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Preparation method of rosuvastatin calcium intermediate

A technology of rosuvastatin calcium and intermediates, applied in the field of organic synthesis, can solve the problems of high price, unfavorable industrial production, low reaction yield and the like, and achieves the effects of simple processing, overcoming harmful emissions and being environmentally friendly

Pending Publication Date: 2022-07-29
重庆普佑生物医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The method disclosed in this patent is currently a common method for preparing compound I, in which DIBAL-H is expensive; the reduction of DIBAL-H needs to be reacted at low temperature, which is not conducive to industrial production; the final step of sodium hypochlorite is easy to oxidize the intermediate alcohol into acid, and the reaction yield not tall

Method used

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  • Preparation method of rosuvastatin calcium intermediate
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  • Preparation method of rosuvastatin calcium intermediate

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preparation example Construction

[0032] A preparation method of rosuvastatin calcium intermediate comprises:

[0033] Step (1), taking p-fluorobenzaldehyde, 2-methyl-3-carbonyl-5-hexene and urea as raw materials to synthesize compound V under the effect of metal catalytic salt;

[0034] Step (2), using an oxidant to oxidize the compound V to obtain the compound IV;

[0035] In step (3), the hydroxyl group of the compound IV is protected to obtain the compound III;

[0036] In step (4), compound III is reacted with N-methylmethanesulfonamide to generate compound II;

[0037] In step (5), compound I is obtained by oxidizing the compound II with ozone,

Embodiment 1

[0039] A preparation method of rosuvastatin calcium intermediate, the concrete steps are:

[0040]

[0041] (1) Synthesis of compound V

[0042] To the reactor were added 2-methyl-3-carbonyl-5-hexene (22.4g, 0.2mol), p-fluorobenzaldehyde (24.8g, 0.2mol), urea (21g, 0.35mol), cuprous chloride (200mg, 0.002mol), sulfuric acid (2ml) and ethanol (250ml), the temperature was raised to reflux, and the reaction was stirred for 16h. After detecting that the reaction was complete, it was cooled to room temperature and a solid was precipitated, suction filtered and dried to obtain compound V (49.5 g, 0.19 mol) with a yield of 95% and a purity of 99.4%.

[0043] (2) Synthesis of compound IV

[0044] Add compound V (39g, 0.15mol) to the reactor, slowly add 60% nitric acid (120ml), then add sodium nitrite (2g, 0.03mol), react at room temperature for 1h, after detecting the reaction is complete, add saturated sodium bicarbonate solution Neutralize and wash, there is solid precipitatio...

Embodiment 2

[0050] (1) Synthesis of compound V

[0051] To the reactor were added 2-methyl-3-carbonyl-5-hexene (22.4g, 0.2mol), p-fluorobenzaldehyde (24.8g, 0.2mol), urea (14.7g, 0.2mol), chloroform Copper (200mg, 0.002mol), sulfuric acid (2ml) and ethanol (250ml) were heated to reflux, and the reaction was stirred for 16h. After detecting that the reaction was completed, it was cooled to room temperature and a solid was precipitated, which was filtered and dried to obtain compound V (41.6 g, 0.16 mol) with a yield of 80% and a purity of 99.2%.

[0052] (2) Synthesis of compound IV

[0053]Compound V (39g, 0.15mol) was added to the reactor, 50% nitric acid (120ml) was slowly added, then sodium nitrite (2g, 0.03mol) was added, and the reaction was carried out at room temperature for 1h. After the reaction was detected, saturated sodium bicarbonate solution was added. Neutralize and wash, there is solid precipitation, suction filtration, and drying to obtain compound IV (33.6 g, 0.13 mol)...

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Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method of a rosuvastatin calcium drug intermediate, which comprises the following steps: by taking p-fluorobenzaldehyde, 2-methyl-3-carbonyl-5-hexene and urea as raw materials, carrying out cyclization, oxidation, substitution, olefin oxidation and the like to obtain the rosuvastatin calcium drug intermediate. Compared with the prior art, the preparation method of the rosuvastatin calcium intermediate 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl) amino] pyrimidine-5-formaldehyde has the advantages that the use of expensive DIBAH is avoided, the generation and emission of aluminum salt are reduced, the preparation method is environment-friendly, and the cost of raw materials is reduced.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of a rosuvastatin calcium intermediate. Background technique [0002] Rosuvastatin calcium, chemical name is bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5 -yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (2:1), CAS No. 147098-20-2, is a selective HMG-CoA reductase inhibitor The agent, developed by AstraZeneca, has been listed in the United States, Japan, Europe, China and other countries and regions. Rosuvastatin calcium can be used to treat hyperlipidemia. [0003] 4-(4-Fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl)amino]pyrimidine-5-carbaldehyde is a key intermediate in the preparation of rosuvastatin calcium, Its CAS number is 147118-37-4, and its structural formula is as follows: [0004] [0005] Patent EP0521471, USRE37314, JP2648897 report a preparation method of rosuvastatin c...

Claims

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Application Information

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IPC IPC(8): C07D239/42
CPCC07D239/42Y02P20/55
Inventor 李彦
Owner 重庆普佑生物医药有限公司
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