CN108440320A - A kind of method of high chiral selectivity synthesis α-disubstituted a-amino acid - Google Patents
A kind of method of high chiral selectivity synthesis α-disubstituted a-amino acid Download PDFInfo
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- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 23
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 33
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 21
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims abstract description 12
- GWJSQKNYHPYZRN-UHFFFAOYSA-N 2-methylpropane-2-sulfonamide Chemical class CC(C)(C)S(N)(=O)=O GWJSQKNYHPYZRN-UHFFFAOYSA-N 0.000 claims abstract description 11
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 11
- LGRLWUINFJPLSH-UHFFFAOYSA-N methanide Chemical compound [CH3-] LGRLWUINFJPLSH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000011701 zinc Substances 0.000 claims abstract description 11
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 11
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940117360 ethyl pyruvate Drugs 0.000 claims abstract description 10
- 235000019270 ammonium chloride Nutrition 0.000 claims abstract description 8
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims abstract description 8
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical class [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims abstract description 7
- 229910001623 magnesium bromide Inorganic materials 0.000 claims abstract description 7
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 35
- 239000000243 solution Substances 0.000 claims description 33
- 239000012074 organic phase Substances 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- 229910001868 water Inorganic materials 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000000376 reactant Substances 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 8
- 239000012266 salt solution Substances 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000908 ammonium hydroxide Substances 0.000 claims description 6
- 239000003729 cation exchange resin Substances 0.000 claims description 6
- 229940023913 cation exchange resins Drugs 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000000284 extract Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000007853 buffer solution Substances 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000005342 ion exchange Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 2
- 235000008206 alpha-amino acids Nutrition 0.000 abstract 1
- 150000001371 alpha-amino acids Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 52
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 239000007788 liquid Substances 0.000 description 13
- 230000008859 change Effects 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 208000012839 conversion disease Diseases 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 3
- 0 CC(C1)C(C)C2C1C*CC2 Chemical compound CC(C1)C(C)C2C1C*CC2 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 125000000746 allylic group Chemical group 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 1
- GOZQARKCLBQQSS-UHFFFAOYSA-N [Mg].[Br-].C(C1=CC=CC=C1)[PH3+] Chemical compound [Mg].[Br-].C(C1=CC=CC=C1)[PH3+] GOZQARKCLBQQSS-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical compound CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention discloses a kind of methods of the high chiral disubstituted alpha amino acids of selectivity synthesis α, it is characterised in that：Include the following steps：Compound C is obtained by the reaction in tetrahydrofuran solvent in step 1, S t-butyl sulfonamides or R t-butyl sulfonamides, R β substitutions ethyl pyruvate, tetraethyl titanate；Step 2, compound C and alkyl-substituted magnesium bromide obtain compound E under the catalysis of zinc methide in tetrahydrofuran；Step 3, compound E obtain compound F under the action of ammonium chloride and anhydrous hydrogen chloride；Step 4, compound F are hydrolyzed in the ethanol water of sodium hydroxide and are obtained the hydrochloride of compound G, then obtain compound G by ion exchange.The present invention substantially increase reaction chiral selectivity reaction, and this method concise in technology, raw material it is cheap and easy to get, it is easy to operate, be particularly well suited for industrialized production, have very extensive industrial applications foreground and market value.
Description
Technical field
The present invention relates to synthetic organic chemical arts, and in particular to a kind of high chiral selectivity synthesis α-disubstituted alpha-amido
The method of acid.
Background technology
A-amino acid is the important composition unit of protein, there is important biological function.Most of a-amino acid is that have hand
Property selectivity, the a-amino acid of chiral purity has very important pharmaceutical active, is also important asymmetric syntheses intermediate
With the chiral source of many chiral drugs.With the growth of the chiral pharmaceutical requirements of medical market, amino acid and its derivative are in hand
Application in property pharmaceutical synthesis is on the increase, and new drug research and the new direction and hot spot of exploitation are become.The conjunction of a-amino acid
There is suitable broad development in the past twenty years at studying, but the synthesis of chiral purity a-amino acid, the method for various classics
Suffer from the limitation of itself：Starting material is expensive；Severe reaction conditions；Reaction amplification is difficult；Product optical purity is more low
Deng.
The disubstituted a-amino acids of α-usually react synthesis by classical Strecker, and such as following formula (1), but the reaction does not have
Chiral selectivity, so chiral product yield is relatively low (US 2015/0175576A1).
The reaction for the synthesis disubstituted a-amino acids of α-that emerging chiral catalyst participates in, such as following formula (2), although chiral choosing
Selecting property is fine, but catalyst is generally all more expensive, recycles difficulty, and industry's enlarging production cost is difficult to bear
(Maruoka,K.Tetrahedron 2010,66,4900-4904)。
Invention content
In view of the above-mentioned problems of the prior art, the object of the present invention is to provide a kind of high chiral selectivity synthesis α-is bis-
The method for replacing a-amino acid, to be applied to industry's enlarging production.
To achieve the above object, the technical solution adopted by the present invention is：
A kind of method of high chiral selectivity synthesis α-disubstituted a-amino acid, includes the following steps：
Step 1, S- t-butyl sulfonamides or R- t-butyl sulfonamides, R- β substitutions ethyl pyruvate, metatitanic acid tetrem
Compound C is obtained by the reaction in tetrahydrofuran solvent in ester；Reaction equation is：
Wherein, R1For alkyl, such as methyl, ethyl, isopropyl, normal-butyl；
Step 2, compound C and alkyl-substituted magnesium bromide are changed under the catalysis of zinc methide in tetrahydrofuran
Close object E；Reaction equation is：
Wherein, R2For alkyl, such as methyl, ethyl, isopropyl, normal-butyl；
Step 3, compound E obtain compound F under the action of ammonium chloride and anhydrous hydrogen chloride；Reaction equation is：
Step 4, compound F are hydrolyzed in the ethanol water of sodium hydroxide and are obtained the hydrochloride of compound G, then lead to
It crosses ion exchange and obtains compound G；Reaction equation is：
Step 1 is S- t-butyl sulfonamides or R- t-butyl sulfonamides and R- β replace ethyl pyruvate, specific to walk
Suddenly it is：S- t-butyl sulfonamides or R- t-butyl sulfonamides, R- β are replaced into ethyl pyruvate, tetraethyl titanate and tetrahydrochysene
THF solvent sequentially adds reaction vessel under nitrogen protection, then by mixture heating reflux reaction 6 hours；After reaction
The reaction is cooled to room temperature, isopropanol is added and saturated salt solution stirs 1 hour, then filters, removes solid, organic phase is used
Organic phase drying revolving dry is obtained compound C by water washing.
Step 2 is the substitution reaction of the alkyl-substituted magnesium bromide of zinc methide catalysis, the specific steps are：By tetrahydrochysene furan
Mutter, zinc methide and alkyl-substituted magnesium bromide are added in reaction vessel under nitrogen protection successively, stir 10 minutes, then will
Reactant cools to -78 DEG C, and then the tetrahydrofuran solution of compound C is slowly added into reaction solution, keeps anti-at -78 DEG C
It answers 2 hours, HPLC tracks reaction result, confirms that reaction conversion is added saturated ammonium chloride solution and reaction is quenched after the completion, uses acetic acid
Ethyl ester and saturated salt solution extract reaction solution, are then spin-dried for organic phase, obtain compound E.
Step 3 is that ammonium chloride and the coefficient chiral t-butyl sulfonamide of anhydrous hydrogen chloride slough reaction, specifically
Step is：It in the methanol hydrochloride solution that compound E is dissolved in, is stirred overnight, is then spin-dried for solvent at room temperature, then to anti-
It answers and hydrochloric acid solution is added in mixture, be then extracted with ethyl acetate, abandon organic phase, it is molten with ammonium hydroxide and ammonium chloride mixing buffering
Liquid adjusts aqueous pH values to 8, is then extracted with dichloromethane, collects organic phase, is dried with anhydrous sodium sulfate, then revolve solvent
It is dry, obtain compound F.
Step 4 is that substrate is answered to obtain chiral purity α-disubstituted a-amino acid by sodium hydroxide hydrolysis and ion exchange, is had
Body step is：Compound F and sodium hydroxide are added sequentially in second alcohol and water, is heated to reflux 4 hours, will be adjusted to hydrochloric acid
Solvent is spin-dried for by pH=7, and reactant is dissolved in the water, and is then purified, is obtained by 732 type storng-acid cation exchange resins
To compound G.
The beneficial effects of the invention are as follows：The method of high chiral selectivity synthesis α-disubstituted a-amino acid of the present invention can be with
Applied to industry's enlarging production.Present invention process is auxiliary as efficient chiral positioning using tert-Butanesulfinamide
Agent substantially increases the chiral selectivity reaction of reaction, and this method concise in technology, raw material are cheap and easy to get, easy to operate, extremely suitable
Together in industrialized production, there is very extensive industrial applications foreground and market value.
Specific implementation mode
A kind of method of high chiral selectivity synthesis α-disubstituted a-amino acid of the present invention, synthetic route are：
Synthesis step is：
Step 1, S- t-butyl sulfonamides or R- t-butyl sulfonamides, R- β substitutions ethyl pyruvate, metatitanic acid tetrem
Compound C is obtained by the reaction in tetrahydrofuran solvent in ester；
Step 2, compound C and alkyl-substituted magnesium bromide are changed under the catalysis of zinc methide in tetrahydrofuran
Close object E；
Step 3, compound E obtain compound F under the action of ammonium chloride and anhydrous hydrogen chloride；
Step 4, compound F are hydrolyzed in the ethanol water of sodium hydroxide and are obtained the hydrochloride of compound G, then lead to
It crosses ion exchange and obtains compound G.
With reference to specific embodiment, the present invention will be further described.According to following embodiments, can be better understood from
The present invention.However, as it will be easily appreciated by one skilled in the art that specific material proportion, process conditions described in embodiment and
Its result is merely to illustrate the present invention, without that should will not limit the present invention described in detail in claims.
Embodiment 1
Synthetic route is：
Synthesis step is：
1.1) by S- t-butyl sulfonamides (20g, 165mmol), ethyl pyruvate (18.99g, 165mmol), metatitanic acid four
Ethyl ester (69.2ml, 330mmol), tetrahydrofuran (150ml) solvent are added sequentially to the there-necked flask of 500ml under nitrogen protection
In.Then by mixture heating reflux reaction 6 hours.The reaction is cooled to room temperatures after reaction, and isopropanol and saturation is added
Saline solution stirs 1 hour.Then it filters, removes solid, organic phase is washed 2 times with water (200ml).Organic phase drying revolving is dry
Obtain product C1 (34.4g, 95%), colourless liquid.
1H-NMR (400MHz, CDCl3), δ ppm 1.33 (m, 12H) 2.48 (s, 3H) 4.19-4.41 (m, 2H)；13C NMR
(125MHz,CDCl3)δ(ppm)13.9,18.2,22.7,25.1,59.1,62.2,163.3,166.7,167.6.HRMS(EI)
calcd for C9H18NO3S[M+H]220.1007,found 220.1011。
1.2) tetrahydrofuran (50ml), the zinc methide (17.1ml, 17.1mmol) of a concentration of 1M and ethylmagnesium bromide
(45.6ml, 136.8mmol) is added in dry there-necked flask under nitrogen protection successively, stirs 10 minutes, then by reactant
- 78 DEG C are cooled to, then the tetrahydrofuran (100ml) of compound C1 (25g, 114mmol) is slowly added into reaction solution, is protected
It holds and is reacted 2 hours at -78 DEG C, HPLC tracks reaction result, confirms that reaction conversion is added saturated ammonium chloride solution and is quenched after the completion
Reaction extracts reaction solution with ethyl acetate and saturated salt solution, is then spin-dried for organic phase, obtain product E1 (26.7g,
94%), colourless liquid.
1H NMR(400MHz,CDCl3), δ (ppm), 0.90 (d, J=6.94Hz, 3H), 0.97 (d, J=6.94Hz, 3H),
1.27 (s, 9H), 1.29 (t, J=7.09Hz, 3H), 2.00-2.18 (m, 1H), 3.71 (dd, J=7.88,5.04Hz, 1H),
4.10 (d, J=7.88Hz, 1H), 4.15-4.29 (m, 2H)13C NMR(125MHz,CDCl3), δ ppm, 14.1,17.3,
19.1,22.7,32.3,56.2,61.5,63.1,173.0.HRMS(EI)calcd for C11H24NO3S[M+H]250.1477,
found 250.1479。
1.3) compound E1 (25g, 100.25mmol) is dissolved in the methanol hydrochloride solution (100ml) of a concentration of 1.5M
In, it is stirred overnight at room temperature.Then solvent is spin-dried for, a concentration of 2M hydrochloric acid solutions is then added into reaction mixture
(100ml) then uses ethyl acetate (200ml) to extract 2 times.Organic phase is abandoned, with the chlorine of a concentration of 1M ammonium hydroxide and a concentration of 1M
Change ammonium mixing buffer solution and adjust aqueous pH values to 8, then dichloromethane (200ml) is used to extract 2 times, organic phase is collected, with nothing
Aqueous sodium persulfate is dried, and is then spin-dried for solvent, is obtained product F1 (13.8g, 95%) colourless liquid.
1H NMR(400MHz,CDCl3), δ (ppm), 0.87 (3H, t, J=7.4Hz), 1.28 (3H, t, J=7Hz), 1.32
(3H, s), 1.57-1.63 (1H, m), 1.74-1.78 (1H, m), 1.97 (2H, broad s), 4.17 (2H, q, J=7Hz)13C
NMR(125MHz,CDCl3), δ (ppm), 8.4,14.2,25.8,33.7,58.1,60.9,177.4.HRMS m/z
calcd.for C7H15NO2:168.0982(M+Na)+,found:168.0995。
1.4) compound F1 (13.8g, 95.0mmol) and sodium hydroxide (7.6g, 190.08mmol) are added sequentially to second
Alcohol and water (volume ratio 1:1) it in mixed solution (200ml), is heated to reflux 4 hours, will be adjusted to the hydrochloric acid of a concentration of 2M
Solvent is spin-dried for by pH=7.Reactant is dissolved in a small amount of water, it is then pure by 732 type storng-acid cation exchange resins
Change, obtains product G1 (10g, 90%), white solid.
[α]D 23=+12.1 ° (c 1.03, H2O)；1H NMR(400MHz,D2O), δ (ppm), 0.86 (t, J=7.2Hz,
3H), 1.46 (s, 3H), 1.78 (td, J=14.4,6.8Hz, 1H), 1.90 (td, J=14.4,7.2Hz, 1H)；13C NMR
(125MHz,D2O), δ (ppm), 8.3,22.5,30.8,62.0,176.1.
Embodiment 2
Synthetic route is：
Synthesis step is：
2.1) by S- t-butyl sulfonamides (20g, 165mmol), ethyl pyruvate (18.99g, 165mmol), metatitanic acid four
Ethyl ester (69.2ml, 330mmol), tetrahydrofuran (150ml) solvent are added sequentially to the there-necked flask of 500ml under nitrogen protection
In.Then by mixture heating reflux reaction 6 hours.The reaction is cooled to room temperatures after reaction, and isopropanol and saturation is added
Saline solution stirs 1 hour.Then it filters, removes solid, organic phase is washed 2 times with water (200ml).Organic phase drying revolving is dry
Obtain product C1 (33.3g, 92%) colourless liquid.
1H-NMR (400MHz, CDCl3), δ ppm1.33 (m, 12H) 2.48 (s, 3H) 4.19-4.41 (m, 2H)；13C NMR
(125MHz,CDCl3)δ(ppm)13.9,18.2,22.7,25.1,59.1,62.2,163.3,166.7,167.6.HRMS(EI)
calcd for C9H18NO3S[M+H]220.1007,found 220.1011。
2.2) tetrahydrofuran (50ml), the zinc methide (17.1ml, 17.1mmol) of a concentration of 1M and allylic bromination magnesium
(42ml, 125.4mmol) is added in dry there-necked flask under nitrogen protection successively, stirs 10 minutes, then drops reactant
Temperature arrives -78 DEG C, and then the tetrahydrofuran (100ml) of compound C2 (25g, 114mmol) is slowly added into reaction solution, protects
It holds and is reacted 2 hours at -78 DEG C, HPLC tracks reaction result, confirms that reaction conversion is added saturated ammonium chloride solution and is quenched after the completion
Reaction extracts reaction solution with ethyl acetate and saturated salt solution, is then spin-dried for organic phase, obtain product E2 (26.8g,
90%), yellow liquid.
1H-NMR (400MHz, CDCl3), δ ppm, 1.16 (9H, s), 1.22 (3H, t, J=7.2Hz), 1.47 (3H, s),
2.55-2.61(2H,m),4.08-4.16(3H,m),5.05-5.09(2H,m),5.68-5.82(1H,m)；13C NMR
(125MHz,CDCl3) δ (ppm), 13.2,21.6,23.1,44.1,55.1,60.6,60.8,118.8,131.1,172.3；
HRMS(ESI):calcd for C9H18NOS(M+-CO2CH2CH3)188.1109,found 188.1110。
2.3) compound E2 (26.8g, 170.47mmol) is dissolved in the methanol hydrochloride solution (100ml) of a concentration of 1.5M
In, it is stirred overnight at room temperature.Then solvent is spin-dried for, the hydrochloric acid solution of a concentration of 2M is then added into reaction mixture
(100ml) then uses ethyl acetate (200ml) to extract 2 times.Organic phase is abandoned, with the ammonium hydroxide of a concentration of 1M and a concentration of 1M
Ammonium chloride mixing buffer solution adjusts aqueous pH values to 8, then dichloromethane (200ml) is used to extract 2 times, collects organic phase, uses
Anhydrous sodium sulfate is dried, and is then spin-dried for solvent, is obtained product F2 (14.8g, 92%) yellow liquid.1H-NMR (400MHz,
CDCl3), δ ppm, 1.31 (t, J=7.1Hz, 3H) 2.26-2.32 (2s, 3H) 4.26 (q, J=7.1Hz, 2H), 7.05-7.72
(m,5H)；13C NMR(125MHz,CDCl3), δ (ppm), 13.9,18.8,23.5,61.4,124.6,125.3,126.3,
126.7,128.5,128.7,137.2,154.2,161.7.
2.4) compound F2 (14.8g, 94.1mmol) and sodium hydroxide (7.6g, 190.08mmol) are added sequentially to second
Alcohol and water (volume ratio 1:1) it in mixed solution (200ml), is heated to reflux 4 hours, pH will be adjusted to the hydrochloric acid of a concentration of 2M
=7, solvent is spin-dried for.Reactant is dissolved in a small amount of water, it is then pure by 732 type storng-acid cation exchange resins
Change, obtains product G2 (11.2g, 89%), white powder.
[α]D 23=-28.3 ° (c 1.23, H2O)；1H NMR (500MHz, D2O), δ ppm, 1.48 (s, 3H), 2.45 (dd,
J=14.4,8.4Hz, 1H), 2.65 (dd, J=14.4,6.6Hz, 1H), 5.34-5.22 (m, 2H), 5.81-5.68 (m, 1H)；13C NMR(125MHz,D2O),δ(ppm),22.0,41.3,60.2,123.5,130.1,173.9。
Embodiment 3
Synthetic route is：
Synthesis step is：
3.1) by S- t-butyl sulfonamides (20g, 165mmol), ethyl ketone (21.48g, 165mmol), metatitanic acid four
Ethyl ester (69.2ml, 330mmol), tetrahydrofuran (150ml) solvent are added sequentially to the there-necked flask of 500ml under nitrogen protection
In.Then by mixture heating reflux reaction 6 hours.The reaction is cooled to room temperatures after reaction, and isopropanol and saturation is added
Saline solution stirs 1 hour.Then it filters, removes solid, organic phase is washed 2 times with water (200ml).Organic phase drying revolving is dry
Obtain product C3 (34.7g, 90%), colourless liquid.
1H NMR (400MHz, CDCl3), δ ppm, 1.19 (t, J=6.8Hz, 3H), 1.26 (s, 9H), 1.35 (t, J=
7.7Hz,3H),2.62(m,2H),4.30(m,2H)；13C NMR(125MHz,CDCl3),δppm,9.2,13.9,22.1,22.5,
31.8,61.9,167.1,170.9；HRMS:calcd for C10H20NO3S[M+H]:234.1158.Found:234.1136。
3.2) tetrahydrofuran (50ml), the zinc methide (16.1ml, 16.1mmol) of a concentration of 1M and allylic bromination magnesium
(39.3ml, 117.9mmol) is added in dry there-necked flask under nitrogen protection successively, stirs 10 minutes, then by reactant
- 78 DEG C are cooled to, then the tetrahydrofuran (100ml) of compound C3 (25g, 107.2mmol) is slowly added into reaction solution,
It keeps reacting 2 hours at -78 DEG C, HPLC tracks reaction result, confirms that saturated ammonium chloride solution is added after the completion of reacting conversion to be quenched
Go out reaction, extract reaction solution with ethyl acetate and saturated salt solution, be then spin-dried for organic phase, obtain product E3 (23.5g,
88%), colourless liquid.
1H NMR(500MHz,CDCl3), δ (ppm) 0.92 (d, J=6.94Hz, 3H), 0.95 (d, J=6.94Hz, 3H),
1.26 (s, 9H), 1.27 (t, J=7.09Hz, 3H), 2.04-2.15 (m, 1H), 3.70 (dd, J=7.88,5.04Hz, 1H),
4.10 (d, J=7.88Hz, 1H), 4.15-4.29 (m, 2H)13C NMR(125MHz,CDCl3),δppm 14.0,17.3,
19.1,22.5,32.3,56.2,61.6,63.5,173.0.HRMS(EI)calcd for C11H24NO3S[M+H]250.1477,
found 250.1469。
3.3) compound E3 (23.5g, 94.24mmol) is dissolved in the methanol hydrochloride solution (100ml) of a concentration of 1.5M
In, it is stirred overnight at room temperature.Then solvent is spin-dried for, the hydrochloric acid solution of a concentration of 2M is then added into reaction mixture
(100ml) then uses ethyl acetate (200ml) to extract 2 times.Organic phase is abandoned, with the chlorine of a concentration of 1M ammonium hydroxide and a concentration of 1M
Change ammonium mixing buffer solution and adjust aqueous pH values to 8, then dichloromethane (200ml) is used to extract 2 times, organic phase is collected, with nothing
Aqueous sodium persulfate is dried, and is then spin-dried for solvent, is obtained product F3 (12.5g, 91%), colourless liquid.
1H NMR(400MHz,CDCl3), δ (ppm), 0.85 (3H, t, J=7.4Hz), 1.26 (3H, t, J=7Hz), 1.30
(3H, s), 1.58-1.63 (1H, m), 1.74-1.76 (1H, m), 1.96 (2H, broad s), 4.18 (2H, q, J=7Hz)13C
NMR(125MHz,CDCl3), δ (ppm), 8.2,14.1,25.6,33.5,58.0,60.5,177.1.HRMS m/z
calcd.for C7H15NO2:168.0982(M+Na)+,found:168.0990。
3.4) compound F3 (12.5g, 86.1mmol) and sodium hydroxide (6.9g, 172.2mmol) are added sequentially to second
Alcohol and water (volume ratio 1:1) it in mixed solution (200ml), is heated to reflux 4 hours, pH will be adjusted to the hydrochloric acid of a concentration of 2M
=7, solvent is spin-dried for.Reactant is dissolved in a small amount of water, it is then pure by 732 type storng-acid cation exchange resins
Change, obtains product G3 (9.0g, 89%), white powder.
[α]D 23=-12.2 ° of (c 1.03, H2O)；1H NMR(400MHz,D2O), δ (ppm), 0.87 (t, J=7.2Hz,
3H), 1.45 (s, 3H), 1.75 (td, J=14.4,6.8Hz, 1H), 1.92 (td, J=14.4,7.2Hz, 1H)；13C NMR
(125MHz,D2O), δ (ppm), 8.3,22.5,30.8,62.0,176.1.
Embodiment 4
Synthetic route is：
Synthesis step is：
4.1) by S- t-butyl sulfonamides (20g, 165mmol), ethyl pyruvate (18.99g, 165mmol), metatitanic acid four
Ethyl ester (69.2ml, 330mmol), tetrahydrofuran (150ml) solvent are added sequentially to the there-necked flask of 500ml under nitrogen protection
In.Then by mixture heating reflux reaction 6 hours.The reaction is cooled to room temperatures after reaction, and isopropanol and saturation is added
Saline solution stirs 1 hour.Then it filters, removes solid, organic phase is washed 2 times with water (200ml).Organic phase drying revolving is dry
Obtain product C1 (35.1g, 97%) colourless liquid.
1H-NMR (400MHz, CDCl3), δ ppm1.33 (m, 12H) 2.48 (s, 3H) 4.19-4.41 (m, 2H)；13C NMR
(125MHz,CDCl3)δ(ppm)13.9,18.2,22.7,25.1,59.1,62.2,163.3,166.7,167.6.HRMS(EI)
calcd for C9H18NO3S[M+H]220.1007,found 220.1011。
4.2) tetrahydrofuran (50ml), the zinc methide (17.1ml, 17.1mmol) of a concentration of 1M and Benzylphosphonium Bromide magnesium
(41.8ml, 125.4mmol) is added in dry there-necked flask under nitrogen protection successively, stirs 10 minutes, then by reactant
- 78 DEG C are cooled to, then the tetrahydrofuran (100ml) of compound C4 (25g, 114mmol) is slowly added into reaction solution, is protected
It holds and is reacted 2 hours at -78 DEG C, HPLC tracks reaction result, confirms that reaction conversion is added saturated ammonium chloride solution and is quenched after the completion
Reaction extracts reaction solution with ethyl acetate and saturated salt solution, is then spin-dried for organic phase, obtain product E4 (32.7g,
92%), weak yellow liquid.
1H NMR(400MHz,CDCl3), δ (ppm) 0.95 (d, J=6.94Hz, 3H), 1.26 (s, 9H), 1.27 (t, J=
7.09Hz, 3H), 2.04-2.15 (m, 1H), 3.70 (dd, J=7.88,5.04Hz, 1H), 4.10 (d, J=7.88Hz, 1H),
4.15-4.29(m,2H),7.07–7.27(5H,C‐H aromatic,m)；13C NMR(125MHz,CDCl3),δppm,17.3,
19.1,22.5,32.3,56.2,61.6,63.5,128.3,128.7,128.9,137.8,173.0.HRMS(EI)calcd for
C16H25NO3S[M+H]312.1678,found 312.1667。
4.3) compound E4 (32.7g, 105mmol) is dissolved in the methanol hydrochloride solution (100ml) of a concentration of 1.5M,
It is stirred overnight at room temperature.Then solvent is spin-dried for, the hydrochloric acid solution of a concentration of 2M is then added into reaction mixture
(100ml) then uses ethyl acetate (200ml) to extract 2 times.Organic phase is abandoned, with the chlorine of a concentration of 1M ammonium hydroxide and a concentration of 1M
Change ammonium mixing buffer solution and adjust aqueous pH values to 8, then dichloromethane (200ml) is used to extract 2 times, organic phase is collected, with nothing
Aqueous sodium persulfate is dried, and is then spin-dried for solvent, is obtained product F4 (19.5g, 90%), weak yellow liquid.
1H NMR(400MHz,CDCl3), δ (ppm), 1.29 (t, 3H, J=7.3Hz), 1.43 (s, 3H), 1.87 (br s,
2H), 2.84 (d, 1H, J=13.2Hz), 3.17 (d, 1H, J=13.2Hz), 4.18 (m, 2H), 7.20 (m, 2H), 7.34-7.24
(m,3H)；13C NMR(125MHz,CDCl3), δ ppm, 14.2,26.6,46.8,58.7,61.1,126.9,128.3,130.0,
136.6,176.9；HRMS-ES(m/z):[M+H]+calcd for C12H18NO2,208.1337；found,208.1334.4) will
Compound F4 (19.5g, 94.1mmol) and sodium hydroxide (7.5g, 188.2mmol) are added sequentially to second alcohol and water (volume ratio 1:
1) it in mixed solution (200ml), is heated to reflux 4 hours, will be adjusted to pH=7 with the hydrochloric acid of a concentration of 2M, solvent is spin-dried for.
Reactant is dissolved in a small amount of water, is then purified by 732 type storng-acid cation exchange resins, obtain product G4
(15.5g, 92%).
[α]D 25=-16.1 ° of (c 1, H2O)]；1H NMR(400MHz,CDCl3), δ (ppm), 1.41 (s, 3H), 2.84 (d,
1H, J=14.1Hz), 3.16 (d, 1H, J=14.5Hz), 7.15-7.10 (m, 2H), 7.30-7.20 (m, 3H)；13C NMR
(125MHz,CDCl3),δppm,22.3,42.6,62.1,127.8,128.9,129.9,134.2,176.1；HRMS-ES(m/
z):[M+H]+calcd for C10H14NO2,180.1024；found,180.1048.4.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (5)
1. a kind of method of high chiral selectivity synthesis α-disubstituted a-amino acid, it is characterised in that：Include the following steps：
Step 1, S- t-butyl sulfonamides or R- t-butyl sulfonamides, R- β substitutions ethyl pyruvate, tetraethyl titanate exist
In tetrahydrofuran solvent, compound C is obtained by the reaction；Reaction equation is：
Wherein, R1For alkyl；
Step 2, compound C and alkyl-substituted magnesium bromide obtain compound under the catalysis of zinc methide in tetrahydrofuran
E；Reaction equation is：
Wherein, R2For alkyl；
Step 3, compound E obtain compound F under the action of ammonium chloride and anhydrous hydrogen chloride；Reaction equation is：
Step 4, compound F are hydrolyzed in the ethanol water of sodium hydroxide and are obtained the hydrochloride of compound G, then by from
Son exchanges and obtains compound G；Reaction equation is：
2. the method for high chiral selectivity synthesis α-disubstituted a-amino acid according to claim 1, it is characterised in that：Step
Rapid one the specific steps are：S- t-butyl sulfonamides or R- t-butyl sulfonamides, R- β are replaced into ethyl pyruvate, metatitanic acid
Tetra-ethyl ester and tetrahydrofuran solvent sequentially add reaction vessel under nitrogen protection, then that mixture heating reflux reaction 6 is small
When；After reaction the reaction is cooled to room temperature, isopropanol is added and saturated salt solution stirs 1 hour, then filters, removal is solid
Organic phase is washed with water body, and organic phase drying revolving dry is obtained compound C.
3. the method for high chiral selectivity synthesis α-disubstituted a-amino acid according to claim 1, it is characterised in that：Step
Rapid two the specific steps are：Tetrahydrofuran, zinc methide and alkyl-substituted magnesium bromide are added under nitrogen protection successively anti-
It answers in container, stirs 10 minutes, reactant is then cooled to -78 DEG C, then slowly adds the tetrahydrofuran solution of compound C
Enter into reaction solution, keep reacting 2 hours at -78 DEG C, HPLC tracks reaction result, confirms and saturation is added after the completion of reaction converts
Reaction is quenched in ammonium chloride solution, extracts reaction solution with ethyl acetate and saturated salt solution, is then spin-dried for organic phase, obtains chemical combination
Object E.
4. the method for high chiral selectivity synthesis α-disubstituted a-amino acid according to claim 1, it is characterised in that：Step
Rapid three the specific steps are：It in the methanol hydrochloride solution that compound E is dissolved in, is stirred overnight, then revolves solvent at room temperature
It is dry, hydrochloric acid solution is then added into reaction mixture, is then extracted with ethyl acetate, organic phase is abandoned, with ammonium hydroxide and chlorination
Ammonium mixing buffer solution adjusts aqueous pH values to 8, is then extracted with dichloromethane, collects organic phase, is dried with anhydrous sodium sulfate,
Then solvent is spin-dried for, obtains compound F.
5. the method for high chiral selectivity synthesis α-disubstituted a-amino acid according to claim 1, it is characterised in that：Step
Rapid four the specific steps are：Compound F and sodium hydroxide are added sequentially in second alcohol and water, is heated to reflux 4 hours, uses hydrochloric acid
It will be adjusted to pH=7, solvent will be spin-dried for, reactant will be dissolved in the water, then pass through 732 type storng-acid cation exchange resins
Purifying, obtains compound G.
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