CN103819433A - Method for synthesizing piperazine-benzofuran compound - Google Patents
Method for synthesizing piperazine-benzofuran compound Download PDFInfo
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- CN103819433A CN103819433A CN201310618007.5A CN201310618007A CN103819433A CN 103819433 A CN103819433 A CN 103819433A CN 201310618007 A CN201310618007 A CN 201310618007A CN 103819433 A CN103819433 A CN 103819433A
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- 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 for synthesizing a piperazine-benzofuran compound. The method comprises the following specific steps: allowing a compound with a formula (II) to react with a compound with a formula (III) in an organic solvent under the actions of an alkali and a catalyst to obtain a compound with a formula (I), namely, the piperazine-benzofuran compound, wherein the organic solvent is prepared by mixing an organic solvent (a) and an organic solvent (b), the organic solvent (a) comprises one or more of methylbenzene, para-xylene, bromobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidinone, chlorobenzene, ortho-dichlorobenzene, para-dichlorobenzene and m-dichlorobenzene, the organic solvent (b) comprises one or more of isopropyl alcohol, n-butyl alcohol, ethyl alcohol, methyl alcohol, propyl alcohol and acetonitrile, and the volume ratio of the organic solvent (a) to the organic solvent (b) is (1-25):1. The method has the advantages that the raw materials are low in price and are easy to obtain; the reaction conditions are mild; the operation is simple and convenient; the post-treatment is simple; the large-scale application is facilitated.
Description
Technical field
The present invention relates to a kind of synthetic method of compound for the treatment of nervous center disease, particularly, relate to a kind of synthetic method of piperazine-benzofuran compounds.
Background technology
Piperazine-benzofuran compounds (I) is the crucial and effective chemical fragment in treatment nervous center aspect disease, and this compound itself is to 5-HT
2cacceptor has selectivity, can be used as combination of serotonin agonist, in treatment Mammals, reduces relevant various diseases with thrombotonin neurotransmission, these diseases comprise: dysthymia disorders, obesity, exessive appetite, premenstrual syndrome or late luteal phase syndromes, senile dementia, social phobia, absent minded hyperkinetic syndrome, obsessional idea disease, chronic fatigue syndrome, premature ejaculation, erection problem, somnopathy, autism, anxiety, epileptic seizures and do not say disease.Its synthetic method is generally by compound (II) and (III) reaction preparation.
Wherein:
X is hydrogen, phenyl, cyano group, the straight chain of C1-C6 or the alkyl with side chain, halogen, COOA, COOPh, COOCH
2ph, COOPy, CONH
2, trifluoromethyl, C
1-C
4alkoxyl group and hydroxyl replace C
1-C
6alkyl etc.;
A is hydrogen, halogen, C
1-C
6straight chain or with the alkyl of side chain;
Ph is phenyl;
Py is pyridyl;
X
1for halogen, hydroxyl etc.;
R
1for hydrogen, benzyl, phenyl, pyridyl, trifluoromethyl, cyano group, C
1-C
4alkoxyl group, C
1-C
4carbalkoxy, C
1-C
6alkyl, or be selected from halogen, C
1-C
4the C that alkoxyl group and hydroxyl replace
1-C
6alkyl, common Ammonia protecting group, as: BOC, CBZ, FMOC etc.;
R
2for hydrogen, trifluoromethyl, phenyl, pyridyl, or C
1-C
6alkyl etc.;
R
3for amino, protected amino, as BOC-NH-, CBZ-NH-, FMOC-NH-etc.;
R
4for hydrogen, halogen, dihalomethyl, trifluoromethyl, 1,1-difluoro second-1-base, cyano group, C
1-C
4alkoxyl group, C
1-C
4carbalkoxy, C
1-C
6alkyl, or be selected from halogen, C
1-C
4the C that the substituting group of alkoxyl group and hydroxyl replaces
1-C
6alkyl.
Patent documentation CN1365359A(is on 08 21st, 2002 in open day) and CN1443162A(within open day, be on 09 17th, 2003) report, when X is hydrogen, halogen, trifluoromethyl or C
1-C
6alkyl; R
1hydrogen; R
2hydrogen, halogen, trifluoromethyl, phenyl or C
1-C
6alkyl; R
4hydrogen, halogen, dihalomethyl, trifluoromethyl, 1,1-difluoro second-1-base, cyano group, C
1-C
4alkoxyl group, C
1-C
4carbalkoxy, C
1-C
6alkyl or quilt are selected from halogen, C
1-C
4the C that the substituting group of alkoxyl group and hydroxyl replaces
1-C
6when alkyl, this compound itself can be used as combination of serotonin agonist and can be used for treating anxiety, depression, hypertension, migraine, obesity, drug abuse and habituation, obsessive-compulsive disorder, schizophrenia, the illnesss such as autism.Patent CN1443162A is mainly the protection that its drug effect is carried out, and its synthetic method is not described.In patent CN1365359A, reported a kind of synthetic method of compound (I), i.e. transition metal coupling process, need to use more expensive palladium catalyst and corresponding part, and production cost is high, is not suitable for industrialization.
For compound (I), work as R
1=R
2=R
4=H, X=COOC
2h
5or CONH
2time, this compound is the key intermediate of antidepressant drug vilazodone, is below disclosed several synthetic method:
1) people such as .Timo Heinrich, at J.Med.Chem.2004, has reported X=COOC in 47,4684-4692
2h
5time synthetic method, as follows:
The method is with the amino cumarone-2-ethyl formate of 5-and N, two (2-chloroethyl) amine hydrochlorates of N-are raw material, take salt of wormwood as acid binding agent, back flow reaction 48 hours in solvent, n-butanol (approximately 124 ℃ of boiling points), then obtain the finished product take methyl alcohol as solvent recrystallization, its yield is only 27%, causes industrial production cost too high, serious three wastes.
2). american documentation literature US5723614A (open day be on 03 03rd, 1998) and European patent EP 1215210A2(are on 06 19th, 2002 in open day) announce X=COOC
2h
5time synthetic method:
But the disclosed content of this patent is that this compounds is had to certain curative effect in the disease for the treatment of nervous center fermentation, very simple to its synthetic method report, what its solvent was selected is lower boiling methylene dichloride, and in actual production, the reaction that this class is closed piperazine ring often needs higher temperature, and while therefore making solvent with methylene dichloride, yield is extremely low.
3). patent documentation CN102633759A(is on 08 15th, 2012 in open day) announce X=COOC
2h
5time synthetic method:
In patent, report that its yield and purity can reach very high, but find that according to repeating experiment result is really not so, key reason is that it does not carry out specific aim explanation to the selection of solvent system, because yield and the purity of the polarity of solvent system to product has a great impact, the method is also unfavorable for large-scale industrial production.
4). patent documentation CN103044370A(is on 04 17th, 2013 in open day) in announced X=CONH
2time synthetic method:
This synthetic route is also first to synthesize X=COOC by piperazine closed loop
2h
5ester, and then ester carried out to ammonia solution obtain X=CONH
2methane amide.But it does not use catalyzer and alkali in the ring-closure reaction of piperazine, cause its actual recovery not high, and purity is lower, is unfavorable for large-scale industrial production.
5). patent documentation CN102863413A(is 2013 01 year 09 day in open day) in announced X=CN and CONH
2synthetic method:
The people such as this synthetic method and Timo Heinrich are at J.Med.Chem.2004,47, the synthesis condition of reporting in 4684-4692 is identical, take propyl carbinol as solvent, salt of wormwood is alkali, react 45 hours, then recrystallizing methanol obtains product at solvent refluxing temperature, but its yield is not high, it is only 50% left and right.
6). patent documentation CN1407981A(is 2003 04 year 02 in open day) in announced X=CONH
2time a kind of synthetic method:
Need under transition metal (palladium) catalysis and part (phosphine) condition, could there is linked reaction in above-mentioned synthetic method, due to palladium catalyst and phosphine part price more expensive, and this linked reaction yield is lower, is not suitable for large-scale industrial production.
7). patent documentation CN102964323A(is on 03 13rd, 2013 in open day) in announced X=CONH
2time another kind of synthetic method:
Although the method has avoided generating the closed reaction of piperazine ring; but 4-piperazine-1-base-phenol is when with polyformaldehyde reaction; reaction conditions is comparatively harsh; need under rare gas element (as nitrogen) protection, use anhydrous reagent; once there be water to exist in reaction system, be difficult to generate target product, therefore the method production cost is high; severe reaction conditions, is also unfavorable for large-scale industrial production.
Summary of the invention
Exist for prior art high, the actual synthesis yield of synthetic method cost on the low side, separating-purifying is difficult, be unfavorable for the defect of suitability for industrialized production, the invention provides a kind of synthetic method of piperazine-benzofuran compounds.
The present invention is achieved through the following technical solutions: a kind of synthetic method of piperazine-benzofuran compounds, its concrete steps are: by formula (II) compound and formula (III) compound in organic solvent, under the effect of alkali and catalyzer, react acquisition formula (I) compound, to obtain final product;
Wherein
X is the straight chain of hydrogen, phenyl, cyano group, C1-C6 or alkyl, halogen, COOA, COOPh, COOCH with side chain
2ph, COOPy, CONH
2, trifluoromethyl, C
1-C
4alkoxyl group and hydroxyl replace C
1-C
6alkyl, A is hydrogen, halogen, C
1-C
6straight chain or with the alkyl of side chain;
Ph is phenyl;
Py is pyridyl;
X
1for halogen or hydroxyl;
R
1for hydrogen, benzyl, phenyl, pyridyl, trifluoromethyl, cyano group, C
1-C
4alkoxyl group, C
1-C
4carbalkoxy, C
1-C
6alkyl or quilt are selected from halogen, C
1-C
4the C that alkoxyl group and hydroxyl replace
1-C
6alkyl;
R
2for hydrogen, trifluoromethyl, phenyl, pyridyl or C
1-C
6alkyl;
R
3for amino, BOC-NH-, CBZ-NH-or FMOC-NH-;
R
4for hydrogen, halogen, dihalomethyl, trifluoromethyl, 1,1-difluoro second-1-base, cyano group, C
1-C
4alkoxyl group, C
1-C
4carbalkoxy, C
1-C
6alkyl or quilt are selected from halogen, C
1-C
4the C that the substituting group of alkoxyl group and hydroxyl replaces
1-C
6alkyl;
Described organic solvent is mixed by organic solvent a and organic solvent b, described organic solvent a is toluene, p-Xylol, bromobenzene, N, any one in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, chlorobenzene, orthodichlorobenzene, santochlor, Meta Dichlorobenzene or two or more mixing; Described organic solvent b is any one or the two or more mixing in Virahol, propyl carbinol, ethanol, methyl alcohol, propyl alcohol, acetonitrile; The volume ratio of described organic solvent a and described organic solvent b is (1～25): 1.
Preferably, the volume ratio of described organic solvent a and described organic solvent b is (8～18): 1.
Preferably, described alkali is one or more mixing of salt of wormwood, sodium carbonate, Quilonum Retard, sodium methylate, sodium ethylate, sodium hydride, hydrolith, lithium hydride, sodium hydroxide, potassium hydroxide, sodium amide, sodium tert-butoxide, potassium tert.-butoxide, trimethyl carbinol lithium, triethylamine, pyridine, diisopropylethylamine, and the ratio of the mole number of described alkali and described formula (II) compound is (0.5-4): 1; Preferred, the ratio of the mole number of described alkali and described formula (II) compound is (1-3): 1.
Preferably, described catalyzer is benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride Tetrabutyl amonium bromide, one or more mixing of tetradecyl trimethyl ammonium chloride tetrabutylammonium chloride, 18 hat 6,15 hats 5, cyclodextrin; The ratio of the mole number of described catalyzer and described formula (II) compound is (0.05-1.5): 1; Preferred, the ratio of the mole number of described catalyzer and described formula (II) compound is (0.1-1): 1.
Preferably, the ratio of the mole number of described formula (III) compound and described formula (II) compound is (0.5-5.0): 1; Preferred, the ratio of the mole number of described formula (III) compound and described formula (II) compound is (0.8-1.2): 1.
Preferably, the temperature of described reaction is 20-200 ℃, and the time of described reaction is 10-40 hour; Preferred, the temperature of described reaction is 70-160 ℃, and the time of described reaction is 20-30 hour.
On the basis of attempting without prejudice to this area, in the present invention, above-mentioned each preferred feature can arbitrary combination, can obtain the each preferred embodiment of the present invention.
Compared with prior art, the present invention has following beneficial effect: in the present invention, by selecting boiling point higher and have the solvent system of certain polarity to synthesize this compounds, be the main innovate point that the present invention invents.Organic solvent a be polarity relatively a little less than, but the higher solvent of boiling point, can promote the dissolving of Compound I I on the one hand, on the other hand, high boiling solvent can make the higher piperazine that impels of temperature of reaction system accelerate closed loop, temperature is higher, closed-loop speed is faster; Organic solvent b polarity is relatively strong, and boiling point is also corresponding lower, and compound III is generally hydrochloride form, and solvent polarity strengthens the dissolving that can impel compound III, is conducive to the carrying out of reaction; On the other hand, reaction is easy to form the transition state form of compound IV, after the adding of solvent b system polarity being increased, and remaining X in IV
1more easily dissociate, make original and X
1connected carbon atom forms carbonium ion, and the lone-pair electron of nitrogen-atoms in carbonium ion attack parahelium are accelerated piperazine ring-closure reaction speed.
Therefore, the solvent system that the present invention uses is solvent system absolutely not arbitrarily, the polarity of the solvent system that the present invention uses has remarkably influenced to reaction yield, synthesis yield is had significantly to be improved, the raw material of the inventive method is cheap and easy to get simultaneously, and reaction conditions gentleness is easy and simple to handle, aftertreatment is simple, is conducive to commercial scale production.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.Following examples will contribute to those skilled in the art further to understand the present invention, but not limit in any form the present invention.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, can also make some distortion and improvement.These all belong to protection scope of the present invention.
Synthesizing of embodiment 1:5-(piperazine-1-yl) coumarilic acid ethyl ester
In the four-hole boiling flask of 1000mL, add p-Xylol (600mL), Virahol (40mL), 41g(0.2mol) amino cumarone-2-the ethyl formate of 5-, 35.7g(0.2mol) two (2-chloroethyl) amine hydrochlorate, 32.2g(0.1mol) Tetrabutyl amonium bromide, 27.6g(0.2mol) salt of wormwood; Reacting by heating mixture, to refluxing (135-137 ℃), reacts 24h; HPLC detection reaction is extremely without the amino cumarone-2-ethyl formate of 5-, stopped reaction; Decompression evaporates solvent (temperature is lower than 70 ℃), steamed, adds dehydrated alcohol (180mL), under stirring, naturally cools to envrionment temperature; After 2h, filter, the cold washing with alcohol of filter cake, 60 ℃ are dried to obtain 5-(piperazine-1-yl) coumarilic acid ethyl ester 57.4g, mp:243-245 ℃, purity 98.5%(HPLC), productive rate 92.5%.
1H?NMR(400MHz,DMSO,ppm)δ9.35(m,2H),7.63(m,2H),7.31(m,2H),4.36(q,2H),3.38(m,4H),3.25(m,4H),1.36(t,3H)
Synthesizing of embodiment 2:5-(piperazine-1-yl) coumarilic acid ethyl ester
In the four-hole boiling flask of 1000mL, add toluene (625mL), propyl alcohol (25mL), 41g(0.2mol) amino cumarone-2-the ethyl formate of 5-, 35.7g(0.2mol) two (2-chloroethyl) amine hydrochlorate, 64.4g(0.2mol) Tetrabutyl amonium bromide, 41.4g(0.3mol) salt of wormwood; Reacting by heating mixture, to refluxing (106-108 ℃), reacts 30h; HPLC detection reaction is extremely without the amino cumarone-2-ethyl formate of 5-, stopped reaction; Decompression evaporates solvent (temperature is lower than 70 ℃), steamed, adds dehydrated alcohol (180mL), under stirring, naturally cools to envrionment temperature; After 2h, filter, the cold washing with alcohol of filter cake, 60 ℃ are dried to obtain 5-(piperazine-1-yl) coumarilic acid ethyl ester 40.4g, mp:243-245 ℃, purity 95.4%(HPLC), productive rate 65.1%.
1H?NMR(400MHz,DMSO,ppm)δ9.35(m,2H),7.63(m,2H),7.31(m,2H),4.36(q,2H),3.38(m,4H),3.25(m,4H),1.36(t,3H)
Synthesizing of embodiment 3:5-(piperazine-1-yl) coumarilic acid ethyl ester
In the four-hole boiling flask of 1000mL, add p-Xylol (535mL), Virahol (107mL), 41g(0.2mol) amino cumarone-2-the ethyl formate of 5-, 35.7g(0.2mol) two (2-chloroethyl) amine hydrochlorate, 32.2g(0.1mol) Tetrabutyl amonium bromide, 27.6g(0.2mol) salt of wormwood; Reacting by heating mixture, to refluxing (134-136 ℃), reacts 20h; HPLC detection reaction is extremely without the amino cumarone-2-ethyl formate of 5-, stopped reaction; Decompression evaporates solvent (temperature is lower than 70 ℃), steamed, adds dehydrated alcohol (180mL), under stirring, naturally cools to envrionment temperature; After 2h, filter, the cold washing with alcohol of filter cake, 60 ℃ are dried to obtain 5-(piperazine-1-yl) coumarilic acid ethyl ester 46.1g, mp:243-245 ℃, purity 97.8%(HPLC), productive rate 74.2%.
1H?NMR(400MHz,DMSO,ppm)δ9.35(m,2H),7.63(m,2H),7.31(m,2H),4.36(q,2H),3.38(m,4H),3.25(m,4H),1.36(t,3H)
Synthesizing of embodiment 4:5-(piperazine-1-yl) benzofuran-2-carboxamides
In the four-hole boiling flask of 1000mL, add toluene (630mL), ethanol (35mL), 35.2g(0.2mol) the amino cumarone-2-methane amide of 5-, 35.7g(0.2mol) two (2-chloroethyl) amine hydrochlorate, 33.9g(0.1mol) 4-butyl ammonium hydrogen sulfate, 30.3g(0.3mol) triethylamine; Reacting by heating mixture, to refluxing (106-108 ℃), reacts 20h; HPLC detection reaction is extremely without the amino cumarone-2-methane amide of 5-, stopped reaction; Decompression evaporates solvent (temperature is lower than 70 ℃), steamed, adds dehydrated alcohol (180mL), under stirring, naturally cools to envrionment temperature; After 2h, filter, the cold washing with alcohol of filter cake, 65 ℃ are dried to obtain 5-(piperazine-1-yl) benzofuran-2-carboxamides 47.4g, purity 98.8%(HPLC), productive rate 84.2%.
1H?NMR(400MHz,DMSO,ppm)δ9.49(m,2H),7.64(m,2H),7.28(m,2H),4.97(m,2H),3.37(m,4H),3.22(m,4H)
Synthesizing of embodiment 5:5-(piperazine-1-yl) benzofuran-2-carboxamides
In the four-hole boiling flask of 1000mL, add toluene (560mL), Virahol (70mL), 35.2g(0.2mol) the amino cumarone-2-methane amide of 5-, 35.7g(0.2mol) two (2-chloroethyl) amine hydrochlorate, 32.2g(0.1mol) Tetrabutyl amonium bromide, 27.6g(0.2mol) salt of wormwood; Reacting by heating mixture, to refluxing (106-108 ℃), reacts 25h; HPLC detection reaction is extremely without the amino cumarone-2-methane amide of 5-, stopped reaction; Decompression evaporates solvent (temperature is lower than 70 ℃), steamed, adds dehydrated alcohol (180mL), under stirring, naturally cools to envrionment temperature; After 2h, filter, the cold washing with alcohol of filter cake, 65 ℃ are dried to obtain 5-(piperazine-1-yl) benzofuran-2-carboxamides 50.8g, purity 99.1%(HPLC), productive rate 90.2%.
1H?NMR(400MHz,DMSO,ppm)δ9.49(m,2H),7.64(m,2H),7.28(m,2H),4.97(m,2H),3.37(m,4H),3.22(m,4H)
Synthesizing of embodiment 6:5-(piperazine-1-yl) cumarone-2-formonitrile HCN
In the four-hole boiling flask of 1000mL, add toluene (600mL), Virahol (40mL), 31.36g(0.2mol) amino cumarone-2-the formonitrile HCN of 5-, 35.7g(0.2mol) two (2-chloroethyl) amine hydrochlorate, 2.78g(0.01mol) tetrabutylammonium chloride, 20.7g(0.15mol) salt of wormwood; Reacting by heating mixture, to refluxing (106-108 ℃), reacts 20h; HPLC detection reaction is extremely without the amino cumarone-2-formonitrile HCN of 5-, stopped reaction; Decompression evaporates solvent (temperature is lower than 70 ℃), steamed, adds dehydrated alcohol (180mL), under stirring, naturally cools to envrionment temperature; After 2h, filter, the cold washing with alcohol of filter cake, 65 ℃ are dried to obtain 5-(piperazine-1-yl) cumarone-2-formonitrile HCN 38.3g, purity 91.2%(HPLC), productive rate 72.7%.
1H?NMR(400MHz,DMSO,ppm)δ9.49(m,2H),7.64(m,2H),7.28(m,2H),3.37(m,4H),3.22(m,4H)
Synthesizing of embodiment 7:5-(piperazine-1-yl) cumarone-2-formonitrile HCN
In the four-hole boiling flask of 1000mL, add toluene (600mL), ethanol (60mL), 31.36g(0.2mol) amino cumarone-2-the formonitrile HCN of 5-, 35.7g(0.2mol) two (2-chloroethyl) amine hydrochlorate, 32.2g(0.1mol) Tetrabutyl amonium bromide, 27.6g(0.2mol) salt of wormwood; Reacting by heating mixture, to refluxing (106-108 ℃), reacts 26h; HPLC detection reaction is extremely without the amino cumarone-2-formonitrile HCN of 5-, stopped reaction; Decompression evaporates solvent (temperature is lower than 70 ℃), steamed, adds dehydrated alcohol (180mL), under stirring, naturally cools to envrionment temperature; After 2h, filter, the cold washing with alcohol of filter cake, 65 ℃ are dried to obtain 5-(piperazine-1-yl) cumarone-2-formonitrile HCN 48.6g, purity 96.6%(HPLC), productive rate 92.4%.
1H?NMR(400MHz,DMSO,ppm)δ9.49(m,2H),7.64(m,2H),7.28(m,2H),3.37(m,4H),3.22(m,4H)
Synthesizing of embodiment 8:7-methoxy-5-piperazine-1-base-coumarilic acid ethyl ester
In the four-hole boiling flask of 1000mL, add p-Xylol (600mL), ethanol (40mL), 47.0g(0.2mol) 5-amino-7 methoxyl group-coumarilic acid ethyl ester, 35.7g(0.2mol) two (2-chloroethyl) amine hydrochlorate, 27.8g(0.1mol) tetrabutylammonium chloride, 27.6g(0.2mol) salt of wormwood; Reacting by heating mixture, to refluxing (135-137 ℃), reacts 24h; HPLC detection reaction is extremely without 5-amino-7 methoxyl group-coumarilic acid ethyl ester, stopped reaction; Decompression evaporates solvent (temperature is lower than 70 ℃), steamed, adds dehydrated alcohol (180mL), under stirring, naturally cools to envrionment temperature; After 2h, filter, the cold washing with alcohol of filter cake, 60 ℃ are dried to obtain 7-methoxy-5-piperazine-1-base-coumarilic acid ethyl ester 61.7g, purity 98.2%(HPLC), productive rate 90.6%.
1H?NMR(400MHz,DMSO,ppm)δ9.35(m,2H),7.63(m,H),7.31(m,2H),4.36(q,2H),3.84(s,3H),3.38(m,4H),3.25(m,4H),1.36(t,3H)
Synthesizing of embodiment 9:7-methoxy-5-piperazine-1-base-coumarilic acid ethyl ester
In the four-hole boiling flask of 1000mL, add toluene (625mL), ethanol (25mL), 47.0g(0.2mol) 5-amino-7 methoxyl group-coumarilic acid ethyl ester, 35.7g(0.2mol) two (2-chloroethyl) amine hydrochlorate, 32.2g(0.1mol) Tetrabutyl amonium bromide, 41.4g(0.3mol) salt of wormwood; Reacting by heating mixture, to refluxing (106-108 ℃), reacts 30h; HPLC detection reaction is extremely without 5-amino-7 methoxyl group-coumarilic acid ethyl ester, stopped reaction.Decompression evaporates solvent (temperature is lower than 70 ℃), steamed, adds dehydrated alcohol (180mL), under stirring, naturally cools to envrionment temperature; After 2h, filter, the cold washing with alcohol of filter cake, 60 ℃ are dried to obtain 7-methoxy-5-piperazine-1-base-coumarilic acid ethyl ester 47.1g, purity 97.3%(HPLC), productive rate 69.2%.
1H?NMR(400MHz,DMSO,ppm)δ9.35(m,2H),7.63(m,H),7.31(m,2H),4.36(q,2H),3.84(s,3H),3.38(m,4H),3.25(m,4H),1.36(t,3H)
Above specific embodiments of the invention are described.It will be appreciated that, the present invention is not limited to above-mentioned specific implementations, and those skilled in the art can make various distortion or modification within the scope of the claims, and this does not affect flesh and blood of the present invention.
Claims (10)
1. the synthetic method of a piperazine-benzofuran compounds, it is characterized in that, its concrete steps are: by formula (II) compound and formula (III) compound in organic solvent, under the effect of alkali and catalyzer, react acquisition formula (I) compound, to obtain final product;
Wherein
X is the straight chain of hydrogen, phenyl, cyano group, C1-C6 or alkyl, halogen, COOA, COOPh, COOCH with side chain
2ph, COOPy, CONH
2, trifluoromethyl, C
1-C
4alkoxyl group and hydroxyl replace C
1-C
6alkyl, A is hydrogen, halogen, C
1-C
6straight chain or with the alkyl of side chain;
Ph is phenyl;
Py is pyridyl;
X
1for halogen or hydroxyl;
R
1for hydrogen, benzyl, phenyl, pyridyl, trifluoromethyl, cyano group, C
1-C
4alkoxyl group, C
1-C
4carbalkoxy, C
1-C
6alkyl or quilt are selected from halogen, C
1-C
4the C that alkoxyl group and hydroxyl replace
1-C
6alkyl;
R
2for hydrogen, trifluoromethyl, phenyl, pyridyl or C
1-C
6alkyl;
R
3for amino, BOC-NH-, CBZ-NH-or FMOC-NH-;
R
4for hydrogen, halogen, dihalomethyl, trifluoromethyl, 1,1-difluoro second-1-base, cyano group, C
1-C
4alkoxyl group, C
1-C
4carbalkoxy, C
1-C
6alkyl or quilt are selected from halogen, C
1-C
4the C that the substituting group of alkoxyl group and hydroxyl replaces
1-C
6alkyl;
Described organic solvent is mixed by organic solvent a and organic solvent b, described organic solvent a is toluene, p-Xylol, bromobenzene, N, any one in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, chlorobenzene, orthodichlorobenzene, santochlor, Meta Dichlorobenzene or two or more mixing; Described organic solvent b is any one or the two or more mixing in Virahol, propyl carbinol, ethanol, methyl alcohol, propyl alcohol, acetonitrile; The volume ratio of described organic solvent a and described organic solvent b is (1～25): 1.
2. the synthetic method of piperazine-benzofuran compounds according to claim 1, is characterized in that, the volume ratio of described organic solvent a and described organic solvent b is (8～18): 1.
3. the synthetic method of piperazine-benzofuran compounds according to claim 1, it is characterized in that, described alkali is one or more mixing of salt of wormwood, sodium carbonate, Quilonum Retard, sodium methylate, sodium ethylate, sodium hydride, hydrolith, lithium hydride, sodium hydroxide, potassium hydroxide, sodium amide, sodium tert-butoxide, potassium tert.-butoxide, trimethyl carbinol lithium, triethylamine, pyridine, diisopropylethylamine, and the ratio of the mole number of described alkali and described formula (II) compound is (0.5-4): 1.
4. the synthetic method of piperazine-benzofuran compounds according to claim 3, is characterized in that, the ratio of the mole number of described alkali and described formula (II) compound is (1-3): 1.
5. the synthetic method of piperazine-benzofuran compounds according to claim 1, it is characterized in that, described catalyzer is benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride Tetrabutyl amonium bromide, one or more mixing of tetradecyl trimethyl ammonium chloride tetrabutylammonium chloride, 18 hat 6,15 hats 5, cyclodextrin; The ratio of the mole number of described catalyzer and described formula (II) compound is (0.05-1.5): 1.
6. the synthetic method of piperazine-benzofuran compounds according to claim 5, is characterized in that, the ratio of the mole number of described catalyzer and described formula (II) compound is (0.1-1): 1.
7. the synthetic method of piperazine-benzofuran compounds according to claim 1, is characterized in that, the ratio of the mole number of described formula (III) compound and described formula (II) compound is (0.5-5.0): 1.
8. the synthetic method of piperazine-benzofuran compounds according to claim 7, is characterized in that, the ratio of the mole number of described formula (III) compound and described formula (II) compound is (0.8-1.2): 1.
9. the synthetic method of piperazine-benzofuran compounds according to claim 1, is characterized in that, the temperature of described reaction is 20-200 ℃, and the time of described reaction is 10-40 hour.
10. the synthetic method of piperazine-benzofuran compounds according to claim 9, is characterized in that, the temperature of described reaction is 70-160 ℃, and the time of described reaction is 20-30 hour.
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| CN111944539A (en) * | 2020-07-31 | 2020-11-17 | 西安瑞联新材料股份有限公司 | Fluropiperazine-based benzoxazole liquid crystal compound and preparation method thereof |
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| WO2013153492A2 (en) * | 2012-04-12 | 2013-10-17 | Alembic Pharmaceuticals Limited | Process for the preparation of vilazodone hydrochloride and its amorphous form |
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| CN111944539A (en) * | 2020-07-31 | 2020-11-17 | 西安瑞联新材料股份有限公司 | Fluropiperazine-based benzoxazole liquid crystal compound and preparation method thereof |
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