CN1155553C - Process for preparing antimer of 2-fluo-alpha-methyl-[1,1'-diphenyl]-4-acetic acid - Google Patents
Process for preparing antimer of 2-fluo-alpha-methyl-[1,1'-diphenyl]-4-acetic acid Download PDFInfo
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Abstract
The present invention relates to a method for preparing the enantiomer of 2-fluoro-alpha-methyl-[1, 1'-diphenyl]-4-acetic acid, namely preparing optical pure 2-fluoro-alpha-methyl-[1, 1'-diphenyl]-4-acetic acid from the racemate of the 2-fluoro-alpha-methyl-[1, 1'-diphenyl]-4-acetic acid by a chemical resolution method. The racemate of the 2-fluoro-alpha-methyl-[1, 1'-diphenyl]-4-acetic acid reacts with (1R, 2S)-or (1S, 2R)-threo-1-R-substituent benzene basal filament propylhomoserin R<1> ester, wherein the R is NO2, CN, CH3CO, R<2>SO2, R<2>S and CF3, the R<1> is alkyl or aryl with C1 to C8, the R<2> is alkyl with C1 to C8, the generated diastereomeric salt is purified by crystallization so as to prepare the salt of optical pure some enantiomer, and the slat is processed by acid or hydrolyzed so as to be converted into (S)-(+)-or (R)-(-)-2-fluoro-alpha-methyl-[1, 1'-diphenyl]-4-acetic acid. The method has the advantages of simple method, 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-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate prepares optically pure 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate.Be a kind of 2-of making fluoro-Alpha-Methyl-[1 furtherly, 1 '-phenylbenzene]-4-acetate raceme and the diastereomeric salt of resolving agent (optically pure amine) reaction generation, again through crystallization purifying, make the salt of optically pure a certain enantiomorph, acid treatment or hydrolysis are converted into (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-short-cut method of 4-acetate or (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)-gastrointestinal toxicity of enantiomorph because (R)-existence of enantiomorph and strengthen greatly (Wechter, W.J., et al, Chirality, 1993,
5, 492).Therefore, compare with raceme, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate can just can reach identical result of treatment with less amount, and reduction is 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); And Wechter, W.J. etc. (Wechter, W.J., et al, Cancer Res., 2000,
60, 2203) and find that also (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate is the medicine of a kind of promising prevention and treatment prostate cancer.
Prepare optically pure 2-fluoro-Alpha-Methyl-[1 with chemical resolution method, 1 '-phenylbenzene]-method of 4-acetate reports in following document: Boots company limited is 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 (U.S.Pat.No.4 from raceme, 209,638); Medice Chem.-Pharm.Fabrik Putter company limited D-(-)-Su-1-p-nitrophenyl-2-aminopropane-1, the 3-glycol makes (S)-enantiomorph as resolving agent, but its optical purity has only 90-95% (U.S.Pat.No.4,973,745); PAZ Arzneimittel-Entwicklungsgesellschaft company 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%, but productive rate is lower than 50% (based on (S)-enantiomorph) (U.S.Pat.No.4,983,765); Sepracor etc. with (1R, 2S)-suitable-1-amido dihydro indenes-2-alcohol makes (S)-enantiomorph as resolving agent, its optical purity has only 44.6% (U.S.Pat.No.5,677,469); Boots company makes (R)-enantiomorph with (R)-Alpha-Methyl benzylamine as resolving agent, obtains (S)-enantiomorph (U.S.Pat.No.5,599,969) with (S)-Alpha-Methyl benzylamine as resolving agent; Zambon group usefulness (1S, 2S)-Su-1-(4-methyl thio phenyl)-2-amine-1, ammediol makes (S)-enantiomorph (U.S.Pat.No.5,840,964) as resolving agent; Usefulness N-octyl group-D-glucosamines such as woods Guoqiang make (S)-enantiomorph as resolving agent, and the ee value is 99%, productive rate be 66.8% (based on (S)-enantiomorph) (CN01113303.1).
So far, from 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-raceme of 4-acetate prepares optically pure (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-the phenylbenzene]-method of 4-acetate and 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-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate prepares optically pure (S)-(+)-or (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate.
Method of the present invention system with (1R, 2S)-or (1S, 2R)-Su Shi-1-R-substituted-phenyl Serine R
1Ester is as resolving agent, wherein R=NO
2, CN, CH
3CO, R
2SO
2, R
2S, CF
3, R
1Be C
1-8Alkyl or aryl, R
2Be C
1-8Alkyl etc.Make 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-raceme and the resolving agent of 4-acetate generate diastereomeric salt, this salt comprises the salt that (S)-enantiomorph and (R)-enantiomorph and resolving agent generate respectively, by separation and purification, can obtain optically pure (S)-(+)-or (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-salt of the enantiomorph of 4-acetate and resolving agent, optically pure (S)-(+) that will obtain-or (R)-(-)-2-fluoro-Alpha-Methyl-[1 then with mineral acid or its aqueous solution, 1 '-phenylbenzene]-salt of the enantiomorph of 4-acetate and resolving agent is converted into (S)-(+)-or (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate.
Method of the present invention is in organic solvent, and the raceme of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 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-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and resolving agent is 1: 0.2～2, and recommending mol ratio is 1: 0.4-1.
Reaction is finished, and room temperature leaves standstill crystallization, filters, and can obtain the salt of the enantiomorph of optically pure (S)-(+)-or (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and resolving agent.Described resolving agent be (1R, 2S)-or (1S, 2R)-Su Shi-1-R-substituted-phenyl Serine R
1Ester, wherein R=NO
2, CN, CH
3CO, R
2SO
2, R
2S, CF
3, R
1Be C
1-8Alkyl or aryl, R
2Be C
1-8Alkyl etc., above-mentioned (1R, 2S)-or (1S, 2R)-Su Shi-1-R-substituted-phenyl Serine R
1Ester be recommended as (1R, 2S)-or (1S, 2R)-Su Shi-1-is to methylsulfonyl Phenserine ethyl ester.
Among the present invention, adopt (1R, 2S)-Su Shi-1-R-substituted-phenyl Serine R
1During ester, obtain (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate; Adopt (1S, 2R)-Su Shi-1-R-substituted-phenyl Serine R
1Can obtain (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate during ester.
(S)-(+)-or (R)-(-)-and the optical purity of the salt of the enantiomorph of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and resolving agent 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, with dehydrated alcohol for well.
Optically pure (S)-(+)-or (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-salt of the enantiomorph 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 can utilize by racemization or/and contain the acid of another a large amount of configurations in the mother liquor of recrystallization again.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, 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-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 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-the raceme 48.8g (200mmol) of 4-acetate and (1R, 2S)-Su Shi-1-is to methylsulfonyl Phenserine ethyl ester 28.7g (100mmol), puts into reaction flask, add dehydrated alcohol 210ml, oil bath reflux 15 minutes.After reaction finished, room temperature left standstill crystallization more than 10 hours, filtered, and got white solid 44.5g.White solid is carried out recrystallization twice, salt/dehydrated alcohol is 1g/8ml, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-Su Shi-1-is to the salt 34.5g (65.0mmol) of methylsulfonyl Phenserine ethyl ester, yield 65.0%.
Get salt 34.5g (65.0mmol), put into round-bottomed flask, add 350ml 2N aqueous sulfuric acid and 230ml 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, be washed to neutrality, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 15.3g (62.7mmol) ([α]
D 20=+44.5 ° (c=1, EtOH)), the ee value is 0.99, yield is 62.7% (based on (S)-enantiomorph).
Aqueous sulfuric acid after the exchange of liquid-liquid adds strong aqua adjust pH to 8, has solid to separate out, filter, (1R, 2S)-Su Shi-1-is to methylsulfonyl Phenserine ethyl ester 18.2g (63.4mmol) ([α]
D 20=+13.6 ° (c=1, DMF)), yield 97.5% (based on salt).
Embodiment 2: racemization
Merge embodiment 1 reaction and recrystallization gained filtrate, concentrating under reduced pressure gets faint yellow solid 43g, puts into reaction flask, adds 200ml 4N sodium hydroxide solution, oil bath reflux 6 hours.After reaction finishes, be cooled to room temperature, add 70ml concentrated hydrochloric acid and 150ml ethyl acetate, stir and make the solid dissolving, carry out the exchange of liquid liquid, the aqueous solution is used ethyl acetate extraction again, and the combined ethyl acetate extraction liquid is washed to neutrality, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and gets raceme 32.2g (132.0mmol) ([α]
D 20=0 ° (c=1, EtOH)), yield 97.8%.
Embodiment 3:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Get 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-the raceme 48.8g (200mmol) of 4-acetate and (1R, 2S)-Su Shi-1-is to methylsulfonyl Phenserine ethyl ester 28.7g (100mmol), puts into reaction flask, add methyl alcohol 210ml, oil bath reflux 15 minutes.After reaction finished, room temperature left standstill crystallization more than 10 hours, filtered, and got white solid 35.7g (67.2mmol), yield 67.2%.
Gained white solid 35.7g (67.2mmol), put into beaker, add the 2150ml water dissolution, under stirring condition, drip the 710ml2N aqueous sulfuric acid then, added the back restir 15 minutes, filter, solid is washed till neutrality with less water, drying, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 15.9g (65.2mmol) ([α]
D 20=+41.0 ° (c=1, EtOH)), the ee value is 0.91, yield is 65.2% (based on (S)-enantiomorph).
Aqueous sulfuric acid after the filtration adds strong aqua adjust pH to 8, has solid to separate out, filter, (1R, 2S)-Su Shi-1-is to methylsulfonyl Phenserine ethyl ester 18.8g (65.5mmol) ([α]
D 20=+13.5 ° (c=1, DMF)), yield 97.5% (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 dehydrated alcohol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1R, 2S)-Su Shi-1-is 200mmol/200mmol/425ml to methylsulfonyl Phenserine ethyl ester/dehydrated alcohol, recrystallization solvent is a Virahol, salt/Virahol is 1g/11ml, through three recrystallizations, gets (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-Su Shi-1-is to methylsulfonyl Phenserine ethyl ester 58.7mmol.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 56.9mmol ([α]
D 20=+45.1 ° (c=1, EtOH)), the ee value is 0.99, yield is 56.9% (based on (S)-enantiomorph).
Embodiment 5:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, reaction and recrystallization solvent are 95% ethanol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1R, 2S)-Su Shi-1-is 200mmol/100mmol/160ml to methylsulfonyl Phenserine ethyl ester/95% ethanol, recrystallization is that salt/95% ethanol is 1g/5.5ml, through three recrystallizations, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-Su Shi-1-is to the salt 62.2mmol of methylsulfonyl Phenserine ethyl ester.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 60.3mmol ([α]
D 20=+44.9 ° (c=1, EtOH)), the ee value is 0.99, yield is 60.3% (based on (S)-enantiomorph).
Embodiment 6:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, reaction and recrystallization solvent are n-Octanol.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1R, 2S)-Su Shi-1-is 200mmol/100mmol/320ml to methylsulfonyl Phenserine ethyl ester/n-Octanol, recrystallization is that salt/n-Octanol is 1g/16ml, through four recrystallizations, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-Su Shi-1-is to the salt 49.8mmol of methylsulfonyl Phenserine ethyl ester.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 48.2mmol ([α]
D 20=+44.7 ° (c=1, EtOH)), the ee value is 0.99, yield is 48.2% (based on (S)-enantiomorph).
Embodiment 7:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, resolving agent is that (1R, 2S)-Su Shi-1-is to the own ester of methylsulfonyl Phenserine, reaction and recrystallization solvent are dehydrated alcohol in the reaction.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1R, 2S)-Su Shi-1-is 200mmol/100mmol/240ml to the own ester/dehydrated alcohol of methylsulfonyl Phenserine, recrystallization is that salt/dehydrated alcohol is 1g/9ml, through three recrystallizations, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-Su Shi-1-is to the salt 53.6mmol of the own ester of methylsulfonyl Phenserine.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 52.1mmol ([α]
D 20=+44.9 ° (c=1, EtOH)), the ee value is 0.99, yield is 52.1% (based on (S)-enantiomorph).
Embodiment 8:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, resolving agent is that (1R, 2S)-Su Shi-1-is to methylsulfonyl Phenserine benzyl ester, reaction and recrystallization solvent are dehydrated alcohol in the reaction.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1R, 2S)-Su Shi-1-is 200mmol/100mmol/240ml to methylsulfonyl Phenserine benzyl ester/dehydrated alcohol, recrystallization is that salt/dehydrated alcohol is 1g/8ml, through three recrystallizations, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-Su Shi-1-is to the salt 47.6mmol of methylsulfonyl Phenserine benzyl ester.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 46.5mmol ([α]
D 20=+45.1 ° (c=1, EtOH)), the ee value is 0.99, yield is 46.5% (based on (S)-enantiomorph).
Embodiment 9:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, resolving agent is that (1R, 2S)-Su Shi-1-p-nitrophenyl serine ethyl ester, reaction and recrystallization solvent are dehydrated alcohol in the reaction.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1R, 2S)-Su Shi-1-p-nitrophenyl serine ethyl ester/dehydrated alcohol is 200mmol/100mmol/200ml, recrystallization is that salt/dehydrated alcohol is 1g/8ml, through four recrystallizations, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-the salt 45.2mmol of Su Shi-1-p-nitrophenyl serine ethyl ester.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 43.8mmol ([α]
D 20=+44.6 ° (c=1, EtOH)), the ee value is 0.99, yield is 43.8% (based on (S)-enantiomorph).
Embodiment 10:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, resolving agent is that (1R, 2S)-Su Shi-1-is to methylthio group phenyl serine ethyl ester, reaction and recrystallization solvent are dehydrated alcohol in the reaction.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1R, 2S)-Su Shi-1-is 200mmol/100mmol/200ml to methylthio group phenyl serine ethyl ester/dehydrated alcohol, recrystallization is that salt/dehydrated alcohol is 1g/8ml, through three recrystallizations, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-Su Shi-1-is to the salt 52.9mmol of methylthio group phenyl serine ethyl ester.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 51.5mmol ([α]
D 20=+44.9 ° (c=1, EtOH)), the ee value is 0.99, yield is 51.5% (based on (S)-enantiomorph).
Embodiment 11:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, resolving agent is that (1R, 2S)-Su Shi-1-is to the third sulfuryl Phenserine ethyl ester, reaction and recrystallization solvent are dehydrated alcohol in the reaction.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1R, 2S)-Su Shi-1-is 200mmol/100mmol/240ml to third sulfuryl Phenserine ethyl ester/dehydrated alcohol, recrystallization is that salt/dehydrated alcohol is 1g/8.5ml, through four recrystallizations, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-Su Shi-1-is to the salt 48.5mmol of the third sulfuryl Phenserine ethyl ester.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 47.0mmol ([α]
D 20=+45.1 ° (c=1, EtOH)), the ee value is 0.99, yield is 47.0% (based on (S)-enantiomorph).
Embodiment 12:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, resolving agent is that (1R, 2S)-Su Shi-1-is to butylthio Phenserine ethyl ester, reaction and recrystallization solvent are dehydrated alcohol in the reaction.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1R, 2S)-Su Shi-1-is 200mmol/100mmol/230ml to butylthio Phenserine ethyl ester/dehydrated alcohol, recrystallization is that salt/dehydrated alcohol is 1g/9ml, through four recrystallizations, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-Su Shi-1-is to the salt 45.9mmol of butylthio Phenserine ethyl ester.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 44.3mmol ([α]
D 20=+44.8 ° (c=1, EtOH)), the ee value is 0.99, yield is 44.3% (based on (S)-enantiomorph).
Embodiment 13:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, resolving agent is that (1R, 2S)-Su Shi-1-is to the acetylphenyl serine ethyl ester, reaction and recrystallization solvent are dehydrated alcohol in the reaction.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization; 1 '-phenylbenzene]-4-acetate/(1R; 2S)-Su Shi-1-is 200mmol/100mmol/220ml to acetylphenyl serine ethyl ester/dehydrated alcohol; recrystallization is that salt/dehydrated alcohol is 1g/9ml; through four recrystallizations; (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene 1-4-acetate and (1R, 2S)-Su Shi-1-is to the salt 41.3mmol of acetylphenyl serine ethyl ester.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 39.9mmol ([α]
D 20=+44.9 ° (c=1, EtOH)), the ee value is 0.99, yield is 39.9% (based on (S)-enantiomorph).
Embodiment 14:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, resolving agent is that (1R, 2S)-Su Shi-1-is to second cyano-phenyl serine ethyl ester, reaction and recrystallization solvent are dehydrated alcohol in the reaction.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1R, 2S)-Su Shi-1-is 200mmol/100mmol/180ml to second cyano-phenyl serine ethyl ester/dehydrated alcohol, recrystallization is that salt/dehydrated alcohol is 1g/7.5ml, through four recrystallizations, A (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-Su Shi-1-is to the salt 45.9mmol of second cyano-phenyl serine ethyl ester.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 44.6mmol ([α]
D 20=+42.9 ° (c=1, EtOH)), the ee value is 0.95, yield is 44.6% (based on (S)-enantiomorph).
Embodiment 15:(S)-(+)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, resolving agent is that (1R, 2S)-Su Shi-1-p-trifluoromethyl phenyl serine ethyl ester, reaction and recrystallization solvent are dehydrated alcohol in the reaction.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1R, 2S)-Su Shi-1-p-trifluoromethyl phenyl serine ethyl ester/dehydrated alcohol is 200mmol/100mmol/220ml, recrystallization is that salt/dehydrated alcohol is 1g/8ml, through four recrystallizations, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-the salt 43.2mmol of Su Shi-1-p-trifluoromethyl phenyl serine ethyl ester.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 41.9mmol ([α]
D 20=+40.8 ° (c=1, EtOH)), the ee value is 0.91, yield is 41.9% (based on (S)-enantiomorph).
Embodiment 16:(R)-(-)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, resolving agent is that (1S, 2R)-Su Shi-1-is to methylsulfonyl Phenserine ethyl ester, reaction and recrystallization solvent are dehydrated alcohol in the reaction.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1S, 2R)-Su Shi-1-is 200mmol/100mmol/210ml to methylsulfonyl Phenserine ethyl ester/dehydrated alcohol, recrystallization is that salt/dehydrated alcohol is 1g/8ml, through three recrystallizations, (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1S, 2R)-Su Shi-1-is to the salt 68.0mmol of methylsulfonyl Phenserine ethyl ester.The salt acidifying is handled, and makes (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 66.2mmol ([α]
D 20=-44.9 ° (c=1, EtOH)), the ee value is 0.99, yield is 66.2% (based on (R)-enantiomorph).
Embodiment 17:(R)-(-)-preparation of 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate
Press embodiment 1 method, resolving agent is that (1S, 2R)-Su Shi-1-p-nitrophenyl serine ethyl ester, reaction and recrystallization solvent are dehydrated alcohol in the reaction.Reaction solution is the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate/(1S, 2R)-Su Shi-1-p-nitrophenyl serine ethyl ester/dehydrated alcohol is 200mmol/100mmol/200ml, recrystallization is that salt/dehydrated alcohol is 1g/8ml, through four recrystallizations, (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1S, 2R)-the salt 44.5mmol of Su Shi-1-p-nitrophenyl serine ethyl ester.The salt acidifying is handled, and makes (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 43.1mmol ([α]
D 20=-45.0 ° (c=1, EtOH)), the ee value is 0.99, yield is 43.1% (based on (R)-enantiomorph).
Embodiment 18:(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/(1R, 2S)-Su Shi-1-is 200mmol/100mmol/210ml to methylsulfonyl Phenserine ethyl ester/dehydrated alcohol, recrystallization is that salt/dehydrated alcohol is 1g/8ml, through three recrystallizations, (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and (1R, 2S)-Su Shi-1-is to the salt 63.9mmol of methylsulfonyl Phenserine ethyl ester.The salt acidifying is handled, and makes (S)-(+)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate 62.0mmol ([α]
D 20=+44.9 ° (c=1, EtOH)), the ee value is 0.99, yield is 62.0% (based on (S)-enantiomorph).
Ee value among the above embodiment is the HPLC method and records.
Claims (10)
1. the raceme from 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate prepares the method for optically pure 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate, it is characterized in that making by following reaction:
(1) .2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-raceme of 4-acetate and resolving agent be in the presence of organic solvent, 10～250 ℃ were reacted 0.1～10 hour, make optically pure (S)-(+)-or (R)-(-)-2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-salt of the enantiomorph of 4-acetate and resolving agent, described resolving agent be (1R, 2S)-or (1S, 2R)-Su Shi-1-R-substituted-phenyl Serine R
1Ester, wherein R=NO
2, CN, CH
3CO, R
2SO
2, R
2S, CF
3, R
1Be C
1-8Alkyl or aryl, R
2Be C
1-8Alkyl, the mol ratio of described 2-fluoro-Alpha-Methyl-[1,1 '-phenylbenzene]-4-acetate and resolving agent is 1: 0.2～2;
(2). above-mentioned optically pure 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, phosphoric acid.
2. preparation method as claimed in claim 1 is characterized in that described (1) optically pure salt need pass through the organic solvent 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 processing in described (2), transfer to pH 〉=8 with alkali, resolving agent promptly is precipitated out, and described alkali is yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, strong aqua, sodium hydroxide solution, potassium hydroxide solution.
5. the described preparation method of claim 1 is characterized in that the organic solvent in described (1) is C
1-10The alcohol and the aqueous solution thereof.
6. the described preparation method of claim 2 is characterized in that described organic solvent is C
1-10The alcohol and the aqueous solution thereof.
7. preparation method as claimed in claim 1 is characterized in that the water-insoluble organic solvent in described (2) is chloroform, methylene dichloride, ethyl acetate, ether.
8. preparation method as claimed in claim 1, it is characterized in that adopting in described (1) the 2-fluoro-Alpha-Methyl that reclaims gained-[1,1 '-phenylbenzene]-4-acetate raceme, (1R, 2S)-or (1S, 2R)-Su Shi-1-R-substituted-phenyl Serine R
1Reclaim the water-insoluble organic solvent of gained in ester or the organic solvent, described (2).
9. preparation method as claimed in claim 1, it is characterized in that reacted mother liquor or/and the mother liquor behind the recrystallization after desolventizing, the gained solid reacted 1～15 hour in alkali or its aqueous solution, 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 the 2-fluoro-Alpha-Methyl-[1 of racemization, 1 '-phenylbenzene]-4-acetate, described alkali is sodium hydroxide, potassium hydroxide, and its concentration of aqueous solution is 1～10N, and described mineral acid is hydrochloric acid, sulfuric acid, phosphoric acid.
10. preparation method as claimed in claim 9 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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