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Synthesis and application of intermediate of tapentadol

A technology of tapentadol and intermediates, applied in the application field of preparing tapentadol and derivatives, can solve the problems of waste, long reaction time, R-configuration products can not be reused and the like

Inactive Publication Date: 2012-05-30
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method overcomes the shortcoming of above-mentioned two kinds of routes, and operation is simple, and yield is higher, but form photoactive (2S)-3-dimethylamino-1-(3-methoxyphenyl) -2-methyl-1-acetone, the reaction time is long, and the yield is only 64%, the R-configuration product cannot be reused, and the waste is serious

Method used

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  • Synthesis and application of intermediate of tapentadol
  • Synthesis and application of intermediate of tapentadol
  • Synthesis and application of intermediate of tapentadol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Example 1 (E, 4R)-3-(3'-m-methoxyphenyl)acryloyl-4-phenyl-2-oxazolidinone

[0087] Add 65g of m-methoxycinnamic acid to a 3L round bottom flask, dissolve it in 2L of tetrahydrofuran, add 94g of triethylamine at 0°C, then add 44g of pivaloyl chloride, stir the mixture for 1h, add 15.5g of lithium chloride, and divide into four times Add R-4-phenyl-2-oxazolidinone (13.5g×4), react at 0°C for 1h, at room temperature for 1h, filter with suction, concentrate, extract the residue with ethyl acetate / water and separate the layers, and the organic layer is washed with sulfuric acid The magnesium was dried, concentrated under reduced pressure, and then 600ml of diethyl ether was added, the temperature was raised slowly, stirred, and filtered to obtain 97g of white solid with a yield of 92%.

[0088] TOF-MS (m / z): 324 [M+1].

[0089] 1 H NMR (300M, CDCl 3 ): δ: 7.93(d, 1H, J=18.0Hz), 7.76(d, 1H, J=18.0Hz), 7.45-7.28(m, 6H), 7.20(d, 1H), 7.11(s, 1H) , 6.96(d, 1H), 5.57(dd, 1H),...

Embodiment 2

[0091] Example 2 (3'R, 4R)-3-(3'-m-methoxyphenyl)pentanoyl-4-phenyl-2-oxazolidinone

[0092] Put 2.46g magnesium bar in 100ml three-necked bottle, 20ml anhydrous tetrahydrofuran, under stirring slowly dropwise the anhydrous tetrahydrofuran solution (10.14g, 20ml) of ethyl bromide, keep reaction in reflux state, after ethyl bromide has been added, Heat to reflux for 1h.

[0093] Add 18.95g of ketone bromide-dimethyl sulfide complex and 100ml of anhydrous tetrahydrofuran into a 1L round bottom flask, cool down to -45°C, slowly add the Grignard reagent prepared above dropwise, react for 2 hours after the dropwise addition, and then Add (E,4R)-3-(3′-m-methoxyphenyl)acryloyl-4-phenyl-2-oxazolidinone in anhydrous tetrahydrofuran solution (20g, 200ml), react for 4h, and use 10 %NH 4 The reaction was terminated by Cl solution, extracted with ethyl acetate (50ml×3), the organic phases were combined, washed with water and saturated brine, dried over magnesium sulfate, concentrated und...

Embodiment 3

[0097] Example 3 (2'R, 3'R, 4R)-3-(2'-methyl-3'-m-methoxyphenyl)pentanoyl-4-phenyl-2-oxazolidinone

[0098] Add 13g (3'R, 4R)-3-(3'-m-methoxyphenyl)pentanoyl-4-phenyl-2-oxazolidinone to a 500ml round bottom flask, dissolve it with 100ml anhydrous tetrahydrofuran, Cool down to -45°C, slowly add 40ml of lithium bis(trimethylsilyl)amide (1M) dropwise, react for 2h, slowly add anhydrous tetrahydrofuran solution (5.48g, 50ml) of methyl iodide dropwise, react for 2h, heat up to - Reaction 2d at 20°C, add 10% NH 4 Cl solution, extracted with ethyl acetate (50ml×3), combined organic phases, washed with water, saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, evaporated to dryness, and purified by column to obtain 10.8g of white solid with a yield of 80%.

[0099] TOF-MS (m / z): 368 [M+1].

[0100] 1 H NMR (300M, CDCl 3 ): δ: 7.33-7.18(m, 6H), 6.78(m, 3H), 4.88(dd, 1H), 4.23(m, 1H), 4.04(t, 1H), 3.98(dd, 1H), 3.81( s, 3H), 2.65(m, 1H), 1.89(m, 1H),...

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Abstract

The invention discloses a preparation method of a key intermediate (1R,2R)-1-ethyl-2-methylphenylethane compound of tapentadol and a method for preparing tapentadol and derivatives thereof from the key intermediate.

Description

technical field [0001] The invention relates to a method for preparing a new intermediate for synthesizing tapentadol, and the application of the key intermediate in preparing tapentadol and its derivatives. Background technique [0002] EP0693475 discloses 1-phenyl-3-dimethylaminopropane active compounds with excellent analgesic activity and very good tolerance, especially tapentadol, the structural formula of which is shown in formula (III), [0003] [0004] The chemical name is (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloric acid, which was launched in November 2008 and is manufactured by Gruenenthal, Germany A new type of central analgesic developed by the company with dual action modes of MOR (μ-opioid receptor) agonism and NE (norepinephrine) reuptake inhibition is used to relieve moderate to severe acute pain in the central nervous system of adults. [0005] The results of the study showed that tapentadol is effective in acute, inflamm...

Claims

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Application Information

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IPC IPC(8): C07D263/22C07C59/64C07C51/09C07C57/72C07C51/60C07C235/34C07C231/02C07C33/22C07C29/147C07C309/68C07C303/28C07C211/27C07C209/50C07C39/02C07C37/055C07C209/68
CPCC07C213/02C07B2200/07C07D263/22C07C51/60C07C231/02C07C213/00C07C215/54C07C217/62C07C235/34C07C57/72
Inventor 冯文化马慧
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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