CN1323067C - Method for synthesizing N-tert-butoxy-oxo-L-isoleucine - Google Patents
Method for synthesizing N-tert-butoxy-oxo-L-isoleucine Download PDFInfo
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- CN1323067C CN1323067C CNB2005100377992A CN200510037799A CN1323067C CN 1323067 C CN1323067 C CN 1323067C CN B2005100377992 A CNB2005100377992 A CN B2005100377992A CN 200510037799 A CN200510037799 A CN 200510037799A CN 1323067 C CN1323067 C CN 1323067C
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- isoleucine
- ethyl acetate
- butoxy
- oxo
- tert
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Abstract
The present invention relates to a method for synthesizing N-boc-L-isoleucine, which beings to the technical field of chemical industry. The present invention is mainly characterized in that in the process of synthesizing N-boc-L-isoleucine, low-cost BOC acid anhydride which is suitable for industrialized production and is largely purchased is used; thereby, the production efficiency is increased, and the production cost is reduced. In the synthesizing technology, the time of adding NaOH solution drop by drop is shortened into several hours from two days in an original synthesizing method, and the production period is largely shortened. More specially, the yield of the product (L-isoleucine) prepared by the technology can reach 105.2%, which is over 20% more than the yield disclosed in documents.
Description
Technical field
The present invention relates to the synthetic method of a kind of N-tert-butoxy-oxo-L-isoleucine of chemical technology field.
Background technology
The N-tert-butoxy-oxo-L-isoleucine is synthetic polypeptide, the critical materials of synthetic drugs, " the 3rd biochemical reagents of modern chemistry reagent handbook () disclose 26 gram L-Isoleucines have been suspended in 80M water and dioxane (1: the 1) solution, stir 28.6 gram BOC (the being tertbutyloxycarbonyl) nitrine of adding down, use N
aIt is 9.8 that OH regulates pH value, drips 2 days, and reaction is yellow transparent, use ethyl acetate extraction, and the water layer acidifying is taken out load with ethyl acetate again, with sodium chloride solution washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, spend the night crystallization, the dry finished product 20.6 that gets restrains.This synthetic method has the following disadvantages: the first, and raw materials used is the BOC nitrine, this raw material can only can not be purchased in batches as agent delivery on market, and price is very high, can't satisfy the suitability for industrialized production needs of N-tert-butoxy-oxo-L-isoleucine; The second, drip N
aThe OH solution time is 2 days, and this step process time is oversize, has elongated the cycle of suitability for industrialized production; The 3rd, product yield is 79.2% (in the L-Isoleucine), and yield is on the low side, and product cost is too high, is unfavorable for the commercialization sale.
Summary of the invention
Purpose of the present invention provides a synthetic method that can be fit to the high N-tert-butoxy-oxo-L-isoleucine of batch process, economical rationality, processing ease and yield at existing N-tert-butoxy-oxo-L-isoleucine synthetic method above shortcomings.
The objective of the invention is to be achieved through the following technical solutions, a kind of synthetic method of N-tert-butoxy-oxo-L-isoleucine, its main technique comprise successively the abundant dissolving stirring of main raw material L-Isoleucine and dioxane water liquid, drip N in above-mentioned mixed solutions
aThe pH value of OH solution regulator solution is used ethyl acetate extraction, uses anhydrous sodium sulfate drying, it is characterized in that:
Also has the BOC acid anhydrides in A, the main raw material, the L-Isoleucine is 1 than BOC acid anhydrides: 1.6-1.7 (mol ratio), the L-Isoleucine is 1 than dioxane: 7.2-7.4 (mol ratio), the L-Isoleucine of said ratio is dissolved in BOC acid anhydrides and the dioxane water liquid mixing solutions, and cool off through icy salt solution;
B, sodium hydroxide solution dropping time were controlled at 1.5-2.5 hour, kept reaction solution pH value 9-10, finished reaction when PH fixes on 9, and temperature is controlled at 15-25 ℃;
C, be no less than twice with ethyl acetate extraction, stay lower layer of water liquid, adding hydrochloric acid, to make the solution pH value be 9, and used extraction agent ethyl acetate is 10-12 than L-Isoleucine: 1 (mol ratio);
D, be no less than twice with ethyl acetate extraction again, stay the upper strata ethyl acetate layer, used extraction agent ethyl acetate is 10-12 than L-Isoleucine: 1 (mol ratio);
Use anhydrous sodium sulfate drying behind E, the extraction ethyl acetate layer, make the ethyl acetate layer clarification, used anhydrous sodium sulphate is 2-3 than L-Isoleucine: 1 (mol ratio);
After the clarification of F, ethyl acetate, filter ethyl acetate, the underpressure distillation ethyl acetate, add sherwood oil stir grind product.
The invention discloses when synthetic N-tert-butoxy-oxo-L-isoleucine, adopt cost of material cheap, be suitable for suitability for industrialized production, the BOC acid anhydrides raw material that can buy has in a large number improved production efficiency, has reduced production cost again, in synthesis technique, uses N
aThe time that OH solution drips shortened to several hours by two days in the former synthetic method, had shortened the production cycle greatly, and the yield that this technology that main is makes product reaches 105.2% in the L-Isoleucine, and is higher more than 20% than the disclosed yield of document.
Embodiment
The present invention synthesizes the N-tert-butoxy-oxo-L-isoleucine, the main raw material that is adopted is the dioxane water liquid of L-Isoleucine, BOC acid anhydrides and 50%, the mol ratio of raw material is 1: 1.66: 7.22, its operation is followed successively by: L-Isoleucine 131.18 grams, BOC acid anhydrides 218 grams and 50% dioxane water liquid, 960 grams are placed in the reactor stir, insert the icy salt solution cooling after the L-Isoleucine is fully dissolved, chemical equation is:
CH
3?H
2H
3C-C-C-C-COOH+(CH
3)
3COC-O-COC(CH
3)
3
H
2 H?NH
2 O O
CH
3
H
3C-CH
2-CH-CH-COON
a
NH +3H
2O
C-O-C(CH
3)
3
O
Dripping the 4N aqueous sodium hydroxide solution 2 hours, is 9-10 to keep reacting system PH value, when pH value is constant when being 9, finishes reaction, and temperature is controlled at 15-25 ℃;
With ethyl acetate 900mL extracting twice, stay lower layer of water liquid, it is 9 that adding hydrochloric acid makes the solution pH value, chemical equation is:
CH
3 CH
3
H
3C-CH
2-CH-CH-COON
a H
3C-CH
2-CH-CH-COOH
NH +HCI NH +N
aCI
C-O-C(CH
3)
3 C-O-C(CH
3)
3
O O
With ethyl acetate 900mL extracting twice, stay the upper strata ethyl acetate layer;
Use anhydrous sodium sulfate drying, make the ethyl acetate layer clarification;
Filter clarifying ethyl acetate layer, the underpressure distillation ethyl acetate is stayed 150mL, and the adding sherwood oil stirs and grinds;
Above-mentioned stirring ground the material drying and got product 138 gram, and in thrown L-Isoleucine, yield is 105.2%
Claims (4)
1, a kind of synthetic method of N-tert-butoxy-oxo-L-isoleucine, its master operation comprises successively main raw material L-Isoleucine dropped into to dissolve in the dioxane water liquid and mixes, dropping sodium solution is regulated pH value in mixed solution, use ethyl acetate extraction, use anhydrous sodium sulfate drying, it is characterized in that:
Also has the BOC acid anhydrides in the main raw material of A, input, the input mol ratio of L-Isoleucine, BOC acid anhydrides, 50% dioxane is 1: 1.6-1.7: 7.2-7.4, the L-Isoleucine of said ratio is dissolved in BOC acid anhydrides and the dioxane water liquid mixing solutions, cools off through icy salt solution;
B, sodium hydroxide dropping time were controlled at 1.5-2.5 hour;
C, be no less than twice with ethyl acetate extraction, stay lower layer of water liquid, adding hydrochloric acid, to make water liquid pH value be 9;
D, be no less than twice with the above-mentioned water liquid of ethyl acetate extraction again, stay the upper strata ethyl acetate layer;
E, with anhydrous sodium sulphate to the ethyl acetate layer drying, make ethyl acetate layer clarification;
F, filter clarifying ethyl acetate, the underpressure distillation ethyl acetate, add sherwood oil stir grind product.
2, the synthetic method of N-tert-butoxy-oxo-L-isoleucine according to claim 1 is characterized in that it is 9-10 that dropping sodium is kept the reaction material liquid PH value, and is constant in 9 when pH value, finishes reaction, and temperature is controlled at 15-25 ℃.
3, the synthetic method of N-tert-butoxy-oxo-L-isoleucine according to claim 1, the mol ratio that it is characterized in that extracting used ethyl acetate and L-Isoleucine is 10-12: 1.
4, the synthetic method of N-tert-butoxy-oxo-L-isoleucine according to claim 1, the mol ratio that it is characterized in that dry used anhydrous sodium sulphate and L-Isoleucine is 2-3: 1.
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|---|---|---|---|
| CNB2005100377992A CN1323067C (en) | 2005-02-06 | 2005-02-06 | Method for synthesizing N-tert-butoxy-oxo-L-isoleucine |
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|---|---|---|---|
| CNB2005100377992A CN1323067C (en) | 2005-02-06 | 2005-02-06 | Method for synthesizing N-tert-butoxy-oxo-L-isoleucine |
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| CN1323067C true CN1323067C (en) | 2007-06-27 |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102936207B (en) * | 2011-08-15 | 2015-06-10 | 苏州百灵威超精细材料有限公司 | New synthesis method of important biochemical reagent L-leucine-4-nitroaniline hydrochloride |
| CN104326944A (en) * | 2014-11-04 | 2015-02-04 | 崇州合瑞科技有限公司 | Method for preparing Boc-L-threonine |
| CN104326960A (en) * | 2014-11-04 | 2015-02-04 | 崇州合瑞科技有限公司 | Method for preparing Boc-L-proline |
| CN104276964A (en) * | 2014-11-04 | 2015-01-14 | 崇州合瑞科技有限公司 | Preparation method of Boc-glycine |
| CN104276966A (en) * | 2014-11-04 | 2015-01-14 | 崇州合瑞科技有限公司 | Preparation method of Boc-L-aspartic acid |
| CN104447415A (en) * | 2014-11-04 | 2015-03-25 | 崇州合瑞科技有限公司 | Method for preparing Boc-L-tyrosine by using (Boc)2O |
| CN104326943A (en) * | 2014-11-04 | 2015-02-04 | 崇州合瑞科技有限公司 | Method for preparing Boc-L-serine |
| CN108084057A (en) * | 2017-12-25 | 2018-05-29 | 常州吉恩药业有限公司 | A kind of industrialized preparing process of high-quality N- tertbutyloxycarbonyls-L-Leu crystallization |
-
2005
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Non-Patent Citations (1)
| Title |
|---|
| N-叔丁氧羰基-β-环己基天冬氨酸苄酯的合成 杨大成，范莉，化学研究与应用，第15卷第4期 2003 * |
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