CN105153108A - Method of preparing R-3, 4-(methylenedioxy) mandelic acid by resolving - Google Patents
Method of preparing R-3, 4-(methylenedioxy) mandelic acid by resolving Download PDFInfo
- Publication number
- CN105153108A CN105153108A CN201510544714.3A CN201510544714A CN105153108A CN 105153108 A CN105153108 A CN 105153108A CN 201510544714 A CN201510544714 A CN 201510544714A CN 105153108 A CN105153108 A CN 105153108A
- Authority
- CN
- China
- Prior art keywords
- mandelic acid
- methylene
- dioxy
- salt
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method of preparing R-3, 4-(methylenedioxy) mandelic acid by resolving, having a structural formula shown below. Raw material 3, 4-(methylenedioxy) mandelic acid and a resolving agent R-1-naphthaleneethylamine are added in solvent alcohol; reacting is enabled for a certain time under reflux condition, and a system is cooled, crystallized and separated to obtain R-1-naphthaleneethylamine salt of R-3, 4-(methylenedioxy) mandelic acid; the salt is recrystallized and acidified to obtain the R-3, 4-(methylenedioxy) mandelic acid; after the solvent alcohol is removed from reaction and recrystallization mother liquor by steaming, the liquor is mixed with a layer of acidification residual water, and operations such as alkalization, organic solvent extracting, drying and concentrating are carried out to recycle the resolving agent R-1-naphthaleneethylamine. The method has the advantages that conditions are mild, operating is simple, the yield of obtained products is good, optical purity is high and the resolving agent is recyclable; the method is very suitable for the preparation and production of the R-3, 4-(methylenedioxy) mandelic 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-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 R-3,4-(methylene-dioxy) mandelic acid becomes problem to be solved by this invention.
Summary of the invention
The present invention adopts R-1-naphthalene ethylamine to be resolving agent, can successfully realize splitting preparation R-3,4-(methylene-dioxy) mandelic acid.Invention operation is as follows: (1) is in suitable alcoholic solvent, raw material 3 is added by certain mol proportion, 4-(methylene-dioxy) mandelic acid and resolving agent R-1-naphthalene ethylamine, after reacting certain hour under reflux conditions, cooling, crystallization, be separated to obtain R-3, the R-1-naphthalene ethylamine salt of 4-(methylene-dioxy) mandelic acid, salt again in the solvent of alcohol recrystallization once the R-1-naphthalene ethylamine salt sterling of R-3,4-(methylene-dioxy) mandelic acid; (2) gained salt in step 1, is dissolved in a certain amount of water, adds a certain amount of acid solution and carries out acidifying, regulate pH value to 1 ~ 5, solution organic solution after acidifying extracts, then drying, concentrated after R-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 organic solution extracts, then carries out drying, concentrated recyclable R-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 R-1-naphthalene ethylamine, and the molar ratio of raw material and resolving agent is 1:1.0 ~ 2.0.Split and recrystallization process in solvent used be methyl alcohol or ethanol, the mass ratio that feeds intake of raw material and solvent is 10 ~ 30; Carrying out acidification acid used to salt is hydrochloric acid or sulfuric acid: 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 3, R-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 R-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 R-1-naphthalene ethylamine 1.80KG.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 R-3, the R-1-naphthalene ethylamine salt 1.40KG of 4-(methylene-dioxy) mandelic acid.By gained 1.40KGR-3, the R-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 R-1-naphthalene ethylamine salt 1.31KG of the R-3 after must refining, 4-(methylene-dioxy) mandelic acid.
(2) acidolysis salt obtains R-3,4-(methylene-dioxy) mandelic acid
By upper step gained R-3, the R-1-naphthalene ethylamine salt 1.30KG 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 R-3, 4-(methylene-dioxy) mandelic acid 0.73KG, relative to R-3 added in system, 4-(methylene-dioxy) mandelic acid yield is 74.5%, and detect gained R-3, the ee value of 4-(methylene-dioxy) mandelic acid is 99.3%.
(3) R-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 R-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 R-1-naphthalene ethylamine 1.70KG, the rate of recovery is 94.4%.
Claims (6)
1. fractionation preparation R-3 disclosed by the invention, the method of 4-(methylene-dioxy) mandelic acid, it is characterized in that the present invention realizes through following steps: (1) is in suitable alcoholic solvent, raw material 3 is added by certain mol proportion, 4-(methylene-dioxy) mandelic acid and resolving agent R-1-naphthalene ethylamine, after reacting certain hour under reflux conditions, cooling, crystallization, be separated to obtain R-3, the R-1-naphthalene ethylamine salt of 4-(methylene-dioxy) mandelic acid, salt again in the solvent of alcohol recrystallization once R-3, the R-1-naphthalene ethylamine salt sterling of 4-(methylene-dioxy) mandelic acid, (2) gained salt in step 1, is dissolved in a certain amount of water, adds a certain amount of acid solution and carries out acidifying, regulate pH value to 1 ~ 5, solution organic solution after acidifying extracts, then drying, concentrated after R-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 organic solution extracts, then carries out drying, concentrated recyclable R-1-naphthalene ethylamine.
2. split preparation R-3 according to claim 1, the method of 4-(methylene-dioxy) mandelic acid, it is characterized in that: raw material used is racemization 3,4-(methylene-dioxy) mandelic acid, 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 preparation R-3 according to claim 1, the method of 4-(methylene-dioxy) mandelic acid, it is characterized in that: split R-3,4-(methylene-dioxy) mandelic acid and the solvent used to product salt recrystallization are methyl alcohol or ethanol, and the mass ratio that feeds intake of raw material and solvent is 10 ~ 30.
4. split the method for preparation R-3,4-(methylene-dioxy) mandelic acid according to claim 1, it is characterized in that: carrying out acidification acid used to salt is hydrochloric acid or sulfuric acid.
5. split the method for preparation R-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 R-3,4-(methylene-dioxy) 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510544714.3A CN105153108A (en) | 2015-08-31 | 2015-08-31 | Method of preparing R-3, 4-(methylenedioxy) mandelic acid by resolving |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510544714.3A CN105153108A (en) | 2015-08-31 | 2015-08-31 | Method of preparing R-3, 4-(methylenedioxy) mandelic acid by resolving |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105153108A true CN105153108A (en) | 2015-12-16 |
Family
ID=54794202
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510544714.3A Pending CN105153108A (en) | 2015-08-31 | 2015-08-31 | Method of preparing R-3, 4-(methylenedioxy) mandelic acid by resolving |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105153108A (en) |
Citations (5)
| 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 |
| CN1171393A (en) * | 1997-06-09 | 1998-01-28 | 吉林大学 | Resolution of (minus and plus) -1-arylethanamine |
| CN102336653A (en) * | 2011-11-08 | 2012-02-01 | 广州辉宏生物医药科技有限公司 | Preparation method of optically pure chiral 2-chloromandelic acid |
-
2015
- 2015-08-31 CN CN201510544714.3A patent/CN105153108A/en active Pending
Patent Citations (5)
| 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 |
| CN1171393A (en) * | 1997-06-09 | 1998-01-28 | 吉林大学 | Resolution of (minus and plus) -1-arylethanamine |
| CN102336653A (en) * | 2011-11-08 | 2012-02-01 | 广州辉宏生物医药科技有限公司 | Preparation method of optically pure chiral 2-chloromandelic acid |
Non-Patent Citations (2)
| Title |
|---|
| 张君仁，藏恒昌: "《体内药物分析》", 30 September 2002 * |
| 王乃兴: "《有机反应-多氮化物的反应及若干理论问题》", 30 June 2004 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101429180B (en) | Process for producing S-tetrahydrochysene furoic acid | |
| CN112047883B (en) | Preparation method of atracurium cis-besylate | |
| CN102020584A (en) | Method for synthesizing intermediate L-2-aminobutyrylamide hydrochloride of chiral drug levetiracetam | |
| CN105130794A (en) | Method for preparing S-4-methoxymandelic acid through splitting S-1-phenylethylamine | |
| CN102311394B (en) | Preparation method for 5-ethyl-5-phenyl barbituric acid | |
| EP3015455B1 (en) | 4-benzyl-1-phenethyl-piperazine-2,6-dione preparation method, and intermediate and preparation method thereof | |
| CN101456833B (en) | Method for purifying pleuromulins compound hydrochloride | |
| CN105153108A (en) | Method of preparing R-3, 4-(methylenedioxy) mandelic acid by resolving | |
| CN108164423B (en) | Preparation method of naftifine hydrochloride | |
| CN112645813B (en) | Preparation method of (R) -3-cyclohexene carboxylic acid | |
| CN105175386A (en) | S-3,4-(methylenedioxy)mandelic acid preparation method | |
| CN105153109A (en) | Method for split preparation of S-3,4-(methylenedioxy) mandelic acid | |
| CN109665970A (en) | A kind of preparation method of D-Val | |
| CN105085243A (en) | Preparing method of (S)-(-)-4-bromine mandelic acid | |
| CN105061190A (en) | Method for preparing S-five-fluorine amygdalic acid through resolution | |
| CN105085247A (en) | Resolution preparation method of R-4-methoxymandelic acid | |
| CN105085248A (en) | Resolution preparation method of S-4-methoxymandelic acid | |
| CN105085236A (en) | Resolution preparation method of R-pentafluoro DL-mandelic acid | |
| CN105085234A (en) | Preparing method of (R)-(-)-4-chloromandelic acid | |
| CN105085244A (en) | Preparing method of (R)-(+)-4-bromomandelic acid | |
| CN105175248A (en) | S-o-chloromandelic acid preparation method | |
| CN114044783B (en) | Preparation method of idosiban and intermediate thereof | |
| CN103333103A (en) | Method for preparing flupirtine maleate by one-pot method | |
| CN116063163B (en) | Preparation method of 7- (benzyloxy) -2,4,5, 6-tetrahydro-1H-cyclobutadiene [ f ] indene-1-one | |
| NO134767B (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20151216 |