A process for the preparation of d-penicillamine using an acidic cation resin

Abstract

The application discloses a process method for preparing D-penicillamine by using an acidic cation resin. The application provides a preparation method of D-penicillamine, which comprises the following steps: compound 1 is reacted with hydrazine hydrate to obtain compound 2, and ring-opening reaction is carried out in the presence of an acidic cation resin to obtain compound 3. The method disclosed by the application does not need to remove inorganic salts separately, effectively reduces the impurities generated by oxidation, and has the advantages of simple operation, high yield, low cost and suitability for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to a process for preparing D-penicillamine using acidic cationic resin. BACKGROUND

[0002] The chemical structure of D-penicillamine is as follows:

[0003]

[0004] D-penicillamine is clinically used for heavy metal detoxification, rheumatoid arthritis, hepatolenticular degeneration, cystinuria, stones, hypertension, and as an immunosuppressant. D-penicillamine can be used as a raw material, and can also be used as an intermediate of a raw material, further processed into a penicillamine derivative or prepared into L-penicillamine.

[0005] The industrial production of D-penicillamine generally adopts the method of degrading penicillin, and most of the post-treatment needs a separate step of removing potassium or sodium, which increases the operation process, which can cause air to enter, oxidize the product to generate more dithiopencillamine impurities, thereby increasing the risk of product quality decline. Because the molecular structure of D-penicillamine contains carboxyl, amino and sulfhydryl groups, it is easy to oxidize and couple sulfhydryl groups in the reaction and post-treatment process, and generate impurities such as dithiopencillamine and decarboxylation. There is also a risk of further oxidation and reaction to generate penicillamine sulfonic acid derivative impurities.

[0006] Xu Suzhen (Antibiotics, 1982, 7(5): 338-339) used penicillin potassium salt and hydrazine hydrate to react in the presence of hydrochloric acid, and then removed the by-product by filtration. Then hydrochloric acid was added to obtain penicillamine hydrochloride, and then triethylamine was used to neutralize and remove hydrogen chloride to obtain the target penicillamine, but the yield and content were low.

[0007] In CN108164444 A, a similar method was used to obtain penicillamine, and a different acid system (concentrated hydrochloric acid, dilute trifluoroacetic acid solution or phosphoric acid solution, etc.) was used to remove potassium salt, and a noble metal catalyst was also used to reduce dithiopencillamine impurities, thereby obtaining penicillamine with high purity.

[0008] Zhang Qianying (Journal of Shanghai University, 2002, 8(5): 456-458) used penicillin potassium salt and aniline to react, and used glacial acetic acid to remove potassium salt. The post-treatment method is similar to the above method, and the steps are more and the operation is more complicated, which increases the operation risk.

[0009] As described above, the prior art for preparing D-penicillamine has the following disadvantages: multiple preparation and post-treatment steps, complicated operation, easy to cause oxidation side reactions, more impurities generated, by-products and impurities difficult to remove, low product content, etc. SUMMARY

[0010] The application aims to overcome the problems in the prior art that inorganic acid is used to remove inorganic salt, and then base is used to neutralize penicillamine-inorganic acid salt to prepare D-penicillamine, so that the operation steps are increased, and the risk of generating disulfide penicillamine impurities by oxidizing penicillamine is increased. The application provides a preparation method of D-penicillamine. The preparation method has high yield, high content, low impurities, simple operation, less pollution, low cost, short production cycle and is suitable for industrial production.

[0011] The application solves the above technical problems through the following technical solutions.

[0012] The application provides a preparation method of D-penicillamine, which comprises the following steps: compound 1 is reacted with hydrazine hydrate to obtain compound 2, and ring-opening reaction is carried out in the presence of an acid cation resin to obtain compound 3.

[0013]

[0014] M + is a monovalent metal cation.

[0015] In the preparation method, the acid cation resin can be a sulfonic acid resin, preferably Amberlyst 15.

[0016] In the preparation method, the mass ratio of the acid cation resin to compound 1 can be 0.5:1 to 3.0:1, preferably 0.5:1 to 2.0:1, more preferably 0.72:1, 0.66:1, 0.8:1 or 2:1, and most preferably 0.72:1.

[0017] In the preparation method, the reaction temperature of the ring-opening reaction can be 40-80℃, preferably 65-75℃.

[0018] In the preparation method, the ring-opening reaction can be carried out under inert gas protection, for example, nitrogen.

[0019] In the preparation method, after the ring-opening reaction is carried out at 65-75℃ for 2-6h, the temperature is lowered to 15-30℃; for example, the reaction is carried out at 65-75℃ for 3h, and then the temperature is lowered to 20-30℃ for 1h.

[0020] The preparation method can be that the acid cation resin is added to compound 2.

[0021] The raw materials of the preparation method can consist of compound 2 and the acid cation resin.

[0022] The preparation method can further comprise the preparation of compound 2, which comprises the following steps: compound 1 is reacted with hydrazine hydrate in water to obtain compound 2.

[0023] In the preparation method of the compound 2, the compound 1 is a penicillin salt, preferably penicillin potassium or penicillin sodium.

[0024] In the preparation method of the compound 2, the molar ratio of the compound 1 to the hydrazine hydrate can be 1:1-1:2, preferably 1:2.

[0025] In the preparation method of the compound 2, the reaction temperature of the reaction can be 0-80℃, preferably 20-30℃.

[0026] In the preparation method of the compound 2, the volume / mass ratio of the water to the compound 1 can be 6-10ml / g, for example 8ml / g.

[0027] In the preparation method of the compound 2, the reaction time of the reaction is not limited, and can be 0.5-5h, preferably 1-2h, until the reaction of the penicillin salt is complete.

[0028] In the preparation method of the compound 2, the reaction can be carried out under inert gas protection, for example nitrogen.

[0029] In the preparation method of the compound 2, the reaction is to add hydrazine hydrate to the compound 1.

[0030] In the preparation method, the compound 2 can be directly used in the next step reaction without treatment.

[0031] In the preparation method, the preparation of the compound 2 and the preparation of the compound 3 are one-pot stepwise feeding.

[0032] In the preparation method, the ring-opening reaction can further include post-treatment.

[0033] The post-treatment of the reaction includes: cooling the reaction solution, filtering, concentrating the filtrate, and purifying.

[0034] In the post-treatment, the cooling of the reaction solution is to cool to 15-30℃.

[0035] In the post-treatment, the filtering includes washing the filter cake with water.

[0036] In the post-treatment, the concentration of the filtrate is to concentrate the filtrate under reduced pressure.

[0037] In the post-treatment, the purification is to add ethanol to the crude product under nitrogen protection, stir at 65-75℃ for 1-2h; cool to 5-15℃, stir for 1-2h, filter the mixture, and dry the filter cake to obtain the compound 3.

[0038] In the preparation method, the ring-opening reaction can further include recovery of the resin.

[0039] The method for recovering the resin can be conventional in the art, for example, including washing with an organic solvent, washing with water, and mixing with an acid.

[0040] In the recovery of the resin, the organic solvent can be selected from one or more of ethanol, methanol, DMF, and DMSO.

[0041] In the recovery of the resin, the acid can be concentrated hydrochloric acid or 50% sulfuric acid.

[0042] In the present application, room temperature is 20-30°C.

[0043] The positive progress effect of the present application is that:

[0044] (1) The yield of D-penicillamine prepared by the preparation method of the present application is high, for example, the yield can reach 74%-96%; the purity is high, for example, the product content is more than 99%.

[0045] (2) The process of the present application is simple in operation, low in cost, less in pollution, and short in production cycle, and is suitable for industrialized production.

[0046] On the basis of not violating the common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, that is, the preferred examples of the present application are obtained.

[0047] The reagents and raw materials used in the present application are commercially available. DETAILED DESCRIPTION

[0048] The present application will be further illustrated by the following examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples are not specified, and are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0049] Example 1

[0050] Penicillin potassium (50 g, 0.134 mol, 1.00 eq) was added to purified water (400 mL, 8V) and replaced with nitrogen for 3 times. Hydrazine hydrate (10.1 g, 0.268 mol, 2.00 eq) was slowly added at a temperature of 20-30°C, and after the addition was completed, the reaction was stirred at a temperature of 20-30°C for 0.5 h. After the reaction was detected to be complete, Amberlyst 15 (36 g, 0.72X) was added, and the reaction was stirred at a temperature of 65-75°C for 3 h. After the reaction was detected to be complete again, the temperature was lowered to 20-30°C, and the reaction was stirred for 1 h. The reaction was filtered, the filter cake was washed with purified water (50 mL), and the filtrate was dried under reduced pressure. Ethanol (200 mL) was added, the temperature was controlled at 65-75°C, and the reaction was stirred for 0.5 h. The temperature was lowered to 5-15°C, and the reaction was stirred for 1 h. The reaction was filtered, and the filter cake was dried under vacuum at a temperature of 35-45°C to obtain D-penicillamine white solid (19.16 g, yield: 95.65%, dithiopencillamine 0.1%, content 99.5%). 1H NMR (400 MHz, D2O, ppm): δ = 1.48 (s, 3H), 1.57 (s, 3H), 3.7 (s, 1H).

[0051] Example 2

[0052] Penicillin potassium (50 g, 0.134 mol, 1.00 eq) was added to purified water (400 mL, 8V), and replaced with nitrogen for 3 times. Hydrazine hydrate (10.1 g, 0.268 mol, 2.00 eq) was slowly added at 20-30°C, and after the addition was completed, stirring was performed at 20-30°C for 0.5 h. After the reaction was confirmed to be completed, Amberlyst 15 (33 g, 0.66X) was added, and the temperature was increased to 65-75°C, and stirring was performed for 3 h. After the reaction was confirmed to be completed again, the temperature was decreased to 20-30°C, and stirring was performed for 1 h. Filtration was performed, the filter cake was rinsed with purified water (50 mL), and the filtrate was dried under reduced pressure. Ethanol (200 mL) was added, and stirring was performed at 65-75°C for 0.5 h. The temperature was decreased to 5-15°C, and stirring was performed for 1 h. Filtration was performed, and the filter cake was dried under vacuum at 35-45°C. The product obtained in Example 1 was used as a reference, and it was confirmed that D-penicillamine white solid (17.16 g, yield: 85.67%, disulfide penicillamine 0.4%, content 99.1%) was obtained.

[0053] Example 3

[0054] Penicillin potassium (50 g, 0.134 mol, 1.00 eq) was added to purified water (400 mL, 8V), and replaced with nitrogen for 3 times. Hydrazine hydrate (10.1 g, 0.268 mol, 2.00 eq) was slowly added at 20-30°C, and after the addition was completed, stirring was performed at 20-30°C for 0.5 h. After the reaction was confirmed to be completed, Amberlyst 15 (40 g, 0.80X) was added, and the temperature was increased to 65-75°C, and stirring was performed for 3 h. After the reaction was confirmed to be completed again, the temperature was decreased to 20-30°C, and stirring was performed for 1 h. Filtration was performed, the filter cake was rinsed with purified water (50 mL), and the filtrate was dried under reduced pressure. Ethanol (200 mL) was added, and stirring was performed at 65-75°C for 0.5 h. The temperature was decreased to 5-15°C, and stirring was performed for 1 h. Filtration was performed, and the filter cake was dried under vacuum at 35-45°C. The product obtained in Example 1 was used as a reference, and it was confirmed that D-penicillamine white solid (17.53 g, yield: 87.51%, disulfide penicillamine 0.1%, content 99.3%) was obtained.

[0055] Example 4

[0056] Penicillin potassium (50 g, 0.134 mol, 1.00 eq) was added to purified water (400 mL, 8V) and replaced with nitrogen for 3 times. Hydrazine hydrate (10.1 g, 0.268 mol, 2.00 eq) was slowly added at 20-30 °C, and after the addition was completed, it was stirred at 20-30 °C for 0.5 h. After the reaction was detected to be complete, Amberlyst 15 (100 g, 2.00X) was added, and the reaction was stirred at 65-75 °C for 3 h. After the reaction was detected to be complete again, it was cooled to 20-30 °C and stirred for 1 h. It was suction filtered, the filter cake was rinsed with purified water (50 mL), and the filtrate was dried under reduced pressure. Ethanol (200 mL) was added, it was stirred at 65-75 °C for 0.5 h, cooled to 5-15 °C and stirred for 1 h, suction filtered, and the filter cake was vacuum dried at 35-45 °C. The product obtained in Example 1 was used as a reference, and D-penicillamine white solid (14.96 g, yield: 74.69%, disulfopencillamine 0.1%, content 99.1%) was confirmed to be obtained.

[0057] Example 5

[0058] Penicillin potassium (1000 g, 2.68 mol, 1.00 eq) was added to purified water (8 L, 8V) and replaced with nitrogen for 3 times. Hydrazine hydrate (202.5 g, 5.36 mol, 2.00 eq) was slowly added at 20-30 °C, and after the addition was completed, it was stirred at 20-30 °C for 0.5 h. After the reaction was detected to be complete, Amberlyst 15 (720 g, 0.72X) was added, and the reaction was stirred at 65-75 °C for 3 h. After the reaction was detected to be complete again, it was cooled to 20-30 °C and stirred for 1 h. It was suction filtered, the filter cake was rinsed with purified water (1 L), and the filtrate was dried under reduced pressure. Ethanol (4 L) was added, it was stirred at 65-75 °C for 0.5 h, cooled to 5-15 °C and stirred for 1 h, suction filtered, and the filter cake was vacuum dried at 35-45 °C. The product obtained in Example 1 was used as a reference, and D-penicillamine white solid (379.2 g, yield: 94.65%, disulfopencillamine 0.1%, content 99.5%) was confirmed to be obtained.

[0059] Comparative Example 1

[0060] Penicillin potassium (50 g, 0.134 mol, 1.00 eq) was added into purified water (400 mL, 8V) and replaced with nitrogen for 3 times. Hydrazine hydrate (10.1 g, 0.268 mol, 2.00 eq) was slowly added at 20-30 °C, and after the addition was completed, it was stirred at 20-30 °C for 0.5 h. After the reaction was detected to be completed, Amberlite IR-120 (33 g, 0.66X) was added, and the reaction was stirred at 65-75 °C for 3 h. After the reaction was detected to be completed again, it was cooled to 20-30 °C and stirred for 1 h. It was filtered, the filter cake was rinsed with purified water (50 mL), and the filtrate was dried under reduced pressure. Ethanol (200 mL) was added, it was stirred at 65-75 °C for 0.5 h, cooled to 5-15 °C and stirred for 1 h, filtered, and the filter cake was dried under vacuum at 35-45 °C. The obtained product was compared with the product obtained in Example 1, and D-penicillamine white solid (8.16 g, yield: 40.73%, dithiopencillamine 0.4%, content 99.1%) was confirmed.

Claims

1. A method for preparing D-penicillamine, characterized in that, It includes the following steps: Compound 1 reacts with hydrazine hydrate to obtain Compound 2, and in the presence of an acidic cation exchange resin, a ring-opening reaction is carried out to obtain Compound 3; Compound 1 is potassium penicillin or sodium penicillin; the acidic cation exchange resin is Amberlyst 15.

2. The preparation method according to claim 1, characterized in that, The mass ratio of the acidic cation exchange resin to compound 1 is 0.5:1 to 3.0:

1.

3. The preparation method according to claim 2, characterized in that, The mass ratio of the acidic cation exchange resin to compound 1 is 0.5:1 to 2.0:

1.

4. The preparation method according to claim 2, characterized in that, The mass ratio of the acidic cation exchange resin to compound 1 is 0.72:1, 0.66:1, 0.8:1, or 2:

1.

5. The preparation method according to claim 2, characterized in that, The mass ratio of the acidic cation exchange resin to compound 1 is 0.72:

1.

6. The preparation method according to claim 1, characterized in that, The reaction temperature for the ring-opening reaction is 40-80℃.

7. The preparation method according to claim 6, characterized in that, The reaction temperature for the ring-opening reaction is 65-75℃.

8. The preparation method according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The ring-opening reaction is carried out under inert gas protection; (2) The ring-opening reaction is carried out at 65-75℃ for 2-6 hours, and then cooled to 15-30℃; (3) The preparation method is to add acidic cation exchange resin to compound 2.

9. The preparation method according to claim 8, characterized in that, The ring-opening reaction is carried out under nitrogen gas protection; and / or, the ring-opening reaction is carried out at 65-75°C for 3 hours, followed by cooling to 20-30°C for 1 hour.

10. The preparation method according to claim 1, characterized in that, It includes the following steps: In water, compound 1 reacts with hydrazine hydrate to give compound 2.

11. The preparation method according to claim 10, characterized in that, It meets one or more of the following conditions: (1) The molar ratio of compound 1 to hydrazine hydrate is 1:1 to 1:2; (2) The reaction temperature is 0-80℃; (3) The volume-to-mass ratio of the water to the compound 1 is 6-10 ml / g; (4) The reaction is carried out under the protection of an inert gas; (5) The reaction is to add hydrazine hydrate to compound 1; (6) Compound 2 can be used directly in the next reaction without any treatment.

12. The preparation method according to claim 10, characterized in that, It meets one or more of the following conditions: (1) The molar ratio of compound 1 to hydrazine hydrate is 1:2; (2) The reaction temperature is 20-30℃; (3) The volume-to-mass ratio of the water to the compound 1 is 8 ml / g; (4) The reaction is carried out under nitrogen protection.

13. The preparation method according to claim 10, characterized in that, The preparation of compound 3 is carried out by a one-pot, stepwise feeding method.

14. The preparation method according to claim 1, characterized in that, The ring-opening reaction includes post-processing, which includes the following steps: cooling the reaction solution, filtering, concentrating the filtrate, and purifying.

15. The preparation method according to claim 14, characterized in that, The post-processing satisfies one or more of the following conditions: (1) The reaction solution is cooled to 15-30℃; (2) The filtration process includes washing the filter cake with water; (3) The filtrate concentration is performed by vacuum concentration of the filtrate; (4) The purification process involves adding ethanol to the crude product under nitrogen protection and stirring at 65-75°C for 1-2 hours; cooling to 5-15°C and stirring for 1-2 hours; filtering the mixture and drying the filter cake to obtain compound 3.

16. The preparation method according to claim 1, characterized in that, The ring-opening reaction includes the recovery of the resin, which includes the following steps: washing with an organic solvent, washing with water, and then mixing with an acid.

17. The preparation method according to claim 16, characterized in that, In the recovery of the resin, the organic solvent is selected from one or more of ethanol, methanol, DMF and DMSO; And / or, the acid is concentrated hydrochloric acid or 50% sulfuric acid.

Images