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Pirlimycin intermediate and preparation method thereof

A technology of pyrithycin and intermediates, applied in the field of drug synthesis, can solve the problems of large amount of catalyst, increased production cost of pyrithycin, low yield of pyrithycin, etc., and achieve the effect of simple preparation process

Inactive Publication Date: 2011-06-01
BEIJING UNIV OF CHEM TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But in above-mentioned method 1) adopt expensive PtO during catalytic hydrogenation reduction 2 As a catalyzer, and the consumption of catalyzer is big, and consumption is 2 times of the quality of raw material to be reduced; 2) in the final product, contain the non-antibacterial isomer of equal proportion with pilinomycin, as shown in formula (4), resulting in lower yields of pirinomycin
In order to obtain high-purity pilinomycin, it is necessary to separate pilinomycin and isomers, which will inevitably increase the production cost of pilinomycin

Method used

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  • Pirlimycin intermediate and preparation method thereof
  • Pirlimycin intermediate and preparation method thereof
  • Pirlimycin intermediate and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0031] 1) Preparation of (2S)-N-tert-butoxycarbonyl-4-ethylene-pipericolic acid:

[0032] Under the condition of nitrogen protection, mix 1.09g of sodium hydride and 10ml of anhydrous dimethyl sulfoxide, cool to 0°C in an ice bath, and then dropwise add 15.96g of ethyltriphenylphosphine bromide and 43ml of anhydrous dimethyl After stirring at room temperature for 60 min, a mixed solution of 2.61 g (2S)-N-tert-butoxycarbonyl-4-oxopiperidine and 8 ml of anhydrous dimethyl sulfoxide was added dropwise. Raise the temperature to 60°C for reaction, and detect by thin-layer chromatography until the reaction of (2S)-N-tert-butoxycarbonyl-4-oxopipercolic acid is complete, then quench the reaction with 5% aqueous potassium bicarbonate solution; then wash the reaction solution with toluene , the aqueous phase was adjusted to pH 2 with 1N hydrochloric acid at 0°C, extracted with ether, and the ether extract was washed with saturated sodium bisulfate solution and aqueous solution successiv...

Embodiment 2

[0038] 1) Preparation of (2S)-N-tert-butoxycarbonyl-4-ethylene-pipericolic acid:

[0039] Under the condition of nitrogen protection, mix 3.07g of sodium amide and 5ml of anhydrous N,N-dimethylformamide, cool to 0°C in an ice bath, and then dropwise add 19.48g of ethyltriphenylphosphine bromide and 20ml of The mixed solution of anhydrous N,N-dimethylformamide was stirred at room temperature for 45min, and then 2.61g (2S)-N-tert-butoxycarbonyl-4-oxopipercolic acid and 5ml of anhydrous N,N-dimethylformamide were added dropwise. The mixed solution of methylformamide, after the dropwise addition, the temperature was raised to 80°C for reaction, and the thin-layer chromatography was detected until the reaction of (2S)-N-tert-butoxycarbonyl-4-oxopipericolic acid was complete, and then 5% bicarbonate Quench the reaction with potassium aqueous solution; then wash the reaction solution with toluene, adjust the pH value of the aqueous phase to 2.5 with 1N hydrochloric acid at 0°C, then ...

Embodiment 3

[0045] 1) Preparation of (2S)-N-tert-butoxycarbonyl-4-ethylene-pipericolic acid:

[0046] Under nitrogen protection conditions, after mixing 1.26g sodium hydride and 15ml anhydrous tetrahydrofuran, cool to 0°C in an ice bath, and then dropwise add a mixed solution of 9.74g ethyltriphenylphosphine bromide and 60ml anhydrous tetrahydrofuran, at room temperature After stirring for 45min, add dropwise a mixed solution of 2.61g (2S)-N-tert-butoxycarbonyl-4-carbonyl pipecolic acid and 35ml of anhydrous tetrahydrofuran. After the dropwise addition, the temperature is raised to 40°C for reaction, and thin-layer chromatography detects until ( 2S) After the reaction of -N-tert-butoxycarbonyl-4-carbonyl pipecolic acid is complete, quench the reaction with 5% potassium bicarbonate aqueous solution; then wash the reaction solution with toluene, and adjust the aqueous phase with 1N hydrochloric acid at 0°C After the pH value reached 3, it was extracted with diethyl ether, and then the dieth...

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Abstract

A pirlimycin intermediate and a preparation method thereof belong to the field of drug synthesis. The chemical name of the pirlimycin intermediate provided by the invention is (2S)-4-ethyl-piperidinecarboxylic acid, the chemical structure is shown as formula (1). The invention obtains (2S)-N-tertbutyloxycarbonyl-4-ethylene-piperidinecarboxylic acid by leading to reaction between (2S)-4-ethyl-piperidinecarboxylic acid and Ethyltriphenylphosphonium bromide in the presence of alkali, and then obtains (2S)- tertbutyloxycarbonyl-4-ethyl-piperidinecarboxylic acid through hydrogenization in the presence of catalyst. The (2S)-N-tertbutyloxycarbonyl-4-ethyl-piperidinecarboxylic acid is stripped of amino protecting group under the action of hydrochloric acid to prepare (2S)-4-ethyl-piperidinecarboxylic acid hydrochloride. The pirlimycin intermediate has simple preparation process, no side product in the preparation process and no pollution to environment and avoids using expensive PtO2 catalysthydrogenated pyridine heterocycle when being used for preparing pirlimycin.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a pilinomycin intermediate and a synthesis method thereof. Background technique [0002] Pirlimycin (Pirlimycin) is a veterinary lincomycin antibacterial drug, and the chemical name of Pirlimycin is 6-(4-ethyl-cis-2(S)piperidine carboxamido)-1 -Thio-7(S)-chloro-6,7,8-trideoxy-L-threo-D-galactopyranoside hydrochloride, the chemical structure is as shown in formula (2): [0003] [0004] In the prior art, mainly adopt US4278789A and J.Med.Chem., 1984,27 (2), the method provided in the documents such as 216-223 synthetic pyrilimycin: pyridine ring intermediate (A) and 7- Cl-MTL condensation gives the intermediate 6-(4-ethyl-2-pyridinecarboxamido)-1-thio-7(S)-chloro-6,7,8-trideoxy-L-threo-D- Galactopyranoside (B), then 6-(4-ethyl-2-pyridinecarboxamido)-1-thio-7(S)-chloro-6,7,8-trideoxy-L- Threo-D-galactopyranoside (B) is subjected to catalytic hydrogenation reduction t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/60
CPCY02P20/55
Inventor 郑国钧宋海勇朱建民张建峰
Owner BEIJING UNIV OF CHEM TECH