CN103509000A - Method for synthesizing medicament intermediate 1-(3-cyanomethylpyridyl-2)-4-methyl-2-phenylpiperazine - Google Patents
Method for synthesizing medicament intermediate 1-(3-cyanomethylpyridyl-2)-4-methyl-2-phenylpiperazine Download PDFInfo
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- CN103509000A CN103509000A CN201310494072.1A CN201310494072A CN103509000A CN 103509000 A CN103509000 A CN 103509000A CN 201310494072 A CN201310494072 A CN 201310494072A CN 103509000 A CN103509000 A CN 103509000A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention relates to a method for synthesizing a medicament intermediate 1-(3-cyanomethylpyridyl-2)-4-methyl-2-phenylpiperazine. The method comprises the following steps: reacting 2-chloro-3-cyano pyridine and 1-methyl-3-phenylpiperazine to prepare 1-(3-cyanomethylpyridyl-2)-4-methyl-2-phenylpiperazine; using triethylamine as an acid-binding agent, and using dimethyl formamide (DMF) as a solvent; in the process of regulating a pH value to be 10, adding a small amount of ethyl acetate in advance, so as to avoid generation of sticky substances, enabling the solution to be in a homogeneous phase, and extracting a reaction liquid by using ethyl acetate. According to the method, the used base is changed from an inorganic base KF to an organic base triethylamine, the triethylamine is used as the acid-binding agent and can form hydrochloride with the generated hydrogen chloride, the reaction is well converted into a forward reaction, and the problem that the equipment is corroded is solved; meanwhile the product is high in yield, high in purity, low in cost and applicable for industrial production.
Description
Technical field
The invention belongs to medicine intermediate field, specifically relate to a kind of improved medicine intermediate 1-(3-cyano-methyl-pyridyl base-2) synthetic method of-4-methyl-2-phenylpiperazine.
Technical background
1-(3-cyano-methyl-pyridyl base-2)-4-methyl-2-phenylpiperazine (chemical compounds I) is the key intermediate of preparing mirtazapine.(English name is mirtazapine to mirtazapine, compound ii) be a kind of effective antidepressant drug (US4062848), it is selective serotonin reuptake inhibitor, this medicine is the exploitation of U.S. Organon company, in 1994 first in Dutch list marketing, in 1996, obtain U.S. FDA approval, many countries widespread use clinically in the whole world at present.
The method of preparing mirtazapine of bibliographical information has several, and US Patent No. 4062848 has been reported by cyano intermediate A and has been hydrolyzed under strong alkaline condition, generates intermediate B, and intermediate B is further reduced into intermediate C again, finally by cyclization, obtains mirtazapine D.As follows:
Patent JP2001/12287 has adopted intermediate A has been reduced into intermediate E, and then synthetic intermediate C, finally prepares the method for mirtazapine, as follows:
Visible, 1-(3-cyano-methyl-pyridyl base-2)-4-methyl-2-phenylpiperazine is the important intermediate of mirtazapine in synthetic, and it is carried out to study on the synthesis and optimization, just can be more excellent prepare mirtazapine product.
Bibliographical information, 1-(3-cyano-methyl-pyridyl base-2)-4-methyl-2-phenylpiperazine synthetic mainly contains following several:
Patent US4062848; reported a kind of 1-(3-cyano-methyl-pyridyl base-2) synthetic method of-4-methyl-2-phenylpiperazine; that to take MPP and 2-chlorine nicotinic acid nitrile be raw material; with KF, make alkali and in dry DMF, be heated to 140 ℃, under nitrogen protection, react 20h, add water after cooling; water is extracted with ethyl acetate; organic phase is dry concentrated that oily matter is 1-(3-cyano-methyl-pyridyl base-2)-4-methyl-2-phenylpiperazine, yield approximately 80%, can directly carry out next step reaction.Synthetic route is as follows:
Alkali used in this reaction scheme is KF, and the HF that generates in industrial production is corrosion and damage equipment easily, and this gas has severe toxicity, has dangerous hidden danger.
Patent US2003069417A1, reported a kind of 1-(3-of preparation cyano-methyl-pyridyl base-2) method of-4-methyl-2-phenylpiperazine, 2-Amino 3 cyano pyridine is dissolved in to 1, in 2-ethylene dichloride, add N-methyl isophthalic acid-phenyl-2, after 2 '-imino-diacetic ethyl muriate, be warming up to 80 ℃ of reaction 6h, cooling rear concentrated except desolventizing, obtain yellow powder and be product, yield approximately 80%.Synthetic route is as follows:
。
The raw material that this reaction scheme is used costliness, is not easy to obtain, is not suitable for large production.
Summary of the invention
The object of the invention is to overcome all above-mentioned 1-(3-cyano-methyl-pyridyls base-2) defect of-4-methyl-2-phenylpiperazine synthesis technique, the preparation method that a kind of low cost, high yield, purity are higher, be applicable to suitability for industrialized production is provided.
Object of the present invention can realize by following technical scheme:
Pharmaceutical intermediate 1-(3-cyano-methyl-pyridyl base-2) synthetic method for-4-methyl-2-phenylpiperazine, is characterized in that comprising the steps:
1) adopt 2-chlorine nicotinic acid nitrile and MPP reaction preparation 1-(3-cyano-methyl-pyridyl base-2)-4-methyl-2-phenylpiperazine;
2) with triethylamine, do attached sour agent, DMF makees solvent;
3) after reaction solution regulates pH to be 2, remove by filter triethylamine hydrochloride, then first in filtrate, add a small amount of ethyl acetate, after stirring, dripping 40% sodium hydroxide solution, to regulate pH be 10;
4) be extracted with ethyl acetate reaction solution;
Its reaction scheme is as follows:
Preferably, in step 1), the mol ratio of 2-chlorine nicotinic acid nitrile and MPP is 1-1.2:1.
Preferably, step 2), the mol ratio of triethylamine and MPP is 1-2:1.
Preferably, regulating pH is 10 o'clock, adds the 1/4-1/2 that the amount of ethyl acetate is the required ethyl acetate volume of extraction.
Preferably, temperature of reaction is 0-160 ℃; Reaction times is 0-2 days.Further preferred, temperature of reaction is 140 ℃; Reaction times is 1 day.
The present invention with respect to the beneficial effect of prior art is: the present invention is changed to organic bases triethylamine by alkali used by mineral alkali KF, triethylamine is as attached sour agent, can form hydrochloride with the hydrogenchloride generating, make preferably reaction carry out to positive reaction reaction, and the corrosion-prone problem of the equipment that solved, product yield is high simultaneously, purity is high, and cost is low, be applicable to suitability for industrialized production.
Embodiment
With specific embodiment, the present invention is described in detail below, but be not limited to this.
embodiment 1:
1-(3-cyano-methyl-pyridyl base-2) preparation of-4-methyl-2-phenylpiperazine:
In the there-necked flask of a 1000ml, add 69.3g(0.5mol) 2-chlorine nicotinic acid nitrile and 88.2g(0.5mol) MPP, add DMF and 55.7g(0.55mol that 300ml is dry) triethylamine, under room temperature, be stirred to molten clear after, start to be warming up to 140 ℃, back flow reaction 24h, be cooled to after approximately 100 ℃, start underpressure distillation, after steaming about 260ml solvent, add 500ml water, drip the about 48ml of concentrated hydrochloric acid and regulate pH to 2, there is solid to separate out, after drip finishing, proceed to stirring and crystallizing 1h in ice-water bath, suction filtration, with a small amount of frozen water washing leaching cake, in filtrate, add 100ml ethyl acetate, after stirring, drip 40% sodium hydroxide solution, regulating pH is 10, then with 300ml ethyl acetate washing 3 times, merge organic relevant dry concentrated, obtain the about 112g of dark-brown oily matter, be 1-(3-cyano-methyl-pyridyl base-2)-4-methyl-2-phenylpiperazine, yield 80.5%, can directly carry out next step reaction.
embodiment 2:
1-(3-cyano-methyl-pyridyl base-2) preparation of-4-methyl-2-phenylpiperazine:
In the there-necked flask of a 1000ml, add 83.16g(0.6mol) 2-chlorine nicotinic acid nitrile and 88.2g(0.5mol) MPP, add DMF and 101.3g(1.0mol that 300ml is dry) triethylamine, under room temperature, be stirred to molten clear after, start to be warming up to 160 ℃, back flow reaction 12h, be cooled to after approximately 100 ℃, start underpressure distillation, after steaming about 280ml solvent, add 500ml water, drip the about 50ml of concentrated hydrochloric acid and regulate pH to 2, there is solid to separate out, after drip finishing, proceed to stirring and crystallizing 1h in ice-water bath, suction filtration, with a small amount of water washing filter cake, in filtrate, add 100ml ethyl acetate, after stirring, drip 40% sodium hydroxide solution, regulating pH is 10, then with 300ml ethyl acetate washing 3 times, merge organic relevant dry concentrated, obtain the about 116g of dark-brown oily matter, be 1-(3-cyano-methyl-pyridyl base-2)-4-methyl-2-phenylpiperazine, yield 83.3%, can directly carry out next step reaction.
Claims (5)
1. pharmaceutical intermediate 1-(3-cyano-methyl-pyridyl base-2) synthetic method for-4-methyl-2-phenylpiperazine, is characterized in that comprising the steps:
1) adopt 2-chlorine nicotinic acid nitrile and MPP reaction preparation 1-(3-cyano-methyl-pyridyl base-2)-4-methyl-2-phenylpiperazine;
2) with triethylamine, do attached sour agent, DMF makees solvent;
3) after reaction solution regulates pH to be 2, remove by filter triethylamine hydrochloride, then first in filtrate, add a small amount of ethyl acetate, after stirring, dripping 40% sodium hydroxide solution, to regulate pH be 10;
4) be extracted with ethyl acetate reaction solution;
Its reaction scheme is as follows:
。
2. pharmaceutical intermediate 1-(3-cyano-methyl-pyridyl according to claim 1 base-2) synthetic method of-4-methyl-2-phenylpiperazine, is characterized in that: in step 1), the mol ratio of 2-chlorine nicotinic acid nitrile and MPP is 1-1.2:1.
3. pharmaceutical intermediate 1-(3-cyano-methyl-pyridyl according to claim 1 base-2) synthetic method of-4-methyl-2-phenylpiperazine, is characterized in that: step 2) in the mol ratio of triethylamine and MPP be 1-2:1.
4. pharmaceutical intermediate 1-(3-cyano-methyl-pyridyl according to claim 1 base-2) synthetic method of-4-methyl-2-phenylpiperazine, is characterized in that: temperature of reaction is 0-160 ℃; Reaction times is 0-2 days; Regulating pH is 10 o'clock, adds the 1/4-1/2 that the amount of ethyl acetate is the required ethyl acetate volume of extraction.
5. pharmaceutical intermediate 1-(3-cyano-methyl-pyridyl according to claim 4 base-2) synthetic method of-4-methyl-2-phenylpiperazine, is characterized in that: temperature of reaction is 140 ℃; Reaction times is 1 day.
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| CN201310494072.1A CN103509000A (en) | 2013-10-21 | 2013-10-21 | Method for synthesizing medicament intermediate 1-(3-cyanomethylpyridyl-2)-4-methyl-2-phenylpiperazine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6495685B1 (en) * | 1999-09-30 | 2002-12-17 | Sumika Fine Chemicals Co., Ltd. | Process for preparing piperazine derivatives |
| US20080182987A1 (en) * | 2004-08-24 | 2008-07-31 | Sumitomo Chemical Company, Limited | Method For Producing 2-(4-Methyl-2-Phenylpiperazine-1-Yl)-3-Cyanopiridine |
| CN101312955A (en) * | 2005-09-26 | 2008-11-26 | 住友化学株式会社 | Process for producing optically active piperazine compound |
-
2013
- 2013-10-21 CN CN201310494072.1A patent/CN103509000A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6495685B1 (en) * | 1999-09-30 | 2002-12-17 | Sumika Fine Chemicals Co., Ltd. | Process for preparing piperazine derivatives |
| US20080182987A1 (en) * | 2004-08-24 | 2008-07-31 | Sumitomo Chemical Company, Limited | Method For Producing 2-(4-Methyl-2-Phenylpiperazine-1-Yl)-3-Cyanopiridine |
| CN101312955A (en) * | 2005-09-26 | 2008-11-26 | 住友化学株式会社 | Process for producing optically active piperazine compound |
Non-Patent Citations (1)
| Title |
|---|
| 丁香园论坛-药物化学讨论版: "如何除去三乙胺盐酸盐", 《百度快照》 * |
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