Process for the synthesis of chiral 1-tetrahydronaphthylamides

Abstract

The application discloses a synthesis method of chiral 1-tetrahydronaphthamide compounds, which comprises the following steps: in an inert gas atmosphere, electrolyte, solvent, alkali and 1-naphthamide or its derivative are sequentially mixed, and then electrochemical reduction reaction is carried out; then, acid and a catalyst are added into the reaction system, hydrogen is filled in for asymmetric hydrogenation, after the reaction is completed, organic solvent is removed, and the residue is separated through column chromatography to obtain the chiral 1-tetrahydronaphthamide compound. The chiral 1-tetrahydronaphthamide compound and its derivative with high added value are synthesized from commercially available or easily synthesized 1-naphthamide and its derivative, and are regulated by electrochemical reduction and asymmetric hydrogenation chiral catalysts, the method has wide applicability, is convenient to operate, has good atom economy, and has little harm to the environment.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of material preparation, and particularly relates to a synthesis method of chiral 1-tetrahydronaphthamide compounds. BACKGROUND

[0002] Chiral 1-tetrahydronaphthamide compounds are a kind of fine chemicals, and have an important position in synthetic chemistry, biochemistry and new drug development. Therefore, people have been committed to developing new and efficient synthesis methods of chiral 1-tetrahydronaphthamide compounds, such as asymmetric hydrogenation of enamide, chiral resolution and the like.

[0003] 1-naphthamide and its derivatives are regarded as ideal raw materials for synthesizing chiral 1-tetrahydronaphthamide in organic chemistry due to their rich structural diversity, wide source and easy-to-synthesize characteristics. However, due to the stability of the aromatic ring, it is difficult to realize asymmetric hydrogenation by directly destroying the aromatic ring of 1-naphthamide. At present, the mainstream method for synthesizing 1-tetrahydronaphthamide is to use tetrahydronaphthalenone as a raw material, to react with trimethylsilyl cyanide (TMSCN) to dehydrate and condense, then to use concentrated sulfuric acid to perform partial hydrolysis to obtain a chiral enamide, and then to perform asymmetric hydrogenation and N-alkylation reaction, so as to finally synthesize a chiral 1-tetrahydronaphthamide compound, and the reaction formula is as follows:

[0004]

[0005] The above indirect method not only has poor economy of synthesis steps, but also causes great harm to the environment.

[0006] In addition, another commonly used method is to directly resolve racemic 1-tetrahydronaphthalene acid or its derivative, and then dehydrate and condense with a corresponding amine to obtain a chiral 1-tetrahydronaphthamide compound, and the reaction formula is as follows:

[0007]

[0008] The above method often needs to use an equivalent amount of chiral resolution reagent, and at the same time, half of the chiral product of another configuration is wasted, and the resolution method cannot be applied to all substrates.

[0009] Therefore, it is an urgent problem to be solved to develop a simple, efficient and convenient method for synthesizing chiral 1-tetrahydronaphthamide compounds and derivatives thereof. SUMMARY

[0010] The present application aims to provide a synthesis method of 1-tetrahydronaphthamide compounds, so as to solve the problems of poor economy, environmental hazards and poor applicability of the existing synthesis method.

[0011] To this end, the present application adopts the following technical solutions:

[0012] A method for synthesizing chiral 1-tetrahydronaphthamide compounds, the synthesis process being as follows:

[0013]

[0014] In an inert gas atmosphere, an electrolyte, a solvent, a base and 1-naphthamide or its derivative are sequentially mixed and then subjected to an electrochemical reduction reaction; then, an acid and a catalyst are added to the reaction system, and hydrogen is charged for asymmetric hydrogenation; after the reaction is completed, the organic solvent is removed, and the residue is separated by column chromatography to obtain a chiral 1-tetrahydronaphthamide compound.

[0015] In the above method, R 1 , R 2 is hydrogen or an alkyl group; Ar is an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group.

[0016] Preferably, the aryl group is a phenyl group, a substituted phenyl group, a thiophene, a furan or a pyrrole; preferably, the substituent on the aryl group is a methoxy group, a halogen, a phenoxy group, a thioaryl group, a dialkylamino group, an arylalkylamino group, a diarylamino group, a 2-oxo-pyrrolidin-1-yl group, a 1-indolyl group, an aryl group, an alkyl group or a hydroxyalkyl group.

[0017] Preferably, the concentration of the 1-naphthamide or its derivative in the solvent is 0.05-0.10 mol / L.

[0018] In the above method, the electrolyte is one or more of tetramethylammonium tetrafluoroborate, tetraethylammonium tetrafluoroborate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium chloride, tetrabutylammonium bromide and tetrabutylammonium acetate, preferably tetramethylammonium tetrafluoroborate or tetrabutylammonium tetrafluoroborate. The molar ratio of the electrolyte to the 1-naphthamide or its derivative is (1-2):5.

[0019] In the above method, the conditions for the electrochemical reduction reaction are as follows: constant-voltage alternating current is passed at -5-10°C, stirring is performed for 2-5 hours, then the reaction system is powered off, and stirring is performed at 60-70°C for 12-36 hours, wherein the constant-voltage alternating current waveform is a square wave, the bias voltage is 4.0-6.0 V, and the frequency is 0.5-5 Hz. Preferably, the electrode used for the electrochemical reduction reaction is one or two of graphite felt, carbon felt, graphite sheet, carbon rod and reticular glassy carbon, and more preferably graphite felt is used as the cathode and the anode.

[0020] In the above method, the catalyst is [(S)-(-)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]ruthenium(II) diacetate, [(S)-(-)-2,2'-bis(diphenyl)-1,1'binaphthalene]ruthenium(II) or [(S)-(-)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl]ruthenium(II) diacetate. Preferably, [(S)-(-)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]ruthenium(II) diacetate is used.

[0021] The molar ratio of the catalyst to the 1-naphthamide or its derivative is (1-5):100.

[0022] In the above method, the reaction conditions of the asymmetric hydrogenation are as follows: the hydrogen pressure is 10-40 atm, the reaction is stirred at 20-50℃ for 18-24 hours.

[0023] In the above method, the base is potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide or potassium tert-butoxide. Preferably, potassium carbonate or potassium phosphate is used. The molar ratio of the base to the 1-naphthamide or its derivative is (2-3):10.

[0024] In the above method, the acid is p-toluenesulfonic acid, acetic acid or benzene sulfonic acid, preferably p-toluenesulfonic acid; the molar ratio of the acid to the 1-naphthamide or its derivative is (3-4):5.

[0025] In the above method, the solvent is methanol, tetrahydrofuran or a mixed solvent of methanol and tetrahydrofuran. In the mixed solvent, the volume ratio of methanol to tetrahydrofuran is (1-1.5):1, and the preferred volume ratio is 1:1.

[0026] In the above method, the inert gas is preferably argon.

[0027] In the above method, the 1-naphthamide or its derivative is any one of the following compounds:

[0028]

[0029]

[0030] The synthesis method of the present application realizes high enantioselective hydrogenation of aromatic ring under mild conditions by the "one-pot" series reaction of electrochemical reduction and asymmetric hydrogenation of commercially available 1-naphthamide or its derivative, base, electrolyte, acid and a small amount of chiral catalyst, to synthesize high-value chiral 1-tetrahydronaphthamide compounds.

[0031] Compared with the prior art, the present application has the following beneficial effects:

[0032] 1. The various reagents used in the present application are mostly commercially available or easy to synthesize, the raw materials are widely available and low in price, and the various reagents can be stored stably at normal temperature and pressure, and the operation is convenient, without the need for special treatment of the reagents, greatly reducing the production cost of chiral 1-tetrahydronaphthamide and its derivatives;

[0033] 2. The present application discards the use of environmentally hazardous reagents such as concentrated sulfuric acid and trimethylsilyl cyanide, and equivalent chiral resolution reagents, and uses mostly environmentally friendly reaction reagents, adopts green electrochemical technology combined with a small amount of chiral catalyst, significantly reduces the production cost and environmental pollution risk, has good atom economy, and has little harm to the environment.

[0034] 3. The present application has wide applicability and strong tolerance to various functional groups (such as hydroxyl, alkoxy, heterocycle, etc.), and various types of 1-naphthamide and its derivatives can be reacted to obtain the corresponding chiral 1-tetrahydronaphthamide product.

[0035] 4. The present application has carried out kilogram-scale experiments, and the reaction is suitable for mass production;

[0036] 5. The present application realizes the enantioselective synthesis of chiral 1-tetrahydronaphthamide compounds or its derivatives in a reaction container through the series connection of electrochemical reduction and asymmetric hydrogenation, only needs conventional electrochemical devices and commercial catalysts, avoids multi-step intermediate separation, has simple operation, efficient post-treatment, and easy product purification, has outstanding step economy, provides an innovative solution for the green synthesis of chiral 1-tetrahydronaphthamide compounds, and has important application prospects in the fields of drug development and fine chemical preparation. DETAILED DESCRIPTION

[0037] The technical solutions of the present application will be clearly and completely described below in combination with the embodiments. Obviously, the following embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor are within the scope of protection of the present application.

[0038] The Chinese-English name correspondence of the compounds in the following examples is as follows:

[0039] NMe4BF4: tetramethylammonium tetrafluoroborate;

[0040] n Bu4NBF4: tetrabutylammonium tetrafluoroborate

[0041] THF / MeOH: tetrahydrofuran, methanol mixed solvent;

[0042] TsOH: p-toluenesulfonic acid;

[0043] PhSO3H: benzenesulfonic acid

[0044] AcOH: acetic acid

[0045] (S)-Segphos-Ru(OAc)2: [(S)-(-)-5,5'-Bis(diphenylphosphino)-4,4'-bi-1,3- benzodioxole]ruthenium(II) acetate;

[0046] (S)-BINAP-Ru(OAc)2: [(S)-(-)-2,2'-Bis(diphenyl)-1,1'binaphthalene]ruthenium(II) acetate;

[0047] (S)-MeO-BIPHEP-Ru(OAc)2: [(S)-(-)-2,2'-Bis(diphenylphosphino)-6,6'-dimethoxy- 1,1'-biphenyl]ruthenium(II) acetate

[0048] The waveforms of the alternating current in the following examples are square waves; the ratio of tetrahydrofuran / methanol in the mixed solvent is volume ratio.

[0049] Example 1

[0050] Synthesis of (R)-N-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (4a).

[0051] The synthetic route is as follows:

[0052]

[0053] The specific synthesis steps are as follows:

[0054] Into a reaction bottle were sequentially added tetramethylammonium tetrafluoroborate (6.4 mg, 0.04 mmol), a mixed solvent of tetrahydrofuran / methanol (2 mL, 1:1), potassium carbonate (8.3 mg, 0.06 mmol), N-methyl-1-naphthamide (1a) (37.0 mg, 0.2 mmol), and electricity was passed (alternating current, non-divided cell, 1.0 Hz, 5.0 V, graphite felt as anode and cathode) at 0 °C to stir the reaction for 4 hours. Then the reaction system was powered off and stirred at 70 °C for 24 hours. Into the reaction system were added p-toluenesulfonic acid (27.5 mg, 0.16 mmol) and [(S)-(-)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]ruthenium(II) acetate (1.6 mg, 0.002 mmol), and after H2was filled (20 atm), stirring was performed at 40 °C for 24 hours. After the reaction was completed, the organic solvent was removed, and the residue was subjected to silica gel column chromatography (eluent was a mixture of ethyl acetate and petroleum ether, the volume ratio of which was 1:1) to obtain 32.0 mg of white solid product 4a, the yield of which was 85%. The ee value was 90% as measured by HPLC.

[0055] The characterization data of the product are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.22 - 7.02 (m, 4H), 5.29 (s, 1H), 3.68 (t, J = 5.3 Hz, 1H), 2.89 - 2.77 (m, 2H), 2.76 (d, J = 4.8 Hz, 3H), 2.40 - 2.29 (m, 1H), 1.98 - 1.90 (m, 1H), 1.84 - 1.77 (m, 1H), 1.76 - 1.70 (m, 1H).

[0056] 13 C NMR (151 MHz, Chloroform-d) δ 175.5, 138.0, 134.1, 130.2, 129.8, 127.4, 126.2, 47.0, 29.2, 27.2, 26.6, 20.2.

[0057] Example 2

[0058] Synthesis of (R)-N-(2-hydroxyethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (4i).

[0059] The synthetic route is as follows:

[0060]

[0061] The specific synthesis steps are as follows:

[0062] In a reaction bottle, tetrabutylammonium tetrafluoroborate (13.2 mg, 0.04 mmol), tetrahydrofuran / methanol mixed solvent (1:1) (3.2 mL), potassium phosphate (12.7 mg, 0.06 mmol), compound N-(2-hydroxyethyl)-1-naphthamide (1i) (43.0 mg, 0.2 mmol) were added in sequence, and the reaction was stirred at -5 °C with electricity (alternating current, non-separation cell, 2.0 Hz, 5.0 V, graphite felt as anode and cathode) for 3 hours. Then the reaction system was powered off and stirred at 70 °C for 24 hours. To the reaction system, p-toluenesulfonic acid (27.5 mg, 0.16 mmol) and diacetate [(S)-(-)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]ruthenium (II) (1.6 mg, 0.002 mmol) were added, and after H2was filled (20 atm), it was stirred at 40 °C for 18 hours. After the reaction was completed, the organic solvent was removed, and the residue was subjected to silica gel column chromatography (eluent was a mixture of ethyl acetate and petroleum ether, the volume ratio of which was 2:1) to obtain 27.0 mg of white solid product 4i, with a yield of 62%, and the ee value was 92% as measured by HPLC.

[0063] The characterization data of the product are as follows:

[0064] 1 H NMR (600 MHz, Chloroform-d) δ 7.22 - 7.07 (m, 4H), 5.81 (s, 1H), 3.69 (t, J = 5.5 Hz, 1H), 3.65 (s, 2H), 3.37 (qd, J = 14.4, 9.2 Hz, 2H), 2.89 (s, 1H), 2.86 - 2.74 (m, 2H), 2.28 (dq, J = 14.1, 4.6 Hz, 1H), 1.97 (ddt, J = 13.7, 10.0, 4.8 Hz, 1H), 1.83 - 1.73 (m, 2H).

[0065] 13 C NMR (151 MHz, Chloroform-d) δ 176.6, 138.0, 133.7, 130.0, 129.9, 127.5, 126.3, 62.7, 47.0, 42.8, 29.2, 27.3, 20.3.

[0066] Example 3

[0067] Synthesis of (R)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (4k).

[0068] The synthesis route is as follows:

[0069]

[0070] The specific synthesis steps are as follows:

[0071] To the reaction flask was added successively tetramethylammonium tetrafluoroborate (12.8 mg, 0.08 mmol), methanol (3.2 mL), potassium hydroxide (3.4 mg, 0.06 mmol), compound N,N-dimethyl-1-naphthalenamide (1k) (39.8 mg, 0.2 mmol), and electricity was applied (AC, unseparated cell, 5.0 Hz, 5.0 V, graphite felt as anode and cathode) at -5 °C for 8 h. The reaction was then turned off and stirred at 70 °C for 24 h. To the reaction was added p-toluenesulfonic acid (27.5 mg, 0.16 mmol) and diacetato[(S)-(-)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzenedimethanol]ruthenium(II) (4.1 mg, 0.005 mmol), and after H2inflation (40 atm) was stirred at 50 °C for 24 h. After the reaction was complete, the organic solvents were removed, and the residue was purified by silica gel column chromatography (eluent: mixture of ethyl acetate and petroleum ether, 1:2 by volume) to give 27.0 mg of the product 4k as colorless oil in 91% yield with 77% ee by HPLC.

[0072] The product was characterized by the following data:

[0073] 1 H NMR (600 MHz, Chloroform-d) δ 7.11 (q, J = 7.6 Hz, 3H), 6.93 (d, J = 7.2 Hz, 1H), 4.17 - 4.06 (m, 1H), 3.11 (s, 3H), 3.04 (s, 3H), 2.92 - 2.84 (m, 1H), 2.81 - 2.74 (m, 1H), 2.09 - 1.94 (m, 3H), 1.77 - 1.69 (m, 1H).

[0074] 13 C NMR (151 MHz, Chloroform-d) δ 175.2, 137.3, 135.3, 129.4, 127.9, 126.4, 126.0, 43.0, 37.8, 36.0, 29.3, 26.9, 21.4.

[0075] Example 4

[0076] Synthesis of (R)-7-methoxy-N-methyl-1,2,3,4-tetrahydronaphthalene-1- carboxamide (4o).

[0077] The synthesis route is as follows:

[0078]

[0079] The specific synthesis steps are as follows:

[0080] To the reaction flask was added successively tetramethylammonium tetrafluoroborate (6.4 mg, 0.04 mmol), a mixed solvent of tetrahydrofuran / methanol (3.2 mL, 1 : 1), potassium carbonate (8.3 mg, 0.06 mmol), 7-methoxy-N-methyl-1-naphthamide (lo) (43.0 mg, 0.2 mmol), and the reaction was stirred at 0 °C with electricity (alternating current, non-divided cell, 1.0 Hz, 5.0 V, graphite felt as anode and cathode) for 5 h. Then the reaction was powered off and stirred at 70 °C for 24 h. To the reaction was added benzenesulfonic acid (25.3 mg, 0.16 mmol) and [(S)-(-)-2,2'-bis(diphenyl)-1,1 '-binaphthalenyl]ruthenium(II) dichloride (1.7 mg, 0.002 mmol), and after H2was charged (40 atm), the reaction was stirred at 40 °C for 24 h. After the reaction was completed, the organic solvent was removed, and the residue was purified by column chromatography on silica gel (eluent: a mixture of ethyl acetate and petroleum ether, 1 : 1 by volume fraction) to give 33.0 mg of the product 40 as a white solid, with a yield of 75% and an ee value of 87% as determined by HPLC.

[0081] The product was characterized by the following data:

[0082] 1 H NMR (600 MHz, Chloroform-d) δ 7.06 (d, J = 8.4 Hz, 1H), 6.79 (dd, J = 8.4, 2.7 Hz, 1H), 6.63 (s, 1H), 5.32 (s, 1H), 3.77 (s, 3H), 3.65 (t, J = 5.0 Hz, 1H), 2.81 - 2.65 (m, 5H), 2.34 - 2.26 (m, 1H), 1.95 - 1.86 (m, 1H), 1.82 - 1.75 (m, 1H), 1.74 - 1.65 (m, 1H).

[0083] 13 C NMR (151 MHz, Chloroform-d) δ 175.4, 157.7, 130.7, 130.0, 114.7, 113.8, 55.3, 47.4, 28.4, 27.2, 26.6, 20.4.

[0084] Example 5

[0085] Synthesis of (R)-N-methyl-6-phenoxy-1,2,3,4-tetrahydronaphthalene-1 - carboxamide (4q).

[0086] The synthesis route is as follows:

[0087]

[0088] The specific synthesis steps are as follows:

[0089] In a reaction bottle, tetraethylammonium tetrafluoroborate (8.7 mg, 0.04 mmol), tetrahydrofuran / methanol mixed solvent (3.2 mL, 1:1), cesium carbonate (19.5 mg, 0.06 mmol), N-methyl-6-phenoxy-1-naphthamide (1q) (55.0 mg, 0.2 mmol) were added in sequence, and the reaction was stirred at 0°C with electricity (alternating current, non-separable cell, 0.5 Hz, 6.0 V, carbon felt as anode and cathode) for 2 hours. Then the reaction system was powered off and stirred at 70°C for 24 hours. Acetic acid (9.6 mg, 0.16 mmol) and diacetate [(S)-(-)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl]ruthenium(II) (1.6 mg, 0.002 mmol) were added to the reaction system, and after H2was filled (15 atm), it was stirred at 20°C for 24 hours. After the reaction was completed, the organic solvent was removed, and the residue was subjected to silica gel column chromatography (eluent was a mixture of ethyl acetate and petroleum ether, the ratio of ethyl acetate to petroleum ether was 1:1 by volume fraction), to obtain 54.0 mg of white solid product 4q, with a yield of 96%, and the ee value of the product was 90% as measured by HPLC.

[0090] The characterization data of the product are as follows:

[0091] 1 H NMR (600 MHz, Chloroform-d) δ 7.34 (t, J = 7.7 Hz, 2H), 7.12 (t, J = 7.5 Hz, 1H), 7.07-6.97 (m, 3H), 6.81 (d, J = 8.5 Hz, 1H), 6.77 (s, 1H), 5.40 (s, 1H), 3.64 (t, 1H), 2.81-2.69 (m, 5H), 2.34-2.27 (m, 1H), 1.96-1.88 (m, 1H), 1.75 (ddd, J = 36.1, 15.3, 8.3 Hz, 2H).

[0092] 13 C NMR (151 MHz, Chloroform-d) δ 175.6, 156.9, 156.4, 139.8, 131.4, 129.8, 128.7, 123.5, 119.1, 119.1, 116.7, 46.4, 29.4, 27.3, 26.6, 20.1.

[0093] Example 6

[0094] Synthesis of (R)-N-methyl-5-(2-thiophenyl)-1,2,3,4-tetrahydronaphthalene-1- carboxamide (4ac).

[0095] The synthetic route is as follows:

[0096]

[0097] The specific synthesis steps are as follows:

[0098] In a reaction bottle, tetrabutylammonium acetate (12.0 mg, 0.04 mmol), a mixed solvent of tetrahydrofuran / methanol (3.2 mL, 1:1), potassium carbonate (8.3 mg, 0.06 mmol), N-methyl-5-(2-thiophenyl)-1-naphthamide (1ac) (53.4 mg, 0.2 mmol) were added in sequence, and the reaction was stirred at 0°C with electricity (alternating current, non-separable cell, 1.0 Hz, 5.0 V, reticulated glassy carbon as anode and cathode) for 4 hours. Then the reaction system was powered off and stirred at 70°C for 24 hours. To the reaction system, p-toluenesulfonic acid (27.5 mg, 0.16 mmol) and diacetate [(S)-(-)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]ruthenium(II) (6.6 mg, 0.008 mmol) were added, and after H2(40 atm) was filled, it was stirred at 40°C for 24 hours. After the reaction was completed, the organic solvent was removed, and the residue was subjected to silica gel column chromatography (eluent was a mixture of ethyl acetate and petroleum ether, the ratio of ethyl acetate to petroleum ether was 1:1 by volume fraction), to obtain 39.0 mg of white solid product 4ac, with a yield of 79% and an ee value of 93% measured by HPLC.

[0099] The characterization data of the product are as follows:

[0100] 1 H NMR (600 MHz, Chloroform-d) δ 9.92 (s, 1H), δ 7.35 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 7.09 (t, J = 4.3 Hz, 1H), 7.02 (d, J = 3.5 Hz, 1H), 5.42 (s, 1H), 3.76 (t, J = 5.4 Hz, 1H), 2.87-2.73 (m, 5H), 2.32-2.26 (m, 1H), 1.96 (dddd, J = 13.6, 10.1, 6.2, 3.2 Hz, 1H), 1.82-1.71 (m, 2H).

[0101] 13C NMR (151 MHz, Chloroform-d) δ 175.5, 142.2, 136.6, 135.1, 134.7, 130.2, 130.1, 127.1, 126.8, 125.9, 125.4, 47.7, 28.4, 26.9, 26.7, 20.6.

[0102] Example 7

[0103] Synthesis of (R)-N-methyl-1-phenyl-4,5,6,7-tetrahydro-1H-indole-4-carboxamide (4ah).

[0104] The synthetic route is as follows:

[0105]

[0106] The specific synthesis steps are as follows:

[0107] Into a reaction bottle were sequentially added tetramethylammonium tetrafluoroborate (6.4 mg, 0.04 mmol), methanol (3.2 mL), potassium tert-butoxide (6.7 mg, 0.06 mmol), N-methyl-1-phenyl-1H-indole-4-carboxamide (1ah) (50.0 mg, 0.2 mmol), and the reaction was stirred at 0 °C with electricity (alternating current, non-separation cell, 1.0 Hz, 4.0 V, reticulated vitreous carbon as anode and cathode) for 4 hours. Then the reaction was powered off and stirred at 70 °C for 18 hours. Into the reaction was added acetic acid (9.6 mg, 0.16 mmol) and diacetate [(S)-(-)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzenedimethanol]ruthenium (II) (1.6 mg, 0.002 mmol), and after H2(30 atm) was charged, the reaction was stirred at 40 °C for 24 hours. After the reaction was completed, the organic solvent was removed, and the residue was subjected to silica gel column chromatography (eluent was a mixture of ethyl acetate and petroleum ether, by volume fraction, the ratio of ethyl acetate to petroleum ether was 1:1) to obtain 32.0 mg of white solid product 4ah, with a yield of 63%, and an ee value of 88% measured by HPLC.

[0108] The characterization data of the product are as follows:

[0109] 1H NMR (600 MHz, Chloroform-d) δ 7.44 (t, J = 7.6 Hz, 2H), 7.32 (dd, J = 18.1, 7.7 Hz, 3H), 6.82 (d, J = 2.8 Hz, 1H), 6.12 (d, J = 2.8 Hz, 1H), 3.58 (t, J = 5.7 Hz, 1H), 2.81 (d, J = 4.7 Hz, 3H), 2.56 (t, J = 6.3 Hz, 2H), 2.16 (d, J = 15.6 Hz, 2H), 2.06 - 1.99 (m, 1H), 1.82 - 1.70 (m, 2H).

[0110] 13 C NMR (151 MHz, Chloroform-d) δ 176.1, 139.8, 129.9, 129.2, 126.7, 124.7, 121.1, 116.3, 108.2, 42.2, 27.8, 26.4, 23.4, 21.3.

[0111] Example 8

[0112] Synthesis of (R)-6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (4al).

[0113] The synthetic route is as follows:

[0114]

[0115] The specific synthesis steps are as follows:

[0116] Into a reaction flask were added tetrabutylammonium tetrafluoroborate (13.2 mg, 0.04 mmol), tetrahydrofuran (3.2 mL), potassium carbonate (8.3 mg, 0.06 mmol), 6-methoxy-1-naphthamide (1al) (41.0 mg, 0.2 mmol) successively, and the reaction was stirred at 0 °C with electricity (alternating current, non-separation cell, 1.0 Hz, 5.0 V, graphite felt as anode and cathode) for 4 hours. Then the reaction system was powered off and stirred at 70 °C for 18 hours. Into the reaction system were added p-toluenesulfonic acid (27.5 mg, 0.16 mmol) and [(S)-(-)-2,2'-bis(diphenyl)-1,1'binaphthyl]ruthenium(II) (1.7 mg, 0.002 mmol), and after H2was filled (20 atm), the reaction was stirred at 40 °C for 24 hours. After the reaction was completed, the organic solvent was removed, and the residue was subjected to silica gel column chromatography (eluent was a mixture of ethyl acetate and petroleum ether, 1:1 by volume fraction) to obtain 29.0 mg of white solid product 4al, with a yield of 71%, and an ee value of 89% measured by HPLC.

[0117] The characterization data of the product are as follows:

[0118] 1 H NMR (600 MHz, Chloroform-d) δ 7.07 (d, J = 8.4 Hz, 1H), 6.74 (dd, J = 8.5, 2.7 Hz, 1H), 6.67 (s, 1H), 5.55 (s, 1H), 5.35 (s, 1H), 3.79 (s, 3H), 3.63 (t, J = 5.3 Hz, 1H), 2.86 - 2.71 (m, 2H), 2.32 - 2.23 (m, 1H), 1.96 (dq, J = 13.6, 6.6 Hz, 1H), 1.80 (dq, J = 10.7, 5.2 Hz, 2H).

[0119] The substrates, reaction conditions and products of Examples 9-39 are shown in Table 1.

[0120] Table 1

[0121]

[0122]

[0123]

[0124]

[0125] The above examples sufficiently demonstrate that the method for electrochemically and asymmetrically hydrogenating 1-naphthamide and its derivatives to chiral 1-tetrahydronaphthamide compounds has mild reaction conditions, is safe, has a wide range of substrates, simple work-up, good atom economy, and good application prospects.

Claims

1. A method for synthesizing a chiral 1-tetrahydronaphthamide compound, characterized by, The synthesis process is as follows: In an inert gas atmosphere, the electrolyte, solvent, base and 1-naphthamide or its derivative are sequentially mixed and then subjected to an electrochemical reduction reaction; then, an acid and a catalyst are added to the reaction system, hydrogen is charged for asymmetric hydrogenation, and after the reaction is completed, the organic solvent is removed, and the residue is separated by column chromatography to obtain a chiral 1-tetrahydronaphthamide compound, wherein: R 1 , R 2 is hydrogen or alkyl; Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl; the concentration of the 1-naphthamide or its derivative in the solvent is 0.05-0.10 mol / L.

2. The method of synthesis of claim 1, wherein: The aryl group is a phenyl group or a substituted phenyl group.

3. The method of synthesis of claim 1, wherein: The substituent group on the substituted aryl group is a methoxy group, a halogen, a phenoxy group, a thioaryl group, a dialkylamino group, an arylalkylamino group, a diarylamino group, a 2-oxo-pyrrolidin-1-yl group, a 1-indolyl group, an aryl group, an alkyl group, or a hydroxyalkyl group.

4. The method of synthesis of claim 1, wherein: The electrolyte is one or more of tetramethylammonium tetrafluoroborate, tetraethylammonium tetrafluoroborate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium acetate; and the molar ratio of the electrolyte to the 1-naphthamide or its derivative is (1-2):

5.

5. The method of synthesis of claim 4, wherein: The electrolyte is tetramethylammonium tetrafluoroborate or tetrabutylammonium tetrafluoroborate.

6. The method of synthesis of claim 1, wherein, The conditions for the electrochemical reduction reaction are as follows: constant-voltage alternating current is passed at -5-10°C, stirring is performed for 2-5 hours, then the reaction system is powered off, and stirring is performed at 60-70°C for 12-36 hours, wherein the constant-voltage alternating current waveform is a square wave, the bias voltage is 4.0-6.0 V, and the frequency is 0.5-5 Hz.

7. The method of synthesis of claim 6, wherein: The electrode used in the electrochemical reduction reaction is one or two of graphite felt, carbon felt, graphite sheet, carbon rod, and reticular glassy carbon.

8. The method of synthesis of claim 7, wherein: The electrochemical reduction reaction uses graphite felt as the cathode and the anode.

9. The method of synthesis of claim 1, wherein: The catalyst is [(S)-(-)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]ruthenium(II) diacetate, [(S)-(-)-2,2'-bis(diphenyl)-1,1'binaphthalene]ruthenium(II), or [(S)-(-)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1,1'-binaphthalene]ruthenium(II) diacetate; and the molar ratio of the catalyst to the 1-naphthamide or its derivative is (1-5):

100.

10. The method of synthesis of claim 9, wherein: The catalyst is [(S)-(-)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]ruthenium(II) diacetate.

11. The method of synthesis of claim 1, wherein, The reaction conditions for the asymmetric hydrogenation are as follows: the hydrogen pressure is 10-40 atm, and stirring is performed at 20-50°C for 18-24 hours.

12. The method of synthesis of claim 1, wherein: The base is potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, or potassium tert-butoxide; and the molar ratio of the base to the 1-naphthamide or its derivative is (2-3):

10.

13. The method of synthesis of claim 12, wherein: The base is potassium carbonate or potassium phosphate.

14. The method of synthesis of claim 1, wherein: The acid is p-toluenesulfonic acid, acetic acid, or benzenesulfonic acid; and the molar ratio of the acid to the 1-naphthamide or its derivative is (3-4):

5.

15. The method of synthesis of claim 14, wherein: The acid is p-toluenesulfonic acid.

16. The method of synthesis of claim 1, wherein, The solvent is methanol, tetrahydrofuran, or a mixed solvent of methanol and tetrahydrofuran, and in the mixed solvent, the volume ratio of methanol to tetrahydrofuran is (1-1.5):

1.

17. The method of synthesis of claim 16, wherein: The volume ratio of methanol to tetrahydrofuran is 1:

1.

18. The method of synthesis of claim 1, wherein, The 1-naphthamide or derivative thereof is any one of the following compounds: 。

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