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2-(alpha-hydroxy amyl) benzamide derivate as well as preparation method, preparation and application thereof

A technology of benzamide and hydroxypentyl group is applied in the field of medicine to achieve the effect of good in vitro stability

Inactive Publication Date: 2015-05-20
YUNNAN HAOPY PHARM LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] So far, there is no butylphthalide prodrug with multiple pharmacological effects, therefore, it is necessary to develop a butylphthalide prodrug with multiple pharmacological effects

Method used

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  • 2-(alpha-hydroxy amyl) benzamide derivate as well as preparation method, preparation and application thereof
  • 2-(alpha-hydroxy amyl) benzamide derivate as well as preparation method, preparation and application thereof
  • 2-(alpha-hydroxy amyl) benzamide derivate as well as preparation method, preparation and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0063] The preparation method of 2-(α-hydroxypentyl) benzamide derivatives of the present invention comprises the following steps:

[0064] A. Dissolve the raw material butylphthalide in a solvent, adjust the pH value to 10~14 with alkali, add diamine with a reaction molar weight more than 1 times, then add a catalyst and stir the reaction for 24~48h at room temperature to obtain the intermediate product a;

[0065] B. Condensing the obtained intermediate product a with a carboxyl-containing compound under the condition of a condensing agent to obtain the target product.

[0066] The solvent described in the A step is a kind of in polar solvent or non-polar solvent.

[0067] The solvent described in step A is one of methanol, ethanol, dimethyl sulfoxide DMF, N-methylpyrrolidone NMP, dichloromethane, and tetrahydrofuran THF.

[0068] The base described in the A step is an inorganic base or an organic base.

[0069] The alkali described in step A is one of sodium hydroxide, po...

Embodiment 1

[0089] Example 1 (E)-N-(4-(3-(4-((1H-imidazolyl)methyl)phenyl)acrylamido)butyl)-2-(1-hydroxypentyl)benzyl Synthesis of Amide (Compound 1)

[0090]

[0091] (1) Synthesis of N-(4-aminobutyl)-2-(1-hydroxypentyl)benzoic acid

[0092] In a 50.0 mL round bottom flask, dissolve butylphthalide (0.19 g, 1 mmol) in 10 mL of dichloromethane, add diisopropylethylamine (0.44 mL, 2.5 mmol) and 4-dimethylaminopyridine (0.0366 g, catalytic amount), after stirring at room temperature for a while, 1,4-butanediamine (0.42 mL, 5 mmol) was added dropwise. After stirring at room temperature for more than 24 hours, after the reaction was detected by TLC, the white solid insoluble matter was removed by filtration, and the mother liquor was concentrated directly to obtain an oily substance, which was separated by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain an oily substance (0.2380g , 90.1%)

[0093] 1 H NMR (600MHz, CDCl 3 )δ:8.34(s,1H),7.55(d,J=7.74Hz,1H),7.40...

Embodiment 2

[0103] Example 2 (E)-N-(2-(2-(3-(4-((1H-imidazolyl)methyl)phenyl)acrylamido)ethoxy)ethoxy)ethyl)- Synthesis of 2-(1-hydroxypentyl)benzamide (compound 2)

[0104]

[0105] (1) Synthesis of N-(2-(2-aminoethoxy)ethyl)-2-(1-hydroxypentyl)benzoic acid

[0106] In a 50.0 mL round bottom flask, dissolve butylphthalide (0.19 g, 1 mmol) in 10 mL of dichloromethane, add diisopropylethylamine (0.44 mL, 2.5 mmol) and 4-dimethylaminopyridine (0.0366 g, catalytic amount), after stirring at room temperature for a while, 1,2-bis(2-aminoethoxy)ethane (0.73 mL, 5 mmol) was added dropwise. TLC detection, stirring at room temperature for more than 24 hours. After the reaction, the mother liquor was concentrated directly to obtain an oil, which was separated by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain an oil (0.2980g, 88.1%)

[0107] 1 HNMR (600MHz, CDCl 3 )δ:8.40(s,1H),7.58(d,J=7.77Hz,1H)), 7.43(m,1H),7.29(dd,J=7.66Hz,J=14.94Hz,2H),4.92(dd ,1H),3.56(m,6H...

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Abstract

The invention discloses a 2-(alpha-hydroxy amyl) benzamide derivate as well as a preparation method, a preparation and an application of the deviate. The structural formula of the 2-(alpha-hydroxy amyl) benzamide derivate is shown in the specification, wherein R1 is a link group; and R2 is a functional group containing carboxyl. The preparation method comprises the following steps: performing ring-opening reaction for butylphthalide serving as the raw material to obtain an intermediate product a; and performing condensation reaction for the intermediate product a and a carboxyl-containing compound. The preparation is prepared by adding pharmaceutically acceptable auxiliary materials and can be in a form of powder, a tablet, a capsule, granules, a dropping pill, a honeyed pill, a lyophilized agent or injection. The application includes the application in preparation of medicines for preventing / treating cardio-cerebral ischemia, cardio-cerebral arterial occlusion, parkinson disease and senile dementia. According to the preparation method, opened-loop butylphthalide and ozagrel or clopidogrel and other medicines with platelet aggregation resisting effects are linked through an amido bond so as to be synthesized into a butylphthalide prodrug with a plurality of pharmacologic effects.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a 2-(α-hydroxypentyl)benzamide derivative and a preparation method, preparation and application thereof. Background technique [0002] Racemic 3-n-butylphthalide (dl-NBP, trade name: Enbipu) is a class of new drugs independently developed by my country for the prevention and treatment of ischemic stroke. Pharmacodynamic studies have shown that dl-NBP acts on multiple pathological links of brain damage caused by ischemic stroke, and has a strong anti-ischemic effect. In 2002, it was approved by the State Food and Drug Administration for the clinical treatment of mild and moderate acute ischemic stroke and other cardiovascular and cerebrovascular diseases [J.Pharmacol.Exp.Ther., 2006,317:973 -979.]. Experimental studies in recent years have found that in addition to resisting brain damage caused by ischemia, NBP also has a protective effect on other nervous system dama...

Claims

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Application Information

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IPC IPC(8): C07D233/58C07D495/04C07K5/078A61K38/05A61K31/4365A61K31/4174A61P9/10A61P25/28A61P25/16
CPCC07D233/58C07D495/04C07K5/06139
Inventor 李彪徐志斌王涌孟子晖赵欢
Owner YUNNAN HAOPY PHARM LTD
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