A kind of resolution method of 3-amino-1,2,3,4-tetrahydrocarbazole

Abstract

The invention relates to a resolution method for 3-amino-1, 2, 3, 4-tetrahydrocarbazole. The method adopts L-tartaric acid or D-tartaric acid as the resolving agent, and takes the mixed solvent of an alcohol solvent and water as the resolving solvent. By regulating the volume ratio of the alcohol solvent and water in the resolving solvent, the 3-amino-1, 2, 3, 4-tetrahydrocarbazole is resolved to obtain R-3-amino-1, 2, 3, 4-tetrahydrocarbazole and S-3-amino-1, 2, 3, 4-tetrahydrocarbazole respectively. The method adopts the cheap L-tartaric acid as the resolving agent to reduce the production cost. Meanwhile, different alcohol-water ratios of one resolving agent realize the unexpected effect of resolution of two enantiomers, the complicated process of needing two chiral resolving agents to obtain two enantiomers in production can be further omitted, and raw materials are saved at the same time. Through further crystallization purification, the resolved salts then react with lye to remove the tartaric acid radical, and the e.e.% of the respectively obtained single enantiomer R-3-amino-1, 2, 3, 4-tetrahydrocarbazole and S-3-amino-1, 2, 3, 4-tetrahydrocarbazole are both greater than 99%.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and particularly relates to a method for splitting 3-amino-1,2,3,4-tetrahydrocarbazole, a key intermediate of ramatroban, a drug for treating allergic rhinitis. Background technique [0002] Ramatroban (ramatroban) was developed by the Bayer company of Germany and first launched in Japan in May 2001. It is a highly efficient and selective TxA2 / PGH2 receptor antagonist, which can specifically bind to the TxA2 receptors of smooth muscle and platelets. Treatment of allergic rhinitis. [0003] 3-amino-1,2,3,4-tetrahydrocarbazole is the racemate of the key intermediate of ramatroban, and its structural formula is: [0004] [0005] (R)-3-amino-1,2,3,4-tetrahydrocarbazole (formula II) and (S)-3-amino-1,2,3,4-tetrahydrocarbazole (formula III) are Its pair of enantiomers, wherein (R)-3-amino-1,2,3,4-tetrahydrocarbazole is the key intermediate for the synthesis of ramatroban bulk drug, t...

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Problems solved by technology

[0008] The literature "Cutting short the asymmetric synthesis of the ramatrobanprecursor by employing ω-transaminases" (Advanced Synthesis and Catalysis, 2014, vol.356, #9, p1937-1942) reported that 1,2,4,9-tetrahydrocarbazole -3-ketone and (R)-1-phenyl-ethyl-amine are first condensed into an imine, reduced, and then hydrogenated to remove the benzyl group to obtain (3R)-3-amino-1,2,3,4 -Tetrahydrocarbazole, but after this method reacts to generate imine, it needs to go through two steps of imine reduction and debenzylation to obtain the product, in which an expensive reducing agent is used, and hydrogen pressure is required during debenzylation , which brings difficulties to industrialization, and the chiral amine obtained according to this induction reaction will not have a high chiral purity, and is not suitable for use as an intermediate in drug synthesis, and needs to be further refined and purified in the form of resolution

[0009] U.S. Patent No. 4,988,820 reported using (+)-mandelic acid as a resolving agent to resolve racemic 3-amino-1,2,3,4-tetrahydrocarbazole to obtain (R)-3-amino- 1,2,3,4-tetrahydrocarbazole, but the resolving agent involved in this method can only obtain a kind of enantiomer by corresponding resolution, and its resolution yield is only 10% on the low side, in addition (+ )-mandelic acid is more expensive, which increases the production cost and is not suitable for industrial production

[0010] PCT patent WO2010 / 078250A and Chinese Patent Publication No. CN102271505A reported the resolution of DBTA, camphorsulfonic acid and 2,2,5,6-di-O-isopropylidene-2-keto-L-gulonic acid Reagent, the racemic 3-amino-1,2,3,4-tetrahydrocarbazole is resolved to obtain formula (3R)-3-amino-1,2,3,4-tetrahydrocarbazole, the The resolving agent involved in the method can only be resolved to obtain one enantiomer, and 2,2,5,6-di-O-isopropylidene-2-keto-L-gulonic acid is expensive , which increases the production cost and is not suitable for industrial production

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