CN114573473B - Preparation method of (R) -alpha-aryl alanine ester derivative - Google Patents

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

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CN114573473B
CN114573473B CN202210206296.7A CN202210206296A CN114573473B CN 114573473 B CN114573473 B CN 114573473B CN 202210206296 A CN202210206296 A CN 202210206296A CN 114573473 B CN114573473 B CN 114573473B
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钟为慧
陈奕锐
成宇琪
凌飞
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Zhejiang University of Technology
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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 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) -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 an (R) -alpha-aryl alanine ester derivative.
Background
Chiral alpha-amino acids find wide application in pharmaceutical, biological and synthetic chemistry fields, the importance of which is self-evident. Among the numerous chiral α -amino acids, chiral α -aryl lactams are extremely widely distributed and their body shadow can be found in pharmaceutical molecules, food additives, etc. Such as Levothyroxine (Levothyroxine) for the treatment of hypothyroidism; ADEP4, beta 2 receptor antagonist CPD-15A5, spectral anticancer agent LY355703, sweetener Aspartame (Aspartame) and the like which can resist multi-drug resistant pathogen infection.
As such, their synthesis is also of great interest. The synthesis of chiral alpha-arylalanines is mainly based on the corresponding asymmetric hydrogenation thereof. In 1972 Kagan reported the first asymmetric hydrogenation of enamides (H.B.Kagan, J.Am.Chem.Soc.,1972,94,6429.) using rhodium complexes of DIOP to yield N-acetyl protected alpha-phenylalanine at 72% ee, after which enamine derivatives were extensively developed as an important class of hydrogenation substrates with a very important set of achievements. In 2002, knowles (W.S.Knowles, angew.Chem., int.Ed.,2002,41,1998-2007) successfully prepared high optical purity L-DOPA (97.5% ee) using a DIPAMP/Rh catalytic system to participate in asymmetric hydrogenation of alpha-phenylalanine, and he thus obtained the Norbeol chemical prize in 2001, which process has remained the dominant method for producing L-DOPA to date.
After that, as for the ligand of asymmetric hydrogenation of the alpha-dehydroarylalanine derivative, excellent effect is obtained like spring bamboo shoot after rain, such as ferrocene skeleton ligand IndoFerroPhos developed by Hu Xiangping subject group (X. -P.Hu, tetrahedron Lett.,2020,61,151860.) can be obtained, but the ee value is at most 97%, and applicability to heterocyclic substrates is poor; the benzoxepin ligand BABIPhos developed by the Shang Wenjun subject group (W.J.Tang, org.Lett.,2018,20,1725-1729.) gives (R) - α -arylalaninate derivatives having an ee value of 99%, but a catalyst TON value of only 100; likewise, the mannitol-derived ferrocenyl cyclic phosphine ligand developed by Zhang Xumu (X.Zhang, org.Lett.,2002,4,4471-4474.) also suffers from the above-mentioned problems.
In 2021, CN112824423a discloses a chiral ferrocene phosphine-indolyl aminophosphine ligand, which can efficiently catalyze and synthesize high optical purity alpha-dehydroamino acid ester, TON can reach 10000, but its enantioselectivity is 96% ee at most. Although there is a great progress in the preparation of (R) -alpha-arylalaninate derivatives by using asymmetric hydrogenation technology, the problems of the catalyst still exist in part, so that a new asymmetric catalytic hydrogenation method with high efficiency, high stereoselectivity and wide substrate applicability is urgently needed.
Disclosure of Invention
The present invention has been made in view of the above-mentioned problems occurring in the prior art, and an object of the present invention is to provide a method for preparing an (R) - α -arylalaninate derivative, which is suitable for industrial production applications, and which can conveniently prepare an (R) - α -arylalaninate derivative having a high degree of kilogram and having a high purity and a high enantioselectivity.
The technical scheme adopted by the invention is as follows:
a process for the preparation of an (R) - α -arylalaninate derivative, comprising the steps of:
1) Under argon atmosphere, metal Rh complex and chiral ligand L * Adding the mixture into the solvent A to react for 0.5 to 6 hours to prepare the metal Rh complex and the chiral ligand L * Coordination bound catalyst [ Rh]/L * ；
2) Adding an alpha-dehydroarylalaninate derivative represented by the formula (2) and the catalyst [ Rh ] prepared as described above to 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, after reacting for 1-24 hours, recovering the solvent B by reduced pressure distillation, adding a proper amount of water, extracting with ethyl acetate, collecting an organic phase, drying, and recovering the solvent by reduced pressure distillation to obtain the (R) -alpha-aryl alanine ester derivative shown in the formula (1);
the specific reaction route is as follows:
in the formula (1) and the formula (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 or nitro; r is R 1 Selected from acetyl, carbobenzoxy, t-butoxycarbonyl; r is R 2 Selected from C1-6 alkyl;
further, the chiral ligand L * The chemical structural formula of (C) is shown as a general formula (L):
in the general formula (L): r is R 3 And R is 4 Each independently substituted or unsubstituted, and when substituted, the substituents R 3 Substituent R 4 Each independently selected from halogen, aryl, C1-C6 alkyl.
Further, chiral ligand L represented by general formula (L) * The chemical structural formula of (C) is shown as 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) X 2 (diphoshine) wherein aryl is aryl and X is BF 4 - 、OTf - 、ClO 4 - 、SbF 6 - 、PF 6 - 、CF 3 SO 3 - Or B (Y) 4 - Y is bis (trifluoromethyl) benzene or fluorobenzene.
Further, in step 2), catalyst [ Rh ]]/L * The molar ratio of the alpha-dehydroarylalaninate derivative to the alpha-dehydroarylalaninate derivative is 1:100-1:100000.
Further, in step 1), a catalyst [ Rh ] is prepared]/L * The temperature is 10-40 ℃, and the reaction time is 0.5-3 hours.
Further, in the step 2), the asymmetric hydrogenation reaction is carried out at a temperature of 10-60 ℃, the hydrogen pressure is 0.1-3.0 MPa, and the reaction time is 4-24 hours.
Further, the concentration of the alpha-dehydroarylalaninate derivative represented by the formula (2) in the solvent B is 0.05mol/L to 5.0mol/L.
Further, the solvent a in step 1) and the solvent B in step 2) are each independently selected from one or two or more mixed solvents of methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, methanol, ethanol, n-propanol, isopropanol, tert-butanol, and the solvent a and the solvent B may be the same.
By adopting the technology, compared with the prior art, the invention has the following characteristics:
the invention develops a catalyst composed of chiral phosphine-spiro indan 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 special purification treatment, 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 consumption (TON is up to 100000), excellent enantioselectivity (ee value is generally over 99 percent), wide substrate applicability and the like, and the method has the advantages of easily available raw materials, simplicity in operation, mild reaction conditions, easiness in industrialization, compliance with the requirements of green chemistry, and great implementation value and social and economic benefits.
Detailed Description
The invention will be further illustrated with reference to specific examples, but the scope of the invention is not limited thereto.
Example 1: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.09 g,4.94 mmol) is obtained, and the yield is: 99%, purity: 99% and the ee value was 99.9%.
Example 2: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (47.3 mg, 55.0. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (20.3 mg, 50.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (30 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) Adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 kg,5.0 mol), the catalyst prepared in the step 1) and methylene dichloride (3.0L) into a reaction bottle, replacing three times by argon and hydrogen respectively, keeping a hydrogen atmosphere of 0.1MPa, reacting for 12 hours at 25 ℃, distilling under reduced pressure to recover a solvent after the reaction is finished, adding a proper amount of water, extracting by ethyl acetate, collecting an organic phase, drying, distilling under reduced pressure to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.07 kg,4.81 mol) with the yield: 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 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacement three times, hydrogen is filled into the reaction bottle to react for 12 hours at 25 ℃, after the reaction is finished, reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the solvent is recovered by reduced pressure distillation, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.07 g,4.85 mmol) is obtained, and the yield is: 97%, purity: 98% ee value was 98.7%.
Example 4: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, tetrahydrofuran (5 mL) was added under argon atmosphere, and the mixture was reacted at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and tetrahydrofuran (15 mL) are added into a reaction bottle, the catalyst and tetrahydrofuran are replaced by argon and hydrogen for three times respectively, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and then dried, the solvent is recovered by reduced pressure distillation, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.08 g,4.89 mmol) is obtained, and the yield is: 98%, purity: 99% and the ee value was 99.1%.
Example 5: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, toluene (5 mL) was added under argon atmosphere, and the mixture was reacted at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and toluene (15 mL) are added into a reaction bottle, the catalyst is replaced by argon and hydrogen for three times respectively, a hydrogen atmosphere of 0.1MPa is maintained, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.06 g,4.80 mmol) is obtained, the yield: 96%, purity: 97% ee value 96.2%.
Example 6: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, methanol (5 mL) was added under argon atmosphere, and the mixture was reacted at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methanol (15 mL) are added into a reaction bottle, the catalyst and methanol are replaced by argon and hydrogen for three times respectively, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.09 g,4.94 mmol) is obtained, the yield: 99%, purity: 99% and the ee value was 99.3%.
Example 7: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was added to a reaction flask, isopropyl alcohol (5 mL) was added under argon atmosphere, and the mixture was reacted at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and isopropyl alcohol (15 mL) are added into a reaction bottle, the catalyst and isopropyl alcohol are replaced by argon and hydrogen for three times respectively, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, the solvent is recovered by reduced pressure distillation, proper water is added, the ethyl acetate is used for extraction, the organic phase is collected and dried, the solvent is recovered by reduced pressure distillation, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.08 g,4.89 mmol) is obtained, and the yield is: 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 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 10 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.04 g,4.69 mmol) is obtained, and the yield is: 94%, purity: 96% ee value was 99.9%.
Example 9: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 40 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.08 g,4.90 mmol) is obtained, and the yield is: 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 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was added to a reaction flask, methylene chloride (5 mL) was added under argon atmosphere, and the mixture was reacted at 25℃for 0.5h,preparing a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 60 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.06 g,4.80 mmol) is obtained, and the yield is: 96%, purity: 97% ee value 96.1%.
Example 11: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 10℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -N-acetylphenylalanine methyl ester (1.06 g,4.80 mmol) is obtained, the yield: 96%, purity: 98% ee value was 98.3%.
Example 12: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 40℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.09 g,4.92 mmol) is obtained, and the yield is: 98%, purity: 99% and the ee value was 99.0%.
Example 13: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (NBD) 2 ]BF 4 (1.87 mg, 5.0. Mu. Mol) was added to a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.09 g,4.94 mmol) is obtained, and the yield is: 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 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]OTf (2.34 mg, 5.0. Mu. Mol) was added to a reaction flask, methylene chloride (5 mL) was added under argon atmosphere, and the mixture was reacted at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.06 g,4.80 mmol) is obtained, and the yield is: 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 (4.73 mg, 5.5. Mu. Mol) was reacted with a metal complex [ Rh (NBD) Cl] 2 (1.15 mg, 2.5. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -N-acetylphenylalanine methyl ester (1.04 g,4.71 mmol) is obtained, the yield: 94%, purity: 98% and ee value of 91.2%.
Example 16: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (C) 2 H 4 ) 2 Cl] 2 (0.97 mg, 2.5. Mu. Mol) was added to a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.05 g,4.75 mmol) is obtained, the yield is: 95%, purity: 97% ee value 92.2%.
Example 17: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-2 (5.28 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.04 g,4.70 mmol) is obtained, and the yield is: 94%, purity: 97% ee value 92.9%.
Example 18: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-3 (4.05 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.04 g,4.68 mmol) is obtained, and the yield is: 94%, purity: 96% ee value was 92.1%.
Example 19: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-4 (3.89 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for replacing three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a reduced pressure distillation is carried out to recover a solvent, proper water is added, ethyl acetate is used for extraction, an organic phase is collected and dried, the reduced pressure distillation is carried out to recover the solvent, and the (R) -alpha-N-acetylphenylalanine methyl ester (1.09 g,4.91 mmol) is obtained, and the yield is: 98%, purity: 99% and an ee value of 98.3%.
Example 20: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) Adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (100 mL) into a high-pressure reaction kettle, sealing the reaction kettle, replacing three times by argon and hydrogen respectively, charging hydrogen to 1.0MPa, reacting for 12h at 25 ℃, decompressing and distilling to recover solvent after the reaction is finished, adding a proper amount of water, extracting by ethyl acetate, collecting an organic phase, drying, decompressing and distilling to recover solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09 g,4.91 mmol) with the yield: 98%, purity 98% and ee value 98.3%.
Example 21: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) Adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1 g,5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (1 mL) into a high-pressure reaction kettle, sealing the reaction kettle, replacing three times by argon and hydrogen respectively, charging hydrogen to 1.0MPa, reacting for 12h at 25 ℃, decompressing and distilling to recover solvent after the reaction is finished, adding a proper amount of water, extracting by ethyl acetate, collecting an organic phase, drying, decompressing and distilling to recover solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.06 g,4.79 mmol) with the yield: 96%, purity 97%, ee value 97.2%.
Examples 22 to 40: preparation of (R) -alpha-arylalaninate derivatives
1) Chiral ligand L-1 (4.73 mg, 5.5. Mu. Mol) was complexed with metal [ Rh (COD) 2 ]BF 4 (2.03 mg, 5.0. Mu. Mol) was charged into a reaction flask, and methylene chloride (5 mL) was added under argon atmosphere to react at 25℃for 0.5h to prepare a catalyst;
2) (Z) -alpha-dehydroarylalaninate derivative (5.0 mmol), the catalyst prepared in the step 1) and methylene dichloride (15 mL) are added into a reaction bottle, argon and hydrogen are respectively used for three times, a hydrogen atmosphere of 0.1MPa is kept, the reaction is carried out for 12 hours at 25 ℃, after the reaction is finished, a proper amount of water is added, ethyl acetate is used for extraction, an organic phase is collected and then dried, the solvent is recovered by reduced pressure distillation, and the yield, purity and ee value of the product are shown in the table 1.
The reaction general formula is as follows:
table 1 experimental results for examples 22 to 40
What has been described in this specification is merely an enumeration of possible forms of implementation for the inventive concept and may not be considered limiting the scope of the present invention to the specific forms set forth in the examples.

Claims (5)

1. A process for the preparation of an (R) -a-arylalaninate derivative comprising the steps of:
1) Under argon atmosphere, metal Rh complex and chiral ligand L * Adding the mixture into the solvent A to react for 0.5 to 6 hours to prepare the metal Rh complex and the chiral ligand L * Coordination bound catalyst [ Rh]/L * ；
2) Adding a-dehydroarylalaninate derivative represented by formula (2) and the catalyst [ Rh ] prepared as described above to 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, after reacting for 1-24 hours, recovering the solvent B by reduced pressure distillation, adding a proper amount of water, extracting with ethyl acetate, collecting an organic phase, drying, and recovering the solvent by reduced pressure distillation to obtain the (R) -a-aryl alanine ester derivative shown in the formula (1);
the specific reaction route is as follows:
in the formula (1) and the formula (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 or nitro; r is R 1 Selected from acetyl, carbobenzoxy, t-butoxycarbonyl; r is R 2 Selected from C1-6 alkyl;
chiral ligand L * The chemical structural formula of (C) is shown as a general formula (L):
in the general formula (L): substituent R 3 Is hydrogen or phenyl; substituent R 4 Is hydrogen, methyl, iodine atom;
the metal Rh complex is [ Rh (C) 2 H 4 ) 2 Cl] 2 、[Rh(NBD)Cl] 2 、[Rh(NBD) 2 ]BF 4 、
[Rh(COD) 2 ]BF 4 、[Rh(COD) 2 ]Any one of OTf;
the solvent A in the step 1) and the solvent B in the step 2) are respectively and independently selected from one or more than two mixed solvents of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, toluene, methanol, ethanol, n-propanol, isopropanol and tertiary butanol;
in step 2), catalyst [ Rh ]]/L * The molar ratio of the alpha-dehydroarylalaninate derivative to the alpha-dehydroarylalaninate derivative is 1:1000-1:100000.
2. The process for producing (R) -a-arylalaninate derivatives, according to claim 1, wherein the chiral ligand L represented by the general formula (L) * The chemical structural formula of (C) is shown as any one of the formulas (L-1) to (L-4):
3. a process for the preparation of (R) -a-arylalaninate derivatives, as claimed in claim 1, wherein in step 1), the catalyst [ Rh ] is prepared]/L * The temperature is 10-40 ℃, and the reaction time is 0.5-3 hours.
4. The process for producing an (R) -a-arylalaninate derivative, according to claim 1, wherein the asymmetric hydrogenation is carried out at a temperature of 10℃to 60℃under a hydrogen pressure of 0.1 to 3.0MPa for a reaction time of 4 to 24 hours in step 2).
5. The process for producing an (R) -a-arylalaninate derivative, according to claim 1, wherein the concentration of the a-dehydroarylalaninate derivative represented by the formula (2) in the solvent B is 0.05mol/L to 5.0mol/L.
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