A process for synthesizing D-penicillamine

Abstract

The invention discloses a process for synthesizing D-penicillamine, wherein penicillin G potassium salt is used as a raw material, and a monosubstituted hydrazine is subjected to condensation ring opening under the action of a catalyst, and after the reaction is completed, an acetic acid solution is added for acidification, and then n-heptane is added for crystallization to obtain D-penicillamine. The method of the invention is simple to operate, has a short cycle, avoids high-temperature heating reaction conditions, improves raw material conversion rate and reaction yield, realizes a "one-pot method" to obtain a high-purity product with stable quality, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical intermediate synthesis, and specifically relates to a process for synthesizing D-penicillamine. Background Art

[0002] D-Penicillamine is a metabolite of penicillin, with the chemical name β,β-dimethylcysteine. It is a non-natural amino acid. Due to the chemical properties of the amino and thiol functional groups in its structure: chelation of heavy metals, condensation ability with aldehydes, and exchange reaction with disulfides, D-penicillamine is used as a specific drug in the clinic to treat heavy metal poisoning, rheumatoid arthritis, chronic active hepatitis and other diseases.

[0003] There are two main methods for preparing D-penicillamine reported in existing literature:

[0004] The first method is to use penicillin G potassium salt as raw material and aniline (or phenylenediamine) compounds as condensing agents in a mixed solvent of water, glacial acetic acid and toluene, and heat and reflux to obtain the product (reference Chem Pham Bull, 1988, 36 (6): 1957-1962 / Hetercocycles, 1988, 27 (6): 1421-1429 / Chem Pham Bull, 1989, 37 (6): 1609-1611). This method is carried out under long-term high-temperature reflux conditions. Since the raw material penicillin G potassium salt is unstable and easily deteriorates under high temperature conditions, and the product D-penicillamine is easily oxidized under high temperature conditions, the reaction conversion rate is reduced, resulting in a low yield of only 51-87%, and a large amount of sulfur-containing odorous byproducts are produced, causing environmental pollution.

[0005] The second method, Chinese patent CN111909067A, reports that D-penicillamine is prepared by using a chiral compound L-serine ester derivative as the starting material through five steps of reaction: Grignard reaction, oxidation reaction, sulfonylation reaction, thioesterification reaction and hydrolysis. The chiral L-serine ester derivative used in this route costs 600-1000 yuan / kg, and the reaction steps are long. The total yield of the five-step reaction is 40.4%, resulting in a high production cost of D-penicillamine, no competitive advantage in the market, and not suitable for industrial production.

[0006] Taking into account the complicated post-processing operation, low conversion rate, high cost, and environmental pollution in the above-mentioned synthetic routes, it is necessary to conduct in-depth research and optimization on the synthetic process of D-penicillamine to develop a better, safer and more stable reaction route that is suitable for industrial production to meet the growing market demand. Summary of the invention

[0007] In order to overcome the above problems, the present invention provides a process for synthesizing D-penicillamine: using penicillin G potassium salt as a raw material, condensing and ring-opening with monosubstituted hydrazine under the action of a catalyst, adding acetic acid solution for acidification after the reaction, and then adding n-heptane for crystallization to obtain D-penicillamine. The method of the present invention is simple to operate, has a short cycle, avoids high-temperature heating reaction conditions, improves the raw material conversion rate and reaction yield, realizes a "one-pot method" to obtain a high-purity product with stable quality, and is suitable for industrial production.

[0008] The present invention provides a process for synthesizing D-penicillamine, comprising the following steps: using penicillin G potassium salt as a raw material, carrying out condensation ring opening with monosubstituted hydrazine in a mixed solvent under the action of a catalyst, adding acetic acid solution for acidification after the reaction, and then adding n-heptane for crystallization to obtain D-penicillamine. The synthesis route is shown as follows:

[0009]

[0010] Furthermore, in the optimized technical solution, the mixed solvent is selected from a mixed solvent of sulfolane / n-butanol.

[0011] Furthermore, in the optimized technical solution, in the monosubstituted hydrazine NH2NHR, R is selected from trimethylsilyl (TMS), triethylsilyl (TES) or triphenylmethyl (Trt).

[0012] Furthermore, in the optimization technical solution, the catalyst is selected from B(C6H5)3 or B(C6F5)3.

[0013] Furthermore, in the optimized technical solution, the molar ratio of penicillin G potassium salt, monosubstituted hydrazine and catalyst is 1.0:1.0-1.05:0.01-0.05.

[0014] Furthermore, in the optimized technical solution, the volume ratio of cyclopentane, n-butanol and n-heptane is 2:1:1-1.2; the amount of n-heptane added during the post-treatment process is very critical. If too much is added, by-product B and inorganic salts will precipitate from the system. The best ratio of the three is 2:1:1.

[0015] Furthermore, in the optimized technical solution, the condensation ring-opening reaction temperature is 30-40° C. After adding a specific Lewis acid boron-containing catalyst, the reaction can complete the ring-opening and acetal exchange reaction at a lower temperature and in a short time.

[0016] Furthermore, in the optimized technical solution, the concentration of the acetic acid solution is 50-80%.

[0017] The present invention has the following advantages:

[0018] 1. The catalyst B(C6H5)3 or B(C6F5)3 is used to improve the reaction activity and reaction speed, shorten the reaction cycle, and avoid the decomposition of the raw material penicillin G potassium and the oxidation and deterioration of the product D-penicillamine under high temperature heating reaction conditions. The reaction yield can reach 82-91%.

[0019] 2. The post-treatment operation is simple. The reaction system adopts sulfolane / n-butanol / water / n-heptane solvent system, which realizes the "one-pot method" to obtain high-purity products with stable quality, which is suitable for industrial production.

[0020] 3. The reaction is divided into two stages from the actual process: amide ring opening and acetal exchange. In the first stage, the ring opening of the nitrogen-containing four-membered ring amide is relatively fast, and the acetal exchange in the second stage is relatively slow.

[0021] The present application first attempts to use hydrazine hydrate to exchange acetals in the presence of a boron-containing Lewis acid B(C6F5)3, which can be completed under reflux conditions for more than 3 hours. During this process, as the reflux time increases, the by-product A increases to 4-8%, and purification is relatively difficult. By optimizing the NH2NH2R substituent, it is found that the use of three substituents, R=SiMe3, SiEt3 and Trs, can quickly complete the acetal exchange and deprotection at a relatively low reaction temperature under the catalysis of B(C6F5)3. After the reaction is completed, by adding a suitable proportion of n-heptane, the product is first precipitated from the sulfolane solution, and other by-products remain in the mother liquor. The mother liquor continues to add n-heptane, and the by-product precipitates. It is confirmed to be compound B after identification. 1 H-NMR(400MHz,DMSO-d6)δ3.98(2H,s,CH2),4.25(1H,s,CH),7.23-7.32(6H,m,Ph,CHNNH),7.82(1H,s,NHCOCH2Ph),11.15(1H,s,NH); LC-MS(m / z)218.08(M+H + ), thereby achieving the purpose of rapid purification. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is the HNMR spectrum of D-penicillamine obtained in Example 1;

[0023] Figure 2 This is the HPLC-MS spectrum of the impurities in Example 5. Specific embodiments

[0024] Example 1

[0025]

[0026] Under nitrogen protection, add penicillin G potassium 74.5g (0.20mol), catalyst B (C6H5) 30.97g (4mmol), trimethylsilylhydrazine 20.8g (0.20mol), cyclopentane 300mL and n-butanol 150mL to the reaction bottle, heat to 30-40°C, keep warm and stir for 1 hour, control the raw material penicillin G potassium <1% in HPLC, the reaction is over, add 70% acetic acid solution 34mL at 30-40°C, stir for 1 hour, add n-heptane 150mL, stir at room temperature for 1 hour, filter to obtain a crude product, under nitrogen protection, add 120mL methanol to the crude product, mix, beat at room temperature for 1 hour, filter, and vacuum dry at 30-40°C for 3 hours to obtain 24.8g of white solid D-penicillamine with a purity of 98.9%, an ee value of 99.3%, and a yield of 83.2%. 1 H-NMR spectrum Figure 1 shown.

[0027] 80% hydrazine hydrate was used to replace trimethylsilylhydrazine, and the temperature was raised to reflux for reaction for 3 hours. Other conditions remained unchanged. After the reaction was completed, 23.6 g of a white crude product was obtained with a yield of 78.9%, a purity of 95.3%, and an impurity A of 4.4%.

[0028] Example 2

[0029]

[0030] Under nitrogen protection, 74.5 g (0.20 mol) of potassium penicillin G, 33.07 g (6 mmol) of catalyst B (C6F5), 33.7 g (0.24 mol) of triethylsilylhydrazine, 300 mL of sulfolane and 150 mL of n-butanol were added to the reaction bottle, heated to 30-40°C, stirred for 1 hour, and the raw material potassium penicillin G was controlled to be <1% in HPLC, and the reaction was completed. 34 mL of 70% acetic acid solution was added dropwise at 30-40°C, stirred for 1 hour, 150 mL of n-heptane was added, stirred at room temperature for 1 hour, filtered to obtain a crude product, and under nitrogen protection, 120 mL of methanol was added to the crude product, mixed, slurried at room temperature for 1 hour, filtered, and dried in vacuo at 30-40°C for 3 hours to obtain 26.4 g of white solid D-penicillamine with a purity of 99.1%, an ee value of 99.2%, and a yield of 88.5%.

[0031] Example 3

[0032]

[0033] Under nitrogen protection, add penicillin G potassium 74.5g (0.20mol), catalyst B (C6F5) 33.07g (6mmol), tritylhydrazine 54.9g (0.20mol), cyclopentane 300mL and n-butanol 150mL to the reaction bottle, heat to 30-40°C, keep warm and stir for 1 hour, control the raw material penicillin G potassium <1% in HPLC, the reaction is completed, add 50mL of 50% acetic acid solution dropwise at 30-40°C, stir for 2 hours, add n-heptane 150mL, stir at room temperature for 1 hour, filter to obtain a crude product, under nitrogen protection, add 120mL of methanol to the crude product, mix, beat at room temperature for 1 hour, filter, and vacuum dry at 30-40°C for 3 hours to obtain 25.4g of white solid D-penicillamine with a purity of 99.0%, an ee value of 99.2%, and a yield of 85.3%.

[0034] Example 4

[0035]

[0036] Under nitrogen protection, 2.98 kg (8.0 mol) of potassium penicillin G, 3122.8 g (0.24 mol) of catalyst B (C6F5), 0.834 kg (8.0 mol) of trimethylsilylhydrazine, 12 L of sulfolane and 6 L of n-butanol were added to the reactor, heated to 30-40°C, stirred for 1 hour, and the raw material potassium penicillin G was controlled to be <1% in HPLC, and the reaction was completed. 1.36 L of 70% acetic acid solution was added dropwise at 30-40°C, stirred for 1 hour, 6 L of n-heptane was added, stirred at room temperature for 1 hour, filtered to obtain a crude product, and under nitrogen protection, 4.8 L of methanol was added to the crude product, mixed, slurried at room temperature for 1 hour, filtered, and dried in vacuo at 30-40°C for 3 hours to obtain 1.08 kg of white solid D-penicillamine with a purity of 99.1%, an ee value of 99.3%, and a yield of 90.7%.

[0037] Example 5

[0038]

[0039] Under nitrogen protection, add 37.2 g (0.10 mol) of penicillin G potassium and 400 mL of n-butanol to a reaction flask connected to a water separator, heat to 40-50°C, add 2.6 g of hydrazine hydrate dropwise, keep warm and stir for 15 minutes, add 6.3 g of concentrated hydrochloric acid dropwise, react for 30 minutes, heat to 80-85°C and react for 1 hour, add 2.6 g of hydrazine hydrate and 6.3 g of concentrated hydrochloric acid respectively, keep warm for 1 hour, add 2.6 g of hydrazine hydrate and 6.3 g of concentrated hydrochloric acid again, keep warm for 4 hours, collect the azeotropic n-butanol and water mixture during reflux, end the reaction, cool to 20-30°C, filter, and rinse the filter cake twice with n-butanol, 100 mL each time. The obtained filter cake was mixed with 110 mL of anhydrous ethanol, concentrated hydrochloric acid was added dropwise to adjust the pH to 1.5-1.7, stirred for 30 minutes, filtered, the filter cake was stirred with 110 mL of anhydrous ethanol for 10 minutes, filtered, the two filtrates were combined, 3.0 g of activated carbon was added to the filtrate, stirred for 1 hour, filtered, 11.9 g of triethylamine was added dropwise to the filtrate to adjust the pH to 6.0-6.8, stirred at 15° C. for 2-3 hours, filtered, the filter cake was washed with 95% ethanol and anhydrous ethanol in turn, and vacuum dried at 50-60° C. for 8 hours to obtain 9.2 g of white solid D-penicillamine with a purity of 97.3% and a yield of 61.7%.

[0040] After the reaction was completed, the filtrate from the first filtration was concentrated under reduced pressure, and the residue was subjected to column chromatography (methanol / chloroform = 1 / 6) to obtain 4.5 g of off-white solid compound A. 1 H-NMR(400MHz,D2O)δ1.36(3H,s,βCH3),1.43(3H,s,βCH3),3.56(1H,s,αH); LC-MS(m / z)297.08(M+H + ); mass spectrum such as Figure 2 As shown, the structure of compound A was identified as D-penicillamine disulfide:

[0041]

[0042] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A process for synthesizing D-penicillamine, characterized in that: The steps include: Penicillin G potassium salt is used as a raw material, and condensation ring opening is carried out with monosubstituted hydrazine in a mixed solvent under the action of a catalyst. After the reaction is completed, acetic acid solution is added for acidification, and then n-heptane is added for crystallization to obtain D-penicillamine; in the monosubstituted hydrazine NH2NHR, R is selected from trimethylsilyl, triethylsilyl or triphenylmethyl; and the catalyst is selected from B(C6H5)3 or B(C6F5)3.

2. The process for synthesizing D-penicillamine according to claim 1, characterized in that: The mixed solvent is selected from a mixed solvent of sulfolane / n-butanol.

3. The process for synthesizing D-penicillamine according to claim 1, characterized in that: The molar ratio of penicillin G potassium salt, monosubstituted hydrazine and catalyst is 1.0:1.0-1.05:0.01-0.

05.

4. The process for synthesizing D-penicillamine according to claim 1, characterized in that: The temperature of the condensation ring-opening reaction is 30-40°C.

5. The process for synthesizing D-penicillamine according to claim 1, characterized in that: The concentration of the acetic acid solution is 50-80%.

6. The process for synthesizing D-penicillamine according to claim 2, characterized in that: The volume ratio of sulfolane, n-butanol and n-heptane is 2:1:1-1.2.

Images