Method for preparing 4,5,6,7-tetrahydromevastatin and sodium salt thereof, and solid crystallization way

A technology of pravastatin sodium and pravastatin, which is applied in the field of preparation 4, can solve the problems of long hydrogenation reaction time, long synthesis steps, and low overall yield, and achieve simplified synthesis technology, simple preparation and operation, and improved yield Effect

Active Publication Date: 2009-01-21
LIVZON NEW NORTH RIVER PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The object of the present invention is to be able to overcome the deficiencies in the prior art such as long synthesis steps, complex reactions, low overall yield, especially long hydrogenation reaction time, etc., and provide a synthetic 4H-Praval with high yield and simple operation. Method and novel catalyst for statin and its sodium salt

Method used

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  • Method for preparing 4,5,6,7-tetrahydromevastatin and sodium salt thereof, and solid crystallization way
  • Method for preparing 4,5,6,7-tetrahydromevastatin and sodium salt thereof, and solid crystallization way
  • Method for preparing 4,5,6,7-tetrahydromevastatin and sodium salt thereof, and solid crystallization way

Examples

Experimental program
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Effect test

Embodiment 1

[0033] The preparation of 8% Pd-carbon nanotubes refers to the methods in the literature (Feng Peng, Lei Zhang, Hongjuan Wang, Ping Lv, Hao Yu, Carbon, 2005, 43, 2405-2408). Add 1.3g of multi-walled carbon nanotubes into 70ml of concentrated sulfuric acid, 2 Reflux at 250°C for 20 hours under airflow, then filter and wash until no sulfate ions are detected, neutralize with NaOH solution and wash until no sodium ions are detected, then add to the solution containing PdCl 2 in the aqueous solution, stirred overnight, filtered, washed with deionized water, dried at 120°C for 12 hours, and passed H2 at 80°C for 12 hours to obtain 1.18g of 8% Pd-carbon nanotubes.

Embodiment 2

[0035]4,5,6, the preparation of 7-tetrahydropravastatin (I):

[0036] Add 2.0g of pravastatin (4.93mmol) and 200ml of ethanol to a 500ml three-necked flask, stir to dissolve, add 0.1g of 10% Pd-C, pass in hydrogen at 120°C and 4mpa until no hydrogen is absorbed, react for about 100min, filter , concentrated to obtain 4,5,6,7-tetrahydropravastatin (I) crude product as a colorless oil 1.84g, yield 91%.

[0037] MS (ESI) m / z: 433.3 (M+Na) + ; 1 H-NMR (CD 3 COCD 3 , 400MHz) δ: 5.20(s, 1H, 13-H), 4.51(s, 1H, 1-H), 4.24(s, 1H, 16-H), 3.76(s, 1H, 3-H), 2.60 -2.54(q, 3H, 15-2H, 20-H), 1.91(m, 3H, 17-2H, 10-H), 1.15(m, 5H, 23-CH 3 , 11-2H), 0.86(t, 3H, J=7.6Hz, 18-CH 3 ), 0.76(t, 3H, J=6.8Hz, 22-CH 3 ); 13 C-NMR (CDCl 3 , 100MHz) δ: 176.1, 170.8, 76.4, 70.0, 65.9, 62.2, 43.0, 42.8, 41.6, 39.7, 39.5, 38.4, 35.9, 35.4, 32.8, 32.5, 28.7, 27.8, 26.5, 24.5, 16.7, 11.6, 11.5 .

Embodiment 3

[0039] 4,5,6, the preparation of 7-tetrahydropravastatin (I):

[0040] Add 2.0g of pravastatin (4.93mmol) and 200ml of ethanol to a 500ml three-necked flask, stir to dissolve, add 0.1g of 8% Pd-carbon nanotubes, feed hydrogen at 120°C and 4mpa until no more hydrogen is absorbed, and react for about 110min , filtered, and concentrated to obtain 1.92 g of crude 4,5,6,7-tetrahydropravastatin (I) as a colorless oil, with a yield of 95%. The spectrum shown in the sample is consistent with the spectrum obtained in Example 2.

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Abstract

The invention relates to a novel method with easy operation for making 4,5,6,7-tetrahydro pravastatin (I) and the sodium salt (II) thereof. The method comprises a one-step deoxidization with pravastatin and sodium pravastatin as starting raw materials respectively to produce 4,5,6,7-tetrahydro pravastatin (I) and 4,5,6,7-tetrahydro pravastatin sodium, and particularly adopts a novel homemade Pd-nanometer tube, thereby overcoming the disadvantages in the prior art including long synthesis procedures, complicated reaction, low total yield and long hydrogenation period, dramatically lowering the production cost, and being greatly suitable for industrialized production. The invention also relates to the method for preparing the solid crystal of 4,5,6,7-tetrahydro pravastatin (I) and the sodium salt (II) thereof.

Description

technical field [0001] The present invention relates to a kind of preparation 4,5,6,7-tetrahydropravastatin and its sodium salt method, the present invention also relates to a kind of solid crystal 4,5,6,7-tetrahydropravastatin and its The preparation method of sodium salt. Background technique [0002] Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, fluvastatin, cerivastatin and their derivatives and analogs are known as HMG-CoA reductase inhibitors and are used as Antihypercholesterolemic drugs are widely used in clinical practice. [0003] For example, it has been reported in the literature that the conjugated double bond in the naphthalene ring structure in pravastatin is reduced and 2H-pravastatin generated by two hydrogens has the effect of inhibiting cholesterol synthesis in the liver, and can be used for hypercholesterolemia and atherosclerosis For the treatment of cirrhosis, the study also pointed out that 2H-pravastatin is more difficult to metabo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/30C07C69/22C07C69/013C07C67/283
Inventor 张雷李环李晶邱科先
Owner LIVZON NEW NORTH RIVER PHARMA
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