WO2011079704A1 - (e)-3-(3-substituted-5-methylphenyl) arylonitrile and preparation methods thereof - Google Patents

(e)-3-(3-substituted-5-methylphenyl) arylonitrile and preparation methods thereof Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
acrylonitrile
methylphenyl
compound
formula
reaction
Prior art date
Application number
PCT/CN2010/079700
Other languages
French (fr)
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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 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 filed Critical 上海特化医药科技有限公司
Publication of WO2011079704A1 publication Critical patent/WO2011079704A1/en

Links

Classifications

    • 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 %.

Landscapes

  • 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

3-(3-substituted-5-methylphenyl) acrylonitrile shown by general formula III, (E)-3-(3-substituted-5-methylphenyl) acrylonitrile shown by general formula I and preparation methods and use thereof are provided. The preparation methods comprise: the compounds shown by general formula II reacting with acrylonitrile in Heck reaction, obtaining the compounds shown by general formula III, and then the obtained compounds being converted to (E)-3-(3-substituted-5-methylphenyl) acrylonitrile shown by general formula I.

Description

(E)-3-(3-取代 -5-甲基苯基)丙烯腈及其制备方法  (E)-3-(3-substituted-5-methylphenyl)acrylonitrile and preparation method thereof
技术领域  Technical field
本发明属于药物化学领域， 更具体而言， 涉及如下通式 III所示的 3-(3- 取代 -5-甲基苯基：)丙烯腈， 特别是通式 I所示的 (E)-3-(3-取代 -5-甲基苯基：) 丙烯腈， 以及它们的制备方法和用途。 背景技术  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
IDX-899, 如下通式 Id所示：  IDX-899, as shown in the following formula Id:
Figure imgf000003_0001
Figure imgf000003_0001
PG  PG
是一种新型的非核苷类逆转录酶抑制剂 (NNRTI) , 主要用于 HIV感染的治 疗。 该产品由美国 Idenix生物制药公司研制， 目前正在进行 II期临床研究。 尽管非核苷类逆转录酶抑制剂被认为是 HIV感染治疗常用的一线治疗方案， 但该类药物中第一个被批准上市的药物依发韦仑 (efavirenz, Sustiva)却已经 出现了耐药的倾向， 同时还伴有中枢神经系统相关的不良反应。 而根据一 系列研究显示， IDX-899的低剂量就已具有较高的效能， 此外， 该产品还拥 有可对抗非核苷类逆转录酶抑制剂耐药菌株的活性。 而从使用的角度来看， 其每天服用一次的剂型不仅为患者治疗带来了便利， 同时也为其与核苷类 逆转录酶抑制剂 (NRTIs)联合用药提供了一种可能的新方案。 美国专利申请 US2008213217A1公开了通式 Id化合物的制备方法: It is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that is mainly used for the treatment of HIV infection. 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. From the point of view of use, the dosage form taken once a day not only facilitates the treatment of patients, but also provides a possible new solution for its combination with nucleoside reverse transcriptase inhibitors (NRTIs). U.S. Patent Application No. US2008213217A1 discloses the preparation of a compound of the formula Id:
Figure imgf000004_0001
Figure imgf000004_0001
但该方法使用正丁基锂和氰甲基磷酸二乙酯， 不仅价格昂贵， 成本高， 而 且对环境污染大； 第二歩 Wittig反应需要无水无氧， 反应条件较为苛刻， 对 反应设备要求高， 不适合用于大规模工业化生产。 因此， 寻找条件温和、 收率高、 成本低、 对环境污染小、 适于工业化生产的制备方法就显得尤为 迫切。 发明内容 However, this method uses n-butyl lithium and diethyl cyanomethyl phosphate, which is not only expensive, high in cost, but also highly polluting to the environment; the second 歩Wittig reaction requires anhydrous and oxygen-free, the reaction conditions are harsh, and the reaction equipment is required. High, not suitable for large-scale industrial production. Therefore, it is particularly urgent to find a preparation method which is mild in conditions, high in yield, low in cost, small in environmental pollution, and suitable for industrial production. Summary of the invention
针对上述不足之处， 本发明的目的是提供一种简便、 安全、 高效、 成 本低、对环境污染小、适合工业化大规模生产的 3-(3-取代 -5-甲基苯基：)丙烯 腈、 特别是 (¾-3-(3-取代 -5-甲基苯基：)丙烯腈的制备方法。  In view of the above insufficiency, 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 process for the preparation of nitriles, in particular (3⁄4-3-(3-substituted-5-methylphenyl:)acrylonitrile.
本发明的还一目的是提供通式 Ia、 lb或 Ic化合物制备成通式 Id化合物 (即 IDX-899) 的用途。  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).
本发明的另一目的是提供一类新的 3-(3-取代 -5-甲基苯基：)丙烯腈，尤其 是 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈。  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.
根据本发明， 本发明提供一种采用 Heck反应制备 3-(3-取代 -5-甲基苯 基：)丙烯腈， 尤其是 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈的方法， 该方法包括： 通式 II所示化合物与丙烯腈进行 Heck反应， 得到通式 III所示的 3-(3-取代 -5-甲基苯基)丙烯腈； 而后非必需地， 所述通式 III所示的 3-(3-取代 -5-甲基 苯基：)丙烯腈， 可通过重结晶、 打浆、 液相分离或双键构型转换等常用分离 方法分离， 得到单一 E或 Z构型的化合物。 According to the present invention, 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, the method 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.
其反应式如下：  Its reaction formula is as follows:
Figure imgf000005_0001
Figure imgf000005_0001
特别地， 在本发明中， 通式 II所示化合物与丙烯腈进行 Heck反应， 得 到以反式为主的通式 III所示化合物， 其中通式 III所示化合物反式与顺式 之比 6 : 4； 而后， 根据通式 III所示化合物顺反异构体的比例采取相应的 分离、 纯化方法， 通过重结晶或打浆得到通式 I所示的 (E)-3-(3-取代 -5-甲基 苯基：)丙烯腈， 或者先进行双键立体构型转换后再进行重结晶或打浆， 得到 通式 I所示的 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈；  In particular, in the present invention, 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. 5-methylphenyl: acrylonitrile, or undergoing double-link stereo configuration conversion followed by recrystallization or beating to obtain (E)-3-(3-substituted-5-methyl group represented by Formula I) Phenyl:) acrylonitrile;
反应式如下：
Figure imgf000005_0002
The reaction formula is as follows:
Figure imgf000005_0002
II III I  II III I
其中， Ri为 N02、 NH2、 NH-W、 Br或 PG， W表示氨基保护基， 且 Ri优选为 N02、 N¾、 Br或 PG， Wherein Ri is N0 2 , NH 2 , NH-W, Br or PG, W represents an amino protecting group, and Ri is preferably N0 2 , N 3⁄4, Br or PG,
PG为
Figure imgf000006_0001
PG is
Figure imgf000006_0001
R2为合适的离去基团， 所述的离去基团例如卤素、 C0C1、 三氟甲磺酰 基、 甲苯磺酰基或甲基磺酰基等， 更优选为卤素或 COC1, 最优选为 Br、 I 或 COC1; 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;
且当！^为^时， R2不为 C1或F。 And when! When ^ is ^, R 2 is not C1 or F.
在本发明中， 所述的卤素为 F、 Cl、 Br或 I。  In the present invention, the halogen is F, Cl, Br or I.
对于氨基保护基， 本领域技术人员熟知的氨基保护基以及脱保护基的 方法参见 《有机合成中的保护基》， 第 4版， T.W. Greene和 P.G.M. Wuts, John Wiley & Sons， 2007， 696页。  For amino protecting groups, methods for protecting the amino protecting groups and deprotecting groups well known to those skilled in the art are described in "Protective Groups in Organic Synthesis", 4th Edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, 2007, page 696.
在本发明上述方法中：  In the above method of the invention:
Figure imgf000006_0002
Figure imgf000006_0002
lla:R1=N02 llla:R1=N02 la:R1=N02  Lla:R1=N02 llla:R1=N02 la:R1=N02
b:R1=NH2;NH-W b:R1=NH2;NH-W b:R1=NH2;NH-W  b: R1=NH2; NH-W b: R1=NH2; NH-W b: R1=NH2; NH-W
c:R1=Br c:R1=Br c:R1=Br  c: R1 = Br c: R1 = Br c: R1 = Br
d:R1=PG d:R1=PG d:R1=PG 通式 II所示化合物与丙烯腈进行 Heck反应， 得到以反式为主的通式 III 所示化合物。 更具体而言， 3,5-二取代甲苯 (通式 II所示化合物)与丙烯腈在 合适的钯催化剂、 合适的碱、 合适的溶剂和合适的温度下反应， 生成 3-(3- 取代 -5-甲基苯基：)丙烯腈 (通式 III化合物)。 其中， 钯催化剂可以为均相钯催 化剂， 例如四 (三苯基膦)合钯 (0) (Pd(PPh3)4)、 氯化钯 (II) (PdCl2)、 醋酸钯 (II) (Pd(OAc)2)、 二 (三苯基膦)二氯化钯 （II) (Pd(PPh3)2Cl2) 或三 (二亚苄 基丙酮)二钯 （ Pd2(dba)3)等， 或者为非均相 Pd催化剂， 例如钯 /碳、 钯 /金属 氧化物或钯 /沸石等； 合适的碱可以为无机碱， 例如碳酸钾、 碳酸钠、 碳酸 铯、 碳酸氢钠、 氢氧化钠或磷酸钾等， 或者为有机碱， 例如三乙胺、 醋酸 钠、 醋酸钾、 Ν,Ν-二甲基苄胺、 Ν,Ν-二乙基乙胺、 三丁基胺或三乙醇胺等； 合适的溶剂可以为 Ν,Ν-二甲基甲酰胺、 乙腈、 四氢呋喃、 二甲亚砜、 对二 甲苯、 水、 1-甲基 -2-吡咯垸酮、 甲苯、 二氧六环、 丙酮或 Ν,Ν-二甲基乙酰 胺等； 反应时间为 0.5-30小时； 反应温度为 20-180°C。 d: R1 = PG d: R1 = PG d: R1 = PG 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. More specifically, 3,5-disubstituted toluene (compound of formula II) is reacted with acrylonitrile in a suitable palladium catalyst, a suitable base, a suitable solvent and a suitable temperature to form a 3-(3-substituent) -5-Methylphenyl:) Acrylonitrile (compound of formula III). Wherein, 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. , potassium acetate, hydrazine, hydrazine-dimethylbenzylamine, hydrazine, hydrazine-diethylethylamine, tributylamine or triethanolamine; suitable solvents may be hydrazine, hydrazine-dimethylformamide, acetonitrile, Tetrahydrofuran, dimethyl sulfoxide, p-xylene, water, 1-methyl-2-pyrrolidone, toluene, dioxane, acetone or hydrazine, hydrazine-dimethylacetamide, etc.; reaction time is 0.5-30 Hour; reaction temperature is 20-180 °C.
通式 II所示化合物与丙烯腈进行 Heck反应， 得到以反式为主的通式 III 所示化合物， 而后， 通式 III所示化合物通过重结晶或打浆得到通式 I所示的 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈， 或者先进行双键立体构型转换后再重结 晶或打浆， 得到通式 I所示的 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈。 特别地： 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. In particular:
1) 当 R1为N02、 N¾或 NH-W时， 通式 III化合物 （即 Ilia或 Illb化合物） 反式（E)占大多数， 可通过重结晶或打浆方法去除顺式（Z) , 得到 (E)-3-(3- 取代 -5-甲基苯基：)丙烯腈（即 la或 lb化合物）。 重结晶和打浆都是本领域技术 人员熟知的纯化方法。 重结晶是将粗品投入溶剂中加热溶解， 必要时加入 活性炭脱色， 再冷却析晶， 过滤； 或者将粗品加入易溶的溶剂中， 再滴加 不易溶的溶剂使之析晶。 打浆是将粗品投入不易溶解产品的溶剂中进行搅 拌， 把易溶于溶剂的杂质溶解后过滤的方法。 所述溶剂可以是单一溶剂或 混合溶剂。 1) When R 1 is N0 2 , N 3⁄4 or NH-W, the compound of formula III (ie, Ilia or Illb compound) has the majority of trans (E), and cis (Z) can be removed by recrystallization or beating. (E)-3-(3-Substituted-5-methylphenyl:)acrylonitrile (i.e., la or lb compound) is obtained. Recrystallization and beating are all purification methods well known to those skilled in the art. 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.
2) 当 R^n 均为 Br时， 顺反式的比例相差不多， 需要通过双键立体构 型转化将不需要的顺式转为需要的反式， 提高收率。 通式 III化合物 （即 IIIc 化合物）通过双键立体构型转换后再重结晶或打浆， 得到 (E)-3-(3-溴 -5-甲基 苯基)丙烯腈 （即 Ic化合物）。 根据文献 （《四面体》 ， 1980, 36(5), 557-604； 《有机化学》 , 1976, 41(20), 3279-83； 《化学试剂》 , 1985, 7(6), 340-5 ) 报 道的方法， 常用的双键立体构型转换的方法有： 1 )在光照下用光敏剂传递 能量使烯烃发生顺、 反异构化。 所用的光敏剂一般为酮或芳香化合物， 如 丙酮、 苯乙酮、 萘乙酮、 甲苯或二甲苯等； 2) 利用酸催化剂如盐酸或自由 基催化剂； 3 )利用加成-消除反应试剂。 在本发明中， 采用方法 3 )， 具体条 件见下面的实验方法及表 1， 加成试剂选用液溴或 Ν-溴代丁二酰亚胺。 优选 条件是： 3-(3-溴 -5-甲基苯基) -2-丙烯腈先与液溴发生加成反应生成 2,3-二溴 -3-(3-溴 -5-甲基苯基) -丙腈， 然后在锌 /醋酸条件下反式消除得到 (Ε)-3-(3-溴 -5-甲基苯基：)丙烯腈， 即通式 Ic化合物。 令人惊奇的是， 与其它条件相比， 使用液溴-锌 /醋酸就能以高纯度、 高转换率获得通式 Ic化合物。 2) When R^n is Br, the ratio of the cis-trans is similar, and it is necessary to convert the undesired cis to the desired trans by double-link stereo configuration to increase the yield. The compound of the formula III (i.e., the compound of IIIc) is converted into a stereo configuration of a double bond and then recrystallized or beaten to obtain (E)-3-(3-bromo-5-methylphenyl)acrylonitrile (i.e., an Ic compound). According to the literature ("Tetrahedron", 1980, 36 (5), 557-604; Organic Chemistry, 1976, 41(20), 3279-83; Chemical Reagents, 1985, 7(6), 340-5) The reported methods, commonly used methods for double-key stereo configuration conversion are: 1) The olefin is subjected to cis and trans isomerization by transferring energy with a photosensitizer under illumination. 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. In the present invention, 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 (Ε)-3-(3-bromo-5-methylphenyl:)acrylonitrile, a compound of formula Ic. Surprisingly, the compound of formula Ic can be obtained in high purity, high conversion with liquid bromine-zinc/acetic acid compared to other conditions.
实验方法：  experimental method:
把 3-(3-溴 -5-甲基苯基) -2-丙烯腈 （E:Z=7:3 ) 溶于有机溶剂中， 加入加 成试剂， 必要时加入引发剂进行反应， 反应毕， 后处理得到的中间体直接 溶于醋酸， 加入锌粉， 室温下搅拌反应 0.5小时， 把反应液倒入冰水中， 用 二氯甲垸萃取， 有机层用 5%碳酸氢钠水溶液洗涤， 再用无水硫酸钠干燥， 过滤， 浓缩获得化合物 Ic。 具体结果如下表所示：  3-(3-bromo-5-methylphenyl)-2-acrylonitrile (E:Z=7:3) is dissolved in an organic solvent, an addition reagent is added, and if necessary, an initiator is added to carry out the reaction. The intermediate obtained by the post-treatment is directly dissolved in acetic acid, and the zinc powder is added thereto, and the reaction mixture is stirred at room temperature for 0.5 hour, and the reaction liquid is poured into ice water, extracted with dichloromethane, and the organic layer is washed with a 5% aqueous sodium hydrogencarbonate solution. Drying over anhydrous sodium sulfate, filtration and concentration gave compound Ic. The specific results are shown in the following table:
Figure imgf000008_0001
Figure imgf000008_0001
3) 当 为81"， R2为 COC1时， 通式 III化合物 （即 IIIc化合物） 直接重结 晶或打浆得到 (E)-3-(3-溴 -5-甲基苯基)丙烯腈 （即 Ic化合物）； 3) When 81", R 2 is COC1, the compound of formula III (ie compound IIIc) is directly re-knotted Crystal or beating to obtain (E)-3-(3-bromo-5-methylphenyl)acrylonitrile (ie, Ic compound);
4) 当 为？0时， 通式 III化合物 （即 Illd化合物） 通过重结晶或打浆得 到 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈 （即 Id化合物）。  4) When? At 0, the compound of the formula III (i.e., the compound of Illd) is obtained by recrystallization or beating to obtain (E)-3-(3-substituted-5-methylphenyl:)acrylonitrile (i.e., compound of Id).
根据本发明的制备 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈的方法， 该方法进 一歩包括将通式 Ia、 lb或 Ic化合物制备成通式 IV化合物和通式 Id化合物， 其中通式 IV化合物是制备通式 Id化合物的关键中间体：  Process for the preparation of (E)-3-(3-substituted-5-methylphenyl:)acrylonitrile according to the invention, which process further comprises preparing a compound of the formula Ia, lb or Ic into a compound of the formula IV and A compound of the formula Id, wherein the compound of the formula IV is a key intermediate for the preparation of a compound of the formula Id:
Figure imgf000009_0001
Figure imgf000009_0001
当 R1为N02时， 通式 la化合物经硝基还原、 重氮化、 碘取代三歩反应得 到化合物 IV； 或者 When R 1 is N0 2 , the compound of the formula la is subjected to nitro reduction, diazotization, or iodine substitution to obtain a compound IV;
当 R1为NH2时，通式 lb化合物经重氮化、碘取代两歩反应得到化合物 IV； 或者 When R 1 is NH 2 , the compound of the formula lb is subjected to diazotization and iodine substitution by two oxime reactions to obtain compound IV;
当 R1为NH-W时， 通式 lb化合物经脱氨基保护基、 重氮化、 碘取代三歩 反应得到化合物 IV； 或者 When 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;
当 1^为81"时， 通式 Ic化合物可参照美国专利申请 US2008213217A1公开 的方法制备得到化合物 IV， 即通式 Ic化合物与碘化钠在碘化亚铜催化下反 应， 得到化合物 IV；  When 1^ is 81", 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;
然后， 同样参照美国专利申请 US2008213217A1公开的方法， 化合物 IV 与 (2-氨基甲酰基 -5-氯 -1H-吲哚 -3-)-次膦酸甲酯进行取代反应， 得到通式 Id 所示的 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈。  The compound IV is then subjected to a substitution reaction with methyl (2-carbamoyl-5-chloro-1H-indole-3-)-phosphinate to give the formula Id as shown in the method disclosed in U.S. Patent Application No. US2008213217A1. (E)-3-(3-Substituted-5-methylphenyl:)acrylonitrile.
更具体地， 所述的硝基还原反应为 (E)-3-(3-硝基 -5-甲基苯基：)丙烯腈 (la) 在还原剂存在下进行还原反应， 生成 (E 3-(3-氨基 -5-甲基苯基：)丙烯腈 (Ib)， 所使用的还原剂选自铁粉、 锌粉、 氯化亚锡、 硫化钠、 二硫化钠、 亚硫酸 钠、亚硫酸氢钠、亚硫酸铵、亚硫酸氢铵和连二亚硫酸钠中；反应温度为 0〜 120°C。 More specifically, 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. , sodium sulfide, sodium disulfide, sodium sulfite, sodium hydrogen sulfite, ammonium sulfite, ammonium hydrogen sulfite and sodium dithionite; reaction temperature is 0 to 120 ° C.
所述的重氮化反应为 (E)-3-(3-氨基 -5-甲基苯基：)丙烯腈 (lb)与亚硝酸钠 和酸在 0〜5°C的低温下反应 0.5〜2小时，生成重氮盐，其中酸可以是无机酸， 如盐酸或硫酸等， 或者可以是有机酸， 如三氟乙酸等。  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.
所述碘取代反应为重氮盐与碘化物反应， 生成 (E 3-(3-碘 -5-甲基苯基：) 丙烯腈 (1\ ， 其中碘化物可以为碘化钾或碘化钠等， 其摩尔用量为重氮盐的 1〜5倍， 反应时间 0.5〜6小时， 反应温度 0〜100°C， 必要时使用催化剂。  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.
在本发明中， 所述采用的原料 （即通式 II化合物）， 3-溴 -5-硝基甲苯可 由市场购买得到， 或参考《药物化学》（1997, 40(4), 437-448)和 《有机化学》 (1990, 55(3), 1040-3)由 4-硝基 -2-甲苯胺或 2-硝基 -4-甲苯胺经溴代、 重氮化、 被氢取代制备得到。 3-碘 -5-硝基甲苯的制备参考欧洲专利申请 EP303387A1 由 2-硝基 -4-甲苯胺经碘代、 重氮化、 被氢取代制备得到。 3-溴 -5-氨基甲苯 可由市场购买， 或由 3-溴 -5-硝基甲苯经还原制备得到。 3-碘 -5-氨基甲苯可 由市场购买， 或由 3-碘 -5-硝基甲苯经还原制备得到。 3,5-二溴甲苯可由市场 购买。 3-溴 -5-碘甲苯可由市场购买， 或参考《英国化学会志》（1928, 1913 - 1916)由 3-溴 -5-硝基甲苯经还原、 重氮化、 碘代制备得到。 3-甲基 -5-硝基苯 甲酰氯的制备参考《抗生素杂志》（1994, 47(12), 1456-65)由 2-硝基 -4-甲苯胺 经溴代、 重氮化、 被氢取代、 氰基取代、 水解、 酰化制备得到。 3-甲基 -5- 氨基苯甲酰氯可由 3-甲基 -5-硝基苯甲酸经还原、 酰化制备得到。 化合物 lid 参照 US2006074054A1制备得到。 In the present invention, 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). Preparation of 3-methyl-5-nitrobenzoyl chloride by reference to the Journal of Antibiotics (1994, 47(12), 1456-65) by 2-nitro-4-toluidine by bromination, diazotization, Hydrogen substitution, cyano substitution, hydrolysis, acylation are prepared. 3-Methyl-5-aminobenzoyl chloride can be obtained by reduction and acylation of 3-methyl-5-nitrobenzoic acid. Compound lid Prepared according to US2006074054A1.
根据本发明， 本发明提供一类新的 3-(3-取代 -5-甲基苯基：)丙烯腈. (E)-3-(3-取代 -5-甲基苯基：)丙烯腈和 (Z)-3-(3-取代 -5-甲基苯基：)丙烯腈， 即： 3-(3-氨基 -5-甲基苯基) -2-丙烯腈
Figure imgf000011_0001
According to the present invention, the present invention provides a novel class of 3-(3-substituted-5-methylphenyl:)acrylonitrile. (E)-3-(3-Substituted-5-methylphenyl:)acrylonitrile And (Z)-3-(3-substituted-5-methylphenyl:)acrylonitrile, ie: 3-(3-amino-5-methylphenyl)-2-acrylonitrile
Figure imgf000011_0001
K3-硝基 -5-甲基苯基 )-2-丙烯腈
Figure imgf000011_0002
 K 3-nitro-5-methylphenyl) -2 -acrylonitrile
Figure imgf000011_0002
Κ3-溴 -5-甲基苯基) -2-丙烯腈
Figure imgf000011_0003
Κ3-bromo-5-methylphenyl)-2-acrylonitrile
Figure imgf000011_0003
(E)-3-(3-氨基 -5-甲基苯基 )-2-丙烯腈
Figure imgf000011_0004
(E)-3-(3-Amino-5-methylphenyl)-2-acrylonitrile
Figure imgf000011_0004
(E)-3-(3-硝基 -5-甲基苯基 )-2-丙烯腈
Figure imgf000011_0005
(E)-3-(3-nitro-5-methylphenyl)-2-acrylonitrile
Figure imgf000011_0005
(Z)-3- 3-氨基 -5-甲基苯基 )-2-丙烯腈 H主
Figure imgf000011_0006
(Z)-3- 3-amino-5-methylphenyl)-2-acrylonitrile H main
Figure imgf000011_0006
(Z)-3-(3-硝基 -5-甲基苯基 )-2-丙烯腈
Figure imgf000012_0001
(Z)-3-(3-nitro-5-methylphenyl)-2-acrylonitrile
Figure imgf000012_0001
(Z)-3-(3-溴 -5-甲基苯基) -2-丙烯腈
Figure imgf000012_0002
(Z)-3-(3-bromo-5-methylphenyl)-2-acrylonitrile
Figure imgf000012_0002
本发明的优点在于， 反应条件温和、 易控制， 操作简便， 对反应设备 要求低， 副反应少， 收率高； 原料和试剂价廉易得， 成本低、 对环境污染 小、 适合于大规模生产； 避免使用价格昂贵的丁基锂和氰甲基磷酸二乙酯。 特别的优点是， Heck反应具有较高的构型选择性， 所得产物构型以反式为 主， 用于制备 (E 3-(3-取代 -5-甲基苯基：)丙烯腈具有较大优势。 具体实施方式  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. Great advantage.
通过以下实施例进一歩说明本发明， 以下实施例仅用于更具体说明本 发明的优选实施方案， 不用于对本发明的技术方案进行限定。 下述实施例 中， 氢谱由 Bruker AMX-300型核磁共振仪测定， TMS为内标， 化学位移 单位为 ppm; 纯度由 Agilent 1100液相色谱仪测定， 色谱柱型号： ZORBAX XDB C8 ； 紫外检测器， 检测波长： 272nm。  The invention is further illustrated by the following examples, which are merely used to illustrate the preferred embodiments of the invention, and are not intended to limit the invention. In the following examples, 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.
实施例 1 3-(3-硝基 -5-甲基苯基: )-2-丙烯腈、 （E)-3-(3-硝基 -5-甲基苯 基：) -2-丙烯腈和 (Z)-3-(3-硝基 -5-甲基苯基: )-2-丙烯腈的合成
Figure imgf000012_0003
Example 1 3-(3-Nitro-5-methylphenyl: )-2-acrylonitrile, (E)-3-(3-nitro-5-methylphenyl:)-2-acrylonitrile Synthesis of (Z)-3-(3-nitro-5-methylphenyl: )-2-acrylonitrile
Figure imgf000012_0003
将 3-溴 -5-硝基甲苯 (42.7 g, 0.2mol)、 丙烯腈 (12.6 g, 0.24mol)、 醋酸钯 (0.45g, 2mmol)、 三乙胺 (28.3g, 0.28mol)、 三苯基膦 (lg, 4mmol)和 Ν,Ν-二甲 基甲酰胺 (300ml)加入反应瓶中， 120°C加热反应 16小时。 而后将反应液冷 却至室温，加入乙酸乙酯 (200ml)稀释并过滤。滤液用 IN HCl(50mlX3)洗涤， 用饱和食盐水 (50mlXl)洗涤， 再用无水 Na2S04干燥。 滤除干燥剂， 浓缩， 得 3-(3-硝基 -5-甲基苯基) -2-丙烯腈 31.7g。 toMR (CDC13) δ 2.51 (s, 3Η), 5.63(d, J- 12.0), 6.03(d, 1H， ]=16.2), 7.42(d, 1H), 7.56 (s, lH),8.10(s, 1H) , 8.13 (s, 1H); HPLC: 反式异构体保留时间 10.903min， 纯度 87%; 顺式异 构体保留时间 10.523min， 纯度 13%。 3-bromo-5-nitrotoluene (42.7 g, 0.2 mol), acrylonitrile (12.6 g, 0.24 mol), palladium acetate (0.45 g, 2 mmol), triethylamine (28.3 g, 0.28 mol), triphenyl Phosphine (lg, 4mmol) and hydrazine, hydrazine-dimethyl The carboxamide (300 ml) was added to the reaction flask, and the reaction was heated at 120 ° C for 16 hours. Then the reaction solution was cooled to room temperature, diluted with ethyl acetate (200 ml) and filtered. The filtrate (50 ml x 3), washed with IN HCl with saturated brine (50mlXl), then dried over anhydrous Na 2 S0 4. The desiccant was filtered off and concentrated to give 31.7 g of 3-(3-nitro-5-methylphenyl)-2- acrylonitrile. toMR (CDC1 3 ) δ 2.51 (s, 3Η), 5.63(d, J-12.0), 6.03(d, 1H, ]=16.2), 7.42(d, 1H), 7.56 (s, lH), 8.10(s , 1H), 8.13 (s, 1H); HPLC: the trans isomer retention time 10.903 min, purity 87%; cis isomer retention time 10.523 min, purity 13%.
(E)-3-(3-硝基 -5-甲基苯基 2-丙烯腈的分离 (E) Separation of -3-(3-nitro-5-methylphenyl 2-acrylonitrile)
将此顺反异构体混合物用乙醚-无水乙醇 （2: 1， 按体积） 重结晶， 得 类白色固体 (E)-3-(3-硝基 -5-甲基苯基:) -2-丙烯腈 23.6g， 收率 63.5%。  The cis-trans isomer mixture was recrystallized from diethyl ether-anield (2:1, vol.) to afford white crystals (E)-3-(3-nitro-5-methylphenyl:) 2-acrylonitrile 23.6 g, yield 63.5%.
mp: 146.9°C (分解)。  Mp: 146.9 ° C (decomposed).
ifiNMR (CDC13) δ 2.51 (s, 3H), 6.03(d, 1H), 7.42(d, 1H), 7.56 (s, 1H) , 8.10(s, lH),8.13(s, 1H)。 IfiNMR (CDC1 3 ) δ 2.51 (s, 3H), 6.03 (d, 1H), 7.42 (d, 1H), 7.56 (s, 1H), 8.10 (s, lH), 8.13 (s, 1H).
HPLC: 保留时间 10.903min， 纯度 98.6%。  HPLC: retention time 10.903 min, purity 98.6%.
(ZV3-(3-硝基 -5-甲基苯基 2-丙烯腈的分离  (Separation of ZV3-(3-nitro-5-methylphenyl 2-acrylonitrile)
将上述顺反异构体混合物重结晶后的母液通过制备型高效液相分离， 得固体 (ZV3-(3-硝基 -5-甲基苯基 2-丙烯腈。  The mother liquor after recrystallization of the above cis-trans isomer mixture was subjected to preparative high-performance liquid phase separation to obtain a solid (ZV3-(3-nitro-5-methylphenyl 2-acrylonitrile).
ifiNMR (CDC13) δ 2.51 (s, 3H), 5.63(d, 1H)， 7.42(d, 1H), 7.56 (s, 1H) , 8.10(s, lH),8.13(s, 1H); IfiNMR (CDC1 3 ) δ 2.51 (s, 3H), 5.63 (d, 1H), 7.42 (d, 1H), 7.56 (s, 1H), 8.10 (s, lH), 8.13 (s, 1H);
HPLC: 保留时间 10.523min。 实施例 2 3-(3-硝基 -5-甲基苯基: )-2-丙烯腈和 (E)-3-(3-硝基 -5-甲基苯 基:) -2-丙烯腈的合成
Figure imgf000014_0001
HPLC: retention time 10.523 min. Example 2 3-(3-Nitro-5-methylphenyl: )-2-acrylonitrile and (E)-3-(3-nitro-5-methylphenyl:)-2-acrylonitrile Synthesis
Figure imgf000014_0001
将 3-溴 -5-硝基甲苯 (15.12g, 70mmol)、 丙烯腈 (5.57g, 105 ol)、 醋酸 钯 (0.8g, 3.56 mmol)、 醋酸钾 (20.6g, 210mmol)、 四丁基溴化铵（1.5g, 4.56 mmol)和 Ν,Ν-二甲基甲酰胺 (100 ml)加入反应瓶中，在 130°C 140°C下反应 6 小时， TLC 检测反应完全 (石油醚 /乙酸乙酯 =4/1 v/v), 停止加热。 待反 应液冷却至 40°C 50°C时， 将其缓慢倒入搅拌的冰水中， 析出固体， 过滤。 滤饼用水 (50mlx3) 冲洗， 再用二氯甲垸 (150ml)溶解，过滤， 回收钯催化剂。 浓缩滤液， 得到粗产物 3-(3-硝基 -5-甲基苯基:) -2-丙烯腈 （HPLC: 反式异构 体保留时间 10.779min， 纯度 82 % ; 顺式异构体保留时间 10.391min， 纯度 18 %。）。 所得粗产物用乙醇或乙醚打浆， 得类白色固体 （E)-3-(3-硝基 -5-甲 基苯基 )-2-丙烯腈 10.7g， 收率 81.2% HPLC: 反式异构体纯度 97 %， 顺式 异构体纯度 2 %  3-Bromo-5-nitrotoluene (15.12 g, 70 mmol), acrylonitrile (5.57 g, 105 ol), palladium acetate (0.8 g, 3.56 mmol), potassium acetate (20.6 g, 210 mmol), tetrabutyl bromide Ammonium (1.5g, 4.56 mmol) and hydrazine, hydrazine-dimethylformamide (100 ml) were added to the reaction flask and reacted at 130 ° C for 140 hours at 140 ° C. The reaction was complete by TLC (petroleum ether / acetic acid B) Ester = 4/1 v/v), stop heating. When the reaction solution was cooled to 40 ° C and 50 ° C, it was slowly poured into stirred ice water, and a solid was precipitated and filtered. The filter cake was washed with water (50 ml x 3), dissolved with dichloromethane (150 ml), and filtered to recover a palladium catalyst. The filtrate was concentrated to give the crude product 3-(3-nitro-5-methylphenyl:)-2- acrylonitrile (HPLC: </RTI> <RTI ID=0.0> Time 10.391min, purity 18%.). The obtained crude product was slurried with ethanol or diethyl ether to give white solid (E) 3-(3-nitro-5-methylphenyl)-2- acrylonitrile 10.7 g, yield: 81.2% HPLC: trans isomer Purity 97%, cis isomer purity 2 %
核磁共振数据同实施例 1 实施例 3 (E)-3-(3-氨基 -5-甲基苯基:) -2-丙烯腈的合成 方法一：
Figure imgf000014_0002
The NMR data was the same as in Example 1 Example 3 (E)-3-(3-Amino-5-methylphenyl:)-2-acrylonitrile.
Figure imgf000014_0002
将 3-溴 -5-氨基甲苯 (5.0g, 26.8mmol)、 丙烯腈 (4.75g, 89.6 mmol)、 醋酸 钯 (1.2g, 5.37 mmol)、 三乙胺（10.9g, 107mmol)、 三 （邻甲苯基） 膦 （8.1g, 26.811 11 01)和乙腈(；50 11 1)加入反应瓶中， 在 140°C下反应 18小时。 冷却后， 将该反应物用硅藻土过滤，把滤液倒入水中，并用二氯甲垸 (15 mlX 3)萃取。 将有机层用硫酸镁干燥， 过滤， 浓缩， 得到粗产物， 用无水乙醇-乙醚重结 晶， 得黄色固体 (E)-3-(3-氨基 -5-甲基苯基: )-2-丙烯腈 3.6g， 收率 84.7 %。 3-bromo-5-aminotoluene (5.0 g, 26.8 mmol), acrylonitrile (4.75 g, 89.6 mmol), palladium acetate (1.2 g, 5.37 mmol), triethylamine (10.9 g, 107 mmol), tris Tolyl)phosphine (8.1 g, 26.811 11 01) and acetonitrile (; 50 11 1) were placed in a reaction flask and reacted at 140 ° C for 18 hours. After cooling, The reaction was filtered through celite, and the filtrate was poured and evaporated and evaporated. The organic layer was dried with MgSO4, EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Acrylonitrile 3.6 g, yield 87.7%.
mp: 95.7°C-98.0°C ;  Mp: 95.7 ° C - 98.0 ° C;
ifiNMR (DMSO-d6) δ 2.17 (s, 3H), 5.18(s, 2H), 6.18(d, 1H),6.43 (s, 1H) , 6.52 (s, 1H) , 6.62(s, 1H)， 7.42(d, 1H)。  IfiNMR (DMSO-d6) δ 2.17 (s, 3H), 5.18 (s, 2H), 6.18 (d, 1H), 6.43 (s, 1H), 6.52 (s, 1H), 6.62 (s, 1H), 7.42 (d, 1H).
Figure imgf000015_0001
Figure imgf000015_0001
(E)-3-(3-硝基 -5-甲基苯基) -2-丙烯腈 (12g, 64mmol)溶于冰醋酸 (100ml) 中， 分批加入锌粉 (12.5g, 0.19mol), 其间， 有热量放出， 控制反应温度在 20°C〜60°C， 加毕， 室温下搅拌反应 2小时。 将反应液过滤， 用少量乙酸冲 洗滤饼， 再将所得到的滤液缓慢倒入搅拌的冰水 OOml)中， 析出固体， 过 滤。 所得滤饼用水冲洗数次， 除去残留的乙酸， 干燥， 得黄色固体 (E)-3-(3- 氨基 -5-甲基苯基:) -2-丙烯腈 9.4g， 收率 93%。 实施例 4 (E)-3-(3-碘 -5-甲基苯基: )-2-丙烯腈的合成
Figure imgf000015_0002
(E)-3-(3-Nitro-5-methylphenyl)-2-acrylonitrile (12 g, 64 mmol) was dissolved in glacial acetic acid (100 ml), and zinc powder (12.5 g, 0.19 mol) was added portionwise. In the meantime, heat is released, and the reaction temperature is controlled at 20 ° C to 60 ° C. After the addition, the reaction is stirred at room temperature for 2 hours. The reaction solution was filtered, and the filter cake was washed with a small amount of acetic acid, and the obtained filtrate was poured slowly into 00 ml of stirred ice water to precipitate a solid, which was filtered. The obtained cake was washed with water several times, and the residual acetic acid was removed, and dried to give (y) y. Example 4 Synthesis of (E)-3-(3-iodo-5-methylphenyl: )-2-acrylonitrile
Figure imgf000015_0002
将 (E)-3-(3-氨基 -5-甲基苯基) -2-丙烯腈 (5.74g, 36.2mmol)与 37 %盐酸 (17ml)和冰水 (11.3g) 混合， 置于 0〜5 °C冰水浴中， 在此温度下缓慢滴加亚 硝酸钠2.76g, 40.0mmoi;)的水 ( .0ml;)溶液进行重氮化反应； 滴加完毕后继续 搅拌 15 分钟得到重氮盐的水溶液。 在另一反应瓶中加入碘化钾 (18g, 109.0mmol)的水 (40.0ml)溶液，在室温 下滴加经过粗过滤后的上述重氮盐的水溶液； 并在室温下搅拌反应 2小时。 加入二氯甲垸 (50ml)萃取， 有机层依次用水 (10ml)、 5%亚硫酸氢钠水溶液 (10ml)和饱和食盐水 (10ml)洗涤 1次， 再用无水 Na2S04干燥。 过滤、 浓缩， 残留物用活性炭脱色后， 再用石油齢 ^乙醚 (2/1, νΛ重结晶， 得到类白色固体 (E)-3-(3-碘 -5-甲基苯基) -2-丙烯腈 6.2g， 收率 63.5%。 (E)-3-(3-Amino-5-methylphenyl)-2-acrylonitrile (5.74 g, 36.2 mmol) was mixed with 37% hydrochloric acid (17 ml) and ice water (11.3 g). In a ~5 ° C ice water bath, slowly add dropwise 2.76 g of sodium nitrite, 40.0 mmoi;) water (.0 ml;) solution to diazotization at this temperature; continue stirring for 15 minutes to obtain diazo An aqueous solution of salt. A solution of potassium iodide (18 g, 109.0 mmol) in water (40.0 ml) was added to another reaction flask, and the crude aqueous solution of the above-mentioned diazonium salt was added dropwise at room temperature; and the reaction was stirred at room temperature for 2 hours. (50ml) was added and extracted of dichloromethane, the organic layer was successively washed with water (10ml), 5% aqueous sodium bisulfite (10ml) and saturated brine (10ml) washed once, and then dried over anhydrous Na 2 S0 4. After filtration and concentration, the residue was decolorized with activated carbon, and then recrystallized from petroleum ether (2/1, ν) to give an off-white solid (E)-3-(3-iodo-5-methylphenyl) -2 - acrylonitrile 6.2 g, yield 63.5%.
mp: 97.8。C-102.9。C。  Mp: 97.8. C-102.9. C.
ifiNMR (CDC13) δ 2.33 (s, 3Η), 5.85(d, 1H), 7.19(s, 1H), 7.25 (d, 1H) , 7.59 (s, 2H)。  IfiNMR (CDC13) δ 2.33 (s, 3Η), 5.85 (d, 1H), 7.19 (s, 1H), 7.25 (d, 1H), 7.59 (s, 2H).
HPLC: 反式异构体保留时间 12.427min， 纯度 99% ; 顺式异构体保留 时间 12.055min, 纯度 0.3 %。 实施例 5 3-(3- -5-甲基苯基) -2-丙 的合成
Figure imgf000016_0001
HPLC: trans isomer retention time 12.427 min, purity 99%; cis isomer retention time 12.055 min, purity 0.3%. Example 5 Synthesis of 3-(3- -5-methylphenyl)-2-propanol
Figure imgf000016_0001
将 3,5-二溴甲苯 （10g， 40mmol)、 丙烯腈 （2.122g， 40mmol)、 醋酸钯 (90mg， 0.4mmol)、 三乙胺（l lml, 56mmol)、 三苯基膦 （210mg， 0.8mmol) 和 N,N-二甲基甲酰胺 （200ml)加入反应瓶中，在氮气保护下， 100°C〜120°C 反应过夜。 将反应溶液冷却至室温， 加入乙酸乙酯 (380ml)萃取， 有机相用 lN HCl (lOOml)洗， 再用水 (50ml)洗， 经无水 Na2S04干燥、 过滤、 浓缩， 残 留物柱层析纯化 (洗脱液为石油醚 /乙酸乙酯 =20:1, v/v),得 3-(3-溴 -5-甲基苯 基) -2-丙烯腈 8.1g， 收率 45.6%。 ifiNMR (CDC13) δ 2.38 (s, 3H), 5.48(d， J = 12.0)， 5.86(d, 1H, J= 16.2), 7.18〜7.40 (m, 4H)。 HPLC: 反式异构体保留 时间 9.964min， 纯度 70% ; 顺式异构体保留时间 9.844min， 纯度 30%。 实施例 6 (E)-3-(3-溴 -5-甲基苯基) -2-丙烯腈的合成
Figure imgf000017_0001
3,5-Dibromotoluene (10 g, 40 mmol), acrylonitrile (2.122 g, 40 mmol), palladium acetate (90 mg, 0.4 mmol), triethylamine (1 ml, 56 mmol), triphenylphosphine (210 mg, 0.8) Methyl) and N,N-dimethylformamide (200 ml) were added to a reaction flask and allowed to react overnight at 100 ° C to 120 ° C under a nitrogen atmosphere. The reaction solution was cooled to room temperature, ethyl acetate (380 ml of). The organic phase was washed with lN HCl (lOOml) wash, and then washed with water (50ml) washed, dried over anhydrous Na 2 S0 4, filtered, concentrated and the residue was column chromatography The product was purified by chromatography (EtOAc/EtOAc/EtOAc/EtOAc/EtOAc/EtOAc/EtOAc/EtOAc . IfiNMR (CDC13) δ 2.38 (s, 3H), 5.48 (d, J = 12.0), 5.86 (d, 1H, J = 16.2), 7.18~7.40 (m, 4H). HPLC: trans isomer retention The time was 9.964 min, the purity was 70%; the cis isomer retention time was 9.844 min, and the purity was 30%. Example 6 Synthesis of (E)-3-(3-bromo-5-methylphenyl)-2-acrylonitrile
Figure imgf000017_0001
把实施例 5制备的 3-(3-溴 -5-甲基苯基) -2-丙烯腈 (2.22g, lO.Ommol)溶于 二氯甲垸 （10ml) 中， 在室温搅拌下滴加液溴 (3.2g, 20.0mmol), 滴加完毕 后继续搅拌反应 3小时， 将反应液直接浓缩得到中间体 2,3-二溴 -3-(3-溴 -5- 甲基苯基) -丙腈；将其溶于冰醋酸（20ml)中，在室温搅拌下加入锌粉 (4.25g, 65.0mmol), 并在室温下搅拌反应 0.5小时， 把反应液倒入冰水 (60ml)中， 用 二氯甲垸 (50ml)萃取， 有机层用 5%碳酸氢钠水溶液 (10ml)洗涤， 再用无水 Na2S04干燥、 过滤、 浓缩， 残留物用无水乙醚打浆， 得类白色固体 1.88g， 收率 84.7%。 HPLC: 反式异构体保留时间 9.990min， 纯度 99.4% ; 顺式异 构体保留时间 9.869min， 纯度 0.6% )。 The 3-(3-bromo-5-methylphenyl)-2-acrylonitrile (2.22 g, 10 mmol) prepared in Example 5 was dissolved in dichloromethane (10 ml) and then stirred at room temperature. Liquid bromine (3.2 g, 20.0 mmol), stirring reaction was continued for 3 hours after completion of the dropwise addition, and the reaction mixture was directly concentrated to give the intermediate 2,3-dibromo-3-(3-bromo-5-methylphenyl)- The product was dissolved in glacial acetic acid (20 ml), and zinc powder (4.25 g, 65.0 mmol) was added with stirring at room temperature, and the reaction was stirred at room temperature for 0.5 hour, and the reaction mixture was poured into ice water (60 ml). (50ml) and extracted with of dichloromethane, the organic layer (10ml) washed with 5% aqueous sodium bicarbonate, dried over anhydrous Na 2 S0 4 dried, filtered, concentrated and the residue was slurried with anhydrous ether to give an off-white solid 1.88 g, yield 84.7%. HPLC: trans isomer retention time 9.000 min, purity 99.4%; cis isomer retention time 9.869 min, purity 0.6%).
ifiNMR (CDC13) δ 2.38 (s, 3H), 5.85(d, 1H), 7.18—7.40 (m, 4H)。 实施例 7 3-(3-溴 -5-甲基苯基) -2-丙烯腈和 (E)-3-(3-溴 -5-甲基苯基) -2- 丙烯腈的合成
Figure imgf000017_0002
IfiNMR (CDC13) δ 2.38 (s, 3H), 5.85 (d, 1H), 7.18-7.40 (m, 4H). Example 7 Synthesis of 3-(3-bromo-5-methylphenyl)-2-acrylonitrile and (E)-3-(3-bromo-5-methylphenyl)-2-acrylonitrile
Figure imgf000017_0002
3-溴 -5-甲基苯甲酸 （8.8g， 0.04mol) 溶于二氯甲垸 （30ml) 中， 滴加 氯化亚砜 （l lg， 0.09mol)， 滴加完毕， 加热回流 1.5 小时， 浓缩至干， 得 酰氯粗品 9.3g， 收率： 97%。 不经纯化， 直接用于下歩反应。 把上述所得酰氯 （9.3g， 0.04mol) 和丙烯腈 （3.2g， 0.06mol) 溶于对 二甲苯（50ml)中， 再加入醋酸钯（lg， 4mmol)和 Ν,Ν-二甲基苄胺（8.1g， 0.06mol) , 在 N2保护下 135 °C回流 18小时。 停止加热， 待反应液自然冷却 后加入乙酸乙酯 (120ml)， 过滤； 浓缩滤液， 残留物中加入石油醚 (120ml)， 室温下搅拌 lOmin, 过滤， 浓缩滤液， 得粗品 3-(3-溴 -5-甲基苯基) -2-丙烯腈 6.4g， HPLC: 反式异构体保留时间 12.088min， 纯度 94 % ; 顺式异构体保 留时间 11.680min， 纯度 6 %。 该粗品用无水乙醇重结晶， 得类白色固体 (E)-3-(3-溴 -5-甲基苯基) -2-丙烯腈 5.4g， 收率 61%， HPLC: 反式异构体保 留时间 12.088min， 纯度 99.5 % ; 顺式异构体保留时间 11.680min， 纯度 0.53-bromo-5-methylbenzoic acid (8.8 g, 0.04 mol) was dissolved in dichloromethane (30 ml), and thionyl chloride (1 lg, 0.09 mol) was added dropwise, and the mixture was heated and refluxed for 1.5 hours. The organic acid was concentrated to dryness to give 9.3 g of crude acid chloride. Yield: 97%. It is used directly in the sputum reaction without purification. The above-obtained acid chloride (9.3 g, 0.04 mol) and acrylonitrile (3.2 g, 0.06 mol) were dissolved in p-xylene (50 ml), then palladium acetate (lg, 4 mmol) and hydrazine, hydrazine-dimethylbenzylamine were added. (8.1 g, 0.06 mol), refluxed at 135 ° C for 18 hours under N 2 protection. After the reaction mixture was cooled, the reaction mixture was cooled with EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -5-Methylphenyl)-2-acrylonitrile 6.4 g, HPLC: trans isomer retention time 12.088 min, purity 94%; cis isomer retention time 11.680 min, purity 6%. The crude product was recrystallized from anhydrous ethanol to give white crystals (E) -3-(3-bromo-5-methylphenyl)-2- acrylonitrile 5.4 g, yield 61%, HPLC: trans isomer The retention time of the body was 12.0088 min, the purity was 99.5 %; the retention time of the cis isomer was 11.680 min, and the purity was 0.5.
0/ 0/
/0 o /0 o
核磁共振数据同实施例 5和 6。 实施例 8 3-甲基 -5-硝基苯腈的合成
Figure imgf000018_0001
The NMR data is the same as in Examples 5 and 6. Example 8 Synthesis of 3-methyl-5-nitrobenzonitrile
Figure imgf000018_0001
在无水干燥过、 氮气保护的反应瓶中， 加入 3-溴 -5-硝基甲苯 （18.6g， 86mmol)、新蒸馏的 Ν,Ν-二甲基甲酰胺（100ml)和干燥过的氰化亚铜（7.84g， 87mmol)， 该反应体系回流过夜。 把反应体系冷到室温， 倒入水 (500ml)中， 用乙酸乙酯 (400ml)萃取， 有机层再依次用水 (50ml)洗、 饱和碳酸氢钠溶液 Oml)洗、再用水 Oml)洗， 然后用无水硫酸钠干燥有机层； 将有机层过滤、 浓缩， 残留物经过柱层析 （石油醚 /乙酸乙酯 =4/1， v/v) 得到浅黄色固体 3- 甲基 -5-硝基苯腈 8.51g， 收率 61%。 实施例 9 3-甲基 -5-硝基苯甲酸的合成
Figure imgf000019_0001
In an anhydrous dry, nitrogen-protected reaction flask, 3-bromo-5-nitrotoluene (18.6 g, 86 mmol), freshly distilled hydrazine, hydrazine-dimethylformamide (100 ml) and dried cyanide were added. Cuprous (7.84 g, 87 mmol), and the reaction was refluxed overnight. The reaction system was cooled to room temperature, poured into water (500 ml), and extracted with ethyl acetate (400 ml). The organic layer was washed successively with water (50 ml), saturated sodium hydrogen carbonate solution (Oml) and then with water (Oml), then The organic layer was dried (MgSO4) The benzonitrile was 8.51 g, and the yield was 61%. Example 9 Synthesis of 3-methyl-5-nitrobenzoic acid
Figure imgf000019_0001
在反应瓶中加入实施例 8制备的 3-甲基 -5-硝基苯腈 (3.73g， 23mmol), 75%硫酸水溶液（50ml)，在 150°C反应 1小时。冷到室温，倒入冰水 (150ml) 中， 用乙酸乙酯 (150ml)萃取， 有机相用无水硫酸钠干燥， 过滤， 浓缩， 得 到类白色固体 3-甲基 -5-硝基苯甲酸 3.22g， 收率 77.4%。  3-methyl-5-nitrobenzonitrile (3.73 g, 23 mmol) prepared in Example 8 and a 75% aqueous sulfuric acid solution (50 ml) were added to the reaction mixture, and the mixture was reacted at 150 ° C for 1 hour. It was cooled to room temperature, poured into ice water (150 ml), EtOAc (EtOAc) 3.22 g, yield 77.4%.
^MR (DMSO-d6) δ 2.38 (s, 3H)， 7.67 ( s， 1H) ,7.74 ( s， 1H)， 7.82 ( s， lH) o 实施例 10 (E)-3-(3-硝基 -5-甲基苯基:) -2-丙烯腈的合成
Figure imgf000019_0002
^MR (DMSO-d6) δ 2.38 (s, 3H), 7.67 (s, 1H), 7.74 (s, 1H), 7.82 (s, lH) o Example 10 (E)-3-(3-nitro -5-Methylphenyl:) Synthesis of -2-acrylonitrile
Figure imgf000019_0002
把氯化亚砜 (2.96g， 24.9mmol)滴加到 3-甲基 -5-硝基苯甲酸 (3.0g， 16.56mmol)的二氯甲垸 （50ml) 溶液中， 加毕， 加热回流 2小时， 浓缩， 得 3-甲基 -5-硝基苯甲酰氯粗品 3.27g， 收率： 99%。 此可直接用于下一歩反应。  Thionyl chloride (2.96 g, 24.9 mmol) was added dropwise to a solution of 3-methyl-5-nitrobenzoic acid (3.0 g, 16.56 mmol) in dichloromethane (50 ml). The oil was concentrated to give 3.27 g of crude 3-methyl-5-nitrobenzoyl chloride. Yield: 99%. This can be used directly in the next reaction.
把 3-甲基 -5-硝基苯甲酰氯 (3.27g， 16.4mmol)和丙烯腈 (1.3g， 24.6mmol) 溶于对二甲苯 (100ml)中， 再加入醋酸钯 (0.42g， 1.87mmol) 和 Ν,Ν-二甲基 苄胺 (3.36g， 24.8mmol), 在 N2保护下 135°C回流 18小时。 待反应液冷却后 加入乙酸乙酯 (100ml), 过滤， 浓缩滤液， 得粗品 3-(3-硝基 -5-甲基苯基: )-2- 丙烯腈 2.53g， HPLC: 反式异构体保留时间 10.760min， 纯度 93 % ; 顺式异 构体保留时间 10.372min， 纯度 7 %。 该粗品经乙醚-无水乙醇 （2: 1 )重结 晶，得类白色固体 2.28g，收率 74%, HPLC:反式异构体保留时间 10.760min， 纯度 99.2 % ; 顺式异构体保留时间 10.372min， 纯度 0.8 %。 实施例 11 N-对甲苯磺酰基 -5-氯 -1H-吲哚 -2-甲酸乙酯的合成
Figure imgf000020_0001
3-Methyl-5-nitrobenzoyl chloride (3.27 g, 16.4 mmol) and acrylonitrile (1.3 g, 24.6 mmol) were dissolved in p-xylene (100 ml), then palladium acetate (0.42 g, 1.87 mmol) And hydrazine, hydrazine-dimethylbenzylamine (3.36 g, 24.8 mmol), was refluxed for 18 hours at 135 ° C under N 2 protection. After the reaction mixture was cooled, ethyl acetate (100 ml) was added, filtered, and the filtrate was concentrated to give crude 3-(3-nitro-5-methylphenyl:)-2- acrylonitrile 2.53 g, HPLC: The retention time was 10.760 min, the purity was 93%; the cis isomer retention time was 10.372 min, and the purity was 7%. The crude product was recrystallized from diethyl ether-ethyl acetate (2:1) to yield white solid (yield: </RTI></RTI><RTIgt; Time 10.372 min, purity 0.8%. Example 11 Synthesis of Ethyl N-p-Toluenesulfonyl-5-chloro-1H-indole-2-carboxylate
Figure imgf000020_0001
5-氯 -1H-吲哚 -2-甲酸乙酯（12.0g， 53.65mmol)溶解在无水 DMF ( lOOml) 中，冷到 0°C时， 向反应液中分批加入 NaH (3.22g， 80.5mmol， 含量 60%); 加完后， 在 0°C搅拌反应 20分钟， 再滴加对甲苯磺酰氯（15.3g， 80.5mmol) 的无水 DMF (20ml)溶液， 整个滴加过程使反应液温度维持在 0〜5 °C， 然 后在室温搅拌反应 1小时。 把反应液倒入冰水 (450ml)中， 析出固体， 过滤， 用水 (100mlx3)冲洗滤饼，干燥得 N-对甲苯磺酰基 -5-氯 -1H-吲哚 -2-甲酸乙酯 18.87g， 收率 93.1%。  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. The 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%.
ifiNMR (CDC13) δ 1.40 (dd, 3H), 2.36(s, 3H), 4.39(m, 2H), 7.05 (s, 1H), 7.27 (t, 2H), 7.37 (dd, 1H), 7.51 (d, 1H), 7.90 (d, 2H), 8.02 (d, 1H)。 实施例 12 N-对甲 磺酰基 -3- :-m-吲哚 -2-甲酸乙酯的合成
Figure imgf000020_0002
IfiNMR (CDC1 3 ) δ 1.40 (dd, 3H), 2.36 (s, 3H), 4.39 (m, 2H), 7.05 (s, 1H), 7.27 (t, 2H), 7.37 (dd, 1H), 7.51 ( d, 1H), 7.90 (d, 2H), 8.02 (d, 1H). Example 12 Synthesis of N-p-Methanesulfonyl-3-:-m-indole-2-carboxylic acid ethyl ester
Figure imgf000020_0002
N-对甲苯磺酰基 -5-氯 -1H-吲哚 -2-甲酸乙酯 (18.0g，47.64mmol)溶于二禁 甲垸 (150ml)中， 加入吡啶 (10ml)， 再滴加液溴（7.63g， 47.64mmol), 加毕， 室温搅拌过夜。反应液用 1N HC1水溶液 (100mlx3)洗涤， 水 (lOOmlx l)洗涤, 无水硫酸钠干燥。过滤， 浓缩，残留物柱层析纯化（石油醚 /乙酸乙酯 =20/1， 按体积）， 得 N-对甲苯磺酰基 -3- :-1Η-吲哚 -2-甲酸乙酯 20.4g， 收率 Ethyl N-p-toluenesulfonyl-5-chloro-1H-indole-2-carboxylate (18.0 g, 47.64 mmol) was dissolved in hexanes (150 ml), pyridine (10 ml) was added, and liquid bromine was added dropwise. (7.63 g, 47.64 mmol), added, stirred at room temperature overnight. The reaction solution was washed with aq. EtOAc (1 mL) (EtOAc) Filtration, concentration and purification by column chromatography (EtOAc/EtOAcEtOAcEtOAcEtOAc. Yield
93.75%。 93.75%.
HNMR (CDC13) δ 1.46 (t, 3H), 2.35(s, 3H), 4.52(m, 2H), 7.22 (s, 2H) 7.37 (dd, 1H), 7.48 (d, 1H), 7.83 (d, 2H), 7.94 (d, 1H)。 实施例 13 (N-对甲苯磺酰基 -2-乙氧羰基 -5-氯 -1H-吲哚 -3-)-次膦酸乙酯的合 成
Figure imgf000021_0001
HNMR (CDC1 3 ) δ 1.46 (t, 3H), 2.35 (s, 3H), 4.52 (m, 2H), 7.22 (s, 2H) 7.37 (dd, 1H), 7.48 (d, 1H), 7.83 (d, 2H), 7.94 (d, 1H). Example 13 Synthesis of (N-p-toluenesulfonyl-2-ethoxycarbonyl-5-chloro-1H-indole-3-)-phosphinic acid ethyl ester
Figure imgf000021_0001
N-对甲苯磺酰基 -3-溴 -5-氯 -1H-吲哚 -2-甲酸乙酯 （11.96g， 26.19mmol) 溶解在无水四氢呋喃 （300ml) 中。 在氮气保护下， 向干冰 /乙醚冷却到 -76.0°C的该溶液中滴加 n-BuLi ( 15.7ml, 2.5M, 39.3mmol)的 THF溶液， 温度控制在 -76.0°C〜- 72.0°C。加完后并在此温度搅拌 20分钟， 再缓慢滴加 氯亚磷酸二乙酯 （4.51g， 28.8mmol), 加完后再在 -76.0°C搅拌反应 2小时。 反应液用乙酸乙酯 (300ml)稀释并升温到 -40°C， 加入 0.5N 的盐酸水溶液 (100ml),然后升到室温搅拌 1小时。分出有机层，水层再用乙酸乙酯 (100ml X I)萃取。 合并有机层， 用饱和食盐水 (80ml X I)洗， 无水硫酸钠干燥后， 过滤， 浓缩， 残留物柱层析 （石油醚 /乙酸乙酯 =15/1， 按体积）， 得类白色 固体标题化合物 9.05g， 收率 73.5%。  Ethyl N-p-toluenesulfonyl-3-bromo-5-chloro-1H-indole-2-carboxylate (11.96 g, 26.19 mmol) was dissolved in anhydrous tetrahydrofurane (300 ml). Under a nitrogen atmosphere, a solution of n-BuLi ( 15.7 ml, 2.5 M, 39.3 mmol) in THF was added dropwise to dry ice/diethyl ether cooled to -76.0 ° C. The temperature was controlled at -76.0 ° C to - 72.0 ° C. . After the completion of the addition, the mixture was stirred at this temperature for 20 minutes, and diethyl chlorophosphite (4.51 g, 28.8 mmol) was added dropwise slowly, and the reaction was stirred at -76.0 ° C for 2 hours. The reaction mixture was diluted with ethyl acetate (300 ml) and evaporated to EtOAc. The organic layer was separated and the aqueous extracted with ethyl acetate (100 mL). The organic layer was combined, washed with EtOAc EtOAc EtOAc EtOAcjjjjjjjj The title compound was 9.05 g, yield 73.5%.
ifiNMR (CDC13) δ 1.30-1.47 (m, 6H), 2.39(d, 3H), 4.09-4.22(m, 2H), 4.49-4.56(m, 2H), 6.75-8.74 (s,s, 0.5H+0.5H), 7.29-7.40 (m, 4H), 7.90-8.02 (m, 3H)。 实施例 14 (N-对甲苯磺酰基 -2-乙氧羰基 -5-氯 -1H-吲哚 -3-基) (3-溴 -5-甲基 苯基:) -次膦酸乙酯的合成
Figure imgf000022_0001
IfiNMR (CDC1 3 ) δ 1.30-1.47 (m, 6H), 2.39(d, 3H), 4.09-4.22(m, 2H), 4.49-4.56(m, 2H), 6.75-8.74 (s,s, 0.5H +0.5H), 7.29-7.40 (m, 4H), 7.90-8.02 (m, 3H). Example 14 (N-p-toluenesulfonyl-2-ethoxycarbonyl-5-chloro-1H-indol-3-yl) (3-bromo-5-methylphenyl:)-phosphinic acid ethyl ester synthesis
Figure imgf000022_0001
在反应瓶中加入 (N-对甲苯磺酰基 -2-乙氧羰基 -5-氯 -1H-吲哚 -3+次膦 酸乙酯 (2.32g， 4.95mmol)， 3,5-二溴甲苯 （2.5g， 9.9mmol)， 四 (三苯基膦) 钯（200mg， 催化量）， 三乙胺（600mg， 5.94mmol)和甲苯 (50ml)， 该反应 液在氮气环境中 110°C搅拌反应 18小时，浓缩去除溶剂，残留物柱层析（石 油醚 /乙酸乙酯 =10/1， 按体积）， 得固体标题化合物 2.15g， 收率 68%。  (N-p-toluenesulfonyl-2-ethoxycarbonyl-5-chloro-1H-indole-3 + phosphinic acid ethyl ester (2.32 g, 4.95 mmol), 3,5-dibromotoluene was added to the reaction flask. (2.5 g, 9.9 mmol), tetrakis(triphenylphosphine) palladium (200 mg, catalytic amount), triethylamine (600 mg, 5.94 mmol) and toluene (50 ml). The reaction mixture was stirred at 110 ° C under nitrogen atmosphere. After 18 hours, the solvent was evaporated. EtOAcjjjjjjjjj
ifiNMR (CDC13) δ 1.30-1.47 (m, 6H), 2.37(d, 6H), 4.07-4.15(m, 2H), 4.47-4.56(m, 2H), 7.27-7.34 (m, 3H), 7.46(s, 1H), 7.52-7.96 (m, 6H)0 实施例 15 (N-对甲苯磺酰基 -2-乙氧羰基- -1H-吲哚 -3-基) (3-溴 -5-甲 基苯基:) -次膦酸甲酯的合成 IfiNMR (CDC1 3 ) δ 1.30-1.47 (m, 6H), 2.37 (d, 6H), 4.07-4.15 (m, 2H), 4.47-4.56 (m, 2H), 7.27-7.34 (m, 3H), 7.46 (s, 1H), 7.52-7.96 (m, 6H) 0 Example 15 (N-p-toluenesulfonyl-2-ethoxycarbonyl-lH-indol-3-yl) (3-bromo-5-methyl) Synthesis of methyl phenyl :) - methyl phosphinate
Figure imgf000022_0002
Figure imgf000022_0002
(N-对甲苯磺酰基 -2-乙氧羰基 -5-氯 -1H-吲哚 -3-基) (3-溴 -5-甲基苯基) -次 膦酸乙酯 (2.0g， 3.13mmol)溶于二氯甲垸 (10ml)中， 冷到 0°C时加入三甲基 溴硅垸 (2.3g， 15.0mmol)， 然后在 40°C反应 1.5小时， 浓缩去除溶剂及过量 的三甲基溴硅垸。 在反应瓶中加入二氯甲垸 (10ml)， 冷到 0°C， 加入草酰氯 (0.6ml, 6.26mmol)及 DMF(0.5ml)， 在室温搅拌反应 1小时， 浓缩去除溶剂 及过量的草酰氯。 在反应瓶中加入二氯甲垸 (10ml)， 冷到 0〜5 °C时加入甲 醇 (30ml)， 在室温搅拌反应 2小时， 浓缩去除溶剂得标题化合物 1.9g， 收率 97.2%。 (N-p-toluenesulfonyl-2-ethoxycarbonyl-5-chloro-1H-indol-3-yl) (3-bromo-5-methylphenyl)-phosphinic acid ethyl ester (2.0 g, 3.13 Methyl) was dissolved in dichloromethane (10 ml), trimethylbromide (2.3 g, 15.0 mmol) was added to 0 ° C, then reacted at 40 ° C for 1.5 hours, concentrated to remove solvent and excess Methyl bromide. Dichloromethane (10 ml) was added to the reaction flask, cooled to 0 ° C, oxalyl chloride (0.6 ml, 6.26 mmol) and DMF (0.5 ml) were added, and the mixture was stirred at room temperature for 1 hour. And an excess of oxalyl chloride. Dichloromethane (10 ml) was added to the reaction flask, and methanol (30 ml) was added to the mixture, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated to give the title compound 1.9 g (yield: 97.2%).
ifiNMR (CDC13) δ 1.40-1.46 (m, 3H), 2.35(d, 6H), 3.90 ( d， 3H)， 4.48-4.55(m, 2H), 7.28-7.35 (m, 3H), 7.46-7.98 (m, 7H)。 实施例 16 (2-羧基 -5-氯 -1H-吲哚 -3-基) (3-溴 -5-甲基苯基) -次膦酸甲酯的 合成 IfiNMR (CDC1 3 ) δ 1.40-1.46 (m, 3H), 2.35 (d, 6H), 3.90 (d, 3H), 4.48-4.55 (m, 2H), 7.28-7.35 (m, 3H), 7.46-7.98 (m, 7H). Example 16 Synthesis of (2-carboxy-5-chloro-1H-indol-3-yl)(3-bromo-5-methylphenyl)-phosphinic acid methyl ester
Figure imgf000023_0001
Figure imgf000023_0001
在反应瓶中加入 (N-对甲苯磺酰基 -2-乙氧羰基 -5-氯 -1H-吲哚 -3-基) (3-溴 -5-甲基苯基) -次膦酸甲酯（1.23g， 1.97mmol) , 一水氢氧化锂 （331mg， 7.88mmol) 与水 （5.6ml) 的溶液， 四氢呋喃 （2.0ml)， 该反应体系在室温 搅拌 16小时。浓缩去除四氢呋喃， 再用 0.5N 盐酸水溶液酸化使 pH 2， 用 乙酸乙酯 （20mlx2 ) 萃取， 有机层用无水硫酸钠干燥， 过滤， 浓缩， 残留 物柱层析 （CH2Cl2/MeOH = 10/l， 按体积）， 得固体标题化合物 620mg， 收 率 71.2%。 Add (N-p-toluenesulfonyl-2-ethoxycarbonyl-5-chloro-1H-indol-3-yl)(3-bromo-5-methylphenyl)-phosphinic acid methyl ester to the reaction flask (1.23 g, 1.97 mmol), a solution of lithium hydroxide monohydrate (331 mg, 7.88 mmol) and water (5.6 ml), tetrahydrofuran (2.0 ml), and the mixture was stirred at room temperature for 16 hours. Concentrated to remove tetrahydrofuran, acidified with 0.5N hydrochloric acid aqueous solution of pH 2, and extracted with ethyl acetate (20 mLx2), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue was column chromatographed (CH 2 Cl 2 / MeOH = 10/l, by volume) gave 620 mg of the title compound.
1HNMR (CDCl3) S 2.33(s,3H), 3.91 (d， 3H)， 7.20(s, 1H)， 7.35 (dd, 1H)， 7.41 (s, 1H)， 7.46(s, 2H), 7.56-7.60 (m, 2H), 10.7 (brs, 1H) 实施例 Π (2-氨基甲酰基 -5-氯 -1H-吲哚 -3-基) (3-溴 -5-甲基苯基) -次膦 酸甲酯的合成
Figure imgf000024_0001
 1 H NMR (CDCl 3 ) S 2.33 (s, 3H), 3.91 (d, 3H), 7.20 (s, 1H), 7.35 (dd, 1H), 7.41 (s, 1H), 7.46 (s, 2H), 7.56 -7.60 (m, 2H), 10.7 (brs, 1H) Example Π (2-carbamoyl-5-chloro-1H-indol-3-yl) (3-bromo-5-methylphenyl) - Synthesis of methyl phosphinate
Figure imgf000024_0001
在反应瓶中加入 (2-羧基 -5-氯 -1H-吲哚 -3-基 )(3-溴 -5-甲基苯基) -次膦酸 甲酯 (550mg， 1.24mmol), Ι , Γ-羰基二咪唑 （402mg， 2.48mmol) , 乙二醇 二甲醚（5.0ml)， 该反应体系室温搅拌 2小时后， 冷到 5 °C， 通入氨气约 10 分钟， 再在氨气环境中室温搅拌 1小时。 反应液中加入水 (8ml)， 用乙酸乙 酯 （10mlx2 ) 萃取， 有机层用无水硫酸钠干燥后过滤， 浓缩， 残留物柱层 析（石油醚 /乙酸乙酯 =10/1，按体积），得固体标题化合物 492mg，收率 89.8%。  (2-Carboxy-5-chloro-1H-indol-3-yl)(3-bromo-5-methylphenyl)-phosphinic acid methyl ester (550 mg, 1.24 mmol), hydrazine, was added to the reaction flask. Γ-carbonyldiimidazole (402 mg, 2.48 mmol), ethylene glycol dimethyl ether (5.0 ml), the reaction system was stirred at room temperature for 2 hours, cooled to 5 ° C, ammonia gas was introduced for about 10 minutes, and then ammonia gas Stir at room temperature for 1 hour in the environment. Water (8 ml) was added to the mixture, and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjj The title compound was 492 mg (yield: 89.8%).
ifiNMR (DMSO-d6) δ 2.32(s,3H), 3.77 ( d， 3H)， 7.34 ( dd, 1H)， 7.47-7.59(m, 5H), 8.04 (brs, 1H), 10.04 (brs, 1H), 12.88 (brs, 1H)。 实施例 18 (2-氨基甲酰基 -5-氯 -1H-吲哚 -3-基) [3-((1Ε)-2-氰基乙烯基) -5-甲 基苯基] -次膦酸甲酯的合成  IfiNMR (DMSO-d6) δ 2.32 (s, 3H), 3.77 (d, 3H), 7.34 ( dd, 1H), 7.47-7.59 (m, 5H), 8.04 (brs, 1H), 10.04 (brs, 1H) , 12.88 (brs, 1H). Example 18 (2-carbamoyl-5-chloro-1H-indol-3-yl) [3-((1Ε)-2-cyanovinyl)-5-methylphenyl]-phosphinic acid Synthesis of methyl ester
Figure imgf000024_0002
Figure imgf000024_0002
在反应瓶中加入 (2-氨基甲酰基 -5-氯 -1H-吲哚 -3-基) (3-溴 -5-甲基苯基) - 次膦酸甲酯 (442mg， l.Ommol), DMF ( 5ml) , 丙烯腈 （64mg， 1.2mmol) , 三乙胺（143mg， 1.4mmol)， 三苯基膦（6mg， 0.02mmol)和醋酸钯（3mg， O.Olmmol) , 该反应液在氮气环境中置于 120°C油浴中反应 8小时。 而后， 停止加热， 冷却至室温， 加入水 (20ml)， 用乙酸乙酯（10mlx3 )萃取， 合并 有机层， 饱和食盐水 （lOmlx l ) 洗， 无水硫酸钠干燥后过滤， 浓缩， 得固 体 322mg， 收率 77.8%。 (2-carbamoyl-5-chloro-1H-indol-3-yl)(3-bromo-5-methylphenyl)-methylphosphinate (442 mg, 1.0 mmol) was added to the reaction flask. , DMF (5ml), acrylonitrile (64mg, 1.2mmol), triethylamine (143mg, 1.4mmol), triphenylphosphine (6mg, 0.02mmol) and palladium acetate (3mg, O.Olmmol), the reaction solution The reaction was carried out in a 120 ° C oil bath for 8 hours under a nitrogen atmosphere. Then, the heating was stopped, cooled to room temperature, water (20 ml) was added, and extracted with ethyl acetate (10 ml×3). The organic layer was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, and evaporated.
^MR (CDCl3) 5 2.39(s, 3H)， 3.87 (d， 3H)， 5.89(d， 1H， J=16.5), 5.96 (brs， 1H)， 7.33-7.67(m, 7H), 10.45 (s， 1H)， 10.88 (brs, 1H); ^MR (CDCl 3 ) 5 2.39(s, 3H), 3.87 (d, 3H), 5.89(d, 1H, J=16.5), 5.96 (brs, 1H), 7.33-7.67(m, 7H), 10.45 ( s, 1H), 10.88 (brs, 1H);
HPLC: 反式异构体保留时间 13.250min， 纯度 76% ; 顺式异构体保留 时间 12.458min， 纯度 24 %。  HPLC: trans isomer retention time 13.250 min, purity 76%; cis isomer retention time 12.458 min, purity 24%.
将此顺反异构体混合物用乙 乙酸乙酯 = 100/1(νΛ打浆 10 分钟， 过 滤， 烘干， 得固体标题化合物 231mg， 收率 56%。 This cis-trans isomer mixture was beaten with ethyl acetate = 100/1 ( v EtOAc) for 10 min, filtered, and dried to give the title compound 231 mg.
^MR (CDCl3) 5 2.39(s, 3H)， 3.87 ( d， 3H)， 5.89(d， 1H)， 5.96 (brs, 1H)， 7.33-7.67(m, 7H), 10.45 (s, 1H)， 10.88 (brs, 1H)。 ^MR (CDCl 3 ) 5 2.39(s, 3H), 3.87 ( d, 3H), 5.89(d, 1H), 5.96 (brs, 1H), 7.33-7.67(m, 7H), 10.45 (s, 1H) , 10.88 (brs, 1H).
HPLC: 反式异构体保留时间 13.250min， 纯度 99.87 % ; 顺式异构体保留时 间 12.458min, 纯度 0.13 %。 HPLC: trans isomer retention time 13.250 min, purity 99.87 %; cis isomer retention time 12.458 min, purity 0.13 %.

Claims

权利要求 Rights request
1、 一种 3-(3-取代 -5-甲基苯基：)丙烯腈的制备方法， 该方法包括： 通式 II所示化合物与丙烯腈进行 Heck反应， 得到通式 III所示的 3-(3- 取代 -5-甲基苯基：)丙烯腈， A method for producing 3-(3-substituted-5-methylphenyl:)acrylonitrile, which comprises: subjecting a compound of the formula II to acrylonitrile to carry out a Heck reaction to obtain a compound of the formula III -(3-substituted-5-methylphenyl:)acrylonitrile,
反应式如下：
Figure imgf000026_0001
The reaction formula is as follows:
Figure imgf000026_0001
II III  II III
其中， R N02、 N¾、 NH-W、 Br或 PG， W表示氨基保护基，Wherein R N0 2 , N3⁄4, NH-W, Br or PG, W represents an amino protecting group,
PG为
Figure imgf000026_0002
PG is
Figure imgf000026_0002
PG  PG
R2为合适的离去基团， 所述合适的离去基团为卤素、 COCl、 三氟甲磺 酰基、 甲苯磺酰基或甲基磺酰基； R 2 is a suitable leaving group, and the suitable leaving group is halogen, COCl, trifluoromethanesulfonyl, tosyl or methylsulfonyl;
且当！^为^时， R2不为 C1或F。 And when! When ^ is ^, R 2 is not C1 or F.
所述的卤素为 F、 Cl、 Br或 I。  The halogen is F, Cl, Br or I.
2、 根据权利要求 1所述的制备方法， 其特征是， 其中通式 II所示化合 物与丙烯腈进行 Heck反应， 得到以反式为主的通式 III所示化合物， 其中 通式 III所示化合物反式与顺式之比 4; 而后， 根据通式 III所示化合物 顺反异构体的比例采取相应的纯化方法，通过重结晶或打浆得到通式 I所示 的 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈， 或者先进行双键立体构型转换后再进 行重结晶或打浆， 得到通式 I所示的 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈； 反应式如下：
Figure imgf000027_0001
The method according to claim 1, wherein the 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 formula III is as shown in the formula III. The ratio of the compound trans to the cis is 4; and then, according to the ratio of the cis-trans isomer of the compound of the formula III, a corresponding purification method is employed, and the formula I is obtained by recrystallization or beating. (E)-3-(3-Substituted-5-methylphenyl:)acrylonitrile, or undergoing double bond stereo configuration conversion followed by recrystallization or beating to obtain (E) of Formula I -3-(3-substituted-5-methylphenyl:)acrylonitrile; the reaction formula is as follows:
Figure imgf000027_0001
II III  II III
其中， R N02、 N¾、 NH-W、 Br或 PG， W表示氨基保护基， Wherein R N0 2 , N3⁄4, NH-W, Br or PG, W represents an amino protecting group,
PG为
Figure imgf000027_0002
PG is
Figure imgf000027_0002
R2为合适的离去基团， 所述合适的离去基团为卤素、 C0C1、 三氟甲磺 酰基、 甲苯磺酰基或甲基磺酰基； R 2 is a suitable leaving group, and the suitable leaving group is halogen, C0C1, trifluoromethanesulfonyl, tosyl or methylsulfonyl;
且当！^为^时， R2不为 C1或F。 And when! When ^ is ^, R 2 is not C1 or F.
所述的卤素为 F、 Cl、 Br或 I。  The halogen is F, Cl, Br or I.
3、根据权利要求 1或 2所述的制备方法，其特征是，所述的 为 N02、 N¾、 Br或 PG。 The preparation method according to claim 1 or 2, wherein the one is N0 2 , N 3⁄4, Br or PG.
4、根据权利要求 1或 2所述的制备方法，其特征是，所述的 为 N02、 NH2、 Br或 PG; 所述的 R2为 Br、 I或 C0C1。 The method according to claim 1 or 2, wherein the one is N0 2 , NH 2 , Br or PG; and the R 2 is Br, I or C0C1.
5、 根据权利要求 1-4中任一项所述的制备方法， 其特征是， 通式 II所 示化合物与丙烯腈进行 Heck反应， 所述 Heck反应是在合适的钯催化剂、 合适的碱、 合适的溶剂和合适的温度下进行， 其中， 合适的钯催化剂为均 相钯催化剂或非均相 Pd催化剂， 所述均相钯催化剂为四 (三苯基膦)合钯 (0) (Pd(PPh3)4)、 氯化钯 (II) ( PdCl2)、 醋酸钯 (II) (Pd(OAc)2)、 二 (三苯基膦) 二氯化钯 (II) (Pd(PPh3)2Cl2) 或三 (二亚苄基丙酮)二钯 （Pd2(dba)3)， 所述非 均相 Pd催化剂为钯 /碳、 钯 /金属氧化物或钯 /沸石； 合适的碱为无机碱或有 机碱， 所述无机碱为碳酸钾、 碳酸钠、 碳酸铯、 碳酸氢钠、 ：化钠或磷 酸钾， 所述有机碱为三乙胺、 醋酸钠、 醋酸钾、 Ν,Ν-二甲基苄胺、 Ν,Ν-二 乙基乙胺、 三丁基胺或三乙醇胺； 合适的溶剂为 Ν,Ν-二甲基甲酰胺、 乙腈、 四氢呋喃、 二甲亚砜、 对二甲苯、 水、 1-甲基 -2-吡咯垸酮、 甲苯、 二氧六 环、 丙酮或 Ν,Ν-二甲基乙酰胺； 反应时间为 0.5-30 小时； 反应温度为 20-180°C。 The process according to any one of claims 1 to 4, wherein the compound of the formula II is subjected to a Heck reaction with acrylonitrile, the Heck reaction being a suitable palladium catalyst, a suitable base, A suitable solvent is carried out at a suitable temperature, wherein a suitable palladium catalyst is a homogeneous palladium catalyst or a heterogeneous Pd catalyst, and the homogeneous palladium catalyst is tetrakis(triphenylphosphine)palladium (0). (Pd(PPh 3 ) 4 ), palladium(II) chloride (PdCl 2 ), palladium(II) acetate (Pd(OAc) 2 ), bis(triphenylphosphine)palladium(II) dichloride (Pd( PPh 3 ) 2 Cl 2 ) or tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), the heterogeneous Pd catalyst is palladium/carbon, palladium/metal oxide or palladium/zeolite; The base is an inorganic base or an organic base, and the inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium or potassium phosphate, and the organic base is triethylamine, sodium acetate, potassium acetate, cesium. , Ν-dimethylbenzylamine, hydrazine, hydrazine-diethylethylamine, tributylamine or triethanolamine; suitable solvents are hydrazine, hydrazine-dimethylformamide, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, Para-xylene, water, 1-methyl-2-pyrrolidone, toluene, dioxane, acetone or hydrazine, hydrazine-dimethylacetamide; reaction time is 0.5-30 hours; reaction temperature is 20-180 °C.
6、 根据权利要求 1-5中任一项所述的制备方法， 其特征是， 通式 II所 示化合物与丙烯腈进行 Heck反应，得到以反式为主的通式 III所示化合物， 而后， 通式 III所示化合物通过重结晶或打浆得到通式 I所示的 (E)-3-(3-取 代 -5-甲基苯基)丙烯腈， 或者先进行双键立体构型转换后再重结晶或打浆， 得到通式 I所示的 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈， g卩：
Figure imgf000028_0001
The process according to any one of claims 1 to 5, wherein 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)-3-(3-substituted- 5 -methylphenyl)acrylonitrile represented by the formula I, or after performing the double bond stereo configuration conversion. Recrystallization or beating to obtain (E)-3-(3-substituted-5-methylphenyl:)acrylonitrile of the formula I, g卩:
Figure imgf000028_0001
lla:R1 =N02 llla:R1=N02 la:R1 =N02  Lla:R1 =N02 llla:R1=N02 la:R1 =N02
b:R1=NH2;NH-W b:R1=NH2;NH-W b:R1=NH2;NH-W  b: R1=NH2; NH-W b: R1=NH2; NH-W b: R1=NH2; NH-W
c:R1=Br c:R1 =Br c:R1=Br  c: R1 = Br c: R1 = Br c: R1 = Br
d:R1 =PG d:R1=PG d:R1=PG  d: R1 = PG d: R1 = PG d: R1 = PG
II III I  II III I
1) 当 R1为N02、 NH2或 NH-W时， 通式 III化合物即 Ilia或 Illb化合物通过 重结晶或打浆方法去除顺式，得到 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈即 la或 lb 化合物； 2) 当 和 R2均为 Br时， 通式 III化合物即 IIIc化合物通过双键立体 构型转换后再重结晶或打浆， 得到 (E)-3-(3-溴 -5-甲基苯基)丙烯腈即 Ic化合 物； 其中所述的双键立体构型转换包括： 3-(3-溴 -5-甲基苯基) -2-丙烯腈先与 液溴或 N-溴代丁二酰亚胺发生加成反应生成 2,3-二溴 -3-(3-溴 -5-甲基苯基) - 丙腈， 然后在锌 /醋酸条件下反式消除得到 (E)-3-(3-溴 -5-甲基苯基)丙烯腈， 即通式 Ic化合物； 1) When R 1 is N0 2 , NH 2 or NH-W, the compound of formula III, i.e., Ilia or Illb, is removed by recrystallization or beating to obtain (E)-3-(3-substituted-5- Methylphenyl:) acrylonitrile ie la or lb compound; 2) When both R 2 and Br are Br, the compound of the formula III, that is, the compound IIIc, is converted by a double bond stereo configuration and then recrystallized or beaten to obtain (E)-3-(3-bromo-5-methylphenyl). Acrylonitrile is an Ic compound; wherein the double bond stereo configuration conversion comprises: 3-(3-bromo-5-methylphenyl)-2-acrylonitrile first with liquid bromine or N-bromosuccinyl The imine undergoes an addition reaction to form 2,3-dibromo-3-(3-bromo-5-methylphenyl)-propionitrile, which is then trans-reduced under zinc/acetic acid conditions to give (E)-3-( 3-bromo-5-methylphenyl)acrylonitrile, a compound of the formula Ic;
3) 当 为 Br， R2为 COC1时， 通式 III化合物即 IIIc化合物直接重结 晶或打浆得到 (E)-3-(3-溴 -5-甲基苯基)丙烯腈即 Ic化合物； 3) When Br, R 2 is COC1, the compound of formula III, that is, the compound IIIc, is directly recrystallized or beaten to obtain (E)-3-(3-bromo-5-methylphenyl)acrylonitrile, that is, an Ic compound;
4) 当 为 PG时， 通式 III化合物即 Illd化合物通过重结晶或打浆得 到 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈即 Id化合物。  4) In the case of PG, the compound of the formula III, i.e., the Illd compound, is obtained by recrystallization or beating to obtain (E)-3-(3-substituted-5-methylphenyl:)acrylonitrile, i.e., an Id compound.
7、 根据权利要求 6所述的制备方法， 其特征是， 当 1^和 R2均为 Br 时，通式 III化合物即 IIIc化合物通过双键立体构型转换后再重结晶或打浆， 得到 (E)-3-(3-溴 -5-甲基苯基)丙烯腈即 Ic化合物； 其中所述的双键立体构型 转换包括： 3-(3-溴 -5-甲基苯基) -2-丙烯腈先与液溴发生加成反应生成 2,3-二 溴 -3-(3-溴 -5-甲基苯基) -丙腈， 然后在锌 /醋酸条件下反式消除得到 (E)-3-(3- 溴 -5-甲基苯基)丙烯腈， 即通式 Ic化合物。 The preparation method according to claim 6, wherein when both 1 and R 2 are Br, the compound of the formula III, that is, the compound IIIc, is converted by a double bond stereo configuration and then recrystallized or beaten to obtain ( E)-3-(3-bromo-5-methylphenyl)acrylonitrile, an Ic compound; wherein the double bond stereoconfiguration conversion comprises: 3-(3-bromo-5-methylphenyl)- 2-Acrylonitrile is first reacted with liquid bromine to form 2,3-dibromo-3-(3-bromo-5-methylphenyl)-propionitrile, which is then deprotected under zinc/acetic acid conditions ( E)-3-(3-Bromo-5-methylphenyl)acrylonitrile, a compound of the formula Ic.
8、 根据权利要求 6所述的制备方法， 其特征是， 该方法进一歩包括将 通式 Ia、 lb或 Ic化合物制备成通式 Id化合物：
Figure imgf000029_0001
8. The process according to claim 6, wherein the process further comprises preparing a compound of the formula Ia, lb or Ic into a compound of the formula Id:
Figure imgf000029_0001
当 R1为N02时， 通式 la化合物经硝基还原、 重氮化、 碘取代三歩反应得 到化合物 IV; 或者 When R 1 is N0 2 , the compound of the formula la is obtained by nitro reduction, diazotization, and iodine substitution of triterpene. To compound IV; or
当 R1为NH2时，通式 lb化合物经重氮化、碘取代两歩反应得到化合物 IV； 或者 When R 1 is NH 2 , the compound of the formula lb is subjected to diazotization and iodine substitution by two oxime reactions to obtain compound IV;
当 R1为NH-W时， 通式 lb化合物经脱氨基保护基、 重氮化、 碘取代三歩 反应得到化合物 IV； 或者 When 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;
当 为81"时，通式 Ic化合物与碘化钠在碘化亚铜催化下反应， 得到化合 物 IV；  When 81", the compound of the formula Ic is reacted with sodium iodide under the catalysis of cuprous iodide to obtain the compound IV;
然后， 化合物 IV与 (2-氨基甲酰基 -5-氯 -1H-吲哚 -3+次膦酸甲酯进行取 代反应， 得到通式 Id所示的 (E)-3-(3-取代 -5-甲基苯基：)丙烯腈。  Then, the compound IV is subjected to a substitution reaction with methyl (2-carbamoyl-5-chloro-1H-indole-3+phosphinate) to obtain (E)-3-(3-substituted- represented by the formula Id. 5-methylphenyl:) acrylonitrile.
9、 根据权利要求 8所述的制备方法， 其特征是， 所述的硝基还原反应 为 (E)-3-(3-硝基 -5-甲基苯基)丙烯腈 (Ia)在还原剂存在下进行还原反应， 生成9. The process according to claim 8, characterized in that the reduction reaction of nitro group (E) - 3 - (3- nitro --5-- methylphenyl) acrylonitrile (Ia) in the reduction Reductive reaction in the presence of a reagent
( -3-(3-氨基 -5-甲基苯基：)丙烯腈 (Ib 所使用的还原剂选自铁粉、 锌粉、 氯 化亚锡、 硫化钠、 二硫化钠、 亚硫酸钠、 亚硫酸氢钠、 亚硫酸铵、 亚硫酸 氢铵和连二亚硫酸钠中； 反应温度为 0〜120°C ; (-3-(3-Amino-5-methylphenyl:)acrylonitrile (the reducing agent used for Ib is selected from the group consisting of iron powder, zinc powder, stannous chloride, sodium sulfide, sodium disulfide, sodium sulfite, sulfurous acid Sodium hydrogen hydride, ammonium sulfite, ammonium hydrogen sulfite and sodium dithionite; reaction temperature is 0~120 ° C;
所述的重氮化反应为 (E)-3-(3-氨基 -5-甲基苯基：)丙烯腈 (lb)与亚硝酸钠 和酸在 0〜5°C的低温下反应 0.5〜2小时， 生成重氮盐， 其中酸为盐酸、硫酸 或三氟乙酸；  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. 2 hours, a diazonium salt is formed, wherein the acid is hydrochloric acid, sulfuric acid or trifluoroacetic acid;
所述碘取代反应为重氮盐与碘化物反应， 生成 (E 3-(3-碘 -5-甲基苯基：) 丙烯腈 0V:>， 其中碘化物为碘化钾或碘化钠， 其摩尔用量为重氮盐的 1〜5 倍， 反应时间 0.5〜6小时， 反应温度 0〜100°C， 必要时使用催化剂。  The iodine substitution reaction is a reaction of a diazonium salt with an iodide to form (E 3-(3-iodo-5-methylphenyl:) acrylonitrile 0V:>, wherein the iodide is potassium iodide or sodium iodide, and the mole thereof The 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.
10、 一类结构式如下的新的 3-(3-取代 -5-甲基苯基：)丙烯腈：  10. A new class of 3-(3-substituted-5-methylphenyl:)acrylonitriles of the formula:
3-(3-氨基 -5-甲基苯基) -2-丙烯腈
Figure imgf000031_0001
3-(3-Amino-5-methylphenyl)-2-acrylonitrile
Figure imgf000031_0001
-(3-硝基 -5-甲基苯基) -2-丙烯腈
Figure imgf000031_0002
-(3-nitro-5-methylphenyl)-2-acrylonitrile
Figure imgf000031_0002
K3-溴 -5-甲基苯基) -2-丙烯腈
Figure imgf000031_0003
K3-bromo-5-methylphenyl)-2-acrylonitrile
Figure imgf000031_0003
(E)-3-(3-氨基 -5-甲基苯基 )-2-丙烯腈
Figure imgf000031_0004
(E)-3-(3-Amino-5-methylphenyl)-2-acrylonitrile
Figure imgf000031_0004
(E)-3-(3-硝基 -5-甲基苯基 )-2-丙烯腈
Figure imgf000031_0005
(E)-3-(3-nitro-5-methylphenyl)-2-acrylonitrile
Figure imgf000031_0005
(Z)-3-(3-氨基 -5-甲基苯基 )-2-丙烯腈
Figure imgf000031_0006
(Z)-3-(3-Amino-5-methylphenyl)-2-acrylonitrile
Figure imgf000031_0006
(Z)-3- 3-硝基 -5-甲基苯基) -2-丙烯腈
Figure imgf000031_0007
(Z)-3- 3-nitro-5-methylphenyl)-2-acrylonitrile
Figure imgf000031_0007
(Z)-3-(3-溴 -5-甲基苯基) -2-丙烯腈 οε (Z)-3-(3-bromo-5-methylphenyl)-2-acrylonitrile Εε
Figure imgf000032_0001
.6.0/OTOZN3/X3d 0L6L0/U0Z OAV
Figure imgf000032_0001
.6.0/OTOZN3/X3d 0L6L0/U0Z OAV
PCT/CN2010/079700 2009-12-30 2010-12-13 (e)-3-(3-substituted-5-methylphenyl) arylonitrile and preparation methods thereof WO2011079704A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200910247676XA CN102115452A (en) 2009-12-30 2009-12-30 (E)-3-(3-substituted-5-methylphenyl)acrylonitrile and preparation method thereof
CN200910247676.X 2009-12-30

Publications (1)

Publication Number Publication Date
WO2011079704A1 true WO2011079704A1 (en) 2011-07-07

Family

ID=44214393

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2010/079700 WO2011079704A1 (en) 2009-12-30 2010-12-13 (e)-3-(3-substituted-5-methylphenyl) arylonitrile and preparation methods thereof

Country Status (2)

Country Link
CN (1) CN102115452A (en)
WO (1) WO2011079704A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103275126B (en) * 2013-05-28 2016-03-23 兰州大学 The method of the phosphonylation indoles in a kind of stereoselective syntheses 3-position
CN110028430B (en) * 2019-05-24 2020-04-10 杭州卢普生物科技有限公司 Preparation method of sulindac
CN110256424A (en) * 2019-07-03 2019-09-20 武汉工程大学 A kind of synthetic method of Pa Boxini key intermediate V

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101048410A (en) * 2004-10-29 2007-10-03 泰博特克药品有限公司 HIV inhibiting bicyclic pyrimidine derivatives
WO2008042240A2 (en) * 2006-09-29 2008-04-10 Idenix Pharmaceuticals, Inc. Enantiomerically pure phosphoindoles as hiv inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101048410A (en) * 2004-10-29 2007-10-03 泰博特克药品有限公司 HIV inhibiting bicyclic pyrimidine derivatives
WO2008042240A2 (en) * 2006-09-29 2008-04-10 Idenix Pharmaceuticals, Inc. Enantiomerically pure phosphoindoles as hiv inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
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 *

Also Published As

Publication number Publication date
CN102115452A (en) 2011-07-06

Similar Documents

Publication Publication Date Title
CN104159898B (en) For the preparation of the method for the fluoro-1H-pyrazolo-pyridines of 5-replacing
RU2502721C2 (en) Method of producing 1-(2-halogen biphenyl-4-yl)-cyclopropane carboxylic acid derivatives
KR20120069783A (en) Method for producing aminothiazole derivative and production intermediate
US9056818B2 (en) Process for the preparation of derivatives of 1-(2-halobiphenyl-4-yl)-cyclopropanecarboxylic acid
JP6699979B2 (en) Synthetic method and crystalline form of silodosin and its intermediates
JP2022534067A (en) Compounds and their use as RET kinase inhibitors
RU2650110C2 (en) Processes for synthesis of 2-amino-4,6-dimethoxybenzamide and other benzamide compounds
WO2009143684A1 (en) Processes for preparing pemetrexed disodium and its intermediate,4-(4-carbomethoxyphenyl)butanal
WO2011079704A1 (en) (e)-3-(3-substituted-5-methylphenyl) arylonitrile and preparation methods thereof
JP5700910B2 (en) Process for the preparation of substituted anisidines
CN114105981B (en) Method for preparing benzimidazole [2,1-a ] isoquinoline-6 (5H) -ketone compound
JPH0995462A (en) Production of alpha-hydroxyphenylacetic acid derivative
TWI725710B (en) SYNTHESIS OF 3-BROMO-5- (2-ETHYLIMIDAZO [1,2a] PYRIDINE-3-CARBONYL) -2-HYDROXYBENZONITRILE
JP3986587B2 (en) Pyrazinedicarboxylic acid derivative and method for producing the same
WO2018099424A1 (en) Preparation method of a pyridinone derivative and an intermediate thereof
CN114773284B (en) Synthesis method of visible light mediated dihydroisoxazole
JP2003192626A (en) Method for producing 2-adamantanone
KR102674919B1 (en) Synthesis of 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile
JP4061333B2 (en) 2- (Pyrazol-1-yl) pyridine derivatives
JP2008222703A6 (en) Entacapone manufacturing method
JP2008222703A (en) Method for producing entacapone
JP3596262B2 (en) 2,3,4-trifluoro-5-trifluoromethylbenzoic acid, esters thereof and process for producing the same
WO2022222473A1 (en) Intermediate of apixaban, and preparation method therefor
JP2021195320A (en) Method for producing 5-bromo-2-halogenated benzoic acid
JP2005015402A (en) METHOD FOR PRODUCING OPTICALLY ACTIVE 3,5-DIHYDRO-4H-DINAPHTHO[2,1-c:1&#39;,2&#39;-e]AZEPINE AND OXALATE THEREOF

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10840493

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10840493

Country of ref document: EP

Kind code of ref document: A1