CN102675122A - A kind of preparation technology of 2,3-dihydro-1H-inden-1-amine - Google Patents

Abstract

The invention relates to the field of medical technology, and in particular to a preparation process of 2,3-dihydro-1H-inden-1-amine. The invention relates to the preparation process of 2,3-dihydro-1H-inden-1-amine, an intermediate for synthesizing rasagiline mesylate. 2,3-dihydro-1H-inden-1-one oxime is reduced with aluminum amalgam in an ethanol aqueous solution to prepare 2,3-dihydro-1H-inden-1-amine, so as to achieve the purpose of synthesizing 2,3-dihydro-1H-inden-1-amine at low cost. The process of the invention has the characteristics of simple process, low cost, easy operation, no danger and high yield.

Description

A kind of preparation technology of 2,3-dihydro-1H-inden-1-amine

technical field

The invention relates to the technical field of medicine, in particular to a preparation process of 2,3-dihydro-1H-inden-1-amine. the

Background technique

2,3-Dihydro-1H-indene-1-amine is an intermediate for the synthesis of rasagiline mesylate, and rasagiline mesylate (Agilect) is a novel and effective second Generation of selective MAo-B inhibitors. The drug was approved for marketing in Israel for the first time in January 2005, and was subsequently approved by the European Union in February 2005. It was first launched in the EU country UK in June 2005. In 2006, FDA approved rasagiline to be marketed in the United States. Named Azilect, it is used as an initial monotherapy for early-stage Parkinson's disease and as a supplement to levodopa in more advanced patients. Compared with the first-generation MAo-B inhibitor selegiline, it has better efficacy and fewer side effects. 2,3-dihydro-1H-inden-1-amine structural formula is as follows (formula II):

Formula II

At present, the synthesis of 2,3-dihydro-1H-inden-1-amine mainly contains the following methods:

The 6th issue of the 12th volume of China's new drug magazine in 2003 reported a kind of 2,3-dihydro-1H-inden-1-amine synthetic method, and this method uses 2,3-dihydro-1H-inden-1-one oxime As a raw material, 2,3-dihydro-1H-indene-1-amine was obtained by reduction with titanium tetrachloride and sodium borohydride in ethylene glycol dimethyl ether solvent, with a yield of 83.0%. This method uses titanium tetrachloride and sodium borohydride, the reagents are relatively expensive, the operation is complicated, and the cost is high. the

WO02/068376A1 uses 2,3-dihydro-1H-inden-1-one as a raw material to condense with benzylamine to form an imine, and the imine is reduced by sodium borohydride to obtain an amine, and then the benzyl group is removed to obtain 1-indene amine. The method has many steps and also uses sodium borohydride, so the yield is not high and the cost is high. the

EP0235590A2 uses 2,3-dihydro-1H-inden-1-one oxime as raw material, catalyzed by Raney nickel, high-pressure hydrogenation under 50 psi pressure, and the yield is 86.4%. This method uses high-pressure hydrogenation reaction, and the operating conditions are relatively harsh, which has certain risks. the

CN200510135287.X uses 2,3-dihydro-1H-inden-1-one and propargylamine to directly synthesize rasagiline through reductive amination. Although the method has simple steps and is completed in one step, there are many impurities in the actual reaction, the yield is low, and the economy is very poor. the

CN200610054243.9 uses 2,3-dihydro-1H-inden-1-one as raw material, reacts with hydroxylamine hydrochloride to generate 2,3-dihydro-1H-inden-1-one oxime, without separation, adds aluminum-nickel alloy And sodium hydroxide, reduction to generate 2,3-dihydro-1H-inden-1-amine, yield 76.5%. The method uses aluminum-nickel alloy to reduce 2,3-dihydro-1H-indene-1-one oxime to 2,3-dihydro-1H-indene-1-amine in the presence of sodium hydroxide, and the amount of aluminum-nickel alloy is large , also use relatively large amount of sodium hydroxide, the cost is higher. the

Contents of the invention

The present invention aims to provide a 2,3-dihydro -The preparation technology of 1H-inden-1-amine. the

To achieve the above object, the present invention adopts the following technical solutions:

A preparation process for 2,3-dihydro-1H-indene-1-amine, using 2,3-dihydro-1H-indene-1-one oxime as raw material to produce 2,3-dihydro-1H-indene- 1-amine, according to the reaction formula shown in formula 1, carry out reaction synthesis

Formula I

Its process steps are:

a. Dissolving 2,3-dihydro-1H-inden-1-one oxime in aqueous ethanol solution, adding aluminum amalgam for reduction reaction;

b, the reactant completed by the reaction in step a is separated by solid-liquid, and the filtrate is evaporated under reduced pressure to obtain the oily crude product of 2,3-dihydro-1H-indene-1-amine; it can be directly used in the production of rasagiline synthesis. the

Described processing step also comprises step c:

c. The crude oil product in step b can be distilled under reduced pressure to obtain the pure product of 2,3-dihydro-1H-inden-1-amine. the

The reaction temperature in the step a is 20°C-90°C, if the temperature is too low, the reaction will be slow, if the temperature is higher than 90°C, side reactions will easily occur, preferably the reaction temperature is between 50°C-80°C. the

The content of ethanol in the ethanol aqueous solution in described step a is 10-98%, because the content is too low, although the ethanol aqueous solution can react, because 1-indoxime has poor solubility in water, and aluminum amalgam consumes too much in pure water. Fast, increase reagent consumption; if the content is too high in ethanol aqueous solution, the reaction speed is slower and the reaction time is longer. The ethanol content in the better ethanol aqueous solution is between 80-95%, and the aluminum amalgam consumption and reaction speed are relatively moderate . the

The amount of aluminum amalgam in the step a is calculated as 1-1.5 times of the theoretical amount of the reduction reaction in terms of metal aluminum. If the amount is lower than 1 time, the reaction will not be carried out thoroughly; if it is higher than 1.5 times, the reaction yield cannot be significantly improved. Greater reagent consumption, and increased processing difficulty, preferably 1.05-1.2 times. the

The completion of the reaction in step a is judged by thin layer chromatography. the

The preparation of the aluminum amalgam is to use metal aluminum as a raw material, soak in a soluble mercury salt solution for 1-10 minutes, when a small amount of bubbles are generated on the surface of the metal aluminum, pour off the aqueous solution, and use pure water to prepare the aluminum amalgam. Wash and serve. the

The preparation technology of the intermediate 2 of the synthetic rasagiline mesylate of the present invention, 3-dihydro-1H-indene-1-amine, adopts 2,3-dihydro-1H-indene-1-one oxime in ethanol In the aqueous solution, 2,3-dihydro-1H-indene-1-amine is obtained by reduction with aluminum amalgam, and the purpose of low-cost synthesis of 2,3-dihydro-1H-indene-1-amine is achieved. The process of the present invention has the advantages of Simple, low cost, easy to operate, no danger, and high yield. the

Detailed ways

The present invention will be further described below in conjunction with specific embodiment:

Step a: Add 14.72 g (0.1 mol) of 2,3-dihydro-1H-inden-1-one oxime to a 500 ml flask equipped with a mechanical stirrer and a constant temperature water bath, add 150 ml of 85% ethanol solution, and heat to 60 ℃, keep a constant temperature of 60 ℃. Add 0.01g of mercury sulfate into a 500ml beaker, add 100ml of water, stir to dissolve, add 4.32g (0.16mol) of aluminum sheet cut into about 0.5cm×0.5cm into the prepared mercury sulfate solution, stir with a glass rod for 1 Minutes, completely infiltrate the aluminum sheet with the solution, observe tiny air bubbles on the aluminum sheet, pour out the mercury sulfate solution, and wash the prepared aluminum amalgam twice with clean water to obtain the aluminum amalgam. Aluminum amalgam is added in the flask, and after reacting for 1 hour, detect 2,3-dihydro-1H-inden-1-one oxime conversion with thin-layer chromatography;

Step b: Cool the reaction material in step a to room temperature, filter, wash the filter cake with ethanol, combine the filtrate and washing liquid, and evaporate the aqueous ethanol solution under reduced pressure to obtain 12.9 g of light yellow oil, with a purity of 98.9% by HPLC. the

Step c: The crude oil product in step b can be distilled under reduced pressure to obtain pure 2,3-dihydro-1H-inden-1-amine with an HPLC purity of 99.99%. the

Introduce below by 2,3-dihydro-1H-indene-1-amine that process of the present invention prepares and carry out the preparation of rasagiline mesylate, reaction formula is as shown in formula III:

Formula III

Proceed as follows:

Step 1, the preparation of rasagiline tartrate

Add 13.32 g (0.1 mol) of 2,3-dihydro-1H-inden-1-amine oily substance prepared in Example b or c into a 500 ml flask, add 100 ml of dichloromethane, stir to dissolve, and cool in an ice-water bath to -4°C, add 100ml of 8% aqueous sodium hydroxide solution, add 21.03g (0.1mol) of propynyl p-toluenesulfonate, stir for 10 minutes, heat and reflux in a water bath for 2 hours, and the thin layer chromatography detects that the reaction is complete, and the reaction solution is cooled to Room temperature, liquid separation, dichloromethane layer washed with 100ml of saturated sodium chloride solution, dried with 10g of anhydrous magnesium sulfate, after drying, filtered, and the filtrate was evaporated under reduced pressure to obtain a light brown oil, which was added to a 250ml flask Add 50ml of isopropanol, stir to dissolve, add 9.31g (0.05mol) of L-tartaric acid, heat until completely dissolved, cool to room temperature, continue stirring for 3 hours, a white solid precipitates, filter and dry to obtain 10.22g of white solid powder, The yield is 41.05% based on 2,3-dihydro-1H-inden-1-amine. HPLC purity 99.5%. The melting point is 174.9-176.3°C. the

Step 2, the preparation of rasagiline mesylate

Add 9.85g (0.02mol) of rasagiline L-tartrate into a 500ml flask, add 50ml of isopropanol, cool to -4°C in an ice bath, drop in 3.85g (0.04mol) of methanesulfonic acid, and continue stirring for 10 minutes , heated in a water bath until all the solids were dissolved, cooled to room temperature, a white solid was precipitated, filtered, and dried to obtain 8.66 g of rasagiline mesylate, with a yield of 81%. The melting point is 150.1-151.0°C. the

The above-described embodiments are only preferred examples of the present invention, and are not intended to limit the scope of the present invention, so all equivalent changes or modifications made according to the structure, features and principles described in the patent scope of the present invention should be Included in the patent application scope of the present invention. the

Claims (7)

1. A preparation process for 2,3-dihydro-1H-indene-1-amine is characterized in that, adopting 2,3-dihydro-1H-indene-1-one oxime is raw material production 2,3-dihydro Hydrogen-1H-inden-1-amine, according to the reaction formula shown in formula one, carry out reaction synthesis

Formula I Its process steps are: a. Dissolving 2,3-dihydro-1H-inden-1-one oxime in aqueous ethanol solution, adding aluminum amalgam for reduction reaction; b. The reactant obtained from the reaction in step a is separated into solid and liquid, and the filtrate is evaporated under reduced pressure to obtain the crude oily product of 2,3-dihydro-1H-inden-1-amine; 2. a kind of 2 according to claim 1, the preparation technology of 3-dihydro-1H-inden-1-amine, is characterized in that, described processing step also comprises step c: c. The crude oil product in step b can be distilled under reduced pressure to obtain the pure product of 2,3-dihydro-1H-inden-1-amine. 3. A process for preparing 2,3-dihydro-1H-inden-1-amine according to claim 1, characterized in that the reaction temperature in step a is 20°C-90°C. 4. The preparation process of a kind of 2,3-dihydro-1H-inden-1-amine according to claim 1, characterized in that, the ethanol content in the ethanol aqueous solution in the step a is 10-98%. 5. a kind of 2 according to claim 1, the preparation technology of 3-dihydro-1H-indene-1-amine is characterized in that, described step a aluminum amalgam consumption is calculated as completing reduction reaction theory with metal aluminum 1-1.5 times the amount. 6. The preparation process of a kind of 2,3-dihydro-1H-inden-1-amine according to claim 1, characterized in that, the completion of the reaction in the step a is determined by thin-layer chromatography. 7. a kind of 2 according to claim 1, the preparation technology of 3-dihydro-1H-indene-1-amine is characterized in that, the preparation of described aluminum amalgam, for adopting metal aluminum as raw material, soaks in Soak in the soluble mercury salt solution for 1-10 minutes, when a small amount of air bubbles appear on the surface of the metal aluminum, pour off the aqueous solution, and wash the prepared aluminum amalgam with pure water.