Unlock instant, AI-driven research and patent intelligence for your innovation.

Method for synthesizing Rimonabant hydrochloride

A technology of rimonabant hydrochloride and its synthesis method is applied in the field of preparation of cannabinoid receptor antagonist rimonabant hydrochloride, which can solve the problems of expensive reagents, unsuitability for industrialization, and increased reaction cost, and achieve simple operation, The effect of mild conditions and easy purification

Inactive Publication Date: 2013-03-13
CHINA PHARM UNIV
View PDF6 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis operation of this method is cumbersome and the yield is low, especially the yield of the ring-synthesized compound 1 is only 22%, and the total yield is less than 10%, which is not suitable for scale-up production
[0020] Method 9 (WO2008101860): This method proposes ethyl 5-(4-chlorophenyl)-4-methyl-3-pyrazolecarboxylate in strong base and bis(dibenzylideneacetone)palladium and 2-bis Phenylphosphorus-2'-(N,N-dimethylamino)biphenyl reacts with 2,4-dichlorobromobenzene to obtain carboxylic acid compound 2 by direct hydrolysis, or first react the raw material with N-aminopiperidine to form The amide is then reacted with 2,4-dichlorobromobenzene under the same conditions to obtain rimonabant, but this method of introducing a phenyl group at the 1-position of pyrazole needs to use expensive reagents, and the reaction cost is greatly increased, so it is not suitable for industrialization
At the same time, this document also proposes to use the raw material and 2,4-dichlorophenylboronic acid to perform a substitution reaction on the 1-position N to obtain an ester compound 1, which can be used to synthesize rimonabant, but this step requires a chromatographic method for the substitution reaction. separation method for purification, so it is not suitable for industrial production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Method for synthesizing Rimonabant hydrochloride
  • Method for synthesizing Rimonabant hydrochloride
  • Method for synthesizing Rimonabant hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

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] + .

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

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, and in particular relates to a preparation method of rimonabant hydrochloride, a cannabinoid receptor antagonist. Background technique [0002] Rimonabant Hydrochloride is a cannabinoid receptor-1 (CB1) antagonist, which can reduce people's appetite and smoking craving by blocking cannabinoid receptors in brain tissue, and can be used for obesity, smoking cravings, The treatment of hypertension, dyslipidemia, type 2 diabetes and metabolic syndrome can lower cholesterol at the same time, and has the effect of preventing heart disease and diabetes in obese people. It has been launched in many countries in 2006. Therefore, the development of a synthetic process for rimonabant hydrochloride with industrial 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 of them...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/14
Inventor 杨照方正王志祥韦萍
Owner CHINA PHARM UNIV