2-amino-3-methyl aza-aniline compound and preparation method thereof

Abstract

The invention discloses a compound as shown in a formula (I) and a preparation method thereof, and relates to application of the compound in preparation of an orexin receptor antagonist. In the compound shown in the formula (I), X represents chlorine or bromine or iodine; one of R1 and R2 represents hydrogen, and the other one represents an amino protecting group; or R1 and R2 are respectively independent amino protecting groups, or R1 and R2 together form an amino protecting group. The compound shown in the formula (I) is obtained by taking 3-methyl-2-nitrobenzoic acid or 3-methyl-2-nitroaniline as an initial raw material through degradation rearrangement or amino protection, halogenation reaction and reduction reaction. The amino protecting group is creatively introduced, generation of 2-position halogenated impurities in the reaction is greatly reduced, the yield is improved, when the compound is used for synthesizing the orexin receptor antagonist, a single target compound is generated, generation of impurities is effectively avoided, the yield is improved, the cost is reduced, and the compound is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and specifically relates to a 2-amino-3-methyl azaniline compound and a preparation method thereof, and to the use thereof in the preparation of medicaments, particularly certain appetite receptor antagonists, such as (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (i.e., daridorexant). BACKGROUND

[0002] Patent CN105793257 and document ChemMedChem.2020, 15, 2286-2305 disclose a synthetic method of daridorexant, as shown in the following route:

[0003]

[0004] When the compound (S)-N-Boc-2-methyl-L-proline is condensed with 6-chloro-2,3-diaminotoluene, since 6-chloro-2,3-diaminotoluene contains two amino groups, the selectivity of the condensation product is not high, and three products will be mainly generated. Although the compound (C1) and the compound (C2) generate the same target compound in the subsequent ring-closing reaction, the two amino groups in the compound (C3) are replaced and cannot proceed to the next ring-closing reaction, but can only exist in the form of impurities, causing the reaction system to be relatively complex, the yield to be not high (the two-step yield is only 49%), and the product purification to be difficult.

[0005] Patent CN110612291 and document ChemMedChem.2020, 15, 2286-2305 report another synthetic route as shown below:

[0006]

[0007] Similarly, when the compound (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carbonyl chloride is condensed with 6-chloro-2,3-diaminotoluene, three compounds will be generated, and the compound (D3) does not participate in the subsequent ring-closing reaction, but can only exist in the form of impurities, causing the reaction system to be relatively complex, the yield to be relatively low (the two-step yield is 72.2%), and industrialized production to be not conducive.

[0008] Patents CN111606928, CN105829305, WO2015 / 092713 and WO2024 / 211244 disclose a method for synthesizing 4-bromo-3-methyl-2-nitroaniline, as shown in the following route, due to the positioning effect of the amino group, and without protection of the amino group and without steric hindrance, there are many impurities of ortho substitution, it is difficult to separate and remove impurities, and the yield is low, which is not suitable for industrial production.

[0009] SUMMARY

[0010] The present application provides a compound represented by formula (I), gives a specific synthesis method, and applies it to the synthesis process of appetite receptor antagonists, effectively avoids the generation of impurities, improves the yield, and is suitable for industrial production.

[0011] The compound represented by formula (I) in the present application is:

[0012]

[0013] Among them,

[0014] X represents chlorine or bromine or iodine.

[0015] R 1 , R 2 One represents hydrogen and the other is an amino protecting group or R 1 , R 2 is an amino protecting group or R 1 and R 2 together constitute an amino protecting group.

[0016] The amino protecting group is selected from trifluoroacetyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, trimethylsilylethyloxycarbonyl, phenylsulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl,

[0017] p-nitrobenzenesulfonyl, trityl, tert-butyl, tert-butylsulfinyl, phthaloyl, and

[0018] R 3 represents (C1-C4)alkyl.

[0019] The present application takes 3-methyl-2-nitrobenzoic acid or 3-methyl-2-nitroaniline as the starting material, synthesizes the compound of formula (III) through degradation reaction or amino protection, synthesizes the compound of formula (II) through halogenation reaction, and then obtains the compound of formula (I) through reduction reaction, and the specific route is as follows:

[0020]

[0021] The halogenating agent used in the halogenation reaction is selected from the group consisting of chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, trichloroisocyanuric acid, sulfuryl chloride, 2-chloro-l,3-bis(methoxycarbonyl)guanidine, hypochlorous acid, tert-butyl hypochlorite, hypochlorite salts, chlorite salts;

[0022] The solvent used is selected from the group consisting of acetic acid, methanesulfonic acid, one or any mixture of aprotic polar solvents;

[0023] The halogenating agent is present in an amount of 1.1 to 2 equivalents relative to the compound of formula (III);

[0024] The halogenation reaction from the compound of formula (III) is suitably performed at a temperature of -5°C to 110°C.

[0025] The catalyst or reducing agent used in the reduction reaction is selected from the group consisting of platinum, platinum oxide, palladium, palladium dichloride, rhodium, ruthenium, nickel, zinc, iron, iron trichloride, zinc chloride, stannous chloride, sodium dithionite, sodium sulfide, ammonium sulfide, sodium borohydride, potassium borohydride, lithium borohydride;

[0026] The hydrogen source used is selected from the group consisting of hydrogen gas, cyclohexadiene, cyclohexene, acetic acid, hydrochloric acid, sulfuric acid, ammonium chloride, formic acid, ammonium formate, sodium formate, hydrazine hydrate;

[0027] The solvent used is selected from the group consisting of water, toluene, one or any mixture of polar solvents;

[0028] The catalyst used is selected from the group consisting of platinum, platinum oxide, palladium, palladium dichloride, nickel, rhodium, ruthenium, iron trichloride, and the catalyst is present in an amount of 0.005 to 0.5 equivalents relative to the compound of formula (II);

[0029] The reducing agent used is selected from the group consisting of stannous chloride, sodium dithionite, sodium sulfide, ammonium sulfide, sodium borohydride, potassium borohydride, lithium borohydride, and the reducing agent is present in an amount of 1 to 5 equivalents relative to the compound of formula (II);

[0030] The hydrogen source is present in an amount of 1 to 10 equivalents relative to the compound of formula (II).

[0031] The reduction of the nitro group from the compound of formula (II) is suitably performed at a temperature of 0°C to 100°C.

[0032] The present application takes 3-methyl-2-nitrobenzoic acid or 3-methyl-2-nitroaniline as starting material, the material source is extensive, and the target compound is synthesized through simple degradation rearrangement or amino protection, halogenation reaction and reduction reaction. The amino protecting group is creatively introduced in the present application, so that when the halogenation reaction is carried out on the compound of formula (III), the steric hindrance around the amino group is increased, the generation of 2-position halogenated impurities is greatly reduced, the yield is improved, the cost is reduced, and the industrial production is suitable. At the same time, in the synthesis of appetite receptor antagonist darirex, such as the following route:

[0033]

[0034] (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxylate is mixed (i.e., contacted) with the compound of formula (I), and the obtained compound is a single product, easy to purify, and has a high yield (reference example three-step yield: 83%~88% compared with two-step yield: 72.2% given in the literature). It should be noted that in the compound of formula (I), the preferred amino protecting groups are acetyl, tert-butoxy carbonyl, di-tert-butoxy carbonyl, benzyloxy carbonyl, p-toluenesulfonyl, tert-butyl and trityl. The above protecting groups are removed from the amino protecting group at the same time in the acid system, such as acetic acid, concentrated hydrochloric acid, hydrogen bromide acetic acid solution, and the cyclization reaction is carried out, so that no additional reaction step is needed, the cost is reduced, and the industrial production is suitable. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 The structural formula of the compound of formula (I) described in the present application is shown. DETAILED DESCRIPTION

[0036] The synthesis route of the compound of formula (I) is as follows:

[0037]

[0038] Example 1

[0039] Synthesis of compound 4-chloro-3-methyl-2-aminophenyl carbamate tert-butyl ester

[0040] The specific reaction equation is shown as follows:

[0041]

[0042] Step A: Synthesis of 3-methyl-2-nitrophenyl carbamate tert-butyl ester

[0043] To a mixture of 3-methyl-2-nitrobenzoic acid (30 g, 166 mmol) in t-butanol (250 mL) was added diphenyl phosphorazide (50.1 g, 182 mmol) and TEA (25.4 mL, 182 mmol). The reaction mixture was stirred at 82 °C for 10 hours, then 2000 mL of water was added. The resulting precipitate was filtered to give the title compound tert-butyl 3-methyl-2-nitrophenylcarbamate (41 g, 135 mmol, 82.0% yield, purity: 98.4%).

[0044] Step B: Synthesis of tert-butyl 4-chloro-3-methyl-2-nitrophenylcarbamate

[0045] The compound tert-butyl 3-methyl-2-nitrophenylcarbamate (100 g, 396 mmol) was dissolved in acetonitrile, N-chlorosuccinimide (58.2 g, 435 mmol) was added portionwise, stirred at 50 °C for 8 hours, after the reaction was detected to be completed, 500 mL of purified water was added to the reaction system, and the filter was extracted to obtain a yellow solid which was dried to obtain 105 g of the title compound with a yield of 92.0% and a purity of 99.7%.

[0046] LC-MS; [M-Boc+H] + = 187.1

[0047] 1 HNMR (400 MHz, D6-DMSO) δ: 9.34 (s, 1H), 7.62-7.64 (d, J = 8.8 Hz, 1H), 7.35-7.37 (d, J = 8.8 Hz, 1H), 2.26 (s, 3H), 1.49 (s, 9H)

[0048] Step C: Synthesis of tert-butyl 4-chloro-3-methyl-2-nitrophenylcarbamate

[0049] Method one, the compound tert-butyl 4-chloro-3-methyl-2-nitrophenylcarbamate (100 g, 349 mmol) was dissolved in 500 mL of tetrahydrofuran, iron trichloride (11 g, 70 mmol) and 20 g of activated carbon were added, the temperature was raised to 60 °C, and hydrazine hydrate (84 g, 2100 mmol) was slowly added dropwise. After the addition was completed, the temperature was kept for 2 hours, then filtered, the filter cake was washed with tetrahydrofuran twice, the filtrate was rotary evaporated, 400 mL of a mixture of methanol and water was added, recrystallized, filtered to obtain a white solid which was dried to obtain 82.5 g of the title compound with a yield of 92.0% and a purity of 99.7%.

[0050] LC-MS; [M+H] + = 257.1

[0051] 1HNMR (400 MHz, D6-DMSO) δ: 8.29 (s, 1H), 7.01-7.03 (d, J = 8.8 Hz, 1H), 6.58-6.60 (d, J = 8.8 Hz, 1H), 4.87 (s, 2H), 2.12 (s, 3H), 1.49 (s, 9H)

[0052] Method two, compound tert-butyl 4-chloro-3-methyl-2-nitrophenylcarbamate (100 g, 349 mmol) was dissolved in 500 mL of tetrahydrofuran, 1 g of platinum carbon was added, hydrogen was replaced three times, hydrogen was introduced to keep the pressure at 1 atmosphere, stirred for 12 hours, filtered, the obtained mother liquor was rotary evaporated, 400 mL of a mixture of methanol and water was added, recrystallized, filtered to obtain white solid, dried to obtain 85 g of the title compound, yield: 94.9%, purity: 99.8%.

[0053] Example 2

[0054] Synthesis of compound 2-(2-amino-4-chloro-3-methylphenyl)isoindoline-1,3-dione.

[0055] The specific reaction equation is shown below:

[0056]

[0057] Step A: Synthesis of 2-(3-methyl-2-nitrophenyl)isoindoline-1,3-dione

[0058] To a mixture of sodium hydroxide (2220 g, 55.5 mol) and water (10 L) was added bromine (322 mL, 6.26 mol) at 0 °C. Then 3-methyl-2-nitrobenzamide (1000 g, 5.55 mol) was added in one portion and the mixture was slowly heated in a water bath. The material quickly darkened in color and at 50-55 °C, oil droplets began to separate. The temperature was gradually increased to 70 °C and maintained at this temperature for 1 hour. 5 kg of sodium hydroxide (14%) in water was added slowly and the temperature was increased to 80 °C and maintained for 1 hour. The reaction was cooled to room temperature and extracted with ethyl acetate. The combined organic layer was dried and concentrated to give 700 g (yield: 82.9%) of 3-methyl-2-nitroaniline.

[0059] Phthalic anhydride (129 g, 0.87 mmol) was added to a mixture of 3-methyl 2-nitroaniline (109 g, 0.72 mmol) in acetic acid (500 mL) and stirred at room temperature for 0.5 hours. Then the mixture was heated to reflux for 20 hours. After cooling, a yellow precipitate was formed, which was collected by filtration. The filtrate was washed with acetic acid and dried under air flow to obtain 182 g of the title compound, yield: 89.6%.

[0060] Step B: Synthesis of 2-(4-chloro-3-methyl-2-nitrophenyl)isoindoline-1,3-dione

[0061] Compound 2-(3-methyl-2-nitrophenyl)isoindoline-1,3-dione (125 g, 0.443 mol) was dissolved in 500 mL DMF, and 1,3-dichloro-5,5-dimethylhydantin (96 g, 0.487 mol) was added in portions at 50 °C for 3 hours. 2 L purified water was added, and filtration under suction gave a yellow solid, which was dried to give 130 g of the title compound at a yield of 92.6% and a purity of 98.7%.

[0062] Step C: Synthesis of 2-(2-amino-4-chloro-3-methylphenyl)isoindoline-1,3-dione

[0063] Compound 2-(4-chloro-3-methyl-2-nitrophenyl)isoindoline-1,3-dione (100 g, 0.316 mol) was dissolved in 500 mL toluene, and 1 g of platinum carbon was added. Hydrogen was replaced three times, and hydrogen was introduced (0.2 MPa), and the mixture was stirred for 3 hours. Filtration under suction, and rotary evaporation of the mother liquor gave 85.8 g of the white title compound at a yield of 94.7% and a purity of 99.7% after recrystallization from a mixture of 500 mL methanol and water (volume ratio: 1:9).

[0064] LC-MS; [M+H] + = 287.1

[0065] 1 HNMR (400 MHz, D6-DMSO) δ: 7.92-7.89 (m, 2H), 7.88-7.86 (m, 2H), 7.01-7.03 (d, J = 8.8 Hz, 1H), 6.58-6.60 (d, J = 8.8 Hz, 1H), 4.86 (s, 2H), 2.12 (s, 3H)

[0066] Example 3

[0067] Synthesis of compound N-(tert-butyl)-4-chloro-3-methylbenzene-1,2-diamine.

[0068] The specific reaction equation is shown below:

[0069]

[0070] Step A: Synthesis of N-(tert-butyl)-3-methyl-2-nitroaniline

[0071] Compound 3-methyl-2-nitroaniline (15.2 g, 0.1 mol) was dissolved in 50 mL of tetrahydrofuran, and concentrated sulfuric acid (0.5 g,) was added, and isobutene was introduced, and stirring was performed at 25°C for 8 hours, 200 mL of purified water was added, and the layers were separated, and extraction was performed, and the organic layer was dried, and the obtained oily substance was recrystallized with methanol water, and suction filtration was performed, and drying was performed to obtain 18.7 g of a yellow solid, and the yield was 89.8%.

[0072] Step B: Synthesis of N-(tert-butyl)-4-chloro-3-methyl-2-nitroaniline

[0073] Compound N-(tert-butyl)-3-methyl-2-nitroaniline (12.1 g, 0.058 mol) was dissolved in 80 mL of DMF, and N-chlorosuccinimide (8.51 g, 0,064 mol) was added in portions while being warmed to 45°C, and stirring was performed at 50°C for 8 hours, and after confirming that the reaction was completed, 400 mL of purified water was added to the reaction system, and suction filtration was performed to obtain a yellow solid, and the yellow solid was washed twice with 50 mL of purified water, and drying was performed to obtain 12.5 g of the title compound, and the yield was 88.8%, and the purity was 98.6%.

[0074] Step C: Synthesis of N-(tert-butyl)-4-chloro-3-methylbenzene-1,2-diamine

[0075] Compound N-(tert-butyl)-4-chloro-3-methyl-2-nitroaniline (10 g, 0.041 mol) was dissolved in 500 mL of tetrahydrofuran, and 0.5 g of platinum carbon was added, and hydrogen gas was introduced three times, and hydrogen gas was introduced (pressure 0.2 MPa), and the system was maintained at 25°C for 3 hours, and suction filtration was performed, and the mother liquor was dried, and 200 mL of a mixture of methanol and water (volume ratio: 1:9) was added to recrystallize, and 8.2 g of off-white title compound was obtained, and the yield was 94.0%, and the purity was 99.6%.

[0076] LC-MS; [M+H] + = 213.1

[0077] 1 HNMR (400 MHz, D6-DMSO) δ: 6.65 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 4.72 (s, 2H), 3.63 (s, 1H), 2.12 (s, 3H), 1.12 (s, 9H)

[0078] Example 4

[0079] Synthesis of compound 2-amino-4-chloro-3-methylphenylcarbamic acid benzyl ester.

[0080] The specific reaction equation is shown below:

[0081]

[0082] Step A: Synthesis of 3-methyl-2-nitrophenyl benzylcarbamate

[0083] To a mixture of 3-methyl-2-nitrobenzoic acid (30 g, 166 mmol) in tetrahydrofuran (250 mL) was added diphenyl phosphorazide (50.1 g, 182 mmol) and TEA (25.4 mL, 182 mmol). The reaction mixture was stirred at 25 °C for 5 hours, after the raw material disappeared, the temperature was raised to 60 °C and benzyl alcohol (53.8 g, 498 mmol) was added dropwise. After the addition was completed, the temperature was raised to 67 °C and kept for 4 hours. The mother liquor was evaporated, 200 mL of purified water was slowly added, the temperature was lowered to room temperature, and the filter was obtained as a yellow solid. After drying, 40.7 g of the title compound was obtained with a yield of 85.6% and a purity of 97.2%.

[0084] Step B: Synthesis of 4-chloro-3-methyl-2-nitrophenyl benzylcarbamate

[0085] Compound 3-methyl-2-nitrophenyl benzylcarbamate (30 g, 105 mmol) was dissolved in DMF, and N-chlorosuccinimide (16.7 g, 126 mmol) was added in portions. It was stirred at 50 °C for 8 hours. After the reaction was detected to be complete, 500 mL of purified water was added to the reaction system, and the filter was obtained as a yellow solid. After drying, 30.8 g of the title compound was obtained with a yield of 91.5% and a purity of 97.9%.

[0086] Step C: Synthesis of 2-amino-4-chloro-3-methylphenyl benzylcarbamate

[0087] Compound 4-chloro-3-methyl-2-nitrophenyl benzylcarbamate (20 g, 62.5 mmol) was dissolved in 500 mL of tetrahydrofuran, and iron trichloride (2 g, 12.5 mmol) and 4 g of activated carbon were added. The temperature was raised to 60 °C, and hydrazine hydrate (12.5 g, 312.5 mmol) was added dropwise. After the addition was completed, the temperature was kept for 2 hours, and the filter was obtained. The filter cake was washed with tetrahydrofuran twice, the filter was evaporated, 200 mL of a mixture of methanol and water was added, recrystallization was performed, and the filter was obtained as a white solid. After drying, 16.6 g of the title compound was obtained with a yield of 91.4% and a purity of 99.2%.

[0088] LC-MS; [M+H] + = 291.1

[0089] 1HNMR (400 MHz, D6-DMSO) δ: 9.22 (s, 1H), 7.28-7.43 (m, 5H), 7.00-7.02 (d, J = 8.8 Hz, 1H), 6.57-6.59 (d, J = 8.8 Hz, 1H), 5.09 (s, 2H), 4.86 (s, 2H), 2.11 (s, 3H)

[0090] Example 5

[0091] Synthesis of compound N-(2-amino-4-chloro-3-methylphenyl)acetamide.

[0092] The specific reaction equation is shown below:

[0093]

[0094] Step A: Synthesis of N-(3-methyl-2-nitrophenyl)acetamide

[0095] Compound 3-methyl-2-nitroaniline (15.2 g, 0.10 mol) was dissolved in 50 mL DMF, triethylamine (12.1 g, 0.12 mmol) was added, and after stirring at 25 °C for 10 min, acetyl chloride (8.63 g, 0.11 mol) was slowly added dropwise, and the reaction was continued for 10 h. 200 mL purified water was added, and the mixture was filtered, and the resulting yellow solid was washed twice with 50 mL purified water and dried to obtain 18.4 g of the title compound, in a yield of 94.8%.

[0096] Step B: Synthesis of N-(4-chloro-3-methyl-2-nitrophenyl)acetamide

[0097] Compound N-(3-methyl-2-nitrophenyl)acetamide (15.0 g, 0.077 mol) was dissolved in 60 mL DMF, and the temperature was lowered to 0 °C, and tert-butyl hypochlorite (10.1 g, 0.093 mol) was slowly added dropwise, and the reaction was stirred for 4 h. After the reaction was determined to be complete, 300 mL purified water was added to the reaction system, and the mixture was filtered to obtain a yellow solid, which was washed twice with 50 mL purified water and dried to obtain 14.8 g of the title compound, in a yield of 84.1% and a purity of 98.5%.

[0098] Step C: Synthesis of N-(2-amino-4-chloro-3-methylphenyl)acetamide

[0099] Compound N-(4-chloro-3-methyl-2-nitrophenyl)acetamide (10 g, 0.044 mol) was dissolved in 200 mL of tetrahydrofuran, 0.3 g of platinum carbon was added, hydrogen was replaced for 3 times, hydrogen was introduced (pressure 0.2 MPa), and the temperature was kept at 25 °C for 4 hours. Filtration was performed, the mother liquor was dried, 90 mL of a mixture of methanol and water (volume ratio: 1:9) was added for recrystallization, and 8.1 g of a white title compound was obtained with a yield of 92.7% and a purity of 99.7%.

[0100] LC-MS; [M+H] + = 199.1

[0101] 1 HNMR (400 MHz, D6-DMSO) δ: 9.03 (s, 1H), 6.83 (d, 1H), 6.63 (d, 1H), 4.75 (s, 2H), 3.63 (s, 1H), 2.17 (s, 3H), 2.07 (s, 3H)

[0102] Example 6

[0103] Synthesis of compound N-Boc-N-(4-chloro-3-methyl-2-aminophenyl) tert-butyl carbamate

[0104] The specific reaction equation is shown as follows:

[0105]

[0106] Step A: Synthesis of N-Boc-N-(3-methyl-2-nitrophenyl) tert-butyl carbamate

[0107] Compound tert-butyl 3-methyl-2-nitrophenylcarbamate (19.2 g, 0.076 mol) was dissolved in 150 mL of dichloromethane, triethylamine (11.51 g, 0.114 mmol) and 2 g of 4-dimethylaminopyridine were added, stirring was performed at room temperature for 10 min, di-tert-butyl dicarbonate (24.9 g, 0.114 mol) was added, and the temperature was kept for 10 hours. 200 mL of a 10% citric acid aqueous solution was added, stirring was performed for 20 min, the organic phase was washed once with 50 mL of purified water, the organic phase was dried, 200 mL of a methanol and water mixture (volume ratio 1:8) was added, the temperature was increased to 50 °C, the temperature was cooled to room temperature, filtration was performed, and 22.3 g of a yellow solid was obtained after drying, which was the title compound with a yield of 83.3%.

[0108] Step B: Synthesis of N-Boc-N-(4-chloro-3-methyl-2-nitrophenyl) tert-butyl carbamate

[0109] Compound N-Boc-N-(3-methyl-2-nitrophenyl)tert-butylcarbamate (15.0 g, 0.043 mol) was dissolved in 50 mL DMF, and heated to 50 °C, N-chlorosuccinimide (6.25 g, 0.047 mol) was added in portions, after the addition was completed, the reaction was stirred for 4 hours, after the reaction was detected to be completed, 250 mL purified water was added to the reaction system, and the filter was extracted to obtain a yellow solid, which was washed twice with 50 mL purified water and dried to obtain 15.4 g of the title compound, yield: 92.6%, purity: 98.9%.

[0110] Step C: Synthesis of N-Boc-N-(4-chloro-3-methyl-2-aminophenyl)tert-butylcarbamate

[0111] Compound N-Boc-N-(4-chloro-3-methyl-2-nitrophenyl)tert-butylcarbamate (10.0 g, 0.026 mol) was dissolved in 100 mL tetrahydrofuran, 0.1 g platinum carbon was added, hydrogen was replaced for 3 times, hydrogen was introduced (pressure 0.2 MPa), and the reaction was stirred at 25 °C for 10 hours, the filter was extracted, the mother liquor was rotary dried, 120 mL of a mixture of methanol and water (volume ratio: 1:9) was added for recrystallization, the filter was extracted, and the solid was dried to obtain 8.8 g of the title compound, yield: 94.8%, purity: 99.8%.

[0112] LC-MS; [M+H] + = 357.2

[0113] 1 HNMR (400 MHz, D6-DMSO) δ: 7.00-7.01 (d, J = 8.8 Hz, 1H), 6.57-6.59 (d, J = 8.8 Hz, 1H), 4.77 (s, 2H), 2.11 (s, 3H), 1.49 (s, 18H)

[0114] Example 7

[0115] Synthesis of compound N-(2-amino-4-chloro-3-methylphenyl)neopentanamide.

[0116] The specific reaction equation is shown below:

[0117]

[0118] Step A: Synthesis of N-(3-methyl-2-nitrophenyl)neopentanamide

[0119] Compound 3-methyl-2-nitroaniline (15.2 g, 0.10 mol) was dissolved in 50 mL of DMF, pyridine (9.5 g, 0.12 mmol) was added, and after stirring at room temperature for 10 min, tert- butyryl chloride (13.3 g, 0.11 mol) was added dropwise slowly, and the reaction was continued for 10 h. 200 mL of purified water was added, and the mixture was filtered, and the obtained yellow solid was washed twice with 50 mL of purified water, and dried to obtain 22.6 g of the title compound at a yield of 95.6%.

[0120] Step B: Synthesis of N-(4-chloro-3-methyl-2-nitrophenyl) neopentanamide

[0121] Compound N-(3-methyl-2-nitrophenyl) neopentanamide (9.5 g, 0.040 mol) was dissolved in 50 mL of DMF, and N-chlorosuccinimide (5.9 g, 0.044 mol) was added in portions while the temperature was raised to 45°C, and the mixture was stirred for 4 h. After confirming the completion of the reaction, 250 mL of purified water was added to the reaction mixture, and the mixture was filtered to obtain a yellow solid, which was washed twice with 50 mL of purified water, and dried to obtain 9.8 g of the title compound at a yield of 90.5% and a purity of 98.6%.

[0122] Step C: Synthesis of N-(2-amino-4-chloro-3-methylphenyl) neopentanamide

[0123] Compound N-(4-chloro-3-methyl-2-nitrophenyl) neopentanamide (5.5 g, 0.020 mol) was dissolved in 80 mL of tetrahydrofuran, and 0.1 g of platinum carbon was added, and the mixture was replaced with hydrogen gas three times, and hydrogen gas was introduced (0.2 MPa), and the mixture was stirred at 25°C for 4 h. The mixture was filtered, and the mother liquor was dried, and recrystallized from a mixture of 50 mL of methanol and water (volume ratio: 1:9) to obtain 4.6 g of the title compound as a white solid at a yield of 95.5% and a purity of 99.8%.

[0124] LC-MS; [M+H] + = 241.1

[0125] 1 HNMR (400 MHz, D6-DMSO) δ: 8.74 (s, 1H), 6.82-6.84 (d, J = 8.8 Hz, 1H), 6.62-6.64 (d, J = 8.8 Hz, 1H), 4.68 (s, 2H), 2.16 (s, 3H), 1.21 (s, 9H)

[0126] Example 8

[0127] Synthesis of compound N-(2-amino-4-chloro-3-methylphenyl)-4-methylbenzenesulfonamide.

[0128] The specific reaction equation is shown below:

[0129]

[0130] Step A: Synthesis of 4-methyl-N-(3-methyl-2-nitrophenyl)benzenesulfonamide

[0131] Compound 3-methyl-2-nitroaniline (15.2 g, 0.10 mol) was dissolved in 50 mL DMF, triethylamine (12.1 g, 0.12 mmol) was added, stirred at room temperature for 10 min, then p-toluenesulfonyl chloride (21.0 g, 0.11 mol) was added, and the reaction was continued for 10 h. 200 mL purified water was added, and the mixture was filtered. The resulting yellow solid was washed twice with 50 mL purified water and dried to obtain 28.8 g of the title compound in a yield of 94.2%.

[0132] Step B: Synthesis of N-(4-chloro-3-methyl-2-nitrophenyl)-4-methylbenzenesulfonamide

[0133] Compound 4-methyl-N-(3-methyl-2-nitrophenyl)benzenesulfonamide (12.0 g, 0.039 mol) was dissolved in 50 mL DMF, and the temperature was raised to 45°C. N-chlorosuccinimide (5.7 g, 0.043 mol) was added in portions, and the reaction was stirred for 4 h. After the reaction was completed, 250 mL purified water was added to the reaction system, and the mixture was filtered to obtain a yellow solid, which was washed twice with 50 mL purified water and dried to obtain 11.3 g of the title compound in a yield of 85.0% and a purity of 98.5%.

[0134] Step C: Synthesis of N-(2-amino-4-chloro-3-methylphenyl)-4-methylbenzenesulfonamide

[0135] Compound N-(4-chloro-3-methyl-2-nitrophenyl)-4-methylbenzenesulfonamide (10 g, 0.029 mol) was dissolved in 80 mL tetrahydrofuran, and 0.2 g platinum carbon was added. The mixture was replaced with hydrogen three times, and hydrogen was introduced (0.2 MPa). The reaction was stirred at 25°C for 7 h. The mixture was filtered, and the mother liquor was dried. The mixture was recrystallized from a mixture of 100 mL methanol and water (volume ratio: 1:9) to obtain 8.51 g of the title compound in a yield of 94.4% and a purity of 99.6%.

[0136] LC-MS; [M+H] + = 311.1

[0137] 1HNMR (400 MHz, CDC13) δ: 7.64 (d, 2H), 7.26 (d, 2H), 6.70 (m, 1H), 6.47 (d, 1H), 6.37 (d, 1H), 4.21 (m, 2H), 2.41 (s, 3H), 2.15 (s, 3H)

[0138] Example 9

[0139] Synthesis of compound tert-butyl 4-bromo-3-methyl-2-aminophenylcarbamate.

[0140] The specific reaction equation is shown below:

[0141]

[0142] Synthesis of compound tert-butyl 4-bromo-3-methyl-2-nitrophenylcarbamate

[0143] The compound tert-butyl 3-methyl-2-nitrophenylcarbamate (10 g, 39.6 mmol) was dissolved in 40 mL of DMF, and warmed to 50°C, and N-bromosuccinimide (7.74 g, 43.5 mmol) was added in portions, and incubated for 8 hours. After the reaction was detected to be complete, 200 mL of purified water was added to the reaction system, and suction filtration was performed to obtain a yellow solid, which was dried to obtain 12.4 g of the title compound, with a yield of 94.5%, and a purity of 98.7%.

[0144] Synthesis of compound tert-butyl 4-bromo-3-methyl-2-nitrophenylcarbamate

[0145] The compound tert-butyl 4-bromo-3-methyl-2-nitrophenylcarbamate (10 g, 0.030 mol) was dissolved in 100 mL of tetrahydrofuran, and 0.1 g of platinum carbon was added, and hydrogen was replaced for 3 times, and hydrogen was introduced (pressure 0.2 MPa), and incubated for 5 hours at 25°C, and suction filtration was performed, and the mother liquor was rotary evaporated, and 120 mL of a mixture of methanol and water (volume ratio: 1:9) was added for recrystallization, to obtain 8.6 g of the title compound in a white color, with a yield of 95.2%, and a purity of 99.5%.

[0146] LC-MS; [M-Boc+H] + = 201.1

[0147] 1 HNMR (DMSO-d6) δ: 8.32 (s, 1H), 7.15 (d, 1H), 6.64 (d, 1H), 4.62 (m, 2H), 2.14 (s, 3H), 1.45 (s, 9H).

[0148] Daridorexant was synthesized using the compound shown in formula (I), and the synthesis route is as follows:

[0149]

[0150] Synthesis of compound (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2- methylpyrrolidin-1-yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride.

[0151] The specific reaction equation is shown below:

[0152]

[0153] Step D: Synthesis of (S)-(4-chloro-2-(1-(5-methoxy-2-(2H-1,2,3-triazol-2- yl)benzoyl)-2-methylpyrrolidine-2-carboxamido)-3-methylphenyl)carbamic acid tert-butyl ester

[0154] Compound (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2- methylpyrrolidine-2-carboxylic acid (214.5 g, 650 mmol) was added into 500 mL of toluene, 5 g of DMF was added, and sulfurous chloride (85 g, 715 mmol) was slowly added dropwise. After the addition was completed, it was incubated for 2 hours, and was used as is.

[0155] Compound 2-amino-4-chloro-3-methylphenylcarbamic acid tert-butyl ester (163 g, 635 mmol) was dissolved in 600 mL of toluene, 192 g of pyridine was added, and the temperature was raised to 50°C. The solution obtained in the previous step was slowly added, and after the addition was completed, the temperature was lowered to 25°C, and it was incubated for 2 hours. A 1000 mL solution of dilute hydrochloric acid (1 mol / L) was added, and the liquid was separated. The organic phase was washed once with 200 mL of dilute sodium hydroxide solution (1 mol / L) and 200 mL of purified water. The organic phase was spin-dried, and a mixture of 2 L of ethyl acetate and n-heptane (volume ratio 1:9) was added. The temperature was raised to 80°C, and it was incubated for 1 hour. The temperature was lowered to 0°C, and it was suction-filtered and dried. 344.0 g of white solid was obtained, with a yield of 95.2% and a purity of 99.2%.

[0156] LC-MS; [M+H] + = 569.2

[0157] 1HNMR (400 MHz, D6-DMSO) δ: 9.32 (s, 1H), 8.01 (s, 2H), 7.91 (s, 1H), 7.72-7.79 (m, 2H), 7.46 (s, 1H), 7.33-7.35 (d, J = 8.8 Hz, 1H), 7.18-7.21 (dd, J1= 2.8 Hz, J2= 8.8 Hz, 1H), 3.83 (s, 3H), 3.62 (m, 1H), 3.19 (m, 1H), 2.26 (m, 1H), 2.14 (s, 3H), 1.98 (s, 3H), 1.49 (m, 2H), 1.43 (s, 1H), 1.14 (s, 9H)

[0158] Step E: Synthesis of (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2- methylpyrrolidin-1-yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride

[0159] The compound (S)-(4-chloro-2-(1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2- methylpyrrolidine-2-carboxamido)-3-methylphenyl)carbamic acid tert-butyl ester (200 g, 351 mmol) was dissolved in 1200 mL of ethanol, 500 mL of concentrated hydrochloric acid was added slowly dropwise, after the addition was completed, the temperature was raised to 80 °C, after stirring for 8 hours, the temperature was lowered to 0 °C, filtration was carried out to obtain a white solid, which was dried to obtain 155 g of the title compound, two-step yield: 90.8%, purity: 99.9%.

[0160] LC-MS; [M+H] + = 451.2

[0161] 1 HNMR (400 MHz, D6-DMSO) δ: 15.26 (br, 1H), 8.03 (s, 2H), 7.74 (s, 1H), 7.73 (d, 1H), 7.64 (d, J = 8.8 Hz 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.14 (dd, J1= 2.8 Hz, J2= 9.2 Hz, 1H), 4.03-4.05 (m, 1H), 3.89 (s, 3H), 3.32-3.35 (m, 1H), 2.74 (s, 3H), 2.53-2.59 (m, 1H), 2.20-2.25 (m, 1H), 2.09-2.13 (m, 2H), 1.94 (s, 3H)

[0162] Example 11

[0163] Synthesis of compound (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2- methylpyrrolidin-1-yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride.

[0164] The specific reaction equation is shown as follows:

[0165]

[0166] Step D: Synthesis of (S)-tert-butyl (4-chloro-2-(1-(5-methoxy-2-(2H-1,2,3-triazol-2- yl)benzoyl)-2-methylpyrrolidine-2-carboxamido)-3-methylphenyl)carbamate

[0167] Compound (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2- carboxylic acid (10 g, 30.3 mmol) was added into 50 mL of toluene, 1 g of DMF was added, and 4.0 g of thionyl chloride (33.6 mmol) was slowly added dropwise. After the addition was completed, the mixture was incubated for 2 hours, and was ready for use.

[0168] Compound tert-butyl N-Boc-N-(4-chloro-3-methyl-2-aminophenyl)carbamate (10.6 g, 29.8 mmol) was dissolved in toluene, 4.8 g of pyridine was added, and the temperature was raised to 55°C. The solution obtained in the previous step was slowly added dropwise. After the addition was completed, the mixture was incubated for 2 hours. When the starting material was detected to be completely consumed, the toluene solution was distilled under reduced pressure to obtain a yellowish oil. The next step was directly performed without further treatment.

[0169] Step E: Synthesis of (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2- methylpyrrolidin-1-yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride

[0170] The oil obtained in the previous step was dissolved in 120 mL of ethanol, and 50 mL of concentrated hydrochloric acid was slowly added dropwise. After the addition was completed, the mixture was stirred for 2 hours. When no gas was emitted, the temperature was raised to 80°C, and the mixture was stirred for 8 hours. After the temperature was lowered to 0°C, the mixture was filtered, and the filter cake was washed twice with 50 mL of purified water to obtain a white solid. After drying, 12.7 g of the title compound was obtained. The three-step yield was 87.6%, and the purity was 99.8%.

[0171] Example 12

[0172] Synthesis of compound (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2- methylpyrrolidin-1-yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride.

[0173] The specific reaction equation is shown below:

[0174]

[0175] Synthesis of compound (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2- methylpyrrolidin-1-yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride.

[0176] Compound (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2- carboxylic acid (10 g, 30.3 mmol) was added to 50 mL of toluene, 1 g of DMF was added, and sulfurous chloride (4.0 g, 33.6 mmol) was slowly added dropwise. After the addition was completed, it was incubated for 2 hours, and then used as is.

[0177] Compound 2-(2-amino-4-chloro-3-methylphenyl)isoindoline-1,3-dione (8.52 g, 29.8 mmol) was dissolved in toluene, 4.8 g of pyridine was added, and the temperature was raised to 50°C. The solution obtained in the previous step was slowly added, and after the addition was completed, it was incubated for 2 hours. When the starting material was detected to be completely consumed, the toluene solution was distilled under reduced pressure, and the next step was performed without further treatment.

[0178] Synthesis of compound (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2- methylpyrrolidin-1-yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride.

[0179] The oil obtained in the previous step was dissolved in 200 mL of ethanol, and 40 mL of an 80% hydrazine hydrate solution was added dropwise. After the addition was completed, the temperature was raised to 80°C, and stirring was performed for 3 hours. Then, 90 mL of concentrated hydrochloric acid was slowly added dropwise, and incubation was continued for 5 hours. Then, the temperature was slowly lowered to 0°C, and filtration was performed. The resulting white solid was washed twice with 50 mL of purified water, and then dried to obtain 12.1 g of the title compound. The three-step yield was 83.5%, and the purity was 99.7%.

[0180] Example 13

[0181] Synthesis of compound (S)-(2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2- methylpyrrolidin-1 -yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrobromide.

[0182] The specific reaction scheme is shown below:

[0183]

[0184] Synthesis of (S)-(4-chloro-2-(1 -(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2- methylpyrrolidine-2-carboxamido)-3-methylphenyl)benzylcarbamate

[0185] Compound (S)-1 -(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2- carboxylic acid (10 g, 30.3 mmol) was added into 50 mL of toluene, 1 g of DMF was added, and sulfurous chloride (4.0 g, 33.6 mmol) was slowly added dropwise. After the addition was completed, the mixture was incubated for 2 hours, and then was used as is.

[0186] Compound 2-amino-4-chloro-3-methylphenyl benzylcarbamate (8.64 g, 29.8 mmol) was dissolved in toluene, 4.8 g of pyridine was added, and the temperature was raised to 55°C. The solution obtained in the previous step was slowly added, and after the addition was completed, the mixture was incubated for 2 hours. When the starting material was determined to be consumed, the toluene solution was distilled under reduced pressure to obtain a light yellow oil. The product was used as is in the next step without further purification.

[0187] Synthesis of (S)-(2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrobromide.

[0188] The oil obtained in the previous step was dissolved in 120 mL of 33% hydrobromic acid in acetic acid, and the temperature was raised to 100°C. After stirring for 8 hours, the temperature was lowered to 80°C, and 100 mL of purified water was slowly added. After stirring for 2 hours, the temperature was allowed to lower to room temperature, and the mixture was filtered. The product was washed twice with 50 mL of purified water, and then was dried to obtain 14.0 g of the title compound. The overall yield of the three steps was 88.5%, and the purity was 99.6%.

[0189] Example 14

[0190] Synthesis of compound (S)-(2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2- methylpyrrolidin-1 -yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrobromide.

[0191] The specific reaction equation is shown below:

[0192]

[0193] Step D: Synthesis of (S)-N-(6-(tert-butylamino)-3-chloro-2-methylphenyl)-1-(5-methoxy- 2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxamide

[0194] Compound (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2- carboxylic acid (10 g, 30.3 mmol) was added into 50 mL of toluene, 1 g of DMF was added, and 4.0 g of thionyl chloride (33.6 mmol) was slowly added dropwise. After the addition was completed, the mixture was incubated for 2 hours, and then used as is.

[0195] Compound N-(tert-butyl)-4-chloro-3-methylbenzene-1,2-diamine (6.30 g, 29.6 mmol) was dissolved in toluene, 4.8 g of pyridine was added, and the mixture was warmed to 50°C. The solution obtained in the previous step was slowly added dropwise, and after the addition was completed, the mixture was incubated for 2 hours. After the temperature was lowered to room temperature, 20 mL of dilute hydrochloric acid solution was added, the organic phase was separated, and the toluene solution was distilled off under reduced pressure to obtain a white solid, which was used directly in the next step.

[0196] Step E: Synthesis of (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1- yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride

[0197] The white solid obtained in the previous step was dissolved in 100 mL of ethanol, 30 mL of concentrated hydrochloric acid was slowly added dropwise, and after the addition was completed, the mixture was warmed to 80°C. After stirring for 4 hours, the temperature was lowered to 0°C, and the mixture was filtered, washed twice with 20 mL of purified water, and dried to obtain 12.4 g of the title compound, with a three-step yield of 86.1% and a purity of 99.8%.

[0198] Example 15

[0199] Synthesis of compound (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1- yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride.

[0200] The specific reaction equation is shown below:

[0201]

[0202] Step D: Synthesis of (S)-N-(6-acetylamino-3-chloro-2-methylphenyl)-1-(5-methoxy- 2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxamide

[0203] Compound (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2- methylpyrrolidine-2-carboxylic acid (10 g, 30.3 mmol) was added into 50 mL of toluene, 1 g of DMF was added, and sulfurous chloride (4.0 g, 33.6 mmol) was slowly added dropwise. After the addition was completed, the mixture was incubated for 2 hours, and then used as is.

[0204] Compound N-(2-amino-4-chloro-3-methylphenyl)acetamide (5.9 g, 29.8 mmol) was dissolved in toluene, 4.8 g of pyridine was added, and the mixture was warmed to 50°C. The solution obtained in the previous step was slowly added dropwise. After the addition was completed, the mixture was incubated for 2 hours. When the starting material was determined to be consumed, the toluene solution was distilled off under reduced pressure to obtain a yellowish oil. The product was used as is in the next step without further purification.

[0205] Step E: Synthesis of (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2- methylpyrrolidin-1-yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride

[0206] The oil obtained in the previous step was dissolved in 150 mL of ethanol, and 50 mL of concentrated hydrochloric acid was slowly added dropwise. After the addition was completed, the mixture was warmed to 80°C. After stirring for 8 hours, the mixture was cooled to 0°C, filtered, and washed twice with 50 mL of purified water to obtain a white solid. After drying, 12.5 g of the title compound was obtained in a three-step yield of 86.2% and a purity of 99.7%.

[0207] Example 16

[0208] Synthesis of compound (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2- methylpyrrolidin-1-yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride.

[0209] The specific reaction equation is shown below:

[0210]

[0211] Step D: Synthesis of (S)-N-(3-chloro-2-methyl-6-((4-methylphenyl)sulfonamido)phenyl)- 1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxamide

[0212] Compound (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2- carboxylic acid (10 g, 30.3 mmol) was added into 50 mL of toluene, 1 g of DMF was added, and 4.0 g of thionyl chloride (33.6 mmol) was slowly added dropwise. After the addition was completed, the mixture was incubated for 2 hours, and then used as is.

[0213] Compound N-(2-amino-4-chloro-3-methylphenyl)-4-methylbenzenesulfonamide (9.24 g, 29.8 mmol) was dissolved in 100 mL of toluene, 4.8 g of pyridine was added, and the mixture was warmed to 50°C. The solution obtained in the previous step was slowly added dropwise. After the addition was completed, the mixture was incubated for 2 hours, and then cooled to room temperature. 50 mL of dilute hydrochloric acid (1 M) was added, and the mixture was extracted and separated. The organic phase was dried by rotary evaporation to obtain a white solid, which was used as is in the next step.

[0214] Step E: Synthesis of (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride

[0215] The white solid obtained in the previous step was dissolved in 150 mL of ethanol, and 50 mL of concentrated hydrochloric acid was slowly added dropwise. After the addition was completed, the mixture was warmed to 80°C, and stirred for 10 hours. The mixture was then cooled to 0°C, filtered, and washed twice with 50 mL of purified water. A white solid was obtained, which was dried to obtain 12.2 g of the title compound. The three-step yield was 84.1%, and the purity was 99.7%.

[0216] Although the present application is described in detail with reference to the above examples, the technical solutions of the present application are not limited to the above examples. Any modification to the technical solutions of the present application without departing from the spirit and principles of the present application will fall within the scope defined by the claims of the present application.

Claims

1. A compound represented by formula (Ⅰ) in, X represents chlorine, bromine, or iodine; R 1 R 2 One is represented by hydrogen and the other by an amino protecting group or R. 1 R 2 Each is an independent amino protecting group or R 1 and R 2 Together they form an amino protecting group.

2. The compound of formula (I) according to claim 1, characterized in that, The amino protecting group is selected from Trifluoroacetyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, benzenesulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, triphenylmethyl, tert-butyl, tert-butylsulfinyl, phthaloyl, and R 3 It is represented as (C1-C4) alkyl.

3. A method for preparing the compound of formula (I) according to any one of claims 1 to 2, characterized in that, Starting with 3-methyl-2-nitrobenzoic acid or 3-methyl-2-nitroaniline, compound (III) is synthesized through degradation reaction or amino protection, compound (II) is synthesized through halogenation reaction, and compound (I) is obtained through reduction reaction. The specific route is as follows: In the formula, X, R 1 R 2 The expression is the same as the definition above.

4. The method for preparing the compound represented by formula (Ⅰ) according to claim 3, characterized in that, The halogenating reagents used in the halogenation reaction are derived from chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, trichloroisocyanuric acid, sulfonyl chloride, 2-chloro-1,3-bis(methoxycarbonyl)guanidine, hypochlorous acid, tert-butyl hypochlorite, hypochlorite, and chlorate.

5. The method for preparing the compound represented by formula (I) according to claim 3, characterized in that, The reducing agent or catalyst used in the reduction reaction is derived from one or more of the following: platinum, platinum oxide, palladium, palladium dichloride, rhodium, ruthenium, nickel, zinc, iron, ferric chloride, zinc chloride, stannous chloride, sodium dithionite, sodium sulfide, ammonium sulfide, sodium borohydride, potassium borohydride, and lithium borohydride. The hydrogen source used comes from one or more of the following: hydrogen gas, cyclohexadiene, acetic acid, hydrochloric acid, sulfuric acid, ammonium chloride, formic acid, ammonium formate, sodium formate, and hydrazine hydrate.

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