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Method for synthesizing paroxetine chiral intermediate

A chiral intermediate and chiral technology, applied in the direction of organic chemistry, can solve the problems of high price of chiral inducing reagents, no application value, high price of chiral alcohol, etc., and achieve high practical value and social and economic benefits, reaction The effect of mild conditions and high reaction yield

Active Publication Date: 2015-09-09
ZHEJIANG HAISEN PHARMACY CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

As reported in patent document WO199907680, the addition reaction of dihydropyridine derivatives synthesized by chiral alcohols and fluorophenylmagnesium bromide to obtain the intermediate of paroxetine, the chiral alcohols used in this method are expensive, difficult to recycle, organic The reaction of magnesium reagent is too active and requires anhydrous and low temperature reaction conditions, so the reaction yield is not high and the selectivity is not good
Such as literature (S.Yamada, I.Jahan.A New Route to 3,4-Disstituted Piperidines:Formal Synthesis of(-)-Paroxetine and(+)-Femoxetine, Tetrahedron Lett.2005,46,8673~8676) with benzene The addition reaction of the base lithium compound and the chiral pyridine oxazolidinone compound is used to obtain the paroxetine intermediate. The same method uses an organolithium reagent, which requires a low temperature system of -78 degrees. The chiral induction reagent is expensive and difficult to recycle. These make it industrially unworthy due to
Also have bibliographical report to synthesize the intermediate of paroxetine with other induction reagents or the method for chiral catalysis in addition, these methods do not have practical application value because synthetic steps are too complicated, literature (Review: C.De Risi, G.Fanton , G.P.Pollini, C.Trapella, F.Valente, V.Zanirato, Tetrahedron Asymmetry 2008,19, 131–155) review these methods

Method used

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  • Method for synthesizing paroxetine chiral intermediate
  • Method for synthesizing paroxetine chiral intermediate
  • Method for synthesizing paroxetine chiral intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Example 1: Synthesis of (3S,4R)-1-methyl-4-p-fluorophenyl-2,6-piperidinedione-3-formic acid ethyl ester

[0036] Reaction steps: add 12mmol N-methylmalonate monoester, 10mL DMSO to the reactor, cool the reactor to -5°C, add 14mmol NaH, stir for 10min, then add chiral fluorocinnamic acid and ( 3R,4S)-Parol formed ester 10mmol. Naturally raised to room temperature until the end of the reaction.

[0037] Post-processing step: add 5% dilute hydrochloric acid aqueous solution to the reactor until the reaction system becomes acidic (pH value is about 2-3), the reaction mixture is extracted twice with ethyl acetate, the combined ethyl acetate is dried and recovered, The crude product was recrystallized from isopropanol to obtain 9 mmol of the desired product with a yield of 85%. The chemical purity is 98%, and the optical purity is 64%. Add 20% NaOH aqueous solution to the acidic aqueous layer after ethyl acetate extraction to make it alkaline, extract it twice with ethyl a...

Embodiment 2

[0038] Example 2: Synthesis of (3S,4R)-1-methyl-4-p-fluorophenyl-2,6-piperidinedione-3-formic acid ethyl ester

[0039] Reaction steps: Add 12mmol N-methylmalonic acid monoester and 10mL DMSO to the reactor, cool the reactor to -10°C, add 14mmol NaH, stir for 10min, then add chiral fluorocinnamic acid and octane 10 mmol of the ester formed by conitine was naturally raised to room temperature until the reaction was completed.

[0040] Post-processing step: add 5% dilute hydrochloric acid aqueous solution to the reactor until the reaction system is acidic (pH refers to about 1-2), the reaction mixture is extracted twice with ethyl acetate, and the combined ethyl acetate is dried and recovered. The crude product was recrystallized from isopropanol to obtain 9.5 mmol of the desired product with a yield of 89%. The chemical purity is 98%, and the optical purity is 77%. Add 20% NaOH aqueous solution to the acidic aqueous layer after ethyl acetate extraction to make it alkaline, extr...

Embodiment 3

[0041] Example 3: Synthesis of (3S,4R)-1-methyl-4-p-fluorophenyl-2,6-piperidinedione-3-formic acid ethyl ester

[0042] Reaction steps: Add 12mmol N-methylmalonic acid monoester and 10mL DMSO to the reactor, cool the reactor to -15°C, add 14mmol NaH, stir for 10min, then add chiral fluorocinnamic acid and quinol 10 mmol of the ester formed by Ning, naturally rose to room temperature until the end of the reaction.

[0043] Post-processing step: add 5% dilute hydrochloric acid aqueous solution to the reactor until the reaction system is acidic (pH refers to about 2-3), the reaction mixture is extracted twice with ethyl acetate, and the combined ethyl acetate is dried and recovered. The crude product was recrystallized from isopropanol to obtain 9.5 mmol of the desired product with a yield of 90%. The chemical purity is 98%, and the optical purity is 83%. Add 20% NaOH aqueous solution to the acidic water layer after ethyl acetate extraction to make it alkaline, extract it twice...

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Abstract

The invention discloses a method for synthesizing a paroxetine chiral intermediate, which comprises the following steps: reacting N-methyl malonic ester and a chiral fluorine cinnamate derivative under alkaline condition, after reaction is finished, post-treatment is carried out to obtain the paroxetine chiral intermediate. The method has the advantage that a chiral aminoalcohol compound is taken for synthesizing fluorine cinnamate as a chiral substrate, then an additive cyclization reaction is carried out with N-methyl malonic ester to obtain the chiral dioxopiperidine, the chiral aminoalcohol is simultaneously recovered, an useless enantiomer can be fully used during a paroxetine production process, environment pressure is reduced, reaction yield is high, operation is simple, raw material is easily available, reaction condition is mild, and post-treatment is simple. The reaction condition of the present invention can be used for massive preparation, the method is suitable for industrial production, and has high utility value and social economic benefit.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing a chiral drug paroxetine intermediate induced by a chiral inducing reagent. Background technique [0002] (3S,4R)-1-methyl-4-p-fluorophenyl-2,6-piperidinedione-3-ethyl carboxylate is an intermediate of the best-selling antidepressant chiral drug paroxetine on the market, and its The structure is as follows: [0003] [0004] Chiral paroxetine is currently mainly obtained by splitting its racemic intermediate (racemate 1). Currently, the most concise method for synthesizing racemate 1 is cinnamate and N-methylmalonic acid The process of monoester condensation and cyclization is shown in the following formula: cinnamate 2 and N-methylmalonate monoester 3 are condensed to obtain racemate 1, and racemate 1 is reduced and resolved to obtain compound 4 , and finally get chiral paroxetine. [0005] [0006] No matter what resolution method is ad...

Claims

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Application Information

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IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 艾林马向阳胡康康李新生林梦迪
Owner ZHEJIANG HAISEN PHARMACY CO LTD
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