WO2011079704A1 - (e)-3-(3-substitué-5-méthylphényl)acrylonitrile et ses procédés de préparation - Google Patents

(e)-3-(3-substitué-5-méthylphényl)acrylonitrile et ses procédés de préparation Download PDF

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Publication number
WO2011079704A1
WO2011079704A1 PCT/CN2010/079700 CN2010079700W WO2011079704A1 WO 2011079704 A1 WO2011079704 A1 WO 2011079704A1 CN 2010079700 W CN2010079700 W CN 2010079700W WO 2011079704 A1 WO2011079704 A1 WO 2011079704A1
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WIPO (PCT)
Prior art keywords
acrylonitrile
methylphenyl
compound
formula
reaction
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PCT/CN2010/079700
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English (en)
Chinese (zh)
Inventor
张容霞
秦茂宣
李剑峰
李海泓
张佩璇
沈敬山
Original Assignee
上海特化医药科技有限公司
山东特珐曼医药原料有限公司
中国科学院上海药物研究所
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Publication of WO2011079704A1 publication Critical patent/WO2011079704A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/35—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms

Definitions

  • the present invention belongs to the field of medicinal chemistry, and more particularly to 3-(3-substituted-5-methylphenyl:)acrylonitrile represented by the following formula III, particularly (E)- represented by Formula I 3-(3-Substituted-5-methylphenyl:) acrylonitrile, and methods for their preparation and use.
  • Background technique 3-(3-substituted-5-methylphenyl:)acrylonitrile represented by the following formula III, particularly (E)- represented by Formula I 3-(3-Substituted-5-methylphenyl:) acrylonitrile
  • NRTI non-nucleoside reverse transcriptase inhibitor
  • the product was developed by the American Idenix Biopharmaceutical Company and is currently undergoing Phase II clinical studies. Although non-nucleoside reverse transcriptase inhibitors are considered to be the first-line treatments commonly used in the treatment of HIV infection, the first approved drug, efavirenz (Sustiva), has developed resistance. The tendency is accompanied by adverse reactions related to the central nervous system. According to a series of studies, IDX-899 has a high efficacy at low doses. In addition, the product has activity against non-nucleoside reverse transcriptase inhibitor-resistant strains.
  • the object of the present invention is to provide a 3-(3-substituted-5-methylphenyl:)propene which is simple, safe, efficient, low in cost, low in environmental pollution, and suitable for industrial mass production.
  • a further object of the present invention is to provide the use of a compound of the formula Ia, lb or Ic to prepare a compound of the formula Id (i.e. IDX-899).
  • Another object of the invention is to provide a new class of 3-(3-substituted-5-methylphenyl:)acrylonitriles, especially (E)-3-(3-substituted-5-methylphenyl: ) Acrylonitrile.
  • the present invention provides a process for preparing 3-(3-substituted-5-methylphenyl:)acrylonitrile using a Heck reaction, especially (E)-3-(3-substituted-5-methylphenyl) :)
  • a method of acrylonitrile comprising: The compound of the formula II is subjected to a Heck reaction with acrylonitrile to obtain 3-(3-substituted-5-methylphenyl)acrylonitrile represented by the formula III; and then optionally, the formula III is 3-(3-Substituted-5-methylphenyl:)acrylonitrile can be isolated by conventional separation methods such as recrystallization, beating, liquid phase separation or double bond configuration to give a single E or Z configuration.
  • a compound of the formula II is subjected to a Heck reaction with acrylonitrile to obtain a compound of the formula III in which trans is predominant, wherein the compound of the formula III has a trans-cis ratio of 6 4; Then, according to the ratio of the cis-trans isomer of the compound of the formula III, the corresponding separation and purification methods are carried out, and (E)-3-(3-substituted- represented by the formula I) is obtained by recrystallization or beating.
  • Ri is N0 2 , NH 2 , NH-W, Br or PG
  • W represents an amino protecting group
  • Ri is preferably N0 2 , N 3 ⁇ 4, Br or PG
  • R 2 is a suitable leaving group such as halogen, C0C1, trifluoromethanesulfonyl, tosyl or methylsulfonyl, more preferably halogen or COC1, most preferably Br, I or COC1;
  • R 2 is not C1 or F.
  • the halogen is F, Cl, Br or I.
  • the palladium catalyst may be a homogeneous palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ), palladium chloride (II) (PdCl 2 ), palladium acetate (II) ( Pd(OAc) 2 ), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 ) or tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ) Etc., or a heterogeneous Pd catalyst such as palladium/carbon, palladium/metal Oxide or palladium/zeolite, etc.; a suitable base may be an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium hydroxide or potassium phosphate, or an organic base such as triethylamine or sodium acetate
  • reaction time is 0.5-30 Hour; reaction temperature is 20-180 °C.
  • the compound of the formula II is subjected to a Heck reaction with acrylonitrile to obtain a compound of the formula III which is mainly trans, and then the compound of the formula III is obtained by recrystallization or beating to obtain (E) of the formula I. -3-(3-Substituted-5-methylphenyl:)acrylonitrile, or first undergoing double bond stereo configuration conversion followed by recrystallization or beating to obtain (E)-3-(3) represented by Formula I - Substituted-5-methylphenyl:) acrylonitrile.
  • the recrystallization is carried out by heating and dissolving the crude product in a solvent, decolorizing by adding activated carbon if necessary, cooling and crystallization, and filtering; or adding the crude product to a solvent which is soluble, and then adding a solvent which is not soluble to cause crystallization.
  • Beating is a method in which a crude product is stirred in a solvent which is not easily dissolved, and a solvent-soluble impurity is dissolved and filtered.
  • the solvent may be a single solvent or a mixed solvent.
  • the photosensitizer used is generally a ketone or an aromatic compound such as acetone, acetophenone, naphthyl ethyl ketone, toluene or xylene, etc.; 2) using an acid catalyst such as hydrochloric acid or a free radical catalyst; 3) using an addition-elimination reaction reagent.
  • the method 3) is employed, and the specific conditions are as follows in the following experimental methods and Table 1, and the addition reagent is selected from liquid bromine or hydrazine-bromosuccinimide.
  • Preferred conditions are: 3-(3-bromo-5-methylphenyl)-2-acrylonitrile is firstly reacted with liquid bromine to form 2,3-dibromo-3-(3-bromo-5-methyl Phenyl)-propionitrile, followed by trans-elimination under zinc/acetic acid conditions affords ( ⁇ )-3-(3-bromo-5-methylphenyl:)acrylonitrile, a compound of formula Ic.
  • the compound of formula Ic can be obtained in high purity, high conversion with liquid bromine-zinc/acetic acid compared to other conditions.
  • R 1 is NH-W
  • the compound of the formula lb is subjected to a deamination protecting group, diazotization, or iodine-substituted triterpene reaction to obtain a compound IV;
  • the compound of the formula Ic can be prepared by the method disclosed in U.S. Patent Application No. US2008213217A1, wherein the compound of the formula Ic is reacted with sodium iodide under the catalysis of cuprous iodide to obtain the compound IV;
  • the nitro reduction reaction is (E)-3-(3-nitro-5-methylphenyl:)acrylonitrile (la)
  • the reduction reaction is carried out in the presence of a reducing agent to form (E 3-(3-amino-5-methylphenyl:)acrylonitrile (Ib), and the reducing agent used is selected from the group consisting of iron powder, zinc powder, and stannous chloride.
  • the reducing agent used is selected from the group consisting of iron powder, zinc powder, and stannous chloride.
  • reaction temperature is 0 to 120 ° C.
  • the diazotization reaction is carried out by reacting (E)-3-(3-amino-5-methylphenyl:)acrylonitrile (lb) with sodium nitrite and acid at a low temperature of 0 to 5 ° C.
  • the diazonium salt is formed in 2 hours, wherein the acid may be a mineral acid such as hydrochloric acid or sulfuric acid or the like, or may be an organic acid such as trifluoroacetic acid or the like.
  • the iodine substitution reaction is carried out by reacting a diazonium salt with an iodide to form (E 3-(3-iodo-5-methylphenyl:) acrylonitrile (1 ⁇ , wherein the iodide may be potassium iodide or sodium iodide, etc.
  • the molar amount is 1 to 5 times that of the diazonium salt, the reaction time is 0.5 to 6 hours, the reaction temperature is 0 to 100 ° C, and a catalyst is used as necessary.
  • the starting material used i.e., the compound of formula II
  • 3-bromo-5-nitrotoluene is commercially available, or reference to "Medicine Chemistry” (1997, 40(4), 437-448) And “Organic Chemistry” (1990, 55 (3), 1040-3) from 4-nitro-2-toluidine or 2-nitro-4-toluidine by bromination, diazotization, hydrogen substitution .
  • the preparation of 3-iodo-5-nitrotoluene is prepared by reference to European Patent Application EP 303 387 A1 by 2-iodo-4-toluidine by iodo, diazotization, by hydrogen substitution.
  • 3-Bromo-5-aminotoluene is commercially available or can be prepared by reduction of 3-bromo-5-nitrotoluene.
  • 3-iodo-5-aminotoluene is commercially available or can be prepared by reduction of 3-iodo-5-nitrotoluene.
  • 3,5-dibromotoluene can be purchased from the market.
  • 3-Bromo-5-iodotoluene can be purchased from the market or prepared by reduction, diazotization or iodo formation of 3-bromo-5-nitrotoluene by reference to the British Chemical Society (1928, 1913-1916).
  • the present invention provides a novel class of 3-(3-substituted-5-methylphenyl:)acrylonitrile.
  • the invention has the advantages of mild reaction condition, easy control, simple operation, low requirements on reaction equipment, less side reactions and high yield; low cost and easy availability of raw materials and reagents, low cost, little environmental pollution, and suitable for large scale Production; Avoid the use of expensive butyl lithium and diethyl cyanomethyl phosphate.
  • a particular advantage is that the Heck reaction has a higher configuration selectivity, and the resulting product configuration is predominantly trans, for the preparation of (E 3-(3-substituted-5-methylphenyl:)acrylonitrile.
  • the hydrogen spectrum was determined by a Bruker AMX-300 nuclear magnetic resonance spectrometer, the TMS was an internal standard, and the chemical shift was in ppm; the purity was determined by an Agilent 1100 liquid chromatograph, column type: ZORBAX XDB C8; UV detection , detection wavelength: 272nm.
  • Ethyl 5-chloro-1H-indole-2-carboxylate (12.0 g, 53.65 mmol) was dissolved in anhydrous DMF (100 ml), and then cooled to 0 ° C, NaH (3.22 g, 80.5mmol, content 60%); After the addition, the reaction was stirred at 0 ° C for 20 minutes, and then a solution of p-toluenesulfonyl chloride (15.3 g, 80.5 mmol) in anhydrous DMF (20 ml) was added dropwise. The liquid temperature was maintained at 0 to 5 ° C, and then the reaction was stirred at room temperature for 1 hour.
  • reaction mixture was poured into ice water (450 ml), solid was precipitated, filtered, and the filter cake was rinsed with water (100 ml ⁇ 3), and dried to give ethyl N-p-toluenesulfonyl-5-chloro-1H-indole-2-carboxylate 18.87 g , the yield was 93.1%.
  • HPLC trans isomer retention time 13.250 min, purity 99.87 %; cis isomer retention time 12.458 min, purity 0.13 %.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un 3-(3-substitué-5-méthylphényl)-acrylonitrile représenté par la formule générale III, un (E)-3-(3-substitué-5-méthylphényl)acrylonitrile représenté par la formule générale I, ainsi que leurs procédés de préparation et leur utilisation. Les procédés de préparation comprennent : la réaction des composés représentés par la formule générale II avec de l'acrylonitrile dans une réaction de Heck, l'obtention des composés représentés par la formule générale III, et la conversion des composés obtenus en (E)-3-(3-substitué-5-méthylphényl)-acrylonitrile représenté par la formule I.
PCT/CN2010/079700 2009-12-30 2010-12-13 (e)-3-(3-substitué-5-méthylphényl)acrylonitrile et ses procédés de préparation WO2011079704A1 (fr)

Applications Claiming Priority (2)

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CN200910247676.X 2009-12-30
CN200910247676XA CN102115452A (zh) 2009-12-30 2009-12-30 (e)-3-(3-取代-5-甲基苯基)丙烯腈及其制备方法

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CN103275126B (zh) * 2013-05-28 2016-03-23 兰州大学 一种立体选择性合成3-位膦酰化吲哚的方法
CN110028430B (zh) * 2019-05-24 2020-04-10 杭州卢普生物科技有限公司 一种舒林酸的制备方法
CN110256424A (zh) * 2019-07-03 2019-09-20 武汉工程大学 一种帕博西尼关键中间体v的合成方法

Citations (2)

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Publication number Priority date Publication date Assignee Title
CN101048410A (zh) * 2004-10-29 2007-10-03 泰博特克药品有限公司 抑制hiv的双环嘧啶衍生物
WO2008042240A2 (fr) * 2006-09-29 2008-04-10 Idenix Pharmaceuticals, Inc. phosphoindoles ÉnantiomÉriquement purs utilisables en tant qu'inhibiteurs du vih

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
CN101048410A (zh) * 2004-10-29 2007-10-03 泰博特克药品有限公司 抑制hiv的双环嘧啶衍生物
WO2008042240A2 (fr) * 2006-09-29 2008-04-10 Idenix Pharmaceuticals, Inc. phosphoindoles ÉnantiomÉriquement purs utilisables en tant qu'inhibiteurs du vih

Non-Patent Citations (2)

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Title
DIDIER SCHILS ET AL.: "Ligandless Heck Coupling between a Halogenated Aniline and Acrylonitrile Catalyzed by Pd/C: Development and Optimization of an Industrial-Scale Heck Process for the Production of a Pharmaceutical Intermediate", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 12, no. 3, 2008, pages 530 - 536 *
LI YANGZHOU ET AL.: "Preparation of a Nafion-Teflon Bimembrane-supported Palladium Catalyst and Its Use in the Heck Reaction", TETRAHEDRON LETTERS, vol. 46, no. 36, 2005, pages 6159 - 6162 *

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