Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/48—Two nitrogen atoms

Definitions

• the invention relates to the field of drug synthesis, in particular to a method for synthesizing etravirine and an intermediate thereof ;
• Etravirine also known as TMC125, is a non-nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus type 1 (HIV-1), which binds directly to HIV-1 reverse transcriptase by disrupting the catalytic site of the enzyme. The RA-dependent and DNA-dependent DNA polymerase activity is blocked, thereby blocking the replication of HIV-1 and exerting an anti-HIV virus effect.
• NRTI non-nucleoside reverse transcriptase inhibitor
• HSV-1 human immunodeficiency virus type 1
• NNRTI has been used to treat HIV for more than 10 years, but its clinical application is limited by the cross-resistance of these drugs. Resistance to one NNRTI usually means resistance to all NNRTIs.
• Etravirine has re-opened a new world of NNRTI-like treatments, providing new antiviral weapons to thousands of HIV-infected patients with NNRTI.
• Etravirine can be combined with other antiretroviral drugs for adult HIV-1 infected patients who have developed resistance after initial treatment with antiretroviral drugs. It is the first confirmed worldwide market to be approved.
• TMC125 A method for the synthesis of TMC125 is reported in the literature Bioorg. Med. Chem ⁇ ett.l 1 (2001) 2235-2239:
• Reagents and conditions (a) sodium ethoxide, ethanol, yield: 76%; (b) P0C1 3 , yield: 86%; (c) Br 2 , NaHC0 3 , H 2 0, MeOH (methanol), yield : 78%; (d) NMP (N-methylpyrrolidone), 1,4-dioxane Hexacyclic, Yield: 45%; (e) NH 3 , i-PrOH (isopropanol), Yield: 41%.
• step d and step e are relatively low, and the total yield is less than 10%, so it is not suitable for large-scale preparation.
• Another method for synthesizing TMC125 is reported in the document Org. Pro. Res. & Dev. 2010, 14, 657-660 and WO2011017079:
• the preparation method of the invention uses the compound hydrazine and the compound hydrazine as raw materials, and the ring-closing reaction is carried out under the action of a base to obtain the compound XIV; the compound XV is further reacted with P0C1 3 ; and the new intermediate compound XVI is obtained by bromination reaction. Further, a substitution reaction with Compound VII gives etravirine (1).
• the preparation method of the present invention is as follows:
• the molar ratio of the compound ⁇ : compound ⁇ : alkali in the above preparation method is preferably 1.0: 1.0-3.0: 1.5 to 4.0.
• the base is preferably sodium ethoxide or potassium t-butoxide.
• the reaction temperature in the XIV step is preferably 70 to 165 in the preparation of the compounds ruthenium and osmium.
• the reaction solvent in this step is preferably ethanol or n-butanol.
• the reaction temperature is preferably 70 to 120 V.
• the brominating agent is preferably bromine or N-bromosuccinimide (NBS).
• NBS N-bromosuccinimide
• the reaction solvent in this step is preferably dichloromethane, acetonitrile or tetrahydrofuran.
• the molar ratio of the compound XVI: the compound VII is preferably 1.0: 1.0 to 2.0.
• the reaction solvent is preferably 1,4-dioxane, N,N-dimethylformamide (DMF) or N-methylpyrrolidone (NMP).
• the reaction temperature in this step is preferably 100 to 180 V.
• compound VII is obtained by reacting 3,5-dimethyl-4-hydroxybenzonitrile with sodium hydride.
• the preparation method of the invention has high reaction selectivity, simple operation and high yield, and the total yield can reach 53.8%, compared with the comparison text.
• the total yield of the offering is much higher, and the reaction conditions are mild, which is suitable for large-scale preparation.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Plural Heterocyclic Compounds (AREA)

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Citations (4)

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• 2012
  • 2012-05-28 CN CN201210169213.8A patent/CN102675220B/zh active Active
• 2013
  • 2013-05-17 WO PCT/CN2013/075791 patent/WO2013178020A1/fr not_active Ceased

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