CN105085235A - Method for splitting and preparing S-4-chloro mandelic acid - Google Patents
Method for splitting and preparing S-4-chloro mandelic acid Download PDFInfo
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- CN105085235A CN105085235A CN201510544783.4A CN201510544783A CN105085235A CN 105085235 A CN105085235 A CN 105085235A CN 201510544783 A CN201510544783 A CN 201510544783A CN 105085235 A CN105085235 A CN 105085235A
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- Prior art keywords
- mandelic acid
- chloro mandelic
- chloro
- resolving agent
- preparation
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- 238000000034 method Methods 0.000 title abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- BWSFWXSSALIZAU-UHFFFAOYSA-N 2-(4-chlorophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)C(O)C1=CC=C(Cl)C=C1 BWSFWXSSALIZAU-UHFFFAOYSA-N 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 239000000284 extract Substances 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000005194 fractionation Methods 0.000 claims description 4
- 239000012452 mother liquor Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N monoethyl amine Natural products CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 abstract 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract 1
- 239000013078 crystal Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000011084 recovery Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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
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- 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 method which takes S-1-naphthyl ethylamine as a chiral resolving agent to split and prepare the S-4-chloro mandelic acid. According to the method provided by the invention, the S-1-naphthyl ethylamine is taken as the chiral resolving agent to split the S-4-chloro mandelic acid to obtain S-1-naphthalene ethyl amine salt of the S-4-chloro mandelic acid, then the crystal separation is carried out to obtain the S-1-naphthalene ethyl amine salt of the S-4-chloro mandelic acid by utilizing the different solubility of two enantiomers in alcohol, and then the acidizing is carried out to obtain the S-4-chloro mandelic acid after the salt is recrystallized; the alkali treatment is carried out to recycle the resolving agent S-1-naphthyl ethylamine after residual solution containing the resolving agent in each step is combined. The method for splitting and preparing the S-4-chloro mandelic acid has the characteristics of mild condition, simple operation, high product yield and high purity, and the resolving agent can be recycled and reused, and is suitable for industrial production of the S-4-chloro mandelic 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 S-1-naphthalene ethylamine for resolving agent splits the method preparing S-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 S-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 S-4-chloro mandelic acid.
Summary of the invention
1. the present invention adopts S-1-naphthalene ethylamine to be resolving agent, can successfully realize splitting preparation S-4-chloro mandelic acid.Invent its concrete operations as follows: add a certain amount of methyl alcohol or ethanol in (1) reactor as solvent, a certain amount of 4-chloro mandelic acid, as fractionation substrate, heats up, stirs; Add resolving agent S-1-naphthalene ethylamine under reflux conditions, add back flow reaction 1.5-2.0h; Cooling, crystallization, suction filtration obtain the S-1-naphthalene ethylamine salt of S-4-chloro mandelic acid; Gained salt is dissolved in a certain amount of methyl alcohol or alcohol solvent and carries out recrystallization; (2) step 1 recrystallization salt be dissolved in a certain amount of water, acid adding regulates pH value to 1-3, extracts, separatory gained organic solvent carries out drying, concentration operation can obtain target product S-4-chloro mandelic acid under this pH value by organic solution; (3) will split and recrystallization mother liquor merge, after heating removes the alcohol in system, it mixed with step 2 acidifying remaining aqueous layer, mixing solutions alkali regulates pH value to 11-13 again, then through recyclable resolving agent S-1-naphthalene ethylamines of operation such as organic solvent extraction, drying, desolventizings.
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 4-chloro mandelic acid; : acid used when the S-1-naphthalene ethylamine of S-4-chloro mandelic acid is acidified is hydrochloric acid or sulfuric acid; The operation alkali used that alkalizes when reclaiming resolving agent S-1-naphthalene ethylamine is sodium hydroxide solution or ammonia soln; Extracting organic solvent used in step 2 and step 3 is methylene dichloride or ethyl acetate.
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 S-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, S-1-naphthalene ethylamine 18.0g is dripped under reflux conditions.Dropwise, back flow reaction 1.5 hours, is down to room temperature, separates out white solid, filters, obtains the S-1-naphthalene ethylamine salt 15.6g of crude product S-4-chloro mandelic acid.The S-1-naphthalene ethylamine salt 15.6g of gained S-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 S-1-naphthalene ethylamine salt 14.4g of the S-4-chloro mandelic acid after must refining.
(2) acidolysis salt obtains S-4-chloro mandelic acid
The S-1-naphthalene ethylamine salt 14.4g of upper step gained S-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 S-4-chloro mandelic acid 7.6g, yield is 40.6%, and the ee value detecting S-4-chloro mandelic acid is 99.4%.
(3) S-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 S-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 S-1-naphthalene ethylamine 20.0g.Dropwise, reflux conditions is down to room temperature after reacting 1.0 hours, separates out white solid, obtains the S-1-naphthalene ethylamine salt 16.1g of crude product S-4-chloro mandelic acid after filtration.The S-1-naphthalene ethylamine salt 16.1g of gained S-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 S-1-naphthalene ethylamine salt 14.7g of the S-4-chloro mandelic acid after must refining.
(2) acidolysis salt obtains S-4-chloro mandelic acid
The S-1-naphthalene ethylamine salt 14.7g of upper step gained S-4-chloro mandelic acid is dissolved in 300ml water, drip hydrochloric 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 S-4-chloro mandelic acid 7.9g, yield is 42.2%, and the ee value detecting S-4-chloro mandelic acid is 99.2%.
(3) S-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 S-1-naphthalene ethylamine 18.2g, the rate of recovery is 91.0%.
Claims (5)
1. the preparation method of a kind of S-4-chloro mandelic acid of disclosure of the invention, its concrete operations are as follows: add a certain amount of methyl alcohol or ethanol in (1) reactor as solvent, and a certain amount of 4-chloro mandelic acid, as fractionation substrate, heats up, stirs; Add resolving agent S-1-naphthalene ethylamine under reflux conditions, add back flow reaction 1.5-2.0h; Cooling, crystallization, suction filtration obtain the S-1-naphthalene ethylamine salt of S-4-chloro mandelic acid; Gained salt is dissolved in a certain amount of methyl alcohol or alcohol solvent and carries out recrystallization; (2) step 1 recrystallization salt be dissolved in a certain amount of water, acid adding regulates pH value to 1-3, extracts, separatory gained organic solvent carries out drying, concentration operation can obtain target product S-4-chloro mandelic acid under this pH value by organic solution; (3) will split and recrystallization mother liquor merge, after heating removes the alcohol in system, it mixed with step 2 acidifying remaining aqueous layer, mixing solutions alkali regulates pH value to 11-13 again, then through recyclable resolving agent S-1-naphthalene ethylamines of operation such as organic solvent extraction, drying, desolventizings.
2. the preparation method of a kind of S-4-chloro 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 4-chloro mandelic acid.
3. the preparation method of a kind of S-4-chloro mandelic acid according to claim 1, is characterized in that: acid used when the S-1-naphthalene ethylamine of S-4-chloro mandelic acid is acidified is hydrochloric acid or sulfuric acid.
4. the preparation method of a kind of S-4-chloro mandelic acid according to claim 1, is characterized in that: when reclaiming resolving agent S-1-naphthalene ethylamine, alkalization operation alkali used is sodium hydroxide solution or ammonia soln.
5. the preparation method of a kind of S-4-chloro mandelic acid according to claim 1, is characterized in that: extracting organic solvent used in step 2 and step 3 is methylene dichloride or ethyl acetate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510544783.4A CN105085235A (en) | 2015-08-31 | 2015-08-31 | Method for splitting and preparing S-4-chloro mandelic acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510544783.4A CN105085235A (en) | 2015-08-31 | 2015-08-31 | Method for splitting and preparing S-4-chloro mandelic acid |
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| CN105085235A true CN105085235A (en) | 2015-11-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510544783.4A Pending CN105085235A (en) | 2015-08-31 | 2015-08-31 | Method for splitting and preparing S-4-chloro mandelic acid |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4259521A (en) * | 1979-10-09 | 1981-03-31 | American Cyanamid Company | Process for resolving DL-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 CN201510544783.4A patent/CN105085235A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4259521A (en) * | 1979-10-09 | 1981-03-31 | American Cyanamid Company | Process for resolving DL-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: 20151125 |