CN106187819A - A kind of preparation method of BOC L asparagine - Google Patents
A kind of preparation method of BOC L asparagine Download PDFInfo
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- CN106187819A CN106187819A CN201610520580.6A CN201610520580A CN106187819A CN 106187819 A CN106187819 A CN 106187819A CN 201610520580 A CN201610520580 A CN 201610520580A CN 106187819 A CN106187819 A CN 106187819A
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- boc
- asparagine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
Abstract
The invention discloses the preparation method of a kind of BOC L asparagine, with L agedoite and Bis(tert-butoxycarbonyl)oxide as raw material, with water as reaction dissolvent, under the conditions of the alkalescence of pH 9～10, reaction generates BOC L asparagine, reactant liquor be acidified to pH 4.0～4.5 separate out BOC L asparagine crude product, through sucking filtration, wash, be dried to obtain BOC L asparagine fine work.The present invention prepares the method reaction condition gentleness of BOC L asparagine, reaction is quick, cost of material is lower, with water as reaction dissolvent, subsequent operation is simple, it is only necessary to acidifying just can separate out BOC L asparagine crystal, being beneficial to industrialization produce, environmental protection, safety coefficient are the highest.
Description
Technical field
The invention belongs to medicinal chemistry arts, be specifically related to the preparation method of a kind of BOC-L-asparagine.
Background technology
Altheine is used for synthesizing Organic Ingredients or pharmaceutical intermediate, when utilizing altheine to carry out compounding design,
Usually needing to protect amido, Boc (tert-butoxy carbonyl) is widely used in synthesis as the preferable amino protecting group of one
In design.BOC-L-agedoite (BOC-L-Asparagine), has another name called: N-tertbutyloxycarbonyl-altheine, white crystals
Shape material, is dissolved in DMF, insoluble in petroleum ether.Molecular formula: C9H16N2O5；Structural formula is as follows:
Qiu Chuanliang etc. have investigated the Bocization research of dibasic amino acid, iminodiacetic acid and aspartic acid alkalescence Isosorbide-5-Nitrae-
With (Boc) in dioxane-aqueous solvent system2O reaction and glutamic acid are at alkalescence 1,4-dioxane and oxolane-aqueous solvent
With (Boc) in system2The yield of O reaction is obviously higher than the reaction yield with tertiary butanol and water as solvent system.But amino two
Room temperature reaction is for up to 32h in organic solvent-water (1:1) for unit's acid, and subsequent operation is loaded down with trivial details.Chinese patent application (CN
1793110A) disclose one and use (Boc)2O prepares L-Aspartic acid ammonia or the method for Pidolidone of BOC protection, with acetone
It is solvent with water, at triethylamine (Et3N), in the presence of, aminoacid and Bis(tert-butoxycarbonyl)oxide react the amino preparing BOC protection
Acid.Although the method reaction condition is gentle, the time is shorter, it is possible to obtain higher yield, but triethylamine has strong
Ammonia taste, and owing to have employed organic solvent-aqueous solvent system, cause subsequent operation loaded down with trivial details, reaction needs to boil off organic after terminating
Solvent, then through extraction, water layer acid adjustment, extract, crystallize, be unfavorable for industrialization, cost, environmental protection, safety also require that extra-high.
Summary of the invention
It is an object of the invention to provide that a kind of reaction condition is gentle, react quick, simple to operate, cost of material is lower
The preparation method of BOC-L-asparagine.
It is an object of the invention to be achieved through the following technical solutions:
The preparation method of a kind of BOC-L-asparagine (N-tertbutyloxycarbonyl-altheine), with altheine
And Bis(tert-butoxycarbonyl)oxide ((Boc) (L-Asn)2O) it is raw material, with water as reaction dissolvent, under the conditions of the alkalescence of pH 9～10
Reaction generates BOC-L-asparagine, and reactant liquor is acidified to pH 4.0～4.5 and separates out BOC-L-asparagine crude product, through taking out
Filter, wash, be dried to obtain BOC-L-asparagine fine work.
The preparation method of BOC-L-asparagine of the present invention, comprises the following steps:
Step (1), altheine, Bis(tert-butoxycarbonyl)oxide are thrown in water；At temperature 25～30 DEG C, while stirring
Dropping alkali liquor, regulation pH value of solution is to 9～10；After dropping, it is warming up to 30～40 DEG C, reacts again under stirring 4～6 hours；
Step (2), reactant liquor are cool below 10 DEG C, regulate reactant liquor pH to 4.0～4.5, separate out BOC-L-Radix Asparagi
Crude amide, sucking filtration, solid washing, be dried to obtain BOC-L-asparagine fine work.
In step (1), described altheine and the mol ratio of Bis(tert-butoxycarbonyl)oxide are 1:1～1.2, preferably 1:
1.1。
30～35 DEG C it are warming up to, stirring reaction 4～5 hours after dropping.
Described alkali liquor be concentration be the sodium hydroxide of 10mol/L.
The rotating speed of stirring is 120 revs/min；Whole system is not homogeneous system, by stirring, makes material the most mixed
Even, increase contact area, dissolving limit, Bis(tert-butoxycarbonyl)oxide limit is reacted with altheine.
In step (2), reactant liquor brine ice is cool below 10 DEG C, dropping hydrochloric acid regulation reactant liquor pH to 4.0～
4.5, preferably 4.3, separate out BOC-L-asparagine crude product, sucking filtration, solid water eccysis goes salinity, temperature 50-60 DEG C to be dried
Obtain BOC-L-asparagine fine work.
Described hydrochloric acid be concentration be the hydrochloric acid of 5mol/L.
Beneficial effects of the present invention:
The present invention prepares the method reaction condition gentleness of BOC-L-asparagine, reaction is quick, cost of material is lower, with
Water is reaction dissolvent, and subsequent operation is simple, it is only necessary to acidifying just can separate out BOC-L-asparagine crystal, beneficially industrialization
Producing, environmental protection, safety coefficient are the highest.The classical technique of BOC protection that the inventive method is totally different from document or textbook,
Compare classical technique, distinguish as follows:
Classical technique is all solvent reaction, such as oxolane, the inventive method water；
Classical technique weak base, such as sodium carbonate, sodium bicarbonate, the inventive method Caustic soda；
Classical technological reaction temperature is less than 5 degree, and needing freezing, the inventive method is about 25～35 DEG C；
Classical technique is first to add alkali, then dropping BOC anhydride, and the inventive method is disposably to add BOC anhydride, then drips
Alkali；
Classical technique weak acid is acidified, such as citric acid, acetic acid, the inventive method hydrochloric acid.
Detailed description of the invention
Embodiment 1
BOC-L-asparagine is prepared according to following preparation process:
In step (1), 3L flask put into 150g L-Asn (1mol), 240g Bis(tert-butoxycarbonyl)oxide (1.1mol) and
700mL water；At temperature 25～30 DEG C, in the case of maintaining rotating speed to be 120 revs/min, drip 300mL while stirring
The NaOH aqueous solution (3mol) of 10mol/L, controls rate of addition so that pH=9～10, in the process L-Asn and two carbonic acid
Di tert butyl carbonate is soluble in water to react；After dropping, it is warming up to 34 DEG C, reacts again under stirring 4 hours；
Step (2), reactant liquor brine ice are cooled to less than 10 DEG C；Being slowly added dropwise 6mol/L hydrochloric acid, dropping process keeps
Temperature is less than 10 DEG C, is acidified to pH4.3, separates out BOC-L-asparagine crude product, sucking filtration, washs solid, solid with 150mL water
56 DEG C of drying, obtain BOC-L-asparagine fine work 192g, weight yield 128% (relative to L-asparagine), mole receipts
Rate 90.5%.
Embodiment 2
BOC-L-asparagine is prepared according to following preparation process:
In step (1), 3L flask put into 150g L-Asn (1mol), 262g Bis(tert-butoxycarbonyl)oxide (1.2mol) and
700mL water；At temperature 25～30 DEG C, in the case of maintaining rotating speed to be 120 revs/min, drip 300mL while stirring
The NaOH aqueous solution (3mol) of 10mol/L, controls rate of addition so that pH=9～10, in the process L-Asn and two carbonic acid
Di tert butyl carbonate is soluble in water to react；After dropping, it is warming up to 34 DEG C, reacts again under stirring 4 hours；
Step (2), reactant liquor brine ice are cooled to, less than 10 DEG C, residual (Boc) be detected2O crystal；It is slowly added dropwise
6mol/L hydrochloric acid, dropping process keeps temperature less than 10 DEG C, is acidified to pH4.3, separates out BOC-L-asparagine crude product, take out
Filter, washs solid, solid 58 DEG C drying with 110mL water, obtains BOC-L-asparagine fine work 217.5g, weight yield 145%
(relative to L-asparagine).
Embodiment 3
BOC-L-asparagine is prepared according to following preparation process:
Step (1), 3L flask put into 150g L-Asn (1mol), 218g Bis(tert-butoxycarbonyl)oxide (1mol) and 700mL
Water；At temperature 25～30 DEG C, in the case of maintaining rotating speed to be 120 revs/min, drip 300mL 10mol/L's while stirring
NaOH aqueous solution (3mol), controls rate of addition so that pH=9～10, L-Asn and Bis(tert-butoxycarbonyl)oxide are molten in the process
Yu Shuizhong reacts；After dropping, it is warming up to 34 DEG C, reacts again under stirring 4 hours；
Step (2), reactant liquor brine ice are cooled to, less than 10 DEG C, residual (Boc) be detected2O crystal；It is slowly added dropwise
6mol/L hydrochloric acid, dropping process keeps temperature less than 10 DEG C, is acidified to pH4.3, separates out BOC-L-asparagine crude product, take out
Filter, washs solid, solid 55 DEG C drying with 100mL water, obtains BOC-L-asparagine fine work 202.5g, weight yield 135%
(relative to L-asparagine).
The testing result of the BOC-L-aspartoyl amine product that table 1 embodiment 1-3 prepares
Conclusion: as L-Asn and (Boc)2When O feeds intake according to mol ratio 1:1.2, yield is the highest, reaches 145%, but reactant liquor
Residual (Boc) it is found to have after cooling2O crystal.(Boc)2Relatively L-Asn is more expensive for the price of O, has (Boc) after the cooling of simultaneous reactions liquid2O
Crystal, the BOC-L-asparagine that during crystallization, meeting and reaction obtain is mixed in together, makes purge process complicated, affects product pure
Degree.As L-Asn and (Boc)2When O feeds intake according to mol ratio 1:1, yield is minimum, is 135%, and unreacted L-Asn can become miscellaneous
Matter, can be precipitated out mixed in together, affect product purity during acidizing crystal.As L-Asn and (Boc)2O is according to mol ratio 1:
1.1 when feeding intake, and reactant liquor is cold goes rear noresidue (Boc)2O crystal.
Claims (8)
1. the preparation method of a BOC-L-asparagine, it is characterised in that be with altheine and Bis(tert-butoxycarbonyl)oxide
Raw material, with water as reaction dissolvent, under the conditions of the alkalescence of pH 9～10, reaction generates BOC-L-asparagine, and reactant liquor is acidified
To pH 4.0～4.5 separate out BOC-L-asparagine crude product, through sucking filtration, wash, be dried to obtain BOC-L-asparagine fine work.
The preparation method of BOC-L-asparagine the most according to claim 1, it is characterised in that comprise the following steps:
Step (1), altheine, Bis(tert-butoxycarbonyl)oxide are thrown in water；At temperature 25～30 DEG C, drip while stirring
Alkali liquor, regulation pH value of solution is to 9～10；After dropping, it is warming up to 30～40 DEG C, reacts again under stirring 4～6 hours；
Step (2), reactant liquor are cool below 10 DEG C, regulate reactant liquor pH to 4.0～4.5, separate out BOC-L-asparagine
Crude product, sucking filtration, solid washing, be dried to obtain BOC-L-asparagine fine work.
The preparation method of BOC-L-asparagine the most according to claim 1 and 2, it is characterised in that described L-Radix Asparagi
The mol ratio of amide and Bis(tert-butoxycarbonyl)oxide is 1:1～1.2.
The preparation method of BOC-L-asparagine the most according to claim 3, it is characterised in that described L-Radix Asparagi acyl
The mol ratio of amine and Bis(tert-butoxycarbonyl)oxide is 1:1.1.
The preparation method of BOC-L-asparagine the most according to claim 2, it is characterised in that in step (1), described
Alkali liquor be concentration be the sodium hydroxide of 10mol/L.
The preparation method of BOC-L-asparagine the most according to claim 2, it is characterised in that in step (1), stirring
Rotating speed be 120 revs/min.
The preparation method of BOC-L-asparagine the most according to claim 2, it is characterised in that in step (2), reaction
Liquid brine ice is cool below 10 DEG C, dropping hydrochloric acid regulation reactant liquor pH to 4.0～4.5, separates out BOC-L-asparagine
Crude product, sucking filtration, solid washing, temperature 50～60 DEG C are dried to obtain BOC-L-asparagine fine work.
The preparation method of BOC-L-asparagine the most according to claim 7, it is characterised in that described hydrochloric acid is dense
Degree is the hydrochloric acid of 5mol/L.
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| CN201610520580.6A CN106187819B (en) | 2016-07-04 | 2016-07-04 | A kind of preparation method of BOC L asparagines |
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| CN201610520580.6A CN106187819B (en) | 2016-07-04 | 2016-07-04 | A kind of preparation method of BOC L asparagines |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040038950A1 (en) * | 2002-08-26 | 2004-02-26 | Sang-Cheol Seong | Pharmaceutical composition for treating IL-1 related diseases or disorders |
| CN1793110A (en) * | 2005-12-20 | 2006-06-28 | 武汉大学 | Process for preparing Boc protected amino acid by (Boc) O |
| CN101120006A (en) * | 2005-02-11 | 2008-02-06 | 赛福伦公司 | Proteasome inhibitors and methods of using the same |
| CN101654473A (en) * | 2009-08-13 | 2010-02-24 | 上海力智生化科技有限公司 | Synthesis method of amino-protecting glycine dipeptidase derivant |
| CN104030943A (en) * | 2014-03-12 | 2014-09-10 | 重庆福安药业(集团)股份有限公司 | A preparing process of lacosamide |
-
2016
- 2016-07-04 CN CN201610520580.6A patent/CN106187819B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040038950A1 (en) * | 2002-08-26 | 2004-02-26 | Sang-Cheol Seong | Pharmaceutical composition for treating IL-1 related diseases or disorders |
| CN101120006A (en) * | 2005-02-11 | 2008-02-06 | 赛福伦公司 | Proteasome inhibitors and methods of using the same |
| CN1793110A (en) * | 2005-12-20 | 2006-06-28 | 武汉大学 | Process for preparing Boc protected amino acid by (Boc) O |
| CN101654473A (en) * | 2009-08-13 | 2010-02-24 | 上海力智生化科技有限公司 | Synthesis method of amino-protecting glycine dipeptidase derivant |
| CN104030943A (en) * | 2014-03-12 | 2014-09-10 | 重庆福安药业(集团)股份有限公司 | A preparing process of lacosamide |
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