CN103524480B

CN103524480B - A kind of preparation method of duloxetine hydrochloride

Info

Publication number: CN103524480B
Application number: CN201310493911.8A
Authority: CN
Inventors: 谢瑞兴; 许卫东
Original assignee: SHANDONG LUYAO PHARMACEUTICAL CO Ltd
Current assignee: SHANDONG LUYAO PHARMACEUTICAL CO Ltd
Priority date: 2013-10-21
Filing date: 2013-10-21
Publication date: 2016-04-20
Anticipated expiration: 2033-10-21
Also published as: CN103524480A

Abstract

The invention provides a kind of preparation method of duloxetine hydrochloride, compound III is instilled the obtained compound ii of reaction in sodium hydroxide by it, compound ii adds solid ammonium chloride in batches and obtains duloxetine and become hydrochloride, first wash with cold diethyl ether, crystallization is carried out again with acetone, thus the obtained duloxetine hydrochloride that purity is high, yield is high.Compared with prior art this substantially reduces the reaction times, within 18 ~ 70 hours by document, foreshorten to 2 ~ 4 hours; In addition utilize duloxetine of the present invention to become hydrochloride more simple and easy to do, and productive rate is higher; Be first wash with cold diethyl ether before carrying out crystallization with acetone, can easierly make duloxetine hydrochloride be precipitated out like this, and purity be high, again need not carry out recrystallization, avoid loss.Synthetic method of the present invention is more simple, substantially increases production efficiency, reduces production cost, can reach more than 17% from starting raw material 2-acetyl thiophene synthetic hydrochloric acid duloxetine overall yield.

Description

A kind of preparation method of duloxetine hydrochloride

Technical field

The present invention relates to a kind of preparation method of duloxetine hydrochloride, belong to organic chemistry and medicinal chemistry art.

Technical background

Duloxetine hydrochloride (duloxetinehydrochloride, formula I), chemistry (+)-(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl by name) propylamin hydrochloride is the thymoleptic that a kind of re-uptake to serotonin and norepinephrine has double inhibition effect.

This Eli-Lilly company of Yao Shi U.S., after fluoxetine Patent expiry, the another new drug of release, commodity are called Cymbalta.In September, 2002, through U.S. FDA approval treatment major depression, uses its hydrochloride clinically.In September, 2004, U.S. FDA have approved to supplement and is suitable for disease, is used for the treatment of diabetic external cause neuralgia.Be clinical preferred thymoleptic now, therefore have great scientific research and economic worth to its research, especially its patent protection expired in 2013, just more seems have a sense of urgency to its research.

From prior art, the synthetic route of duloxetine hydrochloride (formula I) is as follows:

But the synthetic method of prior art exists, and technique is loaded down with trivial details, long reaction time, production cost are high, product purity and the shortcoming such as yield is low, as the current synthesis from compound III to compound ii, reaction times reaches 18 ~ 70 hours, because the present invention is the improvement carried out on forefathers basis, therefore describe the place of improving at this, namely in synthetic route compound III to the synthesis of chemical compounds I, from starting raw material 2-acetyl thiophene to the synthesis of compound III mostly with reference to pertinent literature, do not repeat them here.

Summary of the invention

For the deficiencies in the prior art, the invention provides a kind of preparation method of new duloxetine hydrochloride, the generated time of duloxetine hydrochloride can be shortened, and technique is more simple.

The present invention is achieved through the following technical solutions:

A preparation method for duloxetine hydrochloride, is characterized in that comprising the steps:

A () adds the aqueous sodium hydroxide solution that concentration is 5%-20% in reaction vessel, control temperature 0 DEG C ~ 30 DEG C, drip the DMSO solution of compound III, the mol ratio of solid sodium hydroxide and compound III is 3 ~ 5:1, drips off and is warming up to 40 DEG C ~ 70 DEG C reactions 2 ~ 6 hours, frozen water is poured under stirring, adjust pH to 4.5 ~ 5.5 with acetic acid, with n-hexane extraction twice, water layer adjusts pH to 11-12 with 50% sodium hydroxide again, be extracted with ethyl acetate three times, anhydrous Na ₂sO ₄after drying, control bath temperature and be no more than 48 DEG C of evaporated under reduced pressure ethyl acetate, obtain light brown liquid, i.e. compound ii.

Preferably, compound III drip into naoh concentration be 15%.

Preferably, the mol ratio of solid sodium hydroxide and compound III is 4:1.

Preferably, when compound III drips, described temperature is 20 DEG C.

Preferably, described temperature of reaction is 55 DEG C.

Preferably, acetic acid adjusts pH to 5.

Preferably, the bath temperature of ethyl acetate is steamed in decompression is 45 DEG C.

B (), in reaction vessel, adds compound ii and methyl alcohol, stir after dissolving completely, room temperature lower point 2 ~ 5 batches, often criticizes interval and adds solid ammonium chloride in 5 ~ 25 minutes, and the mol ratio of compound ii and ammonium chloride is 1:1 ~ 1.2, stirred at ambient temperature reaction 1 ~ 3 hour, control bath temperature and be no more than 48 DEG C of evaporated under reduced pressure methyl alcohol, add proper amount of acetone with after appropriate cold ether, stir 1 hour under ice bath, filter, with proper amount of acetone washing, drying obtains compound as white solid I, i.e. duloxetine hydrochloride.

Preferably, divide 3 batches and add ammonium chloride, often criticize interval 15 minutes.

Preferably, the mol ratio of compound ii and ammonium chloride is 1:1.05.

Preferably, the bath temperature of methyl alcohol is steamed in decompression is 40 DEG C.

Its synthetic route is as follows:

Reformed AHP compared with prior art of the present invention is as follows:

1) method of synthetic compound II provided by the invention instills in sodium hydroxide by compound III, contrary with existing method, this substantially reduces the reaction times, within 18 ~ 70 hours by document, foreshortens to 2 ~ 4 hours.

2) method of synthetic hydrochloric acid duloxetine provided by the invention, add solid ammonium chloride under room temperature to carry out duloxetine and become hydrochloride in batches, this method than existing concentrated hydrochloric acid or gas chlorination hydrogen salify all more simple, easy, and productive rate reaches more than 80%, most document is 20% ~ 60%.

3) provided by the inventionly obtain pure duloxetine hydrochloride Solid Method, be first wash with cold diethyl ether before carrying out crystallization with acetone, can easierly make duloxetine hydrochloride be precipitated out like this, and purity be high, again need not carry out recrystallization, avoid loss.

4) duloxetine hydrochloride synthetic method of the present invention is more simple, substantially increase production efficiency, reduce production cost, can more than 17% be reached from starting raw material 2-acetyl thiophene synthetic hydrochloric acid duloxetine overall yield, most document is less than 12%, have minority productive rate to reach more than 20%, but be through test of many times checking all do not reach document description yield.

Embodiment

The present invention is described in detail to use specific embodiment below, but be not limited thereto.

embodiment 1:

A the NaOH aqueous solution of prepare 15% is taken 147g and joins in reaction by (), under vigorous stirring, control temperature about 20 DEG C drips the DMSO solution 450mL being dissolved with 55.5g compound III.Be warming up to 55 DEG C after dripping off, react and after 3 hours, 550g frozen water is poured into wherein, stir after half an hour and adjust pH to 5 with acetic acid, with n-hexane extraction twice.Waterlayer control temperature is no more than 30 DEG C and adjusts pH to 11 ~ 12 with 50% sodium hydroxide, is extracted with ethyl acetate 400mL × 3 time, anhydrous Na ₂sO ₄after drying, control water-bath 45 DEG C of evaporated under reduced pressure ethyl acetate, obtain light brown liquid 39.5g.

B () adds compound ii and the 240mL methyl alcohol of 32.5g in reaction flask, after stirring at room temperature is dissolved completely, add solid ammonium chloride 6.5g, then continue stirring under room temperature 2 hours at interval of 15 minutes points 3 batches.Control bath temperature about 41 DEG C evaporated under reduced pressure methyl alcohol, wash once with cold diethyl ether, then add 220mL acetone, stir 1 hour under ice bath, filter, with proper amount of acetone and washed with ether twice, drying obtains 32.1g white solid, i.e. duloxetine hydrochloride, yield 87.9%, HPLC purity is 99.8%.

embodiment 2:

A the NaOH aqueous solution of prepare 5% is taken 147g and joins in reaction by (), under vigorous stirring, control temperature 30 DEG C of droppings are dissolved with the DMSO solution 450mL of 55.5g compound III.Be warming up to 70 DEG C after dripping off, react and after 2 hours, 550g frozen water is poured into wherein, stir after half an hour and adjust pH to 4.5 with acetic acid, with n-hexane extraction twice.Waterlayer control temperature is no more than 30 DEG C and adjusts pH to 11 ~ 12 with 50% sodium hydroxide, is extracted with ethyl acetate 400mL × 3 time, anhydrous Na ₂sO ₄after drying, control water-bath 40 DEG C of evaporated under reduced pressure ethyl acetate, obtain light brown liquid, 38g.

B () adds compound ii and the 240mL methyl alcohol of 32.5g in reaction flask, after stirring at room temperature is dissolved completely, add solid ammonium chloride 6.5g, then continue stirring under room temperature 1 hour at interval of 5 minutes points 5 batches.Control bath temperature about 40 DEG C evaporated under reduced pressure methyl alcohol, wash once with cold diethyl ether, then add 220mL acetone, stir 1 hour under ice bath, filter, with proper amount of acetone and washed with ether twice, drying obtains 30g white solid, i.e. duloxetine hydrochloride, yield 82.2%, HPLC purity is 99.69%.

embodiment 3:

A the NaOH aqueous solution of prepare 20% is taken 147g and joins in reaction by (), under vigorous stirring, control temperature 30 DEG C of droppings are dissolved with the DMSO solution 450mL of 55.5g compound III.Be warming up to 40 DEG C after dripping off, react and after 6 hours, 550g frozen water is poured into wherein, stir after half an hour and adjust pH to 5.5 with acetic acid, with n-hexane extraction twice.Waterlayer control temperature is no more than 30 DEG C and adjusts pH to 11 ~ 12 with 50% sodium hydroxide, is extracted with ethyl acetate 400mL × 3 time, anhydrous Na ₂sO ₄after drying, control water-bath 40 DEG C of evaporated under reduced pressure ethyl acetate, obtain light brown liquid, 39.4g.

B () adds compound ii and the 240mL methyl alcohol of 32.5g in reaction flask, after stirring at room temperature is dissolved completely, add solid ammonium chloride 6.5g, then continue stirring under room temperature 3 hours at interval of 20 minutes points 2 batches.Control bath temperature about 40 DEG C evaporated under reduced pressure methyl alcohol, wash once with cold diethyl ether, then add 220mL acetone, stir 1 hour under ice bath, filter, with proper amount of acetone and washed with ether twice, drying obtains 30.7g white solid, i.e. duloxetine hydrochloride, yield 84.1%, HPLC purity is 99.7%.

Claims

1. a preparation method for duloxetine hydrochloride, is characterized in that comprising the steps:

A () adds the aqueous sodium hydroxide solution that concentration is 5%-20% in reaction vessel, control temperature 0 DEG C ~ 30 DEG C, drip the DMSO solution of compound III, the mol ratio of solid sodium hydroxide and compound III is 3 ~ 5:1, drips off and is warming up to 40 DEG C ~ 70 DEG C reactions 2 ~ 6 hours, frozen water is poured under stirring, adjust pH to 4.5 ~ 5.5 with acetic acid, with n-hexane extraction twice, water layer adjusts pH to 11-12 with 50% sodium hydroxide again, be extracted with ethyl acetate three times, anhydrous Na ₂sO ₄after drying, control bath temperature and be no more than 48 DEG C of evaporated under reduced pressure ethyl acetate, obtain light brown liquid, i.e. compound ii; The naoh concentration starting to join reaction vessel is 15%; The mol ratio of described solid sodium hydroxide and compound III is 4:1; The dropping temperature of described compound III controls at 20 DEG C; Dripping the temperature of reaction after compound III is 55 DEG C; Bath temperature during described decompression steaming ethyl acetate is 45 DEG C,

B (), in reaction vessel, adds compound ii and methyl alcohol, stir after dissolving completely, room temperature lower point 2 ~ 5 batches, often criticizes interval and adds solid ammonium chloride in 5 ~ 25 minutes, and the mol ratio of compound ii and ammonium chloride is 1:1 ~ 1.2, stirred at ambient temperature reaction 1 ~ 3 hour, control bath temperature and be no more than 48 DEG C of evaporated under reduced pressure methyl alcohol, add proper amount of acetone with after appropriate cold ether, stir 1 hour under ice bath, filter, with proper amount of acetone washing, drying obtains compound as white solid I, i.e. duloxetine hydrochloride; Divide 3 batches and add ammonium chloride, often criticize interval 15 minutes; The mol ratio of compound ii and ammonium chloride is 1:1.05; The bath temperature that methyl alcohol is steamed in decompression is 40 DEG C;

Its synthetic route is as follows:

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