Method for synthesizing atorvastatin calcium intermediate by multi-component one-pot method

A kind of atorvastatin calcium, multi-component technology, applied in the one-pot synthesis of 4--2--3-phenyl-4-oxo-N-phenylbutanamide, multi-component one-pot method In the field of synthesizing atorvastatin calcium intermediates, it can solve the problems of high odor, high heat, irritation and corrosion.

Active Publication Date: 2020-11-10
ZHEJIANG HONGYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still many technical defects: (1) the smell is relatively large in the preparation process of phenylacetyl chloride, and high activity SOCl is used 2 As a chlorination reagent, a large amount of HCl and SO are produced during the reaction 2 Gas, acid waste gas is more, the environment is not friendly; (2) bromine atoms are first introduced in the process, and then bromine atoms are removed, and the atom economy is poor; (3) a large amount of acid gas HCl will also be produced in the Friedel-Crafts reaction process , the heat in the reaction quenching process is large, the risk of EHS is high, and there are more salty wastewater; (4) Although the process avoids the use of expensive metal catalysts, the use of bromine reagent liquid bromine has strong irritation and corrosion, and the environment unfriendly

Method used

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  • Method for synthesizing atorvastatin calcium intermediate by multi-component one-pot method
  • Method for synthesizing atorvastatin calcium intermediate by multi-component one-pot method
  • Method for synthesizing atorvastatin calcium intermediate by multi-component one-pot method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1: the preparation of formula III ligand

[0064] Preparation of Compound IV-1:

[0065]

[0066] 10 g of N-tert-butoxycarbonylaminocyclohexyl-2-carboxylic acid (41 mmol), 5.5 g of m-methoxyaniline (44.7 mmol, 1.08 eq) and 50 mL of dichloromethane were added to a 250 ml reaction flask. Stir and cool down to 0-10°C, then add 15.7g 1-propyl phosphoric acid cyclic anhydride (49mmol, 1.2eq), 1.5g 4-dimethylaminopyridine (12mmol, 0.3eq), 9.1g triethylamine (90mmol , 2.2eq). After the addition, keep the temperature at 0-10°C and stir the reaction for 8h. After the reaction, the reaction solution was concentrated to dryness under reduced pressure. Add 45mL of isopropanol to the concentrate and stir to make it clear, add dropwise 15mL of water, stir and crystallize at 0-10°C for 2h. After filtering, the filter cake was dried under reduced pressure at 35-45°C for 6-10 hours to obtain 13.6 g of compound IV-1. Yield 95.1%, HPLC purity 98.6%. ESI-MS: m / z 349.31[M+...

Embodiment 2

[0076] Embodiment 2: the preparation of formula III ligand

[0077] Preparation of Compound IV-2:

[0078]

[0079] 10 g of N-tert-butoxycarbonylaminocyclohexyl-2-carboxylic acid (41 mmol), 4.75 g of m-methylaniline (44.3 mmol, 1.08 eq) and 50 mL of dichloromethane were added to a 250 mL reaction flask. Stir and cool down to 0-10°C, add 17.3g 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (90mmol, 2.2eq), 1.5g 4-diimide hydrochloride to the reaction mixture Methylaminopyridine (12mmol, 0.3eq), 9.1g triethylamine (90mmol, 2.2eq). After the addition is complete, keep the temperature at 0-10°C and stir for 8 hours. After the reaction, the reaction solution was concentrated to dryness under reduced pressure. Add 45mL of isopropanol to the concentrate and stir to dissolve, add dropwise 15mL of water to the solution, and stir at 0-10°C for 2h. After filtering, the filter cake was dried under reduced pressure at 35-45°C for 6-10 hours to obtain 13.0 g of compound IV...

Embodiment 3

[0089] Embodiment 3: the preparation of formula III ligand

[0090] Preparation of compound IV-3:

[0091]

[0092] 10 g of N-tert-butoxycarbonylaminocyclohexyl-2-carboxylic acid (41 mmol), 6.05 g of m-dimethylaminoaniline (44.4 mmol, 1.08 eq) and 50 mL of dichloromethane were added to a 250 mL reaction flask. Stir the solution, cool the solution to 0-10°C, add 18.6g of dicyclohexylcarbodiimide (90mmol, 2.2eq), 1.5g of 4-dimethylaminopyridine (12mmol, 0.3eq), 9.1g of three Ethylamine (90mmol, 2.2eq). After the addition is complete, keep the temperature at 0-10°C and stir for 8 hours. After the reaction, the reaction solution was concentrated to dryness under reduced pressure. Add 45mL of isopropanol to the concentrate and stir to dissolve it, add dropwise 15mL of water to the solution, and stir and crystallize at 0-10°C for 2h. After filtration, the filter cake was dried under reduced pressure at 35-45°C for 6-10 hours to obtain 14.1 g of compound IV-3. Yield 95.3%, HP...

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Abstract

The invention provides a method for synthesizing an atorvastatin calcium intermediate by a multi-component one-pot method, and particularly provides a one-pot method for synthesizing 4-(4-fluorophenyl)-2-(2methylpropionyl)-3-phenyl 4-oxo-N-phenyl butyramide. The preparation method is characterized in that N-phenyl phenylpropiolamide, 4-fluorobenzaldehyde and isobutyraldehyde are synthesized by a one-pot method under the action of Cu(SbF6)2 and a Pd-ligand catalyst to obtain a target compound. The one-pot method conforms to the characteristics of green chemistry and high atom economy, and emission of three wastes and pollution factors is remarkably reduced; the reaction steps are short, and the yield (about 80-87%) is obviously higher than that of the technical scheme of the existing multi-step synthesis method; raw materials are easily available; the process operation is simple; the EHS risk is low; and the industrialized feasibility is high.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry and medicinal chemistry, and relates to a method for synthesizing an atorvastatin calcium intermediate in a multi-component one-pot method. More specifically, the present invention relates to the one-pot synthesis of 4-(4-fluorophenyl)-2-(2-methylpropionyl)-3-phenyl-4-oxo-N-phenylbutanamide . Background technique [0002] Atorvastatin Calcium (Atorvastatin Calcium), chemical name: bis{(3R,5R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl- 4-Anilinocarbonyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid} calcium salt trihydrate, an oral hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor drug, developed and successfully commercialized by Pfizer. The drug was first approved in the United States in February 1997 for the treatment of adult hypercholesterolemia. It reduces the levels of cholesterol and lipoproteins in plasma by inhibiting the synthesis of HMG-CoA reductase and choleste...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C235/80B01J31/22C07D273/04C07C239/18
CPCC07C231/12B01J31/1805C07D273/04C07C239/18B01J2531/824B01J2231/32C07C235/80
Inventor 汪海波梅光耀金辉况洪福张伟邱进富徐陈力刘战雨刘学晟
Owner ZHEJIANG HONGYUAN PHARMA
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