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CN-122010799-A - Preparation method of DL-green enzyme amine

CN122010799ACN 122010799 ACN122010799 ACN 122010799ACN-122010799-A

Abstract

The invention discloses a preparation method of DL-green enzyme amine, which comprises the steps of reacting penicillin G potassium with hydrazine hydrate for ring opening, reacting with formaldehyde for cracking, racemizing and hydrolyzing to obtain DL-green enzyme amine; the synthesis scheme directly takes penicillin G potassium as the initial raw material, adopts a one-pot scheme to synthesize DL-green enzymatic amine through four-step reaction, has low-cost and easily-obtained raw materials, is simple to operate, and is suitable for industrial production.

Inventors

  • REN JIANQIANG
  • WU XIAOKAI
  • Fei huahui

Assignees

  • 福建福瑞明德药业有限公司

Dates

Publication Date
20260512
Application Date
20260126

Claims (6)

  1. 1. The preparation method of the DL-green enzyme amine is characterized by comprising the following steps: (1) Ring opening, namely reacting a penicillin G potassium compound II with hydrazine hydrate to obtain a compound III; (2) Cracking, namely reacting the compound III obtained in the previous step with formaldehyde to obtain a compound IV and a byproduct compound V; (3) Racemization, namely racemizing the compound IV obtained in the previous step to obtain a compound VI; (4) Hydrolysis, namely, carrying out hydrolysis reaction on the compound VI obtained in the previous step to obtain a DL-green enzyme amine compound I; the reaction flow chart is as follows: 。
  2. 2. the method for preparing DL-cyan enzyme amine according to claim 1, wherein the four steps are completed by a one-pot scheme.
  3. 3. The method for producing DL-cyan enzyme amine according to claim 2, wherein the reaction solvent in the step (1) is n-butanol.
  4. 4. The method for preparing DL-cyan enzyme amine according to claim 2, wherein in the step (3), the racemization reaction is performed under the combined catalysis of acetic acid and formaldehyde.
  5. 5. The method for preparing DL-cyan enzyme amine according to claim 2, wherein in the step (4), triphenylphosphine is added during the hydrolysis reaction to prevent the formation of blue enzyme amine disulfide.
  6. 6. The method for preparing DL-green enzyme amine according to claim 1, wherein after the reaction in the step (4), the solvent is distilled off under reduced pressure, the temperature is reduced to 10-15 ℃, the solid is filtered, the pH value of the filtrate is adjusted to 5.5-6.5 by alkali, the filtrate is filtered to obtain white-like solid powder, the white-like solid powder is soaked and washed by ethanol, and the white-like powder is obtained by filtering.

Description

Preparation method of DL-green enzyme amine Technical Field The invention belongs to the field of pharmaceutical chemical industry, and in particular relates to a preparation method of DL-green enzymatic amine which is a key raw material for synthesizing various medicines. Background DL-green enzyme amine is an intermediate of specific medicine, is used for synthesizing HIV-1 protease inhibitor, has strong antiviral capability, and has obvious effects of preventing and treating AIDS. Chinese patent publication No. CN112500323B, which uses D-cyan enzyme amine as initial raw material, reacts with acetone to obtain isopropyl-D-cyan enzyme And reacting the amine with ethyl formate to obtain N-formyl isopropyl-D-cyan enzyme amine, racemizing, hydrolyzing and neutralizing to obtain DL-cyan enzyme amine. The reaction formula is as follows: Chinese patent publication No. CN117843538A, which uses D-cyan enzyme amine as initial raw material, reflux-flows in acetone and acetic acid system to obtain isopropyl-DL-cyan enzyme amine, and then hydrolysis is carried out to obtain DL-cyan enzyme amine. The two routes are both to use D-cyan enzyme amine as the initial raw material, so that the cost is high, and the operation is stepwise and complicated. Disclosure of Invention Aiming at the defects existing in the prior art, the invention provides a preparation method of DL-green enzymatic amine, and compared with the prior art, the preparation method uses cheaper and easily obtained penicillin G potassium and hydrazine hydrate as starting materials, and obtains the DL-green enzymatic amine with the chemical purity of more than 98 percent through a four-step reaction and a one-pot boiling scheme, thereby conforming to the quality expectation of the pharmaceutical industry on key intermediates. In order to achieve the above purpose, the present invention is realized by the following technical scheme: the preparation method of the DL-green enzyme amine is characterized by comprising the following steps: (1) Ring opening, namely reacting a penicillin G potassium compound II with hydrazine hydrate to obtain a compound III; (2) Cracking, namely reacting the compound III obtained in the previous step with formaldehyde to obtain a compound IV and a byproduct compound V; (3) Racemization, namely racemizing the compound IV obtained in the previous step to obtain a compound VI; (4) Hydrolysis, namely, carrying out hydrolysis reaction on the compound VI obtained in the previous step to obtain a DL-green enzyme amine compound I; the reaction flow chart is as follows: further, the method is characterized in that the four steps are completed by adopting a one-pot method. Further, in the step (1), the reaction solvent is n-butanol. Further characterized in that in step (3), the racemization reaction is performed under the combined catalysis of acetic acid and formaldehyde. Further, in the step (4), triphenylphosphine is added during the hydrolysis reaction to prevent the formation of amine disulfide of the enzyme. Further, after the reaction in the step (4), the solvent is distilled off under reduced pressure, the temperature is reduced to 10-15 ℃, solids are filtered, the pH value of the filtrate is regulated to 5.5-6.5 by alkali, the filtrate is filtered to obtain white solid powder, and the white solid powder is soaked and washed by ethanol and filtered to obtain white powder. Compared with the DL-green enzyme amine method reported in the prior literature, the invention has the main advantages that: The invention adopts penicillin G potassium as the initial raw material, omits the steps of synthesis and purification of D-penicillamine, adopts a one-pot scheme, has simple operation flow and improved yield, has obvious advantages in production cost, and is suitable for industrial production. Drawings FIG. 1 shows a chemical purity HPLC detection chromatogram of DL-penicillamine (Compound I) prepared in example 1; FIG. 2 shows a ratio HPLC detection chromatogram of DL-penicillamine (compound I) D-form to L-form prepared in example 1; FIG. 3 shows the HNMR spectrum of DL-penicillamine (compound I) prepared in example 1. Detailed Description The foregoing of the invention will be described in further detail by way of embodiments represented by the following specific examples, but it should not be construed that the scope of the above subject matter of the invention is limited to the following specific embodiments. All techniques based on the above-described experiments of the present invention are within the scope of the present invention. Example 1 First step, open loop 1200 Ml of n-butanol, 31.3G (0.5 mol) of hydrazine hydrate (80% aqueous solution) are added into a 2000 ml reaction flask, cooled to 0-5 ℃, 149G (0.4 mol) of penicillin G potassium compound II are added under stirring, heated to 20-30 ℃ and stirred for 0.5 hours under heat preservation. Second step, cracking 68 G (0.8 mol) of formaldehyde (36% aqueous solution) was added to t