Preparation method of high-purity statin drug intermediate

A high-purity, intermediate technology, applied in the field of pharmaceutical intermediates, can solve the problems of long synthesis route, high risk and high activity, and achieve the effects of mild reaction conditions, low environmental pollution and high ee value

Inactive Publication Date: 2017-08-04
南京大学淮安高新技术研究院 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] But this method synthetic route is long, and method is complicated; The n-butyllithium reagent that adopts in the last step wittig reaction, activity is higher and the risk of operation is higher, and reaction condition is difficult to control, and product yield is not high, and is harmful to environment friendly, not suitable for industrial production

Method used

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  • Preparation method of high-purity statin drug intermediate
  • Preparation method of high-purity statin drug intermediate
  • Preparation method of high-purity statin drug intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: Provide the preparation method of 3-tert-butyldimethylsiloxy glutaric anhydride (J1), its steps are as follows:

[0030] (1) Add 20.4g (0.3mol) of imidazole and 75g of dichloromethane into the flask, stir and dissolve, add 20g (0.13mol) TBDMSCl, and stir for 30min; drop in 20.4g (0.1mol) of J0- 1. React at room temperature for 18 hours; wash the reaction mixture with 5 g of water, and then wash with saturated saline three times; concentrate under reduced pressure below 40°C to obtain 40 g of a light yellow liquid, namely J0-2, distill out dichloromethane and use it directly;

[0031] (2) Put 80g methanol, 12g (0.3mol) NaOH, and 1.8g water into a 200mL three-necked flask, stir to dissolve, cool down to room temperature, add dropwise a solution of J0-2 oil (0.1mol) and 16g anhydrous methanol, and keep The temperature was 20-30°C, followed by TLC, and the reaction was complete; the temperature was lowered in frozen brine, and stirred for 2 hours below 10°C; f...

Embodiment 2

[0033] Embodiment 2: Provide the preparation method of (3R)-3-tert-butyldimethylsilyloxy-glutaric acid, 1-[(R)-mandelic acid] ester (J3), the steps are as follows:

[0034] (1) Add 36g tetrahydrofuran to the three-necked flask, cool down to -25°C, add 6.7g (0.025mol, 2.5mol / L) of n-butyllithium, and keep warm for 10 minutes; continue to cool down to below -40°C, drop 5.5g (0.026mol) hexamethyldisilazane and 5g tetrahydrofuran solution, add and keep warm for 20 minutes;

[0035] (2) Continue to cool down to below -60°C, add 6.1g (0.0252mol) of benzyl mandelate and 18g of tetrahydrofuran dropwise, and control the temperature at -60°C to -90°C during the dropwise addition. To below -80°C, add J1 (4g, 0.016mol) and tetrahydrofuran 18g solution dropwise, and keep warm for 2h after dropping;

[0036] (3) add acid to neutralize, separate layers, wash with water to neutrality, and obtain J2 reaction solution;

[0037] (4) J2 reaction solution is dropped in the hydrogenation kettle, ...

Embodiment 3

[0038] Embodiment 3: Provide the preparation method of (3R)-3-tert-butyldimethylsilyloxy-glutaric acid monomethyl ester (J4), its steps are as follows:

[0039](1) Add anhydrous potassium carbonate 8g (0.058mol), anhydrous methanol 32g, N 2 Protect and lower the temperature, add J3 5g (0.0126mol), control the reaction temperature not to exceed 28°C, and stir overnight;

[0040] (2) After the reaction is completed, the reaction solution is dropped into a reaction flask equipped with 10 g of ice, 50 g of dichloromethane, and 13 g of concentrated hydrochloric acid under stirring conditions, and the pH is adjusted to 2. The layers are left to stand, and the water organic layer is washed with water, and the TLC is sampled. Determine that the mandelic acid generated by the reaction is completely removed;

[0041] (3) add 5g of anhydrous magnesium sulfate to dry, suck and filter, the filter cake is washed with dichloromethane, concentrated under reduced pressure, and evaporated to d...

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PUM

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Abstract

The invention relates to a preparation method of a high-purity statin drug intermediate. The preparation method is characterized in that 3-hydroxyl ethyl glutarate is used as the initial raw material to prepare (3R)-tert-butyl dimethyl silyloxy-5-oxo-6-triphenyl phosphine caproate (abbreviated as J6) through substitution reaction, hydrolysis reaction, cyclization reaction, resolution reaction, hydrogenation reaction, acylation reaction and Wittig reaction. The preparation method is mild in condition, stable in process, cheap in raw material, easy in raw material obtaining, easy in three-waste treatment, low in preparation cost, high in product purity and suitable for industrial production.

Description

technical field [0001] The invention relates to a drug intermediate, in particular to a preparation method of a high-purity statin drug intermediate. Background technique [0002] Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which control the synthesis of cholesterol through the liver, so as to achieve the effect of lowering blood lipids. Rosuvastatin and pitavastatin are new drugs that have been launched in recent years. They are known as "super statins" due to their multiple advantages such as good therapeutic effect, less administration, strong patient tolerance and high safety. Pitavastatin calcium and rosuvastatin calcium have the same chiral side chain (3R)-tert-butyldimethylsilyloxy-5-oxo-6-triphenylphosphonene hexanoate (abbreviated as J6) , so the synthesis of J6 is particularly important. [0003] Literature (J.Org.Chem.Vol.59, No.25, 7849-7854, 1994) discloses the method for preparing J6 with acid anhydride compounds as raw materials, ...

Claims

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Application Information

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IPC IPC(8): C07F9/535
CPCC07F9/5352
Inventor 沈洪春何闻毛苏雅
Owner 南京大学淮安高新技术研究院
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