Synthetic method for aromatic cyclourea spiral medicine template and application of template in antineoplastic drugs
A technology of aromatic rings and ureas, which is applied in the field of synthesis of aromatic ring urea spirocyclic drug templates, can solve the problems of long reaction steps, unsuitability for large-scale derivative synthesis, low efficiency, etc., and achieve fewer reaction steps and easy scale-up The effect of simple preparation and process
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Embodiment 1
[0039]
[0040] 1. Synthesis of 2-(propylamine)-2,3-dihydro-1H-indene-2-carbonitrile
[0041] Dissolve 2-indanone (4 g, 30.3 mmol) and propylamine hydrochloride (3.1 g, 32.6 mmol) in water (60 mL), stir at room temperature for 60 minutes; then add sodium cyanide (1.62 g, 33.1 mmol) , continue stirring at room temperature for 15 hours. The reaction system was extracted with dichloromethane (120 mL), washed with saturated brine (3×100 mL), and the organic phase was washed with Na 2 SO 4 Drying, removal of solvent to obtain 2-(propylamine)-2,3-dihydro-1H-indene-2-carbonitrile crude product 5.6 g, MS (m / z): 201 (M+1); directly applied to Next step.
[0042] 2. Synthesis of 2-(aminomethyl)-N-propyl-2,3-dihydro-1H-inden-2-amine
[0043] Dissolve 5.6 g (purity 30%, 12.6 mmol) of 2-(propylamine)-2,3-dihydro-1H-indene-2-carbonitrile crude product obtained in step 1 in 150 mL of anhydrous ether and cool in an ice bath To below 5 degrees, add lithium aluminum hydride (0.95 g, 2...
Embodiment 2
[0048]
[0049] 1. Synthesis of 2-(Benzylamine)-2,3-dihydro-1H-indene-2-carbonitrile
[0050] Dissolve 2-indanone (3.58 g, 27 mmol) and benzylamine hydrochloride (4.27 g, 29.7 mmol) in water (350 mL), stir at room temperature for 60 minutes; then add sodium cyanide (1.46 g, 29.7 mmol ), and continued stirring at room temperature for 15 hours. The reaction system was extracted with dichloromethane (1000 mL), washed with saturated brine (3×100 mL), and the organic phase was washed with Na 2 SO 4 Drying, removal of solvent to obtain 7 g of crude product 2-(benzylamine)-2,3-dihydro-1H-indene-2-carbonitrile, MS (m / z): 249 (M+1); direct application without purification in the next step.
[0051] 2. Synthesis of 2-(aminomethyl)-N-benzyl-2,3-dihydro-1H-inden-2-amine
[0052] Dissolve 7 g (purity 31 %, 12.1 mmol) of 2-(benzylamine)-2,3-dihydro-1H-indene-2-carbonitrile crude product obtained in step 1 in 200 mL of anhydrous ether and place in an ice bath Cool to below 5°C, add...
Embodiment 3
[0057]
[0058] 1. Synthesis of 2-(aniline)-2,3-dihydro-1H-indene-2-carbonitrile
[0059] Dissolve 2-indanone (10 g, 0.075 mol) and aniline hydrochloride (7.67 g, 82.5 mmol) in water (120 mL), stir at room temperature for 30 minutes; then add sodium cyanide (4.04 g, 82.5 mmol) , continue stirring at room temperature for 15 hours. The reaction system was extracted with dichloromethane (250 mL), washed with saturated brine, and the organic phase was washed with Na 2 SO 4 Drying and removing the solvent gave 14.71 g of crude product 2-(isopropylamine)-2,3-dihydro-1H-indene-2-carbonitrile, MS (m / z): 235 (M+1); directly used without purification in the next step.
[0060] 2. Synthesis of 2-(aminomethyl)-N-phenyl-2,3-dihydro-1H-inden-2-amine
[0061] 14.71 g (purity 70%, 63 mmol) of 2-(aniline)-2,3-dihydro-1H-indene-2-carbonitrile crude product obtained in step 1 was dissolved in 250 mL of anhydrous ether, and cooled in an ice bath to Below 5°C, add lithium aluminum hydride ...
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