Method for preparing solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate

A technology of tert-butyl acetate and 4r-cis, applied in the field of medicine and chemical industry, can solve problems such as difficult separation, storage, purification and purification, etc., and achieve the effects of simple operation, saving man-hours, and reducing costs.

Active Publication Date: 2016-04-20
VALIANT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the methods reported in the literature all have deficiencies. The method conditions are relatively harsh or the obtained product is oily, and the product has low purity and is not easy to store.
[0015] For example, "Preparation of hypocholesterolemic and hypolipidemic N-alkylpyrroles as HMGCo-Areductase inhibitors" whose publication number is WO2005056004A1 in the world, "A kind of (4R-cis)-6-formyl-2,2-dimethyl-1 , the synthetic method of 3-dioxane-4-acetic acid tert-butyl ester", the Swern oxidation method reported in "The method for preparing pitavastatin calcium bulk drug by asymmetric hydrogenation" whose Chinese invention patent authorization announcement number is CN101386592B, using The dimethyl sulfoxide/oxalyl chloride/triethylamine reaction system requires low temperature of -78°C and anhydrous operation. The reaction conditions are harsh, and dimethyl ether is formed, which has a foul smell and is not easy to remove. Moreover, the obtained product is oily and contains unremoved Dimethyl sulfoxide, affecting subsequent reactions
[0016] For example, the World Invention Patent Application Publication No. WO20081059519A "Process for the preparation of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-Nmethyl-sulfonylamino)-5-pyrimidinecarboxaldehydeandtert-butyl2-[(4R,6S)-6- formyl-2,2-dimethyl-1,3-dioxan-4-yl]-acetate,keyintermediatesofrosuvastatin" and the Chinese invention patent application publication number is CN102617540A "(S)-3,6-dioxo-5,6-di The pyridine sulfur trioxide complex oxidation method reported in "Preparation method of tert-butyl hydroxyhexanoate", the pyridine sulfur trioxide complex is highly corrosive, has high requirements for production equipment, and reacts violently with water, hydrolyzes into a strongly acidic pyridinium salt, which is not conducive to the maintenance of equipment
[0017] For example, the "Preparation Method of (3R,5S)-3,5-Dihydroxy-6-oxohexanoic Acid Ester Derivatives", whose publication number is CN101747313A, uses the TEMPO/NaBr/TCCA method to generate hydrochloric acid during the reaction pro

Method used

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  • Method for preparing solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate
  • Method for preparing solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate
  • Method for preparing solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The preparation method of the solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester of this embodiment comprises the following steps:

[0050] (1) Dissolve 60.0g (0.198mol) of compound III in a mixed solvent of 360.0g methanol and 36.0g water, add 5.5g (0.0396mol) potassium carbonate, stir at 0°C for hydrolysis reaction, follow the reaction by GC, and complete the reaction (Compound III is less than <0.1%), remove potassium carbonate by filtration, rinse the filter cake with 20g of methanol, spin evaporate (45°C,-0.09Mpa) to remove the methanol in the filtrate, then add 480g of toluene to dissolve, wash with 200g×3 water, The toluene solution of compound II was obtained as a light yellow clear solution with a GC purity of 99.3%, which was directly used in the next oxidation reaction;

[0051] The structural formula of compound III is as follows:

[0052]

[0053] The structural formula of compound II is as follows:

[0054]

[0055] (2)...

Embodiment 2

[0060] The preparation method of the solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester of this embodiment comprises the following steps:

[0061] (1) 60.0g (0.198mol) compound III is dissolved in the mixed solvent of 480.0g methanol and 24.0g, adds 13.7g (0.0991mol) potassium carbonate, stirs at 15 ℃ and carries out hydrolysis reaction, GC tracking reaction, reaction complete ( Compound III is less than < 0.1%), remove potassium carbonate by filtration, rinse the filter cake with 20g methanol, spin evaporate (45°C, -0.09Mpa) to remove methanol in the filtrate, then add 600g dichloromethane to dissolve, wash with 200g×3 , the dichloromethane solution of compound II was obtained, which was a light yellow clear solution with a GC purity of 99.5%, which was directly used in the next oxidation reaction;

[0062] The structural formula of compound III is as follows:

[0063]

[0064] The structural formula of compound II is as follows:

[0065] ...

Embodiment 3

[0071] The preparation method of the solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester of this embodiment comprises the following steps:

[0072] (1) Dissolve 60.0g (0.198mol) of compound III Compound III in a mixed solvent dissolved in 480.0g of methanol and 4.8g, add 27.4g (0.198mol) of potassium carbonate, stir at 30°C for hydrolysis reaction, and follow the reaction by GC , after the reaction is complete (compound III is less than <0.1%), remove salt of wormwood by filtration, rinse the filter cake with 20g methanol, evaporate the methanol of the gained filtrate, then add 600g dichloromethane to dissolve, after 200g × 3 washings, obtain compound II Dichloromethane solution, GC purity 99.4%, directly used in the next oxidation reaction;

[0073] The structural formula of compound III is as follows:

[0074]

[0075] The structural formula of compound II is as follows:

[0076]

[0077] (2) Add 0.15g (0.99mmol) TEMPO, 2.36g (0.0198mol) p...

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Abstract

The invention discloses a method for preparing solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate and belongs to the pharmaceutical and chemical field. The method includes the following steps that a compound III is dissolved in a mixed solvent of methanol and water, potassium carbonate is added for hydrolysis, potassium carbonate is filtered out and removed, methanol is removed through distillation, an organic solvent is added, and an organic solvent solution of a compound II is obtained after washing; secondly, TEMPO, potassium bromide and sodium bicarbonate are added, stirred, mixed and cooled, then a sodium hypochlorite solution is added dropwise, stirring reaction is carried out, after reaction, a sodium thiosulfate solution is quenched, washed, dried and condensed, and a crude product of a compound I is obtained; thirdly, an organic solvent is added, cooled and stirred after being heated and dissolved and is crystallized and filtered to obtain solid crystal of the compound I. The preparation method is safe, environmentally friendly, easy and convenient to operate, high in yield, high in purify and capable of facilitating large-scale production.

Description

technical field [0001] The invention relates to (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester in the solid state of synthetic intermediate of rosuvastatin calcium The preparation method belongs to the field of medicine and chemical industry. Background technique [0002] (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester is an important intermediate in the synthesis of the blood lipid-lowering drug rosuvastatin calcium, referred to as D7, CAS number: 124752-23-4, molecular formula: C 13 h 22 o 5 , molecular weight: 258.31, melting point: 58-60°C. [0003] Rosuvastatin calcium is a new type of HMG-CoA reductase inhibitor developed by AstraZeneca. It has a strong blood lipid lowering effect, and it is more powerful than other statins when used alone. It is called "super statin". Because rosuvastatin calcium has the advantages of strong lipid-lowering effect and less toxic and side effects, it will surely occupy an importa...

Claims

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Application Information

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IPC IPC(8): C07D319/06
CPCC07D319/06
Inventor 高健刘盛华孙蕊杜体建肖景超房立平
Owner VALIANT CO LTD
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