CN105111124A - Method for producing D-tryptophan - Google Patents
Method for producing D-tryptophan Download PDFInfo
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- CN105111124A CN105111124A CN201510596202.1A CN201510596202A CN105111124A CN 105111124 A CN105111124 A CN 105111124A CN 201510596202 A CN201510596202 A CN 201510596202A CN 105111124 A CN105111124 A CN 105111124A
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- trp
- water
- tryptophan
- methyl esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention discloses a method for producing D-tryptophan. The method comprises the following steps: 1) L-tryptophan is stirred in methanol and cooled to 10 DEG C, thionyl chloride is added dropwise; after the adding, the temperature rises to 20 DEG C, heat insulation is performed for 5 h, methanol is concentrated, water is added, the pH is adjusted to 7-8 with ammonia water, L-tryptophan methyl ester is crystallized and filtered and dried for standby application; 2) L-tryptophan methyl ester is dissolved in the methanol, D-tartaric acid and 3% of trimethylacetaldehyde are added at room temperature, the temperature rises to 70 DEG C, backflow is performed for 5 h, cooling is performed, and double salt is obtained; 3) the double salt is dissolved in water, the pH is adjusted to 7-8 with ammonia water, and D-tryptophan methyl ester is obtained through crystallization and filtration; 4) D-tryptophan methyl ester is dissolved in water at room temperature, the pH is adjusted to over 12 with 20% of sodium hydroxide, heat insulation is performed for 4 h, crude D-tryptophan is obtained through crystallization and filtration and stirred and washed for 1 h with water, and the product D-tryptophan is obtained through centrifugation. The method belongs to asymmetric conversion and is simple to operate, high in yield and low in cost.
Description
Technical field
The present invention relates to chemosynthesis technical field, be specifically related to a kind of method of producing D-trp.
Background technology
D-trp, as a kind of non-protein optically active amino acids, has special physiological characteristics, in food, fodder industry and agricultural, all have certain value, can as non-nutritive sweetener, fodder additives, plant growth agent.Particularly in pharmaceutical industries, D-trp is the important synthesis precursor of carcinostatic agent and immunosuppressor.
In prior art, mainly there is following several defect in the preparation method about D-trp:
1) with L-Trp synthesis N-acetyl-DL-Trp, with the enzymic hydrolysis of L-aminoacylates, obtain D-acetyltryptophan at hydrochloric acid hydrolysis, this method, because be that 50% fractionation transforms, adds last hydrochloric acid hydrolysis, so yield is lower, add last hydrochloric acid hydrolysis, add that indole ring easily decomposes in acid, lower to the finished product yield, thus this technique relative cost is higher, thus market value is higher;
2) split with DL-Trp camphorsulfonic acid, this fractionation can only be equally also 50% fractionation, do not accomplish 100% conversion, and the chirality that therefore the method splits does not accomplish more than 99, so there is no way and realize industrialization;
3) split by glycolylurea method, because need to use two kinds of enzymes, therefore cost is relatively high, and same market value also can be higher, is difficult to realize industrialization.
Summary of the invention
The present invention is directed to the deficiency that above-mentioned prior art exists, provide a kind of method of producing D-trp, belong to asymmetric transformation, reactions steps is few, simple to operate, and yield is high, and cost is low.
For solving above-mentioned prior art Problems existing, the technical scheme that the present invention takes is: a kind of method of producing D-trp, comprises the steps:
1) L-Trp opens stirring in methyl alcohol, and lower the temperature at 10 degree of dropping sulfur oxychlorides, be warmed up to 20 degree after adding and be incubated 5 hours, concentrate the water that methyl alcohol adds 4 times of weight, regulate pH to 7-8 with ammoniacal liquor, L-Trp methyl esters crystallizes out, stand-by after filtration drying;
2) L-Trp methyl esters dissolves in methyl alcohol, add under room temperature D-tartrate and 3% special valeral be warmed up to 70 degree and reflux 5 hours, terminate rear cooling, obtain double salt;
3) double salt dissolves in the water of 3 times of weight, regulates pH to 7-8 with ammoniacal liquor, and crystallization is filtered and obtained D-trp methyl esters;
4) D-trp methyl esters room-temperature dissolution in the water of 3 times of weight, is adjusted to more than 12 with the sodium hydroxide of 20%, is incubated 4 hours, and crystallization is filtered and obtained D-trp crude product, and crude product stirs with the water of 3 times and washes 1 hour, centrifugally obtains product D-trp.
In step 1), the mol ratio of L-Trp and methyl alcohol is 1:30.
The mol times that in step 1), sulfur oxychloride adds is the 1.0-1.4 of L-Trp.
Step 2) in the weight ratio of L-Trp methyl esters and methyl alcohol be 1:(3.8-4.2).
Step 2) in D-tartrate and 3% the mol times added of special valeral be 1 times of L-Trp methyl esters.
The present invention is relative to the advantage of prior art:
1. reactions steps is few, environmental protection, simple to operate.
2. belong to asymmetric transformation, can theoretical 100% conversion, therefore yield is high a lot, and cost is much lower relative to other technique.
3. whole processing condition are gentle, and process stabilizing, easily realizes industrialized production.
Embodiment
Embodiment 1
1) 204kgL-tryptophane opens stirring in 960kg methyl alcohol, lowers the temperature and drips the sulfur oxychloride of 142kg at 10 degree, be warmed up to 20 degree and be incubated 5 hours after adding, the water of 800kg is added after reclaiming methyl alcohol, regulate pH to 7-8 with ammoniacal liquor, L-Trp methyl esters crystallizes out, and filtration drying obtains 209kg.
2) L-Trp methyl esters 209kg dissolves in 836kg methyl alcohol, and the special valeral of the D-tartrate and 6.27kg that add 144kg under room temperature is warmed up to 70 degree and refluxes 5 hours, terminates rear cooling, obtains double salt 380kg wet product.
3) 380kg double salt dissolves in 1140kg water, regulates pH to 7-8 with ammoniacal liquor, and crystallization is filtered and obtained D-trp methyl esters 200kg wet product;
4) D-trp methyl esters 200kg wet product in the water of 540kg room-temperature dissolution with 20% sodium hydroxide regulate pH to more than 12, be incubated 4 hours, crystallization is filtered and is obtained D-trp crude product, and crude product stirs with the water of 3 times and washes 1 hour, centrifugally obtains product D-trp 163kg.
Purity: 99.5% (HPLC)
Chiral purity: 99.9%.
The present embodiment produces according to the amount of industrialized production, is different from the experiment condition in laboratory, through a large amount of experimental verifications before carrying out industrialization, then carries out enlarged experiment, obtain this technique after stably manufactured 20 batches.Process stabilizing of the present invention and yield is high.
Claims (5)
1. produce a method for D-trp, it is characterized in that, comprise the steps:
1) L-Trp opens stirring in methyl alcohol, and lower the temperature at 10 degree of dropping sulfur oxychlorides, be warmed up to 20 degree after adding and be incubated 5 hours, concentrate the water that methyl alcohol adds 4 times of weight, regulate pH to 7-8 with ammoniacal liquor, L-Trp methyl esters crystallizes out, stand-by after filtration drying;
2) L-Trp methyl esters dissolves in methyl alcohol, add under room temperature D-tartrate and 3% special valeral be warmed up to 70 degree and reflux 5 hours, terminate rear cooling, obtain double salt;
3) double salt dissolves in the water of 3 times of weight, regulates pH to 7-8 with ammoniacal liquor, and crystallization is filtered and obtained D-trp methyl esters;
4) D-trp methyl esters room-temperature dissolution in the water of 3 times of weight, the sodium hydroxide with 20% regulates pH to more than 12, be incubated 4 hours, and crystallization filtration obtains D-trp crude product, and crude product stirs with the water of 3 times and washes 1 hour, centrifugally obtains product D-trp.
2. a kind of method of producing D-trp according to claim 1, is characterized in that, in step 1), the mol ratio of L-Trp and methyl alcohol is 1:30.
3. a kind of method of producing D-trp according to claim 1, is characterized in that, the mol times that in step 1), sulfur oxychloride adds is the 1.0-1.4 of L-Trp.
4. a kind of method of producing D-trp according to claim 1, is characterized in that, step 2) in the weight ratio of L-Trp methyl esters and methyl alcohol be 1:(3.8-4.2).
5. a kind of method of producing D-trp according to claim 1, is characterized in that, step 2) in D-tartrate and 3% the mol times added of special valeral be 1 times of L-Trp methyl esters.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510596202.1A CN105111124B (en) | 2015-09-18 | 2015-09-18 | A kind of method for producing D tryptophans |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510596202.1A CN105111124B (en) | 2015-09-18 | 2015-09-18 | A kind of method for producing D tryptophans |
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| Publication Number | Publication Date |
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| CN105111124A true CN105111124A (en) | 2015-12-02 |
| CN105111124B CN105111124B (en) | 2017-08-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510596202.1A Active CN105111124B (en) | 2015-09-18 | 2015-09-18 | A kind of method for producing D tryptophans |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108147974A (en) * | 2017-12-28 | 2018-06-12 | 山东新华制药股份有限公司 | The preparation process of L-methyldopa methyl esters |
| CN110982858A (en) * | 2019-11-13 | 2020-04-10 | 上海星酶生物科技有限公司 | Production process of D-tryptophan |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1876631A (en) * | 2006-07-17 | 2006-12-13 | 安徽省恒锐新技术开发有限责任公司 | Method for preparing D-tryptophan using asymmetric conversion method |
| CN103342676A (en) * | 2013-07-24 | 2013-10-09 | 马鞍山德鸿生物技术有限公司 | Method for synthetizing D-tryptophan |
-
2015
- 2015-09-18 CN CN201510596202.1A patent/CN105111124B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1876631A (en) * | 2006-07-17 | 2006-12-13 | 安徽省恒锐新技术开发有限责任公司 | Method for preparing D-tryptophan using asymmetric conversion method |
| CN103342676A (en) * | 2013-07-24 | 2013-10-09 | 马鞍山德鸿生物技术有限公司 | Method for synthetizing D-tryptophan |
Non-Patent Citations (2)
| Title |
|---|
| 唐林淋: "D-色氨酸的合成工艺研究", 《化学世界》 * |
| 翟立海: "两种 D-型酸性氨基酸的制备研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108147974A (en) * | 2017-12-28 | 2018-06-12 | 山东新华制药股份有限公司 | The preparation process of L-methyldopa methyl esters |
| CN110982858A (en) * | 2019-11-13 | 2020-04-10 | 上海星酶生物科技有限公司 | Production process of D-tryptophan |
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| Publication number | Publication date |
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| CN105111124B (en) | 2017-08-25 |
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Denomination of invention: Method for producing D-tryptophan Effective date of registration: 20190111 Granted publication date: 20170825 Pledgee: Zijin Branch of Nanjing Bank Co., Ltd. Pledgor: NANJING REDWOOD BIOTECHNOLOGY CO., LTD. Registration number: 2019320000032 |