CN108329223B - Method for synthesizing non-nibutate - Google Patents
Method for synthesizing non-nibutate Download PDFInfo
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- CN108329223B CN108329223B CN201810176214.2A CN201810176214A CN108329223B CN 108329223 B CN108329223 B CN 108329223B CN 201810176214 A CN201810176214 A CN 201810176214A CN 108329223 B CN108329223 B CN 108329223B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention relates to the technical field of drug intermediate synthesis, in particular to a method for synthesizing non-nifurt, which comprises the steps of condensing benzaldehyde and nitromethane as raw materials under the action of benzylamine to form trans-nitrostyrene, carrying out Michelal addition with diethyl malonate in the presence of catalytic amount of sodium ethoxide, carrying out catalytic hydrogenation with raney nickel, and finally hydrolyzing in hydrochloric acid solution to obtain the non-nifurt. The invention provides a non-Nenitt synthesis method which has low requirement on equipment, is simple to operate in the whole process, has short route, is easy for industrial production and reduces the possibility of nitromethane explosion.
Description
Technical Field
The invention relates to the technical field of synthesis of drug intermediates, in particular to a method for synthesizing non-nifurtt.
Background
Non-nit, chemical name: 4-amino-3-phenylbutyric acid hydrochloride CAS: 1078-21-3. Is often used for preparing antidepressants and is a very important medical intermediate. The current literature reports methods such as: (1) benzoyl chloride and ethyl acetoacetate are used as raw materials, benzoyl acetate and ethyl acetoacetate are condensed and hydrolyzed, benzaldehyde and nitromethane are condensed to generate trans-form nitrostyrene, then the benzoyl chloride and the ethyl acetoacetate are subjected to Michelal addition, the addition product is subjected to catalytic hydrogenation by Raney nickel, and finally, the trans-form nitrostyrene is hydrolyzed in concentrated hydrochloric acid to prepare non-Neibutt [ reference: guo et al [ J ]. CN104402746,2015 ]. The production method has the advantages of long steps, various main raw materials, high requirement on equipment for hydrogenation reaction (4MPa) pressure and low overall yield. (2) Using benzyl cyanide as a raw material, synthesizing 3-cyano-ethyl phenylpropionate by using lithium isopropylamide as a base and ethyl bromoacetate at a low temperature of (-78 ℃), reducing the ethyl 3-cyano-ethyl phenylpropionate under CoCl2/NaBH4, and finally hydrolyzing the ethyl 3-cyano-ethyl phenylpropionate in hydrochloric acid to synthesize non-nilotint [ reference: kulig K.et al [ J ]. Polish Journal of Chemistry,2009,83(9):1628-1636 ]. The method has the advantages of expensive raw materials, harsh conditions, difficult industrialization and difficult mass production.
Disclosure of Invention
In view of the above problems, the invention provides a non-nebutamide synthesis method which has low requirements on equipment, is simple to operate in the whole process, has a short route, is easy for industrial production and reduces the possibility of nitromethane explosion.
In order to achieve the above object, the present invention provides the following technical solutions: the reaction steps are as follows:
benzaldehyde and nitromethane are used as raw materials, trans-form nitrostyrene is condensed under the action of benzylamine, Micheal addition is carried out on the trans-form nitrostyrene and diethyl malonate in the presence of catalytic amount of sodium ethoxide, raney nickel is used for catalytic hydrogenation, and finally hydrolysis is carried out in hydrochloric acid solution to obtain the fenofibrate. The whole process only needs four steps of reaction, and the total yield is up to more than 46.9%.
The invention discloses a method for synthesizing non-niblet, which comprises the following steps:
s1: A1000L reaction kettle is cleaned, a proper amount of benzaldehyde, nitromethane, 150kg of glacial acetic acid and 23kg of benzylamine are pumped in vacuum, a kettle cover is covered, stirring is started, the temperature is raised to a proper temperature for reaction, and HPLC (high performance liquid chromatography) detects that the raw materials disappear. Cooling to 50 deg.C, vacuum pumping 400kg water, cooling to below 10 deg.C for crystallization, centrifuging, dissolving solid with 540kg toluene, washing with water, heating organic phase to evaporate 50kg toluene, and pumping the above solution into overhead tank.
S2: and (3) pumping a proper amount of diethyl malonate and 13kg of sodium ethoxide solution into the kettle in vacuum, stirring for 30min, dripping the solution in the head tank at room temperature, reacting for 2h after dripping, and detecting the disappearance of the raw materials by HPLC. Adding industrial hydrochloric acid to adjust the pH value to be weak acidity. 100kg of saturated saline solution was sucked in under vacuum, the layers were separated, toluene was concentrated, and the residue was dissolved in 700kg of methanol.
S3: and (2) pumping the solution into a hydrogenation kettle in vacuum, adding raney nickel, replacing for 3 times with nitrogen and 3 times with hydrogen, keeping the pressure of 5kg at 50 ℃, reacting for 18 hours, filter-pressing raney nickel while hot, concentrating most of mother liquor, cooling to about 5 ℃, crystallizing, and centrifuging to obtain 200kg of solid.
S4: and transferring the solid into a reaction kettle, pumping 60kg of water and a proper amount of industrial hydrochloric acid in vacuum, heating to a proper temperature to start reaction, cooling to about 5 ℃ to crystallize, centrifuging, and drying to obtain 143kg of the solid. The yield thereof was found to be 46.9%.
Preferably, in the step S1, the weight ratio of the benzaldehyde to the nitromethane is 3:1 to 1: 1.
Preferably, in the step S1, the reaction temperature is 75-80 ℃ and the reaction time is 5 h.
Preferably, in the step S2, the weight ratio of the diethyl malonate to the benzaldehyde added into the system is 2: 1-1: 1.
Preferably, in the step S3, the weight ratio of the raney nickel added to the benzaldehyde added to the system is 15: 1-5: 1.
Preferably, in the step S4, the weight ratio of the industrial hydrochloric acid to the raney nickel added to the system is 15: 1-12: 1.
Preferably, in step S4, the reaction conditions are heating to about 100 ℃ and the reaction time is at least 15 h.
The invention has the advantages and beneficial effects that: the non-Neutrol synthetic method has the advantages of low requirement on equipment, simple operation in the whole process, short route, easiness in industrial production and reduction of the possibility of nitromethane explosion. The method has the advantages of cheap raw materials, short steps, high total yield and easy industrial production. The method adopts benzaldehyde, nitromethane and diethyl malonate as main raw materials, the non-niblet is prepared by four-step reaction, the benzaldehyde and the nitromethane are condensed under an acidic condition, the possibility of nitromethane explosion is reduced, the hydrogenation reaction pressure is 0.5MPa, and the requirement on equipment is low.
Detailed Description
The following further describes embodiments of the present invention with reference to examples. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1
S1: A1000L reaction kettle is cleaned, 150kg of benzaldehyde, 93kg of nitromethane, 150kg of glacial acetic acid and 23kg of benzylamine are pumped in vacuum, a kettle cover is covered, stirring is started, the temperature is increased to 75 ℃ for reaction for 5 hours, and HPLC (high performance liquid chromatography) detects that the raw materials disappear. Cooling to 50 deg.C, vacuum pumping 400kg water, cooling to below 10 deg.C for crystallization, centrifuging, dissolving solid with 540kg toluene, washing with water, heating organic phase to evaporate 50kg toluene, and pumping the above solution into overhead tank.
S2: and (3) pumping 200kg of diethyl malonate and 13kg of sodium ethoxide solution into the kettle in vacuum, stirring for 30min, dripping the solution in the head tank at room temperature, reacting for 2h after dripping, and detecting the disappearance of the raw materials by HPLC. Adding industrial hydrochloric acid to adjust the pH value to be weak acidity. 100kg of saturated saline solution was sucked in under vacuum, the layers were separated, toluene was concentrated, and the residue was dissolved in 700kg of methanol.
S3: and (3) pumping the solution into a hydrogenation kettle in vacuum, adding 20kg of Raney nickel, replacing for 3 times with nitrogen, replacing for 3 times with hydrogen, keeping the pressure of 5kg at 50 ℃, reacting for 18 hours, carrying out hot filter pressing on the Raney nickel, concentrating most of mother liquor, cooling to about 5 ℃, crystallizing, and centrifuging to obtain 200kg of solid.
S4: and transferring the solid into a reaction kettle, pumping 60kg of water and 240kg of industrial hydrochloric acid in vacuum, heating to about 100 ℃, reacting for 15 hours, cooling to about 5 ℃, crystallizing, centrifuging, and drying to obtain 143kg of the solid. The yield thereof was found to be 46.9%.
Example 2
S1: A1000L reaction kettle is cleaned, 300kg of benzaldehyde, 150kg of nitromethane, 150kg of glacial acetic acid and 23kg of benzylamine are pumped in vacuum, a kettle cover is covered, stirring is started, the temperature is increased to 80 ℃ for reaction for 5 hours, and HPLC (high performance liquid chromatography) detects that the raw materials disappear. Cooling to 50 deg.C, vacuum pumping 400kg water, cooling to below 10 deg.C for crystallization, centrifuging, dissolving solid with 540kg toluene, washing with water, heating organic phase to evaporate 50kg toluene, and pumping the above solution into overhead tank.
S2: 300kg of diethyl malonate and 13kg of sodium ethoxide solution are pumped into the kettle in vacuum, the mixture is stirred for 30min, the solution in the head tank is dripped at room temperature, the reaction lasts for 2h after the dripping is finished, and the disappearance of the raw materials is detected by HPLC. Adding industrial hydrochloric acid to adjust the pH value to be weak acidity. 100kg of saturated saline solution was sucked in under vacuum, the layers were separated, toluene was concentrated, and the residue was dissolved in 700kg of methanol.
S3: and (3) pumping the solution into a hydrogenation kettle in vacuum, adding 30kg of Raney nickel, replacing for 3 times with nitrogen, replacing for 3 times with hydrogen, keeping the pressure of 5kg at 50 ℃, reacting for 18 hours, carrying out hot filter pressing on the Raney nickel, concentrating most of mother liquor, cooling to about 5 ℃, crystallizing, and centrifuging to obtain 200kg of solid.
S4: transferring the solid into a reaction kettle, pumping 60kg of water and 360kg of industrial hydrochloric acid in vacuum, heating to about 100 ℃, reacting for 18h, cooling to about 5 ℃, crystallizing, centrifuging, and drying to obtain 291kg of solid. The yield thereof was found to be 48%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (7)
1. A method of synthesizing a non-nifurtt, comprising the steps of:
s1: cleaning a 1000L reaction kettle, pumping a proper amount of benzaldehyde, nitromethane, 150kg of glacial acetic acid and 23kg of benzylamine in vacuum, covering a kettle cover, stirring, starting heating to a proper temperature for reaction, and detecting the disappearance of raw materials by HPLC; cooling to 50 deg.C, vacuum pumping 400kg water, cooling to below 10 deg.C for crystallization, centrifuging, dissolving solid with 540kg toluene, washing with water, heating organic phase to evaporate 50kg toluene, and pumping the above solution into head tank;
s2: pumping a proper amount of diethyl malonate and 13kg of sodium ethoxide solution into the kettle in vacuum, stirring for 30min, dripping the solution in the elevated tank at room temperature, reacting for 2h after dripping, and detecting the disappearance of the raw materials by HPLC; adding industrial hydrochloric acid to adjust the pH value to be weak acidity; vacuum pumping 100kg of saturated salt water, layering, concentrating toluene, and dissolving the residual solution with 700kg of methanol;
s3: pumping the solution into a hydrogenation kettle in vacuum, adding raney nickel, replacing with nitrogen for 3 times, replacing with hydrogen for 3 times, maintaining 5kg of pressure, reacting at 50 ℃ for 18h, press-filtering raney nickel while hot, concentrating most of mother liquor, cooling to 5 ℃ for crystallization, and centrifuging to obtain 200kg of solid;
s4: and transferring the solid into a reaction kettle, pumping 60kg of water and a proper amount of industrial hydrochloric acid into the reaction kettle in vacuum, heating the reaction kettle to a proper temperature to start reaction, cooling the reaction kettle to 5 ℃ for crystallization, centrifuging the reaction product, and drying the product to obtain 143kg of the product with the yield of 46.9%.
2. The method of claim 1, wherein in step S1, the weight ratio of benzaldehyde to nitromethane is 3: 1-1: 1.
3. The method of claim 1, wherein in step S1, the reaction temperature is 75-80 ℃ and the reaction time is 5 h.
4. The method of claim 1, wherein in step S2, the weight ratio of diethyl malonate to benzaldehyde added to the system is 2: 1-1: 1.
5. The method of claim 1, wherein in step S3, the weight ratio of Raney nickel added to benzaldehyde added to the system is 15: 1-5: 1.
6. The method for synthesizing nifedipine according to claim 1, wherein the weight ratio of the industrial hydrochloric acid added to the raney nickel added to the system in step S4 is 15: 1-12: 1.
7. The method of claim 1, wherein in step S4, the reaction is carried out under heating to 100 ℃ for at least 15 h.
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| CN101033195A (en) * | 2007-04-17 | 2007-09-12 | 安徽省郎溪县科联实业有限公司 | Method of preparing 4-amino-3-phenyl butyric hydrochloride |
| LV14983B (en) * | 2013-10-15 | 2015-06-20 | Olainfarm, A/S | Method for producing intermediates of phenibut |
| CN105153006A (en) * | 2015-10-08 | 2015-12-16 | 常州强达宝成化工有限公司 | Synthetic method for 4-phenyl-2-pyrrolidone |
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