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

Abstract

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

A kind of preparation method of (R)-α-arylalanine ester derivative

technical field

The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of a (R)-α-arylalanine ester derivative.

Background technique

Chiral α-amino acids have a wide range of applications in the fields of pharmacy, biology and synthetic chemistry, and their importance is self-evident. Among many chiral α-amino acids, chiral α-arylalanine is widely distributed, and can be found in drug molecules, food additives, etc. Such as levothyroxine (Levothyroxine) for the treatment of hypothyroidism; ADEP4 against multidrug-resistant bacterial infection, β2 receptor antagonist CPD-15A5, spectrum anticancer agent LY355703 and sweetener Aspartame (Aspartame) and so on.

For this reason, their synthetic methods have also attracted much attention. The synthesis of chiral α-arylalanine is mainly based on its corresponding asymmetric hydrogenation. In 1972, Kagan reported the first case of asymmetric hydrogenation of enamides (H.B.Kagan, J.Am.Chem.Soc., 1972, 94, 6429.), which used the rhodium complex of DIOP with an ee of 72%. In the case of N-acetyl-protected α-phenylalanine, alkenine derivatives have been extensively studied as a class of important hydrogenation substrates since then, and a series of very important results have been achieved. In 2002, Knowles (W.S.Knowles, Angew.Chem., Int.Ed., 2002,41,1998-2007.) used DIPAMP/Rh catalytic system to participate in the asymmetric hydrogenation of α-phenylalanine, and successfully prepared high optical The purity of L-DOPA (97.5% ee), for which he won the Nobel Prize in Chemistry in 2001, is still the mainstream method for the production of L-DOPA.

Since then, ligands for asymmetric hydrogenation of α-dehydroarylalanine derivatives have sprung up and achieved excellent results. For example, Hu Xiangping's group (X.-P.Hu, Tetrahedron Lett., 2020 , 61, 151860.) developed the ferrocene framework ligand IndoFerroPhos, which can obtain (R)-α-arylalanine ester derivatives in high yields, but its ee value is only 97% at the highest, and it is not suitable for heterocycles. Poor substrate applicability; the benzoxaphosphorus ligand BABIPhos developed by Tang Wenjun's group (W.J.Tang, Org. Lett., 2018, 20, 1725-1729.) can obtain (R)- α-Arylalanine ester derivatives, but its catalyst TON value is only 100; Similarly, the mannitol-derived dimethylocene developed by Professor Zhang Xumu (X. Zhang, Org. Lett., 2002, 4, 4471-4474.) The iron-skeleton cyclic phosphine ligands also suffer from the above problems.

In 2021, CN112824423A disclosed a chiral ferrocene phosphine-indoleaminophosphine ligand, which can efficiently catalyze the synthesis of high optical purity α-dehydroamino acid esters, with a TON of up to 10,000, but the highest enantioselectivity is 96%ee. Although considerable progress has been made in the preparation of (R)-α-arylalanine ester derivatives by asymmetric hydrogenation technology, the reported catalysts still have some of the above-mentioned problems, so it is urgent to find an efficient and high stereoselectivity , a new method for asymmetric catalytic hydrogenation with wide substrate applicability.

SUMMARY OF THE INVENTION

In view of the above-mentioned problems existing in the prior art, the object of the present invention is to provide a preparation method of (R)-α-arylalanine ester derivatives, which is suitable for industrial production applications, and can be more conveniently prepared in kilograms and (R)-α-Arylalanine ester derivatives with high purity and high enantioselectivity.

The technical scheme adopted in the present invention is:

A preparation method of (R)-α-arylalanine ester derivative, comprising the steps:

1) Under an argon atmosphere, the metal Rh complex and the chiral ligand L ^* are added to the solvent A to react for 0.5 to 6 hours to obtain a catalyst in which the metal Rh complex is coordinated with the chiral ligand L ^* . [Rh]/L ^* ;

2) Add the α-dehydroarylalanine ester derivative represented by the formula (2), the catalyst [Rh]/L ^* obtained above and the solvent B into the autoclave, and heat it at 10°C to 80°C and The asymmetric hydrogenation reaction is carried out under the hydrogen pressure of 0.1-6.0 MPa. After the reaction for 1-24 hours, the solvent B is recovered by distillation under reduced pressure, then an appropriate amount of water is added, extracted with ethyl acetate, the organic phase is collected, dried, and distilled under reduced pressure. Recover solvent to obtain (R)-α-arylalanine ester derivative shown in formula (1);

The specific reaction route is as follows:

In formula (1) and formula (2), the aryl group Ar is selected from phenyl, heterocyclyl, naphthyl or substituted phenyl, and the substituents in the substituted phenyl are C1-6 alkyl, C1-6 alkoxy or halogen, nitro; R ¹ is selected from acetyl, benzyloxycarbonyl, tert-butoxycarbonyl; R ² is selected from C1-6 alkyl;

Further, the chemical structural formula of the chiral ligand L ^* is shown in the general formula (L):

In the general formula (L): R ³ and R ⁴ are each independently substituted or unsubstituted, and when substituted, the substituent R ³ and the substituent R ⁴ are each independently selected from halogen, aryl, and C1-C6 alkyl.

Further, the chemical structural formula of the chiral ligand L ^* represented by the general formula (L) is represented by any one of the formulas (L-1) to (L-4):

Further, the metal Rh complexes are [Rh(C ₂ H ₄ ) ₂ Cl] ₂ , [Rh(NBD)Cl] ₂ , [Rh(COD)Cl] ₂ , [Rh(NBD) ₂ ] BF ₄ , [Rh(COD) ₂ ]X, Rh(ethylene) ₂ (acac), [Rh(acac)(CO)] ₂ , [Rh(C ₂ H ₄ ) ₂ Cl] ₂ , RhCl(PPh ₃ ) ₃ , [Rh(CO) ₂ C1] ₂ , Rh(arene)X ₂ (diphosphine), Rh(aryl group)X ₂ , Rh(COD)(COT), Rh(COD)(COT)X, Rh(COD )(methallyl) ₂ , RhX ₂ (diphosphine), RhCl ₂ (COD), RhX ₂ (cymene), Rh(arylgroup)X ₂ (PPh ₃ ) ₃ , Rh(methallyl) ₂ (diphosphine) and Rh(aryl group) Any one of X ₂ (diphosphine), wherein aryl is an aryl group, and X is BF ₄ ^- , OTf ^- , ClO ₄ ^- , SbF ₆ ^- , PF ₆ ^- , CF ₃ SO ₃ ^- or B(Y) ₄ ^- In any one, Y is bis(trifluoromethyl)benzene or fluorobenzene.

Further, in step 2), the molar ratio of the catalyst [Rh]/L ^* to the α-dehydroarylalanine ester derivative is 1:100˜1:100000.

Further, in step 1), the temperature for preparing the catalyst [Rh]/L ^* is 10°C to 40°C, and the reaction time is 0.5 to 3 hours.

Further, in step 2), the temperature for the asymmetric hydrogenation reaction is 10°C to 60°C, the hydrogen pressure is 0.1 to 3.0 MPa, and the reaction time is 4 to 24 hours.

Further, the concentration of the α-dehydroarylalanine ester derivative represented by the formula (2) in the solvent B is 0.05 mol/L to 5.0 mol/L.

Further, solvent A in step 1) and solvent B in step 2) are independently selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, methanol, ethanol, n-propyl One or more mixed solvents of alcohol, isopropanol and tert-butanol, solvent A and solvent B can be the same.

By adopting the above-mentioned technology, compared with the prior art, the present invention has the following characteristics:

The invention develops a catalyst composed of a chiral phosphine-spirodihydroindene phosphoramidite bidentate ligand and a metal complex containing a ferrocene skeleton, and the catalyst is easy to prepare; the catalyst prepared by the invention does not require special The purification treatment can be directly used for the reaction of catalytic hydrogenation to prepare (R)-α-arylalanine ester derivatives; compared with the existing asymmetric hydrogenation method, the present invention has a lower 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, the reaction conditions are mild, and it is easy to industrialize. It meets the requirements of green chemistry and has a large implementation value and social and economic benefits.

Detailed ways

The present invention will be further described below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto.

Embodiment 1: the preparation of (R)-α-N-acetyl phenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 25°C for 0.5h to prepare a catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, kept 0.1MPa hydrogen atmosphere, and reacted at 25 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.09 g, 4.94 mmol), yield: 99%, purity: 99%, and ee value of 99.9%.

Embodiment 2: the preparation of (R)-α-N-acetyl phenylalanine methyl ester

1) The chiral ligand L-1 (47.3mg, 55.0μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (20.3mg, 50.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (30 mL) was reacted at 25°C for 0.5 h to obtain a catalyst;

2) In the reaction flask, add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1kg, 5.0mol), the prepared catalyst of step 1) and dichloromethane (3.0L). ), replaced three times with argon and hydrogen respectively, maintained a hydrogen atmosphere of 0.1MPa, and reacted at 25 °C for 12 h. After the reaction was completed, the solvent was recovered by distillation under reduced pressure, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected. After drying, the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.07 kg, 4.81 mol), yield: 96%, purity: 98%, and ee value of 99.0%.

Embodiment 3: the preparation of (R)-α-N-acetyl phenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 25°C for 0.5h to prepare a catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen, respectively, filled with hydrogen to 3.0MPa, and reacted at 25 ° C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected. After drying, the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.07 g, 4.85 mmol), yield: 97%, purity: 98%, and ee value of 98.7%.

Embodiment 4: the preparation of (R)-α-N-acetyl phenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Tetrahydrofuran (5mL) was reacted at 25°C for 0.5h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and tetrahydrofuran (15 mL) to the reaction flask, respectively. Replaced with argon and hydrogen three times, maintained a hydrogen atmosphere of 0.1 MPa, and reacted at 25 ° C for 12 h. After the reaction, the solvent was recovered by distillation under reduced pressure, and then an appropriate amount of water was added, and extracted with ethyl acetate. After collecting the organic phase, it was dried and reduced. The solvent was recovered by pressure distillation to obtain (R)-α-N-acetylphenylalanine methyl ester (1.08 g, 4.89 mmol), yield: 98%, purity: 99%, and ee value of 99.1%.

Example 5: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Toluene (5mL) was reacted at 25°C for 0.5h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and toluene (15 mL) to the reaction flask, respectively. Replaced with argon and hydrogen three times, maintained a hydrogen atmosphere of 0.1 MPa, and reacted at 25 ° C for 12 h. After the reaction, the solvent was recovered by distillation under reduced pressure, and then an appropriate amount of water was added, and extracted with ethyl acetate. After collecting the organic phase, it was dried and reduced. The solvent was recovered by pressure distillation to obtain (R)-α-N-acetylphenylalanine methyl ester (1.06 g, 4.80 mmol), yield: 96%, purity: 97%, and ee value of 96.2%.

Example 6: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Methanol (5mL) was reacted at 25°C for 0.5h to prepare the catalyst;

2) Into the reaction flask, add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and methanol (15 mL), respectively. Replaced with argon and hydrogen three times, maintained a hydrogen atmosphere of 0.1 MPa, and reacted at 25 ° C for 12 h. After the reaction, the solvent was recovered by distillation under reduced pressure, and then an appropriate amount of water was added, and extracted with ethyl acetate. After collecting the organic phase, it was dried and reduced. The solvent was recovered by distillation under pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.09 g, 4.94 mmol), yield: 99%, purity: 99%, and ee value of 99.3%.

Embodiment 7: the preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Isopropanol (5mL) was reacted at 25°C for 0.5h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and isopropanol (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, kept 0.1MPa hydrogen atmosphere, and reacted at 25 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.08 g, 4.89 mmol), yield: 98%, purity: 98%, and ee value of 97.9%.

Example 8: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 25°C for 0.5h to prepare a catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , respectively replaced three times with argon and hydrogen, kept 0.1MPa hydrogen atmosphere, and reacted at 10 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.04 g, 4.69 mmol), yield: 94%, purity: 96%, and ee value of 99.9%.

Example 9: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 25°C for 0.5h to prepare a catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, maintained a hydrogen atmosphere of 0.1MPa, and reacted at 40 ° C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.08 g, 4.90 mmol), yield: 98%, purity: 98%, and ee value of 99.0%.

Example 10: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 25°C for 0.5h to prepare a catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, kept a hydrogen atmosphere of 0.1MPa, and reacted at 60 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.06 g, 4.80 mmol), yield: 96%, purity: 97%, and ee value of 96.1%.

Example 11: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5 mL) was reacted at 10 °C for 0.5 h to prepare a catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, kept 0.1MPa hydrogen atmosphere, and reacted at 25 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-N-acetylphenylalanine methyl ester (1.06 g, 4.80 mmol), yield: 96%, purity: 98%, and ee value of 98.3%.

Example 12: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 40°C for 0.5h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, kept 0.1MPa hydrogen atmosphere, and reacted at 25 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.09 g, 4.92 mmol), yield: 98%, purity: 99%, and ee value of 99.0%.

Example 13: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(NBD) ₂ ]BF ₄ (1.87mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 25°C for 0.5h to prepare a catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, kept 0.1MPa hydrogen atmosphere, and reacted at 25 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.09 g, 4.94 mmol), yield: 97%, purity: 98%, and ee value of 97.3%.

Example 14: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]OTf (2.34mg, 5.0μmol) were added to the reaction flask, and two Methyl chloride (5 mL) was reacted at 25°C for 0.5 h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, kept 0.1MPa hydrogen atmosphere, and reacted at 25 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.06 g, 4.80 mmol), yield: 96%, purity: 98%, and ee value of 96.8%.

Example 15: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(NBD)Cl] ₂ (1.15mg, 2.5μmol) were added to the reaction flask, and two were added under an argon atmosphere. Methyl chloride (5 mL) was reacted at 25°C for 0.5 h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, kept 0.1MPa hydrogen atmosphere, and reacted at 25 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-N-acetylphenylalanine methyl ester (1.04 g, 4.71 mmol), yield: 94%, purity: 98%, and ee value of 91.2%.

Example 16: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73 mg, 5.5 μmol) and the metal complex [Rh(C ₂ H ₄ ) ₂ Cl] ₂ (0.97 mg, 2.5 μmol) were added to the reaction flask, and the mixture was heated under argon. Dichloromethane (5 mL) was added under the atmosphere and reacted at 25°C for 0.5 h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, kept 0.1MPa hydrogen atmosphere, and reacted at 25 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.05 g, 4.75 mmol), yield: 95%, purity: 97%, and ee value of 92.2%.

Example 17: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-2 (5.28mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 25°C for 0.5h to prepare a catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, kept 0.1MPa hydrogen atmosphere, and reacted at 25 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.04 g, 4.70 mmol), yield: 94%, purity: 97%, and ee value of 92.9%.

Example 18: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-3 (4.05mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 25°C for 0.5h to prepare a catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, kept 0.1MPa hydrogen atmosphere, and reacted at 25 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.04 g, 4.68 mmol), yield: 94%, purity: 96%, and ee value of 92.1%.

Example 19: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-4 (3.89mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 25°C for 0.5h to prepare a catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1 g, 5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) to the reaction flask , replaced three times with argon and hydrogen respectively, kept 0.1MPa hydrogen atmosphere, and reacted at 25 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, and then an appropriate amount of water was added, extracted with ethyl acetate, and the organic phase was collected and dried. , and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.09 g, 4.91 mmol), yield: 98%, purity: 99%, and ee value of 98.3%.

Example 20: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 25°C for 0.5h to prepare a catalyst;

2) in the autoclave, add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), step 1) prepared catalyst and dichloromethane ( 100mL), after sealing the reactor, replace it with argon and hydrogen three times respectively, fill it with hydrogen to 1.0MPa, and react at 25°C for 12h. After the reaction, the solvent is recovered by distillation under reduced pressure, and then an appropriate amount of water is added and extracted with ethyl acetate. , the organic phase was collected and dried, and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.09g, 4.91mmol), yield: 98%, purity 98%, ee The value is 98.3%.

Example 21: Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 25°C for 0.5h to prepare a catalyst;

2) in the autoclave, add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), step 1) prepared catalyst and dichloromethane ( 1mL), after sealing the reaction kettle, replace it with argon and hydrogen three times respectively, fill with hydrogen to 1.0MPa, and react at 25 ° C for 12h. After the reaction is completed, the solvent is recovered by vacuum distillation, and then an appropriate amount of water is added and extracted with ethyl acetate. , the organic phase was collected and dried, and the solvent was recovered by distillation under reduced pressure to obtain (R)-α-N-acetylphenylalanine methyl ester (1.06g, 4.79mmol), yield: 96%, purity 97%, ee The value is 97.2%.

Examples 22-40: Preparation of (R)-α-arylalanine ester derivatives

1) The chiral ligand L-1 (4.73mg, 5.5μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) were added to the reaction flask, and added under argon atmosphere Dichloromethane (5mL) was reacted at 25°C for 0.5h to prepare a catalyst;

2) Add (Z)-α-dehydroarylalanine ester derivative (5.0 mmol), the catalyst obtained in step 1) and dichloromethane (15 mL) into the reaction flask, and use argon and hydrogen respectively. Replaced three times, kept 0.1MPa hydrogen atmosphere, and reacted at 25 °C for 12 h. After the reaction, the solvent was recovered by vacuum distillation, then an appropriate amount of water was added, extracted with ethyl acetate, the organic phase was collected, dried, and the solvent was recovered by vacuum distillation. The (R)-α-arylalanine ester derivative was obtained. The yield, purity and ee value of the product are shown in Table 1.

The general reaction formula is as follows:

Table 1 Experimental results of Examples 22-40

The content described in this specification is only an enumeration of the implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms stated in the embodiments.

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:

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):

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):

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.