CN114573473A - Preparation method of (R) -alpha-aryl alanine ester derivative - Google Patents

Preparation method of (R) -alpha-aryl alanine ester derivative Download PDF

Info

Publication number
CN114573473A
CN114573473A CN202210206296.7A CN202210206296A CN114573473A CN 114573473 A CN114573473 A CN 114573473A CN 202210206296 A CN202210206296 A CN 202210206296A CN 114573473 A CN114573473 A CN 114573473A
Authority
CN
China
Prior art keywords
alpha
solvent
ester derivative
reaction
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202210206296.7A
Other languages
Chinese (zh)
Other versions
CN114573473B (en
Inventor
钟为慧
陈奕锐
成宇琪
凌飞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang University of Technology
Original Assignee
Zhejiang University of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang University of Technology filed Critical Zhejiang University of Technology
Priority to CN202210206296.7A priority Critical patent/CN114573473B/en
Publication of CN114573473A publication Critical patent/CN114573473A/en
Application granted granted Critical
Publication of CN114573473B publication Critical patent/CN114573473B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2282—Unsaturated compounds used as ligands
    • B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2495—Ligands comprising a phosphine-P atom and one or more further complexing phosphorus atoms covered by groups B01J31/1845 - B01J31/1885, e.g. phosphine/phosphinate or phospholyl/phosphonate ligands
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/08—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0225—Complexes comprising pentahapto-cyclopentadienyl analogues
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
    • B01J2531/0241—Rigid ligands, e.g. extended sp2-carbon frameworks or geminal di- or trisubstitution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
    • B01J2531/0263—Planar chiral ligands, e.g. derived from donor-substituted paracyclophanes and metallocenes or from substituted arenes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/822—Rhodium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/84—Metals of the iron group
    • B01J2531/842—Iron
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明公开了一种(R)‑α‑芳基丙氨酸酯衍生物的制备方法，向高压釜中加入α‑脱氢芳基丙氨酸酯衍生物、催化剂[Rh]/L*和溶剂B，于10℃～80℃以及0.1～6.0MPa的氢气压力下进行不对称加氢反应，反应1～24小时后，减压蒸馏回收溶剂B，再加入适量水，用乙酸乙酯萃取，收集有机相后经干燥，减压蒸馏回收溶剂，得到(R)‑α‑芳基丙氨酸酯衍生物。本发明方法具有较低的催化剂用量(TON高达100,000)、优异的对映选择性(ee值一般在99％以上)，底物适用性广等优点，且原料易得、操作简单，反应条件温和，易于工业化，符合绿色化学的要求，具有较大的实施价值和社会经济效益。The invention discloses a preparation method of (R)-α-arylalanine ester derivatives. The α-dehydroarylalanine ester derivatives, catalyst [Rh]/L * and Solvent B is subjected to asymmetric hydrogenation at 10°C to 80°C and a hydrogen pressure of 0.1 to 6.0 MPa. After 1 to 24 hours of reaction, solvent B is recovered by distillation under reduced pressure, and then an appropriate amount of water is added to extract with ethyl acetate. After collecting the organic phase, it is dried, and the solvent is recovered by distillation under reduced pressure to obtain the (R)-α-arylalanine ester derivative. The method of the invention has the advantages of low catalyst dosage (TON up to 100,000), excellent enantioselectivity (the ee value is generally above 99%), wide substrate applicability, etc., and the raw materials are easily available, the operation is simple, and the reaction conditions are mild. , easy to industrialize, meet the requirements of green chemistry, and have great implementation value and social and economic benefits.

Description

Preparation method of (R) -alpha-aryl alanine ester derivative
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a (R) -alpha-aryl alanine ester derivative.
Background
Chiral alpha-amino acids have a wide range of applications in the fields of pharmacy, biology and synthetic chemistry, and their importance is self-evident. Among a plurality of chiral alpha-amino acids, the chiral alpha-aryl alanine is extremely widely distributed, and the body shadow of the chiral alpha-aryl alanine can be found in drug molecules, food additives and the like. Such as Levothyroxine (Levothyroxine) for the treatment of hypothyroidism; ADEP4 capable of resisting multi-drug resistant germ infection, beta 2 receptor antagonist CPD-15A5, spectral anticancer agent LY355703, sweetener Aspartame (Aspartame), and the like.
As such, their synthesis methods are also receiving much attention. The synthesis of chiral alpha-aryl alanine is mainly based on the corresponding asymmetric hydrogenation. In 1972, Kagan reported the first asymmetric hydrogenation of enamides (h.b. Kagan, j.am. chem. soc.,1972,94,6429.), which system used rhodium complexes of DIOP to give N-acetyl protected α -phenylalanine at 72% ee, after which the ene acid derivatives were extensively studied make internal disorder or usurp as an important hydrogenation substrate, with a series of very important results. In 2002, Knowles (w.s.knowles, angelw.chem., int.ed.,2002,41,1998-2007.) involved in asymmetric hydrogenation of α -phenylalanine using a DIPAMP/Rh catalytic system, successfully prepared L-DOPA (97.5% ee) with high optical purity, which was thus awarded for nobel chemical prize in 2001, which was still the mainstream method for producing L-DOPA.
Then, ligands for asymmetric hydrogenation of α -dehydroarylalanine derivatives have emerged as spring shoots after rain, and excellent effects have been obtained, such as the ferrocene skeleton ligand IndoFerroPhos developed in the kupffer topic group (x. — p. hu, Tetrahedron lett.,2020,61, 151860), which can give high yields of (R) - α -arylalanine ester derivatives, but the ee value is only 97% at the highest and the applicability to heterocyclic substrates is poor; the benzoxaphosphine ligand BABIPhos developed by the Thomujin project group (W.J.Tang, org.Lett.,2018,20,1725-1729.) can obtain the (R) -alpha-aryl alanine ester derivative with the ee value of 99%, but the catalyst TON value is only 100; also, the mannitol-derivatized ferrocene-skeleton cyclic phosphine ligands developed by professor Zhang, org.Lett.,2002,4,4471-4474 have the above-mentioned problems.
In 2021, CN112824423A discloses a chiral ferrocenylphosphine-indolylaminophosphine ligand, which can efficiently catalyze and synthesize alpha-dehydroamino acid ester with high optical purity, wherein TON can reach 10000, but the enantioselectivity is 96% ee at most. Although the preparation of (R) -alpha-aryl alanine ester derivatives by asymmetric hydrogenation technology has been developed, the reported catalyst still has some problems, so a new asymmetric catalytic hydrogenation method with high efficiency, high stereoselectivity and wide substrate applicability is urgently needed to be found.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a method for preparing (R) - α -aryl alanine ester derivatives, which is suitable for industrial production and can conveniently prepare kilogram-level (R) - α -aryl alanine ester derivatives with high purity and high enantioselectivity.
The technical scheme adopted by the invention is as follows:
a method for preparing an (R) -alpha-aryl alanine ester derivative, comprising the steps of:
1) under argon atmosphere, metal Rh complex and chiral ligand L*Adding the obtained product into a solvent A to react for 0.5 to 6 hours to obtain a metal Rh complex and a chiral ligand L*Coordination bound catalysts [ Rh]/L*；
2) Adding alpha-dehydro aryl alanine ester derivative shown as formula (2) and the prepared catalyst [ Rh ] into an autoclave]/L*And solvent B, carrying out asymmetric hydrogenation reaction at 10-80 ℃ and under the hydrogen pressure of 0.1-6.0 MPa, and carrying out reactionAfter reacting for 1-24 hours, carrying out reduced pressure distillation to recover the solvent B, adding a proper amount of water, extracting with ethyl acetate, collecting an organic phase, drying, and carrying out reduced pressure distillation to recover the solvent to obtain the (R) -alpha-aryl alanine ester derivative shown in the formula (1);
the specific reaction route is as follows:
Figure BDA0003529283720000031
in the formulas (1) and (2), the aryl Ar is selected from phenyl, heterocyclic group, naphthyl or substituted phenyl, and the substituent in the substituted phenyl is C1-6 alkyl, C1-6 alkoxy or halogen, nitro; r is1Selected from acetyl, benzyloxycarbonyl, tert-butoxycarbonyl; r2Selected from C1-6 alkyl;
further, the chiral ligand L*The chemical structural formula of (A) is shown as the general formula (L):
Figure BDA0003529283720000032
in the general formula (L): r3And R4Each independently substituted or unsubstituted, when substituted, the substituent R3And a substituent R4Each independently selected from halogen, aryl, C1-C6 alkyl.
Further, a chiral ligand L represented by the general formula (L)*The chemical structural formula of (A) is shown in any one of formulas (L-1) to (L-4):
Figure BDA0003529283720000041
further, the metal Rh complex is [ Rh (C)2H4)2Cl]2、[Rh(NBD)Cl]2、[Rh(COD)Cl]2、[Rh(NBD)2]BF4、[Rh(COD)2]X、Rh(ethylene)2(acac)、[Rh(acac)(CO)]2、[Rh(C2H4)2Cl]2、RhCl(PPh3)3、[Rh(CO)2C1]2、Rh(arene)X2(diphosphine)、Rh(aryl group)X2、Rh(COD)(COT)、Rh(COD)(COT)X、Rh(COD)(methallyl)2、RhX2(diphosphine)、RhCl2(COD)、RhX2(cymene)、Rh(arylgroup)X2(PPh3)3、Rh(methallyl)2(diphosphine) and Rh (aryl group) X2(diphosphine) wherein aryl is aryl and X is BF4 -、OTf-、ClO4 -、SbF6 -、PF6 -、CF3SO3 -Or B (Y)4 -Y is bis (trifluoromethyl) benzene or fluorobenzene.
Further, in step 2), catalyst [ Rh ] is added]/L*The molar ratio of the alpha-dehydroaryl alanine ester derivative to the alpha-dehydroaryl alanine ester derivative is 1: 100-1: 100000.
Further, in step 1), a catalyst [ Rh ] was prepared]/L*The temperature of the reaction is 10-40 ℃, and the reaction time is 0.5-3 hours.
Further, in the step 2), the temperature for carrying out the asymmetric hydrogenation reaction is 10-60 ℃, the hydrogen pressure is 0.1-3.0 MPa, and the reaction time is 4-24 hours.
Further, the concentration of the α -dehydroarylalanine ester derivative represented by the formula (2) in the solvent B is from 0.05mol/L to 5.0 mol/L.
Further, the solvent A in the step 1) and the solvent B in the step 2) are respectively and independently selected from one or a mixture of more than two of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, methanol, ethanol, n-propanol, isopropanol and tert-butanol, and the solvent A and the solvent B can be the same.
By adopting the technology, compared with the prior art, the invention has the following characteristics:
the invention develops a catalyst consisting of chiral phosphine-spiroindane phosphoramidite bidentate ligand containing ferrocene skeleton and metal complex, and the catalyst is easy to prepare; the catalyst prepared by the invention does not need to be specially purified and can be directly used for the reaction of preparing the (R) -alpha-aryl alanine ester derivative by catalytic hydrogenation; compared with the existing asymmetric hydrogenation method, the method has the advantages of low catalyst dosage (TON is as high as 100000), excellent enantioselectivity (ee value is generally more than 99%), wide substrate applicability and the like, and has the advantages of easily available raw materials, simple operation, mild reaction conditions, easy industrialization, accordance with the requirements of green chemistry, great implementation value and social and economic benefits.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
Figure BDA0003529283720000051
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09g,4.94mmol), wherein the yield is as follows: 99%, purity: 99% and an ee value of 99.9%.
Example 2: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(47.3mg, 55.0. mu. mol) and metal complex [ Rh (COD)2]BF4Adding the mixture (20.3mg,50.0 mu mol) into a reaction bottle, adding dichloromethane (30mL) under the argon atmosphere, and reacting at 25 ℃ for 0.5h to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1kg, 5.0mol), the catalyst prepared in the step 1) and dichloromethane (3.0L) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12 hours, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding a proper amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.07kg,4.81mol), wherein the yield is as follows: 96%, purity: 98% and an ee value of 99.0%.
Example 3: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, filling hydrogen to 3.0MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.07g,4.85mmol), wherein the yield is as follows: 97%, purity: 98% and an ee value of 98.7%.
Example 4: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg,5.0 μmol) is added into a reaction bottle, tetrahydrofuran (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at 25 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and tetrahydrofuran (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding a proper amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.08g,4.89mmol), wherein the yield is as follows: 98%, purity: 99% and an ee value of 99.1%.
Example 5: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg,5.0 mu mol) is added into a reaction bottle, toluene (5mL) is added under the argon atmosphere, and the reaction lasts for 0.5h at 25 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and toluene (15mL) into a reaction bottle, replacing three times with argon and hydrogen respectively, keeping the hydrogen atmosphere at 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting the organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.06g,4.80mmol), wherein the yield is as follows: 96%, purity: 97% and ee value 96.2%.
Example 6: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg,5.0 mu mol) is added into a reaction bottle, methanol (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and methanol (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09g,4.94mmol), wherein the yield is as follows: 99%, purity: 99% and an ee value of 99.3%.
Example 7: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligandsL-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, isopropanol (5mL) is added under the atmosphere of argon, and the mixture reacts for 0.5h at 25 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and isopropanol (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, maintaining a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.08g,4.89mmol), wherein the yield is as follows: 98%, purity: 98% and an ee value of 97.9%.
Example 8: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg,5.0 mu mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction lasts for 0.5h at 25 ℃, thus obtaining the catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 10 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.04g,4.69mmol), wherein the yield is as follows: 94%, purity: 96% and an ee value of 99.9%.
Example 9: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in step 1) and dichloromethane (15mL) into a reaction bottle, replacing with argon and hydrogen for three times respectively, keeping the hydrogen atmosphere at 0.1MPa, reacting at 40 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting the organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.08g,4.90mmol), wherein the yield is as follows: 98%, purity: 98% and an ee value of 99.0%.
Example 10: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and metal complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 60 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.06g,4.80mmol), wherein the yield is as follows: 96%, purity: 97% and ee value 96.1%.
Example 11: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the mixture reacts for 0.5h at the temperature of 10 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -N-acetylphenylalanine methyl ester (1.06g,4.80mmol), wherein the yield is as follows: 96%, purity: 98% and an ee value of 98.3%.
Example 12: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 40 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09g,4.92mmol), wherein the yield is as follows: 98%, purity: 99% and an ee value of 99.0%.
Example 13: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) was reacted with a metal complex [ Rh (NBD) ]2]BF4(1.87mg,5.0 mu mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09g,4.94mmol), wherein the yield is as follows: 97%, purity: 98% and an ee value of 97.3%.
Example 14: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]OTf (2.34mg, 5.0. mu. mol) plusPutting the mixture into a reaction bottle, adding dichloromethane (5mL) under the argon atmosphere, and reacting for 0.5h at 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in step 1) and dichloromethane (15mL) into a reaction bottle, replacing with argon and hydrogen for three times respectively, keeping the hydrogen atmosphere at 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting the organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.06g,4.80mmol), wherein the yield is as follows: 96%, purity: 98% and an ee value of 96.8%.
Example 15: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) was reacted with metal complex [ Rh (NBD) Cl]2(1.15mg, 2.5. mu. mol) into a reaction bottle, adding dichloromethane (5mL) under argon atmosphere, and reacting at 25 ℃ for 0.5h to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -N-acetylphenylalanine methyl ester (1.04g,4.71mmol), wherein the yield is as follows: 94%, purity: 98% and ee value 91.2%.
Example 16: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) was reacted with a metal complex [ Rh (C)2H4)2Cl]2(0.97mg, 2.5. mu. mol) into a reaction bottle, adding dichloromethane (5mL) under argon atmosphere, and reacting at 25 ℃ for 0.5h to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.05g,4.75mmol), wherein the yield is as follows: 95%, purity: 97% and an ee value of 92.2%.
Example 17: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-2(5.28mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.04g,4.70mmol), wherein the yield is as follows: 94%, purity: 97% and an ee value of 92.9%.
Example 18: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-3(4.05mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.04g,4.68mmol), wherein the yield is as follows: 94%, purity: 96% and an ee value of 92.1%.
Example 19: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-4(3.89mg, 5.5. mu. mol) and metal complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09g,4.91mmol), wherein the yield is as follows: 98%, purity: 99% and ee value 98.3%.
Example 20: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg,5.0 mu mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction lasts for 0.5h at 25 ℃, thus obtaining the catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (100mL) into a high-pressure reaction kettle, sealing the reaction kettle, replacing the reaction kettle with argon and hydrogen for three times respectively, filling hydrogen to 1.0MPa, reacting at 25 ℃ for 12 hours, after the reaction is finished, recovering the solvent by reduced pressure distillation, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, recovering the solvent by reduced pressure distillation, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09g,4.91mmol), wherein the yield is as follows: 98%, purity 98%, ee value 98.3%.
Example 21: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) was added to the reaction flask under an argon atmosphereAdding dichloromethane (5mL) to react for 0.5h at 25 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (1mL) into a high-pressure reaction kettle, sealing the reaction kettle, replacing the reaction kettle with argon and hydrogen for three times respectively, filling hydrogen to 1.0MPa, reacting at 25 ℃ for 12 hours, after the reaction is finished, recovering the solvent by reduced pressure distillation, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, recovering the solvent by reduced pressure distillation, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.06g,4.79mmol), wherein the yield is as follows: 96%, purity 97%, ee value 97.2%.
Examples 22 to 40: preparation of (R) -alpha-aryl alanine ester derivatives
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -alpha-dehydro-aryl alanine ester derivative (5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining the (R) -alpha-aryl alanine ester derivative, wherein the yield, the purity and the ee value of the product are shown in Table 1.
The reaction formula is as follows:
Figure BDA0003529283720000141
TABLE 1 Experimental results for examples 22 to 40
Figure BDA0003529283720000151
Figure BDA0003529283720000161
The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.

Claims (9)

1. A method for preparing an (R) -alpha-aryl alanine ester derivative, which is characterized by comprising the following steps:
1) under argon atmosphere, metal Rh complex and chiral ligand L*Adding the obtained product into a solvent A to react for 0.5-6 hours to obtain a metal Rh complex and a chiral ligand L*Coordination bound catalysts [ Rh]/L*；
2) Adding alpha-dehydro aryl alanine ester derivative shown as formula (2) and the prepared catalyst [ Rh ] into an autoclave]/L*And a solvent B, carrying out asymmetric hydrogenation reaction at 10-80 ℃ and under the hydrogen pressure of 0.1-6.0 MPa, reacting for 1-24 hours, carrying out reduced pressure distillation to recover the solvent B, adding a proper amount of water, extracting with ethyl acetate, collecting an organic phase, drying, and carrying out reduced pressure distillation to recover the solvent to obtain the (R) -alpha-aryl alanine ester derivative shown in the formula (1);
the specific reaction route is as follows:
Figure FDA0003529283710000011
in the formulas (1) and (2), the aryl Ar is selected from phenyl, heterocyclic group, naphthyl or substituted phenyl, and the substituent in the substituted phenyl is C1-6 alkyl, C1-6 alkoxy or halogen, nitro; r1Selected from acetyl, benzyloxycarbonyl, tert-butoxycarbonyl; r2Selected from C1-6 alkyl.
2. The method for preparing (R) - α -arylalanine ester derivatives according to claim 1, wherein the chiral ligand L*The chemical structural formula of (A) is shown as the general formula (L):
Figure FDA0003529283710000021
in the general formula (L): r3And R4Each independently substituted or unsubstituted, when substituted, the substituent R3And a substituent R4Each independently selected from halogen, aryl, C1-C6 alkyl.
3. The method for preparing (R) - α -arylalanine ester derivatives according to claim 2, wherein the chiral ligand L is represented by the formula (L)*The chemical structural formula of (A) is shown as any one of the formulas (L-1) to (L-4):
Figure FDA0003529283710000022
4. the method for preparing (R) - α -arylalanine ester derivative according to claim 1, wherein said metal Rh complex is [ Rh (C)2H4)2Cl]2、[Rh(NBD)Cl]2、[Rh(COD)Cl]2、[Rh(NBD)2]BF4、[Rh(COD)2]X、Rh(ethylene)2(acac)、[Rh(acac)(CO)]2、[Rh(C2H4)2Cl]2、RhCl(PPh3)3、[Rh(CO)2C1]2、Rh(arene)X2(diphosphine)、Rh(aryl group)X2、Rh(COD)(COT)、Rh(COD)(COT)X、Rh(COD)(methallyl)2、RhX2(diphosphine)、RhCl2(COD)、RhX2(cymene)、Rh(arylgroup)X2(PPh3)3、Rh(methallyl)2(diphosphine) and Rh (aryl group) X2(diphosphine) wherein aryl is aryl and X is BF4 -、OTf-、ClO4 -、SbF6 -、PF6 -、CF3SO3 -And B (Y)4 -Y is bis (trifluoromethyl) benzene or fluorobenzene.
5. The method for preparing (R) - α -arylalanine ester derivative according to claim 1, wherein in the step 2), the catalyst [ Rh ] is added]/L*The molar ratio of the alpha-dehydroaryl alanine ester derivative to the alpha-dehydroaryl alanine ester derivative is 1: 100-1: 100000.
6. The method for preparing (R) - α -arylalanine ester derivative according to claim 1, wherein in the step 1), the catalyst [ Rh ] is prepared]/L*The temperature of the reaction is 10-40 ℃, and the reaction time is 0.5-3 hours.
7. The method for preparing an (R) - α -arylalanine ester derivative according to claim 1, wherein the asymmetric hydrogenation is carried out at 10-60 ℃ under a hydrogen pressure of 0.1-3.0 MPa for 4-24 hours in step 2).
8. The process for producing an (R) - α -arylalanine ester derivative according to claim 1, wherein the concentration of the α -dehydroarylalanine ester derivative represented by the formula (2) in the solvent B is from 0.05mol/L to 5.0 mol/L.
9. The method for preparing an (R) - α -arylalanine ester derivative according to claim 1, wherein the solvent A in the step 1) and the solvent B in the step 2) are independently selected from one or more mixed solvents of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, methanol, ethanol, n-propanol, isopropanol and tert-butanol.
CN202210206296.7A 2022-03-03 2022-03-03 Preparation method of (R) -alpha-aryl alanine ester derivative Active CN114573473B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210206296.7A CN114573473B (en) 2022-03-03 2022-03-03 Preparation method of (R) -alpha-aryl alanine ester derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210206296.7A CN114573473B (en) 2022-03-03 2022-03-03 Preparation method of (R) -alpha-aryl alanine ester derivative

Publications (2)

Publication Number Publication Date
CN114573473A true CN114573473A (en) 2022-06-03
CN114573473B CN114573473B (en) 2023-11-28

Family

ID=81775994

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210206296.7A Active CN114573473B (en) 2022-03-03 2022-03-03 Preparation method of (R) -alpha-aryl alanine ester derivative

Country Status (1)

Country Link
CN (1) CN114573473B (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1579627A (en) * 2003-08-05 2005-02-16 中国科学院大连化学物理研究所 Chiral ligand metal complex catalyst system, and its preparation method and use
CN1768944A (en) * 2004-11-01 2006-05-10 中国科学院大连化学物理研究所 Catalyst using phosphine-phosphoramidite ester as ligand, its preparation method and application
CN101775035A (en) * 2009-12-25 2010-07-14 青岛科技大学 Synthesis of class of amino acid type amphoteric water-soluble chiral phosphine ligand and application thereof in asymmetric catalytic hydrogenation
CN112824422A (en) * 2019-11-21 2021-05-21 中国科学院大连化学物理研究所 Chiral ferrocene-indole diphosphine ligand as well as preparation method and application thereof
CN112824423A (en) * 2019-11-21 2021-05-21 中国科学院大连化学物理研究所 Chiral ferrocenylphosphine-indolylaminophosphine ligand and preparation method and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1579627A (en) * 2003-08-05 2005-02-16 中国科学院大连化学物理研究所 Chiral ligand metal complex catalyst system, and its preparation method and use
CN1768944A (en) * 2004-11-01 2006-05-10 中国科学院大连化学物理研究所 Catalyst using phosphine-phosphoramidite ester as ligand, its preparation method and application
CN101775035A (en) * 2009-12-25 2010-07-14 青岛科技大学 Synthesis of class of amino acid type amphoteric water-soluble chiral phosphine ligand and application thereof in asymmetric catalytic hydrogenation
CN112824422A (en) * 2019-11-21 2021-05-21 中国科学院大连化学物理研究所 Chiral ferrocene-indole diphosphine ligand as well as preparation method and application thereof
CN112824423A (en) * 2019-11-21 2021-05-21 中国科学院大连化学物理研究所 Chiral ferrocenylphosphine-indolylaminophosphine ligand and preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
曾庆恒: "手性磷配体的设计、合成及其在不对称催化氢化反应中的应用研究", 中国博士学位论文全文数据库工程科技I辑 *

Also Published As

Publication number Publication date
CN114573473B (en) 2023-11-28

Similar Documents

Publication Publication Date Title
Miyano et al. Axially dissymmetric bis (aminophosphine) s derived from 2, 2'-diamino-1, 1'-binaphthyl. Synthesis and application to rhodium (I)-catalyzed asymmetric hydrogenations.
CN114315917B (en) Chiral ferrocene PNNO tetradentate ligand and application thereof in asymmetric hydrogenation reaction
CN108774271A (en) A kind of chiral nitrogen nitrogen phosphine tridentate ligand and its application based on ferrocene frame having ferrocene frame
CN102417523B (en) Preparation and catalytic application of nitrogen heterocyclic ligand transition metal complex
CN106892935A (en) A kind of immobilized copper catalysis of shitosan prepare method and the application of organoboron compound
CN106831550A (en) A kind of optical activity two（It is miscellaneous）Aryl methyl alcohol and its method of asymmetric synthesis
CN106103413A (en) Process for producing optically active compounds
CN115536708A (en) A chiral bisphosphine ligand with a ferrocene skeleton and its preparation method and application
CN102984945B (en) An enantioselective process for cycloalkenyl [beta]-substituted alanines
WO2014036702A1 (en) New metal ruthenium complex having nitrogen ligand, preparation method therefor, and uses thereof
CN1579627A (en) Chiral ligand metal complex catalyst system, and its preparation method and use
CN112358379B (en) Preparation method of optically pure S-shaped 1,1-bis- (4-fluorophenyl) -2-propanol
CN109824579B (en) Preparation method of (S) -phenyl (pyridine-2-yl) methanol derivative
CN114573473B (en) Preparation method of (R) -alpha-aryl alanine ester derivative
CN103111323B (en) Chirality N, N-dialkyl-1, 2-diaminocyclohexane catalyst as well as preparation method and application thereof
CN111848483B (en) Asymmetric catalytic preparation method of brivaracetam
CN116063355A (en) A Chiral Multidentate Ligand and Its Application in Asymmetric Hydrogenation
KR101579992B1 (en) Trisubstituted 3,4-dihydro-1h-isoquinolin compound, process for its preparation, and its use
CN1166672C (en) Metal complex of C2 uncymmetric chira biphosphine ligand, its synthesizing process and its application in unsymmetric catalytic hydrogenation of ketone
CN111333573A (en) Preparation process of dextromethorphan intermediate
CN106632361B (en) A kind of method of synthesizing optical Pure biotin intermediate lactone
CN107690436B (en) Methods for forming complexes, complexes and their uses
WO2014077323A1 (en) Method for producing optically active isopulegol and optically active menthol
CN114524745A (en) Preparation method of (R) -N-acetyl-alpha-arylethylamine derivative
CN105085513B (en) The method that one kind prepares (R) 3 quinine cyclol

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant