CN1785959A - Preparation method of N,N-dimethyl-3-hydroxy-3-aryl propyl amine - Google Patents
Preparation method of N,N-dimethyl-3-hydroxy-3-aryl propyl amine Download PDFInfo
- Publication number
- CN1785959A CN1785959A CN 200510122281 CN200510122281A CN1785959A CN 1785959 A CN1785959 A CN 1785959A CN 200510122281 CN200510122281 CN 200510122281 CN 200510122281 A CN200510122281 A CN 200510122281A CN 1785959 A CN1785959 A CN 1785959A
- Authority
- CN
- China
- Prior art keywords
- dimethyl
- solvent
- reaction
- oxo
- arylprop
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The present invention discloses a preparation method of N,N-dimethyl-3-hydroxy-3-arylpropylamine. Said method includes the following steps: adding phenyl methyl ketone or 2-acetyl thiophenol and N,N-dimethylformamide dimethyl acetal into solvent including benzene and N,N-dimethylformamide, after the reaction is completed, evaporating solvent, cooling to obtain yellow crystal product, using solvent of ethyl acetate, etc, to make recrystallization and obtain N,N-dimethyl-3-oxo-3-aryl propyleneamine; adopting lithium aluminium hydride as reducing agent, adding N,N-dimethyl-3-oxo-3-aryl propyleneamine and reducing agent into the solvents of benzene, etc., making reaction to obtain product; or adopting sodium borohydride as reducing agent, adding N,N-dimethyl-3-oxo-3-aryl propyleneamine and reducing agent into solvents of acetic acid, etc., making reaction to obtain product; making said product undergo the process of phase separation, evaporating the organic phase obtained by means of phase separation so as to obtain N,N-dimethyl-3-hydrox-3-arylpropylamine.
Description
Technical field
The present invention relates to a kind of N, the preparation method of N-dimethyl-3-hydroxyl-3-aryl propyl amine belongs to the technology of preparing of the important intermediate of multiple antidepressant drug.
Background technology
N, N-dimethyl-3-hydroxyl-3-aryl propyl amine compounds is important pharmaceutical intermediate, can be used to medicines such as synthetic hydrochloric acid fluoxetine, tomoxetine hydrochloride, duloxetine hydrochloride.This class medicine has been widely used in the treatment of dysthymia disorders, has obtained general application in the whole world.Therefore lot of documents has been reported the synthetic method of relevant such intermediate.
N, N-dimethyl-3-hydroxyl-known preparation method's of 3-aryl propyl amine compounds example comprises: [US 4314081 in many patents, US 4194009, and EP 529842 etc.] in the synthetic of fluoxetine Hydrochloride described, important intermediate is N, N-dimethyl-3-hydroxyl-3-phenylpropylamine, it is a raw material with methyl phenyl ketone, Paraformaldehyde 96, Dimethylammonium chloride, in the presence of ethanol and hydrochloric acid, generate N by the Mannich reaction, N-dimethyl-3-oxo-3-phenylpropylamine then carries out reduction reaction with sodium borohydride and prepares in ethanol.
Gift comes the Weigel L. and co-worker [the Tetrahedron Letters thereof of company, Vol.31, No.49, pp 7101-7104,1990] and the Berglund R.A. of the said firm and co-worker thereof [US 5362886, US 5023269] reported the synthetic of duloxetine hydrochloride, important intermediate is N, N-dimethyl-3-hydroxyl-3-(2-thiophene phenyl) propylamine, it is with 2-acetyl thiophene phenol, Paraformaldehyde 96, Dimethylammonium chloride is a raw material, generate N by the Mannich reaction in the presence of ethanol or Virahol and hydrochloric acid, N-dimethyl-3-oxo-3-(2-thiophene phenyl) propylamine then carries out reduction reaction with sodium borohydride and prepares in ethanol.
But shortcomings such as the Mannich reaction yield is low, long reaction time, complicated operation that above-mentioned preparation method exists are therefore of crucial importance to the study on the synthesis of such intermediate.
Summary of the invention
The object of the present invention is to provide a kind of N, the preparation method of N-dimethyl-3-hydroxyl-3-aryl propyl amine, this method operating process is simple, is easy to industrialization.
The present invention is realized by following technical proposals, a kind of N, and the preparation method of N-dimethyl-3-hydroxyl-3-aryl propyl amine is characterized in that comprising following process;
1. synthetic N, N-dimethyl-3-oxo-3-arylprop enamine: with methyl phenyl ketone or 2-acetyl thiophene phenol and N, dinethylformamide dimethylacetal (DMFDMA) is 1 in molar ratio: 0.5-10 adds benzene, toluene, dimethylbenzene, chlorobenzene, pentane, hexane, hexanaphthene, heptane, ether, tetrahydrofuran (THF) diox, methyl alcohol, ethanol, Virahol, N, dinethylformamide or N, in the N-dimethylacetamide solvent, stir down 0-150 ℃ of reaction 1-10 hour, after reaction is finished, steam solvent, cooling obtains yellow crystalline product, use ethyl acetate, butylacetate, methylene dichloride, trichloromethane, tetracol phenixin, benzene, toluene or xylene solvent recrystallization, make N, N-dimethyl-3-oxo-3-arylprop enamine.
The reduction N, N-dimethyl-3-oxo-3-arylprop enamine prepares N, N-dimethyl-3-hydroxyl-3-aryl propyl amine:
The employing lithium aluminum hydride is a reductive agent, with N, N-dimethyl-3-oxo-3-arylprop enamine and reductive agent in molar ratio 1: 0.5-15 adds in benzene,toluene,xylene, chlorobenzene, pentane, hexane, hexanaphthene, heptane, ether, the tetrahydrofuran (THF) Huo diox solvent, stir down 0-150 ℃ of reaction 1-10 hour product; Or employing sodium borohydride, sodium cyanoborohydride, lithium borohydride or POTASSIUM BOROHYDRIDE are reductive agent, with N, N-dimethyl-3-oxo-3-arylprop enamine and reductive agent in molar ratio 1: 0.5-15 adds in the protic polar solvent of methyl alcohol, ethanol, formic acid, acetate, Monochloro Acetic Acid, dichloro acetic acid, methylsulfonic acid or tosic acid, stir down 0-150 ℃ of reaction 1-10 hour product; Reacted product is separated, and when using with water that the solvent of mixing is not made reaction solvent, adds water and makes and be separated; Use when doing reaction solvent with the solvent of water mixing, add and water the methylene chloride of mixing or chloroform be not to be separated, contained solvent steams in the organic phase that will obtain through being separated, and obtains N, N-dimethyl-3-hydroxyl-3-aryl propyl amine.
Above-mentioned methyl phenyl ketone or 2-acetyl thiophene phenol and N, dinethylformamide dimethylacetal are 1 in molar ratio: 1-4; Methyl phenyl ketone or 2-acetyl thiophene phenol and N, the solvent of dinethylformamide dimethylacetal reaction is N, dinethylformamide or N,N-dimethylacetamide or toluene; Methyl phenyl ketone or 2-acetyl thiophene phenol and N, the temperature of reaction of dinethylformamide dimethylacetal is 25-110 ℃; Recrystallization solvent is an ethyl acetate.
Above-mentioned reductive agent is lithium aluminum hydride, sodium borohydride or sodium cyanoborohydride; N, the mol ratio 1 of N-dimethyl-3-oxo-3-arylprop enamine and reductive agent: 1-4; The solvent that reduction is adopted is toluene or tetrahydrofuran (THF); The protic polar solvent is an acetate; Reduction reaction temperature is 25-100 ℃.
The invention has the advantages that its preparation process is simple, easy handling, the reaction times is short, yield is high, be easy to suitability for industrialized production.
Embodiment
Provide embodiment below illustrating in greater detail the present invention, but scope of the present invention is not limited to these embodiment.
Embodiment 1
Add 2-acetyl thiophene phenol (50.5g in the reaction flask, 0.4mol), DMFDMA (95.2g, 0.8mol) and N, dinethylformamide (250ml), be warming up to 100 ℃ of reactions 3 hours, decompression steams the solvent cooling and obtains yellow crystal, with ethyl acetate (400ml) recrystallization, obtains light yellow crystallization N, N-dimethyl-3-oxo-3-(2-thiophene phenyl) allylamine (67.4g, 92.1%).mp.117～119℃。MS?m/z：180.9，148.0，110.9，98.0，55.0，42.0。
Embodiment 2
Add lithium aluminum hydride (38g in the reaction flask, 1.0mol) and tetrahydrofuran (THF) (300ml), add N under the room temperature, and N-dimethyl-3-oxo-3-(2-thiophene phenyl) allylamine (36.2g, 0.2mol), finish, room temperature reaction 10 hours, cooling slowly adds entry (200ml) down, continue to stir 30 minutes, filter filtrate dichloromethane extraction (100ml * 3), drying, filter, steaming desolventizes and obtains light yellow thick oily matter N, N-dimethyl-3-hydroxyl-3-(2-thiophene phenyl) propylamine (33.5g, 82.4%), cooling curing obtains white solid, mp.70～73 ℃.MS?m/z：185.1，113.0，85.0，58.1，30.1。
Embodiment 3
Add methyl phenyl ketone (60.0 in the reaction flask, 0.5), DMFDMA (119g, 1.0mol) and N, dinethylformamide (300ml), be warming up to 100 ℃ of reactions 4 hours, decompression steams the solvent cooling and obtains yellow crystal, with ethyl acetate (450ml) recrystallization, obtains light yellow crystallization N, N-dimethyl-3-oxo-3-phenyl allylamine (78.9g, 90.1%).mp.93～94℃。MS?m/z：175.0，158.0，131.0，98.0，77.0，42.0。
Embodiment 4
(38g 1.0mol) and tetrahydrofuran (THF) (300ml), adds N under the room temperature to add lithium aluminum hydride in the reaction flask, (35g 0.2mol), finishes N-dimethyl-3-oxo-3-phenyl allylamine, room temperature reaction 12 hours, cooling slowly adds entry (200ml) down, continue to stir 30 minutes, filter filtrate dichloromethane extraction (100ml * 3), drying is filtered, and steams to desolventize to obtain light yellow thick oily matter N, N-dimethyl-3-hydroxyl-3-phenylpropylamine (29.3g, 81.8%).MS?m/z：179.1，105.0，77.0，58.1。
Embodiment 5
Add N in the reaction flask, N-dimethyl-3-oxo-3-phenyl allylamine (35g, 0.2mol), acetate (30g, 0.5mol) and benzene (300ml), stir and add sodium borohydride (7.6g down, 0.2mol), be warming up to 85 ℃ of reactions 3 hours, be cooled to room temperature, slowly add 10% sodium hydroxide solution (200ml), continue to stir 30 minutes, standing demix is told toluene liquid, washing (50ml * 3), drying is filtered, and steams to desolventize to obtain light yellow thick oily matter N, N-dimethyl-3-hydroxyl-3-phenylpropylamine (27.2g, 75.9%).MS?m/z：179.1，105.0，77.0，58.1。
Claims (3)
1. N, the preparation method of N-dimethyl-3-hydroxyl-3-aryl propyl amine is characterized in that comprising following process;
1) synthetic N, N-dimethyl-3-oxo-3-arylprop enamine: with methyl phenyl ketone or 2-acetyl thiophene phenol and N, the dinethylformamide dimethylacetal is 1 in molar ratio: 0.5-10 adds benzene, toluene, dimethylbenzene, chlorobenzene, pentane, hexane, hexanaphthene, heptane, ether, tetrahydrofuran (THF) diox, methyl alcohol, ethanol, Virahol, N, dinethylformamide or N, in the N-dimethylacetamide solvent, stir down 0-150 ℃ of reaction 1-10 hour, after reaction is finished, steam solvent, cooling obtains yellow crystalline product, use ethyl acetate, butylacetate, methylene dichloride, trichloromethane, tetracol phenixin, benzene, toluene or xylene solvent recrystallization, make N, N-dimethyl-3-oxo-3-arylprop enamine;
2) reduction N, N-dimethyl-3-oxo-3-arylprop enamine prepares N, N-dimethyl-3-hydroxyl-3-aryl propyl amine: the employing lithium aluminum hydride is a reductive agent, with N, N-dimethyl-3-oxo-3-arylprop enamine and reductive agent in molar ratio 1: 0.5-15 adds in benzene,toluene,xylene, chlorobenzene, pentane, hexane, hexanaphthene, heptane, ether, the tetrahydrofuran (THF) Huo diox solvent, stir down 0-150 ℃ of reaction 1-10 hour product; Or employing sodium borohydride, sodium cyanoborohydride, lithium borohydride or POTASSIUM BOROHYDRIDE are reductive agent, with N, N-dimethyl-3-oxo-3-arylprop enamine and reductive agent in molar ratio 1: 0.5-15 adds in the protic polar solvent of methyl alcohol, ethanol, formic acid, acetate, Monochloro Acetic Acid, dichloro acetic acid, methylsulfonic acid or tosic acid, stir down 0-150 ℃ of reaction 1-10 hour product; Reacted product is separated, and when using with water that the solvent of mixing is not made reaction solvent, adds water and makes and be separated; Use when doing reaction solvent with the solvent of water mixing, add and water the methylene chloride of mixing or chloroform be not to be separated, contained solvent steams in the organic phase that will obtain through being separated, and obtains N, N-dimethyl-3-hydroxyl-3-aryl propyl amine.
2. by the described N of claim 1, the preparation method of N-dimethyl-3-hydroxyl-3-aryl propyl amine is characterized in that, methyl phenyl ketone or 2-acetyl thiophene phenol and N, dinethylformamide dimethylacetal are 1 in molar ratio: 1-4; Methyl phenyl ketone or 2-acetyl thiophene phenol and N, the solvent of dinethylformamide dimethylacetal reaction is N, dinethylformamide or N,N-dimethylacetamide or toluene; Methyl phenyl ketone or 2-acetyl thiophene phenol and N, the temperature of reaction of dinethylformamide dimethylacetal is 25-110 ℃; Recrystallization solvent is an ethyl acetate.
3. by the described N of claim 1, the preparation method of N-dimethyl-3-hydroxyl-3-aryl propyl amine is characterized in that reductive agent is lithium aluminum hydride, sodium borohydride or sodium cyanoborohydride; N, the mol ratio 1 of N-dimethyl-3-oxo-3-arylprop enamine and reductive agent: 1-4; The solvent that reduction is adopted is toluene or tetrahydrofuran (THF); The protic polar solvent is an acetate; Reduction reaction temperature is 25-100 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101222819A CN1304360C (en) | 2005-12-12 | 2005-12-12 | Preparation method of N,N-dimethyl-3-hydroxy-3-aryl propyl amine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101222819A CN1304360C (en) | 2005-12-12 | 2005-12-12 | Preparation method of N,N-dimethyl-3-hydroxy-3-aryl propyl amine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1785959A true CN1785959A (en) | 2006-06-14 |
| CN1304360C CN1304360C (en) | 2007-03-14 |
Family
ID=36783578
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005101222819A Expired - Fee Related CN1304360C (en) | 2005-12-12 | 2005-12-12 | Preparation method of N,N-dimethyl-3-hydroxy-3-aryl propyl amine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1304360C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101260062B (en) * | 2008-04-18 | 2010-06-02 | 浙江工业大学 | Method for synthesizing beta-aminopropenone compounds |
| CN108658930A (en) * | 2018-07-11 | 2018-10-16 | 浙江工业大学 | A kind of 2- acetyl thiophenes prepare the synthetic method of duloxetine hydrochloride key intermediate |
| CN110028486A (en) * | 2019-04-28 | 2019-07-19 | 山东睿智医药科技有限公司 | A kind of extracting method of duloxetine intermediate |
| CN114790146A (en) * | 2022-05-19 | 2022-07-26 | 河南省科学院高新技术研究中心 | Preparation method of 3- (methylamino) -1-aryl acetone |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4314081A (en) * | 1974-01-10 | 1982-02-02 | Eli Lilly And Company | Arloxyphenylpropylamines |
| US4194009A (en) * | 1974-01-10 | 1980-03-18 | Eli Lilly And Company | Aryloxyphenylpropylamines for obtaining a psychotropic effect |
| US4956388A (en) * | 1986-12-22 | 1990-09-11 | Eli Lilly And Company | 3-aryloxy-3-substituted propanamines |
| US5362886A (en) * | 1993-10-12 | 1994-11-08 | Eli Lilly And Company | Asymmetric synthesis |
-
2005
- 2005-12-12 CN CNB2005101222819A patent/CN1304360C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101260062B (en) * | 2008-04-18 | 2010-06-02 | 浙江工业大学 | Method for synthesizing beta-aminopropenone compounds |
| CN108658930A (en) * | 2018-07-11 | 2018-10-16 | 浙江工业大学 | A kind of 2- acetyl thiophenes prepare the synthetic method of duloxetine hydrochloride key intermediate |
| CN110028486A (en) * | 2019-04-28 | 2019-07-19 | 山东睿智医药科技有限公司 | A kind of extracting method of duloxetine intermediate |
| CN110028486B (en) * | 2019-04-28 | 2021-10-29 | 山东睿智医药科技有限公司 | Method for extracting duloxetine intermediate |
| CN114790146A (en) * | 2022-05-19 | 2022-07-26 | 河南省科学院高新技术研究中心 | Preparation method of 3- (methylamino) -1-aryl acetone |
| CN114790146B (en) * | 2022-05-19 | 2024-03-29 | 河南省科学院高新技术研究中心 | Preparation method of 3- (methylamino) -1-aryl acetone |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1304360C (en) | 2007-03-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100334585B1 (en) | Asymmetric Synthesis | |
| EP2114912B1 (en) | Process for making duloxetine and related compounds | |
| CN1304360C (en) | Preparation method of N,N-dimethyl-3-hydroxy-3-aryl propyl amine | |
| CN101607955A (en) | A kind of preparation method of low-residue lipoic acid | |
| CN101391991A (en) | Method for preparing duloxetine | |
| JP2005519077A (en) | Production of N-methyl-3-hydroxy-3- (2-thienyl) propylamine via a novel thiophene derivative having a carbamate group as an intermediate | |
| CN102229538B (en) | Method for synthesizing dapoxetine | |
| CN108947946B (en) | Brain injury resistant deuterated compound and medical application thereof | |
| CN103288630A (en) | Synthesizing method of Salvianic acid A sodium | |
| CN102070592B (en) | Synthesis method of dihydroquercetin | |
| CN101389621A (en) | Process for the preparation of (s)-(-)-n,n-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a duloxetine intermediate | |
| CN1837193A (en) | Process for preparing diindolylmethane derivatives | |
| CN108658930A (en) | A kind of 2- acetyl thiophenes prepare the synthetic method of duloxetine hydrochloride key intermediate | |
| CN106632233B (en) | A kind of purification process preparing high-purity duloxetine hydrochloride intermediate | |
| CN107235887A (en) | A kind of polysubstituted diindolylmethane derivative and preparation method thereof | |
| CN1817829A (en) | Production of aryl-group-aryl biphenyl compound | |
| CN101585829B (en) | Resolution method of N-methyl Dutoxetine | |
| CN102070602A (en) | Process for synthesizing duloxetine hydrochloride | |
| CN101012220A (en) | Method of preparing N-methyl-3-hydroxy-3-(2-thiophene)propylamine | |
| CN103551191B (en) | Application of chiral amphiphilic block copolymer in chiral synthesis | |
| CN1274692C (en) | Total synthesizing meethod for pyrrole heterocyclic alkaloid aldisin | |
| CN101003486B (en) | Preparation method of chiral alicyclic amino-alcohol | |
| CN103360365A (en) | New preparation process of medicinal raw material duloxetine hydrochloride of antidepressant drug | |
| CN1510024A (en) | Compound for preparing citalopram enantiomer and its production | |
| CN110117270B (en) | Preparation method of 3- (thiophene-2-yl) cyclohexanone framework compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |