Rilpivirine intermediate and preparation method and application thereof

A technology of rilpivirine and intermediates, applied in the field of drug synthesis, can solve the problems of not being suitable for industrial production requirements, unavailable prices of raw materials, high total cost, etc., to meet the needs of large-scale industrial production, simple preparation method and low cost synthetic effect

Inactive Publication Date: 2013-07-03
SHANGHAI DESANO PHARMA INVESTMENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The above-mentioned patent route is based on 4-(4-chloro-pyrimidinyl-2-ylamino)-benzonitrile or 4-(6-oxo-1,6-dihydro-pyrimidinyl-2-ylamino)-benzonitrile Raw materials, there are problems that raw materials are not easy to obtain and expensive, so that the total cost is still high, and it is still not suitable for industrial production needs

Method used

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  • Rilpivirine intermediate and preparation method and application thereof
  • Rilpivirine intermediate and preparation method and application thereof
  • Rilpivirine intermediate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1: preparation intermediate of the present invention

[0051]

[0052] Step A: Synthesis of 3-(4-amino-3,5-dimethyl-phenyl)-acrylonitrile III

[0053] Under the protection of argon, dissolve 20.0g (0.10mol) of 4-bromo-2,6-dimethyl-aniline II in 100ml of N,N-dimethylformamide (DMF), stir to dissolve, add sodium iodide 0.75 g (5mmol), after heating to 80°C for 0.5 hours, add sodium acetate 9.84g (0.12mol), 1.1g palladium carbon (Pd / C, 10%), acrylonitrile 6.36g (0.12mol) successively, and heat to React at 140°C for 8 hours; cool to room temperature, filter, concentrate the filtrate to dryness, add 200ml ethyl acetate to dissolve, wash twice with saturated brine, dry over anhydrous magnesium sulfate, concentrate to dryness, and recrystallize from acetonitrile to obtain: 3- (4-Amino-3,5-dimethyl-phenyl)-acrylonitrile III 14.74g (0.0857mol), the molar yield is 85.7%; 1 HNMR (DMSO) δ: 2.35 (6H, s), 4.0 (2H, s), 5.88 (1H, d), 6.66 (2H, s), 7.38 (1H, d).

[0054...

Embodiment 2

[0060] Embodiment 2: preparation intermediate of the present invention

[0061]

[0062] Step C: Synthesis of 3-(4-amino-3,5-dimethyl-phenyl)-acrylamide V

[0063] Under the protection of argon, dissolve 20.0g (0.100mol) of 4-bromo-2,6-dimethyl-aniline II in 100ml of acetonitrile, stir to dissolve; add 0.75g (0.005mol) of sodium iodide, and heat to reflux; reflux After reacting for 0.5 hours, 2.24 g (0.010 mol) of palladium acetate, 6.09 g (0.020 mol) of tris(2-methylphenyl) phosphorus, 6.36 g (0.12 mol) of acrylamide and 14.6 g (0.200 mol) of ethylenediamine were added successively. mol), heated to reflux; after 8 hours of reflux reaction, cooled to room temperature, added 500ml of ethyl acetate to dissolve, washed once with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, concentrated to dryness, and distilled with isopropyl Ether recrystallized to obtain: 3-(4-amino-3,5-dimethyl-phenyl)-acrylamide V 15.9 g (0.0837 mol), ...

Embodiment 3

[0068] Embodiment 3: preparation intermediate of the present invention

[0069]

[0070] Step C: the same as that described in step C in Example 2.

[0071] Step F: Synthesis of 3-(4-amino-3,5-dimethyl-phenyl)-acrylonitrile III

[0072] Under the protection of argon, 9.5 g (0.050 mol) of (4-amino-3,5-dimethyl-phenyl)-acrylamide V was added into 100 ml of acetonitrile, cooled to 0°C, and 38.33 g of phosphorus oxychloride was added dropwise ( 0.250mol); after dropping, warm up to room temperature, stir for 2 hours, then heat to reflux; after reflux reaction for 3 hours, concentrate under reduced pressure to dryness; add 50ml of water and 100ml of ethyl acetate to dissolve, adjust the reaction solution to Neutral, liquid separation; the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to dry crude product 9.7g, recrystallized from acetonitrile to obtain: 3-(4-am...

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PUM

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Abstract

The invention discloses a rilpivirine intermediate, a preparation method and an application thereof. The intermediate has a chemical structure general formula as shown in the description; when the intermediate of the invention is used for rilpivirine synthesis, a rilpivirine end product with an HPLC purity of more than 99% can be obtained only by recrystallization with acetonitrile; the preparation method of the intermediate is simple, mild in reaction conditions, cheap and easily available in used raw materials, has a total mole yield of up to more than 80%, and the HPLC purity is up to more than 98.0%; the preparation method of the invention can meet requirements for large-scale industrial production of rilpivirine, and has practical value.

Description

technical field [0001] The invention relates to a rilpivirine intermediate and its preparation method and application, belonging to the technical field of drug synthesis. Background technique [0002] Rilpivirine (Rilpivirine, TMC-278), chemical name: 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino ]-2-pyrimidinyl] amino] benzonitrile, its chemical structural formula is as follows: [0003] [0004] Rilpivirine is a brand-new non-nucleoside reverse transcription inhibitor (NNRTI) developed by Tibotec Pharmaceuticals. So far, only five NNRTI anti-HIV drugs have been marketed, namely nevirapine, efavirenz, delavirdine, etravirine, and rilpivirine. Compared with old drugs such as nevirapine, delavirdine, and etravirine, rilpivirine has the advantages of 1 tablet once a day, the first-line drug, extremely low drug resistance, and high safety. It is as effective as efavirenz and has a better safety profile, so rilpivirine can be used as a new treatment for HIV-1 in...

Claims

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Application Information

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IPC IPC(8): C07D239/48
Inventor 李金亮蔡志刚邵兰英周夏君
Owner SHANGHAI DESANO PHARMA INVESTMENT
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