2-Chloro-4-(trifluoromethyl)pyridine, 98+%, Thermo ...

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The present invention relates to be a kind of synthetic Stogar key intermediate 2-chloro-4-(piperidino methyl) pyridine realize industrialized synthesis technique, belong to the synthetic field of medicine.

Lafutidine ( 1 ) be a kind of anti-ulcerative drug that (Fujirebio) company and roc (Taiho) company develop jointly, this product is strong effect, long lasting s-generation histamine H 2 Receptor antagonist has unique stomach provide protection.Go on the market in Japan in April, , trade(brand)name is respectively Storga and Protecadin.Along with the share of market and the big in recent years rapid growth of the market share of anti-ulcerative drug lafutidine, significantly increase for the demand of the bulk drug of lafutidine is inevitable.Therefore, develop a low cost, oligosaprobic lafutidine synthetic route has great society and economic benefit.Synthetic route about the lafutidine bulk drug has more patent and bibliographical information at present, but route is all complicated, and step is tediously long.Through furtheing investigate the synthetic route of existing lafutidine, find 2-chloro-4-(piperidino methyl) pyridine ( 2 ) be the critical materials of synthetic lafutidine, how to obtain this intermediate through easy steps, determined the synthetic cost of synthetic lafutidine.And at present traditional synthetic this intermediate needs the reaction of 5 steps at least, complex steps, and cost is higher.

Summary of the invention

For addressing the above problem, the problem that promptly lafutidine synthesis technique cost is high, step is long the invention provides a kind of compound 2-chloro-4-(piperidino methyl) pyridine synthetic simple method, thereby can high yield, synthetic lafutidine cheaply.

The present invention is a starting raw material with 2-amino-4-methyl pyrrole, under phosphorus oxychloride and the effect of chlorination sulfone, through the reaction of two one-step chlorinations, obtains key intermediate 2-bromo-4-(piperidino methyl) pyridine with the piperidines condensation then.Present method provides a kind of step simple, the method for high yield Synthetic 2-bromo-4-(piperidino methyl) pyridine.

Reaction formula following:

The synthesis method of 2-chloro-4-of the present invention (piperidino methyl) pyridine, carry out according to following step:

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(1) bathes freezing conditions at cryosel; In acid and 2-amino-4-picoline, dripping the nitrite aqueous solution reacts; Be warming up to 70-100 &#; then; After 15-30 minute, pH value 6.0-8.0 is transferred in cooling; Be heated to 60 &#; then; Ethyl acetate extraction thermal response liquid, recrystallization obtains white solid product.

(2) in the gained white solid, add POCl 3, be heated to 80-110 &#;, agitation condition refluxed 5-15 hour, cold water and ammoniacal liquor are carefully injected in cooling, keep 20-35 &#; of temperature, in cryosel is bathed, transfer PH to 10.0-11.5 with ammoniacal liquor, and underpressure distillation obtains compound 2-chloro-4-picoline.

(3) with CCl 4Be solvent, in compound 2-chloro-4-picoline, drip SO 2Cl 2, in the dropping process, add radical initiator in batches, reacted 2-8 hour, after the cooling, transfer pH value to 6.0-8.0 with saturated sodium bicarbonate, underpressure distillation promptly gets compound 2-chloro-4-chloromethylpyridine.

(4) with DMF be solvent, salt of wormwood is acid binding agent, and 2-chloro-4-chloromethylpyridine and piperidines condensation obtain 2-chloro-4-(piperidino methyl) pyridine.

Wherein used acid is the vitriol oil, concentrated hydrochloric acid or concentrated nitric acid in the step (1); Nitrite is Sodium Nitrite or potassium nitrite, and wherein acid is 1:0.5-1:5 with the mol ratio of 2-amino-4-picoline; The mol ratio of nitrite and 2-amino-4-picoline is 1:1-1:3;

POCl in the step (2) wherein 3With the mol ratio of 2-amino-4-picoline be 1/3:1-3:1.

Wherein used radical initiator is Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile), cyclohexanone peroxide, dibenzoyl peroxide or tertbutyl peroxide in the step (3), SO 2Cl 2With the mol ratio of 2-chloro-4-picoline be 0.5:1-0.5:3; The mol ratio of radical initiator and 2-chloro-4-picoline is 1:-1:100.

Wherein the mol ratio of salt of wormwood and 2-chloro-4-chloromethylpyridine is 0.5:1-2:1 in the step (3), and the mol ratio of piperidines and 2-chloro-4-chloromethylpyridine is 1:1-1:5.

Synthesis method according to the invention is compared with traditional Synthetic 2-chloro-4-(piperidino methyl) pyridine method, and step is simple, only needs three-step reaction, overall yield to reach more than 32%, and cost of material is cheap.The synthetic cost of lafutidine is reduced greatly.

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