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CN-121974817-A - Industrial preparation method of 4-acetamido butyrate

CN121974817ACN 121974817 ACN121974817 ACN 121974817ACN-121974817-A

Abstract

The invention discloses an industrial preparation method of 4-acetamido butyrate, which comprises the following steps of adding water and an organic phase into a ton kettle, sequentially adding 4-aminobutyric acid and inorganic base, dropwise adding an acylating agent, heating for reaction, evaporating organic solvent after the reaction is finished, adding ethanol, cooling for crystallization, filtering, leaching and drying to obtain the 4-acetamido butyrate. The invention adopts a one-pot method to complete three steps of acylation, salification and crystallization, avoids solvent loss caused by intermediate purification in conventional stepwise synthesis, shortens the reaction time, reduces the cost, has cheap and easily obtained raw materials, has the molar yield of more than 90 percent and has wide market application prospect.

Inventors

  • PENG XUEDONG
  • ZHANG MEI
  • ZHAO JINZHAO

Assignees

  • 苏州满元生物科技有限公司

Dates

Publication Date
20260505
Application Date
20251216

Claims (10)

  1. 1. A process for the industrial preparation of 4-acetamidobutyrate, comprising the steps of: adding water and an organic phase into a ton kettle, sequentially adding 4-aminobutyric acid and inorganic base, dropwise adding an acylating agent, heating for reaction, evaporating an organic solvent after the reaction is finished, adding ethanol, cooling for crystallization, filtering, leaching, and drying to obtain 4-acetamidobutyrate.
  2. 2. The industrial preparation method of the 4-acetamidobutyrate according to claim 1, which is characterized by comprising the following steps of adding water and an organic phase into a ton kettle, sequentially adding 4-aminobutyric acid and inorganic base, dropwise adding an acylating agent at 0-10 ℃, heating to 15-30 ℃ to react for 1.5-3 h, evaporating an organic solvent after the reaction is finished, adding ethanol with the weight of 1-4 times of 4-aminobutyric acid, reducing to 0-10 ℃, crystallizing, filtering, leaching with cold ethanol, and drying to obtain white solid 4-acetamidobutyrate.
  3. 3. The industrial preparation method of the 4-acetamidobutyrate according to claim 2, which is characterized by comprising the following steps of adding water and an organic phase into a ton kettle, sequentially adding 4-aminobutyric acid and inorganic base, dropwise adding an acylating agent at 0-10 ℃, heating to 30 ℃ for reaction for 2 hours, steaming out an organic solvent after the reaction is finished, adding ethanol with the weight being 2 times that of the 4-aminobutyric acid, reducing to 0-10 ℃ for crystallization, leaching with cold ethanol, and drying to obtain white solid 4-acetamidobutyrate.
  4. 4. The industrial process for producing 4-acetamidobutyrate according to claim 1, wherein the organic phase is at least one selected from tetrahydrofuran, acetone, methylene chloride, chloroform and toluene.
  5. 5. The process for the industrial preparation of 4-acetamidobutyrate according to claim 1, wherein the mass ratio of water to organic phase is 1-1.3:1.
  6. 6. The industrial preparation method of 4-acetamidobutyrate according to claim 1, wherein the inorganic base is selected from one of hydroxide, carbonate and bicarbonate, and the salt in 4-acetamidobutyrate is selected from one of sodium salt, magnesium salt, calcium salt, potassium salt, lithium salt and zinc salt.
  7. 7. The method for industrially producing 4-acetamidobutyrate according to claim 6, wherein the inorganic base is one selected from the group consisting of sodium hydroxide, magnesium carbonate, calcium carbonate, potassium hydroxide, lithium hydroxide and zinc hydroxide.
  8. 8. The industrial process for producing 4-acetamidobutyrate according to claim 1, wherein the acylating agent is one selected from acetyl chloride and acetic anhydride.
  9. 9. The process for the industrial production of 4-acetamidobutyrate according to claim 1, wherein the molar ratio of 4-aminobutyric acid, inorganic base and acylating agent is 1 (2-2.6): 1-1.3.
  10. 10. The industrial process for producing 4-acetamidobutyrate according to claim 9, wherein the mass ratio of organic phase to 4-aminobutyric acid is 1.5-4:1.

Description

Industrial preparation method of 4-acetamido butyrate Technical Field The invention relates to the technical field of organic chemical synthesis, in particular to an industrial preparation method of 4-acetamido butyrate. Background The 4-acetamido butyrate is prepared by amino acetylation of 4-aminobutyric acid and salifying carboxyl, is applied to auxiliary treatment of central nervous regulation related diseases in the field of medicine, and is partially researched and shown to be applicable to relieving neuropathic pain or serving as an auxiliary drug for improving nerve functions of cerebral vascular diseases (such as cerebral infarction recovery period). The compound can be used as a health care product for improving sleep and resisting fatigue, is assisted for relieving anxiety and tension, is commonly used in emotion management health care products, is easier to be absorbed by intestinal tracts (bioavailability is improved) after being orally taken due to the structural optimization of acetylation and salification compared with unmodified 4-aminobutyric acid, is easier to be prepared into common dosage forms such as tablets, capsules, oral liquid and the like, and is more suitable for being used as a raw material of medicines or health care products due to the combination of the two. In the prior art, few patents exist for synthesizing 4-acetamidobutyrate, and parts mainly related to salification are not disclosed, and the synthesis of 4-acetamidobutyrate is mentioned in relevant literature. Most of the method uses 4-aminobutyric acid as raw material, acetic anhydride or acetyl chloride as acylating agent, although the yield is considerable, the byproduct acetic acid can be removed by pulping and purifying with organic solvent for multiple times in the post-treatment, if the product is not purified completely, the salt formation in the next step can be influenced, the energy consumption of equipment can be increased due to the introduced organic solvent, and the solvent residue in the product can be caused. Disclosure of Invention The technical problem to be solved by the invention is to provide an industrial preparation method of 4-acetamido butyrate aiming at the defects in the prior art. The invention takes 4-aminobutyric acid as raw material and adopts Schotten-Baumann reaction (Shotten Bowman acylation reaction) one-pot method to synthesize 4-acetamido butyrate. In order to achieve the aim, the technical scheme adopted by the invention is that the industrial preparation method of the 4-acetamido butyrate comprises the following steps: adding water and an organic phase into a ton kettle, sequentially adding 4-aminobutyric acid and inorganic base, dropwise adding an acylating agent, heating for reaction, evaporating an organic solvent after the reaction is finished, adding ethanol, cooling for crystallization, filtering, leaching, and drying to obtain 4-acetamidobutyrate. Preferably, the industrial preparation method of the 4-acetamidobutyrate comprises the following steps of adding water and an organic phase into a ton kettle, sequentially adding 4-aminobutyric acid and inorganic base, dropwise adding an acylating agent at 0-10 ℃, heating to 15-30 ℃ for reacting 1.5-3 h, steaming out an organic solvent after the reaction is finished, adding ethanol with the weight of 1-4 times of 4-aminobutyric acid, reducing the temperature to 0-10 ℃, crystallizing, filtering, eluting with cold ethanol, and drying to obtain white solid 4-acetamidobutyrate. Preferably, the reaction temperature may be 15, 20, 25, 30 or any value between them, and in order to keep the reaction fast, the reaction temperature is preferably 30 ℃. Preferably, the reaction time may be 1.5, 2, 2.5, 3 h or any number of the two, and the confirmation of the end point of the reaction is based on the pH of the aqueous phase of 6.5-7.0. Preferably, the industrial preparation method of the 4-acetamidobutyrate comprises the following steps of adding water and an organic phase into a ton kettle, sequentially adding 4-aminobutyric acid and inorganic base, dropwise adding an acylating agent at 0-10 ℃, heating to 30 ℃ for reaction for 2 hours, evaporating off an organic solvent after the reaction is finished, adding ethanol with the weight being 2 times that of the 4-aminobutyric acid, reducing to 0-10 ℃ for crystallization, filtering, leaching with cold ethanol, and drying to obtain white solid 4-acetamidobutyrate. Preferably, the organic phase is selected from at least one of tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, more preferably tetrahydrofuran. Preferably, the mass ratio of water to organic phase is 1-1.3:1, e.g., 1:1, 1.1:1, 1.2:1, 1.3:1 or any number therebetween, more preferably, the ratio is 1:1. Preferably, the inorganic base is a base formed from one of hydroxide, carbonate and bicarbonate, and more preferably a base formed from hydroxide. The salt in the 4-acetamido butyrate is one of sodium salt, magnesium salt,