CN1162389C - Prepn of 2-(3-benzoylphenyl) propionic acid enantiomer - Google Patents
Prepn of 2-(3-benzoylphenyl) propionic acid enantiomer Download PDFInfo
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- CN1162389C CN1162389C CNB011321016A CN01132101A CN1162389C CN 1162389 C CN1162389 C CN 1162389C CN B011321016 A CNB011321016 A CN B011321016A CN 01132101 A CN01132101 A CN 01132101A CN 1162389 C CN1162389 C CN 1162389C
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Abstract
The present invention relates to a method for preparing (S)-(+)-2-(3-benzoylphenyl) propionic acid from racemate of 2-(3-benzoylphenyl propionic acid by a chemical resolution method, namely a simple and convenient method that the recemate of 2-(3-benzoylphenyl propionic acid and alkyl amino-D-glucose alcohol of (-)-1-deoxy-1-C1 to 15 react to generate diastereomeric salt, then the diastenomeric salt is converted into (S)-(+)-2-(3-benzoylphenyl) propionic acid through crystallisation, purification, acid treatment or hydrolysis. The present invention is simple and convenient, has the advantages of high yield, low cost and complete resolution and is suitable for industrial production.
Description
Technical field
The present invention relates to the method that a kind of raceme from 2-(3-benzoyl phenyl) propionic acid prepares optically pure (S)-(+)-2-(3-benzoyl phenyl) propionic acid.Be that the optically pure amine reaction of a kind of 2-of making (3-benzoyl phenyl) propionic acid raceme and resolving agent generates diastereomeric salt furtherly, again through crystallization purifying, acid treatment or hydrolysis are converted into the short-cut method of (S)-(+)-2-(3-benzoyl phenyl) propionic acid.
Background technology
2-(3-benzoyl phenyl) propionic acid is a kind of non-steroid antiinflammatory drug, and its mechanism of action is to suppress the cyclooxygenase system, can anti-inflammatory analgesic, be used for the treatment of rheumatism, sell in the market and clinical application be its raceme.
Raceme contains a pair of enantiomorph of 2-(3-benzoyl phenyl) propionic acid, but its pharmacologically active is inequality, Brune, K. etc. (Brune, K, et a1, Experientia, 1991,
47, 257) and the antiphlogistic activity of finding 2-(3-benzoyl phenyl) propionic acid is mainly from its (S)-enantiomorph, (R)-enantiomorph then lacks significant cyclooxygenase and suppresses active.Therefore, compare with raceme, (S)-(+)-2-(3-benzoyl phenyl) propionic acid can just can reach identical result of treatment with less amount, so be necessary to obtain optically pure (S)-enantiomorph with a kind of simple method.
The method for preparing optically pure (S)-(+)-2-(3-benzoyl phenyl) propionic acid with chemical resolution method is reported in following document: (1R such as Sepracor, 2S)-suitable-1-amido dihydro indenes-2-alcohol makes (S)-enantiomorph as resolving agent, its optical purity is 97.2% (U.S.Pat.No.5,677,469); Sumitomo chemistry company limited makes (S)-enantiomorph with (S)-(-)-N-(p-hydroxybenzene)-1-phenylethylamine as resolving agent, and its optical purity is 58.2%, and yield is 43.1% (U.S.Pat.No.5,510,519); Nagase﹠amp; Company company limited makes (S)-enantiomorph with (S)-3-methyl-2-PHENTERMINE as resolving agent, and its optical purity is 99+%, and yield is 55-75% (based on (S)-enantiomorph) (European Patent No.703212); Open application number WO 94/06747 and 92/18455 (Ethyl Corp.) of PCT and WO 92/18455 disclose a kind of usefulness (-)-Cinchonidune respectively and have made (S)-enantiomorph as resolving agent, its optical purity is 97%, yield be 31% and Alpha-Methyl benzylamine and dehydroabietylamine make (S)-enantiomorph as resolving agent; In addition, Japanese Patent (JP02289536) reported with optically pure α-ethyl benzyl amine and made (S)-enantiomorph as resolving agent, and its optical purity is 99%, and yield is 44% (based on (S)-enantiomorph); Kim, J.W. etc. once used (S)-(+)-2-amino-1-butanols as resolving agent make (S)-enantiomorph (Kim, J.W, et al, Arch.Pharmacal Res., 1987,
10, 25);
Syntex company prepares optically pure Naproxen Base (U.S.Pat.No.4,246,193 and 4,515,811) with N-methyl D-glucosamine (U.S.Pat.No.4,246,164) and other N-alkyl-D-glucosamine as resolving agent; The said firm also splits Ibuprofen BP/EP with N-methyl D-glucosamine and N-octyl group-D-glucosamine, (S)-productive rate of Ibuprofen BP/EP is respectively 73.2% and 74% (based on (S)-enantiomorph), its ee value is respectively 99% and 99.9% (U.S.Pat.No.5,621,140); Human N-octyl groups such as woods Guoqiang-D-glucosamine split Flurbiprofen, (S)-productive rate of Flurbiprofen is 66.8% (based on (S)-enantiomorph), its ee value is 99% (CN01113303.1).
So far, the method for preparing optically pure (S)-(+)-2-(3-benzoyl phenyl) propionic acid from the raceme of 2-(3-benzoyl phenyl) propionic acid is still the problem of various countries' research.
Summary of the invention
Purpose of the present invention just provides the method that a kind of raceme from 2-(3-benzoyl phenyl) propionic acid prepares optically pure (S)-(+)-2-(3-benzoyl phenyl) propionic acid.(-)-1-deoxidation-1-C of system
1-15Alkyl amido-D-sorbitol as resolving agent, described C
1-15Alkyl comprise C
1-15Alkyl, C
3-8Cycloalkyl, phenyl, C
1-4Alkyl-substituted phenyl etc.Make the raceme and the resolving agent of 2-(3-benzoyl phenyl) propionic acid generate diastereomeric salt, the separable purifying of this salt, the pure diastereomer that will obtain with mineral acid or its aqueous solution is converted into (S)-(+)-2-(3-benzoyl phenyl) propionic acid.
Method of the present invention is in organic solvent, and the raceme of 2-(3-benzoyl phenyl) propionic acid and resolving agent were 10～250 ℃ of reactions 0.1～10 hour, and the recommendation response temperature is the reflux temperature, and the reaction times is 0.25～0.5 hour.The mol ratio of described 2-(3-benzoyl phenyl) propionic acid and resolving agent is 1: 0.2～2, and recommending mol ratio is 1: 0.5-1.
Reaction is finished, and leaves standstill crystallization at 5～25 ℃, and recommended temperature is 5～10 ℃, if non-crystallizable, can add small amount of seeds, filters, and can obtain the optically pure diastereomeric salt of (S)-enantiomorph.Described resolving agent is (-)-1-deoxidation-1-C
1-15Alkyl amido-D-sorbitol, described C
1-15Alkyl comprise C
1-15Alkyl, C
3-8Cycloalkyl, phenyl, C
1-4Alkyl-substituted phenyl etc., above-mentioned (-)-1-deoxidation-1-C
1-15Alkyl amido-D-sorbitol be recommended as (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol.Described organic solvent is C
1-10The alcohol and the aqueous solution thereof, can use separately, also capable of being combined or mix to use, be recommended as Virahol.
The optical purity of diastereomeric salt is not if reach requirement, can carry out repeatedly recrystallization till reach requirement in organic solvent, and described organic solvent is C
1-10The alcohol and the aqueous solution thereof, can use separately, also capable of being combined or mix to use, be recommended as Virahol.
Diastereomeric salt is with mineral acid or its acidified aqueous solution; transfer pH≤6, recommending pH is 0.5～3, (S)-(+)-2-that dissociates (3-benzoyl phenyl) propionic acid; filter or extract, can obtain optically pure (S)-(+)-2-(3-benzoyl phenyl) propionic acid with water-insoluble organic solvent.Used mineral acid can be sulfuric acid, hydrochloric acid, phosphoric acid etc., concentration 1～10N, and recommending souring soln is the 1-2N aqueous sulfuric acid, and used extraction solvent can be chloroform, methylene dichloride, ethyl acetate, ether etc., and the recommendation solvent is an ethyl acetate.
Solution behind the resolution reaction can utilize by racemization or/and contain a large amount of (R)-(-)-and the acid and the salt of residual a spot of (S)-(+)-2-(3-benzoyl phenyl) propionic acid in the mother liquor of recrystallization again.Promptly desolventize, as mother liquor is concentrated, evaporated under reduced pressure solvent, the gained solid reacted 1～15 hour in alkali or its aqueous solution under normal pressure or pressurized conditions, 80～250 ℃ of temperature of reaction, wherein (R)-
(-)-can be 1: 1～100 with residual a spot of (S)-(+)-2-(the 3-benzoyl phenyl) acid of propionic acid and the mol ratio of salt and alkali; used alkali can be sodium hydroxide, potassium hydroxide etc.; concentration is 1～10N, recommends to react under the reflux temperature condition of normal pressure 6～8 hours with 2～4N aqueous sodium hydroxide solution.Reaction is finished, and reaction solution transfers to acidity with mineral acid, filters or extracts with water-insoluble organic solvent, can obtain 2-(the 3-benzoyl phenyl) propionic acid of racemization, and its composition is identical with starting raw material, recycling preparation (S)-enantiomorph.Used mineral acid can be hydrochloric acid, sulfuric acid, phosphoric acid etc., is recommended as concentrated hydrochloric acid; Used extraction solvent can be chloroform, methylene dichloride, ethyl acetate, ether etc., is recommended as ethyl acetate.
Handle the last inorganic acid aqueous solution of salt and transfer to pH7.5～14 with alkali, resolving agent is promptly free to be precipitated out, used alkali can be yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, strong aqua, sodium hydroxide solution, potassium hydroxide solution etc., recommends to use strong aqua.
Not only method is easy, productive rate is high, cost is low to adopt method of the present invention; and split fully, product optical purity height, reacted 2-(3-benzoyl phenyl) propionic acid and resolving agent can reclaim; and being used further to prepare optically pure enantiomorph, method of the present invention is suitable for suitability for industrialized production.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.Ee value among the embodiment is high pressure liquid chromatography (HPLC) method and records.
Embodiment 1:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Get the raceme 100g (394mmol) and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol 57.6g (197mmol) of 2-(3-benzoyl phenyl) propionic acid, put into reaction flask, add Virahol 750ml, oil bath reflux 15 minutes.After reaction finishes; the salt that adds a small amount of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol is as crystal seed; 5～10 ℃ leave standstill crystallization more than 10 hours, filter, and get white solid 91.7g (168mmol) ([α]
D 20=-14.8 ° (c=1, MeOH)), yield 85.2%.
Above-mentioned white solid 5～10 ℃ through twice recrystallization, salt/Virahol is 1g/7ml, white solid 74g (135mmol) ([α]
D 20=-16.4 ° (c=1, MeOH)), yield 68.8%.
Get crystallization gained solid 74g (135mmol) for the third time; put into round-bottomed flask, add 740ml 2N aqueous sulfuric acid and 500ml ethyl acetate, stir and make the solid dissolving; carry out liquid-liquid exchange; the aqueous solution is used ethyl acetate extraction again, combined ethyl acetate extraction liquid, washing; anhydrous sodium sulfate drying; filter, filtrate decompression concentrates, and gets (S)-(+)-2-(3-benzoyl phenyl) propionic acid 33.2g (131mmol) ([α]
D 20=+55.2 ° of (c=1, CHCl
3)), the ee value is 0.99, and yield is 66.4% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Aqueous sulfuric acid after liquid-liquid exchange adds strong aqua adjust pH to 8, has solid to separate out, and filters, and gets (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol 38.8g (132mmol) ([α]
D 20=-15.1 ° (c=1, MeOH)), yield 98.0% (based on salt).
Embodiment 2: racemization
Merge embodiment 1 reaction and recrystallization gained filtrate, concentrating under reduced pressure gets faint yellow solid 83g, puts into reaction flask, adds 400ml 4N sodium hydroxide solution, oil bath reflux 6 hours.After reaction finishes, be cooled to room temperature, add 140ml concentrated hydrochloric acid and 300ml ethyl acetate, stir and make the solid dissolving, carry out the exchange of liquid liquid, the aqueous solution is used ethyl acetate extraction again, combined ethyl acetate extraction liquid, washing, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and gets raceme 62.7g ([α]
D 20=0 ° of (c=1, CHCl
3)), yield 95.6%.
Embodiment 3:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Get the raceme 100g (394mmol) and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol 57.6g (197mmol) of 2-(3-benzoyl phenyl) propionic acid, put into reaction flask, add dehydrated alcohol 540ml, oil bath reflux 15 minutes.After reaction finishes, add small amount of seeds, room temperature leaves standstill crystallization more than 10 hours, filters, and gets white solid 49.1g (89.8mmol) ([α]
D 20=-15.3 ° (c=1, MeOH)), yield 45.6%.
Gained white solid 49.1g (89.8mmol) puts into round-bottomed flask, and adding 500ml2N aqueous sulfuric acid stirred 2 hours, filtered, and solid is washed with a small amount of, and drying gets (S)-(+)-2-(3-benzoyl phenyl) propionic acid 21.6g (85.0mmol) ([α]
D 20=+51.2 ° of (c=1, CHCl
3)), the ee value is 0.93, and yield is 43.2% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Aqueous sulfuric acid after the filtration adds strong aqua adjust pH to 8, has solid to separate out, and filters, and gets (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol 25.7g (87.7mmol) ([α]
D 20=-15.1 ° (c=1, MeOH)), yield 97.7% (based on salt).
Embodiment 4:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, reaction solvent is a Virahol.Reaction solution be racemization 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-n-octyl amine base-D-sorbitol/Virahol is 200mmol/100mmol/380ml; recrystallization solvent is a dehydrated alcohol; salt/dehydrated alcohol is 1g/5ml; through twice recrystallization, get the salt 60.9mmol ([α] of the 2-of (S)-(+) (3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol
D 20=-16.2 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 59.2mmol ([α]
D 20=+54.9 ° of (c=1, CHCl
3)), the ee value is 0.99, and yield is 59.2% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 5:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, reaction and recrystallization solvent are anhydrous methanol.Reaction solution be racemization 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-n-octyl amine base-D-sorbitol/anhydrous methanol is 200mmol/200mmol/270ml; recrystallization is that salt/anhydrous methanol is 1g/5ml; through twice recrystallization, get the salt 39.2mmol ([α] of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol
D 20=-16.3 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 37.4mmol ([α]
D 20=+55.1 ° of (c=1, CHCl
3)), the ee value is 0.99, and yield is 37.4% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 6:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, resolving agent is (-)-1-deoxidation-1-ethylamino--D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution be racemization 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-ethylamino--D-sorbitol/Virahol is 200mmol/100mmol/320ml; recrystallization is that salt/Virahol is 1g/7ml; through three recrystallizations, get the salt 23.9mmol ([α] of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-ethylamino--D-sorbitol
D 20=-16.8 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 22.6mmol ([α]
D 20=+53.9 ° of (c=1, CHCl
3)), the ee value is 0.98, and yield is 22.6% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 7:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, resolving agent is (-)-1-deoxidation-1-isobutyl amine-D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution be racemization 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-isobutyl amine-D-sorbitol/Virahol is 200mmol/100mmol/340ml; recrystallization is that salt/Virahol is 1g/7ml; through three recrystallizations, get the salt 33.5mmol ([α] of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-isobutyl amine-D-sorbitol
D 20=-16.9 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 31.9mmol ([α]
D 20=+55.2 ° of (c=1, CHCl
3)), the ee value is 0.99, and yield is 31.9% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 8:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, resolving agent is (-)-1-deoxidation-1-normal hexyl Amine base-D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution be racemization 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-normal hexyl Amine base-D-sorbitol/Virahol is 200mmol/100mmol/360ml; recrystallization is that salt/Virahol is 1g/7ml; through twice recrystallization, get the salt 51.9mmol ([α] of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-normal hexyl Amine base-D-sorbitol
D 20=-16.6 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 49.8mmol ([α]
D 20=+54.8 ° of (c=1, CHCl
3)), the ee value is 0.99, and yield is 49.8% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 9:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, resolving agent is the positive amino dodecane base of (-)-1-deoxidation-1--D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution is that positive amino dodecane base-D-sorbitol/Virahol is 200mmol/100mmol/420ml for 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-of racemization; recrystallization is that salt/Virahol is 1g/7ml; through twice recrystallization, get the salt 47.1mmol ([α] of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and the positive amino dodecane base of (-)-1-deoxidation-1--D-sorbitol
D 20=-15.7 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 45.6mmol ([α]
D 20=+54.0 ° of (c=1, CHCl
3)), the ee value is 0.98, and yield is 45.6% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 10:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, resolving agent is (-)-1-deoxidation-1-cyclohexylamino-D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution be racemization 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-cyclohexylamino-D-sorbitol/Virahol is 200mmol/100mmol/360ml; recrystallization is that salt/Virahol is 1g/7ml; through three recrystallizations, get the salt 43.1mmol ([α] of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-cyclohexylamino-D-sorbitol
D 20=-16.7 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 41.3mmol ([α]
D 20=+55.0 ° of (c=1, CHCl
3)), the ee value is 0.99, and yield is 41.3% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 11:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, resolving agent is (-)-1-deoxidation-1-anilino-D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution be racemization 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-anilino-D-sorbitol/Virahol is 200mmol/100mmol/360ml; recrystallization is that salt/Virahol is 1g/7ml; through three recrystallizations, get the salt 36.6mmol ([α] of the 2-of (S)-(+) (3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-anilino-D-sorbitol
D 20=-14.0 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 35.2mmol ([α]
D 20=+51.2 ° of (c=1, CHCl
3)), the ee value is 0.93, and yield is 35.2% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 12:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, resolving agent is (-)-1-deoxidation-1-benzamido group-D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution be racemization 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-benzamido group-D-sorbitol/Virahol is 200mmol/100mmol/370ml; recrystallization is that salt/Virahol is 1g/7ml; through three recrystallizations, get the salt 35.5mmol ([α] of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-benzamido group-D-sorbitol
D 20=-14.5 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 33.8mmol ([α]
D 20=+52.4 ° of (c=1, CHCl
3)), the ee value is 0.95, and yield is 33.8% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 13:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, resolving agent is (-)-1-deoxidation-1-phenylpropyl alcohol amido-D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution be racemization 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-phenylpropyl alcohol amido-D-sorbitol/Virahol is 200mmol/100mmol/390ml; recrystallization is that salt/Virahol is 1g/7ml; through three recrystallizations, get the salt 36.1mmol ([α] of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-phenylpropyl alcohol amido-D-sorbitol
D 20=-14.4 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 34.2mmol ([α]
D 20=+49.6 ° of (c=1, CHCl
3)), the ee value is 0.90, and yield is 34.2% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 14:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, resolving agent is (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol in the reaction, and reaction and recrystallization solvent are 95% ethanol.Reaction solution be racemization 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-n-octyl amine base-D-sorbitol/95% ethanol is 200mmol/100mmol/270ml; recrystallization is that salt/95% ethanol is 1g/5ml; through twice recrystallization, get the salt 51.5mmol ([α] of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol
D 20=-16.3 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 49.6mmol ([α]
D 20=+54.9 ° of (c=1, CHCl
3)),, the ee value is 0.99, and yield is 49.6% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 15:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, resolving agent is (-)-1-deoxidation-1-normal hexyl Amine base-D-sorbitol in the reaction, and reaction and recrystallization solvent are n-hexyl alcohol.Reaction solution be racemization 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-normal hexyl Amine base-D-sorbitol/n-hexyl alcohol is 200mmol/100mmol/470ml; recrystallization is that salt/n-hexyl alcohol is 1g/9ml; through three recrystallizations, get the salt 46.3mmol ([α] of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-normal hexyl Amine base-D-sorbitol
D 20=-16.7 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 44.6mmol ([α]
D 20=+54.9 ° of (c=1, CHCl
3)), the ee value is 0.99, and yield is 44.6% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 16:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, resolving agent is (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol in the reaction, and reaction and recrystallization solvent are n-Octanol.Reaction solution be racemization 2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-n-octyl amine base-D-sorbitol/n-Octanol is 200mmol/100mmol/550ml; recrystallization is that salt/n-Octanol is 1g/10ml; through three recrystallizations, get the salt 40.7mmol ([α] of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol
D 20=-16.2 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 39.2mmol ([α]
D 20=+55.2 ° of (c=1, CHCl
3)), the ee value is 0.99, and yield is 39.2% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 17:(S)-(+)-preparation of 2-(3-benzoyl phenyl) propionic acid
Press embodiment 1 method, reaction substrate and solvent are the recovery gained.Reaction solution is that racemization (S)-(+)-2-(3-benzoyl phenyl) propionic acid/(-)-1-deoxidation-1-n-octyl amine base-D-sorbitol/Virahol is 200mmol/100mmol/380ml; recrystallization is that salt/Virahol is 1g/7ml; through twice recrystallization, get the salt 65.6mmol ([α] of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol
D 20=-16.4 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-(3-benzoyl phenyl) propionic acid 63.8mmol ([α]
D 20=+54.8 ° of (c=1, CHCl
3)), the ee value is 0.99, and yield is 63.8% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Claims (9)
1. the raceme from 2-(3-benzoyl phenyl) propionic acid prepares the method for optically pure (S)-(+)-2-(3-benzoyl phenyl) propionic acid, it is characterized in that making by following reaction:
(1), the raceme of 2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-C
1-15Alkyl amido-D-sorbitol in the presence of organic solvent, 10～250 ℃ the reaction 0.1～10 hour, make optically pure diastereomeric salt, described C
1-15Alkyl comprise C
1-15Alkyl, C
3-8Cycloalkyl, phenyl or C
1-4Alkyl-substituted phenyl, the raceme of described 2-(3-benzoyl phenyl) propionic acid and (-)-1-deoxidation-1-C
1-15The mol ratio of alkyl amido-D-sorbitol be 1: 0.2～2;
(2), diastereomeric salt is with mineral acid or its acidified aqueous solution, filters or with the water-insoluble organic solvent extraction, makes optically pure (S)-(+)-2-(3-benzoyl phenyl) propionic acid, described mineral acid is hydrochloric acid, sulfuric acid, phosphoric acid.
2. preparation method as claimed in claim 1 is characterized in that the optically pure diastereomeric salt described in 1 (1) is through recrystallization.
3. preparation method as claimed in claim 1 is characterized in that temperature of reaction is a reflux temperature.
4. preparation method as claimed in claim 1, it is characterized in that the inorganic acid aqueous solution after the described processing of claim 1 (2), transfer to pH7.5～14 with alkali, optically pure amine promptly is precipitated out, and described alkali is yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, strong aqua, sodium hydroxide solution or potassium hydroxide solution.
5. preparation method as claimed in claim 1 is characterized in that described organic solvent is the alcohol and the aqueous solution thereof of C1-10, can use separately, and also capable of being combined or mixing is used.
6. preparation method as claimed in claim 1 is characterized in that described water-insoluble organic solvent is chloroform, methylene dichloride, ethyl acetate or ether.
7. preparation method as claimed in claim 1 is characterized in that adopting raceme, (-)-1-deoxidation-1-C of 2-(the 3-benzoyl phenyl) propionic acid that reclaims gained
1-15Alkyl amido-D-sorbitol or organic solvent.
8. preparation method as claimed in claim 1; it is characterized in that reacted mother liquor or/and the mother liquor behind the recrystallization; gained solid (R)-(-) after desolventizing-and the acid of residual a spot of (S)-(+)-2-(3-benzoyl phenyl) propionic acid and salt under normal pressure or pressurized conditions; (R)-(-)-and residual a spot of (S)-(+)-2-(the 3-benzoyl phenyl) acid of propionic acid and the mol ratio of salt and alkali be 1: 1～100; in alkali or its aqueous solution, reacted 1～15 hour; 80～250 ℃ of temperature of reaction; reaction is finished; reaction solution is with mineral acid or its acidified aqueous solution; filter or extract with water-insoluble organic solvent; reclaim 2-(the 3-benzoyl phenyl) propionic acid of racemization; described alkali is sodium hydroxide or potassium hydroxide; its concentration of aqueous solution is 1～10N, and described mineral acid is a hydrochloric acid; sulfuric acid or phosphoric acid.
9. preparation method as claimed in claim 8 is characterized in that described aqueous sodium hydroxide solution is 2～4N, and temperature of reaction is a reflux temperature, reacts under condition of normal pressure 6～8 hours.
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