CN101012181B - Resolution method of DL-p-chlorophenylalanine - Google Patents
Resolution method of DL-p-chlorophenylalanine Download PDFInfo
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- CN101012181B CN101012181B CN2007100369995A CN200710036999A CN101012181B CN 101012181 B CN101012181 B CN 101012181B CN 2007100369995 A CN2007100369995 A CN 2007100369995A CN 200710036999 A CN200710036999 A CN 200710036999A CN 101012181 B CN101012181 B CN 101012181B
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- fenclonine
- tartaric acid
- splitting
- dibenzoyl tartaric
- resolving agent
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Abstract
The invention discloses a detaching method of DL-p-chlorochlorophenylalanine, which comprises the following steps: adopting DL-p-chlorochlorophenylalanine as raw material; reacting with detacher L-dibenzoylmethyl tartaric acid in the alcaine-alcohol system; obtaining L-dibenzoylmethyl tartaric acid D-p-chlorochlorophenylalanine; filtering the reacting liquid to obtain crystal and mother liquid; obtaining D-p-chlorochlorophenylalanine ([alpha]D20+3.2o(c 1, 1mol/L HCl)) with receiving rate at 78-84% and fusing point at 261 deg.c and L-p-chlorochlorophenylalanine ([alpha]D20 -3.1o(c 1, 1mol/L HCl)) with receiving rate at 78-81% and fusing point at 263 deg.c.
Description
Technical field
The present invention relates to a kind of method for splitting of DL-fenclonine.
Background technology
The DL-fenclonine is a kind of important biology, pharmaceutical intermediate; L-and D-type fenclonine play an important role in physiology and polypeptide drug are synthetic; Wherein the L-fenclonine can suppress the formation of serotonine, improves drug effect thereby the D-fenclonine is used for the synthetic degradation time that can prolong polypeptide drug of LHRH antagonistic analogs.
In the prior art, the method for splitting of DL-fenclonine has enzyme to split and two kinds of chemistry fractionations.1994 the 1st phases of chemistry circular, 50 pages of methods that disclosed with immobilized aminoacylase fractionation DL-fenclonine: with the DL-fenclonine is raw material; Under alkaline condition, carry out acetylize with diacetyl oxide; Obtain the N-Ac-DL-fenclonine; The N-Ac-DL-fenclonine is made into the solution of 0.033mol/L, regulates PH7.0, CoCl
2Concentration be 5 * 10-4mol/L, (the rice koji fermentation, extract and to obtain L-Aminoacylase, use cross-linked TMSDMA N dimethylamine methyl-acrylic amide immobilization again through immobilized enzyme then; Obtain immobilized enzyme) post, 37 ℃ of column temperatures, flow velocity is merely 8ml/h; The effluent collection is concentrated, add ethanol, parse L-fenclonine white solid; Mother liquor is used concentrated hydrochloric acid hydrolysis after reclaiming ethanol, resolves to obtain the D-fenclonine.
The 3247th page of Tetrahedron:Asymmetry 1998 the 9th volume reported that crystallization induces the method for asymmetric transformation approach preparation (R)-4-chlorophenylalanine methyl esters.The DL-fenclonine carries out esterification in hydrogenchloride/methanol solution, obtain DL-4-chlorophenylalanine methyl ester hydrochloride, uses K again
2CO
3Solid is removed the DL-4-chlorophenylalanine methyl esters that hydrogenchloride obtains free amine group; Use (2S then; 3S)-tartrate splits in methanol solution as resolving agent and obtains (R)-4-chlorophenylalanine methyl esters; Utilize salicylic aldehyde as catalyzer simultaneously, adopt asymmetric transformation approach to obtain (R)-4-chlorophenylalanine methyl esters.
In the above-mentioned method for splitting, the facility investment of enzyme Split Method is big, produces Rong Bixiao, catalyst recovery difficulty, unstable product quality; Chemical resolution method need be derived to the DL-fenclonine, splits again, has increased reactions step, complex operation.
Summary of the invention
The technical problem that the present invention solves provides a kind of method for splitting of DL-fenclonine, and the enzyme Split Method produces Rong Bixiao in the prior art to overcome, and catalyzer is not easy to reclaim unstable product quality, the defective of chemical resolution method complex operation.
Technical conceive of the present invention is such: with the DL-fenclonine is raw material; In hydrochloric acid-ethanol system; React with resolving agent L-dibenzoyl tartaric acid; Obtain L-dibenzoyl tartaric acid D-fenclonine, from the crystal that reacting liquid filtering obtains, resolve and obtain the D-fenclonine, from the mother liquor that reacting liquid filtering obtains, resolve and obtain the L-fenclonine.
Split process of the present invention is following:
Method of the present invention comprises the steps:
(1) the DL-fenclonine is added in the aqueous solution of hydrochloric acid, 80-90 ℃, splash into the ethanolic soln of resolving agent L-dibenzoyl tartaric acid in 0.5-1.0 hour, 60-70 ℃ of reaction 4-6 hour, reaction solution is cooled to room temperature;
(2) with last reacting liquid filtering in the step (1), the L-dibenzoyl tartaric acid D-fenclonine crystal that obtains adds in the 3mol/L-5mol/L hydrochloric acid, 20-25 ℃ of decomposition; Separate out resolving agent; Remove by filter resolving agent, filtrating concentrates, under 0-5 ℃ condition; Alkaline solution is regulated pH value, in alcohol solvent, separates out D-fenclonine white crystal;
(3) last reacting liquid filtering in the step (1), the mother liquor that obtains containing L-fenclonine hydrochloride concentrates, and under 0-5 ℃ the condition, alkaline solution is regulated pH value, in alcohol solvent, separates out L-fenclonine white crystal.
According to the present invention, the concentration of said hydrochloric acid soln is 3mol/L-5mol/L, and the quality percentage composition of said alkaline solution is the ammonia soln of 10%-25%, preferred 25% ammonia soln, and it is PH=7 that alkaline solution is regulated pH value.
The proportioning of reactant of the present invention is the DL-fenclonine: hydrochloric acid soln: resolving agent L-dibenzoyl tartaric acid=1.0: 0.5-1.0: 0.5-1.0, mol ratio.
The mass volume ratio of resolving agent L-dibenzoyl tartaric acid and consumption of ethanol is a resolving agent L-dibenzoyl tartaric acid in the step of the present invention (1): ethanol=1.0: 2.0-2.2.
The proportioning of L-dibenzoyl tartaric acid D-fenclonine and hydrochloric acid is 1 in the step of the present invention (2): 3.5-6.5, mol ratio.
Resolve respectively with method for splitting of the present invention and to obtain two kinds of enantiomers; D-fenclonine yield 78-84% wherein;
(c 1; 1mol/L HCl); Fusing point is 261 ℃ (dec), L-fenclonine yield 78-81%, and
(c 1; 1mol/L HCl), fusing point is 263 ℃ (dec).
Raw material DL-fenclonine used in the present invention can prepare according to document " chemistry circular " the 1st phase in 1994 50 pages of disclosed methods.
Beneficial effect of the present invention:
1. the present invention adopts and to have optically active resolving agent L-dibenzoyl tartaric acid and directly the DL-fenclonine is split, and is easy and simple to handle;
2. raw material sources of the present invention are extensive, cheap;
3. the constant product quality of the present invention's acquisition is suitable for suitability for industrialized production.
Embodiment
Through embodiment the present invention is described further below, but embodiment does not limit protection scope of the present invention.
Embodiment 1
The hydrochloric acid that in the reactor drum that has heating, stirring, TM, dropper, adds 320ml water and 21 ml 5mol/L respectively; Stir to form aqueous solution of hydrochloric acid, add DL-fenclonine 40g (0.2mol), stir down heat temperature raising to 85 ± 5 ℃ the DL-fenclonine is dissolved fully; 0.5 splash into L-dibenzoyl tartaric acid 3 8g (0.11mol) and 80ml alcoholic acid solution in hour; Slowly cooling is incubated 60 ℃, reacts 6 hours postcooling to room temperature.Reacting liquid filtering obtains L-dibenzoyl tartaric acid D-fenclonine white crystal 54.1 g (0.097mol) and contains the mother liquor of L-fenclonine hydrochloride, carries out following processing respectively:
(1) above-mentioned white crystal adds 20-25 ℃ of stirring of 1 20ml 5mol/L hydrochloric acid 1 hour, and the solid that filtration obtains is through washing, and drying obtains L-dibenzoyl tartaric acid 34.2g (reclaim, circulation re-uses), and the recovery is 90%; Filtered liq carries out concentrating under reduced pressure to 100ml; Using 25% ammoniacal liquor to regulate PH at 0-5 ℃ is that 7 backs add 100ml ethanol; Placement is spent the night, and obtains D-fenclonine white crystal 15.6g, yield 78%;
(c 1,1mol/L HCl).
(2) mother liquor of the above-mentioned L-of containing fenclonine hydrochloride carries out underpressure distillation; Mother liquor is concentrated to 200ml; At 0-5 ℃; Using 25% ammoniacal liquor to regulate PH is that 7 backs add 200ml ethanol, separates out L-fenclonine white crystal 16.2g, yield 81%;
(c 1,1mol/L HCl).
Embodiment 2
The hydrochloric acid that in the reactor drum that has heating, stirring, TM, dropper, adds 320ml water and 21ml 5mol/L respectively; Stir and form aqueous solution of hydrochloric acid; Add DL-fenclonine 40g (0.2mol), add the hydrochloric acid soln of 320ml water, stir down heat temperature raising to 85 ± 5 ℃ the DL-fenclonine is dissolved fully; 1.0 add L-dibenzoyl tartaric acid 71.6g (0.2mol) and 160ml alcoholic acid solution in hour; Slowly cooling is incubated 65 ± 5 ℃, reacts 4 hours postcooling to room temperature.The mother liquor that reacting liquid filtering obtains L-dibenzoyl tartaric acid D-fenclonine white crystal 89.3g (0.16mol) and contains L-fenclonine hydrochloride carries out following processing respectively:
(1) above-mentioned white crystal is with adding 200ml 3mol/L hydrochloric acid, and 20-25 ℃ was stirred 1 hour, and the solid that filtration obtains is through washing, and drying obtains L-dibenzoyl tartaric acid 61.6g (reclaim, circulation re-uses), and the recovery is 86%; Filtered liq carries out concentrating under reduced pressure to 100ml; Using 25% ammoniacal liquor to regulate PH at 0-5 ℃ is that 7 backs add 100ml ethanol; Placement is spent the night, and obtains D-fenclonine white crystal 16.8g, yield 84%;
(c1,1mol/L HCl).
(2) mother liquor of the above-mentioned L-of containing fenclonine hydrochloride carries out underpressure distillation; Mother liquor is concentrated to 200ml; Using 25% ammoniacal liquor to regulate PH at 0-5 ℃ is that 7 backs add 200ml ethanol; Separate out L-fenclonine white crystal 15.6g; Yield 78%,
(c1,1mol/L HCl).
Claims (6)
1. the method for splitting of a DL-fenclonine is characterized in that comprising the steps:
(1) the DL-fenclonine is added in the aqueous solution of hydrochloric acid, 80-90 ℃, splash into the ethanolic soln of resolving agent L-dibenzoyl tartaric acid in 0.5-1.0 hour, 60-70 ℃ of reaction 4-6 hour, reaction solution is cooled to room temperature;
(2) with last reacting liquid filtering in the step (1), the L-dibenzoyl tartaric acid D-fenclonine crystal that obtains adds in the 3mol/L-5mol/L hydrochloric acid, 20-25 ℃ of decomposition; Separate out resolving agent; Remove by filter resolving agent, filtrating concentrates, under 0-5 ℃ condition; Alkaline solution is regulated the pH value, in alcohol solvent, separates out D-fenclonine white crystal;
(3) last reacting liquid filtering in the step (1) obtains containing the mother liquor of L-fenclonine hydrochloride, and mother liquor concentrates, and under 0-5 ℃ the condition, alkaline solution is regulated the pH value, in alcohol solvent, separates out L-fenclonine white crystal.
2. the method for splitting of DL-fenclonine according to claim 1 is characterized in that, described alkaline solution is the ammonia soln of quality percentage composition 10%-25%.
3. according to the method for splitting of each described DL-fenclonine of claim 1-2, it is characterized in that the pH value that alkaline solution is regulated is 7.
4. the method for splitting of DL-fenclonine according to claim 1 is characterized in that, the mole proportioning of reactant is the DL-fenclonine: hydrochloric acid soln: resolving agent L-dibenzoyl tartaric acid=1.0: 0.5-1.0: 0.5-1.0.
5. the method for splitting of DL-fenclonine according to claim 1 is characterized in that, resolving agent L-dibenzoyl tartaric acid and consumption of ethanol mass volume ratio are resolving agent L-dibenzoyl tartaric acid in the step (1): ethanol=1.0: 2.0-2.2.
6. the method for splitting of DL-fenclonine according to claim 1 is characterized in that, the mole proportioning of L-dibenzoyl tartaric acid D-fenclonine and hydrochloric acid is 1 in the step (2): 3.5-6.5.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100369995A CN101012181B (en) | 2007-01-31 | 2007-01-31 | Resolution method of DL-p-chlorophenylalanine |
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| CN2007100369995A CN101012181B (en) | 2007-01-31 | 2007-01-31 | Resolution method of DL-p-chlorophenylalanine |
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| CN101012181B true CN101012181B (en) | 2012-08-08 |
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| KR20170119447A (en) * | 2016-04-19 | 2017-10-27 | 주식회사 아미노로직스 | Method for the preparation of D-4,4'-Biphenylalanine or L-4,4'-Biphenylalanine from DL-4,4'-Biphenylalanine |
| CN110467539B (en) * | 2019-08-30 | 2023-01-06 | 浙江普洛家园药业有限公司 | Resolution method of 2,6-dimethyl tyrosine ester and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1566080A (en) * | 2003-07-08 | 2005-01-19 | 丁大为 | Resolution of DL-phenylalanine |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1566080A (en) * | 2003-07-08 | 2005-01-19 | 丁大为 | Resolution of DL-phenylalanine |
Non-Patent Citations (1)
| Title |
|---|
| Cynthia A. Maryanoff.A crystallization-induced asymmetric transformation to prepare (R)-4-chlorophenylalanine methyl ester.《Tetrahedron: Asymmetry》.1998,第9卷第3247–3250页. * |
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Inventor after: Jie Yuanping Inventor after: Liao Benren Inventor after: Yuan Zhenwen Inventor after: Li Hui Inventor after: Pan Guojun Inventor before: Jie Yuanping Inventor before: Liao Benren Inventor before: Yuan Zhenwen |
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Effective date of registration: 20161214 Address after: 201512 Shanghai City, Jinshan District Jinshanwei Zhen Hua Road No. 200 Building 1 Patentee after: SHANGHAI SHISI CHEMICAL PRODUCT CO., LTD. Address before: 200333 Putuo District True North Road, No. 401, Shanghai Patentee before: Shanghai Chemical Reagent Research Institute Co., Ltd. |