Synthesis method of nitrendipine metabolite

Abstract

The invention discloses a synthesis method of nitrendipine metabolite. The method takes 4-(benzyloxy)-3-ethyl oxo-butyrate and 3-hydroxypropionitrile as starting raw materials to synthesize the nitrendipine metabolite through 6-step reaction. A lot of experiments are carried out to screen optimal preparation steps and reaction conditions; a whole technology is reasonably designed and strong in operability; the chemical purity of the nitrendipine metabolite prepared by the synthesis method can reach 99 percent or more and the yield is high. The nitrendipine metabolite prepared by the synthesismethod provides a standard product for metabolic mechanism researches of a nitrendipine medicine and can be used for exploring a metabolic process of the medicine in organisms; the nitrendipine metabolite has a relatively good potential hypertension-resisting effect and has extremely application and research value in clinical pharmacokinetics researches.

Description

technical field

[0001] The invention relates to a synthesis method of a compound, in particular to a method for synthesizing a nitrendipine metabolite by a chemical method, and belongs to the field of drug metabolism. Background technique

[0002] Nitrendipine (nitrendipine) tablet is developed by Bayer (Bayer) pharmaceutical company in Germany, and is used for coronary heart disease and hypertension, especially patients suffering from these two diseases, and can also be used for congestive heart failure. The Chinese chemical name of nitrendipine: ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrobenzene)-3,5-pyridinedicarboxylate; English chemical name: 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethylmethyl ester; molecular formula: C17H15N2NaO7; molecular weight: 382.30; CAS registration number: 39562-70-4.

[0003] Nitrendipine, as a second-generation dihydropyridine compound, is a highly effective blocker of calcium ion channels in vascular s...

Examples

Embodiment 1

[0034] Embodiment 1 A kind of synthetic method of nitrendipine metabolite, it comprises the following steps:

[0035] Such as figure 1 Shown is the reaction flow diagram of the present invention:

[0036] Step (1): Take a 1-liter flask and add 750 ml of toluene (newly opened, AR), add 35 g of 4-(benzyloxy)-3-oxobutanoic acid ethyl ester (I), add 70 mL of 3-hydroxypropionitrile (II), react at 130°C for 10 hours. TLC (sampling, DCM dilution plate), the reaction of raw materials is complete. The reaction mixture was cooled to room temperature, 200ml of water was added to the reaction solution, directly shaken and separated, the organic phase was concentrated by rotary evaporation at 40°C and then purified by column chromatography (developing solvent: petroleum ether: dichloromethane = 100:1), and the pure The mobile phase was concentrated to obtain 32.70g of intermediate III with a yield of 88.49%.

[0037] 1H NMR (600MHz, CDCl3) δ7.36(m,5H),4.60(s,2H),4.29(t,2H),4.14(s,3H),3...

Embodiment 2

[0053] The antihypertensive effect of embodiment 2 end product IX

[0054] The end product IX nitrendipine metabolites were used for antihypertensive experiments, and 60 hypertensive patients were selected, including 30 males and 30 females, aged 35 to 75 years, with an average age of 45 years. 60 hypertensive patients took the final product IX once a day, 10 mg once, and the total effective rate was 82%. Shows good potential antihypertensive effects.

technical field

[0001] The invention relates to a synthesis method of a compound, in particular to a method for synthesizing a nitrendipine metabolite by a chemical method, and belongs to the field of drug metabolism. Background technique

[0002] Nitrendipine (nitrendipine) tablet is developed by Bayer (Bayer) pharmaceutical company in Germany, and is used for coronary heart disease and hypertension, especially patients suffering from these two diseases, and can also be used for congestive heart failure. The Chinese chemical name of nitrendipine: ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrobenzene)-3,5-pyridinedicarboxylate; English chemical name: 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethylmethyl ester; molecular formula: C17H15N2NaO7; molecular weight: 382.30; CAS registration number: 39562-70-4.

[0003] Nitrendipine, as a second-generation dihydropyridine compound, is a highly effective blocker of calcium ion channels in vascular s...

Examples

Embodiment 1

[0034] Embodiment 1 A kind of synthetic method of nitrendipine metabolite, it comprises the following steps:

[0035] Such as figure 1 Shown is the reaction flow diagram of the present invention:

[0036] Step (1): Take a 1-liter flask and add 750 ml of toluene (newly opened, AR), add 35 g of 4-(benzyloxy)-3-oxobutanoic acid ethyl ester (I), add 70 mL of 3-hydroxypropionitrile (II), react at 130°C for 10 hours. TLC (sampling, DCM dilution plate), the reaction of raw materials is complete. The reaction mixture was cooled to room temperature, 200ml of water was added to the reaction solution, directly shaken and separated, the organic phase was concentrated by rotary evaporation at 40°C and then purified by column chromatography (developing solvent: petroleum ether: dichloromethane = 100:1), and the pure The mobile phase was concentrated to obtain 32.70g of intermediate III with a yield of 88.49%.

[0037] 1H NMR (600MHz, CDCl3) δ7.36(m,5H),4.60(s,2H),4.29(t,2H),4.14(s,3H),3...

Embodiment 2

[0053] The antihypertensive effect of embodiment 2 end product IX

[0054] The end product IX nitrendipine metabolites were used for antihypertensive experiments, and 60 hypertensive patients were selected, including 30 males and 30 females, aged 35 to 75 years, with an average age of 45 years. 60 hypertensive patients took the final product IX once a day, 10 mg once, and the total effective rate was 82%. Shows good potential antihypertensive effects.

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