CN101104614A - Method of preparing (S)-dulouxetine key intermediate - Google Patents
Method of preparing (S)-dulouxetine key intermediate Download PDFInfo
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- CN101104614A CN101104614A CNA2007100283640A CN200710028364A CN101104614A CN 101104614 A CN101104614 A CN 101104614A CN A2007100283640 A CNA2007100283640 A CN A2007100283640A CN 200710028364 A CN200710028364 A CN 200710028364A CN 101104614 A CN101104614 A CN 101104614A
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- thienyl
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- propylamine
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Abstract
The present invention provides a new method for synthesizing the(S)-N, N-dimethyl-3-hydroxy-3-(2-thiophene)-propylamine which is an important intermediate of duloxetine. The invention takes 3-dimethoxy-1-(2-thiophene yl) -1-acetone hydrochlorate as raw material, adopts chiral sulfonyl-diamine ruthenium catalyst and choose formate as hydrogen source reagent to prepare (S)-N, N-dimethyl-3-hydroxy-3-(2-thiophene)-propylamine hydrochlorate in an appropriate organic solvent through the asymmetric transfer hydrogenation reaction. The method can be without the protection of nitrogen gas, which is provided with mild reaction conditions, simple operation, and high reaction yield and enantioselectivity. Therefore, the invention is expected to provide a simple and effective method for the industrialized production of (S)-duloxetine.
Description
Specification sheets
Technical field
The invention provides important intermediate (the S)-N of a kind of synthetic duloxetine, the novel method of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine.
Background technology
Duloxetine hydrochloride [(Duloxetine), chemical name is (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamin hydrochloride] be serotonin and NRI, be the medicine that is used for nervous system disorders by Lilly Co., Eli. (Eli Lilly) and Boehringer Ingelheim company (Boehinger Ingelheim) cooperative development.The clinical treatment that is mainly used in dysthymia disorders also is unique medicine that is used for the diabetes-alleviating peripheral neuralgia of present FDA approval.
At present the first-selected route of synthetic (S)-duloxetine is to be raw material with the 2-acetyl thiophene; with dimethylamine hydrochloride and Paraformaldehyde 96 the Mannich reaction taking place obtains 3-dimethylin-1-(2-thienyl)-1-acetone hydrochloride; be reduced into (R/S)-N then, N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine.Split (the S)-N that obtains high-optical-purity with (S)-(+)-amygdalic acid, N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine, obtain (S)-(+)-N with the reaction of 1-fluoronaphthalene again, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamin hydrochloride, after sloughing a methyl, N obtains duloxetine [Tetrahedron Lett at last, 1990,31 (49): 7101-7104; US5362886,1994-11-08; EP457559].At present synthetic key intermediate (S)-N, the method report of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine is more, and the method that all adopts chemistry to split basically splits [Yu Xinhong as employing (S)-(+)-amygdalic acids such as Yu Xinhong, Chinese Journal of Pharmaceuticals, 2006,37 (6)], Liu, H. wait the people to adopt lipase to split [Liu, H.Chirality, 2000,12 (1): 26-29].The highest yield of disassemble technique of this quasi-tradition is lower than 50%, and a large amount of R isomer are difficult to be fully used, thereby causes the cost of bulk drug higher.Recently, people such as Zhang X.M. adopt the hydrogenation of the complex-catalyzed 3-methylamino-1-of Rh-Duanphos (2-thienyl)-1-acetone, with very high enantioselectivity obtain intermediate (S)-N-methyl-3-hydroxyl-3-(2-thienyl) propylamine, and then synthesized (S)-duloxetine.But the synthetic difficulty of the chiral phosphine ligand Duanphos that this method is used, very responsive to oxygen, reaction needed is carried out [Zhang, X.M.et al.Angew.Chem.2005,117,1715-1717] under the oxygen free condition of strictness.Daniel, G. wait the people to adopt similar response strategy, with the Ru-bicp title complex as catalyzer, under 7 atmospheric hydrogen pressures, finish the synthetic [Daniel of intermediate (S)-N-methyl-3-hydroxyl-3-(2-thienyl) propylamine, G.et al.Angew.Chem.Int.Ed.2004,43,2816-2819].
Summary of the invention: the present invention aims to provide a kind of synthetic (S)-duloxetine important intermediate (S)-N, the novel method of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (I).This method is a raw material with 3-dimethylin-1-(2-thienyl)-1-acetone hydrochloride, adopt single sulfonic acid diamine part of chirality and the catalyzer that metal Ru constitutes, with formate as hydrogen source reagent, in appropriate organic solvent, by asymmetric transfer hydrogenation preparation (S)-N, N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamin hydrochloride.
The feature of present method is as follows:
(1) [RuX
2R
3]
2With single sulfonic acid diamine part of chirality, in the presence of triethylamine,, make the chiral ruthenium catalyst of (II) in 70-100 ℃ of following backflow 1-3 hour;
Wherein, R
1, R
2, R
4Be alkyl, thiazolinyl or aromatic group; R
3Phenyl for phenyl or replacement; X is halogen atom such as Cl, Br, I etc.
(2) after 3-dimethylin-1-(2-thienyl)-1-acetone salt (III) is dissolved in suitable organic solvent, the catalyzer (II) and the formate of mole number (III) more than 100% that add (III) mole number 0.1-20%, made (S)-N, N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (I) in 2-15 days in 20 ℃-80 ℃ reactions.
Optimum condition of the present invention is:
R in (II) in the step (1)
1And R
2Can be respectively aromatic nucleus, the aromatic nucleus of replacement, the chain type alkane of chain type alkane or replacement; R
3Benzene for benzene or alkyl replacement; X is Cl, Br, I.R
1And R
2Be preferably phenyl; R
3Be preferably 1-sec.-propyl-4-methylbenzene; The preferred Cl of X;
Temperature of reaction in the step (1) is preferably 85 ℃, and the reaction times is preferably 1.5 hours;
The solvent of being mentioned in the step (2) is methyl alcohol, ethanol, methylene dichloride, chloroform, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, benzene, toluene etc., is preferably methyl alcohol;
Formate is sodium formiate, potassium formiate, ammonium formate, magnesium formiate, calcium formiate etc. in the step (2), is preferably sodium formiate;
Catalyst consumption is the 0.1-20% of raw material (III) mole number in the step (2), is preferably 1.5-5%;
Temperature of reaction in the step (2) is 10-80 ℃, preferred 35-50 ℃; Reaction times 2-15 days, be preferably 4-8 days.
Present method reaction conditions gentleness can be reacted under the protection of nitrogen gas need not; Simple to operate, the yield of reaction and enantioselectivity height are compared with traditional method for splitting, have saved the synthetic cost of (S)-duloxetine bulk drug greatly, for the suitability for industrialized production of (S)-duloxetine provides a kind of simple and direct effective novel method.
Further specify the present invention below by embodiment.What answer correct understanding is: the preparation method in the embodiments of the invention is only used for the present invention is described and provides; rather than limitation of the present invention; so, under conception prerequisite of the present invention, simple modifications of the present invention is all belonged to the scope of protection of present invention.
Embodiment 1:
(0.8g 3.9mmol), adds 3mL methyl alcohol stirring and dissolving, adds the 0.2mL triethylamine to add 3-dimethylin-1-(2-thienyl)-1-acetone hydrochloride (III) in the round-bottomed flask of 50mL.Accurately take by weighing (IV) catalyzer (37mg, 0.061mmol) join in the above-mentioned solution after, add again sodium formiate (0.3g, 4.0mmol), in 45 ℃ the reaction 5 days.In reaction solution, add the 20mL frozen water, add NaCl again to saturated.It is 12 that water layer after the filtration is under agitation regulated pH value with the NaOH solution of 5N, with ethyl acetate extraction (20mL * 3).Merge organic layer, anhydrous Na
2SO
4Drying is filtered evaporate to dryness and is obtained (S)-N, and N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (I) (0.58g, 3.8mmol), productive rate 88%.The enantiomeric purity of product is 95%ee through gas chromatographic analysis.
Ts＝4-CH
3-C
3H
4SO
2-
Embodiment 2:
(0.8g 3.9mmol), adds 3mL methylene dichloride stirring and dissolving, adds the 0.2mL triethylamine to add 3-dimethylin-1-(2-thienyl)-1-acetone hydrochloride (III) in the round-bottomed flask of 50mL.Take by weighing (IV) catalyzer (37mg, 0.061mmol) join in the above-mentioned solution after, add again sodium formiate (0.3g, 4.0mmol), in 45 ℃ the reaction 5 days.Reaction finishes the back and add the 20mL frozen water in reaction solution, adds NaCl again to saturated.It is 12 that water layer after the filtration is under agitation regulated pH value with the NaOH solution of 5N, with ethyl acetate extraction (20mL * 3).Merge organic layer, anhydrous Na
2SO
4Drying is filtered evaporate to dryness and is obtained (S)-N, and N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (I) (0.3g, 2.1mmol), productive rate 46%.The enantiomeric purity of product is 68%ee through gas chromatographic analysis.
Embodiment 3:
(0.8g 3.9mmol), adds 3mLN, and dinethylformamide (DMF) stirring and dissolving adds the 0.2mL triethylamine to add 3-dimethylin-1-(2-thienyl)-1-acetone hydrochloride (III) in the round-bottomed flask of 50mL.Take by weighing (IV) catalyzer (37mg 0.061mmol) joins in the above-mentioned solution, add again sodium formiate (0.3g, 4.0mmol), in 45 ℃ the reaction 5 days.In reaction solution, add the 20mL frozen water, add NaCl again to saturated.It is 12 that water layer after the filtration is under agitation regulated pH value with the NaOH solution of 5N, with ethyl acetate extraction (20mL * 3).Merge organic layer, anhydrous Na
2SO
4Drying is filtered evaporate to dryness and is obtained (S)-N, and N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (I) (0.22g, 1.3mmol), productive rate 31%.The enantiomeric purity of product is 91%ee through gas chromatographic analysis.
Embodiment 4:
(0.8g 3.9mmol), adds 3mL methyl alcohol stirring and dissolving, adds the 0.2mL triethylamine to add 3-dimethylin-1-(2-thienyl)-1-acetone hydrochloride (III) in the round-bottomed flask of 50mL.Accurately take by weighing (IV) catalyzer (37mg, 0.061mmol) join in the above-mentioned solution after, add again sodium formiate (0.3g, 4.0mmol), in 55 ℃ the reaction 5 days.In reaction solution, add the 20mL frozen water, add NaCl again to saturated.It is 12 that water layer after the filtration is under agitation regulated pH value with the NaOH solution of 5N, with ethyl acetate extraction (20mL * 3).Merge organic layer, anhydrous Na
2SO
4Drying is filtered evaporate to dryness and is obtained (S)-N, and N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (I) (0.42g, 2.6mmol), productive rate 61%.The enantiomeric purity of product is 82%ee through gas chromatographic analysis.
Embodiment 5:
(0.8g 3.9mmol), adds 3mL methyl alcohol stirring and dissolving, adds the 0.2mL triethylamine to add 3-dimethylin-1-(2-thienyl)-1-acetone hydrochloride (III) in the round-bottomed flask of 50mL.Accurately take by weighing (IV) catalyzer (148mg, 0.24mmol) join in the above-mentioned solution after, add again sodium formiate (0.3g, 4.0mmol), in 45 ℃ the reaction 5 days.In reaction solution, add the 20mL frozen water, add NaCl again to saturated.It is 12 that water layer after the filtration is under agitation regulated pH value with the NaOH solution of 5N, with ethyl acetate extraction (20mL * 3).Merge organic layer, anhydrous Na
2SO
4Drying is filtered evaporate to dryness and is obtained (S)-N, and N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (I) (0.44g, 2.8mmol), productive rate 71%.The enantiomeric purity of product is 93%ee through gas chromatographic analysis.
Claims (7)
1. important intermediate (the S)-N of synthetic (S)-duloxetine, the method of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (I), this method may further comprise the steps: 3-dimethylin-1-(2-thienyl)-1-acetone or its hydrochloride (III) are dissolved in organic solvent, under single sulfonic acid diamine-ruthenium catalyst (II) catalysis of chirality, react as hydrogen source reagent generation hydrogen transfer reduction with formate, 10-80 ℃ was reacted 1-10 days down, make target product (S)-N, N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (I).
2. according to right 1 described method, it is characterized in that temperature of reaction is 10-80 ℃.Preferential 35-50 ℃.
3. method according to claim 1 is characterized in that, reaction times 1-10 days, and preferential 4-8 days.
4. method according to claim 1 is characterized in that, (II) R in
1And R
2Can be respectively aromatic nucleus, the aromatic nucleus of replacement, the chain type alkane of chain type alkane or replacement; R
3Benzene for benzene or alkyl replacement; X is Cl, Br, I.Preferred R
1And R
2Be phenyl, R
3Be 1-sec.-propyl-4-methylbenzene; X is Cl.
5. method according to claim 1 is characterized in that, the hydrogen source reagent formate that adds in the reaction system comprises sodium formiate, potassium formiate, ammonium formate, magnesium formiate, calcium formiate etc., preferable formic acid sodium.
6. method according to claim 1 is characterized in that, the consumption of single sulphonamide-ruthenium catalyst is the 0.1-20% of raw material formula (III) mole number, is preferably 1.5-5%.
7. method according to claim 1 is characterized in that reaction solvent is methyl alcohol, ethanol, methylene dichloride, chloroform, tetrahydrofuran (THF), DMSO, acetonitrile, benzene, toluene etc., is preferably methyl alcohol.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010003942A2 (en) * | 2008-07-07 | 2010-01-14 | Krka, D.D. Novo Mesto | Preparation of duloxetine and its pharmaceutically acceptable salts by the use of asymmetric transfer hydrogenation process |
| EP2426116A1 (en) * | 2010-08-30 | 2012-03-07 | Saltigo GmbH | Method for producing (S)-3-N-Methylamino-1-(2-thienyl)-1-propanol |
| CN102532097A (en) * | 2011-10-19 | 2012-07-04 | 华东理工大学 | Asymmetric synthesis method of duloxetine intermediate-(S)-N, N-dimethyl-3-hydroxy-3-(2-thienyl)-1-propylamine |
| US9162934B2 (en) | 2010-05-13 | 2015-10-20 | Kanto Kagaku Kabushiki Kaisha | Process for producing optically active alcohol |
| CN109633046A (en) * | 2019-02-22 | 2019-04-16 | 成都倍特药业有限公司 | A method of detecting dimethylamine from duloxetine hydrochloride |
-
2007
- 2007-05-30 CN CNA2007100283640A patent/CN101104614A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010003942A2 (en) * | 2008-07-07 | 2010-01-14 | Krka, D.D. Novo Mesto | Preparation of duloxetine and its pharmaceutically acceptable salts by the use of asymmetric transfer hydrogenation process |
| WO2010003942A3 (en) * | 2008-07-07 | 2010-07-22 | Krka, D.D. Novo Mesto | Preparation of duloxetine and its pharmaceutically acceptable salts by the use of asymmetric transfer hydrogenation process |
| US9162934B2 (en) | 2010-05-13 | 2015-10-20 | Kanto Kagaku Kabushiki Kaisha | Process for producing optically active alcohol |
| EP2426116A1 (en) * | 2010-08-30 | 2012-03-07 | Saltigo GmbH | Method for producing (S)-3-N-Methylamino-1-(2-thienyl)-1-propanol |
| WO2012028545A1 (en) * | 2010-08-30 | 2012-03-08 | Saltigo Gmbh | Process for preparing (s)-3-n-methylamino-1-(2-thienyl)-1-propanol |
| CN102532097A (en) * | 2011-10-19 | 2012-07-04 | 华东理工大学 | Asymmetric synthesis method of duloxetine intermediate-(S)-N, N-dimethyl-3-hydroxy-3-(2-thienyl)-1-propylamine |
| CN109633046A (en) * | 2019-02-22 | 2019-04-16 | 成都倍特药业有限公司 | A method of detecting dimethylamine from duloxetine hydrochloride |
| CN109633046B (en) * | 2019-02-22 | 2021-12-21 | 成都倍特药业股份有限公司 | Method for detecting dimethylamine from duloxetine hydrochloride |
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