CN114163402B - Industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile - Google Patents
Industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile Download PDFInfo
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- CN114163402B CN114163402B CN202111516485.6A CN202111516485A CN114163402B CN 114163402 B CN114163402 B CN 114163402B CN 202111516485 A CN202111516485 A CN 202111516485A CN 114163402 B CN114163402 B CN 114163402B
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- C07—ORGANIC CHEMISTRY
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
The invention relates to an industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile, which comprises the following steps: step 1, dissolving 2-methoxy phenylpiperazine in an organic solvent according to the mass-volume ratio of the 2-methoxy phenylpiperazine to the organic solvent of 1:1-10 to obtain a 2-methoxy phenylpiperazine solution; step 2, according to the mole ratio of 2-methoxy phenylpiperazine to acrylonitrile of 1:1.0 to 1.5, adding acrylonitrile after heating 2-methoxy phenyl piperazine solution, then reacting for 0.5 to 5 hours at a reaction temperature of 30 to 60 ℃, and ending the reaction to obtain 3- [4- (2-methoxy phenyl) piperazine-1-yl ] propionitrile solution; and 3, cooling and crystallizing the 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile solution, filtering and drying to obtain a final product. The invention is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of urapidil synthesis, and particularly relates to an industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile.
Background
3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile is a pharmaceutical intermediate of urapidil. Urapidil (Urapidil) was first marketed in germany in 1981, and japan became its second market in 1989, and is currently approved for marketing in more than 30 countries of english, law, etc. The medicine is a first-choice medicine for treating severe hypertension clinically, and is used for treating primary renal hypertension, pheochromocytoma, heart failure and the like.
At present, most of the reported preparation processes of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile are also laboratory-stage preparation methods, and the main problems are as follows: the production equipment is complex, the method is not suitable for industrial production, 2) the impurity content is high, and the yield is low; 3) The large dosage of acrylonitrile, because of its genotoxicity and potential safety hazard, all of the above problems limit the industrial production of 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile.
Therefore, development of an industrial preparation method of 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile, improvement of product yield and purity, simplification of production process, reduction of requirements on equipment and application of the method to industrial production are urgently needed.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and provides an industrialized preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile, which reduces the dosage of acrylonitrile, improves the production safety, and the obtained 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile product has good yield and high purity, omits a subsequent purification process, reduces the control difficulty and the production cost of impurities, has low equipment requirement, and is suitable for industrialized production.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
an industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile comprises the following steps:
step 1, dissolving 2-methoxy phenylpiperazine in an organic solvent according to the mass-volume ratio of the 2-methoxy phenylpiperazine to the organic solvent of 1:1-10 to obtain a 2-methoxy phenylpiperazine solution;
step 2, according to the mole ratio of 2-methoxy phenylpiperazine to acrylonitrile of 1:1.0 to 1.5, adding acrylonitrile after heating 2-methoxy phenyl piperazine solution, then reacting for 0.5 to 5 hours at a reaction temperature of 30 to 60 ℃, and ending the reaction to obtain 3- [4- (2-methoxy phenyl) piperazine-1-yl ] propionitrile solution;
and 3, cooling and crystallizing the 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile solution, filtering and drying to obtain a final product.
Further, acrylonitrile is added into the 2-methoxy phenylpiperazine solution in a dropwise or fed-batch manner.
Furthermore, the time of the drop addition or the flow addition of the acrylonitrile is controlled to be within 10-90 min.
Further, the organic solvent adopts one or more of an ester organic solvent, an alcohol organic solvent and a ketone organic solvent.
Further, the organic solvent is an alcohol organic solvent.
Further, the organic solvent adopts one or more of absolute ethyl alcohol, ethyl acetate, methanol and acetone.
Further, the organic solvent is ethanol or methanol.
Further, in the step 1, the mass-volume ratio of the 2-methoxyphenylpiperazine to the organic solvent is 1:3 to 8; 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8 may be employed;
in step 2, the molar ratio of 2-methoxyphenylpiperazine to acrylonitrile is 1:1.1 to 1.3; 1:1.1, 1:1.2, or 1:1.3 may be employed.
Further, in the step 2, the reaction temperature is 40-60 ℃, the reaction time is 0.5-2 h, the reaction temperature can be 40 ℃,45 ℃,50 ℃,55 ℃,60 ℃, and the reaction time can be 0.5h,0.6h,0.7h,0.8h,0.9h,1.0h,1.1h,1.2h,1.3h,1.4h,1.5h,1.6h,1.7h,1.8h,1.9h,2.0h.
Further, the temperature of cooling crystallization is-20 ℃.
Further, the temperature of cooling crystallization is-20-0 ℃.
In the present invention,
the reaction equation involved is as follows:
compared with the prior art, the invention has the beneficial effects that:
1. the invention introduces the solvent in the reaction stage, not only ensures the reaction progress of the reaction, but also has the function of crystallization solvent, and the product can be obtained by cooling and crystallization, which not only ensures the yield of 3- [4- (2-methoxy phenyl) piperazine-1-yl ] propionitrile, but also improves the purity, reduces the single impurity from 4% to below 0.2%, improves the purity from 95% to above 99.5%, omits the subsequent complex purification process, reduces the workload of researching medicine impurities, reduces the production cost, has simple preparation process and low equipment requirement, and is more suitable for industrial production without the procedures of high equipment requirement such as evaporation, and the like.
2. The molar ratio of the 2-methoxyphenylpiperazine to the acrylonitrile is only 1:1.0 to 1.5, the consumption of the acrylonitrile is less, the production rate of potential safety hazards caused by genotoxicity of the acrylonitrile in the production process is reduced, the used solvent has high safety, the flammable and explosive solvents such as diethyl ether and the like are not used, the production process is easy to control, and the cost is low.
Detailed Description
The technical solutions of the present invention will be clearly and fully described below with reference to specific embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The raw materials and the reagents used in the invention are all commercially available.
Example 1:
an industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile comprises the following steps:
50g of 2-methoxyphenyl piperazine and 150ml of absolute ethyl alcohol are added into a reaction bottle, after stirring, the temperature is raised to 45-50 ℃ of the feed liquid, 17g of acrylonitrile (in the embodiment, the mol ratio of the 2-methoxyphenyl piperazine to the acrylonitrile is 1:1.23) is added dropwise, the dropwise addition is completed within 15min, the reaction is completed after the dropwise addition is carried out for 2 hours at 45-50 ℃, the reaction is completed, the temperature is reduced to-10 ℃, the filtration and the drying are carried out for 3 hours, and 58.9g of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile product is obtained.
Example 2:
an industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile comprises the following steps:
50g of 2-methoxyphenyl piperazine and 300ml of ethyl acetate are added into a reaction bottle, after stirring, the temperature is raised to 40-45 ℃ of the feed liquid, 15.2g of acrylonitrile (in the embodiment, the mol ratio of the 2-methoxyphenyl piperazine to the acrylonitrile is 1:1.10) is then added dropwise, the dropwise addition is completed within 20min, the reaction is completed after the dropwise addition is completed at 40-45 ℃ for 1 hour, the reaction is completed, the temperature is reduced to-15 ℃, the filtration and the drying are carried out for 3 hours, and 56.4g of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile product is obtained.
Example 3:
an industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile comprises the following steps:
50g of 2-methoxyphenyl piperazine and 400ml of methanol are added into a reaction bottle, after stirring, the temperature is raised to 50-60 ℃ of the feed liquid, 17.9g of acrylonitrile (in the embodiment, the mol ratio of the 2-methoxyphenyl piperazine to the acrylonitrile is 1:1.30) is added dropwise, the dropwise addition is completed within 15min, the reaction is finished after the dropwise addition is completed at 50-60 ℃ for 0.5 hours, the reaction is finished, the temperature is reduced to 0 ℃, the filtration and the drying are carried out for 3 hours, and 57.5g of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile product is obtained.
Example 4:
an industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile comprises the following steps: 50g of 2-methoxyphenyl piperazine and 200ml of acetone are added into a reaction bottle, after stirring, the temperature is raised to 40-45 ℃ of the feed liquid, 16g of acrylonitrile (in the embodiment, the mol ratio of the 2-methoxyphenyl piperazine to the acrylonitrile is 1:1.16) is added dropwise, the dropwise addition is completed within 15min, the reaction is completed after the dropwise addition is completed at 40-45 ℃ for 1 hour, the reaction is completed, the temperature is reduced to-20 ℃, the filtration and the drying are carried out for 3 hours, and 54.8g of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile product is obtained.
Example 5:
an industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile comprises the following steps: 2kg of 2-methoxyphenylpiperazine and 6kg of absolute ethyl alcohol are added into a reaction bottle, after stirring, the temperature is raised to 40-50 ℃ of the feed liquid, then 0.75kg of acrylonitrile (in the embodiment, the mol ratio of the 2-methoxyphenylpiperazine to the acrylonitrile is 1:1.36) is added, dripping is completed within 1.5h, after dripping is completed, the reaction is completed at 40-50 ℃ for 1 hour, the reaction is completed, the temperature is reduced to-10 ℃, filtering and drying are carried out for 3 hours, and 2.35kg of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile product is obtained.
Comparative example 1:
an industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile comprises the following steps:
to the reaction flask was added 38.5g (0.20 mol) of 2-methoxyphenylpiperazine, 11.7g (0.22 mol) of acrylonitrile was added dropwise over 15 minutes, and after the completion of the addition, the mixture was stirred at 55℃for 2 hours, and then allowed to stand at room temperature overnight, filtered (a very small amount of mother liquor), and dried at 50℃for 3 hours to obtain 44.0g of a 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile product.
Comparative example 2:
an industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile comprises the following steps:
1000mL of ethanol was added to the reaction flask, 55g (0.286 mol) of 2-methoxyphenylpiperazine and 50g (0.940 mol) of acrylonitrile were sequentially added with stirring, and then heated to reflux and maintained for 1 hour; after that, the volatiles were distilled off under reduced pressure, followed by drying at 50℃for 3 hours to obtain 64.1g (91.3%) of a 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile product.
Effect example 1:
the quality of 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile of each of the examples and comparative examples was examined, and the results are shown in Table 1.
TABLE 1
The above described embodiments are only preferred examples of the invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications thereof, which would be apparent to those skilled in the art without departing from the principles and spirit of the present invention, should be considered to be included within the scope of the appended claims.
Claims (9)
1. The industrial preparation method of 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile is characterized by comprising the following steps:
step 1, dissolving 2-methoxy phenylpiperazine in an organic solvent according to the mass volume ratio of 1g to 1-10 mL of the 2-methoxy phenylpiperazine to the organic solvent to obtain a 2-methoxy phenylpiperazine solution;
step 2, according to the mole ratio of 2-methoxy phenylpiperazine to acrylonitrile of 1:1.0 to 1.5, adding acrylonitrile after heating 2-methoxy phenyl piperazine solution, then reacting for 0.5 to 5 hours at a reaction temperature of 30 to 60 ℃, and ending the reaction to obtain 3- [4- (2-methoxy phenyl) piperazine-1-yl ] propionitrile solution; the acrylonitrile is added into the 2-methoxy phenylpiperazine solution in a dropwise or fed-batch manner.
And 3, cooling and crystallizing the 3- [4- (2-methoxyphenyl) piperazine-1-yl ] propionitrile solution, filtering and drying to obtain a final product.
2. The industrial preparation method of 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile according to claim 1, wherein the time of dropwise adding or flowing adding of the acrylonitrile is controlled to be within 10-90 min.
3. The industrial preparation method of 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile according to claim 1,
the organic solvent adopts one or more of ester organic solvents, alcohol organic solvents and ketone organic solvents.
4. A process for the industrial preparation of 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile according to claim 3,
the organic solvent adopts an alcohol organic solvent.
5. A process for the industrial preparation of 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile according to claim 3,
the organic solvent adopts one or more of absolute ethyl alcohol, ethyl acetate, methanol and acetone.
6. The industrial preparation method of 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile according to claim 1,
in the step 1, the mass volume ratio of the 2-methoxy phenylpiperazine to the organic solvent is 1g: 3-8 mL;
in step 2, the molar ratio of 2-methoxyphenylpiperazine to acrylonitrile is 1:1.1 to 1.3.
7. The industrial preparation method of 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile according to claim 1,
in the step 2, the reaction temperature is 40-60 ℃ and the reaction time is 0.5-2 h.
8. The industrial preparation method of 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile according to claim 1,
the temperature of cooling crystallization is-20 ℃.
9. The industrial preparation method of 3- [4- (2-methoxyphenyl) piperazin-1-yl ] propionitrile according to claim 8,
the temperature of cooling crystallization is-20 to 0 ℃.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005037281A1 (en) * | 2003-10-15 | 2005-04-28 | Ranbaxy Laboratories Limited | 1-alkylpiperazinyl-pyrrolidin-2, 5-dione derivatives as adrenergic receptor antagonist |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005037281A1 (en) * | 2003-10-15 | 2005-04-28 | Ranbaxy Laboratories Limited | 1-alkylpiperazinyl-pyrrolidin-2, 5-dione derivatives as adrenergic receptor antagonist |
Non-Patent Citations (2)
| Title |
|---|
| Erik S Vermeulen 等.Novel 5-HT7 receptor inverse agonists. Synthesis and molecular modeling of arylpiperazine- and 1,2,3,4-tetrahydroisoquinoline-based arylsulfonamides.《Journal of medicinal chemistry》.2004,第47卷(第22期),第5460页右栏第4段. * |
| VALENTA, V 等.POTENTIAL NEUROLEPTICS OF THE ORTHOPRAMIDE SERIES - SYNTHESIS OF N-(3-(TERT.AMINO)PROPYL)-5-SULFAMOYL-2-METHOXYBENZAMIDES.《COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS》.1990,第55卷(第3期),第805页第4段. * |
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