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Method for synthesizing rosuvastatin calcium intermediate impurity

A technology of rosuvastatin calcium and a synthesis method, which is applied in the field of chemical pharmacy to achieve the effects of strengthening control, cheap raw materials, and improving accurate positioning and characterization

Inactive Publication Date: 2018-06-22
江苏悦兴医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

After searching, there is no bibliographical report about the synthesis of this impurity, therefore, it is of great practical significance to provide a synthetic method of the impurity of rosuvastatin calcium intermediate for the preparation of impurity standard

Method used

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  • Method for synthesizing rosuvastatin calcium intermediate impurity
  • Method for synthesizing rosuvastatin calcium intermediate impurity
  • Method for synthesizing rosuvastatin calcium intermediate impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Preparation of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl)amino]pyrimidine-5-methanol (3)

[0016]

[0017] Add 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl)amino]pyrimidine-5-carboxylic acid methyl ester (2) to a 1000ml three-necked flask (95.4g, 0.25mol), methanol 477ml, start stirring, add sodium borohydride (23.7g, 0.625mol) in batches at room temperature, after the addition, slowly heat up to reflux and stir the reaction, point TLC to detect, it is found that the reaction 4h raw materials disappeared. After the reaction is over, cool down to 0~10℃, add 20% dilute hydrochloric acid dropwise to adjust the system pH=4~5, filter by suction, and concentrate by the hydraulic pressure until almost no distillate flows out. Add 500ml dichloromethane and 300ml purified water to the residue and stir. Separate the liquids, wash the organic phase with 300 ml purified water once, collect the organic phase, concentrate under reduced pressure to dr...

Embodiment 2

[0020] Preparation of (5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine (4)

[0021]

[0022] Add 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl)amino]pyrimidine-5-methanol (3) (70g, 0.2mol) and 420ml of dichloromethane, cooled to 0-10°C in an ice bath with stirring, dropwise add phosphorus tribromide (59.0g, 0.22mol) to the reaction system, stirred for 1h, and TLC detected the completion of the reaction. Add 250ml of water and stir to separate the liquids. Wash the organic layer with 200ml of 8% sodium bicarbonate solution and 200ml of purified water respectively. Collect the organic phase and concentrate to dryness under reduced pressure. Add 200ml of petroleum ether to the residue to be slurried at room temperature for 2h, and filter. The filter cake was dried to obtain 75.4 g of the compound (4) with a yield of 90.6%. HPLC detected 98.9%.

[0023] 1 HNMR (600MHz, DMSO-d6, δppm): 7.82 (m, 2H), 7.25 (m, 2H), 4.51 (s, 2H), 3...

Embodiment 3

[0025] N,N'-(5,5'-(oxybis(methylene))bis(4-(4-fluorophenyl)-6-isopropylpyrimidine-5,2-diyl))bis(N -Methanesulfonamide) (1) Preparation

[0026]

[0027] Add (5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine (4) (70g, 0.17mol), 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl)amino]pyrimidine-5-methanol (3) (63.6g, 0.18 mol), potassium carbonate (47.0g, 0.34mol) and toluene 560ml, stir, stir and heat to reflux reaction for 12h, TLC test the end of the reaction, use 20% dilute hydrochloric acid to adjust the system pH = 6-7, suction filter, filter cake add 420ml methanol Recrystallization, filtration and drying to obtain 95.4 g of the target product (1) with a yield of 82.4%, 99.2% by HPLC.

[0028] 1 HNMR (600MHz, DMSO-d6, δppm): 7.80 (m, 4H), 7.24 (m, 4H), 4.50 (s, 4H), 3.56 (s, 6H), 3.46 (s, 6H), 1.42 (d, 12H).

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Abstract

The invention discloses a method for synthesizing a rosuvastatin calcium intermediate impurity. The method comprises the following steps: preparing 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine-5-methanol (3) from 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine-5-methyl carboxylate (2) through reduction; preparing 5-(bromine methyl)-4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidine (4) from the compound (3) through bromination; coupling the compound (4) with the 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine-5-methanol (3) to generate N,N'-(5,5'-(oxo-di(methylene)) bi(4-(4-fluorophenyl)-6-isopropyl pyrimidine-5,2-di-yl)) bi(N-methyl methanesulfonamide) (1), so as toobtain the rosuvastatin calcium intermediate impurity with high impurity. The synthesized rosuvastatin calcium intermediate impurity can be used as an impurity standard substance in rosuvastatin calcium raw material detection and analysis, and accurate positioning and qualification of impurities in rosuvastatin calcium raw material detection and analysis can be improved; the method disclosed by the invention is cheap and easy in raw material obtaining and simple in operation, the product yield is 65+ / -5%, and the HPLC (High Performance Liquid Chromatography) purity is greater than or equal to99%.

Description

Technical field [0001] The invention belongs to the technical field of chemical pharmacy, and specifically relates to a rosuvastatin calcium intermediate impurity N,N'-(5,5'-(oxybis(methylene))bis(4-(4-fluorophenyl) )-6-isopropylpyrimidine-5,2-diyl)) bis(N-methylmethanesulfonamide) synthesis method. Background technique [0002] Rosuvastatin calcium is an anti-hyperlipidemia drug, a HMG-CoA reductase inhibitor, suitable for primary hypercholesterolemia (type Ⅱa, including heterozygous familial hypercholesterolemia) or mixed lipids Adjuvant treatment for patients with blood disorders (type IIb) when dieting or exercise therapy is not ideal; this product can reduce elevated LDL-cholesterol, total cholesterol, triglycerides and ApoB, and increase HDL-cholesterol; also suitable for homozygous Patients with familial hypercholesterolemia can be used alone or in conjunction with diet or other lipid-lowering methods (such as LDL removal). Rosuvastatin calcium is the statin with the str...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 郑剑波翟富民花海堂包华兰石文革
Owner 江苏悦兴医药技术有限公司
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