CN114573473B - Preparation method of (R)-α-arylalanine 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 an asymmetric hydrogenation reaction at 10°C to 80°C and a hydrogen pressure of 0.1 to 6.0MPa. After the reaction for 1 to 24 hours, solvent B is recovered by distillation under reduced pressure, then an appropriate amount of water is added, and extracted with ethyl acetate. The organic phase is collected and dried, and the solvent is recovered by distillation under reduced pressure to obtain the (R)-α-arylalanine ester derivative. The method of the present invention has the advantages of low catalyst dosage (TON up to 100,000), excellent enantioselectivity (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 for industrialization, meets the requirements of green chemistry, and has great implementation value and social and economic benefits.

Description

Preparation method of (R)-α-arylalanine ester derivative

Technical field

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

Background technique

Chiral α-amino acids are widely used in the fields of medicine, biology and synthetic chemistry, and their importance is self-evident. Among many chiral α-amino acids, chiral α-arylalanine is extremely widely distributed and can be found in drug molecules, food additives, etc. For example, Levothyroxine (Levothyroxine) treats hypothyroidism; ADEP4 can fight multi-drug-resistant bacterial infections, β2 receptor antagonist CPD-15A5, spectrum anti-cancer agent LY355703, and sweetener Aspartame (Aspartame), etc.

For this reason, their synthesis 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 asymmetric hydrogenation of enamide (H.B.Kagan, J.Am.Chem.Soc., 1972, 94, 6429.). This system used DIOP's rhodium complex with an ee value of 72%. After arriving at N-acetyl-protected α-phenylalanine, enoline derivatives have been widely studied as an important class of hydrogenation substrates, 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 the 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 2001 Nobel Prize in Chemistry, is still the mainstream method for producing L-DOPA.

Since then, ligands for the asymmetric hydrogenation of α-dehydroarylalanine derivatives have sprung up, and have achieved excellent results, such as Hu Xiangping's research group (X.-P. Hu, Tetrahedron Lett., 2020 , 61, 151860.) The ferrocene skeleton ligand IndoFerroPhos developed by The substrate applicability is poor; the benzoxaphosphorus ligand BABIPhos developed by Tang Wenjun's research group (W.J.Tang, Org.Lett., 2018, 20, 1725-1729.) can obtain (R)- with an ee value of 99% α-arylalanine ester derivatives, but their catalyst TON value is only 100; similarly, mannitol-derived dicyclopentane developed by Professor Zhang Xumu (X. Zhang, Org. Lett., 2002, 4, 4471-4474.) Iron skeleton cyclic phosphine ligands also have the above problems.

In 2021, CN112824423A disclosed a chiral ferrocenephosphine-indole aminophosphine ligand, which can efficiently catalyze the synthesis of high optical purity α-dehydrogenated amino acid esters, with a TON of up to 10,000, but its highest enantioselectivity is 96%ee. Although great progress has been made in the preparation of (R)-α-arylalanine ester derivatives using asymmetric hydrogenation technology, the catalysts reported so far still have some of the above problems, so there is an urgent need to find an efficient and highly stereoselective catalyst. , a new asymmetric catalytic hydrogenation method with wide substrate applicability.

Contents 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 more easily prepare kilogram-level and (R)-α-arylalanine ester derivatives with high purity and high enantioselectivity.

The technical solution adopted by the present invention is:

A method for preparing (R)-α-arylalanine ester derivatives, including the following steps:

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

2) Add the α-dehydroarylalanine ester derivative shown in formula (2), the catalyst [Rh]/L ^* and solvent B prepared above to the autoclave, and heat at 10°C to 80°C and Carry out an asymmetric hydrogenation reaction under a hydrogen pressure of 0.1 to 6.0 MPa. After the reaction for 1 to 24 hours, recover solvent B by distillation under reduced pressure, then add an appropriate amount of water, extract with ethyl acetate, collect the organic phase, dry and distill under reduced pressure. The solvent is recovered to obtain the (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 and 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 as general formula (L):

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

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

Further, the metal Rh complex is [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 )} ^, where ^{aryl is} _an ^aryl group _, ^and Any one of them, Y is bis(trifluoromethyl)benzene or fluorobenzene.

Further, in step 2), the molar ratio of catalyst [Rh]/L ^* and α-dehydroarylalanine ester derivative is 1:100 to 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 asymmetric hydrogenation reaction is carried out at a temperature of 10°C to 60°C, a hydrogen pressure of 0.1 to 3.0MPa, and a reaction time of 4 to 24 hours.

Further, the concentration of the α-dehydroarylalanine ester derivative represented by formula (2) in 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 each independently selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, methanol, ethanol, n-propyl ether. One or two or more mixed solvents among alcohol, isopropyl alcohol and tert-butyl alcohol, solvent A and solvent B can be the same.

By adopting the above technology, compared with the existing technology, the present invention has the following characteristics:

The present invention develops a catalyst composed of a chiral phosphine-spiroindene phosphoramidite bidentate ligand and a metal complex containing a ferrocene skeleton. The catalyst is easy to prepare; the catalyst prepared by the present invention does not require special preparation. The purification treatment can be directly used in 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 (ee value is generally above 99%), wide substrate applicability, etc., and the raw materials are easily available, simple to operate, mild reaction conditions, easy to industrialize, meet the requirements of green chemistry, and have greater implementation value and social and economic benefits.

Detailed ways

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

Example 1 Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 25°C for 0.5h to prepare the catalyst;

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

Example 2 Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) Add the chiral ligand L-1 (47.3 mg, 55.0 μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (20.3 mg, 50.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (30mL), react at 25°C for 0.5h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1kg, 5.0mol), the catalyst prepared in step 1) and dichloromethane (3.0L) into the reaction bottle ), replace them with argon and hydrogen three times respectively, maintain a hydrogen atmosphere of 0.1MPa, and react at 25°C for 12 hours. After the reaction is completed, recover the solvent by distillation under reduced pressure, then add an appropriate amount of water, extract with ethyl acetate, collect the organic phase and Dry and distill under reduced pressure to recover the solvent to obtain (R)-α-N-acetylphenylalanine methyl ester (1.07kg, 4.81mol). Yield: 96%, purity: 98%, ee value: 99.0%.

Example 3 Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 25°C for 0.5h to prepare the catalyst;

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

Example 4 Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Tetrahydrofuran (5mL), react at 25°C for 0.5h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in step 1) and tetrahydrofuran (15mL) into the reaction bottle, respectively. Replace with argon and hydrogen three times, maintain a 0.1MPa hydrogen atmosphere, and react at 25°C for 12 hours. After the reaction is completed, recover the solvent by distillation under reduced pressure, add an appropriate amount of water, and extract with ethyl acetate. Collect the organic phase and dry it. The solvent was recovered by pressure distillation to obtain (R)-α-N-acetylphenylalanine methyl ester (1.08g, 4.89mmol), with a yield of 98%, a purity of 99%, and an ee value of 99.1%.

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

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Toluene (5mL), react at 25°C for 0.5h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in step 1) and toluene (15mL) into the reaction bottle, respectively. Replace with argon and hydrogen three times, maintain a 0.1MPa hydrogen atmosphere, and react at 25°C for 12 hours. After the reaction is completed, recover the solvent by distillation under reduced pressure, add an appropriate amount of water, and extract with ethyl acetate. Collect the organic phase and dry it. The solvent was recovered by pressure distillation to obtain (R)-α-N-acetylphenylalanine methyl ester (1.06g, 4.80mmol), with a yield of 96%, a purity of 97%, and an ee value of 96.2%.

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

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Methanol (5mL), react at 25°C for 0.5h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in step 1) and methanol (15mL) into the reaction bottle, respectively. Replace with argon and hydrogen three times, maintain a 0.1MPa hydrogen atmosphere, and react at 25°C for 12 hours. After the reaction is completed, recover the solvent by distillation under reduced pressure, add an appropriate amount of water, and extract with ethyl acetate. Collect the organic phase and dry it. The solvent was recovered by pressure distillation to obtain (R)-α-N-acetylphenylalanine methyl ester (1.09g, 4.94mmol), with a yield of 99%, a purity of 99%, and an ee value of 99.3%.

Example 7 Preparation of (R)-α-N-acetylphenylalanine methyl ester

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Isopropyl alcohol (5mL), react at 25°C for 0.5h to prepare the catalyst;

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

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

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 25°C for 0.5h to prepare the catalyst;

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

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

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 25°C for 0.5h to prepare the catalyst;

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

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

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 25°C for 0.5h to prepare the catalyst;

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

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

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 10°C for 0.5h to prepare the catalyst;

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

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

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 40°C for 0.5h to prepare the catalyst;

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

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

1) Add the chiral ligand L-1 (4.73 mg, 5.5 μmol) and the metal complex [Rh(NBD) ₂ ]BF ₄ (1.87 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 25°C for 0.5h to prepare the catalyst;

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

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

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]OTf (2.34 mg, 5.0 μmol) into the reaction bottle, and add two Methyl chloride (5mL), react at 25°C for 0.5h to prepare the catalyst;

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

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

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(NBD)Cl] ₂ (1.15 mg, 2.5 μmol) into the reaction bottle, and add two Methyl chloride (5mL), react at 25°C for 0.5h to prepare the catalyst;

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

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

1) Add 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) into the reaction bottle, and add it under argon gas Add dichloromethane (5mL) under the atmosphere and react at 25°C for 0.5h to prepare the catalyst;

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

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

1) Add chiral ligand L-2 (5.28mg, 5.5μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03mg, 5.0μmol) into the reaction bottle, and add under argon atmosphere Dichloromethane (5mL), react at 25°C for 0.5h to prepare the catalyst;

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

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

1) Add the chiral ligand L-3 (4.05 mg, 5.5 μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 25°C for 0.5h to prepare the catalyst;

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

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

1) Add the chiral ligand L-4 (3.89 mg, 5.5 μmol) and the metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 25°C for 0.5h to prepare the catalyst;

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

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

1) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 25°C for 0.5h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in step 1) and dichloromethane ( 100mL), 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 12 hours. After the reaction is completed, recover the solvent by distillation under reduced pressure, then add an appropriate amount of water, and extract with ethyl acetate , collect the organic phase, dry it, and recover the solvent 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) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 25°C for 0.5h to prepare the catalyst;

2) Add (Z)-N-acetyl-α-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in step 1) 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 12 hours. After the reaction is completed, recover the solvent by distillation under reduced pressure, then add an appropriate amount of water, and extract with ethyl acetate , collect the organic phase, dry it, and recover the solvent 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) Add chiral ligand L-1 (4.73 mg, 5.5 μmol) and metal complex [Rh(COD) ₂ ]BF ₄ (2.03 mg, 5.0 μmol) into the reaction bottle under an argon atmosphere. Dichloromethane (5mL), react at 25°C for 0.5h to prepare the catalyst;

2) Add (Z)-α-dehydroarylalanine ester derivative (5.0 mmol), the catalyst prepared in step 1) and dichloromethane (15 mL) into the reaction bottle, and use argon and hydrogen respectively. Replace three times, maintain a hydrogen atmosphere of 0.1MPa, and react at 25°C for 12 hours. After the reaction is completed, recover the solvent by distillation under reduced pressure, then add an appropriate amount of water, and extract with ethyl acetate. Collect the organic phase and dry it, and recover the solvent by distillation under reduced pressure. (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 to 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 considered to be limited to the specific forms stated in the embodiments.

Claims (5)

1. A method for preparing (R)-a-arylalanine ester derivatives, comprising the following steps: 1) Under an argon atmosphere, the metal Rh complex and the chiral ligand L ^* are added to the solvent A and react for 0.5 to 6 hours to prepare a catalyst in which the metal Rh complex and the chiral ligand L ^* are coordinately combined [Rh]/L ^* ; 2) Add the a-dehydroarylalanine ester derivative shown in formula (2), the catalyst [Rh]/L ^* and solvent B prepared above to the autoclave, and heat at 10°C to 80°C and Carry out an asymmetric hydrogenation reaction under a hydrogen pressure of 0.1 to 6.0 MPa. After the reaction for 1 to 24 hours, recover solvent B by distillation under reduced pressure, then add an appropriate amount of water, extract with ethyl acetate, collect the organic phase, dry and distill under reduced pressure. The solvent is recovered to obtain the (R)-a-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 and C1-6 alkoxy. Or halogen, nitro; R ¹ is selected from acetyl, benzyloxycarbonyl, tert-butoxycarbonyl; R ² is selected from C1~6 alkyl; The chemical structural formula of the chiral ligand L ^* is shown as general formula (L): In the general formula (L): the substituent R ³ is hydrogen or phenyl; the substituent R ⁴ is hydrogen, methyl, or iodine atom; The metal Rh complexes are [Rh(C ₂ H ₄ ) ₂ Cl] ₂ , [Rh(NBD)Cl] ₂ , [Rh(NBD) ₂ ]BF ₄ , Any one of [Rh(COD) ₂ ]BF ₄ and [Rh(COD) ₂ ]OTf; Solvent A in step 1) and solvent B in step 2) are each independently selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, methanol, ethanol, n-propanol, isopropanol, One or more mixed solvents from propanol and tert-butanol; In step 2), the molar ratio of catalyst [Rh]/L ^* and a-dehydroarylalanine ester derivative is 1:1000~1:100000. 2. The preparation method of a (R)-a-arylalanine ester derivative according to claim 1, characterized in that the chemical structural formula of the chiral ligand L ^* represented by the general formula (L) It is represented by any one of formula (L-1) to formula (L-4): 3. The preparation method of a (R)-a-arylalanine ester derivative according to claim 1, characterized in that in step 1), the temperature for preparing catalyst [Rh]/L ^* is 10°C ~40℃, reaction time is 0.5~3 hours. 4. The preparation method of a (R)-a-arylalanine ester derivative according to claim 1, characterized in that in step 2), the temperature at which the asymmetric hydrogenation reaction is carried out is 10°C to 60°C. , the hydrogen pressure is 0.1~3.0MPa, and the reaction time is 4~24 hours. 5. The preparation method of a (R)-a-arylalanine ester derivative according to claim 1, characterized in that the a-dehydroarylalanine ester derivative shown in formula (2) The concentration of the substance in solvent B is 0.05mol/L~5.0mol/L.