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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

Active Publication Date: 2018-07-20
YANGTZE RIVER PHARM GRP CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Although (5R,11S)-5,6,7,8,9,10,11,12-octahydro-3-methoxy-5-methyl-5,11- Methylenebenzocyclodecen-13-one can avoid the pollution and cost caused by racemic resolution and low-selectivity asymmetric synthesis process, and greatly improve production efficiency; but high stereoselective synthesis (5R,11S)- 5,6,7,8,9,10,11,12-Octahydro-3-methoxy-5-methyl-5,11-methylenebenzocyclodecen-13-one (Compound 3) There are two: on the one hand, in the structure of (1R)-1-(5-bromopentyl)-7-methoxy-1-methyl-tetralone (compound 2), it contains an all-carbon chiral quaternary carbon center , using asymmetric catalytic construction has considerable challenges (see Quaternary stereocenters: challenges and solutions for organic synthesis Edited by Christoffers, J.; Baro, A. 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim); The separation process cannot be advanced, such as advancing the resolution of the penultimate step to compound 2 or 3. Compounds 2 and 3 have only one phenolic hydroxyl group and carbonyl group. The phenolic hydroxyl group is weakly acidic and cannot be effectively resolved with conventional chiral bases.

Method used

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  • Asymmetric synthesis method of dezocine key intermediate
  • Asymmetric synthesis method of dezocine key intermediate
  • Asymmetric synthesis method of dezocine key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Preparation of (1R)-1-(5-bromopentyl)-7-methoxy-1-methyl-tetralone

[0054] In a 250ml three-necked flask, 7-methoxy-1-methyl-2-tetralone (2.5g, 13mmol), 1,5-dibromopentane (7.55g, 32.8mmol), cinchoni Butyl derivative catalyst (0.75g, 1.3mmol R is 2,4-difluorobenzyl, X is Br) and methyl tert-butyl ether (150ml, 55V), under nitrogen protection, under dark conditions, add 40wt% of KOH aqueous solution (KOH 7.3g, 130mmol), the reaction temperature is controlled at 5-15°C, after 3 hours of reaction, the liquids are separated, the aqueous phase is extracted three times with methyl tert-butyl ether (10ml each time), the organic phases are combined, and 3% The organic phase was washed with HCl; the aqueous phase was discarded, and the organic phase was washed with saturated NaCl solution until pH = 7.0-8.0; the organic phase was dried over anhydrous sodium sulfate. After concentrating under reduced pressure, 3.4 g of oil was obtained, with a yield of 78%; [α] D 20 =+24 (c=1...

Embodiment 2

[0058] Preparation of (1R)-1-(5-bromopentyl)-7-methoxy-1-methyl-tetralone

[0059] In a 500ml three-necked flask, 7-methoxy-1-methyl-2-tetralone (5.0g, 26.3mmol), 1,5-dibromopentane (15.1g, 65.7mmol), cinchor Nitin derivative catalyst (0.75g, 1.3mmol, R is 2-fluoro-4-trifluoromethylbenzyl, X is BF 4 ) and dichloromethane (150ml, 30V), under nitrogen protection, under dark conditions, 10wt% LiOH aqueous solution (LiOH 9.4g, 394.5mmol) was added dropwise, the reaction temperature was controlled at 5-15°C, after 6h of reaction, the 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 to pH=7.0-8.0 with saturated NaCl solution; anhydrous sodium sulfate The organic phase is dried. After concentrating under reduced pressure, 6.7 g of oil was obtained, with a yield of 76%; [α] D 20 =+25(...

Embodiment 3

[0061] Preparation of (1R)-1-(5-bromopentyl)-7-methoxy-1-methyl-tetralone

[0062] In a 5L three-necked flask, 7-methoxy-1-methyl-2-tetralone (50g, 263mmol), 1,5-dibromopentane (151g, 657.5mmol), cinchonidine derivatized Catalyst (14.1g, 26.3mmol, R is 3-fluoro-4-trifluoromethylbenzyl, X is Br) and toluene (1.65L, 35V), nitrogen protection, under dark conditions, drop 30wt% of CsOH aqueous solution (CsOH 587g, 3.945mol), the reaction temperature is controlled at 10-15°C, after 1h of reaction, the liquid is separated, the aqueous phase is extracted three times with toluene (250ml each time), the organic phase is combined, and the organic phase is washed with 5% HCl 2 times; 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 over anhydrous sodium sulfate. After concentrating under reduced pressure, 72.2 g of oil was obtained, with a yield of 81%; [α] D 20 =+23 (c=1.0.CHC1 3 ), the HPLC det...

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Abstract

The invention discloses an asymmetric synthesis method of a dezocine key intermediate, namely, (5R,11S)-5,6,7,8,9,10,11,12-octahydro-3-methoxy-5-methyl-5,11-methylenebenzocyclodecene-13-one. The synthesis method comprises the steps as follows: 7-methoxy-1-methyl-2-tetralone is adopted as a raw material, and an alkylation reaction intermediate, namely, (1R)-1-(5-bormopentyl)-7-methoxy-1-methyl-tetralone, is synthesized in a stereoselective manner under the catalysis of a cinchonidine derivative; ring formation under the alkaline action is performed, and (5R,11S)-5,6,7,8,9,10,11,12-octahydro-3-methoxy-5-methyl-5,11-methylenebenzocycldecene-13-one with high chiral purity is obtained through recrystallization. The method is high in reaction yield, low in cost, mild in condition and suitable for efficient synthesis of dezocine on a large scale.

Description

technical field [0001] The present invention relates to the synthesis of pharmaceutical compounds, in particular to the key intermediate (5R,11S)-5,6,7,8,9,10,11,12-octahydro-3-methoxy- Asymmetric synthesis of 5-methyl-5,11-methylenebenzocyclodecen-13-one. Background technique [0002] Dezocine, English name Dezocine, chemical name (-)-[5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro -5-methyl-5,11-methylenebenzocyclodecen-3-ol, the chemical structural formula is as shown in I: [0003] [0004] Dezocine, developed by Astrazeneca, is a potent opioid analgesic that mainly acts on μ and κ receptors. The analgesic effect of dezocine is equivalent to that of morphine, with less addiction and milder adverse reactions than similar drugs. It is suitable for the treatment of moderate to severe pain after surgery, visceral colic and pain in patients with advanced cancer. One of the most widely used drugs for analgesia. [0005] There are three consecutive chiral center...

Claims

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Application Information

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IPC IPC(8): C07C45/68C07C49/755C07C45/67C07B53/00
CPCC07B53/00C07B2200/07C07C45/67C07C45/673C07C45/68C07C49/755
Inventor 黄翔徐镜人肖志超要世伟蔡伟任中杰张海波袁晓林王佩强张小军
Owner YANGTZE RIVER PHARM GRP CO LTD
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