CN1939918B - Production of midanping - Google Patents
Production of midanping Download PDFInfo
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- CN1939918B CN1939918B CN 200510105688 CN200510105688A CN1939918B CN 1939918 B CN1939918 B CN 1939918B CN 200510105688 CN200510105688 CN 200510105688 CN 200510105688 A CN200510105688 A CN 200510105688A CN 1939918 B CN1939918 B CN 1939918B
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Abstract
Production of Mirtapine is carried out by taking 3-methylol-2-amino-pyridine as initial raw material, butt jointing with 1-methyl-3-phenylpeperazine, synthesizing critical intermediate minitrogen alcohol, and ic reacting to obtain the final product. It's cheap, stable and simple, has better yield and can be used for industrial production.
Description
Invention field
The present invention relates to the preparation route of a kind of mirtazapine (Mirtapine).
Background of invention
The chemical structural formula of mirtazapine (Mirtapine) is as follows:
Mirtazapine (Mirtapine) is 5-HT optionally
2, 5-HT
3And a
2-adrenoceptor antagonists is used for the treatment of psychosis such as spirit depressing, is developed by U.S. Organon company.
According to bibliographical information, mirtazapine (Mirtapine) has many synthetic routes, and these methods exist that step is long, separation and purification is difficult, reaction system is complicated and shortcoming such as wayward.
U.S. Pat 4062848 has been reported the hydrolysis under strong alkaline condition by cyano intermediate A, synthetic carboxy intermediate B, and carboxy intermediate B further is reduced into hydroxy intermediate C again, and last cyclization obtains the finished product mirtazapine.But this carboxy intermediate purification difficult causes cost to rise, and is shown below:
The resulting carboxy intermediate B purifying of this method difficulty is big, and need use the expensive original reagent lithium aluminium hydride of going back from intermediate B synthesis of hydroxy intermediate C, causes cost to rise.
Patent JP2001/12287 and CN1429819 have adopted intermediate A, are reduced to aldehyde radical intermediate D, and the method for further again synthetic intermediate C and mirtazapine is shown below:
This method has been used the composite reduction reagent of Raney-Ni and ortho phosphorous acid, and cost is higher; Solvent for use is the complex system of water-acetic acid-pyridine, causes environmental issue easily; Gained intermediate D chemical property is active, is difficult for preserving.
In view of above each preparation method's shortcoming, be necessary to seek one more economically, preparation method efficiently.
Goal of the invention
The invention provides a kind of method for preparing mirtazapine (Mirtapine) simple, practical, that easily control.
Summary of the invention
The present invention adopts following process to prepare mirtazapine:
Present method principal reaction step is as follows:
(1) preparation 1-(3-4-hydroxymethylpiperidine base-2-)-4-methyl-2-phenylpiperazine:
With 3-methylol-2-chloropyridine is that starting raw material docks reaction and makes 1-(3-4-hydroxymethylpiperidine base-2-)-4-methyl-2-phenylpiperazine with the 1-methyl-3-phenyl piperazine.Wherein the mol ratio of 3-4-hydroxymethylpiperidine base-2-chloropyridine and 1-methyl-3-phenyl piperazine is 1:0.9～5, preferred 1:0.9～2.0; Temperature of reaction is between 10～180 ℃, and preferred 120～150 ℃, reaction solvent is ethers, the N of C1～C6, dinethylformamide or N,N-dimethylacetamide etc., preferred dimethylformamide, more preferably N, dinethylformamide.
(2) preparation mirtazapine:
(3-4-hydroxymethylpiperidine base-2-)-4-methyl-2-phenylpiperazine cyclization in the presence of condensing agent obtains mirtazapine with step (1) gained 1-.Condensing agent is sulfuric acid, concentrated hydrochloric acid, picric acid, trifluoroacetic acid, phosphoric acid, phosphorus trichloride, polyphosphoric acid, phosphorus oxychloride, boron trifluoride or zirconium tetrachloride or the like, is preferably sulfuric acid.Temperature of reaction is 0～150 ℃, and preferred 70～100 ℃, the reaction times is 1～10 hour.
Distinguishing feature of the present invention is: route is brief, is that starting raw material makes target product through two-step reaction with 3-4-hydroxymethylpiperidine base-2-chloropyridine.Synthetic route provided by the invention has been avoided synthetic rice nitronic acid and the complicated purification and the last handling process that cause on the one hand, has also avoided synthetic rice nitrogen aldehyde time to use the reductive agent and the water-acetic acid-pyridine system of costliness on the other hand.The result shows, this route is the route of lower, simple to operate, the stable and controllable for quality and suitable suitability for industrialized production of cost.
This patent embodiment
The present invention will be helped to understand by following embodiment, but content of the present invention can not be limited to.
Embodiment one:1-(the preparation of 3-4-hydroxymethylpiperidine base-2-)-4-methyl-2-phenylpiperazine
In the 1L there-necked flask, add 27.8g3-methylol-2-chloropyridine (0.2mol), 35.2g1-methyl-3-phenyl piperazine (0.2mol) and 500ml DMF under the nitrogen protection, stir, add 34.8g Potassium monofluoride (0.6mol), be suspension liquid.Heating reflux reaction, TLC detect to raw material and disappear.Cooling is poured reaction solution in the 2500ml distilled water into.With ethyl acetate 600ml extraction 4 times.Combined ethyl acetate, saturated 600ml salt solution washing 4 times.Anhydrous magnesium sulfate drying.Suction filtration, the filtering siccative.Filtrate is concentrated into dried, gets light yellow solid 48.2g, yield 85%.
Embodiment two:1-(the preparation of 3-4-hydroxymethylpiperidine base-2-)-4-methyl-2-phenylpiperazine
In the 2L there-necked flask, add 55.6g (0.4mol) 3-methylol-2-chloropyridine, 70.4g1-methyl-3-phenyl piperazine (0.4mol) and 1000ml DMA under the nitrogen protection, stir adding 69.6g (1.2mol) Potassium monofluoride down, be suspension liquid.Be heated to 120 ℃ of reactions, TLC detects to raw material and disappears.Cooling is poured reaction solution in the 5000ml ice mixed solution into.2000ml ethyl acetate extraction 3 times.Combined ethyl acetate, 2000ml saturated common salt water washing 3 times.The anhydrous magnesium sulfate drying organic phase.Suction filtration, the filtering siccative.Filtrate is concentrated into dried.Get light yellow solid 90.7g, yield 80%.
Embodiment three:The preparation of mirtazapine
In the 250ml there-necked flask, add the 100ml vitriol oil, cryosel is bathed and is cooled to 10 ℃, adding 36.0g (0.127mol) 1-(3-4-hydroxymethylpiperidine base-2-)-4-methyl-2-phenylpiperazine, stirring at room 4 hours, slow heat temperature raising to 45 within 1.5～2.0 hours～50 ℃.Cooling, in the frozen water with the slow impouring stirring of reaction solution, it is 9.0 that strong aqua is regulated the pH value.Dichloromethane extraction.Merge organic phase, anhydrous magnesium sulfate drying, suction filtration, filtering siccative.Filtrate is concentrated into dried 29.0g mirtazapine, yield 86%.
Claims (6)
1. the preparation method of a mirtazapine (Mirtapine), the feature of this method comprises the steps:
(1) 3-methylol-2-chloropyridine, 1-methyl-3-phenyl piperazine, solvent and Potassium monofluoride reaction, and preparation 1-(3-4-hydroxymethylpiperidine base-2-)-4-methyl-2-phenylpiperazine;
(2) vitriol oil and 1-(3-4-hydroxymethylpiperidine base-2-)-4-methyl-2-phenylpiperazine reaction, latter's cyclization, preparation mirtazapine;
Wherein the solvent in (1) is a non-protonic solvent, is selected from ethers, the N of C1-C6, dinethylformamide or N,N-dimethylacetamide.
2. preparation method according to claim 1, wherein the used non-protonic solvent of (1) reaction is N, dinethylformamide or N,N-dimethylacetamide.
3. preparation method according to claim 1, wherein step (1) is specially:
Under the nitrogen protection, 3-methylol-2-chloropyridine, 1-methyl-3-phenyl piperazine, DMF and Potassium monofluoride mix, heating reflux reaction, cooling; reaction solution is poured in the distilled water, used ethyl acetate extraction, combined ethyl acetate washs with salt solution; anhydrous magnesium sulfate drying, suction filtration, filtrate concentrate drying.
4. preparation method according to claim 3 is specially:
In the 1L there-necked flask, add 27.8g 3-methylol-2-chloropyridine, 35.2g1-methyl-3-phenyl piperazine and 500ml DMF under the nitrogen protection, stir, add the 34.8g Potassium monofluoride; be suspension liquid, heating reflux reaction, TLC detect to raw material and disappear; cooling is poured reaction solution in the 2500ml distilled water into, with ethyl acetate 600ml extraction 4 times; combined ethyl acetate; saturated 600ml salt solution washing 4 times, anhydrous magnesium sulfate drying, suction filtration; the filtering siccative, filtrate is concentrated into dried.
5. preparation method according to claim 1, wherein step (1) is specially:
Under the nitrogen protection; 3-methylol-2-chloropyridine, 1-methyl-3-phenyl piperazine, DMA and Potassium monofluoride mix; be heated to 120 ℃ of reactions, cooling is poured reaction solution in the frozen water into; use ethyl acetate extraction; combined ethyl acetate is used the saturated common salt water washing, anhydrous magnesium sulfate drying; suction filtration, the filtrate concentrate drying.
6. preparation method according to claim 5; be specially: in the 2L there-necked flask, add 55.6g3-methylol-2-chloropyridine, 70.4g 1-methyl-3-phenyl piperazine and 1000ml DMA under the nitrogen protection; stir and add the 69.6g Potassium monofluoride down; be suspension liquid; be heated to 120 ℃ of reactions; TLC detects to raw material and disappears; 2000ml ethyl acetate extraction 3 times is poured reaction solution in the 5000ml ice mixed solution in cooling; combined ethyl acetate; 2000ml saturated common salt water washing 3 times, anhydrous magnesium sulfate drying organic phase, suction filtration; the filtering siccative, filtrate is concentrated into dried.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510105688 CN1939918B (en) | 2005-09-30 | 2005-09-30 | Production of midanping |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510105688 CN1939918B (en) | 2005-09-30 | 2005-09-30 | Production of midanping |
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| Publication Number | Publication Date |
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| CN1939918A CN1939918A (en) | 2007-04-04 |
| CN1939918B true CN1939918B (en) | 2010-09-01 |
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| CN 200510105688 Expired - Fee Related CN1939918B (en) | 2005-09-30 | 2005-09-30 | Production of midanping |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107266447A (en) * | 2017-06-14 | 2017-10-20 | 江西永通科技股份有限公司 | A kind of preparation method of Mirtazapine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4062848A (en) * | 1975-04-05 | 1977-12-13 | Akzona Incorporated | Tetracyclic compounds |
| CN1429819A (en) * | 2001-12-29 | 2003-07-16 | 中国科学院上海药物研究所 | Method of preparing anti-depression medicine Midanping |
-
2005
- 2005-09-30 CN CN 200510105688 patent/CN1939918B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4062848A (en) * | 1975-04-05 | 1977-12-13 | Akzona Incorporated | Tetracyclic compounds |
| CN1429819A (en) * | 2001-12-29 | 2003-07-16 | 中国科学院上海药物研究所 | Method of preparing anti-depression medicine Midanping |
Non-Patent Citations (2)
| Title |
|---|
| 郭春，陆文超.米氮平合成路线图解.中国医药工业杂志35 3.2004,35(3),186-187. |
| 郭春,陆文超.米氮平合成路线图解.中国医药工业杂志35 3.2004,35(3),186-187. * |
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| CN1939918A (en) | 2007-04-04 |
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