Preparation process of key intermediate 2-cyano pyrimidine of bosentan

Abstract

The invention discloses a preparing method of key Boston drug intermediate 2-cyano pyrimidine, which comprises the following steps: adopting alkyl benzene as reacting solvent; making 5-30% cuprous iodide, 1.5-3% potassium iodide and 1-1.5% N, N'-dimethyl ethanediamine as composite catalyst; reacting 2-bromine pyrimidine and sodium cyanide with molar rate at 1: 1.0-2.0 protected by nitrogen at 100-150 Deg C for 20-48h; filtering; washing the filtrate; drying; condensing; recrystallizing to separate to form the product through ligroine.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation process of 2-cyanopyrimidine, a key intermediate of bosentan medicine. Background technique [0002] Bosentan (Bosentan) is a new type of non-peptide, non-selective endothelin receptor antagonist developed by Swiss Actelion Company, which was approved by FDA in 2001 and listed in the United States. Mainly used in the treatment of pulmonary hypertension. 2-cyanopyrimidine is a key intermediate in the synthesis of bosentan. There are three main synthetic routes about 2-cyanopyrimidine reported in the literature. Route one Pharm.Bull.(Tokyo), 1955, 3 (1): 173-174 takes 2-sodium pyrimidine sulfonate as raw material, uses potassium cyanide as nucleophile, generates target compound through heating reaction, simple to operate, but The yield is very low, only 20%. Route 2 J.Am.Chem.Soc.1959,81(4):905-906 uses trimethylpyrimidinium-2-ammonium chlor...

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Problems solved by technology

Route 2 J.Am.Chem.Soc.1959,81(4):905-906 uses trimethylpyrimidinium-2-ammonium chloride as a raw material and potassium cyanide as a nucleophile to react in acetamide to generate the target Compound; the operation is more complicated, the reaction time is long, and the yield is only 40%

Route three Monatsh, 1956,87 (3): 526-536 uses trimethylpyrimidinium-2-ammonium chloride as a raw material, and tetraethyl cyanamide as a nucleophile reacts in dichloromethane to generate the target compound; The operation is simple and the reaction conditions are mild, but the nucleophile tetraethylcyanoammonium is not easy to buy, and the price is very expensive. The preparation of tetraethylcyanoammonium in the laboratory needs to use an ion exchange column, which has a long operation cycle and the initial product The recrystallization process is cumbersome and the yield is not high.

The above-mentioned synthesis process conditions are harsh, or many experimental processes involve various problems such as low yield and complicated post-processing.

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