CN112321470A - Preparation method of high-purity D-cystine - Google Patents
Preparation method of high-purity D-cystine Download PDFInfo
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- CN112321470A CN112321470A CN202011461469.7A CN202011461469A CN112321470A CN 112321470 A CN112321470 A CN 112321470A CN 202011461469 A CN202011461469 A CN 202011461469A CN 112321470 A CN112321470 A CN 112321470A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/22—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/22—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides
- C07C319/24—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides by reactions involving the formation of sulfur-to-sulfur bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/26—Separation; Purification; Stabilisation; Use of additives
- C07C319/28—Separation; Purification
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Abstract
The invention discloses a preparation method of high-purity D-cystine, which comprises the steps of firstly hydrolyzing D-2, 2-dimethylthiazolidine-4-carboxylic acid, L-tartrate, and then converting hydrolysate, specifically converting L-tartaric acid in the hydrolysate into L-bitartrate, and separating out the L-bitartrate as precipitate; then, before the filtrate is oxidized, the pH value is reduced, so that more impurities are introduced in the oxidation process, and the D-cystine with high purity and high yield is obtained; the whole preparation method has simple production flow, safe and easily controlled used raw materials, no high-temperature and high-pressure reaction, less equipment investment and easy production operation.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to a synthesis method of high-purity D-cystine, which has low production cost, convenient operation and high yield.
Background
D-cysteine is an important intermediate of cefamandole sodium which is a third generation cephalosporin antibiotic drug. The action property of the cefminox sodium is similar to that of the third generation cephalosporin, and the finished product is heptahydrate, which has antibacterial effect on escherichia coli, streptococcus, Klebsiella, Haemophilus influenzae, Bacteroides and the like and also has the effect of preventing the peptidoglycan in the bacterial wall from generating lipoprotein. Lipoprotein structures are unique to gram-negative bacteria and, therefore, have a stronger effect on gram-negative bacteria than other similar drugs. Meanwhile, D-cysteine hydrochloride is also a strong inhibitor of Escherichia coli and an effective reliever of acute alcoholism. With the increasing use of cefminox sodium, the demand for its intermediate D-cysteine hydrochloride is increasing.
The methods proposed by domestic and foreign related documents are all to obtain D-cysteine by racemization and re-resolution of L-cysteine. L-cysteine racemization is a method for generating D-cysteine by taking L-cysteine as a raw material and L-tartaric acid as a resolving agent through asymmetric transformation of D-2, 2-dimethylthiazolidine-4-carboxylic acid-L tartrate.
Chinese patent (application No. 201010158954.7) discloses a preparation method of D-cysteine hydrochloride monohydrate, which is characterized in that D-2, 2-dimethylthiazolidine-4-carboxylic acid-L-tartrate is adjusted to pH 3.6 by triethylamine and then hydrolyzed to prepare D-cysteine. The product obtained from the above reaction is D-cysteine. Because the preparation method easily leads the D-2, 2 '-dimethylthiazolidine-4-carboxylic acid tartrate to carry the L-2, 2' -dimethylthiazolidine-4-carboxylic acid tartrate or the L-cysteine, the optical purity of the formed salt is not high, the D-cysteine is easy to oxidize, the carried L-tartaric acid is difficult to completely remove, and the method has poor applicability.
Disclosure of Invention
The invention provides a method for synthesizing high-purity D-cystine, which comprises the steps of firstly obtaining D-2, 2-dimethylthiazolidine-4-carboxylic acid.L-tartrate by the prior art, and then obtaining the high-purity D-cystine with low production cost, convenient operation and high yield by optimizing reaction conditions, wherein the method has stronger applicability.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of high-purity D-cystine comprises the following steps:
(1) firstly carrying out hydrolysis reaction on D-2, 2-dimethylthiazolidine-4-carboxylic acid L-tartrate, then adding carbonate into the hydrolysate to ensure that L-tartaric acid in the hydrolysate forms L-tartrate hydrogen salt precipitate, and filtering to remove the precipitate;
(2) adding hydrogen peroxide into the filtrate obtained in the step (1) for oxidation reaction to prepare D-cystine.
Further, the step (1) is specifically: adding D-2, 2-dimethyl thiazolidine-4-carboxylic acid L-tartrate into purified water with the weight of 8-15 times of that of the D-2, 2-dimethyl thiazolidine-4-carboxylic acid L-tartrate, carrying out reduced pressure hydrolysis at the temperature of 20-30 ℃ for 0.5 hour, then cooling the hydrolysate to the temperature of 0-5 ℃, adjusting the pH to be =4.2-4.5 by using carbonate, generating L-tartrate precipitate, filtering, and reserving filtrate for later use.
Further, it is preferable to add 10 times by weight of purified water.
Further, the carbonate is one of potassium carbonate and sodium carbonate.
Further, the step (2) is specifically: adjusting the pH of the filtrate to be 4.0-5.0 by using 5% sodium carbonate aqueous solution and 5% diluted hydrochloric acid, controlling the temperature to be 5-10 ℃, slowly dropwise adding 12.5% hydrogen peroxide for oxidation, keeping the temperature and stirring for 1 hour at the temperature after dropwise adding, wherein the pH of the detection feed liquid is 6.5-7.0; filtering and washing; obtaining a wet D-cystine product; drying at 60-70 deg.C under reduced pressure to obtain pure white crystal powder, i.e. D-cystine.
Further, it is characterized in that the filtrate is adjusted to pH =4.2-4.8 with 5% aqueous sodium carbonate solution and 5% dilute hydrochloric acid.
The invention optimizes the optimal reaction parameters of each step of reaction through a large amount of practices, and designs a feasible production process flow.
The preparation method of D-cystine provided by the invention comprises the steps of firstly hydrolyzing D-2, 2-dimethylthiazolidine-4-carboxylic acid L-tartrate, then converting hydrolysate, specifically converting L-tartaric acid in the hydrolysate into L-bitartrate, and separating out the L-bitartrate as precipitate; then, before the filtrate is oxidized, the pH value is reduced, so that more impurities are introduced in the oxidation process, and the D-cystine with high purity and high yield is obtained; the whole preparation method has simple production flow, safe and easily controlled used raw materials, no high-temperature and high-pressure reaction, less equipment investment and easy production operation.
Detailed Description
The invention will now be further described by reference to specific examples, which are intended to be illustrative only and not limiting in nature.
In the following examples, each raw material was a commercially available product.
The method for producing the starting material, D-2, 2-dimethylthiazolidine-4-carboxylic acid L-tartrate, according to the present invention is a conventional method. For example: reacting L-cysteine with acetone and L-tartaric acid in a glacial acetic acid solvent at 50-90 ℃, stirring for 15-50 minutes to dissolve solids, wherein the molar ratio of the L-cysteine to the L-tartaric acid to the acetone to the glacial acetic acid is 1: 1: 6-7: 6-7;
2) adding salicylaldehyde after the solid in the step 1) is completely dissolved, and continuously stirring for 8-16 hours, wherein the molar ratio of the salicylaldehyde to the raw material L-cysteine is 1: 10;
3) cooling the reaction solution obtained in the step 2) in ice water for half an hour, filtering, and washing with ethyl acetate for 2-3 times to obtain a white solid of D-2, 2-dimethylthiazolidine-4-carboxylic acid L-tartrate.
Example 1 a process for the preparation of D-cystine, comprising the steps of:
(1) adding 100g D-2, 2-dimethylthiazolidine-4-carboxylic acid L-tartrate into purified water with the weight of 8 times of that of the L-tartrate, carrying out reduced pressure hydrolysis at the temperature of 20 ℃ for 0.5 hour, then cooling the hydrolysate to 0 ℃, adjusting the pH to be =4.2-4.5 by potassium carbonate, generating L-potassium hydrogen tartrate precipitate, filtering to remove the L-potassium hydrogen tartrate, and keeping the filtrate for later use; after drying, the potassium hydrogen L-tartrate was weighed out with a yield of 98.2%.
(2) And (3) oxidation reaction: the method specifically comprises the following steps: adjusting the pH of the filtrate to be 4.0-5.0 by using a 5% sodium carbonate aqueous solution and 5% diluted hydrochloric acid, controlling the temperature to be 5 ℃, slowly dropwise adding 15g of 12.5% hydrogen peroxide for oxidation, keeping the temperature and stirring for 1 hour at the temperature after dropwise adding, wherein the pH of the detected feed liquid is 6.5-7.0; filtering and washing; obtaining a wet D-cystine product; drying at 60 deg.C under reduced pressure to obtain pure white crystal powder, i.e. D-cystine, with yield of 98.5% and purity of 99.6%.
Example 2 a method for preparing D-cystine, comprising the steps of:
(1) adding 100g D-2, 2-dimethylthiazolidine-4-carboxylic acid L-tartrate into 15 times of purified water by weight, carrying out reduced pressure hydrolysis at 30 ℃ for 0.5 hour, then cooling the hydrolysate to 5 ℃, adjusting the pH value to be =4.2-4.5 by using sodium carbonate, generating L-sodium hydrogen tartrate precipitate, filtering to remove L-potassium hydrogen tartrate, and reserving the filtrate for later use; after drying, the L-sodium hydrogen tartrate is weighed, and the yield is 98%.
(2) And (3) oxidation reaction: the method specifically comprises the following steps: adjusting the pH of the filtrate to be 4.2-4.8 by using a 5% sodium carbonate aqueous solution and 5% diluted hydrochloric acid, controlling the temperature to be 10 ℃, slowly dropwise adding 15g of 12.5% hydrogen peroxide for oxidation, keeping the temperature and stirring for 1 hour at the temperature after dropwise adding, wherein the pH of the detected feed liquid is 6.5-7.0; filtering and washing; obtaining a wet D-cystine product; drying at 70 deg.C under reduced pressure to obtain pure white crystal powder, i.e. D-cystine, with yield of 98.7% and purity of 99.5%.
Example 3 a method for preparing D-cystine, comprising the steps of:
(1) adding 100g D-2, 2-dimethylthiazolidine-4-carboxylic acid L-tartrate into 10 times of purified water by weight, carrying out hydrolysis under reduced pressure at 25 ℃ for 0.5 hour, then cooling the hydrolysate to 3 ℃, adjusting the pH to be 4.2-4.5 by using potassium carbonate, generating L-potassium hydrogen tartrate precipitate, filtering to remove the L-potassium hydrogen tartrate, and keeping the filtrate for later use; after drying, the potassium hydrogen L-tartrate was weighed out with a yield of 98.5%.
(2) And (3) oxidation reaction: the method specifically comprises the following steps: adjusting the pH of the filtrate to be 4.0-5.0 by using 5% sodium carbonate aqueous solution and 5% diluted hydrochloric acid, controlling the temperature to be 8 ℃, slowly dropwise adding 15g of 12.5% hydrogen peroxide for oxidation, keeping the temperature and stirring for 1 hour at the temperature after dropwise adding, and detecting the pH of the feed liquid to be 6.5-7.0; filtering and washing; obtaining a wet D-cystine product; drying at 66 deg.C under reduced pressure to obtain pure white crystal powder, i.e. D-cystine, with yield of 99% and purity of 99.6%.
Comparative example 1A 1L reaction flask was charged with 93.4g of D-2, 2-dimethylthiazolidine-4-carboxylic acid L-tartrate, and 500ml of purified water was added thereto to conduct hydrolysis at 60 ℃ under normal pressure for 3 hours; adjusting pH of hydrolysate with ammonia water to =3.5, filtering to remove L-ammonium hydrogen tartrate (40 g of L-ammonium hydrogen tartrate is obtained after drying, only 80% of the theoretical amount of the L-ammonium hydrogen tartrate has yellow color and has D-cystine and impurity residues), adjusting pH of filtrate with ammonia water to =5.0, dropwise adding 68g of 30% hydrogen peroxide, filtering to obtain wet D-cystine, washing twice, and drying under reduced pressure to obtain 28.1g of yellow D-cystine, wherein the yield is only 78% and the purity is 98.3%.
Comparative example 2 a method for preparing high-purity D-cystine, which is different from example 3 in that the amount of purified water used in step (1) is 5 times the amount of D-2, 2-dimethylthiazolidine-4-carboxylic acid, L-tartrate, and the finally obtained D-cystine has a pale yellow crystalline powder appearance; the yield was 97.8% and the purity was 96.5%.
Comparative example 3 a method for preparing high-purity D-cystine, which is different from example 3 in that the temperature of the reduced pressure hydrolysis in the step (1) is 50-60 c to obtain the final D-cystine; the appearance is light yellow crystal powder, and the yield is 89.6%; the purity was 96%.
Comparative example 4 differs from example 3 in that in step (1) potassium carbonate was used to adjust the pH =3.5-4.0, giving an amount of 86.8% of theoretical amount of potassium L-hydrogen tartrate; potassium hydrogen L-tartrate does not achieve effective separation.
Comparative example 5 a process for preparing high purity D-cystine, which is different from example 3, the filtrate in step (2) is adjusted to pH =5.5-6.5 with 5% sodium carbonate aqueous solution and 5% diluted hydrochloric acid, when the oxidation is finished, the pH of the reaction solution is detected to be 7.5-8.0, and after filtering, water washing and drying, D-cystine is obtained, which is pale yellow crystalline powder in appearance, with a yield of 88.4% and a purity of 98.1%.
Comparative example 6 a method for preparing high purity D-cystine, which is different from example 3, the filtrate in step (2) was adjusted to pH =3.0-3.5 with 5% sodium carbonate aqueous solution and 5% diluted hydrochloric acid, when the oxidation was completed, the pH of the reaction solution was detected to be 5.5-6.0, and the reaction solution was filtered, washed with water and dried to obtain D-cystine as pure white crystalline powder in appearance with a yield of 72.5% and a purity of 99.3%.
Comparative example 7 a method for preparing high purity D-cystine, which is different from example 3 in that the temperature during the hydrogen peroxide oxidation in the step (2) is 30 ℃, the finally obtained D-cystine is pale yellow crystal powder in appearance, the yield is 98.1%, and the purity is 98.5%.
Comparative example 8 a process for preparing high purity D-cystine, which is different from example 3 in that triethylamine is used to adjust pH =4.2-4.5 in step (1), the resulting D-cystine is pale yellow crystalline powder in appearance, yield 86.2%, and purity 98.2%.
It should be noted that the above-mentioned embodiments are only some of the preferred modes for implementing the invention, and not all of them. Obviously, all other embodiments obtained by persons of ordinary skill in the art based on the above-mentioned embodiments of the present invention without any creative effort shall fall within the protection scope of the present invention.
Claims (6)
1. A preparation method of high-purity D-cystine is characterized by comprising the following steps:
(1) firstly carrying out hydrolysis reaction on D-2, 2-dimethylthiazolidine-4-carboxylic acid L-tartrate, then adding carbonate into the hydrolysate to ensure that L-tartaric acid in the hydrolysate forms L-tartrate hydrogen salt precipitate, and filtering to remove the precipitate;
(2) adding hydrogen peroxide into the filtrate obtained in the step (1) for oxidation reaction to prepare D-cystine.
2. The method for preparing high-purity D-cystine according to claim 1, characterized in that the step (1) is specifically as follows: adding D-2, 2-dimethyl thiazolidine-4-carboxylic acid L-tartrate into purified water with the weight of 8-15 times of that of the D-2, 2-dimethyl thiazolidine-4-carboxylic acid L-tartrate, carrying out reduced pressure hydrolysis at the temperature of 20-30 ℃ for 0.5 hour, then cooling the hydrolysate to the temperature of 0-5 ℃, adjusting the pH to be =4.2-4.5 by using carbonate, generating L-tartrate precipitate, filtering, and reserving filtrate for later use.
3. The method for preparing high purity D-cystine according to claim 2, characterized in that 10 times of purified water is preferably added.
4. The method of claim 2, wherein the carbonate is one of potassium carbonate and sodium carbonate.
5. The method for preparing high-purity D-cystine according to claim 1, characterized in that said step (2) is specifically: adjusting the pH of the filtrate to be 4.0-5.0 by using 5% sodium carbonate aqueous solution and 5% diluted hydrochloric acid, controlling the temperature to be 5-10 ℃, slowly dropwise adding 12.5% hydrogen peroxide for oxidation, keeping the temperature and stirring for 1 hour at the temperature after dropwise adding, wherein the pH of the detection feed liquid is 6.5-7.0; filtering and washing; obtaining a wet D-cystine product; drying at 60-70 deg.C under reduced pressure to obtain pure white crystal powder, i.e. D-cystine.
6. The method of claim 5, wherein the filtrate is adjusted to pH =4.2-4.8 with 5% sodium carbonate aqueous solution and 5% diluted hydrochloric acid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113277941A (en) * | 2021-05-14 | 2021-08-20 | 湖北新生源生物工程有限公司 | Method for recovering L-tartaric acid from D-cysteine conversion hydrolysate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51100023A (en) * | 1975-02-25 | 1976-09-03 | Fujisawa Pharmaceutical Co | dd shisuchinno seizoho |
| CN102219719A (en) * | 2011-02-28 | 2011-10-19 | 曹县思达化工有限公司 | Method for preparing D-cysteine hydrochloride-hydrate |
| CN102267892A (en) * | 2011-08-08 | 2011-12-07 | 天津市化学试剂研究所 | Preparation method of potassium hydrogen tartrate used as pH reference reagent |
| CN102351764A (en) * | 2011-09-20 | 2012-02-15 | 重庆惠健生物科技有限公司 | Method for preparing high optical purity D-cystine |
-
2020
- 2020-12-14 CN CN202011461469.7A patent/CN112321470A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51100023A (en) * | 1975-02-25 | 1976-09-03 | Fujisawa Pharmaceutical Co | dd shisuchinno seizoho |
| CN102219719A (en) * | 2011-02-28 | 2011-10-19 | 曹县思达化工有限公司 | Method for preparing D-cysteine hydrochloride-hydrate |
| CN102267892A (en) * | 2011-08-08 | 2011-12-07 | 天津市化学试剂研究所 | Preparation method of potassium hydrogen tartrate used as pH reference reagent |
| CN102351764A (en) * | 2011-09-20 | 2012-02-15 | 重庆惠健生物科技有限公司 | Method for preparing high optical purity D-cystine |
Non-Patent Citations (1)
| Title |
|---|
| 马世昌: "《化学物质辞典》", 30 April 1999, 陕西科学技术出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113277941A (en) * | 2021-05-14 | 2021-08-20 | 湖北新生源生物工程有限公司 | Method for recovering L-tartaric acid from D-cysteine conversion hydrolysate |
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