Preparation of 2-chloro-3-amino-4-methylpyridine_Industrial additives

Preparation background and overview of 2-chloro-3-amino-4-methylpyridine

2-Chloro-3-amino-4-methylpyridine is a key intermediate for the anti-AIDS drug Nevirapine. Nevirapine, chemical name 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[1,4]diazepine-6-one, was developed by the German company Boehringer Ingelheim in the 1990s. A kind of non-nucleoside HIV reverse enzyme inhibitors (NNRTIs) developed in the early 1990s can be used alone or in combination with drugs to treat adults with HIV infection and AIDS. It can effectively resist human immunodeficiency virus-1 (HIV-1). It mainly prevents HIV replication. It is currently one of the most widely used anti-AIDS drugs. It is mainly used to prevent mother-to-child virus transmission. Compared with other anti-AIDS drugs, 2-chloro-3-amino-4-methylpyridine has strong antiviral effect, long half-life, high bioavailability, good tolerance and low cost. Judging from the geographical distribution of AIDS incidence, the vast majority of AIDS patients are in areas with backward economic and medical conditions. 2-Chloro-3-amino-4-methylpyridine is the most practical, most effective and least expensive ideal anti-AIDS drug.

2-Chloro-3-amino-4-methylpyridine

Preparation and application of 2-chloro-3-amino-4-methylpyridine

2-Chloro-3-amino-4-methylpyridine is a key pharmaceutical intermediate for the synthesis of the anti-AIDS drug nevirapine. It is widely used in the synthesis and research and development of medicines, pesticides, and veterinary drugs, and has high application value and market value.

Preparation of 2-chloro-3-amino-4-methylpyridine

There are currently three main routes for the synthesis of nevirapine. The most important route is to use 2-chloro-3-amino-4-methylpyridine and 2-chloronicotinic acid chloride for amidation reaction and then condense with cyclopropylamine to obtain N- (2-Chloro-4-methylpyridin-3-yl)-2-cyclopropylaminonicotinic acid amide is then refluxed and closed under the action of NaH in DMF solvent to obtain the product. 2-Chloro-3-amino-4-methylpyridine (CAPIC) has become a key intermediate.

The synthesis methods of CAPIC reported in the literature mainly include the following:

Method 1: Using 2-hydroxy-3-nitro-4-methylpyridine as raw material, CAPIC is obtained through chlorination and reduction of pyridinium chlorochromate salt. However, the raw materials for this method are not easy to obtain (US5366972).

Method 2: Use 2-amino-4-methylpyridine as raw material. It is obtained by diazotization first, then nitrification, chlorination, hydrogenation reduction, and finally chlorination. The raw materials of this method are cheap and easy to obtain, but there are serious shortcomings, mainly in that the nitrification products are almost non-selective, and at the same time, a large amount of waste acid and waste water are produced, causing environmental pollution, so it can only be limited to small experiments in laboratories.

Method 3: Using 2-chloro-3-aminopyridine and methylmercaptan as starting materials (US5654429). The reaction of this method is too complex, the cost is high, the yield is low, and it is difficult to industrialize.

Method 4: Using ethyl acetoacetate and cyanoacetamide as starting materials (US5668287). The characteristic of this method is that it avoids the shortcomings of the nitrification process. However, the hydrogenation reduction reaction requires the use of expensive palladium chloride or palladium carbon catalysts. Therefore, the cost of industrialization is higher.

Method 5: Using ethyl cyanoacetate and crotonaldehyde as starting materials, ethyl cyanoacetate is first chlorinated, and then reacted with crotonaldehyde, cyclized, ester hydrolyzed, reacted with sulfoxide chloride, ammonia solution and finally degradation (Regioselective synthesis of 2-chloro-3-pyridinecarboxylates. Tetrahedron, 1995, 51(48): 77-84). In this method, the addition reaction speed is very slow and the cyclization yield is very low.

Method 6: Use malononitrile and acetone as raw materials. Malononitrile and acetone are condensed, reacted with an acetic anhydride solution of triethyl orthoformate, cyclized under anhydrous NH3/ethanol, diazotized and hydrolyzed with sodium nitrite, and then chlorinated with phosphorus oxychloride. The concentrated sulfuric acid is hydrolyzed to obtain the amide, which is finally degraded to obtain the finished product (US6111112). This method has a long process route, serious environmental pollution, and low overall yield.

Method 7: Using ethyl cyanoacetate and acetone as starting materials (US6136982). First, ethyl cyanoacetate and acetone are condensed to obtain 3-methyl-2-cyano-2-butenoic acid acetic acid, which is then reacted with dimethylformamide dimethyl acetal to obtain conjugated enamine, conjugated enamine Cyclization with ethanol hydrochloride gives 2-chloro-4-methyl-nicotinic acid ethyl ester. The ester is hydrolyzed to give acid, which is converted into acid chloride by using thionyl chloride, and then ammoniated to give 2-chloro-4-methyl-nicotinamide. Finally, it degrades to produce the finished product. At present, this method is widely used, but the original route has many reaction steps, with a total of seven steps from starting material to product. In the current market competition, cost pressure is rising.