Preparation method of DL-green enzyme amine

Abstract

The invention discloses a preparation method of DL-penicillin amine, which comprises the following steps: reacting penicillin G potassium with hydrazine hydrate for ring opening, and then reacting with formaldehyde for cracking, racemization and hydrolysis to obtain the DL-penicillin amine; according to the synthesis scheme, the penicillin G potassium is directly used as a starting raw material, the DL-penicillin amine is synthesized by adopting a one-pot boiling scheme through four-step reaction, the raw materials are low in cost and easy to obtain, the operation is simple, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a method for preparing DL-penicillamine, a key raw material for the synthesis of various drugs. Background Technology

[0002] DL-penicillamine is an intermediate in the synthesis of HIV-1 protease inhibitors, which has strong antiviral capabilities and significant preventive and therapeutic effects against AIDS.

[0003] Chinese Patent Publication No. CN112500323B discloses the reaction of D-penicillamine as a starting material with acetone to obtain isopropyl-D-penicillamine. The amine is then reacted with ethyl formate to give N-formylisopropyl-D-penicillamine, which is then racemized, hydrolyzed, and neutralized to give DL-penicillamine.

[0004] The reaction formula is as follows: Chinese Patent Publication No. CN117843538A describes a process that uses D-penicillamine as a starting material, refluxes it in an acetone and acetic acid system to obtain isopropyl-DL-penicillamine, and then hydrolyzes it to obtain DL-penicillamine.

[0005] Both of the above routes use D-penicillamine as the starting material, which is relatively expensive and involves multiple steps, making them quite complicated. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a method for preparing DL-penicillin. Compared to known literature methods, this invention uses cheaper and more readily available penicillin G potassium and hydrazine hydrate as starting materials, and obtains DL-penicillin with a chemical purity of over 98% through a four-step reaction and one-pot cooking method, which meets the pharmaceutical industry's quality expectations for key intermediates.

[0007] To achieve the above objectives, the present invention provides the following technical solution: A method for preparing DL-penicillamine, characterized by comprising the following steps: (1) Ring opening: reacting penicillin G potassium compound II with hydrazine hydrate to obtain compound III; (2) Crack: The compound III obtained in the previous step is reacted with formaldehyde to obtain compound IV and byproduct compound V; (3) Racemization: The compound IV obtained in the previous step is racemized to obtain compound VI; (4) Hydrolysis: The compound VI obtained in the previous step was hydrolyzed to obtain DL-penicillamine compound I; The reaction flow chart is as follows: Furthermore, the feature is that the four steps are completed in a single pot.

[0008] Furthermore, the characteristic feature is that in step (1), the reaction solvent is n-butanol.

[0009] Furthermore, the characteristic feature is that in step (3), the racemic reaction is carried out under the combined catalysis of acetic acid and formaldehyde.

[0010] Furthermore, the feature is that in step (4), triphenylphosphine is added during the hydrolysis reaction to prevent the formation of penicillin disulfide.

[0011] Furthermore, after the reaction in step (4) is completed, the solvent is removed by vacuum distillation, the temperature is lowered to 10-15℃, the solid is filtered off, the pH of the filtrate is adjusted to 5.5-6.5 with alkali, filtered, and an off-white solid powder is obtained. The powder is then soaked and washed with ethanol, filtered, and an off-white powder is obtained.

[0012] Compared to the DL-penicillin method reported in existing literature, the main advantages of this invention are: The starting material of this invention is potassium penicillin G, which omits the synthesis and purification steps of D-penicillamine and adopts a one-pot cooking method, which simplifies the operation process and improves the yield. This invention has a significant advantage in production cost and is suitable for industrial production. Attached Figure Description

[0013] Figure 1 Example 1: HPLC chromatogram of the chemical purity of DL-penicillamine (compound I) prepared; Figure 2 Example 1: HPLC chromatogram of the D-type and L-type ratios of DL-penicillamine (compound I) prepared; Figure 3 : DL-penicillamine (compound I) prepared in Example 1 HNMR spectrum. Detailed Implementation

[0014] The following detailed description of the present invention, through several specific examples, further illustrates the above-described contents of the invention. However, this should not be construed as limiting the scope of the invention to the following specific embodiments. All techniques experimented with based on the above-described contents of the present invention fall within the scope of the present invention.

[0015] Example 1 Step 1: Open loop Add 1200 mL of n-butanol and 31.3 g (0.5 mol) of hydrazine hydrate (80% aqueous solution) to a 2000 mL reaction flask, cool to 0-5 °C, add 149 g (0.4 mol) of penicillin G potassium compound II while stirring, heat to 20-30 °C, and keep warm and stir for 0.5 hours.

[0016] Step 2: Pyrolysis Add 68 grams (0.8 mol) of formaldehyde (36% aqueous solution) to the reaction solution of the first step, heat to 45-55℃, and stir for 1 hour.

[0017] Step 3: Elimination Add 97.3 g (0.8 mol) hydrochloric acid (30% aqueous solution) and 48 g (0.8 mol) acetic acid to the reaction solution in the second step, and keep it at 45-55℃ and stir for 3 hours.

[0018] Step 4: Hydrolysis The reaction solution was subjected to vacuum distillation to remove n-butanol, cooled to 20-30°C, and 1000 mL of water was added. The mixture was stirred until homogeneous, and the solid was filtered off at room temperature. The filtrate was added to a reaction flask, along with 10.5 g (0.04 mol) of triphenylphosphine and 73 g (0.6 mol) of hydrochloric acid (30% aqueous solution). The mixture was stirred until homogeneous, and nitrogen was bubbled under the liquid surface three times. The temperature was then raised to 80-85°C, and the mixture was stirred for 3 hours. The solvent was then evaporated under vacuum to a final volume of 150-200 mL, cooled to 10-15°C, and the solid was filtered off. The filtrate was adjusted to pH 5.5-6.5 with 5% potassium hydroxide solution and kept at this temperature for 0.5 hours. After filtration, an off-white solid powder was obtained. The powder was slurried with 100 mL of 75% ethanol, filtered, and washed with 15 mL of anhydrous ethanol to obtain 49.4 g of off-white powder. The powder was dried under vacuum at 60 °C to obtain 46.2 g (0.31 mol) of off-white powder, with a yield of 77% and a purity of 98.97%. The penicillamine disulfide content was 0.31%, and the ratio of D-penicillamine to L-penicillamine was 49.8:50.2.

[0019] The HNMR spectrum is attached. Figure 3 , 1 H-NMR (D2O-d2), 3.58 (s, 1H), 1.45 (s, 3H), 1.37 (s, 3H).

Claims

1. A method for preparing DL-penicillamine, characterized in that... Includes the following steps: (1) Ring opening: reacting penicillin G potassium compound II with hydrazine hydrate to obtain compound III; (2) Crack: The compound III obtained in the previous step is reacted with formaldehyde to obtain compound IV and byproduct compound V; (3) Racemization: The compound IV obtained in the previous step is racemized to obtain compound VI; (4) Hydrolysis: The compound VI obtained in the previous step was hydrolyzed to obtain DL-penicillamine compound I; The reaction flow chart is as follows: 。 2. The method for preparing DL-penicillamine according to claim 1, characterized in that... The four steps are completed using a one-pot cooking method.

3. The method for preparing DL-penicillamine according to claim 2, characterized in that... In step (1), the reaction solvent is n-butanol.

4. The method for preparing DL-penicillamine according to claim 2, characterized in that... In step (3), the racemic reaction is carried out under the combined catalysis of acetic acid and formaldehyde.

5. The method for preparing DL-penicillamine according to claim 2, characterized in that... In step (4), triphenylphosphine is added during the hydrolysis reaction to prevent the formation of penicillin disulfide.

6. The method for preparing DL-penicillamine according to claim 1, characterized in that... After the reaction in step (4) is completed, the solvent is removed by vacuum distillation, the temperature is lowered to 10-15℃, the solid is filtered off, the pH of the filtrate is adjusted to 5.5-6.5 with alkali, filtered, and an off-white solid powder is obtained. The powder is then soaked and washed with ethanol, filtered, and an off-white powder is obtained.

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