Preparation method of omeprazole midbody

A technology of chloromethyl and methoxypyridine, which is applied in the field of preparation of pharmaceutical intermediates, can solve problems such as fire, corrosion, and flammability, and achieve high yield, mild reaction conditions, and high environmental protection.

Active Publication Date: 2019-10-11
FUZHOU SANHE PHARMACHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Contact with organic matter will catch fire, flammable, easy to irritate mucous membranes, corrosive, toxic

Method used

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  • Preparation method of omeprazole midbody
  • Preparation method of omeprazole midbody
  • Preparation method of omeprazole midbody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Preparation of Raney Ni

[0051]

[0052] Add 5g (12.5mmol) NaOH, heat 25ml water to 50°C and stir, after 10min, add 4.5g aluminum-nickel alloy in small amounts (0.2~0.4g) to 20% sodium hydroxide solution in batches, and finish adding aluminum within 1h -After the nickel alloy, stir for 4 hours; add 20ml of water and stir for 30min, wash three times, and wash with ethanol (3×20ml) to obtain Raney Ni, which spontaneously ignites in air (deactivation after long-term storage), and is directly used in the reduction reaction.

Embodiment 2

[0054] Synthesis of 2,3,5-trimethyl-4-methoxypyridine

[0055]

[0056] At room temperature, 20.0g (0.12mol) 2,3,5-trimethyl-4-methoxypyridine-N-oxide, add 2.0g (10wt.%) Raney Ni prepared in Example 1, 200ml methanol In the reaction flask; after the air was pumped out, hydrogen gas was introduced, and the temperature was raised to 60°C and the reaction was stirred for 6h. After the reaction, filter with suction, spin off methanol, add 50ml of dichloromethane, extract with saturated brine (3×50ml), dry the organic layer with anhydrous sodium sulfate, remove the solvent, and dry to obtain 17.5g of a colorless transparent oily liquid 2,3,5-Trimethyl-4-methoxypyridine, yield 96.8%. 1 H NMR (400MHz, CDCl 3 )δ: 2.15(s, 3H, CH 3 ), 2.18(s, 4H, CH 3 ), 2.42 (s, 4H, CH 3 ), 3.70 (s, 3H, OCH 3 ), 8.08 (s, 1H, pyridine ring-H).

Embodiment 3

[0058] Preparation of 2,3,5-trimethyl-4-methoxypyridine

[0059]

[0060] Add 90mmol 2,3,5-trimethyl-4-methoxypyridine-N-oxide, 1.5g Raney nickel and 200ml ethyl acetate into a 500ml flask, feed hydrogen, stir at 40°C for 5.0h; TLC monitoring After the reaction, after the reaction was completed, suction filtration, precipitation, separation and purification gave 13.12 g of brown liquid 2,3,5-trimethyl-4-methoxypyridine, with a yield of 96.4%.

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Abstract

The invention relates to a preparation method of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine shown in a chemical structural formula I. The method is characterized by comprising the steps of a catalytic hydrogenation reaction, wherein Raney nickel or Pd/C is selected as a catalyst; a chlorination reaction, wherein YCln is selected from N-chloroacetamides or N-chlorosuccinimide or 1,3-dichloro-5,5-dimethylhydantoin or dichlord isocyanurice acid or symclosene; n is selected from 3 or 2 or 1; m is selected from 0 or 1 or 2.

Description

technical field [0001] The invention relates to a new preparation method of a pharmaceutical intermediate, in particular to a preparation method of omeprazole intermediate-2-chloromethyl-3,5-dimethyl-4-methoxypyridine. Background technique [0002] Omeprazole (Omeprazole), chemical name 5-methoxy-2-[(3,5-dimethyl-4-methoxypyridyl) methylsulfinyl]-1H-benzimidazole, is relatively The earliest developed benzimidazole proton pump inhibitors are used for the treatment of peptic ulcer, esophageal reflux disease, gastrinoma syndrome and Helicobacter pylori. 2-Chloromethyl-3,5-dimethyl-4-methoxypyridine is a key intermediate for the preparation of omeprazole. 2-Chloromethyl-3,5-dimethyl-4-methoxypyridine is called Ogilvy chloride for short. The preparation method of Ogilvy chloride and its hydrochloride is as follows: [0003] Junggren et al. [US 4255431] and Brandstrom et al. [US 4620008] describe the synthesis of omeprazole and its intermediate 2-chloromethyl-3,5-dimethyl-4-met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/68C07D251/36
CPCC07D213/68C07D251/36
Inventor 胡艾希陈阿欢谢步云俞农
Owner FUZHOU SANHE PHARMACHEM
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