CN105061190A - Method for preparing S-five-fluorine amygdalic acid through resolution - Google Patents
Method for preparing S-five-fluorine amygdalic acid through resolution Download PDFInfo
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- CN105061190A CN105061190A CN201510554344.1A CN201510554344A CN105061190A CN 105061190 A CN105061190 A CN 105061190A CN 201510554344 A CN201510554344 A CN 201510554344A CN 105061190 A CN105061190 A CN 105061190A
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- fluorine
- mandelic acid
- fluorine mandelic
- naphthalene ethylamine
- resolving agent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention discloses a method for preparing S-five-fluorine amygdalic acid through resolution. According to specific operation, racemization five-fluorine amygdalic acid serves as raw materials, S-1-naphthyl ethylamine serves as a resolution agent, a reaction is performed in an alcohol solvent, S-1-naphthyl ethylamine salt of the five-fluorine amygdalic acid is obtained, and S-five-fluorine amygdalic acid is obtained through hydrochlorination processing; after a solution containing the resolution agent is subjected to dealcoholization and alkalinization, the resolution agent S-1-naphthyl ethylamine can be recyclined. The method has the advantages that the condition is moderate, operation is easy, the product yield is high, and optical purity is high, the resolution agent can be recycled and cyclically utilized, and the method is particularly suitable for producing the S-five-fluorine amygdalic acid.
Description
Technical field
The present invention relates to the fractionation preparation method that a kind of optical homochiral has compound, particularly relate to and a kind ofly prepare the method for S-five fluorine mandelic acid with S-1-naphthalene ethylamine for resolving agent splits.
Background technology
Five fluorine mandelic acids, as a kind of compound of chirality, have R type and S type two kinds of enantiomorph configurations, have important application in multiple fields such as medicine production, asymmetric synthesis, optical resolution.But at present in research, the fractionation report about five fluorine mandelic acids is then comparatively rare, so how to prepare S-five fluorine mandelic acid to become problem to be solved by this invention.
Summary of the invention
The present invention adopts S-1-naphthalene ethylamine to be resolving agent, can successfully realize splitting preparation S-five fluorine mandelic acid.Invention operation is as follows:
The present invention is for raw material with five fluorine mandelic acids, S-1-naphthalene ethylamine is resolving agent, reacts in alcoholic solvent, obtains the S-1-naphthalene ethylamine salt of five fluorine mandelic acids, obtained the S-1-naphthalene ethylamine salt of S-five fluorine mandelic acid by cooling, Crystallization Separation, salt to obtain S-five fluorine mandelic acid with sour dissociating; Reaction mother liquor to add water after cooling and alkali dissociates after steaming and desolventizing alcohol, then through extraction, dry, concentrated recyclable resolving agent S-1-naphthalene ethylamine.Be S-1-naphthalene ethylamine according to resolving agent used in described the present invention, in system, added in molar amounts is 1.0 ~ 2.0 times of five fluorine mandelic acids.Concrete steps are prepared as follows: with five fluorine mandelic acids for raw material according to the fractionation of described S-five fluorine mandelic acid, S-1-naphthalene ethylamine is resolving agent, react in methyl alcohol or alcohol solvent, obtain the S-1-naphthalene ethylamine salt of five fluorine mandelic acids, the quality of the required solvent of reaction is 10-30 times of S-five fluorine mandelic acid, through cooling after reaction terminates, crystallization, be separated the S-1-naphthalene ethylamine salt obtaining S-five fluorine mandelic acid, gained salt utilizes hydrochloric acid or sulfuric acid to dissociate, again through the extraction of organic solvent dichloromethane or ethyl acetate, dry, concentrate to obtain S-five fluorine mandelic acid.It is as follows according to resolving agent S-1-naphthalene ethylamine recycling step used in described the present invention: after the methyl alcohol in reaction mother liquor or ethanol are steamed, mother liquor after concentrated adds a certain amount of sodium hydroxide or ammoniacal liquor, regulate pH value to 11 ~ 13, then through the extraction of organic solvent dichloromethane or ethyl acetate, drying, concentratedly to obtain S-1-naphthalene ethylamine.
Use the present invention, not only successfully achieve fractionation five fluorine mandelic acid and prepare S-five fluorine mandelic acid, and the finished product yield is high, optical purity is good.Resolving agent used is easy to recycling simultaneously, can reduce fractionation cost greatly.
Specific implementation method:
Embodiment 1
The fractionation of (1) five fluorine mandelic acid
In 50L reactor, add 35L methyl alcohol as solvent, 2.42KG racemization five fluorine mandelic acid, open stirring, heat up.Under reflux conditions, in system, drip S-1-naphthalene ethylamine 1.90KG.Dropwise, reflux conditions is down to room temperature after reacting 1.0 hours, will separate out white solid and filter, and obtain the S-1-naphthalene ethylamine salt 1.71KG of crude product S-five fluorine mandelic acid.The S-1-naphthalene ethylamine salt of gained 1.71KGS-five fluorine mandelic acid is joined in the methanol solution with 15L, heats up and dissolve, after waiting solid to dissolve completely, lower the temperature, after being down to room temperature, crystalline solid is filtered, the S-1-naphthalene ethylamine salt 1.50KG of the S-five fluorine mandelic acid after must refining.
(2) acidolysis salt obtains S-five fluorine mandelic acid
The S-1-naphthalene ethylamine salt 1.50KG of upper step gained S-five fluorine mandelic acid is dissolved in 5KG water, drip hydrochloric acid and reconcile pH value to 4,1.5L methylene dichloride is added in system, extract, after separatory, upper aqueous layer uses 0.7L washed with dichloromethane twice again, carry out drying by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrate to obtain S-five fluorine mandelic acid 0.87KG, be 71.9% relative to S-five fluorine mandelic acid yield added in system, and the ee value detecting gained S-five fluorine mandelic acid is 99.4%.
(3) S-1-naphthalene ethylamine is reclaimed
The mother liquor of fractionation five fluorine mandelic acid is concentrated, steams except methyl alcohol.After cooling, the water layer that the mother liquor after concentrated and acidolysis obtain S-five fluorine mandelic acid is concentrated in together, use 40%NaOH solution adjustment pH value to 12.After regulating pH value, in system, add 3.0L methylene dichloride, extract, after separatory, upper aqueous layer uses 1.0L washed with dichloromethane twice again, and carry out drying by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrate to obtain S-1-naphthalene ethylamine 1.76KG, the rate of recovery is 92.6%.
Embodiment 2
The fractionation of (1) five fluorine mandelic acid
In 50L reactor, add 40L ethanol as solvent, 2.42KG racemization five fluorine mandelic acid, open stirring, heat up.Under reflux conditions, in system, drip S-1-naphthalene ethylamine 2.00KG.Dropwise, reflux conditions is down to room temperature after reacting 1.5 hours, will separate out white solid and filter, and obtain the S-1-naphthalene ethylamine salt 1.65KG of crude product S-five fluorine mandelic acid.The S-1-naphthalene ethylamine salt of gained 1.65KGS-five fluorine mandelic acid is joined in the ethanolic soln with 15L, heats up and dissolve, after waiting solid to dissolve completely, lower the temperature, after being down to room temperature, crystalline solid is filtered, the S-1-naphthalene ethylamine salt 1.42KG of the S-five fluorine mandelic acid after must refining.
(2) acidolysis salt obtains S-five fluorine mandelic acid
The S-1-naphthalene ethylamine salt 1.42KG of upper step gained S-five fluorine mandelic acid is dissolved in 5KG water, drip hydrochloric acid and reconcile pH value to 4,1.5L methylene dichloride is added in system, extract, after separatory, upper aqueous layer uses 0.7L washed with dichloromethane twice again, carry out drying by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrate to obtain S-five fluorine mandelic acid 0.84KG, be 69.4% relative to S-five fluorine mandelic acid yield added in system, and the ee value detecting gained S-five fluorine mandelic acid is 99.6%.
(3) S-1-naphthalene ethylamine is reclaimed
The mother liquor of fractionation five fluorine mandelic acid is concentrated, steams except ethanol.After cooling, the water layer that the mother liquor after concentrated and acidolysis obtain S-five fluorine mandelic acid is concentrated in together, use ammoniacal liquor adjustment pH value to 12.After regulating pH value, in system, add 3.0L methylene dichloride, extract, after separatory, upper aqueous layer uses 1.0L washed with dichloromethane twice again, and carry out drying by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrate to obtain S-1-naphthalene ethylamine 1.88KG, the rate of recovery is 94.0%.
Claims (6)
1. the preparation method of a S-five fluorine mandelic acid is characterized in that: the present invention is for raw material with five fluorine mandelic acids, S-1-naphthalene ethylamine is resolving agent, react in alcoholic solvent, obtain the S-1-naphthalene ethylamine salt of five fluorine mandelic acids, reaction system cooling, crystallization, suction filtration obtain the S-1-naphthalene ethylamine salt of S-five fluorine mandelic acid, and alcohol recrystallization used again by salt; After recrystallization salt through acidifying, extraction, drying, concentrated to obtain S-five fluorine mandelic acid; Allly to dissociate with alkali containing after the dealcoholysis of resolving agent solution, then through extraction, dry, concentrated recyclable resolving agent S-1-naphthalene ethylamine.
2. the fractionation preparation method of a kind of S-five fluorine mandelic acid according to claim 1, it is characterized in that: resolving agent used in the present invention is S-1-naphthalene ethylamine, in system, added in molar amounts is 1.0 ~ 2.0 times of five fluorine mandelic acids.
3. the fractionation preparation method of a kind of S-five fluorine mandelic acid according to claim 1, is characterized in that: split and recrystallization so solvent alcohol is methyl alcohol or ethanol.
4. the fractionation preparation method of a kind of S-five fluorine mandelic acid according to claim 1, is characterized in that: acidified acid used is hydrochloric acid or sulfuric acid.
5. the fractionation preparation method of a kind of S-five fluorine mandelic acid according to claim 1, is characterized in that: extraction process extraction agent used that is acidified and that reclaim resolving agent alkalization is methylene dichloride or ethyl acetate.
6. the fractionation preparation method of a kind of S-five fluorine mandelic acid according to claim 1, is characterized in that: the alkali that resolving agent S-1-naphthalene ethylamine reclaims alkalinization used is sodium hydroxide solution or ammonia soln.
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| CN201510554344.1A CN105061190A (en) | 2015-09-02 | 2015-09-02 | Method for preparing S-five-fluorine amygdalic acid through resolution |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4224239A (en) * | 1977-03-24 | 1980-09-23 | Nippon Kayaku Kabushiki Kaisha | Process for preparing optically active amino acid or mandelic acid |
| JPS55147236A (en) * | 1979-05-08 | 1980-11-17 | Hiroyuki Nohira | Optical resolution of ( )-mandelic acid |
| CN1835909A (en) * | 2003-06-13 | 2006-09-20 | 艾夫西亚药品有限公司 | Process for the preparation of aromatic amines |
| CN102548965A (en) * | 2009-09-25 | 2012-07-04 | 安斯泰来制药株式会社 | Substituted amide compound |
-
2015
- 2015-09-02 CN CN201510554344.1A patent/CN105061190A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4224239A (en) * | 1977-03-24 | 1980-09-23 | Nippon Kayaku Kabushiki Kaisha | Process for preparing optically active amino acid or mandelic acid |
| JPS55147236A (en) * | 1979-05-08 | 1980-11-17 | Hiroyuki Nohira | Optical resolution of ( )-mandelic acid |
| CN1835909A (en) * | 2003-06-13 | 2006-09-20 | 艾夫西亚药品有限公司 | Process for the preparation of aromatic amines |
| CN102548965A (en) * | 2009-09-25 | 2012-07-04 | 安斯泰来制药株式会社 | Substituted amide compound |
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Application publication date: 20151118 |