A process for the preparation of L-penicillamine from D-penicillamine

Abstract

The application belongs to the technical field of medicine and chemical industry, and particularly discloses a method for preparing L-penicillamine from D-penicillamine. The D-penicillamine is first refluxed in an acetic acid / acetone system to obtain a DL-penicillamine intermediate; then the obtained DL-penicillamine intermediate is reduced in pressure and refluxed in water to generate DL-penicillamine; then the DL-penicillamine is mixed with methanol, L-tartaric acid and glacial acetic acid to perform a reflux reaction, so as to obtain L-tartaric acid-L-penicillamine; finally, the L-tartaric acid-L-penicillamine is separated and purified to obtain L-penicillamine. The disclosed preparation method has less reaction steps, and the reaction condition is mild and controllable. Meanwhile, the method avoids the problems of the existing method, such as complex racemization of DL-penicillamine, complex total process and unsuitability for scale-up production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical technology, and in particular to a method for preparing L-penicillamine from D-penicillamine. Background Technology

[0002] Penicillamine is a colorless to off-white powdery crystalline substance with optical activity, existing in both D- and L-forms. Currently, the preparation of D-penicillamine mainly relies on the degradation of penicillin. For example, industrial production primarily involves reacting potassium penicillin with hydrazine hydrate in n-butanol, followed by acid hydrolysis and other processes to prepare D-penicillamine. D-penicillamine is used clinically as a metal chelating agent, mainly for heavy metal poisoning, Wilson's disease, and can also be used for autoimmune diseases such as rheumatoid arthritis and chronic active hepatitis.

[0003] Further research on penicillamine has revealed that L-penicillamine also possesses significant medicinal value, serving as an inducer of convulsions and seizures. As a key intermediate in the synthesis of HIV-1 protease inhibitors, L-penicillamine can be used in new research and pharmacological and toxicological experiments of new drugs, and can also be used as a raw material in the production of AIDS treatment drugs. Currently, there is considerable production of D-penicillamine both domestically and internationally, while reports on the development of L-penicillamine are scarce.

[0004] US Patent 3980666 starts with DL-penicillamine hydrochloride, and after reflux in acetone, a first-step intermediate (DL-2,2,5,5-tetramethylthiazolidin-4-carboxylic acid hydrochloride) is obtained. The first-step intermediate and sodium acetate react in a formic acid / acetic anhydride system to obtain a second-step intermediate (DL-3-formyl-2,2,5,5-tetramethylthiazolidin-4-carboxylic acid). The second-step intermediate forms salts with L-(+)-threo-1-(4-nitrophenyl)-2-amino-1,3-propanediol in different solvents. Taking advantage of the difference in solubility of non-corresponding isomer salts, L-(+)-threo-1-(4-nitrophenyl)-2-amino-1,3-propanediol salt of L-3-formyl-2,2,5,5-tetramethylthiazolidin-4-carboxylic acid is precipitated. This non-corresponding isomer salt is then freed and acidified to obtain the target product L-penicillamine. Chinese patent application CN113307754A uses a similar method, starting with D-penicillamine, and prepares the same intermediate through acetone protection and acetylation. It then uses (D)-(+)-1-phenylethylamine for resolution, followed by a five-step process including hydrolysis to prepare L-penicillamine. This method also suffers from long reaction steps, complex operations, and low overall yield, making it unsuitable for industrial production. A paper published by Sun Yuesheng et al. in the journal *Chemical World* (Issue 16, 2006) describes a method using D-penicillamine as a starting material, racemizing and acylating it in an acetyl chloride / acetic acid system to obtain DL-acetylopyramine; then using L-chloramphenicol as a resolving agent to obtain the L-chloramphenicol salt of L-acetylopyramine; finally, through freeing and acid hydrolysis, the target product L-penicillamine is obtained. All of these synthetic methods involve harsh reaction conditions and complex reaction processes (especially in the racemization step of DL-penicillamine), making them unsuitable for large-scale production.

[0005] Therefore, the key to industrial production lies in how to disclose a method for preparing L-penicillamine using D-penicillamine as a raw material through efficient racemization, shorter operation steps, and high yield. Summary of the Invention

[0006] In view of this, the present invention provides a method for preparing L-penicillamine from D-penicillamine, in order to solve the problems of complex preparation process of DL-penicillamine, multiple operation steps and low yield in the preparation process of L-penicillamine in the existing L-penicillamine preparation methods.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] A method for preparing L-penicillamine from D-penicillamine includes the following steps:

[0009] 1) D-Penicillamine was refluxed in an acetic acid / acetone system to obtain the DL-penicillamine intermediate;

[0010] 2) The DL-penicillamine intermediate obtained in step 1) is refluxed in water under reduced pressure to generate DL-penicillamine;

[0011] 3) The DL-penicillamine obtained in step 2) is mixed with methanol, L-tartaric acid and glacial acetic acid and subjected to reflux reaction to obtain L-tartaric acid-L-penicillamine.

[0012] 4) The L-tartaric acid-L-penicillamine obtained in step 3) is separated and purified to obtain L-penicillamine.

[0013] Preferably, in step 1), the mass ratio of D-penicillamine, acetic acid, and acetone is 1:6 to 20:2 to 8.

[0014] Preferably, the reflux reaction temperature in step 1) is 90–98°C, and the reaction time is 8–12 h.

[0015] Preferably, in step 2), the mass ratio of water to the raw material D-penicillamine, which is the intermediate of DL-penicillamine, is 10 to 50:1.

[0016] Preferably, in step 2), the vacuum degree of the reduced pressure reflux is 0.05-0.08 MPa, the temperature of the reduced pressure reflux is 70-90°C, and the reaction endpoint of the reduced pressure reflux is the disappearance of the DL-penicillamine intermediate in the reduced pressure reflux system.

[0017] Preferably, the time for depressurization reflux is 3 to 10 hours.

[0018] As can be seen from the above technical solution, compared with the prior art, the present invention has the following beneficial effects:

[0019] 1. The L-penicillamine preparation method disclosed in this invention has a short reaction step, requiring only two steps to complete the racemization reaction, and the racemization yield is high. The preparation of the racemate from the DL intermediate (DL-penicillamine intermediate) is basically a quantitative reaction.

[0020] 2. The reaction process disclosed in this invention generates less pollution from waste, the reaction conditions are mild, and there are no hazardous reactions;

[0021] 3. The reaction method for preparing L-penicillamine from D-penicillamine disclosed in this invention has a high overall yield, is simple, and is easy to promote and scale up production. Detailed Implementation

[0022] This invention provides a method for preparing L-penicillamine from D-penicillamine, comprising the following steps:

[0023] 1) D-Penicillamine was refluxed in an acetic acid / acetone system to obtain the DL-penicillamine intermediate;

[0024] 2) The DL-penicillamine intermediate obtained in step 1) is refluxed in water under reduced pressure to generate DL-penicillamine;

[0025] 3) The DL-penicillamine obtained in step 2) is mixed with methanol, L-tartaric acid and glacial acetic acid and subjected to reflux reaction to obtain L-tartaric acid-L-penicillamine.

[0026] 4) The L-tartaric acid-L-penicillamine obtained in step 3) is separated and purified to obtain L-penicillamine.

[0027] In this invention, the separation and purification in step 4) is preferably carried out by mixing with triethylamine and ethanol and centrifuging to obtain L-penicillamine.

[0028] In this invention, steps 1) to 4) correspond to reaction formulas 1 to 4 in sequence.

[0029] Reaction 1:

[0030] Reaction 2:

[0031] Reaction 3:

[0032] Reaction 4:

[0033] In this invention, the mass ratio of D-penicillamine, acetic acid and acetone in step 1) is 1:6 to 20:2 to 8, preferably 1:6 to 10:2 to 6, further preferably 1:6 to 8:2 to 4, and even more preferably 1:6 to 2.

[0034] In this invention, the temperature of the reflux reaction in step 1) is 90-98°C, specifically 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, or 97°C; the reaction time is 8-12 hours, specifically 9 hours, 10 hours, or 11 hours.

[0035] In this invention, the mass ratio of water to the raw material D-penicillamine of DL-penicillamine intermediate in step 2) is 10-50:1, preferably 15-40:1, more preferably 20-30:1, and even more preferably 25:1.

[0036] In this invention, the vacuum degree of the reduced pressure reflux in step 2) is 0.05-0.08 MPa, specifically 0.055 MPa, 0.06 MPa, 0.065 MPa, 0.07 MPa, or 0.075 MPa; the temperature of the reduced pressure reflux is 70-90°C, specifically 72°C, 75°C, 78°C, 80°C, 82°C, 84°C, 85°C, or 88°C; the reaction endpoint of the reduced pressure reflux is the disappearance of the DL-penicillamine intermediate in the reduced pressure reflux system.

[0037] In this invention, concentration is carried out during depressurization reflux.

[0038] In this invention, the time for pressure reduction and reflux is 3 to 10 hours, specifically 4 hours, 5 hours, 6 hours, 8 hours, or 9 hours.

[0039] In this invention, if the DL-penicillamine intermediate does not completely disappear within the specified depressurized reflux time, the method further includes: continuing to add water, maintaining depressurized reflux, and concentrating until the DL-penicillamine intermediate disappears.

[0040] In this invention, the ratio of the amount of water added to the mass of water is 5:20 to 30, preferably 5:22 to 28, more preferably 5:24 to 26, and even more preferably 5:25.

[0041] In this invention, the purpose of depressurization reflux in step 2) is to remove the acetone fork protection.

[0042] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0043] Example 1

[0044] Reaction Step 1 (Preparation of DL-Penicillamine Intermediate)

[0045] Add acetone (4.0 kg) and acetic acid (12.0 kg) to a 50 L glass reactor, start stirring, then add D-penicillamine (2.0 kg), heat to 95 °C, and maintain the temperature for 10 h. Samples are then taken for testing—specifically, TLC (transient chromatography). When the D-penicillamine spot is smaller than the control or the spot no longer decreases, heating is stopped, the mixture is cooled to room temperature, centrifuged, and dried to obtain the DL-penicillamine intermediate.

[0046] Reaction step 2 (Preparation of DL-penicillamine)

[0047] The obtained DL-penicillamine intermediate (all) was mixed with purified water (25 kg), heated to 80 °C to dissolve, and concentrated under a vacuum of 0.06 MPa for 5 h. A sample was taken for TLC analysis, and the mixture was concentrated until no liquid dripped out. The material was removed, transferred to a 50 L container, and anhydrous ethanol was added. The mixture was stirred, centrifuged, and dried under vacuum at 50 °C to obtain approximately 1.8 kg of DL-penicillamine (a specific yield of 90% relative to D-penicillamine). The content and specific rotation (optical rotation 0°) were determined.

[0048] Reaction step 3 (Preparation of L-tartaric acid-L-penicillamine)

[0049] Methanol (12.5 kg) was added to the reactor and stirred. L-tartaric acid (1.8 kg) was added and stirred until the material dissolved. Glacial acetic acid (8.0 kg) and DL-penicillamine (1.8 kg) were added. The mixture was heated to 75°C (the material will not completely dissolve) and kept at this temperature for 2 hours. The temperature was then lowered to 25°C, the material was discharged, centrifuged, and the filter cake was transferred to the original reactor. Glacial acetic acid (8.0 kg) was added, and the mixture was stirred and washed at 20°C for 1 hour. The mixture was then centrifuged and vacuum dried at 80°C until the loss on drying was less than 1.0%, yielding approximately 1.1 kg of L-penicillamine-L-tartrate. The yield was 61.1%, and the specific rotation was measured to be +56°.

[0050] Reaction step 4 (Preparation of L-penicillamine)

[0051] Anhydrous ethanol (5 kg) was added to a 10 L reactor, and stirring was started. L-Penicillamine-L-tartrate (1.1 kg) was added, and the mixture was heated to 25 °C. Triethylamine was added dropwise, and the pH was adjusted to 7. After the addition was complete, the reaction was maintained at 20 °C for 1 h. The mixture was centrifuged, and the filter cake was washed with anhydrous ethanol (0.5 kg), centrifuged again, and dried under vacuum at 55 °C to constant weight, yielding approximately 0.52 kg of L-penicillamine (a yield of 94.9%). The purity was determined to be 100%, and the specific rotation was 63°.

[0052] Example 2

[0053] Reaction Step 1 (Preparation of DL-Penicillamine Intermediate)

[0054] Add acetone (4.0 kg) and acetic acid (12.0 kg) to a 50 L glass reactor, start stirring, then add D-penicillamine (2.0 kg), heat to 95 °C, and maintain the temperature for 10 h. Samples are then taken for testing—specifically, TLC (transient chromatography). When the D-penicillamine spot is smaller than the control or the spot no longer decreases, heating is stopped, the mixture is cooled to room temperature, centrifuged, and dried to obtain the DL-penicillamine intermediate.

[0055] Reaction step 2 (Preparation of DL-penicillamine)

[0056] The obtained DL-penicillamine intermediate (all) was mixed with purified water (20 kg), heated to 85°C to dissolve, and concentrated under a vacuum of 0.05 MPa for 5 h. A sample was taken for TLC analysis, and the mixture was concentrated until no liquid dripped out. The material was removed, transferred to a 50 L container, and anhydrous ethanol was added. The mixture was stirred, centrifuged, and dried under vacuum at 50°C to obtain approximately 1.9 kg of DL-penicillamine (a specific yield of 95% relative to D-penicillamine). The content and specific rotation (optical rotation should be 0°) were determined.

[0057] Reaction step 3 (Preparation of L-tartaric acid-L-penicillamine)

[0058] Methanol (12.5 kg) was added to the reactor and stirred. L-tartaric acid (1.9 kg) was added and stirred until the material dissolved. Glacial acetic acid (8.0 kg) and DL-penicillamine (1.9 kg) were added. The mixture was heated to 75°C (the material will not completely dissolve) and kept at this temperature for 2 hours. The mixture was then cooled to 25°C, discharged, centrifuged, and the filter cake was transferred to the original reactor. Glacial acetic acid (8.0 kg) was added, and the mixture was stirred and washed at 20°C for 1 hour. The mixture was then centrifuged and vacuum dried at 80°C until the loss on drying was less than 1.0%, yielding approximately 1.2 kg of L-penicillamine-L-tartrate. The yield was 63.2%, and the specific rotation was measured to be +56°.

[0059] Reaction step 4 (Preparation of L-penicillamine)

[0060] Anhydrous ethanol (5 kg) was added to a 10 L reactor, and stirring was started. L-Penicillamine-L-tartrate (1.2 kg) was added, and the mixture was heated to 25 °C. Triethylamine was added dropwise, and the pH was adjusted to 7. After the addition was complete, the reaction was maintained at 20 °C for 1 h. The mixture was centrifuged, and the filter cake was washed with anhydrous ethanol (0.5 kg), centrifuged again, and dried under vacuum at 55 °C to constant weight, yielding approximately 0.56 kg of L-penicillamine (a yield of 93.6%). The purity was determined to be 100%, and the specific rotation was 63°.

[0061] Example 3

[0062] Reaction Step 1 (Preparation of DL-Penicillamine Intermediate)

[0063] Add acetone (4.0 kg) and acetic acid (12.0 kg) to a 50 L glass reactor, start stirring, then add D-penicillamine (2.0 kg), heat to 95 °C, and maintain the temperature for 10 h. Samples are then taken for testing—specifically, TLC (transient chromatography). When the D-penicillamine spot is smaller than the control or the spot no longer decreases, heating is stopped, the mixture is cooled to room temperature, centrifuged, and dried to obtain the DL-penicillamine intermediate.

[0064] Reaction step 2 (Preparation of DL-penicillamine)

[0065] The obtained DL-penicillamine intermediate (all) was mixed with purified water (25 kg), heated to 75°C to dissolve, and concentrated under vacuum of 0.08 MPa for 5 hours. If the DL-penicillamine intermediate did not completely disappear, 5 kg of purified water was added, and concentration under reduced pressure continued until the DL-penicillamine intermediate completely disappeared. A sample was taken for TLC analysis, and the mixture was concentrated until no liquid dripped. The material was removed, transferred to a 50 L container, and anhydrous ethanol was added. The mixture was stirred, centrifuged, and dried under vacuum at 50°C to obtain approximately 1.8 kg of DL-penicillamine (a yield of 90% relative to D-penicillamine). The content and specific rotation (optical rotation should be 0°) were determined.

[0066] Reaction step 3 (Preparation of L-tartaric acid-L-penicillamine)

[0067] Methanol (12.5 kg) was added to the reactor and stirred. L-tartaric acid (1.8 kg) was added and stirred until the material dissolved. Glacial acetic acid (8.0 kg) and DL-penicillamine (1.8 kg) were added. The mixture was heated to 75°C (the material will not completely dissolve) and kept at this temperature for 2 hours. The mixture was then cooled to 25°C, discharged, centrifuged, and the filter cake was transferred to the original reactor. Glacial acetic acid (8.0 kg) was added, and the mixture was stirred and washed at 20°C for 1 hour. The mixture was then centrifuged and vacuum dried at 80°C until the loss on drying was less than 1.0%, yielding approximately 1.2 kg of L-penicillamine-L-tartrate. The yield was 66.7%, and the specific rotation was measured to be +56°.

[0068] Reaction step 4 (Preparation of L-penicillamine)

[0069] Anhydrous ethanol (5 kg) was added to a 10 L reactor, and stirring was started. L-Penicillamine-L-tartrate (1.2 kg) was added, and the mixture was heated to 25 °C. Triethylamine was added dropwise, and the pH was adjusted to 7. After the addition was complete, the reaction was maintained at 20 °C for 1 h. The mixture was centrifuged, and the filter cake was washed with anhydrous ethanol (0.5 kg), centrifuged again, and dried under vacuum at 55 °C to constant weight, yielding approximately 0.57 kg of L-penicillamine (a yield of 95.3%). The purity was determined to be 100%, and the specific rotation was 63°.

[0070] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to each other.

[0071] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing L-penicillamine from D-penicillamine, characterized in that, Includes the following steps: 1) D-Penicillamine was refluxed in an acetic acid / acetone system to obtain the DL-penicillamine intermediate; 2) The DL-penicillamine intermediate obtained in step 1) is refluxed under reduced pressure in water to generate DL-penicillamine; 3) The DL-penicillamine obtained in step 2) is mixed with methanol, L-tartaric acid and glacial acetic acid and subjected to reflux reaction to obtain L-tartaric acid-L-penicillamine; 4) Mix the L-tartaric acid-L-penicillamine obtained in step 3) with triethylamine and ethanol, and centrifuge to obtain L-penicillamine.

2. The method for preparing L-penicillamine from D-penicillamine according to claim 1, characterized in that, In step 1), the mass ratio of D-penicillamine, acetic acid, and acetone is 1:6~20:2~8.

3. The method for preparing L-penicillamine from D-penicillamine according to claim 2, characterized in that, In step 1), the reflux reaction temperature is 90~98℃ and the reaction time is 8~12h.

4. A method for preparing L-penicillamine from D-penicillamine according to any one of claims 1 to 3, characterized in that, In step 2), the mass ratio of water to the raw material D-penicillamine, which is the intermediate of DL-penicillamine, is 10~50:

1.

5. The method for preparing L-penicillamine from D-penicillamine according to claim 4, characterized in that, In step 2), the vacuum degree of the depressurized reflux is 0.05~0.08MPa, the temperature of the depressurized reflux is 70~90℃, and the reaction endpoint of the depressurized reflux is the disappearance of the DL-penicillamine intermediate in the depressurized reflux system.

6. The method for preparing L-penicillamine from D-penicillamine according to claim 5, characterized in that, The time for depressurization reflux is 3~10h.