CN105085247A - Resolution preparation method of R-4-methoxymandelic acid - Google Patents
Resolution preparation method of R-4-methoxymandelic acid Download PDFInfo
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- CN105085247A CN105085247A CN201510554141.2A CN201510554141A CN105085247A CN 105085247 A CN105085247 A CN 105085247A CN 201510554141 A CN201510554141 A CN 201510554141A CN 105085247 A CN105085247 A CN 105085247A
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- mandelic acid
- methoxv mandelic
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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
- C07B57/00—Separation of optically-active compounds
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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
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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 resolution preparation method of R-4-methoxymandelic acid. The method comprises steps as follows: 4-methoxymandelic acid after racemization reacts with a resolving agent (R)-(+)-1-(1-naphthyl)ethylamine, and on the basis of difference of solubility of generated salt with two configurations including R and S in an alcohol solvent after the reaction, (R)-(+)-1-(1-naphthyl)ethylamine salt of R-4-methoxymandelic acid is obtained through crystallization and separation; R-4-methoxymandelic acid is obtained after the salt is recrystallized, acidized, extracted with an organic solvent and concentrated; a reacted mother solution after alcohol removal through evaporation is mixed with another solution containing (R)-(+)-1-(1-naphthyl)ethylamine, and (R)-(+)-1-(1-naphthyl)ethylamine can be recycled after the mixed solution is alkalinized, extracted with an organic solvent and concentrated. The resolution preparation method of R-4-methoxymandelic acid has the advantages that conditions are mild, the operation is simple, the product yield and the optical purity are high, the resolving agent can be recycled and the like, and the method is very suitable for preparing and producing R-4-methoxymandelic acid.
Description
Technical field
The present invention relates to a kind of fractionation preparation method of chirality ɑ hydroxycarboxylic acid, particularly relate to a kind of R-4-methoxv mandelic acid and split preparation method.
Background technology
4-methoxv mandelic acid, as a kind of chirality ɑ hydroxycarboxylic acid, has R type and S type two kinds of enantiomorph configurations, has important application in multiple fields such as medicine production, asymmetric synthesis.In current report, preparation R-4-methoxv mandelic acid method can be divided into asymmetric hydrolysis method and dissymmetric synthesis.Asymmetric is hydrolysis, for raw material with D-4-methoxv mandelic acid methyl esters, R-4-methoxv mandelic acid (CanadianJournalofChemistry is obtained by the method for enzymatic asymmetric hydrolysis, vol.68, 314-316), and asymmetric synthesis rule is aubepine is raw material, asymmetry catalysis synthesis R-4-methoxv mandelic acid (JournaloftheChemicalSociety.PerkinTransactions2, 1996, 12.2615-2622), chemical resolution method, then use (2S, 3S)-2, 3-benzyloxy-1, 4-bis-(oxyamine) butane is that resolving agent fractionation 4-methoxv mandelic acid obtains R-4-methoxv mandelic acid (TetrahedronAsymmetry, vol.19, 21.2536-2541).All there is the not high shortcoming of products obtained therefrom optical purity in the several method reported, resolving agent simultaneously used in biological catalyst used and chemical resolution method in asymmetric hydrolysis also also exist comparatively expensive, be difficult to the problem that obtains.So the R-4-methoxv mandelic acid how simply preparing high-optical-purity becomes problem to be solved by this invention.
Summary of the invention
The present invention adopts R-1-naphthalene ethylamine comparatively cheap and easy to get to be resolving agent, can successfully realize splitting preparation R-4-methoxv mandelic acid.Invention operation is as follows: (1) is in the solvent of methyl alcohol or ethanol, the ratio of 1:1.0 ~ 2.0 adds raw material 4-methoxv mandelic acid and resolving agent R-1-naphthalene ethylamine in molar ratio, after reacting certain hour under reflux conditions, cooling, crystallization, be separated to obtain the R-1-naphthalene ethylamine salt of R-4-methoxv mandelic acid, salt again in the solvent of methyl alcohol or ethanol recrystallization once the R-1-naphthalene ethylamine salt sterling of R-4-methoxv mandelic acid; (2) gained salt in step 1, is dissolved in a certain amount of water, adds hydrochloric acid or sulfuric acid carries out acidifying, and regulate pH value to 1 ~ 5, the solution with dichloromethane after acidifying or ethyl acetate extract, then drying, concentrated after R-4-methoxv mandelic acid; (3) 4-methoxv mandelic acid fractionation mother liquor and the heating of salt recrystallization mother liquor are steamed except after alcohol, merge with remaining aqueous layer after acidifying, pH value to 11 ~ 13 are regulated with NaOH solution or ammoniacal liquor, after alkalization, solution with dichloromethane or ethyl acetate extract, then carry out drying, concentrated recyclable R-1-naphthalene ethylamine.According to described, the present invention's raw material used is racemization 4-methoxv mandelic acid, and resolving agent is R-1-naphthalene ethylamine, and the molar ratio of raw material and resolving agent is 1:1.0 ~ 2.0.Solvent used in split process is methyl alcohol or ethanol, and the mass ratio that feeds intake of raw material and solvent is 10 ~ 30.Be methylene dichloride or ethyl acetate according to extracting organic solvent used in described step 2 and step 3.Can reclaim by step 3 operation according to described R-1-naphthalene ethylamine, removal process use, the alkali used that alkalizes is NaOH solution or ammonia soln.
The present invention successfully achieves fractionation 4-methoxv mandelic acid and prepares R-4-methoxv mandelic acid, and the gentleness that satisfies the requirements, simple to operate, products obtained therefrom yield is good, optical purity is high, resolving agent can the feature such as recycle and reuse, and pole of the present invention is suitable for preparation, produces R-4-methoxv mandelic acid.
Specific implementation method:
Embodiment 1
(1) fractionation of 4-methoxv mandelic acid
In 1000ML round-bottomed flask, add 400ML methyl alcohol as solvent, 18.2G racemization 4-methoxv mandelic acid, open stirring, heat up.Under reflux conditions, in system, drip R-1-naphthalene ethylamine 18.0G.Dropwise, after reflux conditions reacts 1.5 hours, be down to 0 DEG C, white solid will be separated out and filter, and obtain the R-1-naphthalene ethylamine salt 14.9G of crude product R-4-methoxv mandelic acid.The R-1-naphthalene ethylamine salt of gained 14.9GR-4-methoxv mandelic acid is joined in the methanol solution with 150ML, intensification is dissolved, after dissolving completely Deng solid, lower the temperature, after being down to 0 DEG C, crystalline solid is filtered, the R-1-naphthalene ethylamine salt 13.4G of the R-4-methoxv mandelic acid after must refining.
(2) acidolysis salt obtains R-4-methoxv mandelic acid
The R-1-naphthalene ethylamine salt 13.4G of upper step gained R-4-methoxv mandelic acid is dissolved in 400ML water, drip hydrochloric acid and reconcile pH value to 4,150ML methylene dichloride is added in system, extract, after separatory, upper aqueous layer uses 50ML washed with dichloromethane twice again, carry out drying by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrate to obtain R-4-methoxv mandelic acid 7.0G, be 76.9% relative to R-4-methoxv mandelic acid yield added in system, and the ee value detecting gained R-4-methoxv mandelic acid is 99.4%.
(3) R-1-naphthalene ethylamine is reclaimed
The mother liquor splitting 4-methoxv mandelic acid is concentrated, steams except methyl alcohol.After cooling, the water layer that the mother liquor after concentrated and acidolysis obtain R-4-methoxv mandelic acid is concentrated in together, use 40%NaOH solution adjustment pH value to 12.After regulating pH value, in system, add 200L methylene dichloride, extract, after separatory, upper aqueous layer uses 100L washed with dichloromethane twice again, and carry out drying by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrate to obtain R-1-naphthalene ethylamine 17.1G, the rate of recovery is 95.0%.
Embodiment 2
(1) fractionation of 4-methoxv mandelic acid
In 1000ML round-bottomed flask, add 300ML ethanol as solvent, 18.2G racemization 4-methoxv mandelic acid, open stirring, heat up.Under reflux conditions, in system, drip R-1-naphthalene ethylamine 20.0G.Dropwise, after reflux conditions reacts 1.5 hours, be down to 0 DEG C, white solid will be separated out and filter, and obtain the R-1-naphthalene ethylamine salt 15.6G of crude product R-4-methoxv mandelic acid.The R-1-naphthalene ethylamine salt of gained 15.6GR-4-methoxv mandelic acid is joined in the ethanolic soln with 150ML, intensification is dissolved, after dissolving completely Deng solid, lower the temperature, after being down to 0 DEG C, crystalline solid is filtered, the R-1-naphthalene ethylamine salt 14.4G of the R-4-methoxv mandelic acid after must refining.
(2) acidolysis salt obtains R-4-methoxv mandelic acid
The R-1-naphthalene ethylamine salt 14.4G of upper step gained R-4-methoxv mandelic acid is dissolved in 500ML water, drip hydrochloric acid and reconcile pH value to 4,150ML methylene dichloride is added in system, extract, after separatory, upper aqueous layer uses 50ML washed with dichloromethane twice again, carry out drying by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrate to obtain R-4-methoxv mandelic acid 7.4G, be 81.3% relative to R-4-methoxv mandelic acid yield added in system, and the ee value detecting gained R-4-methoxv mandelic acid is 99.0%.
(3) R-1-naphthalene ethylamine is reclaimed
The mother liquor splitting 4-methoxv mandelic acid is concentrated, steams except ethanol.After cooling, the water layer that the mother liquor after concentrated and acidolysis obtain R-4-methoxv mandelic acid is concentrated in together, use ammoniacal liquor adjustment pH value to 13.After regulating pH value, in system, add 300ML methylene dichloride, extract, after separatory, upper aqueous layer uses 100ML washed with dichloromethane twice again, and carry out drying by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrate to obtain R-1-naphthalene ethylamine 18.2G, the rate of recovery is 91.0%.
Claims (5)
1. split the method preparing R-4-methoxv mandelic acid and it is characterized in that it realizes through following steps: (1) is in alcoholic solvent, raw material 4-methoxv mandelic acid and resolving agent R-1-naphthalene ethylamine is dropped into by certain mol proportion, after reacting certain hour under reflux conditions, cooling, crystallization, be separated to obtain the R-1-naphthalene ethylamine salt of R-4-methoxv mandelic acid; Salt again in the solvent of alcohol recrystallization once the R-1-naphthalene ethylamine salt of the R-4-methoxv mandelic acid after purifying; (2) gained salt in step 1, is dissolved in a certain amount of water, adds acid solution and carries out acidifying, and regulate pH value to 1 ~ 5, the solution organic solvent after acidifying extracts, then drying, concentrated etc. operates to obtain R-4-methoxv mandelic acid; (3) 4-methoxv mandelic acid is split mother liquor and the heating of salt recrystallization mother liquor is steamed except after alcohol, merges with remaining aqueous layer after acidifying, regulate pH value to 11 ~ 13 with alkali, the rear solution organic solvent of alkalization extracts, then drying, concentration and recovery obtain R-1-naphthalene ethylamine.
2. split the method preparing R-4-methoxv mandelic acid according to claim 1, it is characterized in that: the present invention is raw materials used is racemization 4-methoxv mandelic acid, and resolving agent is R-1-naphthalene ethylamine, and the molar ratio of raw material and resolving agent is 1:1.0 ~ 2.0.
3. split the method preparing R-4-methoxv mandelic acid according to claim 1, it is characterized in that: splitting the solvent used with recrystallization is methyl alcohol or ethanol, and the mass ratio that feeds intake of raw material and solvent is 10 ~ 30.
4. split according to claim 1 and prepare the method for R-4-methoxv mandelic acid, it is characterized in that: extracting organic solvent used in step 2 and step 3 is methylene dichloride or ethyl acetate.
5. split the method preparing R-4-methoxv mandelic acid according to claim 1, it is characterized in that: R-1-naphthalene ethylamine can reclaim by step 3 operation, and removal process use, the alkali used that alkalizes is NaOH solution or ammonia soln.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6342636B1 (en) * | 1997-11-06 | 2002-01-29 | Yamakawa Chemical Industry Co., Ltd. | Process for preparing optically active amines and optically active carboxylic acids, and intermediates for preparation |
| 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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- 2015-09-02 CN CN201510554141.2A patent/CN105085247A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6342636B1 (en) * | 1997-11-06 | 2002-01-29 | Yamakawa Chemical Industry Co., Ltd. | Process for preparing optically active amines and optically active carboxylic acids, and intermediates for preparation |
| 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: 20151125 |