CN105085234A - Preparing method of (R)-(-)-4-chloromandelic acid - Google Patents
Preparing method of (R)-(-)-4-chloromandelic acid Download PDFInfo
- Publication number
- CN105085234A CN105085234A CN201510544713.9A CN201510544713A CN105085234A CN 105085234 A CN105085234 A CN 105085234A CN 201510544713 A CN201510544713 A CN 201510544713A CN 105085234 A CN105085234 A CN 105085234A
- Authority
- CN
- China
- Prior art keywords
- mandelic acid
- chloro mandelic
- ethylamine
- naphthalene ethylamine
- 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
- 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
-
- 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
- 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
-
- 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)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparing method of (R)-(-)-4-chloromandelic acid through resolution by taking (R)-(+)-1-(1-naphthyl)ethylamine as a chiral resolution agent. 4-chloromandelic acid and the chiral resolution agent (R)-(+)-1-(1-naphthyl)ethylamine react in a suitable alcohol solvent to generate (R)-(+)-1-(1-naphthyl)ethylamine salt of the 4-chloromandelic acid, by using different solubilities of an enantiomer salt, crystallizing and suction filtration are performed to obtain the (R)-(+)-1-(1-naphthyl)ethylamine salt of the (R)-(-)-4-chloromandelic acid, and after salt recrystallization, the (R)-(-)-4-chloromandelic acid can be obtained by acidizing; after the solution containing the (R)-(+)-1-(1-naphthyl)ethylamine is combined, alkalization treatment is performed, the resolution agent (R)-(+)-1-(1-naphthyl)ethylamine can be recycled. The preparing method has the characteristics of mild conditions, simple operation, good product yield and high optical purity. The resolution agent can be recycled for use, and is extremely suitable for industrial production of (R)-(-)-4-chloromandelic acid.
Description
Technical field
The present invention relates to a kind of chemical method to split and prepare the method for chipal compounds, particularly relate to a kind of with R-1-naphthalene ethylamine for resolving agent splits the method preparing R-4-chloro mandelic acid.
Background technology
4-chloro mandelic acid, has R type and S type two kinds of enantiomorph configurations, is all widely used in multiple fields such as medicine production, asymmetric synthesis, optical resolution.Preparation method at present about R-4-chloro mandelic acid has no report.Therefore, the problem to be solved in the present invention is become about the simple and easy to get preparation realizing R-4-chloro mandelic acid.
Summary of the invention
The present invention adopts R-1-naphthalene ethylamine to be resolving agent, can successfully realize splitting preparation R-4-chloro mandelic acid.Invention operation is as follows: the present invention is in suitable alcoholic solvent, R-1-naphthalene ethylamine is the reaction of chiral selectors 4-chloro mandelic acid, generate the R-1-naphthalene ethylamine salt of 4-chloro mandelic acid, utilize different enantiomorph different solubility, crystallization, suction filtration can obtain the R-1-naphthalene ethylamine salt of R-4-chloro mandelic acid, after salt recrystallization, more acidified, extraction, the operation such as dry, concentrated can obtain R-4-chloro mandelic acid; Solution containing R-1-naphthalene ethylamine merges together, through recyclable resolving agent R-1-naphthalene ethylamines of operation such as alkalizing, extract, be dry, concentrated.
Be R-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 4-chloro mandelic acid.Suitable alcohol used in reaction is methyl alcohol or ethanol.During the R-1-naphthalene ethylamine salt of acidification R-4-chloro mandelic acid, acid used is hydrochloric acid or sulfuric acid.During alkali goods recovery R-1-naphthalene ethylamine, alkali used is sodium hydroxide solution or ammonia soln.
The present invention possesses simple to operate, technical maturity, mild condition, and split efficiency high, good product purity, resolving agent is easy to the features such as recovery.Be suitable for very much suitability for industrialized production R-4-chloro mandelic acid.
Specific implementation method:
Embodiment 1
(1) fractionation of 4-chloro mandelic acid
In 500ml round-bottomed flask, add 400ml methyl alcohol, 18.7g racemization 4-chloro mandelic acid, open stirring, heat up.In system, R-1-naphthalene ethylamine 18.0g is dripped at 50 DEG C.Dropwise, back flow reaction 1.5 hours, is down to room temperature, separates out white solid, filters, obtains the R-1-naphthalene ethylamine salt 16.3g of crude product R-4-chloro mandelic acid.The R-1-naphthalene ethylamine salt 16.3g of gained R-4-chloro mandelic acid is joined in the methanol solution with 160ml, heats up and dissolve, after waiting solid to dissolve completely, lower the temperature, be down to 0 DEG C, crystalline solid is filtered, the R-1-naphthalene ethylamine salt 14.4g of the R-4-chloro mandelic acid after must refining.
(2) acidolysis salt obtains R-4-chloro mandelic acid
The R-1-naphthalene ethylamine salt 14.4g of upper step gained R-4-chloro mandelic acid is dissolved in 200ml water, drip hydrochloric acid and reconcile pH value to 4, in system, add 100ml methylene dichloride, extract, after separatory, upper aqueous layer uses 50ml washed with dichloromethane twice again, merging extracting the methylene dichloride obtained several times, after anhydrous sodium sulfate drying, concentrating to obtain R-4-chloro mandelic acid 7.9g, yield is 42.2%, and the ee value detecting R-4-chloro mandelic acid is 99.5%.
(3) R-1-naphthalene ethylamine is reclaimed
The mother liquor splitting 4-chloro mandelic acid and recrystallization is steamed except after methyl alcohol, combines with the remaining aqueous layer of acidolysis process, use 40%NaOH solution to regulate pH value to 12.After regulating pH value, 150ml methylene dichloride is added in system, extract, after separatory, upper aqueous layer uses 50ml washed with dichloromethane twice again, combine extracting the methylene dichloride obtained several times, then with anhydrous sodium sulfate drying, concentrated to obtain R-1-naphthalene ethylamine 17.1G, the rate of recovery is 95.0%.
Embodiment 2
(1) fractionation of 4-chloro mandelic acid
In 500ml round-bottomed flask, add 300ml ethanol, 18.7g racemization 4-chloro mandelic acid, open stirring, heat up, under 55 DEG C of conditions, in system, drip R-1-naphthalene ethylamine 20.0g.Dropwise, reflux conditions is down to room temperature after reacting 1.0 hours, separates out white solid, obtains the R-1-naphthalene ethylamine salt 15.6g of crude product R-4-chloro mandelic acid after filtration.The R-1-naphthalene ethylamine salt 15.6g of gained R-4-chloro mandelic acid is joined in the ethanolic soln with 150ml, heats up and dissolve, after waiting solid to dissolve completely, lower the temperature, after being down to 0 DEG C, crystalline solid is filtered, the R-1-naphthalene ethylamine salt 14.2g of the R-4-chloro mandelic acid after must refining.
(2) acidolysis salt obtains R-4-chloro mandelic acid
The R-1-naphthalene ethylamine salt 14.2g of upper step gained R-4-chloro mandelic acid is dissolved in 300ml water, drip 1mol/L sulfuric acid and reconcile pH value to 4, in system, add 150ml ethyl acetate, extract, after separatory, lower aqueous layer washes twice by 50ml ethyl acetate again, merging extracting the ethyl acetate obtained several times, after carrying out drying by anhydrous sodium sulphate, concentrating to obtain R-4-chloro mandelic acid 7.5g, yield is 40.1%, and the ee value detecting R-4-chloro mandelic acid is 99.4%.
(3) R-1-naphthalene ethylamine is reclaimed
4-chloro mandelic acid and recrystallization mother liquor will be split steam except after ethanol, combine with acidolysis process remaining aqueous layer, and use ammonia soln to regulate pH value to 12.After regulating pH value, in system, add 200ml ethyl acetate, extract, after separatory, upper aqueous layer washes twice by 50ml ethyl acetate again, will extract ethyl acetate used several times and merge, after carrying out drying by anhydrous sodium sulphate, concentrate to obtain R-1-naphthalene ethylamine 18.2g, the rate of recovery is 91.0%.
Claims (5)
1. the preparation method of a R-4-chloro mandelic acid is characterized in that: the present invention utilizes R-1-naphthalene ethylamine for chiral selectors, react with 4-chloro mandelic acid in suitable alcoholic solvent, generate the R-1-naphthalene ethylamine salt of 4-chloro mandelic acid, utilize different enantiomorph different solubility, crystallization, suction filtration can obtain the R-1-naphthalene ethylamine salt of R-4-chloro mandelic acid, after salt recrystallization, acidifying obtains R-4-chloro mandelic acid; Solution containing R-1-naphthalene ethylamine merges together, and alkalize recyclable resolving agent R-1-naphthalene ethylamine.
2. a kind of preparation method of R-4-chloro mandelic acid is characterized in that according to claim 1: resolving agent used in the present invention is R-1-naphthalene ethylamine, and in system, added in molar amounts is 1.0 ~ 2.0 times of 4-chloro mandelic acid.
3. a kind of preparation method of R-4-chloro mandelic acid is characterized in that according to claim 1: alcohol used in the resolution reaction of R-4-chloro mandelic acid is methyl alcohol or ethanol.
4. a kind of preparation method of R-4-chloro mandelic acid is characterized in that according to claim 1: acid used when the R-1-naphthalene ethylamine of R-4-chloro mandelic acid is acidified is hydrochloric acid or sulfuric acid.
5. a kind of preparation method of R-4-chloro mandelic acid is characterized in that according to claim 1: the operation alkali used that alkalizes when reclaiming resolving agent R-1-naphthalene ethylamine is sodium hydroxide solution or ammonia soln.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510544713.9A CN105085234A (en) | 2015-08-31 | 2015-08-31 | Preparing method of (R)-(-)-4-chloromandelic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510544713.9A CN105085234A (en) | 2015-08-31 | 2015-08-31 | Preparing method of (R)-(-)-4-chloromandelic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105085234A true CN105085234A (en) | 2015-11-25 |
Family
ID=54566669
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510544713.9A Pending CN105085234A (en) | 2015-08-31 | 2015-08-31 | Preparing method of (R)-(-)-4-chloromandelic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105085234A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232237A (en) * | 2018-09-12 | 2019-01-18 | 通化师范学院 | The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate |
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
- 2015-08-31 CN CN201510544713.9A patent/CN105085234A/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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232237A (en) * | 2018-09-12 | 2019-01-18 | 通化师范学院 | The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103113250A (en) | Preparation method of D-para hydroxybenzene glycine methyl ester | |
| CN109608365B (en) | Preparation method of taurine | |
| CN105085234A (en) | Preparing method of (R)-(-)-4-chloromandelic acid | |
| CN105130794A (en) | Method for preparing S-4-methoxymandelic acid through splitting S-1-phenylethylamine | |
| CN102757367A (en) | Splitting process of racemic ethyl benzene sulfonic acid | |
| CN106349144A (en) | Preparation method of (S)-oxiracetam intermediate | |
| CN105085243A (en) | Preparing method of (S)-(-)-4-bromine mandelic acid | |
| CN105061219A (en) | Method for preparing S-1-aminoindane | |
| CN112645813B (en) | Preparation method of (R) -3-cyclohexene carboxylic acid | |
| CN109665970A (en) | A kind of preparation method of D-Val | |
| CN105085235A (en) | Method for splitting and preparing S-4-chloro mandelic acid | |
| CN105085244A (en) | Preparing method of (R)-(+)-4-bromomandelic acid | |
| CN101955439A (en) | Method for resolving alpha-substituted-2-amino acetamide | |
| CN101514163A (en) | Optically pure Sibutramine and process for preparing salt derivative thereof | |
| CN105175248A (en) | S-o-chloromandelic acid preparation method | |
| CN101735070A (en) | Resolution method of R-(+)-1-(1-naphthyl) ethylamine | |
| CN105085245A (en) | Preparing method of (R)-(+)-4-fluoromandelic acid | |
| CN105152913A (en) | Preparation method of S-4-fluoromandelic acid | |
| CN104211634A (en) | Synthetic method of 2-bromocarbazole | |
| CN104725259A (en) | Preparation method for levodopa intermediate derivative | |
| CN105061190A (en) | Method for preparing S-five-fluorine amygdalic acid through resolution | |
| CN105175270A (en) | Method for preparing R-5-trifluoromethyl-1-aminoindane | |
| CN105085247A (en) | Resolution preparation method of R-4-methoxymandelic acid | |
| CN109705064B (en) | A kind of preparation technology of optically pure 2-tetrahydrofuroic acid | |
| CN105153109A (en) | Method for split preparation of S-3,4-(methylenedioxy) mandelic acid |
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: 20151125 |