阅读说明：本技术 一种3，5-二甲基金刚烷胺盐酸盐的制备方法 (Preparation method of 3, 5-dimethyl amantadine hydrochloride ) 是由 沈建伟 于 2021-09-17 设计创作，主要内容包括：本发明公开了一种3,5-二甲基金刚烷胺盐酸盐的制备方法,将1-硝基-3,5-二甲基金刚烷加入第一溶剂中,并在催化剂存在下进行氢化反应,氢化物料经脱溶后加水采用水蒸汽蒸馏,蒸馏液用第二溶剂萃取后加入盐酸共沸脱水后结晶分离得3,5-二甲基金刚烷胺盐酸盐。本发明方法原料便宜易得,反应条件温和,产率高,产品质量好,易于实现工业化生产。(The invention discloses a preparation method of 3, 5-dimethyl amantadine hydrochloride, which comprises the steps of adding 1-nitro-3, 5-dimethyl amantadine into a first solvent, carrying out hydrogenation reaction in the presence of a catalyst, desolventizing a hydrogenated material, adding water, distilling by adopting steam, extracting a distillate by using a second solvent, adding hydrochloric acid, carrying out azeotropic dehydration, and carrying out crystallization separation to obtain the 3, 5-dimethyl amantadine hydrochloride. The method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, high yield, good product quality and easy realization of industrial production.)

1. A preparation method of 3, 5-dimethyl amantadine hydrochloride is characterized in that 1-nitro-3, 5-dimethyl amantadine is added into a first solvent, hydrogenation reaction is carried out in the presence of a catalyst, water is added into the hydrogenation material after desolventization, steam distillation is carried out, hydrochloric acid is added into the distillate after extraction by a second solvent, azeotropic dehydration is carried out, and crystallization separation is carried out to obtain the 3, 5-dimethyl amantadine hydrochloride.

2. The method of claim 1, wherein the first solvent is one or more of methanol, ethanol, propanol, and isopropanol.

3. The method of claim 1, wherein the catalyst is one or more of alnico, and alnico.

4. The method for preparing 3, 5-dimethyladamantane hydrochloride according to claim 1, wherein the mass ratio of the 1-nitro-3, 5-dimethyladamantane to the catalyst to the first solvent is 1: 0.02-0.5: 2-10; the hydrogen pressure of the hydrogenation reaction is 0.5-5.0 MPa, the reaction temperature is 50-120 ℃, and the reaction time is 3-20 hours.

5. The method for preparing 3, 5-dimethyladamantane hydrochloride according to claim 1, wherein the mass ratio of the 1-nitro-3, 5-dimethyladamantane to the catalyst to the first solvent is 1: 0.05-0.1: 4-6; the hydrogen pressure of the hydrogenation reaction is 2.0-3.0 MPa, and the reaction temperature is 70-90 ℃; the reaction time is 8-12 hours.

6. The method of claim 1, wherein the second solvent is one or more of pure benzene, toluene, n-hexane, and n-heptane.

7. The method for preparing 3, 5-dimethyladamantane hydrochloride according to claim 1, wherein the concentration of hydrochloric acid is 5% to 36%.

8. The method for preparing 3, 5-dimethyladamantane hydrochloride according to claim 1, wherein the crystallization temperature is 0 to 5 ℃ and the crystallization time is 2 to 3 hours.

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a preparation method of 3, 5-dimethyl amantadine hydrochloride.

Background

3, 5-dimethyl amantadine hydrochloride, chemical name 3, 5-dimethyl tricyclo [3, 3, 1, 13, 7] decan-1-amine hydrochloride. The CAS number is [41100-52-1], and the structural formula is as follows:

amantadine hydrochloride, an excellent dementia therapeutic drug developed by Merz, germany. The product is a voltage-dependent, intermediate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, and can block neuronal damage caused by pathological elevation of glutamate concentration. Amantadine hydrochloride is effective in treating mild Alzheimer Disease (AD), can remarkably improve curative effect when used together with acetylcholinesterase inhibitor, and is a neuroprotective drug for treating dementia (especially AD).

The synthesis of amantadine hydrochloride has been reported. The following methods are mainly used:

bromide synthesis method

The Chinese invention patent CN 103965058A and the world patent WO 2010067252A 1 adopt 1-bromo-3, 5-dimethyl adamantane as raw materials, firstly acetylate reaction is carried out in the presence of acetonitrile and concentrated sulfuric acid, then alkaline hydrolysis is carried out to obtain 1-amino-3, 5-dimethyl adamantane, and the product is obtained after salification and refining. The method uses a large amount of concentrated sulfuric acid, so that the environmental pollution is serious; alkaline high-temperature hydrolysis, harsh reaction conditions, more steps and greater industrialization difficulty.

Direct synthesis of adamantane

The Anhui medicine 2013, 1, 17(1) reports that 1, 3-dimethyl adamantane is used as a raw material, the acetylamino reaction is directly carried out in the presence of acetonitrile, concentrated sulfuric acid and tert-butyl alcohol, then the alkaline hydrolysis is carried out to obtain 1-amino-3, 5-dimethyl adamantane, and the product is obtained by salifying and refining. The method omits the bromination step, but still needs a large amount of concentrated sulfuric acid, so the environmental pollution is serious; alkaline high-temperature hydrolysis, harsh reaction conditions and large industrialization difficulty.

Nitration hydrogenation process

The literature, journal 2009, 1, 40(4), reports that 1, 3-dimethyl adamantane is used as a raw material, and the 1-amino-3, 5-dimethyl adamantane is obtained through nitration, Pd/C catalytic hydrogenation, salification and refining to obtain the product. The method uses expensive noble metal catalyst, the production cost is high, and the product content synthesized by the method is only 98 percent, which is difficult to reach the requirement of drug production.

Disclosure of Invention

The invention aims to provide a preparation method of 3, 5-dimethyl amantadine hydrochloride, which has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, high yield, good product quality and easy realization of industrial production.

In order to achieve the purpose, the technical scheme of the invention is to design a preparation method of 3, 5-dimethyl amantadine hydrochloride, which comprises the steps of adding 1-nitro-3, 5-dimethyl amantadine into a first solvent, carrying out hydrogenation reaction in the presence of a catalyst, desolventizing a hydrogenation material, adding water, distilling by adopting steam, extracting distillate by using a second solvent, adding hydrochloric acid, carrying out azeotropic dehydration, and carrying out crystallization separation to obtain the 3, 5-dimethyl amantadine hydrochloride. The method specifically comprises the following steps:

(1) 1-nitro-3, 5-dimethyl adamantane (structural formula II) is dissolved in a first solvent and subjected to hydrogenation reaction in the presence of a catalyst. The hydrogenated material is desolventized, added with water and distilled by steam to obtain the 3, 5-dimethyl amantadine (structural formula III) with high purity.

(2) Extracting the water solution with a second solvent, adding hydrochloric acid for azeotropic dehydration, and crystallizing to obtain the high-purity product 3, 5-amantadine hydrochloride (structural formula I).

Preferably, the first solvent is one or more of methanol, ethanol, propanol and isopropanol.

Preferably, the catalyst is one or more of alnico, and alnico.

Preferably, the mass ratio of the 1-nitro-3, 5-dimethyl adamantane, the catalyst and the first solvent is 1: 0.02-0.5: 2-10; the hydrogen pressure of the hydrogenation reaction is 0.5-5.0 MPa, the reaction temperature is 50-120 ℃, and the reaction time is 3-20 hours.

Preferably, the mass ratio of the 1-nitro-3, 5-dimethyl adamantane, the catalyst and the first solvent is 1: 0.05-0.1: 4-6; the hydrogen pressure of the hydrogenation reaction is 2.0 to

3.0MPa, and the reaction temperature is 70-90 ℃; the reaction time is 8-12 hours.

Preferably, the second solvent is one or more of pure benzene, toluene, n-hexane and n-heptane.

Preferably, the concentration of the hydrochloric acid is 5-36%.

Preferably, the mass ratio of the 3, 5-dimethyl amantadine to the second solvent in the salt formation reaction is 1: 8-10; the mol ratio of the 3, 5-dimethyl amantadine to the hydrochloric acid is 1: 1.2-1.6, the crystallization temperature is 0-5 ℃, and the crystallization time is 2-3 hours.

The invention has the advantages and beneficial effects that:

1. the hydrogenation of the invention adopts a three-way catalyst, which can be repeatedly recycled and has low production cost.

2. The method adopts a steam distillation method to purify the intermediate, is simple and feasible, and the obtained intermediate 3, 5-dimethyl amantadine has high purity and is easy to realize industrialization.

3. The reaction process of the present invention includes hydrogenation and salt formation. The reaction conditions are mild, the side reactions are less, the pollution is less, the yield is high, and the product quality is good.

Detailed Description

The following further describes embodiments of the present invention with reference to examples. The following examples are only for illustrating the technical solutions more clearly, and are not intended to limit the scope of the present invention.

Example 1: synthesis of 3, 5-dimethyl amantadine hydrochloride

(1) Synthesis of 1-amino-3, 5-dimethyladamantane

Adding 30.0g of 1-nitro-3, 5-dimethyl adamantane, 150ml of methanol and 3.0g of ternary catalyst into a 500ml pressure kettle, sealing the pressure kettle, performing hydrogen replacement for three times, increasing the pressure to 0.1MPa, starting stirring and heating, increasing the temperature to 70 ℃, increasing the hydrogen pressure to 2.5MPa, controlling the hydrogenation temperature to be about 80 ℃, hydrogenating under the condition that the hydrogenation pressure is 2.0-2.5 MPa until hydrogen is not absorbed, and continuously preserving the temperature for 30 min.

After hydrogenation, discharging, filtering, washing with methanol, recycling the catalyst, combining the filtrate and the washing liquid, and removing the solvent under reduced pressure. And (3) after the solvent is removed completely, adding 300ml of water, heating for distillation, supplementing water according to conditions, carrying out steam distillation, distilling 400-450 ml of water, and ending the distillation of the oil-free substances.

(2) Extraction and salification:

adding 200ml toluene into the water solution, stirring for layering, and extracting the water layer with 100ml toluene once. The toluene layers were combined and slowly added with 20g of concentrated hydrochloric acid under stirring, and after the addition was completed, stirring was continued for 30 min. Then heating reflux azeotropic dehydration is carried out, water is removed completely, and a large amount of solid is precipitated. Dewatering, cooling, and freezing. Cooling to below 5 ℃, and continuously stirring for crystallization for 2-3 hrs. Suction filtration, washing with cold toluene, and drying at 60 deg.C to obtain 29.7g white powdery solid. The content is 99.8 percent, and the two-step yield is 96.1 percent. The product was analyzed by nuclear magnetic resonance and its hydrogen spectrum was 1HNMR (CDCl3), 0.85(s, 6H), 1.15(m, 2H), 1.27(q, J ═ 12.5Hz, 4H), 1.65(m, J ═ 11.5Hz, 4H), 1.86(s, 2H), 8.27(s, 3H).

Examples 2 to 5:

the following examples 2 to 5 were all operated as in example 1, and only the three-way catalyst was reused for different times. The results are shown in the following table:

examples 2 to 5 Experimental results

Example 6: synthesis of 3, 5-dimethyl amantadine hydrochloride

(1) Synthesis of 1-amino-3, 5-dimethyladamantane

30.0g of 1-nitro-3, 5-dimethyladamantane, 150ml of ethanol and 3.0g of a three-way catalyst were placed in a 500ml autoclave. The autoclave was closed and hydrogen replaced three times. Adding the pressure to 0.1MPa, starting stirring and heating, raising the temperature to 70 ℃, raising the hydrogen pressure to 2.5MPa, controlling the hydrogenation temperature to be about 80 ℃, hydrogenating under the condition that the hydrogenation pressure is 2.0-2.5 MPa until hydrogen is not absorbed, and continuously preserving the temperature for 30 min.

After hydrogenation, discharging, filtering, washing with methanol, recycling the catalyst, combining the filtrate and the washing liquid, and removing the solvent under reduced pressure. And (3) after the solvent is removed completely, adding 300ml of water, heating for distillation, supplementing water according to conditions, carrying out steam distillation, distilling 400-450 ml of water, and ending the distillation of the oil-free substances.

(2) Extraction and salification:

adding 200ml of n-heptane into the water solution, stirring for layering, and extracting the water layer with 100ml of n-heptane once. The toluene layers were combined and slowly added with 18g of concentrated hydrochloric acid under stirring, and after the addition was completed, stirring was continued for 30 min. Then heating reflux azeotropic dehydration is carried out, water is removed completely, and a large amount of solid is precipitated. Dewatering, cooling, and freezing. Cooling to below 5 ℃, and continuously stirring for crystallization for 2-3 hrs. Suction filtration, washing with cold n-heptane, and drying at below 60 deg.C to obtain white powdery solid 30.1 g. The content is 99.1 percent, and the two-step yield is 97.4 percent.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.