Method for synthesizing key intermediate of rosuvastatin calcium

Abstract

The invention relates to a method for synthesizing a key intermediate 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonylamino)]-pyrimidine-5-formaldehyde of rosuvastatin calcium. The method comprises the steps of cyclizing, halogenating, coupling and aminating, wherein a skeleton of a pyrimidine ring is synthesized from readily-accessible urea and isobutyryl acetate in the presence of alkali in one step, an aldehyde group is inserted to the pyrimidine ring while a hydroxyl group on the pyrimidine ring is halogenated in the presence of a Weilsmeier reagent, thus, the consumption of substances, such as DDQ, m-CPBA, DIBAL-H and TPAP, is avoided, a compound II is obtained through coupling a halide and a p-fluorophenyl boron compound by suzuki, and the compound II and N-methyl-N-methylsulfonamide are subjected to heat-insulated reaction in a solvent, thereby preparing a compound I. During suzuki coupling reaction, the reaction is insensitive to water, and inorganic byproducts are non-toxic and are easily removed. The method is high in yield, short in reaction route, easy in raw material obtaining, easy in reaction condition control and good in process safety performance, is applicable to laboratories and can be applied to industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a method for synthesizing a key intermediate of rosuvastatin calcium. Background technique [0002] Rosuvastatin calcium, CAS No: 147098-20-2, chemical name: (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2 - Calcium (N-methyl-N-methanesulfonamide)-5-pyrimidine]-3,5-dihydroxy-6-heptenoate. In the 1980s, it was first synthesized by the Japanese Shionogi Pharmaceutical Company. Rosuvastatin is the third-generation fully synthetic HMG-CoA reductase inhibitor, and its effects of lowering low-density lipoprotein cholesterol and raising high-density cholesterol are the best among the statins on the market. Its structural formula is as follows: [0003] [0004] Compound Ⅰ: 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonamido)]-pyrimidine-5-carbaldehyde is the preparation of rosuvastatin calcium key intermediates. Its preparation met...

AI Technical Summary

Problems solved by technology

There is following defect in this synthetic method: After p-fluorobenzaldehyde is condensed with isobutyryl ethyl ester, HMPA is used as solvent in the process of condensation with S-methylthiourea to form a ring, which is not easy to obtain; In the process of oxidation to pyrimidine ring, DDQ and benzene are used, where DDQ is a highly toxic substance and benzene is a carcinogen; In the process of oxidizing sulfide into sulfone, the peroxide m-CPBA is used, and there are great safety hazards in the feeding and post-treatment process; NaH is used to extract hydrogen when introducing methylsulfonyl group on amino group. NaH is very easy to spontaneously ignite when wet during use, and there is a big safety hazard; In the process of converting ester groups into aldehyde groups, DIBAL-H and TPAP need to be used, which are expensive; The synthetic route is as long as 8 steps, and there are many places that need to be reacted at low temperature or column purification, especially the reduction of DIBAL-H needs to be reacted at -74°C; The yield is low, the published molar yield is 14.1%

The disadvantages of this method are: High-risk NaH that remains wet when wet is still used, and the condensation yield of p-fluoroacetophenone and ethyl isobutyrate is not high; The highly toxic methyl iodide is used in the process; The use of NBS as a brominating agent has high cost, difficulty in separation of by-products, difficulty in controlling the selective bromination of methyl and isopropyl groups, and the inevitable generation of polybromides, which leads to increased product impurities and is difficult to purify; The reaction route is as long as seven steps, and the yield is as low as 57%, which is not suitable for industrial production

[0008] In summary, the key intermediate in the synthesis of rosuvastatin calcium——4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) In the method of ]-pyrimidine-5-carboxaldehyde, there are low yields, long reaction routes, the use of highly toxic and expensive raw materials or the use of solvents that are not easy to get and unsuitable for use, or there are harsh conditions such as ultra-low temperature in the reaction process. The reaction conditions and other issues

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