CN105175386A - S-3,4-(methylenedioxy)mandelic acid preparation method - Google Patents
S-3,4-(methylenedioxy)mandelic acid preparation method Download PDFInfo
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- CN105175386A CN105175386A CN201510554269.9A CN201510554269A CN105175386A CN 105175386 A CN105175386 A CN 105175386A CN 201510554269 A CN201510554269 A CN 201510554269A CN 105175386 A CN105175386 A CN 105175386A
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- mandelic acid
- methylene
- dioxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a S-3,4-(methylenedioxy)mandelic acid spliting preparation method. According to the method, in an solvent alcohol, 3,4-(methylenedioxy)mandelic acid is adopted as a raw material, S-1-naphthyl ethylamine is adopted as a splitting agent, a reaction is performed for a certain time under a reflux condition, the system is subjected to cooling, crystallization and separation to obtain a S-1-naphthyl ethylamine salt of the S-3,4-(methylenedioxy)mandelic acid, the salt is re-crystallized, acidification is performed to obtain the S-3,4-(methylenedioxy)mandelic acid, the solution containing the splitting agent is subjected to merging and alkalization, and extraction with an organic solvent, concentration and other operations are performed to recover the splitting agent S-1-naphthyl ethylamine. According to the present invention, the preparation method has characteristics of mild condition, simple operation, good product yield, high product optical purity, splitting agent recycling and the like, and is suitable for the preparation and the production of the S-3,4-(methylenedioxy)mandelic acid.
Description
Technical field
The present invention relates to a kind of fractionation preparation method of optical homochiral compound, particularly relate to a kind of S-3,4-(methylene-dioxy) mandelic acid and split preparation method.
Background technology
3,4-(methylene-dioxy) 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, optical resolution.But at present in research, the fractionation report about 3,4-(methylene-dioxy) mandelic acid is then comparatively rare, so how to prepare S-3,4-(methylene-dioxy) mandelic acid becomes 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-3,4-(methylene-dioxy) 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 3 in molar ratio, 4-(methylene-dioxy) mandelic acid and resolving agent S-1-naphthalene ethylamine, after reacting certain hour under reflux conditions, cooling, crystallization, be separated to obtain S-3, the S-1-naphthalene ethylamine salt of 4-(methylene-dioxy) mandelic acid, salt again in the solvent of methyl alcohol or ethanol recrystallization once the S-1-naphthalene ethylamine salt sterling of S-3,4-(methylene-dioxy) 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, regulate pH value to 1 ~ 5, solution with dichloromethane after acidifying or ethyl acetate extract, then drying, concentrated after S-3,4-(methylene-dioxy) mandelic acid; (3) by 3,4-(methylene-dioxy) mandelic acid splits mother liquor and the heating of salt recrystallization mother liquor is 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 S-1-naphthalene ethylamine.According to described, the present invention's raw material used is racemization 3,4-(methylene-dioxy) mandelic acid, and resolving agent is S-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 S-1-naphthalene ethylamine, removal process use, the alkali used that alkalizes is NaOH solution or ammonia soln.
The present invention successfully achieves fractionation 3, S-3 prepared by 4-(methylene-dioxy) mandelic acid, 4-(methylene-dioxy) mandelic acid, and the gentleness that satisfies the requirements, simple to operate, products obtained therefrom yield is good, optical purity is high, and resolving agent can the feature such as recycle and reuse, pole of the present invention is suitable for preparation, produces S-3,4-(methylene-dioxy) mandelic acid.
Specific implementation method:
Embodiment 1
The fractionation of (1) 3,4-(methylene-dioxy) mandelic acid
In 50L reactor, add 40L methyl alcohol as solvent, 1.96KG racemization 3,4-(methylene-dioxy) mandelic acid, open stirring, heat up.Under reflux conditions, in system, drip S-1-naphthalene ethylamine 1.80KG.Dropwise, after reflux conditions reacts 1.0 hours, be down to 0 DEG C, white solid will be separated out and filter, and obtain crude product S-3, the S-1-naphthalene ethylamine salt 1.37KG of 4-(methylene-dioxy) mandelic acid.By gained 1.40KGS-3, the S-1-naphthalene ethylamine salt of 4-(methylene-dioxy) mandelic acid joins in the methanol solution with 12L, intensification is dissolved, after dissolving completely Deng solid, lower the temperature, after being down to 0 DEG C, crystalline solid is filtered, the S-1-naphthalene ethylamine salt 1.26KG of the S-3 after must refining, 4-(methylene-dioxy) mandelic acid.
(2) acidolysis salt obtains S-3,4-(methylene-dioxy) mandelic acid
By upper step gained S-3, the S-1-naphthalene ethylamine salt 1.26KG of 4-(methylene-dioxy) 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 0.5L washed with dichloromethane twice again, drying is carried out by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrate to obtain S-3, 4-(methylene-dioxy) mandelic acid 0.69KG, relative to S-3 added in system, 4-(methylene-dioxy) mandelic acid yield is 70.4%, and detect gained S-3, the ee value of 4-(methylene-dioxy) mandelic acid is 99.4%.
(3) S-1-naphthalene ethylamine is reclaimed
The mother liquor that will split 3,4-(methylene-dioxy) mandelic acid concentrates, and steams except methyl alcohol.After cooling, the water layer that the mother liquor after concentrated and acidolysis obtain S-3,4-(methylene-dioxy) 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 1.65KG, the rate of recovery is 91.7%.
Embodiment 2
The fractionation of (1) 3,4-(methylene-dioxy) mandelic acid
In 50L reactor, add 30L ethanol as solvent, 1.96KG racemization 3,4-(methylene-dioxy) mandelic acid, open stirring, heat up.Under reflux conditions, in system, drip S-1-naphthalene ethylamine 2.00KG.Dropwise, after reflux conditions reacts 1.5 hours, be down to 0 DEG C, white solid will be separated out and filter, and obtain crude product S-3, the S-1-naphthalene ethylamine salt 1.52KG of 4-(methylene-dioxy) mandelic acid.By gained 1.52KGS-3, the S-1-naphthalene ethylamine salt of 4-(methylene-dioxy) mandelic acid joins in the ethanolic soln with 13L, intensification is dissolved, after dissolving completely Deng solid, lower the temperature, after being down to 0 DEG C, crystalline solid is filtered, the S-1-naphthalene ethylamine salt 1.40KG of the S-3 after must refining, 4-(methylene-dioxy) mandelic acid.
(2) acidolysis salt obtains S-3,4-(methylene-dioxy) mandelic acid
By upper step gained S-3, the S-1-naphthalene ethylamine salt 1.40KG of 4-(methylene-dioxy) 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 0.5L washed with dichloromethane twice again, drying is carried out by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrate to obtain S-3, 4-(methylene-dioxy) mandelic acid 0.72KG, relative to S-3 added in system, 4-(methylene-dioxy) mandelic acid yield is 73.5%, and detect gained S-3, the ee value of 4-(methylene-dioxy) mandelic acid is 99.2%.
(3) S-1-naphthalene ethylamine is reclaimed
The mother liquor that will split 3,4-(methylene-dioxy) mandelic acid concentrates, and steams except ethanol.After cooling, the water layer that the mother liquor after concentrated and acidolysis obtain S-3,4-(methylene-dioxy) mandelic acid is concentrated in together, use ammoniacal liquor adjustment pH value to 13.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 1.81KG, the rate of recovery is 90.5%.
Claims (6)
1. a S-3, the fractionation preparation method of 4-(methylene-dioxy) mandelic acid, it is characterized in that it realizes through following steps: (1) is in alcoholic solvent, raw material 3 is added by certain mol proportion, 4-(methylene-dioxy) mandelic acid and resolving agent S-1-naphthalene ethylamine, after back flow reaction certain hour, cooling, crystallization, suction filtration obtain S-3, the S-1-naphthalene ethylamine salt of 4-(methylene-dioxy) mandelic acid, salt again in alcoholic solvent recrystallization once the S-1-naphthalene ethylamine salt sterling of S-3,4-(methylene-dioxy) mandelic acid; (2) gained salt in step 1, is dissolved in a certain amount of water, adds acid and carries out acidifying, regulates pH value to 1 ~ 5, the solution organic solvent extraction after acidifying, then drying, concentrated after S-3,4-(methylene-dioxy) mandelic acid; (3) by 3,4-(methylene-dioxy) mandelic acid splits mother liquor and the heating of salt recrystallization mother liquor is steamed except after alcohol, merges with remaining aqueous layer after acidifying, regulates pH value to 11 ~ 13 with alkali, after alkalization, solution organic solvent extracts, then carries out drying, concentrated recyclable S-1-naphthalene ethylamine.
2. split preparation S-3 according to claim 1, the method of 4-(methylene-dioxy) mandelic acid, it is characterized in that: the present invention is raw materials used is racemization 3,4-(methylene-dioxy) mandelic acid, resolving agent is S-1-naphthalene ethylamine, and the molar ratio of raw material and resolving agent is 1:1.0 ~ 2.0.
3. split the method for preparation S-3,4-(methylene-dioxy) mandelic acid according to claim 1, it is characterized in that: to split and recrystallization solvent used is methyl alcohol or ethanol, the mass ratio that feeds intake of raw material and solvent is 10 ~ 30.
4. split the method for preparation S-3,4-(methylene-dioxy) mandelic acid according to claim 1, it is characterized in that: acidified process acid used is hydrochloric acid or sulfuric acid.
5. split the method for preparation S-3,4-(methylene-dioxy) mandelic acid according to claim 1, it is characterized in that: extracting organic solvent used in step 2 and step 3 is methylene dichloride or ethyl acetate.
6. split the method for preparation S-3,4-(methylene-dioxy) mandelic acid according to claim 1, it is characterized in that: S-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 |
|---|---|---|---|---|
| JPS5318529A (en) * | 1976-08-04 | 1978-02-20 | Nippon Kayaku Co Ltd | Optically active mandelic acid phenylglycinol salt and its preparation |
| US4198524A (en) * | 1977-03-24 | 1980-04-15 | Nippon Kayaku Kabushiki Kaisha | Optically active amino acid-mandelic acid complexes |
| JPS55147236A (en) * | 1979-05-08 | 1980-11-17 | Hiroyuki Nohira | Optical resolution of ( )-mandelic acid |
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2015
- 2015-09-02 CN CN201510554269.9A patent/CN105175386A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5318529A (en) * | 1976-08-04 | 1978-02-20 | Nippon Kayaku Co Ltd | Optically active mandelic acid phenylglycinol salt and its preparation |
| US4198524A (en) * | 1977-03-24 | 1980-04-15 | Nippon Kayaku Kabushiki Kaisha | Optically active amino acid-mandelic acid complexes |
| JPS55147236A (en) * | 1979-05-08 | 1980-11-17 | Hiroyuki Nohira | Optical resolution of ( )-mandelic acid |
Non-Patent Citations (1)
| Title |
|---|
| KINBARA, K.；等: "Effect of a Substituent on an Aromatic Group in Diastereomeric Resolution", 《TETRAHEDRON》 * |
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