~ 10 ~ COOCH3 <~ ~ ~COOCH3 OH (18) OH (19) compounds (18~ and (19) were separated from their diastereomers by repeated recrystallization. The specific rotation of compound (18) was determined to be +41.97~ in diethyl ether~ That of compound (19) was-40.42.
Via oxidation of the hydroxyl ~roup (c.f. example VIII) the 15 corresponding lS-oxo-prostynoates were prepared (compounds (20) and (21)) :, o COOCH3 <~ ~ COOC~3 o (20) ~1 t21) The specifio rotations were +56.12 and^52.12, respectively.
i3 - 3$ _ - Another aspect of this invention are the 7-oxa~ deoxy prostaglandin analogues of the formula R;~
\~/ v~ 3~ 4~R5 - wherein the C13-Cl~ bond i~ a single bond, cis double bond, OF
- 5 - trans double bond, or triple bond; Rl is ~.
R' R' -C-C-C C-C~COCH; -C-C-C=C-C-COOH;
.~ ~" R"
; .
. . , R~
10 or ~ C - C - C: - C - C - COOH, wherein . R"
R' and R" are each H, CH3, C2H5 or C3H7, R2 iS C=O OF C~OH; R3 is CH2, C=O, C , C~ C~OH ~ C~OH9 0H 0H ~H ~ CH3 ,~H
~4 is CH2, C-O~ C,, J C~H' C~OH ~
C~ , or C~ , R5 is C2H5 or C4Hg;
and esters and salts thereof~
Preferred herein are the compounds wherein R5 is C4Hg.
The substituent Rl is preferably ~2~3 .
- C - C - t:-C-C-COOH
R"
The C13-C14 bond is preferably a double bond or a triple bond, more preferably a triple bond.
Preferred al50 are compounds wherein R3 is ~ H ~H ~ CH3 C , C , C , or C
NaHCO3 was added, with stirring. After 45 min., the mixture was transferred to a separatory funnel with 100 ml H2O, and extracted with three 50 ml portions of ethyl acetate. The organic layers were combined, dried (molecular sieves), filtered, and concentrated to give the crude product, 15 purified by f3ash chromatography (1:1 hexane:ethyl acetate) ~o give keto alcohol (7) (0.0603g, 90% yield).
IR (Neat): 3450, 2190(w), 1730(br) cm H ~IMR (60 MHz): delta 4.S-4.15(m,1H), 4.2-3.4(rn,3H), 3.6(s,3H) C NMR(22.5MHz): 213.59(C9); 174.35(Cl); 85.90(C8); 84.53, 84.21(C13,14); 71.28(C6); 62.47(C15);
51.57(O-CH3h 37.99, 34.~7, 34.01(~C), 31.53, 29.37, 25.52, 24.93, 24.67, 22.65, 14.03 pprn.
3~ 3 Example XI
By varying the l-alkyne reagent in the re2ction of Example V, different prostanoid precursors could be synthesized. Thus, 2-alpha-hydroxy-1-alpha-methoxymethoxy-3-beta-(3 dimethyl-t-butyl silyloxy)-l-octynylcyclopentane (8) was prepared from epoxy ether (13 by 5 reaction with an alane rea~ent derived from 3-(dimethyl-t-butyl silyloxy)-l-octyne, exactly following the experimental procedure previously.
described for the synthesis of compound (2) (Example V). Thus, 1.26g (8.75 mmole) epoxide (1), upon treatment with 2 equivalents of the above, gave a crude product (Rf 0.37 using 3:1 hexane:ethyl acetate on silica gel), which 10 was purified by flash chromatography with 4.5:1 hexane:ethyl acetate to ~ive 1.45~ pure product (43% yield).
IR (Neat): 3490, 1460, 222û, 1250, 835 cm H NMR(60 MHz): delta 4.6 (s, 2H), 3.7-4.3(m,3H), 3.3(S~3H), 1.8(s,9H), O.l(s,6H) 13C NMR (22.5 MHz) 96.09, 85.45, 83.62, 79.12, 78.27, 63.12, S5.55, 38.84, 35.58, 31.40, 27.94, 27.68, 25.78, 25.00, 22.52, 18.21, 13~979 4.44, 4.96 ppm.
- 3~ -E
.
ay the Williamson synthesis of Example VI, Compound (8) was converted to t-bu~yl 9-alpha-methoxymethoxy~7-oxa-lS-dime~hyl-t-butyl-silyloxy-prost-13,14-ynoate (9).
The latter compound was prepared from alcohol (8) by a Williarnson 5 ether synthesis exactly as described for compound t3) (Example VI). From 1.7g (4.42 mmol) of alcohol (8) was obtained l.l4~ of 9 (46% yield) and 0.85g recorered (8) (S0~ recoveryk the Rf values on silica gel using 5:1 hexane:ethyl acetate were Q.46 and 0.31, respecti~rely. The separasion was effected by flash chromatography with 7:i hexane:ethyl acetate.
~ IR (Neat): 173û cm H NMR (60 MHz): delta4.S(s,2H), 3.8~.35(m,2H), 3.2-3.75(m,3H), 3.2(s,3H), 2.7(m71H), 1.3S(s,9H), 0.8(s,9H), 0.05(s76H~
13C NM~ (22.5 N!Hz): 172.S9(CI)~, 9s.38(O-c:H2-O);
8~.36~C8,C13), 82.90(C14); 79.44tO-C
Me3k 76.18(c9k 70.17(C7k 62.99(C15); 55.03 (OCH3); 38.71, 3S.25, 32.57, 31.27, 29.~4, 27.87(3C), 27.55, 25.65(3-4C), ~4.74, 22.39, 18.0Z, 13.77, 4.57, S.09 ppm (~ ~,J
E~
Due to ~he choice of me protection group of ~e hydroxyl at the 15 position, this hytroxyl was deprotected selectively to give t-butyl-15-hydroxy-9-alpha-methoxymethoxy-7-oxa-pr~st-13,14-ynoate (10), as follows:
410mg (0.74 rnmol) silyl ether (9) was dissolved in 4.4rnl d~y THF and - cooled to 0C under argon. Tetrabutylammonium fluoride (IM in THF, 1048ml, 2 equiv.~ was added dropwise via syringe. After 5 mir~. the solution was allowed to warm up to 25C, and stirring was continued for 40 min. llle reaction mixture was then added to a separatory funnel with lOOml Ir~l - 10 NaHC03. and was extracted with 3 40ml portions of ethyl acetate. The organic layers were combined, drled (molecular sieves), filtered, and concentrated under vacuum. This crude extract was puri~ied by flash chromatography (3:1 hexane.ethyl acetate) to ~ive 335mg pure alcohol (100%
; yield).
H N MR (60 MHz): delta 4.6(s,2H), 3 .8-4 .5(m,2H), 3.3-3.7(m,3H), 3.25(s,3H), 2.5-3.0(m,2H), 1.4(s,9H).
3C NMR (22.5 MHzk 173.18(Cl); 9S.56(0-CH2-53);
87.21(C13~; 8~.69(C8); 82.77(C14);
- 20 79.96(0-C Me3); 76.37(C9), 70.37(C7);
62.40(~15); 55.29(OC}13); 38.19, 3S.51, 32.77, 31.59, ~9.57, 28.13(3C), 27.94, 27.81, 25.65, 24.94, 22.65~ 14.03 ppm .. .. .. ..
(- ~
After t~e selective deprotection of the hydroxyl at the 15 position, (10) was oxidized to ~he ketone t-butyl ,9-alpha-methoxy~nethoxy-7-oxa-15-oxo-prost 13,14-ynoa~e(ll).
A solution of 0.67g C:rO3, 1.07ml pyridine, and 17ml CHiC12 was stirred 15 min. at 2SC. A solution of 17ml C~52C12 was added, and the resultin~ mixture was stirred 15 min. more. After adding lOOml Et20, the mixture was filtered through a shori silica gel column, starting with 50ml ethyl acetate. The combined effluent was concentrated ~mder vacuurn, and - purified by prep tlc (4 x 500u, 20 x 20cm silica gel plates with 4:1 hexane:ethyl acetate) to give 260mg pure ketone (80% yield).
, IR (Neat): 2200(s), 1725(s); 1670~s) cm . l H NMR (60 MHz): delta 4.6(s,2H), 4.1(m,1H), : ~ 3.4-3.9(mq3H), 3.3(s,3H), l.4(s,9H) 13C NMR (22.5 MHz3: 188.06(C15); 172.85(Cl);
95.83(C 13);95.56(0~CH2-O);
- 86.43(t::8~; 81.40(C14); 79.83(0-C
Me3k 76.05(C9)9 70.63(C7);
S5.35(0CH3); 45.50, 35.44, 32.83, 31.14, 29.579 ~.07(3-4C), 27.15, 25.59, 24.87, 23.83, 22.39, 13.84 ppm (~ ~f, , .
Example XV
Compound (I l) was converted to methyl ~-alpha-hydroxy-7-oxa-lS-oxo-prost-13914-ynoate(12) as follows.
Ketone(11)(220mg,0.5m mol) was dissolved ~ 1.4 ml C H2Cl~
and cooled ~o -lSC under argor~ trifluoroace~ic acid (1.4ml, cooled to 0C) 5 was added, with stirrlng. Af~er 10 min.the cooling bath was removed, alld the reaction stirred for 90 min. more. The reaction mixture was concentrated under vacuum and passed through a silica gel column (elution with 94:3:3 CHC13:methanol:acetic acid). llle 147mg crude acid thus obtain~d was esterified with CH2N2 by the usual method to give crude methyl ester, 10 which was purified by preparative tlc (3 x 500~ silica gel plates, developed with l.W hexan~.ethyl ace~ate) to give 90m~ pure ester (65% overall yield).
H NMR (60 MHz): delta 4.0-4.3(m,1H), 3.5-3.9(m-3~1)7 3.7(s,3H), 2.8-3.1(m,1H) C NMR (22.S MHz): 188.12(C15); 173.90(Cl); 95.63(C13);
86.88(C8); 8l.53(Cl~k 71.48, - ~0.63(C7,9k 51.~4(0CH3), 45.50, 33.88, 32.96, 31.14, 29.90, 2g.44, 27;6~, 25.59, 24.61, 23.83, 22.39, 13.84 ppm ( ` ~.t~' Example XVI
The prostynoate prepared acccrding to example VII (Compoun~ (4)) was hydrogenated to the corresponding as pro6tenoate, ~ethyl 9-alpha hydroxy-15-hydroxy 7 oxa-c s-prost-13,1~enoate (13) ~ ~ follows.
A solution of 410m~ (1.16mmol3 diol (4) in 20ml absolute ~thanol was 5 hydrogena~ed over SOmg Lindlar ca~alyst at 760mm. After I equivalent of hydrogen was consumed, ~he mixture was filtered, concentra~ed, and purified (flash chromatography, 1:1 hexan#ethyl acetate) to give 410mg c~s-olefin (99æ
yield). Spec~ral data (below) ir!dicate a 1:1 mix~ure of diastereorn~rs.
H NMR (90 MHz): delta 5.1-5.9(rn,2H), 3.7~s,3H) C NMR (22.5 MHz): 173.96, 135.78, 134.73~ 134.34, 133.36(C13,14); 87.60, 87.21(C8b 70.69, -- 70.43, 70O30~ 69.91, 67.95, 66.45(C7,9,15); 51.44t~CH3); 40.21, .; 15 39.88, 37.799 36.75, 33.~8, 32~0~, 31.92, - 3~.16, 29.83, 29.63, 29.1~, 27.68, 26.96, 25.65, 25.46, 2S.26, 25.13, 24.67, 24.54, 22.65, 14.03 ppm :~ .
In the same manner, compound ~7) (Example X) was converted to the 20 corresponding keto prostenoate: methyl-lS-hydroxy-7-oxa-9-oxo-cis-prost- 13-14-enoate (14).
.
J~I
' ' ! : ! rr Example XVII
The 9,1S-dihydroxy prostynoate of Example VII (Compound (4)) was hydro~enated to the corresponding pros~anoate (ISt, (15) was subsequently oxidized to ~e 9,1S dioxo analogue (16).
A solution of 30Smg (0.86mmol) diol (4) in 25ml abs. ethanol was hydrogenated over 30mg catalyst (50%Pd/C) at 760mm. After 2 equivalen~s of . hydrogen uptake, the mixture was filtered and concentrated under vacuum to give crude olefin, which could be purified (flash chromatography using 1:1 hexane-.ethyl acetate) or used directly in the next step.
A mixture of i.S4g chromium trioxide, 2.48ml pyridine, and 35ml methylene chloride was stirred 15 min. at 2SC. The crude diol ~15) was added as a solution in 2ml methylene chloride~ A~ter lS min., ~e crude diketone was isolated by the usual method and purified by flash chromatography (25:1 hexane:ethyl aceta~e) to give 250mg pure diketone (82~6 overall yield~.
For Diol (15)~
lS 13C NMR (22.5 MHz~: 174.02, 87.60, 71.93, 71.74, 70.83, 69.91, Sl.44, 41.32, 41.06, 37.60, 37.~0, 35.77, 33.88, 31.~2, 30.35, 29.57, ~6.57, 26.37, 25.72, 25.33, 2~.61, 22.S8, 13.97 ppm For Diketone ( 16): -C NMR ~22.5 MHz): 216.58(ClS)o, 210.26(C9); 173.70(Cl);
87.08(C8h 70.56(C6); 31.18(0CH33;
42.56, 41.19, 39.9S, 34~79, 33.75, 3 1.20, 29.50, 27.5~, ~S.46, ~4.~4, ~3.30(2C);
22.26,13.71 ppm .
, -~ ' . ,.
: Example xvm Cornpound (14) (Example XVI~ was converted ~o ~he ~rans isomer ~: methyl-15_hydroxy-7-oxa-9-oxo trans-prost-13,14-enoate (17) as described below. This cis-trans isomeriza~ion reaction is described in more detail by C-Moussebois and J. Dale9 ~ ~ 206 (1966).
` 5 To a solution of S8mg ke~o ~Icohol (1~) 30.16mmol, Lsorner "r') in 4.Sml cyclohexane was added 36mg dipihenyl disulfide. Aftç~r p~i~g with argon, the :stirred solution WZIS ~rradiat~d ( 3SOnm) for 90 min. wirlg a Rayonet photochemical reactorA The reac~ion mixture was then concentrated and 10 purified by flash chromatography (using 1 A hexane:ethyl aceta~e) to giYe some recoveret starting material (ca. 25mg, impure) and product (14.Smg, 25%
yield) with Rf values of 0.52 and 0.28, respec~ively (silica gel, 1:1 hexane:ethyl acetate).
IR (Nea~): 3490, 1740(br), 970(m) cm AH NMR (60 MHz): del~a 5.3~.0(m,211), 3.7(s,3H), 3.5(d,1H;
3-11 Hz) C NMR (22.5 MHz): 215.74, 174.22, 134A92, 131.14, 86.43, 72.65, 71.09, Sl.50, 44.98, 37,4~, 34.79, 34.01, 31.79, 29.57, 25.599 25.13, 24.74, 23.63, 22.~5, 14.03 ppm Exarnple XDC
-By its nature, the synthesis described in Examples IV through XVIII
produces racemic mixtures of the 7 oxa prostanoic acicl deri~atives. Optically pure compounds were prepared as follows~
dl-l-Octyn-3-o1 was resolved to (S)-l-octyn-3-o1 using 5 l(-)-alpha-methyl benzylamine. ~S)-l-Octyn-3-ol was used in the synthesis of methyl-(S)-lS-hydroxy-7-oxa-9-oxo-prost-13,14-ynoate (18) in the manner described in Examples V throu~h VII and IX-X. Similarly, me~hyl-(R)-15-hydroxy-7-oxa-9-oxo-~rost-13,14^ynoate (19) was prepared from l-octyn-3-ol, ` ~ 10 ~ COOCH3 <~ ~ ~COOCH3 OH (18) OH (19) compounds (18~ and (19) were separated from their diastereomers by repeated recrystallization. The specific rotation of compound (18) was determined to be +41.97~ in diethyl ether~ That of compound (19) was-40.42.
Via oxidation of the hydroxyl ~roup (c.f. example VIII) the 15 corresponding lS-oxo-prostynoates were prepared (compounds (20) and (21)) :, o COOCH3 <~ ~ COOC~3 o (20) ~1 t21) The specifio rotations were +56.12 and^52.12, respectively.
i3 - 3$ _ - Another aspect of this invention are the 7-oxa~ deoxy prostaglandin analogues of the formula R;~
\~/ v~ 3~ 4~R5 - wherein the C13-Cl~ bond i~ a single bond, cis double bond, OF
- 5 - trans double bond, or triple bond; Rl is ~.
R' R' -C-C-C C-C~COCH; -C-C-C=C-C-COOH;
.~ ~" R"
; .
. . , R~
10 or ~ C - C - C: - C - C - COOH, wherein . R"
R' and R" are each H, CH3, C2H5 or C3H7, R2 iS C=O OF C~OH; R3 is CH2, C=O, C , C~ C~OH ~ C~OH9 0H 0H ~H ~ CH3 ,~H
~4 is CH2, C-O~ C,, J C~H' C~OH ~
C~ , or C~ , R5 is C2H5 or C4Hg;
and esters and salts thereof~
Preferred herein are the compounds wherein R5 is C4Hg.
The substituent Rl is preferably ~2~3 .
- C - C - t:-C-C-COOH
R"
The C13-C14 bond is preferably a double bond or a triple bond, more preferably a triple bond.
Preferred al50 are compounds wherein R3 is ~ H ~H ~ CH3 C , C , C , or C
11 0~ o R4 is preferably CH2, C,~ 9 or C~ , most pre~erably CH2o C~3 3 A number of ~e 7-oxa prostanoic acid derivatives has been tested 10 for cytoprotectiYe activity In rats. In this test, Sprague-Dawley rats are -fasted for 24 hours prior ~o the pretreatment. The pretreatment is oral administration of a Smg per kg body weight dose of the prostanoid in 2.5ml of a vehicle consistin~ of"Tween 80'~0.75~6) and the balance water. The control animals are given 2.5ml of the vehicle, without prostanoid. A half hour after 15 the pretreatment7 absolute ethanol is administered orally to the animals, in a dose of l0ml per kg bo~y weight. One hour later the animal~ are sacrificed, their stomachs disseeted out, opened along the greater curvature and the mucose examined for lesions. lhe average lesion length is expressed as percenta~e oE the average lesion length found in the stornach mucosa of 20 conerol animals.
Importantlys this test measures the active cytoprotective properties of the prostanoids, independen~ o~ the gastric secretion inhibition that these compounds may or may not show. The test is discussed more fully ~y Robert et al., G~ 77 (1979) 433. ~ r_~ _ * Trademark ~or po1yoxyethy1ene (20) sorbitan ~onooleate;
it is a non1Onic surfactant.
.. -- 40 ^
Example XX
methyl-7-oxa-9-oxo-Prostanoa~e derivatives were tested for cytoprotective properties. ll~e compounds differed with respect to the nature of the C13-C~ bond (ttiple, cis or trans double, or single)g the - . substituent(~) at the lS-position and at the 16-position. The following results 5 were ob~ained.
- : Table I . . ~ - .
Cytoprotect;ve properties of 7 oxa-9-oxo-methyl prostanoate ~~derivatives having different substituents at the 15 and 16 positions.
., COMPOUND LESIONS
C13 14 15-subst. 16-subst.% control% reduceion triple (R,S)OH H,H 31 69 cis (R,S)OH H,H 31 69 triple oxo H7H 4 96 cis oxo H,H 113 -13 trans oxo H,H 118 -18 single oxo H,H 128 -28 triple (S)OH H ,H 4 96 triple (R,S)OH,Me H,H 82 18 cis (R,S)OH,Me H,H 71 29 trans (R,S)OH,Me H,H 54 46 single (R,S)OH,Me H,H 67 33 triple H,H H,H 81 19 triple oxo Me,Me 16 84 The results indicate that for optimum cytoprotecti~e properties it is highly desirable that the substituent at the 15-position be either oxo or (S)OH.If the substituent is oxo, the C13-C14 bond preferably is a triple bond.
A number of me~hyl-?-oxa-9-alpha-hydroxy prost-13,1~-ynoate derivatives was ~ested for cycloprotective properties. The resul~s are presented in Table II~
Table II
COMPOUND L~SIONS
C13 14 15-subst. 16-subst. % control % reduction triple H,H H,H 90 10 triple (R,S)OH H,H 93 7 triple (R9S)OH Me,Me 83 17 triple (S)OH lH,H 45 S5 15triple (R)OH H1H 101 _1 triple oxo H,H 20 80 triple oxo H,H 7 ) 93 I) Acid rather than methyl ester.
As in the preYious example, oxo and S(OH) appear to be the preferred 20 substituents at the 15-posi~ion.
( C-J
~2~
42. ~
Example XXII
The optically pure eompounds of Example XIX were tested for cytoprotec~ive activity. The $ollowing results were obtained tTable lil).
Table lli C~ Number % Protection ),1~ ~0 ~./ COOC~3 i~ (18) 96 .` ~~~
OH
~4 0 ~ COOCH3 ~", (19) -34 y~
. OH
O
O ~ (:OOCH3 (20) 96 ~~
o O
~COOCH3 (21) 96 O
~1'2~
- 43^
.1 1 ,, rr The activity of the enantiomers (20) and ~21) was the same (and was the sarne also for the rasemate, Table 1, line 3). This sugges~s that the activity is independent of the stereochemistry at the positions 8 and 12 of the 9-oxo compounds. The striklng difference between the activities of (18) and 5 (19) must then be due to the C-15 stereochemistry.The absolute configurations of the compounds were not established. In view of ~he high cytoprotective activity it is assumed that compound (18) has the confi~uration as indicated, since this is the natural con:Eiguration.
. . .
.. . - ' : ,.
;,. .... . A . _ _ .... _ ~ . . __ . _ _ .. __ _ ~_. , _ . . _ " .. ,._ _,.. . _~.. ,.. . _ ~ .. , ,_ _.. ... .
Importantlys this test measures the active cytoprotective properties of the prostanoids, independen~ o~ the gastric secretion inhibition that these compounds may or may not show. The test is discussed more fully ~y Robert et al., G~ 77 (1979) 433. ~ r_~ _ * Trademark ~or po1yoxyethy1ene (20) sorbitan ~onooleate;
it is a non1Onic surfactant.
.. -- 40 ^
Example XX
methyl-7-oxa-9-oxo-Prostanoa~e derivatives were tested for cytoprotective properties. ll~e compounds differed with respect to the nature of the C13-C~ bond (ttiple, cis or trans double, or single)g the - . substituent(~) at the lS-position and at the 16-position. The following results 5 were ob~ained.
- : Table I . . ~ - .
Cytoprotect;ve properties of 7 oxa-9-oxo-methyl prostanoate ~~derivatives having different substituents at the 15 and 16 positions.
., COMPOUND LESIONS
C13 14 15-subst. 16-subst.% control% reduceion triple (R,S)OH H,H 31 69 cis (R,S)OH H,H 31 69 triple oxo H7H 4 96 cis oxo H,H 113 -13 trans oxo H,H 118 -18 single oxo H,H 128 -28 triple (S)OH H ,H 4 96 triple (R,S)OH,Me H,H 82 18 cis (R,S)OH,Me H,H 71 29 trans (R,S)OH,Me H,H 54 46 single (R,S)OH,Me H,H 67 33 triple H,H H,H 81 19 triple oxo Me,Me 16 84 The results indicate that for optimum cytoprotecti~e properties it is highly desirable that the substituent at the 15-position be either oxo or (S)OH.If the substituent is oxo, the C13-C14 bond preferably is a triple bond.
A number of me~hyl-?-oxa-9-alpha-hydroxy prost-13,1~-ynoate derivatives was ~ested for cycloprotective properties. The resul~s are presented in Table II~
Table II
COMPOUND L~SIONS
C13 14 15-subst. 16-subst. % control % reduction triple H,H H,H 90 10 triple (R,S)OH H,H 93 7 triple (R9S)OH Me,Me 83 17 triple (S)OH lH,H 45 S5 15triple (R)OH H1H 101 _1 triple oxo H,H 20 80 triple oxo H,H 7 ) 93 I) Acid rather than methyl ester.
As in the preYious example, oxo and S(OH) appear to be the preferred 20 substituents at the 15-posi~ion.
( C-J
~2~
42. ~
Example XXII
The optically pure eompounds of Example XIX were tested for cytoprotec~ive activity. The $ollowing results were obtained tTable lil).
Table lli C~ Number % Protection ),1~ ~0 ~./ COOC~3 i~ (18) 96 .` ~~~
OH
~4 0 ~ COOCH3 ~", (19) -34 y~
. OH
O
O ~ (:OOCH3 (20) 96 ~~
o O
~COOCH3 (21) 96 O
~1'2~
- 43^
.1 1 ,, rr The activity of the enantiomers (20) and ~21) was the same (and was the sarne also for the rasemate, Table 1, line 3). This sugges~s that the activity is independent of the stereochemistry at the positions 8 and 12 of the 9-oxo compounds. The striklng difference between the activities of (18) and 5 (19) must then be due to the C-15 stereochemistry.The absolute configurations of the compounds were not established. In view of ~he high cytoprotective activity it is assumed that compound (18) has the confi~uration as indicated, since this is the natural con:Eiguration.
. . .
.. . - ' : ,.
;,. .... . A . _ _ .... _ ~ . . __ . _ _ .. __ _ ~_. , _ . . _ " .. ,._ _,.. . _~.. ,.. . _ ~ .. , ,_ _.. ... .
Claims (14)
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for synthesizing 7-oxy-11-deoxy prostaglandin analogues of the formula wherein the C13-C14 bond is a single bond, cis double bond, or trans double bond, or triple bond; R1 is R'and R" are each H, CH3, C2H5 or C3H7;
; and R5 is C2H5 or C4H9;
and esters and salts thereof, comprising the steps of a) reacting protected cis-2,3-epoxycyclopentan-1-ol with an alkynylalane reagent; and b) reacting the product of step a) with an ester of an omega-iodo alkanoic acid, containing from 3 to 12 carbon atoms, and, if required, converting the product of step (b) with one or more of the following steps:
c) reacting one or more of the hydroxy groups of the prostaglandin analogue with chromium trioxide;
d) reacting the prostaglandin analogues with hydrogen in the presence of a Lindlar catalyst;
e) reacting the prostaglandin analogue with hydrogen in the presence of a coal-supported palladium catalyst; or f) reacting the prostaglandin analogue with diphenyl disulphide, followed by irradiation with u.v.
light.
; and R5 is C2H5 or C4H9;
and esters and salts thereof, comprising the steps of a) reacting protected cis-2,3-epoxycyclopentan-1-ol with an alkynylalane reagent; and b) reacting the product of step a) with an ester of an omega-iodo alkanoic acid, containing from 3 to 12 carbon atoms, and, if required, converting the product of step (b) with one or more of the following steps:
c) reacting one or more of the hydroxy groups of the prostaglandin analogue with chromium trioxide;
d) reacting the prostaglandin analogues with hydrogen in the presence of a Lindlar catalyst;
e) reacting the prostaglandin analogue with hydrogen in the presence of a coal-supported palladium catalyst; or f) reacting the prostaglandin analogue with diphenyl disulphide, followed by irradiation with u.v.
light.
2. The process of claim 1 wherein the alkynylalane reagent is derived from a compound selected from the group consisting of 1-octyne;
(R,S)-1-octyn-3-ol;(R)-1-octyn-3-ol;(S)-1-octyn-3-ol;3-methyl (S)-octyn-3-ol;4-methyl(R,S)-1-octyn-3-ol;4-methyl (R)-1-octyn-3-ol;4 methyl(S)-1-octyn-3-ol;4,4 dimethyl (R,S)-1-octyn-3-ol;4,4 dimethyl(R)-1-octyn-3-ol; 4,4 dimethyl (S)-1-octyn-3-ol;(R,S)-1-octyn-4-ol;(R)-1-octyn-4-ol;-(S)-1-octyn-4-ol;and 4 methyl-1-octyn-4-ol.
(R,S)-1-octyn-3-ol;(R)-1-octyn-3-ol;(S)-1-octyn-3-ol;3-methyl (S)-octyn-3-ol;4-methyl(R,S)-1-octyn-3-ol;4-methyl (R)-1-octyn-3-ol;4 methyl(S)-1-octyn-3-ol;4,4 dimethyl (R,S)-1-octyn-3-ol;4,4 dimethyl(R)-1-octyn-3-ol; 4,4 dimethyl (S)-1-octyn-3-ol;(R,S)-1-octyn-4-ol;(R)-1-octyn-4-ol;-(S)-1-octyn-4-ol;and 4 methyl-1-octyn-4-ol.
3. The process of claim 1 wherein the alkynylalane reagent is derived from a compound selected from the group consisting of 1-octyne;
(R,S)-1-octyn-3-ol;(S)-1-octyn-3-ol;and 3-methyl(S)-1-octyn-3-ol.
(R,S)-1-octyn-3-ol;(S)-1-octyn-3-ol;and 3-methyl(S)-1-octyn-3-ol.
4. The process of claim 1 wherein the alkynylalane reagent is derived from (R,S)-1-octyn-3-ol or (S) 1-octyn-3-ol.
The process of claim 1 wherein the omega-iodo alkanoic acid ester
The process of claim 1 wherein the omega-iodo alkanoic acid ester
5.
is of the formula I - C - R1 - COO t-Bu wherein R1 is and R2 and R3 are each H,CH3,C2H5 or C3H7.
is of the formula I - C - R1 - COO t-Bu wherein R1 is and R2 and R3 are each H,CH3,C2H5 or C3H7.
6 . The process of claim 1 wherein the omega-iodo-alkanoic acid ester is t-butyl 6-iodohexanoate.
7 . The process of claim 1 wherein the prostaglandin analogue compound which is prepared is of the formula wherein said compound is made by (a) reacting cis-2, 3-epoxycyclopentan-1-ol with an alkynylalane reagent derived from (S)-1-octyn-3-ol; and (b) reacting the product of step (a) with 6-iodo hexanoate.
8. The process of claim 7 wherein the prostaglandin analogue compound which is prepared is of the formula wherein the product of step (b) is selectively oxidized at the 9 position with chromium trioxide.
9. The process of claim 7 wherein the prostaglandin analogue compound which is prepared is of the formula wherein the product of step (b) is selectively oxidized at the 15 position with chromium trioxide.
10. The process of claim 7 wherein the prostaglandin analogue compound which is prepared is of the formula wherein the product of step (b) is selectively oxidized at the 9 and 15 positions with chromium trioxide.
11. A prostaglandin analogue compound of the formula when prepared by the process of claim 7 or by an obvious chemical equivalent thereof.
12. A prostaglandin analogue compound of the formula when prepared by the process of claim 8 or by an obvious chemical equivalent thereof.
13. A prostaglandin analogue compound of the formula when prepared by the process of claim 9 or by an obvious chemical equivalent thereof.
14. A prostaglandin analogue compound of the formula when prepared by the process of claim 10 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000492580A CA1221963A (en) | 1981-03-02 | 1985-10-09 | Prostaglandin analogues and process for making same |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/239,765 US4345984A (en) | 1981-03-02 | 1981-03-02 | Novel prostaglandin analogues and process for making same |
| US239,765 | 1981-03-02 | ||
| CA000397348A CA1210016A (en) | 1981-03-02 | 1982-03-01 | Prostaglandin analogues and process for making same |
| CA000492580A CA1221963A (en) | 1981-03-02 | 1985-10-09 | Prostaglandin analogues and process for making same |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000397348A Division CA1210016A (en) | 1981-03-02 | 1982-03-01 | Prostaglandin analogues and process for making same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1221963A true CA1221963A (en) | 1987-05-19 |
Family
ID=25669600
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000492580A Expired CA1221963A (en) | 1981-03-02 | 1985-10-09 | Prostaglandin analogues and process for making same |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1221963A (en) |
-
1985
- 1985-10-09 CA CA000492580A patent/CA1221963A/en not_active Expired
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