Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method of chiral aminoheterocyclic compound and derivative thereof

A technology for aminoheterocycles and compounds, applied in the field of preparation of chiral aminoheterocycles and their derivatives, capable of solving the limitations of large-scale industrial production of 3-aminopyrrolidine and its derivatives, the starting material R-3 - tert-butoxycarbonylpyrrolidine is expensive, restricts mass production and application, and achieves short reaction time, simple and easy method, and mild conditions

Active Publication Date: 2017-05-17
ASYMCHEM LAB TIANJIN +4
View PDF8 Cites 10 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the method has short reaction steps, the starting material R-3-tert-butoxycarbonylpyrrolidine is also very expensive, which limits its mass production application
[0008] Patent CN200710037261 uses relatively cheap starting material 3-(N-ethoxycarbonylmethyleneamino) ethyl propionate, although R-(-)-1 benzyloxycarbonyl-3-aminopyrrolidine and its salts are also realized The preparation of acid salt, and the ee value of the product reaches 99%, but this method involves chiral resolution, and the theoretical maximum yield of the target product is only 50%, which wastes a lot of product, and the synthesis process needs condensation, cyclization, Decarboxylation, oximation, reduction, resolution and other multi-step reactions, the process is relatively cumbersome
[0009] Patents WO2004013097, WO2007112368 and WO2008102720 also respectively reported the chemical synthesis methods of 3-aminopyrrolidine and its derivatives. The reaction process involves the toxic reagent hydroxylamine hydrochloride ring closure, the strong reducing reagent lithium aluminum hydride reduction, kinetic resolution and other processes. Greatly limit the large-scale industrial production of 3-aminopyrrolidine and its derivatives
[0010] In the synthesis of chiral amine compounds, the use of enzyme asymmetric synthesis is the most economical and effective method, and its theoretical maximum yield is 100%. The method of pyrrolidine and its derivatives has not been reported yet

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of chiral aminoheterocyclic compound and derivative thereof
  • Preparation method of chiral aminoheterocyclic compound and derivative thereof
  • Preparation method of chiral aminoheterocyclic compound and derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1: Transaminases from different sources catalyze the transamination of N-Cbz-3-pyrrolidone to generate chiral benzyloxycarbonyl-3-aminopyrrolidine

[0068] Add 0.2g substrate N-Cbz-3-pyrrolidone to a 50ml reaction bottle, add 2mgPLP and 10wt crude enzyme solution of corresponding transaminase (see Table 1) in Table 1, 900mg glucose, 290mgD / L-alanine, 20mg coenzyme Glucose dehydrogenase, 20mg coenzyme formate dehydrogenase, system pH=8.0, reaction temperature 30°C, react with 200rpm for 40h; use 10N NaOH to adjust pH=10 to terminate the reaction, extract with 10ml dichloromethane, centrifuge at 12000rpm for 5min, The reaction conversion rate and product chirality were detected by organic phase HPLC. The experimental results are shown in Table 1.

[0069] Table 1 Source and catalytic result of transaminase

[0070]

[0071]

[0072]

[0073] "-" means not detected.

[0074] According to the results in Table 1, it can be known that transaminase 1 (deriv...

Embodiment 2

[0075] Example 2: Cloning and expression of transaminase recombinant strains

[0076] The transaminase 1 gene containing compatible restriction enzyme sites was double-digested with NdeI and XhoI, and the expression vector pET-22b (+) was double-digested at the same time (purchased from Novagen, product number 69744 ), the digested target gene and the larger fragment of the plasmid were ligated with T4 ligase, and the ligated product was transformed into competent cells of the DH5α strain to construct a cloned strain. Inoculate the monoclonal colonies of the cloned strains in LB liquid medium containing 50 μg / ml ampicillin, culture overnight at 37°C with shaking, collect the bacteria for plasmid extraction, PCR identification and double enzyme digestion identification, and transform the correctly identified recombinant vector Into BL21 (DE3) competent cells to construct expression strain 1. The PCR identification map is attached figure 1 .

[0077] Take the transaminase 2 g...

Embodiment 3

[0080] Example 3: Biocatalytic transamination of N-Cbz-3-pyrrolidone to generate (R)-1-benzyloxycarbonyl-3-aminopyrrolidine

[0081] Add 1g of substrate N-Cbz-3-pyrrolidone to a 250ml reaction bottle, add 45ml of phosphate buffer (100mM, pH=8.0), add 10mg of PLP, 4.5g of glucose, 1.45g of D-alanine, 0.1g of coenzyme glucose Hydrogenase, 0.1g coenzyme formate dehydrogenase and 1wt transaminase crude enzyme solution derived from Aspergillus fumigatus (prepared in Example 2), the system pH=8.0, the reaction temperature is 40°C, react with 200rpm for 16h; use 50ml dichloro Methane stopped the reaction, filtered with 50g diatomaceous earth, extracted twice with 50ml dichloromethane, static liquid separation, the organic phase was dried, filtered, and concentrated to obtain the crude product (R)-1-benzyloxycarbonyl-3-aminopyrrolidine: The proportion of system (R)-1-benzyloxycarbonyl-3-aminopyrrolidine is 97-99%, the ee value is greater than 99%, and the yield is 80%-86%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to a preparation method of a chiral aminoheterocyclic compound and a derivative thereof. The preparation method comprises the following step: under the action of an aminotransferase catalyst, a ketone compound, which is as shown in the formula I, reacts with an amino donor to obtain chiral amine as shown in the formula II. The method is simple and feasible. By generating a chiral amino compound from a corresponding ketone compound through one step, the reaction step is greatly shortened, yield reaches 70-90%, optical purity of the product is high, and ee value is stabilized at 96% and above, and the technological condition is stable. In comparison with a traditional chemical method, the method has the following advantages: reaction condition is mild; use of a strong oxidant, a strong reducer and dangerous reagents is avoided; reaction time is short; preparation cost is low; condition is mild; and the process causes little pollution to the environment. The reaction route is as shown in the specification.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a preparation method of chiral amino heterocyclic compounds and derivatives thereof. Background technique [0002] 3-Aminopyrrolidine derivatives and their optical isomers are key intermediates for the synthesis of a large number of chiral drugs. There are many routes for the chemical synthesis of 3-aminopyrrolidine derivatives reported at home and abroad, including patents US4851418 and J.M.C1992 , 35, 1764 reported a five-step synthetic route to (S)-1-benzyl-3-pyrrolidinol as a starting material: [0003] [0004] The ee value of the product obtained by this method is 92%. Since the optical purity of the product obtained by this method is not very high, and the starting materials are relatively expensive, there is no large-scale application in China at present. At the same time, harmful reagents are used in the synthesis process Sodium azide has high requirements...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C12P17/10
CPCC12P17/10
Inventor 洪浩詹姆斯·盖吉卢江平刘芳张娜刘治王祖建
Owner ASYMCHEM LAB TIANJIN
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com