2-(2,3-dicarboxycyclopropyl) glycine and method for producing the same
AssigneeSuntory Limited
InventorsYasufumi Ohfune, Keiko Shimamoto, Haruhiko Shinozaki, Michiko Ishida
Life of this patent
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Abstract
(2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)-glycine (DCG-I) and (2S,1'S,2'S,3'S)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-II), as well as methods for synthesizing these compounds are provided. Studies on L-glutamate receptors with the use of DCG-I and DCG-II, which are agonists for NMDA receptors, contribute to the development of remedies for various nervous disorders. Further, DCG-I and DCG-II selectively inhibit monosynaptic reflex even at a low concentration, which makes them useful as a remedy for spastic palsy, an anesthetic and an analgesic.
Claims5
(2S, 1'R, 2'R, 3'R)-2-(2,3-dicarboxycyclopropyl)-glycine represented by the following formula (1):
- ##STR6##
(2S, 1'S, 2'S, 3'S)-2-(2,3-dicarboxycyclopropyl)-glycine represented by the following formula (2):
- ##STR7##
A method for producing (2S, 1'R, 2'R, 3'R)-2-(2,3-dicarboxycyclopropyl)glycine represented by the following formula (1):
- ##STR8## which comprises:
- (a) removing the t-butyldimethylsilyl group of (1R, 7S, 8R, 9R)-3-aza-9-t-butyldimethylsilyloxymethyl-4,4-dimethyl-5-oxatricyclo-[6.1. 0.0.sup.3,7 ]nonan-2-one represented by the following formula (3):
- ##STR9## wherein TBS represents a t-butyldimethylsilyl group;
- to thereby give an alcohol represented by the following formula (4):
- ##STR10## (b) next, hydrolyzing said alcohol with an alkali and then t-butoxycarbonylating to thereby give (2S, 1'R, 2'R, 3'R)-N-t-butoxycarbonyl-2-(2-carboxy-3-hydroxymethylcyclopropyl)glycinol represented by the following formula (5):
- ##STR11## wherein Boc represents a t-butoxycarbonyl group;
- (c) next, converting the compound of the formula (5) into a methyl ester to thereby give (2S, 1'R, 2'R, 3'R)-N-t-butoxycarbonyl-2-(2-methoxycarbonyl-3-hydroxymethylcyclopropyl)gl ycinol represented by the following formula (6):
- ##STR12## (d) next, oxidizing said alcohol to thereby give a carboxylic acid and then converting the obtained carboxylic acid into a methyl ester to thereby give (2S,1'R,2'R,3'R)-N-t-butoxycarbonyl-2(2,3-dimethoxycarbonylcyclopropyl)gly cine methyl ester represented by the following formula (7):
- ##STR13## (e) finally, hydrolyzing said ester to thereby give the compound of the formula (1).
A method for producing (2S, 1'S,2'S,3'S)-2-(2,3-dicarboxycyclopropyl)glycine represented by the following formula (2):
- ##STR14## which comprises:
- (a) removing the t-butyldimethylsilyl group of (1S,7S,8S,9S)-3-aza-9-t-butyldimethylsilyloxymethyl-4,4-dimethyl-5-oxatric yclo-[6.1.0.0.sup.3'7 ]nonan-2-one represented by the following formula (8):
- ##STR15## wherein TBS represents a t-butyldimethylsilyl group;
- to thereby give an alcohol represented by the following formula (9):
- ##STR16## (b) next, hydrolyzing said alcohol with an alkali and then t-butoxycarbonylating to thereby give (2S,1'S,2'S, 3'S)-N-t-butoxycarbonyl-2-(2-carboxy-3-hydroxymethylcyclopropyl)glycinol represented by the following formula (10):
- ##STR17## wherein Boc represents a t-butoxycarbonyl group;
- (c) next, converting the compound of the formula (10) into a methyl ester to thereby give (2S,1'S,2'S,3'S)-N-t-butoxycarbonyl-2-(2-methoxycarbonyl-3-hydroxymethylcy clopropyl)glycinol represented by the following formula (11):
- ##STR18## (d) next, oxidizing said alcohol to thereby give a carboxylic acid and then converting the obtained carboxylic acid into a methyl ester to thereby give (2S,1'S,2'S,3'S)-N-t-butoxycarbonyl-2(2,3-dimethoxycarbonylcyclopropyl)gly cine methyl ester represented by the following formula (12):
- ##STR19## (e) finally, hydrolyzing said ester to thereby give the compound of the formula (2).
A method for producing (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine represented by the following formula (1):
- ##STR20## which comprises:
- (a) treating (2S,1'S,2'S,3'R)-N-t-butoxycarbonyl-2-(3-t-butyldimethylsilyloxymethyl-2-m ethoxycarbonylcyclopropyl) glycinol-t-butyldimethylsilyl ether represented by the following formula (13):
- ##STR21## wherein TBS represents a t-butyldimethylsilyl group;
- and
- Boc represents a t-butoxycarbonyl group;
- with dl-camphorsulfonic acid and 2,2-dimethoxypropane to thereby give (1S,5R,6S,4'S)-6-[N-(t-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]-3 -oxabicyclo[3.1.0]hexan-2-one represented by the following formula (14):
- ##STR22## wherein Boc represents a t-butoxycarbonyl group;
- (b) next, hydrolyzing the obtained compound of the formula (14) with an alkali, converting into a methyl ester and then protecting the hydroxyl group with a t-butyldimethylsilyl group again to thereby give (4S,1'S,2'S,3'R)-N-t-butoxycarbonyl-2,2-dimethyl-4-[3-(t-butyldimethylsily l)oxymethyl-2-methoxycarbonyl-cyclopropyl]-1,3-oxazolidine represented by the following formula (15):
- ##STR23## wherein TBS represents a t-butyldimethylsilyl group;
- and
- Boc represents a t-butoxycarbonyl group;
- (c) next, treating the compound of the formula (15) with potassium bistrimethylsilylamide to thereby convert it into (4S,1'S,2'R,3'R)-N-t-butoxycarbonyl-2,2-dimethyl-4-[3-(t-butyldimethylsily l)oxymethyl-2-methoxycarbonylcyclopropyl]-1,3-oxazolidine represented by the following formula (16):
- ##STR24## wherein TBS represents a t-butyldimethylsilyl group;
- and
- Boc represents a t-butoxycarbonyl group;
- (d) next, treating the compound of the formula (16) with trifluoroacetic acid and di-t-butyl dicarbonate to thereby give (2S,1'S,2'R,3'R)-N-t-butoxycarbonyl-2-(3-hydroxymethyl-2-methoxycarbonylcy clopropyl)glycinol represented by the following formula (17):
- ##STR25## wherein TBS represents a t-butyldimethylsilyl group;
- and
- Boc represents a t-butoxycarbonyl group;
- (e) then, converting the compound of the formula (17) into (2S,1'R,2'R,3'R)-N-t-butoxycarbonyl-2-(2,3-dimethoxycarbonyl-cyclopropyl)g lycine methyl ester represented by the following formula (7):
- ##STR26## wherein Boc represents a t-butoxycarbonyl group;
- via Jones' oxidation, methyl-esterification and treatment with lithium hydroxide;
- and
- (f) finally, hydrolyzing the compound of the formula (7) to thereby give the above-mentioned compound represented by the formula (1).
Dependencies are inferred from the claim text.