CN108299506A - N- heterocycle carbine ruthenium complexs and its preparation method and application - Google Patents

N- heterocycle carbine ruthenium complexs and its preparation method and application Download PDF

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CN108299506A
CN108299506A CN201810081473.7A CN201810081473A CN108299506A CN 108299506 A CN108299506 A CN 108299506A CN 201810081473 A CN201810081473 A CN 201810081473A CN 108299506 A CN108299506 A CN 108299506A
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preparation
heterocycle
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solvent
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王启卫
刘情情
田福宁
韩洁
黄晴菲
朱槿
黄金昆
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Chengdu Organic Chemicals Co Ltd of CAS
University of Chinese Academy of Sciences
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Chengdu Organic Chemicals Co Ltd of CAS
University of Chinese Academy of Sciences
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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
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
    • C07F15/0046—Ruthenium compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2265—Carbenes or carbynes, i.e.(image)
    • B01J31/2269—Heterocyclic carbenes
    • B01J31/2273—Heterocyclic carbenes with only nitrogen as heteroatomic ring members, e.g. 1,3-diarylimidazoline-2-ylidenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F132/00—Homopolymers of cyclic compounds containing no unsaturated aliphatic radicals in a side chain, and having one or more carbon-to-carbon double bonds in a carbocyclic ring system
    • C08F132/08—Homopolymers of cyclic compounds containing no unsaturated aliphatic radicals in a side chain, and having one or more carbon-to-carbon double bonds in a carbocyclic ring system having condensed rings
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F4/00—Polymerisation catalysts
    • C08F4/42—Metals; Metal hydrides; Metallo-organic compounds; Use thereof as catalyst precursors
    • C08F4/72—Metals; Metal hydrides; Metallo-organic compounds; Use thereof as catalyst precursors selected from metals not provided for in group C08F4/44
    • C08F4/80—Metals; Metal hydrides; Metallo-organic compounds; Use thereof as catalyst precursors selected from metals not provided for in group C08F4/44 selected from iron group metals or platinum group metals
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/50—Redistribution or isomerisation reactions of C-C, C=C or C-C triple bonds
    • B01J2231/54—Metathesis reactions, e.g. olefin metathesis
    • B01J2231/543—Metathesis reactions, e.g. olefin metathesis alkene metathesis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0225—Complexes comprising pentahapto-cyclopentadienyl analogues
    • B01J2531/0233—Aza-Cp ligands, i.e. [CnN(5-n)Rn]- in which n is 0-4 and R is H or hydrocarbyl, or analogous condensed ring systems
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/821—Ruthenium
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention provides one kind N heterocycle carbine ruthenium complexs as shown in formula (I)：Wherein, X is oxygen or sulphur；L is selected fromR1、R2Separately it is selected from fluorine, chlorine, bromine, iodine, RCOO, R C1‑C8Alkyl；R3Selected from C1‑C8Alkyl, C1‑C8Alkoxy, substituted or unsubstituted C3‑C8Naphthenic base, substituted or unsubstituted C3‑C8Heterocycle, substituted or unsubstituted C6‑C15Aryl, substituted or unsubstituted C6‑C15Heteroaryl；R4、R5、R6、R7Separately it is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1‑C8Alkyl, C1‑C8Alkoxy, substituted or unsubstituted C3‑C8Naphthenic base, substituted or unsubstituted C3‑C8Heterocycle, substituted or unsubstituted C6‑C15Aryl, substituted or unsubstituted C6‑C15Heteroaryl, amide groups, sulfoamido.The complex compound of the present invention is used for olefin metathesis reaction, has many advantages, such as that dosage is low, easy to operate, high income, at low cost, has a vast market application prospect.

Description

N- heterocycle carbine ruthenium complexs and its preparation method and application
Technical field
The present invention relates to the technical fields of catalyst preparation in olefin metathesis reaction, and it is miscellaneous to relate more specifically to a kind of N- Ring Cabbeen ruthenium complex and its preparation method and application.
Background technology
Olefin metathesis reaction refers to by the unsaturated carbon-carbon double bond of metal olefin complex compound (also known as metal carbene) catalysis Or the three carbon skeleton rearrangement reactions between key, the reaction are broadly divided into following 4 major class：(1) ring opening metathesis polymerzation (Ring-opening metathesis polymerization, ROMP)；(2) cultural care (Ring-closing Metathesis, RCM)；(3) cross-metathesis (Cross metathesis, CM)；(4) ring opening cross-metathesis reaction (Ring-opening cross metathesis, ROCM).
As the catalyst of olefin metathesis reaction key factor, development is broadly divided into two stages：First stage is 20th century, the 50's to middle 1960s, the structural formula of the olefin metathesis catalyst of this period is indefinite, main To be mixed by transition metal salt and main group alkyl reagent or solid support substrate, the advantages of this kind of catalyst be it is at low cost, It is easily-synthesized, is convenient for commercial Application, the disadvantage is that short life, being also easy to produce side reaction, being especially quick to the impurity in air, steam and system Sense, generally requires the compounds such as strong lewis acid as co-catalyst；Second stage be middle 1960s so far, this section The structure of the olefin metathesis catalyst of time is specific, and the research of this section of period catalyst is concentrated mainly on transition metal On the complex compound of Ti, Ta, W, Mo, Ru, Os etc., main catalyst system and catalyzing is W, Mo, Ru, wherein the most prominent with Ru.This be because Although very high for tungsten carbone catalyst catalytic activity, stability is poor, to air, water sensitive, and it is simultaneous with substrate functional group Capacitive is very poor；The catalytic activity of molybdenum carbone catalyst is very high, sensitive to functional groups such as carbonyl, hydroxyls in empty gas and water and substrate； And the oxytropism of ruthenium is low, and good stability is shown to a large amount of polarized functional groups, and ruthenium carbone catalyst to empty gas and water, Functional group in substrate has preferable compatibility, therefore the application of ruthenium carbone catalyst is more extensive compared with tungsten, molybdenum.
But current ruthenium catalyst promoting olefin metathesis reaction has the following problems：
(1) target product low yield can not make full use of raw material when preparing target product, cause the wave in resource Take；
(2) dosage of ruthenium catalyst is big, is easy to cause overrun metal content in target product, on the one hand increases succeeding target The processing work of product influences the production efficiency of target product；Another aspect catalyst amount is big, the longer increasing of product process cycle Production cost is added.
For example, 2010011566 A1 of WO are disclosed prepares anti-hepatitis drug lattice drawing using the catalysis of zhan 1B ruthenium catalysts The intermediate of Rui Wei (Grazoprevir Hydrate), yield 25%；2007014926 A1 of WO are disclosed using H-G first The intermediate of anti-hepatitis drug Xi Meiruiwei (Simeprevir Sodium), yield 60% are prepared for catalyst； US8299021B2 is disclosed prepares anti-hepatitis drug Dan Nuoruiwei sodium (Danoprevir using H-G second generation catalysts Sodium intermediate), yield 52%；Document Org.Lett., 1999,1,953-956 is reported to be urged using the Grubbs second generations Reaction prepares 3- cyclopentene -1,1- dicarboxylic acid methyl esters to agent under 45 degrees Celsius in methylene chloride, and catalyst amount is up to 5% and rubs You, be easy to cause metal Ru too high levels in product；CN1571791A discloses a kind of new catalyst ruthenium complex, uses Dosage when promoting olefin metathesis reacts is up to 1% mole；CN102643175 discloses a kind of solid carrying ruthenium complex and urges Agent, dosage when being reacted for catalyzed alkene intramolecular metathesis cyclization are up to 2% mole.
Invention content
In view of problems of the prior art, the first object of the present invention is to propose a kind of N- heterocycle carbine ruthenium networks Object is closed, can effectively solve the problem that in current ruthenium catalyst promoting olefin metathesis reaction that target yield is low, ruthenium catalyst dosage Big the problem of leading to overrun metal content in target product.
In order to reach the above-mentioned purpose of the present invention, the present invention proposes a kind of preparation method of N- heterocycle carbines ruthenium complex, It is with N- heterocycle carbine ruthenium complexs simple for process, can efficiently obtaining stable structure.
Another object of the present invention is to provide N- heterocycle carbine ruthenium complexs to make catalyst in olefin metathesis reaction Purposes, specifically, the olefin metathesis double decomposition in the molecule in the olefin metathesis metathesis reaction, polymerisation of cyclization is anti- The purposes of Ying Zhongzuo catalyst；More specifically, 3- cyclopentene -1,1- dicarboxylic acid methyl ester, HCV inhibitor are being prepared Make the purposes of catalyst in the key intermediate of Danoprevir.
In order to reach the above-mentioned purpose of the present invention, the present invention provides N- heterocycle carbine ruthenium complexs as catalyst preparation 3- cyclopentene -1,1- dicarboxylic acid methyl esters, HCV inhibitor Danoprevir key intermediate method.
One kind N- heterocycle carbine ruthenium complexs as shown in formula (I)：
Wherein, X is oxygen or sulphur；L is selected fromR1、R2Separately be selected from fluorine, chlorine, bromine, Iodine, RCOO-, R C1-C8Alkyl；R3Selected from C1-C8Alkyl, C1-C8Alkoxy, substituted or unsubstituted C3-C8Naphthenic base takes Generation or unsubstituted C3-C8Heterocycle, substituted or unsubstituted C6-C15Aryl, substituted or unsubstituted C6-C15Heteroaryl；R4、 R5、R6、R7Separately it is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C8Alkyl, C1-C8Alkoxy, substitution do not take The C in generation3-C8Naphthenic base, substituted or unsubstituted C3-C8Heterocycle, substituted or unsubstituted C6-C15Aryl, substitution or unsubstituted C6-C15Heteroaryl, amide groups, sulfoamido.
Further, X is oxygen.
Further, R1、R2Selected from chlorine.
Further, R3Selected from isopropyl.
Further, R4、R5、R6、R7Selected from hydrogen.
Further, the N- heterocycle carbines ruthenium complex is following compound：
The present invention also provides a kind of preparation methods of above-mentioned N- heterocycle carbines ruthenium complex, include the following steps：
(1) ruthenium complex shown in modus ponens 3 and N- heterocycle carbines imidazole hydrochloride (LHCl), in a solvent, in 40~100 DEG C reaction to get compound shown in formula 4；
(2) compound shown in modus ponens 4 is reacted with compound shown in formula 2, in a solvent, in 40~100 DEG C of reactions to get formula (I) ruthenium complexs of N- heterocycle carbines shown in.
Further, in step (1), the solvent is non-protonic solvent；Preferably n-hexane, normal heptane, toluene；More Preferably n-hexane；The reaction temperature is 60 DEG C；
In step (2), the solvent is non-protonic solvent；Preferably n-hexane, normal heptane, toluene, dichloromethane；More Preferably n-hexane；The reaction temperature is 40 DEG C.
The present invention also provides a kind of preparation methods of 3- cyclopentene -1,1- dicarboxylic acid methyl ester, it includes the following steps：
Solvent is added in compound shown in modus ponens 6 and above-mentioned N- heterocycle carbines ruthenium complex, react 60 in 60~110 DEG C~ 120 minutes to get compound shown in formula 7.
Further, the solvent is non-protonic solvent；Preferably tetrahydrofuran, toluene, n-hexane, normal heptane；More Preferably normal heptane；
The reaction temperature is 100 DEG C；The reaction time is 120 minutes.
Further, 6 compound of formula and the molar ratio of N- heterocycle carbine ruthenium complexs shown in formula (I) are 1:0.0001~ 0.0005；Preferably 1:0.0002.
The present invention also provides a kind of preparation method of the key intermediate of HCV inhibitor Danoprevir, it include with Lower step：
Compound shown in modus ponens 8 and claim 1-5 any one of them N- heterocycle carbine ruthenium complexs, are added solvent, 8~12 hours are reacted in 40~110 DEG C to get compound shown in formula 9.
Further, the solvent is non-protonic solvent；Preferably tetrahydrofuran, toluene, dichloromethane；More preferably Toluene；
The reaction temperature is 70 DEG C；The reaction time is 10 hours.
The present invention also provides the purposes that above-mentioned N- heterocycle carbines ruthenium complex makees catalyst in olefin metathesis reaction.
Further, the olefin metathesis reaction is the olefin metathesis metathesis reaction of intramolecular cyclization, polymerize instead Olefin metathesis metathesis reaction in answering.
Further, above-mentioned N- heterocycle carbines ruthenium complex generates dicyclopentadiene in catalysis dicyclopentadiene ring-opening polymerisation (Polydicyclopentadiene) during, relatively good activity is also shown.
For the above it should be noted that in the present invention, " substitution " refer to hydrogen atom in molecule by it is other not Same atom or molecule is replaced.
The minimum value and maximum value of carbon content are indicated by prefix in hydrocarbon group, for example, prefix (Ca~Cb) alkyl Show any alkyl containing " a " to " b " a carbon atom.For example, (C1~C4) alkyl refers to the alkyl for including 1~4 carbon atom.
The C1~C8Alkyl refers to C1、C2、C3、C4、C5、C6、C7、C8Alkyl, i.e., with 1~8 carbon atom straight chain Or the alkyl of branch, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, sec-butyl, amyl, hexyl, heptan Base, octyl etc..C1-C8Alkoxy, C3-C8Naphthenic base, C3-C8Heterocycle, C6-C15Aryl, C6-C15Heteroaryl also has and it The corresponding meaning of group.For example, the C3-C8Naphthenic base refers to C3、C4、C5、C6、C7、C8Naphthenic base, such as cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, suberyl, cyclooctyl etc..
Abbreviation and abbreviation：
The advantageous effect that the present invention reaches：The present invention provides a kind of efficient N- heterocycle carbine ruthenium complex catalysts, It has the advantages that structural stability is high, is readily synthesized；It can be widely applied to the olefin metathesis reaction of intramolecular cyclization, gathers Reaction etc. is closed, there is extensive market application value；In addition, its when preparing target product with the spy that high income, dosage are low Point also can guarantee that tenor is within standard level in product, simplify product while improving target product output Subsequent processing work, to reduce the input cost of associated products production.
In addition to this, the preparation method provided by the invention for preparing the catalyst its with easy to operate, high income, input Advantage at low cost.
In addition, application of the N- heterocycle carbines ruthenium complex provided by the invention in olefin metathesis reaction, for preparationization The fields such as work new material and pharmaceutical synthesis provide a kind of new preparation method, with easy to operate, high income, input cost Low advantage.
Specific implementation mode
The specific implementation mode of form by the following examples remakes further specifically the above of the present invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on the above of the present invention The technology realized all belongs to the scope of the present invention.
The preparation route of L：
Compound L is prepared by above-mentioned route.Grubbs first generation catalyst (compound A) is bought from Suzhou Xin Nuoke. Solvent for use is reacted to buy from Chengdu Ke Long chemical reagents factory.N-hexane, dichloromethane pass through under nitrogen atmosphere CaH2The 10h that flows back removes water deoxygenation.Nuclear-magnetism instrument is that (CDCl3 is solvent to 300 type Nuclear Magnetic Resonance of Bruker AVANCE, and TMS is Internal standard)；Mass spectrometer is Bruker microTOF-Q high-resolution mass spectrometers.
Embodiment 1
The preparation of the ruthenium complexs of N- heterocycle carbines shown in 5a：Under the conditions of anhydrous and oxygen-free, in 50 milliliters schlenk bottles successively 1000 mg (1.22mmol) compounds A, 1320mg (2.46mmol) compound 3a and 205mg (1.83mmol) tert-butyl alcohol is added 40mL toluene is added in potassium.It is reacted 5 hours at 70 DEG C under stirring.It is spin-dried for solvent, uses petroleum ether:Ethyl acetate=20:1 does and flows Phase, column chromatography obtain red brown solid powder intermediate 4a, 637mg, yield 50.2%；
Under the conditions of anhydrous and oxygen-free, 637mg complexs 4a (0.61mmol) intermediate obtained in the previous step is dissolved in 30mL In dichloromethane, 72mg (0.73mmol) stannous chloride is added and stirs 5 minutes, then by 99mg (0.61mmol) 2- isopropoxy benzenes Ethylene is added into reaction, is warming up to 40 DEG C, reacts 1 hour, stops reaction, (whether is mobile phase by the direct column chromatography of reaction solution For petroleum ether:Ethyl acetate=20:1) brown solid powder 5a, 355mg, yield 71.0%, are obtained.1H NMR(300MHz, CDCl3) δ 16.71 (s, 1H), 7.55 (t, J=7.7Hz, 2H), 7.42 (t, J=7.8Hz, 1H), 7.32 (d, J=7.7Hz, 4H), 7.13 (s, 2H), 6.94 (d, J=7.3Hz, 1H), 6.80 (dd, J=11.1,8.0Hz, 2H), 4.97-4.81 (m, 1H), 2.88-2.71 (m, 4H), 1.61 (dddd, J=32.7,21.0,13.4,6.6Hz, 18H), 1.35 (d, J=6.0Hz, 6H), 0.77 (dt, J=14.3,7.3Hz, 25H) .13C NMR (75MHz, CDCl3) δ 178.23,152.55,146.21, 144.22,137.05,128.80,128.23,125.90,125.43,122.06,121.71,112.84,75.00, 40.76, 28.11,25.36,21.51,11.89,10.31.；HR-MS(ESI)m/z:Calcd for C45H64Cl2N2ORu{[M-Cl] +} 820.3439,found 785.3877。
Embodiment 2
The preparation of 3- cyclopentene -1,1- dicarboxylic acid methyl esters：1g diallyl dimethyl malenates are weighed, 2mL positive heptan is added Alkane is passed through nitrogen stirring at normal temperature 20 minutes；0.78mg catalyst 5a are weighed, is dissolved and is added into reactor with 1mL normal heptanes, It is warming up to 100 DEG C, reacts 90 minutes, the reaction was complete, is spin-dried for normal heptane, obtains white solid powder, 0.85 gram, yield： 98.5%.
Embodiment 3
The preparation of 3- cyclopentene -1,1- dicarboxylic acid methyl esters：10g diallyl dimethyl malenates are weighed, 25mL is being added just Heptane is passed through nitrogen stirring at normal temperature 20 minutes；7.80mg catalyst 5a are weighed, dissolved with 5mL normal heptanes and are added to reactor In, it is warming up to 100 DEG C, reacts 100 minutes, the reaction was complete, is spin-dried for normal heptane, obtains white solid powder, 8.52 grams, yield： 98.5%.
Embodiment 4
The preparation of 3- cyclopentene -1,1- dicarboxylic acid methyl esters：50g diallyl dimethyl malenates are weighed, 135mL is being added just Heptane is passed through nitrogen stirring at normal temperature 20 minutes；39.0mg catalyst 5a are weighed, dissolved with 15mL normal heptanes and are added to reactor In, it is warming up to 100 DEG C, reacts 120 minutes, the reaction was complete, is spin-dried for normal heptane, obtains white solid powder, 42.8 grams, yield： 98.7%.
Embodiment 5
The preparation of Danoprevir intermediates：50mg compounds 8 are weighed, the dissolving of 5mL toluene is added.Nitrogen room temperature is passed through to stir It mixes 20 minutes, weighs 0.3mg catalyst 5a and be added in reactor, be warming up to 70 DEG C, react 10 hours, the reaction was complete, column layer Analyse (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 36.1mg, yield 75.3%.
Embodiment 6
The preparation of Danoprevir intermediates：500mg compounds 8 are weighed, the dissolving of 50mL toluene is added.It is passed through nitrogen room temperature Stirring 20 minutes, weighs 3.0mg catalyst 5a and is added in reactor, is warming up to 70 DEG C, reacts 10 hours, the reaction was complete, column Chromatograph (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 362.0mg, yield 75.5%.
Embodiment 7
The preparation of Danoprevir intermediates：500mg compounds 8 are weighed, the dissolving of 50mL toluene is added.It is passed through nitrogen room temperature Stirring 20 minutes, weighs 3.0mg catalyst 5a and is added in reactor, is warming up to 90 DEG C, reacts 8 hours, the reaction was complete, column Chromatograph (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 350.0mg, yield 73.0%.
Embodiment 8
The preparation of Danoprevir intermediates：500mg compounds 8 are weighed, the dissolving of 50mL toluene is added.It is passed through nitrogen room temperature Stirring 20 minutes, weighs 3.0mg catalyst 5a and is added in reactor, is warming up to 110 DEG C, reacts 7 hours, the reaction was complete, column Chromatograph (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 335.6mg, yield 70.0%.
Embodiment 9
The preparation of Danoprevir intermediates：500mg compounds 8 are weighed, the dissolving of 50mL toluene is added.It is passed through nitrogen room temperature Stirring 20 minutes, weighs 3.0mg catalyst 5a and is added in reactor, is warming up to 50 DEG C, reacts 12 hours, the reaction was complete, column Chromatograph (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 341.4mg, yield 71.2%.
Embodiment 10
The preparation of Danoprevir intermediates：5.0g compounds 8 are weighed, the dissolving of 500mL toluene is added.It is passed through nitrogen room temperature Stirring 20 minutes, weighs 30.0mg catalyst 5a and is added in reactor, is warming up to 70 DEG C, reacts 10 hours, and the reaction was complete, Column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 3.65g, yield 76.1%.
Embodiment 11
The preparation of dicyclopentadiene：It weighs 1.000g dicyclopentadienes to be added into reaction bulb, 19mL is added at 35 DEG C Under nitrogen protection, 0.20mg (monomers are added in toluene stirring and dissolving:Catalyst=32000:1) catalyst 5a is warming up to 50 DEG C and stirs It mixes 30 minutes, methanol is added, polymer is precipitated, polymer is crushed, it is small to be placed in 110 DEG C of dryings 24 in vacuum drying chamber by filtering When, conversion ratio 97.1%.
Embodiment 12
The preparation of dicyclopentadiene：It weighs 10.000g dicyclopentadienes to be added into reaction bulb, be added at 35 DEG C Under nitrogen protection, 1.94mg (monomers are added in 190mL toluene stirring and dissolvings:Catalyst=32000:1) catalyst 5a is warming up to 50 DEG C are stirred 30 minutes, methanol are added, polymer is precipitated, polymer is crushed, is placed in 110 DEG C of dryings in vacuum drying chamber by filtering 24 hours, conversion ratio 97.5%.
Comparative example 1
The preparation of 3- cyclopentene -1,1- dicarboxylic acid methyl esters：1g diallyl dimethyl malenates are weighed, 2mL positive heptan is added Alkane is passed through nitrogen stirring at normal temperature 20 minutes；Weigh 5.9mgGrubbs second generation catalyst, dissolved with 1mL normal heptanes and be added to In reactor, it is warming up to 100 DEG C, reacts 90 minutes, the reaction was complete, is spin-dried for normal heptane, obtains white solid powder, 0.52 gram, Yield：60.0%.
Comparative example 2
The preparation of 3- cyclopentene -1,1- dicarboxylic acid methyl esters：1g diallyl dimethyl malenates are weighed, 40mL dichloros are added Methane is passed through nitrogen stirring at normal temperature 20 minutes；147.6mg Grubbs second generation catalyst is weighed, simultaneously with the dissolving of 6mL normal heptanes It is added into reactor, is warming up to reflux, react 30 minutes, the reaction was complete, is spin-dried for dichloromethane, obtains white solid powder, 0.85 gram, yield：97%.
Comparative example 3
The preparation of 3- cyclopentene -1,1- dicarboxylic acid methyl esters：1g diallyl dimethyl malenates are weighed, 45mL positive heptan is added Alkane is passed through nitrogen stirring at normal temperature 20 minutes；14.7mg Grubbs second generation catalyst is weighed, is dissolved and is added with 5mL normal heptanes Into reactor, it is warming up to reflux, reacts 150 minutes, the reaction was complete, is spin-dried for normal heptane, obtains white solid powder, and 0.77 Gram, yield：89%.
Comparative example 4
The preparation of Danoprevir intermediates：50mg compounds 8 are weighed, the dissolving of 5mL toluene is added.Nitrogen room temperature is passed through to stir It mixes 20 minutes, weighs 1.15mg catalyst Hoveyda-Grubbs second generation catalyst and be added in reactor, be warming up to 70 DEG C, it reacts 10 hours, the reaction was complete, column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 24.0mg, yield 50.1%.
Comparative example 5
The preparation of Danoprevir intermediates：50mg compounds 8 are weighed, the dissolving of 5mL toluene is added.Nitrogen room temperature is passed through to stir It mixes 20 minutes, weighs 2.31mg Hoveyda-Grubbs second generation catalyst and be added in reactor, be warming up to 70 DEG C, reaction 10 hours, the reaction was complete, column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) white solid powder 18.3mg is obtained, it receives Rate 38.1%.
Comparative example 6
The preparation of Danoprevir intermediates：50mg compounds 8 are weighed, the dissolving of 15mL dichloromethane is added.It is passed through nitrogen Stirring at normal temperature 20 minutes weighs 2.68mg catalyst Z han-1B catalyst and is added in reactor, is warming up to reflux, reaction 10 Hour, the reaction was complete, column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 27.8mg, yield 58%.
Comparative example 7
The preparation of Danoprevir intermediates：50mg compounds 8 are weighed, the dissolving of 5mL toluene is added.Nitrogen room temperature is passed through to stir It mixes 20 minutes, weighs 0.27mg Zhan-1B catalyst and be added in reactor, be warming up to 70 DEG C, react 10 hours, column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 14.4mg, yield 30%.
Comparative example 8
Since amide H has acidity in compound 8, the activity of cyclization metathesis catalyst can be influenced, and be easy to cause Impurity generates, therefore obtains compound 8a, then pass through cyclization using the amino in benzoyl protection compound 8 in building-up process Double decomposition obtains intermediate 9, to advanced optimize the preparation process of compound 9.
The preparation of Danoprevir intermediates：50mg compound 8a are weighed, the dissolving of 5mL toluene is added.It is passed through nitrogen room temperature Stirring 20 minutes, weighs 0.23mg catalyst Z han-1B catalyst and is added in reactor, is warming up to 70 DEG C, reaction 10 is small When, column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 30.4mg, yield 63%.
Comparative example 9
The preparation of Danoprevir intermediates：500mg compound 8a are weighed, the dissolving of 50mL toluene is added.It is normal to be passed through nitrogen Temperature stirring 20 minutes, weighs 2.3mg catalyst Z han-1B catalyst and is added in reactor, is warming up to 70 DEG C, reaction 10 is small When, column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 313mg, yield 65%.
Catalyst 5a has in preparing 3- cyclopentene -1,1- dicarboxylic acid methyl esters, Danoprevir intermediates preferably to be urged Change effect, and the correlated response of the two is the olefin metathesis metathesis reaction of intramolecular cyclization；In addition prepared by catalyst 5a Has preferable catalytic effect during dicyclopentadiene, this reaction is the olefin metathesis metathesis reaction in polymerisation. Thus summarize and show that catalyst 5a i.e. N- heterocycle carbines ruthenium complex can be applied to olefin metathesis reaction.
The above, only presently preferred embodiments of the present invention, are not intended to limit the invention, patent protection model of the invention It encloses and is subject to claims, equivalent structure variation made by every description with the present invention should all include similarly Within the scope of the present invention.

Claims (15)

1. a kind of N- heterocycle carbine ruthenium complexs as shown in formula (I)：
Wherein, X is oxygen or sulphur；
L is selected from
R1、R2Separately it is selected from fluorine, chlorine, bromine, iodine, RCOO-, R C1-C8Alkyl；
R3Selected from C1-C8Alkyl, C1-C8Alkoxy, substituted or unsubstituted C3-C8Naphthenic base, substituted or unsubstituted C3-C8It is miscellaneous Ring group, substituted or unsubstituted C6-C15Aryl, substituted or unsubstituted C6-C15Heteroaryl；
R4、R5、R6、R7Separately it is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C8Alkyl, C1-C8Alkoxy, substitution Or unsubstituted C3-C8Naphthenic base, substituted or unsubstituted C3-C8Heterocycle, substituted or unsubstituted C6-C15Aryl, substitution or Unsubstituted C6-C15Heteroaryl, amide groups, sulfoamido.
2. N- heterocycle carbines ruthenium complex according to claim 1, it is characterised in that：X is oxygen.
3. N- heterocycle carbines ruthenium complex according to claim 1, it is characterised in that：R1、R2Selected from chlorine.
4. N- heterocycle carbines ruthenium complex according to claim 1, it is characterised in that：R3Selected from isopropyl.
5. N- heterocycle carbines ruthenium complex according to claim 1, it is characterised in that：R4、R5、R6、R7Selected from hydrogen.
6. according to claim 1-5 any one of them N- heterocycle carbine ruthenium complexs, it is characterised in that：The N- heterocycle carbines Ruthenium complex is following compound：
7. the preparation method of claim 1-6 any one of them N- heterocycle carbine ruthenium complexs, it is characterised in that：The preparation Method includes the following steps：
(1) ruthenium complex shown in modus ponens 3 and N- heterocycle carbines imidazole hydrochloride (LHCl), it is in a solvent, anti-in 40~100 DEG C It should be to get compound shown in formula 4；
(2) compound shown in modus ponens 4 is reacted with compound shown in formula 2, in a solvent, in 40~100 DEG C of reactions to get formula (I) Shown N- heterocycle carbines ruthenium complex.
8. preparation method according to claim 7, it is characterised in that：In step (1), the solvent is that aprotic is molten Agent, the reaction temperature are 60 DEG C；
In step (2), the solvent is non-protonic solvent, and the reaction temperature is 40 DEG C.
9. a kind of preparation method of 3- cyclopentene -1,1- dicarboxylic acid methyl ester, it is characterised in that：The preparation method includes following step Suddenly：
Compound shown in modus ponens 6 and claim 1-6 any one of them N- heterocycle carbine ruthenium complexs, are added solvent, in 60 ~110 DEG C are reacted 60~120 minutes to get compound shown in formula 7.
10. preparation method according to claim 9, it is characterised in that：The solvent is non-protonic solvent, the reaction Temperature is 100 DEG C；The reaction time is 120 minutes.
11. preparation method according to claim 9 or 10, it is characterised in that：6 compound of formula and N- heterocycles shown in formula (I) The molar ratio of Cabbeen ruthenium complex is 1:0.0001~0.0005.
12. a kind of preparation method of the key intermediate of HCV inhibitor Danoprevir, it is characterised in that：The preparation method Include the following steps：
Compound shown in modus ponens 8 and claim 1-6 any one of them N- heterocycle carbine ruthenium complexs, are added solvent, in 40 ~110 DEG C are reacted 8~12 hours to get compound shown in formula 9.
13. preparation method according to claim 12, it is characterised in that：The solvent is non-protonic solvent, described anti- It is 70 DEG C to answer temperature；The reaction time is 10 hours.
14. the N- heterocycle carbine ruthenium complexs described in claim 1-6 make the purposes of catalyst in olefin metathesis reaction.
15. purposes according to claim 14, it is characterised in that：The olefin metathesis reaction is intramolecular cyclization Olefin metathesis metathesis reaction in olefin metathesis metathesis reaction, polymerisation.
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CN110105400A (en) * 2019-05-31 2019-08-09 上海化工研究院有限公司 A kind of temperature sensitive type ruthenium carbene complex and its preparation method and application
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