阅读说明：本技术 一种托法替尼中间体的合成方法 (Synthesis method of tofacitinib intermediate ) 是由 魏峰 葛二鹏 于 2019-12-04 设计创作，主要内容包括：本发明提供一种托法替尼中间体的合成方法,所述顺-(4-甲基哌啶-3-基)氨基甲酸甲酯的合成是以(4-甲基吡啶-3-基)氨基甲酸甲酯为起始原料,以碘化钐为加氢剂,以水为氢源发生反应生成的。本发明副产物少,操作简单,产品收率和纯度高,三废量少,所述方法具有优异的经济和环保效益。(The invention provides a synthetic method of a tofacitinib intermediate, wherein the cis- (4-methylpiperidin-3-yl) methyl carbamate is synthesized by taking (4-methylpyridine-3-yl) methyl carbamate as a starting material, samarium iodide as a hydrogenation agent and water as a hydrogen source. The method has the advantages of less by-products, simple operation, high product yield and purity, and less three wastes, and has excellent economic and environmental benefits.)

1. The method for synthesizing the tofacitinib intermediate is characterized in that the tofacitinib intermediate is synthesized by taking (4-methylpyridin-3-yl) methyl carbamate as a raw material through the following reactions:

in the method, the methyl (4-methylpyridine-3-yl) carbamate takes samarium iodide as a hydrogenation agent and water as a hydrogen source to carry out hydrogenation reaction to generate a product.

2. The route according to claim 1, characterized in that said steps comprise: adding a tetrahydrofuran solution of samarium iodide into (4-methylpyridine-3-yl) methyl carbamate, then dropwise adding purified water, and stirring for reaction to obtain a compound A.

3. The method of claim 2, wherein in step (ii), the molar ratio of methyl (4-methylpyridin-3-yl) carbamate to samarium iodide is 1: 6 to 6.2. The reaction temperature is 20-25 ℃.

4. The method of claim 2, wherein the step reaction time is 1 to 2 hours.

The technical field is as follows:

the invention relates to the field of medicinal chemistry, in particular to a novel synthesis method of cis- (4-methylpiperidine-3-yl) methyl carbamate.

Background art:

cis- (4-methylpiperidin-3-yl) carbamate is an important pharmaceutical product, and has the following structural formula:

regarding the synthesis of cis- (4-methylpiperidin-3-yl) methyl carbamate, the current method is mainly a high-pressure hydrogenation reaction of methyl (4-methylpyridin-3-yl) carbamate in the presence of a rhodium catalyst and a palladium-carbon catalyst. Such as CN201510104199.7, CN200680027901, etc. The biggest problems of the method are that the requirement on equipment is high, a high-pressure reaction kettle is needed, and the safety risk is high.

Disclosure of Invention

The invention aims to overcome the defects in the prior art and provide a preparation method of cis- (4-methylpiperidine-3-yl) methyl carbamate with high yield and environmental protection, and the specific synthetic route is as follows:

the synthesis scheme preferably comprises the following steps:

at room temperature, adding 0.1mol/L tetrahydrofuran solution of samarium iodide and methyl (4-methylpyridine-3-yl) carbamate into a reaction bottle, then slowly dropwise adding purified water, slowly changing the reaction liquid from light blue to light yellow, and stirring and reacting at room temperature for 1-2 hours after dropwise adding. Slowly adding 2mol/L dilute hydrochloric acid, stirring at room temperature for 1 hour, adding ethyl acetate, washing for 2 times, separating out a water layer, adjusting the pH of the water layer to be more than 12 by using 2mol/L sodium hydroxide water solution, extracting for 3 times by using ethyl acetate, combining organic layers, washing with saturated salt water for 1 time, and concentrating the organic layer at 40-45 ℃ under reduced pressure to obtain colorless liquid. Thus obtaining the product.

The sodium hydroxide aqueous solution and the saturated salt solution can be continuously used in the next production after being supplemented with corresponding inorganic salts, and the ethyl acetate can be recycled and reused.

Compared with the prior art, the invention has the advantages that:

1. compared with the traditional catalytic hydrogenation method of palladium or rhodium, the method has the advantages that although the cost is higher, water is used as a hydrogen source, hydrogen high-pressure reaction is not needed, the safety is improved, the requirement on reaction equipment is reduced, the reaction can be carried out by an enamel reaction kettle commonly used in chemical plants or pharmaceutical factories, the later separation is simple and convenient, the operation is simple, and the industrial production is facilitated;

2. compared with the traditional catalytic hydrogenation method, the samarium iodide has stronger reaction activity, so that the raw materials can be completely converted in a parallel reaction within about 1-2 hours without refluxing for about 24-48 hours like the traditional catalytic hydrogenation method, the time is obviously shortened, and the yield is equivalent to that of the traditional method and can reach 92-96%.

Drawings

FIG. 1 is a GC detection spectrum of compound B (target product).

FIG. 2 is a reaction scheme diagram and an abstract figure.

Detailed Description

In order to make the technical means, creation features, working procedures and using methods of the present invention easily understood and appreciated, the present invention is further described below.

At room temperature, 600ml (0.06mol) of 0.1mol/L tetrahydrofuran solution of samarium iodide and 1.66g (0.01mol) of (4-methylpyridin-3-yl) methyl carbamate are added into a reaction bottle, then 9.9ml of purified water is slowly dripped, the reaction solution is slowly changed from light blue to light yellow, and after the dripping is finished, the reaction solution is stirred at room temperature for reaction for 1-2 hours. Slowly adding 600ml of 2mol/L diluted hydrochloric acid, stirring at room temperature for 1 hour, adding 600ml of ethyl acetate, washing for 2 times, separating out a water layer, adjusting the pH of the water layer to be more than 12 by using 2mol/L sodium hydroxide water solution, extracting for 3 times by using 600ml of ethyl acetate, combining organic layers, washing for 1 time by using 300ml of saturated salt water, and concentrating the organic layer at 40-45 ℃ under reduced pressure to obtain 1.65g of colorless liquid. The product is obtained, the yield is 95.8 percent, and the GC detection content is 98.15 percent.

The GC assay of the product is shown in FIG. 1.

Nuclear magnetic data:

NMR ¹H(400MHz,CDCl₃):d 6.83(d,1H),3.57(m,3H),3.47(m,1H),2.73(m,2H),2.50(m,2H),2.41(m,1H),1.73(d,1H),1.28(d,2H),0.80(d,3H).

the foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.