CN1181035C - Process for preparing optic pure 2-fluoro-alphar-methyl-[1,1'-diphenyl]-4-acetic acid - Google Patents
Process for preparing optic pure 2-fluoro-alphar-methyl-[1,1'-diphenyl]-4-acetic acid Download PDFInfo
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- CN1181035C CN1181035C CNB011133031A CN01113303A CN1181035C CN 1181035 C CN1181035 C CN 1181035C CN B011133031 A CNB011133031 A CN B011133031A CN 01113303 A CN01113303 A CN 01113303A CN 1181035 C CN1181035 C CN 1181035C
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Abstract
The present invention relates to a method for preparing optical pure 2-fluoro-alpha-methyl-[1, 1'-diphenyl]-4-acetic acid from a 2-fluoro-alpha-methyl-[1, 1'-diphenyl]-4-acetic acid racemic body by a chemical disassembling method. The present invention not only has a simple method, high yield and low cost, but also has complete disassembly, so the present invention is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of method for preparing optical purity 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate from 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate raceme.Be a kind of 2-of making fluoro-Alpha-Methyl-[1 furtherly, 1 '-phenylbenzene]-4-acetate raceme and the diastereomeric salt of optically pure amine reaction generation, again through crystallization purifying, acid treatment or hydrolysis are converted into (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-short-cut method of 4-acetate and (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate.
Background technology
2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 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-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate, but its pharmacologically active is inequality, so be necessary to obtain optically pure enantiomorph with a kind of simple method.Brune, K. etc. (Brune, K., et al, Experientia, 1991,
47, 257) and find 2-fluoro-Alpha-Methyl-[1,1 '-the phenylbenzene]-antiphlogistic activity of 4-acetate mainly from its (S)-enantiomorph, (R)-enantiomorph then lacks significant cyclooxygenase and suppresses active; In addition, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-gastrointestinal toxicity of 4-acetate because (R)-(-)-existence of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and strengthen greatly (Wechter, W.J., et al, Chirality, 1993,
5, 492).Therefore, compare with raceme, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-amount that 4-acetate can be less just can reach identical result of treatment, and reduce owing to use the side effect that (R)-enantiomorph brings in the raceme.
On the other hand, (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate can block the injured induction of mouse, show that it has different pain relieving mechanism, therefore (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate might use (Brune as anodyne, K., et al, Experientia, 1991
47, 257).
The method for preparing optically pure 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate with chemical resolution method is mentioned in some documents.
U.S.Pat.No.4,209,638 (The Boots Company Limited) are by heating 2-fluoro-Alpha-Methyl-[1 in appropriate solvent, 1 '-phenylbenzene]-raceme of 4-acetate and the salt of nitrogenous organic base (for example Alpha-Methyl benzylamine), can from raceme, improve the ratio of needed enantiomorph, but in certain embodiments, reaction conditions is very violent, heat a couple of days as reflux temperature, and do not allow to obtain optically pure compound from raceme.
U.S.Pat.No.4,973,745 (Medice Chem.-Pharm.Fabrik Putter GmbH ﹠amp; Co.KG) with optically pure Soviet Union-1-p-nitrophenyl-2-aminopropane-1, the 3-glycol is as resolving agent, make (S)-enantiomorph from the raceme of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate, but its optical purity has only 90-95%.
U.S.Pat.No.4,983,765 (PAZ Arzneimittel-Entwicklungsgesellschaft mbH) with phenylethylamine as resolving agent from 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-make (S)-enantiomorph in the mixture of the raceme of 4-acetate or (S)-and (R)-enantiomorph, though its optical purity is greater than 99%, productive rate lower (being lower than 50%).
U.S.Pat.No.5,677,469 (Sepracor Inc.) makes (S)-enantiomorph with optically pure 1-amido dihydro indenes-2-alcohol as resolving agent, and its optical purity has only 44.6%.
U.S.Pat.No.5,599,969 (The Boots Company PLC) make (R)-enantiomorph as resolving agent from the raceme of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate with (R)-Alpha-Methyl benzylamine, obtain (S)-enantiomorph with (S)-Alpha-Methyl benzylamine as resolving agent.
U.S.Pat.No.5,840,964 (Zambon Group S.P.A.) are with optically pure Soviet Union-1-(4-methyl thio phenyl)-2-amine-1, and ammediol makes (S)-enantiomorph as resolving agent.
U.S.Pat.No.4,246,164 (Syntex Corporation) N-methyl D-glucosamine, U.S.Pat.No.4,246,193 and 4,515,811 (Syntex Corporation) prepare optically pure Naproxen Base with other N-alkyl-D-glucosamine as resolving agent.
U.S.Pat.No.5,621,140 (Syntex (U.S.A.) Inc.) split Ibuprofen BP/EP with N-methyl D-glucosamine and N-octyl group-D-glucosamine, (S)-and the productive rate of Ibuprofen BP/EP is respectively 73.2% and 74%, and its ee value is respectively 99% and 99.9%.
Summary of the invention
Purpose of the present invention just provides a kind of from 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate raceme prepares optically pure (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-method of 4-acetate, be usefulness (-)-1-deoxidation-1-C
1-15Alkyl amido-D-sorbitol or (+)-dehydroabietylamine as resolving agent, described C
1-15Alkyl comprise C
1-15Alkyl, C
3-8Cycloalkyl, phenyl, C
1-4Alkyl-substituted phenyl etc.Make 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate raceme and optically pure amine generates optically pure (+)-(S)-or (-)-(R)--2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-the diastereomeric salt of 4-acetate and resolving agent, the separable purifying of this salt, the pure diastereomer that will obtain with mineral acid or its aqueous solution is converted into (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate.
Method of the present invention is in organic solvent, 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-raceme of 4-acetate and optically pure amine 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.Reaction is finished, and room temperature leaves standstill crystallization, filters, and can obtain optically pure (+)-(S)-or (-)-(R)--the diastereomeric salt of diastereomeric salt of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and resolving agent.Described optically pure amine is (-)-1-deoxidation-1-C
1-15Alkyl amido-D-sorbitol and (+)-dehydroabietylamine, 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.The mol ratio of described 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and optically pure amine is 1: 0.2～2, and recommending mol ratio is 1: 0.5-1.
Described organic solvent is C
1-10Alcohol and the aqueous solution, C
3-10The ketone and the aqueous solution thereof, can use separately, also capable of being combined or mix to use, be recommended as Virahol.
Among the present invention, adopt (-)-1-deoxidation-1-C
1-15Alkyl amido-D-sorbitol the time, obtain (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate; Can obtain (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate when adopting (+)-dehydroabietylamine.
Optically pure (+)-(S)-or (-)-(R)--2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-optical purity of the diastereomeric salt of 4-acetate and resolving agent is not if reach requirement, can carry out repeatedly recrystallization till reach requirement in organic solvent, described organic solvent is C
1-10Alcohol and the aqueous solution, C
3-10The ketone and the aqueous solution thereof, can use separately, also capable of being combined or mix to use, be recommended as Virahol.
Optically pure (+)-(S)-or (-)-(R)--2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-the diastereomeric salt of 4-acetate and resolving agent is with mineral acid or its acidified aqueous solution, transfer pH≤6, recommending pH is 0.5～3, (S)-(+)-or (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-the phenylbenzene]-4-acetate that dissociates filters or extracts with water-insoluble organic solvent, can obtain optically pure (S)-(+)-or (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate.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 or/and contain in the mother liquor of recrystallization a large amount of (R)-(-)-and residual a spot of (S)-(+)-acid and salt, can utilize again by racemization.Be about to that mother liquor concentrates, the evaporated under reduced pressure solvent, the gained solid is under normal pressure or pressurized conditions, in alkali or its aqueous solution, reacted 1～15 hour, 80～250 ℃ of temperature of reaction, 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 the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate, its composition is identical with starting raw material, recycling preparation (S)-or (R)-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 pH 〉=8 with alkali, optically pure amine 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-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 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.
Embodiment 1:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Get the raceme 100g (409mmol) and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol 60g (204.5mmol) of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate, put into reaction flask, add Virahol 1500ml, oil bath reflux 15 minutes.After reaction finished, room temperature left standstill crystallization more than 10 hours, filtered, and got white solid 95g (177mmol) ([α]
D 20=-17.8 ° (c=1, MeOH)), yield 86.4%.
Above-mentioned white solid is through twice recrystallization, and salt/Virahol is 1g/13.5ml, gets white solid 80g (149mmol) ([α]
D 20=-19.0 ° (c=1, MeOH)), yield 72.7%.
Get crystallization gained solid 80g (149mmol) for the third time, put into round-bottomed flask, add 900ml2N aqueous sulfuric acid and 600ml ethyl acetate, stirring makes the solid dissolving, carry out liquid-liquid exchange, the aqueous solution is used ethyl acetate extraction again, the combined ethyl acetate extraction liquid, washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 33.4g (137mmol) ([α]
D 20=+44.5 ° (c=1, EtOH)), the ee value is 0.99, and yield is 66.8% (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 42.8g (146mmol) ([α]
D 20=-15.1 ° (c=1, MeOH)), yield 97.9% (based on salt).
Embodiment 2: racemization
Merge embodiment 1 reaction and recrystallization gained filtrate, concentrating under reduced pressure gets faint yellow solid 80g, puts into reaction flask, adds the 400ml4N 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 59.7g ([α]
D 20=0 ° (c=1, MeOH)), yield 93.8%.
Embodiment 3:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Get 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-the raceme 100g (409mmo1) and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol 60g (204.5mmol) of 4-acetate, put into reaction flask, add dehydrated alcohol 1400ml, oil bath reflux 15 minutes.After reaction finished, room temperature left standstill crystallization more than 10 hours, filtered, and got white solid 59.2g (110mmol) ([α]
D 20=-18.3 ° (c=1, MeOH)), yield 53.6%.
Gained white solid 59.2g (110mmol) puts into round-bottomed flask, adds the 670ml2N aqueous sulfuric acid, stirs 2 hours, filter, solid is washed drying with a small amount of, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 25.2g (103mmol) ([α]
D 20=+42.6 ° (c=1, EtOH)), the ee value is 0.95, and yield is 50.4% (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 31.4g (107mmol) ([α]
D 20=-15.1 ° (c=1, MeOH)), yield 97.2% (based on salt).
Embodiment 4:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, reaction solvent is a Virahol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-n-octyl amine base-D-sorbitol/Virahol is 100mmol/50mmol/360ml, recrystallization solvent is a dehydrated alcohol, salt/dehydrated alcohol is 1g/12ml, through twice recrystallization, the salt 30.1mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol
D 20=-18.9 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 27.6mmol ([α]
D 20=+44.9 ° (c=1, EtOH)), the ee value is 0.99, and yield is 55.2% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 5:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, reaction and recrystallization solvent are anhydrous methanol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-n-octyl amine base-D-sorbitol/anhydrous methanol is 100mmol/100mmol/340ml, recrystallization is that salt/anhydrous methanol is 1g/11.5ml, through three recrystallizations, the salt 23.9mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol
D 20=-18.7 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 21.8mmol ([α]
D 20=+44.9 ° (c=1, EtOH)), the ee value is 0.99, and yield is 41.6% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 6:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine is (-)-1-deoxidation-1-ethylamino--D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-ethylamino--D-sorbitol/Virahol is 100mmol/50mmol/270ml, recrystallization is that salt/Virahol is 1g/8ml, through four recrystallizations, the salt 12.2mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-ethylamino--D-sorbitol
D 20=-18.3 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 11.3mmol ([α]
D 20=+41.9 ° (c=1, EtOH)), the ee value is 0.93, and yield is 22.6% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 7:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine is (-)-1-deoxidation-1-isobutyl amine-D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-isobutyl amine-D-sorbitol/Virahol is 100mmol/50mmol/290ml, recrystallization is that salt/Virahol is 1g/9ml, through four recrystallizations, the salt 18.4mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-isobutyl amine-D-sorbitol
D 20=-17.4 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 16.9mmol ([α]
D 20=+40.7 ° (c=1, EtOH)), the ee value is 0.90, and yield is 33.8% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 8:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine is (-)-1-deoxidation-1-normal hexyl Amine base-D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-normal hexyl Amine base-D-sorbitol/Virahol is 100mmol/50mmol/330ml, recrystallization is that salt/Virahol is 1g/11ml, through twice recrystallization, the salt 29.7mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-normal hexyl Amine base-D-sorbitol
D 20=-18.8 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 26.8mmol ([α]
D 20=+44.8 ° (c=1, EtOH)), the ee value is 0.99, and yield is 53.6% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 9:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine 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 the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-the positive amino dodecane base of 4-acetate/(-)-1-deoxidation-1--D-sorbitol/Virahol is 100mmol/50mmol/390ml, recrystallization is that salt/Virahol is 1g/14.5ml, through twice recrystallization, the salt 26.1mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and the positive amino dodecane base of (-)-1-deoxidation-1--D-sorbitol
D 20=-17.9 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 24.3mmol ([α]
D 20=+44.0 ° (c=1, EtOH)), the ee value is 0.98, and yield is 48.6% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 10:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine is (-)-1-deoxidation-1-cyclohexylamino-D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-cyclohexylamino-D-sorbitol/Virahol is 100mmol/50mmol/320ml, recrystallization is that salt/Virahol is 1g/10.5ml, through three recrystallizations, the salt 21.7mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-cyclohexylamino-D-sorbitol
D 20=-19.2 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 19.6mmol ([α]
D 20=+45.0 ° (c=1, EtOH)), the ee value is 0.99, and yield is 39.2% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 11:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine is (-)-1-deoxidation-1-anilino-D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-anilino-D-sorbitol/Virahol is 100mmol/50mmol/310ml, recrystallization is that salt/Virahol is 1g/10ml, through three recrystallizations, the salt 18.4mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-anilino-D-sorbitol
D 20=-15.7 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 16.9mmol ([α]
D 20=+39.8 ° (c=1, EtOH)), the ee value is 0.88, and yield is 33.8% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 12:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine is (-)-1-deoxidation-1-benzamido group-D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-benzamido group-D-sorbitol/Virahol is 100mmol/50mmol/330ml, recrystallization is that salt/Virahol is 1g/10ml, through three recrystallizations, the salt 15.8mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-benzamido group-D-sorbitol
D 20=-15.5 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 14.8mmol ([α]
D 20=+41.5 ° (c=1, EtOH)), the ee value is 0.92, and yield is 29.6% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 13:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine is (-)-1-deoxidation-1-phenylpropyl alcohol amido-D-sorbitol in the reaction, and reaction and recrystallization solvent are Virahol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-phenylpropyl alcohol amido-D-sorbitol/Virahol is 100mmol/50mmol/350ml, recrystallization is that salt/Virahol is 1g/11ml, through three recrystallizations, the salt 17.8mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-phenylpropyl alcohol amido-D-sorbitol
D 20=-15.7 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 16.4mmol ([α]
D 20=+40.8 ° (c=1, EtOH)), the ee value is 0.91, and yield is 32.8% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 14:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine is (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol in the reaction, and reaction and recrystallization solvent are 95% ethanol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-n-octyl amine base-D-sorbitol/95% ethanol is 100mmol/50mmol/330ml, recrystallization is that salt/95% ethanol is 1g/9ml, through twice recrystallization, the salt 22.9mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol
D 20=-18.8 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 21.3mmol ([α]
D 20=+45.1 ° (c=1, EtOH)), the ee value is 0.99, and yield is 42.6% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 15:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine is (-)-1-deoxidation-1-normal hexyl Amine base-D-sorbitol in the reaction, and reaction and recrystallization solvent are n-hexyl alcohol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-normal hexyl Amine base-D-sorbitol/n-hexyl alcohol is 100mmol/50mmol/390ml, recrystallization is that salt/n-hexyl alcohol is 1g/14.5ml, through three recrystallizations, the salt 19.2mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-normal hexyl Amine base-D-sorbitol
D 20=-18.6 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 17.3mmol ([α]
D 20=+44.9 ° (c=1, EtOH)), the ee value is 0.99, and yield is 34.6% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 16:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine is (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol in the reaction, and reaction and recrystallization solvent are n-Octanol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-n-octyl amine base-D-sorbitol/n-Octanol is 100mmol/50mmol/400ml, recrystallization is that salt/n-Octanol is 1g/14ml, through three recrystallizations, the salt 15.3mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol
D 20=-19.0 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 13.8mmol ([α]
D 20=+44.9 ° (c=1, EtOH)), the ee value is 0.99, and yield is 27.6% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 17:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine is (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol in the reaction, and reaction and recrystallization solvent are 90% acetone.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-n-octyl amine base-D-sorbitol/90% acetone is 100mmol/50mmol/280ml, recrystallization is that salt/90% acetone is 1g/9ml, through three recrystallizations, the salt 14.3mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol
D 20=-18.7 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 12.9mmol ([α]
D 20=+44.6 ° (c=1, EtOH)), the ee value is 0.98, and yield is 25.8% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 18:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, optically pure amine is (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol in the reaction, and reaction and recrystallization solvent are methyln-hexyl ketone.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-n-octyl amine base-D-sorbitol methyln-hexyl ketone is 100mmol/50mmol/360ml, recrystallization is that salt/methyln-hexyl ketone is 1g/12.5ml, through four recrystallizations, the salt 10.9mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol
D 20=-19.1 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 9.9mmol ([α]
D 20=+44.4 ° (c=1, EtOH)), the ee value is 0.98, and yield is 19.8% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 19:(R)-(-)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Get 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-the raceme 100mmol of 4-acetate and (+)-dehydroabietylamine 100mmol, put into reaction flask, add methyl alcohol 190ml, stirred overnight at room temperature, removal of solvent under reduced pressure gets salt 41.3mmol, uses recrystallizing methanol then, and salt/methyl alcohol is 1g/5ml, through four recrystallizations, all the other operations make (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 26.8mmol ([α] with embodiment 1
D 20=-32.9 ° (c=1, EtOH)), the ee value is 0.73, and yield is 53.6% (based on (R)-enantiomorph), and chemical purity is greater than 98%.
Embodiment 20:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, reaction substrate and solvent are the recovery gained.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(-)-1-deoxidation-1-n-octyl amine base-D-sorbitol/Virahol is 100mmol/50mmol/360ml, recrystallization is that salt/Virahol is 1g/13.5ml, through twice recrystallization, the salt 35.0mmol ([α] of (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (-)-1-deoxidation-1-n-octyl amine base-D-sorbitol
D 20=-18.9 ° (c=1, MeOH)).The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 32.2mmol ([α]
D 20=+44.9 ° (c=1, EtOH)), the ee value is 0.99, and yield is 64.4% (based on (S)-enantiomorph), and chemical purity is greater than 98%.
Ee value among the above embodiment is the HPLC method and records.
Claims (9)
1. one kind prepares the method for optical purity 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate from 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate raceme, it is characterized in that deoxidation-1-C with (-)-1-
1-15Alkyl amido-D-sorbitol or (+)-dehydroabietylamine as resolving agent, described C
1-15Alkyl be C
1-15Alkyl, C
3-8Cycloalkyl, phenyl or C
1-4Alkyl-substituted phenyl.
2. the method for claim 1 is characterized in that making by following reaction:
(1) .2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate raceme and resolving agent be in the presence of organic solvent, 10～250 ℃ were reacted 0.1～10 hour, make (S)-(+) or (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-the optically pure diastereomeric salt of 4-acetate, described resolving agent is (-)-1-deoxidation-1-C
1-15Alkyl amido-D-sorbitol or (+)-dehydroabietylamine, the mol ratio of described 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and resolving agent is 1: 0.2～2;
(2). diastereomeric salt is with mineral acid or its acidified aqueous solution, filter or extract with water-insoluble organic solvent, make optically pure (S)-(+)-or (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate, described mineral acid is hydrochloric acid, sulfuric acid or phosphoric acid.
3. preparation method as claimed in claim 2 is characterized in that the optically pure diastereomeric salt described in (1) is through recrystallization.
4. preparation method as claimed in claim 2 is characterized in that temperature of reaction is a reflux temperature.
5. preparation method as claimed in claim 2, it is characterized in that the inorganic acid aqueous solution after (2) described processing, transfer to pH 〉=8 with alkali, be settled out resolving agent, described alkali is yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, strong aqua, sodium hydroxide solution or potassium hydroxide solution.
6. as claim 2 or 3 described preparation methods, it is characterized in that with described preparation feedback or/and the mother liquor evaporated under reduced pressure solvent of recrystallization, the gained solid is under normal pressure or pressurized conditions, 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-fluoro-Alpha-Methyl-[1,1 '-the phenylbenzene]-4-acetate of racemization, described alkali is sodium hydroxide, potassium hydroxide, its concentration of aqueous solution is 1～10N, and described mineral acid is a hydrochloric acid, sulfuric acid or phosphoric acid.
7. preparation method as claimed in claim 2, the organic solvent that it is characterized in that described (1) is C
1～10Alcohol and the aqueous solution or C
3-10The ketone and the aqueous solution thereof, can use separately, also capable of being combined or mix to use.
8. preparation method as claimed in claim 2 is characterized in that described water-insoluble organic solvent is chloroform, methylene dichloride, ethyl acetate or ether.
9. preparation method as claimed in claim 2 is characterized in that 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate raceme, (-)-1-deoxidation-1-C
1-15Alkyl amido-D-sorbitol, (+)-dehydroabietylamine and organic solvent be to reclaim gained.
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| CNB011133031A CN1181035C (en) | 2001-07-06 | 2001-07-06 | Process for preparing optic pure 2-fluoro-alphar-methyl-[1,1'-diphenyl]-4-acetic acid |
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| CNB011133031A CN1181035C (en) | 2001-07-06 | 2001-07-06 | Process for preparing optic pure 2-fluoro-alphar-methyl-[1,1'-diphenyl]-4-acetic acid |
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