Preparation method of olanzapine
A compound and water-absorbing agent technology, applied in the direction of organic chemistry, can solve the problems of reducing product purity, affecting the quality of olanzapine pharmaceutical products, and difficult removal of impurities, so as to achieve the effect of improving purity and yield
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Embodiment 1
[0034] 1, the preparation of 2-amino-5 methyl-3-thiophenecarbonitrile
[0035] Sulfur (21.8g, 0.68mol), propionaldehyde (47.3g, 0.81mol) and DMF (135ml) were added to the reaction flask, and triethylamine (57.6mol, 0.41mol) was added dropwise at 5-10°C for about 30 minutes After the addition is completed, react at 18-20°C for 1 hour, add a mixture of malononitrile (45g, 0.68mol) and DMF (90ml) dropwise, and add it for about 1 hour, then continue to react at 15-20°C for 1 hour, and the reaction The solution was washed into ice water to produce a yellow precipitate, which was allowed to stand, filtered, washed with water, and dried under pressure to obtain a yellow solid (70 g), yield 74.6%, mp 99-100°C.
[0036]
[0037] 2. Preparation of 2-(2-nitrophenylamine)-5 methyl-3-thiophenecarbonitrile
[0038] In a solution of sodium hydride (14.4g, 50%, 0.3mol) and THF (50ml), 2-fluoronitrobenzene (28.2g, 0.2mol) and 2-amino-5methyl-3-thienylbenzene were added dropwise The mixtur...
Embodiment 2
[0052] 1, the preparation of olanzapine
[0053] 2-Methyl-4-amino-1OH-thieno[2,3-b][1,5]benzodiazepine hydrochloride (50g, 0.19mol, refer to Example 1 for preparation), anhydrous piperidine Put oxazine (200g, 2.3mol), DMSO (250ml), toluene (250ml), and calcium oxide (2.5g) into the reaction bottle, heat to reflux for 20 hours, let cool to 50°C, pour 1000ml of 0-10°C saturated Sodium bicarbonate solution, placed, filtered, washed with water, dried to obtain a yellow solid, put this solid into a 1L reaction flask, add DMSO (500ml), 37% formaldehyde (14.6g, 0.18mol), 98% formic acid (8.4 g, 0.18mol), stirred and reacted at 80°C for 2 hours, poured into ice water, filtered, washed with water, dried to obtain the crude product of olanzapine (47g), yield 80%, HPLC: olanzapine: 88%, formula (VII) impurity 6.8%, no impurity represented by formula (VI) was detected.
[0054]
[0055] 2. Refined
[0056] Take the crude product of olanzapine (47g), ethanol (500ml), and activated ca...
Embodiment 3
[0060] 1, the preparation of olanzapine
[0061] 2-Methyl-4-amino-1OH-thieno[2,3-b][1,5]benzodiazepine hydrochloride (50g, 0.19mol, refer to Example 1 for preparation), anhydrous piperidine Put oxazine (200g, 2.3mol), DMSO (250ml), toluene (250ml), and calcium oxide (2.5g) into the reaction bottle, heat and reflux for 20 hours, let cool to 50°C, and pour 1000ml of 0-10°C saturated carbonic acid Sodium hydrogen solution, placed, filtered, washed with water, dried to obtain a yellow solid, put this solid into a 1L reaction flask, add DMSO (500ml), 37% formaldehyde (14.6g, 0.18mol), 85% formic acid (9.7g , 0.18mol), stirred and reacted at 80°C for 2 hours, poured into ice water, filtered, washed with water, dried to obtain the crude product of olanzapine (50g), yield 85%, HPLC: olanzapine 90%, undetected Formula (VI) impurity, formula (VII) impurity 2.3%.
[0062]
[0063] 2. Refined
[0064] Take crude olanzapine (50g), ethanol (500ml), and activated carbon (2.5g) in a rea...
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