CN103232389A - Preparation method of 2-chloromethyl-4-methoxyl-3,5-dimethyl pyridine hydrochloride - Google Patents
Preparation method of 2-chloromethyl-4-methoxyl-3,5-dimethyl pyridine hydrochloride Download PDFInfo
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- CN103232389A CN103232389A CN2013101663892A CN201310166389A CN103232389A CN 103232389 A CN103232389 A CN 103232389A CN 2013101663892 A CN2013101663892 A CN 2013101663892A CN 201310166389 A CN201310166389 A CN 201310166389A CN 103232389 A CN103232389 A CN 103232389A
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Abstract
The invention discloses a preparation method of 2-chloromethyl-4-methoxyl-3,5-dimethyl pyridine hydrochloride. The preparation method sequentially comprises the following steps of: dissolving 2-hydroxymethyl-4-methoxyl-3,5-dimethyl pyridine into toluene; adding a toluene solution of triphosgene dropwise at 0 to 10 DEG C; after the reaction is finished, adding a small amount of methanol dropwise; removing acidic gas under reduced pressure; and centrifuging and drying the reaction liquid to obtain the 2-chloromethyl-4-methoxyl-3,5-dimethyl pyridine hydrochloride. The preparation method of the 2-chloromethyl-4-methoxyl-3,5-dimethyl pyridine hydrochloride has the advantages of simpleness in operation, high yield, high purity and few three wastes.
Description
Technical field
The present invention relates to proton pump inhibitor key intermediate 2-chloromethyl-4-methoxyl group-3, the preparation method of 5-dimethyl pyrazole thiamine hydrochloride.
Background technology
2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride is mainly used in organic synthesis, and 2 chloromethyl and other reagent (as sulfydryl, amino, phenol etc.) reaction obtains various derivatives.Its derivative such as omeprazole [Omeprazole; chemistry 5-methoxyl group by name-2-{[(4-methoxyl group-3; 5-dimethyl-2 pyridine) methyl] sulfinyl-the 1H-benzoglyoxaline-], levo-omeprazole (esomeprazole; Esomeprazole), tenatoprazole (Tenatoprazole; chemistry 5-methoxyl group-2-(4-methoxyl group-3,5-lutidine-2-methylsulfinyl) imidazo by name (4,5-b) pyridine) etc.These PPI inhibitor chemical stabilities are good, and the gastric acid secretion that histamine, pentagastrin, vagusstoff, food and vagus nerve stimulation etc. are caused all has strong and lasting restraining effect.Aspect the treatment digestive tract ulcer, compare H
2The effect of receptor antagonist such as Cimitidine Type A/AB and Ranitidine HCL is better, has rapid alleviating pain, short treating period, advantage that the pathology healing rate is high.This medicine does not have severe side effect, and tolerance is good, is applicable to treatment gastric and duodenal ulcer, reflux esophagitis, Zhuo-Emhorn syndromes, is medicine commonly used in the acid inhibitor of having found at present.
Synthetic (WO2012024620) that it also is used for oneself the plain inhibitor of chemotactic (autotaxin inhibitors) is used for the treatment of chronic inflammatory diseases, autoimmune disease, fibrotic disease, sacred disease and tumor disease etc.
2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride is synthesizing heterocyclic compounds important intermediate, existing synthetic method substantially all is to be solvent with haloalkane (methylene dichloride, chloroform), sulfur oxychloride is chlorizating agent, reaction boils off solvent after finishing, add another kind of solvent (mixed solvent of acetone, Virahol, ethyl acetate or itself and sherwood oil, ether) again, filter, dry salable product, yield 86 ~ 92.7%(DE3840372; ES2024357; CN101648907; Fine chemistry industry, 2004,21 (1): 67-69; Chinese Journal of Pharmaceuticals, 2004,35 (5): 261-262; The Shanxi chemical industry, 2005,25 (4): 9-10).All to boil off reaction solvent in these methods, add another kind of crystallization or dispersed solvent again, product perishable (mainly be that methoxyl group demethylation under acidic conditions in 4-position becomes phenol, impurity (III) structure is as follows) in the still-process can cause yield low and product is defective.And solvent recovering rate is low, causes bigger pollution.
Also be to be that solvent, sulfur oxychloride are to add methyl alcohol after reagent, reaction finish to remove the suspension that excessive sulfur oxychloride obtains product with toluene among the WO2004035565.Do not mention aftertreatment in the patent.Owing in the suspension more sour gas is arranged, separation yield is descended greatly, there is more hydrochloride to exist in the mother liquor with the oily situation.
And in the above document chlorination reagent all usefulness be sulfur oxychloride, emit a large amount of sulfurous gas in the reaction process, smell is heavier.
Summary of the invention
The purpose of this invention is to provide a kind of simple to operate, the three wastes are few, have the 2-chloromethyl-4-methoxyl group-3 of stronger industrial application value, the preparation method of 5-dimethyl pyrazole thiamine hydrochloride, the product yield height of gained, purity height.
2-chloromethyl of the present invention-4-methoxyl group-3, the preparation method of 5-dimethyl pyrazole thiamine hydrochloride, step is as follows:
With 2-methylol-4-methoxyl group-3, the 5-lutidine is dissolved in the toluene, the preparation mass concentration is 2-methylol-4-methoxyl group-3 of 20%～30%, the toluene solution of 5-lutidine, drip the toluene solution that mass concentration is 40%～50% triphosgene at 0～10 ℃, 2-methylol-4-methoxyl group-3, the mol ratio of 5-lutidine and triphosgene is 1:0.35～0.37, high performance liquid chromatography monitoring reaction, after reaction finishes, drip methyl alcohol, 2-methylol-4-methoxyl group-3, the mol ratio of 5-lutidine and methyl alcohol are 1:0.10～0.25, and sour gas is sloughed in decompression then, reaction solution is through centrifugal, oven dry obtains 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride.
Concrete synthetic route is as follows:
Structural formula (
) be 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride; The structure formula II is 2-methylol-4-methoxyl group-3, the 5-lutidine.
Preparation method of the present invention is simple to operate, and the three wastes are few, is triphosgene with the chlorination reagent, emits carbonic acid gas in the reaction process, more is conducive to environmental protection, and product yield can reach more than 96.0%, the purity height.
Embodiment
Example 1
Drop in the there-necked flask of 1000ml toluene (320.0g, 370mL), 2-methylol-4-methoxyl group-3, the 5-lutidine (80.0g, 480mmol), stirring and dissolving.(49.8g is 168mmol) with toluene (74.7g, mixing solutions 86mL) for 10 ℃ of dropping triphosgene (BTC), added the back stirring at room 3 hours, high performance liquid chromatography monitoring reaction is after reaction finishes, drip methyl alcohol (1.5g, 48mmol), stirred 1 hour, be cooled to 5 ℃, sour gas is sloughed in decompression, it is 2-chloromethyl-4-methoxyl group-3 of 99.74% that reaction solution obtains content through centrifugal, oven dry, 5-dimethyl pyrazole thiamine hydrochloride (105.6g, yield 97.51%).
Example 2
Drop in the there-necked flask of 1000ml toluene (240.0g, 277mL), 2-methylol-4-methoxyl group-3, the 5-lutidine (80.0g, 480mmol), stirring and dissolving.(51.3g is 172mmol) with toluene (62.7g, mixing solutions 72mL) for 5 ℃ of dropping triphosgene (BTC), added the back stirring at room 3 hours, high performance liquid chromatography monitoring reaction is after reaction finishes, drip methyl alcohol (3.1g, 96mmol), stirred 1 hour, be cooled to 5 ℃, sour gas is sloughed in decompression, it is 2-chloromethyl-4-methoxyl group-3 of 99.83% that reaction solution obtains content through centrifugal, oven dry, 5-dimethyl pyrazole thiamine hydrochloride (105.8g, yield 97.79%).
Example 3
Drop in the there-necked flask of 1000ml toluene (186.0g, 215mL), 2-methylol-4-methoxyl group-3, the 5-lutidine (80.0g, 480mmol), stirring and dissolving.(52.8g is 178mmol) with toluene (52.8g, mixing solutions 61mL) for 0 ℃ of dropping triphosgene (BTC), added the back stirring at room 3 hours, high performance liquid chromatography monitoring reaction is after reaction finishes, drip methyl alcohol (3.8g, 120mmol), stirred 1 hour, be cooled to 5 ℃, sour gas is sloughed in decompression, it is 2-chloromethyl-4-methoxyl group-3 of 99.88% that reaction solution obtains content through centrifugal, oven dry, 5-dimethyl pyrazole thiamine hydrochloride (105.6g, yield 97.70%).
Claims (1)
1.2-chloromethyl-4-methoxyl group-3, the preparation method of 5-dimethyl pyrazole thiamine hydrochloride, step is as follows:
With 2-methylol-4-methoxyl group-3, the 5-lutidine is dissolved in the toluene, the preparation mass concentration is 2-methylol-4-methoxyl group-3 of 20%～30%, the toluene solution of 5-lutidine, drip the toluene solution that mass concentration is 40%～50% triphosgene at 0～10 ℃, 2-methylol-4-methoxyl group-3, the mol ratio of 5-lutidine and triphosgene is 1:0.35～0.37, high performance liquid chromatography monitoring reaction, after reaction finishes, drip methyl alcohol, 2-methylol-4-methoxyl group-3, the mol ratio of 5-lutidine and methyl alcohol are 1:0.10～0.25, and sour gas is sloughed in decompression then, reaction solution is through centrifugal, oven dry obtains 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664750A (en) * | 2013-12-09 | 2014-03-26 | 惠州市莱佛士制药技术有限公司 | Synthetic method of prazole chloride |
| CN107011252A (en) * | 2017-06-09 | 2017-08-04 | 浙江工业大学 | The method for drawing azole intermediate and medicine is prepared using the green technology for substituting the poisonous and harmful substances such as phosgene, thionyl chloride |
Citations (4)
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| US20050038076A1 (en) * | 2003-07-15 | 2005-02-17 | Garst Michael E. | Process for preparing isomerically pure prodrugs of proton pump inhibitors |
| US20080004447A1 (en) * | 2002-10-18 | 2008-01-03 | Anders Gustavsson | Method for the Synthesis of a Benzimidazole Compound |
| CN100374423C (en) * | 2001-12-11 | 2008-03-12 | 西巴特殊化学品控股有限公司 | Process for the preparation of 4-methyl-7-aminoquinolones |
| CN102887886A (en) * | 2012-10-26 | 2013-01-23 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of pantoprazole sodium |
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2013
- 2013-05-08 CN CN2013101663892A patent/CN103232389A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100374423C (en) * | 2001-12-11 | 2008-03-12 | 西巴特殊化学品控股有限公司 | Process for the preparation of 4-methyl-7-aminoquinolones |
| US20080004447A1 (en) * | 2002-10-18 | 2008-01-03 | Anders Gustavsson | Method for the Synthesis of a Benzimidazole Compound |
| US20050038076A1 (en) * | 2003-07-15 | 2005-02-17 | Garst Michael E. | Process for preparing isomerically pure prodrugs of proton pump inhibitors |
| CN102887886A (en) * | 2012-10-26 | 2013-01-23 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of pantoprazole sodium |
Non-Patent Citations (1)
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664750A (en) * | 2013-12-09 | 2014-03-26 | 惠州市莱佛士制药技术有限公司 | Synthetic method of prazole chloride |
| CN107011252A (en) * | 2017-06-09 | 2017-08-04 | 浙江工业大学 | The method for drawing azole intermediate and medicine is prepared using the green technology for substituting the poisonous and harmful substances such as phosgene, thionyl chloride |
| CN107011252B (en) * | 2017-06-09 | 2018-06-08 | 浙江工业大学 | The method for drawing azole intermediate and drug is prepared using the green technology for substituting the poisonous and harmful substances such as phosgene, thionyl chloride |
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