CN112480021A - Preparation method of 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole - Google Patents
Preparation method of 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole Download PDFInfo
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- CN112480021A CN112480021A CN202011388486.2A CN202011388486A CN112480021A CN 112480021 A CN112480021 A CN 112480021A CN 202011388486 A CN202011388486 A CN 202011388486A CN 112480021 A CN112480021 A CN 112480021A
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- oxadiazole
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- trifluoroacetyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
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Abstract
The invention relates to a preparation method of sitagliptin intermediate 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole. The method comprises the following steps: taking 1- (chloroacetyl) -2- (trifluoroacetyl) hydrazine as a raw material, heating to react with phosphorus oxychloride in the presence of a solvent to obtain a product solution, cooling, dropwise adding water for cracking, layering, washing an organic layer with a sodium bicarbonate aqueous solution to be neutral, and concentrating and recovering the solvent to obtain the 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole. The invention obviously improves the defects of the existing production process, has simple operation, convenient solvent recovery, easy amplification production, good product purity and high yield.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole.
Background
5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole is an important intermediate of sitagliptin phosphate developed by the merck corporation of the united states. Sitagliptin phosphate is a dipeptidyl peptidase-4 (DDP-4) inhibitor, has a trade name of enoxine, is approved by the US FDA to be marketed in 2006 and 10 months, and is a hypoglycemic drug effective for treating type II diabetes. The oral hypoglycemic agent has been approved and used in 80 countries worldwide, can respond to glucose all the day, can reduce postprandial blood sugar and fasting blood sugar simultaneously, thereby effectively reducing the blood sugar level, has good tolerance and safety, does not increase the weight of patients, has obvious curative effect compared with the traditional oral hypoglycemic agent which is easy to increase the weight at present, and is a safe, effective and good-market-prospect oral hypoglycemic agent for treating type II diabetes.
At present, few synthesis routes of 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole are reported at home and abroad, and WO2005003135 reports that 1- (chloroacetyl) -2- (trifluoroacetyl) hydrazine is used as a starting material, acetonitrile is used as a solvent, the starting material and phosphorus oxychloride react to prepare a 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole mixed solution, isopropyl acetate and water are added for disintegration and extraction, an organic layer is washed by a sodium bicarbonate aqueous solution, and the solvent is concentrated and recovered to obtain the 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole. In CN 103923087A, acetonitrile is also used as a solvent for reaction, and after the reaction is finished, ethyl acetate is used for extraction three times and drying to obtain the target product.
The water-soluble solvent acetonitrile is used as a reaction solvent in the technical route, the acetonitrile is high in price, after the aftertreatment is cracked by isopropyl acetate or ethyl acetate and water, the acetonitrile enters a water layer, a large amount of organic waste liquid is generated, the water in the recovered acetonitrile is difficult to remove, the mechanical difficulty is high, the cost is high, and the industrial production is not facilitated.
Disclosure of Invention
The invention aims to provide a preparation method of 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole, which has the advantages of simple operation, convenient solvent recovery, little pollution, good product purity, high yield and easy industrial production. In order to achieve the purpose, the invention provides the following technical scheme:
taking 1- (chloracetyl) -2- (trifluoroacetyl) hydrazine as a raw material, heating to react with phosphorus oxychloride in the presence of a solvent to obtain a product solution, cooling, dropwise adding water to crack, layering, washing an organic layer with a sodium bicarbonate aqueous solution to be neutral, and concentrating and recovering the solvent to obtain the 5- (trifluoromethyl) -2- (chloromethyl) -1,3,4 oxadiazole.
In the technical scheme, the solvent is one or a mixture of more than one of dichloromethane, chloroform, carbon tetrachloride, 1, 1-dichloroethane, 1, 2-dichloroethane, toluene, xylene and methyl tert-butyl ether;
in the technical scheme, the temperature rise reaction temperature is 40-110 ℃;
in the technical scheme, the molar ratio of the 1- (chloroacetyl) -2- (trifluoroacetyl) hydrazine to the phosphorus oxychloride is 1: 1.0 to 3.0;
in the technical scheme, the mass ratio of the 1- (chloroacetyl) -2- (trifluoroacetyl) hydrazine to the solvent is 1: 1-10.
The invention improves the defects in the prior art, and has convenient solvent recovery, low cost and little pollution; because the acetonitrile solvent has high polarity, strong reaction activity, more impurities and low purity, the invention selects the solvent to react the product with good purity and high yield, and particularly adopts 1, 2-dichloroethane as the reaction solvent, thereby not only having higher yield but also having purity as high as 97.3 percent, being obviously improved compared with the acetonitrile system, and having good economic benefit and social benefit.
Detailed Description
Example 1
Adding 200g of 1, 2-dichloroethane and 40.8g of 1- (chloracetyl) -2- (trifluoroacetyl) hydrazine into a 500ml reaction bottle, adding 61.32g of phosphorus oxychloride while stirring at room temperature, heating to 80-85 ℃, keeping the temperature for reaction for 20-24 hours, cooling to below 10 ℃, dropwise adding 200g of water, separating an organic layer, adding 100g of 5% sodium bicarbonate aqueous solution, stirring and washing to be neutral, separating the organic layer, concentrating and recovering 1, 2-dichloroethane, obtaining 33.64g of oily product, wherein the yield is 90.2%, and the purity is 97.3%.
Example 2
Adding 150g of toluene and 40.8g of 1- (chloracetyl) -2- (trifluoroacetyl) hydrazine into a 500ml reaction bottle, adding 45.99g of phosphorus oxychloride into the reaction bottle under stirring at room temperature, heating the mixture to 95-100 ℃, keeping the temperature for reaction for 20-24 hours, cooling the mixture to below 10 ℃, dropwise adding 200g of water into the reaction bottle, separating an organic layer, adding 100g of 5% sodium bicarbonate aqueous solution, stirring and washing the mixture to be neutral, separating the organic layer, concentrating and recovering toluene to obtain 33.31g of oily product, wherein the yield is 89.3 percent and the purity is 96.8 percent.
Comparative example
Adding 150g of acetonitrile and 40.8g of 1- (chloracetyl) -2- (trifluoroacetyl) hydrazine into a 500ml reaction bottle, adding 45.99g of phosphorus oxychloride into the reaction bottle under stirring at room temperature, heating to 80-85 ℃, keeping the temperature for reaction for 20-24 hours, cooling to below 10 ℃, dropwise adding 450g of water, adding 450g of toluene for extraction, separating an organic layer, adding 100g of 5% sodium bicarbonate aqueous solution, stirring and washing to be neutral, separating the organic layer, concentrating and recovering the toluene to obtain 32.12g of oily product, wherein the yield is 86.1%, and the purity is 94.2%.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (5)
1. A preparation method of 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole is characterized in that 1- (chloroacetyl) -2- (trifluoroacetyl) hydrazine is used as a raw material, the raw material and phosphorus oxychloride react at a high temperature in the presence of a solvent to obtain a product solution, the product solution is cooled and dripped into water to crack, layering is carried out, an organic layer is washed to be neutral by sodium bicarbonate aqueous solution, and finally the solvent is concentrated and recovered to obtain the 5- (trifluoromethyl) -2- (chloromethyl) -1,3,4 oxadiazole;
wherein the solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 1-dichloroethane, 1, 2-dichloroethane, toluene, xylene and methyl tert-butyl ether.
2. The method of claim 1, wherein: the solvent is 1, 2-dichloroethane or toluene.
3. The process according to claim 1 or 2, wherein the reaction temperature is raised to 40 to 110 ℃.
4. The process according to claim 1 or 2, characterized in that the molar ratio of 1- (chloroacetyl) -2- (trifluoroacetyl) hydrazine to phosphorus oxychloride in the reaction is 1: 1.0 to 3.0.
5. The method according to claim 1 or 2, wherein the mass ratio of 1- (chloroacetyl) -2- (trifluoroacetyl) hydrazine to the solvent in the reaction is 1: 1-10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011388486.2A CN112480021A (en) | 2020-12-01 | 2020-12-01 | Preparation method of 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011388486.2A CN112480021A (en) | 2020-12-01 | 2020-12-01 | Preparation method of 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole |
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| CN112480021A true CN112480021A (en) | 2021-03-12 |
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| CN202011388486.2A Pending CN112480021A (en) | 2020-12-01 | 2020-12-01 | Preparation method of 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114516847A (en) * | 2022-03-09 | 2022-05-20 | 台州达辰药业有限公司 | Preparation method of sitagliptin intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090156579A1 (en) * | 2005-10-25 | 2009-06-18 | Hasegawa Philip A | Combination of a Dipeptidyl Peptidase-4 Inhibitor and an Anti-Hypertensive Agent for the Treatment of Diabetes and Hypertension |
| CN103923087A (en) * | 2014-04-21 | 2014-07-16 | 南京靖龙药物研发有限公司 | Method for preparing deuterium-labeled sitagliptin |
-
2020
- 2020-12-01 CN CN202011388486.2A patent/CN112480021A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090156579A1 (en) * | 2005-10-25 | 2009-06-18 | Hasegawa Philip A | Combination of a Dipeptidyl Peptidase-4 Inhibitor and an Anti-Hypertensive Agent for the Treatment of Diabetes and Hypertension |
| CN103923087A (en) * | 2014-04-21 | 2014-07-16 | 南京靖龙药物研发有限公司 | Method for preparing deuterium-labeled sitagliptin |
Non-Patent Citations (2)
| Title |
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| 唐红等: "西他列汀侧链哌嗪盐酸盐制备的工艺优化", 《云南化工》 * |
| 田志高等: "3-三氟甲基-5,6,7,8-四氢-1,2,4-三唑[4,3-α]吡嗪盐酸盐的制备", 《中国医药工业杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114516847A (en) * | 2022-03-09 | 2022-05-20 | 台州达辰药业有限公司 | Preparation method of sitagliptin intermediate |
| CN114516847B (en) * | 2022-03-09 | 2024-01-30 | 台州达辰药业有限公司 | Preparation method of sitagliptin intermediate |
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Application publication date: 20210312 |