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A method for producing ticagrelor chiral pharmaceutical intermediates using Candida antarctica lipase b

A technology of Candida Antarctica and ticagrelor, applied in the field of enzyme engineering, can solve the problems of large amount of CALB enzyme and low purity of acetylated products, etc.

Active Publication Date: 2017-02-22
BEIJING UNIV OF CHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Mark J. Mulvihill (Enzymatic Resolution of Aminocyclopentenols as Precursors to D-and L-Carbocyclic Nucleosides, J.Org.Chem, 1998) reported the use of Candida antarctica lipase B to catalyze racemic cbz or Boc group-protected 4- Amino-2-cyclopenten-1-ol, the acylation reaction to produce the corresponding acetylated product with the configuration (1S, 4R), the purity of the (1S, 4R) acetylated product obtained is low, and the ee value is only 90 %, and consume more CALB enzyme
In addition, there is no other report on the production of (1S,4R) 4-amino-2-cyclopenten-1-ol by biocatalysis

Method used

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  • A method for producing ticagrelor chiral pharmaceutical intermediates using Candida antarctica lipase b
  • A method for producing ticagrelor chiral pharmaceutical intermediates using Candida antarctica lipase b
  • A method for producing ticagrelor chiral pharmaceutical intermediates using Candida antarctica lipase b

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] This example is the synthesis of the racemic ticagrelor drug intermediate with Cbz protecting group by organic chemistry; and the application of CALB in the resolution of the racemic drug intermediate with Cbz protecting group.

[0037] The CALB can be obtained by the following method, and its amino acid sequence is (GenBank accession No.Z30645.1);

[0038] A. Gene cloning and expression; references: Sun Jinpeng et al. (Study on the expression and enzymatic properties of Candida antarctica lipase B in Pichia pastoris, 2011).

[0039] B. The commercialized Candida antarctica lipase B was purchased from the market.

[0040] The method for synthesizing several classes of racemic ticagrelor pharmaceutical intermediates by the organic chemical method is as follows:

[0041] A. Synthesis steps of N-Benoxycarbonyl Hydroxylamine: Dissolve hydroxylamine hydrochloride (1.5mmol) and anhydrous potassium carbonate (0.75mmol) in a mixed solvent of ether: water 1:1, stir for about 1h...

Embodiment 2

[0057] The present embodiment is a preferred scheme based on the method in Example 1, and the improvements are as follows:

[0058] In the application of the CALB in racemic ticagrelor pharmaceutical intermediates:

[0059] Take CALB, add 1ml pH5 universal buffer, the enzyme concentration is preferably 0.08mg / ml, cancel the racemic ticagrelor intermediate and suspend evenly in the reaction solution, the substrate concentration is preferably 20g / L, wherein:

[0060] (1) The reaction temperature of cis-1-propionyloxy-N-benzyloxycarbonyl-4 amino-2-cyclopentene is preferably 60°C, and the reaction time is 8h. content, the obtained substrate resolution ee value is above 95%, the product (1S,4R) N-benzyloxycarbonyl-4-amino-2-cyclopenten-1-ol ee value can reach 99%, and the conversion rate is 45% %above.

[0061] figure 1 It is the HPLC chiral spectrum of racemic cis-1-propionyloxy-N-benzyloxycarbonyl-4 amino-2-cyclopentene, as a blank chiral HPLC spectrum; figure 1 Among them, p...

Embodiment 3

[0070] This example is the synthesis of cis-1-acetoxy-N-tert-butoxycarbonyl-4-amino-2-cyclopentene with a Boc protecting group by organic synthesis; and the use of CALB to replace the racemate Resolution studies performed on intermediate compounds of cagrel.

[0071] Described cis-1-acetoxy group-N-tert-butoxycarbonyl-4-amino-2-cyclopentene synthesis method is similar to the method described in Example 1, and the chloroformic acid in the A step in Example 1 is The ester was replaced by di-tert-butyl dicarbonate (Boc 2 O), and the rest of the steps are the same.

[0072] The application of the CALB in cis-1-acetoxy-N-tert-butoxycarbonyl-4-amino-2-cyclopentene is as follows:

[0073] Take CALB, add 1ml pH5 universal buffer, the enzyme concentration is about 0.08mg / ml, cancel the racemic ticagrelor intermediate and suspend evenly in the reaction solution, make the substrate concentration 20g / L, react at 60°C 4h, obtain reaction solution;

[0074] The reaction solution was ext...

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Abstract

The invention discloses a method for using Candida antarctica lipase B to produce a ticagrelor chiral medicine intermediate, and belongs to the technical filed of enzyme engineering. The Candida antarctica lipase B (called CALB for short) is used for converting racemic ticagrelor with the structural formula represented by formula (a) to a single configuration intermediate of a formula (b). In the formula (a) and (b), R is CnH2n+1CO or CnH2n-1CO (n is 2-6), and R' is Cbz or Boc. The configuration of the product (b) obtained through splitting the racemic medicine intermediate by the CALB is (1S,4R). The method using the CALB to split the above substrate has a high catalysis efficiency, and the purity of the product of the formula (b) obtained in the invention is high.

Description

technical field [0001] The invention belongs to the technical field of enzyme engineering, and specifically relates to a method of splitting a racemic ticagrelor intermediate having the structural formula (a) by using CALB, wherein R=C n h 2n+1 CO or C n h 2n-1 CO (n=2~6), R'=Cbz or Boc, the method of obtaining the intermediate (b) with a single configuration after transformation. [0002] R=C n h 2n+1 CO or C n h 2n-1 CO (n=2~6), R'=Cbz or Boc [0003] R'=Cbz or Boc Background technique [0004] (1S,4R) 4-amino-2-cyclopenten-1-ol can be used as a key chiral intermediate of ticagrelor. [0005] Mark J. Mulvihill (Enzymatic Resolution of Aminocyclopentenols as Precursors to D-and L-Carbocyclic Nucleosides, J.Org.Chem, 1998) reported the use of Candida antarctica lipase B to catalyze racemic cbz or Boc group-protected 4- Amino-2-cyclopenten-1-ol, the acylation reaction to produce the corresponding acetylated product with the configuration (1S, 4R), the purity of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P41/00C12P13/00C12R1/72
Inventor 郑国钧陈清
Owner BEIJING UNIV OF CHEM TECH
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