Intermediate for preparing rosuvastatin and preparation method and application thereof

A technology for rosuvastatin and its uses, which is applied in chemical instruments and methods, compounds of elements of Group 5/15 of the periodic table, compounds of elements of Group 4/14 of the periodic table, etc., can solve serious corrosion of equipment, separation and purification Difficulty, long reaction steps and other problems, to achieve the effect of improving total yield, high reaction yield and short reaction steps

Active Publication Date: 2012-07-18
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] The purpose of the present invention is to overcome the disadvantages of the reagents used in the above-mentioned prior art, such as high toxicity, severe equipment corrosion, difficult separation and purification, long reaction steps, and difficulty in industrialization, and provide a new intermediate compound for the preparation of rosuvastatin and related preparation methods

Method used

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  • Intermediate for preparing rosuvastatin and preparation method and application thereof
  • Intermediate for preparing rosuvastatin and preparation method and application thereof
  • Intermediate for preparing rosuvastatin and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Embodiment 1: the preparation of formula 2-1 compound

[0065]

[0066] In a 500ml three-necked flask equipped with a thermometer, nitrogen atmosphere and a constant pressure dropping funnel, add iodine (66g, 260mmol), 100ml of dichloromethane, stir at room temperature, dropwise add hexamethyldisilane (40g, 280mmol), dropwise After completion, keep stirring at 15-30°C for 30 minutes, raise the temperature to 45-70°C and react for 2-4 hours until the system becomes colorless and clear, cool to -20-0°C, add R-epichlorohydrin (36g, 400 mmol) of dichloromethane solution, stirred at this temperature for 3 to 10 hours after the dropwise addition, and evaporated to dryness to obtain 110 g of the compound shown in Formula 2-1 as a slightly yellowish liquid with a yield of 98%.

[0067] 1 HNMR (400MHz, CDCl 3 ): δ=0.190 (S, 9H), δ=3.26-3.298 (dd, 1H, J=4.8, 10.4Hz), δ=3.322-3.362 (dd, 1H, J=4.8, 10.4Hz), δ=3.518 -3.601 (m, 2H), δ=3.753-3.806 (m, 1H).

[0068] MS(EI+): 292...

Embodiment 2

[0069] Embodiment 2: the preparation of formula 2-2 compound

[0070]

[0071] In a 500ml three-necked flask equipped with a thermometer, nitrogen atmosphere and a constant pressure dropping funnel, add iodine (66g, 260mmol), 100ml of dichloromethane, stir at room temperature, dropwise add hexamethyldisilane (40g, 280mmol), dropwise After completion, keep stirring at 15-30°C for 30 minutes, raise the temperature to 45-70°C and react for 2-4 hours until the system becomes colorless and clear, cool to -20-0°C, add R-epibromopropane (54g, 394mmol) of dichloromethane solution, stirred at this temperature for 2.5 to 12 hours after the dropwise addition, and evaporated to dryness to obtain 127g of the compound shown in formula 2-2 as a light yellow liquid with a yield of 96%.

[0072] MS(EI+): 338[M+], 336[M+].

Embodiment 3

[0073] Embodiment 3: the preparation of formula 3-1 compound

[0074]

[0075] Equip a 500ml single-necked bottle with a stirrer, add the compound of formula 2-1 (110g, 400mmol), triphenylphosphine (20g, 75mmol), heat up to 70-90°C and stir for 10-15 hours, cool, add 50-200ml of toluene , filtered, and the filtrate can be reused after precipitation. The filter cake was washed with 20-50 ml of toluene and dried to obtain 28 g of the compound shown in Formula 3-1 as a yellowish solid with a yield of 90%.

[0076] 1 HNMR (400MHz, DMSO): δ=0.289(S, 9H), δ=3.766-3.841(m, 2H), δ=3.847-3.941(m, 1H), δ=4.172-4.220(m, 1H), δ =4.260-4.355 (m, 1H).

[0077] MS(EI+): 554[M+].

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Abstract

The invention relates to the technical field of heterocyclic chemistry, particularly relates to the technical field of the heterocyclic chemistry containing 1,3-diazine cyclic, specifically relates to an intermediate for preparing rosuvastatin and a preparation method and application. An intermediate compound for preparing the rosuvastatin has the following structure as shown in the formula (A), wherein X is halogen, R1 is hydrogen or trimethyl silane, R2 is iodine methyl or a group with the structure in the following formula.

Description

technical field [0001] The invention relates to the technical field of heterocyclic chemistry, in particular to the technical field of heterocyclic chemistry containing 1,3-diazine ring. Background technique [0002] Rosuvastatin Calcium (Rosuvastatin Calcium), chemical name: (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl -N-methylsulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-calcium heptenoate, its structural formula is as follows: [0003] [0004] The drug was developed by the Japanese company Shionogi (Osaka Shionogi), and was transferred to the British company Zeneca in April 1998, and it was named rosuvastatin. In February 1999, the Phase I, Phase IIa and Phase IIb clinical verification of the drug was completed in the United States, and Phase III clinical verification was accelerated. In December 2000, AstraZeneca designated the trade name of rosuvastatin as Crestor. From the perspective of its existing clinical verification results and comparison ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42C07F9/54C07F7/18
Inventor 朱国良张斌高红军车大庆
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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