CN103664911A - Method of preparing vilazodone and intermediate thereof - Google Patents

Method of preparing vilazodone and intermediate thereof Download PDF

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Publication number
CN103664911A
CN103664911A CN201210335254.XA CN201210335254A CN103664911A CN 103664911 A CN103664911 A CN 103664911A CN 201210335254 A CN201210335254 A CN 201210335254A CN 103664911 A CN103664911 A CN 103664911A
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palladium
phosphine
compound
chloride
methyl
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CN103664911B (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 R&D 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

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Abstract

The invention provides a method of preparing vilazodone and an intermediate thereof. The method comprises the following steps: obtaining the intermediate shown as a formula (V) through a coupling reaction; and obtaining vilazodone by reducing an acetylenic bond and removing an N protective radical for the intermediate shown as the formula (V); or further converting to obtain vilazodone. The method provided by the invention overcomes the deficiencies in existing preparation of vilazodone and the intermediate thereof. The raw material is easy to obtain, the reaction yield is high, and the method is suitable for industrialized production and has a greater application value.

Description

The method of preparing vilazodone and intermediate thereof
Technical field
The present invention relates to a kind of linked reaction by metal catalytic and prepare the method for vilazodone and intermediate thereof.
Background technology
Vilazodone (Vilazodone), chemical name 5-(4-(4-(5-cyanoindole-3-yl) butyl) piperazine-1-yl) benzofuran-2-carboxamides, its structure is suc as formula shown in (I).On January 21st, 2011, Vilazodone Hydrochloride (biibryd) sheet of Trovis company exploitation obtains U.S. FDA approval listing, is used for the treatment of adult's severe depression obstacle (MDD), is first indolyl amine novel antidepressant.This medicine is used for the treatment of or prevention of depression, anxiety disorder, bipolar disorder, manic, dull-witted, relevant with mentation material mental disorder, sexual dysfunction, eating disorder, obesity, fibromyalgia, somnopathy, psychosis sample mental disorder, cerebral infarction, anxiety, hypertension therapeutic in side effect, brain illness, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome and unwanted postpartum milk secretion.
Synthesizing in US Patent No. 5532241 and WO0072832 of vilazodone and intermediate thereof has and describes.
The following several method of open employing is prepared vilazodone both at home and abroad at present:
A) CN1106811A discloses and take 3-(4-chlorobutyl) indoles-5-formonitrile HCN and prepare vilazodone as intermediate.Route is as follows:
Figure BDA00002124307300012
3-(4-chlorobutyl) indoles-5-formonitrile HCN and 5-(piperazine-1-yl) coumarilic acid condensation, obtain 5-(4-(4-(5-cyanoindole-3-yl) butyl) piperazine-1-yl) coumarilic acid, then with 2-chloro-1-picoline mesylate and ammonia react, obtain vilazodone.
The method adopts pyridinium salt compound to carry out acylation reaction, is not suitable for a large amount of suitability for industrialized production.
B) CN1330635A and CN1140171A disclose the synthetic method of 3-(4-chlorobutyl) indoles-5-formonitrile HCN, and have synthesized vilazodone.
Figure BDA00002124307300021
Indoles-5-formonitrile HCN of take is raw material; under the catalysis of isobutyl-chlorination aluminium; carry out friedel-crafts acylation with 4-chlorobutanoylchloride; obtain 3-(4-chlorobutyryl) indoles-5-formonitrile HCN; under the catalysis of isobutyl-chlorination aluminium, adopt sodium borohydride reduction carbonyl again; obtain 3-(4-chlorobutyl) indoles-5-formonitrile HCN, then by itself and 5-(piperazine-1-yl) benzofuran-2-carboxamides condensation, obtain vilazodone.
The method all adopts isobutyl-chlorination aluminium as catalyzer at synthetic 3-(4-chlorobutyl) indoles-5-formonitrile HCN and while carrying out reduction reaction.This catalyzer is difficult to preparation, extremely unstable in air, and storage and transportation cost are high,, be not suitable for a large amount of suitability for industrialized production.
C) WO2006/114202 and CN101163698A disclose a kind of method of preparing vilazodone.
Figure BDA00002124307300022
3-(4-hydroxybutyl) indoles-5-formonitrile HCN of take is raw material, after processing through sulphur trioxide and pyridine mixture, obtain 3-(4-oxo butyl) indoles-5-formonitrile HCN, again with 5-piperazinyl benzo furans-2-formamide, and through sodium cyanoborohydride reduction amination, obtain vilazodone.
The method has adopted large, the expensive sodium cyanoborohydride of toxicity as reductive agent, is not suitable for a large amount of suitability for industrialized production.
D) WO2006/114202 and CN101163698A also disclose a kind of method of reacting synthetic vilazodone by Buchwald.
Figure BDA00002124307300031
In the method, 3-(4-piperazine butyl) indoles-5-formonitrile HCN is as intermediate, under sodium tert-butoxide exists, under three (dibenzalacetone) two palladiums and tri-tert phosphine catalyst, carry out Buchwald coupling with 5-bromine cumarone-2-methane amide, obtain vilazodone.
In the method, Buchwald reaction conditions is comparatively harsh, and reaction yield is not high, is not suitable for a large amount of suitability for industrialized production.
Summary of the invention
The invention provides a kind of linked reaction by metal catalytic and prepare the method for vilazodone and intermediate thereof.Comprise that step is as follows:
(1) formula (II) compound reacts and obtains formula (III) compound under the existence of alkali,
Figure BDA00002124307300032
(2) formula (III) compound and formula (IV) compound make formula (V) compound by linked reaction,
Figure BDA00002124307300033
(3) formula (V) compound obtains formula (I) compound vilazodone through a step or polystep reaction,
Figure BDA00002124307300041
Preferably, R 8be selected from h or amino protecting group; R 1for CN or COR 2; R 2be selected from H, OR 5or NR 6r 7; R 5, R 6, R 7independently selected from H or C 1-12alkyl; R 5, R 6, R 7more preferably independently selected from H or C 1-6alkyl;
R 9be selected from I, Br, Cl, OTs, OMs or OTf;
R 3for H or amino protecting group;
R 4be selected from I, Br, Cl or OTf;
Work as R 3, R 8while being all amino protecting group, R 3, R 8be amino protecting group independently of one another.
In step (1), preferably reaction conditions is:
Described alkali is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, cesium carbonate, Quilonum Retard, silver carbonate, sodium bicarbonate, potassiumphosphate, sodium phosphate, Potassium ethanoate, sodium-acetate, Trimethylamine 99, triethylamine, Tributylamine, 4-dimethylamino pyridine, N, N-xylidene(s), 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, N-methylmorpholine, N, N-diisopropylethylamine, pyridine, 2,6-lutidine, imidazoles, N, N, N ', one or more in N '-Tetramethyl Ethylene Diamine etc.;
Reaction solvent is selected from N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, methane amide, methylene dichloride, trichloromethane, N-Methyl pyrrolidone, tetrahydrofuran (THF), methyltetrahydrofuran, t-butyl methyl ether, isopropyl ether, acetonitrile, 1, 4-dioxane, 1, 2-glycol dimethyl ether, 2-methyl cellosolve, cellosolvo, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, ethyl acetate, methyl acetate, isopropyl acetate, ethyl formate, methyl-sulphoxide, toluene, dimethylbenzene, chlorobenzene, anisole, HMPA, the combination of one or more in water etc.,
Temperature of reaction is 20～80 ℃.
In step (2), preferably reaction conditions is:
Under catalyst action, there is linked reaction in formula (III) compound and formula (IV) compound;
The mol ratio of formula (III) compound and formula (IV) compound is 1: 3～3: 1, is further preferably 1: 2～2: 1, then is preferably further 1: 1.3～1.3: 1;
Temperature of reaction is 20～150 ℃, is preferably further 30～130 ℃, then is preferably further 40～120 ℃;
Reaction times is 1h～96h; Be preferably further 2h～48h;
The solvent using in reaction is selected from N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, methane amide, methylene dichloride, trichloromethane, N-Methyl pyrrolidone, tetrahydrofuran (THF), methyltetrahydrofuran, t-butyl methyl ether, isopropyl ether, acetonitrile, 1, 4-dioxane, 1, 2-glycol dimethyl ether, 2-methyl cellosolve, cellosolvo, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, ethyl acetate, methyl acetate, isopropyl acetate, ethyl formate, acetone, butanone, methyl butyl ketone, methyl iso-butyl ketone (MIBK), methyl-sulphoxide, toluene, dimethylbenzene, chlorobenzene, anisole, HMPA, diethylamine, triethylamine, the combination of one or more in water etc.
At catalyzer described in step (2) preferably from palladium catalyst, nickel catalyzator, copper catalyst, cobalt catalyst, platinum catalyst, rhodium catalyst, iridium catalyst, ruthenium catalyst, iron catalyst; Further preferably from palladium catalyst, nickel catalyzator or copper catalyst; When catalyzer is non-copper catalyst, can add copper catalyst as promotor.
Described palladium catalyst is selected from palladium, propionic acid palladium, palladous oxide, Palladous nitrate, palladous sulfate, palladium trifluoroacetate, palladium acetylacetonate, PIVALIC ACID CRUDE (25) palladium, palladium chloride, dibrominated palladium, palladium diiodide, dichloro four ammino palladiums, acetic acid four ammino palladiums, palladium hydroxide, palladium charcoal, tetrakis triphenylphosphine palladium, three (dibenzalacetone) two palladiums, (1,1 '-bis-Diphenyl phosphino ferrocenes) palladium chloride, two (triphenylphosphine) palladium chloride, two (tricyclohexyl phosphine) palladium chloride, two (tri-butyl phosphine) palladium, (two (diphenylphosphine) propane of 1,3-) palladium chloride, (1,5-cyclooctadiene) palladium chloride, (2,2 '-dipyridyl) palladium chloride, two (diphenylphosphine) ethane palladium chlorides of 1,2-, Isosorbide-5-Nitrae-bis-(diphenylphosphine) butane palladium chloride, two (triphenylphosphine) palladium, quadrol palladium chloride, two (cyano group benzene) palladium chloride, two (phenylsulfinyl) ethane palladium diacetates of 1,2-, (1,10-phenanthroline) palladium chloride, two (three-o-toluene phosphine) palladium chloride, hexafluoroacetylacetone palladium, two [two (diphenylphosphino) ethane of 1,2-] palladium, two [three (2-tolyl) phosphine] palladium, two (triethyl phosphine) palladium chloride, two (acetonitrile) palladium chloride, two (dibenzalacetone) palladium, two (methyldiphenyl base phosphine) palladium chloride, four (acetonitrile) Tetrafluoroboric acid palladium, (dicyclo [2.2.1] heptan-2,5-diene) dichloro palladium, 1,1 '-bis-(di-t-butyl phosphino-) ferrocene palladium chloride, 1,1 '-bis-(dicyclohexyl phosphino-) ferrocene palladium chloride, 1,1 '-bis-(di-isopropyl phosphino-) ferrocene palladium chloride, (N,N,N′,N′ tetramethylethylene diamine) palladium chloride, two [dicyclohexyl (4-dimethylamino phenyl) phosphine] palladium chloride, two [di-t-butyl (4-fluoroform phenyl) phosphine] palladium chloride, tetrachloro closes palladium acid sodium, one or more in palladium charcoal.
Described nickel catalyzator is selected from two (triphenylphosphine) Nickel Chlorides, Nickel Chloride, dichloro two (tributylphosphine) nickel, two (trimethyl-phosphine) Nickel Chloride, two (tributylphosphine) Nickel Bromide, two (tricyclohexyl phosphine) Nickel Chloride, two (triphenylphosphine) Nickel Bromide, two (triphenylphosphine) dicarbapentaborane nickel, [1, two (diphenylphosphine) propane of 3-] Nickel Chloride, [1, two (diphenylphosphine) ethane of 2-] Nickel Chloride, [1, 1 '-bis-(diphenylphosphine) ferrocene] Nickel Chloride, two (sec.-propyl cyclopentadiene) nickel, one or more in four (triphenylphosphine) nickel.
Described copper catalyst is selected from that cuprous iodide, cuprous bromide, cuprous chloride, Red copper oxide, cupric oxide, cupric chloride, neutralized verdigris, copper sulfate, cupric nitrate, cupric acetylacetonate, trifluoromethayl sulfonic acid copper (II), trifluoromethayl sulfonic acid copper (I), Tetrafluoroboric acid tetrem cyanogen copper (I), thiophene-2-carboxylic acid are cuprous, one or more in trifluoroacetic acid copper, trifluoromethanesulfonic acid tetrem cyanogen copper, Tetrafluoroboric acid copper (I), phosphofluoric acid copper (I), phosphofluoric acid tetrem cyanogen copper (I).
Described palladium catalyst, nickel catalyzator and copper catalyst can also with ligand united use, described part is selected from triphenylphosphine, triethyl phosphine, tributylphosphine, tri-butyl phosphine, tricyclohexyl phosphine, triple phenoxyl phosphine, three (o-methyl-phenyl-) phosphine, three (p-methoxyphenyl) phosphine, methyldiphenyl base phosphine, dicyclohexyl Phenylphosphine, di-tert-butyl-phenyl phosphine, dicyclohexyl (4-dimethylamino phenyl) phosphine, di-t-butyl (4-fluoroform phenyl) phosphine, 1, two (diphenylphosphine) ethane of 2-, 1, two (diphenylphosphine) propane of 3-, 1, two (diphenylphosphine) butane of 4-, 1, two (phenylsulfinyl) ethane of 2-, 2, 2 '-bis-diphenyl phosphine-1, 1 '-dinaphthalene, 1, 1 '-bis-Diphenyl phosphino ferrocenes, 1, 1 '-bis-(di-t-butyl phosphino-) ferrocene, 1, 1 '-bis-(dicyclohexyl phosphino-) ferrocene, 1, 1 '-bis-(di-isopropyl phosphino-) ferrocene, 2, 3-O-isopropyl alkene-2, 3-dihydroxyl-1, one or more in the two diphenylphosphine butane of 4-.
In step (2), can also add alkali, described alkali is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, cesium carbonate, Quilonum Retard, silver carbonate, sodium bicarbonate, potassiumphosphate, sodium phosphate, Potassium ethanoate, sodium-acetate, Trimethylamine 99, diethylamine, triethylamine, Tributylamine, 4-dimethylamino pyridine, Pyrrolidine, piperidines, N, N-xylidene(s), 1, 8-diazabicylo [5.4.0] 11 carbon-7-alkene, N-methylmorpholine, N, N-diisopropylethylamine, pyridine, 2, 6-lutidine, imidazoles, N, N, N ', one or more in N '-Tetramethyl Ethylene Diamine etc.
In step (3):
Work as R 3, R 8during for H, formula (V) compound obtains through hydro-reduction
Figure BDA00002124307300061
after, can make vilazodone according to prior art;
Work as R 3for H, R 8during for amino protecting group, can obtain by hydro-reduction, Deprotection after, can make vilazodone according to prior art;
Work as R 3for H, R 8for time, R 1for COR 2, R 2for NR 6r 7, R 6, R 7during for H, formula (V) compound can make vilazodone through hydro-reduction;
Work as R 3for H, R 8for
Figure BDA00002124307300071
time, R 1for CN or COR 2; R 2be selected from H, OR 5or NR 6r 7; R 5, R 6, R 7independently selected from H or C 1-12alkyl, and R 6, R 7while being hydrogen when different, formula (V) compound is through hydro-reduction, by R 1be transformed into CONH 2can make vilazodone, by R 1be transformed into CONH 2vilazodone can be made and existing techniques in realizing can be passed through;
Work as R 3for amino protecting group, R 8during for H, formula (V) compound obtains through Deprotection, hydro-reduction after, can make vilazodone according to prior art;
Work as R 3for amino protecting group, R 8for
Figure BDA00002124307300073
time, R 1for COR 2, R 2for NR 6r 7, R 6, R 7during for H, formula (V) compound can make vilazodone through hydro-reduction, Deprotection;
Work as R 3, R 8while being all amino protecting group, can obtain by Deprotection, hydrogenation after, according to prior art, prepare vilazodone; Or prepare vilazodone according to method in embodiment 4; Work as R 3for amino protecting group, R 8for
Figure BDA00002124307300075
time, R 1for COR 2, R 2for NR 6r 7, R 6, R 7during for H, formula (V) compound can make vilazodone through hydro-reduction, Deprotection;
Work as R 3for amino protecting group, R 8for
Figure BDA00002124307300076
time, R 1for CN or COR 2; R 2be selected from H, OR 5or NR 6r 7; R 5, R 6, R 7independently selected from H or C 1-12alkyl, and R 6, R 7while being hydrogen when different, formula (V) compound is through hydro-reduction, Deprotection, by R 1be transformed into CONH 2can make vilazodone, by R 1be transformed into CONH 2vilazodone can be made and existing techniques in realizing can be passed through.
The invention still further relates to the compound of new intermediate formula (III) and the compound of formula (V) of preparing vilazodone.
The compound of formula (III), is characterized in that:
Figure BDA00002124307300081
R 8be selected from
Figure BDA00002124307300082
h or amino protecting group;
R 1for CN or COR 2; R 2be selected from H, OR 5or NR 6r 7; R 5, R 6, R 7independently selected from H or C 1-12alkyl.
The compound of formula (V), is characterized in that:
Figure BDA00002124307300083
R 3for H or amino protecting group;
R 8be selected from
Figure BDA00002124307300084
h or amino protecting group;
R 1for CN or COR 2; R 2be selected from H, OR 5or NR 6r 7; R 5, R 6, R 7independently selected from H or C 1-12alkyl; R 5, R 6, R 7more preferably independently selected from H or C 1-6alkyl;
Work as R 3, R 8while being all amino protecting group, R 3, R 8be amino protecting group independently of one another.
Term in the present invention, except special instruction, generally has following implication.
Protecting group is a concept in organic synthesis, is to make particular functional group in organic molecule that the reaction of wishing occur, and suppresses the reaction of other functional groups simultaneously and by particular agent, a part of functional group is reversibly changed into the strategy of inertia group.
" amino protecting group " normally known and to refer to that such group, this group are suitable for protection amino, make amino not carry out chemical reaction, but this group is easily removed after other parts of molecule complete required chemical reaction.Because amino protecting group is removed after required reaction, thus its size and character be not critical.
Protecting group > > in < < organic synthesis (translate, Rong Guobin school, press of East China University of Science, 2004 by organic chemistry teaching and research room of East China University of Science; Former book is Protective Groups in Organic Synthesis (third edition), Theodora W.Greene and Peter G.M.Wuts work) in protection one chapter of amido amido protecting group has been done to detailed introduction.This specification sheets is quoted the part as this specification sheets using 494-653 page in the protecting group > > in < < organic synthesis.
" amino protecting group " includes but not limited to following group:
1)
Figure BDA00002124307300091
r wherein a1include but not limited to: methyl, 9-fluorene methyl, 9-(2-sulfo-) fluorene methyl, 9-(2,7-, bis-bromos) fluorene methyl, 17-tetra-benzos [a, c, g, i] fluorene methyl, the chloro-3-indenes of 2-methyl, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrochysene sulfo-xanthene) methyl, 1,1-dioxo benzo [b] thiophene-2-methyl, ethyl, 2,2,2-, tri-chloroethyls, 2-trimethylsilyl ethyl, 2-styroyl, 1-(1-adamantyl)-1-methylethyl, 2-chloroethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-bis-bromotrifluoromethanes, 1,1-dimethyl-2,2,2-, tri-chloroethyls, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-(3,5-di-tert-butyl-phenyl)-1-methylethyl, 2-(2 '-and 4 ' pyridyl) ethyl, two (4 '-nitrophenyl) ethyls of 2,2-, N-(2-pivalyl amido)-1,1-dimethyl ethyl, 2-[(2-nitrophenyl) dithio]-1-styroyl, 2-(N, N-dicyclohexyl carbonamido) ethyl, the tertiary butyl, 1-adamantyl, 2-adamantyl, vinyl, allyl group, 1-sec.-propyl allyl group, cinnamyl, 4-nitro cinnamyl, 3-(3 '-pyridyl) allyl group, 8-quinolyl, N-hydroxy piperidine base, alkyl dithio, benzyl, to methoxy-benzyl, to nitrobenzyl, to bromobenzyl, p-chlorobenzyl, 2,4-dichloro benzyl, 4-methylsulfinyl benzyl, 9-anthryl methyl, diphenyl methyl, 2-methyl thio-ethyl, 2-methyl sulphonyl ethyl, 2-(p-toluenesulfonyl) ethyl, [2-(1,3 dithia cyclohexyl)] methyl, 4-methyl thio-phenyl, 2,4-dimethyl thio-phenyl, 2-phosphorus base ethyl, 1-methyl isophthalic acid-(triphenyl phosphorus) ethyl, 1,1-dimethyl-2-cyanoethyl, 2-dansyl ethyl, 2-(4-nitrophenyl) ethyl, 4-phenylacetyl oxygen benzyl, 4-azido-benzyl, 4-nitrine methoxy-benzyl, m-chloro is to acyl-oxygen benzyl, p-(dihydroxyl boryl) benzyl, 5-benzisoxa oxazole methyl, 2-(trifluoromethyl)-6-chromone methyl, m-nitro base, 3,5-dimethoxy-benzyl, 1-methyl isophthalic acid-(3,5-dimethoxy phenyl) ethyl, Alpha-Methyl nitro piperonyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, adjacent nitrobenzyl methyl, 2-(2-nitrophenyl) ethyl, 6-nitro-3,4-dimethyl benzyl, 4-methoxybenzoyl methyl, 3 '-5 '-dimethoxy bitter almond oil camphor, tert-pentyl, butynyl, to cyano group benzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl methyl, to oxy-benzyl in the last of the ten Heavenly stems, di-isopropyl methyl, 2,2-dimethoxycarbonyl vinyl, o-(N ', N '-dimethylformamide base) benzyl, 1,1-dimethyl-3-(N ', N '-dimethylformamide base) propyl group, 1,1-alkynyl dimethyl, two (2-pyridyl) methyl, furfuryl, 2-iodine ethyl, isobornyl, isobutyl-, different nicotinoyl, p-(to anisole azo-group) benzyl, 1-methyl cyclobutyl, 1-methylcyclohexyl, 1-methyl isophthalic acid-cyclopropyl methyl, 1-methyl isophthalic acid-(to benzeneazo phenyl) ethyl, 1-methyl isophthalic acid-phenylethyl, 1-methyl isophthalic acid-(4 '-pyridyl) ethyl, phenyl, to phenylazo-benzyl, 2,4,6-tri-tert benzyl, 4-(Trimethylamine 99) benzyl, 2,4,6-trimethyl benzyl, 2,4-dimethyl-3-amyl group,
2) -C (O) NHSO 2c 6h 4-p-CH 3,-C (S) NHC 6h 5or
Figure BDA00002124307300102
(CH 3cH 2) 2nC (O)-;
3) carboxyl groups, includes but not limited to: formyl radical, ethanoyl, chloracetyl, tribromo-acetyl base, trifluoroacetyl group, phenylacetyl, 3-hydrocinnamoyl, 4-pentenoyl, 2-pyridine acyl, 3-pyridine acyl ,-C (O) CH (NHCOC 6h 5) CH 2c 6h 5, benzoyl, to toluene benzoyl, ortho-nitrophenyl ethanoyl, ortho-nitrophenyl oxygen ethanoyl, 3-O-Nitrophenylfluorone propionyl, 2-methyl-2-ortho-nitrophenyl oxygen base propionyl, 3-methyl-3-nitro butyryl radicals, adjacent nitro cinnamoyl, o-nitrobenzoyl, 2, 2-dimethyl-3-(the 4-tertiary butyl-2, 6-dinitrophenyl) propionyl, adjacent (benzoyl yloxymethyl) benzoyl, (2-acetyl-o-methyl) benzoyl, 2-[(tert-butyl diphenyl siloxy) methyl] benzoyl, 3-(2 ', 4 ', 5 '-trimethylammonium-3 ', 6 '-dioxy-1 ', 4 '-cyclohexadienyl)-3, 3-dimethyl propylene acyl group, adjacent hydroxyl-trans-cinnamoyl, the adjacent benzeneazo phenoxy group of 2-methyl-2-propionyl, 4-chlorobutyryl, acetoacetyl, 3-p-hydroxybenzene propionyl, (N '-dithio carbobenzoxy-(Cbz) amido) ethanoyl, dichloro-acetyl, valeryl,
4) methyl, the tertiary butyl, allyl group, [2-(trimethyl silicon based) oxyethyl group] methyl, 3-acetoxyl group propyl group, cyano methyl, 1-sec.-propyl-4-nitro-2-oxo-3-pyrrolinyl, 2,4-dimethoxy-benzyl, 2-azepine norbornene, 2,4-dinitrophenyl, benzyl, 4-methoxy-benzyl, 2,4-dimethoxy-benzyl, 2-hydroxybenzyl, diphenyl methyl, two (4-p-methoxy-phenyl) methyl, 5-dibenzo suberyl, trityl group, (4-p-methoxy-phenyl) diphenyl-methyl, 9-phenyl fluorenyl, ferrocenyl methyl, vinyl, 2-chloroethyl, (1-oxyethyl group) ethyl, 2-(2 '-pyridyl) ethyl, 2-(4 '-pyridyl) ethyl, 2-(4-nitrophenyl) ethyl, 3,4-dimethoxy-benzyl, 3-methoxy-benzyl, 3,5-dimethoxy-benzyl, 2-dinitrophenyl, 4-dinitrophenyl, phenacyl, trityl, diphenyl-methyl, (phenylbenzene-4-picolyl), hydroxymethyl, methoxymethyl, diethoxymethyl, ethoxyl methyl, [2-(trimethyl silicon based) oxyethyl group] methyl, tertiary butyl methyl, tertiary butyl dimethyl Si ylmethyl, oxy acid methyl neopentyl, benzyloxymethyl, N, N dimethylamine ylmethyl, 2-THP trtrahydropyranyl,
5) (5,5-dimethyl-3-oxo-1-cyclohexenyl), 2, the chloro-9-fluorenyl of 7-bis-methylene radical, 2-(4,4-dimethyl-2,6-dioxo cyclohexyl subunit) ethyl, 4, the fluoro-3-oxo-1-butylene of 4-tri-base, 1-sec.-propyl-4-nitro-2-oxo-3-pyrrolinyl;
6) Ph 2p (O)-, (CH 3) 2p (S)-, Ph 2p (S)-, (R a2o) 2p (O)-, (BnO) 2p (O)-, (PhO) 2p (O)-, be R a2for alkyl, preferred C 1-C 12alkyl;
7) t-Butyldimethylsilyl, trimethyl silicon based, triisopropylsilyl, triethyl is silica-based, tert-butyl diphenyl is silica-based;
8) phenyl sulfinyl, O-Nitrophenylfluorone sulfinyl, 2,4-dinitrobenzene sulfinyl, pentachlorobenzene sulfinyl, 2-nitro-4-anisole sulfinyl, trityl sulfinyl, 1-(2,2,2-tri-is fluoro-1,1-phenylbenzene) ethyl sulfinyl, 3-nitro-2-pyridine sulfinyl;
9) p-toluenesulfonyl, benzenesulfonyl, 2, 3, 6-trimethylammonium-4-anisole alkylsulfonyl, 2, 4, 6-trimethoxy benzenesulfonyl, 2, 6-dimethyl-4-anisole alkylsulfonyl, pentamethylbenzene alkylsulfonyl, 2, 3, 5, 6-tetramethyl--4-anisole alkylsulfonyl, 4-anisole alkylsulfonyl, 2, 4, 6-Three methyl Benzene alkylsulfonyl, 2, 6-dimethoxy-4 '-Methyl benzenesulfonyl base, 3-methoxyl group-4-tert.-butylbenzene alkylsulfonyl, 2, 2, 5, 7, 8-pentamethyl-benzo dihydropyrane-6-alkylsulfonyl, 2--oil of mirbane alkylsulfonyl, 4-oil of mirbane alkylsulfonyl, 2, 4-dinitrobenzene sulphur-oil of mirbane alkylsulfonyl, benzothiazole 2-alkylsulfonyl, pyridine-2-sulfuryl base, methylsulfonyl, 2-(trimethylsilyl) ethylsulfonyl, 9-anthracene alkylsulfonyl, 4-(4 ', 8 '-dimethoxy menaphthyl) benzenesulfonyl, benzyl alkylsulfonyl, trifluoromethyl sulfonyl, phenacyl alkylsulfonyl, tertiary butyl alkylsulfonyl, N, N-dimethyl methyl acyl group.
Amino protecting group further preferably from benzyl, to methoxy-benzyl, tertbutyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl, trifluoroacetyl group, t-Butyldimethylsilyl, p-toluenesulfonyl, carbobenzoxy-(Cbz), 9-fluorenylmethyloxycarbonyl, 2; 2; 2-trichloro-ethoxycarbonyl, the trimethyl silicon based ethoxycarbonyl of 2-, trityl, 2,4-dimethoxy-benzyl, methylsulfonyl.Again further preferably from benzyl, to methoxy-benzyl, tertbutyloxycarbonyl, t-Butyldimethylsilyl, p-toluenesulfonyl.
In the present invention, except special instruction, writing a Chinese character in simplified form of term has following implication:
Figure BDA00002124307300111
Figure BDA00002124307300121
Term in the present invention, except special instruction, generally has following implication.
Term " alkyl " expression has the straight or branched saturated hydrocarbyl of the carbon atom of described number.The specific examples of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl etc.Term " C 1-C 12alkyl " refer to the straight or branched saturated hydrocarbyl with 1-12 carbon atom.Term " C 1-C 6alkyl " refer to the straight or branched saturated hydrocarbyl with 1-6 carbon atom.
Term " halogen " is fluorine, chlorine, bromine or iodine.
In the present invention, palladium catalyst can be selected from palladium, propionic acid palladium, palladous oxide, Palladous nitrate, palladous sulfate, palladium trifluoroacetate, palladium acetylacetonate, PIVALIC ACID CRUDE (25) palladium, palladium chloride, dibrominated palladium, palladium diiodide, dichloro four ammino palladiums, acetic acid four ammino palladiums, palladium hydroxide, palladium charcoal, tetrakis triphenylphosphine palladium, three (dibenzalacetone) two palladiums, (1,1 '-bis-Diphenyl phosphino ferrocenes) palladium chloride, two (triphenylphosphine) palladium chloride, two (tricyclohexyl phosphine) palladium chloride, two (tri-butyl phosphine) palladium, (two (diphenylphosphine) propane of 1,3-) palladium chloride, (1,5-cyclooctadiene) palladium chloride, (2,2 '-dipyridyl) palladium chloride, two (diphenylphosphine) ethane palladium chlorides of 1,2-, Isosorbide-5-Nitrae-bis-(diphenylphosphine) butane palladium chloride, two (triphenylphosphine) palladium, quadrol palladium chloride, two (cyano group benzene) palladium chloride, two (phenylsulfinyl) ethane palladium diacetates of 1,2-, (1,10-phenanthroline) palladium chloride, two (three-o-toluene phosphine) palladium chloride, hexafluoroacetylacetone palladium, two [two (diphenylphosphino) ethane of 1,2-] palladium, two [three (2-tolyl) phosphine] palladium, two (triethyl phosphine) palladium chloride, two (acetonitrile) palladium chloride, two (dibenzalacetone) palladium, two (methyldiphenyl base phosphine) palladium chloride, four (acetonitrile) Tetrafluoroboric acid palladium, (dicyclo [2.2.1] heptan-2,5-diene) dichloro palladium, 1,1 '-bis-(di-t-butyl phosphino-) ferrocene palladium chloride, 1,1 '-bis-(dicyclohexyl phosphino-) ferrocene palladium chloride, 1,1 '-bis-(di-isopropyl phosphino-) ferrocene palladium chloride, (N,N,N′,N′ tetramethylethylene diamine) palladium chloride, two [dicyclohexyl (4-dimethylamino phenyl) phosphine] palladium chloride, one or more in two [di-t-butyl (4-fluoroform phenyl) phosphine] palladium chloride.Described palladium catalyst can also with ligand united use, described part is selected from triphenylphosphine, triethyl phosphine, tributylphosphine, tri-butyl phosphine, tricyclohexyl phosphine, triple phenoxyl phosphine, three (o-methyl-phenyl-) phosphine, three (p-methoxyphenyl) phosphine, methyldiphenyl base phosphine, dicyclohexyl Phenylphosphine, di-tert-butyl-phenyl phosphine, dicyclohexyl (4-dimethylamino phenyl) phosphine, di-t-butyl (4-fluoroform phenyl) phosphine, 1, two (diphenylphosphine) ethane of 2-, 1, two (diphenylphosphine) propane of 3-, 1, two (diphenylphosphine) butane of 4-, 1, two (phenylsulfinyl) ethane of 2-, 2, two diphenyl phosphine-1 of 2'-, 1 '-dinaphthalene, 1, 1 '-bis-Diphenyl phosphino ferrocenes, 1, 1 '-bis-(di-t-butyl phosphino-) ferrocene, 1, 1 '-bis-(dicyclohexyl phosphino-) ferrocene, 1, 1 '-bis-(di-isopropyl phosphino-) ferrocene, 2, 3-O-isopropyl alkene-2, 3-dihydroxyl-1, the two diphenylphosphine butane of 4-, tetrachloro closes palladium acid sodium, one or more in palladium charcoal.
In the present invention, non-palladium catalyst is selected from nickel catalyzator, copper catalyst, cobalt catalyst, platinum catalyst, rhodium catalyst, iridium catalyst, ruthenium catalyst, iron catalyst; Preferably from nickel catalyzator, cobalt catalyst.Described nickel catalyzator is selected from two (triphenylphosphine) Nickel Chlorides, Nickel Chloride, two (tributylphosphine) Nickel Chloride, dichloro two (trimethyl-phosphine) nickel, two (tributylphosphine) Nickel Bromide, two (tricyclohexyl phosphine) Nickel Chloride, two (triphenylphosphine) Nickel Bromide, two (triphenylphosphine) dicarbapentaborane nickel, [1, two (diphenylphosphine) propane of 3-] Nickel Chloride, [1, two (diphenylphosphine) ethane of 2-] Nickel Chloride, [1, 1 '-bis-(diphenylphosphine) ferrocene] Nickel Chloride, two (sec.-propyl cyclopentadiene) nickel, one or more in four (triphenylphosphine) nickel.Described copper catalyst is selected from that cuprous iodide, cuprous bromide, cuprous chloride, Red copper oxide, cupric oxide, cupric chloride, neutralized verdigris, copper sulfate, cupric nitrate, cupric acetylacetonate, trifluoromethayl sulfonic acid copper (II), trifluoromethayl sulfonic acid copper (I), Tetrafluoroboric acid tetrem cyanogen copper (I), thiophene-2-carboxylic acid are cuprous, one or more in trifluoroacetic acid copper, trifluoromethanesulfonic acid tetrem cyanogen copper, Tetrafluoroboric acid copper (I), phosphofluoric acid copper (I), phosphofluoric acid tetrem cyanogen copper (I).Described nickel catalyzator and copper catalyst can also with ligand united use, described part is selected from triphenylphosphine, triethyl phosphine, tributylphosphine, tri-butyl phosphine, tricyclohexyl phosphine, triple phenoxyl phosphine, three (o-methyl-phenyl-) phosphine, three (p-methoxyphenyl) phosphine, methyldiphenyl base phosphine, dicyclohexyl Phenylphosphine, di-tert-butyl-phenyl phosphine, dicyclohexyl (4-dimethylamino phenyl) phosphine, di-t-butyl (4-fluoroform phenyl) phosphine, 1, two (diphenylphosphine) ethane of 2-, 1, two (diphenylphosphine) propane of 3-, 1, two (diphenylphosphine) butane of 4-, 1, two (phenylsulfinyl) ethane of 2-, 2, 2 '-bis-diphenyl phosphine-1, 1 '-dinaphthalene, 1, 1 '-bis-Diphenyl phosphino ferrocenes, 1, 1 '-bis-(di-t-butyl phosphino-) ferrocene, 1, 1 '-bis-(dicyclohexyl phosphino-) ferrocene, 1, 1 '-bis-(di-isopropyl phosphino-) ferrocene, 2, 3-O-isopropyl alkene-2, 3-dihydroxyl-1, one or more in the two diphenylphosphine butane of 4-.
The present invention provides a kind of effective preparation method for vilazodone.
In the mode of embodiment, the present invention is further illustrated more below, provides implementation detail of the present invention, but be not to be intended to limit protection scope of the present invention.
Specific embodiment mode
Embodiment 1:
Figure BDA00002124307300141
(1) preparation of 5-(4-(3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides
In reaction flask, add 5-(piperazine-1-yl) benzofuran-2-carboxamides 24.5g (100mmol), sodium phosphate dodecahydrate 57.1g (150mmol), 500ml tetrahydrofuran (THF), 125ml water, under normal temperature, drip the bromo-ethyl acetylene 33.0g of 4-(250mmol), be then heated to 65 ℃ and stir 18h.Stop heating, and divide to fall while hot water layer.By organic phase evaporated under reduced pressure, 500ml alcohol at normal temperature making beating for solid, filtered and obtains yellow solid 25.6g, yield 86.2% after two hours.MS-ESI[M+H] +：298
1H?NMR:(400MHz,d 6-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) preparation of 3-(4-(4-(2-carbamyl cumarone-5-yl) piperazine-1-yl)-ethyl acetylene base)-5-cyanoindole-1-t-butyl formate
In reaction flask, add 5-(4-(3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides 25.6g (86.1mmol); 5-cyano group-3-iodine indoles-1-t-butyl formate 28.8g (78.2mmol); (1; 1 '-bis-(Diphenyl phosphino ferrocene) palladium chloride 1.2g (1.6mmol); cuprous iodide 1.5g (7.8mmol) and methylene dichloride 600ml, stir 6h be heated to 40 ℃ after argon replaces three times under argon shield.Stop heating, cool to room temperature, filters, and filtrate is added to 300ml saturated aqueous common salt and 100ml ammoniacal liquor, and after extraction, separatory is removed water layer.Organic layer is removed under reduced pressure, and the mixing solutions making beating of 300ml acetonitrile and 300ml water for solid, filtered after one hour, and filtration cakes torrefaction, obtains yellow solid 33.6g, yield 80.0%.MS-ESI[M+H] +：538
1H?NMR:(400MHz,d 6-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) preparation of 3-(4-(4-(2-carbamyl cumarone-5-yl) piperazine-1-yl) butyl)-5-cyanoindole-1-t-butyl formate
In reaction flask, add 3-(4-(4-(2-carbamyl cumarone-5-yl) piperazine-1-yl)-ethyl acetylene base)-5-cyanoindole-1-t-butyl formate 33.6g (62.6mmol); 3.4g 10% palladium carbon (moisture approximately 50%); with 200ml tetrahydrofuran (THF), dissolve, with hydrogen exchange, lead to afterwards hydrogen stirring at normal temperature 24h three times.Filter, filtrate decompression is concentrated, and ethanol making beating obtains faint yellow solid 29.3g, yield 86.2%.
MS-ESI[M+H] +：542
1H?NMR:(400MHz,d 6-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-yl) butyl) piperazine-1-yl) benzofuran-2-carboxamides adds 3-(4-(4-(2-carbamyl cumarone-5-yl) piperazine-1-yl) butyl)-5-cyanoindole-1-t-butyl formate 29.3g in reaction flask; use 200ml dissolve with methanol; splash into 3ml concentrated hydrochloric acid; stirring at normal temperature 12h, adds K 2cO 3to neutral.Filter, concentrated, column chromatography obtains light yellow crystal 19.3g, yield 81.1%.
MS-ESI[M+H] +：442
1H?NMR:(400MHz,d 6-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:
Figure BDA00002124307300161
(1) preparation of 5-(4-(3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides
In reaction flask, add 5-(piperazine-1-yl) benzofuran-2-carboxamides 24.5g (100mmol), sodium carbonate 27.6g (200mmol), 300ml tetrahydrofuran (THF), 200ml water, under normal temperature, drip the iodo-ethyl acetylene 36.0g of 4-(200mmol), be then heated to 65 ℃ and stir 18h.Stop heating, and divide to fall while hot water layer.By organic phase evaporated under reduced pressure, 500ml alcohol at normal temperature making beating for solid, filtered and obtains yellow solid 24.2g, yield 81.5% after two hours.
(2) preparation of 5-(4-(4-(1-benzyl-5-cyanoindole-3-yl)-3-fourth-alkynyl) piperazine-1-yl) benzofuran-2-carboxamides
In reaction flask, add 5-(4-(3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides 24.2g (81.5mmol); 1-benzyl-3-iodine indoles-5-formonitrile HCN 29.2g (81.5mmol); (1; 1 '-bis-(Diphenyl phosphino ferrocene) palladium chloride 1.2g (1.6mmol); cuprous iodide 1.5g (7.8mmol) and methylene dichloride 600ml, stir 6h be heated to 40 ℃ after argon replaces three times under argon shield.Stop heating, cool to room temperature, filters, and filtrate is added to 300ml saturated aqueous common salt and 100ml ammoniacal liquor, and after extraction, separatory is removed water layer.Organic layer is removed under reduced pressure, and the mixing solutions making beating of 300ml acetonitrile and 300ml water for solid, 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-yl) butyl) piperazine-1-yl) benzofuran-2-carboxamides
In reaction flask, add 5-(4-(4-(1-benzyl-5-cyanoindole-3-yl)-3-fourth-alkynyl) piperazine-1-yl) benzofuran-2-carboxamides 37.3g (70.8mmol), 3.7g 10% palladium carbon (moisture approximately 50%), with 200ml tetrahydrofuran (THF), dissolve, with hydrogen exchange, lead to afterwards hydrogen stirring at normal temperature 24h three times.Filter, filtrate decompression is concentrated, and ethanol making beating obtains faint yellow solid 24.3g, yield 77.9%.
Embodiment 3:
(1) preparation of 5-(4-(3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides
In reaction flask, add 5-(piperazine-1-yl) benzofuran-2-carboxamides 24.5g (100mmol), triethylamine 30.3g (300mmol), 300ml tetrahydrofuran (THF), 100ml water, under normal temperature, drip the iodo-ethyl acetylene 45.0g of 4-(250mmol), be then heated to 80 ℃ and stir 12h.Stop heating, and divide to fall while hot water layer.By organic phase evaporated under reduced pressure, 500ml alcohol at normal temperature making beating for solid, filtered and obtains yellow solid 22.9g, yield 77.1% after one hour.
(2) preparation of 5-(4-(4-(5-cyano group-1-(4-methoxy-benzyl) indol-3-yl)-3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides
In reaction flask, add 5-(4-(3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides 22.9g (77.1mmol), 1-(4-methoxy-benzyl)-3-bromo indole-5-formonitrile HCN 30.6g (90mmol), palladium 0.224g (1mmol), triphenylphosphine 0.78g (3mmol), cuprous iodide 0.75g (3.9mmol) and tetrahydrofuran (THF) 400ml, be heated to 65 ℃ and stir 6h.Stop heating, cool to room temperature, filters, and the concentrated rear making beating of the mixing solutions with 300ml acetonitrile and 100ml ammoniacal liquor, filtered after one hour, and 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-yl) butyl) piperazine-1-yl) benzofuran-2-carboxamides
In reaction flask, add 5-(4-(4-(5-cyano group-1-(4-methoxy-benzyl) indol-3-yl)-3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides 33.9g (60.8mmol), 3.4g 10% palladium carbon (moisture approximately 50%), use 200ml dissolve with methanol, with hydrogen exchange, lead to afterwards hydrogen stirring at normal temperature 24h three times.Filter, filtrate decompression is concentrated, and ethanol making beating obtains faint yellow solid 21.2g, yield 79.1%.
Embodiment 4:
Figure BDA00002124307300181
(1) preparation of 4-(3-butynyl) piperazine-1-t-butyl formate
In reaction flask, add piperazine-1-t-butyl formate 18.6g (100mmol), Potassium ethanoate 28.2g (300mmol), with toluene 500ml, under normal temperature, drip 4-toluene sulfonic acide fourth-3-alkynes ester 22.4g (100mmol), be then heated to 80 ℃ and stir 36h.Stop heating, cool to room temperature, filters, and filtrate is added in 800ml ethyl acetate, stirs after 1h, filters, dry, obtains brown color solid 20.6g, yield 86.6%.
MS-ESI(M+1)：239
(2) preparation of 4-(4-(1-benzyl-5-cyanoindole-3-yl)-3-butynyl) piperazine-1-t-butyl formate
In reaction flask, add 4-(3-butynyl) piperazine-1-t-butyl formate 20.6g (86.6mmol); 1-benzyl-3-iodine indoles-5-formonitrile HCN 38.1g (106.5mmol); cesium carbonate 65.2g (200mmol); two (dibenzalacetone) palladium 1.15g (2mmol) and N; dinethylformamide 300ml, stirs 6h be heated to 80 ℃ after argon replaces three times under argon shield.Stop heating, cool to room temperature, filters, and filtrate is added in 600ml water, stirs after 0.5h, filters, and dry, column chromatography obtains faint yellow solid 30.5g, yield 75.3%.
MS-ESI[M+H] +：469
(3) preparation of 4-(4-(5-cyanoindole-3-yl) butyl) piperazine-1-t-butyl formate
In reaction flask, add 4-(4-(1-benzyl-5-cyanoindole-3-yl)-3-butynyl) piperazine-1-t-butyl formate 30.5g (65.2mmol), 1.5g 10% palladium carbon (moisture approximately 50%), with 300ml tetrahydrofuran (THF), dissolve, stirring at normal temperature 24h, leads to hydrogen stirring at normal temperature 16h three times afterwards with hydrogen exchange.Filter, filtrate decompression is concentrated, and column chromatography obtains white solid 16.3g, yield 65.5%.
MS-ESI[M+H] +：383
(4) preparation of 3-(4-(piperazine-1-yl) butyl) indoles-5-formonitrile HCN
In reaction flask, add 4-(4-(5 cyanoindoles-3-yl) butyl) piperazine-1-t-butyl formate 16.3g, with 200ml methylene dichloride, dissolve, under ice bath, splash into 200ml trifluoroacetic acid, remove ice bath, stirring at normal temperature 8 hours.With sodium carbonate solution, reaction solution washing is extremely alkaline, concentrated organic phase, column chromatography obtains white solid 8.8g, yield 73%.
MS-ESI[M+H] +：283
(5) preparation of 5-(4-(4-(5-cyanoindole-3-yl) butyl) piperazine-1-yl) benzofuran-2-carboxamides
In reaction flask, add 3-(4-(piperazine-1-yl) butyl) indoles-5-formonitrile HCN 5.4g, add 5-bromine cumarone-2-methane amide 4.60g, add tetrakis triphenylphosphine palladium 0.44g and 5.1g sodium carbonate, use 150ml N, dinethylformamide dissolves, and is warmed up to 80 ℃ and stirs 48h.Reaction solution is added in 100ml water and has solid to separate out, filter and obtain solid and use column chromatography obtaining white solid 2.4g, productive rate 27.8%.
Embodiment 5:
Figure BDA00002124307300191
(1) preparation of 5-(4-(3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides
In reaction flask, add 5-(piperazine-1-yl) benzofuran-2-carboxamides 24.5g (100mmol), salt of wormwood 41.4g (300mmol), N, dinethylformamide 300ml, under normal temperature, drip the bromo-ethyl acetylene 26.6g of 4-(200mmol), be then heated to 60 ℃ and stir 8h.Stop heating, filter, filtrate slowly joins in 1000ml water, separates out solid.Filter the dry solid 22.7g, yield 76.3% of obtaining.
(2) preparation of 5-(4-(4-(5-cyanoindole-3-yl)-3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides
In reaction flask, add 5-(4-(3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides 22.5g (75.7mmol); 3-bromo indole-5-formonitrile HCN 20.1g (90.9mmol); two (triphenylphosphine) palladium chloride 2.7g (3.8mmol); cuprous bromide 1.1g (7.6mmol); diethylamine 11.0g (151mmol) and N; N-N,N-DIMETHYLACETAMIDE 400ml, stirs 8h be heated to 60 ℃ after argon replaces three times under argon shield.Stop heating, cool to room temperature, filters, and filtrate is added in 800ml water, stirs after 0.5h, filters, and 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-yl) butyl) piperazine-1-yl) benzofuran-2-carboxamides
In reaction flask, add 5-(4-(4-(5-cyanoindole-3-yl)-3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides 23.6g (53.9mmol), 2.4g 10% palladium carbon (moisture approximately 50%), use 200ml dissolve with methanol, with hydrogen exchange, lead to afterwards hydrogen stirring at normal temperature 24h three times.Filter, filtrate decompression is concentrated, and ethanol making beating obtains faint yellow solid 19.9g, yield 83.6%.
Embodiment 6:
Figure BDA00002124307300201
(1) preparation of 5-(4-(3-butynyl) piperazine-1-yl) coumarilic acid ethyl ester
In reaction flask, add 5-(piperazine-1-yl) coumarilic acid ethyl ester 27.4g (100mmol), salt of wormwood 41.4g (300mmol), with N-Methyl pyrrolidone 400ml, under normal temperature, drip the bromo-ethyl acetylene 16.2g of 4-(120mmol), be then heated to 60 ℃ and stir 10h.Stop heating, cool to room temperature, filters, and filtrate is added in 1000ml water, stirs after 0.5h, filters, and column chromatography obtains title compound 22.9g, yield 70.2%.
MS-ESI[M+H] +：327
(2) preparation of 5-(4-(4-(1-t-Butyldimethylsilyl-5-cyanoindole-3-yl)-3-butynyl) piperazine-1-yl) coumarilic acid ethyl ester
In reaction flask, add 5-(4-(3-butynyl) piperazine-1-yl) coumarilic acid ethyl ester 22.7g (69.5mmol), 1-t-Butyldimethylsilyl-3-iodine indoles-5-formonitrile HCN 23.9g (62.6mmol), NiCl 2(PPh 3) 22.3g (3.5mmol), cuprous iodide 1.3g (7.0mmol), triethylamine 14.1g (139mmol) and dioxane 300ml, stir 24h be heated to 80 ℃ after argon replaces three times under argon shield.Stop heating, cool to room temperature, filters, and filtrate is added in 600ml water, stirs after 1h, filters, and dry, column chromatography obtains title compound 28.3g, yield 77.9%.
MS-ESI[M+H] +：581
(3) preparation of 5-(4-(4-(1-t-Butyldimethylsilyl-5-cyanoindole-3-yl) butyl) piperazine-1-yl) coumarilic acid ethyl ester
In reaction flask, add 5-(4-(4-(1-t-Butyldimethylsilyl-5-cyanoindole-3-yl)-3-butynyl) piperazine-1-yl) coumarilic acid ethyl ester 28.0g (48.2mmol), 2.8g 10% palladium carbon (moisture approximately 50%), with 300ml tetrahydrofuran (THF), dissolve, with hydrogen exchange, lead to afterwards hydrogen stirring at normal temperature 8h three times.Filter, filtrate decompression is concentrated, obtain faint yellow solid 26.8g, yield 95.2%.
MS-ESI[M+H] +：585
(4) preparation of 5-(4-(4-(5-cyanoindole-3-yl) butyl) piperazine-1-yl) coumarilic acid ethyl ester
In reaction flask, add 5-(4-(4-(1-t-Butyldimethylsilyl-5-cyanoindole-3-yl) butyl) piperazine-1-yl) coumarilic acid ethyl ester 26.5g (45.3mmol), with 300ml tetrahydrofuran (THF), dissolve, splash into 30ml 2mol/L hydrochloric acid, stirring at normal temperature 3h, adds K 2cO 3to neutral.Filter, concentrated, by re-crystallizing in ethyl acetate, obtain light yellow crystal 16.7g, productive rate 78.3%.
MS-ESI[M+H] +：471
(5) preparation of 5-(4-(4-(5-cyanoindole-3-yl) butyl) piperazine-1-yl) benzofuran-2-carboxamides
In reaction flask, add 1500ml ammoniacal liquor, under stirring, in 30min, add 5-(4-(4-(5-cyanoindole-3-yl) butyl) piperazine-1-yl)-coumarilic acid ethyl ester solid 16.3g (34.6mmol), under normal temperature, continue to stir 36 hours, filtration obtains solid and uses column chromatography obtaining white solid 11.3g, productive rate 73.8%.
Embodiment 7:
Figure BDA00002124307300211
The preparation of 3-(4-(4-(2-carbamyl cumarone-5-yl) piperazine-1-yl)-ethyl acetylene base)-5-cyanoindole-1-t-butyl formate
In reaction flask, add 5-(4-(3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides 2.97g (10mmol); 5-cyano group-3-iodine indoles-1-t-butyl formate 3.68g (10mmol); four (triphenylphosphine) nickel 0.55g (0.5mmol); cuprous iodide 0.19g (1.0mmol); potassium hydroxide 0.84g (15mmol) and Virahol 50ml, stir 20h be heated to 80 ℃ after argon replaces three times under argon shield.Stop heating, cool to room temperature, filters, and the concentrated rear column chromatography of filtrate decompression is obtained to yellow solid 4.3g, yield 80.0%.
Embodiment 8:
Figure BDA00002124307300221
The preparation of 3-(4-(4-(2-carbamyl cumarone-5-yl) piperazine-1-yl)-ethyl acetylene base)-5-cyanoindole-1-t-butyl formate
In reaction flask, add 5-(4-(3-butynyl) piperazine-1-yl) benzofuran-2-carboxamides 2.97g (10mmol); 5-cyano group-3-iodine indoles-1-t-butyl formate 3.68g (10mmol); cuprous iodide 0.19g (1.0mmol); triphenylphosphine 0.52g (2.0mmol); salt of wormwood 2.1g (15mmol) and methyl-sulphoxide 50ml, stir 16h be heated to 120 ℃ after argon replaces three times under argon shield.Stop heating, cool to room temperature, filters, and filtrate is added in 100ml water, after stirring 0.5h, filters, and filter cake column chromatography obtains yellow solid 4.0g, yield 74.4%.

Claims (13)

1. a method of preparing formula V compound, is characterized in that formula (III) compound and formula (IV) compound make formula (V) compound by linked reaction;
Figure FDA00002124307200011
R 3for H or amino protecting group;
R 4be selected from I, Br, Cl or OTf;
R 8be selected from
Figure FDA00002124307200012
h or amino protecting group;
R 1for CN or COR 2; R 2be selected from H, OR 5or NR 6r 7; R 5, R 6, R 7independently selected from H or C 1-12alkyl;
Work as R 3, R 8while being all amino protecting group, R 3, R 8be amino protecting group independently of one another.
2. according to the preparation method described in claim 1, it is characterized in that:
Under catalyst action, there is linked reaction in formula (III) compound and formula (IV) compound;
The mol ratio of formula (III) compound and formula (IV) compound is 1: 3～3: 1;
Temperature of reaction is 20～150 ℃;
Described catalyzer is selected from palladium catalyst, nickel catalyzator, copper catalyst, cobalt catalyst, platinum catalyst, rhodium catalyst, iridium catalyst, ruthenium catalyst, iron catalyst.
3. according to the preparation method described in claim 2, it is characterized in that:
The mol ratio of formula (III) compound and formula (IV) compound is 1: 2～2: 1;
Temperature of reaction is 30～130 ℃;
Reaction times is 1h～96h;
Described catalyzer is palladium catalyst, nickel catalyzator or copper catalyst;
The solvent using in reaction is selected from N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, methane amide, methylene dichloride, trichloromethane, N-Methyl pyrrolidone, tetrahydrofuran (THF), methyltetrahydrofuran, t-butyl methyl ether, isopropyl ether, acetonitrile, 1, 4-dioxane, 1, 2-glycol dimethyl ether, 2-methyl cellosolve, cellosolvo, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, ethyl acetate, methyl acetate, isopropyl acetate, ethyl formate, acetone, butanone, methyl butyl ketone, methyl iso-butyl ketone (MIBK), methyl-sulphoxide, toluene, dimethylbenzene, chlorobenzene, anisole, HMPA, diethylamine, triethylamine, the combination of one or more in water.
4. according to the preparation method described in claim 2 or 3, it is characterized in that: when described catalyzer is non-copper catalyst, add copper catalyst as promotor.
5. according to the preparation method described in claim 4, it is characterized in that:
The mol ratio of formula (III) compound and formula (IV) compound is 1: 1.3～1.3: 1;
Temperature of reaction is 40～120 ℃;
Reaction times is 2h～48h;
R 5, R 6, R 7independently selected from H or C 1-6alkyl;
Described palladium catalyst is selected from palladium, propionic acid palladium, palladous oxide, Palladous nitrate, palladous sulfate, palladium trifluoroacetate, palladium acetylacetonate, PIVALIC ACID CRUDE (25) palladium, palladium chloride, dibrominated palladium, palladium diiodide, dichloro four ammino palladiums, acetic acid four ammino palladiums, palladium hydroxide, palladium charcoal, tetrakis triphenylphosphine palladium, three (dibenzalacetone) two palladiums, (1,1 '-bis-(Diphenyl phosphino ferrocene) palladium chloride, two (triphenylphosphine) palladium chloride, two (tricyclohexyl phosphine) palladium chloride, two (tri-butyl phosphine) palladium, (two (diphenylphosphine) propane of 1,3-) palladium chloride, (1,5-cyclooctadiene) palladium chloride, (2,2 '-dipyridyl) palladium chloride, two (diphenylphosphine) ethane palladium chlorides of 1,2-, Isosorbide-5-Nitrae-bis-(diphenylphosphine) butane palladium chloride, two (triphenylphosphine) palladium, quadrol palladium chloride, two (cyano group benzene) palladium chloride, two (phenylsulfinyl) ethane palladium diacetates of 1,2-, (1,10-phenanthroline) palladium chloride, two (three-o-toluene phosphine) palladium chloride, hexafluoroacetylacetone palladium, two [two (diphenylphosphino) ethane of 1,2-] palladium, two [three (2-tolyl) phosphine] palladium, two (triethyl phosphine) palladium chloride, two (acetonitrile) palladium chloride, two (dibenzalacetone) palladium, two (methyldiphenyl base phosphine) palladium chloride, four (acetonitrile) Tetrafluoroboric acid palladium, (dicyclo [2.2.1] heptan-2,5-diene) dichloro palladium, 1,1 '-bis-(di-t-butyl phosphino-) ferrocene palladium chloride, 1,1 '-bis-(dicyclohexyl phosphino-) ferrocene palladium chloride, 1,1 '-bis-(di-isopropyl phosphino-) ferrocene palladium chloride, (N,N,N′,N′ tetramethylethylene diamine) palladium chloride, two [dicyclohexyl (4-dimethylamino phenyl) phosphine] palladium chloride, two [di-t-butyl (4-fluoroform phenyl) phosphine] palladium chloride, tetrachloro closes palladium acid sodium, one or more in palladium charcoal,
Described nickel catalyzator is selected from two (triphenylphosphine) Nickel Chlorides, Nickel Chloride, dichloro two (tributylphosphine) nickel, two (trimethyl-phosphine) Nickel Chloride, two (tributylphosphine) Nickel Bromide, two (tricyclohexyl phosphine) Nickel Chloride, two (triphenylphosphine) Nickel Bromide, two (triphenylphosphine) dicarbapentaborane nickel, [1, two (diphenylphosphine) propane of 3-] Nickel Chloride, [1, two (diphenylphosphine) ethane of 2-] Nickel Chloride, [1, 1 '-bis-(diphenylphosphine) ferrocene] Nickel Chloride, two (sec.-propyl cyclopentadiene) nickel, one or more in four (triphenylphosphine) nickel,
Described copper catalyst is selected from that cuprous iodide, cuprous bromide, cuprous chloride, Red copper oxide, cupric oxide, cupric chloride, neutralized verdigris, copper sulfate, cupric nitrate, cupric acetylacetonate, trifluoromethayl sulfonic acid copper (II), trifluoromethayl sulfonic acid copper (I), Tetrafluoroboric acid tetrem cyanogen copper (I), thiophene-2-carboxylic acid are cuprous, one or more in trifluoroacetic acid copper, trifluoromethanesulfonic acid tetrem cyanogen copper, Tetrafluoroboric acid copper (I), phosphofluoric acid copper (I), phosphofluoric acid tetrem cyanogen copper (I).
6. according to the preparation method described in claim 5, it is characterized in that described palladium catalyst, nickel catalyzator or copper catalyst and ligand united use, described part is selected from triphenylphosphine, triethyl phosphine, tributylphosphine, tri-butyl phosphine, tricyclohexyl phosphine, triple phenoxyl phosphine, three (o-methyl-phenyl-) phosphine, three (p-methoxyphenyl) phosphine, methyldiphenyl base phosphine, dicyclohexyl Phenylphosphine, di-tert-butyl-phenyl phosphine, dicyclohexyl (4-dimethylamino phenyl) phosphine, di-t-butyl (4-fluoroform phenyl) phosphine, two (diphenylphosphine) ethane of 1,2-, two (diphenylphosphine) propane of 1,3-, Isosorbide-5-Nitrae-bis-(diphenylphosphine) butane, two (phenylsulfinyl) ethane of 1,2-, 2,2 '-bis-diphenyl phosphine-1,1 '-dinaphthalene, 1,1 '-bis-Diphenyl phosphino ferrocenes, 1,1 '-bis-(di-t-butyl phosphino-) ferrocene, 1,1 '-bis-(dicyclohexyl phosphino-) ferrocene, 1,1 '-bis-(di-isopropyl phosphino-) ferrocene, 2,3-O-isopropyl alkene-2, one or more in 3-dihydroxyl-Isosorbide-5-Nitrae-bis-diphenylphosphine butane.
7. according to the preparation method described in any one in claim 1 to 6, it is characterized in that adding alkali in reaction, described alkali is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, cesium carbonate, Quilonum Retard, silver carbonate, sodium bicarbonate, potassiumphosphate, sodium phosphate, Potassium ethanoate, sodium-acetate, Trimethylamine 99, diethylamine, triethylamine, Tributylamine, 4-dimethylamino pyridine, Pyrrolidine, piperidines, N, N-xylidene(s), 1, 8-diazabicylo [5.4.0] 11 carbon-7-alkene, N-methylmorpholine, N, N-diisopropylethylamine, pyridine, 2, 6-lutidine, imidazoles, N, N, N ', one or more in N '-Tetramethyl Ethylene Diamine.
8. according to the preparation method described in any one in claim 1 to 6; it is characterized in that amino protecting group be selected from benzyl, to methoxy-benzyl, tertbutyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl, trifluoroacetyl group, t-Butyldimethylsilyl, p-toluenesulfonyl, carbobenzoxy-(Cbz), 9-fluorenylmethyloxycarbonyl, 2; 2; 2-trichloro-ethoxycarbonyl, the trimethyl silicon based ethoxycarbonyl of 2-, trityl, 2,4-dimethoxy-benzyl or methylsulfonyl.
9. according to the preparation method described in any one in claim 1 to 6, it is characterized in that formula (III) compound is reacted and obtains under the existence of alkali by formula (II) compound;
Figure FDA00002124307200031
R 9be selected from I, Br, Cl, OTs, OMs or OTf;
Described alkali is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, cesium carbonate, Quilonum Retard, silver carbonate, sodium bicarbonate, potassiumphosphate, sodium phosphate, Potassium ethanoate, sodium-acetate, Trimethylamine 99, triethylamine, Tributylamine, 4-dimethylamino pyridine, N, N-xylidene(s), 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, N-methylmorpholine, N, N-diisopropylethylamine, 2,6-lutidine, pyridine, imidazoles, N, N, N ', one or more in N '-Tetramethyl Ethylene Diamine;
Reaction solvent is selected from N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, methane amide, methylene dichloride, trichloromethane, N-Methyl pyrrolidone, tetrahydrofuran (THF), methyltetrahydrofuran, t-butyl methyl ether, isopropyl ether, acetonitrile, 1, 4-dioxane, 1, 2-glycol dimethyl ether, 2-methyl cellosolve, cellosolvo, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, ethyl acetate, methyl acetate, isopropyl acetate, ethyl formate, methyl-sulphoxide, toluene, dimethylbenzene, chlorobenzene, anisole, HMPA, the combination of one or more in water,
Temperature of reaction is 20～80 ℃.
10. a method for preparation formula (I) compound, is characterized in that the formula that in claim 1 to 6, the preparation method described in any one makes (V) compound obtains formula (I) compound through a step or polystep reaction:
Figure FDA00002124307200041
The compound of 11. formulas (III), is characterized in that:
R 8be selected from
Figure FDA00002124307200043
h or amino protecting group;
R 1for CN or COR 2; R 2be selected from H, OR 5or NR 6r 7; R 5, R 6, R 7independently selected from H or C 1-12alkyl.
The compound of 12. formulas (V), is characterized in that:
Figure FDA00002124307200044
R 3for H or amino protecting group;
R 8be selected from
Figure FDA00002124307200045
h or amino protecting group;
R 1for CN or COR 2; R 2be selected from H, OR 5or NR 6r 7; R 5, R 6, R 7independently selected from H or C 1-12alkyl;
Work as R 3, R 8while being all amino protecting group, R 3, R 8be amino protecting group independently of one another.
13. according to the compound described in any one in claim 11 or 12, it is characterized in that:
Amino protecting group is selected from benzyl, to methoxy-benzyl, tertbutyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl, trifluoroacetyl group, t-Butyldimethylsilyl, p-toluenesulfonyl, carbobenzoxy-(Cbz), 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, the trimethyl silicon based ethoxycarbonyl of 2-, trityl, 2,4-dimethoxy-benzyl or methylsulfonyl;
R 5, R 6, R 7independently selected from H or C 1-6alkyl.
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