Imatinib intermediate and preparation method thereof
A technology for intermediates and compounds, applied in the pharmaceutical field, can solve problems such as large environmental pollution, and achieve the effects of simple and easy process conditions, mild process conditions, and easy realization.
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[0050] (2) Preparation method of imatinib intermediate V
[0051] The present invention secondly provides a method for preparing imatinib intermediate V as described in (1), said method comprising:
[0052] The following ring closure reaction occurs between the compound shown in formula III and the compound shown in formula IV under alkaline environment, so as to obtain the compound shown in formula V:
[0053]
[0054] Among them, R is selected from C 1 ~C 8 straight-chain or branched-chain alkanes, or benzyl.
[0055] Preferably, the molar ratio of the compound represented by formula III to the compound represented by formula IV is 1:(0.8-1.5), more preferably 1:(1.0-1.2). If the above-mentioned ratio is too low, the feeding amount of formula IV will be increased unnecessarily, which will not only increase the cost of preparing formula V, but also affect the purity of intermediate V; if the above-mentioned ratio is too high, the reaction of intermediate III will be inc...
Embodiment 1
[0082] Example 1: Preparation of the key intermediate 2-methoxy-4-(3-pyridyl)pyrimidine (Formula V):
[0083] Add 176g (1.00mol) of raw material III and 121.6g (1.10mol) of the hydrochloride salt of raw material IV whose R is a methyl group to 44g (1.1mol) of sodium hydroxide / 1000ml of methanol solution that has been stirred and dissolved, and heat up to reflux The reaction was carried out for 8 hours, and the reaction temperature was 65°C. After the reaction, desolvate under reduced pressure at 50°C (that is, remove the solvent, the same below), then add 400ml of dichloromethane and 400ml of pure water to dissolve, stir, extract and separate, and the organic layer is washed once with 400ml of pure water. 50 g of anhydrous sodium sulfate was dried for 1 hour, suction filtered, and the solvent was removed to obtain 173.7 g of a light yellow oily substance, namely 2-methoxy-4-(3-pyridyl)pyrimidine. The molar yield is 92.8%. HPLC purity was 98.72%.
[0084] The nuclear magneti...
Embodiment 2
[0085] Example 2: Preparation of the key intermediate 2-methoxy-4-(3-pyridyl)pyrimidine (Formula V):
[0086] Add 176g (1.00mol) of raw material III and 121.6g (1.10mol) of the hydrochloride salt of raw material IV whose R is a methyl group to the 44g (1.1mol) sodium hydroxide / 1000ml ethanol solution that has been stirred and dissolved, and heat up to reflux The reaction was carried out for 6 hours, and the reaction temperature was 77°C. After the reaction, desolvate under reduced pressure at 50°C, then add 400ml of dichloromethane and 400ml of pure water for dissolution, stirring, extraction, and liquid separation, and the organic layer is washed once with 400ml of pure water. 50 g of anhydrous sodium sulfate was dried for 1 hour, suction filtered, and the solvent was removed to obtain 172.1 g of light yellow oily substance, namely 2-methoxy-4-(3-pyridyl)pyrimidine. The molar yield is 91.9%, and the HPLC purity is 98.56%.
[0087] The NMR and mass spectrometry detection dat...
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