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

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...

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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 process. , causing the ketal protecting group to be easily hydrolyzed, affecting the yield and purity of the product

[0018] 如美国发明专利申请公开号为US20060004200A1的《Chemoselectivecatalyticoxidativeprocessestoproducealdehydegroup-containingintermediatesforrosuvastatinpreparation》、世界发明专利申请公开号为WO2011132172A1的《Processforpreparationofnovelintermediatesforrosuvastatin》、世界发明专利申请号为WO2011086584A2的《Processforpreparationofrosuvastatincalcium》、世界发明专利申请号为WO2010047296A的《 According to the TEMPO / NaBr / NaClO oxidation reported in NovelpyrimidinederivativeandmethodforproducingHMG-CoAreductaseinhibitorintermediate, the obtained compound Ⅰ has a low purity and is oily, leaving more compound Ⅱ. Compound Ⅰ and compound Ⅱ are difficult to separate, difficult to refine and purify, and difficult to store and easy to deteriorate

Chinese invention patent application announcement number is CN103502234A " 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl) tert-butyl acetate "Manufacturing method" reported the synthesis method of compound I in a solid state, but the product obtained was of low purity, and after being concentrated under reduced pressure by a water pump, it was in the form of oil, which could only be solidified after decompression and drying by an oil pump, and the obtained product was a yellow-white solid. The purity can only reach the standard greater than 98%, and the product contains more impurities, which affects the reaction yield and purity of synthetic rosuvastatin calcium; the Chinese invention patent application announcement number is CN104520294A "Crystal 2-[(4R, 6S)- 6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] tert-butyl acetate and its preparation method" reported that a compound with higher purity can be obtained by controlling the drip rate of sodium hypochlorite Ⅰ, but sodium hypochlorite needs to be poured quickly to obtain high-purity and solid compound Ⅰ. Rapidly poured in, the reaction is violently exothermic, and the reaction temperature is difficult to control, which is not conducive to the safety of the operation, and is difficult to apply to industrial production.

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