CA1280432C - Method of resolving cis 3-amino-4-[2-(2-furyl)eth-1-yl]-1-methoxycarbonylmethyl- azetidin-2-one and malic acid salts thereof - Google Patents
Method of resolving cis 3-amino-4-[2-(2-furyl)eth-1-yl]-1-methoxycarbonylmethyl- azetidin-2-one and malic acid salts thereofInfo
- Publication number
- CA1280432C CA1280432C CA000611218A CA611218A CA1280432C CA 1280432 C CA1280432 C CA 1280432C CA 000611218 A CA000611218 A CA 000611218A CA 611218 A CA611218 A CA 611218A CA 1280432 C CA1280432 C CA 1280432C
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- malic acid
- cis
- amino
- azetidin
- furyl
- Prior art date
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- Plural Heterocyclic Compounds (AREA)
Abstract
Abstract Cis .alpha..alpha./.beta..beta.-3-amino4[2-(2-furyl)eth-1-yl]-1-methoxycarbonylmethyl-azetidin-2-one is resolved via optically active malic acid.
Description
~ 3~ 3 METHOD OF RESOLVING CIS 3-AMINO-4-[2-(2-FURYL)ETH-l-YL]-l-METHOXYCARBONYLMEI~YL-AZETIDIN-2-ONE AND
MALIC ACID SALTS THEREOF
An important clinical trial candidate, (6R,7S) 7 (R)-phenylglycylinamido-3-chloro-l~azabicyclo[4.2.0]-oct-2-en-8-on-2-carboxylic acid (loracarbef) may be synthesized by various routes. One of the more note-worthy total syntheses of loracarbef is that madepossible by Evans and Sjogren, U.S. Patent 4,665,171.
The Evans and Sjogren methodology provides a chiral 2+2 (ketene plus imine) cycloaddition, and accordingly, entry to a wide variety of chiral cis ~-lactams.
However, the Evans and Sjogren methodology provides for the utilization of a chiral auxiliary of the formula Il 20 ~
O N~CH2(~C~X' Ar in the 2+2 cycloaddition with a Schiff's base, wherein X' is chloro, bromo, trifluoroacetoxy, or -OP(=)X2, wherein X is halogen. The above chiral auxiliary is s~nthesized in seven steps from L-phenylglycine. The r ~2~3~2 resulting cycloaddition provides compo-unds of the formula Ar S ~ H
y~
O ,~N~
0 C:~ ~
whexein Ar is phenyl, C1-C4 alkylphenyl, halophenyl, C1 C~ alkox~phenyl, naphthyl, thienyl, furyl, benzothienyl, or benzofuryl; R is phenyl, C1 -C4 alkylpherlyl, C1-C~ alkoxyphenyl, or halophenyl; Y is -CH=CH-, or CH2-CH2-; and R' is phenyl, C1-C~
alkylphenyl, C1-C4 alkoxyphenyl, halophenyl, furyl or naphthyl.
The obvious shortcomings of the Evans and Sjogren route are that a very expensive starting material, L phenylglycine, is used, -the chiral auxiliary is synthesized in several steps in linear fashion; and further, the chiral auxiliary is removed and discarded using Li/N~I3/t-C4HgOH to provide a free 3~amino-azetidinone.
As an achiral alternative, Hatanaka et al., Tetrahedron Letters Vol. 24, No. 49, pp 4837-4838 ~1983), provides a method of preparing a 3-hydroxy(i~-1-carbacephalosporin via a 2+2 cycloaddition much in the same fashion as that of Evans and Sjogren, but without the use of a chiral auxiliary as the ketene source. The Hatanaka methodology provides many of the same inter-mediates as does the Evans and Sjogren synthesis, albeit in achiral form. The advantage of the achiral synthesis is economy of steps and starting material.
The present inven-tion affords a useful alter-native to the challenge of synthesizing l-carba(1-dethia~cephalosporins by providing a method for resolu-tion of a key achiral cis-azetidinone intermediate provided by achiral cis-2+2 cycloaddition. In partic-ular, the present invention provides a method for resolution of a crucial achiral intermediate in the total synthesis of l-carba(1-dethia)cephalsoporins using L-malic acid.
Cis 3-amino-4-[2-(2-furyl)eth-l yl]-1-methoxy-carbonylme-thyl-azetidin-2-one is resolved by the practice of this invention into its enantiomeric cis ~,~ and cis ~,~ components whereby the desired cis ~,~ enantiomer is selectively crystallized from solution using S(-)-malic acid.
The present invention provides a method for resolving cis ~ -3~amino-4-~2-(2-furyl)eth-1-yl]-1-methoxycarbonylmethyl-azetidin-2-one into its component enantiomers, which comprises the steps:
(a) con-tacting a polar organic solution of the cis ~ racemate with at least about 0.5 mole-equivalents of an optically active malic acid; and (b) separating the insoluble salt formed thereby.
According to this invention the cis ~
azetidinone mixture is represented by -the following two enantiomers:
~2~ 3Z
2N, N CO2~3 \v~ and ~ N~V~CO2CH3 (I) (II) (~
to yield optically pure isomers, each free of the other. This resolution is accomplished by dissolving a racemic mixture of I and II in 2 polar organic solvent, preferably tetrahydrofuran, and warming the solution to approximately 50C or at least a temperature sufficient to dissolve the racemate (I and II) and the malic acid.
S~ malic acid is then added and the solutions allowed to cool to room temperatuxe gradually overnight, thus ~orming the diasteromenic S(-)-malic acid salt of (I) in excellent yield and outstanding optical purity. The resulting free amino enantiomer (I) is then provided by standard acid/base workup. Order of addition to the polar organic solution is, of course, not critical.
The corresponding ~,~ enantiomer (II) is provided by -the same manipulations as above by merely substituting R-(+) malic acid for S(-)-malic acid.
Alterna~ively, in a method to provide optically pure cis ~,~ isomer, one could use R-(+)-malic acid as the resolving agent and exhaustively crystallize the cis ~,~ isomer away from the solution, ~2~ 3~
thereby leaving the mother liquors with an enhanced concentration of cis ~,~ isomer.
As a urther aspect of the presen-t invention, in addition to the process for resolving the racemic mixture of I and II above, there is provided the S(-)-malic acid salt of (I~ and the R(~)-malic acid salt of (II~.
The diastereomeric salt formed is separated from the resolution mixture and the free amino azeti-dinone is recovered from the salt form by conventionalmethods. For example, the salt is treated in an aqueous medium with a base to form the free amine which can be extracted from the aqueous phase with a water immiscible solvent such as ethyl acetate. The process provides a high degree of separation of the two enantlomeric azetidinones as reflected by the observed enantiomeric excess (ee) of the product.
It is noteworthy that a number of optically active acids were tried as potential resolving agents albeit none were successful except for malic acid.
These acids include: D-(-)-mandelic acid, d-10-camphor-sulfonic acid, (+)-tartaric acid, dibenzoyl~(l)-tartaric, ditoluyl-(D)-tartaric, N-benzoyl alanine (L), guinic acid, ~-camphoric, L-pyroglutamic, (-~pinane carboxylic acid, and abietic acid. Thus, the two optically pure malic acids ((+) and (-)) appear to be unique as readily available, efficient resolving agen-ts for cis-3~amino-4-[2-(2-furyl)eth-1-yl]-1-methoxy-carbonylmethyl-azetidin-2 one.
In each of the resolution attempts, four solvents were evaluated: tetrahydrofuran, ethyl acetate, acetonitrile, and 1,2-dichloroethane. As noted X-76~6 - 6 -above, only malic acid was shown to be an effective resolving agent, and further, only in tetrahydrofuran.
However, one skilled in the art will recognize that the possibility exists that the diaskereomer formed by admixture of S(-)-malic acid and (I) (or R(+)-malic and II) may also selectively crystallize from other solvents of like polarity and solvent effects. In this regard, it must be emphasized that the choice of solvent systems in the above is by no means exhaustive and others may be considered to be equivalent in their utility.
One skilled in the art will appreciate that the selective crystallization of one diastereomer from a polar organic solution is also affected by concentra-tion. A relatively low concentration provides pure diastereomer of generally higher purity but lower yield, while the utilization of a higher concentration of racemate and resolving agent will normally provide higher yields of solid, many times at the expense of optical purity. Thus, the preferred concentration range for the present invention in tetrahydrofuran is about 0.25 M to about 0.75 M, preferably about 0.5 M.
The invention is further described by the following examples but is not to be construed as limiting any aspect of the invention.
Example 1 A 0.5 g portion of the oxalate salt of cis ~ , 3-amino-4-[2-(furyl)ethyl]-1-methoxycarbonyl-azetidin-2-one was slurried in 10 ml of water, neutral-ized to pH = 7.5 with saturated Na~CO3 solution and extracted with CH2Cl2. The CH2C12 solution was dried 3~3f~
over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the racemic free-amine.
A 0.232 g sample of the resulting racemic free amine was then dissolved in tetrahydrofuran (2 ml) and heated to about 50C. A 0.134 g portion of S(-)-malic acid was then added and the resulting solu-tion was allowed to stand overnight.
The containing vessel was wrapped in insulation, thereby allowing the solution to gradually cool to room temperature. The resulting crystalline solid was then filtered and washed with l ml te-trahydrofuran to provide 40 mg (22% yield) of the S( )-malic acid salt of cis ~ 3-amino-4-[2-(2-furyl)eth-1-yl]-1-methoxycarbonyl-methyl-azetidin-2-one.
5 mg (14 ~m) of the L-malic salt was dissolved in a mixture of 1 ml H20, 3.5 mg (3 meq) NaHCO3, and 1 ml acetonitrile. 3.2 mg (14 ~m) 3,5-di-nitrobenzoyl chloride was added and the reaction stirred for 16 hr at room temperature. After 5 ml H20 ~as added, the reacti.on was vacuum filtered and washed with ~2 0 (2 x 1 ml portions), cold isopropanol (2 x 1 ml portions) and diethyl ether (2 x 2 ml) to isolate 2.5 mg of the 3,5-dinitrobenzamide (85 area % by gradient reverse phase HPLC).
The amide solution in te-trahydrofuran was injected on both a YMC-AK03S-5300A, 25 cm, 4.6 mm OD
chiral column (YMC Corporation) and a Pirkle covalent D-naph-thylalanine chiral column ~egis~ to show a 99%
ee (enantiomeric excess). Also, the ~-DNB amide made from a chiral ~-lactam made by -the Evans and Sjogren route and the analogous racemic DNB amide was injected ~-7626 - 8 -on both systems to confirm the retention times of both the ~- and the ~-DNB amides.
Example 2 Th~ procedure for isolation of the ~,~ isomer was identical to that of Example 1, substituting R(+)-malic acid as resolving agent to provide the a,~ isomer (27% yield, 99% ee).
MALIC ACID SALTS THEREOF
An important clinical trial candidate, (6R,7S) 7 (R)-phenylglycylinamido-3-chloro-l~azabicyclo[4.2.0]-oct-2-en-8-on-2-carboxylic acid (loracarbef) may be synthesized by various routes. One of the more note-worthy total syntheses of loracarbef is that madepossible by Evans and Sjogren, U.S. Patent 4,665,171.
The Evans and Sjogren methodology provides a chiral 2+2 (ketene plus imine) cycloaddition, and accordingly, entry to a wide variety of chiral cis ~-lactams.
However, the Evans and Sjogren methodology provides for the utilization of a chiral auxiliary of the formula Il 20 ~
O N~CH2(~C~X' Ar in the 2+2 cycloaddition with a Schiff's base, wherein X' is chloro, bromo, trifluoroacetoxy, or -OP(=)X2, wherein X is halogen. The above chiral auxiliary is s~nthesized in seven steps from L-phenylglycine. The r ~2~3~2 resulting cycloaddition provides compo-unds of the formula Ar S ~ H
y~
O ,~N~
0 C:~ ~
whexein Ar is phenyl, C1-C4 alkylphenyl, halophenyl, C1 C~ alkox~phenyl, naphthyl, thienyl, furyl, benzothienyl, or benzofuryl; R is phenyl, C1 -C4 alkylpherlyl, C1-C~ alkoxyphenyl, or halophenyl; Y is -CH=CH-, or CH2-CH2-; and R' is phenyl, C1-C~
alkylphenyl, C1-C4 alkoxyphenyl, halophenyl, furyl or naphthyl.
The obvious shortcomings of the Evans and Sjogren route are that a very expensive starting material, L phenylglycine, is used, -the chiral auxiliary is synthesized in several steps in linear fashion; and further, the chiral auxiliary is removed and discarded using Li/N~I3/t-C4HgOH to provide a free 3~amino-azetidinone.
As an achiral alternative, Hatanaka et al., Tetrahedron Letters Vol. 24, No. 49, pp 4837-4838 ~1983), provides a method of preparing a 3-hydroxy(i~-1-carbacephalosporin via a 2+2 cycloaddition much in the same fashion as that of Evans and Sjogren, but without the use of a chiral auxiliary as the ketene source. The Hatanaka methodology provides many of the same inter-mediates as does the Evans and Sjogren synthesis, albeit in achiral form. The advantage of the achiral synthesis is economy of steps and starting material.
The present inven-tion affords a useful alter-native to the challenge of synthesizing l-carba(1-dethia~cephalosporins by providing a method for resolu-tion of a key achiral cis-azetidinone intermediate provided by achiral cis-2+2 cycloaddition. In partic-ular, the present invention provides a method for resolution of a crucial achiral intermediate in the total synthesis of l-carba(1-dethia)cephalsoporins using L-malic acid.
Cis 3-amino-4-[2-(2-furyl)eth-l yl]-1-methoxy-carbonylme-thyl-azetidin-2-one is resolved by the practice of this invention into its enantiomeric cis ~,~ and cis ~,~ components whereby the desired cis ~,~ enantiomer is selectively crystallized from solution using S(-)-malic acid.
The present invention provides a method for resolving cis ~ -3~amino-4-~2-(2-furyl)eth-1-yl]-1-methoxycarbonylmethyl-azetidin-2-one into its component enantiomers, which comprises the steps:
(a) con-tacting a polar organic solution of the cis ~ racemate with at least about 0.5 mole-equivalents of an optically active malic acid; and (b) separating the insoluble salt formed thereby.
According to this invention the cis ~
azetidinone mixture is represented by -the following two enantiomers:
~2~ 3Z
2N, N CO2~3 \v~ and ~ N~V~CO2CH3 (I) (II) (~
to yield optically pure isomers, each free of the other. This resolution is accomplished by dissolving a racemic mixture of I and II in 2 polar organic solvent, preferably tetrahydrofuran, and warming the solution to approximately 50C or at least a temperature sufficient to dissolve the racemate (I and II) and the malic acid.
S~ malic acid is then added and the solutions allowed to cool to room temperatuxe gradually overnight, thus ~orming the diasteromenic S(-)-malic acid salt of (I) in excellent yield and outstanding optical purity. The resulting free amino enantiomer (I) is then provided by standard acid/base workup. Order of addition to the polar organic solution is, of course, not critical.
The corresponding ~,~ enantiomer (II) is provided by -the same manipulations as above by merely substituting R-(+) malic acid for S(-)-malic acid.
Alterna~ively, in a method to provide optically pure cis ~,~ isomer, one could use R-(+)-malic acid as the resolving agent and exhaustively crystallize the cis ~,~ isomer away from the solution, ~2~ 3~
thereby leaving the mother liquors with an enhanced concentration of cis ~,~ isomer.
As a urther aspect of the presen-t invention, in addition to the process for resolving the racemic mixture of I and II above, there is provided the S(-)-malic acid salt of (I~ and the R(~)-malic acid salt of (II~.
The diastereomeric salt formed is separated from the resolution mixture and the free amino azeti-dinone is recovered from the salt form by conventionalmethods. For example, the salt is treated in an aqueous medium with a base to form the free amine which can be extracted from the aqueous phase with a water immiscible solvent such as ethyl acetate. The process provides a high degree of separation of the two enantlomeric azetidinones as reflected by the observed enantiomeric excess (ee) of the product.
It is noteworthy that a number of optically active acids were tried as potential resolving agents albeit none were successful except for malic acid.
These acids include: D-(-)-mandelic acid, d-10-camphor-sulfonic acid, (+)-tartaric acid, dibenzoyl~(l)-tartaric, ditoluyl-(D)-tartaric, N-benzoyl alanine (L), guinic acid, ~-camphoric, L-pyroglutamic, (-~pinane carboxylic acid, and abietic acid. Thus, the two optically pure malic acids ((+) and (-)) appear to be unique as readily available, efficient resolving agen-ts for cis-3~amino-4-[2-(2-furyl)eth-1-yl]-1-methoxy-carbonylmethyl-azetidin-2 one.
In each of the resolution attempts, four solvents were evaluated: tetrahydrofuran, ethyl acetate, acetonitrile, and 1,2-dichloroethane. As noted X-76~6 - 6 -above, only malic acid was shown to be an effective resolving agent, and further, only in tetrahydrofuran.
However, one skilled in the art will recognize that the possibility exists that the diaskereomer formed by admixture of S(-)-malic acid and (I) (or R(+)-malic and II) may also selectively crystallize from other solvents of like polarity and solvent effects. In this regard, it must be emphasized that the choice of solvent systems in the above is by no means exhaustive and others may be considered to be equivalent in their utility.
One skilled in the art will appreciate that the selective crystallization of one diastereomer from a polar organic solution is also affected by concentra-tion. A relatively low concentration provides pure diastereomer of generally higher purity but lower yield, while the utilization of a higher concentration of racemate and resolving agent will normally provide higher yields of solid, many times at the expense of optical purity. Thus, the preferred concentration range for the present invention in tetrahydrofuran is about 0.25 M to about 0.75 M, preferably about 0.5 M.
The invention is further described by the following examples but is not to be construed as limiting any aspect of the invention.
Example 1 A 0.5 g portion of the oxalate salt of cis ~ , 3-amino-4-[2-(furyl)ethyl]-1-methoxycarbonyl-azetidin-2-one was slurried in 10 ml of water, neutral-ized to pH = 7.5 with saturated Na~CO3 solution and extracted with CH2Cl2. The CH2C12 solution was dried 3~3f~
over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the racemic free-amine.
A 0.232 g sample of the resulting racemic free amine was then dissolved in tetrahydrofuran (2 ml) and heated to about 50C. A 0.134 g portion of S(-)-malic acid was then added and the resulting solu-tion was allowed to stand overnight.
The containing vessel was wrapped in insulation, thereby allowing the solution to gradually cool to room temperature. The resulting crystalline solid was then filtered and washed with l ml te-trahydrofuran to provide 40 mg (22% yield) of the S( )-malic acid salt of cis ~ 3-amino-4-[2-(2-furyl)eth-1-yl]-1-methoxycarbonyl-methyl-azetidin-2-one.
5 mg (14 ~m) of the L-malic salt was dissolved in a mixture of 1 ml H20, 3.5 mg (3 meq) NaHCO3, and 1 ml acetonitrile. 3.2 mg (14 ~m) 3,5-di-nitrobenzoyl chloride was added and the reaction stirred for 16 hr at room temperature. After 5 ml H20 ~as added, the reacti.on was vacuum filtered and washed with ~2 0 (2 x 1 ml portions), cold isopropanol (2 x 1 ml portions) and diethyl ether (2 x 2 ml) to isolate 2.5 mg of the 3,5-dinitrobenzamide (85 area % by gradient reverse phase HPLC).
The amide solution in te-trahydrofuran was injected on both a YMC-AK03S-5300A, 25 cm, 4.6 mm OD
chiral column (YMC Corporation) and a Pirkle covalent D-naph-thylalanine chiral column ~egis~ to show a 99%
ee (enantiomeric excess). Also, the ~-DNB amide made from a chiral ~-lactam made by -the Evans and Sjogren route and the analogous racemic DNB amide was injected ~-7626 - 8 -on both systems to confirm the retention times of both the ~- and the ~-DNB amides.
Example 2 Th~ procedure for isolation of the ~,~ isomer was identical to that of Example 1, substituting R(+)-malic acid as resolving agent to provide the a,~ isomer (27% yield, 99% ee).
Claims (6)
1. A method for resolving cis .alpha..alpha./.beta..beta.-3-amino-4 [2-(2-furyl)eth-1 yl]-l-methoxycarbonylmethyl-azetidin-
2-one into its component enantiomers, which comprises the steps:
(a) contacting a polax organic solution of the cis .alpha..alpha./.beta..beta. racemate with at least about 0.5 mole-equivalents of an optically active malic acid; and (b) separating the insoluble salt formed thereby.
2. A process according to claim 1 wherein the polar organic solvent employed is tetrahydrofuran.
(a) contacting a polax organic solution of the cis .alpha..alpha./.beta..beta. racemate with at least about 0.5 mole-equivalents of an optically active malic acid; and (b) separating the insoluble salt formed thereby.
2. A process according to claim 1 wherein the polar organic solvent employed is tetrahydrofuran.
3. A process according to claim 2 wherein S(-)-malic is used as resolving agent.
4. A process according to claim 2 wherein R(+)- malic acid is employed as resolving agent.
5. The S(-)-malic acid salt of cis .beta..beta.-3-amino-4-[2-(2-furyl)eth-1-yl]-1-methoxycarbonylmethyl-azetidin-2-one .
6. The R(+)-malic acid salt of cis .alpha..alpha.-3-amino-4-[2-(2-furylteth-l yl]-1-methoxycarbonylmethyl-azetidin-2-one.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000611218A CA1280432C (en) | 1988-10-17 | 1989-09-13 | Method of resolving cis 3-amino-4-[2-(2-furyl)eth-1-yl]-1-methoxycarbonylmethyl- azetidin-2-one and malic acid salts thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/258,919 | 1988-10-17 | ||
| CA000611218A CA1280432C (en) | 1988-10-17 | 1989-09-13 | Method of resolving cis 3-amino-4-[2-(2-furyl)eth-1-yl]-1-methoxycarbonylmethyl- azetidin-2-one and malic acid salts thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1280432C true CA1280432C (en) | 1991-02-19 |
Family
ID=4140589
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000611218A Expired - Lifetime CA1280432C (en) | 1988-10-17 | 1989-09-13 | Method of resolving cis 3-amino-4-[2-(2-furyl)eth-1-yl]-1-methoxycarbonylmethyl- azetidin-2-one and malic acid salts thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1280432C (en) |
-
1989
- 1989-09-13 CA CA000611218A patent/CA1280432C/en not_active Expired - Lifetime
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