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Preparation method of amlodipine key intermediate

A technology of amlodipine and intermediates, which is applied in the field of drug synthesis, can solve the problems of high price of McBurney's acid, increased equipment investment, raw materials and solvent costs, "three wastes" treatment costs, etc., and achieves easy large-scale industrial production and low raw material prices. Inexpensive and easy-to-obtain raw materials

Active Publication Date: 2020-06-19
CHANGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] Compared with the method of the present invention, the disadvantage of the route reported by US6562983 is that McBurney's acid is expensive, and the unit price is 2.5 times that of monoethyl malonate potassium salt. In addition, the synthetic route has two more steps than the present invention, which means It is necessary to add two more sets of reaction and post-processing equipment, which increases equipment investment, raw materials, solvent costs and corresponding "three wastes" treatment costs

Method used

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  • Preparation method of amlodipine key intermediate
  • Preparation method of amlodipine key intermediate
  • Preparation method of amlodipine key intermediate

Examples

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Embodiment 1

[0032] The synthesis of embodiment 1,2-(2-(1,3-dioxoisoindoline-2-yl) ethoxy) acetaldehyde

[0033]

[0034] Add 39.7g of oxalyl chloride in dichloromethane solution (200mL) into a 500mL three-necked flask, cool to -60°C, slowly drop in 30.9g of DMSO in dichloromethane solution (50mL), keep stirring for 0.5 h, add dropwise 47.8g of 2-[2-(2-hydroxyethoxy)ethyl]isoindoline-1,3-dione in dichloromethane solution (100mL), and keep warm at -60°C 2h, then slowly drop 61g of triethylamine, keep warm for 0.5h, then naturally warm up to room temperature. Wash 3 times with 5% dilute sulfuric acid (the aqueous phases are combined to adjust to alkaline, dichloromethane extraction can recover triethylamine, the recovery rate> 98%), the organic phase is washed 2 times with saturated brine, and dried over anhydrous sodium sulfate , filtered, and the solvent was evaporated to dryness to obtain a pale yellow oil, which was directly used in the next reaction without further purification. 1 ...

Embodiment 2

[0041] Embodiment 2, the synthesis of (2-(1,3-dioxaisoindoline-2-yl)ethoxy)-3-oxabutanoic acid ethyl ester (1)

[0042]

[0043] Add 3.5g of stannous chloride in dichloromethane solution (20mL) into a 500mL three-necked flask, cool to 0°C, dissolve 20.9g of ethyl diazoacetate in dichloromethane solution (80mL), dropwise into the three-necked flask, keep warm and stir for 10min, add 42.4g of (2-phthalimideethoxy) acetaldehyde in dichloromethane solution (150mL) into the three-necked flask, naturally raise the temperature to 25°C and keep it warm until The reaction ended (TLC monitored the progress of the reaction). The reaction solution was washed successively with saturated brine and saturated sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered, 2 g of silica gel was added to the filtrate, stirred for 0.5 h, filtered, and the filtrate was evaporated to dryness to obtain a light brown oil. 1 H NMR (300MHz, CDCl 3 )δ7.88(d×d, J=6.0Hz, 3.0Hz, 2H), 7.75...

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Abstract

The invention discloses a preparation method of an amlodipine key intermediate, which relates to the field of drug synthesis. The preparation method comprises the following specific steps of reactinga compound 3 (2-(2-(2-hydroxyethoxy) ethyl) isoindoline-1, 3-diketone) with DMSO (dimethyl sulfoxide) and oxalyl chloride to obtain a compound 2 (2-(2-(1, 3-dioxaisoindoline-2-yl) ethoxy) acetaldehyde), then, enabling the compound 2 and ethyl diazoacetate to be subjected to a C-H bond insertion reaction under the catalysis of Lewis (Lewis) acid, and acquiring a compound 1 ((2-(1, 3-dioxaisoindoline-2-yl) ethoxy)-3-oxabutyrate). According to the preparation method, a NaH route commonly adopted in current production is avoided, the total yield is equivalent to that of the NaH route, and the rawmaterials are cheaper and easier to obtain, so that the safety and the production efficiency are greatly improved, the total cost is reduced by about 30%, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing a key intermediate of amlodipine. Background technique [0002] Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist) used for the treatment of various types of hypertension and angina pectoris. Amlodipine has the following three advantages: (1), low incidence of side effects; (2), has a long half-life, only needs to be taken once a day, which greatly improves patient compliance, and can ensure that the drug is administered within 24 hours. (3) Within the therapeutic dose range, it has a strong vasodilation effect, but it does not inhibit myocardial contractility like other conventional calcium antagonists. Therefore, in addition to being used in the treatment of hypertension and angina pectoris, It is very promising to be applied to the treatment of heart failure, which is not available in general calcium antagonists. [0003] The lite...

Claims

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Application Information

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IPC IPC(8): C07D209/48
CPCC07D209/48
Inventor 张跃严生虎辜顺林刘建武岳家委周晨涛朱佳慧李孟金
Owner CHANGZHOU UNIV
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