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Synthetic method of 1-bromo-4-fluorin-5-isopropyl-2-metoxybenzene

A technology of tetramethyldisiloxane and compound is applied in the field of synthesis of 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene, and can solve the problems of expensive raw materials, low yield, heavy metal Pollution and other problems, to achieve the effect of mild reaction conditions, high product purity, and simple processing

Inactive Publication Date: 2012-07-25
PHARMABLOCK SCIENCES (NANJING) INC
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Problems solved by technology

It mainly solves the technical problems in the existing preparation route of 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene that the raw materials are expensive, the yield is low, the intermediates are difficult to purify, heavy metal pollution, and cannot be mass-produced

Method used

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  • Synthetic method of 1-bromo-4-fluorin-5-isopropyl-2-metoxybenzene
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  • Synthetic method of 1-bromo-4-fluorin-5-isopropyl-2-metoxybenzene

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Embodiment 1

[0031] Synthesis of Compound VI:

[0032]

[0033] AlCl 3 (1000g, 7.500mol, 1.5eq) was added to 1,2-dichloroethane (DCE) (5000mL), and compound IX (630.0g, 5.000mol, 1.0eq) was added slowly under an ice-water bath. After the addition, Ac at 0~5℃ 2 O (510.5 g, 5.000 mol, 1.0 eq). Then the mixture was reacted at room temperature for 3 h. The reaction solution was poured into 5000 g of ice, the organic phase was separated, and then the organic phase was washed with 8% NaOH aqueous solution (5000 mL), and then washed with 5000 mL of saturated brine. Anhydrous Na 2 SO 4 Dry and concentrate. The crude product was recrystallized from petroleum ether (PE) to obtain 708.1 g of compound VI as a white solid, yield: 85%. 1 H NMR (400M Hz, CDCl3) δ (ppm) 7.90 (t, J = 8.80Hz, 1H), 6.76 (dd, J = 2.36, 8.84Hz, 1H), 6.63 (dd, J = 2.36, 13.08Hz, 1H ), 3.88 (s, 3H), 2.61 (d, J=5.20Hz, 1H).

[0034] Synthesis of Compound VII:

[0035]

[0036] Add magnesium chips (112.4g, 4.625mol...

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Abstract

The invention relates to the field of synthesis of a medicament intermediate, in particular to a synthetic method of 1-bromo-4-fluorin-5-isopropyl-2-metoxybenzene. The preparation method is characterized by comprising the following steps of: I, reacting 3-fluoroanisole serving as a raw material under the actions of AlCl3 and Ac2O to obtain a compound VI; II, reacting with a Grignard reagent to obtain a compound VII; III, undergoing a reduction reaction to obtain a compound VIII; and IV, preparing a compound I under the action of NBS (N-bromosuccinimide). The preparation method has mild reaction conditions and high yield, and is suitable for industrial mass production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene. Background technique [0002] 1-Bromo-4-fluoro-5-isopropyl-2-methoxybenzene is a key intermediate of the very useful clinical investigational drug Anacetrapib. Anacetrapib is a cholesteryl ester transfer protein [CETP] inhibitor that increases high-density lipoprotein (HDL) cholesterol and decreases low-density lipoprotein (LDL) cholesterol. CETP inhibitors may be a new effective way to reduce the incidence of atherosclerosis. Studies have shown that cholesterol-lowering drugs like Lipitor and Zocor can reduce the incidence of cardiovascular diseases such as heart attacks in one-third of patients, while Merck's new drug Anacetrapib is expected to help the other two-thirds patients with reduced morbidity. A Novel Cholesteryl Ester Transfer Protein (CETP) Inhibitor (Anacetrapib) Lipid-Lo...

Claims

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Application Information

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IPC IPC(8): C07C43/247C07C41/22
Inventor 李进朱经纬杨民民吴希罕
Owner PHARMABLOCK SCIENCES (NANJING) INC
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