CN104326960A - Method for preparing Boc-L-proline - Google Patents
Method for preparing Boc-L-proline Download PDFInfo
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- CN104326960A CN104326960A CN201410611009.6A CN201410611009A CN104326960A CN 104326960 A CN104326960 A CN 104326960A CN 201410611009 A CN201410611009 A CN 201410611009A CN 104326960 A CN104326960 A CN 104326960A
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- proline
- boc
- pro
- adjusted
- method preparing
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The invention provides a method for preparing Boc-L-proline. The method comprises the following steps: mixing L-proline with an aqueous solution of one of sodium hydroxide and sodium carbonate, adding (Boc)2O in batches, and controlling reaction conditions to obtain Boc-L-proline with high yield. The method provided by the invention is low in cost, simple and convenient in method, safe to operate, small in pollution and high in yield, is easy to achieve industrial production, and provides a new method for industrially producing Boc-L-proline.
Description
Technical field
The invention belongs to organic synthesis field, be specifically related to a kind of method of synthesizing Boc-L-proline(Pro).
Background technology
Boc-L-proline(Pro) is mainly used in Peptide systhesis, is mainly used in the application of multi-medicament and biotechnology.
Proline(Pro) is one of important amino acid of synthesized human protein, is the important source material of amino acid transfusion, is also synthesis captopril, enalapril etc. the main intermediate of line antihypertensive drugs, has been widely used in the industry such as food and medicine.Can be used for amino acid injection, aminoacids complex transfusion, foodstuff additive, nutritional supplement liquid etc.; Can be used for Biochemical Research, supplementing pharmaceutically for malnutrition, hypoproteinosis, gastroenteropathy, scald and postoperative protein; Can be used for accessory substance, flavour agent, with sugar common heat, amino-carbonyl occurs and react, special fragrance matter can be generated, can be used as spices by China GB2760-86 regulation; Can be used for Branchamin, is one of amino acid infusion solutions raw material, for malnutrition, and hypoproteinosis, serious intestines and stomach illness, the Protein intake of scald and surgical site infections; Can be used for medical material and foodstuff additive.
Boc-L-proline synthesis method has multiple, and method more common at present has following a few class:
A.L-proline(Pro), Boc-N3, triethylamine reacts acquisition in DMF.But present method raw material Boc-N3 easily explodes in distillation purifying process, abnormally dangerous.And the HN3 that reaction produces has very large toxicity, and people can be made to suffer a shock.
B.L-proline(Pro), Boc-Cl, sodium hydroxide, tetrahydrofuran (THF) in water less than 0 DEG C react acquisition.This method condition is comparatively harsh, needs to carry out at low temperatures.And Boc-Cl be easy to decompose, cause consumption excessive and produce impurity, be difficult to purifying.
C.L-proline(Pro), Boc-O-C6H5, potassium hydroxide heats 90-100 DEG C of reaction and obtains in dimethyl sulfoxide (DMSO).Because condition is harsh, easily there is product racemization and the more situation of impurity.And the reagent dimethyl sulfoxide (DMSO) that the method uses easily decomposites the thioether with foul smell, use and can environmental pollution be caused in treating processes.
In sum, all there is certain defect and certain limitation in the method preparing Boc-L-proline(Pro) of existing bibliographical information.
Summary of the invention
The present invention is intended to the limitation overcoming above-mentioned existing Boc-L-proline synthesis method, a kind of synthetic method of Boc-L-proline(Pro) is provided, the present invention is by under aqueous solution condition wherein a kind of to L-PROLINE, sodium hydroxide or potassium hydroxide, adds (Boc) in batches
2o, by controlling reaction conditions, high yield obtains Boc-L-proline(Pro).Adopt the present invention, with low cost, method is easy, operational safety, and pollute little, productive rate is high, easily realizes suitability for industrialized production.For suitability for industrialized production Boc-L-proline(Pro) provides a kind of new method.
For achieving the above object, the technical solution used in the present invention is as follows:
Prepare a method for Boc-L-proline(Pro), it is characterized in that step is as follows:
(1) L-PROLINE is adjusted to alkalescence;
(2) repeatedly add (Boc) in batches
2o reacts;
(3) impurity is removed in extraction;
(4) acidity is adjusted to, reextraction;
(5) merge organic layer, be washed till neutrality, dry;
(6) crystallization is filtered, and obtains Boc-L-proline(Pro).
Further, in described (1), L-PROLINE is adjusted to alkalescence, concrete steps are for adding sodium hydroxide or sodium carbonate dissolves in water to L-PROLINE, PH >=12.
Further, in described (3), impurity is removed in extraction, and concrete steps, for adding sherwood oil repeatedly extracting impurities, remove the organic layer comprising impurity.
Further, be adjusted to acidic twice extraction in described (4), concrete steps, for adding hydrochloric acid soln, after being adjusted to acid PH=1 ~ 3, adding ethyl acetate and repeatedly extract.
Further, merge organic layer, be washed till neutrality in described (5), dry, adopt salt to be washed to neutral for good, time of drying controls at 10 ~ 12h.
Further, in described (6), crystallization is filtered, and concrete steps, for adding sherwood oil crystallization and filtering, obtain Boc-L-proline(Pro).
Beneficial effect of the present invention is as follows:
The present invention is suitable for simple condition low cost production Boc-L-proline(Pro).The present invention adopts nontoxic non-hazardous (Boc)
2o as protection reagent, by changing alkaline condition, by controlling inventory and feed way one-step synthesis target compound.
Produce Boc-L-proline(Pro) with method provided by the invention, yield reaches more than 90%, and comparatively previous methods improves a lot.The present invention produces product and easily to process and foreign matter content is extremely low, and Boc-L-proline(Pro) purity can reach more than 99%.The present invention due to reaction conditions simple, use materials safety environmental protection, very friendly with personnel to production environment.
The present invention is with low cost, and method is easy, operational safety, and pollute little, productive rate is high, easily realizes suitability for industrialized production.For suitability for industrialized production Boc-L-proline(Pro) provides a kind of new method.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example, all technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment one:
1. by 18.1g L-PROLINE, 100ml water is added in reaction flask, stirs.The 0.1mol/L alkali lye adding the configuration of 16g sodium hydroxide is adjusted to alkalescence.Add again (Boc) of 8g
2o reacts 1 hour, then adds (Boc) of 8g
2o reacts 1 hour, finally adds (Boc) of 9g
2o reacts 3 hours.
2. use sherwood oil 10ml/ time, extracting impurities three times.After 3mol/L hydrochloric acid regulates PH=3, then use ethyl acetate 0.5L/ time, extracted products three times.Merge ester layer, wash neutrality with salt.Add 15 grams of anhydrous sodium sulfate dryings 6 hours.
3. filter, filtrate reduced in volume is done, and adds the crystallization of 50ml petroleum ether and stirring.Centrifugal go out product, dry.Obtain product 26.3g.Productive rate 93.57%.
Embodiment two:
1. by the L-PROLINE of 1kg, 5.5L water is added in reaction flask, stirs.The 0.5mol/L alkali lye adding the configuration of 884g sodium carbonate is adjusted to alkalescence.Add again (Boc) of 442g
2o reacts 2 hours, then adds (Boc) of 442g
2o reacts 2 hours, finally adds (Boc) of 497g
2o reacts 4 hours.
2. use sherwood oil 500ml/ time, extracting impurities four times.After 6mol/L hydrochloric acid regulates PH=3, then use ethyl acetate 1L/ time, extracted products four times.Merge ester layer, wash neutrality with salt.Add 300 grams of anhydrous sodium sulfate dryings 8 hours.
3. filter, filtrate reduced in volume is done, and adds the crystallization of 2L petroleum ether and stirring.Leach product, dry.Obtain product 1642g.Productive rate 94.79%.
Claims (6)
1. prepare a method for Boc-L-proline(Pro), it is characterized in that step is as follows:
(1) L-PROLINE is adjusted to alkalescence;
(2) repeatedly add (Boc) in batches
2o reacts;
(3) impurity is removed in extraction;
(4) acidity is adjusted to, reextraction;
(5) merge organic layer, be washed till neutrality, dry;
(6) crystallization is filtered, and obtains Boc-L-proline(Pro).
2. a kind of method preparing Boc-L-proline(Pro) according to claim 1, is characterized in that: in described (1), L-PROLINE is adjusted to alkalescence, and concrete steps are for adding sodium hydroxide or sodium carbonate dissolves in water to L-PROLINE, PH >=12.
3. a kind of method preparing Boc-L-proline(Pro) according to claim 1, is characterized in that: in described (3), impurity is removed in extraction, and concrete steps, for adding sherwood oil repeatedly extracting impurities, remove the organic layer comprising impurity.
4. a kind of method preparing Boc-L-proline(Pro) according to claim 1, is characterized in that: be adjusted to acidic twice extraction in described (4), concrete steps, for adding hydrochloric acid soln, after being adjusted to acid PH=1 ~ 3, adding ethyl acetate and repeatedly extract.
5. a kind of method preparing Boc-L-proline(Pro) according to claim 1, is characterized in that: merge organic layer in described (5), be washed till neutrality, dry, and adopt salt to be washed to neutral for good, time of drying controls at 10 ~ 12h.
6. a kind of method preparing Boc-L-proline(Pro) according to claim 1, is characterized in that: in described (6), crystallization is filtered, and concrete steps, for adding sherwood oil crystallization and filtering, obtain Boc-L-proline(Pro).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201410611009.6A CN104326960A (en) | 2014-11-04 | 2014-11-04 | Method for preparing Boc-L-proline |
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| CN201410611009.6A CN104326960A (en) | 2014-11-04 | 2014-11-04 | Method for preparing Boc-L-proline |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106543062A (en) * | 2016-05-22 | 2017-03-29 | 上海清松制药有限公司 | A kind of preparation method of medicine intermediate N-Boc- allohydroxyprolines |
| CN114436930A (en) * | 2022-02-15 | 2022-05-06 | 重庆市碚圣医药科技股份有限公司 | Synthesis method of Boc-L-hydroxyproline |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1785974A (en) * | 2005-12-14 | 2006-06-14 | 郑州大学 | (4S)-1-tert butoxy carbonyl-4-amino-L-ethyl prolinate and its synthesis technology |
| CN1793110A (en) * | 2005-12-20 | 2006-06-28 | 武汉大学 | Process for preparing Boc protected amino acid by (Boc) O |
| CN1814585A (en) * | 2005-02-06 | 2006-08-09 | 扬州宝盛生物化工有限公司 | Method for synthesizing N-tert-butoxy-oxo-L-isoleucine |
| CN1986547A (en) * | 2005-12-22 | 2007-06-27 | 上海药明康德新药开发有限公司 | Industrial preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptance in one cauldron |
| CN101597288A (en) * | 2008-06-02 | 2009-12-09 | 北京大学 | 2-aminoacyl-β-Ka Lin-3-formyl tryptophan benzyl ester and its production and application |
| CN103360367A (en) * | 2013-07-31 | 2013-10-23 | 西北大学 | Chiral amine derived from proline and preparation method |
| WO2014120786A1 (en) * | 2013-01-29 | 2014-08-07 | Naurex, Inc. | Spiro-lactam nmda receptor modulators and uses thereof |
-
2014
- 2014-11-04 CN CN201410611009.6A patent/CN104326960A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1814585A (en) * | 2005-02-06 | 2006-08-09 | 扬州宝盛生物化工有限公司 | Method for synthesizing N-tert-butoxy-oxo-L-isoleucine |
| CN1785974A (en) * | 2005-12-14 | 2006-06-14 | 郑州大学 | (4S)-1-tert butoxy carbonyl-4-amino-L-ethyl prolinate and its synthesis technology |
| CN1793110A (en) * | 2005-12-20 | 2006-06-28 | 武汉大学 | Process for preparing Boc protected amino acid by (Boc) O |
| CN1986547A (en) * | 2005-12-22 | 2007-06-27 | 上海药明康德新药开发有限公司 | Industrial preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptance in one cauldron |
| CN101597288A (en) * | 2008-06-02 | 2009-12-09 | 北京大学 | 2-aminoacyl-β-Ka Lin-3-formyl tryptophan benzyl ester and its production and application |
| WO2014120786A1 (en) * | 2013-01-29 | 2014-08-07 | Naurex, Inc. | Spiro-lactam nmda receptor modulators and uses thereof |
| CN103360367A (en) * | 2013-07-31 | 2013-10-23 | 西北大学 | Chiral amine derived from proline and preparation method |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106543062A (en) * | 2016-05-22 | 2017-03-29 | 上海清松制药有限公司 | A kind of preparation method of medicine intermediate N-Boc- allohydroxyprolines |
| CN114436930A (en) * | 2022-02-15 | 2022-05-06 | 重庆市碚圣医药科技股份有限公司 | Synthesis method of Boc-L-hydroxyproline |
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Application publication date: 20150204 |