CN103896910B - A kind of synthetic method of duloxetine - Google Patents

A kind of synthetic method of duloxetine Download PDF

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CN103896910B
CN103896910B CN201210577678.7A CN201210577678A CN103896910B CN 103896910 B CN103896910 B CN 103896910B CN 201210577678 A CN201210577678 A CN 201210577678A CN 103896910 B CN103896910 B CN 103896910B
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base
methyl
carbamate
equal
chloroethyl
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CN103896910A (en
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刘景�
徐开辉
郭礼新
郭晖
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Chengdu state bio medicine Co., Ltd.
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CHENGDU GUOHONG MEDICINE Co Ltd
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    • 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
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Abstract

A kind of by water, tetrahydrofuran (THF) or dioxane, 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) carbamate, alkali reacts under 20 DEG C-reflux temperature preferably 50 DEG C-reflux temperature, after reacting completely, concentration of reaction solution, the method of the solution containing duloxetine is obtained after adding another organic solvent extraction again, the method is compared with the existing method preparing duloxetine, overcome that the prior art reaction times is long or temperature of reaction is too high, power consumption is large, production cycle is long, yield poorly, or produce the industrial effluent being difficult to treatment and discharge in a large number, be unfavorable for environmental protection, or the reagent adopted is inflammable and explosive, the shortcoming that potential safety hazard is large, there is temperature of reaction low, reaction times is short, the industrial effluent produced is few, environmental protection, security is high, be applicable to the advantage of large-scale industrial production duloxetine.

Description

A kind of synthetic method of duloxetine
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of synthetic method of duloxetine.
Background technology
Duloxetine (Duloxetine), chemical name (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine:
This medicine is a kind of serotonin and the dual reuptake inhibithors of norepinephrine.By suppressing serotonin and norepinephrine dual reuptake simultaneously, strengthen the function of maincenter serotonin and norepinephrine neurotransmitter, and play antidepressant effect, meanwhile, it is to unrestraint effects such as monoamine oxidase, and side effect is little, rapid-action, life-time service is safe and effective.
Duloxetine calendar year 2001 goes on the market in Europe, and FDA ratifies it for dysthymia disorders on September 17th, 2002, and now jointly sold by Li Lai company and vigorous Lin Gelinhan company, within 2007, in Discussion on Chinese Listed, trade(brand)name glad hundred reaches.In recent years, pharmaceutical industry is very extensive to duloxetine research, and synthetic route is numerous.
Yuan Yan company discloses in the embodiment 11 of its preparation technology patent CN87108175 and adopts trichloroethyl chloroformate and (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, be heated to 85 DEG C and stir aftertreatment in 3 hours, stir one hour at adding active zinc powder and 15 DEG C, formic acid and at room temperature spend the night, after aftertreatment, obtaining duloxetine.Because trichloroethyl chloroformate is expensive, about 2000 yuan/kg, and the method aftertreatment is loaded down with trivial details, therefore the method production duloxetine cost is high, is not suitable for industrialization scale operation duloxetine.The embodiment 2 of CN87108175 discloses (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine and phenyl chloroformate reaction, question response terminates aftertreatment, then in propylene glycol solution, 110 DEG C of reaction 75min are heated to the 5NNaOH aqueous solution, cooling, dilute with water also uses ether extraction, to prepare the method for duloxetine, but the method temperature of reaction is too high, not only power consumption is large, there is certain potential safety hazard simultaneously, and ether is inflammable, explosive, this reaction also can produce the industrial effluent being difficult to treatment and discharge in a large number aborning, be unfavorable for environmental protection, therefore be not suitable for being applied to large-scale industrial production.
CN200910216339.4 discloses (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine and phenyl chloroformate reaction, question response terminates aftertreatment, then add dimethyl sulfoxide (DMSO) and the NaOH aqueous solution and be heated to 70 DEG C of reactions 48 hours, add the dilution of a large amount of frozen water, after a large amount of acetic acid adjust ph, add a large amount of normal hexane again, layering, after water layer adds a large amount of NaOH adjust pH, repeatedly extract with a large amount of ethyl acetate and prepare duloxetine, because the time of this reaction is longer, cause the production cycle long, yield poorly, power consumption is large, cost is high, the industrial effluent being difficult to treatment and discharge in a large number can be produced simultaneously, be unfavorable for environmental protection, therefore be not suitable for being applied to large-scale industrial production.
The people such as Guo Kefei are at Chinese Journal of Pharmaceuticals 2008, and 39 (12), P883 disclose (±) N-Benzyl-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-1-propylamine, Vinyl chloroformate, NaHCO 3aftertreatment has been reacted in toluene, then DMSO is added, the KOH aqueous solution, be heated to 120 DEG C of reactions 3 hours, ice acetic acid adjust pH after question response completes, adds a large amount of n-hexane, layering, water layer, with after NaOH solution adjust pH, repeatedly extracts with a large amount of ethyl acetate, obtains the method for duloxetine.But the method temperature of reaction is too high, not only power consumption is large, and simultaneously too high temperature of reaction exists certain potential safety hazard in production, and this reaction also can produce the industrial effluent being difficult to treatment and discharge in a large number aborning, be unfavorable for environmental protection, be therefore not suitable for being applied to large-scale industrial production.
US20090093645A1 embodiment 6 discloses (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine and chloroformate-1-chloro-ethyl ester post-reaction treatment in toluene, add methyl alcohol 25 DEG C to stir 16 hours, 30 DEG C are stirred 24 hours, add the method that acetone stirs 2 days crystallizatioies prepare duloxetine hydrochloride at 20 DEG C.This technology reaction and the crystallization time all oversize, cause the production cycle long, yield poorly, production cost is high, and the yield of duloxetine hydrochloride prepared by the method is lower, the yield of starting at the duloxetine hydrochloride obtained from (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine one step only 39%, is not suitable for large-scale industrial production.
The preparation method of duloxetine disclosed in prior art all exists that the reaction times is long or temperature of reaction is too high, power consumption is large, production cycle is long, yield poorly, or produce the industrial effluent being difficult to treatment and discharge in a large number, be unfavorable for environmental protection, or the reagent adopted is inflammable and explosive, potential safety hazard is large, is not suitable for the shortcoming of large-scale industrial production duloxetine.
Summary of the invention
The invention provides a kind of synthetic method of duloxetine, the method compared with prior art, has temperature of reaction low, and the reaction times is short, and the industrial effluent produced is few, environmental protection, and security is high, is applicable to the advantage of large-scale industrial production duloxetine.
The invention provides a kind of synthetic method of duloxetine, its reactions steps is as follows:
By water, the first organic solvent, 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) carbamate, alkali reacts under 20 DEG C-reflux temperature preferably 50 DEG C-reflux temperature, after reacting completely, concentration of reaction solution, the toluene solution containing duloxetine is obtained after adding the second organic solvent extraction again, wherein
The first organic solvent described be selected from tetrahydrofuran (THF) or dioxane one or both, and the first solvent and 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) the volume mass ratio of carbamate is more than or equal to 1(ml:g), be less than or equal to 30(ml:g); Be preferably greater than and equal 2(ml:g), be less than or equal to 20(ml:g), be more preferably and be more than or equal to 4(ml:g), be less than or equal to 10(ml:g).
Described alkali is selected from one or more in KOH, NaOH, LiOH, and the mole number of described alkali is more than or equal to 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) mole number of carbamate; Be preferably greater than and equal 1, be less than or equal to 5; Be more preferably 2.
The volume of described water is more than or equal to 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) 0.5 times (ml:g) of carbamate quality, be preferably greater than and equal 2 times (ml:g), be less than or equal to 20 times (ml:g), most preferably be and be more than or equal to 4 times (ml:g), be less than or equal to 10 times (ml:g).
The first organic solvent described is preferably tetrahydrofuran (THF), and described the second organic solvent is preferably toluene.
The present invention still further provides a kind of 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) preparation method of carbamate, it contains following steps:
At (S)-N, in the toluene solution of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, add N, N-diisopropylethylamine, chloroformate-1-chloro-ethyl ester, in the reaction of 20 DEG C-reflux temperature, preferably 35 DEG C-45 DEG C reactions, react rear washing, concentration of reaction solution, wherein:
Described N, the mole number of N-diisopropylethylamine is (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine mole number 1% and more than, be preferably greater than and equal (S)-N, 5% of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine mole number, be less than or equal to the mole number of (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine;
The mole number of described chloroformate-1-chloro-ethyl ester is more than or equal to (S)-N, 90% of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine mole number, be less than or equal to 5 times of (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine mole number; Be preferably greater than and equal 1.1 times, be less than or equal to 2 times; Be more preferably and equal 1.2 times.
Washing step after described reaction completes is the solution washing of the aqueous solution using mineral alkali successively, dilute hydrochloric acid, mineral alkali; Or first with dilute hydrochloric acid washing, then with the solution washing of mineral alkali; Or first use the aqueous solution of mineral alkali, dilute hydrochloric acid washs, then with one or both washings in water, saturated aqueous common salt.The aqueous solution of wherein said mineral alkali is selected from the NaOH aqueous solution, the KOH aqueous solution, the LiOH aqueous solution, NaHCO 3the aqueous solution, Na 2cO 3the aqueous solution, KHCO 3the aqueous solution, K 2cO 3the aqueous solution, LiHCO 3the aqueous solution, Li 2cO 3one or more in the aqueous solution, ammoniacal liquor.
The processing mode that the present invention further provides again the above-mentioned toluene solution containing duloxetine is as follows: add oxalic acid-ethanolic soln, stirs, and filters, adds ethyl acetate, water, K 2cO 3, stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride.
Present invention applicant finds when conventionally disclosed synthetic method synthesizes duloxetine, (S)-N, ester hydrolysis reaction is there is in the intermediate methyl generated after N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine and phenyl chloroformate or Vinyl chloroformate react-[3-(1-naphthyloxy)-3-(2-thienyl)] third phenyl carbamate or methyl-[3-(1-naphthyloxy)-3-(2-thienyl)] propyl urethane in propylene glycol or DMSO, temperature of reaction is when 50-60 DEG C, react completely and need expend about 50-55 hour, temperature of reaction is 70 DEG C-90 DEG C time, react completely and need expend 35-48 hour, when temperature of reaction reaches 110 DEG C-reflux temperature, although reaction can at 1.5 hours-3 hours energy completely, but because temperature of reaction is too high, cause in production and be difficult to control, bring too high energy consumption simultaneously, therefore, long reaction times when temperature is lower and too high temperature of reaction are for production, all larger unfavorable factors.
The solvent that present inventor attempts reacting by changing (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine and phenyl chloroformate or Vinyl chloroformate the rear intermediate basic hydrolysis generated obtains preferably reaction effect.Present inventor is known when the reaction solvent using dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, tetrahydrofuran (THF) etc. as basic hydrolysis one step in an experiment, when 50 DEG C of reactions, reacts and just can carry out completely in 50-60 hour.When macromolecule alkali for hydrolysis in methyl alcohol, ethanol, Virahol, butanols equal solvent in time carrying out for 50 DEG C, the time reacted completely was more than 50 hours.Investigate with toluene further, methylene dichloride, trichloromethane, 2-methyltetrahydrofuran, hexones etc. are as the solvent of methyl-[3-(1-naphthyloxy)-3-(2-thienyl)] third phenyl carbamate or methyl-[3-(1-naphthyloxy)-3-(2-thienyl)] propyl urethane basic hydrolysis, but reaction is carried out extremely slow, consider to add benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, three normal-butyl ammoniums, chain polyoxyethylene glycol, the phase-transfer catalysts such as cyclic crown ether are in order to improve speed of reaction, found that and add phase-transfer catalyst in above-mentioned solvent, although the speed of reaction of reacting and carrying out when lesser temps can be improved, but post-reaction treatment difficulty is larger, organic solvent and the waste liquid amount of the required use of extraction roll up.
US20090093645A1 embodiment 6 discloses with (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine and chloroformate-1-chloro-ethyl ester post-reaction treatment in toluene, add methyl alcohol, 25 DEG C are stirred 16 hours, 30 DEG C are stirred 24 hours, add the method that acetone stirs 2 days crystallizatioies prepare duloxetine hydrochloride at 20 DEG C, the present inventor is on the basis of the prior art, this reaction reflux in methyl alcohol is attempted to carry out, although find that the reaction times shortens to 10 hours and can react completely, but generate relatively large by product, purifying further, greatly reduce product yield, present inventor attempts using ethanol instead, other conventional alcoholic solvents such as Virahol are as reaction solvent, and raise temperature of reaction to backflow, TLC monitors, reaction completes 15 hours and 20 hours respectively, and the by product of reaction is still more, attempt with ethyl acetate, acetonitrile, methyl tertiary butyl ether, isopropyl acetate, the alternative acetone such as methyl isopropyl Ketone, to crystallization time shorten can be made, but discovery crystallization time in above-mentioned solvent is still extremely slow, and the crystalline state separated out is superfine little, be difficult to suction filtration.
The present inventor attempts 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine and chloroformate-1-chloro-ethyl ester post-reaction treatment in toluene obtained)-propyl group) in all kinds of SOLVENTS, there is macromolecule alkali for hydrolysis in carbamate.Through lot of experiments, obtain 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) carbamate in tetrahydrofuran (THF) or dioxane in 20 DEG C-reflux temperature generation macromolecule alkali for hydrolysis, the simultaneously volume of tetrahydrofuran (THF) or dioxane and 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) mass ratio of carbamate is for being more than or equal to 1(ml:g), be less than or equal to 30(ml:g), the quality of water is more than or equal to 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) 0.5 times (ml:g) of carbamate quality time, reaction can be carried out completely in 25 hours, and due to the boiling point of tetrahydrofuran (THF) and dioxane lower, employing is not needed to add large water gaging during aftertreatment, the mode repeatedly extracted with a large amount of organic solvent again after adjust ph is carried out, make the amount of the industrial effluent produced in reacting compared with prior art, greatly reduce, environmental protection, and temperature of reaction is low, reaction times is short, operation is succinct, energy consumption is low, very be applicable to industrialization scale operation duloxetine.And when temperature of reaction is carried out at 50 DEG C-reflux temperature, reaction can be carried out completely in 3-7 hour.
When the volume of water is more than or equal to 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) 2 times (ml:g) of carbamate quality, be less than or equal to 20 times (ml:g), most preferably be and be more than or equal to 4 times (ml:g), be less than or equal to 10 times (ml:g); The volume of organic solvent and 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) mass ratio of carbamate is preferably greater than and equals 2(ml:g), be less than or equal to 20(ml:g), most preferably be and be more than or equal to 4(ml:g), be less than or equal to 10(ml:g), can promote that reaction is carried out smoothly, the Industry Waste liquid measure produced in reacting can be controlled again better.
Mole number and 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base when alkali)-propyl group) ratio of mole number of carbamate is more than or equal to 1, be less than or equal to 5, when most preferably being 2, can promote that reaction is carried out smoothly, the amount of more alkali, can not obtain more useful effect.
Present invention applicant finds that monitoring reaction at TLC carries out completely, concentration of reaction solution is extremely without after tetrahydrofuran (THF) or dioxane, if add the duloxetine product of ethyl acetate, butylacetate, methyl tertiary butyl ether, methyl iso-butyl ketone (MIBK) equal solvent extraction generation, after generating the solution of duloxetine, add the alcohol solution salify of oxalic acid again or add hydrochloric acid salify, can cause separate out Duloxetine oxalate or hydrochloride very tiny, be difficult to stir and filter.When adopting toluene as the organic solvent of extraction duloxetine after reaction, and becoming oxalate or hydrochloride in the toluene solution of the duloxetine formed, crystallization can be made comparatively large, easily stir and filter.
comparative example 1
According to the method for Chinese patent CN200910216339.4 or the method according to US Patent No. 5491243 embodiment 2, by (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine 1.41mol (441g) and diisopropyl ethyl amine, phenyl chloroformate react complete and successively with the NaHCO3 aqueous solution in toluene, dilute hydrochloric acid, after NaHC03 solution washing, boil off toluene, add 4L dimethyl sulfoxide (DMSO), solution is heated to 45 DEG C, then slowly drips 226g (5.60mol) NaOH/1200ml water.This alkaline solution is heated to 70 DEG C and stirs 48h, add the dilution of 5L frozen water, then adding 2160ml acetic acid adjust pH is 5.0 ~ 5.5.Add 4500ml normal hexane, by solution stirring 10 minutes, layering.It is 11 ~ 12 that aqueous phase adds 1000g50%NaOH adjust pH, then adds 2500ml × 3 extraction into ethyl acetate, and the saturated NaCI solution in organic phase 300ml × 2 is washed, and then boils off ethyl acetate, dry, obtains succinol 420g.
This succinol is dissolved in toluene, adds oxalic acid-ethanolic soln 532g (177g oxalic acid dihydrate/355g dehydrated alcohol), stir, filter, add ethyl acetate 2.5L, water, K 2cO 3560g, stirs, separates ethyl acetate layer, add concentrated hydrochloric acid 58.1g, stir, filter, obtain duloxetine hydrochloride 198.1g, from (S)-N, it is 42% that N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine plays total recovery, optical purity 99.9%, purity 99.8%.
comparative example 2
According to method disclosed in US2009/0093645A1 embodiment 6, by S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine 850g is dissolved in 5L toluene, with diisopropyl ethyl amine, chloroformate-1-chloro-ethyl ester is after completion of the reaction with after NaOH solution 2L washing, add 5L methyl alcohol, stir 16 hours at 25 DEG C, 30 DEG C are stirred 24 hours, methyl alcohol at 30 DEG C by evaporate to dryness, add 5L acetone, 2 days crystallizatioies are stirred at 20 DEG C, filter, filter cake washing (3 × 0.5L), dry, obtain duloxetine hydrochloride 356.5g, from (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine plays total recovery 39%, optical purity 99.2%, purity 98.5%.
comparative example 3
Disclosed in the embodiment 2 of the Chinese patent CN87108175 applied for according to Yuan Yan company, method is by (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine 1.79g (0.0058mol) and phenyl chloroformate react complete and successively with the NaOH aqueous solution in toluene, hydrochloric acid soln, after the NaCl aqueous solution and water washing, boil off toluene, the carbamate 2.4g (0.0058mol) obtained is dissolved in propylene glycol (100ml), 110 DEG C of reaction 75min are heated to the 5NNaOH aqueous solution (11.5ml), cooling, dilute with 100ml water and use ether 90ml × 3 to extract, organic phase washed with water and saturated nacl aqueous solution washing, organic phase is through anhydrous sodium sulfate drying, obtain 1.4g oily matter.
According to the salifying method identical with comparative example 1 and ratio, oily matter is dissolved in toluene, adds oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3, stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 776mg, from (S)-N, it is 40.2% that N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine plays total recovery, optical purity 99.5%, purity 99.5%.
comparative example 4
By (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine 158g (0.508mol) and chloroformate-1-chloro-ethyl ester 79.9g(0.559mol), diisopropyl ethyl amine 6.5g(0.0508mol) in toluene solution 35 DEG C-45 DEG C react completely after, use the 5%NaOH aqueous solution successively, 5% hydrochloric acid soln, 5%NaHCO 3after solution washing, concentrating under reduced pressure flows out to without toluene fraction, is added by THF1L, water 1L is added, stirs, then add KOH(57g, 1.1mol) stir, be warmed up to 60 DEG C, be incubated 4 hours, TLC monitoring reacts completely, and 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 1L to extract, toluene layer tap water 500mL × 2 wash twice, and salt solution 500mL washs once, obtains the toluene solution of duloxetine.
According to the salifying method identical with comparative example 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3, stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 88.36g, from (S)-N, it is 52.0% that N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine plays total recovery, optical purity 99.9%, purity 99.8%.
About in above-mentioned comparative example, urethane reaction becomes generation, the temperature of reaction of this step waste reaction solution of duloxetine, the contrast in reaction times etc. is as shown in the table, wherein, in industrialization scale operation, every batch of 100kg(S) industrial effluent waste liquid (L)/100kg raw material that the carbamate of-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine produces represents:
Comparative example Urethane reaction becomes the time of duloxetine Carbamate hydrolysising reacting temperature Waste liquid (L)/100kg raw material Other
1 48 hours 70℃ 5750 ---------------------
2 40 hours (crystallization also needs 48 hours) 25℃-30℃ 1176 Yield and the purity of the method gained duloxetine hydrochloride are lower, if again to finished product recrystallization, though can promote purity, yield will decline further
3 75 minutes 110℃ 26899 Too high temperature of reaction, makes there is certain risk to operator during monitoring temperature in reaction process, and power consumption is large, and ether is inflammable, explosive, is not too applicable to being applied to large-scale industrial production
4 4 hours 60℃ 1898 ----------------
As can be seen from above comparative example, the prior art that urethane reaction of the present invention becomes the preparation method of duloxetine more above-mentioned than other is more suitable for large-scale industrial production duloxetine.
Below in conjunction with specific embodiment, set forth the present invention further.But these embodiments are only limitted to the present invention instead of the further restriction to protection scope of the present invention are described.
embodiment 1
(S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propanamine oxalate (204g, 0.508mol) is added flask, adds toluene 1L, water 1L, stir, add K 2cO 3200g, stirs 30min, and after dissolution of solid is complete, layering, toluene layer tap water 500mL washs 1 time, then washs 1 time with salt solution 500mL, MgSO 4drying, filters, adds N in toluene, N-diisopropylethylamine (6.5g, 0.0508mol) stirs, by chloroformate-1-chloro-ethyl ester (87.2g, 0.61) be added drop-wise in reaction solution, control temperature is at 35 DEG C-45 DEG C, and insulated and stirred 3h, TLC monitoring reacts completely after conversion, cool to 20 DEG C, add 5%NaOH aqueous solution 500mL to wash, toluene layer washs once with 5% hydrochloric acid 500mL again, 5%NaHCO 3salt solution 500mL washs once, and 55 DEG C of concentrating under reduced pressure flow out to without toluene fraction, obtain 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) carbamate (184.7g, 0.46mol)
THF1L is added, water 1L is added, stir, then add KOH(57g, 1.1mol) stir, be warmed up to 55 DEG C, insulation 4h, TLC monitoring reacts completely, and 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 1L and extract.
In the toluene solution of duloxetine, add oxalic acid-ethanolic soln (oxalic acid dihydrate 64g/128g dehydrated alcohol), stir, filter, add ethyl acetate 1.2L, water, K 2cO 3259g, stir, separate ethyl acetate layer, add concentrated hydrochloric acid 29.5g, stir, filter, obtain duloxetine hydrochloride 100.7g, playing total recovery from (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propanamine oxalate is 59.4%, optical purity 99.9%, purity 99.8%.
embodiment 2
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), THF2020ml, water 2020ml, stir, add NaOH(80g again, 2mol) stir, be warmed up to reflux temperature, be incubated 3 hours, TLC monitoring reacts completely, 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 2000ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3, stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 197g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 59.0% carbamate, optical purity 99.9%, purity 99.7%.
embodiment 3
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), THF808ml, water 808ml, stir, add NaOH(200g again, 5mol) stir, be warmed up to 55 DEG C, be incubated 4 hours, TLC monitoring reacts completely, 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 808ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 180.6g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 54.0% carbamate, optical purity 99.9%, purity 99.6%.
embodiment 4
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), THF808ml, water 8080ml, stir, add NaOH(80g again, 2mol) stir, be warmed up to 55 DEG C, be incubated 4 hours, TLC monitoring reacts completely, 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 4040ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 184.6g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 55.2% carbamate, optical purity 99.9%, purity 99.6%.
embodiment 5
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), THF8080ml, water 808ml, stir, add NaOH(80g again, 2mol) stir, be warmed up to 55 DEG C, be incubated 4 hours, TLC monitoring reacts completely, 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 404ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 185.3g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 55.4% carbamate, optical purity 99.9%, purity 99.6%.
embodiment 6
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), THF4040ml, water 4040ml, stir, add NaOH(80g again, 2mol) stir, be warmed up to 50 DEG C, be incubated 4 hours, TLC monitoring reacts completely, 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 2020ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 195.3g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 58.4% carbamate, optical purity 99.9%, purity 99.8%.
embodiment 7
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), THF12120ml, water 1616ml, stir, add NaOH(80g again, 2mol) stir, be warmed up to 55 DEG C, be incubated 4 hours, TLC monitoring reacts completely, 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 1500ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 194.3g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 58.1% carbamate, optical purity 99.8%, purity 99.8%.
embodiment 8
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), THF1616ml, water 12120ml, stir, add NaOH(80g again, 2mol) stir, be warmed up to 55 DEG C, be incubated 4 hours, TLC monitoring reacts completely, 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 6060ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 184.3g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 55.1% carbamate, optical purity 99.8%, purity 99.8%.
embodiment 9
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), THF404ml, water 2020ml, stir, add NaOH(80g again, 2mol) stir, be warmed up to 55 DEG C, be incubated 4 hours, TLC monitoring reacts completely, 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 2000ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 167.6g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 50.1% carbamate, optical purity 99.6%, purity 99.5%.
embodiment 10
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), THF2020ml, water 202ml, stir, add NaOH(80g again, 2mol) stir, be warmed up to 55 DEG C, be incubated 4 hours, TLC monitoring reacts completely, 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 200ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 168.9g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 50.5% carbamate, optical purity 99.5%, purity 99.5%.
embodiment 11
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), dioxane 2020ml, water 2020ml, stir, add NaOH(80g again, 2mol) stir, be warmed up to 50 DEG C, be incubated 7 hours, TLC monitoring reacts completely, 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 2000ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 195.7g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 58.5% carbamate, optical purity 99.8%, purity 99.8%.
embodiment 12
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), dioxane 2020ml, water 2020ml, stir, add NaOH(80g again, 2mol) stir, be warmed up to reflux temperature, be incubated 5 hours, TLC monitoring reacts completely, 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 2000ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 196.7g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 58.8% carbamate, optical purity 99.8%, purity 99.8%.
embodiment 13
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), THF2020ml, water 2020ml, stirs, then adds NaOH(40g, 1mol) stir, 20 DEG C of insulations 20 hours, TLC monitoring reacts completely, and 50 DEG C are evaporated to and flow out without THF, cool to 20 DEG C, add toluene 2000ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 182.3g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 54.5% carbamate, optical purity 99.6%, purity 99.7%.
embodiment 14
1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base is added in reaction vessel)-propyl group) carbamate 404g (1mol), dioxane 2020ml, water 2020ml, stirs, then adds NaOH(40g, 1mol) stir, 20 DEG C of insulations 25 hours, TLC monitoring reacts completely, and 50 DEG C are evaporated to and flow out without THF, cool to 20 DEG C, add toluene 200ml and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 184.3g, from 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) total recovery is 55.1% carbamate, optical purity 99.7%, purity 99.6%.
embodiment 15
At (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine (206.8g, N is added in toluene solution 0.508mol), N-diisopropylethylamine (3.29g, 0.0254mol) stir, by chloroformate-1-chloro-ethyl ester (145.3g, 1.01mol) be added drop-wise in reaction solution, control temperature is at reflux temperature, insulated and stirred 1 hour, after TLC monitoring reacts completely and transforms, cool to 20 DEG C, add 5%NaOH aqueous solution 500mL to wash, toluene layer washs once with 5% hydrochloric acid 500mL again, water 500ml washs once, salt solution 500mL washs once, 55 DEG C of concentrating under reduced pressure flow out to without toluene fraction, obtain 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) carbamate (176.5g, 0.44mol)
THF1L is added, water 1L is added, stir, then add KOH(57g, 1.1mol) stir, be warmed up to 55 DEG C, insulation 4h, TLC monitoring reacts completely, and 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 1L and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3, stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 88.4g, from S)-N, it is 52.0% that N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine plays total recovery, optical purity 99.7%, purity 99.5%.
embodiment 16
By (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine (206.8g, add DIPEA (65.7g, 0.508mol) in toluene solution 0.508mol) to stir, by chloroformate-1-chloro-ethyl ester (79.9g, 0.56mol) be added drop-wise in reaction solution, control temperature at 20 DEG C, insulated and stirred 5 hours, TLC monitoring adds 5%NaHCO after reacting completely and transforming 3aqueous solution 500mL washs, toluene layer washs once with 5% hydrochloric acid 500mL again, water 500ml washs once, salt solution 500mL washs once, 55 DEG C of concentrating under reduced pressure flow out to without toluene fraction, obtain 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) carbamate (180.6g, 0.45mol)
THF1L is added, water 1L is added, stir, then add KOH(57g, 1.1mol) stir, be warmed up to 55 DEG C, insulation 4h, TLC monitoring reacts completely, and 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 1L and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3, stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 92.6g, from (S)-N, it is 54.5% that N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine plays total recovery, optical purity 99.6%, purity 99.6%.
embodiment 17
By (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine (206.8g, add DIPEA (0.66g, 0.00508mol) in toluene solution 0.508mol) to stir, by chloroformate-1-chloro-ethyl ester (87.2g, 0.61mol) be added drop-wise in reaction solution, control temperature at 40 DEG C, insulated and stirred 8 hours, after TLC monitoring reacts completely, add 5%KHCO 3aqueous solution 500mL washs, toluene layer washs once with 5% hydrochloric acid 500mL again, water 500ml washs once, salt solution 500mL washs once, 55 DEG C of concentrating under reduced pressure flow out to without toluene fraction, obtain 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) carbamate (165.6g, 0.41mol)
THF1L is added, water 1L is added, stir, then add KOH(56g, 1.0mol) stir, be warmed up to 55 DEG C, insulation 4h, TLC monitoring reacts completely, and 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 1L and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3, stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 80.7g, from (S)-N, it is 47.5% that N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine plays total recovery, optical purity 99.5%, purity 99.5%.
embodiment 18
By (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine (206.8g, add DIPEA (78.9g, 0.6mol) in toluene solution 0.508mol) to stir, by chloroformate-1-chloro-ethyl ester (65.8g, 0.46mol) be added drop-wise in reaction solution, control temperature at 40 DEG C, insulated and stirred 3 hours, after TLC monitoring reacts completely, add 5%KHCO 3aqueous solution 500mL washs, toluene layer washs once with 5% hydrochloric acid 500mL again, water 500ml washs once, salt solution 500mL washs once, 55 DEG C of concentrating under reduced pressure flow out to without toluene fraction, obtain 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) carbamate (169.6g, 0.42mol)
THF1L is added, water 1L is added, stir, then add KOH(56g, 1.0mol) stir, be warmed up to 55 DEG C, insulation 4h, TLC monitoring reacts completely, and 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 1L and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3, stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 87.2g, from (S)-N, it is 51.3% that N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine plays total recovery, optical purity 99.7%, purity 99.6%.
embodiment 19
By (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine (206.8g, add DIPEA (6.5g, 0.05mol) in toluene solution 0.508mol) to stir, by chloroformate-1-chloro-ethyl ester (363.2g, 2.54mol) be added drop-wise in reaction solution, control temperature at 40 DEG C, insulated and stirred 3 hours, after TLC monitoring reacts completely, add 5%KHCO 3aqueous solution 500mL washs, toluene layer washs once with 5% hydrochloric acid 500mL again, water 500ml washs once, salt solution 500mL washs once, 55 DEG C of concentrating under reduced pressure flow out to without toluene fraction, obtain 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) carbamate (161.6g, 0.40mol)
THF1L is added, water 1L is added, stir, then add KOH(56g, 1.0mol) stir, be warmed up to 55 DEG C, insulation 4h, TLC monitoring reacts completely, and 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 1L and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3, stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 78.3g, from (S)-N, it is 46.1% that N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine plays total recovery, optical purity 99.5%, purity 99.5%.
embodiment 20
By (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine (206.8g, add DIPEA (6.5g, 0.05mol) in toluene solution 0.508mol) to stir, by chloroformate-1-chloro-ethyl ester (145.3g, 1.01mol) be added drop-wise in reaction solution, control temperature at 40 DEG C, insulated and stirred 3 hours, after TLC monitoring reacts completely, add 5%KHCO 3aqueous solution 500mL washs, toluene layer washs once with 5% hydrochloric acid 500mL again, water 500ml washs once, salt solution 500mL washs once, 55 DEG C of concentrating under reduced pressure flow out to without toluene fraction, obtain 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) carbamate (174.4g, 0.43mol)
THF1L is added, water 1L is added, stir, then add KOH(56g, 1.0mol) stir, be warmed up to 55 DEG C, insulation 4h, TLC monitoring reacts completely, and 50 DEG C are evaporated to without THF outflow, cool to 20 DEG C, add toluene 1L and extract.
According to the salifying method identical with embodiment 1 and ratio, in the toluene solution of duloxetine, add oxalic acid-ethanolic soln, stir, filter, add ethyl acetate, water, K 2cO 3, stir, separate ethyl acetate layer, add concentrated hydrochloric acid, stir, filter, obtain duloxetine hydrochloride 93.8g, from (S)-N, it is 55.3% that N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine plays total recovery, optical purity 99.7%, purity 99.7%.

Claims (11)

1. prepare the method for duloxetine for one kind, it is characterized in that water, the first organic solvent, 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) carbamate, alkali reacts under 50 DEG C-reflux temperature, after reacting completely, concentration of reaction solution, the solution containing duloxetine is obtained after adding the second organic solvent extraction again, wherein, the first organic solvent described is tetrahydrofuran (THF), and the first organic solvent and 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) the volume mass ratio of carbamate is more than or equal to 1(ml:g), be less than or equal to 30(ml:g), described the second organic solvent is toluene, described alkali is selected from one or more in KOH, NaOH, LiOH, and the mole number of described alkali is greater than 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) mole number of carbamate, the volume of described water is more than or equal to 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) 0.5 times (ml:g) of carbamate quality,
Wherein, described 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) preparation method of carbamate contains following steps: at (S)-N, in the toluene solution of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, add N, N-diisopropylethylamine, chloroformate-1-chloro-ethyl ester, react at 20 DEG C-reflux temperature, react rear washing, concentration of reaction solution, wherein: described N, the mole number of N-diisopropylethylamine is for being more than or equal to (S)-N, 5% of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine mole number, be less than or equal to (S)-N, the mole number of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, the mole number of described chloroformate-1-chloro-ethyl ester is for being more than or equal to (S)-N, 1.1 times of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine mole number, be less than or equal to 2 times of (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine mole number.
2. preparation method according to claim 1, it is characterized in that the volume of water is more than or equal to 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) 2 times (ml:g) of carbamate quality, be less than or equal to 20 times (ml:g).
3. preparation method according to claim 1, it is characterized in that the volume of water is more than or equal to 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) 4 times (ml:g) of carbamate quality, be less than or equal to 10 times (ml:g).
4. preparation method according to claim 1, it is characterized in that the first organic solvent and 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) ratio of volume mass of carbamate is for being more than or equal to 2(ml:g), be less than or equal to 20(ml:g).
5. preparation method according to claim 4, it is characterized in that the first organic solvent and 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) ratio of volume mass of carbamate is for being more than or equal to 4(ml:g), be less than or equal to 10(ml:g).
6. preparation method according to claim 1, is characterized in that alkali and 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) ratio of mole number of carbamate is greater than 1, is less than or equal to 5.
7. preparation method according to claim 6, is characterized in that alkali and 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) ratio of mole number of carbamate is 2.
8. preparation method according to claim 1, is characterized in that the mole number of described chloroformate-1-chloro-ethyl ester is 1.2 times of (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine mole number.
9. preparation method according to claim 1, it is characterized in that described (S)-N, in the toluene solution of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, add DIPEA, the post-reacted temperature of chloroformate-1-chloro-ethyl ester is 35 DEG C-45 DEG C.
10. preparation method according to claim 1, it is characterized in that described 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-oxygen base)-3-(thiophene-2-base)-propyl group) carbamate preparation method in reacted after washing step be the solution washing of the aqueous solution using mineral alkali successively, dilute hydrochloric acid, mineral alkali; Or first with dilute hydrochloric acid washing, then with the solution washing of mineral alkali; Or first use the aqueous solution of mineral alkali, dilute hydrochloric acid washs, then with one or both washings in water, saturated aqueous common salt.
11. preparation methods according to claim 10, is characterized in that the aqueous solution of described mineral alkali is selected from the NaOH aqueous solution, the KOH aqueous solution, the LiOH aqueous solution, NaHCO 3the aqueous solution, Na 2the CO3 aqueous solution, KHCO 3the aqueous solution, K 2cO 3the aqueous solution, LiHCO 3the aqueous solution, Li 2cO 3one or more in the aqueous solution, ammoniacal liquor.
CN201210577678.7A 2012-12-27 2012-12-27 A kind of synthetic method of duloxetine Expired - Fee Related CN103896910B (en)

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