CN103664911B - The method for preparing vilazodone and its intermediate - Google Patents

The method for preparing vilazodone and its intermediate Download PDF

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CN103664911B
CN103664911B CN201210335254.XA CN201210335254A CN103664911B CN 103664911 B CN103664911 B CN 103664911B CN 201210335254 A CN201210335254 A CN 201210335254A CN 103664911 B CN103664911 B CN 103664911B
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palladium
double
phosphine
formula
compound
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CN103664911A (en
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廖明毅
朱溪
陈琪
朱玉成
陈伟
张连第
丁磊
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Jiangsu Simcere Pharmaceutical Co Ltd
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Jiangsu Simcere Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2

Abstract

The present invention provides a kind of method for preparing vilazodone and its intermediate, and formula (V) intermediate can be obtained by coupling reaction, and formula (V) intermediate can obtain vilazodone by the reduction of acetylene bond and the removing of N protection groups；Or by obtaining vilazodone by further conversion.Defect in being prepared instant invention overcomes existing vilazodone and its intermediate, raw material is easy to get, and reaction yield is high, is suitable for industrialized production, there is larger application value.

Description

The method for preparing vilazodone and its intermediate
Technical field
The present invention relates to a kind of method that coupling reaction by metal catalytic prepares vilazodone and its intermediate.
Background technology
Vilazodone (Vilazodone), chemical name 5- (- 4- (4- (5- cyanoindole -3- bases) butyl) piperazine -1- bases) Benzofuran-2-carboxamides, shown in its structure such as formula (I).On January 21st, 2011, the hydrochloric acid Wella assistant of Trovis companies exploitation Ketone (biibryd) piece obtains U.S. FDA approval listing, is first indolyl alkyl-amine for treating severe adult's depressive disorder (MDD) Class novel antidepressant.The medicine be used for treat or prevent depression, anxiety disorder, bipolar disorder, it is manic, dull-witted, with The relevant phrenoblabia of mentation material, sex dysfunction, eating disorder, obesity, fibromyalgia, sleep-disorder, mental disease Side effect, brain disorder in sample phrenoblabia, cerebral infarction, anxiety, hypertension therapeutic, chronic ache, acromegalia, sexual gland Hypofunction, secondary amenorrhea, premenstrual syndrome and unwanted postpartum milk secretion.
The synthesis of vilazodone and its intermediate has been described in United States Patent (USP) US5532241 and WO0072832.
It is disclosed both at home and abroad at present that vilazodone is prepared using following several method：
A) CN1106811A is disclosed using 3- (4- chlorobutyls) indoles -5- formonitrile HCNs as intermediate and is prepared vilazodone.Route It is as follows：
3- (4- chlorobutyls) indoles -5- formonitrile HCNs are condensed with 5- (piperazine -1- bases) coumarilic acid, obtain 5- (4- (4- (5- cyanoindole -3- bases) butyl) piperazine -1- bases) coumarilic acid, then with the chloro- 1- picolines first of 2- Sulfonate and ammonia reaction, obtain vilazodone.
This method carries out acylation reaction using pyridinium compound, is not suitable for a large amount of industrialized productions.
B) CN1330635A and CN1140171A disclose the synthetic method of 3- (4- chlorobutyls) indoles -5- formonitrile HCNs, and close Into vilazodone.
Using indoles -5- formonitrile HCNs as raw material, under isobutyl group aluminum chloride-catalyzed, friedel-crafts acylation is carried out with 4- chlorobutanoylchlorides, 3- (4- chlorobutyryls) indoles -5- formonitrile HCNs are obtained, then sodium borohydride reduction carbonyl is used under isobutyl group aluminum chloride-catalyzed, are obtained 3- (4- chlorobutyls) indoles -5- formonitrile HCNs, then it is condensed with 5- (piperazine -1- bases) benzofuran-2-carboxamides, obtain Wella assistant Ketone.
This method uses isobutyl group aluminium chloride when synthesizing 3- (4- chlorobutyls) indoles -5- formonitrile HCNs and carrying out reduction reaction It is used as catalyst.The catalyst is difficult to prepare, extremely unstable in atmosphere, and storage and cost of transportation are high, be not suitable for a large amount of industry Metaplasia is produced.
C) WO2006/114202 and CN101163698A disclose a kind of method for preparing vilazodone.
Using 3- (4- hydroxybutyls) indoles -5- formonitrile HCNs as raw material, after the processing by sulfur trioxide and pyridine complex Obtain 3- (4- oxos butyl) indoles -5- formonitrile HCNs, then with 5- piperazinyl benzofuran -2- formamides, and pass through cyano group boron Sodium hydride reduction amination, obtains vilazodone.
The process employs toxicity is big, expensive sodium cyanoborohydride as reducing agent, be not suitable for a large amount of industrialization Production.
D) WO2006/114202 and CN101163698A also disclose a kind of by Buchwald reaction synthesis vilazodones Method.
In this method, indoles -5- formonitrile HCNs are as intermediate by 3- (4- piperazines butyl), in the presence of sodium tert-butoxide, three (two BENZYLIDENE ACETONE) under two palladiums and tri-tert phosphine catalyst, Buchwald couplings are carried out with 5- bromobenzofuran -2- formamides, are obtained To vilazodone.
In this method, Buchwald reaction conditions are more harsh, and reaction yield is not high, are not suitable for a large amount of industrialized productions.
The content of the invention
The present invention provides a kind of method that coupling reaction by metal catalytic prepares vilazodone and its intermediate.Including Step is as follows：
(1) formula (II) compound reacts the formula of obtaining (III) compound in the presence of base,
(2) formula (V) compound is made by coupling reaction with formula (IV) compound in formula (III) compound,
(3) formula (V) compound obtains formula (I) compound vilazodone by one or multi-step reaction,
Preferably, R8It is selected fromH or amino protecting group；R1For CN or COR2；R2Selected from H, OR5Or NR6R7；R5、R6、R7Independently selected from H or C1-12Alkyl；R5、R6、R7More preferably independently selected from H or C1-6Alkyl；
R9Selected from I, Br, Cl, OTs, OMs or OTf；
R3For H or amino protecting group；
R4Selected from I, Br, Cl or OTf；
Work as R3、R8When being all amino protecting group, R3、R8It is each independently amino protecting group.
In step (1), preferably reaction condition is：
The alkali is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, carbonic acid Silver, sodium acid carbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, trimethylamine, triethylamine, tri-n-butylamine, 4- dimethylamino pyridines, N, N- dimethylaniline, the carbon -7- alkene of 1,8- diazabicylos [5.4.0] 11, N-methylmorpholine, DIPEA, pyrrole Pyridine, 2,6- lutidines, imidazoles, N, N, N ', the one or more in N '-tetramethylethylenediamine etc.；
Reaction dissolvent is selected from DMF, DMA, formamide, dichloromethane, three chloromethanes Alkane, 1-METHYLPYRROLIDONE, tetrahydrofuran, methyltetrahydrofuran, t-butyl methyl ether, isopropyl ether, acetonitrile, Isosorbide-5-Nitrae-dioxy six Ring, 1,2- dimethoxy-ethanes, 2-methyl cellosolve, cellosolvo, methanol, ethanol, isopropanol, the tert-butyl alcohol, acetic acid second Ester, methyl acetate, isopropyl acetate, Ethyl formate, dimethyl sulfoxide, toluene, dimethylbenzene, chlorobenzene, methoxybenzene, hexamethyl phosphinylidyne One or more combinations in triamine, water etc.；
Reaction temperature is 20~80 DEG C.
Preferably reaction condition is in step (2)：
With formula (IV) compound under catalyst action coupling reaction occurs for formula (III) compound；
The mol ratio of formula (III) compound and formula (IV) compound is 1: 3~3: 1, is further preferably 1: 2~2: 1, It is preferably yet further 1: 1.3~1.3: 1；
Reaction temperature is 20~150 DEG C, further preferably 30~130 DEG C, yet further preferably 40~120 ℃；
Reaction time is 1h~96h；It is preferably further 2h~48h；
The solvent used in reaction is selected from DMF, DMA, formamide, dichloromethane Alkane, chloroform, 1-METHYLPYRROLIDONE, tetrahydrofuran, methyltetrahydrofuran, t-butyl methyl ether, isopropyl ether, acetonitrile, 1, 4- dioxane, 1,2- dimethoxy-ethanes, 2-methyl cellosolve, cellosolvo, methanol, ethanol, isopropanol, tertiary fourth Alcohol, ethyl acetate, methyl acetate, isopropyl acetate, Ethyl formate, acetone, butanone, methyl butyl ketone, methyl iso-butyl ketone (MIBK), two One kind in first sulfoxide, toluene, dimethylbenzene, chlorobenzene, methoxybenzene, HMPA, diethylamine, triethylamine, water etc. or A variety of combinations.
Catalyst preferably is selected from palladium catalyst, Raney nickel, copper catalyst, Co catalysts, platinum catalysis described in step (2) Agent, rhodium catalyst, iridium catalyst, ruthenium catalyst, iron catalyst；Further preferably from palladium catalyst, Raney nickel or copper catalysis Agent；When catalyst is non-copper catalyst, copper catalyst can be added as co-catalyst.
The palladium catalyst is selected from palladium, propionic acid palladium, palladium oxide, palladium nitrate, palladium sulfate, palladium trifluoroacetate, levulinic Ketone palladium, neopentanoic acid palladium, palladium chloride, dibrominated palladium, palladium diiodide, the ammino palladium of dichloro four, the ammino palladium of acetic acid four, palladium dydroxide, It is palladium charcoal, tetrakis triphenylphosphine palladium, three (dibenzalacetone) two palladium, (1,1 '-bis- Diphenyl phosphino ferrocenes) palladium chloride, double (triphenylphosphine) palladium chloride, double (tricyclohexyl phosphine) palladium chlorides, double (tri-butyl phosphine) palladiums, (1,3- pairs (diphenylphosphine) Propane) palladium chloride, (1,5- cyclo-octadiene) palladium chloride, (bipy 2,2' bipyridyl) palladium chloride, double (diphenylphosphine) second of 1,2- Double (diphenylphosphine) the butane palladium chlorides of alkane palladium chloride, 1,4-, double (triphenylphosphine) palladiums, ethylenediamine palladium chloride, two Double (phenylsulfinyl) the ethane palladium diacetates of (cyano group benzene) palladium chloride, 1,2-, (1,10- phenanthroline) palladium chloride, double (three-o- Toluene phosphine) palladium chloride, hexafluoroacetylacetone palladium, double [1,2- double (diphenylphosphino) ethane] palladiums, double [three (2- tolyls) Phosphine] palladium, double (triethyl phosphine) palladium chlorides, double (acetonitrile) palladium chlorides, double (dibenzalacetone) palladiums, double (methyldiphenyl bases Phosphine) palladium chloride, four (acetonitrile) tetrafluoro boric acid palladiums, (bicyclic [2.2.1] hept- 2,5- diene) dichloro palladium, 1,1 '-bis- (two tertiary fourths Base phosphino-) ferrocene palladium chloride, 1,1 '-bis- (dicyclohexyl phosphino-) ferrocene palladium chlorides, 1,1 '-bis- (diisopropyl phosphines Base) ferrocene palladium chloride, (TEMED) palladium chloride, double [dicyclohexyl (4- dimethyl phenalgins Base) phosphine] palladium chloride, double [di-t-butyl (4- fluoroforms phenyl) phosphine] palladium chlorides, tetrachloro close one kind in the sour sodium of palladium, palladium charcoal Or it is a variety of.
The Raney nickel is selected from double（Triphenylphosphine）Nickel Chloride, Nickel Chloride, dichloro two（Tributylphosphine）It is nickel, double （Trimethyl-phosphine）It is Nickel Chloride, double（Tributylphosphine）It is Nickel Bromide, double（Tricyclohexyl phosphine）It is Nickel Chloride, double（Triphenylphosphine）Two It is nickelous bromide, double（Triphenylphosphine）Dicarbapentaborane nickel, [1,3- is double（Diphenylphosphine）Propane] Nickel Chloride, [1,2- is double（Diphenylphosphine） Ethane] Nickel Chloride, [1,1 '-bis-（Diphenylphosphine）Ferrocene] it is Nickel Chloride, double（Isopropylcyclopentadiene）Nickel, four（Triphen Base phosphine）One or more in nickel.
The copper catalyst is selected from cuprous iodide, cuprous bromide, stannous chloride, cuprous oxide, cupric oxide, copper chloride, vinegar Sour copper, copper sulphate, copper nitrate, cupric acetylacetonate, trifluoromethayl sulfonic acid copper (II), trifluoromethayl sulfonic acid copper (I), tetrafluoro boric acid Tetrem cyanogen copper (I), thiophene -2-carboxylic acid are cuprous, trifluoroacetic acid copper, trifluoromethanesulfonic acid tetrem cyanogen copper, tetrafluoro boric acid copper (I), hexafluoro One or more in cupric phosphate (I), hexafluorophosphoric acid tetrem cyanogen copper (I).
The palladium catalyst, Raney nickel and copper catalyst can also be used with ligand united, and the part is selected from triphen Base phosphine, triethyl phosphine, tributylphosphine, tri-butyl phosphine, tricyclohexyl phosphine, triple phenoxyl phosphine, three (o-methyl-phenyl) phosphines, three (p-methoxyphenyl) phosphine, methyldiphenyl base phosphine, dicyclohexlphenylphosphine, di-tert-butyl-phenyl phosphine, dicyclohexyl (4- dimethyl Aminophenyl) phosphine, di-t-butyl (4- fluoroforms phenyl) phosphine, 1,2- be double（Diphenylphosphine）Ethane, 1,3- are double（Diphenylphosphine）Propane, Isosorbide-5-Nitrae-bis-（Diphenylphosphine）Double (phenylsulfinyl) ethane of butane, 1,2-, 2,2 '-bis- diphenyl phosphine -1,1 '-dinaphthalene, 1,1 '-bis- two Phenylphosphine ferrocene, 1,1 '-bis- (di-t-butyl phosphino-) ferrocene, 1,1 '-bis- (dicyclohexyl phosphino-) ferrocene, 1,1 '-it is bis- One kind or many in the double diphenylphosphine butane of (diisopropyl phosphino-) ferrocene, 2,3-O- isopropyl alkene -2,3- dihydroxy -1,4- Kind.
Alkali can also be added in step (2), described alkali is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, carbonic acid Potassium, sodium carbonate, cesium carbonate, lithium carbonate, silver carbonate, sodium acid carbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, trimethylamine, two Ethamine, triethylamine, tri-n-butylamine, 4- dimethylamino pyridines, nafoxidine, piperidines, N, N- dimethylanilines, 1,8- diazabicylos [5.4.0] 11 carbon -7- alkene, N-methylmorpholine, DIPEA, pyridine, 2,6- lutidines, imidazoles, N, N, N ', N ' one or more in-tetramethylethylenediamine etc..
In step (3)：
Work as R3、R8During for H, formula (V) compound is obtained by hydro-reductionAfterwards, may be used Vilazodone is made according to prior art；
Work as R3For H, R8During for amino protecting group, it can be obtained by hydro-reduction, DeprotectionAfterwards, vilazodone can be made according to prior art；
Work as R3For H, R8ForWhen, R1For COR2, R2For NR6R7, R6、R7During for H, formula (V) compound warp Over hydrogenation reduction can be prepared by vilazodone；
Work as R3For H, R8ForWhen, R1For CN or COR2；R2Selected from H, OR5Or NR6R7；R5、R6、R7It is independent Ground is selected from H or C1-12Alkyl, and R6、R7When being asynchronously hydrogen, formula (V) compound is by hydro-reduction, by R1It is transformed into CONH2I.e. Vilazodone can be made, by R1It is transformed into CONH2Can be prepared by vilazodone can be achieved by the prior art；
Work as R3For amino protecting group, R8During for H, formula (V) compound is obtained by Deprotection, hydro-reductionAfterwards, vilazodone can be made according to prior art；
Work as R3For amino protecting group, R8ForWhen, R1For COR2, R2For NR6R7, R6、R7During for H, formula (V) Compound can be prepared by vilazodone by hydro-reduction, Deprotection；
Work as R3、R8When being all amino protecting group, it can be obtained by Deprotection, hydrogenation Afterwards, vilazodone is prepared according to prior art；Or prepare vilazodone according to method in embodiment 4；Work as R3For Amino protecting group, R8ForWhen, R1For COR2, R2For NR6R7, R6、R7During for H, formula (V) compound is through over hydrogenation Reduction, Deprotection can be prepared by vilazodone；
Work as R3For amino protecting group, R8ForWhen, R1For CN or COR2；R2Selected from H, OR5Or NR6R7；R5、 R6、R7Independently selected from H or C1-12Alkyl, and R6、R7When being asynchronously hydrogen, formula (V) compound is by hydro-reduction, deprotection Base, by R1It is transformed into CONH2Vilazodone is can be prepared by, by R1It is transformed into CONH2Can be prepared by vilazodone can be by existing Technology is realized.
The invention further relates to the compound of the compound and formula (V) for the new intermediate formula (III) for preparing vilazodone.
The compound of formula (III), it is characterised in that：
R8It is selected fromH or amino protecting group；
R1For CN or COR2；R2Selected from H, OR5Or NR6R7；R5、R6、R7Independently selected from H or C1-12Alkyl.
The compound of formula (V), it is characterised in that：
R3For H or amino protecting group；
R8It is selected fromH or amino protecting group；
R1For CN or COR2；R2Selected from H, OR5Or NR6R7；R5、R6、R7Independently selected from H or C1-12Alkyl；R5、R6、R7More Preferably separately it is selected from H or C1-6Alkyl；
Work as R3、R8When being all amino protecting group, R3、R8It is each independently amino protecting group.
Term in the present invention unless otherwise indicated, typically with following implication.
Protection group is a concept in organic synthesis, is particular functional group in organic molecule is occurred desired reaction, Suppress the reaction of other functional groups simultaneously and a part of functional group is reversibly changed into the plan of inertia group by particular agent Slightly.
" amino protecting group " is commonly known and refers to such group, and the group is suitable for protecting amino, makes amino Without chemical reaction, but after being chemically reacted needed for the other parts of molecule are completed, the group is easily removed.Due to amino Protection group is removed after required reaction, therefore its size and property are not critical.
《Protection group in organic synthesis》(organic chemistry teaching and research room of East China University of Science translates, Rong Guobin schools, East China science and engineering University press, 2004；Former book is Protective Groups in Organic Synthesis (third edition), Theodora W.Greene and Peter G.M.Wuts write) in the chapter of protection one of amido detailed Jie has been done to amido protection group Continue.This specification will《Protection group in organic synthesis》In the 494-653 pages be incorporated as this specification a part.
" amino protecting group " includes but is not limited to following group：
1)Wherein Ra1Including but not limited to：Methyl, 9- fluorene methyls, 9- (2- is thio) fluorene methyl, 9- (2,7- bis- bromo) fluorene methyl, the benzos of 17- tetra- [a, c, g, i] fluorene methyl, the chloro- 3- indenes methyl of 2-, 2,7- di-t-butyls-[9- (10,10- dioxos -10,10, the thio xanthene of 10,10- tetrahydrochysenes) methyl, 1,1- dioxos benzo [b] thiophene -2- methyl, second Base, 2,2,2- trichloroethyls, 2- trimethylsilyls ethyl, 2- phenethyls, 1- (1- adamantyls) -1- Methylethyls, 2- chloroethyls, 1,1- dimethyl -2- haloethyls, 1,1- dimethyl -2,2- dibromoethyl, 1,1- dimethyl -2,2,2- trichloroethyls, 1- methyl - 1- (4- xenyls) ethyl, 1- (3,5- di-tert-butyl-phenyl) -1- Methylethyls, 2- (2 '-and 4 ' pyridine radicals) ethyl, 2,2- are double (4 '-nitrobenzophenone) ethyl, N- (2- pivaloyls amido) -1,1- dimethyl ethyls, 2- [(2- nitrobenzophenones) two is thio] -1- benzene Ethyl, 2- (N, N- dicyclohexyl carbonamido) ethyl, the tert-butyl group, 1- adamantyls, 2- adamantyls, vinyl, pi-allyl, 1- isopropylallyls, cinnamyl, 4- nitrocinnamyls base, 3- (3 '-pyridine radicals) pi-allyl, 8- quinolyls, N- hydroxy piperidines base, Alkyl two is thio, benzyl, to methoxy-benzyl, to nitrobenzyl, to bromobenzyl, p-chlorobenzyl, 2,4- dichloro benzyls, 4- methyl Sulfinyl benzyl, 9- anthrylmethyls, diphenyl methyl, 2- methylthioethyls, 2- methysulfonylethyls, 2- are (to toluene Sulfonyl) ethyl, [2- (1,3 dithia cyclohexyl)] methyl, 4- methylthiophenyis, 2,4- dimethyl thio phenyl, 2- phosphorus Base ethyl, 1- methyl isophthalic acids-(triphenyl phosphorus) ethyl, 1,1- dimethyl -2- cyanoethyls, 2- dansyls ethyl, 2- (4- nitrobenzene Base) ethyl, 4- phenylacetyl oxygen benzyl, 4- azidos benzyl, 4- nitrine methoxy-benzyl, m-chloro is to acyl-oxygen benzyl, p- (two Hydroxyl boryl) benzyl, 5- benzo isoxazoles methyl, 2- (trifluoromethyl) -6- chromones methyl, m-nitro base, 3,5- diformazans Oxy-benzyl, 1- methyl isophthalic acids-(3,5- dimethoxy phenyl) ethyl, Alpha-Methyl nitropiperonyl, adjacent nitro benzyl, 3,4- dimethoxies Base -6- nitrobenzyls, adjacent nitro benzyl methyl, 2- (2- nitrobenzophenones) ethyl, 6- nitro -3,4- dimethyl benzyls, 4- methoxies Base phenacyl, 3 ' -5 '-dimethoxy benzoin, tertiary pentyl, butynyl, to cyanobenzyls, cyclobutyl, cyclohexyl, ring penta Base, Cvclopropvlmethvl, to decyloxy benzyl, diisopropyl methyl, 2,2- dimethoxycarbonyls vinyl, o- (N ', N '-dimethyl Amide groups) benzyl, 1,1- dimethyl -3- (N ', N '-dimethyl acylamino) propyl group, 1,1- alkynyl dimethyls, two (2- pyridines Base) methyl, 2- furfuryls, 2- iodine ethyl, isobornyl, isobutyl group, different nicotinoyl base, p- (to methoxybenzene azo group) benzyl Base, 1- methyl-cyclobutyls, 1- methylcyclohexyls, 1- methyl isophthalic acids-Cvclopropvlmethvl, 1- methyl isophthalic acids-(to benzeneazo phenyl) ethyl, 1- methyl isophthalic acids-phenylethyl, 1- methyl isophthalic acids-(4 '-pyridine radicals) ethyl, phenyl, to phenylazo benzyl, 2,4,6- tri-terts Benzyl, 4- (trimethylamine) benzyl, 2,4,6- trimethyl benzyls, 2,4- dimethyl -3- amyl groups；
2)-C(O)NHSO2C6H4-p-CH3、-C(S)NHC6H5Or (CH3CH2)2NC(O)-、；
3) carboxyl groups, includes but is not limited to：Formoxyl, acetyl group, chloracetyl, tribromo-acetyl base, trifluoroacetyl group, Phenylacetyl group, 3- hydrocinnamoyls, 4- pentenoyls, 2- pyridine acyls, 3- pyridine acyls ,-C (O) CH (NHCOC6H5)CH2C6H5、 Benzoyl, to toluene benzoyl, ortho-nitrophenyl acetyl group, ortho-nitrophenyl oxygen acetyl group, 3- O-Nitrophenylfluorones propiono, 2- Methyl -2- ortho-nitrophenyl epoxides propiono, 3- methyl-3-nitros bytyry, adjacent nitro cinnamoyl, o-nitrobenzoyl, 2,2- dimethyl -3- (4- tert-butyl groups -2,6- dinitrophenyl) propiono, neighbour (benzoyl yloxymethyl) benzoyl, (2- acetyl Oxygen methyl) benzoyl, 2- [(tert-butyl diphenyl siloxy) methyl] benzoyl, 3- (2 ', 4 ', 5 '-trimethyl -3 ', 6 '-dioxy -1 ', 4 '-cyclohexadienyl) -3,3- Dimethylpropanoyls, adjacent hydroxyl-trans- cinnamoyl, the adjacent benzene of 2- methyl -2- is even Pyridine epoxide propiono, 4- chlorobutyryls, acetoacetyl, 3- p-hydroxybenzenes propiono, (the thio benzyloxycarbonyl group amine of N '-two Base) acetyl group, dichloro-acetyl, valeryl；
4) methyl, the tert-butyl group, pi-allyl, [2- (trimethyl silicon substrate) ethyoxyl] methyl, 3- acetyloxypropyls, cyano group first Base, 1- isopropyl -4- nitro -2- oxo -3- pyrrolinyls, 2,4- dimethoxy-benzyls, 2- azepines norbornene, 2,4- bis- Nitrobenzophenone, benzyl, 4- methoxy-benzyls, 2,4- dimethoxy-benzyls, 2- hydroxybenzyls, diphenyl methyl, double (4- methoxyl groups Phenyl) methyl, 5- dibenzocycloheptyls, trityl group, (4- methoxyphenyls) benzhydryl, 9- phenylfluorenyls, ferrocene Ylmethyl, vinyl, 2- chloroethyls, (1- ethyoxyls) ethyl, 2- (2 '-pyridine radicals) ethyl, 2- (4 '-pyridine radicals) ethyl, 2- (4- nitrobenzophenones) ethyl, 3,4- dimethoxy-benzyls, 3- methoxy-benzyls, 3,5- dimethoxy-benzyls, 2- dinitrophenyls, 4- dinitrophenyls, phenacyl, trityl, benzhydryl, (diphenyl -4- picolyls), hydroxymethyl, methoxyl group Methyl, diethoxymethyl, ethoxyl methyl, [2- (trimethyl silicon substrate) ethyoxyl] methyl, tertbutyl methyl, tert-butyl group diformazan Base silica ylmethyl, oxy acid methyl neopentyl, benzyloxymethyl, N, TMSDMA N dimethylamine ylmethyl, 2- THP trtrahydropyranyls；
5) (5,5- dimethyl -3- oxo -1- cyclohexenyl groups), the chloro- 9- fluorenyls methylene of 2,7- bis-, 2- (4,4- dimethyl - 2,6- dioxocyclohexyls subunit) ethyl, the fluoro- 3- oxos -1- cyclobutenyls of 4,4- tri-, 1- isopropyl -4- nitro -2- oxos -3- Pyrrolinyl；
6)Ph2P(O)-、(CH3)2P(S)-、Ph2P(S)-、(Ra2O)2P(O)-、(BnO)2P(O)-、(PhO)2P (O)-, it is Ra2For alkyl, preferably C1-C12Alkyl；
7) t-Butyldimethylsilyl, trimethyl silicon substrate, triisopropylsilyl, triethyl group silicon substrate, tert-butyl diphenyl silicon Base；
8) phenylsufinyl, onitrophenylsulfenyl, 2,4- dinitro benzenes sulfinyl, pentachloro- phenylsulfinyl Base, 2- nitro -4- methoxybenzenes sulfinyl, trityl sulfinyl, 1- (2,2,2- tri- fluoro- 1,1- diphenyl) ethyl are sub- Sulfonyl, 3- nitro -2- pyridine sulfenyls；
9) p-toluenesulfonyl, benzenesulfonyl, 2,3,6- trimethyl -4- MethOxybenzenesulfonyls, 2,4,6- trimethoxies Benzenesulfonyl, 2,6- dimethyl -4- MethOxybenzenesulfonyls, pentamethylbenzene sulfonyl, 2,3,5,6- tetramethyl -4- methoxybenzenes Sulfonyl, 4- MethOxybenzenesulfonyls, 2,4,6- trimethylphenysulfonyls, 2,6- dimethoxy-4 's-Methyl benzenesulfonyl base, 3- first Epoxide -4- tert-butyl benzenes sulfonyl, 2,2,5,7,8- pentamethyl benzodihydropyran -6- sulfonyls, 2-- nitrobenzenesulfonyls, 4- nitrobenzenesulfonyls, 2,4- dinitro benzenes sulphur-nitrobenzenesulfonyl, benzothiazole 2- sulfonyls, pyridine-2-sulfuryl base, first Sulfonyl, 2- (trimethylsilyl) ethylsulfonyl, 9- anthracenes sulfonyl, 4- (4 ', 8 '-dimethoxy menaphthyl) benzenesulfonyl, benzyl Sulfonyl, trifluoromethyl sulfonyl, phenacyl sulfonyl, tert. butylsulfonyl, N, N- dimethyl methyl acyl groups.
Amino protecting group further preferably from benzyl, to methoxy-benzyl, tertbutyloxycarbonyl, methoxycarbonyl group, carbethoxyl group, Allyloxycarbonyl, trifluoroacetyl group, t-Butyldimethylsilyl, p-toluenesulfonyl, benzyloxycarbonyl group, 9- fluorenylmethyloxycarbonyls, 2,2,2- trichloro-ethoxycarbonyls, 2- trimethyl silicon substrates carbethoxyl group, trityl, 2,4- dimethoxy-benzyls, mesyl.Again Further preferably from benzyl, to methoxy-benzyl, tertbutyloxycarbonyl, t-Butyldimethylsilyl, p-toluenesulfonyl.
In the present invention unless otherwise indicated, term is write a Chinese character in simplified form with following meanings：
Term in the present invention unless otherwise indicated, typically with following implication.
Term " alkyl " represents the straight or branched saturated hydrocarbyl of the carbon atom with the number.The instantiation of alkyl Including but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, new penta Base, n-hexyl, isohesyl, 2,2- dimethylbutyls and 2,3- dimethylbutyls etc..Term " C1-C12Alkyl " refers to 1-12 The straight or branched saturated hydrocarbyl of individual carbon atom.Term " C1-C6Alkyl " refers to that the straight or branched with 1-6 carbon atom is satisfied And alkyl.
Term " halogen " is fluorine, chlorine, bromine or iodine.
Palladium catalyst can be selected from palladium, propionic acid palladium, palladium oxide, palladium nitrate, palladium sulfate, trifluoroacetic acid in the present invention Palladium, palladium acetylacetonate, neopentanoic acid palladium, palladium chloride, dibrominated palladium, palladium diiodide, the ammino palladium of dichloro four, the ammino palladium of acetic acid four, Palladium dydroxide, palladium charcoal, tetrakis triphenylphosphine palladium, three (dibenzalacetone) two palladium, (1,1 '-bis- Diphenyl phosphino ferrocenes) dichloro Change palladium, double (triphenylphosphine) palladium chlorides, double (tricyclohexyl phosphine) palladium chlorides, double (tri-butyl phosphine) palladiums, (1,3- double (two Phenylphosphine) propane) palladium chloride, (1,5- cyclo-octadiene) palladium chloride, (bipy 2,2' bipyridyl) palladium chloride, the double (hexichol of 1,2- Base phosphine) ethane palladium chloride, double (diphenylphosphine) the butane palladium chlorides of 1,4-, double (triphenylphosphine) palladiums, ethylenediamine dichloros Change double (phenylsulfinyl) the ethane palladium diacetates of palladium, two (cyano group benzene) palladium chlorides, 1,2-, it is (1,10- phenanthroline) palladium chloride, double (three-o- toluene phosphines) palladium chloride, hexafluoroacetylacetone palladium, double [double (diphenylphosphino) ethane of 1,2-] palladiums, double [three (2- first Phenyl) phosphine] palladium, double (triethyl phosphine) palladium chlorides, double (acetonitrile) palladium chlorides, double (dibenzalacetone) palladiums, double (methyl two Phenylphosphine) palladium chloride, four (acetonitrile) tetrafluoro boric acid palladiums, (bicyclic [2.2.1] hept- 2,5- diene) dichloro palladium, 1,1 '-bis- (two Tert. butylphosphino) ferrocene palladium chloride, 1,1 '-bis- (dicyclohexyl phosphino-) ferrocene palladium chlorides, 1,1 '-bis- (diisopropyls Base phosphino-) ferrocene palladium chloride, (TEMED) palladium chloride, double [dicyclohexyl (4- dimethylaminos Phenyl) phosphine] palladium chloride, the one or more in double [di-t-butyl (4- fluoroforms phenyl) phosphine] palladium chlorides.The palladium is urged Agent can also be used with ligand united, and the part is selected from triphenylphosphine, triethyl phosphine, tributylphosphine, tri-butyl phosphine, three Cyclohexyl phosphine, triple phenoxyl phosphine, three (o-methyl-phenyl) phosphines, three (p-methoxyphenyl) phosphines, methyldiphenyl base phosphine, dicyclohexyl Phenylphosphine, di-tert-butyl-phenyl phosphine, dicyclohexyl (4- dimethylaminos phenyl) phosphine, di-t-butyl (4- fluoroforms phenyl) phosphine, 1, 2- is double（Diphenylphosphine）Ethane, 1,3- are double（Diphenylphosphine）Propane, Isosorbide-5-Nitrae-bis-（Diphenylphosphine）Butane, 1,2- are double (phenylsulfinyl) Double diphenyl phosphine -1 of ethane, 2,2'-, 1 '-dinaphthalene, 1,1 '-bis- Diphenyl phosphino ferrocenes, 1,1 '-bis- (di-t-butyl phosphino-s) two Luxuriant iron, 1,1 '-bis- (dicyclohexyl phosphino-) ferrocene, 1,1 '-bis- (diisopropyl phosphino-) ferrocene, 2,3-O- isopropyls alkene -2, The double diphenylphosphine butane of 3- dihydroxy -1,4-, tetrachloro close the one or more in the sour sodium of palladium, palladium charcoal.
Non-palladium catalyst is selected from Raney nickel, copper catalyst, Co catalysts, platinum catalyst, rhodium catalyst, iridium in the present invention Catalyst, ruthenium catalyst, iron catalyst；It preferably is selected from Raney nickel, Co catalysts.The Raney nickel is selected from double（Triphenylphosphine） It is Nickel Chloride, Nickel Chloride, double（Tributylphosphine）Nickel Chloride, dichloro two（Trimethyl-phosphine）It is nickel, double（Tributylphosphine）Dibrominated It is nickel, double（Tricyclohexyl phosphine）It is Nickel Chloride, double（Triphenylphosphine）It is Nickel Bromide, double（Triphenylphosphine）Dicarbapentaborane nickel, [1,3- is double （Diphenylphosphine）Propane] Nickel Chloride, [1,2- is double（Diphenylphosphine）Ethane] Nickel Chloride, [1,1 '-bis-（Diphenylphosphine）Two cyclopentadienyls Iron] it is Nickel Chloride, double（Isopropylcyclopentadiene）Nickel, four（Triphenylphosphine）One or more in nickel.The copper catalyst choosing From cuprous iodide, cuprous bromide, stannous chloride, cuprous oxide, cupric oxide, copper chloride, copper acetate, copper sulphate, copper nitrate, acetyl Pyruvic acid copper, trifluoromethayl sulfonic acid copper (II), trifluoromethayl sulfonic acid copper (I), tetrafluoro boric acid tetrem cyanogen copper (I), thiophene -2-carboxylic acid Cuprous, trifluoroacetic acid copper, trifluoromethanesulfonic acid tetrem cyanogen copper, tetrafluoro boric acid copper (I), hexafluorophosphoric acid copper (I), hexafluorophosphoric acid tetrem cyanogen One or more in copper (I).The Raney nickel and copper catalyst can also be used with ligand united, and the part is selected from three Phenylphosphine, triethyl phosphine, tributylphosphine, tri-butyl phosphine, tricyclohexyl phosphine, triple phenoxyl phosphine, three (o-methyl-phenyl) phosphines, three (p-methoxyphenyl) phosphine, methyldiphenyl base phosphine, dicyclohexlphenylphosphine, di-tert-butyl-phenyl phosphine, dicyclohexyl (4- dimethyl Aminophenyl) phosphine, di-t-butyl (4- fluoroforms phenyl) phosphine, 1,2- be double（Diphenylphosphine）Ethane, 1,3- are double（Diphenylphosphine）Propane, Isosorbide-5-Nitrae-bis-（Diphenylphosphine）Double (phenylsulfinyl) ethane of butane, 1,2-, 2,2 '-bis- diphenyl phosphine -1,1 '-dinaphthalene, 1,1 '-bis- two Phenylphosphine ferrocene, 1,1 '-bis- (di-t-butyl phosphino-) ferrocene, 1,1 '-bis- (dicyclohexyl phosphino-) ferrocene, 1,1 '-it is bis- One kind or many in the double diphenylphosphine butane of (diisopropyl phosphino-) ferrocene, 2,3-O- isopropyl alkene -2,3- dihydroxy -1,4- Kind.
The present invention provides a kind of effective preparation method for vilazodone.
The present invention is further illustrated by way of examples again below, provides the implementation detail of the present invention, still It is not intended to restriction protection scope of the present invention.
Specific embodiment mode
Embodiment 1：
(1) preparation of 5- (4- (3- butynyls) piperazine -1- bases) benzofuran-2-carboxamides
5- (piperazine -1- bases) benzofuran-2-carboxamides 24.5g (100mmol), 12 hydration phosphorus are added in reaction bulb The bromo- 1- butine 33.0g (250mmol) of 4- are added dropwise under sour sodium 57.1g (150mmol), 500ml tetrahydrofurans, 125ml water, normal temperature, It is then heated to 65 DEG C of stirring 18h.Stop heating, and divide to fall water layer while hot.By organic phase evaporated under reduced pressure, solid 500ml second Alcohol normal temperature is beaten, and yellow solid 25.6g, yield 86.2% are filtrated to get after two hours.MS-ESI[M+H]+：298
1H NMR:(400MHz,d6-DMSO)δ8.03(s,1H),7.61(s,1H),7.48(d,J=9.6Hz,1H),7.42 (s,1H),7.16~7.18(m,2H),3.11(t,J=4.8Hz,4H),2.79(s,1H),2.58(t,J=4.8Hz,4H),2.54 (t,J=7.6Hz,2H),2.37(t,J=7.6Hz,2H)。
(2) 3- (4- (4- (2- carbamyl benzofuran -5- bases) piperazine -1- bases) -1- butynyls) -5- cyanoindoles - The preparation of 1- t-butyl formates
5- (4- (3- butynyls) piperazine -1- bases) benzofuran-2-carboxamides 25.6g is added in reaction bulb (86.1mmol), 5- cyano group -3- iodine indoles -1- t-butyl formates 28.8g (78.2mmol), (1,1 '-it is bis- that (diphenylphosphine two is luxuriant Iron) palladium chloride 1.2g (1.6mmol), cuprous iodide 1.5g (7.8mmol) and dichloromethane 600ml, are replaced three times with argon gas 40 DEG C of stirring 6h are heated under argon gas protection afterwards.Stop heating, be cooled to room temperature, filter, filtrate is added into 300ml saturations eats Salt solution and 100ml ammoniacal liquor, point liquid removes water layer after extraction.Organic layer is removed under reduced pressure, solid 300ml acetonitriles and 300ml water Mixed solution mashing, filtered after one hour, filtration cakes torrefaction obtains yellow solid 33.6g, yield 80.0%.MS-ESI[M+H ]+：538
1H NMR:(400MHz,d6-DMSO)δ8.18(d,J=8.4Hz,1H),8.08(s,1H),8.04(s,1H),8.00 (s,1H),7.78(d,J=8.4Hz,1H),7.62(s,1H),7.48(d,J=9.6Hz,1H),7.42(s,1H),7.18(m, 2H),3.16(m,4H),2.72(m,4H),2.67(m,4H),1.64(s,9H)。
(3) 3- (4- (4- (2- carbamyl benzofuran -5- bases) piperazine -1- bases) butyl) -5- cyanoindole -1- formic acid The preparation of the tert-butyl ester
In reaction bulb add 3- (4- (4- (2- carbamyl benzofuran -5- bases) piperazine -1- bases) -1- butynyls) - 5- cyanoindole -1- t-butyl formates 33.6g (62.6mmol), 3.4g 10% palladium carbon（Aqueous about 50%）, use 200ml tetrahydrochysenes Furans dissolves, and leads to hydrogen stirring at normal temperature 24h after being replaced three times with hydrogen.Filtering, filtrate decompression is concentrated, and ethanol mashing obtains light Yellow solid 29.3g, yield 86.2%.
MS-ESI[M+H]+：542
1H NMR:(400MHz,d6-DMSO)δ8.20(s,1H),8.17(d,J=8.8Hz,1H),8.04(s,1H),7.71 (d,J=8.8Hz,1H),7.61(m,2H),7.48(d,J=9.6Hz,1H),7.42(s,1H),7.15~7.16(m,2H),3.10 (m,4H),2.72(t,J=7.2Hz,2H),2.51(m,4H),2.37(t,J=7.2Hz,2H),1.68(m,2H),1.64(s, 9H),1.54(m,2H)。
(4) preparation of 5- (- 4- (4- (5- cyanoindole -3- bases) butyl) piperazine -1- bases) benzofuran-2-carboxamides exists 3- (4- (4- (2- carbamyl benzofuran -5- bases) piperazine -1- bases) butyl) -5- cyanoindole -1- first is added in reaction bulb Tert-butyl acrylate 29.3g, is dissolved with 200ml methanol, instills 3ml concentrated hydrochloric acids, and stirring at normal temperature 12h adds K2CO3To neutrality.Filtering, Concentration, column chromatography obtains light yellow crystal 19.3g, yield 81.1%.
MS-ESI[M+H]+：442
1H NMR:(400MHz,d6-DMSO)δ11.3(s,1H),8.03(s,1H),8.03(s,1H),7.60(s,1H), 7.49(m,2H),7.40(d,J=5.2Hz,2H),7.31(s,1H),7.16(d,J=5.2Hz,2H)3.10(s,4H),2.74(t, J=7.2Hz,2H),2.51(s,4H),2.38(t,J=7.2Hz,2H),1.68(m,2H),1.54(m,2H)。
Embodiment 2：
(1) preparation of 5- (4- (3- butynyls) piperazine -1- bases) benzofuran-2-carboxamides
5- (piperazine -1- bases) benzofuran-2-carboxamides 24.5g (100mmol), sodium carbonate is added in reaction bulb The iodo- 1- butine 36.0g (200mmol) of 4- are added dropwise under 27.6g (200mmol), 300ml tetrahydrofurans, 200ml water, normal temperature, then It is heated to 65 DEG C of stirring 18h.Stop heating, and divide to fall water layer while hot.By organic phase evaporated under reduced pressure, solid is normal with 500ml ethanol Temperature mashing, is filtrated to get yellow solid 24.2g, yield 81.5% after two hours.
(2) 5- (4- (4- (1- benzyl -5- cyanoindole -3- bases) -3- butyl- alkynyl) piperazine -1- bases) benzofuran -2- first The preparation of acid amides
5- (4- (3- butynyls) piperazine -1- bases) benzofuran-2-carboxamides 24.2g is added in reaction bulb (81.5mmol), 1- benzyl -3- iodine indoles -5- formonitrile HCNs 29.2g (81.5mmol), (1,1 '-bis- (Diphenyl phosphino ferrocene) dichloros Change palladium 1.2g (1.6mmol), cuprous iodide 1.5g (7.8mmol) and dichloromethane 600ml, in argon gas after being replaced three times with argon gas 40 DEG C of stirring 6h are heated under protection.Stop heating, be cooled to room temperature, filter, by filtrate add 300ml saturated aqueous common salts and 100ml ammoniacal liquor, point liquid removes water layer after extraction.Organic layer is removed under reduced pressure, the mixing of solid 300ml acetonitriles and 300ml water Solution is beaten, and is filtered after one hour, and filtration cakes torrefaction obtains yellow solid 37.3g, yield 86.7%.MS-ESI[M+H]+：528
(3) preparation of 5- (- 4- (4- (5- cyanoindole -3- bases) butyl) piperazine -1- bases) benzofuran-2-carboxamides
5- (4- (4- (1- benzyl -5- cyanoindole -3- bases) -3- butyl- alkynyl) piperazine -1- bases) benzene is added in reaction bulb And furans -2- formamides 37.3g (70.8mmol), 3.7g 10% palladium carbon（Aqueous about 50%）, dissolved with 200ml tetrahydrofurans, Lead to hydrogen stirring at normal temperature 24h after being replaced three times with hydrogen.Filtering, filtrate decompression is concentrated, and ethanol mashing obtains faint yellow solid 24.3g, yield 77.9%.
Embodiment 3：
(1) preparation of 5- (4- (3- butynyls) piperazine -1- bases) benzofuran-2-carboxamides
5- (piperazine -1- bases) benzofuran-2-carboxamides 24.5g (100mmol), triethylamine is added in reaction bulb The iodo- 1- butine 45.0g (250mmol) of 4- are added dropwise under 30.3g (300mmol), 300ml tetrahydrofurans, 100ml water, normal temperature, then It is heated to 80 DEG C of stirring 12h.Stop heating, and divide to fall water layer while hot.By organic phase evaporated under reduced pressure, solid is normal with 500ml ethanol Temperature mashing, is filtrated to get yellow solid 22.9g, yield 77.1% after one hour.
(2) 5- (4- (4- (5- cyano group -1- (4- methoxy-benzyls) indol-3-yl) -3- butynyls) piperazine -1- bases) benzo The preparation of furans -2- formamides
5- (4- (3- butynyls) piperazine -1- bases) benzofuran-2-carboxamides 22.9g is added in reaction bulb (77.1mmol), 1- (4- methoxy-benzyls) -3- bromo indole -5- formonitrile HCNs 30.6g (90mmol), palladium 0.224g (1mmol), Triphenylphosphine 0.78g (3mmol), cuprous iodide 0.75g (3.9mmol) and tetrahydrofuran 400ml, are heated to 65 DEG C of stirring 6h. Stop heating, be cooled to room temperature, filter, be beaten after concentration with the mixed solution of 300ml acetonitriles and 100ml ammoniacal liquor, after one hour Filtering, filtration cakes torrefaction obtains yellow solid 33.9g, yield 79.1%.
MS-ESI[M+H]+：558
(3) preparation of 5- (- 4- (4- (5- cyanoindole -3- bases) butyl) piperazine -1- bases) benzofuran-2-carboxamides
5- (4- (4- (5- cyano group -1- (4- methoxy-benzyls) indol-3-yl) -3- butynyls) piperazines are added in reaction bulb Piperazine -1- bases) benzofuran-2-carboxamides 33.9g (60.8mmol), the palladium carbons of 3.4g 10%（Aqueous about 50%）, use 200ml first Alcohol dissolves, and leads to hydrogen stirring at normal temperature 24h after being replaced three times with hydrogen.Filtering, filtrate decompression is concentrated, and ethanol mashing obtains yellowish Color solid 21.2g, yield 79.1%.
Embodiment 4：
(1) preparation of 4- (3- butynyls) piperazine -1- t-butyl formates
Piperazine -1- t-butyl formates 18.6g (100mmol), potassium acetate 28.2g (300mmol) are added in reaction bulb, and 4- toluene sulfonic acide butyl- 3- alkynes ester 22.4g (100mmol) are added dropwise under toluene 500ml, normal temperature, 80 DEG C of stirrings are then heated to 36h.Stop heating, be cooled to room temperature, filter, filtrate is added in 800ml ethyl acetate, after stirring 1h, filter, dry, obtain To yellow-brown solid 20.6g, yield 86.6%.
MS-ESI(M+1)：239
(2) preparation of 4- (4- (1- benzyl -5- cyanoindole -3- bases) -3- butynyls) piperazine -1- t-butyl formates
4- (3- butynyls) piperazine -1- t-butyl formates 20.6g (86.6mmol), 1- benzyls -3- is added in reaction bulb Iodine indoles -5- formonitrile HCNs 38.1g (106.5mmol), cesium carbonate 65.2g (200mmol), double (dibenzalacetone) palladium 1.15g (2mmol) and DMF 300ml, is heated to 80 DEG C of stirring 6h under argon gas protection after being replaced three times with argon gas. Stop heating, be cooled to room temperature, filter, filtrate is added in 600ml water, after stirring 0.5h, filter, dry, column chromatography is obtained Faint yellow solid 30.5g, yield 75.3%.
MS-ESI[M+H]+：469
(3) preparation of 4- (4- (5- cyanoindole -3- bases) butyl) piperazine -1- t-butyl formates
4- (4- (1- benzyl -5- cyanoindole -3- bases) -3- butynyls) tertiary fourth of piperazine -1- formic acid is added in reaction bulb Ester 30.5g (65.2mmol), 1.5g 10% palladium carbon（Aqueous about 50%）, dissolved with 300ml tetrahydrofurans, stirring at normal temperature 24h, Lead to hydrogen stirring at normal temperature 16h after being replaced three times with hydrogen.Filtering, filtrate decompression is concentrated, column chromatography obtains white solid 16.3g, yield 65.5%.
MS-ESI[M+H]+：383
(4) preparation of 3- (4- (piperazine -1- bases) butyl) indoles -5- formonitrile HCNs
4- (4- (5 cyanoindole -3- bases) butyl) piperazine -1- t-butyl formate 16.3g are added in reaction bulb, are used 200ml dichloromethane is dissolved, and 200ml trifluoroacetic acids are instilled under ice bath, ice bath, stirring at normal temperature 8 hours is removed.Use sodium carbonate liquor Reaction solution is washed to alkalescence, organic phase is concentrated, column chromatography obtains white solid 8.8g, yield 73%.
MS-ESI[M+H]+：283
(5) preparation of 5- (- 4- (4- (5- cyanoindole -3- bases) butyl) piperazine -1- bases) benzofuran-2-carboxamides
Addition 3- (4- (piperazine -1- bases) butyl) indoles -5- formonitrile HCN 5.4g in reaction bulb, addition 5- bromobenzofuran - 2- formamide 4.60g, add four（Triphenylphosphine）Palladium 0.44g and 5.1g sodium carbonate, it is molten with 150ml DMFs Solution, is warming up to 80 DEG C of stirring 48h.Reaction solution, which is added in 100ml water, solid precipitation, is filtrated to get solid and is divided with column chromatography From obtaining white solid 2.4g, yield 27.8%.
Embodiment 5：
(1) preparation of 5- (4- (3- butynyls) piperazine -1- bases) benzofuran-2-carboxamides
5- (piperazine -1- bases) benzofuran-2-carboxamides 24.5g (100mmol), potassium carbonate is added in reaction bulb The bromo- 1- butine 26.6g (200mmol) of 4- are added dropwise under 41.4g (300mmol), DMF 300ml, normal temperature, then It is heated to 60 DEG C of stirring 8h.Stop heating, filtering, filtrate is slowly added in 1000ml water, separates out solid.Filtering, dry To solid 22.7g, yield 76.3%.
(2) system of 5- (4- (4- (5- cyanoindole -3- bases) -3- butynyls) piperazine -1- bases) benzofuran-2-carboxamides It is standby
5- (4- (3- butynyls) piperazine -1- bases) benzofuran-2-carboxamides 22.5g is added in reaction bulb (75.7mmol), 3- bromo indole -5- formonitrile HCNs 20.1g (90.9mmol), double (triphenylphosphine) palladium chloride 2.7g (3.8mmol), Cuprous bromide 1.1g (7.6mmol), diethylamine 11.0g (151mmol) and DMA 400ml, are replaced with argon gas 60 DEG C of stirring 8h are heated to after three times under argon gas protection.Stop heating, be cooled to room temperature, filter, filtrate is added into 800ml water In, after stirring 0.5h, filter, dry, column chromatography obtains faint yellow solid 24.0g, yield 72.5%.
MS-ESI[M+H]+：438
(3) preparation of 5- (- 4- (4- (5- cyanoindole -3- bases) butyl) piperazine -1- bases) benzofuran-2-carboxamides
In reaction bulb add 5- (4- (4- (5- cyanoindole -3- bases) -3- butynyls) piperazine -1- bases) benzofuran - 2- formamides 23.6g (53.9mmol), 2.4g 10% palladium carbon（Aqueous about 50%）, dissolved, replaced with hydrogen with 200ml methanol Lead to hydrogen stirring at normal temperature 24h after three times.Filtering, filtrate decompression is concentrated, and ethanol mashing obtains faint yellow solid 19.9g, yield 83.6%.
Embodiment 6：
(1) preparation of 5- (4- (3- butynyls) piperazine -1- bases) coumarilic acid ethyl ester
5- (piperazine -1- bases) coumarilic acid ethyl ester 27.4g (100mmol), potassium carbonate is added in reaction bulb The bromo- 1- butine 16.2g (120mmol) of 4- are added dropwise under 41.4g (300mmol), and 1-METHYLPYRROLIDONE 400ml, normal temperature, then It is heated to 60 DEG C of stirring 10h.Stop heating, be cooled to room temperature, filter, filtrate is added in 1000ml water, after stirring 0.5h, mistake Filter, column chromatography obtains title compound 22.9g, yield 70.2%.
MS-ESI[M+H]+：327
(2) 5- (4- (4- (1- t-Butyldimethylsilyl -5- cyanoindole -3- bases) -3- butynyls) piperazine -1- bases) benzene And the preparation of furans -2- Ethyl formates
5- (4- (3- butynyls) piperazine -1- bases) coumarilic acid ethyl ester 22.7g is added in reaction bulb (69.5mmol), 1- t-Butyldimethylsilyl -3- iodine indoles -5- formonitrile HCNs 23.9g (62.6mmol), NiCl2(PPh3)22.3g (3.5mmol), cuprous iodide 1.3g (7.0mmol), triethylamine 14.1g (139mmol) and dioxane 300ml, are put with argon gas Change and be heated to 80 DEG C of stirring 24h after three times under argon gas protection.Stop heating, be cooled to room temperature, filter, filtrate is added In 600ml water, after stirring 1h, filter, dry, column chromatography obtains title compound 28.3g, yield 77.9%.
MS-ESI[M+H]+：581
(3) 5- (4- (4- (1- t-Butyldimethylsilyl -5- cyanoindole -3- bases) butyl) piperazine -1- bases) benzo furan Mutter the preparations of -2- Ethyl formates
5- (4- (4- (1- t-Butyldimethylsilyl -5- cyanoindole -3- bases) -3- butynyls) are added in reaction bulb Piperazine -1- bases) coumarilic acid ethyl ester 28.0g (48.2mmol), the palladium carbons of 2.8g 10%（Aqueous about 50%）, use 300ml tetrahydrofurans dissolve, and lead to hydrogen stirring at normal temperature 8h after being replaced three times with hydrogen.Filtering, filtrate decompression is concentrated, obtains light Yellow solid 26.8g, yield 95.2%.
MS-ESI[M+H]+：585
(4) preparation of 5- (4- (4- (5- cyanoindole -3- bases) butyl) piperazine -1- bases) coumarilic acid ethyl ester
In reaction bulb add 5- (4- (4- (1- t-Butyldimethylsilyl -5- cyanoindole -3- bases) butyl) piperazine - 1- yls) coumarilic acid ethyl ester 26.5g (45.3mmol), is dissolved with 300ml tetrahydrofurans, instills 30ml 2mol/L salt Acid, stirring at normal temperature 3h adds K2CO3To neutrality.Filtering, concentration, with re-crystallizing in ethyl acetate, obtains light yellow crystal 16.7g, Yield 78.3%.
MS-ESI[M+H]+：471
(5) preparation of 5- (- 4- (4- (5- cyanoindole -3- bases) butyl) piperazine -1- bases) benzofuran-2-carboxamides
1500ml ammoniacal liquor is added in reaction bulb, 5- (4- (4- (5- cyanoindole -3- bases) are added under stirring in 30min Butyl) piperazine -1- bases)-coumarilic acid ethyl ester solid 16.3g (34.6mmol), persistently stir 36 hours under normal temperature, It is filtrated to get solid and uses column chromatography and obtains white solid 11.3g, yield 73.8%.
Embodiment 7：
3- (4- (4- (2- carbamyl benzofuran -5- bases) piperazine -1- bases) -1- butynyls) -5- cyanoindole -1- first The preparation of tert-butyl acrylate
5- (4- (3- butynyls) piperazine -1- bases) benzofuran-2-carboxamides 2.97g is added in reaction bulb (10mmol), 5- cyano group -3- iodine indoles -1- t-butyl formates 3.68g (10mmol), four（Triphenylphosphine）Nickel 0.55g (0.5mmol), cuprous iodide 0.19g (1.0mmol), potassium hydroxide 0.84g (15mmol) and isopropanol 50ml, are replaced with argon gas 80 DEG C of stirring 20h are heated to after three times under argon gas protection.Stop heating, be cooled to room temperature, filter, after filtrate decompression is concentrated Column chromatography obtains yellow solid 4.3g, yield 80.0%.
Embodiment 8：
3- (4- (4- (2- carbamyl benzofuran -5- bases) piperazine -1- bases) -1- butynyls) -5- cyanoindole -1- first The preparation of tert-butyl acrylate
5- (4- (3- butynyls) piperazine -1- bases) benzofuran-2-carboxamides 2.97g is added in reaction bulb (10mmol), 5- cyano group -3- iodine indoles -1- t-butyl formates 3.68g (10mmol), cuprous iodide 0.19g (1.0mmol), three Phenylphosphine 0.52g (2.0mmol), potassium carbonate 2.1g (15mmol) and dimethyl sulfoxide 50ml, in argon gas after being replaced three times with argon gas 120 DEG C of stirring 16h are heated under protection.Stop heating, be cooled to room temperature, filter, filtrate is added in 100ml water, stirring Filtered after 0.5h, filter cake column chromatography obtains yellow solid 4.0g, yield 74.4%.

Claims (13)

1. a kind of method for preparing formula (V) compound, it is characterised in that formula (III) compound passes through coupling with formula (IV) compound Obtained formula (V) compound of reaction；
R3For H or amino protecting group；
R4Selected from I or Br；
R8It is selected fromOr amino protecting group；
R1For CN or COR2；R2Selected from H, OR5Or NR6R7；R5、R6、R7Independently selected from H or C1-12Alkyl；
Work as R3、R8When being all amino protecting group, R3、R8It is each independently amino protecting group.
2. the preparation method according to claim 1, it is characterised in that：
With formula (IV) compound under catalyst action coupling reaction occurs for formula (III) compound；
The mol ratio of formula (III) compound and formula (IV) compound is 1:3~3:1；
Reaction temperature is 20~150 DEG C；
The catalyst is selected from palladium catalyst, Raney nickel, copper catalyst, Co catalysts, platinum catalyst, rhodium catalyst, iridium and urged Agent, ruthenium catalyst, iron catalyst.
3. the preparation method according to claim 2, it is characterised in that：
The mol ratio of formula (III) compound and formula (IV) compound is 1:2~2:1；
Reaction temperature is 30~130 DEG C；
Reaction time is 1h~96h；
The catalyst is palladium catalyst, Raney nickel or copper catalyst；
The solvent used in reaction is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, formamide, dichloromethane, three Chloromethanes, 1-METHYLPYRROLIDONE, tetrahydrofuran, methyltetrahydrofuran, t-butyl methyl ether, isopropyl ether, acetonitrile, 1,4- dioxies Six rings, 1,2- dimethoxy-ethanes, 2-methyl cellosolve, cellosolvo, methanol, ethanol, isopropanol, the tert-butyl alcohol, acetic acid Ethyl ester, methyl acetate, isopropyl acetate, Ethyl formate, acetone, butanone, methyl butyl ketone, methyl iso-butyl ketone (MIBK), dimethyl sulfoxide, One or more groups in toluene, dimethylbenzene, chlorobenzene, methoxybenzene, HMPA, diethylamine, triethylamine, water Close.
4. the preparation method according to claim 3, it is characterised in that：When the catalyst is non-copper catalyst, add Copper catalyst is used as co-catalyst.
5. the preparation method according to claim 4, it is characterised in that：
The mol ratio of formula (III) compound and formula (IV) compound is 1:1.3~1.3:1；
Reaction temperature is 40~120 DEG C；
Reaction time is 2h~48h；
R5、R6、R7Independently selected from H or C1-6Alkyl；
The palladium catalyst be selected from palladium, propionic acid palladium, palladium oxide, palladium nitrate, palladium sulfate, palladium trifluoroacetate, palladium acetylacetonate, Neopentanoic acid palladium, palladium chloride, dibrominated palladium, palladium diiodide, the ammino palladium of dichloro four, the ammino palladium of acetic acid four, palladium dydroxide, palladium charcoal, Tetrakis triphenylphosphine palladium, three (dibenzalacetone) two palladium, (1,1'- double (Diphenyl phosphino ferrocene) palladium chloride, double (triphens Base phosphine) palladium chloride, double (tricyclohexyl phosphine) palladium chlorides, double (tri-butyl phosphine) palladiums, (1,3- double (diphenylphosphine) propane) Double (diphenylphosphine) ethane two of palladium chloride, (1,5- cyclo-octadiene) palladium chloride, (bipy 2,2' bipyridyl) palladium chloride, 1,2- Double (diphenylphosphine) the butane palladium chlorides of palladium bichloride, 1,4-, double (triphenylphosphine) palladiums, ethylenediamine palladium chloride, two (cyano group Benzene) palladium chloride, double (phenylsulfinyl) the ethane palladium diacetates of 1,2-, (1,10- phenanthroline) palladium chloride, double (three-o- toluene Phosphine) palladium chloride, hexafluoroacetylacetone palladium, double [1,2- double (diphenylphosphino) ethane] palladiums, double [three (2- tolyls) phosphines] palladiums, Double (triethyl phosphine) palladium chlorides, double (acetonitrile) palladium chlorides, double (dibenzalacetone) palladiums, double (methyldiphenyl base phosphine) dichloros Change palladium, four (acetonitrile) tetrafluoro boric acid palladiums, (bicyclic [2.2.1] hept- 2,5- diene) dichloro palladium, 1,1 '-bis- (di-t-butyl phosphino-s) Ferrocene palladium chloride, 1,1 '-bis- (dicyclohexyl phosphino-) ferrocene palladium chlorides, the cyclopentadienyl of 1,1 '-bis- (diisopropyl phosphino-s) two Iron palladium chloride, (N,N,N',N' tetramethylethylene diamine) palladium chloride, double [dicyclohexyl (4- dimethylaminos phenyl) phosphines] two Palladium bichloride, double [di-t-butyl (4- fluoroforms phenyl) phosphine] palladium chlorides, tetrachloro close the one or more in the sour sodium of palladium, palladium charcoal；
The Raney nickel is selected from double (triphenylphosphine) Nickel Chloride, Nickel Chloride, dichloro two (tributylphosphine) nickel, double (front threes Base phosphine) Nickel Chloride, double (tributylphosphine) Nickel Bromides, double (tricyclohexyl phosphine) Nickel Chlorides, double (triphenylphosphine) dibrominateds Nickel, double (triphenylphosphine) dicarbapentaborane nickel, [double (diphenylphosphine) propane of 1,3-] Nickel Chloride, [double (diphenylphosphine) ethane of 1,2-] Nickel Chloride, [1,1 '-bis- (diphenylphosphine) ferrocene] Nickel Chloride, double (isopropylcyclopentadiene) nickel, four (triphenylphosphines) One or more in nickel；
The copper catalyst be selected from cuprous iodide, cuprous bromide, stannous chloride, cuprous oxide, cupric oxide, copper chloride, copper acetate, Copper sulphate, copper nitrate, cupric acetylacetonate, trifluoromethayl sulfonic acid copper (II), trifluoromethayl sulfonic acid copper (I), tetrafluoro boric acid tetrem Cyanogen copper (I), thiophene -2-carboxylic acid are cuprous, trifluoroacetic acid copper, trifluoromethanesulfonic acid tetrem cyanogen copper, tetrafluoro boric acid copper (I), hexafluorophosphoric acid One or more in copper (I), hexafluorophosphoric acid tetrem cyanogen copper (I).
6. the preparation method according to claim 5, it is characterised in that the palladium catalyst, Raney nickel or copper catalyst Used with ligand united, the part be selected from triphenylphosphine, triethyl phosphine, tributylphosphine, tri-butyl phosphine, tricyclohexyl phosphine, Triple phenoxyl phosphine, three (o-methyl-phenyl) phosphines, three (p-methoxyphenyl) phosphines, methyldiphenyl base phosphine, dicyclohexlphenylphosphine, two Double (the hexichol of tert-butyl-phenyl phosphine, dicyclohexyl (4- dimethylaminos phenyl) phosphine, di-t-butyl (4- fluoroforms phenyl) phosphine, 1,2- Base phosphine) ethane, double (diphenylphosphine) propane of 1,3-, double (diphenylphosphine) butane of 1,4-, 1,2- double (phenylsulfinyl) ethane, 2, Double diphenyl phosphine -1,1'- the dinaphthalenes of 2'-, the double Diphenyl phosphino ferrocenes of 1,1'-, 1,1 '-bis- (di-t-butyl phosphino-) ferrocene, 1, 1 '-bis- (dicyclohexyl phosphino-) ferrocene, 1,1 '-bis- (diisopropyl phosphino-) ferrocene, 2,3-O- isopropyl alkene -2,3- dihydroxies One or more in the double diphenylphosphine butane of base -1,4-.
7. according to the preparation method any one of claim 1 to 6, it is characterised in that add alkali, described alkali choosing in reaction From potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, silver carbonate, sodium acid carbonate, phosphoric acid Potassium, sodium phosphate, potassium acetate, sodium acetate, trimethylamine, diethylamine, triethylamine, tri-n-butylamine, 4- dimethylamino pyridines, nafoxidine, Piperidines, N, N- dimethylanilines, the carbon -7- alkene of 1,8- diazabicylos [5.4.0] 11, N-methylmorpholine, N, N- diisopropyl second Amine, pyridine, 2,6- lutidines, imidazoles, N, N, N ', the one or more in N '-tetramethylethylenediamine.
8. preparation method according to any one of claim 1 to 6, it is characterised in that amino protecting group is selected from benzyl, right Methoxy-benzyl, tertbutyloxycarbonyl, methoxycarbonyl group, carbethoxyl group, allyloxycarbonyl, trifluoroacetyl group, tert-butyldimethyl silyl Base, p-toluenesulfonyl, benzyloxycarbonyl group, 9- fluorenylmethyloxycarbonyls, 2,2,2- trichloro-ethoxycarbonyls, 2- trimethyl silicon substrate ethoxy carbonyls Base, trityl, 2,4- dimethoxy-benzyls or mesyl.
9. preparation method according to any one of claim 1 to 6, it is characterised in that formula (III) formula (II) Compound is reacted in the presence of base to be obtained；
R9Selected from I, Br, Cl, OTs, OMs or OTf；
The alkali be selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, silver carbonate, Sodium acid carbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, trimethylamine, triethylamine, tri-n-butylamine, 4- dimethylamino pyridines, N, N- Dimethylaniline, the carbon -7- alkene of 1,8- diazabicylos [5.4.0] 11, N-methylmorpholine, N, N- diisopropylethylamine, 2,6- bis- Picoline, pyridine, imidazoles, N, N, N ', the one or more in N '-tetramethylethylenediamine；
Reaction dissolvent is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, formamide, dichloromethane, chloroform, N- Methyl pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, t-butyl methyl ether, isopropyl ether, acetonitrile, 1,4- dioxane, 1,2- Dimethoxy-ethane, 2-methyl cellosolve, cellosolvo, methanol, ethanol, isopropanol, the tert-butyl alcohol, ethyl acetate, acetic acid Methyl esters, isopropyl acetate, Ethyl formate, dimethyl sulfoxide, toluene, dimethylbenzene, chlorobenzene, methoxybenzene, HMPA, water In one or more combinations；
Reaction temperature is 20~80 DEG C.
10. a kind of method for preparing formula (I) compound, it is characterised in that the preparation method any one of claim 1 to 6 Obtained formula (V) compound obtains formula (I) compound by one or multi-step reaction：
11. the compound of formula (III), it is characterised in that：
R8It is selected from
R1For CN or COR2；R2Selected from H, OR5Or NR6R7；R5、R6、R7Independently selected from H or C1-12Alkyl.
12. the compound of formula (V), it is characterised in that：
R3For H or amino protecting group；
R8It is selected fromOr amino protecting group；
R1For CN or COR2；R2Selected from H, OR5Or NR6R7；R5、R6、R7Independently selected from H or C1-12Alkyl；
Work as R3、R8When being all amino protecting group, R3、R8It is each independently amino protecting group.
13. compound according to claim 12, it is characterised in that：
Amino protecting group be selected from benzyl, to methoxy-benzyl, tertbutyloxycarbonyl, methoxycarbonyl group, carbethoxyl group, allyloxycarbonyl, Trifluoroacetyl group, t-Butyldimethylsilyl, p-toluenesulfonyl, benzyloxycarbonyl group, 9- fluorenylmethyloxycarbonyls, the chloroethenes of 2,2,2- tri- Oxygen carbonyl, 2- trimethyl silicon substrates carbethoxyl group, trityl, 2,4- dimethoxy-benzyls or mesyl；
R5、R6、R7Independently selected from H or C1-6Alkyl.
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