CN112500323B - Preparation method of L-penicillamine - Google Patents
Preparation method of L-penicillamine Download PDFInfo
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- CN112500323B CN112500323B CN202011494912.0A CN202011494912A CN112500323B CN 112500323 B CN112500323 B CN 112500323B CN 202011494912 A CN202011494912 A CN 202011494912A CN 112500323 B CN112500323 B CN 112500323B
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Abstract
The invention discloses a method for preparing L-penicillamine, which comprises the following steps: firstly, acetone and ethyl formate are adopted to protect sulfydryl and amino in D-penicillamine to obtain N-formyl isopropyl-D-penicillamine; then racemizing the N-formyl isopropyl-D-penicillamine by adopting acetic acid or a mixed solution of the acetic acid and toluene to obtain N-formyl isopropyl-D, L-penicillamine; reacting N-formyl isopropyl-D, L-penicillamine with hydrochloric acid to prepare N-formyl isopropyl-D, L-penicillamine hydrochloride; dissociating N-formyl isopropyl-D, L-penicillamine hydrochloride in lower alcohol through organic base to obtain dissociative racemate D, L-penicillamine; D. reacting the L-penicillamine with resolving agent L-tartaric acid to obtain L-penicillamine L-tartrate; l-penicillamine L-tartrate is hydrolyzed by organic base to obtain L-penicillamine. The preparation method has the advantages of low cost of the resolving reagent, mild reaction conditions and high product yield, and provides feasibility for industrial mass production of L-penicillamine.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a method for preparing L-penicillamine by taking D-penicillamine as an initial raw material.
Background
The cyanine is an optically active substance having D-form, L-form and D, L-form. D-penicillamine is a colorless powdery crystal, has weak odor of amino sulfur, is easy to dissolve in water, is slightly soluble in ethanol, and is hardly soluble in ether, chloroform, carbon tetrachloride, aliphatic hydrocarbon or aromatic hydrocarbon. The only role of penicillamine was originally in the total synthesis of penicillin, which is central to the structural unit of penicillin and is a key material that can be used to elucidate the structure of penicillin. By 1956, it was first introduced into the drug as a chelating agent to promote the removal of heavy metals and non-physiological heavy metals (antidotes to heavy metal poisoning) at higher than physiological concentrations. Increasingly, D-penicillamine has become increasingly important as a primary therapeutic agent for rheumatoid arthritis (chronic polyarthritis) and has some new therapeutic indications, such as for chronic aggressive hepatitis and scleral ulcers. In addition, in recent years, it has been found that D-penicillamine also has a preventive effect on retinopathy of prematurity.
With further research on penicillamine, L-penicillamine is found to have higher medicinal value than D-penicillamine, can be used as a spasmolytic and convulsive inducer, can also be used for new research, new medicine pharmacology and toxicity experiments, and also can be used as a raw material for producing drugs for treating AIDS.
Penicillium amine is an intermediate of a specific medicine, is used for synthesizing an HIV-1 protease inhibitor, has strong antiviral ability, and has obvious effects of preventing and treating AIDS. At present, the production of D-Qinghuo amine is more at home and abroad, but the current report on the development of L-penicillamine is less. For example, Sunyishen, Shouxingqing, et al, published in the chemical world, 2006, 16, on the basis of the paper, research on the preparation of L-penicillamine, in which D-penicillamine reacts with acetyl chloride to racemize and then hydrolyzes to obtain racemic penicillamine, and then L-chloromycelamine is used for resolution, dissociation and hydrolysis to obtain the target L-penicillamine. This method has two major drawbacks: one is the drawback of the reaction itself: acetyl chloride as a racemization reagent has the disadvantages of great environmental pollution, more reaction impurities, low product yield and poor quality. Secondly, the resolving agent clotrimazole is expensive, the production cost of the product is multiplied if the resolving agent clotrimazole is not recovered, and the reaction steps are increased if the resolving agent clotrimazole is recovered, so that the raw materials, energy and manpower are greatly wasted, and the resolving agent is not suitable for industrial mass production. Therefore, in order to meet the market demand, the preparation of L-penicillamine needs to be intensively studied.
Disclosure of Invention
The invention aims to provide a method for preparing L-penicillamine, which is suitable for industrial production, environment-friendly and low in cost, aiming at the current situations that the related research on the production technology of the existing preparation method of L-penicillamine is less and the technology is not mature enough.
The invention provides a method for preparing L-penicillamine, which is a method for preparing the L-penicillamine by taking D-penicillamine as an initial raw material, and comprises the following steps:
s1, taking D-penicillamine as an initial raw material, and stirring and reacting the D-penicillamine and acetone at the reaction temperature of 50-60 ℃ for 2 hours to obtain isopropyl-D-penicillamine.
S2, reacting the isopropyl-D-penicillamine prepared in the step S1 with ethyl formate at 53 ℃ for 5 hours to obtain the N-formyl isopropyl-D-penicillamine.
S3, racemizing the N-formyl isopropyl-D-penicillamine prepared in the step S2 by using acetic acid or a mixed solution of acetic acid and toluene, wherein the N-formyl isopropyl-D-penicillamine and the acetic acid are subjected to reflux reaction for 1 hour at 90-100 ℃, preferably 98 ℃, to obtain the N-formyl isopropyl-D, L-penicillamine, or the N-formyl isopropyl-D-penicillamine and the mixed solution of the acetic acid and the toluene are subjected to reflux reaction for 1 hour at 98 ℃ to obtain the N-formyl isopropyl-D, L-penicillamine.
S4, heating N-formyl isopropyl-D, L-penicillamine and hydrochloric acid to 90-100 ℃ for reflux reaction for 1h under the protection of nitrogen, wherein the optimal temperature is 95 ℃, and obtaining D, L-penicillamine hydrochloride;
s5, adding D, L-penicillamine hydrochloride and an anhydrous alcohol solvent into a reaction container under the protection of nitrogen, cooling to 5 ℃, dropwise adding an organic base while stirring, and adjusting the pH value of the solution to 5-7 to obtain D, L-penicillamine;
s6, reacting D, L-penicillamine with resolving agent L-tartaric acid in an anhydrous alcohol solvent to obtain L-penicillamine L-tartrate;
s7, adding L-penicillamine L-tartrate into anhydrous alcohol solvent, dropwise adding organic base while stirring at room temperature, adjusting the pH of the solution to 6.5-7.0, filtering, washing a filter cake with the anhydrous alcohol solvent, and drying in vacuum to obtain the L-penicillamine.
Preferably, the anhydrous alcohol solvent is anhydrous lower alcohol, and more preferably is anhydrous ethanol.
Preferably, the organic base is triethylamine.
In a preferred embodiment, the process for producing L-penicillamine of the present invention comprises steps S1 to S4 continuously performed in the same reaction tank a, and the reaction tank does not need to be replaced in the middle. In the specific process operation, the following operations can be carried out:
s1, adding D-penicillamine and acetone into a reaction tank A for reaction, stirring and reacting for 2 hours at the reaction temperature of 50-60 ℃, heating and evaporating to remove excessive acetone, and obtaining isopropyl-D-penicillamine in the reaction tank.
S2, directly adding ethyl formate into the reaction tank of the step S1, reacting at 53 ℃ for 5 hours, evaporating to remove excessive ethyl formate, and obtaining the N-formyl isopropyl-D-penicillamine in the reaction tank.
S3, adding acetic acid or a mixed solution of acetic acid and toluene into the reaction tank of the step S2, refluxing and reacting for 1h at 98 ℃, and then removing the acetic acid and the toluene by reduced pressure evaporation to obtain the N-formyl isopropyl-D, L-penicillamine in the reaction tank.
S4, introducing nitrogen into the reaction tank in the step S3 to remove air, then adding hydrochloric acid, heating to 95 ℃, refluxing and reacting for 1h, cooling to room temperature after the reaction is finished, extracting by isopropyl ether, concentrating the extracted water phase to dryness to obtain white needle-shaped hygroscopic solid, and drying in vacuum to obtain the D, L-penicillamine hydrochloride intermediate. The steps S1-S4 are continuously completed in the same reaction tank A, and the reaction tank does not need to be replaced midway, so that the process operation flow is simplified, the evaporated solvent can be recycled, and the cost is saved.
And S5, adding the D, L-penicillamine hydrochloride intermediate and an anhydrous alcohol solvent into another reaction tank B under the protection of nitrogen, cooling to 5 ℃, dropwise adding an organic base while stirring, adjusting the pH value of the solution to 5-7, filtering, washing a filter cake, and drying to obtain the racemized penicillamine solid D, L-penicillamine.
S6, mixing L-tartaric acid and an anhydrous alcohol solvent in a reaction tank C, stirring and dissolving the mixture to be clear, then dropwise adding a D, L-penicillamine glacial acetic acid solution, continuing stirring for 0.5 hour after the addition is finished, filtering, washing a filter cake, and performing vacuum drying to obtain penicillamine L-tartrate.
S7, adding L-penicillamine L-tartrate and anhydrous alcohol solvent into another reaction tank D, adding organic base, filtering, washing filter cake with anhydrous alcohol solvent, and vacuum drying to obtain L-penicillamine.
In the process operation process, the steps S1-S4 are continuously completed in the same reaction tank, and the reaction tank does not need to be replaced midway. The evaporated solvent can be recycled, so that the cost is saved. The whole preparation process only needs to replace the reaction tank for 3 times, and uses 4 reaction tanks in total, thereby simplifying the process operation process and being beneficial to industrial production.
In another embodiment, in the preparation method of the present invention, the steps S1 to S4 may be performed independently in different reaction tanks, and after the reaction in each step is completed, the intermediate product is separated from the reaction tank and then used in the next step. The specific operation is as follows:
s1, firstly adding D-penicillamine and acetone into a reaction tank for reaction, stirring and reacting for 2 hours at the reaction temperature of 50-60 ℃, then cooling to 5 ℃, stirring for 1 hour, filtering to obtain a white filter cake, and drying to obtain isopropyl-D-penicillamine.
S2, adding isopropyl-D-penicillamine and ethyl formate into a reaction tank, heating to 53 ℃, carrying out reflux reaction for 5 hours, then cooling to room temperature, stirring at 5 ℃ for 1 hour, filtering, and drying to obtain white powdery N-formyl isopropyl-D-penicillamine.
S3, adding N-formyl isopropyl-D-penicillamine and acetic acid into a reaction tank, or adding N-formyl isopropyl-D-penicillamine, acetic acid and toluene into the reaction tank, carrying out reflux reaction at 98 ℃ for 1h, then cooling, filtering, washing and drying in vacuum to obtain the N-formyl isopropyl-D, L-penicillamine.
S4, adding N-formyl isopropyl-D, L-penicillamine and hydrochloric acid into a reaction tank, heating to 95 ℃ under the condition of introducing nitrogen into the reaction tank, refluxing and reacting for 1h, cooling to room temperature after the reaction is finished, extracting by isopropyl ether, concentrating the extracted water phase to dryness to obtain white needle-shaped hygroscopic solid, and drying in vacuum to obtain the D, L-penicillamine hydrochloride intermediate.
S5, adding the D, L-penicillamine hydrochloride intermediate and an anhydrous alcohol solvent into a reaction tank, cooling to 5 ℃, dropwise adding an organic base while stirring, adjusting the pH of the solution to 6.5-7, filtering, washing a filter cake with anhydrous alcohol, and drying to obtain D, L-penicillamine.
S6, mixing L-tartaric acid and absolute ethyl alcohol at room temperature, stirring and dissolving, then adding D, L-penicillamine glacial acetic acid mixed solution dropwise, continuing stirring for 1h after adding dropwise, filtering, and washing a filter cake by absolute ethyl alcohol to obtain L-penicillamine L-tartrate.
S7, adding L-penicillamine L-tartrate and an anhydrous alcohol solvent into a reaction tank, dropwise adding organic base triethylamine under stirring at room temperature, adjusting the pH of the solution to 6.5-7.0, filtering, washing a filter cake with the anhydrous alcohol solvent, and drying in vacuum to obtain the L-penicillamine.
Compared with the prior art, the invention has the advantages that:
firstly, acetone and ethyl formate are adopted to form propylidene protection on sulfydryl and primary amino of D-penicillamine, and simultaneously, the solvents acetone and ethyl formate are convenient to recycle and reuse, so that the method is environment-friendly and economical; the racemization reaction of the N-formyl isopropyl D-penicillamine adopts acetic acid or a composition of toluene and acetic acid, and a single solvent, namely acetic acid, is used as a racemization reagent and a solvent, so that the environment is protected, and the recovery and the application are convenient; the N-formyl-isopropyl-D, L-penicillamine obtained by racemization reaction is not directly resolved by using an alkaline resolving agent in the step, but the N-formyl-isopropyl-D, L-penicillamine is directly hydrolyzed to remove a protecting group to obtain the racemic penicillamine (D, L-penicillamine). Finally, the L-penicillamine is obtained by resolving with L- (+) -tartaric acid. The preparation method has the advantages that the resolution step is finally carried out, so that the product yield is favorably improved, the product quality is controlled, the product purity is high, the resolution reagent is easy to obtain, the resolution cost is low, and the method with high feasibility is provided for the industrial mass production of the L-penicillamine.
Secondly, in the preparation method, the steps S1-S4 can be continuously completed in the same reaction tank, the reaction tank does not need to be replaced midway, the next step of reaction is directly carried out through solvent replacement after the reaction in each step reaches the end point through on-line monitoring, the solvent is recovered and reused, the operation is more convenient, the labor and the energy are saved, the production period from the D-penicillamine to the L-penicillamine can be shortened, the labor and the energy cost are saved, the reaction condition is mild, the yield is quantitative, the quality is stable, and the method is suitable for industrial mass production of the L-penicillamine.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
FIG. 1 is a mass spectrum of the product L-penicillamine prepared in example 2.
FIG. 2 is the NMR spectrum of the product L-penicillamine prepared in example 2.
Figure 3 is the nuclear magnetic resonance hydrogen spectrum of the product L-penicillamine prepared in example 2.
Detailed Description
The preferred embodiments of the present invention will be described in conjunction with the accompanying drawings, and it should be understood that they are presented herein only to illustrate and explain the present invention and not to limit the present invention.
The preparation method of the L-penicillamine of the invention has the corresponding chemical reaction processes as follows:
example 1
A preparation method of L-penicillamine comprises the steps of S1-S7, wherein the steps are independently carried out in respective reaction tanks, an intermediate product is separated from the reaction tanks after the reaction of each step is finished, and then the intermediate product is reused in the next step. The method comprises the following steps:
s1, Synthesis of isopropyl-D-Penicillin amine
Adding 149.5g of D-penicillamine and 450ml of acetone into a 1L three-neck bottle in sequence, stirring and heating to 55 ℃, tracking the reaction by using a thin layer (the volume ratio of n-butyl alcohol to glacial acetic acid to water is 4: 1: 1), finishing the reaction after 2 hours, then concentrating under reduced pressure at normal temperature to remove part of acetone so that the volume of the reaction solution is reduced to one third of the original volume, cooling to 5 ℃, stirring for 1 hour, filtering to obtain a white filter cake, drying in the air to obtain white powdery isopropyl-D-penicillamine, weighing 172.8g, and obtaining the yield: 91.2 percent. And (Mp): 169.6-170.7 ℃.
S2 preparation of N-formyl isopropyl-D-penicillamine
A1L three-necked flask was charged with 172.5 g of isopropyl-D-penicillamine and 517.5ml of ethyl formate, heated to 53 ℃ under reflux, and the reaction was monitored with a thin layer (methanol: dichloromethane volume ratio: 1: 9) and was complete after 5 hours. Then concentrating under reduced pressure at normal temperature to remove part of ethyl formate to reduce the volume of the reaction liquid to one third of the original volume, stirring at the low temperature of 5 ℃ for 1 hour, and filtering to obtain white fine powder solid, namely N-formyl isopropyl-D-penicillamine, weighing 178.7 g after drying, and obtaining the yield of 90.1%. And Mp: 173 ℃, specific rotation: +53.3 ° (C ═ 1, anhydrous methanol).
Preparation of S3, N-formyl isopropyl-D, L-penicillamine
Adding 178.4g of N-formyl isopropyl-D-penicillamine, 360ml of toluene and 178.4ml of acetic acid into a 1L three-necked bottle in turn, refluxing for 1 hour at 98 ℃, then evaporating and concentrating under reduced pressure at 40 ℃ to reduce the volume of reaction liquid to one third of the original volume, stirring for 1 hour at 5 ℃, filtering, washing a filter cake by using 178 ml of toluene at low temperature, and drying in vacuum to obtain a target white fine granular crystal of N-formyl isopropyl-D, L-penicillamine, wherein the weight is 172.3g, and the yield is as follows: 96.8 percent. And Mp: 140.5-141.4 ℃, specific rotation: [ alpha ] of]D 20 0. (C ═ 1, absolute ethanol).
Synthesis of S4, D, L-penicillamine hydrochloride
Adding 172.0 g of N-formyl isopropyl-D, L-penicillamine and 516 ml of hydrochloric acid with the mass percentage concentration of 15% into a 1L three-necked bottle, heating to 95 ℃ under the protection of nitrogen, refluxing, monitoring the reaction by a thin layer (N-butyl alcohol: glacial acetic acid: water volume ratio is 4: 1: 1), completely reacting after 1 hour, cooling to room temperature, extracting by 170ml of isopropyl ether, concentrating the extracted water phase to dryness to obtain a white needle-like hygroscopic solid, and drying in vacuum to obtain D, L-penicillamine hydrochloride with the weight of 133.5 g and the yield: 90.5 percent.
Preparation of S5, D, L-penicillamine
D, L-penicillamine hydrochloride 133.5 g and anhydrous ethanol 333.8ml are added into a 1L three-neck bottle, the temperature is reduced to 5 ℃, and the triethyl is added dropwise while stirringAnd (3) amine, adjusting the pH value of a system to be 6.5-7, filtering, washing a filter cake for three times by 100 ml of absolute ethyl alcohol, and drying to obtain racemized D, L-penicillamine solid with the weight of 106.4 g and the yield of 99.1%. Specific rotation degree: [ alpha ] to]D 20 ＝0°。(C＝1，1NNaOH)。
S6 preparation of L-penicillamine L-tartrate
In a 2L three-necked bottle, 106.5 g of L-tartaric acid and 530ml of absolute ethyl alcohol are mixed, stirred and dissolved at room temperature, D.L-penicillamine glacial acetic acid mixed solution (106 g of racemic penicillamine and 630 ml of glacial acetic acid) is dropwise added, stirring is continued for 0.5h after the addition is finished, filtering is carried out, 106 ml of absolute ethyl alcohol is used for washing a filter cake, and vacuum drying is carried out, so that L-penicillamine L-tartrate is obtained, the weight is 68.3g, and the yield is 64.1%. Specific rotation degree: [ alpha ] to]D 20 ＝+53.6°，(C＝1，1NNaOH)。
S7 preparation of L-penicillamine
Adding 68 g of L-penicillamine L-tartrate and 204ml of absolute ethyl alcohol into a 500ml three-necked bottle in sequence, dropwise adding triethylamine while stirring at room temperature, adjusting the pH value to 6.5-7.0, filtering, washing a filter cake by 50ml of absolute ethyl alcohol, and drying in vacuum to obtain 32.3 g of L-penicillamine with the yield of 95.2%. Mp 190-] D 20 +61.5 °, (C-1, 1N NaOH). pH 4.82, content: 98.55%, optical purity: 99.5 percent.
Example 2
A process for producing L-penicillamine, wherein steps S1 to S4 are continuously carried out in the same reaction tank without replacing the reaction tank in the middle of the process. The method comprises the following steps:
s1, 149.5g of D-penicillamine and 450ml of acetone are added into a reaction tank A, the temperature is heated to 55 ℃, the thin layer (the volume ratio of n-butyl alcohol to glacial acetic acid to water is 4: 1: 1) is used for tracking reaction, the reaction is finished after 2h, then, the residual acetone is evaporated under reduced pressure at normal temperature, and the isopropyl-D-penicillamine is obtained in the reaction tank.
S2, directly adding 517.5ml of ethyl formate into the reaction tank of the step S1, carrying out reflux reaction at the temperature of 53 ℃, monitoring the reaction by using a thin layer (methanol: dichloromethane volume ratio is 1: 9), completely reacting after 5 hours, evaporating at normal temperature under reduced pressure to remove the residual ethyl formate, and obtaining the N-formyl isopropyl-D-penicillamine in the reaction tank.
S3, adding 178.4ml of acetic acid and 360ml of toluene into the reaction tank of the step S2, refluxing and reacting for 1h at 98 ℃, then evaporating under reduced pressure at 40 ℃ to remove the acetic acid and the toluene, and obtaining the N-formyl isopropyl-D, L-penicillamine in the reaction tank.
S4, introducing nitrogen into the reaction tank in the step S3 to remove air, adding 516.ml hydrochloric acid with the mass percentage concentration of 15%, heating to 95 ℃ for reflux reaction, monitoring the reaction by using a thin layer (the volume ratio of N-butyl alcohol to glacial acetic acid to water is 4: 1: 1), cooling to room temperature after 1 hour, extracting by using isopropyl ether, concentrating the extracted water phase to dryness to obtain a white needle-shaped hygroscopic solid, and drying in vacuum to obtain the N-formyl isopropyl-D, L-penicillamine hydrochloride intermediate. Steps S1 to S4 were continuously completed in the same reaction tank A, and the reaction tank was not replaced in the middle of the process. The evaporated solvent can be recycled, so that the cost is saved.
S5, adding all the N-formyl isopropyl-D, L-penicillamine hydrochloride intermediates obtained in the step S4 and 333.8ml of absolute ethyl alcohol into another reaction tank B, cooling to 5 ℃, dropwise adding triethylamine while stirring, adjusting the pH value of the solution to 6.5-7, filtering, washing a filter cake, and drying to obtain racemization penicillamine solid D, L-penicillamine.
S6, mixing 106.5 g of L-tartaric acid and 530ml of anhydrous alcohol solvent in a reaction tank C at room temperature, stirring and dissolving the mixture to be clear, then adding D, L-penicillamine (106.0 g) of glacial acetic acid (530ml) dropwise, continuing stirring for 0.5 hour after the addition is finished, filtering, washing a filter cake, and drying in vacuum to obtain penicillamine L-tartrate.
S7, adding all the L-penicillamine L-tartrate obtained in the step S6 and 204ml of absolute ethyl alcohol into another reaction tank D, stirring at room temperature, dropwise adding triethylamine, adjusting the pH value of the solution to 6.5-7.0, filtering, washing a filter cake with the absolute ethyl alcohol, and drying in vacuum to obtain the final product L-penicillamine.
FIG. 1 is a high resolution mass spectrometry analysis chart of the final product L-penicillamine. Wherein M/z 148.0435 corresponds to the peak of theoretical molecular weight (149.05) M-1 of L-penicillamine. Thereby proving that the final product is L-penicillamine
FIG. 2 NMR of the final product L-penicillamineAnd (4) a spectrogram. Wherein, delta 4.303-NH 2 δ3.592—CHδ1.458-CH 3 δ1.373-CH 3 Thus, the final product is proved to be L-penicillamine.
FIG. 3 is a nuclear magnetic resonance carbon spectrum of the final product L-penicillamine (FIG. 3 is too large and therefore stands upright). Wherein, delta 171.366-COOH delta 64.668-C (NH) 2 )Hδ43.823-CH(CH 3 ) 2 δ30.276-CH 3 δ27.739-CH 3 Thus, the final product is proved to be L-penicillamine.
The final product is clearly demonstrated to be L-penicillamine by the above mass spectrometry and nuclear magnetic resonance analysis.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. A process for the preparation of L-penicillamine, comprising the steps of:
s1, taking D-penicillamine as an initial raw material, and reacting the D-penicillamine with acetone to obtain isopropyl-D-penicillamine;
s2, carrying out reflux reaction on the isopropyl-D-penicillamine prepared in the step S1 and ethyl formate at the temperature of 53 ℃ for 5 hours to obtain N-formyl isopropyl-D-penicillamine;
s3, racemizing the N-formyl isopropyl-D-penicillamine prepared in the step S2 by adopting acetic acid or a mixed solution of the acetic acid and toluene to obtain N-formyl isopropyl-D, L-penicillamine;
s4, under the protection of nitrogen, reacting N-formyl isopropyl-D, L-penicillamine with hydrochloric acid to prepare D, L-penicillamine hydrochloride;
s5, adding D, L-penicillamine hydrochloride and an anhydrous alcohol solvent into a reaction container, cooling to 5 ℃, dropwise adding an organic base while stirring, and adjusting the pH of the solution to 5-7 to obtain D, L-penicillamine;
s6, reacting D, L-penicillamine with resolving agent L-tartaric acid in an anhydrous alcohol solvent to obtain L-penicillamine L-tartrate;
s7, dissolving L-penicillamine L-tartrate in anhydrous alcohol solvent, and hydrolyzing the salt with organic base to obtain the L-penicillamine.
2. The method for producing L-penicillamine according to claim 1, wherein in step S1, the reaction between D-penicillamine and acetone is carried out at a reaction temperature of 50 to 60 ℃ for 2 hours with stirring.
3. The method for producing L-penicillamine according to claim 1, wherein in step S3, the N-formylisopropyl-D-penicillamine and acetic acid or the mixture of the N-formylisopropyl-D-penicillamine, acetic acid and toluene are reacted at 90 to 100 ℃ under reflux for 1 hour to obtain the N-formylisopropyl-D, L-penicillamine.
4. The method for producing L-penicillamine according to claim 1, wherein the reaction of N-formylisopropyl-D, L-penicillamine with hydrochloric acid in step S4 is performed by heating to 90 to 100 ℃ and refluxing for 1 hour.
5. The process for the preparation of L-penicillamine according to any one of claims 1 to 4, wherein steps S1-S4 are carried out continuously in the same reaction tank, and steps S1-S4 are carried out as follows:
s1, adding D-penicillamine and acetone into a reaction tank for reaction, after the reaction is finished, evaporating to remove redundant acetone, and obtaining isopropyl-D-penicillamine in the reaction tank;
s2, directly adding ethyl formate into the reaction tank of the step S1, reacting at the temperature of 53 ℃ for 5 hours, and evaporating to remove redundant ethyl formate to obtain N-formyl isopropyl-D-penicillamine in the reaction tank;
s3, adding acetic acid or a mixed solution of the acetic acid and toluene into the reaction tank of the step S2 to carry out racemization reaction, and after the racemization reaction is finished, removing the acetic acid and the toluene by reduced pressure evaporation to obtain the N-formyl isopropyl-D, L-penicillamine in the reaction tank;
s4, adding hydrochloric acid into the reaction tank in the step S3, reacting under the condition of introducing nitrogen into the reaction tank, cooling to room temperature after the reaction is finished, extracting by isopropyl ether, concentrating the extracted water phase to dryness to obtain white needle-like hygroscopic solid, and drying in vacuum to obtain the D, L-penicillamine hydrochloride.
6. The process for the preparation of L-penicillamine according to any one of claims 1 to 4, wherein steps S1-S4 are carried out in separate reaction tanks, and steps S1-S4 are performed as follows:
s1, adding D-penicillamine and acetone into a reaction tank for reaction, cooling to 5 ℃ after the reaction is finished, stirring for 1h, filtering to obtain a white filter cake, and drying to obtain isopropyl-D-penicillamine;
s2, adding isopropyl-D-penicillamine and ethyl formate into a reaction tank, heating to 53 ℃, carrying out reflux reaction for 5 hours, then cooling to room temperature, stirring at 5 ℃ for 1 hour, filtering, and drying to obtain white powdery N-formyl isopropyl-D-penicillamine;
s3, adding N-formyl isopropyl-D-penicillamine and acetic acid into a reaction tank, or adding N-formyl isopropyl-D-penicillamine, acetic acid and toluene into the reaction tank, cooling, filtering, washing and vacuum drying after racemization reaction is finished to obtain N-formyl isopropyl-D, L-penicillamine;
s4, adding N-formyl isopropyl-D, L-penicillamine and hydrochloric acid into a reaction tank, reacting in the reaction tank under the condition of introducing nitrogen, cooling to room temperature after the reaction is finished, extracting by adopting isopropyl ether, concentrating the extracted water phase to dryness to obtain white needle-shaped hygroscopic solid, and drying in vacuum to obtain D, L-penicillamine hydrochloride.
7. The process for the preparation of L-penicillamine according to claim 1, wherein said step S5 is in particular: adding D, L-penicillamine hydrochloride and an anhydrous alcohol solvent into a reaction tank, cooling to 5 ℃, dropwise adding an organic base while stirring, adjusting the pH of the solution to 6.5-7, filtering, washing a filter cake, and drying to obtain racemization penicillamine solid D, L-penicillamine.
8. The process for the preparation of L-penicillamine according to claim 1, wherein said step S6 is in particular: mixing L-tartaric acid and anhydrous alcohol solvent in a reaction tank, stirring and dissolving, then dripping D, L-penicillamine glacial acetic acid solution, continuing stirring for 0.5h after the addition is finished, filtering, washing a filter cake, and drying in vacuum to obtain penicillamine L-tartrate.
9. The process for the preparation of L-penicillamine according to claim 1, wherein said step S7 is in particular: adding L-penicillamine L-tartrate and anhydrous alcohol solvent into a reaction tank, adding organic base, filtering, washing filter cake with the anhydrous alcohol solvent, and drying in vacuum to obtain the L-penicillamine.
10. The process for the preparation of L-penicillamine according to claim 1, wherein said anhydrous alcohol solvent is an anhydrous lower alcohol and said organic base is triethylamine.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB585436A (en) * | 1944-11-10 | 1947-02-06 | Wellcome Found | Improvements in and relating to the production of dl-n-formyl-isopropylidene-penicillamine |
| GB585413A (en) * | 1944-06-19 | 1947-02-06 | Wellcome Found | Improved method for the resolution of penicillamine |
| BE823426A (en) * | 1973-12-17 | 1975-06-16 | METHOD FOR THE RACEMIC DEDOUBEMENT OF D, L-PENICILLAMINE | |
| US3980665A (en) * | 1973-01-27 | 1976-09-14 | Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler | Optically active salt of protected D-penicillamine and L-lysine |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB585413A (en) * | 1944-06-19 | 1947-02-06 | Wellcome Found | Improved method for the resolution of penicillamine |
| GB585436A (en) * | 1944-11-10 | 1947-02-06 | Wellcome Found | Improvements in and relating to the production of dl-n-formyl-isopropylidene-penicillamine |
| US3980665A (en) * | 1973-01-27 | 1976-09-14 | Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler | Optically active salt of protected D-penicillamine and L-lysine |
| BE823426A (en) * | 1973-12-17 | 1975-06-16 | METHOD FOR THE RACEMIC DEDOUBEMENT OF D, L-PENICILLAMINE |
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