CN105085245A - Preparing method of (R)-(+)-4-fluoromandelic acid - Google Patents
Preparing method of (R)-(+)-4-fluoromandelic acid Download PDFInfo
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- CN105085245A CN105085245A CN201510544811.2A CN201510544811A CN105085245A CN 105085245 A CN105085245 A CN 105085245A CN 201510544811 A CN201510544811 A CN 201510544811A CN 105085245 A CN105085245 A CN 105085245A
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- Prior art keywords
- amygdalic acid
- acid
- fluorine amygdalic
- fluorine
- salt
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- 238000000034 method Methods 0.000 title claims abstract description 11
- RWCMOQXHIDWDDJ-SSDOTTSWSA-N (2r)-2-(4-fluorophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)[C@H](O)C1=CC=C(F)C=C1 RWCMOQXHIDWDDJ-SSDOTTSWSA-N 0.000 title abstract 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 19
- 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 10
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 49
- 239000011737 fluorine Substances 0.000 claims description 49
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 49
- 229960002510 mandelic acid Drugs 0.000 claims description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 238000010306 acid treatment Methods 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 239000001117 sulphuric acid Substances 0.000 claims 1
- 235000011149 sulphuric acid Nutrition 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 2
- RTCUCQWIICFPOD-SECBINFHSA-N (1r)-1-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C([C@H](N)C)=CC=CC2=C1 RTCUCQWIICFPOD-SECBINFHSA-N 0.000 abstract 5
- RWCMOQXHIDWDDJ-UHFFFAOYSA-N 2-(4-fluorophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)C(O)C1=CC=C(F)C=C1 RWCMOQXHIDWDDJ-UHFFFAOYSA-N 0.000 abstract 2
- 238000009776 industrial production Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005194 fractionation Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- -1 dry Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000000926 separation method Methods 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
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
-
- 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
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparing method of (R)-(+)-4-fluoromandelic acid through resolution by taking (R)-(+)-1-(1-Naphthyl)ethylamine as a chiral resolution agent. 4-fluoromandelic acid as a raw material and the resolution agent (R)-(+)-1-(1-Naphthyl)ethylamine react to generate an enantiomer salt, by using different solubilities of enantiomer salts in R and S forms in an alcohol solvent, crystallizing and separating are performed to obtain the (R)-(+)-1-(1-Naphthyl)ethylamine salt of the (R)-(+)-4-fluoromandelic acid, and after salt purifying, the (R)-(+)-4-fluoromandelic acid can be obtained by acidizing; after the solution containing the resolution agent (R)-(+)-1-(1-Naphthyl)ethylamine component is combined, alkalization treatment is performed, the resolution agent is recycled, and the recycled (R)-(+)-1-(1-Naphthyl)ethylamine can be reused for the resolution of the 4-fluoromandelic acid. 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-fluoromandelic acid.
Description
Technical field
The present invention relates to and a kind ofly utilize chemical method to split prepare the method for R configuration chiral alpha alcohol acid, particularly relate to a kind of with R-1-naphthalene ethylamine for the method for R-4-fluorine amygdalic acid is prepared in resolving agent fractionation.
Background technology
4-fluorine amygdalic 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-fluorine amygdalic acid rarely has report.Therefore, how the simple and easy to get preparation realizing R-4-fluorine amygdalic acid becomes the problem to be solved in the present invention.
Summary of the invention
The present invention adopts R-1-naphthalene ethylamine to be resolving agent, can successfully realize splitting preparation R-4-fluorine amygdalic acid.Invention operation is as follows:
The present invention is for raw material with 4-fluorine amygdalic acid, R-1-naphthalene ethylamine is resolving agent, reacts in corresponding solvent, obtains the R-1-naphthalene ethylamine salt of 4-fluorine amygdalic acid, can be obtained the R-1-naphthalene ethylamine salt of R-4-fluorine amygdalic acid by Crystallization Separation, salt dissociates through acid can obtain R-4-fluorine amygdalic acid; Reaction mother liquor, through concentration and recovery, adds alkali and dissociates, recyclable resolving agent R-1-naphthalene ethylamine.
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-fluorine amygdalic acid.
Realize particular by following operation according to the fractionation preparation of described R-4-fluorine amygdalic acid: with 4-fluorine amygdalic acid for raw material, R-1-naphthalene ethylamine is resolving agent, react in the solvent that methyl alcohol or ethanol and water are prepared with 1:0.2-3 volume ratio, obtain the R-1-naphthalene ethylamine salt of 4-fluorine amygdalic acid, the total mass number of the required solvent of reaction is 10-30 times of R-4-fluorine amygdalic acid, through cooling after reaction terminates, crystallization, be separated the R-1-naphthalene ethylamine salt obtaining R-4-fluorine amygdalic acid, hydrochloric acid or sulfuric acid is utilized to dissociate after gained salt alcoholic solvent recrystallization, again through the extraction of organic solvent dichloromethane or ethyl acetate, dry, concentrate to obtain R-4-fluorine amygdalic acid.
Can be reclaimed by following operation according to described resolving agent R-1-naphthalene ethylamine: after the methyl alcohol in reaction and recrystallization mother liquor or ethanol are steamed, merge with acidification remaining aqueous layer, a certain amount of alkali is added in mixing solutions, regulate pH value to 11 ~ 13, then through the extraction of organic solvent dichloromethane or ethyl acetate, drying, concentratedly to obtain R-1-naphthalene ethylamine.
Use the present invention to prepare R-4-fluorine amygdalic acid, R-4-fluorine amygdalic acid can reach more than 30% relative to the yield of racemization 4-fluorine amygdalic acid, and the ee value that can realize product is greater than 99%.
Meanwhile, the present invention also 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-fluorine amygdalic acid.
Specific implementation method:
Embodiment 1
(1) fractionation of 4-fluorine amygdalic acid
In 500ml round-bottomed flask, add the mixing solutions of 300ml methyl alcohol and 100ml water, 17.0g racemization 4-fluorine amygdalic acid, open stirring, heat up.In system, drip R-1-naphthalene ethylamine (ee value is 99.7%) 22.0g at 50 DEG C, dropwise, back flow reaction 1.5 hours, is down to room temperature, crystallize out, filters, obtains the R-1-naphthalene ethylamine salt 14.5 of crude product R-4-fluorine amygdalic acid.The R-1-naphthalene ethylamine salt 14.5g of gained R-4-fluorine amygdalic acid is joined in the methanol solution with 140ml, heats up and dissolve, after waiting solid to dissolve completely, lower the temperature, be down to room temperature, crystalline solid is filtered, the R-1-naphthalene ethylamine salt 13.2g of the R-4-fluorine amygdalic acid after must refining.
(2) acidolysis salt obtains R-4-fluorine amygdalic acid
The R-1-naphthalene ethylamine salt 13.2g of upper step gained R-4-fluorine amygdalic 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-fluorine amygdalic acid 6.4g, yield is 37.6%, and the ee value detecting R-4-fluorine amygdalic acid is 99.5%.
(3) R-1-naphthalene ethylamine is reclaimed
The mother liquor splitting 4-fluorine amygdalic 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, combines extracting the methylene dichloride obtained several times, then with anhydrous sodium sulfate drying, concentrated to obtain R-1-naphthalene ethylamine 21.0G, the rate of recovery is 95.5%, ee value is 99.6%.
(4) recycling of resolving agent
In 500ml round-bottomed flask, add the mixing solutions of 200ml ethanol and 200ml water, 17.0g racemization 4-fluorine amygdalic acid, open stirring, heat up.Drip in system at 50 DEG C and reclaim R-1-naphthalene ethylamine (ee value is 99.6%) 21.0g, dropwise, back flow reaction 2.0 hours, is down to room temperature, crystallize out, filters, obtains the R-1-naphthalene ethylamine salt 14.1 of crude product R-4-fluorine amygdalic acid.The R-1-naphthalene ethylamine salt 14.1g of gained R-4-fluorine amygdalic acid is joined in the ethanolic soln with 140ml, heats up and dissolve, after waiting solid to dissolve completely, lower the temperature, be down to room temperature, crystalline solid is filtered, the R-1-naphthalene ethylamine salt 12.8g of the R-4-fluorine amygdalic acid after must refining.
(5) acidolysis salt obtains R-4-fluorine amygdalic acid
The R-1-naphthalene ethylamine salt 12.8g of upper step gained R-4-fluorine amygdalic acid is dissolved in 200ml water, drip hydrochloric acid and reconcile pH value to 3, in system, add 100ml ethyl acetate, extract, after separatory, lower aqueous layer washes twice by 50ml ethyl acetate again, merging extracting the ethyl acetate obtained several times, after anhydrous sodium sulfate drying, concentrating to obtain R-4-fluorine amygdalic acid 6.1g, yield is 35.9%, and the ee value detecting R-4-fluorine amygdalic acid is 99.6%.
(6) R-1-naphthalene ethylamine is reclaimed
The mother liquor splitting 4-fluorine amygdalic acid and recrystallization in step 4 is steamed except after ethanol, combine with the remaining aqueous layer of acidolysis process, use ammonia soln to regulate pH value to 13.After regulating pH value, 150ml ethyl acetate is added in system, extract, after separatory, lower aqueous layer washes twice by 50ml ethyl acetate again, combines extracting the ethyl acetate obtained several times, then with anhydrous sodium sulfate drying, concentrated to obtain R-1-naphthalene ethylamine 19.7g, the rate of recovery is 93.8%, ee value is 99.6%.
Claims (5)
1. the preparation method of a kind of R-4-fluorine amygdalic acid disclosed by the invention, it is characterized in that: with 4-fluorine amygdalic acid for raw material, react in the mixed solvent of alcohol and water with resolving agent R-1-naphthalene ethylamine and generate enantiomorph salt, utilize R, S configuration enantiomorph salt different solubility in a solvent, crystallization, be separated to obtain the R-1-naphthalene ethylamine salt of R-4-fluorine amygdalic acid, after salt purifying, then obtain R-4-fluorine amygdalic acid with acid treatment; After solution containing resolving agent R-1-naphthalene ethylamine composition merges, carrying out alkalinisation treatment can reclaim resolving agent.
2. the preparation method of a kind of R-4-fluorine amygdalic acid according to claim 1, it is characterized in that: resolving agent used in the present invention is R-1-naphthalene ethylamine, in system, added in molar amounts is 1.0 ~ 2.0 times of 4-fluorine amygdalic acid.
3. the preparation method of a kind of R-4-fluorine amygdalic acid according to claim 1, is characterized in that: split and alcoholic solvent that recrystallization reacts used is methyl alcohol or ethanol.
4. the preparation method of a kind of R-4-fluorine amygdalic acid according to claim 1, is characterized in that: acidified process acid used is hydrochloric acid or sulphuric acid soln.
5. the preparation method of a kind of R-4-fluorine amygdalic acid according to claim 1, is characterized in that: reclaiming the alkali that in resolving agent process, alkalinisation treatment is used is sodium hydroxide solution or ammonia soln.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510544811.2A CN105085245A (en) | 2015-08-31 | 2015-08-31 | Preparing method of (R)-(+)-4-fluoromandelic acid |
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| CN201510544811.2A CN105085245A (en) | 2015-08-31 | 2015-08-31 | Preparing method of (R)-(+)-4-fluoromandelic acid |
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| CN201510544811.2A Pending CN105085245A (en) | 2015-08-31 | 2015-08-31 | Preparing method of (R)-(+)-4-fluoromandelic acid |
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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 CN201510544811.2A patent/CN105085245A/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 |
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