CN103508998A - Method for preparing intermediate of duloxetine hydrochloride - Google Patents

Method for preparing intermediate of duloxetine hydrochloride Download PDF

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Publication number
CN103508998A
CN103508998A CN201310493983.2A CN201310493983A CN103508998A CN 103508998 A CN103508998 A CN 103508998A CN 201310493983 A CN201310493983 A CN 201310493983A CN 103508998 A CN103508998 A CN 103508998A
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Prior art keywords
compound
formula
duloxetine hydrochloride
preparation
formula iii
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谢瑞兴
许卫东
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SHANDONG LUYAO PHARMACEUTICAL CO Ltd
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SHANDONG LUYAO PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Abstract

The invention relates to a method for preparing an intermediate of duloxetine hydrochloride. The method comprises the following steps: adding 2-acetylthiophene into concentrated hydrochloric acid for reacting, preparing a compound of a formula II, adding NaBH4 for reacting, and refining to prepare a compound of a formula III; taking the compound of the formula III and methyl tertiary butyl ether, adding S-mandelic acid for reacting, filtering, spraying, drying to obtain a white granular solid, dissolving the white granular solid in water, regulating a pH value, extracting by using dichloromethane, drying, and preparing S-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl) propylamine (a compound of a formula I) after drying. The invention provides a simple method, so that the raw materials are completely dissolved, namely the consumption of NaBH4 is reduced, a reduction reaction can be completely carried out, and the maximum reaction rate can be 95.6 percent. Meanwhile, the invention provides a method for improving resolution yield and purity, and the maximum yield can be 47.6 percent. According to the improved process, the reaction time is greatly reduced, the operation is simplified, and the total yield of the compound of the formula I which is synthesized in three steps is more than 36 percent.

Description

A kind of preparation method of intermediate of duloxetine hydrochloride
Technical field
The present invention relates to a kind of preparation method of intermediate of Antidepressant Drug Duloxetine Hydrochloride, belong to organic chemistry and pharmaceutical chemistry field.
Technical background
Duloxetine hydrochloride is the dual reuptake inhibitor of a kind of effective thrombotonin and nor-epinephrine, and it has suitable affinity in the transhipment position in conjunction with thrombotonin and nor-epinephrine.Therefore, duloxetine hydrochloride is used for the treatment of the various diseases that relates to this function always.Duloxetine hydrochloride is mainly used in treating heavy dysthymia disorders after coming out, but in September, 2004, and U.S. FDA has ratified to supplement applicable disease, is used for the treatment of diabetic external cause neuralgia.Ci Yaoshi U.S. Eli-Lilly company releases, and commodity are called Cymbalta, are the thymoleptic that a kind of re-uptake to serotonin and norepinephrine has double inhibition effect.Be clinical preferred thymoleptic now, therefore its research had to great scientific research and economic worth.
Duloxetine hydrochloride is optically active substance, and its enantiomer does not have antidepressant.Therefore, in duloxetine hydrochloride raw material, must carry out limit to its optical purity, make splitting step seem more important.Existing preparation technology exists material dissolution incomplete, reduce not thorough, impact reduction yield and purity, to such an extent as to the chiral separation walking under more serious impact, so the inventor determines this to carry out process modification.
By studying document carefully, and some documents have been carried out to actually operating checking, find that existing technology exists serious deficiency: for example, while reducing, some documents carry out pH regulator with 50% sodium hydroxide, when pH is adjusted to 12, still there is a large amount of insolubless, have a strong impact on reduction ratio; During some document reduction, first adding a part of water, reinforcing body sodium hydroxide again, although can make material dissolution like this, easily violent heat release during reinforcing body sodium hydroxide inward, must strengthen cooling dynamics and lower the temperature, and the very exothermic of moment is easy to raw material to produce unknown destruction.After regulating pH with sodium hydroxide solution, just filter and want filter cake splitting a lot of documents of a step, easily like this cause residual a part of product in filtrate, through contriver's experimental verification rate of loss, reach 3-10%; When splitting, also have a lot of documents to adopt first and filter, with methylene dichloride, filtrate is extracted afterwards, although reduced like this rate of loss, greatly increased labor capacity.
Summary of the invention
For overcoming the deficiencies in the prior art, the invention provides a kind of preparation method of intermediate of duloxetine hydrochloride, the processing requirement that it is more applicable to reduction and splits, shortened the reaction times greatly, reduce unnecessary loss, operated easylier, be more suitable for suitability for industrialized production.
Object of the present invention can realize by following technical scheme:
The preparation method of intermediate, it is characterized in that comprising the steps:
(a) preparation of formula II compound
In reaction vessel, add successively starting raw material 2-acetyl thiophene, Dimethylammonium chloride, paraformaldehyde and Virahol, under stirring at room, splash into concentrated hydrochloric acid, the mol ratio of 2-acetyl thiophene and Dimethylammonium chloride and paraformaldehyde is 1:1.1 ~ 1.6:1.2 ~ 2, the molar weight of concentrated hydrochloric acid is 3 ~ 13% of 2-acetyl thiophene, slowly be warming up to 70 ~ 84 ℃, react after 6 ~ 20 hours, being cooled to 0 ℃ stirs 2 hours, filter, with cold ethanol making beating, wash once, drip washing twice, obtains brilliant white crystal on chip, i.e. formula II compound after oven dry.
Preferably, the mol ratio of 2-acetyl thiophene and Dimethylammonium chloride and paraformaldehyde is 1:1.33:1.5.Preferably, temperature of reaction is 84 ℃ of reflux temperatures.Preferably, concentrated hydrochloric acid consumption is 10% of 2-acetyl thiophene molar weight.
(b) preparation of formula III compound
In reaction flask, adding formula II compound and ethanol, control temperature and be no more than 20 ℃, stir 3 ~ 15% sodium hydroxide solutions that lower dropping prepares in advance, till adjusting pH to 12, is now clear liquid in reaction flask.Control temperature is no more than 30 ℃ and adds NaBH in batches 4, NaBH 4consumption and the mol ratio of formula II compound be 0.5 ~ 1.3:1, add and be slowly warming up to 40 ~ 70 ℃ afterwards, react after 2 ~ 10 hours, first filter, rear filtrate control temperature is no more than 30 ℃ and slowly adds proper amount of acetone, continue to stir 0.5 hour, decompression evaporates organic phase, adds suitable quantity of water, is extracted with ethyl acetate three times, salt washing twice, anhydrous Na 2sO 4evaporated under reduced pressure ethyl acetate after dry, obtains white solid, i.e. formula III compound after oven dry.
Preferably, the naoh concentration preparing is in advance 10%.Preferably, NaBH 4consumption be 0.6 times of formula II compound molar weight.Preferably, temperature of reaction is 60 ℃.
(c) S-(-)-N, the preparation of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (formula I compound)
In reaction flask, add formula III compound and methyl tertiary butyl ether, under stirring, be warming up to 40 ~ 53 ℃, the ethanolic soln of the S-MA that slowly dropping prepares in advance, the mol ratio of formula III compound and S-MA is 1:0.5 ~ 0.9, after dripping off, is warming up to reflux state, react after 0.5 ~ 3 hour, be cooled to 0 ℃ and stir 1 hour, filter, with ethanol making beating, wash once, once, post-drying of methyl tertiary butyl ether drip washing obtains white granular solid to drip washing filter cake; This solid is water-soluble, control temperature and be no more than 20 ℃ with after 50% sodium hydroxide tune pH to 8, add appropriate methylene dichloride, continue tune pH to 11 ~ 12, layering after fully stirring, water layer continues to use twice of dichloromethane extraction, merge three a small amount of washings twice for methylene dichloride, anhydrous Na 2sO 4evaporated under reduced pressure methylene dichloride after dry, controls oven temperature and is no more than after 50 ℃ of oven dry to obtain white solid, i.e. formula I compound, target product of the present invention.
Preferably, the mol ratio of formula III compound and S-MA is 1:0.65.Preferably, the ethanolic soln dropping temperature of S-MA is 50 ℃.Preferably, temperature of reaction is reflux temperature, and reflux temperature of the present invention is 56 ℃.Preferably, the reaction times is 2 hours.
Its synthetic route is as follows:
Figure 2013104939832100002DEST_PATH_IMAGE002
Improvement compared with prior art innovation of the present invention is as follows:
1) the invention provides the preparation of formula III compound, is with 10% sodium hydroxide, to carry out the adjusting of pH, and the sodium hydroxide of this concentration is adjusted after pH to 12, and in bottle, material dissolves completely, can obtain clear liquid, can make NaBH like this 4reduction effect better, reduced NaBH 4consumption.
2) reduction reaction temperature provided by the invention is 60 ℃, and this temperature can shorten the reduction reaction time greatly, improves reduction efficiency, has reduced production cost.
3) reduction post-treating method provided by the invention, for first filtering out the not tolerant acetone that adds again, so both can have been saved the consumption of acetone greatly, also makes evaporated under reduced pressure organic phase was used afterwards time still less.
4) fractionation aftertreatment scheme provided by the invention adds methylene dichloride after adjusting pH to 8 with 50% sodium hydroxide, continue again to adjust pH, so direct extraction can reduce greatly only filters the loss of wanting filter cake method, also avoided first filtering and extracted afterwards the loaded down with trivial details of filtrate method, overcome the drawback of filtering-depositing in prior art, greatly saved the time, improved productive rate simultaneously.
5) to prepare scheme more simple for duloxetine hydrochloride intermediate of the present invention, and effect is good, has greatly improved production efficiency, has reduced production cost, and three step overall yields can reach more than 36%.
Embodiment
With specific embodiment, the present invention is described in detail below, but be not limited to this.
embodiment 1:
(a) preparation of formula II compound
In reaction flask, add 2-acetyl thiophene 100g, Dimethylammonium chloride 86g, paraformaldehyde 35.6g, Virahol 300mL, adds concentrated hydrochloric acid 10mL under stirring, be slowly warming up to reflux state.After back flow reaction 8 hours, be cooled to 0 ℃, continue to stir 2 hours, filter, with cold ethanol making beating, wash once, drip washing twice, obtains brilliant white tabular crystal 163.5g, yield 94% after oven dry.
(b) preparation of formula III compound
In reaction flask, add 132.7g formula II compound and 400mL ethanol, under ice bath, with 10% sodium hydroxide, adjust pH to 12, control temperature and be no more than 30 ℃ of NaBH that in batches add 14g 4, add stirring and after 15 minutes, be slowly warmed up to 60 ℃ of reactions 4 hours.Filter, appropriate alcohol flushing filter cake, control temperature is no more than under 30 ℃ of stirrings and slowly adds 50mL acetone to filtrate, stirs 0.5 hour, and decompression evaporates organic phase, adds 150mL water, is extracted with ethyl acetate 200mL * 3 time, salt washing 70mL * 2 time, anhydrous Na 2sO 4after dry, decompression evaporates solvent, dries to obtain 107g white solid, 95.6% productive rate.
(c) S-(-)-N, the preparation of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (formula I compound)
Modus ponens III compound 103g, methyl tertiary butyl ether 650mL join in reaction flask, are warming up to 50 ℃ under stirring.Now the 170mL ethanolic soln of the 60g S-MA preparing is added drop-wise in reaction flask, after dripping off, is warming up to back flow reaction 2 hours.Under ice bath, stir 1 hour, filter, filter cake is washed once with cold ethanol making beating, and once, methyl tertiary butyl ether drip washing once, is dried to obtain white granular solid 96g in drip washing.
This solid is dissolved in to 400mL water, controls temperature and be no more than 20 ℃ with after 50% sodium hydroxide tune pH to 8, add 200mL methylene dichloride, continue to adjust pH to 11 ~ 12, layering after fully stirring, water layer continues with dichloromethane extraction 150mL * 2 time, merge methylene dichloride washing 70mL * 2 time three times, anhydrous Na 2sO 4evaporated under reduced pressure methylene dichloride after dry, controls after oven temperature is no more than 55 ℃ of oven dry and obtains white solid 49g, yield 47.6%.
embodiment 2:
(a) preparation of formula II compound
In reaction flask, add 2-acetyl thiophene 100g, Dimethylammonium chloride 70.1g, paraformaldehyde 28.5g, Virahol 300mL, adds concentrated hydrochloric acid 3mL under stirring, be slowly warming up to reflux state.After back flow reaction 20 hours, be cooled to 0 ℃, continue to stir 2 hours, filter, with cold ethanol making beating, wash once, drip washing twice, obtains brilliant white tabular crystal 160g, yield 92% after oven dry.
(b) preparation of formula III compound
In reaction flask, add 132.7g formula II compound and 400mL ethanol, under ice bath, with 3% sodium hydroxide, adjust pH to 12, control temperature and be no more than 30 ℃ of NaBH that in batches add 11.5g 4, add stirring and after 15 minutes, be slowly warmed up to 70 ℃ of reactions 10 hours.Filter, appropriate alcohol flushing filter cake, control temperature is no more than under 30 ℃ of stirrings and slowly adds 50mL acetone to filtrate, stirs 0.5 hour, and decompression evaporates organic phase, adds 150mL water, is extracted with ethyl acetate 200mL * 3 time, salt washing 70mL * 2 time, anhydrous Na 2sO 4after dry, decompression evaporates solvent, dries to obtain 103.5g white solid, yield 92.5%.
(c) S-(-)-N, the preparation of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (formula I compound)
Modus ponens III compound 103g, methyl tertiary butyl ether 650mL join in reaction flask, are warming up to 40 ℃ under stirring.Now the 140mL ethanolic soln of the 42.4g S-MA preparing is added drop-wise in reaction flask, after dripping off, is warming up to back flow reaction 3 hours.Under ice bath, stir 1 hour, filter, filter cake is washed once with cold ethanol making beating, and once, methyl tertiary butyl ether drip washing once, is dried to obtain white granular solid 92g in drip washing.This solid is dissolved in to 400mL water, controls temperature and be no more than 20 ℃ with after 50% sodium hydroxide tune pH to 8, add 200mL methylene dichloride, continue to adjust pH to 11 ~ 12, layering after fully stirring, water layer continues with dichloromethane extraction 150mL * 2 time, merge methylene dichloride washing 70mL * 2 time three times, anhydrous Na 2sO 4evaporated under reduced pressure methylene dichloride after dry, controls after oven temperature is no more than 55 ℃ of oven dry and obtains white solid 45g, yield 42.8%.
embodiment 3:
(a) preparation of formula II compound
In reaction flask, add 2-acetyl thiophene 100g, Dimethylammonium chloride 102g, paraformaldehyde 47.5g, Virahol 300mL, adds concentrated hydrochloric acid 13mL under stirring, be slowly warming up to reflux state.After back flow reaction 6 hours, be cooled to 0 ℃, continue to stir 2 hours, filter, with cold ethanol making beating, wash once, drip washing twice, obtains brilliant white tabular crystal 158.4g, yield 91.1% after oven dry.
(b) preparation of formula III compound
In reaction flask, add 132.7g formula II compound and 400mL ethanol, under ice bath, with 15% sodium hydroxide, adjust pH to 12, control temperature and be no more than 30 ℃ of NaBH that in batches add 29.8g 4, add stirring and after 15 minutes, be slowly warmed up to 40 ℃ of reactions 2 hours.Filter, appropriate alcohol flushing filter cake, control temperature is no more than under 30 ℃ of stirrings and slowly adds 50mL acetone to filtrate, stirs 0.5 hour, and decompression evaporates organic phase, adds 150mL water, is extracted with ethyl acetate 200mL * 3 time, salt washing 70mL * 2 time, anhydrous Na 2sO 4after dry, decompression evaporates solvent, dries to obtain 106g white solid, yield 94.8%.
(c) S-(-)-N, the preparation of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (formula I compound)
Modus ponens III compound 103g, methyl tertiary butyl ether 650mL join in reaction flask, are warming up to 50 ℃ under stirring.Now the 200mL ethanolic soln of the 76g S-MA preparing is added drop-wise in reaction flask, after dripping off, is warming up to back flow reaction 0.5 hour.Under ice bath, stir 1 hour, filter, filter cake is washed once with cold ethanol making beating, and once, methyl tertiary butyl ether drip washing once, is dried to obtain white granular solid 93.9g in drip washing.This solid is dissolved in to 400mL water, controls temperature and be no more than 20 ℃ with after 50% sodium hydroxide tune pH to 8, add 200mL methylene dichloride, continue to adjust pH to 11 ~ 12, layering after fully stirring, water layer continues with dichloromethane extraction 150mL * 2 time, merge methylene dichloride washing 70mL * 2 time three times, anhydrous Na 2sO 4evaporated under reduced pressure methylene dichloride after dry, controls after oven temperature is no more than 55 ℃ of oven dry and obtains white solid 46.1g, yield 44.8%.

Claims (4)

1. a preparation method for the intermediate of duloxetine hydrochloride, is characterized in that comprising the steps:
(a) in reaction vessel, add successively starting raw material 2-acetyl thiophene, Dimethylammonium chloride, paraformaldehyde
And Virahol, under stirring at room, splash into concentrated hydrochloric acid, the mol ratio of 2-acetyl thiophene and Dimethylammonium chloride and paraformaldehyde is 1:1.1 ~ 1.6:1.2 ~ 2, and the molar weight of concentrated hydrochloric acid is 3 ~ 13% of 2-acetyl thiophene, slowly be warming up to 70 ~ 84 ℃, react after 6 ~ 20 hours, be cooled to 0 ℃ and stir 2 hours, filter, with cold ethanol making beating, wash once, drip washing twice, obtains brilliant white crystal on chip, i.e. formula II compound after oven dry;
(b) in reaction flask, adding formula II compound and ethanol, control temperature and be no more than 20 ℃, stir 3 ~ 15% sodium hydroxide solutions that lower dropping prepares in advance, till adjusting pH to 12, is now clear liquid in reaction flask; Control temperature is no more than 30 ℃ and adds NaBH in batches 4, NaBH 4consumption and the mol ratio of formula II compound be 0.5 ~ 1.3:1, add and be slowly warming up to 40 ~ 70 ℃ afterwards, react after 2 ~ 10 hours, first filter, rear filtrate control temperature is no more than 30 ℃ and slowly adds proper amount of acetone, continue to stir 0.5 hour, decompression evaporates organic phase, adds suitable quantity of water, is extracted with ethyl acetate three times, salt washing twice, anhydrous Na 2sO 4evaporated under reduced pressure ethyl acetate after dry, obtains white solid, i.e. formula III compound after oven dry;
(c) in reaction flask, add formula III compound and methyl tertiary butyl ether, under stirring, be warming up to 40 ~ 53 ℃, the ethanolic soln of the S-MA that slowly dropping prepares in advance, the mol ratio of formula III compound and S-MA is 1:0.5 ~ 0.9, after dripping off, is warming up to reflux state, react after 0.5 ~ 3 hour, be cooled to 0 ℃ and stir 1 hour, filter, with ethanol making beating, wash once, once, post-drying of methyl tertiary butyl ether drip washing obtains white granular solid to drip washing filter cake; This solid is water-soluble, control temperature and be no more than 20 ℃ with after 50% sodium hydroxide tune pH to 8, add appropriate methylene dichloride, continue tune pH to 11 ~ 12, layering after fully stirring, water layer continues to use twice of dichloromethane extraction, merge three a small amount of washings twice for methylene dichloride, anhydrous Na 2sO 4evaporated under reduced pressure methylene dichloride after dry, controls after oven temperature is no more than 55 ℃ of oven dry and obtains white solid, i.e. the intermediate formula I compound of duloxetine hydrochloride.
2. the preparation method of the intermediate of duloxetine hydrochloride according to claim 1, is characterized in that: in step (a), the mol ratio of described 2-acetyl thiophene and Dimethylammonium chloride and paraformaldehyde is 1:1.33:1.5; Concentrated hydrochloric acid consumption is 10% of 2-acetyl thiophene molar weight.
3. the preparation method of the intermediate of duloxetine hydrochloride according to claim 1, is characterized in that: in step (b), described naoh concentration is 10%; The described NaBH that adds 4after temperature of reaction be 60 ℃.
4. the preparation method of the intermediate of duloxetine hydrochloride according to claim 1, is characterized in that: in step (c), the mol ratio of formula III compound and S-MA is 1:0.65; The ethanolic soln dropping temperature of S-MA is 50 ℃.
CN201310493983.2A 2013-10-21 2013-10-21 Method for preparing intermediate of duloxetine hydrochloride Pending CN103508998A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111793056A (en) * 2020-07-27 2020-10-20 广州康瑞泰药业有限公司 Preparation method of duloxetine intermediate
CN115286613A (en) * 2022-10-08 2022-11-04 潍坊市海欣药业有限公司 Preparation method of duloxetine hydrochloride

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Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111793056A (en) * 2020-07-27 2020-10-20 广州康瑞泰药业有限公司 Preparation method of duloxetine intermediate
CN115286613A (en) * 2022-10-08 2022-11-04 潍坊市海欣药业有限公司 Preparation method of duloxetine hydrochloride
CN115286613B (en) * 2022-10-08 2023-01-31 潍坊市海欣药业有限公司 Preparation method of duloxetine hydrochloride

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Application publication date: 20140115