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Method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid

A technology of methylmethanesulfonamide group and methylmethanesulfonamide is applied in the field of pharmaceutical preparation, can solve the problems of complicated operation, high cost, unstable yield and the like, and achieves the effects of easy industrialization, simple operation and easy operation

Active Publication Date: 2011-10-19
SHANGHAI JINGXIN BIOLOGICAL MEDICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The preparation process of rosuvastatin has been reported in numerous documents and patents. Compound 4 (structural formula 4) is an important intermediate for preparing rosuvastatin calcium. Patent WO2002 / 098854 discloses the preparation of rosuvastatin calcium -6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-carbaldehyde and 2-[(4R,6S)-2,2-dimethyl-6-[ (1-phenyl-1H-1,2,3,4,-tetrazol-5-yl)methyl]-1,3-dioxane-4-carboxylate reacts to obtain the method of compound 4 , the step-by-step yield is better, but the process of docking the N-methylmethanesulfonamide and the pyrimidine ring first, and then connecting the side chain is complicated, and the overall yield is not ideal
Patent WO 2005 / 030758 and document J.M.C., 2008.Vol51.No.9, pp2722-2733 disclose another preparation method, but the yield of this method is extremely unstable, and a large amount of by-products are easily produced in the reaction, which is difficult for industrial production
[0006] In summary, the above-mentioned preparation method has the defects of complicated operation, time-consuming, unstable yield and high cost.

Method used

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  • Method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid
  • Method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid
  • Method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] In a 1000mL three-neck flask, add 15.0g of compound 1, 22.1 (1.05eq)g of compound 2, under argon protection, add 300mL of anhydrous tetrahydrofuran, cool to -60°C in a dry ice acetone bath, and drop 56mL of 1M hexamethyl The tetrahydrofuran solution of lithium disilazide was added, and the temperature was raised to room temperature 25° C. within 2 hours. Under the protection of argon, 4.1 g of 60% sodium hydrogen was added, and 7.62 g of N-methylmethanesulfonamide was added, and the reaction was carried out overnight. Under cooling, add 100mL ethyl acetate, 20mL saturated aqueous ammonium chloride solution, 20mL water, separate the liquids, extract the water phase with 200mL ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, 30°C The solvent was removed by rotary evaporation in a water bath to obtain the product (3R, 5S, E)-7-(2-(N-methylmethylsulfonamido)-4-(4-fluorophenyl)-6-isopropyl-pyrimidine- 5-yl)-2,2-...

Embodiment 2

[0024] In a 1000mL three-neck flask, add 15.0g of compound 1, 22.1g of compound 2, under argon protection, add 300mL of anhydrous tetrahydrofuran, cool to -60°C in a dry ice acetone bath, and add 70mL of 1M hexamethyldisilazylamine dropwise at this temperature Lithium base, after addition, rise to room temperature 25°C within 2 hours, under the protection of argon, add 3.73 grams of 60% sodium hydrogen and 10.16 grams of N-methylmethanesulfonamide, react overnight at 20-30°C, under cooling, add 100mL ethyl acetate, 20mL saturated aqueous ammonium chloride solution, 20mL water, separate the liquids, extract the aqueous phase with 200mL ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and remove by rotary evaporation in a water bath at 30°C. solvent to give the product (3R,5S,E)-7-(2-(N-methylmethylsulfonamido)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl) - tert-butyl 2,2-dimethyl-3,5-dioxane-6-heptenoate (18.95 g...

Embodiment 3

[0026] In a 1000mL three-neck flask, add 15.0g of compound 1, 22.1g of compound 2, under argon protection, add 300mL of anhydrous tetrahydrofuran, cool to -60°C in a dry ice acetone bath, add 6.52g of 60% sodium hydrogen in batches at this temperature After the addition is completed, the temperature rises to 20-30°C within 2 hours, and 10.16 g of N-methylmethanesulfonamide is added to react overnight at 20-30°C. Under cooling, add 100 mL of ethyl acetate, 20 mL of saturated ammonium chloride aqueous solution, and 20 mL of water , liquid separation, the aqueous phase was extracted with 200mL ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation in a water bath at 30°C to obtain the product (3R, 5S, E)-7-( 2-(N-Methylmethanesulfonamido)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl)-2,2-dimethyl-3,5-dioxo tert-butyl hexacyclo-6-heptenoate (18.31 g, yield: 68.1...

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Abstract

The invention relates to a method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid (compound shown by a formula 4) which is an important intermediate of Rosuvastatin Calcium in a one-pot way. The method comprises the steps of adding a compound in the formula 1 and a compound in the formula 2 into a solvent under protection of dried inert gas, adding a certain amount of strong base at minus 60 DEG C, then slowly increasing temperature to room temperature, supplementing the strong base after a compound in the formula 3 is completely produced, adding N-methylsulphonylamino, and reacting to produce a compound in the formula 4 at the room temperature. The method is stable in yield and easy to operate, and provides a method for preparing Rosuvastatin, and the method has lower cost, is simplified for operation and easy for industrialization. The formula 1, 2, 3, and 4 are shown in the description, wherein R1 is shown in description, and R2 is alkyl, naphthenic base or benzyl, and preferably methyl, ethyl or tertiary butyl.

Description

technical field [0001] The invention relates to the preparation of medicines, in particular to a one-pot method for preparing an important intermediate of rosuvastatin calcium (3R, 5S, E)-7-(2-(N-methylmethylsulfonyl)-4-(4 -Fluorophenyl)-6-isopropyl-pyrimidin-5-yl)-2,2-dimethyl-3,5-dioxane-6-heptenoate method. Background technique [0002] As a new type of lipid-lowering drug, rosuvastatin was first approved for marketing in the Netherlands in November 2002. It was approved by the US FDA in August 2003. It was approved and launched in my country in 2006. It is currently on the market in more than 60 countries. , is the most widely used statin drug. Its structural formula is 5 (compound 5): [0003] [0004] [0005] The preparation process of rosuvastatin has been reported in numerous documents and patents. Compound 4 (structural formula 4) is an important intermediate for preparing rosuvastatin calcium. Patent WO2002 / 098854 discloses the preparation of rosuvastatin c...

Claims

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Application Information

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IPC IPC(8): C07D405/06
Inventor 徐锋黄悦王光强张凯毅洪赟飞龚汉芳金彩芬
Owner SHANGHAI JINGXIN BIOLOGICAL MEDICAL
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