CA1190230A - Process for the resolution of pyrano[3,4-b]indole- 1-acetic acids - Google Patents
Process for the resolution of pyrano[3,4-b]indole- 1-acetic acidsInfo
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- CA1190230A CA1190230A CA000420416A CA420416A CA1190230A CA 1190230 A CA1190230 A CA 1190230A CA 000420416 A CA000420416 A CA 000420416A CA 420416 A CA420416 A CA 420416A CA 1190230 A CA1190230 A CA 1190230A
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- acetic acid
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Abstract
ABSTRACT
Mixtures of racemic (?)pyrano[3,4-b]indole-1-acetic acids are resolved with (-)-borneol to obtain the substantially pure (+) and (-)-enantiomers. The resolution involves the formation of a mixture of the diastereoisomeric pyrano[3,4-b]indole-acetic acid, (-)-borneol esters, separation of the diastereoisomeric esters, and hydrolysis of the latter esters.
Mixtures of racemic (?)pyrano[3,4-b]indole-1-acetic acids are resolved with (-)-borneol to obtain the substantially pure (+) and (-)-enantiomers. The resolution involves the formation of a mixture of the diastereoisomeric pyrano[3,4-b]indole-acetic acid, (-)-borneol esters, separation of the diastereoisomeric esters, and hydrolysis of the latter esters.
Description
3~
PROCESS FOR THE RESOLUTION OF PYRAN0[3,4-b3 INDOLE-l-ACETIC ACIDS
~ ,.
This invention relates ts a process for the resolution of t+~pyran~
[3,4-b] indol~l-acetic aci~ to obtain the separate corresponding t+) and (-) optical 5 enantiomers.
The racemic (+~pyrano~3,4-b] indole-l-acetic acids are well knuwn anti-inflammAtory and analgesic agents described by C.A. Demerson et ~1., U.S~
P~tent 3,939,178, issued Pebruary 17,1976; C.A. Demerson et al., J. Med. Chem., 18,189 (lg75) and 19, 391 (197B).
The process of this invention involves the condensation of a racemic (~pyrano[3,4-b~ indole-l-acetic acid with (-~borneol to obtain a separable di-asteroisomeric mixt~e of the corresponding esters and hydrolyzing the (~) and (-) diastereoisomeric esters. A limited number of esterifications of a racemic acid with an opffcally acffve alcohol to give diastereoisomeric esters are de-15 scribed, for example, P.H. Boyle9 Quarterly Reviews, 25, 323 (1971). In addition, a few total syntheses of optieally active acids using optically active ~lcohols are des~ibed, for example E. Wehinger et Ml., Abstr. Pa,pers Am. Chem. Soe.
1~2 Meeî. MEI)I 64fl981; B. Laangstroem et al., Chem. Abstr. 91,193607 p (1979) for Chem. Scr., 13, 4g (1979); and P.E. Krieger et ~1., J. Org. Chem., 43, 4~47 20 (1978).
The above described uses of optically active alcohols are for specific syntheses of various acids in limited quantities. Such use of optically active alcohols are known to be of little importance for the general resolution of racemic acids, see P.H~ Boyle9 cited above, at p.325. Usually the mixture OI diastereo-25 isomeric esters c~nnot be separated to obtain the individual enantiomers.
-- The process of this invention res~dted from the discoYery ~at a dia-stereoisomeric mia~ture of pyranot3,4-b] indole-l-aeetic acid (-)-bornçol esterscan be easily separated. This process gives individual (+) and (-~enantiomers of a pyrano[3,4-b] indol~l-acetic acid in a commercially feasible operation and 30 in high yield.
The process of this invention comprises:
a) esterifying a racemic (;~)pyranoE3,4-b3 indole l-acetic acid of formul~ I
r
PROCESS FOR THE RESOLUTION OF PYRAN0[3,4-b3 INDOLE-l-ACETIC ACIDS
~ ,.
This invention relates ts a process for the resolution of t+~pyran~
[3,4-b] indol~l-acetic aci~ to obtain the separate corresponding t+) and (-) optical 5 enantiomers.
The racemic (+~pyrano~3,4-b] indole-l-acetic acids are well knuwn anti-inflammAtory and analgesic agents described by C.A. Demerson et ~1., U.S~
P~tent 3,939,178, issued Pebruary 17,1976; C.A. Demerson et al., J. Med. Chem., 18,189 (lg75) and 19, 391 (197B).
The process of this invention involves the condensation of a racemic (~pyrano[3,4-b~ indole-l-acetic acid with (-~borneol to obtain a separable di-asteroisomeric mixt~e of the corresponding esters and hydrolyzing the (~) and (-) diastereoisomeric esters. A limited number of esterifications of a racemic acid with an opffcally acffve alcohol to give diastereoisomeric esters are de-15 scribed, for example, P.H. Boyle9 Quarterly Reviews, 25, 323 (1971). In addition, a few total syntheses of optieally active acids using optically active ~lcohols are des~ibed, for example E. Wehinger et Ml., Abstr. Pa,pers Am. Chem. Soe.
1~2 Meeî. MEI)I 64fl981; B. Laangstroem et al., Chem. Abstr. 91,193607 p (1979) for Chem. Scr., 13, 4g (1979); and P.E. Krieger et ~1., J. Org. Chem., 43, 4~47 20 (1978).
The above described uses of optically active alcohols are for specific syntheses of various acids in limited quantities. Such use of optically active alcohols are known to be of little importance for the general resolution of racemic acids, see P.H~ Boyle9 cited above, at p.325. Usually the mixture OI diastereo-25 isomeric esters c~nnot be separated to obtain the individual enantiomers.
-- The process of this invention res~dted from the discoYery ~at a dia-stereoisomeric mia~ture of pyranot3,4-b] indole-l-aeetic acid (-)-bornçol esterscan be easily separated. This process gives individual (+) and (-~enantiomers of a pyrano[3,4-b] indol~l-acetic acid in a commercially feasible operation and 30 in high yield.
The process of this invention comprises:
a) esterifying a racemic (;~)pyranoE3,4-b3 indole l-acetic acid of formul~ I
r
-2- AHP-8211 R.~ ( ~ ~,COOH
R H
in which Rl is lower alk~ d R2 and R3 eaeh is hydrogen, lower al1cyl or halo with (-~borneol to obtQin ~ diastereoisomeric mixture of a corresponding com~
pound of formlda Il H3C ~ 7 R J ~ 2~
in which Rl, Ra and R3 are as defined above, b) separ~ting the diastereoisomers;
c) hydrolyzing the (+) or ~-~diastereoisomer of formula Il under 20 alkaline conditions; and d) isolating the corresp~nding (+) or (-~enantiomer of formula I in which Rl, R2 and R3 are as defined herein.
In a prefe~Ted process, ~+~1,8-diethyl-1,3,4~9-tetrahydropyrano[3,4~
indol~l-acetic acid is resolved with (-~borneol to obtain ~+~1,8-diethyl-1,3,4,~-25 tetrahydropyranot3,4-b]indole-1-acetic acid.
. ~a~=
The t~rm ~o~er alkyr' a~ used herein means straight and branched chain alkyl ~dicals ~ontaining from one to five carbon atoms and includes methyl, ethyl, propyl, I-methylethyl, butyl, lgl-dimethylethyl and the like7 unless stated 30 otherwise.
The term 'thalo" as used herein meQns bromo, chloro, 1uoro and iodo, unless stated otherwise.
R H
in which Rl is lower alk~ d R2 and R3 eaeh is hydrogen, lower al1cyl or halo with (-~borneol to obtQin ~ diastereoisomeric mixture of a corresponding com~
pound of formlda Il H3C ~ 7 R J ~ 2~
in which Rl, Ra and R3 are as defined above, b) separ~ting the diastereoisomers;
c) hydrolyzing the (+) or ~-~diastereoisomer of formula Il under 20 alkaline conditions; and d) isolating the corresp~nding (+) or (-~enantiomer of formula I in which Rl, R2 and R3 are as defined herein.
In a prefe~Ted process, ~+~1,8-diethyl-1,3,4~9-tetrahydropyrano[3,4~
indol~l-acetic acid is resolved with (-~borneol to obtain ~+~1,8-diethyl-1,3,4,~-25 tetrahydropyranot3,4-b]indole-1-acetic acid.
. ~a~=
The t~rm ~o~er alkyr' a~ used herein means straight and branched chain alkyl ~dicals ~ontaining from one to five carbon atoms and includes methyl, ethyl, propyl, I-methylethyl, butyl, lgl-dimethylethyl and the like7 unless stated 30 otherwise.
The term 'thalo" as used herein meQns bromo, chloro, 1uoro and iodo, unless stated otherwise.
3~
-3- AH~8211 The first step in the process for resolving a racernic compound of formula I in which Rl, R2 and R3 are as defined herein involves the esterification of the compound of formula I with (-~borneol to obtain the diastereoisomeric mixture of the corresponding compound of formula lI in whîch Rl, Ra and R3 are as defined herein. A number of the methods known in the art can be utilized 5 for this esterification, for example, use of an acid chloride or bromide of the &cid of formvla I; acid catalyzed esterification; use of a dehydrating ~gent, i.e.
a dia3kylcarbodiiDlide; and use OI a dehydr~ting agent in the presence of an esteri-fication catalyst, i.e. N-hydroxysuccinimide, 2,4,5-trichlorophenol, l-hydroxy-benzotriazole and 4-dimethylaminopyridine. In the preferred method of esteri-10 iication, the racemlc compound of ~ormL~a I is condensed with abvut 1.0 to 1.5molar equivalents of (-~borneol in the presence of about 1.0 to 1.5 molar equiva-l~nts of N,N'-dicyclohexylcarbodiimide and about 0.1 to 0.15 molar equivalents of 4-dimethylaminewridine in an inert organic solvent, for example, diethyl ether, diisopropyl ether, chloroform or dimethylIormamide. The condensation 15 reactiorl is allowed ~ proceed at about 15 to 30D C for about 10 to 30 hours. A~ter a standard work-up, a diastereoisomeric rnixture o the ~orresponding compo~mds of formul~ II are obhined. The diastereoisomeric mixture can be separated to obtain the individual diastereoisomers by using chromatography orl a silic~
gel adsorbant with a suitable eluant. The chromatography can be ~onducted 20 by using ~ thin layer of adsorbant on plates9 a column of ~dsor~nt at atmospheric pressure or a column o~ adsorb~nt under high press~e. A preferred eluant for the chromatography is about 3 to 10 percent ethyl acetate in hexane.
~ 3ach of the separated diastereoisomers of forrn~a II is hydrolyzed under aL'caline conditions to obtain the corresponding (~) or ~-) enantiomer o~
25 form~a I in whi~ Rl, R2 and R3 are as defined herein. Preferred eonditions for the hyd~olysis involve reacting the individual diastereoisomers of form~da II with ~n ~queous solution of about two to five molar ~quivalents of an ~Ltcalihydroxide oP ~arbonate, pre~erably sodium or potassium Iydroxide, ~nd a water miscible organic solvent, preferably methanol or ethanol at about 60 to 80 C
30 for one to ten hours. After hydrolysis is complete, the a~aline solucion is acidi-fied, preferably with a dilute mineral acid, and the individual en~ntiomers of form~da I are extracted and purified.
-3- AH~8211 The first step in the process for resolving a racernic compound of formula I in which Rl, R2 and R3 are as defined herein involves the esterification of the compound of formula I with (-~borneol to obtain the diastereoisomeric mixture of the corresponding compound of formula lI in whîch Rl, Ra and R3 are as defined herein. A number of the methods known in the art can be utilized 5 for this esterification, for example, use of an acid chloride or bromide of the &cid of formvla I; acid catalyzed esterification; use of a dehydrating ~gent, i.e.
a dia3kylcarbodiiDlide; and use OI a dehydr~ting agent in the presence of an esteri-fication catalyst, i.e. N-hydroxysuccinimide, 2,4,5-trichlorophenol, l-hydroxy-benzotriazole and 4-dimethylaminopyridine. In the preferred method of esteri-10 iication, the racemlc compound of ~ormL~a I is condensed with abvut 1.0 to 1.5molar equivalents of (-~borneol in the presence of about 1.0 to 1.5 molar equiva-l~nts of N,N'-dicyclohexylcarbodiimide and about 0.1 to 0.15 molar equivalents of 4-dimethylaminewridine in an inert organic solvent, for example, diethyl ether, diisopropyl ether, chloroform or dimethylIormamide. The condensation 15 reactiorl is allowed ~ proceed at about 15 to 30D C for about 10 to 30 hours. A~ter a standard work-up, a diastereoisomeric rnixture o the ~orresponding compo~mds of formul~ II are obhined. The diastereoisomeric mixture can be separated to obtain the individual diastereoisomers by using chromatography orl a silic~
gel adsorbant with a suitable eluant. The chromatography can be ~onducted 20 by using ~ thin layer of adsorbant on plates9 a column of ~dsor~nt at atmospheric pressure or a column o~ adsorb~nt under high press~e. A preferred eluant for the chromatography is about 3 to 10 percent ethyl acetate in hexane.
~ 3ach of the separated diastereoisomers of forrn~a II is hydrolyzed under aL'caline conditions to obtain the corresponding (~) or ~-) enantiomer o~
25 form~a I in whi~ Rl, R2 and R3 are as defined herein. Preferred eonditions for the hyd~olysis involve reacting the individual diastereoisomers of form~da II with ~n ~queous solution of about two to five molar ~quivalents of an ~Ltcalihydroxide oP ~arbonate, pre~erably sodium or potassium Iydroxide, ~nd a water miscible organic solvent, preferably methanol or ethanol at about 60 to 80 C
30 for one to ten hours. After hydrolysis is complete, the a~aline solucion is acidi-fied, preferably with a dilute mineral acid, and the individual en~ntiomers of form~da I are extracted and purified.
-4- AH~8all l~e following examples illustrate further this invention~
1,~-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b] indol~l-Acetic acid, (-)-borneol Esters A mixh~re consisting of (+)-1,8-diethyl-1,3,499-tetrahydrpyrano~3,~b~-indole-l-acetic acid (100 g, 0~34,8 mol), (-)-borneol (64.46 g, 0.418 mol), ~dimethyl-S aminopyridine (S.09 g, 0.0417 mol) and N,N'~icyclohe~ylcarbodiimide (86.2d~ g, 0.418 mol) in 1.5 liters of diethyl ether was stirred at 2~ C for 18 hours. Thereaction was c~oled in an ic~water bath and filtered. The filtrate was washed once with 5% ~queous sodium hydroxide, twice with 5% hydrochloric acid and twice with water. After drying over magnesium s~fate and evflporation o~ the solvent9 160.3 g of a semisolid was obtained. Filtration through 1.5 kg of silica gel using 10% ethyl ~cetate in hexane as eluant afforded 119.3 g of the mixture as Q solid. Preparative high pressure liquid chromatography (using batehes of 20-25 g) using Prepak 5ûO silica gel cartridges and 3% ethyl acetate in hexane as eluant separ~ted the (+) and ~-) esters of the fftle compound. Evaporation OI the ~ppropri~te elu~tes gave 52.33 g of the (+~diastereoisomer: mp 142-143 C;
t~l D+ 47 4 (1% in eth~nol); and Anal. C lcd for C27H3yNO3~ C, 76.56% H, 8.81% N, 3.31% and Pound: C, 76.60% Hg 8.71% N, 3.28%. The (-)-diastereoisomer (53.33 g) had mp 93-~6VC; [c~]D-61.4 (1% in ethQnol); and Anal. Fowld: C, 76.71%
H, 8.72% N, 3.21%.
~XAMPL3; 2 Hydrolyses of Borneol Esters The ~-~diastereoisomeric ester, obtRlned from Example 1, was dissolved in methanol (1 liter) contair~ing potassium hydroxide (34.8 g) and water (260 ml~.
The mixture was re~ ed while stlrring for 3 hr. Most of the methanol was distilled 25 oi~, water (500 ml) was added and the mixture was extracted with toluene. Theaqueous phase was acidified ~nth BN hydroehloric aeid and extrRcted with chlor~
form. The ehloroform e~racts were washed with water~ dried ~nd the solvent removed to afford crude (+) enantiomer ~32.5 g) which was purified by chroma-tography on 1 Icg of silic~ gel impregnated with phosphoric acid by stirring the30 silica gel with a 1% solution of phosophoric acid in methanol, followed by air
1,~-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b] indol~l-Acetic acid, (-)-borneol Esters A mixh~re consisting of (+)-1,8-diethyl-1,3,499-tetrahydrpyrano~3,~b~-indole-l-acetic acid (100 g, 0~34,8 mol), (-)-borneol (64.46 g, 0.418 mol), ~dimethyl-S aminopyridine (S.09 g, 0.0417 mol) and N,N'~icyclohe~ylcarbodiimide (86.2d~ g, 0.418 mol) in 1.5 liters of diethyl ether was stirred at 2~ C for 18 hours. Thereaction was c~oled in an ic~water bath and filtered. The filtrate was washed once with 5% ~queous sodium hydroxide, twice with 5% hydrochloric acid and twice with water. After drying over magnesium s~fate and evflporation o~ the solvent9 160.3 g of a semisolid was obtained. Filtration through 1.5 kg of silica gel using 10% ethyl ~cetate in hexane as eluant afforded 119.3 g of the mixture as Q solid. Preparative high pressure liquid chromatography (using batehes of 20-25 g) using Prepak 5ûO silica gel cartridges and 3% ethyl acetate in hexane as eluant separ~ted the (+) and ~-) esters of the fftle compound. Evaporation OI the ~ppropri~te elu~tes gave 52.33 g of the (+~diastereoisomer: mp 142-143 C;
t~l D+ 47 4 (1% in eth~nol); and Anal. C lcd for C27H3yNO3~ C, 76.56% H, 8.81% N, 3.31% and Pound: C, 76.60% Hg 8.71% N, 3.28%. The (-)-diastereoisomer (53.33 g) had mp 93-~6VC; [c~]D-61.4 (1% in ethQnol); and Anal. Fowld: C, 76.71%
H, 8.72% N, 3.21%.
~XAMPL3; 2 Hydrolyses of Borneol Esters The ~-~diastereoisomeric ester, obtRlned from Example 1, was dissolved in methanol (1 liter) contair~ing potassium hydroxide (34.8 g) and water (260 ml~.
The mixture was re~ ed while stlrring for 3 hr. Most of the methanol was distilled 25 oi~, water (500 ml) was added and the mixture was extracted with toluene. Theaqueous phase was acidified ~nth BN hydroehloric aeid and extrRcted with chlor~
form. The ehloroform e~racts were washed with water~ dried ~nd the solvent removed to afford crude (+) enantiomer ~32.5 g) which was purified by chroma-tography on 1 Icg of silic~ gel impregnated with phosphoric acid by stirring the30 silica gel with a 1% solution of phosophoric acid in methanol, followed by air
-5- AHP-8211 drying. Elution with 10% acetone in toluene gave ~7e pure (+~enantiomer. It was obtained ~s a solid by dissolving in benzene (100 ml) and pouring into cold petroleum ether (bp 30-60 C, 1.2 liters) with stirring. Subsequent crystalli7ation from benzen~petroleum ether (bp 30-60 C) gave the pure ~nantiomer, (+h,8-diethyl-193,4,9-tetrahydropyrano~3,4-b] indol~l-acetic acid ~24.02 g): mp 13~-5 140 C; [] D+ 25.2 (3% in ethanol); and Anal. Calcd for C17H2~NO3: C, 71.05%H, 7.37% N, 4.88% and Found: C, 71.14% H, 7.36% N, 4.81%. In the same manner, the (+~diastereoisomeric ester, obtained from Example 1, gave (-~1,8-diethyl-1,3,4J9-tetrahydropyrano[3,4-b] indole-l-acetic ~cid (21.46 g). mp 139-141 C;
~a~ D- 25.6 (3% in ethanol); and Anal. F~und: C~ 71.09% H, 7.37% N, 4.84%.
E~AMPLI~ 3 Effect on Primary InflammAtion of Adjuvant Induced Arthritis The method used was a modification of that described by J~ Wax et al., J. Pharmac. Exp. Ther., 192,166 (1975). Groups of rats were injected intra-dermally in the left hindpaw (injected hindpaw) with 0.1 rnl of a fine suspension 15 of killed ~nd dried Mycobacterium butyricum (Difco) at a concentration of 5 mg/ml in liquid paraf~in (Freund's complete adjuvant). Drugs were administered immedi-ately before the adjuvant, 24 h and 48 h after the adjuvant (day 0,1 and 2). Theinjected hindpaw volume w ~ measured before the adjuvant and 24 after the l~st drug administration (day 3). The difference between the hindleg volume 20 before the adjuvant injection and the day 3 reading represented the edema volume.
Rats showing an inhibition of hindpaw edema of 25% Gr more when compared to the mean edema volume of the control group ~10 rats) were considered to exhibit an anti-in~lammatory effect. The dose which produced a positive ef~ect in half the rats (ED50~ was calculated by probit analysis. (D.J. FiMey, Statistical Method 25 in Biologic~l Assay9 MacMillan, New York, 1978). There were 10 to 20 rats perdose and 4 dose levels were used. An adjuvant-injeeted control group receiving water only was also included. Hindleg volume was determined by a mercury displ~eement method. Hindlegs were dipped in mercury up to the hairline and the amount displaced wss read in grams on a direct reading balance. It repre-30 sented the volume of the hindleg (13.6 g of mercury = 1 ml). Male Charles Riveralbino rats weighing 180 to 200 g were used. The results are expressed as ED50,S, the dose which reduces, by 25% the edema of primary adjuvant arthritis in 50%
OI the rats. In this model the ED5~ for (+~1,8-diethyl-1,3,4,9-tetrahydropyran~
3~
~a~ D- 25.6 (3% in ethanol); and Anal. F~und: C~ 71.09% H, 7.37% N, 4.84%.
E~AMPLI~ 3 Effect on Primary InflammAtion of Adjuvant Induced Arthritis The method used was a modification of that described by J~ Wax et al., J. Pharmac. Exp. Ther., 192,166 (1975). Groups of rats were injected intra-dermally in the left hindpaw (injected hindpaw) with 0.1 rnl of a fine suspension 15 of killed ~nd dried Mycobacterium butyricum (Difco) at a concentration of 5 mg/ml in liquid paraf~in (Freund's complete adjuvant). Drugs were administered immedi-ately before the adjuvant, 24 h and 48 h after the adjuvant (day 0,1 and 2). Theinjected hindpaw volume w ~ measured before the adjuvant and 24 after the l~st drug administration (day 3). The difference between the hindleg volume 20 before the adjuvant injection and the day 3 reading represented the edema volume.
Rats showing an inhibition of hindpaw edema of 25% Gr more when compared to the mean edema volume of the control group ~10 rats) were considered to exhibit an anti-in~lammatory effect. The dose which produced a positive ef~ect in half the rats (ED50~ was calculated by probit analysis. (D.J. FiMey, Statistical Method 25 in Biologic~l Assay9 MacMillan, New York, 1978). There were 10 to 20 rats perdose and 4 dose levels were used. An adjuvant-injeeted control group receiving water only was also included. Hindleg volume was determined by a mercury displ~eement method. Hindlegs were dipped in mercury up to the hairline and the amount displaced wss read in grams on a direct reading balance. It repre-30 sented the volume of the hindleg (13.6 g of mercury = 1 ml). Male Charles Riveralbino rats weighing 180 to 200 g were used. The results are expressed as ED50,S, the dose which reduces, by 25% the edema of primary adjuvant arthritis in 50%
OI the rats. In this model the ED5~ for (+~1,8-diethyl-1,3,4,9-tetrahydropyran~
3~
-6- AHP-8~11 [3,4-b] indol~l-aeetic acid was 0.7 ~ 0.3 mg/kg, while the (-)-enantiomer was inactive. The ED50 P the (+~racemate in this test was 1P1 + 0~5 mg/kg.
s ._ .
s ._ .
Claims (9)
1. A process for resolving a racemic (?)-compound of formula I
(I) in which R1 is lower alkyl, and R2 and R3 each is hydrogen, lower alkyl or halo to obtain the corresponding (+) or (-)-enantiomer of formula I in which R1, R2 and R3 are as defined herein, which comprises:
a) esterifying a racemic (?)-compound of formula I in which R1, R2 and R3 are as defined herein with (-)-borneol to obtain a diastereoisomeric mixture of a corresponding compound of formula II
(II) in which R1, R2 and R3 are as defined herein;
b) separating the diastereoisomers;
c) hydrolyzing the diastereoisomers of formula II in which R1, R2 and R3 are as defined herein with an aqueous alkaline solution; and d) isolating the substantially pure corresponding (+) or (-)-enan-tiomer of formula I in which R1, R2 and R3 are as defined herein.
(I) in which R1 is lower alkyl, and R2 and R3 each is hydrogen, lower alkyl or halo to obtain the corresponding (+) or (-)-enantiomer of formula I in which R1, R2 and R3 are as defined herein, which comprises:
a) esterifying a racemic (?)-compound of formula I in which R1, R2 and R3 are as defined herein with (-)-borneol to obtain a diastereoisomeric mixture of a corresponding compound of formula II
(II) in which R1, R2 and R3 are as defined herein;
b) separating the diastereoisomers;
c) hydrolyzing the diastereoisomers of formula II in which R1, R2 and R3 are as defined herein with an aqueous alkaline solution; and d) isolating the substantially pure corresponding (+) or (-)-enan-tiomer of formula I in which R1, R2 and R3 are as defined herein.
2. The process of claim 1 wherein a) the racemic (?)-compound of formula I in which R1, R2 and R3 are as defined herein is esterified with (-)-borneol in the presence of N, N'-dicyclohexylcarbodiimide to obtain a diastereoisomeric mixture of a corresponding compound of formula II in which R1, R2 and R3 are as defined herein;
b) separating the diastereoisomers by chromatography through an adsorbent of silica gel;
c) hydrolyzing the diastereoisomers of formula II in which R1, R2 and R3 are as defined herein with an aqueous solution of sodium hydroxide or potassium hydroxide; and d) acidifying the alkaline hydrolysis solution with a mineral acid and isolating the corresponding (+) or (-)-enantiomer of formula I in which R1, R2 and R3 are as defined herein.
b) separating the diastereoisomers by chromatography through an adsorbent of silica gel;
c) hydrolyzing the diastereoisomers of formula II in which R1, R2 and R3 are as defined herein with an aqueous solution of sodium hydroxide or potassium hydroxide; and d) acidifying the alkaline hydrolysis solution with a mineral acid and isolating the corresponding (+) or (-)-enantiomer of formula I in which R1, R2 and R3 are as defined herein.
3. The process of claim 2 wherein the esterification of step (a) is conducted in the presence of a catalytic amount of 4-dimethylaminopyridine,
4. A process for resolving racemic (+)-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-1-acetic acid to obtain (+)-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-1-acetic acid, which comprises:
a) esterifying racemic (+)-1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid with (-)-borneol to obtain a diastereoisomeric mixture of (+) and (-)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-acetic acid, (-)-borneol ester.
b) separating the (-)-diastereoisomer;
c) hydrolyzing the (-)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid, (-)-borneol ester with an aqueous alkaline solution; and d) isolating the substantially pure enantiomer (+)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b] indole-1-acetic acid.
a) esterifying racemic (+)-1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid with (-)-borneol to obtain a diastereoisomeric mixture of (+) and (-)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-acetic acid, (-)-borneol ester.
b) separating the (-)-diastereoisomer;
c) hydrolyzing the (-)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid, (-)-borneol ester with an aqueous alkaline solution; and d) isolating the substantially pure enantiomer (+)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b] indole-1-acetic acid.
5. The process of claim 4 wherein a) the racemic (+)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid is esterified with (-)-borneol in the presence of N,N'dicyclohexyl-carbodiimide to obtain a diastereoisomeric mixture of (+) and (-)-1,8-diethyl-1,3,-4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, (-)-borneol ester;
b) separating the (-)-diastereoisomer by chromatography through a column of silica gel;
c) hydrolyzing (-)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, (-)-borneol ester with an aqueous solution of sodium hydroxide or potassium hydroxide; and d) acidifying the alkaline hydrolysis solution with a mineral acid and isolating the substantially pure enantiomer (+)-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-1-acetic acid.
b) separating the (-)-diastereoisomer by chromatography through a column of silica gel;
c) hydrolyzing (-)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, (-)-borneol ester with an aqueous solution of sodium hydroxide or potassium hydroxide; and d) acidifying the alkaline hydrolysis solution with a mineral acid and isolating the substantially pure enantiomer (+)-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-1-acetic acid.
6. The process of claim 5 wherein the esterification of step (a) is conducted in the presence of a catalytic amount of 4-dimethylaminopyridine and the chromatography in separation step (b) is conducted with an eluant of three to 10 percent of ethyl acetate in hexane.
7. A (+) enantiomer of a compound of formula I
(I) in which R1 is lower alkyl, and R2 and R3 each is hydrogen, lower alkyl or halo,when prepared by the process of claim 1, or an obvious chemical equivalent thereof.
(I) in which R1 is lower alkyl, and R2 and R3 each is hydrogen, lower alkyl or halo,when prepared by the process of claim 1, or an obvious chemical equivalent thereof.
8. A (-) enantiomer of a compound of formula I
(I) in which R1 is lower alkyl, and R2 and R3 each is hydrogen, lower alkyl or halo,when prepared by the process of claim 1, or an obvious chemical equivalent thereof.
(I) in which R1 is lower alkyl, and R2 and R3 each is hydrogen, lower alkyl or halo,when prepared by the process of claim 1, or an obvious chemical equivalent thereof.
9. (+)-1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, when prepared by the process of claim 4, or an obvious chemical equivalentthereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000420416A CA1190230A (en) | 1983-01-28 | 1983-01-28 | Process for the resolution of pyrano[3,4-b]indole- 1-acetic acids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000420416A CA1190230A (en) | 1983-01-28 | 1983-01-28 | Process for the resolution of pyrano[3,4-b]indole- 1-acetic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1190230A true CA1190230A (en) | 1985-07-09 |
Family
ID=4124438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000420416A Expired CA1190230A (en) | 1983-01-28 | 1983-01-28 | Process for the resolution of pyrano[3,4-b]indole- 1-acetic acids |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1190230A (en) |
-
1983
- 1983-01-28 CA CA000420416A patent/CA1190230A/en not_active Expired
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