Method for synthesizing alpha-amino acid compounds by reducing imines and use thereof

Abstract

The application provides a method for efficiently reducing imines to synthesize alpha-amino acid compounds and application thereof, and belongs to the technical field of chemical synthesis. The method comprises the following steps: using hydroxyacetone as a reducing agent, and reducing imines under the catalysis of aza-cycloalkyl carbine catalysts to obtain alpha-amino acid compounds. The method uses hydroxyacetone as a reducing agent, and adopts aza-cycloalkyl carbine catalysts to realize the reduction of imines under mild conditions. The method is simple in operation, low in cost, green and pollution-free, suitable for industrial production, and solves the problems of non-cleanness caused by the use of metal catalysts in the existing imine reduction method, use of dangerous and unstable reducing agents, harsh reaction conditions and high production cost.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing alpha-amino acid compounds by green and efficient reduction of imines and application thereof. BACKGROUND

[0002] Alpha-amino acids exist widely in organisms and medicines and pesticides, and a large number of literature reviews emphasize the importance of alpha-amino acid skeletons in medicines. For example, carmofur, a famous anticholinergic drug, is famous for its smooth muscle relaxation characteristics; JNJ-A07, a drug specially developed for dengue fever treatment; in addition, clopidogrel plays a crucial role in inhibiting platelet aggregation and preventing and treating heart, brain and other arterial circulatory diseases caused by high platelet aggregation. Therefore, an effective method for synthesizing functional molecules based on alpha-amino acids has attracted widespread attention.

[0003] The development of catalytic reduction of C=N bonds is a hot and important field in the chemical field, and has broad application prospects in the preparation of complex functional molecules. Common synthesis 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 gas; (2) these methods have limited tolerance to other reducible functional groups, especially under high-pressure conditions; (3) the catalysts used have problems such as high pollution and high synthesis cost, which limit their industrial application.

[0004] Although literature research has found that nitrogen heterocyclic carbine catalysis (NHC) can realize the hydrogenation acylation reaction of ketone groups using aldehyde as a reducing agent, however, due to the instability and high price of aldehyde groups, the actual application has been hindered. To realize an efficient and inexpensive synthesis process, the following problems need to be solved: (1) to find a simple, stable, safe and green reducing agent; (2) to realize the scale reduction of imines by nitrogen heterocyclic carbine catalysts under mild conditions; (3) to realize the asymmetric reduction of imines by chiral nitrogen heterocyclic carbine catalysts. SUMMARY

[0005] In order to solve the problems of harsh reaction conditions and metal catalyst pollution existing in the existing imine reduction method, the application provides a method for green and efficient reduction of imine to synthesize alpha-amino acid compounds, which uses hydroxy pinacol as a reducing agent and adopts a nitrogen heterocyclic carbene catalyst to realize the reduction of imine under mild conditions, and the method is simple in operation, low in cost, green and pollution-free, suitable for industrial production, and solves the problems of non-cleanliness, use of dangerous and unstable reducing agent, harsh reaction conditions and high production cost caused by the use of metal catalyst in the existing imine reduction method.

[0006] The application also provides an application of the method for green and efficient reduction of imine to synthesize alpha-amino acid compounds in preparation of a JNJ-A07 intermediate.

[0007] The application achieves the above-mentioned purposes through the following technical scheme.

[0008] The application provides a method for green and efficient reduction of imine to synthesize alpha-amino acid compounds, which comprises the following steps.

[0009] Hydroxy pinacol is used as a reducing agent to reduce imine under the catalysis of a nitrogen heterocyclic carbene catalyst, so as to obtain alpha-amino acid compounds.

[0010] Further, the structural general formulae of the imine, the nitrogen heterocyclic carbene catalyst and the alpha-amino acid compounds are shown in formula 1 to formula 3.

[0011]

[0012] wherein, R 1 including a substituted phenyl or other aromatic group, R 2 including an electron-withdrawing group, R 3 including a nitrogen atom protection group.

[0013] In the application, R 1 is an aromatic group and R 2 is an electron-withdrawing group, so as to ensure that the reaction proceeds smoothly, R 3 is a protection group, also for the purpose of ensuring that the reaction proceeds smoothly.

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

[0015] Further, the method specifically comprises the following steps.

[0016] The imine, the hydroxy pinacol, the nitrogen heterocyclic carbene catalyst and a base are dispersed in an organic solvent to obtain a mixed solution.

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

[0018] Further, the imine, the acetoin, the carbene catalyst and the base are dispersed in an organic solvent to obtain a mixed solution, and the mixed solution is subjected to a reduction reaction at 25-60 DEG C to obtain the alpha-amino acid compound.

[0019] The imine, the acetoin, the carbene catalyst and the base are dispersed in an organic solvent to obtain a mixed solution;

[0020] 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 25-60 DEG C to obtain the alpha-amino acid compound, and the mixed solution is subjected to a reduction reaction at 25-60 DEG C to obtain the alpha-amino acid compound.

[0023] The mixed solution is subjected to a reduction reaction at 25-60 DEG C to obtain the alpha-amino acid compound.

[0024] Based on the same inventive concept, the present application provides an application of a method for green and efficient reduction of imine to synthesize alpha-amino acid compounds in preparation of a JNJ-A07 intermediate.

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

[0026] The compound I, the acetoin, the carbene catalyst and the base are dispersed in an organic solvent to obtain a mixed solution;

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

[0028] The compound I and the JNJ-A07 intermediate have structural formulas as 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 25-60 DEG C to obtain the JNJ-A07 intermediate, and the mixed solution is subjected to a reduction reaction at 25-60 DEG C to obtain the JNJ-A07 intermediate.

[0032] After the reduction reaction at 60℃, the reaction time is 24h, and the JNJ-A07 intermediate is obtained.

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

[0034] 1. The method for synthesizing alpha-amino acid compounds by green and efficient reduction of imines, which uses hydroxy pinacol as a reducing agent and adopts nitrogen heterocyclic carbene catalysts to realize the reduction of imines under mild conditions, has the advantages of simple operation, low cost, green and pollution-free, suitability for industrial production, and solving the problems of non-cleanliness caused by metal catalysts, use of dangerous and unstable reducing agents, harsh reaction conditions and high production cost in the existing imine reduction methods.

[0035] 2. The method for synthesizing alpha-amino acid compounds by green and efficient reduction of imines, in which the nitrogen electrophilic imine is reduced by the Breslow intermediate formed by hydroxy pinacol and catalyzed by nitrogen heterocyclic carbene catalysts to obtain alpha-amino acid compounds, has good universality, excellent yield of up to 99%, and the yield remains at 96% even when the imine mass is scaled up to 20g with a low catalyst loading of 2mol%, and the method can be used to synthesize the key intermediate of the medicine JNJ-A07, which is effective for dengue fever.

[0036] 3. The method for synthesizing alpha-amino acid compounds by green and efficient reduction of imines, which realizes one-step efficient reduction of imines by designing routes, optimizing conditions, and studying universality and scaling up synthesis reactions, uses low-loading nitrogen heterocyclic carbene catalysts (5mol%) and the mild, efficient and economical reducing agent hydroxy pinacol to achieve one-step efficient reduction of imines, and obtains the target product with a yield of up to 99%, and uses chiral nitrogen heterocyclic carbene catalysts to achieve certain chiral control during the reduction process, and high enantioselective products can be obtained by recrystallization. In addition, the reaction scale can be scaled up to 20g with a lower catalyst loading of 2mol%, which has the potential for industrial production. Moreover, the reduction method of the present application does not involve high temperature and high pressure, and the use of toxic and harmful substances, greatly reducing the production cost and ensuring the safety and cleanliness of the reaction process. BRIEF DESCRIPTION OF DRAWINGS

[0037] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following will briefly introduce the drawings needed in the embodiment description. Obviously, the drawings in the following description are some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor.

[0038] Figure 1 Synthesis route map of compound 3a.

[0039] Figure 2 A scale-up reaction scheme for compound 3a.

[0040] Figure 3 A chiral synthesis example scheme for compound 3a'.

[0041] Figure 4 A HPLC scheme for compound 3a.

[0042] Figure 5 A HPLC scheme for compound 3a'.

[0043] Figure 6 A HPLC scheme for compound 3a' after recrystallization.

[0044] Figure 7 Partial examples and results for general studies using the developed catalytic process.

[0045] Figure 8 A general synthesis scheme for pharmaceutical JNJ-A07.

[0046] Figure 9 A key synthesis scheme for pharmaceutical JNJ-A07. DETAILED DESCRIPTION

[0047] The present application will be described in detail below with specific embodiments and examples, and the advantages and various effects of the present application will be more clearly presented thereby. Those skilled in the art should understand that these specific embodiments and examples are used to illustrate the present application, rather than limit the present application.

[0048] Throughout the specification, unless otherwise specifically indicated, the terms used herein are understood to have the same meaning as commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. If there is a conflict between the present specification and the prior art, the present specification takes precedence.

[0049] Unless otherwise specifically indicated, various materials, reagents, instruments and equipment and the like used in the present application can be purchased from the market or can be prepared by existing methods.

[0050] The experimental methods used in the following examples are conventional methods unless otherwise specified.

[0051] The following will be combined with examples and experimental data to explain the method of the present application for green and efficient reduction of imines to synthesize α-amino acid compounds in detail.

[0052] Unless otherwise stated, all chemicals were purchased commercially available and did not require further purification. Thin-layer chromatography (TLC) was performed using (HSGF 254) silica gel plates. Silica gel column chromatography was performed using Qingdao Marine silica gel (200-300 mesh). TLC development was performed using UV light (254 nm). 1H NMR spectra were characterized using a Bruker 400 NMR instrument. 1 The H NMR is 400MHz. 13 The C NMR was performed at 100 MHz using CDCl3 as the solvent. Chemical shifts are measured in ppm, and coupling constants are measured in 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, arylimide ester 1a was used as a model substrate to explore the optimal reaction conditions for the process route of this invention. First, using tetrahydrofuran as the solvent, carbene catalysts were screened using potassium carbonate as the base. The screening revealed that catalyst C exhibited superior performance compared to other catalysts. Then, using C as the catalyst, bases were screened, and cesium carbonate and potassium carbonate showed similar performance. Finally, using potassium carbonate as the base, solvents were screened, and toluene showed the best performance, achieving a yield of 99%. The optimization process of the reaction conditions is shown in Table 1. Table 1 shows that the optimal reaction conditions are for entry 13.

[0057] Table 1 Results of Optimization of Reaction Conditions

[0058]

[0059] In Table 1: Unless otherwise specified, the reaction conditions are as follows: 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 is 10% of the total imine), solvent (2 mL), 45 °C, N2 protection, 8 h. [b] Separation yield 3a.

[0060] 2. Universality Experiment

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

[0062] To a 4 mL oven-dried vial equipped with a magnetic stir bar, add imine 1 (0.5 mmol), a nitrogen-containing heterocyclic carbene catalyst (0.1 mmol), and a base (K₂CO₃) (0.25 mmol). Vacuum the vial using the Schlenk technique and backfill with N₂, then add anhydrous toluene (2 mL), acetoin (0.6 mmol), and methanol (0.6 mmol). Stir the reaction mixture in an oil bath at 45 °C until imine 1 is completely consumed (monitored by TLC). Concentrate the mixture under reduced pressure. Separate by column chromatography with polar eluent (petroleum ether / ethyl acetate = 10 / 1) to give the desired product 3.

[0063] 3. Scale-up reaction

[0064] like Figure 2 As shown, a magnetic stir bar was added to a 500 ml round-bottom flask, and then 1a (74.27 mmol, 20.00 g), a nitrogen-containing 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 sequentially. The mixture was stirred at 60 °C for 72 h under nitrogen protection, and the reaction progress was monitored by TLC. Post-processing: The reaction system was filtered, and the filtrate was wet-filtered using silica gel. The eluent (petroleum ether: ethyl acetate = 10:1) was used to evaporate the solvent to obtain product 3a (16.2 g, 80%).

[0065] 4. Asymmetric reduction

[0066] like Figure 3 As shown, a magnetic stir bar was added to a 10 ml Shrek tube, and then 1a (5 mmol, 1.35 g), a nitrogen-containing 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 sequentially. 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 packed with a chiral column. Post-processing: The reaction system was filtered, and the filtrate was filtered through silica gel and wet-mounted. The eluent (petroleum ether: ethyl acetate = 10:1) was used to evaporate the solvent to obtain product 3a' (1.05 g, 95%, 83:17er).

[0067] Recrystallization: Prepare a saturated solution and recrystallize by evaporating the solvent. When solids precipitate, start testing the enantioselectivity of the solution. If it does not meet the standard, test the enantioselectivity of the solution every 2 hours until the requirement is met.

[0068] Transformation of 3a’: In a 25 ml round bottom flask was charged with 3a’ (150 mg, 0.55 mmol, 94:6 er), followed by acetonitrile (5 ml), then cerium ammonium nitrate (CAN, 667 mg, 1.21 mmol) dissolved in water (1.5 ml) at 0 °C and stirred for 30 min. After that, the pH was adjusted to 1 using 2M hydrochloric acid, extracted using EA (15 ml X 3), the lower aqueous layer was retained, immediately neutralized using saturated sodium bicarbonate and extracted using CH2Cl2(15 ml x 3), the lower organic layer was retained and filtered using anhydrous sodium sulfate, the solvent was evaporated to give the a-amino ester 4 (75.0 mg, 82%, 92:8 er).

[0069] 5. Product Characterization

[0070]

[0071] Example 2

[0072] As Figure 7 shown, compounds 3b-3y were synthesized using the same method as Example 1, the reaction scheme 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 (400 MHz, CDCl3) δ 7.51 - 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 = 5.3 Hz, 1H), 4.66 (d, J = 5.2 Hz, 1H), 3.71 (s, 3H), 3.69 (s, 3H).

[0078] 13 C NMR (101 MHz, CDCl3) δ 172.6, 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): Calcd for C 16 H 17 NO3Na + [M+Na]+ :294.1101, found: 294.1091.

[0080]

[0081] 1 H NMR (400 MHz, CDCb) d 7.50 - 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 (101 MHz, CDCb) d 172.4, 162.7 (d, J = 247.1 Hz), 152.6, 138.8, 133.6 (d, J = 3.4 Hz), 128.9 (d, J = 8.2 Hz), 115.8 (d, J = 21.7 Hz), 114.9, 114.8, 60.9, 54.8, 52.8.

[0083] 19 F NMR (376 MHz, CDCb) d -113.88.

[0084] HRMS (ESI, m / z): Calcd for C 16 H 16 F NO3Na + [M+Na] + :312.1006, found: 312.0997.

[0085] 1 H NMR (400 MHz, CDCb) d 7.47 - 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 = 5.5 Hz, 1H), 4.69 (d, J = 5.5 Hz, 1H), 3.73 (s, 3H), 3.70 (s, 3H).

[0086] 13 C NMR (101 MHz, CDCb) d 172.1, 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): Calcd for C 16 H 16 ClNO3Na + [M+Na] + :328.0711, found:328.0698.

[0088]

[0089] 1 H NMR (400 MHz, CDC13) δ 7.52 - 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 = 5.3 Hz, 1H), 4.70 (d, J = 5.4 Hz, 1H), 3.73 (s, 3H), 3.70 (s, 3H).

[0090] 13 C NMR (101 MHz, CDC13) δ 171.8, 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): Calcd for C 16 H 16 BrNO3Na + [M+Na] + :350.0386, found:350.03811.

[0092]

[0093] 1 H NMR (400 MHz, CDC13) δ 7.39 - 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 (101 MHz, CDC13) δ 172.8, 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): Calcd for C 16 H 17 NO3Na + [M+Na] + : 308.1258, found: 308.1255.

[0096]

[0097] 1 H NMR (400 MHz, CDC13) δ 7.46 - 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 (101 MHz, CDC13) δ 172.9, 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): Calcd for C 17 H 19 NO4Na + [M+Na] + : 324.1207, found: 324.1202.

[0100]

[0101] 1 H NMR (400 MHz, CDC13) δ 7.34 - 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 (101 MHz, CDC13) δ 171.9, 163.13 (d, J = 247.0 Hz), 152.7, 140.55 (d, J = 6.8 Hz), 139.8, 130.37 (d, J = 8.4 Hz), 122.98 (d, J = 3.0 Hz), 115.29 (d, J = 21.2 Hz), 114.9, 114.8, 114.31 (d, J = 22.5 Hz), 61.2, 61.2, 55.7, 52.9.

[0103] 19 F NMR (376 MHz, CDC13) δ -112.23.

[0104] HRMS (ESI, m / z): Mass calcd. for C 16 H 16 F NO3Na + [M + Na] + , 290.1187; found: 290.1186.

[0105]

[0106] 1 H NMR (400 MHz, CDC13) δ 7.50 (q, J = 1.4 Hz, 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 (101 MHz, CDC13) δ 171.9, 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 Cl NO3H + [M + H] + , 306.08914; found 306.0881. Methyl 2-((4-methoxyphenyl)amino)-2-(3- methoxyphenyl)acetate (3i)

[0109]

[0110] 1 H NMR (400 MHz, CDCb) d 7.29 - 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 (101 MHz, CDCb) d 172.5, 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): Calcd for C17H19NO4Na+[M+Na]+: 324.1207, found: 324.1205.

[0113]

[0114] 1 H NMR (400 MHz, CDCb) d 7.42 (td, J = 7.7, 1.9 Hz, 1H), 7.15 - 7.03 (m, 2H), 6.76 - 6.66 (m, 2H), 6.59 - 6.53 (m, 2H), 5.38 (d, J = 6.4 Hz, 1H), 4.69 (d, J = 6.1 Hz, 1H), 3.72 (s, 3H), 3.69 (s, 3H).

[0115] 13 C NMR (101 MHz, CDCb) d 170.3, 150.7 143.1, 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 (377 MHz, CDCb) d -118.48.

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

[0118]

[0119] 1 H NMR (400 MHz, CDC13) δ 7.51 - 7.36 (m, 2H), 7.22 (dd, J = 6.0, 3.5 Hz, 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 (101 MHz, CDC13) δ 172.1, 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): Calcd for Ci6Hi6CIN03Na+ [M+Na]+: 328.0711, found: 328.0698.

[0122]

[0123] 1 H NMR (400 MHz, CDC13) δ 7.94 (d, J = 1.9 Hz, 1H), 7.84 - 7.74 (m, 3H), 7.58 (dd, J = 8.5, 1.9 Hz, 1H), 7.49 - 7.37 (m, 2H), 6.74 - 6.64 (m, 2H), 6.61 - 6.49 (m, 2H), 5.16 (d, J = 5.4 Hz, 1H), 4.82 (d, J = 5.3 Hz, 1H), 3.67 (s, 3H), 3.64 (s, 3H).

[0124] 13 C NMR (101 MHz, CDC13) δ 172.6, 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): Calcd for Ci6Hi6CIN03Na+ [M+Na]+: 344.1257, found: 344.1253.

[0126]

[0127] 1 H NMR (500 MHz, CDC13 ) δ 8.91 (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 = 2.2 Hz, 1H), 4.24 (s, 1H), 3.73 (s, 3H).

[0128] 13 C NMR (101 MHz, CDC13 ) δ 169.9, 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; found 355.1410.

[0130]

[0131] 1 H NMR (500 MHz, CDC13 ) δ 7.24 (dd, J = 5.1, 1.3 Hz, 1H), 7.12 (dt, J = 3.6, 1.1 Hz, 1H), 6.98 (dd, J = 5.1, 3.5 Hz, 1H), 6.78 - 6.72 (m, 2H), 6.65 - 6.58 (m, 2H), 5.28 (d, J = 0.9 Hz, 1H), 4.63 (s, 1H), 3.77 (s, 3H), 3.72 (s, 3H).

[0132] 13 C NMR (101 MHz, CDC13 ) δ 171.7, 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 (500 MHz, CDC13 ) δ 7.51 - 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 = 7.0 Hz, 1H), 3.81 (s, 3H), 3.79 (d, J = 6.3 Hz, 1H), 3.74 (s, 3H).

[0151] 13 C NMR (101 MHz, CDC13 ) δ 160.4, 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 (500 MHz, CDC13 ) δ 7.86 - 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 = 7.0 Hz, 1H), 5.78 (d, J = 7.0 Hz, 1H), 3.77 (s, 3H).

[0155] 13 C NMR (101 MHz, CDC13 ) δ 172.1, 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 (500 MHz, CDC13 ) δ 8.67 - 8.65 (m, 1H), 7.76 (td, J = 7.7, 1.8 Hz, 1H), 7.51 (dd, J = 7.9, 1.2 Hz, 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 (101 MHz, CDC13 ) δ 154.0, 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 (500 MHz, CDC13 ) δ 7.55 - 7.47 (m, 2H), 7.46 - 7.32 (m, 3H), 7.16 (dd, J = 5.1, 1.2 Hz, 1H), 6.94 (dd, J = 5.1, 3.4 Hz, 1H), 6.86 (dd, J = 3.5, 1.1 Hz, 1H), 4.82 (s, 1H), 3.17 - 2.96 (m, 4H), 1.63 (s, 1H).

[0163] 13 C NMR (101 MHz, CDC13 ) δ 141.5, 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 (101 MHz, CDC13) δ 176.1, 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): Calcd. for C 24 H 24 N2ONa + [M+Na] + : 377.1624, found: 377.1626.

[0173]

[0174] 1 H NMR (400 MHz, CDC13) δ 7.37 - 7.19 (m, 5H), 6.86 (s, 2H), 6.74 (d, J = 2.6 Hz, 1H), 6.69 (dd, J = 8.5, 2.6 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 4.91 (d, J = 15.5 Hz, 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 (101 MHz, CDC13) δ 175.7, 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): Calcd. 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] As Figure 8 , 9To a solution of 4-(3-amino-5-methoxyphenoxy)butanoic acid tert-butyl ester (0.76 g, 2.7 mmol) in toluene (30 mL), p-toluenesulfonic acid monohydrate (51 mg, 270 μmol) was added. To this solution, 1-(4-chlorophenyl)-2-(6-(trifluoromethoxy)indolin-1-yl)ethane-1,2-dione (1.0 g, 2.7 mmol) was added. The solution was then heated to reflux under air (Dean-Stark conditions) to azeotropically remove water for 6 h. The mixture was then cooled and separated by column chromatography, eluent polarity (toluene / ethyl acetate = 10 / 1) to give 6.

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

[0180] To an oven-dried 4 mL vial equipped with a magnetic stir bar, imine 6 (0.50 mmol, 316.53 mg), N-heterocyclic carbene catalyst (0.10 mmol, 16.56 mg) and K2CO3(0.25 mmol, 34.55 mg) were added. The vial was evacuated using Schlenk technique and backfilled with N2, then anhydrous toluene (2 ml), pinacol (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 complete consumption of imine 6 (monitored by TLC). The mixture was concentrated under reduced pressure. Separation by column chromatography, eluent polarity (toluene / ethyl acetate = 5 / 1) gave 7 (yield: 96%).

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

[0182]

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

[0184] 13 C NMR (101 MHz, CDC13) δ 172.6, 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 = 228.0 Hz), 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 (377 MHz, CDC13) δ -57.82.

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

[0187] The application realizes one-step efficient reduction of imine by using low load of carbene catalyst (5 mol%), mild and efficient and economic reductant ethylidene, and the yield of the target product is as high as 99%. By using chiral carbene catalyst, certain chiral control in the reduction process is realized, and high enantioselective product is obtained by recrystallization. Moreover, the reaction scale is enlarged to 20 g with lower catalyst load (2 mol%), which has the potential for industrial production. Moreover, the reduction method of the application does not involve high temperature and high pressure, and the use of toxic and harmful substances, which greatly reduces the production cost and ensures the safety and cleanliness of the reaction process.

[0188] Finally, it should also be noted that the terms "comprising", "containing" or any other variant thereof are intended to cover non-exclusive inclusion, so that processes, methods, articles or equipment including a series of elements not only include those elements, but also include other elements not explicitly listed, or inherent to such processes, methods, articles or equipment.

[0189] Although the preferred embodiments of the application have been described, those skilled in the art can make further changes and modifications to the embodiments once they know the basic inventive concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications falling within the scope of the application.

[0190] Obviously, those skilled in the art can make various modifications and variations to the application without departing from the spirit and scope of the application. Thus, if these modifications and variations of the application fall within the scope of the claims of the application and their equivalent technologies, the application also intends to include these modifications and variations.

Claims

1. A method for synthesizing α-amino acid compounds by reducing imine, characterized in that, The method includes: Using acetoin as a reducing agent, imines were reduced under the catalysis of a nitrogen-containing heterocyclic carbene catalyst to obtain α-amino acid compounds; 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 It is any one of phenyl, naphthyl, thiophene, pyridyl and substituted phenyl, wherein the substituent of the substituted phenyl is any one of F, Cl, Br, methyl and methoxy; R 2 R is any one of ester, cyano, and amide groups. 3 It is a nitrogen-protecting group.

2. The method for synthesizing α-amino acid compounds by reducing imine according to claim 1, characterized in that, The R 3 It is any one of n-propylthiophene, benzoyl, and substituted phenyl; The substituent of the substituted phenyl group is methyl or methoxy.

3. The method for synthesizing α-amino acid compounds by reducing imine according to claim 1, characterized in that, The method specifically includes: The imine, the acetoin, the nitrogen-containing heterocyclic carbene catalyst, and the base are dispersed together in an organic solvent to obtain a mixture; The mixture was subjected to a reduction reaction at 25°C to 60°C to obtain the α-amino acid compound.

4. The method for synthesizing α-amino acid compounds by reducing imine according to claim 3, characterized in that, The step of dispersing the imine, the acetoin, the nitrogen-containing heterocyclic carbene catalyst, and the base together in an organic solvent to obtain a mixture specifically includes: The imine, the acetoin, the nitrogen-containing heterocyclic carbene catalyst, and the base are dispersed together in an organic solvent to obtain a mixture; The organic solvent is any one of tetrahydrofuran, dichloromethane, ethyl acetate, acetonitrile, and toluene; The molar ratio of the imine to the acetoin is 1:1.

2.

5. The method for synthesizing α-amino acid compounds by reducing imine according to claim 3, characterized in that, The mixture is subjected to a reduction reaction at 25℃~60℃ to obtain the α-amino acid compound, specifically comprising: The α-amino acid compound is obtained by reducing the mixture of K2CO3, Cs2CO3, or DBU at 25°C to 60°C.

6. The application of the method for synthesizing α-amino acid compounds by reducing imine as described in any one of claims 1-5 in the preparation of the JNJ-A07 intermediate, characterized in that, The structural formula of the JNJ-A07 intermediate is shown in Formula 5:

7. A method for preparing JNJ-A07 intermediate, characterized in that, The method includes: Compound I, acetoin, a nitrogen-heterocyclic carbene catalyst, and a base were co-dispersed in an organic solvent to obtain a mixture. The mixture was subjected to a reduction reaction at 25℃~60℃ to obtain the JNJ-A07 intermediate; The structural formula of compound I is shown in Formula 4:

8. The method for preparing JNJ-A07 intermediate according to claim 7, characterized in that, The molar ratio of compound I to acetoin is 1:1.2; The mixture is subjected to a reduction reaction at 25℃~60℃ to obtain the JNJ-A07 intermediate, which specifically includes: The intermediate JNJ-A07 was then subjected to a reduction reaction at 60℃ for 24 hours to obtain the intermediate.

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