Asymmetric synthesis method of dezocine key intermediate
A synthesis method and intermediate technology, applied in the field of synthesis of pharmaceutical compounds, can solve the problem that the racemization resolution process cannot be advanced, and achieve the effects of low cost, simple steps and mild conditions
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[0052] Example 1
[0053] (1R)-1-(5-Bromopentyl)-7-methoxy-1-methyl-tetralone
[0054] In a 250ml three-necked flask, add 7-methoxy-1-methyl-2-tetralone (2.5g, 13mmol), 1,5-dibromopentane (7.55g, 32.8mmol), cinchoni Butane derivative catalyst (0.75g, 1.3mmolR is 2,4-difluorobenzyl, X is Br) and methyl tert-butyl ether (150ml, 55V), protected by nitrogen and protected from light, add 40wt% of KOH aqueous solution (KOH 7.3g, 130mmol), the reaction temperature is controlled at 5-15℃, after 3 hours of reaction, the liquids are separated, the aqueous phase is extracted three times with methyl tert-butyl ether (10ml each time), and the organic phases are combined with 3% The organic phase was washed with HCl; the aqueous phase was discarded, and the organic phase was washed with saturated NaCl solution to pH=7.0-8.0; the organic phase was dried with anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 3.4 g of oily substance with a yield of 78%; [α] D 20 =+24(c=1.0.CH...
Example Embodiment
[0057] Example 2
[0058] (1R)-1-(5-Bromopentyl)-7-methoxy-1-methyl-tetralone
[0059] In a 500ml three-necked flask, add 7-methoxy-1-methyl-2-tetralone (5.0g, 26.3mmol), 1,5-dibromopentane (15.1g, 65.7mmol), and Sink Nidin derivative catalyst (0.75g, 1.3mmol, R is 2-fluoro-4-trifluoromethylbenzyl, X is BF 4 ) And dichloromethane (150ml, 30V), protected by nitrogen and protected from light, add 10wt% LiOH aqueous solution (LiOH 9.4g, 394.5mmol) dropwise, the reaction temperature is controlled at 5-15℃, after 6h reaction, liquid separation , The aqueous phase was extracted three times with dichloromethane (25ml each time), the organic phases were combined, and the organic phase was washed with 1% HCl; the aqueous phase was discarded, and the organic phase was washed with saturated NaCl solution to pH=7.0-8.0; anhydrous sodium sulfate Dry the organic phase. Concentrate under reduced pressure to obtain 6.7 g of oily substance with a yield of 76%; [α] D 20 =+25(c=1.0.CHC1 3 ), the ee...
Example Embodiment
[0060] Example 3
[0061] (1R)-1-(5-Bromopentyl)-7-methoxy-1-methyl-tetralone
[0062] In a 5L three-necked flask, add 7-methoxy-1-methyl-2-tetralone (50g, 263mmol), 1,5-dibromopentane (151g, 657.5mmol), cinchonidine derivative Compound catalyst (14.1g, 26.3mmol, R is 3-fluoro-4-trifluoromethylbenzyl, X is Br) and toluene (1.65L, 35V), protected by nitrogen and protected from light, add 30wt% of CsOH aqueous solution (CsOH 587g, 3.945mol), the reaction temperature is controlled at 10-15℃, after reacting for 1h, the liquids are separated, the aqueous phase is extracted three times with toluene (250ml each time), the organic phases are combined, and the organic phases are washed with 5% HCl 2 Times; discard the water phase, wash the organic phase with saturated NaCl solution to pH=7.0-8.0; dry the organic phase with anhydrous sodium sulfate. Concentrated under reduced pressure to obtain 72.2g of oily substance with a yield of 81%; [α] D 20 =+23(c=1.0.CHC1 3 ), the ee value of 78% d...
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