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Preparation method of moxifloxacin intermediate compound

A compound and donor technology, applied in the field of preparation of moxifloxacin intermediate compounds, can solve the problems of low product ee value, complicated process and high cost

Active Publication Date: 2018-02-13
SHANGHAI PUYI CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] The technical problem to be solved by this invention is to overcome the key chiral intermediate (4aS, 7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine (I) preparation method of moxifloxacin in the prior art The defects of high cost, complex process and low product ee value in the present invention provide a preparation method of moxifloxacin intermediate compound

Method used

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  • Preparation method of moxifloxacin intermediate compound
  • Preparation method of moxifloxacin intermediate compound
  • Preparation method of moxifloxacin intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] 1. Transamination reaction

[0062]

[0063] Add 15.0 g of ethyl 3-(3-bromopropyl)-4-oxopyrrolidine-1-carboxylate (3-1) into 400 mL of distilled water, add 20 mL of DMSO to aid dissolution, and add R- 10.0 g of methylbenzylamine and hydrochloric acid adjust the pH of the reaction solution to about 8.0, then add 30.0 g of ω-transaminase and 0.08 g of pyridoxal phosphate (PLP), wherein the amino acid sequence of ω-transaminase is as shown in the sequence table SEQ ID NO .1 shown; keep the temperature at 25-30°C, pH around 8.0, react for 20 hours, the TLC raw material basically reacts completely, stop the reaction. Use concentrated hydrochloric acid to adjust the pH of the system to 2-3, add diatomaceous earth to filter after stirring, rinse the filter cake with water, extract impurities from the filtrate with dichloromethane, and adjust the pH of the water phase to above 10 with 30% sodium hydroxide aqueous solution , and then extracted with dichloromethane, the combi...

Embodiment 2

[0069] 1. Transamination reaction

[0070]

[0071] Add 10.0g of ethyl 3-(3-chloropropyl)-4-oxopyrrolidine-1-carboxylate (3-2) into 300mL of distilled water, add 15mL of DMSO to aid dissolution, and add 4.0g of Isopropylamine and hydrochloric acid adjust the pH of the reaction solution to about 9.0, then add 20.0 g of ω-transaminase and 0.05 g of pyridoxal phosphate (PLP), wherein the amino acid sequence of ω-transaminase is shown in the sequence table SEQID NO.2; Raise the temperature to 45-50°C, keep the pH at about 9.0, and after 12 hours of heat preservation reaction, the TLC raw material basically reacts completely, and the reaction is stopped. Use concentrated hydrochloric acid to adjust the pH of the system to 2-3, add diatomaceous earth to filter after stirring, rinse the filter cake with water, extract impurities from the filtrate with dichloromethane, and adjust the pH of the water phase to above 10 with 30% sodium hydroxide aqueous solution , and then extracted ...

Embodiment 3

[0076] 1. Transamination reaction

[0077]

[0078] Add 20.0g of 3-(1-benzyl-4-oxypyrrolidin-3-yl)propyl methanesulfonate (1-3) into 600mL of distilled water, add 10.0g of D-alanine and ammonia water while stirring Adjust the pH of the reaction solution to about 10.0, then add 40g of ω-transaminase and 0.10g of pyridoxal phosphate (PLP), wherein the amino acid sequence of ω-transaminase is as shown in the sequence table SEQ ID NO.3; the temperature is raised to 45- 50°C, keep the pH at about 10.0, and after 2 hours of heat preservation reaction, the TLC raw material basically reacted completely, and the reaction was stopped. Use concentrated hydrochloric acid to adjust the pH of the system to 2-3, add diatomaceous earth to filter after stirring, rinse the filter cake with water, extract impurities from the filtrate with dichloromethane, and adjust the pH of the water phase to above 10 with 30% sodium hydroxide aqueous solution , and then extracted with dichloromethane, the...

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Abstract

The invention discloses a preparation method of a moxifloxacin intermediate compound. The preparation method comprises the following step of under the actions of omega-transaminase and / or immobilizingtype thereof and ammonia donor, performing the following ammonia conversion reaction on a compound shown in a formula (III) in a solvent, so as to prepare a compound shown in a formula (II), whereinan amino acid sequence of the omega-transaminase is shown in SEQ ID NO.1, SEQ ID NO.2 or SEQ ID NO.3 in a sequence table; X is chloride, bromine, iodine, methanesulfonate or tosylate; R is C1-4 carbalkoxy, carbobenzoxy or benzyl. The preparation method has the advantage that the cost is low, the fewer steps are required, the operation is simple, the ee value of a product reaches 99% or above, andthe preparation method is more suitable for industrialization production. (The formulas are shown in the attached figures.).

Description

technical field [0001] The invention relates to a preparation method of a moxifloxacin intermediate compound. Background technique [0002] Moxifloxacin is a third-generation quinolone spectrum antibacterial drug. It was launched in 1999 and has been widely used clinically to treat respiratory tract infections such as acquired pneumonia, acute exacerbation of chronic bronchitis, and acute bacterial sinusitis. [0003] [0004] (4aS, 7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine (I) is the key chiral intermediate of moxifloxacin, and its molecular structure has two skeleton structures of piperidine and pyrrolidine and two Chiral centers, the reported preparation methods are mainly divided into the following categories: [0005] Route 1: Piperidine route [0006] [0007] The piperidine route has more reports on synthetic methods, and it is also a process currently used in industrial production. These processes all use 3,4-pyridinedicarboxylic acid as the starting material,...

Claims

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Application Information

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IPC IPC(8): C12P17/16
CPCC12P17/165
Inventor 杨汉荣谢凌拾陶荣盛李涛王博
Owner SHANGHAI PUYI CHEM CO LTD
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