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New method of pitavastatin calcium key intermediate

A technology for pitavastatin calcium and intermediates, which is applied in the field of preparation of key intermediates of pitavastatin calcium by highly active organic zinc reagents, and can solve the problems of low yield, difficult separation and purification, and many Z-isomer residues. Achieve the effect of high configuration purity, simple purity, and mild reaction conditions

Active Publication Date: 2014-04-02
北京华禧联合科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The present invention aims at the above-mentioned deficiencies existing in the prior art, provides a kind of preparation method of the key intermediate of pitavastatin calcium, solves the problem that the existing Z-form isomer of pitavastatin calcium has many residues, great difficulty in separation and purification and relatively low yield. low technical issues

Method used

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  • New method of pitavastatin calcium key intermediate
  • New method of pitavastatin calcium key intermediate
  • New method of pitavastatin calcium key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Preparation of lithium naphthalene reagent:

[0030] Under the protection of nitrogen, metal lithium (0.4 g, 60 mmol) was added to anhydrous naphthalene (2.6 g, 20 mmol), and stirred at 20-25° C. for 2 h to obtain lithium naphthalene reagent.

[0031] The preparation of organic zinc reagent (Ⅲ), reaction formula is as follows:

[0032]

[0033] Operation steps: under the protection of nitrogen, add compound (II) (10.7g, 30mmol) and 50ml of anhydrous tetrahydrofuran to a 250ml reaction flask, stir and cool to 10-20°C, add zinc bromide (13.5g, 60mmol) in batches , stirred for 10 minutes, added dropwise the above naphthalenelithium reagent, after the reaction temperature was stabilized, heated to reflux (65-75°C), and stirred for 5-6h. The resulting reaction solution is the organozinc reagent (Ⅲ).

[0034] The preparation of compound (I), reaction formula is as follows:

[0035]

[0036] Operation steps: add K to the organozinc reagent (Ⅲ) 2 CO 3 (12.4g, 90mmol)...

Embodiment 2

[0040] The preparation of organic zinc reagent (Ⅲ), reaction formula is as follows:

[0041]

[0042] Operation steps: under the protection of nitrogen, add compound (II) (10.7g, 30mmol) and 50ml of anhydrous tetrahydrofuran into a 250ml reaction flask, stir and cool to 10-20°C, add zinc bromide (13.5g, 60mmol), stir For 10 minutes, lithium metal (0.4 g, 60 mmol) was added in batches, and after the reaction temperature stabilized, it was heated to reflux (65-75° C.), and stirred for 5-6 hours. The resulting reaction solution is the organozinc reagent (Ⅲ).

[0043] The preparation of compound (I), reaction formula is as follows:

[0044]

[0045] Operation steps: Add potassium carbonate (12.4g, 90mmol) to organozinc reagent (Ⅲ), stir at 0-10°C under temperature control; dissolve compound (Ⅳ) (7.8g, 30mmol) in tetrahydrofuran (15ml) and stir to dissolve and clarify , drop into the above-mentioned organozinc reagent (Ⅲ), about 0.5h drop. The temperature was raised to 25-...

Embodiment 3

[0049] Preparation of lithium naphthalene reagent:

[0050] Under the protection of nitrogen, metal lithium (0.4 g, 60 mmol) was added to anhydrous naphthalene (2.6 g, 20 mmol), and stirred at 20-25° C. for 2 h to obtain lithium naphthalene reagent.

[0051] The preparation of organic zinc reagent (Ⅲ), reaction formula is as follows:

[0052]

[0053] Operation steps: under the protection of nitrogen, add compound (II) (10.7g, 30mmol) and 50ml of anhydrous tetrahydrofuran into a 250ml reaction flask, stir and cool to 10-20°C, add zinc bromide (13.5g, 60mmol) in batches , stirred for 10 minutes, added dropwise the above naphthalenelithium reagent, after the reaction temperature was stabilized, heated to reflux (65-75°C), and stirred for 5-6h. The resulting reaction solution is the organozinc reagent (Ⅲ).

[0054] The preparation of compound (I), reaction formula is as follows:

[0055]

[0056] Operation steps: add K to the organozinc reagent (Ⅲ) 2 CO 3 (12.4g, 90mmo...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of a pitavastatin calcium key intermediate. The method comprises a step of preparing an organic zinc reagent by using high-activity zinc and 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline methylene bromide. The organic zinc reagent generates a Witting reaction with (3R, 5S)-6-oxo-3,5-dihydroxyl-3,5-O-isopropylidene tert-butyl caproate to generate (3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolone-3-yl]-3,5-dihydroxyl-3,5- O-isopropylidene-6-tert-butyl heptenate which is recrystallized to obtain the pitavastatin calcium key intermediate. The synthesis method provided by the invention has the characteristics of high purity of E construction, simple process, high yield and the like.

Description

technical field [0001] The invention relates to a new method for preparing a key intermediate of pitavastatin calcium with a highly active organic zinc reagent. Background technique [0002] Pitavastatin calcium is an HMG-CoA reductase inhibitor and a blood lipid-lowering drug. Pitavastatin Calcium was developed by Nissan Chemical Industry Co., Ltd., Japan, and was launched in Japan in July 2003. It is used for the treatment of hypercholesterolemia. The trade name is "LIVALO", and the preparation specifications are film-coated tablets of 1 mg and 2 mg. . [0003] [0004] After searching the prior art, in the patent EP304063, E-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline-2-propenal was docked with ethyl acetoacetate After reduction, resolution and salt formation, pitavastatin calcium is obtained. The method has long steps and harsh process, and first docks and then splits, and screens one of the four optical isomers to form a salt, and the yield is very low. [00...

Claims

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Application Information

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IPC IPC(8): C07D405/06
CPCC07D405/06
Inventor 张家亮庄伟平毕华
Owner 北京华禧联合科技发展有限公司
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