CN103172610B - A kind of preparation method of duloxetine hydrochloride - Google Patents
A kind of preparation method of duloxetine hydrochloride Download PDFInfo
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- CN103172610B CN103172610B CN201110437902.8A CN201110437902A CN103172610B CN 103172610 B CN103172610 B CN 103172610B CN 201110437902 A CN201110437902 A CN 201110437902A CN 103172610 B CN103172610 B CN 103172610B
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- duloxetine
- hydrochloride
- ethyl acetate
- methylene dichloride
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Abstract
The present invention relates to a kind of method preparing duloxetine hydrochloride, become hydrochloride to react by duloxetine, described reaction with the not miscible organic solvent of water for reaction solvent, add saturated brine solution in simultaneous reactions liquid, to add concentration be the hydrochloric acid of 1 ~ 8N is 1 ~ 5 to reaction solution pH.Salifying method reaction conditions of the present invention is gentle, simple to operate, and substantially increases product yield and optical purity, reduces operation easier and danger, is more suitable for suitability for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, be specifically related to a kind of preparation method of duloxetine hydrochloride.
Background technology
Duloxetine hydrochloride (DuloxetineHydrochloride, structural formula is such as formula shown in I), chemical name is (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thiophene)-propylamine, a kind of 5-hydroxyl look ammonia and NRI (SNRI) developed by EliLilly company of the U.S., in August, 2004 U.S. FDA approval listing, commodity are called Cymbalta(glad hundred and reach), be used for the treatment of dysthymia disorders.
。
Duloxetine hydrochloride is optically active substance, and its enantiomer does not have antidepressant activity.Therefore, must limit its optical purity in duloxetine hydrochloride raw material.
Salifying method in duloxetine hydrochloride preparation method disclosed in prior art document mainly contains following several.
1. concentrated hydrochloric acid is adopted to be souring agent, as:
CN102070602 discloses a kind of synthesis technique of duloxetine hydrochloride, and salifying process is wherein: dissolved by duloxetine anhydrous diethyl ether, at-1 ~ 0 DEG C, add concentrated hydrochloric acid inwards to stir, then add acetone crystallization, obtain duloxetine hydrochloride, yield about 68%, as shown in flow process 1:
Flow process 1
In present method, adopt concentrated hydrochloric acid to be souring agent salify, easily produce by product and chiral structure racemization, reduce optical purity, the quality of product is affected; Use ether to do reaction solvent, production uses more dangerous, not easily industrialization.
2. the organic solvent solution of hydrochloric acid is adopted to be souring agent, as:
CN101391991 discloses a kind of preparation method of duloxetine, salifying process is wherein: by duloxetine acetic acid ethyl dissolution, at-5 DEG C, add hydrochloric ethyl acetate solution, stirring and crystallizing, then place in refrigerator-freezer and spend the night, filtering and washing, obtain duloxetine hydrochloride, yield about 55%, as shown in flow process 2:
Flow process 2
In present method, at-5 DEG C of crystallizatioies, then growing the grain in refrigerator-freezer, use temperature is lower, more difficult control, and yield is low, only has about 55%.
3. dry hydrogen chloride gas is adopted to be souring agent, as:
Chinese Journal of New Drugs 2005,14 (1), 74-76 discloses a kind of preparation method of duloxetine, and salifying process disclosed in it is: take Duloxetine oxalate as raw material, uses ethyl acetate and water as solvent, after ammonia neutralization, ethyl acetate is concentrated into dry mutually, then uses ether dissolution, then logical dry hydrogen chloride gas, obtain duloxetine hydrochloride crude product, yield about 58%.As shown in flow process 3:
Flow process 3
In present method, use ether to do reaction solvent, and use hydrogen chloride gas salify, operate more difficult control, production uses more dangerous, not easily industrialization, big for environment pollution.
4. chlorination ammonium salt is adopted to be souring agent, as:
Czech patents CZ297555 discloses a kind of preparation method of duloxetine hydrochloride, and salifying method disclosed in it is: duloxetine and following structural compounds carry out salt-forming reaction, and temperature of reaction is back flow reaction, and yield is 55%,
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To sum up, the operation of the salifying process of duloxetine hydrochloride preparation method disclosed in prior art is difficult to control, and product yield is low, and gained crude product optical purity is poor, need carry out purifying, be unfavorable for industrialization through repeatedly recrystallization.
Summary of the invention
In view of prior art Problems existing, contriver has carried out large quantity research for the salt-forming reaction technique being prepared duloxetine hydrochloride by duloxetine, adopt ethanol solution hydrochloride, hydrochloric acid acetone soln, dilute hydrochloric acid etc. to be souring agent as attempted, although the optical purity of duloxetine hydrochloride crude product can be improved in various degree, but yield is still lower, have even no more than prior art yield, as adopt dilute hydrochloric acid be souring agent, product yield only has about 50%.Accidental, contriver, when adopting dilute hydrochloric acid to be souring agent, adds saturated nacl aqueous solution in reaction solution, unexpected discovery, products obtained therefrom not only optical purity reaches more than 98%, and yield also increases substantially, unexpectedly reach more than 90%, and reaction conditions is gentle, easy handling.
Therefore, main purpose of the present invention there are provided a kind of method preparing duloxetine hydrochloride, become hydrochloride to react by duloxetine, it is characterized in that, described reaction take water-insoluble organic solvents as reaction solvent, add saturated brine solution in simultaneous reactions liquid, to add concentration be the hydrochloric acid of 1 ~ 8N is 1 ~ 5 to reaction solution pH.
Wherein: in described saturated brine solution, the weight ratio of salt and duloxetine is 1 ~ 20:1,1 ~ 10:1 is preferably; Described salt is selected from one or more the mixture in sodium-chlor, ammonium chloride, brometo de amonio, ammonium sulfate, is preferably sodium-chlor, ammonium chloride.
Described concentration of hydrochloric acid is preferably 1 ~ 4N.
The described organic solvent not miscible with water refers to completely water insoluble or in water, has the organic solvent of less solubleness, is preferably solubleness in water and is less than the organic solvent of 10g/100g water (15 ~ 25 DEG C).Preferably, reaction solvent is selected from C
1 ~ 4halohydrocarbon, C
2 ~ 6ester in one or more mixed solvent; Wherein, described C
1 ~ 4halohydrocarbon be selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, 1,1-ethylene dichloride, consider from the ready availability and toxicity angle of raw material, be preferably methylene dichloride; C
2 ~ 6ester be selected from methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, butylacetate, consider from the ready availability and toxicity angle of raw material, be preferably ethyl acetate.When reaction solvent be methylene dichloride and ethyl acetate mixed solvent time, reaction and aftertreatment best results, the volume ratio of methylene dichloride and ethyl acetate is 1:1 ~ 20, preferably 1:1 ~ 10.
The added hydrochloric acid content of reaction be preferably to reaction solution pH be 2 ~ 4.
Temperature of reaction is 10 ~ 50 DEG C, is preferably 20 ~ 35 DEG C.
Beneficial effect of the present invention is: 1. saturated brine solution and hydrochloric acid soln are mixed to form buffer system, makes salt-forming reaction mild condition, avoids the racemization of duloxetine chiral centre, and products obtained therefrom optical purity is high, and namely crude product reaches more than 98%; 2. use saturated salt solution, decrease duloxetine hydrochloride content in aqueous phase, greatly improve product yield, reach more than 90%.3. use low-concentration hcl, reduce operation easier and danger, be more suitable for suitability for industrialized production.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiments do not form any restriction to the present invention.
Embodiment 1: the preparation of duloxetine hydrochloride (I)
In a kettle., add duloxetine 1Kg(3.36mol), 1L methylene dichloride, 5L ethyl acetate, adds 8Kg saturated ammonium chloride solution under stirring, dripping 1N hydrochloric acid soln at 20 DEG C to pH is 1 ~ 2, stirring reaction 2h.Phase-splitting, aqueous phase 2L extraction into ethyl acetate.Merge organic phase, decompression removing methylene dichloride, then add ethyl acetate 3L, stirring at room temperature 30min.Filter, washing, dry, obtain white solid 1.07Kg, yield 95%, HPLC purity 99.2%, optical purity (ee%) 98.5%.
Embodiment 2: the preparation of duloxetine hydrochloride (I)
In a kettle., add duloxetine 1Kg(3.36mol), 1L methylene dichloride, 10L ethyl acetate, adds 6Kg saturated ammonium chloride solution under stirring, dripping 2N hydrochloric acid soln at 30 DEG C to pH is 3 ~ 4, stirring reaction 1h.Phase-splitting, aqueous phase 2L extraction into ethyl acetate.Merge organic phase, decompression removing methylene dichloride, stirring at room temperature 30min.Filter, washing, dry, obtain white solid 1.04Kg, yield 93%, HPLC purity 99.1%, optical purity (ee%) 98.3%.
Embodiment 3: the preparation of duloxetine hydrochloride (I)
In a kettle., add duloxetine 1Kg(3.36mol), 1L methylene dichloride, 20L ethyl acetate, adds 4Kg saturated nacl aqueous solution under stirring, dripping 4N hydrochloric acid soln at 25 DEG C to pH is 4 ~ 5, stirring reaction 2h.Phase-splitting, organic phase decompression removing methylene dichloride, stirring at room temperature 30min.Filter, washing, dry, obtain white solid 1.0Kg, yield 90%, HPLC purity 99.0%, optical purity (ee%) 98.1%.
Embodiment 4: the preparation of duloxetine hydrochloride (I)
In reaction flask, add duloxetine 10g(0.0336mol), 10mL methylene dichloride, 50mL ethyl acetate, dripping 1N hydrochloric acid soln at 20 DEG C to pH is 3 ~ 4, stirring reaction 1h.Phase-splitting, aqueous phase 20mL extraction into ethyl acetate.Merge organic phase, decompression removing methylene dichloride, stirring at room temperature 30min.Filter, washing, dry, obtain white solid 5.9g, yield 52.4%, HPLC purity 98.7%, optical purity (ee%) 97.5%.
Embodiment 5: the preparation of duloxetine hydrochloride (I)
In reaction flask, add duloxetine 10g(0.0336mol), 60mL ethyl acetate, dripping 1N ethanol solution hydrochloride at 20 DEG C to pH is 2 ~ 3, stirring reaction 2h, filters, and washing is dry, obtain white solid 6.4g, yield 57.6%, HPLC purity 97.2%, optical purity (ee%) 95.3%.
Claims (3)
1. prepare the method for duloxetine hydrochloride for one kind, be become hydrochloride to react by duloxetine, it is characterized in that, in a kettle., add duloxetine 1Kg, 1L methylene dichloride, 5L ethyl acetate, adds 8Kg saturated ammonium chloride solution under stirring, dripping 1N hydrochloric acid soln at 20 DEG C to pH is 1 ~ 2, stirring reaction 2h, phase-splitting, aqueous phase 2L extraction into ethyl acetate, merge organic phase, decompression removing methylene dichloride, then add ethyl acetate 3L, stirring at room temperature 30min, filter, washing, dry, obtain duloxetine hydrochloride.
2. prepare a method for duloxetine hydrochloride, be become hydrochloride to react by duloxetine, it is characterized in that, in a kettle., add duloxetine 1Kg, 1L methylene dichloride, 10L ethyl acetate, add 6Kg saturated ammonium chloride solution under stirring, dripping 2N hydrochloric acid soln at 30 DEG C to pH is 3 ~ 4, stirring reaction 1h, phase-splitting, aqueous phase 2L extraction into ethyl acetate, merges organic phase, decompression removing methylene dichloride, stirring at room temperature 30min, filters, washing, dry, obtain duloxetine hydrochloride.
3. prepare a method for duloxetine hydrochloride, be become hydrochloride to react by duloxetine, it is characterized in that, in a kettle., add duloxetine 1Kg, 1L methylene dichloride, 20L ethyl acetate, adds 4Kg saturated nacl aqueous solution under stirring, dripping 4N hydrochloric acid soln at 25 DEG C to pH is 4 ~ 5, stirring reaction 2h, phase-splitting, organic phase decompression removing methylene dichloride, stirring at room temperature 30min, filters, washing, drying, obtains duloxetine hydrochloride.
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| CN101631783A (en) * | 2006-06-23 | 2010-01-20 | 箭锋国际有限公司 | Crystalline duloxetine hydrochloride |
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| CN101631783A (en) * | 2006-06-23 | 2010-01-20 | 箭锋国际有限公司 | Crystalline duloxetine hydrochloride |
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Effective date of registration: 20201130 Address after: 050035 No. 226, the Yellow River Avenue, hi tech Industrial Development Zone, Hebei, Shijiazhuang Patentee after: CSPC ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) Co.,Ltd. Patentee after: CSPC PHARMACEUTICAL GROUP OUYI PHARMA Co.,Ltd. Address before: 050035 No. 226, the Yellow River Avenue, Shijiazhuang, Hebei Patentee before: CSPC ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) Co.,Ltd. |
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