阅读说明：本技术 一种6-溴己基三甲基溴化铵的制备方法 (Preparation method of 6-bromohexyltrimethylammonium bromide ) 是由 孙玉明 江立鼎 于 2020-06-23 设计创作，主要内容包括：本发明属于医药中间体制备技术领域,具体涉及一种6-溴己基三甲基溴化铵的制备方法。该方法包括如下步骤：将原料6-溴基己胺与碳酸二甲酯在有机溶剂中于加热状态下发生反应,反应结束后,缓慢加入HBr溶液,减压浓缩、过滤、重结晶得纯净产物。本发明采用相对便宜的6-溴基己胺与碳酸二甲酯为原料采用相对温和、易于控制的条件下制得目标6-溴己基三甲基溴化铵,该反应产物收率及纯度均可达到80％以上,适于规模化生产。(The invention belongs to the technical field of preparation of medical intermediates, and particularly relates to a preparation method of 6-bromohexyltrimethylammonium bromide. The method comprises the following steps: reacting raw materials 6-bromohexylamine and dimethyl carbonate in an organic solvent in a heating state, slowly adding HBr solution after the reaction is finished, and carrying out reduced pressure concentration, filtration and recrystallization to obtain a pure product. The invention adopts relatively cheap 6-bromohexylamine and dimethyl carbonate as raw materials to prepare the target 6-bromohexyltrimethylammonium bromide under relatively mild and easily controlled conditions, the yield and purity of the reaction product can reach more than 80 percent, and the method is suitable for large-scale production.)

1. A preparation method of 6-bromohexyltrimethylammonium bromide comprises the following steps:

reacting raw materials 6-bromohexylamine and dimethyl carbonate in an organic solvent in a heating state, slowly adding HBr solution after the reaction is finished, and carrying out reduced pressure concentration, filtration and recrystallization to obtain a pure product.

2. The method of claim 1, wherein the organic solvent is toluene containing not more than 5 vol% ethanol.

3. The method of claim 1, wherein the molar ratio of 6-bromohexyltrimethylammonium bromide to dimethyl carbonate is 1: 3-4.

4. The method for producing 6-bromohexyltrimethylammonium bromide according to claim 1, wherein the reaction temperature of the reaction is 45 to 90 ℃.

5. The method for producing 6-bromohexyltrimethylammonium bromide according to claim 1, wherein the reaction pressure is 0.1 to 2 MPa.

6. The method for producing 6-bromohexyltrimethylammonium bromide according to claim 1, wherein the reaction time of the reaction is 1 to 8 hours.

7. The method for producing 6-bromohexyltrimethylammonium bromide according to claim 1, wherein the solvent used for recrystallization is at least one of diethyl ether, acetone, dichloromethane, chloroform, methanol, ethanol and isopropanol.

8. The method according to claim 1, wherein the HBr solution is 3-10% HBr in ethanol.

9. The method of preparing 6-bromohexyltrimethylammonium bromide according to claim 1, comprising the steps of: reacting raw material 6-bromohexylamine with dimethyl carbonate in an organic solvent under a heating state, slowly adding HBr solution after the reaction is finished, concentrating under reduced pressure, filtering to obtain a crude product 1 and a filtrate 1, recrystallizing the filtrate 1, mixing the crude product 2 and the crude product 1, recrystallizing with a recrystallization solvent again, and filtering to obtain a pure product.

Technical Field

The invention belongs to the technical field of preparation of medical intermediates, and particularly relates to a preparation method of 6-bromohexyltrimethylammonium bromide.

Background

6-bromohexyltrimethylammonium bromide is an important intermediate in the synthesis process of the medicine colesevelam hydrochloride for treating hyperlipidemia. The structural formula is as follows:

at present, forPreparation of 6-bromohexyltrimethylammonium bromide is mainly carried out by the following methods, Allan P.Grav et al¹The report reports that 1, 6-dibromohexane is used as a raw material, benzene is used as a solvent, and no excessive ammonia gas is introduced, so that the required product can be obtained after the reaction is finished, the yield reaches 95%, and the reaction equation is as follows:

the reaction principle is simple, but the reaction raw materials are relatively expensive and not easy to obtain, and the amount of the trimethylamine gas introduced is not well controlled, so that the method is not suitable for large-scale production from the aspects of economy, simplicity and convenience in operation and the like.

Murakama et al²The desired product is obtained by using (6-alcoholic hydroxyl) -trimethyl ammonium bromide as a raw material and adding PBr3 under an acidic condition to substitute hydroxyl by halogen atoms, wherein the reported yield is about 53%, and the reaction equation is as follows:

the reaction is simple to operate, but the reaction raw materials are difficult to obtain and the reaction yield is not high, so that the method cannot be applied to large-scale industrial production.

Hejun in his Master's academic paper, "the research on the synthesis process of colesevelam hydrochloride", proposed that 1, 6-dibromohexane is used as a raw material, ether is used as a solvent, and trimethylamine alcohol solution is added dropwise to react to obtain the desired product, wherein the yield reaches 81.6%, and the reaction equation is as follows:

the method is relatively simple to operate, raw materials are easy to obtain, but the reaction process of the reaction requires three days of reaction at room temperature in a dark environment, the reaction time is long, and the reaction efficiency is low. The reaction efficiency is too low for industrial production.

The invention provides a preparation method of 6-bromohexyltrimethylammonium bromide, which has high reaction efficiency and is suitable for large-scale industrial production.

Reference documents:

1.Allan P.Gray,Dorothy C Schlieper,et al.The prepration of some w-bromoalkyl quarternary ammonium salts[J].Makromol.Chem,1994(6):29-31.

2.Murakamy,Yukito et al.Carbon-skeleton rearrangement via formationof host-guest complxes derived from an azaparacyclophane[J].Journal ofChemical Society,1988,24(7).

disclosure of Invention

In order to overcome the problems in the prior art, the invention aims to provide a preparation method of 6-bromohexyltrimethylammonium bromide, which is simple to operate, high in product efficiency and suitable for large-scale industrial production.

In order to achieve the above purpose, the invention provides the following technical scheme:

a preparation method of 6-bromohexyltrimethylammonium bromide comprises the following steps: reacting raw materials 6-bromohexylamine and dimethyl carbonate in an organic solvent in a heating state, slowly adding HBr solution after the reaction is finished, and carrying out reduced pressure concentration, filtration and recrystallization to obtain a pure product.

The reaction equation for the reaction is as follows:

preferably, the molar ratio of the 6-bromohexylamine to the dimethyl carbonate is 1: 3-4.

Preferably, the organic solvent is toluene containing no more than 5 vol% ethanol. The nonpolar solvent containing a small amount of polar solvent is used as the reaction solvent, which is beneficial to the separation of the reaction product at the end of the reaction.

Further preferably, the organic solvent is toluene containing 0.5 to 3 vol% ethanol.

Preferably, the reaction temperature of the reaction is 45-90 ℃.

Preferably, the reaction pressure is from 0.1 to 2MPa, more preferably from 0.5 to 1.5MPa, and still more preferably from 0.8 to 1 MPa. In the experimental process, the inventor has interestingly found that when the pressure in the reaction kettle is 0.1-2MPa, the yield of the reaction product is improved, but when the pressure is more than 2MPa, the yield, the purity and the like of the reaction are not obviously influenced, and when the pressure is more than a certain degree, the yield of the reaction is reduced, and when the pressure is too high, the reaction by-products are increased.

Preferably, the reaction time of the reaction is 1 to 8 hours.

Preferably, the solvent used for the reactive recrystallization is at least one of diethyl ether, acetone, dichloromethane, chloroform, methanol, ethanol and isopropanol.

Preferably, the HBr solution has a mass concentration of 3-10% HBr in ethanol.

Preferably, the preparation method comprises the following steps: reacting raw material 6-bromohexylamine with dimethyl carbonate in an organic solvent under a heating state, slowly adding HBr solution after the reaction is finished, concentrating under reduced pressure, filtering to obtain a crude product 1 and a filtrate 1, recrystallizing the filtrate 1, mixing the crude product 2 and the crude product 1, recrystallizing with a recrystallization solvent again, and filtering to obtain a pure product.

Further preferably, the filtrate is recrystallized by the following operations:

concentrating the filtrate 1 until no solvent is evaporated, dissolving with recrystallization solvent under heating condition, stirring for 20-60min while maintaining the temperature, cooling to-5 deg.C to-15 deg.C, filtering to obtain crude product, and repeating the above recrystallization operation for 1-2 times to obtain pure product.

Further preferably, the recrystallization solvent is heated to 50 ℃ for dissolution, and the procedure of stepwise cooling from 50 ℃ to-5 ℃ is as follows: firstly, cooling to 10-15 ℃ within 1-2h, and continuously stirring for 20-50min under heat preservation; then naturally cooling to 0-4 ℃ and continuing to stir for 20-50 min; finally, cooling to-5 to-15 ℃ within 1-2h, and continuing to stir for 1-2h under heat preservation.

Compared with the prior art, the invention has the following beneficial effects:

(1) the invention adopts relatively cheap 6-bromohexylamine and dimethyl carbonate as raw materials to prepare the target 6-bromohexyltrimethylammonium bromide under relatively mild and easily controlled conditions, the yield and purity of the reaction product can reach more than 80 percent, and the method is suitable for large-scale production.

(2) By adopting the reaction solvent system and the reaction conditions provided by the invention, the reaction time can be shortened to be within 5 hours, the production efficiency is greatly improved, the time cost of a factory is saved, and greater benefits can be created for enterprises.

(3) The method provided by the invention has few byproducts, can realize the purification of the product only by recrystallization in the post-treatment, has simple procedures and is suitable for continuous and automatic production.

Detailed Description

The method of the present invention is described below with reference to specific examples to make it easier to understand and understand the technical solution of the present invention, but the present invention is not limited thereto. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.