Method for synthesizing Rimonabant hydrochloride

Abstract

The invention discloses a method for synthesizing Rimonabant hydrochloride. The method comprises the following steps: 4-corobenzaldehyde is condensed with nitroethane under a base catalysis effect so as to obtain 1-parachloropenyl-2-nitropropene (II); D-glucose reacts with 2,4-dichloro-phenylhydrazine to obtain a phenylhydrazone compound (III); the 1-parachloropenyl-2-nitropropene (II) is cyclized with the phenylhydrazone compound (III) under an alkali condition so as to obtain a pyrazole compound (IV); by using KMnO4 as a catalyst, the pyrazole compound (IV) is oxidized in an alkaline solution of NaIO4 so as to obtain a carboxylic acid compound (V); and the carboxylic acid compound (V) reacts with N-aminopiperidine after being chloroformylated by using a chlorinated reagent so as to prepare amide and the amide is salified to obtain the Rimonabant hydrochloride (I). The method provided by the invention has the advantages of reasonable synthesis route, low raw material price, mild reaction condition, higher total yield, easiness for controlling the quality of a reaction intermediate, industrial production potential, high product purity and stable quality.

Description

technical field

[0001] The invention belongs to the technical field of chemical pharmacy, in particular to a preparation method of cannabinoid receptor antagonist rimonabant hydrochloride. Background technique

[0002] Rimonabant Hydrochloride is a cannabinoid receptor-1 (CB1) antagonist, which reduces human appetite and smoking addiction by blocking cannabinoid receptors in brain tissue. It can be used for obesity, smoking addiction, The treatment of high blood pressure, dyslipidemia and type 2 diabetes and metabolic syndrome, while lowering cholesterol, has the effect of preventing heart disease and diabetes in obese people, and has been launched in many countries in 2006. Therefore, the development of the synthesis process of rimonabant hydrochloride with industrialization potential has broad market prospects. In view of its obvious economic benefits and social value, people have researched and developed several different synthetic methods, but all have disadvantages suc...

Examples

Embodiment 1

[0050] Example 1: Preparation of 1-p-chlorophenyl-2-nitropropene (II).

[0051] Dissolve p-chlorobenzaldehyde (14.1g, 0.1mol) in absolute ethanol (100mL), add nitroethane (8.6mL, 0.12mol) and 2 drops of piperidine to the solution, reflux at 80°C for 12h, and concentrate the solution to 40mL, left to stand for crystallization to obtain 15.7g of pale yellow flaky crystals with a yield of 79.2%. M.p=84.6~85.6℃; ESI-MS: m / z=198.0[M+H] + .

Embodiment 2

[0052] Example 2: Preparation of D-glucose-2,4-dichlorophenylhydrazone (III).

[0053] Add sodium acetate (6.6g, 0.1mol) and D-glucose (36.0g, 0.2mol) to a solution of 2,4-dichlorophenylhydrazine hydrochloride (21.3g, 0.1mol) dissolved in water (150mL), Stir at 25°C for 12h, wash the solution with toluene (30mL×2), extract the aqueous layer with ethyl acetate (50mL×4), combine the ethyl acetate layers, wash the organic layer with saturated NaCl solution (50mL), anhydrous NaCl 2 SO 4 Dry, filter, and concentrate to obtain 26.5 g of a yellow solid, with a yield of 78.2%. M.p=43.2~46.6℃; ESI-MS: m / z=339.0[M+H] + .

Embodiment 3

[0054] Example 3: (1R, 2S, 3R, 4R)-1-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole- Preparation of 3-yl]pentapentanol (IV)

[0055] Compound II (1.97g, 0.01mol) prepared by the method of Example 1 and Compound III (3.39g, 0.01mol) prepared by the method of Example 2 were dissolved in N, N-dimethylformamide (20mL), and mixed Add sodium methoxide (0.54g, 0.01mol) to the solution, stir at 25°C for 5d, filter to remove a small amount of insoluble matter, evaporate the filtrate to remove the solvent under reduced pressure, add ethyl acetate (2mL) to triturate and precipitate a solid, filter to obtain the crude product, and recrystallize from methanol to obtain White solid powder 3.65g, yield 74.8%. M.p=145.5~147.0℃; ESI-MS: m / z=487.1[M+H] + .

technical field

[0001] The invention belongs to the technical field of chemical pharmacy, in particular to a preparation method of cannabinoid receptor antagonist rimonabant hydrochloride. Background technique

[0002] Rimonabant Hydrochloride is a cannabinoid receptor-1 (CB1) antagonist, which reduces human appetite and smoking addiction by blocking cannabinoid receptors in brain tissue. It can be used for obesity, smoking addiction, The treatment of high blood pressure, dyslipidemia and type 2 diabetes and metabolic syndrome, while lowering cholesterol, has the effect of preventing heart disease and diabetes in obese people, and has been launched in many countries in 2006. Therefore, the development of the synthesis process of rimonabant hydrochloride with industrialization potential has broad market prospects. In view of its obvious economic benefits and social value, people have researched and developed several different synthetic methods, but all have disadvantages suc...

Examples

Embodiment 1

[0050] Example 1: Preparation of 1-p-chlorophenyl-2-nitropropene (II).

[0051] Dissolve p-chlorobenzaldehyde (14.1g, 0.1mol) in absolute ethanol (100mL), add nitroethane (8.6mL, 0.12mol) and 2 drops of piperidine to the solution, reflux at 80°C for 12h, and concentrate the solution to 40mL, left to stand for crystallization to obtain 15.7g of pale yellow flaky crystals with a yield of 79.2%. M.p=84.6~85.6℃; ESI-MS: m / z=198.0[M+H] + .

Embodiment 2

[0052] Example 2: Preparation of D-glucose-2,4-dichlorophenylhydrazone (III).

[0053] Add sodium acetate (6.6g, 0.1mol) and D-glucose (36.0g, 0.2mol) to a solution of 2,4-dichlorophenylhydrazine hydrochloride (21.3g, 0.1mol) dissolved in water (150mL), Stir at 25°C for 12h, wash the solution with toluene (30mL×2), extract the aqueous layer with ethyl acetate (50mL×4), combine the ethyl acetate layers, wash the organic layer with saturated NaCl solution (50mL), anhydrous NaCl 2 SO 4 Dry, filter, and concentrate to obtain 26.5 g of a yellow solid, with a yield of 78.2%. M.p=43.2~46.6℃; ESI-MS: m / z=339.0[M+H] + .

Embodiment 3

[0054] Example 3: (1R, 2S, 3R, 4R)-1-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole- Preparation of 3-yl]pentapentanol (IV)

[0055] Compound II (1.97g, 0.01mol) prepared by the method of Example 1 and Compound III (3.39g, 0.01mol) prepared by the method of Example 2 were dissolved in N, N-dimethylformamide (20mL), and mixed Add sodium methoxide (0.54g, 0.01mol) to the solution, stir at 25°C for 5d, filter to remove a small amount of insoluble matter, evaporate the filtrate to remove the solvent under reduced pressure, add ethyl acetate (2mL) to triturate and precipitate a solid, filter to obtain the crude product, and recrystallize from methanol to obtain White solid powder 3.65g, yield 74.8%. M.p=145.5~147.0℃; ESI-MS: m / z=487.1[M+H] + .

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