CN1623980A - Method for preparing optical pure N-tertiary butyl oxycarbonyl-beta-difluorine phenylalanine - Google Patents
Method for preparing optical pure N-tertiary butyl oxycarbonyl-beta-difluorine phenylalanine Download PDFInfo
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- CN1623980A CN1623980A CN 200310109061 CN200310109061A CN1623980A CN 1623980 A CN1623980 A CN 1623980A CN 200310109061 CN200310109061 CN 200310109061 CN 200310109061 A CN200310109061 A CN 200310109061A CN 1623980 A CN1623980 A CN 1623980A
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- fluorophenylalanine
- tertiary butyl
- oxygen carbonyl
- butyl oxygen
- ben yian
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- 230000003287 optical effect Effects 0.000 title claims description 21
- 238000000034 method Methods 0.000 title description 15
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 title description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 title description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- QOOQLKSEGVNYLA-UHFFFAOYSA-N 1-$l^{1}-oxidanylbutane Chemical group CCCC[O] QOOQLKSEGVNYLA-UHFFFAOYSA-N 0.000 claims description 38
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 13
- 238000000605 extraction Methods 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- -1 salt compound Chemical class 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000013507 mapping Methods 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 238000011084 recovery Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 description 11
- 238000005194 fractionation Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 239000003814 drug Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000003672 processing method Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 238000011914 asymmetric synthesis Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 2
- 229960004770 esomeprazole Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Abstract
A process for preparing the optical-purity N-tert-butyloxycarbonyl-beta-difluorophenylalanine includes such steps as reaction between optical-purity R-(+)-alpha-phenylethane or S-(-)-alpha-phenylethane and the recemate of N-tert-butyloxycarbonyl-beta-difluorophenylalanine, separating, and acidifying to obtain R (or S)-N-tert-butyloxy carbonyl-beta-difluorophenylanine.
Description
Technical field: the present invention relates to a kind of preparation method of optical purity two fluorophenylalanine, particularly a kind of racemic modification optical resolution with chipal compounds is used to prepare the method for optical purity N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine.
Background technology: chirality is one of natural essential attribute.Constituting some important biomacromolecules of life system, as protein, polysaccharide, nucleic acid and enzyme etc., almost is chirality entirely.Therefore, the intravital molecular recognition system of life often can be distinguished two enantiomorphs, and their effect and reactions in vivo exist tangible difference.This shows that in new drug research, the compound that obtains optical purity (or mapping is pure) seems very necessary for chemistry, biology or pharmacological application purpose.In the chemicals that uses at present, major part also has chirality, its pharmacological action be by and body in strict chirality coupling and molecular recognition between the macromole realize.Have chiral compounds to contain two chemical structures and physical structure identical, and the different isomer of optical texture, i.e. enantiomorph (genus optical isomer).As a rule, biological effect and pharmacological action with two kinds of enantiomorphs in the medicine of optical isomer have very big difference, have only a kind of enantiomorph that pharmacological action is arranged usually.
Rose in 1992, FDA (Food and Drug Adminstration) (FDA) is regulation just, must all will narrate clear to the effect of each isomer when declaring chiral drug.Since the nineties, the kind of chiral drug and sales volume sharp increase, chiral drug is being contained huge market and is being impelled the chiral technology revolution.Chiral technology is exactly the method that use to split, the method and the asymmetry catalysis method of chiral adjuvant, with invalid in the medicine, poor efficiency or there is the enantiomorph of side effect to remove, is prepared into the homochiral medicine with single oriented structure (single enantiomer).This class pharmaceutical cpd is purer, rapid-action, short treating period when the treatment disease.As novel proton pump inhibitor esomeprazole (esomeprazole), be exactly the pure levoisomer of omeprazole.
Though method of asymmetric synthesis is the modern a kind of important method that obtains chipal compounds, and obtained developing fast, asymmetric synthesis is fired one's imagination really from angle of aesthetics, goes in the suitability for industrialized production but can really be applied in the existing method of asymmetric synthesis, and is still rarely found.Disassemble technique is a kind of method of more traditional acquisition chipal compounds, and the chipal compounds that great majority have formed industrial scale production all obtain by chiral separation.
A-amino acid is the important source material of synthetic biologically active peptide, also is the valuable chiral source of a class in the asymmetric synthesis.The method that obtains the pure a-amino acid of mapping is a lot, and for example, studying more asymmetric hydrogenation recently is exactly an example, and it generally obtains structure earlier and is
Intermediate.Then, add chirality assistant agent and hydrogenation catalyst, optionally obtain wherein a kind of dominant configuration.
In addition, the method for utilizing Evans or Myers to grow up also can obtain the pure a-amino acid of mapping; The chiral separation technology has obtained general application in the pure a-amino acid of two kinds of mappings of acquisition, relatively Chang Yong chiral separation technology has: formation and the fractionation that separates diastereoisomer, chromatography split, form the fractionation of mixture etc.
Phenylalanine is owing to the existence of its side-chain benzene ring, and it has brought into play important effect in part-receptor acting.Therefore hydrogen atom is replaced by fluorine on the phenyl ring, does not change the atom size, but has changed the πDian Zi cloud on the phenyl ring, has just changed the effect between phenyl ring and the acceptor, and in many peptide chains with physiological action, containing fluorophenylalanine usually is its active centre.In a series of polypeptide compounds of our synthetic, need a large amount of pure β-two fluorophenylalanine of mapping of preparation.
That related to the present invention is the preparation method of the pure N-tertiary butyl of mapping oxygen carbonyl-β-two fluorophenylalanine, target compound I, and II, its structural formula is:
Compound I (S-configuration), or Compound I I (R-configuration)
Wherein, (F)
2---represent two and be arranged in fluorine atom on any position of phenyl ring.Be positioned at prosposition on the phenyl ring or 2,4 or 2,5 or 2,6 or 3,4 or 3,5 etc. as, F atom.
Document have report (J.Am.Chem.Soc.1994:116, β 4101-4102)-two fluorophenylalanine obtain wherein a kind of enantiomorph by asymmetric hydrogenation, shown in 1:
Formula 1.
This reaction needed with a kind of catalyzer that contains Rh (I) hydrogenation reaction at normal temperatures, obtains the e.e. value and is 96.2% enantiomorph under 30～40Psi pressure.
In above-mentioned route, reaction need under high pressure be carried out, and the difficult preparation of employed catalyzer, and this is in industrial very difficult realization.And, can only obtain a kind of enantiomorph at last, use to such an extent that raw material also is difficult to obtain in the reaction.In addition, (Tetrahydron, lett.2002 923-928) utilize enzymatic hydrolysis method to obtain, but this method is difficult to carry out industrialized production bibliographical information.
Summary of the invention: the technical issues that need to address of the present invention are: solved two enantiomorphs of existing raceme and split problem; solved the too high problem of cost that exists in the existing chirality synthetic technology; having solved existing chirality synthetic technology needs high pressure and uses chemical reagent and the catalyzer problem that is difficult to obtain; solved the problem that existing chirality synthetic technology can only obtain a kind of chirality enantiomorph; solved the mass-producing of chirality enantiomorph Phenylalamine derivatives involved in the present invention; repeatability production problem.
Thinking of the present invention is: by enantiomorph resolving agent R-(+)-α-Ben Yian or S-(-)-α-Ben Yian and the effect of β-two fluorophenylalanine, obtain optically pure R-(+)-β-two fluorophenylalanine or S-(-)-β-two fluorophenylalanine.This technological operation is simple, and is convenient and easy, is fit to very much the suitability for industrialized production requirement.
Technical scheme of the present invention: the present invention relates to a kind of optically pure N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine preparation method, its operational path is
Steps A:
Compound (I) (S)-α-Ben Yian salt compound (I)
Step B:
Compound (II) (R)-α-Ben Yian salt compound (II)
The present invention adopts racemic N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine (Compound I, II) be raw material, with the pure R-of resolving agent mapping (+)-α-Ben Yian or S-(-)-α-Ben Yian reaction, obtain compound (I) S-α-Benzethonium salt or compound (II) R-α-Benzethonium salt, acidified again extraction obtains compound (I) (S-configuration, the optical purity free ammonia) and Compound I I (R-configuration, optical purity free ammonia).To the recovery resolving agent that alkalizes of the water behind the acidizing extraction.
In the chiral separation technology involved in the present invention, racemize N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine and S-(-)-α-Ben Yian effect obtains the described crystal salt of technology (I), mother liquor (I).S-(-)-α-Ben Yian consumption is 1 molar equivalent.Solvent adopts ethyl acetate, and consumption is 1.0mL～3.0mL ethyl acetate/every gram N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine.Temperature adopts room temperature (20～30 ℃) to reflux temperature.Citric acid solution is adopted in acidifying, and organic phase is an extraction agent with ethyl acetate, methylene dichloride, ether.Alkaline matter is adopted in alkalization, as solution such as sodium hydroxide, potassium hydroxide, lithium hydroxides.
Racemize N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine and R-(+)-α-Ben Yian effect, processing mode is the same.
The present invention can repeatedly split for improving productive rate, and method for dividing and processing is the same.
The invention has the beneficial effects as follows: the present invention has used chiral separation solvent and the effect of racemize N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine that is easy to get, one-tenth salts out, through acidifying, extraction has obtained optically pure N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine S configuration and R configuration respectively, the simple easy handling of technology of the present invention, the efficient height, good reproducibility can be used for large-scale preparation.
Description of drawings:
Accompanying drawing is a chiral separation process flow sheet of the present invention.
Among the figure: the S-phenylethylamine is S-(-)-α-Ben Yian, and the R-phenylethylamine is R-(+)-α-Ben Yian,
Pure S-type amino acid is optical purity S-(-)-β-two fluorophenylalanine, and pure R-type amino acid promptly
Be optical purity R-(+)-β-two fluorophenylalanine.
Embodiment: with reference to accompanying drawing,
Embodiment 1
The fractionation of N-tertiary butyl oxygen carbonyl-3.5-two fluorophenylalanine
N-tertiary butyl oxygen carbonyl-3.5-two fluorophenylalanine (20.46g, 68mmol), be dissolved in the ethyl acetate (50mL), reaction is from room temperature, be heated to 77 ℃ of backflows, solid dissolves fully, drips S-(-)-α-Ben Yian (8.22g, 68mmol) cool to room temperature slowly, placement is spent the night, there are a large amount of white solids to separate out, filter, get crystal salt (9.08g), recrystallization once in ethyl acetate, resulting ammonium salt { [α]=37.8 ° (c=2, EtOH) } extracts in ethyl acetate/citric acid ice solution, obtains (S)-N-tertiary butyl oxygen carbonyl-3.5-two fluorophenylalanine (5.92g, e.e 98.8%, yield 58%), and [α]=-2.2 ° (c=1, MeOH).[annotate: the e.e. value records on the asymmetric post of Daicel OJ 0.46*25cm, and moving phase is cyclohexane: Virahol=95: 5 (containing 0.2%TFA), 30 ℃ of column temperatures]
Merge and split for the first time and recrystallization mother liquor, free acid mixt (14.31g) with ethyl acetate/R-configuration that the aqueous citric acid solution extraction obtains, without purification, directly split: free acid (14.31g with R-(+)-α-Ben Yian, 47.6mmol) be dissolved in fully in the ethyl acetate of 30mL, add R-(+)-α-Ben Yian (5.75g, 47.6mmol) place and spend the night, obtain white solid (17.32g), [α]=-32.9 ° (c=1, EtOH) recrystallization in ethyl acetate, resulting amine salt extracts in ethyl acetate/aqueous citric acid solution, obtains R-N-tertiary butyl oxygen carbonyl-3.5-two fluorophenylalanine (7.24g, e.e.95.3%, yield 71%), and [α]=+ 2.1 ° (c=1, MeOH).
The solution that merges fractionation for the second time and recrystallization once more, obtain the free acid mixt (6.82g) of S-configuration with ethyl acetate/aqueous citric acid solution extraction, without purification, directly S-(-)-α-Ben Yian splits: free acid (6.82g, 22.7mmol) be dissolved in fully in the ethyl acetate (15mL), add S-(-)-α-Ben Yian (2.74g, 22.7mmol) place and spend the night, obtain solid (6.26g), recrystallization once, the amine salt of gained extracts in ethyl acetate/aqueous citric acid solution, obtains S-N-tertiary butyl oxygen carbonyl-3.5-two fluorophenylalanine (2.76, e.e:95.7%), S-amino acid total recovery is 84%.
The solution that merges fractionation for the third time and recrystallization obtains the free acid mixt (3.8g) of R-configuration with ethyl acetate/aqueous citric acid solution extraction; All waters are alkalized, and basifier is a sodium hydroxide, reclaims S-(-)-α-Ben Yian (9.5g), R-(+)-α-Ben Yian (5.2g).
1H?NMR(400MHz，DMSO-d
6)：12.69(brs，1H)，7.12(d，J＝8.8Hz，1H)，6.95(m，3H)，4.12(m，1H)，3.05(dd，J＝14.0?&?4.4Hz，1H)，2.93(dd，J＝14.0&10.8Hz，1H)1.29(s，9H)；MS：302(M
++1)。
Embodiment 2
The fractionation of N-tertiary butyl oxygen carbonyl-2.3-two fluorophenylalanine
Adopt the processing method identical to split N-tertiary butyl oxygen carbonyl-2.4-two fluorophenylalanine with the foregoing description 1.Extraction agent adopts methylene dichloride, and the reaction reagent consumption should carry out according to above-mentioned example 1 described reaction equivalent, and Heating temperature is 50 ℃, and the water basifier is selected lithium hydroxide for use, and the result is the same substantially.[annotate: the e.e. value records on the asymmetric post of DaicelOJ 0.46*25cm, and moving phase is 95: the 5=cyclohexane: Virahol (containing 0.2%TFA), 30 ℃ of column temperatures.]
1H?NMR(400MHz，DMSO-d
6)：12.62(brs，1H)，7.30(m，2H)，7.13(d，J＝8.8Hz，1H)，7.10(m，1H)，4.10(m，1H)，3.08(dd，J＝14.0&4.4Hz，1H)，2.92(dd，J＝14.0&10.0Hz，1H)1.28(s，9H)；MS：302(M
++1)。
Embodiment 3
The fractionation of N-tertiary butyl oxygen carbonyl-2.4-two fluorophenylalanine
Adopt the processing method identical to split N-tertiary butyl oxygen carbonyl-3.4-two fluorophenylalanine with the foregoing description 1.Extraction agent adopts ether, and the reaction reagent consumption should carry out according to above-mentioned example 1 described reaction equivalent, and Heating temperature is 60 ℃, and the water basifier is selected potassium hydroxide for use, and the result is the same substantially.[annotate: the e.e. value records on the asymmetric post of DaicelOJ 0.46*25cm, and moving phase is 95: the 5=cyclohexane: Virahol (containing 0.2%TFA), 30 ℃ of column temperatures.]
1H?NMR(400MHz，DMSO-d
6)：12.67(brs，1H)，7.12(d，J＝8.8Hz，1H)，6.95(m，3H)，4.12(m，1H)，3.05(dd，J＝14.0&4.4Hz，1H)，2.93(dd，J＝14.0&10.8Hz，1H)1.29(s，9H)；MS：302(M
++1)。
Embodiment 4
The fractionation of N-tertiary butyl oxygen carbonyl-2.5-two fluorophenylalanine
Adopt the processing method identical to split N-tertiary butyl oxygen carbonyl-2.5-two fluorophenylalanine with the foregoing description 1.The reaction reagent consumption should carry out according to above-mentioned example 1 described reaction equivalent, and the result is the same substantially.[annotate: the e.e. value records on the asymmetric post of Daicel OJ 0.46*25cm, and moving phase is 95: the 5=cyclohexane: Virahol (containing 0.2%TFA), 30 ℃ of column temperatures.]
1H?NMR(400MHz，DMSO-d
6)：12.63(brs，1H)，7.21(m，1H)，7.12(d，J＝8.8Hz，1H)，7.08(m，3H)，4.10(m，1H)，3.05(dd，J＝14.0&4.4Hz，1H)，2.92(dd，J＝14.0&10.8Hz，1H)1.28(s，9H)；MS：302(M
++1)。
Embodiment 5
The fractionation of N-tertiary butyl oxygen carbonyl-2.6-two fluorophenylalanine
Adopt the processing method identical to split N-tertiary butyl oxygen carbonyl-2.5-two fluorophenylalanine with the foregoing description 1.The reaction reagent consumption should carry out according to above-mentioned example 1 described reaction equivalent, and the result is the same substantially.[annotate: the e.e. value records on the asymmetric post of Daicel OJ 0.46*25cm, and moving phase is 95: the 5=cyclohexane: Virahol (containing 0.2%TFA), 30 ℃ of column temperatures.]
1H?NMR(400MHz，DMSO-d
6)：12.64(brs，1H)，7.29(m，1H)，7.13(d，J＝8.4Hz，1H)，7.01(m，2H)，4.08(m，1H)，3.05(dd，J＝13.6&6.4Hz，1H)，2.93(dd，J＝13.6?&?9.6Hz，1H)1.28(，9H)；MS：302(M
++1)。
Embodiment 6
The fractionation of N-tertiary butyl oxygen carbonyl-3.4-two fluorophenylalanine
Adopt the processing method identical to split N-tertiary butyl oxygen carbonyl-2.5-two fluorophenylalanine with the foregoing description 1.The reaction reagent consumption should carry out according to above-mentioned example 1 described reaction equivalent, and the result is the same substantially.[annotate: the e.e. value records on the asymmetric post of Daicel OJ 0.46*25cm, and moving phase is 95: the 5=cyclohexane: Virahol (containing 0.2%TFA), 30 ℃ of column temperatures.]
1H?NMR(400MHz，DMSO-d
6)：12.60(brs，1H)，7.30(m，2H)，7.12(d，J＝8.4Hz，1H)，7.07(m，1H)，4.07(m，1H)，3.03(dd，J＝14.0&4.0Hz，1H)，2.93(dd，J＝14.0&10.4Hz，1H)1.27(s，9H)；MS：302(M
++1)。
Claims (6)
1, a kind of preparation method of optical purity N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine, it is characterized in that: adopting racemic N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine is raw material, with the pure R-of resolving agent mapping (+)-α-Ben Yian or S-(-)-α-Ben Yian reaction, obtain N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine S-(-)-α-Ben Yian salt or N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine R-(+)-α-Ben Yian salt, acidified again extraction obtains optical purity S-N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine and optically pure R-N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine.
2, the preparation method of a kind of optical purity N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine according to claim 1, it is characterized in that: reaction formula is
Steps A:
Compound (I) (S)-α-Ben Yian salt compound (I)
Step B:
Compound (II) (R)-α-Ben Yian salt compound (II)
3, the preparation method of a kind of optical purity N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine according to claim 1 and 2 is characterized in that: the optical purity N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine chemical structural formula that makes is as follows:
Compound I (S-configuration), or Compound I I (R-configuration)
Wherein, (F)
2Two of-expressions are arranged in fluorine atom on any position of phenyl ring, that is, two fluorine atoms are positioned at (prosposition), (2,4), (2,5), (2,6), (3,4), (3,5) on the phenyl ring.
4, the preparation method of a kind of optical purity N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine according to claim 1 and 2, it is characterized in that: to the recovery resolving agent that alkalizes of the water behind the acidizing extraction, basifier is selected a kind of in sodium hydroxide, potassium hydroxide, the lithium hydroxide solution for use.
5, the preparation method of a kind of optical purity N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine according to claim 1 and 2, it is characterized in that: the resolving agent consumption is 1 equivalent mole, solvent adopts ethyl acetate, consumption is 1.0mL～3.0mL ethyl acetate/every gram N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine, citric acid solution is adopted in acidifying, organic phase is an extraction agent with ethyl acetate, methylene dichloride, ether, and temperature of reaction is 20 ℃～77 ℃.
6, the preparation method of a kind of optical purity N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine according to claim 1 and 2, it is characterized in that racemic N-tertiary butyl oxygen carbonyl-β-two fluorophenylalanine has been carried out repeatedly splitting, use for the first time S-(-)-α-Ben Yian or R-(+)-α-Ben Yian, use for the second time R-(+)-α-Ben Yian or S-(-)-α-Ben Yian, use S-(-)-α-Ben Yian or R-(+)-α-Ben Yian for the third time, so be used alternatingly.
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Cited By (3)
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| KR20110116167A (en) * | 2009-01-13 | 2011-10-25 | 제지앙 지우조우 파마슈티칼 컴퍼니 리미티드 | Process for manufacture and resolution of 2-acylamino-3-diphenylpropanoic acid |
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| US4209638A (en) * | 1977-03-08 | 1980-06-24 | The Boots Company Limited | Preparation of therapeutic agents |
| DE3824353A1 (en) * | 1988-07-19 | 1990-01-25 | Paz Arzneimittelentwicklung | METHOD FOR SEPARATING MIXED ENANTIOMER ARYLPROPIONIC ACIDS |
| CN1102137C (en) * | 2000-03-16 | 2003-02-26 | 武汉大学 | Method for splitting ibuprofen by two-component chiral reagent |
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| KR20110116167A (en) * | 2009-01-13 | 2011-10-25 | 제지앙 지우조우 파마슈티칼 컴퍼니 리미티드 | Process for manufacture and resolution of 2-acylamino-3-diphenylpropanoic acid |
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| KR101699095B1 (en) * | 2009-01-13 | 2017-01-23 | 제지앙 지우조우 파마슈티칼 컴퍼니 리미티드 | Process for manufacture and resolution of 2-acylamino-3-diphenylpropanoic acid |
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