CN106542961B - A kind of synthetic method of racecadotril intermediate - Google Patents

A kind of synthetic method of racecadotril intermediate Download PDF

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Publication number
CN106542961B
CN106542961B CN201610962067.2A CN201610962067A CN106542961B CN 106542961 B CN106542961 B CN 106542961B CN 201610962067 A CN201610962067 A CN 201610962067A CN 106542961 B CN106542961 B CN 106542961B
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racecadotril
synthetic method
added
reaction
benzyl acrylic
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CN106542961A (en
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赵孝杰
张敏
刘远慧
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Shandong Baoyuan Pharmaceutical Co ltd
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SHANDONG BOYUAN PHARMACEUTICAL CO Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42Separation; Purification; Stabilisation; Use of additives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00Preparation of carboxylic acid esters
    • C07C67/30Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Abstract

The invention discloses provide a kind of synthetic method of racecadotril intermediate.After this method is reacted using phenylpropyl alcohol acetoacetic ester, dimethylamine and metaformaldehyde, benzyl acrylic ethyl ester is obtained through HCl treatment, then hydrolyzes to obtain benzyl acrylic under alkaline condition.Synthetic method of the invention shortens synthetic route with the benzenpropanoic acid ethyl substituted benzyl chloride being more toxic, and improves yield, is suitable for industrialized production.

Description

A kind of synthetic method of racecadotril intermediate
Technical field
The present invention relates to a kind of synthetic methods of racecadotril intermediate, belong to technical field of medicine synthesis.
Background technique
Racecadotril is a kind of anti diar rhea medicine of new mechanism of action, directly inhibition enteron aisle excessive secretion, is quickly improved Symptom of diarrhea, treatment infant rotaviral diarrhea is significant in efficacy, and the pain that can be obviously shortened the course of disease, reduce infant is suitable for Adult and the January above baby and children acute diarrhea.Racecadotril earliest by France Bioprojet company research and development at Function, in 1993 first in France with trade name Tiorfan listing, soon, Canadian paediatrics association and U.S.'s disease are pre- for listing Anti- center (abbreviation CDC) is just included in racecadotril the indispensable medication of children's diarrhae treatment, has also been included in Chinese state within 2011 The recommended drug of family's paediatrics diarrhoeal diseases treatment common recognition.At present the pediatrician of a domestic clinical line using racecadotril as The highly effective and safe drug of clinical children's diarrhae treatment.
Benzyl acrylic is an important intermediate used in racecadotril synthesis process.Existing main conjunction At route are as follows: benzyl chloride and diethyl malonate reaction generate diethyl benzyl malonate, then hydrolyze under the action of acid or alkali Generate benzyl malonic acid, then with formaldehyde or paraformaldehyde and diethylamine reaction generate benzyl acrylic (Wang Guiwen, Gu Zhiping, The synthesising process research Chinese Pharmaceutical Association Annual Conference .2004 of Lee's wind pretty young woman's racecadotril).
Said synthesis route is longer, and uses with very big toxicity and irritating raw material benzyl chloride, easily makes to production environment At very big pollution, huge pressure is brought to environmental protection, production cost is higher, is unfavorable for industrialized production.
Summary of the invention
The present invention overcomes above-mentioned the deficiencies in the prior art, a kind of racecadotril intermediate benzyl acrylic is provided Synthetic method.After this method carries out Mannich reaction using phenylpropyl alcohol acetoacetic ester, dimethylamine and metaformaldehyde, obtained through HCl treatment Then benzyl acrylic ethyl ester hydrolyzes to obtain benzyl acrylic under alkaline condition.Synthetic method of the invention is with phenylpropyl alcohol acetoacetic ester Instead of the benzyl chloride being more toxic, and synthetic route is shortened, improve yield, is suitable for industrialized production.
The technical solution of the present invention is as follows: a kind of synthetic method of racecadotril intermediate benzyl acrylic, including it is following Step:
(1) phenylpropyl alcohol acetoacetic ester (chemical compounds I), metaformaldehyde (compound ii) and dimethylamine (compound III) are reacted Afterwards, then through HCl treatment benzyl acrylic ethyl ester (compound III) is obtained;
(2) benzyl acrylic ethyl ester (compound III) hydrolyzes obtain benzyl acrylic (compound VI) under alkaline condition.
Chemical equation is as follows:
Said synthesis route specifically includes the following steps:
(1) phenylpropyl alcohol acetoacetic ester and solvent ethyl acetate are added in reaction vessel, it is water-soluble to be cooled to 0-10 DEG C of dropwise addition dimethylamine Liquid;It is added dropwise, the reaction was continued 0.5~1.5 hour for 10-15 DEG C of temperature control;Then metaformaldehyde, temperature rising reflux reaction 2 are added ~5 hours;It is down to room temperature after the reaction was completed, hydrochloric acid is added and water is stirred to react rear stratification, organic layer depressurizes after washing It is concentrated to dryness to obtain benzyl acrylic ethyl ester;
(2) methylene chloride, sodium hydroxide solution and ethyl alcohol or methanol, control are then added into benzyl acrylic ethyl ester Warm 10-20 DEG C is reacted 2~5 hours;Hydrochloric acid tune pH=1 is added into organic layer for stratification after completion of the reaction;It stands and divides again Layer, organic layer washed, dry after be concentrated to dryness to obtain benzyl acrylic crude product;Product is obtained after recrystallizing again.
Preferably, the concentration of step (1) dimethylamine agueous solution is 30~50%, more preferable 40%.
Preferably, step (1) the phenylpropyl alcohol acetoacetic ester, dimethylamine, metaformaldehyde molar ratio be 1:1.1~1.5:0.35 ~0.45.
Preferably, the molar ratio of step (1) the phenylpropyl alcohol acetoacetic ester and hydrochloric acid is 1:1.0~1.5.
Preferably, step (2) concentration of sodium hydroxide solution is 15~30%, more preferable 20%.The benzenpropanoic acid second The molar ratio of ester and sodium hydroxide is 1:1.0~1.5.
Preferably, step (2) recrystallization is using dehydrated alcohol as solvent.The process specifically recrystallized is as follows: benzyl Dehydrated alcohol, temperature rising reflux are added in base acrylic acid crude product, until being cooled to -5 DEG C of crystallizations under stirring after whole dissolved clarifications, filters, Filter cake decompression drying at 40-50 DEG C obtains product.
Preferably, the amount ratio of methylene chloride and ethyl alcohol is 8~12:1 in the step (2).
The beneficial effects of the present invention are: synthetic method of the invention is with the benzenpropanoic acid ethyl substituted benzyl chloride being more toxic, And synthetic route is shortened, product yield height (>=90.0%), (>=99.5%) with high purity is easy to industrialized production.
Specific embodiment
Technical solution of the present invention is further illustrated with reference to embodiments, but the present invention is not limited thereto.
Embodiment 1:
(1) 70g phenylpropyl alcohol acetoacetic ester and 400ml ethyl acetate are added into 1000ml reaction flask, stirs evenly, cools down, control The dimethylamine of 0-10 DEG C of temperature dropwise addition 54.7g concentration 40%, is added dropwise in reaction flask processed, and 10-15 DEG C of temperature control is reacted 1 hour, Then 14.2g metaformaldehyde, back flow reaction 3 hours after heating are added;It is down to room temperature after the reaction was completed, concentrated hydrochloric acid (concentration is added 35%, similarly hereinafter) 56g, purified water 60ml, it stirs 40 minutes, stratification, organic layer washed once with 200ml purified water, decompression Concentration of organic layers is to dry;
(2) then be added 500ml methylene chloride, 20% sodium hydroxide solution 80g and 50g dehydrated alcohol, 10-20 DEG C of temperature control Reaction 4 hours;After standing, water layer is separated, 40g concentrated hydrochloric acid tune pH=1 is added into organic layer;Water layer is separated again, uses 300ml Water washing organic layer is purified, is concentrated to dryness after the drying of 25g anhydrous sodium sulfate is added into organic layer;Then be added 130g without Water-ethanol, temperature rising reflux filter, filter cake decompression drying at 40-50 DEG C until being cooled to -5 DEG C of crystallizations under stirring after whole dissolved clarifications Obtain white crystalline solid 58.8g, purity 99.8%, yield 92.3%.
Embodiment 2:
(1) 70g phenylpropyl alcohol acetoacetic ester and 400ml ethyl acetate are added into 1000ml reaction flask, stirs evenly, cools down, control The dimethylamine of 0-10 DEG C of temperature dropwise addition 55.0g concentration 40%, is added dropwise in reaction flask processed, and 10-15 DEG C of temperature control is reacted 50 minutes, Then 14.5g metaformaldehyde, back flow reaction 2.5 hours after heating are added;It is down to room temperature after the reaction was completed, it is (dense that concentrated hydrochloric acid is added 35%) 58g, purified water 65ml are spent, is stirred 40 minutes, stratification, organic layer washed once with 200ml purified water, depressurize dense Contracting organic layer is to dry;
(2) then be added 500ml methylene chloride, 20% sodium hydroxide solution 85g and 50g dehydrated alcohol, 10-20 DEG C of temperature control Reaction 3.5 hours;After standing, water layer is separated, 45g concentrated hydrochloric acid tune pH=1 is added into organic layer;Water layer is separated again, is used 300ml purifies water washing organic layer, is concentrated to dryness after the drying of 25g anhydrous sodium sulfate is added into organic layer;Then it is added 150g dehydrated alcohol, temperature rising reflux filter until being cooled to -5 DEG C of crystallizations under stirring after whole dissolved clarifications, and filter cake subtracts at 40-50 DEG C Pressure dries to obtain white crystalline solid 59.1g, purity 99.8%, yield 92.8%.
Embodiment 3:
(1) 70g phenylpropyl alcohol acetoacetic ester and 400ml ethyl acetate are added into 1000ml reaction flask, stirs evenly, cools down, control The dimethylamine of 0-10 DEG C of temperature dropwise addition 54.5g concentration 40%, is added dropwise in reaction flask processed, and 10-15 DEG C of temperature control is reacted 70 minutes, Then 14.0g metaformaldehyde, back flow reaction 3.5 hours after heating are added;It is down to room temperature after the reaction was completed, it is (dense that concentrated hydrochloric acid is added 35%) 55g, purified water 60ml are spent, is stirred 40 minutes, stratification, organic layer washed once with 200ml purified water, depressurize dense Contracting organic layer is to dry;
(2) then be added 500ml methylene chloride, 20% sodium hydroxide solution 80g and 50g dehydrated alcohol, 10-20 DEG C of temperature control Reaction 4 hours;After standing, water layer is separated, 40g concentrated hydrochloric acid tune pH=1 is added into organic layer;Water layer is separated again, uses 300ml Water washing organic layer is purified, is concentrated to dryness after the drying of 25g anhydrous sodium sulfate is added into organic layer;Then be added 130g without Water-ethanol, temperature rising reflux filter, filter cake decompression drying at 40-50 DEG C until being cooled to -5 DEG C of crystallizations under stirring after whole dissolved clarifications Obtain white crystalline solid 58.6g, purity 99.9%, yield 92.0%.

Claims (9)

1. a kind of synthetic method of racecadotril intermediate,
The racecadotril intermediate be benzyl acrylic, it the following steps are included:
(1) phenylpropyl alcohol acetoacetic ester and solvent ethyl acetate are added in reaction vessel, is cooled to 0-10 DEG C of dropwise addition dimethylamine agueous solution;Drop Add complete, the reaction was continued 0.5~1.5 hour for 10-15 DEG C of temperature control;Then metaformaldehyde is added, temperature rising reflux reaction 2~5 is small When;It is down to room temperature after the reaction was completed, hydrochloric acid is added and water is stirred to react rear stratification, organic layer is concentrated under reduced pressure into after washing Do to obtain benzyl acrylic ethyl ester;
(2) methylene chloride, sodium hydroxide solution and ethyl alcohol or methanol, temperature control are then added into benzyl acrylic ethyl ester 10-20 DEG C is reacted 2~5 hours;Hydrochloric acid tune pH=1 is added into organic layer for stratification after completion of the reaction;It stands and divides again Layer, organic layer washed, dry after be concentrated to dryness to obtain benzyl acrylic crude product;Product is obtained after recrystallizing again.
2. a kind of synthetic method of racecadotril intermediate as described in claim 1, characterized in that the step (1) two The concentration of methylamine water solution is 30~50%.
3. a kind of synthetic method of racecadotril intermediate as claimed in claim 2, characterized in that the step (1) two The concentration of methylamine water solution is 40%.
4. a kind of synthetic method of racecadotril intermediate as described in claim 1, characterized in that step (1) benzene Ethyl propionate, dimethylamine, metaformaldehyde molar ratio be 1:1.1~1.5:0.35~0.45.
5. a kind of synthetic method of racecadotril intermediate as described in claim 1, characterized in that step (1) benzene The molar ratio of ethyl propionate and hydrochloric acid is 1:1.0~1.5.
6. a kind of synthetic method of racecadotril intermediate as described in claim 1, characterized in that step (2) hydrogen Sodium hydroxide solution concentration is 15~30%.
7. a kind of synthetic method of racecadotril intermediate as claimed in claim 6, characterized in that the sodium hydroxide is molten Liquid concentration is 20%.
8. a kind of synthetic method of racecadotril intermediate as described in any one of claim 1-7, characterized in that institute Step (2) recrystallization is stated using dehydrated alcohol as solvent.
9. a kind of synthetic method of racecadotril intermediate as described in right wants 8, characterized in that the process of the recrystallization It is as follows: dehydrated alcohol, temperature rising reflux to be added in benzyl acrylic crude product, until being cooled to -5 DEG C of analysis under stirring after whole dissolved clarifications Crystalline substance, filtering, filter cake decompression drying at 40-50 DEG C obtain product.
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CN109580825B (en) * 2018-12-27 2021-07-02 山东铂源药业有限公司 Method for detecting p-toluenesulfonate substances in racecadotril

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EP0061745A1 (en) * 1981-03-27 1982-10-06 Tanabe Seiyaku Co., Ltd. Tetrahydroisoquinoline compounds, processes for preparation thereof and pharmaceutical composition containing them
US4889869A (en) * 1986-02-07 1989-12-26 Ciba-Geigy Corporation Antihypertensive 5-amino-4-hydroxyvaleryl derivatives substituted by sulphur-containing groups
US5312838A (en) * 1992-09-21 1994-05-17 G. D. Searle & Co. β-alanineamide aryl/alkylsulfide/sulfonyl-terminated amino-diol compounds for treatment of hypertension

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Patentee after: Shandong Baoyuan Pharmaceutical Co.,Ltd.

Address before: Strong in Jiyang County of Ji'nan City, 251400 North Street, Shandong Province Economic Development Zone

Patentee before: SHANDONG BOYUAN PHARMACEUTICAL Co.,Ltd.