Process method for preparing D-penicillamine by using acidic cationic resin

Abstract

The invention discloses a process method for preparing D-penicillamine by using acidic cationic resin. The invention provides a preparation method of D-penicillamine, which comprises the following steps: reacting a compound 1 with hydrazine hydrate to obtain a compound 2, and carrying out ring-opening reaction in the presence of acidic cationic resin to obtain a compound 3. The method disclosed by the invention does not need to independently remove inorganic salt, effectively reduces impurities generated by oxidation, and has the advantages of simplicity in operation, high yield, low cost, suitability for industrial production and the like. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a process for preparing D-penicillamine by utilizing acidic cationic resin. Background Art

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

[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 drug or as an intermediate for raw material drugs, and further processed into penicillamine derivatives or prepared into L-penicillamine.

[0005] The industrial production of D-penicillamine is generally produced by the penicillin degradation method. Most post-treatments require a separate potassium or sodium removal step, which increases the operation process, which will cause air to enter, and the oxidation product to generate dithiopenicillamine impurities will increase, thereby causing the risk of product quality degradation. Since D-penicillamine contains carboxyl, amino and thiol groups in its molecular structure, it is very easy for thiol groups to undergo oxidative coupling when exposed to air during the reaction and post-treatment process, resulting in the risk of generating dithiopenicillamine impurities and decarboxylation. There is also the risk of continued oxidation and the formation of penicillamine sulfonic acid derivative impurities.

[0006] Xu Suzhen (Antibiotics, 1982, 7(5): 338-339) used penicillin potassium salt to react with hydrazine hydrate, filtered out byproducts under the action of hydrochloric acid, then added hydrochloric acid to obtain penicillamine hydrochloride, which was then neutralized with triethylamine to remove hydrogen chloride to obtain the target penicillamine, and the yield and content were both low.

[0007] In CN108164444 A, a similar method is used to obtain penicillamine, using different acid systems (concentrated hydrochloric acid, dilute trifluoroacetic acid solution or phosphoric acid solution, etc.) to remove potassium salt, and a precious metal catalyst is needed to reduce the dithiopenicillamine impurity, thereby obtaining penicillamine with high purity.

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

[0009] As described above, the existing technology for preparing D-penicillamine has the following disadvantages: multiple preparation and post-processing steps, cumbersome operation, easy to cause oxidation side reactions, more impurities generated, by-products and impurities are difficult to remove, and the product content is low. Summary of the invention

[0010] The purpose of the present invention is to overcome the problem that in the existing process technology, inorganic acid is used to remove inorganic salts, and then alkali is used to neutralize penicillamine-inorganic acid salt to prepare D-penicillamine, which increases the number of operation steps and amplifies the risk of oxidizing penicillamine to generate dithiopenicillamine impurities. The present application provides a preparation method of D-penicillamine. The preparation method of the present application has high yield, high content, low impurities, simple operation, less pollution, low cost, short production cycle, and is suitable for industrial production.

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

[0012] The present invention provides a method for preparing D-penicillamine, which comprises the following steps: compound 1 reacts with hydrazine hydrate to obtain compound 2, and in the presence of an acidic cationic resin, a ring-opening reaction is performed to obtain compound 3;

[0013]

[0014] M + It is a monovalent metal cation.

[0015] In the preparation method, the acidic cationic resin may be a sulfonic acid resin, preferably Amberlyst 15.

[0016] In the preparation method, the mass ratio of the acidic cationic 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°C, preferably 65-75°C.

[0018] In the preparation method, the ring-opening reaction can be carried out under the protection of an inert gas, such as nitrogen.

[0019] In the preparation method, the ring-opening reaction can be carried out at 65-75° C. for 2-6 hours and then cooled to 15-30° C.; for example, at 65-75° C. for 3 hours and then cooled to 20-30° C. for 1 hour.

[0020] The preparation method may be to add the acidic cationic resin into compound 2.

[0021] The raw materials of the preparation method may consist of compound 2 and acidic cationic resin.

[0022] The preparation method may also include the preparation of compound 2, which includes the following steps: in water, compound 1 reacts with hydrazine hydrate 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 to 1:2, preferably 1:2.

[0025] In the method for preparing the compound 2, the reaction temperature of the reaction can be 0-80°C, preferably 20-30°C.

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

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

[0028] In the preparation method of the compound 2, the reaction can be carried out under the protection of an inert gas, such as 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 reaction without treatment.

[0031] In the preparation method, the preparation of compound 2 and compound 3 are performed by adding materials in one pot step by step.

[0032] In the preparation method, the ring-opening reaction may 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 reaction solution is cooled to 15-30°C.

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

[0036] In the post-treatment, the filtrate is concentrated by concentrating the filtrate under reduced pressure.

[0037] In the post-treatment, the purification is performed by adding ethanol to the crude product under nitrogen protection, stirring at 65-75° C. for 1-2 h; cooling to 5-15° C., stirring for 1-2 h, filtering the mixture, and drying the filter cake to obtain compound 3.

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

[0039] The resin may be recovered by any conventional method in the art, for example, washing with an organic solvent, washing with water, and then mixing with an acid.

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

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

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

[0043] The positive and progressive effects of the present invention are:

[0044] (i) The D-penicillamine prepared by the preparation method of the present invention has a high yield, for example, the yield can reach 74%-96%; and a high purity, for example, the product content is above 99%.

[0045] (ii) The process of the present invention is simple to operate, low in cost, less polluting, and has a short production cycle, and is suitable for industrial production.

[0046] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

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

[0048] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0049] Example 1

[0050] Add penicillin potassium (50g, 0.134mol, 1.00eq) to purified water (400mL, 8V) and replace with nitrogen 3 times. Slowly drip hydrazine hydrate (10.1g, 0.268mol, 2.00eq) at 20-30℃. After the addition is complete, stir at 20-30℃ for 0.5h. After the reaction is complete, add Amberlyst 15 (36g, 0.72X), heat to 65-75℃ and stir for 3h. After the reaction is complete, cool to 20-30℃, keep warm and stir for 1h, filter, rinse the filter cake with purified water (50mL), and decompress the filtrate to dryness. Add ethanol (200 mL), control the temperature at 65-75 ° C and stir for 0.5 h, cool to 5-15 ° C and stir for 1 h, filter, and vacuum dry the filter cake at 35-45 ° C to obtain D-penicillamine as a white solid (19.16 g, yield: 95.65%, dithiopenicillamine 0.1%, content 99.5%). 1H NMR (400 MHz, D 2 O, ppm): δ = 1.48 (s, 3H), 1.57 (s, 3H), 3.7 (s, 1H).

[0051] Example 2

[0052] Add potassium penicillin (50g, 0.134mol, 1.00eq) to purified water (400mL, 8V) and replace with nitrogen 3 times. Slowly drip hydrazine hydrate (10.1g, 0.268mol, 2.00eq) at 20-30℃. After the addition is complete, stir at 20-30℃ for 0.5h. After the reaction is complete, add Amberlyst 15 (33g, 0.66X), heat to 65-75℃ and stir for 3h. After the reaction is complete, cool to 20-30℃, keep warm and stir for 1h, filter, rinse the filter cake with purified water (50mL), and decompress the filtrate to dryness. Add ethanol (200 mL), control the temperature at 65-75 ° C and stir for 0.5 h, cool to 5-15 ° C and stir for 1 h, filter, and vacuum dry the filter cake at 35-45 ° C. Compare with the product obtained in Example 1, and confirm that D-penicillamine is obtained as a white solid (17.16 g, yield: 85.67%, dithiopenicillamine 0.4%, content 99.1%).

[0053] Example 3

[0054] Add penicillin potassium (50g, 0.134mol, 1.00eq) to purified water (400mL, 8V) and replace with nitrogen 3 times. Slowly drip hydrazine hydrate (10.1g, 0.268mol, 2.00eq) at 20-30℃. After the addition is complete, stir at 20-30℃ for 0.5h. After the reaction is complete, add Amberlyst 15 (40g, 0.80X), heat to 65-75℃ and stir for 3h. After the reaction is complete, cool to 20-30℃, keep warm and stir for 1h, filter, rinse the filter cake with purified water (50mL), and decompress the filtrate to dryness. Add ethanol (200 mL), control the temperature at 65-75 ° C and stir for 0.5 h, cool to 5-15 ° C and stir for 1 h, filter, and vacuum dry the filter cake at 35-45 ° C. Compare with the product obtained in Example 1, and confirm that D-penicillamine is obtained as a white solid (17.53 g, yield: 87.51%, dithiopenicillamine 0.1%, content 99.3%).

[0055] Example 4

[0056] Add potassium penicillin (50g, 0.134mol, 1.00eq) to purified water (400mL, 8V) and replace with nitrogen 3 times. Slowly drip hydrazine hydrate (10.1g, 0.268mol, 2.00eq) at 20-30℃. After the addition is complete, stir at 20-30℃ for 0.5h. After the reaction is complete, add Amberlyst 15 (100g, 2.00X), heat to 65-75℃ and stir for 3h. After the reaction is complete, cool to 20-30℃, keep warm and stir for 1h, filter, rinse the filter cake with purified water (50mL), and decompress the filtrate to dryness. Add ethanol (200 mL), control the temperature at 65-75 ° C and stir for 0.5 h, cool to 5-15 ° C and stir for 1 h, filter, and vacuum dry the filter cake at 35-45 ° C. Compare with the product obtained in Example 1 to confirm that D-penicillamine is a white solid (14.96 g, yield: 74.69%, dithiopenicillamine 0.1%, content 99.1%).

[0057] Example 5

[0058] Add penicillin potassium (1000g, 2.68mol, 1.00eq) to purified water (8L, 8V) and replace with nitrogen 3 times. Slowly drip hydrazine hydrate (202.5g, 5.36mol, 2.00eq) at 20-30℃. After the addition is complete, stir at 20-30℃ for 0.5h. After the reaction is complete, add Amberlyst 15 (720g, 0.72X), heat to 65-75℃ and stir for 3h. After the reaction is complete, cool to 20-30℃, keep warm and stir for 1h, filter, rinse the filter cake with purified water (1L), and decompress the filtrate to dryness. Add ethanol (4 L), control the temperature at 65-75 ° C and stir for 0.5 h, cool to 5-15 ° C and stir for 1 h, filter, and vacuum dry the filter cake at 35-45 ° C. Compare with the product obtained in Example 1, and confirm that D-penicillamine is a white solid (379.2 g, yield: 94.65%, dithiopenicillamine 0.1%, content 99.5%).

[0059] Comparative Example 1

[0060] Add potassium penicillin (50g, 0.134mol, 1.00eq) to purified water (400mL, 8V) and replace with nitrogen 3 times. Slowly drip hydrazine hydrate (10.1g, 0.268mol, 2.00eq) at 20-30℃. After the addition is complete, stir at 20-30℃ for 0.5h. After the reaction is complete, add Amberlite IR-120 (33g, 0.66X), heat to 65-75℃ and stir for 3h. After the reaction is complete, cool to 20-30℃, keep warm and stir for 1h, filter, rinse the filter cake with purified water (50mL), and decompress the filtrate to dryness. Add ethanol (200 mL), control the temperature at 65-75 ° C and stir for 0.5 h, cool to 5-15 ° C and stir for 1 h, filter, and vacuum dry the filter cake at 35-45 ° C. Compare with the product obtained in Example 1, and confirm that D-penicillamine is obtained as a white solid (8.16 g, yield: 40.73%, dithiopenicillamine 0.4%, content 99.1%).

Claims

1. A method for preparing D-penicillamine, characterized in that: The method comprises the following steps: compound 1 reacts with hydrazine hydrate to obtain compound 2, and in the presence of an acidic cationic resin, a ring-opening reaction is performed to obtain compound 3; M + It is a monovalent metal cation.

2. The preparation method according to claim 1, characterized in that The acidic cationic resin is a sulfonic acid resin, preferably Amberlyst 15.

3. The preparation method according to claim 1, characterized in that: The mass ratio of the acidic cationic resin to the compound 1 is 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.

4. The preparation method according to claim 1, characterized in that: The reaction temperature of the ring-opening reaction is 40-80°C, preferably 65-75°C.

5. 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 the protection of an inert gas, such as nitrogen; (2) the ring-opening reaction is reacted at 65-75° C. for 2-6 hours, and then cooled to 15-30° C.; for example, reacted at 65-75° C. for 3 hours, and then cooled to 20-30° C. for 1 hour; (3) The preparation method is to add an acidic cationic resin to compound 2.

6. The preparation method according to claim 1, characterized in that: The preparation method also includes the preparation of compound 2, which includes the following steps: in water, compound 1 reacts with hydrazine hydrate to obtain compound 2; Preferably, the preparation of compound 2 satisfies one or more of the following conditions: (1) The compound 1 is penicillin potassium or penicillin sodium; (2) The molar ratio of the compound 1 to the hydrazine hydrate is 1:1 to 1:2, preferably 1:2; (3) The reaction temperature of the reaction is 0-80°C, preferably 20-30°C; (4) The volume mass ratio of the water to the compound 1 is 6-10 ml / g, for example 8 ml / g; (5) The reaction is carried out under the protection of an inert gas, such as nitrogen; (6) The reaction is to add hydrazine hydrate to compound 1; (7) The compound 2 can be directly used in the next reaction without further treatment.

7. The preparation method according to claim 6, characterized in that: The preparation of compound 3 is carried out by adding materials in one pot step by step.

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

9. The preparation method according to claim 8, characterized in that: The post-processing meets one or more of the following conditions: (1) the reaction solution is cooled to 15-30° C.; (2) the filtration includes washing the filter cake with water; (3) the filtrate is concentrated by reducing the pressure on the filtrate; (4) The purification is as follows: under nitrogen protection, ethanol is added to the crude product, and the mixture is stirred at 65-75°C for 1-2 hours; the mixture is cooled to 5-15°C, stirred for 1-2 hours, and the mixture is filtered. The filter cake is dried to obtain compound 3.

10. 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 mixing with an acid; Preferably, 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.

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