CA2187431A1 - Methods for the synthesis of 9-cis retinoids and their novel intermediates - Google Patents
Methods for the synthesis of 9-cis retinoids and their novel intermediatesInfo
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- CA2187431A1 CA2187431A1 CA002187431A CA2187431A CA2187431A1 CA 2187431 A1 CA2187431 A1 CA 2187431A1 CA 002187431 A CA002187431 A CA 002187431A CA 2187431 A CA2187431 A CA 2187431A CA 2187431 A1 CA2187431 A1 CA 2187431A1
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- cis
- nitrile
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- alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/02—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains containing only carbon and hydrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/14—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by doubly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/18—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
Methods for the synthesis of 9-cis retinoids, novel intermediates and methods for the synthesis of cyclohexadienyne nitriles and 9-cis alkyl cisoid nitriles, as well as 9-cis retinoids made using such methods are provided.
Description
~1$7~31 ~W095132946 . - , : P~
METIIODS FOR TIIE SYNTElESlS
TEIEIR NOVEL INTERMEDL~TES
Field of the Invention The present invention relates to the synthesis of 9-cis retinoid ~nmro~n~lC and in particular to the synthesis of 9-cis retinoic acid and related , 15, as well as to their novel ;~llr~
Ba~ ' of the Invention The role of retinoids such as all-trans retinoic acid, 13-cis retinoic acid and synthetic retinoic acid analogs in mediating cell growth and d;~. ~ ioll has generated interest in their ~ nlng;~ -l utility for controlling the treatment of d~ lùg~ diseases~ such as psoriasis and acne, as well as oncological A~ _ such as ~,I..,.~U~ yand chemoprevention. Significant advances in elucidating the molecular basis of retinoid action now offer the potential for designing retinoid compounds with improved therapeutic indices.
To datel several receptors for retinoic acid have been identified. These receptors are members of a au~J~,ILllily of ;llil~ lluldl receptors which function as ligand dependent L~Al.a~ iUII factors. At presentl these receptors have been classified into two subfamilies, the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). The ~ ;"" ofthese subfamilies is based primarily on differences in amino acid structure, taiJv~ , to different naturally occurring and synthetic retinoids, and ability to modulate expression of different target genes. Each RAR and RXR subfamily has three distinct isoforms designated RARo~ RAR~ and RAR~, and RXRa, R~R~ and R~Rl/. The discovery of multiple retinoid receptors raises questions of the functional properties of the distinct subfamilies and their isoforms.
Recentlyl it has been discovered that 9-cis RA, and other retinoids having a 9-10 cis olefin at~l ~O~,Il.,lllialy, are capable of binding to and modulating gene expression via the RARs and RXRs. Heyman et al., ~Ç~l 68:397 (1992). However, to date, the art has only 3û provided low y-ield, non-selective, high cost methods of making such ~ ' For example, the literature has provided non-selective means of generating 9-10 cis olefin retinoids, see e.~., Robson et al., J. Am. ~`hPm SOC.~ 77:4111 (1955), Matsui et al, L
ViatminoJ.~ 4:178 ~1958), German Patent No. DEI 068719, and Aurell et al., Tetrahedrorl l,ett., 31:5791(1990), aswellasmethodsforthes~ o~ ;v~preparationofthe 13-14 olefin bond, see e. ., Pattenden et al., J. Chem. Soc. (C)~ 1984 (1968) and Mayer et al., F~F~ori~nti~. 34:11ûS (1978).
, . . ... . . . . .
WO 95/32946 218 i ~ 31 r~ f Further, Ernst et al. J. Or~. Chem.. s2:398 (i987) provides methods for the preparation of alkyl- and ~ yl~;lyl-substituted retinoids via conjugate addition of cuprates to acetylenic esters, which use an excessive number of steps, and ;III~VOl L~ullly, the oxidation of an allylic alcohol to an aldehyde, thereby destroying the integrity of any 9-10 cis 5 olefin bonds present in the resulting retinoids.
Accordingly, it would be desirable to prepare retinoid compounds having the 9-10olefin bond in the cis cu~ ;uldLiull in a selective, low cost manner.
Summar~ of the Invention 1 û The ptesent invention provides methods for the synthesis of 9-cis retinoids, preferably, 9-cis retinoic acid in a selective, low-cost manner. In particular~ the present invention provides a method for producing a 9-cis retinoid comprising (a) reducing a UYIIOI~ Y ketone in the presence of base to form a uy. 1~ ii J.I_, (b) condensing the ~jyl ~ yllC with an cl~cll~ . ' ' nitrile source to form a cy, '-' ' ,l.c nitrile, (c) 15 adding an alkyl group, in a 1,4 conjugate fashion, to the ~y~ ..e nitrjle to form a Uy~h)ll~ LIk~ nitrile,(d) reducingthecy~1 1, All; nitriletothe~u" t~
uy~ ' ' aidehyde, and (e) extending the uyl.l~ aldehyde with a carbanion equivalent formed by the addition of a base to a r' A ~ ' or phosphjne salt to form a reaction product comprising a mixture of retinoid ester ~Ic~ c~;~U~ wherein the olefin 20 bond between carbons 9-10 is in the cis ~ , and the olefin bonds between carbons 11-12, and 13-14 can be in either the trans or cis 5" Thereafter, the retinoid esters can be hydrolyzed to yield a mixture of retinoic acid ~ ù;~ . which in turn can be separated to provide individual retinoic acid ~Lcl c~ , preferably, 9-cis rctinoic acid.
Also provided, is a method for producing a 9-cis retinoid comprising (a) reducing a 25 1y~ h.,Acll~ll ketone in the presence of base arid an dc~,L- r ~ '' nitrile source to form a ~y~ .1..1,_. ~.i:. ..~.,_ nitrile, (b) adding an alkyl group, in a 1,4 conjugate fashion, to the uy~ .,e nitrile to form a "y~ rlitrile, (c) reducing the ,,y~,ll ,l A l, ;. ~
nitrile to the cu" C~ "A;..g uyl Ihl' _ Al l; aldehyde, and (d) extending the uy~ .1.~1~ Al l ;....
aldehyde with a carbanion equivaAent formed by the addition of a base to a ~ or 30phosphine salt to form a reaction product comprising a mixture of retinoid ester ~L~;I C~ VIII~ wherein the olefin bond between carbons 9-10 is in the cis ~ 5~, , and the olefin bonds between carbons 11-12, and 13-14 can be in either the trans or cis t~nfiellrptirm In addition, the present invention provides a method for producing a 3~~:y~ Ihl;. A l:, _ nitrile olefin comprising reducing a ~;y. ' - ' ~ I ketone in the presence of base and an ~ lu~JLIl;c nitrile source to form a ~y~ .. _ nitrile.
~ WO 9S/3Z946 2 1 8 7 a 3 1 r~
. t. ~
Further, the present invention provides a method for producing a 9-cis alkyl cisoid nitrile comprising (a) condensing a ey~ lo~ e with an el~,LIul~lhl~, nitrile source to form a cy~ hPYA~iPnyne nitrile, and (b) adding an alkyl group, in a 1,4 conjugate fashion, to the ~;y~ to form a 9-cis alkyl cisoid nitrile, wherein the 9-10 olefin bond is in the S cis .,.~
Further yet, the present invention provides a 9-cis retinoid made according to the method described above. Preferably such 9~cis retinoid comprises 9-cis retinoic acid, 9,11-dicis retinoic acid, 9,13-dicis retinoic acid and 9,11,13-tricis retinoic acid. These and various other advantages and features of novelty which cL. ~ el ;4~ the invention are pointed 10 out with p~ y in the claims annexed hereto and forming a part hereof However, for a better ' " ~, of the invention, its advantages, and objects obtained by its use, reference should be had to the ac~,ul~ ."~ g drawings and descriptive matter, in which there is illustrated and described preferred ~I"I,od;ll,~ of the invention woss/32s46 21~ 31 Detailed Description of ` - '' of the Invention In accordance with a first aspect of the present invention, we have developed a method to synthesize retinoids. The sequence of steps for this method is shown below.
R~ R2 0 1, LDA, THF, -78C R~2 ~,H 1. n-BuLi, THF ~ ,~CN
METIIODS FOR TIIE SYNTElESlS
TEIEIR NOVEL INTERMEDL~TES
Field of the Invention The present invention relates to the synthesis of 9-cis retinoid ~nmro~n~lC and in particular to the synthesis of 9-cis retinoic acid and related , 15, as well as to their novel ;~llr~
Ba~ ' of the Invention The role of retinoids such as all-trans retinoic acid, 13-cis retinoic acid and synthetic retinoic acid analogs in mediating cell growth and d;~. ~ ioll has generated interest in their ~ nlng;~ -l utility for controlling the treatment of d~ lùg~ diseases~ such as psoriasis and acne, as well as oncological A~ _ such as ~,I..,.~U~ yand chemoprevention. Significant advances in elucidating the molecular basis of retinoid action now offer the potential for designing retinoid compounds with improved therapeutic indices.
To datel several receptors for retinoic acid have been identified. These receptors are members of a au~J~,ILllily of ;llil~ lluldl receptors which function as ligand dependent L~Al.a~ iUII factors. At presentl these receptors have been classified into two subfamilies, the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). The ~ ;"" ofthese subfamilies is based primarily on differences in amino acid structure, taiJv~ , to different naturally occurring and synthetic retinoids, and ability to modulate expression of different target genes. Each RAR and RXR subfamily has three distinct isoforms designated RARo~ RAR~ and RAR~, and RXRa, R~R~ and R~Rl/. The discovery of multiple retinoid receptors raises questions of the functional properties of the distinct subfamilies and their isoforms.
Recentlyl it has been discovered that 9-cis RA, and other retinoids having a 9-10 cis olefin at~l ~O~,Il.,lllialy, are capable of binding to and modulating gene expression via the RARs and RXRs. Heyman et al., ~Ç~l 68:397 (1992). However, to date, the art has only 3û provided low y-ield, non-selective, high cost methods of making such ~ ' For example, the literature has provided non-selective means of generating 9-10 cis olefin retinoids, see e.~., Robson et al., J. Am. ~`hPm SOC.~ 77:4111 (1955), Matsui et al, L
ViatminoJ.~ 4:178 ~1958), German Patent No. DEI 068719, and Aurell et al., Tetrahedrorl l,ett., 31:5791(1990), aswellasmethodsforthes~ o~ ;v~preparationofthe 13-14 olefin bond, see e. ., Pattenden et al., J. Chem. Soc. (C)~ 1984 (1968) and Mayer et al., F~F~ori~nti~. 34:11ûS (1978).
, . . ... . . . . .
WO 95/32946 218 i ~ 31 r~ f Further, Ernst et al. J. Or~. Chem.. s2:398 (i987) provides methods for the preparation of alkyl- and ~ yl~;lyl-substituted retinoids via conjugate addition of cuprates to acetylenic esters, which use an excessive number of steps, and ;III~VOl L~ullly, the oxidation of an allylic alcohol to an aldehyde, thereby destroying the integrity of any 9-10 cis 5 olefin bonds present in the resulting retinoids.
Accordingly, it would be desirable to prepare retinoid compounds having the 9-10olefin bond in the cis cu~ ;uldLiull in a selective, low cost manner.
Summar~ of the Invention 1 û The ptesent invention provides methods for the synthesis of 9-cis retinoids, preferably, 9-cis retinoic acid in a selective, low-cost manner. In particular~ the present invention provides a method for producing a 9-cis retinoid comprising (a) reducing a UYIIOI~ Y ketone in the presence of base to form a uy. 1~ ii J.I_, (b) condensing the ~jyl ~ yllC with an cl~cll~ . ' ' nitrile source to form a cy, '-' ' ,l.c nitrile, (c) 15 adding an alkyl group, in a 1,4 conjugate fashion, to the ~y~ ..e nitrjle to form a Uy~h)ll~ LIk~ nitrile,(d) reducingthecy~1 1, All; nitriletothe~u" t~
uy~ ' ' aidehyde, and (e) extending the uyl.l~ aldehyde with a carbanion equivalent formed by the addition of a base to a r' A ~ ' or phosphjne salt to form a reaction product comprising a mixture of retinoid ester ~Ic~ c~;~U~ wherein the olefin 20 bond between carbons 9-10 is in the cis ~ , and the olefin bonds between carbons 11-12, and 13-14 can be in either the trans or cis 5" Thereafter, the retinoid esters can be hydrolyzed to yield a mixture of retinoic acid ~ ù;~ . which in turn can be separated to provide individual retinoic acid ~Lcl c~ , preferably, 9-cis rctinoic acid.
Also provided, is a method for producing a 9-cis retinoid comprising (a) reducing a 25 1y~ h.,Acll~ll ketone in the presence of base arid an dc~,L- r ~ '' nitrile source to form a ~y~ .1..1,_. ~.i:. ..~.,_ nitrile, (b) adding an alkyl group, in a 1,4 conjugate fashion, to the uy~ .,e nitrile to form a "y~ rlitrile, (c) reducing the ,,y~,ll ,l A l, ;. ~
nitrile to the cu" C~ "A;..g uyl Ihl' _ Al l; aldehyde, and (d) extending the uy~ .1.~1~ Al l ;....
aldehyde with a carbanion equivaAent formed by the addition of a base to a ~ or 30phosphine salt to form a reaction product comprising a mixture of retinoid ester ~L~;I C~ VIII~ wherein the olefin bond between carbons 9-10 is in the cis ~ 5~, , and the olefin bonds between carbons 11-12, and 13-14 can be in either the trans or cis t~nfiellrptirm In addition, the present invention provides a method for producing a 3~~:y~ Ihl;. A l:, _ nitrile olefin comprising reducing a ~;y. ' - ' ~ I ketone in the presence of base and an ~ lu~JLIl;c nitrile source to form a ~y~ .. _ nitrile.
~ WO 9S/3Z946 2 1 8 7 a 3 1 r~
. t. ~
Further, the present invention provides a method for producing a 9-cis alkyl cisoid nitrile comprising (a) condensing a ey~ lo~ e with an el~,LIul~lhl~, nitrile source to form a cy~ hPYA~iPnyne nitrile, and (b) adding an alkyl group, in a 1,4 conjugate fashion, to the ~;y~ to form a 9-cis alkyl cisoid nitrile, wherein the 9-10 olefin bond is in the S cis .,.~
Further yet, the present invention provides a 9-cis retinoid made according to the method described above. Preferably such 9~cis retinoid comprises 9-cis retinoic acid, 9,11-dicis retinoic acid, 9,13-dicis retinoic acid and 9,11,13-tricis retinoic acid. These and various other advantages and features of novelty which cL. ~ el ;4~ the invention are pointed 10 out with p~ y in the claims annexed hereto and forming a part hereof However, for a better ' " ~, of the invention, its advantages, and objects obtained by its use, reference should be had to the ac~,ul~ ."~ g drawings and descriptive matter, in which there is illustrated and described preferred ~I"I,od;ll,~ of the invention woss/32s46 21~ 31 Detailed Description of ` - '' of the Invention In accordance with a first aspect of the present invention, we have developed a method to synthesize retinoids. The sequence of steps for this method is shown below.
R~ R2 0 1, LDA, THF, -78C R~2 ~,H 1. n-BuLi, THF ~ ,~CN
2. ClP~Ol(o,~tk O~' ~ ~R3 3. LDA; H20 2 PhO-CN
(One pot reaction) -78C to 25C
¦ R4Li, Cul I THF, -78 R~ 1 n-BuL, DMPU, THF [~ Dibal-H, -78'C 1~
R3 I;~j (Ro)2P(o~CH2C~Rs)=Co2R5 R3 CHO Hexanes R3 CN
Rs~
CO2Rs -78'C to 25'C
¦ 1. KOH, EtOH
70'C
R1 R2 R~
R5~
Co2R7 In the above process sequences. R~ and R2 each can; ~ y represent lû hydrogen or a lower straight chain or branched alkyl having 1-5 carbon atoms;R3 represents hydrogen or a lower branched or straight chain alkyl, alkene or alkyne having 1-6 carbon atoms;
R~ and R5 each can ;~ ly represent hydrogen or a lower branched or straight chain alkyl, alkene, aryl or aralkyl having 1-12 carbon atoms;
R6 represents a lower straight chain or branched alkyl, alkene or alkyne having 1-5 carbon atoms;
R7 represents hydrogen or a ~ 7 acceptable salt; and , .. . .. . . .
~ WO 95132946 ~ 7~ ~ 31 r~
s the dashed lines in the structures between carbons 11-12, and 13-14, depict olefin bonds that can be in either the tra~ls or cis CUI.fi~5ul dLiu...
As used in this disclosure, pl,.l"l . "y acceptable salts include, but are not limited to pyridine,: --- ' piperazine, d.~ ,' ",;. u~ f~, formic, urea, sodium,5 potassium, calcium, m~r~ci.--n zinc, lithium, ~ L~ly~ ..o, Ll;r~ v, ~I;
and tris(hydoxymethyl) ' ' Additional ~ 'y acceptable salts are known to those skilled in the art The process sequence of the method begins with the reduction of a cy~,loll~ ..ylketone 1, such as ,3-ionone (available from Aldrich Chemical, Milwaukee, WI), in presence 10 of a base, such as lithium d;;suyl UyJ~ ' ' (LDA), and a ul~lvl ~ li, ' ~ s, ' - ~ such as diethyl - ' ' u~ , to form a cy, ' ' '' Jllt 2, such as 4-(1-[2,6,6-Lli~ yl~,yl,lvll~".~,.. 1-yl])-(but-3-ene-]-yne) In addition to LDA as a base, which is preferred, other non-limiting examples of bases useful in this step of the method of the present invention include sodium hydride (NaH), potassium hydride (KH), n-butyl lithium (n-BuLi), s-butyl lithium (s-BuLi), t-15 butyl lithium (t-BuLi), sodium amide (NaNH~), and lithium, potassium or sodium hexamethyl disylazide The second step consists of the ~ -, of the ~,y~ ' ' '' J lle 2 to a l~;y~ Jne nitrile 3, such as 5-(1-[2,6,6-trimethyl-1-cyclohexen-1-yl])-pent-2-yn-4-enenitrile, utilizing an Cl~ , ' ''' nitrile source, such as phenyl cyanate or cyanogen 2û bromide in the presence of base The third step of this sequence involves the addition of an alkyl group, in a 1,4 conjugate fashion, to Cyl ' ' - '' ,..c nitrile 3 to form an essentially pure cy, ' ' nitrile 4, such as (2Z,4E)-3-methyl-5-(1-[2,6,6-trimethyl-1--,y..lul..,Aul. l-yl])-2,4-y. ..l .~ l. with the 9-lû double bond in the cls ~ In this regard, the addition of the alkyl group according to this aspect of the method can be ~.. ~ .. l.~ .h?d using a number of techniques and methods well known to those of skiU in the art, but preferably the addition reaction is - ~ u~ l in nonpolar solvents, most preferably in hexanes or heptane In the fourth step, the ~y~ ;- -- nitrile 4 is reduced to the cul~ y~
3û uy~ ; aldehyde 5 ((2Z,4E)-3-methyl-5-(1-[2,6,6-trimethyl-1-cyclohexen-1-yl])-2,4-y. .,1,..1;. .1 - -~) via a standard DIBAL (diisobutyl aluminum hydride) reduction in hexanes.
The fifth step of the sequence involves the extension of the cy 1. .l ,. - -l,; aldehyde 5 with a carbanion equivalent formed by the addition of a base (e.g., n-BuLi) to a i ' I ' , such as diethyl-3-~llu~y.,.,.bu..~l 2-methylprop-2-enyl ~.I..,~I,h.~ ., or a 35 phosphine salt (e.g. triphenyl phosphine) to yield a mixture of ~l~l CiU;~VI~ of retinoates (retinoid esters) 6, including, primarily ethyl-3,7-~ ' 9 (2,6,6-trimethyl-1-cyclohexen l yl)-2-frans-4-trans-6-cis-8-irans-~ f ~ lv~lr 111 this rega~d, the retinûate ~e,~ù;~vl~
W095/32946 ;~ PCT/US9s/06580~
6 display over a 15:1 prevalence of the 13-14 olefin bond in the ~a~s versus cisconfiguration I~T '- " ' ,, examples of bases useful in this aspect of the method of the present invention include sodium hydride (NaH), potassium hydride (KH), n-butyl lithium (n-BuLi), s-butyl lithium (s-BuLi), t-butyl lithium (t-BuLi), and sodium amide (Na~H~), in the 5 presence of DMPU.
The sixth and final step in the process involves the hydrolysis of retinoates 6 with aqueous methanolic hydroxide (MeOH/ KOH) to give retinoic acid isomers 7. Examples of retinoid isomers 7 include, without limitation, the primary component, 3,7-dimethyl-9-(2,6,6-trimethyl-1-~iy~ l,.,A~..yl)-2-1rans-4-tranS-6-cis-8-bans-nona-tetraenoic acid (9-ci, IQ retinoic acid), and detectable amounts of 3,7-dimethyl-9-(2,6,6-trimethyl- 1 -CYUIO~ IYI)-2-cis-4-~ans-6-cis-8-~rans-nona-tetraenoic acid (9,13 dtcis retinoic acid) and 3,7-dimethyl-9-(2,6,6-trimethyl-1--,y, ' ' Iyl)-2-trans-4-cis-6-cis-8-~rans-nona-tetraenoic acid (9,11 dlci.
retinoic acid). After hydrolysis, a desired retinoic acid isomer 7 can be selectively crystallized from the aqueous methanolic hydroxide solution, or alternatively purified by semi 15 preparative reverse-phase (ODS) high ~ r -,, ~ liquid .,lu~ (HPLC).
It will be understood by those skilled in the art that certain, ~ I:r, ~ can be made to the above-described methods that remain within the scope to the present invention. For eYample, steps one and two (i.e. the r.. .~ of c,y~ . 2) can be combined into a one step, one pot, reaction, by quenching reduced CY~IOII~A~I~YI ketone I with a 20 lithium anion and an electophilic nitrile source, such as phenyl cyanate in the presence of base, instead of with water in the presence of base, to directly yield ;y ~ nitrile 3.
rul Ll-~ .,.~,. c, it will also be understood by those skilled in the art that the synthesis of the present invention can have broader application beyond the synthesis of the retinoids 25 shown above. For example, the respective r, ~ and addition of steps two and three can be used to form a variety alkyl cisoid nitriles and their derivatives (e.g., amines, acids, aldehydes, esters) with the 9-10 olefin bond selectively produced in the cts ..G. ~I~;ul a~;OII.
The synthesis methods described above provide a number of advantages over those currently available, including, importantly, cost. In this regard, the methods of the present 30 invention utilizes C~JIIU~ , and readily available starting materials such as ~-ionone versus more typical starting materials utilized in eY~isting ~ r~d-~lr,; ~, such as ,~-cyclocitral, which are at least twenty to forty times more expensive on average than the starting materials utilized in the methods of the present invention. In addition, the third step in the synthesis method (i.e. addition of the alkyl group, in a 1,4 conjugate fashion, to the 3 5 cyrlr~h~Y?~h~nyne nitrile 3 to form the cyl Ir~h ~ 1 l; nitrile 4) allows for the selective ' ~dU~,IilJll of the 9-10 double bond in the cts CGIlf~;ul dliOI~, as well as the ability to place a wide variety of ~ such as an alkyl, alkene, aryl, aralkyl etc. .. , at carbon number 9.
~ w~ 95l32946 ` 2 ~ 8 ~ 31 r ~
Further, the reagents used throughout the method are standard, readily available and A~ IV~ organic or inorganic chemicals with no hazardous risks reported The invention will be further illustrated by reference to the following non-limiting Example.
EXAMPLE I
Synthesis of the retinoids of the present invention are exemplified by the following synthesis scheme for 9-cis retinoic acid.
(One pot reaction) -78C to 25C
¦ R4Li, Cul I THF, -78 R~ 1 n-BuL, DMPU, THF [~ Dibal-H, -78'C 1~
R3 I;~j (Ro)2P(o~CH2C~Rs)=Co2R5 R3 CHO Hexanes R3 CN
Rs~
CO2Rs -78'C to 25'C
¦ 1. KOH, EtOH
70'C
R1 R2 R~
R5~
Co2R7 In the above process sequences. R~ and R2 each can; ~ y represent lû hydrogen or a lower straight chain or branched alkyl having 1-5 carbon atoms;R3 represents hydrogen or a lower branched or straight chain alkyl, alkene or alkyne having 1-6 carbon atoms;
R~ and R5 each can ;~ ly represent hydrogen or a lower branched or straight chain alkyl, alkene, aryl or aralkyl having 1-12 carbon atoms;
R6 represents a lower straight chain or branched alkyl, alkene or alkyne having 1-5 carbon atoms;
R7 represents hydrogen or a ~ 7 acceptable salt; and , .. . .. . . .
~ WO 95132946 ~ 7~ ~ 31 r~
s the dashed lines in the structures between carbons 11-12, and 13-14, depict olefin bonds that can be in either the tra~ls or cis CUI.fi~5ul dLiu...
As used in this disclosure, pl,.l"l . "y acceptable salts include, but are not limited to pyridine,: --- ' piperazine, d.~ ,' ",;. u~ f~, formic, urea, sodium,5 potassium, calcium, m~r~ci.--n zinc, lithium, ~ L~ly~ ..o, Ll;r~ v, ~I;
and tris(hydoxymethyl) ' ' Additional ~ 'y acceptable salts are known to those skilled in the art The process sequence of the method begins with the reduction of a cy~,loll~ ..ylketone 1, such as ,3-ionone (available from Aldrich Chemical, Milwaukee, WI), in presence 10 of a base, such as lithium d;;suyl UyJ~ ' ' (LDA), and a ul~lvl ~ li, ' ~ s, ' - ~ such as diethyl - ' ' u~ , to form a cy, ' ' '' Jllt 2, such as 4-(1-[2,6,6-Lli~ yl~,yl,lvll~".~,.. 1-yl])-(but-3-ene-]-yne) In addition to LDA as a base, which is preferred, other non-limiting examples of bases useful in this step of the method of the present invention include sodium hydride (NaH), potassium hydride (KH), n-butyl lithium (n-BuLi), s-butyl lithium (s-BuLi), t-15 butyl lithium (t-BuLi), sodium amide (NaNH~), and lithium, potassium or sodium hexamethyl disylazide The second step consists of the ~ -, of the ~,y~ ' ' '' J lle 2 to a l~;y~ Jne nitrile 3, such as 5-(1-[2,6,6-trimethyl-1-cyclohexen-1-yl])-pent-2-yn-4-enenitrile, utilizing an Cl~ , ' ''' nitrile source, such as phenyl cyanate or cyanogen 2û bromide in the presence of base The third step of this sequence involves the addition of an alkyl group, in a 1,4 conjugate fashion, to Cyl ' ' - '' ,..c nitrile 3 to form an essentially pure cy, ' ' nitrile 4, such as (2Z,4E)-3-methyl-5-(1-[2,6,6-trimethyl-1--,y..lul..,Aul. l-yl])-2,4-y. ..l .~ l. with the 9-lû double bond in the cls ~ In this regard, the addition of the alkyl group according to this aspect of the method can be ~.. ~ .. l.~ .h?d using a number of techniques and methods well known to those of skiU in the art, but preferably the addition reaction is - ~ u~ l in nonpolar solvents, most preferably in hexanes or heptane In the fourth step, the ~y~ ;- -- nitrile 4 is reduced to the cul~ y~
3û uy~ ; aldehyde 5 ((2Z,4E)-3-methyl-5-(1-[2,6,6-trimethyl-1-cyclohexen-1-yl])-2,4-y. .,1,..1;. .1 - -~) via a standard DIBAL (diisobutyl aluminum hydride) reduction in hexanes.
The fifth step of the sequence involves the extension of the cy 1. .l ,. - -l,; aldehyde 5 with a carbanion equivalent formed by the addition of a base (e.g., n-BuLi) to a i ' I ' , such as diethyl-3-~llu~y.,.,.bu..~l 2-methylprop-2-enyl ~.I..,~I,h.~ ., or a 35 phosphine salt (e.g. triphenyl phosphine) to yield a mixture of ~l~l CiU;~VI~ of retinoates (retinoid esters) 6, including, primarily ethyl-3,7-~ ' 9 (2,6,6-trimethyl-1-cyclohexen l yl)-2-frans-4-trans-6-cis-8-irans-~ f ~ lv~lr 111 this rega~d, the retinûate ~e,~ù;~vl~
W095/32946 ;~ PCT/US9s/06580~
6 display over a 15:1 prevalence of the 13-14 olefin bond in the ~a~s versus cisconfiguration I~T '- " ' ,, examples of bases useful in this aspect of the method of the present invention include sodium hydride (NaH), potassium hydride (KH), n-butyl lithium (n-BuLi), s-butyl lithium (s-BuLi), t-butyl lithium (t-BuLi), and sodium amide (Na~H~), in the 5 presence of DMPU.
The sixth and final step in the process involves the hydrolysis of retinoates 6 with aqueous methanolic hydroxide (MeOH/ KOH) to give retinoic acid isomers 7. Examples of retinoid isomers 7 include, without limitation, the primary component, 3,7-dimethyl-9-(2,6,6-trimethyl-1-~iy~ l,.,A~..yl)-2-1rans-4-tranS-6-cis-8-bans-nona-tetraenoic acid (9-ci, IQ retinoic acid), and detectable amounts of 3,7-dimethyl-9-(2,6,6-trimethyl- 1 -CYUIO~ IYI)-2-cis-4-~ans-6-cis-8-~rans-nona-tetraenoic acid (9,13 dtcis retinoic acid) and 3,7-dimethyl-9-(2,6,6-trimethyl-1--,y, ' ' Iyl)-2-trans-4-cis-6-cis-8-~rans-nona-tetraenoic acid (9,11 dlci.
retinoic acid). After hydrolysis, a desired retinoic acid isomer 7 can be selectively crystallized from the aqueous methanolic hydroxide solution, or alternatively purified by semi 15 preparative reverse-phase (ODS) high ~ r -,, ~ liquid .,lu~ (HPLC).
It will be understood by those skilled in the art that certain, ~ I:r, ~ can be made to the above-described methods that remain within the scope to the present invention. For eYample, steps one and two (i.e. the r.. .~ of c,y~ . 2) can be combined into a one step, one pot, reaction, by quenching reduced CY~IOII~A~I~YI ketone I with a 20 lithium anion and an electophilic nitrile source, such as phenyl cyanate in the presence of base, instead of with water in the presence of base, to directly yield ;y ~ nitrile 3.
rul Ll-~ .,.~,. c, it will also be understood by those skilled in the art that the synthesis of the present invention can have broader application beyond the synthesis of the retinoids 25 shown above. For example, the respective r, ~ and addition of steps two and three can be used to form a variety alkyl cisoid nitriles and their derivatives (e.g., amines, acids, aldehydes, esters) with the 9-10 olefin bond selectively produced in the cts ..G. ~I~;ul a~;OII.
The synthesis methods described above provide a number of advantages over those currently available, including, importantly, cost. In this regard, the methods of the present 30 invention utilizes C~JIIU~ , and readily available starting materials such as ~-ionone versus more typical starting materials utilized in eY~isting ~ r~d-~lr,; ~, such as ,~-cyclocitral, which are at least twenty to forty times more expensive on average than the starting materials utilized in the methods of the present invention. In addition, the third step in the synthesis method (i.e. addition of the alkyl group, in a 1,4 conjugate fashion, to the 3 5 cyrlr~h~Y?~h~nyne nitrile 3 to form the cyl Ir~h ~ 1 l; nitrile 4) allows for the selective ' ~dU~,IilJll of the 9-10 double bond in the cts CGIlf~;ul dliOI~, as well as the ability to place a wide variety of ~ such as an alkyl, alkene, aryl, aralkyl etc. .. , at carbon number 9.
~ w~ 95l32946 ` 2 ~ 8 ~ 31 r ~
Further, the reagents used throughout the method are standard, readily available and A~ IV~ organic or inorganic chemicals with no hazardous risks reported The invention will be further illustrated by reference to the following non-limiting Example.
EXAMPLE I
Synthesis of the retinoids of the present invention are exemplified by the following synthesis scheme for 9-cis retinoic acid.
4-(1-[2.6.6-T~ I.,y. l~ . I-yll)-(but-3-ene-1-Yne) 2 The ' 4-(1-[2,6,6-trimethyl~y~,lol..,A~ .. I-yl])-(but-3-ene-~-yne) 2 was prepared from ~-ionone I (available from Aldrich Chemicals Inc.) according to the procedures disclosed in E.l. Negishi et al., J. Org (`hPm 45 2526 (1980), the disclosure of which is herein i~l~,ul~uld~d by reference.
5-(2,6,6-TrimethYI-1-~iy 1)1 -~ 1-yl)-~ent-2 yn 1 ~ 3:
A 100 mL flame dried flask was charged with the ' 4-(1-[2,6,6-trimethylcy~,loll~ ". I-yl])-(but-3-ene-1-yne) 2 (1.045 g, 6.0 mmol) in ~ yJIurul~
(THF) (30 mL) and cooled to -78C. A solution of n-BuLi in hexanes (2.25 M; 2.75 mL, 6.15 mmol) was slowly added and the slightly dark mixture was stitred for 10 min. Phenyl cYanate (prepared from phenol and cyanogen bromide according to a procedure of R.E.
Murray et al., Syn~esis, 150 ( 1980), the disclosure of which is herein ~ UI ~JUld~c;d by reference) (750 IlL, 6.6 mmol) was introduced and the mixture allowed to warm to room t~ J... d~Ul ~ (e.g., ~ l uAil~ lely 20-25C). Sodium hydroxide (2 mL of 6 N solution) was added and the mixture extracted with ethyl acetate (50 mL). The organic laye} was further washed with NaOH (2 x 10 mL), water (3 x 10 ml) and brine (2 x 10 mL), dried over MgSO4 and the solvents evaporated. The residue obtained was virtually pure (by TLC) and was filtered through a short pad of silica gel using hexanes as eluent in order to remove some baseline materials. The solvent was evaporated to give 1.088 g (91% yield) of a slightlyyellowoil. RfO.75(hexanes),1R(neat)2933,2320,2251 (CN), 1590cm~l; IH
NMR (CDC13) o 7.11 (d, J = 16.4Hz, I H), 5.54 (d, J = 16.4 Hz, I H), 2.07 (t, J =4.0 Hz, 2 H), 1.76 (s, 3 H), 1.60 (m, 2 H), 1.46 (m, 2 H), 1.04 (s, 6 H).
p wo 9s/32s46 2 1 ~ 7~
(2Z~4E)-3-Methvl-5-(2.6,6-trimethYI-I-cYclohexen-l-YI)-2~4-1, rliPnitrile~ 4: ~
A 50 mL flame-dried round bottomed flask was charged with anhydrous copper iodide ( 1.09 g, 5.70 mmol) and THF (20 ml) and cooled to 0C. A solution of methyl lithium (4.28 mL of a 1.4 M solution in Et2o) was slowly added over a 10 min. period until S the solution became clear and colorless. The cuprate solution was cooled at -78C using a dry ice-acetone bath, and a solution of 5-(2,6,6-trimethyl-1-~iy~,lul.~Au.. I-yl)-pent-2-yn-4-enenitrile 3 (544 mg, 2.73 mmol), in THF (10 mL). was added dropwise. See e.A~., H.
Westmijze et al., Tetralledron letJers, 3327 (1979), and Synthesls, 454 (1978), the disclosures of which are herein i..,,U.~,u.dL~d by reference. The mixture was stirred at this 10 L~,,J.,.dlu,~ for 45 minutes~ and a saturated ammonium chloride solution (10 mL) was added. The reaction mixture was then allowed to warm to room t~ dlUI~. EtOAc (50mL) was added and the mixture was washed with 2% NaOH (2 x 10 mL), followed by washings with saturated NH4CI (2 x 10 mL), water (2 x 10 mL) and brine (2 x 10 mL).
The organic layers were dried over MgSO4 and the solvents evaporated The residueobtained was virtually pure (by TLC) and was filtered through a short pad of silica gel using hr-YAnrcFt/)Ac(9:1)aseluentinordertoremovesomebaselinematerials Thesolventwas evaporated to give 53 8 mg (92% yield) of a slightly yellow-orange oil. Rf 0.75 (hexanes:EtOAc (9:1)), IR (neat) 2933, 2250 (CN), 1590 cm~l, lH NMR (CDC13) o 6.70 (d,J=16Hz,lH),6.59(d,J=16.4Hz lH),5.09(s(lH),2.06(s3H),2.07(t,J=4.0 Hz, 2 H), 1.75 (s, 3 H), 1.62 (m, 2 H), 1.47 (m, 2 H), 1.04 (s, 6 H).
(2Z,4E)-3-Methyl-5-(2,6~6-trimethvl-1-cyclûhexen-l-yl)-2~4-~
A 25 mL flame-dried round~bottomed flask was charged with (2Z,4E)-2,4-F` ~ l;1 -3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl) 4 (94.2 mg, 0.438 mmol) and hexanes (5 . O mL) and cooled to -78C. Diisobutyl aluminum hydride (480 ~LL of a I . O M
solution in hexanes, 0.480 mmol) was added dropwise at such a rate that the intemal reaction l~ .,.dlUI~ did not exceed -70C. The mrxture was stirred for S min., and a thin-layer chromotography (TLC) analysis (hrYqA~rc FtoAc (9:1)) indicated the reaction was complete (Starting material Rf 0. 75; product Rf 0.70). A saturated solution of Rochelle salt (1.0 mL) was added, and the mixture wammed to room I , dlul~. EtOAc (10 mL) was added and the mixture washed using water (2 x 10 mL) and brine (2 x 10 mL). The organic layers were dried over MgSO4 and the solvents evaporated. The residue obtained was virtually pure (by TLC), 90.5 mg, 95% yield; IR (neat): 2958, 2928, 2866, 1668 (C=O), 1614(C=C)cm~l; IHNMR(CDCl3;400MHz)o(ppm): 10.16(d,J=8.0Hz,CHO), 7.16 (d, J = 16.0 Hz, vinyl-CH, trans), 6.63 (d, J = 16.0 Hz, vinyl-CH, trans), 5.88 (d, J =
A 100 mL flame dried flask was charged with the ' 4-(1-[2,6,6-trimethylcy~,loll~ ". I-yl])-(but-3-ene-1-yne) 2 (1.045 g, 6.0 mmol) in ~ yJIurul~
(THF) (30 mL) and cooled to -78C. A solution of n-BuLi in hexanes (2.25 M; 2.75 mL, 6.15 mmol) was slowly added and the slightly dark mixture was stitred for 10 min. Phenyl cYanate (prepared from phenol and cyanogen bromide according to a procedure of R.E.
Murray et al., Syn~esis, 150 ( 1980), the disclosure of which is herein ~ UI ~JUld~c;d by reference) (750 IlL, 6.6 mmol) was introduced and the mixture allowed to warm to room t~ J... d~Ul ~ (e.g., ~ l uAil~ lely 20-25C). Sodium hydroxide (2 mL of 6 N solution) was added and the mixture extracted with ethyl acetate (50 mL). The organic laye} was further washed with NaOH (2 x 10 mL), water (3 x 10 ml) and brine (2 x 10 mL), dried over MgSO4 and the solvents evaporated. The residue obtained was virtually pure (by TLC) and was filtered through a short pad of silica gel using hexanes as eluent in order to remove some baseline materials. The solvent was evaporated to give 1.088 g (91% yield) of a slightlyyellowoil. RfO.75(hexanes),1R(neat)2933,2320,2251 (CN), 1590cm~l; IH
NMR (CDC13) o 7.11 (d, J = 16.4Hz, I H), 5.54 (d, J = 16.4 Hz, I H), 2.07 (t, J =4.0 Hz, 2 H), 1.76 (s, 3 H), 1.60 (m, 2 H), 1.46 (m, 2 H), 1.04 (s, 6 H).
p wo 9s/32s46 2 1 ~ 7~
(2Z~4E)-3-Methvl-5-(2.6,6-trimethYI-I-cYclohexen-l-YI)-2~4-1, rliPnitrile~ 4: ~
A 50 mL flame-dried round bottomed flask was charged with anhydrous copper iodide ( 1.09 g, 5.70 mmol) and THF (20 ml) and cooled to 0C. A solution of methyl lithium (4.28 mL of a 1.4 M solution in Et2o) was slowly added over a 10 min. period until S the solution became clear and colorless. The cuprate solution was cooled at -78C using a dry ice-acetone bath, and a solution of 5-(2,6,6-trimethyl-1-~iy~,lul.~Au.. I-yl)-pent-2-yn-4-enenitrile 3 (544 mg, 2.73 mmol), in THF (10 mL). was added dropwise. See e.A~., H.
Westmijze et al., Tetralledron letJers, 3327 (1979), and Synthesls, 454 (1978), the disclosures of which are herein i..,,U.~,u.dL~d by reference. The mixture was stirred at this 10 L~,,J.,.dlu,~ for 45 minutes~ and a saturated ammonium chloride solution (10 mL) was added. The reaction mixture was then allowed to warm to room t~ dlUI~. EtOAc (50mL) was added and the mixture was washed with 2% NaOH (2 x 10 mL), followed by washings with saturated NH4CI (2 x 10 mL), water (2 x 10 mL) and brine (2 x 10 mL).
The organic layers were dried over MgSO4 and the solvents evaporated The residueobtained was virtually pure (by TLC) and was filtered through a short pad of silica gel using hr-YAnrcFt/)Ac(9:1)aseluentinordertoremovesomebaselinematerials Thesolventwas evaporated to give 53 8 mg (92% yield) of a slightly yellow-orange oil. Rf 0.75 (hexanes:EtOAc (9:1)), IR (neat) 2933, 2250 (CN), 1590 cm~l, lH NMR (CDC13) o 6.70 (d,J=16Hz,lH),6.59(d,J=16.4Hz lH),5.09(s(lH),2.06(s3H),2.07(t,J=4.0 Hz, 2 H), 1.75 (s, 3 H), 1.62 (m, 2 H), 1.47 (m, 2 H), 1.04 (s, 6 H).
(2Z,4E)-3-Methyl-5-(2,6~6-trimethvl-1-cyclûhexen-l-yl)-2~4-~
A 25 mL flame-dried round~bottomed flask was charged with (2Z,4E)-2,4-F` ~ l;1 -3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl) 4 (94.2 mg, 0.438 mmol) and hexanes (5 . O mL) and cooled to -78C. Diisobutyl aluminum hydride (480 ~LL of a I . O M
solution in hexanes, 0.480 mmol) was added dropwise at such a rate that the intemal reaction l~ .,.dlUI~ did not exceed -70C. The mrxture was stirred for S min., and a thin-layer chromotography (TLC) analysis (hrYqA~rc FtoAc (9:1)) indicated the reaction was complete (Starting material Rf 0. 75; product Rf 0.70). A saturated solution of Rochelle salt (1.0 mL) was added, and the mixture wammed to room I , dlul~. EtOAc (10 mL) was added and the mixture washed using water (2 x 10 mL) and brine (2 x 10 mL). The organic layers were dried over MgSO4 and the solvents evaporated. The residue obtained was virtually pure (by TLC), 90.5 mg, 95% yield; IR (neat): 2958, 2928, 2866, 1668 (C=O), 1614(C=C)cm~l; IHNMR(CDCl3;400MHz)o(ppm): 10.16(d,J=8.0Hz,CHO), 7.16 (d, J = 16.0 Hz, vinyl-CH, trans), 6.63 (d, J = 16.0 Hz, vinyl-CH, trans), 5.88 (d, J =
8.û Hz. IH, CH CHO), 2.69 (s, 2 H, ring), 2.14 (s, 3 H, -C-(CH3)=CH-CHO, cis), 1.80 (s, 3 H~ CH3, ring), I.11 (s, 6 H, gem- 2x CH3).
~ W095/32946 21~743i r~,v- r Ethyl-3,7-flimPtlsyl-9-(2.6.6-trimethyl-l-cvclohexen-l-vl)-2-tra~1s-4-tran.~-6- is-8-fra~.s-IIUIIa~ t~, 6 , , = . i A solution of diethyl-3-eLI-u~y.,albul~yl-2-methylprop-2-c~ , ' (354 mg, 1.34 mmol) in anhydrous THF (5.0 mL) was cooled to 0C and added with anhydrous DMPU (0.5 mL) and n-BuLi in hexanes (0.56 mL of 2.35 M solution, 1 33 mmol). Themixture was stirred at this i . d~ule for 20 minutes, then cooled to -78C. A solution of (2Z,4E)-3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-~ lf~ir ~ ~l 5 (241 mg, I.115 mmol) in THF (3.0 mL) was slowly added and the reaction mixture stirred at -78C
for an additional 60 min. The mixture was allowed to warm to 0C as the reaction went to cfl~rlPtif~n~ as monitored by TLC. A saturated solution of âmmonium chloride (5 mL) was added, and the mixture extracted using EtOAc (3 xl0 mL). The organic layer was washed with water (2 x 5 mL) and brine (10 mL). dried over MgSO4 and ~f...~,cllildle.l. The residue was purified on a short silica gel ~,lllullluLu~la~lly (sgc) column to give 296 mg (78% yield) ofthe desired ester in a ~15:1 ratio of 13-trans:13-cis isomers. IR (neat): 2928, 1709 cm~l;
IH NMR (CDC13; 400 MHz) o (ppm): 7.08 (dd, J = 15, 11.3 Hz, I H), 6.65 (d, J = 16 Hz, lH),6.29(d,J=15Hz, lH),6,23(d,J=15Hz. lH),6.06(d,J=11.3Hz lH),4.17 (m,J=7Hz,2H),2.7(s,2H),2.33(s,3H),2.03(s3H), 1.82(s,3H)1.29(t,J=7Hz,3 H), 1.1 (s, 6 H) 3,7_~ ottl,v1-9-(2.6~6- ' ~ I~CYSI I ,')-2-fran.~-4-frans-6-f,is-8-fra~1s-~r~nA-tetrAPnr,ir AriA 7 A solution of ethyl-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexen- I -yl)-2-fra~ -4-tra~1s-6-cis-8-trans- ' ' -' ' 6 (275 mg, 8.25 mmol) in ethanol (10 mL) was treated with I N KOH (10 mL) at 70C for 3 hours, cooled to room ~I,llllJ~,lalule, acidified with 10% (v:v) HCI, and extracted with EtOAc (2 x 20 mL). The organic layer was washed with water (2 x 5 mL) and brine (2 x 5 mL), dried over MgS04 arld the solvent was evaporated.
The residue was Ic~,ly~àlli~ d (2 times) by dissolving it in a minimum volume of a 9:1 mixture of e~llallol. ~ 20 ml per gram of material). The desired 9-cis retinoic acid was thus obtained in a highly pure form (by IH NMR) as Gght yellow solid, yield 85%; mp. 188-190C; IR (KBr, cm~1) 2914, 1670, 1583; IH NMR (CDC13; 400 MHz): o (ppm) 7.20 (dd, J=15.OHz,lH),6.65(d,J=16.0Hz,lH),6.28(d,J=16.0Hz,lH),6.25(d,J=15.0 Hz, l H), 6.06 (d, J = ll.O Hz, l H), 5.80 (s. 1 H). 2.35 (s, 3 H), 2.05 (t, J = 6.6Hz, 2H), 2 01 (s, 3 H)~ 1.75 (s, 3 H), 1.64 (m, 2 H), 1.49 (m, 2 H), 1.04 (s, 6 H).
While in accordance with the patent statutes, description of the preferred .,I.drJU '' ' and processing condGtions have been pro~ided, the scope of the invention is not WO 95/32946 218 7 4 31 r~
to be limited thereto or thereby. Various "~ and alterations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit ofthe present invention.
ly, for an ul.J. . ~L~nlJ~ of the scope of the present invention, reference is made to the following claims.
~ W095/32946 21~743i r~,v- r Ethyl-3,7-flimPtlsyl-9-(2.6.6-trimethyl-l-cvclohexen-l-vl)-2-tra~1s-4-tran.~-6- is-8-fra~.s-IIUIIa~ t~, 6 , , = . i A solution of diethyl-3-eLI-u~y.,albul~yl-2-methylprop-2-c~ , ' (354 mg, 1.34 mmol) in anhydrous THF (5.0 mL) was cooled to 0C and added with anhydrous DMPU (0.5 mL) and n-BuLi in hexanes (0.56 mL of 2.35 M solution, 1 33 mmol). Themixture was stirred at this i . d~ule for 20 minutes, then cooled to -78C. A solution of (2Z,4E)-3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-~ lf~ir ~ ~l 5 (241 mg, I.115 mmol) in THF (3.0 mL) was slowly added and the reaction mixture stirred at -78C
for an additional 60 min. The mixture was allowed to warm to 0C as the reaction went to cfl~rlPtif~n~ as monitored by TLC. A saturated solution of âmmonium chloride (5 mL) was added, and the mixture extracted using EtOAc (3 xl0 mL). The organic layer was washed with water (2 x 5 mL) and brine (10 mL). dried over MgSO4 and ~f...~,cllildle.l. The residue was purified on a short silica gel ~,lllullluLu~la~lly (sgc) column to give 296 mg (78% yield) ofthe desired ester in a ~15:1 ratio of 13-trans:13-cis isomers. IR (neat): 2928, 1709 cm~l;
IH NMR (CDC13; 400 MHz) o (ppm): 7.08 (dd, J = 15, 11.3 Hz, I H), 6.65 (d, J = 16 Hz, lH),6.29(d,J=15Hz, lH),6,23(d,J=15Hz. lH),6.06(d,J=11.3Hz lH),4.17 (m,J=7Hz,2H),2.7(s,2H),2.33(s,3H),2.03(s3H), 1.82(s,3H)1.29(t,J=7Hz,3 H), 1.1 (s, 6 H) 3,7_~ ottl,v1-9-(2.6~6- ' ~ I~CYSI I ,')-2-fran.~-4-frans-6-f,is-8-fra~1s-~r~nA-tetrAPnr,ir AriA 7 A solution of ethyl-3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexen- I -yl)-2-fra~ -4-tra~1s-6-cis-8-trans- ' ' -' ' 6 (275 mg, 8.25 mmol) in ethanol (10 mL) was treated with I N KOH (10 mL) at 70C for 3 hours, cooled to room ~I,llllJ~,lalule, acidified with 10% (v:v) HCI, and extracted with EtOAc (2 x 20 mL). The organic layer was washed with water (2 x 5 mL) and brine (2 x 5 mL), dried over MgS04 arld the solvent was evaporated.
The residue was Ic~,ly~àlli~ d (2 times) by dissolving it in a minimum volume of a 9:1 mixture of e~llallol. ~ 20 ml per gram of material). The desired 9-cis retinoic acid was thus obtained in a highly pure form (by IH NMR) as Gght yellow solid, yield 85%; mp. 188-190C; IR (KBr, cm~1) 2914, 1670, 1583; IH NMR (CDC13; 400 MHz): o (ppm) 7.20 (dd, J=15.OHz,lH),6.65(d,J=16.0Hz,lH),6.28(d,J=16.0Hz,lH),6.25(d,J=15.0 Hz, l H), 6.06 (d, J = ll.O Hz, l H), 5.80 (s. 1 H). 2.35 (s, 3 H), 2.05 (t, J = 6.6Hz, 2H), 2 01 (s, 3 H)~ 1.75 (s, 3 H), 1.64 (m, 2 H), 1.49 (m, 2 H), 1.04 (s, 6 H).
While in accordance with the patent statutes, description of the preferred .,I.drJU '' ' and processing condGtions have been pro~ided, the scope of the invention is not WO 95/32946 218 7 4 31 r~
to be limited thereto or thereby. Various "~ and alterations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit ofthe present invention.
ly, for an ul.J. . ~L~nlJ~ of the scope of the present invention, reference is made to the following claims.
Claims (13)
1. A method for producing a 9-cis retinoid comprising:
(a) reducing a cyclohexenyl ketone in the presence of base to form a cyclohexadienyne of the formula:
(b) condensing the cyclohexadienyne with an electrophilic nitrile source to form a cyclohexadienyne nitrile;
(c) adding an alkyl, alkene, aryl or aralkyl group, in a 1,4 conjugate fashion, to the cyclohexadienyne nitrile to form a cyclohexatriene nitrile of the formula:
(d) reducing the cyclohexatriene nitrile to the corresponding cyclohexatriene aldehyde; and (e) extending the cyclohexatriene aldehyde with a carbanion equivalent formed bythe addition of a base to a phosphonate or phosphine salt to form a reaction product comprising a mixture of retinoid ester stereoisomers having the general formula:
wherein, R1 and R2 each can independently represent hydrogen or a lower straight chain or branched alkyl having 1-5 carbon atoms; R3 represents hydrogen or a lower branched or straight chain alkyl, alkene or alkyne having 1-6 carbon atoms; R4 and R5 each can independently represent hydrogen or a lower branched or straight chain alkyl, alkene, aryl or aralkyl having 1-12 carbon atoms; R6 represents a lower straight chain or branched alkyl, alkene or alkyne having 1-5 carbon atoms; and the dashed lines in the structures between carbons 11-12, and 13-14, depict olefin bonds that can be in either the trans or cis configuration.
(a) reducing a cyclohexenyl ketone in the presence of base to form a cyclohexadienyne of the formula:
(b) condensing the cyclohexadienyne with an electrophilic nitrile source to form a cyclohexadienyne nitrile;
(c) adding an alkyl, alkene, aryl or aralkyl group, in a 1,4 conjugate fashion, to the cyclohexadienyne nitrile to form a cyclohexatriene nitrile of the formula:
(d) reducing the cyclohexatriene nitrile to the corresponding cyclohexatriene aldehyde; and (e) extending the cyclohexatriene aldehyde with a carbanion equivalent formed bythe addition of a base to a phosphonate or phosphine salt to form a reaction product comprising a mixture of retinoid ester stereoisomers having the general formula:
wherein, R1 and R2 each can independently represent hydrogen or a lower straight chain or branched alkyl having 1-5 carbon atoms; R3 represents hydrogen or a lower branched or straight chain alkyl, alkene or alkyne having 1-6 carbon atoms; R4 and R5 each can independently represent hydrogen or a lower branched or straight chain alkyl, alkene, aryl or aralkyl having 1-12 carbon atoms; R6 represents a lower straight chain or branched alkyl, alkene or alkyne having 1-5 carbon atoms; and the dashed lines in the structures between carbons 11-12, and 13-14, depict olefin bonds that can be in either the trans or cis configuration.
2. A method according to claim 1, further comprising, after the extending step, hydrolyzing the reaction product with an aqueous methanolic hydroxide to form a mixture of retinoid stereoisomers.
3. A method according to claim 2, further comprising, after the hydrolyzing step, isolating a retinoid stereoisomer having the general formula:
wherein R1 to R5 have the meaning specified in claim 1, R7 represents hydrogen or a pharmaceutically acceptable salt and the 11-12 and 13-14 olefin bonds are in either the trans or cis configuration.
wherein R1 to R5 have the meaning specified in claim 1, R7 represents hydrogen or a pharmaceutically acceptable salt and the 11-12 and 13-14 olefin bonds are in either the trans or cis configuration.
4. A method according to claim 1, wherein the electrophilic nitrile source comprises phenyl cyanate or cyanogen bromide.
5. A method according to claim 1, wherein the phosphonate or phosphine salt comprises diethyl-3-ethoxycarbonyl-2-methylprop-2-enylphosphonate.
6. A method according to claim 31 wherein the 9-cis retinoid is selected from the group consisting of 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2-trans-4-trans-6-cis-8-trans-nonatetraeonic acid, 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2-cis-4-trans-6-cis-8-trans-nonatetraeonic acid, and 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2-trans-4-cis-6-cis-8-trans-nonatetraeonic acid.
7. A method for producing a 9-cis retinoid comprising:
(a) reducing a cyclohexenyl ketone in the presence of base and an electrophilic nitrile source to form a cyclohexadienyne nitrile of the formula:
(b) adding an alkyl, alkene, aryl or aralkyl group, in a 1,4 conjugate fashion, to the cyclohexadienyne nitrile to form a cyclohexatriene nitrile;
(c) reducing the cyclohexatriene nitrile to the corresponding cyclohexatriene aldehyde; and (d) extending the cyclohexatriene aldehyde with a carbanion equivalent formed bythe addition of a base to a phosphonate or phosphine salt to form a reaction product comprising a mixture of retinoid ester stereoisomers having the general formula:
wherein, R1 and R each can independently represent hydrogen or a lower straight chain or branched alkyl having 1-5 carbon atoms; R3 represents hydrogen or a lower branched or straight chain alkyl, alkene or alkyne having 1-6 carbon atoms; R4 and R5 each can independently represent hydrogen or a lower branched or straight chain alkyl, alkene, aryl or aralkyl having 1-12 carbon atoms; R6 represents a lower straight chain or branched alkyl, alkene or alkyne having 1-5 carbon atoms; and the dashed lines in the structures between carbons 11-12, and 13-14, depict olefin bonds that can be in either the trans or cis configuration.
(a) reducing a cyclohexenyl ketone in the presence of base and an electrophilic nitrile source to form a cyclohexadienyne nitrile of the formula:
(b) adding an alkyl, alkene, aryl or aralkyl group, in a 1,4 conjugate fashion, to the cyclohexadienyne nitrile to form a cyclohexatriene nitrile;
(c) reducing the cyclohexatriene nitrile to the corresponding cyclohexatriene aldehyde; and (d) extending the cyclohexatriene aldehyde with a carbanion equivalent formed bythe addition of a base to a phosphonate or phosphine salt to form a reaction product comprising a mixture of retinoid ester stereoisomers having the general formula:
wherein, R1 and R each can independently represent hydrogen or a lower straight chain or branched alkyl having 1-5 carbon atoms; R3 represents hydrogen or a lower branched or straight chain alkyl, alkene or alkyne having 1-6 carbon atoms; R4 and R5 each can independently represent hydrogen or a lower branched or straight chain alkyl, alkene, aryl or aralkyl having 1-12 carbon atoms; R6 represents a lower straight chain or branched alkyl, alkene or alkyne having 1-5 carbon atoms; and the dashed lines in the structures between carbons 11-12, and 13-14, depict olefin bonds that can be in either the trans or cis configuration.
8. A method according to claim 7, further comprising, after the extending step, hydrolyzing the reaction product with an aqueous methanolic hydroxide to form a mixture of retinoid stereoisomers.
9. A method according to claim 8, further comprising, after the hydrolyzing step, isolating a retinoid stereoisomer having the general formula:
wherein R1 to R5 have the meaning specified in claim 7, R7 represents hydrogen or a pharmaceutically acceptable salt and the 11-12 and 13-14 olefin bonds are in either the trans or cis configuration.
wherein R1 to R5 have the meaning specified in claim 7, R7 represents hydrogen or a pharmaceutically acceptable salt and the 11-12 and 13-14 olefin bonds are in either the trans or cis configuration.
10. A method according to claim 9, wherein the 9-cis retinoid is selected from the group consisting of 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2-trans-4-trans-6-cis-8-trans-nonatetraenoic acid, 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2-cis-4-trans-6-cis-8-trans-nonatetraenoic acid, and 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2-trans 4-cis-6-cis-8-trans-nonatetraenoic acid.
11. A method for producing a cyclohexadienyne nitrile olefin comprising reducing a cyclohexenyl ketone in the presence of base and an electrophilic nitrile source to form a cyclohexadienyne nitrile of the formula:
wherein, R1 and R? each can independently represent hydrogen or a lower straight chain or branched alkyl having 1-5 carbon atoms, and R3 represents hydrogen or a lower branched or straight chain alkyl, alkene or alkyne having 1-6 carbon atoms.
wherein, R1 and R? each can independently represent hydrogen or a lower straight chain or branched alkyl having 1-5 carbon atoms, and R3 represents hydrogen or a lower branched or straight chain alkyl, alkene or alkyne having 1-6 carbon atoms.
12. A method for producing a 9-cis alkyl cisoid nitrile comprising:
(a) condensing a cyclohexadienyne with an electrophilic nitrile source to form acyclohexadienyne nitrile, and (b) adding an alkyl, alkene, aryl or aralkyl group, in a 1,4 conjugate fashion, to the cyclohexadienyne to form a 9-cis alkyl cisoid nitrile of the formula:
wherein, R1 and R each can independently represent hydrogen or a lower straight chain or branched alkyl having 1-5 carbon atoms, R3 represents hydrogen or a lower branched or straight chain alkyl, alkene or alkyne having 1-6 carbon atoms: R4 represents hydrogen or a lower branched or straight chain alkyl, alkene, aryl or aralkyl having 1-6 carbon, and the 9-10 bond is in the cis configuration.
(a) condensing a cyclohexadienyne with an electrophilic nitrile source to form acyclohexadienyne nitrile, and (b) adding an alkyl, alkene, aryl or aralkyl group, in a 1,4 conjugate fashion, to the cyclohexadienyne to form a 9-cis alkyl cisoid nitrile of the formula:
wherein, R1 and R each can independently represent hydrogen or a lower straight chain or branched alkyl having 1-5 carbon atoms, R3 represents hydrogen or a lower branched or straight chain alkyl, alkene or alkyne having 1-6 carbon atoms: R4 represents hydrogen or a lower branched or straight chain alkyl, alkene, aryl or aralkyl having 1-6 carbon, and the 9-10 bond is in the cis configuration.
13. 5-(2,6,6-Trimethyl-1-cyclohexen-1-yl)-pent-2-yn-4-enentrile.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25027594A | 1994-05-27 | 1994-05-27 | |
| US08/250,275 | 1994-05-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2187431A1 true CA2187431A1 (en) | 1995-12-07 |
Family
ID=22947079
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002187431A Abandoned CA2187431A1 (en) | 1994-05-27 | 1995-05-24 | Methods for the synthesis of 9-cis retinoids and their novel intermediates |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0760810A1 (en) |
| JP (1) | JPH10501232A (en) |
| AU (1) | AU2603095A (en) |
| CA (1) | CA2187431A1 (en) |
| WO (1) | WO1995032946A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110337430B (en) | 2016-11-17 | 2023-02-03 | 德布勒森大学 | Precursor compounds of retinoids providing the vitamin A5 pathway and uses thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0839788A1 (en) * | 1993-04-21 | 1998-05-06 | Ligand Pharmaceuticals, Inc. | Stereospecific synthesis of polyene compounds |
-
1995
- 1995-05-24 AU AU26030/95A patent/AU2603095A/en not_active Abandoned
- 1995-05-24 JP JP8501015A patent/JPH10501232A/en active Pending
- 1995-05-24 CA CA002187431A patent/CA2187431A1/en not_active Abandoned
- 1995-05-24 WO PCT/US1995/006580 patent/WO1995032946A1/en not_active Application Discontinuation
- 1995-05-24 EP EP95920644A patent/EP0760810A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| JPH10501232A (en) | 1998-02-03 |
| EP0760810A1 (en) | 1997-03-12 |
| WO1995032946A1 (en) | 1995-12-07 |
| AU2603095A (en) | 1995-12-21 |
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