CN109422722A - A kind of preparation method of benzothienyl compounds intermediate - Google Patents
A kind of preparation method of benzothienyl compounds intermediate Download PDFInfo
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- CN109422722A CN109422722A CN201710758862.4A CN201710758862A CN109422722A CN 109422722 A CN109422722 A CN 109422722A CN 201710758862 A CN201710758862 A CN 201710758862A CN 109422722 A CN109422722 A CN 109422722A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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Abstract
The present invention provides a kind of new according to a preparation among piperazine azoles, and this method is to be obtained the halogenated benzo of compound 4- [b] thiophene and N-protected piperazine coupling reaction by alkali in the presence of cuprous catalysis agent and ligand.Compared with prior art, the present invention can substitute precious metal palladium using cheap cuprous iodide under suitable ligand, and the obtaining of high conversion reacts safer simplicity according to a piperazine azoles midbody compound, cost price is cheap, environmental pollution is less, easy to operate, can be adapted for industrialization industry.
Description
Technical field
The present invention relates to a kind of preparation methods of benzothienyl compounds intermediate.
Background technique
The dopamine D 2 and 5- researched and developed jointly according to piperazine azoles (Brexpiprazole) by Japanese big tomb pharmacy and Denmark's Lundbeck
HT2AReceptor modulators, entitled 7- (4- (4- (benzo [B] thiophene -4- base-piperazine -1- base) the butoxy) -1H- quinoline -2- of chemistry
Ketone, this product treat adjuvant drug, and adult treatment of schizophrenia medicine as adult severe depression (MDD).
Patent CN101155804B, CN101155804A, CN105461703A are reported according to a piperazine azoles
(Brexpiprazole) entitled 7- (4- (4- (benzo [B] thiophene -4- base-piperazine -1- base) butoxy) -1H- quinoline-of chemistry
2- ketone is condensed to yield by the coupling of key intermediate 4- (1- piperazinyl) benzo [b] thiophene, and structural formula is as follows:
Wherein, compound 1 is used as key intermediate, there is following several synthetic methods:
Big tomb patent CN101155804B discloses a kind of use sodium tert-butoxide/tris(dibenzylideneacetone) dipalladium/1,1'-
Compound 2,3 is carried out the coupling of carbon nitrogen and constructs the method for obtaining compound 1 by the bis- diphenyl phosphine systems of dinaphthalene -2,2'-, and route is as follows:
Separately have patent CN103717587A further disclose Metal Palladium various ligands in tertiary phosphine system, by 2,3
Or derivatives thereof coupling compound 1 is prepared, route is as follows:
Above-mentioned two methods prepare compound 1 has used Buchwald-Hartwig carbon-to-nitrogen coupling system, i.e., heavy
Catalyzing by metal palladium reaction, expensive, post-processing is complicated, and is easy to produce following two impurity (CN103717587A):
AndInfluence product quality.
There is patent CN105461703A, CN105399736A report to use 4- amino benzo [b] thiophene and bis- (2- chloroethenes
Base) amine hydrochlorate para toluene sulfonamide effect under be coupled, alkalization compound 1 is prepared, synthetic route is as follows:
Raw material 4- amino benzo [b] thiophene of the route need to be made by oneself to obtain, more difficult purchase in the market, and the reaction needs cyclization
Piperazine ring is obtained, conversion ratio is not high, is unfavorable for industrialized production.
The coupling reaction of fragrant alkyl halide and amine is typical necleophilic reaction, widely thinks that typically reaction is at present
Buchwald-Hartwig, i.e., fragrant halides are coupled to obtain virtue with amine under the palladium effect of the electrophilic ligand of catalytic amount
Fragrant amine, the regeneration of catalyst must have the presence of one quasi-alkali of sodium tert-butoxide.Two above-mentioned patents are also referring to this catalysis
System synthesizes to have obtained compound 1.
It is badly in need of improving the preparation of compound 1 at present, inquires into that a kind of technique is simple and direct, at low cost, high conversion rate, green
Environmentally friendly synthesis method, this will be of great significance to the exploitation according to piperazine azoles and its intermediate.
Summary of the invention
The object of the invention is to hold high to overcome to prepare in the prior art according to raw materials technology existing for piperazine azoles intermediate
Expensive, the problems such as industrialization is at high cost, reaction condition is harsh, unfriendly to environment, provides a kind of new according to piperazine azoles intermediate
Preparation method, the preparation method cost price is cheap, environmental pollution is less, easy to operate, can be adapted for industrialization industry.
In order to achieve the above object, the technical solution adopted by the present invention is as follows:
The preparation method of following formula: compound 1, this method are in the presence of cuprous catalysis agent and ligand, by alkali by compound
The halogenated benzo of 4- [b] thiophene and N-protected piperazine coupling reaction obtain compound 1
The cuprous catalysis agent is one of cuprous bromide, stannous chloride, cuprous iodide and cuprous oxide or a variety of.
It is preferred that cuprous iodide.
The preparation method of the compounds of this invention 1, the dosage of the cuprous catalysis agent can generally be catalyzed the reaction into
The molar ratio preferred 0.05-10:1, further preferably 0.1-2 of row, cuprous catalysis agent and the halogenated benzo of 4- [b] thiophene:
1, most preferred dosage molar ratio range is in 0.1-0.5:1.
The preparation method of the compounds of this invention 1, the ligand are L-PROLINE, in 1,10- ferrosin, 7- oxyquinoline
One or more, preferred L-PROLINE.The preferred 0.1-10:1 of molar ratio of ligand and the halogenated benzo of 4- [b] thiophene, further
Preferably 1-5:1, most preferred dosage molar ratio range is in 1:1-2:1.
The preparation method of the compounds of this invention 1, reaction organic solvent can be DMF, DMSO, DMAC, N- crassitude
One of ketone etc. is a variety of, preferably DMF.The volume mass ratio (ml/g) of organic solvent and the halogenated benzo of 4- [b] thiophene is preferred
1-20:1, more preferable 5-10:1.
The preparation method of the compounds of this invention 1, the alkali are not particularly limited, using conventional inorganic base,
Such as potassium carbonate, saleratus.
Beneficial effects of the present invention:
Prepare in the prior art raw materials technology according to piperazine azoles intermediate is expensive, industrialization is at high cost, reaction condition is harsh,
It is unfriendly to environment, it is difficult to industrial applications.Applicant of the present invention chances on, using cheap cuprous iodide suitable
Precious metal palladium can be substituted under ligand, high conversion is obtained according to a piperazine azoles midbody compound 1.
Using cuprous iodide etc. relative to the safer simplicity of palladium acetate, and its commercially available price is (about well below palladium acetate
It is 1/10th of palladium acetate), therefore provided by the invention according to a preparation among piperazine azoles, cost price is cheap, environment
It is of reduced contamination, easy to operate, it can be adapted for industrialization industry.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
The halogenated benzothiophene of raw material 4- and piperazine are by commercially available.N-boc piperazine can by patent (CN105237496A)
?
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.The reagents and materials used in the present invention are commercially available.
Embodiment 1
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25mlDMF (5V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, are concentrated to dryness, and 75ml toluene, 0~10 DEG C of dropwise addition dense salt of about 3ml is added
White solid is precipitated in system in acid, and 0~10 DEG C of stirring 1h filters out solid, and 45 DEG C dry to obtain 4.8g off-white powder, yield
80.54%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 2
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25mlDMF (5V), 0.27g L-PROLINE (2.3mmol,
0.1eq), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection are lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor 200ml methylene chloride extract primary, 0~10 DEG C of instillation 3ml concentrated hydrochloric acid, system precipitation white solid, and column chromatographs
3.0g off-white powder, yield 50.34%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 3
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25mlDMF (5V), 27g L-PROLINE (230mmol,
10.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection are lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out
Solid, mother liquor are extracted once with 200ml methylene chloride, are concentrated to dryness, and 75ml toluene is added, and 0~10 DEG C of dropwise addition about 3ml is dense
White solid is precipitated in system in hydrochloric acid, and 0~10 DEG C of stirring 1h filters out solid, and 45 DEG C dry to obtain 3.5g off-white powder, yield
58.73%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 4
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25mlDMF (5V), 1.35g L-PROLINE (11.7mmol,
0.5eq), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection are lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, are concentrated to dryness, and 75ml toluene, 0~10 DEG C of dropwise addition dense salt of about 3ml is added
White solid is precipitated in system in acid, and 0~10 DEG C of stirring 1h filters out solid, and 45 DEG C dry to obtain 3.4g off-white powder, yield
57.05%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 5
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25mlDMF (5V), 13.5g L-PROLINE (117mmol,
5.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection are lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, and 0~10 DEG C of instillation 3ml concentrated hydrochloric acid, column chromatographs to obtain 3.0g off-white powder,
Yield 50.34%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79
~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~7.01
(1H, d, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 6
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25mlDMF (5V), 5.4g L-PROLINE (46.9mmol,
2.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection are lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, are concentrated to dryness, and 75ml toluene, 0~10 DEG C of dropwise addition dense salt of about 3ml is added
White solid is precipitated in system in acid, and 0~10 DEG C of stirring 1h filters out solid, and 45 DEG C dry to obtain 4.0g off-white powder, yield
67.11%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 7
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 44.7g CuI (234.64mmol, 10eq), 25mlDMF (5V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, are concentrated to dryness, and 75ml toluene, 0~10 DEG C of dropwise addition dense salt of about 3ml is added
White solid is precipitated in system in acid, and 0~10 DEG C of stirring 1h filters out solid, and 45 DEG C dry to obtain 3.4g off-white powder, yield
57.05%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 8
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 8.9g CuI (46.93mmol, 2.0eq), 25mlDMF (5V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, and 0~10 DEG C of instillation 3ml concentrated hydrochloric acid, column chromatographs to obtain 3.0 off-white powders,
Yield 50.34%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79
~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~7.01
(1H, d, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 9
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 2.2g CuI (11.73mmol, 0.5eq), 25mlDMF (5V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, are concentrated to dryness, and 75ml toluene, 0~10 DEG C of dropwise addition dense salt of about 3ml is added
White solid is precipitated in system in acid, and 0~10 DEG C of stirring 1h filters out solid, and 45 DEG C dry to obtain 3.7 off-white powders, yield
62.1%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 10
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25mlDMF (5V), 42.3g 1,10- ferrosin
(234.64mmol, 10eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills
75ml water filters out solid, and mother liquor is extracted once with 200ml methylene chloride, is concentrated to dryness, addition 75ml toluene, and 0~10 DEG C
About 3ml concentrated hydrochloric acid is added dropwise, is precipitated white solid in system, 0~10 DEG C of stirring 1h filters out solid, 45 DEG C dry 3.3g class is white
Color solid, yield 55.37%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 11
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (4mmol, 2eq), 25mlDMF (5V), 4.2g 1.10- ferrosin (23.5mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection are lower to keep the temperature 110 DEG C of stirring 14h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, are concentrated to dryness, and 75ml toluene, 0~10 DEG C of dropwise addition dense salt of about 3ml is added
White solid~10 DEG C are precipitated in system and stir 1h, filter out solid, 45 DEG C dry to obtain 4.1g off-white powder, yield for acid
68.79%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 12
In 100ml there-necked flask be added 5g 4- bromobenzothiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous (70mmol,
3.0eq), 0.45gCuI (2.3mmol, 0.1eq), 0.42g 1,10- ferrosin (2.3mmol, 0.1eq), 25ml DMF
(5V), 3.2g K2CO3 (23.5mmol, 1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq), lower 110 DEG C of the heat preservation of N2 protection
14h is stirred, 75ml water is instilled, filters out solid, mother liquor is extracted once with 200ml DCM, is concentrated to dryness, and 75ml first is added
White solid is precipitated in system for benzene, 0~10 DEG C of dropwise addition about 3ml concentrated hydrochloric acid, and 0~10 DEG C of stirring 1h filters out solid, 45 DEG C of drying
Obtain 3.5g off-white powder, yield 58.73%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83
(1H, d, J=8.0Hz), 7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J
=16Hz), 7.06~7.01 (1H, d, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 13
In 100ml there-necked flask be added 5g 4- bromobenzothiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous (70mmol,
3.0eq), 0.45gCuI (2.3mmol, 0.1eq), 21.14g 1,10- ferrosin (117.32mmol, 5eq), 25ml DMF
(5V), 3.2g K2CO3 (23.5mmol, 1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq), the lower heat preservation 110 of N2 protection
DEG C stirring 14h, instills 75ml water, filters out solid, mother liquor 200ml DCM extracts primary, 0~10 DEG C of instillation 3ml concentrated hydrochloric acid, column
Chromatograph to obtain 3.0g off-white powder, yield 50.34%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 14
In 100ml there-necked flask be added 5g 4- bromobenzothiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous (70mmol,
3.0eq), 0.45gCuI (2.3mmol, 0.1eq), 8.5g 1,10- ferrosin (46.92mmol, 2.0eq), 25ml DMF
(5V), 3.2g K2CO3 (23.5mmol, 1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq), lower 110 DEG C of the heat preservation of N2 protection
14h is stirred, 75ml water is instilled, filters out solid, mother liquor 200ml DCM extracts primary, 0~10 DEG C of instillation 3ml concentrated hydrochloric acid, column layer
Analyse to obtain 3.2g off-white powder, yield 53.69%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 15
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6.1 Piperazine anhydrous are added in 100ml there-necked flask
(70.4mmol, 3.0eq), 0.45gCuI (2.35mmol, 0.1eq), 3.2g potassium carbonate (23.46mmol, 1.0eq), 0.68g
7- oxyquinoline (4.7mmol, 0.2eq), 25mlDMF (5V), 3.2g K2CO3 (23.5mmol, 1.0eq), the lower heat preservation of N2 protection
110 DEG C of stirring 14h instill 75ml water, filter out solid, and mother liquor is extracted once with 200ml DCM, is concentrated to dryness, and are added
75ml toluene, 0~10 DEG C of dropwise addition about 3ml concentrated hydrochloric acid are precipitated white solid in system, 0~10 DEG C of stirring 1h, filter out solid, and 45
DEG C dry to obtain 3.5g off-white powder, yield 58.73%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~
7.83 (1H, d, J=8.0Hz), 7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38
(1H, t, J=16Hz), 7.06~7.01 (1H, d, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09
[M+H ]+
Embodiment 16
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6.1 Piperazine anhydrous are added in 100ml there-necked flask
(70.4mmol, 3.0eq), 0.45gCuI (2.35mmol, 0.1eq), 3.2g potassium carbonate (23.46mmol, 1.0eq), 0.34g
7- oxyquinoline (2.3mmol, 0.1eq), 25mlDMF (5V), 3.2g K2CO3 (23.5mmol, 1.0eq), the lower heat preservation of N2 protection
110 DEG C of stirring 14h instill 75ml water, filter out solid, and mother liquor 200ml DCM extracts primary, 0~10 DEG C of dense salt of instillation 3ml
Acid, column chromatograph to obtain 2.8g off-white powder, yield 46.98%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 17
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6.1 Piperazine anhydrous are added in 100ml there-necked flask
(70.4mmol, 3.0eq), 0.45gCuI (2.35mmol, 0.1eq), 3.2g potassium carbonate (23.46mmol, 1.0eq), 34.1g
7- oxyquinoline (234.64mmol, 10eq), 25mlDMF (5V), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection is lower to be protected
110 DEG C of stirring 14h of temperature instill 75ml water, filter out solid, and mother liquor is extracted once with 200ml DCM, is concentrated to dryness, and are added
75ml toluene, 0~10 DEG C of dropwise addition about 3ml concentrated hydrochloric acid are precipitated white solid in system, 0~10 DEG C of stirring 1h, filter out solid, and 45
DEG C dry to obtain 3.5g off-white powder, yield 58.73%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~
7.83 (1H, d, J=8.0Hz), 7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38
(1H, t, J=16Hz), 7.06~7.01 (1H, d, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09
[M+H ]+
Embodiment 18
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6.1 Piperazine anhydrous are added in 100ml there-necked flask
(70.4mmol, 3.0eq), 0.45gCuI (2.35mmol, 0.1eq), 3.2g potassium carbonate (23.46mmol, 1.0eq), 17.0g
7- oxyquinoline (117.3mmol, 5eq), 25mlDMF (5V), 3.2g K2CO3 (23.5mmol, 1.0eq), the lower heat preservation of N2 protection
110 DEG C of stirring 14h instill 75ml water, filter out solid, and mother liquor 200ml DCM extracts primary, 0~10 DEG C of dense salt of instillation 3ml
Acid, column chromatograph to obtain 3.0g off-white powder, yield 50.34%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 19
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6.1 Piperazine anhydrous are added in 100ml there-necked flask
(70.4mmol, 3.0eq), 0.45gCuI (2.35mmol, 0.1eq), 3.2g potassium carbonate (23.46mmol, 1.0eq), 3.4g
7- oxyquinoline (23.46mmol, 1.0eq), 25mlDMF (5V), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection is lower to be protected
110 DEG C of stirring 14h of temperature instill 75ml water, filter out solid, and mother liquor is extracted once with 200ml DCM, is concentrated to dryness, and are added
75ml toluene, 0~10 DEG C of dropwise addition about 3ml concentrated hydrochloric acid, 0~10 DEG C of stirring 1h filter out solid, 45 DEG C dry 3.7g off-white color is solid
Body, yield 62.1%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 20
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6.1 Piperazine anhydrous are added in 100ml there-necked flask
(70.4mmol, 3.0eq), 0.45gCuI (2.35mmol, 0.1eq), 3.2g potassium carbonate (23.46mmol, 1.0eq), 6.8g
7- oxyquinoline (46.93mmol, 2.0eq), 25mlDMF (5V), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection is lower to be protected
110 DEG C of stirring 14h of temperature instill 75ml water, filter out solid, and mother liquor is extracted once with 200ml DCM, and 0~10 DEG C of instillation 3ml is dense
Hydrochloric acid, column chromatograph to obtain 3.0g off-white powder, yield 50.34%.1H-NMR(DMSO-d6,400MHz):9.54 (2H,s),
7.85~7.83 (1H, d, J=8.0Hz), 7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7.
38 (1H, t, J=16Hz), 7.06~7.01 (1H, d, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:
219.09[M+H ]+
Embodiment 21
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.34g CuBr (2.3mmol, 0.1eq), 25mlDMF (5V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, and 0~10 DEG C of instillation 3ml concentrated hydrochloric acid, column chromatographs to obtain 2.0g off-white powder, are received
Rate 33.56%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 22
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.34g CuBr (2.3mmol, 0.1eq), 25mlDMF (5V), 2.7g L-PROLINE (23mmol,
1.0eq).4.2g 1.10- ferrosin (23.5mmol, 1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq), under N2 protection
110 DEG C of stirring 14h are kept the temperature, 75ml water is instilled, filter out solid, mother liquor 200ml methylene chloride extracts primary, 0~10 DEG C of instillation
3ml concentrated hydrochloric acid, column chromatograph to obtain 2.2g off-white powder, yield 36.91%.1H-NMR(DMSO-d6,400MHz):9.54 (2H,
S), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42
~7. 38 (1H, t, J=16Hz), 7.06~7.01 (1H, d, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/
z:219.09[M+H ]+
Embodiment 23
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6.1 Piperazine anhydrous are added in 100ml there-necked flask
(70.4mmol, 3.0eq), 0.34CuBr (2.35mmol, 0.1eq), 3.2g potassium carbonate (23.46mmol, 1.0eq), 3.4g
7- oxyquinoline (23.46mmol, 1.0eq), 25mlDMF (5V), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection is lower to be protected
110 DEG C of stirring 14h of temperature instill 75ml water, filter out solid, and mother liquor is extracted once with 200ml DCM, and 0~10 DEG C of instillation 3ml is dense
Hydrochloric acid, column chromatograph to obtain 1.8g off-white powder, yield 30.2%.1H-NMR(DMSO-d6,400MHz):9.54 (2H,s),
7.85~7.83 (1H, d, J=8.0Hz), 7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7.
38 (1H, t, J=16Hz), 7.06~7.01 (1H, d, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:
219.09[M+H ]+
Embodiment 24
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.23g CuCl (2.3mmol, 0.1eq), 25mlDMF (5V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, and 0~10 DEG C of instillation 3ml concentrated hydrochloric acid, column chromatographs to obtain 2.0g off-white powder, are received
Rate 33.56%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 25
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.23g CuCl (2.3mmol, 0.1eq), 25mlDMF (5V), 2.7g L-PROLINE (23mmol,
1.0eq).Keep the temperature 110 DEG C of stirring 10h, 4.2g 1.10- ferrosins (23.5mmol, 1.0eq), 3.2g K2CO3 (23.5mmol,
1.0eq), N2 protection is lower keeps the temperature 110 DEG C of stirring 14h, instills 75ml water, filters out solid, mother liquor is extracted with 200ml methylene chloride
Once, 0~10 DEG C of instillation 3ml concentrated hydrochloric acid, column chromatograph to obtain 2.2g off-white powder, yield 36.91%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 26
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6.1 Piperazine anhydrous are added in 100ml there-necked flask
(70.4mmol, 3.0eq), 0.23CuCl (2.35mmol, 0.1eq), 3.2g potassium carbonate (23.46mmol, 1.0eq), 3.4g
7- oxyquinoline (23.46mmol, 1.0eq), 25mlDMF (5V), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection is lower to be protected
110 DEG C of stirring 14h of temperature instill 75ml water, filter out solid, and mother liquor is extracted once with 200ml DCM, and 0~10 DEG C of instillation 3ml is dense
Hydrochloric acid, column chromatograph to obtain 1.8g off-white powder, yield 30.2%.1H-NMR(DMSO-d6,400MHz):9.54 (2H,s),
7.85~7.83 (1H, d, J=8.0Hz), 7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7.
38 (1H, t, J=16Hz), 7.06~7.01 (1H, d, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:
219.09[M+H ]+
Embodiment 27
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.34g Cu2O (2.3mmol, 0.1eq), 25mlDMF (5V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, and 0~10 DEG C of instillation 3ml concentrated hydrochloric acid, column chromatographs to obtain 2.0g off-white powder, are received
Rate 33.56%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 28
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.34g Cu2O (2.3mmol, 0.1eq), 25mlDMF (5V), 2.7g L-PROLINE (23mmol,
1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, 4.2g 1.10- ferrosin (23.5mmol, 1.0eq), 3.2g K2CO3
(23.5mmol, 1.0eq), N2 protection is lower to keep the temperature 110 DEG C of stirring 14h, instills 75ml water, filters out solid, mother liquor 200ml bis-
Chloromethanes extraction is primary, and 0~10 DEG C of instillation 3ml concentrated hydrochloric acid, column chromatographs to obtain 2.2g off-white powder, yield 36.91%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 29
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6.1 Piperazine anhydrous are added in 100ml there-necked flask
(70.4mmol, 3.0eq), 0.34Cu2O (2.35mmol, 0.1eq), 3.2g potassium carbonate (23.46mmol, 1.0eq), 3.4g
7- oxyquinoline (23.46mmol, 1.0eq), 25mlDMF (5V), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection is lower to be protected
110 DEG C of stirring 14h of temperature instill 75ml water, filter out solid, and mother liquor is extracted once with 200ml DCM, and 0~10 DEG C of instillation 3ml is dense
Hydrochloric acid, column chromatograph to obtain 1.8g off-white powder, yield 30.2%.1H-NMR(DMSO-d6,400MHz):9.54 (2H,s),
7.85~7.83 (1H, d, J=8.0Hz), 7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7.
38 (1H, t, J=16Hz), 7.06~7.01 (1H, d, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:
219.09[M+H ]+
Embodiment 30
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 5mlDMF (1V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, are concentrated to dryness, and 75ml toluene, 0~10 DEG C of dropwise addition dense salt of about 3ml is added
White solid is precipitated in system in acid, and 0~10 DEG C of stirring 1h filters out solid, and 45 DEG C dry to obtain 3.5g off-white powder, yield
58.73%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 31
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 100mlDMF (20V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, are concentrated to dryness, and 75ml toluene, 0~10 DEG C of dropwise addition dense salt of about 3ml is added
White solid is precipitated in system in acid, and 0~10 DEG C of stirring 1h filters out solid, and 45 DEG C dry to obtain 3.8g off-white powder, yield
63.76%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4 H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 32
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 50mlDMF (10V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, are concentrated to dryness, and 75ml toluene, 0~10 DEG C of dropwise addition dense salt of about 3ml is added
White solid is precipitated in system in acid, and 0~10 DEG C of stirring 1h filters out solid, and 45 DEG C dry to obtain 4.0g off-white powder, yield
67.11%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 33
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25ml DMSO (5V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, are concentrated to dryness, and 75ml toluene is added, the dense salt of about 3ml is added dropwise at room temperature
White solid is precipitated in system in acid, and 0~10 DEG C of stirring 1h filters out solid, and 45 DEG C dry to obtain 3.7g off-white powder, yield
62.08%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 34
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 100ml DMSO (20V), 2.7g L-PROLINE
(23mmol, 1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml
Water filters out solid, and mother liquor is extracted once with 200ml methylene chloride, is concentrated to dryness, and 75ml toluene, 0~10 DEG C of dropwise addition is added
About 3ml concentrated hydrochloric acid, is precipitated white solid in system, 0~10 DEG C of stirring 1h, filters out solid, 45 DEG C dry 3.7g off-white color is solid
Body, yield 62.08%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz),
7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~
7.01 (1H, d, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 35
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 5ml DMSO (1V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, and 0~10 DEG C of instillation 3ml concentrated hydrochloric acid, column chromatographs to obtain 3.0g off-white powder, are received
Rate 50.34%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 36
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 13.2g N-Boc piperazine are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25mlDMF (5V), 2.7g L-PROLINE (23mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml water, filters out solid
Body, mother liquor are extracted once with 200ml methylene chloride, and 0~10 DEG C of instillation 8ml concentrated hydrochloric acid, column chromatographs to obtain 3.2g off-white powder, are received
Rate 53.69%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4 H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 37
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 13.2g N-Boc piperazine are added in 100ml there-necked flask
(70.4mmol, 3.0eq), 0.23CuCl (2.35mmol, 0.1eq), 3.2g potassium carbonate (23.46mmol, 1.0eq), 3.4g 7-
Oxyquinoline (23.46mmol, 1.0eq), 25mlDMF (5V), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection is lower to be protected
110 DEG C of stirring 14h of temperature instill 75ml water, filter out solid, and mother liquor 200ml DCM extracts primary, 0~10 DEG C of dense salt of instillation 8ml
Acid, column chromatograph to obtain 2.1g off-white powder, yield 35%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4 H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 38
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 13.2g N-Boc piperazine are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (4mmol, 2eq), 25mlDMF (5V), 4.2g 1.10- ferrosin (23.5mmol,
1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq), N2 protection are lower to keep the temperature 110 DEG C of stirring 14h, instills 75ml water, filters out solid
Body, water phase mother liquor 200ml methylene chloride extract primary, 0~10 DEG C of instillations 8ml concentrated hydrochloric acid, column chromatograph 3.3g off-white color is consolidated
Body, yield 55.37%.1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz),
7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7. 38 (1H, t, J=16Hz), 7.06~
7.01 (1H, d, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 39
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 13.2g N-Boc piperazine are added in 100ml there-necked flask
(70.4mmol, 3.0eq), 0.23CuCl (2.35mmol, 0.1eq), 3.2g potassium carbonate (23.46mmol, 1.0eq), 3.4g
7- oxyquinoline (23.46mmol, 1.0eq), 25mlDMAC (5V), 3.2g K2CO3 (23.5mmol, 1.0eq), under N2 protection
110 DEG C of stirring 14h are kept the temperature, 75ml water is instilled, filter out solid, mother liquor is extracted once with 200ml DCM, and 0~10 DEG C of instillation 8ml is dense
Hydrochloric acid, column chromatograph to obtain 2.1g off-white powder, yield 35%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4 H, s) .MS/ES:m/z:219.09 [M+H]+
Embodiment 40
5g 4- bromobenzene simultaneously [b] thiophene (23.5mmol, 1.0eq), 6g Piperazine anhydrous are added in 100ml there-necked flask
(70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25mlN- methyl pyrrolidone (5V), 2.7g L-PROLINE
(23mmol, 1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq).N2 protection is lower to keep the temperature 110 DEG C of stirring 10h, instills 75ml
Water filters out solid, and mother liquor is extracted once with 200ml methylene chloride, is concentrated to dryness, and 75ml toluene, 0~10 DEG C of dropwise addition is added
About 3ml concentrated hydrochloric acid, is precipitated white solid in system, 0~10 DEG C of stirring 1h, filters out solid, 45 DEG C dry 2.4g off-white color is solid
Body, yield 40.27%.
1H-NMR (DMSO-d6,400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~
7.77 (1H, d, J=8.0H z), 7.62~7.61 (1H, m), 7.42~7.38 (1H, t, J=16Hz), 7.06~7.01 (1H,
D, J=8Hz), 3.44 (4H, s), 3.39 (4H, s) .MS/ES:m/z:219.09 [M+H]+.
Claims (10)
1. the preparation method of following formula: compound 1, this method is in the presence of cuprous catalysis agent and ligand, by alkali by compound 4-
Halogenated benzo [b] thiophene and N-protected piperazine coupling reaction obtain compound 1
The cuprous catalysis agent is one of cuprous bromide, stannous chloride, cuprous iodide and cuprous oxide or a variety of.
2. the preparation method of compound 1 as described in claim 1, it is characterised in that: the cuprous catalysis agent is that iodate is sub-
Copper.
3. the preparation method of compound 1 as described in claim 1, it is characterised in that: the ligand be L-PROLINE, 1,
One of 10- ferrosin, 7- oxyquinoline are a variety of.
4. the preparation method of compound 1 as claimed in claim 3, it is characterised in that: the ligand is L-PROLINE.
5. the preparation method of compound 1 as described in claim 1, it is characterised in that: the cuprous catalysis agent and 4- are halogenated
The molar ratio of benzo [b] thiophene is 0.1-2:1.
6. the preparation method of compound 1 as claimed in claim 5, it is characterised in that: the cuprous catalysis agent and 4- are halogenated
The molar ratio of benzo [b] thiophene is 0.1-0.5:1.
7. the preparation method of compound 1 as described in claim 1, it is characterised in that: the halogenated benzo of ligand and 4- [b]
The molar ratio of thiophene is 1-5:1.
8. the preparation method of compound 1 as claimed in claim 8, it is characterised in that: the halogenated benzo of ligand and 4- [b]
The molar ratio of thiophene is 1:1-2:1.
9. the preparation method of compound 1 as described in claim 1, it is characterised in that: reaction organic solvent be DMF, DMSO,
One of DMAC, N-Methyl pyrrolidone etc. are a variety of.
10. the preparation method of compound 1 as claimed in claim 9, it is characterised in that: organic solvent and the halogenated benzo of 4- [b]
The volume mass ratio (ml/g) of thiophene is 1-20:1.
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Cited By (5)
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| CN109970705A (en) * | 2019-05-14 | 2019-07-05 | 浙江工业大学 | A method of it is standby according to piperazine azoles intermediate and according to a piperazine azoles using cheap metal copper |
| CN110092778A (en) * | 2019-05-14 | 2019-08-06 | 浙江工业大学 | A method of using cheap metal copper for vilazodone intermediate and vilazodone drug |
| CN115677655A (en) * | 2022-09-26 | 2023-02-03 | 湖南省湘中制药有限公司 | Synthesis method of brexpiprazole intermediate |
| CN116120276A (en) * | 2022-11-28 | 2023-05-16 | 安徽省化工研究院 | Synthesis method of benzothiophene derivative |
| CN118580229A (en) * | 2024-08-07 | 2024-09-03 | 湖南一格制药有限公司 | Preparation method of bripiprazole |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109970705A (en) * | 2019-05-14 | 2019-07-05 | 浙江工业大学 | A method of it is standby according to piperazine azoles intermediate and according to a piperazine azoles using cheap metal copper |
| CN110092778A (en) * | 2019-05-14 | 2019-08-06 | 浙江工业大学 | A method of using cheap metal copper for vilazodone intermediate and vilazodone drug |
| CN115677655A (en) * | 2022-09-26 | 2023-02-03 | 湖南省湘中制药有限公司 | Synthesis method of brexpiprazole intermediate |
| CN115677655B (en) * | 2022-09-26 | 2023-12-08 | 湖南省湘中制药有限公司 | Synthesis method of epinastine intermediate |
| CN116120276A (en) * | 2022-11-28 | 2023-05-16 | 安徽省化工研究院 | Synthesis method of benzothiophene derivative |
| CN116120276B (en) * | 2022-11-28 | 2024-07-09 | 安徽省化工研究院 | Synthesis method of benzothiophene derivative |
| CN118580229A (en) * | 2024-08-07 | 2024-09-03 | 湖南一格制药有限公司 | Preparation method of bripiprazole |
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