- Synthesis method of pimobendan
-
The invention provides a synthesis method of pimobendan, and belongs to the technical field of pharmaceutical chemicals. The synthesis method comprises the following steps: (1) in an organic solvent,taking acetanilide and 2-chloropropionyl chloride as raw materials, generating a compound I under the action of a Lewis acid catalyst; (2) in acid anhydride, the compound I and nitric acid are subjected to a nitration reaction to produce a compound II; (3) carrying out nucleophilic substitution reaction on the compound II and diethyl malonate in a reaction reagent under the action of sodium methoxide, carrying out hydrolysis reaction in the reaction reagent under the action of sodium hydroxide, and regulating the pH value of the reaction system to 3-4 by using diluted hydrochloric acid to generate a compound III; (4) reacting the compound III with a decarboxylation reagent to generate a compound IV; (5) reacting the compound IV with hydrazine hydrate in a reaction solvent in the presence of a noble metal catalyst to generate a compound V; and (6) reacting the compound V with p-methoxybenzaldehyde in a reaction solvent under the action of a catalyst to generate pimobendan VI. The pimobendan prepared by the method is simple in preparation method and low in reagent toxicity and has excellent clinical curative effect and clinical safety.
- -
-
-
- Preparation method of key intermediate of Pimobendan
-
The invention discloses a preparation method of a key intermediate of Pimobendan. The method comprises steps as follows: (i) a compound I is synthesized; (ii) the compound I is subjected to nucleophilic substitution, and a compound II is produced; (iii) t
- -
-
-
- Chemical synthesis method of Pimobendan
-
The invention discloses a chemical synthesis method of Pimobendan. The method comprises steps as follows: acetanilide and 2-methyl-3-(chloroformyl)propionate react to produce 3-p-acetylaminobenzoyl methyl butyrate in a mixed organic solvent under the action of a composite catalyst, 3-p-acetylaminobenzoyl methyl butyrate reacts with a nitration reagent, 3-(4-acetamido-3-nitrobenzoyl)-methyl butyrate is produced and subjected to a reflux reaction with alkali in an alcohol solvent to produce 3-(4-amino-3-nitrobenzoyl) butyrate, 3-(4-amino-3-nitrobenzoyl) butyrate and hydrazine hydrate are subjected to a reflux reaction, 4,5-dihydro-5-methyl-6-(4-amino-3-nitrophenyl)-3(2H)-pyridazinone is produced and reduced with zinc powder in absolute methanol, 4,5-dihydro-5-methyl-6-(3,4-diaminophenyl)-3(2H)-pyridazinone is produced and subjected to a reflux reaction with p-anisaldehyde, and Pimobendan is obtained. The method comprises a few reaction steps, operation is safe and convenient, and the cost is low.
- -
-
-
- Preparation of 6-(3,4-diamino phenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-ketone key intermediate of 2-(4-methoxyphenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)benzimidazole
-
The invention relates to preparation of a 6-(3,4-diamino phenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-ketone key intermediate for synthesizing 2-(4-methoxyphenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)benzimidazole. The technology is short in synthetic route and easy to operate and has an industrialized enlarged production prospect.
- -
-
Paragraph 0008; 0016; 0017; 0018; 0019
(2017/04/03)
-
- Synthesis of novel pyridazinonylbenzotriazoles
-
4-Chlorobenzaldehyde (1) was reacted with crotononitrile (2) in the presence of sodium cyanide yielding 4-(4-chlorophenyl)-3-methyl- 4-oxobutyronitrile (3) which on refluxing with concentrated HCl gave 4-(4-chlorophenyl)-3-methyl-4-oxobutyric acid (4). The latter, on treatment with fuming nitric acid, yielded 4-(4-chloro-3-nitrophenyl)-3-methyl-4-oxobutyric acid (5), which on treatment with hydrazine hydrate gave 6-(4-chloro-3-nitrophenyl)-5-methyl-4,5-dihydro-2H-pyridazine-3-one (6). Azidation and reduction of 6 with sodium azide gave the amino derivative 7 which on reductive alkylation gave 10(a-i) followed by reduction with commercially available sodium hydrogen sulphide solution gave the substituted diamine derivative 11(a-i). The compound 7 directly undergoes reduction with sodium hydrogen sulphide yielding (8). Finally, 8 and 11(a-i) was converted into the target compounds by diazotized-cyclization with sodium nitrite giving pyridazinonylbenzotriazoles 9 and 12(a-i).
- Reddy, S. Shashidhar,Vineel, B. George,Venkataiah,Naidu,Dubey
-
p. 3633 - 3638
(2015/12/24)
-
- Synthesis of novel Pyridazinonylbenzotriazoles
-
4-Chlorobenzaldehyde (1) was reacted with crotononitrile (2) in the presence of sodium cyanide yielding 4-(4-chlorophenyl)-3-methyl-4-oxobutyronitrile (3) which on refluxing with concentrated HCl gave 4-(4-chlorophenyl)-3-methyl-4-oxobutyric acid (4). The latter, on treatment with fuming nitric acid, yielded 4-(4-chloro-3-nitrophenyl)-3-methyl-4-oxobutyric acid (5), which on treatment with hydrazine hydrate gave 6-(4-chloro-3-nitrophenyl)-5-methyl-4,5-dihydro-2H-pyridazine-3-one (6). Azidation and reduction of 6 with sodium azide gave the amino derivative 7 which on reductive alkylation gave 10(a-i) followed by reduction with commercially available sodium hydrogen sulphide solution gave the substituted diamine derivative 11(a-i). The compound 7 directly undergoes reduction with sodium hydrogen sulphide yielding (8). Finally, 8 and 11(a-i) was converted into the target compounds by diazotized-cyclization with sodium nitrite giving pyridazinonylbenzotriazoles 9 and 12(a-i).
- Shashidhar Reddy,George Vineel,Venkataiah,Naidu,Dubey
-
p. 3633 - 3638
(2015/12/30)
-
- PIMOBENDAN MANUFACTURING PROCESS
-
The present invention generally relates to an improved process for the manufacture of a non- solvated crystalline compound of formula (I). The invention further relates to a new valuable intermediate compound for the commercial synthesis of pimobendan, which is a compound according to formula (I) n MeOH, wherein n is from 1 to 2 molar equivalents. Still further, the invention relates to the use of said intermediate compound or a compound according to formula (I) obtained by the process of the invention, for the manufacture of a pharmaceutical composition.
- -
-
Page/Page column 21-22
(2011/10/31)
-
- CRYSTALLINE PIMOBENDAN, PROCESS FOR THE PREPARATION THEREOF, PHARMACEUTICAL COMPOSITION AND USE
-
The invention relates to a pharmaceutical composition containing pimobendan as an active ingredient. The invention also relates to a crystalline form of pimobendan, as well as to a combination of said crystalline form with at least one other therapeutically active ingredient. Moreover, the invention relates to uses of said crystalline form, as well as to a pharmaceutical composition containing it. Finally, the invention relates to a process for preparing a crystalline form of pimobendan.
- -
-
Page/Page column 4-5
(2011/07/06)
-
- Synthesis and biological activities of meribendan and related heterocyclic benzimidazolo-pyridazinones
-
The synthesis of a new heterocyclic benzimidazolo-pyridazinones is described.The new compounds were evaluated as inotropic agents with 'calcium-sensitizing' effects. 5-Methyl-6--2,3,4,5-tetrahydro-pyridazin-3-one hydrochloride (meribendan) turned out to be the most interesting compound and was chosen for development as a positive inotrope. benzimidazole / calcium sensivity / cardiotonics / inotropes / phosphodiesterase / papillary muscle / pyridazinone
- Jonas, R,Klockow, M,Lues, I,Pruecher, H,Schliep, H J,Wurziger, H
-
p. 129 - 140
(2007/10/02)
-
- Pyridazinone derivatives
-
A pyridizinone derivative of the formula I STR1 wherein R is F, Cl, Br, I or R1 R2 N, R1 and R2 are each H, C1-4 -alkyl or benzyl, R3, R4 and R5 are each H or C1-4 -alkyl and wherein it is only possible for R to be benzylamino, R3 to be CH3 and R4 to H at the same time if R5 is alkyl, and salts thereof display positive inotropic properties and vasodilative properties and can be used, in particular, as intermediate products in the production of other pharmaceutical agents.
- -
-
-
