CN1429819A - Method of preparing anti-depression medicine Midanping - Google Patents
Method of preparing anti-depression medicine Midanping Download PDFInfo
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- CN1429819A CN1429819A CN 01145561 CN01145561A CN1429819A CN 1429819 A CN1429819 A CN 1429819A CN 01145561 CN01145561 CN 01145561 CN 01145561 A CN01145561 A CN 01145561A CN 1429819 A CN1429819 A CN 1429819A
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Abstract
A process for preparing an antidepresant "Midanping" includes such steps as reaction of 2-Cl-3-cyanopyridine on 1-methyl-3-phenylpiperazine to obtain 1-(3-cyanopyridyl-2-)-2-phenyl-4- methylpiperazine, catalytic reducing to obtain 1-(3-alpyridyl-2)-2-phenyl-4-methylpiperazine, further reducing by sodium borohydride to obtain 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4- methylpiperazine, and cyclizing by concentrated sulfuric acid. Its advantages are simple post-treating and high output rate.
Description
Technical field
The present invention relates to the improvement of compounds process for production thereof, more specifically to anti-depression medicine Midanping preparation method's improvement.
Background technology
Mirtazapine (mirtazapine) is the highly effective antidepressant drug (Drugs of future, 1989,14,1211) of U.S. Organon company exploitation.It is a kind of selective serotonin reuptake inhibitor (SSRIs).Mirtazapine has several synthetic methods, but there is the separation and purification difficulty in existing method, and step is long, the not high shortcoming of yield.As U.S. Pat 4062848 usefulness 2-chloro-3-cyanopyridines and 1-methyl-3-phenyl piperazine react cyano compound, the hydrolysis of cyano compound strong basicity becomes the carboxylic acid thing, uses tetrahydrochysene lithium aluminium reducing then.The carboxylic acid thing is that amphoteric substance is difficult for purifying in this method, and the reduction with the costliness and be difficult to operate tetrahydrochysene lithium aluminium.WO 00162782 method synthesis step is longer.
Summary of the invention
The purpose of this invention is to provide a kind of easy practicable mirtazapine new synthetic method.Another object of the present invention provides the simple synthesis of mirtazapine analogue.
The compound that the present invention relates to can be expressed from the next:
The present invention implements by following key step:
1.2-chloro-3-cyanopyridine and 1-methyl-3-phenyl piperazine get Compound I at exsiccant dimethyl formamide or dimethyl sulfoxide (DMSO) condensation,
2. Compound I is with Raney-Ni, ortho phosphorous acid sodium reduction, and water/acetate/pyridine mixtures is made solvent, and temperature of reaction is controlled 0-100 ℃ again, preferably again 50-60 ℃, key intermediate Compound I I,
3. Compound I I further is reduced into alcohol with sodium borohydride or POTASSIUM BOROHYDRIDE with aldehyde radical, makees solvent with methyl alcohol or ethanol, Virahol, and temperature of reaction is controlled at 0-80 ℃, room temperature preferably, compound III,
4. compound III at 10-100 ℃ of dehydration condensation, gets final product mirtazapine 4 with the vitriol oil, and the reaction optimum temps is 50-60 ℃.Thick product activated carbon decolorizing, recrystallization solvent can be that the different ratios that sherwood oil, ethanol and water are formed gets mixed solvent.
The thick product of 1-3 step reaction does not all need to be further purified, and can be directly used in the synthetic of the 4th step, and this makes method provided by the present invention very easy, is fit to scale operation.
The present invention can implement by following more detailed steps: step 1.
Reaction solvent is anhydrous polar aprotic solvent, as anhydrous dimethyl formamide, and dimethyl sulfoxide (DMSO), dimethyl pyrrolidone, pyridine etc.This step carries out under anhydrous condition.Temperature of reaction from room temperature to the solvent refluxing temperature all can, top condition is 120-140 ℃.Reaction uses KF or NaF to have katalysis concurrently as alkali.Reaction times, the best was 20-24 hour from 1 hour to 2 days.Reactant can be used ethyl acetate, chloroform methylene dichloride, ether etc. when aqueous phase extracts.Post-reaction treatment gained crude product need not be further purified, and can carry out next step reaction.
Step 2.
In the reduction reaction, reductive agent be Raney-Ni, inferior sodium phosphate or sylvite, amine salt all can, best with sodium salt.Reaction solvent is different ratios (volume ratio) blended water, acetate, pyridine, buffer system, and best ratio is a water: acetate: pyridine=1: 1: 2.Temperature of reaction is from room temperature to 100 ℃, and optimum is 50-60 ℃.Reaction is finished, and uses alkali such as potassium hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash to regulate PH greater than 7, and best PH is 10.The solvent of product extraction is ethyl acetate, chloroform, methylene dichloride, sherwood oil.The thick product of gained does not need to be further purified, and can be directly used in the next step.
Step 3.
Aldehyde cpd is reduced into alkylol cpd.Reductive agent can adopt boracic negative hydrogen ion reductive agent such as POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, sodium cyanoborohydride etc.Reaction solvent is alcoholic solvents such as methyl alcohol, ethanol, Virahol, propyl carbinol, also available pure water mixed solvent.Temperature of reaction is from 0 ℃ to 80 ℃, and optimum temps is a room temperature.Recrystallization is ethanol, methyl alcohol, ether, ethyl acetate, sherwood oil, water, chloroform, methylene dichloride, acetone etc., also available above-mentioned two components or multi-component mixed solvent recrystallization, best recrystallisation solvent are ethyl acetate and 1: 1 by volume mixed solvent of ether.Reaction times is 1-10 hour, and the best is 2 hours.
Step 4.
Use vitriol oil dehydration condensation.The envelope-bulk to weight ratio of the vitriol oil and compound III is 1-10: 1, and the best is 1.5-3: 1, temperature of reaction is 20-100 ℃, and Optimal Temperature is 50-60 ℃, and the reaction times is 3 hours to 3 days.Product can be a chloroform with chloroform, methylene dichloride, ethyl acetate, the extraction of ether equal solvent, best extraction solvent.Thick product can be used ethanol-water mixed solvent, recrystallizations such as sherwood oil 1-3 time, and the best is 2 times.Can obtain the mirtazapine of medicinal standard.
Embodiment
Below with embodiment the present invention is described, but they do not limit spirit of the present invention:
Fusing point is measured with capillary tube technique, and thermometer is not calibrated; Nuclear magnetic resonance analyser is Gemini-2000 (300MHz).Embodiment 1 1-(3-cyanopyridine-based-2)-2-phenyl-4-methylpiperazine [US 4062848]
Under agitation 2-chloro-3-cyanopyridine (34.6 gram), 1-methyl-3-phenyl piperazine (44 gram), exsiccant KF (45 gram) are joined among the DMF (500 milliliters) successively, suspended substance is at N
2Protection is down in 140 ℃ of reactions 20 hours.After reaction finished, pressure reducing and steaming part DMF (surplus 150 milliliters approximately) cooled off while hot, adds water (500 milliliters) dilution, water extracts with ethyl acetate (200 milliliters * 4), combined ethyl acetate, water (100 milliliters * 2) washing, drying, concentrate, obtain faint yellow oily thing 55.2 grams, yield 80%.This step need not made with extra care and can be carried out the next step.Also the crude product silica gel column chromatography can be obtained faint yellow solid with acetone-sherwood oil (1: 5) wash-out.Mp66.5-67.5℃。
1H-NMR (CDCl
3, δ): 2.59 (s, 3H); 2.62 (m, 1H); 2.79 (m, 2H); 2.97 (m, 1H); 3.61 (m, 1H); 3.84 (m, 1H); 5.47 (t, J=4.67Hz, 1H); 6.78 (dd, J=7.69,4.94Hz, 1H); 7.15-7.28; 7.38 (J=7.42Hz, 1H); 7.77 (dd, J=7.69,1.92Hz, 1H); 8.29 (dd, J=4.95,1.92Hz, 1H). embodiment 2 1-(3-aldehyde radical pyridyl-2)-2-phenyl-4-methylpiperazine
Raney-Ni (1.8 gram) is added to 1-(3-cyanopyridine-based-2)-2-phenyl-3-methylpiperazine (2.78 gram) under the room temperature in batches, inferior sodium phosphate (3.53 gram), water/acetate/pyridine (1: 1: 2, v/v) in the mixture of (50 milliliters), add the back and continued stirring reaction 5 hours at 50-60 ℃, filter, filtrate is regulated pH value to 10 with solid sodium hydroxide, with ethyl acetate (40 milliliters * 3) extraction.Ethyl acetate layer water (30 milliliters * 2) washing again, anhydrous sodium sulfate drying, steaming desolventizes and obtains faint yellow oily thing 1-(3-aldehyde radical pyridyl-2)-2-phenyl-4-methylpiperazine (2.70 gram).Yield 96.1%.
1H-NMR (CDCl
3, δ): 2.35 (s, 3H); 2.60 (m, 2H); 2.73 (m, 1H); 2.89 (m, 1H); 3.29-3.42 (m, 2H); 4.98 (dd, J=3.29,8.42,2H); 6.92 (dd, J=3.76,7.79Hz, 1H); 7.07-7.37 (m, 5H); 7.97 (dd, J=2.19,7.68Hz, 1H); 8.32 (dd, J=2.20,4.76Hz, 1H). embodiment 3 1-(3-4-hydroxymethylpiperidine base-2)-2-phenyl-3-methylpiperazine
Sodium borohydride (0.4 gram) is added to 1-(3-aldehyde radical pyridyl-2)-2-phenyl-3-methylpiperazine (2.70 gram) under the room temperature is dissolved in the solution of methyl alcohol (50 milliliters) in batches.Add the back and under identical temperature, reacted 2 hours, add the sodium borohydride of Glacial acetic acid (0.7 milliliter) with decomposing excessive.Remove solvent under reduced pressure, residuum adds methylene dichloride (50 milliliters), and 1 hour after-filtration of stirring at room is collected filtrate, be concentrated into driedly, obtain 1-(3-4-hydroxymethylpiperidine base-2)-2-phenyl-3-methylpiperazine (2.3 gram) with ethylacetate/ether (volume ratio is 1: 1) mixed solvent recrystallization.Yield 84.5%.Mp124-126 ℃ [US 4062848]
1H-NMR (CDCl
3, δ): 2.40 (s, 1H); 2.43 (m, 1H); 2.52 (m, 1H); 3.07 (dd, J=, 2H); 3.18 (dd, J=, 2H); 4.62 (d, J=13.91Hz, 1H); 4.83 (d, J=13.91Hz, 1H); 4.73 (dd, J=2.75,10.80Hz, 1H); 6.86 (m, 1H); 7.03-7.12 (m, 5H); 7.38 (m, 1H); 8.12 (dd, J=2.01,4.94Hz, 1H). the preparation of embodiment 4 mirtazapines [US 4062848]
The frozen water cooling drops to the vitriol oil (4.3 milliliters) down in 1-(3-4-hydroxymethylpiperidine base-2)-2-phenyl-3-methylpiperazine (2.3 gram), drip off in room temperature and continued stirring reaction about 1 hour, reheat is to 50-60 ℃, solid is molten intact after 3 hours, the reaction system uniform solution that takes on a red color, cooling, reaction solution is poured in the ice (60 gram), regulate pH value to 10 (solution presents muddiness) with solid NaOH, with chloroform (15 milliliters * 3) extraction, combined chloroform solution, water (20 milliliters) washing, anhydrous sodium sulfate drying, concentrate, obtain mirtazapine crude product 2.4 grams (faint yellow syrupy shape material), the crude product decolorizing with activated carbon, the sherwood oil recrystallization obtains purified mirtazapine 1.54 grams, yield 71.5% for twice.Mp：114-116℃。
1H-NMR(CDCl
3，δ)：2.63(s，3H)；2.74(td，J＝11.55，3.12Hz，1H)；2.83(t，J＝11.00Hz，1H)；3.20(d，J＝11.36Hz，1H)；3.33(d，J＝10.92Hz，1H)；3.42(d，J＝13.19Hz，1H)；3.72(td，J＝11.55，2.75Hz，1H)；3.87(dt，J＝13.32，2.85Hz，1H)；4.47(d，J＝13.19Hz，1H)；4.70(dd，J＝10.45，2.02Hz，1H)；6.77(dd，J＝7.33，4.95Hz，1H)；7.14-7.19(m，4H)；7.33(dd，J＝7.15，1.83Hz，1H0；8.15(dd，J＝4.95，1.83Hz，1H).
Claims (7)
1. one kind by the improving one's methods of 2-chloro-3-cyanopyridine and 1-methyl-3-phenyl piperazine prepared in reaction anti-depression medicine Midanping, and it is characterized in that the following Compound I I of structural formula is a key intermediate
2. according to claim 1 a kind of by the improving one's methods of 2-chloro-3-cyanopyridine and 1-methyl-3-phenyl piperazine prepared in reaction mirtazapine, it is characterized in that obtaining through four-step reaction by key intermediate Compound I I:
1) starting raw material 2-chloro-3-cyanopyridine and the condensation of 1-methyl-3-phenyl piperazine get compound 1-(3-cyanopyridine-based-2)-2-phenyl-4-methylpiperazine I;
2) Compound I gets compound 1-(3-aldehyde radical pyridyl-2)-2-phenyl-4-methylpiperazine (II) through catalytic reduction;
3) Compound I I further reduce compound 1-(3-4-hydroxymethylpiperidine base-2)-2-phenyl-4-methylpiperazine (III);
4) III gets mirtazapine with vitriol oil cyclization.
3. improving one's methods of preparation mirtazapine according to claim 1 is characterized in that step 1) 2-chloro-3-cyanopyridine and 1-methyl-3-phenyl piperazine at anhydrous dimethyl formamide, and condensation gets Compound I in the dimethyl sulfoxide (DMSO).
4. improving one's methods of preparation mirtazapine according to claim 1 is characterized in that step 2) in the Compound I reduction reaction, reductive agent is Raney-Ni, inferior sodium phosphate or sylvite.Reaction solvent is the mixture of water, acetate, pyridine composition.
5. its method of the improvement of preparation mirtazapine according to claim 1, be characterised in that it is boron negative hydrogen ion borane reducing agent potassium hydride KH, sodium borohydride, lithium borohydride, sodium cyanoborohydride that step 3) aldehyde cpd II is reduced into its reductive agent of alkylol cpd, reaction solvent is methyl alcohol, ethanol, Virahol, propyl carbinol solvent, also available pure water mixed solvent.
6. improving one's methods of preparation mirtazapine according to claim 1 is characterized in that step 4) compound III dehydration condensation.
7. improving one's methods of preparation mirtazapine according to claim 1 is characterized in that step 1 to step 3 intermediate can not purifiedly be directly used in the synthetic of mirtazapine in the step 4.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01145561 CN1429819A (en) | 2001-12-29 | 2001-12-29 | Method of preparing anti-depression medicine Midanping |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 01145561 CN1429819A (en) | 2001-12-29 | 2001-12-29 | Method of preparing anti-depression medicine Midanping |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006321780A (en) * | 2004-08-24 | 2006-11-30 | Sumitomo Chemical Co Ltd | Method for producing 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine |
| CN1939918B (en) * | 2005-09-30 | 2010-09-01 | 北京德众万全医药科技有限公司 | Production of midanping |
| JP2016153379A (en) * | 2015-02-20 | 2016-08-25 | 株式会社トクヤマ | Method for producing 1-(3-hydroxymethylpyridyl-2-)-2-phenyl-4-methylpiperazine |
| CN109988148A (en) * | 2018-01-02 | 2019-07-09 | 北京哈三联科技有限责任公司 | 1-(3- cyanopyridine -2) -2- phenyl -4- methyl piperazine oxalates preparation method |
| CN111187264A (en) * | 2018-11-14 | 2020-05-22 | 上海上药信谊药厂有限公司 | Preparation method of mirtazapine and intermediate product thereof |
-
2001
- 2001-12-29 CN CN 01145561 patent/CN1429819A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006321780A (en) * | 2004-08-24 | 2006-11-30 | Sumitomo Chemical Co Ltd | Method for producing 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine |
| CN1939918B (en) * | 2005-09-30 | 2010-09-01 | 北京德众万全医药科技有限公司 | Production of midanping |
| JP2016153379A (en) * | 2015-02-20 | 2016-08-25 | 株式会社トクヤマ | Method for producing 1-(3-hydroxymethylpyridyl-2-)-2-phenyl-4-methylpiperazine |
| CN109988148A (en) * | 2018-01-02 | 2019-07-09 | 北京哈三联科技有限责任公司 | 1-(3- cyanopyridine -2) -2- phenyl -4- methyl piperazine oxalates preparation method |
| CN111187264A (en) * | 2018-11-14 | 2020-05-22 | 上海上药信谊药厂有限公司 | Preparation method of mirtazapine and intermediate product thereof |
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