Method for synthesizing alpha-amino acid compound by green and efficient reduction of imine and application of alpha-amino acid compound

Abstract

The invention provides a method for synthesizing an alpha-amino acid compound through green and efficient reduction of imine and application of the method, and belongs to the technical field of chemical synthesis.The method comprises the steps that acetoin serves as a reducing agent, imine is reduced under catalysis of an N-heterocyclic carbene catalyst, and the alpha-amino acid compound is obtained. According to the method, acetoin serves as a reducing agent, an N-heterocyclic carbene catalyst is adopted to achieve imine reduction under the mild condition, and the method is easy to operate, low in cost, environmentally friendly, free of pollution and suitable for industrial production; the method solves the problems of uncleanness caused by using a metal catalyst, use of a dangerous and unstable reducing agent, harsh reaction conditions and high production cost in the existing imine reduction method.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a green and efficient method for synthesizing alpha-amino acid compounds by reducing imine and application thereof. Background Art

[0002] α-amino acids are widely present in organisms and pharmaceutical pesticides, and a large number of literature reviews have emphasized the importance of containing α-amino acid skeletons in drugs. For example: Camirofen, a well-known anticholinergic drug, is known for its smooth muscle relaxant properties; JNJ-A07, a specially developed therapeutic drug for dengue fever; in addition, clopidogrel is an inhibitor of platelet aggregation and plays a vital role in the prevention and treatment of heart, brain and other arterial circulation diseases caused by platelet hyperaggregation. Therefore, effective methods for synthesizing functional molecules based on α-amino acids have received widespread attention.

[0003] The development of catalytic reduction reactions of C=N bonds is a hot and important field in the field of chemistry, with broad application prospects in the preparation of complex functional molecules. Commonly used synthetic methods include metal-catalyzed coupling and addition reactions. However, these methods have their advantages and inherent limitations. For example, (1) metal-catalyzed reactions involving olefins and imines often need to be carried out under dangerous conditions, such as high temperature or high pressure reduction using highly active and flammable hydrogen; (2) these methods have limited tolerance for other reducible functional groups, especially under high pressure conditions; (3) the catalysts used have problems such as high pollution and high synthesis cost, which are limited in industrial application.

[0004] Although literature research has shown that the use of nitrogen heterocyclic carbene catalysis (NHC) can realize the hydrogenation acylation of ketones using aldehydes as reducing agents, the aldehyde compounds are active and unstable, and are expensive, which hinders their practical application. The following problems need to be solved in order to achieve efficient and inexpensive synthetic process production: (1) Find a simple, stable, safe and green reducing agent; (2) Under mild conditions, achieve large-scale reduction of imines using nitrogen heterocyclic carbene catalysts; (3) Realize the asymmetric reduction of imines catalyzed by chiral nitrogen heterocyclic carbene catalysts. Summary of the invention

[0005] In order to solve the problems of harsh reaction conditions and metal catalyst pollution in the existing imine reduction method, the present invention provides a green and efficient method for reducing imine to synthesize α-amino acid compounds. The method uses acetoin as a reducing agent and adopts a nitrogen heterocyclic carbene catalyst to achieve the reduction of imine under mild conditions. The method is simple to operate, low in cost, green and pollution-free, suitable for industrial production, and solves the problems of uncleanness caused by the use of metal catalysts in the existing imine reduction method, the use of dangerous and unstable reducing agents, harsh reaction conditions and high production costs.

[0006] The present invention also provides a green and efficient method for synthesizing α-amino acid compounds by reducing imines and its application in preparing JNJ-A07 intermediates.

[0007] The present invention is achieved through the following technical solutions:

[0008] The present invention provides a green and efficient method for synthesizing α-amino acid compounds by reducing imines, the method comprising:

[0009] Using acetoin as a reducing agent, the imine is reduced under the catalysis of a nitrogen heterocyclic carbene catalyst to obtain an α-amino acid compound.

[0010] Furthermore, the general structural formulas of the imine, the nitrogen heterocyclic carbene catalyst and the α-amino acid compound are shown in Formulas 1 to 3 respectively:

[0011]

[0012] Among them, R 1 Including substituted phenyl or other aromatic groups, R 2 Including electron-withdrawing groups, R 3 This includes nitrogen atom protecting groups.

[0013] In the present invention, R 1 is an aromatic group and R 2 The electron-withdrawing group can ensure the smooth progress of the reaction. 3 It is a protecting group, and its purpose is also to protect the smooth progress of the reaction.

[0014] Preferably, the R 2 Including any one of an ester group, a cyano group and an amide group, the R 3 This includes any of alkyl groups, substituted phenyl groups, and other aromatic groups.

[0015] Furthermore, the method specifically comprises:

[0016] Dispersing the imine, the acetoin, the nitrogen heterocyclic carbene catalyst and a base in an organic solvent to obtain a mixed solution;

[0017] The mixed solution is subjected to a reduction reaction at 25° C. to 60° C. to obtain the α-amino acid compound.

[0018] Furthermore, the imine, the acetoin, the nitrogen heterocyclic carbene catalyst and the base are dispersed together in an organic solvent to obtain a mixed solution, which specifically includes:

[0019] Dispersing the imine, the acetoin, the nitrogen heterocyclic carbene catalyst and a base in an organic solvent to obtain a mixed solution;

[0020] Wherein, the organic solvent includes any one of tetrahydrofuran, dichloromethane, ethyl acetate, acetonitrile and toluene;

[0021] The molar ratio of the imine to the acetoin is 1:1.2.

[0022] Further, the mixed solution is subjected to a reduction reaction at 25°C to 60°C to obtain the α-amino acid compound, specifically comprising:

[0023] The mixed solution is subjected to reduction reaction at 25° C. to 60° C. with K2CO3 or Cs2CO3 or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) to obtain the α-amino acid compound.

[0024] Based on the same inventive concept, the present invention provides a green and efficient method for synthesizing α-amino acid compounds by reducing imines and its application in preparing JNJ-A07 intermediates.

[0025] Based on the same inventive concept, the present invention provides a method for preparing a JNJ-A07 intermediate, the method comprising:

[0026] Dispersing compound I, acetoin, a nitrogen heterocyclic carbene catalyst and a base in an organic solvent to obtain a mixed solution;

[0027] The mixed solution is subjected to a reduction reaction at 25° C. to 60° C. to obtain a JNJ-A07 intermediate;

[0028] Wherein, the structural formulas of the compound I and the JNJ-A07 intermediate are shown in Formula 4 and Formula 5, respectively:

[0029]

[0030] Further, the molar ratio of the compound I to the acetoin is 1:1.2;

[0031] The mixed solution is subjected to a reduction reaction at 25°C to 60°C to obtain a JNJ-A07 intermediate, which specifically comprises:

[0032] Then, a reduction reaction was carried out at 60°C for 24 h to obtain the JNJ-A07 intermediate.

[0033] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0034] 1. The present invention discloses a green and efficient method for reducing imines to synthesize α-amino acid compounds. The method uses acetoin as a reducing agent and a nitrogen heterocyclic carbene catalyst to achieve the reduction of imines under mild conditions. The method is simple to operate, low in cost, green and pollution-free, suitable for industrial production, and solves the problems of the existing imine reduction method, such as the use of metal catalysts, the use of dangerous and unstable reducing agents, harsh reaction conditions and high production costs.

[0035] 2. The present invention discloses a green and efficient method for synthesizing α-amino acid compounds by reducing imines. The nitrogen electrophilic imine is reduced by a Breslow intermediate formed by acetoin catalyzed by a nitrogen heterocyclic carbene catalyst to obtain an α-amino acid compound. The method has good universality and an excellent yield of up to 99%. When the mass of the imine is enlarged to 20 g, the yield is still maintained at 96% using a low-loaded catalyst (2 mol%). The method can be used to synthesize the key intermediate of the medicine JNJ-A07, which has a special effect on dengue fever.

[0036] 3. The present invention discloses a green and efficient method for reducing imines to synthesize α-amino acid compounds. The method designs routes, optimizes conditions, conducts universal research, and scales up synthesis reactions. In the experiment, a low-loaded nitrogen heterocyclic carbene catalyst (5 mol%) and a mild, efficient, and economical reducing agent, acetoin, are used to achieve one-step efficient reduction of imines, and the yield of the target product is as high as 99%. The chiral nitrogen heterocyclic carbene catalyst is used to achieve a certain chirality control during the reduction process, and a product with high enantioselectivity can be obtained by recrystallization. Moreover, a good yield can be maintained by scaling up the reaction scale to 20 g with a lower catalyst loading (2 mol%), and the method has the potential for industrial production. In addition, the reduction method of the present invention does not involve high temperature and high pressure, and the use of toxic and hazardous substances, which greatly reduces the production cost and ensures the safety and cleanliness of the reaction process. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0038] Figure 1 The synthetic route of compound 3a.

[0039] Figure 2 This is the enlarged reaction diagram of compound 3a.

[0040] Figure 3 This is an example diagram of the chiral synthesis of compound 3a'.

[0041] Figure 4 This is the HPLC diagram of compound 3a.

[0042] Figure 5 This is the HPLC diagram of compound 3a'.

[0043] Figure 6 This is the HPLC phase diagram of compound 3a' after recrystallization.

[0044] Figure 7 Some examples and results of universal studies using the developed catalytic method are presented.

[0045] Figure 8 This is the overall synthesis step of the drug JNJ-A07.

[0046] Fig. 9 It is a key synthesis step for the drug JNJ-A07. DETAILED DESCRIPTION

[0047] The present invention will be described in detail below in conjunction with specific implementations and examples, and the advantages and various effects of the present invention will be more clearly presented. It should be understood by those skilled in the art that these specific implementations and examples are used to illustrate the present invention, rather than to limit the present invention.

[0048] Throughout the specification, unless otherwise specifically stated, the terms used herein should be understood as meanings commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. In the event of a conflict, the present specification takes precedence.

[0049] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0050] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0051] The green and efficient method for synthesizing α-amino acid compounds by reducing imines of the present invention will be described in detail below in combination with examples and experimental data.

[0052] Unless otherwise stated, chemicals were purchased from commercial products and were not further purified. Thin layer chromatography (TLC) was performed using silica gel plates (HSGF 254). Silica gel column chromatography used Qingdao Marine Silica Gel (200-300 mesh). TLC was developed using UV light (254 nm). 1HNMR spectra were characterized using a Bruker 400 NMR instrument. 1 H NMR is 400 MHz, 13 C NMR is 100 MHz, with CDCl3 as solvent. The unit of chemical shift is ppm, and the unit of coupling constant is Hz.

[0053] Example 1

[0054] This embodiment provides a green and efficient method for synthesizing α-amino acid compounds by reducing imines.

[0055] 1. Optimization of reaction conditions

[0056] like Figure 1 As shown, the optimal reaction conditions of the process route of the present invention are explored by taking aromatic imine ester 1a as a model reaction substrate. First, under the condition of tetrahydrofuran as solvent, the carbene catalyst is first screened by using potassium carbonate as a base. After screening, it is found that the effect of C catalyst is better than other catalysts; then C is used as a catalyst, and the base is screened, and it is found that cesium carbonate and potassium carbonate have the same effect; finally, potassium carbonate is used as a base, and the solvent is screened, and it is found that toluene shows the best effect, and the yield reaches 99%. The optimization process of the reaction conditions is shown in Table 1, and it can be seen from Table 1 that the optimal reaction condition is entry 13.

[0057] Table 1 Optimization results of reaction conditions

[0058]

[0059] In Table 1, unless otherwise specified, the reaction conditions are 1a (0.50 mmol), 2a (0.6 mmol), base (0.25 mmol), methanol (0.6 mmol) (methanol is used to activate the catalyst), carbene precursor (0.1 mmol, 10 mol% - the amount of carbene precursor accounts for 10% of the total amount of imine), solvent (2 mL), 45 ° C, N2 protection, 8 h, [b] Isolated yield 3a.

[0060] 2. Universal Experiment

[0061] The preparation implementation method and conditions are as follows:

[0062] To an oven-dried 4 mL vial equipped with a magnetic stirring bar, imine 1 (0.5 mmol), a nitrogen heterocyclic carbene catalyst (0.1 mmol) and a base (K2CO3) (0.25 mmol) were added. The Schlenk technique was used to evacuate and backfill the vial with N2, and then anhydrous toluene (2 mL), acetoin (0.6 mmol) and methanol (0.6 mmol) were added. The reaction mixture was stirred in an oil bath at 45 ° C until the imine 1 was completely consumed (monitored by TLC). The mixture was concentrated under reduced pressure. Separated by column chromatography, eluent polarity (petroleum ether / ethyl acetate=10 / 1), to obtain the desired product 3.

[0063] 3. Amplification reaction

[0064] like Figure 2 As shown, a magnetic stirrer was added to a 500 ml round-bottom flask, and 1a (74.27 mmol, 20.00 g), a nitrogen heterocyclic carbene catalyst (1.49 mmol, 491.83 mg), K2CO3 (37.13 mmol, 5.13 g), acetoin (81.69 mmol, 7.13 ml), and methanol (81.69 mmol, 3.31 ml) were added in sequence, and stirred at 60 ° C for 72 h under nitrogen protection, and the reaction progress was monitored by TLC. Post-treatment: The reaction system was filtered, and the filtrate was wet-filtered on silica gel, and the eluent (petroleum ether: ethyl acetate = 10: 1) was evaporated to obtain the product 3a (16.2 g, 80%).

[0065] 4. Asymmetric reduction

[0066] like Figure 3 As shown, a magnetic stirrer was added to a 10 ml Shrek tube, and 1a (5 mmol, 1.35 g), a nitrogen heterocyclic carbene catalyst (a chiral catalyst was used here) (0.5 mmol, 209.62 mg), K2CO3 (2.5 mmol, 345.51 mg), acetoin (5.5 mmol, 0.48 ml), and methanol (5.5 mmol, 0.23 ml) were added in sequence. The mixture was stirred at 0°C for 48 h under nitrogen protection. The reaction progress was monitored by TLC, and the enantioselectivity was detected by liquid chromatography equipped with a chiral column. Post-treatment: The reaction system was filtered, and the filtrate was wet-filtered on silica gel. The eluent (petroleum ether: ethyl acetate = 10:1) was used to evaporate the solvent to obtain the product 3a' (1.05 g, 95%, 83:17 er).

[0067] Recrystallization: Prepare a saturated solution and recrystallize by evaporating the solvent. When solid precipitates, start to detect the enantioselectivity of the clear solution. If it does not meet the standard, then detect the enantioselectivity of the solution every 2 hours until it meets the requirement.

[0068] Conversion of 3a': 3a' (150 mg, 0.55 mmol, 94:6er) was added to a 25 ml round-bottom flask, followed by acetonitrile (5 ml), and then cerium ammonium nitrate (CAN, 667 mg, 1.21 mmol) dissolved in water (1.5 ml) was added at 0°C and stirred for 30 min. Then, 2M hydrochloric acid was used to adjust pH = 1, and EA (15 ml x 3) was used for extraction. The lower aqueous layer was retained, and saturated sodium bicarbonate was added immediately for neutralization and extracted with CH2Cl2 (15 ml x 3). The lower organic layer was retained and filtered with anhydrous sodium sulfate, and the solvent was evaporated to obtain α-amino ester 4 (75.0 mg, 82%, 92:8er).

[0069] 5. Product Characterization

[0070]

[0071] Example 2

[0072] like Figure 7 As shown, compounds 3b to 3y were synthesized by the same method as in Example 1, and the reaction formula is as follows:

[0073]

[0074] The reaction conditions are shown in Table 1, entry 13.

[0075] The experimental characterization of the synthesized compounds is as follows:

[0076]

[0077] 1 H NMR (400MHz, CDCl3) δ7.51–7.45(m,2H),7.38–7.27(m,3H),6.75–6.68(m,2H),6.57– 6.49(m,2H),5.02(d,J=5.3Hz,1H),4.66(d,J=5.2Hz,1H),3.71(s,3H),3.69(s,3H).

[0078] 13 C NMR (101MHz, CDCl3) δ172.6,152.5,140.2,137.8,128.8,128.3,127.3,114.9,114.8,61.6,55.7,52.7.

[0079] HRMS(ESI,m / z):Calculated for C 16 H 17 NO3Na + [M+Na]+ :294.1101,found:294.1091.

[0080]

[0081] 1 H NMR(400MHz,CDCl3)δ7.50–7.41(m,2H),7.07–6.99(m,2H),6.74–6.68(m,2H),6.54–6.48(m,2H),4.99(s,1H),4.69(s,1H),3.71(s,3H),3.69(s,3H).

[0082] 13 C NMR(101MHz,CDCl3)δ172.4,162.7(d,J=247.1Hz),152.6,138.8,133.6(d,J=3.4Hz),128.9(d,J=8.2Hz),115.8(d,J=21.7Hz),114.9,114.8,60.9,54.8,52.8.

[0083] 19 F NMR(376MHz,CDCl3)δ-113.88.

[0084] HRMS(ESI,m / z):Calculated for C 16 H 16 FNO3Na + [M+Na] + :312.1006,found:312.0997.

[0085] 1 H NMR(400MHz,CDCl3)δ7.47–7.39(m,2H),7.37–7.29(m,2H),6.76–6.68(m,2H),6.55–6.45(m,2H),4.98(d,J=5.5Hz,1H),4.69(d,J=5.5Hz,1H),3.73(s,3H),3.70(s,3H).

[0086] 13 C NMR(101MHz,CDCl3)δ172.1,152.7,139.8,136.4,134.1,129.1,128.7,114.9,114.8,61.0,55.7,52.9.

[0087] HRMS(ESI,m / z):Calculated for C 16 H 16 ClNO3Na + [M+Na] + :328.0711,found:328.0698.

[0088]

[0089] 1 H NMR(400MHz,CDCl3)δ7.52–7.44(m,2H),7.41–7.33(m,2H),6.76–6.67(m,2H),6.54–6.45(m,2H),4.97(d,J=5.3Hz,1H),4.70(d,J=5.4Hz,1H),3.73(s,3H),3.70(s,3H).

[0090] 13 C NMR(101MHz,CDCl3)δ171.8,152.6,139.7,137.0,132.0,129.0,122.2,114.9,114.8,61.0,55.7,52.9.

[0091] HRMS(ESI,m / z):Calculated for C 16 H 16 BrNO3Na + [M+Na] + :350.0386,found:350.03811.

[0092]

[0093] 1 H NMR(400MHz,CDCl3)δ7.39–7.31(m,2H),7.17–7.10(m,2H),6.74–6.67(m,2H),6.55–6.49(m,2H),4.98(s,1H),4.63(s,1H),3.69(s,3H),3.68(s,3H),2.32(s,3H).

[0094] 13 C NMR(101MHz,CDCl3)δ172.8,152.5,140.3,138.1,134.9,129.6,127.2,114.9,114.8,61.4,55.7,52.7,21.2.

[0095] HRMS(ESI,m / z):Calculated for C 16 H 17 NO3Na + [M+Na] + :308.1258,found:308.1255.

[0096]

[0097] 1 H NMR(400MHz,CDCl3)δ7.46–7.34(m,2H),6.92–6.83(m,2H),6.76–6.66(m,2H),6.58–6.49(m,2H),4.96(s,1H),4.60(s,1H),3.78(s,3H),3.71(s,3H),3.70(s,3H).

[0098] 13 C NMR(101MHz,CDCl3)δ172.9,159.6,152.5,140.3,129.8,128.4,114.9,114.8,114.3,61.0,55.7,55.3,52.7.

[0099] HRMS(ESI,m / z):Calculated for C 17 H 19 NO4Na + [M+Na] + :324.1207,found:324.1202.

[0100]

[0101] 1 H NMR(400MHz,CDCl3)δ7.34–7.25(m,2H),7.03–6.93(m,1H),6.75–6.68(m,2H),6.55–6.46(m,2H),5.00(s,1H),4.73(s,1H),3.71(s,3H),3.68(s,3H).

[0102] 13C NMR (101MHz, CDCl3) δ171.9, 163.13 (d, J = 247.0Hz), 152.7, 140.55 (d, J = 6.8Hz), 139.8, 130.37 (d, J = 8.4Hz) ), 122.98 (d, J = 3.0Hz), 115.29 (d, J = 21.2Hz), 114.9, 114.8, 114.31 (d, J = 22.5Hz), 61.2, 61.2, 55.7, 52.9.

[0103] 19 F NMR (376MHz,CDCl3)δ-112.23.

[0104] HRMS(ESI,m / z):Mass calcd.for C 16 H 16 FNO3Na + [M+Na] + ,290.1187;found:290.1186.

[0105]

[0106] 1 H NMR(400MHz, CDCl3)δ7.50(q,J=1.4Hz,1H),7.41–7.34(m,1H),7.30–7.25(m,2H),6.75–6 .69(m,2H),6.53–6.47(m,2H),4.97(s,1H),4.81–4.55(m,1H),3.72(s,3H),3.69(s,3H).

[0107] 13 C NMR (101MHz, CDCl3) δ171.9,152.7,140.1,139.8,134.8,130.1,128.5,127.5,125.5,114.9,114.8,61.2,55.7,52.9.

[0108] HRMS(ESI,m / z):Mass calcd.for C 16 H 16 ClNO3H + [M+H] + ,306.08914; found306.0881.2-(3-methoxyphenyl)-2-((4-methoxyphenyl)amino)acetic acid methyl ester (3i)

[0109]

[0110] 1 H NMR(400MHz,CDCl3)δ7.29–7.20(m,1H),7.10–6.99(m,2H),6.86-6.78(m,1H),6.75–6.67(m,2H),6.57–6.47(m,2H),4.98(s,1H),4.67(s,1H),3.76(s,3H),3.70(s,3H),3.68(s,3H).

[0111] 13 C NMR(101MHz,CDCl3)δ172.5,160.1,152.6,140.3,139.5,129.9,119.7,114.9,114.8,113.8,112.9,61.7,55.7,55.3,52.8.

[0112] HRMS(ESI,m / z):Calculated for C17H19NO4Na+[M+Na]+:324.1207,found:324.1205.

[0113]

[0114] 1 H NMR(400MHz,CDCl3)δ7.42(td,J=7.7,1.9Hz,1H),7.15–7.03(m,2H),6.76–6.66(m,2H),6.59–6.53(m,2H),5.38(d,J=6.4Hz,1H),4.69(d,J=6.1Hz,1H),3.72(s,3H),3.69(s,3H).

[0115] 13 C NMR(101MHz,CDCl3)δ170.3,150.7143.1,139.7,132.2,129.0,129.4,129.3,127.7,110.3,112.3,58.8,55.4,54.1.

[0116] 19 F NMR(377MHz,CDCl3)δ-118.48.

[0117] HRMS(ESI,m / z):Calculated for C16H16ClNO3Na+[M+Na]+:328.0711,found:328.0698.

[0118]

[0119] 1 H NMR(400MHz,CDCl3)δ7.51–7.36(m,2H),7.22(dd,J=6.0,3.5Hz,2H),6.77–6.66(m,2H),6.58–6.51(m,2H),5.54(s,1H),4.77(s,1H),3.72(s,3H),3.69(s,3H).

[0120] 13 C NMR(101MHz,CDCl3)δ172.1,152.7,141.4,137.0,134.2,123.0,129.4,128.3,127.5,114.9,114.8,58.0,55.7,52.9.

[0121] HRMS(ESI,m / z):Calculated for C16H16ClNO3Na+[M+Na]+:328.0711,found:328.0698.

[0122]

[0123] 1 H NMR(400MHz,CDCl3)δ7.94(d,J=1.9Hz,1H),7.84–7.74(m,3H),7.58(dd,J=8.5,1.9Hz,1H),7.49–7.37(m,2H),6.74–6.64(m,2H),6.61–6.49(m,2H),5.16(d,J=5.4Hz,1H),4.82(d,J=5.3Hz,1H),3.67(s,3H),3.64(s,3H).

[0124] 13 C NMR(101MHz,CDCl3)δ172.6,152.6,140.3,135.5,133.5,133.3,128.8,128.2,127.8,126.6,126.4,126.4,125.1,114.9,61.9,55.7,52.8.

[0125] HRMS(ESI,m / z):Calculated for C16H16ClNO3Na+[M+Na]+:344.1257,found:344.1253.

[0126]

[0127] 1 H NMR(500MHz,CDCl3)δ8.91(s,1H),7.55–7.50(m,2H),7.50–7.44(m,2H),7.40–7.31(m,3H),7.31–7.25(m,2H),6.81–6.76(m,2H),6.69–6.64(m,2H),4.75(d,J=2.2Hz,1H),4.24(s,1H),3.73(s,3H).

[0128] 13 C NMR(101MHz,CDCl3)δ169.9,153.6,141.3,138.6,137.4,129.3,129.0,128.8,127.4,124.6,119.9,115.4,115.0,66.2,56.4.

[0129] HRMS(ESI,m / z):Mass calcd.for C 21 H 20 N2O2Na + [M+Na] + ,355.1417;found355.1410.

[0130]

[0131] 1 H NMR(500MHz,CDCl3)δ7.24(dd,J=5.1,1.3Hz,1H),7.12(dt,J=3.6,1.1Hz,1H),6.98(dd,J=5.1,3.5Hz,1H),6.78–6.72(m,2H),6.65–6.58(m,2H),5.28(d,J=0.9Hz,1H),4.63(s,1H),3.77(s,3H),3.72(s,3H).

[0132] 13 C NMR(101MHz,CDCl3)δ171.7,153.0,141.5,140.0,127.1,125.7,125.5,115.3,114.0,57.8,55.6,52.9.

[0133] HRMS(ESI,m / z):Mass calcd.for C 14 H 16 NO3SNa + [M+Na + ] +,278.0845;found:278.0848.

[0134]

[0135] 1 H NMR(500MHz,CDCl3)δ7.61–7.52(m,2H),7.47–7.36(m,3H),6.86–6.79(m,2H),6.77–6.69(m,2H),5.31(s,1H),3.89–3.77(m,1H),3.74(s,3H). 13 C NMR(101MHz,CDCl3)δ154.1,138.7,134.2,129.4,129.3,127.3,118.6,116.3,115.0,55.7,51.5.

[0136] HRMS(ESI,m / z):Mass calcd.for C 14 H 14 NO + [M-CN - ] + ,212.1070;found:212.1070.

[0137]

[0138] 1 H NMR(500MHz,CDCl3)δ7.57–7.50(m,2H),7.13–7.05(m,2H),6.84–6.78(m,2H),6.75–6.68(m,2H),5.29(s,1H),3.89(d,J=17.8Hz,1H),3.73(s,3H).

[0139] 13 C NMR(101MHz,CDCl3)δ163.2(d,J=249.1Hz),154.1,138.5,130.1(d,J=3.1Hz),129.2(d,J=8.2Hz),118.5,116.5,116.2(d,J=21.8Hz),115.0,55.6,50.9. 19 FNMR(376MHz,CDCl3)δ-111.70.

[0140] HRMS(ESI,m / z):Mass calcd.for C 14 H 13 FNO + [M-CN- ] + ,230.0976;found:230.0978.

[0141]

[0142] 1 H NMR(500MHz,CDCl3)δ7.54–7.46(m,2H),7.42–7.36(m,2H),6.85–6.77(m,2H),6.75–6.67(m,2H),5.30(d,J=9.0Hz,1H),3.86(d,J=9.1Hz,1H),3.74(s,3H).

[0143] 13 C NMR(101MHz,CDCl3)δ154.3,138.2,135.5,132.7,129.4,128.6,118.1,116.6,115.0,55.6,51.1.

[0144] HRMS(ESI,m / z):Mass calcd.for C 14 H 13 ClNO + [M-CN - ] + ,246.0680;found:246.0679.

[0145]

[0146] 1 H NMR(500MHz,CDCl3)δ7.58–7.50(m,2H),7.48–7.39(m,2H),6.86–6.77(m,2H),6.75–6.67(m,2H),5.28(s,1H),3.89(d,J=21.0Hz,1H),3.74(s,3H).

[0147] 13 C NMR(101MHz,CDCl3)δ154.9,138.3,133.2,132.5,128.9,124.3,118.7,116.6,115.0,55.6,51.1.

[0148] HRMS(ESI,m / z):Mass calcd.for C 14 H 13 BrNO + [M-CN - ] +,290.0175;found:290.0166.

[0149]

[0150] 1 H NMR(500MHz,CDCl3)δ7.51–7.42(m,2H),6.95–6.90(m,2H),6.86–6.79(m,2H),6.75–6.70(m,2H),5.25(d,J=7.0Hz,1H),3.81(s,3H),3.79(d,J=6.3Hz,1H),3.74(s,3H).

[0151] 13 C NMR(101MHz,CDCl3)δ160.4,154.1,138.7,128.6,126.2,118.7,116.3,115.0,114.6,55.7,55.4,51.0.

[0152] HRMS(ESI,m / z):Mass calcd.for C 15 H 16 NO2 + [M-CN - ] + ,242.1176;found:242.1174.

[0153]

[0154] 1 H NMR(500MHz,CDCl3)δ7.86–7.79(m,2H),7.54–7.48(m,1H),7.47–7.41(m,4H),7.41–7.30(m,3H),7.17(d,J=7.0Hz,1H),5.78(d,J=7.0Hz,1H),3.77(s,3H).

[0155] 13 C NMR(101MHz,CDCl3)δ172.1,166.6,136.6,133.6,131.9,129.0,128.6,127.3,127.2,56.8,52.9.

[0156] HRMS(ESI,m / z):Mass calcd.for C 16 H 15 NO3Na + [M+Na + ] +,292.0944;found:292.0940.

[0157]

[0158] 1 H NMR(500MHz,CDCl3)δ8.67–8.65(m,1H),7.76(td,J=7.7,1.8Hz,1H),7.51(dd,J=7.9,1.2Hz,1H),7.36–7.32(m,1H),6.86–6.77(m,4H),5.40(s,1H),4.79(s,1H),3.75(s,3H).

[0159] 13 C NMR(101MHz,CDCl3)δ154.0,152.5,149.9,138.5,137.7,124.3,122.2,118.2,116.4,115.0,55.6,52.2.

[0160] HRMS(ESI,m / z):Mass calcd.for C 14 H 14 N3OH + [M+H + ] + ,240.1131;found:240.1122.

[0161]

[0162] 1 H NMR(500MHz,CDCl3)δ7.55–7.47(m,2H),7.46–7.32(m,3H),7.16(dd,J=5.1,1.2Hz,1H),6.94(dd,J=5.1,3.4Hz,1H),6.86(dd,J=3.5,1.1Hz,1H),4.82(s,1H),3.17–2.96(m,4H),1.63(s,1H).

[0163] 13 C NMR(101MHz,CDCl3)δ141.5,134.6,129.1,129.1,129.0,127.3,126.9,125.3,124.0,118.7,54.4,48.3,30.1.

[0164] HRMS(ESI,m / z):Mass calcd.for C 14 H 14 N2SH+ [M+H + ] + ,243.0950;found:

[0165] yield,129mg,m.p.124.1-126.3℃.

[0166] 1 H NMR(400MHz,CDCl3)δ7.29(t,J=7.7Hz,1H),7.09(d,J=7.3Hz,1H),6.98(t,J=7.5Hz,1H),6.91–6.79(m,3H),4.72(s,1H),3.38(s,1H),3.20(s,3H),2.28(s,6H),2.26(s,3H).

[0167] 13 C NMR(101MHz,CDCl3)δ175.9,143.7,141.0,133.1,132.1,130.0,129.7,129.1,128.1,124.8,122.7,108.2,58.9,26.3,20.7,18.7.

[0168] HRMS(ESI,m / z):Calculated for C 18 H 20 N2ONa + [M+Na] + :303.1468,found:303.1475.

[0169]

[0170] 1 H NMR(400MHz,CDCl3)δ7.36–7.22(m,5H),7.21–7.12(m,2H),6.95(t,J=7.5Hz,1H),6.86(s,2H),6.75(d,J=7.9Hz,1H),4.94(d,J=15.5Hz,1H),4.81(d,J=14.7Hz,2H),3.39(s,1H),2.30(s,6H),2.26(s,3H).

[0171] 13C NMR (101MHz, CDCl3) δ176.1,143.4,140.4,135.9,132.2,130.1,129.7,129. 0,128.8,127.9,127.7,127.6,124.5,122.2,109.1,59.7,43.8,21.6,18.1.

[0172] HRMS(ESI,m / z):Calculated for C 24 H 24 N2O + [M+Na] + :377.1624,found:377.1626.

[0173]

[0174] 1 H NMR (400MHz, CDCl3) δ7.37–7.19(m,5H),6.86(s,2H),6.74(d,J=2.6Hz,1H),6.69(dd,J=8.5,2.6Hz,1H),6.62(d,J =8.5Hz,1H),4.91(d,J=15.5Hz,1H),4.83–4.72(m,2H),3.65(s,3H),3.54–3.15(m,1H),2.30(s,6H),2.25(s,3H).

[0175] 13 C NMR (101MHz, CDCl3) δ175.7,156.0,140.8,136.2,135.9,132.3,130.2,129.0,129.1,128.8, 127.7,127.5,113.6,112.0,109.6,59.1,55.7,43.9,20.7,18.7.HRMS(ESI,m / z):Calculated for C 25 H 26 N2O2Na + [M+Na] + :409.1886,found:409.1889.

[0176] Example 3

[0177] This example provides a method for synthesizing the drug JNJ-A07.

[0178] like Figure 8 , 9As shown, 2-(4-chlorophenyl)-2-oxoacetic acid (2.0 g, 1.8 mmol) and 6-(trifluoromethoxy)indoline (2.2 g, 1.8 mmol) were dissolved in DMF. Then, HOBT (1.8 g, 13.0 mmol) was added to the mixture, and then DCC (2.7 g, 13.0 mmol) was added in batches. The reaction was stirred at room temperature overnight until completion. The reaction mixture was then quenched with water and extracted with EA. The organic layer was washed with saturated NaCl solution, dried with Na2SO4, filtered, and concentrated under vacuum. The crude residue was separated by column chromatography, and the eluent polarity (petroleum ether / ethyl acetate=10 / 1) gave 5 (yield: 85%).

[0179] To a solution of tert-butyl 4-(3-amino-5-methoxyphenoxy)butyrate (0.76 g, 2.7 mmol) in toluene (30 mL), toluene acid monohydrate (51 mg, 270 μmol) was added. 1-(4-chlorophenyl)-2-(6-(trifluoromethoxy)indolin-1-yl)ethane-1,2-dione (1.0 g, 2.7 mmol) was added to the solution. The solution was then heated under reflux under air (Dean-Stark conditions) and water was removed azeotropically for 6 hours. The mixture was then cooled and separated by column chromatography with an eluent polarity of (petroleum ether / ethyl acetate = 10 / 1) to give 6.

[0180] To an oven-dried 4 mL vial equipped with a magnetic stirring bar, imine 6 (0.50 mmol, 316.53 mg), a nitrogen heterocyclic carbene catalyst (0.10 mmol, 16.56 mg) and K2CO3 (0.25 mmol, 34.55 mg) were added. The vial was evacuated and backfilled with N2 using Schlenk technique, and then anhydrous toluene (2 ml), acetoin (0.60 mmol, 53 μl) and methanol (0.6 mmol, 25 μl) were added. The reaction mixture was stirred in an oil bath at 60 ° C until the imine 6 was completely consumed (monitored by TLC). The mixture was concentrated under reduced pressure. 7 was obtained by column chromatography separation with an eluent polarity (petroleum ether / ethyl acetate=5 / 1) (yield: 96%).

[0181] t 4-(3-((1-(4-chlorophenyl)-2-oxo-2-(6-(trifluoromethoxy)

[0182]

[0183] 8.4Hz,2H),7.33(d,J=8.4Hz,2H),7.13(d,J=8.2Hz,1H),6.94–6.84(m,1H),5.86(t,J=2.1Hz,1H),5.81(dt,J=6.5,2.1Hz,2H),5.29(d,J=7.7Hz,1H),5.16(d,J=7.4Hz,1H),4.29(td,J=10.2,6.0Hz,1H),3.96(dd,J=10.1,6.9Hz,1H),3.89(t,J=6.2Hz,2H),3.70(s,3H),3.24-3.16(m,1H),3.12-3.04(m,1H),2.39(t,J=7.3Hz,2H),2.01(p,J=6.7Hz,2H),1.44(s,9H).

[0184] 13 C NMR(101MHz,CDCl3)δ172.6,168.8,161.6,161.0,148.6,147.6,143.8,135.6,134.4,129.6,129.4,129.3,121.8(q,J=228.0Hz).,117.0,116.9,111.10,92.9,92.6,91.0,80.4,66.7,59.6,55.1,48.3,32.0,28.1,27.6,24.7.

[0185] 19 F NMR(377MHz,CDCl3)δ-57.82.

[0186] HRMS(ESI,m / z):Calculated for C 32 H 34 ClF3N2O6H + [M+H] + :635.2130,found:635.2127.

[0187] This application is through designing routes, optimizing conditions, universal research to amplifying synthetic reactions. In the experiment, a low-loaded carbene catalyst (5mol%) and a mild, efficient and economical reducing agent acetoin were used to achieve one-step efficient reduction of imines, and the yield of the target product was as high as 99%. The use of a chiral carbene catalyst achieved a certain chiral control during the reduction process, and a highly enantioselective product was obtained by recrystallization. Not only that, scaling up the reaction scale to 20g with a lower catalyst loading (2mol%) can also maintain a good yield and have the potential for industrial production. In addition, the reduction method of the present invention does not involve high temperature and high pressure, as well as the use of toxic and hazardous substances, which greatly reduces the production cost and ensures the safety and cleanliness of the reaction process.

[0188] Finally, it should be noted that the terms "comprises," "includes," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements that are inherent to such process, method, article, or apparatus.

[0189] Although the preferred embodiments of the present invention have been described, those skilled in the art may make other changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0190] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A green and efficient method for synthesizing α-amino acid compounds by reducing imines, characterized in that: The method comprises: Using acetoin as a reducing agent, the imine is reduced under the catalysis of a nitrogen heterocyclic carbene catalyst to obtain an α-amino acid compound.

2. A green and efficient method for synthesizing α-amino acid compounds by reducing imine according to claim 1, characterized in that: The general structural formulas of the imine, the nitrogen heterocyclic carbene catalyst and the α-amino acid compound are shown in Formulas 1 to 3 respectively: Among them, R 1 Including substituted phenyl or other aromatic groups, R 2 Including electron-withdrawing groups, R 3 This includes nitrogen atom protecting groups.

3. A green and efficient method for synthesizing α-amino acid compounds by reducing imine according to claim 2, characterized in that: The R 2 Including any one of an ester group, a cyano group and an amide group, the R 3 This includes any of alkyl groups, substituted phenyl groups, and other aromatic groups.

4. The green and efficient method for synthesizing α-amino acid compounds by reducing imine according to claim 1, characterized in that: The method specifically comprises: Dispersing the imine, the acetoin, the nitrogen heterocyclic carbene catalyst and a base in an organic solvent to obtain a mixed solution; The mixed solution is subjected to a reduction reaction at 25° C. to 60° C. to obtain the α-amino acid compound.

5. A green and efficient method for synthesizing α-amino acid compounds by reducing imine according to claim 4, characterized in that: The dispersing of the imine, the acetoin, the nitrogen heterocyclic carbene catalyst and the base in an organic solvent to obtain a mixed solution specifically comprises: Dispersing the imine, the acetoin, the nitrogen heterocyclic carbene catalyst and a base in an organic solvent to obtain a mixed solution; Wherein, the organic solvent includes any one of tetrahydrofuran, dichloromethane, ethyl acetate, acetonitrile and toluene; The molar ratio of the imine to the acetoin is 1:1.

2.

6. The green and efficient method for synthesizing α-amino acid compounds by reducing imine according to claim 4, characterized in that: The mixed solution is subjected to a reduction reaction at 25°C to 60°C to obtain the α-amino acid compound, which specifically comprises: The mixed solution is subjected to reduction reaction with K2CO3 or Cs2CO3 or DBU at 25°C to 60°C to obtain the α-amino acid compound.

7. Use of a green and efficient method for synthesizing α-amino acid compounds by reducing imine as described in any one of claims 1 to 6 in the preparation of JNJ-A07 intermediate.

8. A method for preparing a JNJ-A07 intermediate, characterized in that: The method comprises: Dispersing compound I, acetoin, a nitrogen heterocyclic carbene catalyst and a base in an organic solvent to obtain a mixed solution; The mixed solution is subjected to a reduction reaction at 25° C. to 60° C. to obtain a JNJ-A07 intermediate; Wherein, the structural formulas of the compound I and the JNJ-A07 intermediate are shown in Formula 4 and Formula 5, respectively:

9. A method for preparing a JNJ-A07 intermediate according to claim 8, characterized in that: The molar ratio of the compound I to the acetoin is 1:1.2; The mixed solution is subjected to a reduction reaction at 25°C to 60°C to obtain a JNJ-A07 intermediate, which specifically comprises: Then, a reduction reaction was carried out at 60°C for 24 h to obtain the JNJ-A07 intermediate.

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