CN103382187A - 3-chloro-7(5)-bromo-benzo-isoxazole compounding method - Google Patents
3-chloro-7(5)-bromo-benzo-isoxazole compounding method Download PDFInfo
- Publication number
- CN103382187A CN103382187A CN2013103417089A CN201310341708A CN103382187A CN 103382187 A CN103382187 A CN 103382187A CN 2013103417089 A CN2013103417089 A CN 2013103417089A CN 201310341708 A CN201310341708 A CN 201310341708A CN 103382187 A CN103382187 A CN 103382187A
- Authority
- CN
- China
- Prior art keywords
- chloro
- bromo
- fluoro
- isoxzzole
- petroleum ether
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a 3-chloro-7(5)-bromo-benzo-isoxazole compounding method which includes utilizing bromofluorobenzene as a raw material, acidizing the raw material to obtain 2-fluoro-3-bromobenzoic-acid, esterifying the 2-fluoro-3-bromobenzoic-acid to obtain 2-fluoro-3-methyl-bromobenzoate, enabling the 2-fluoro-3-methyl-bromobenzoate to react with N-acetyl-hydroxylamine to obtain 7-bromo-3-benzo-isoxazolone, and finally chloridizing the 7-bromo-3-benzo-isoxazolone to obtain 3-chloro-7-bromo-benzo-isoxazole; utilizing 2-fluoro-5-bromobenzoic-acid as a raw material, esterifying the 2-fluoro-5-bromobenzoic-acid to obtain 2-fluoro-5-methyl-bromobenzoate, enabling the 2-fluoro-5-methyl-bromobenzoate to react with the N-acetyl-hydroxylamine to obtain 5-bromo-3-benzo-isoxazolone, and finally chloridizing the 5-bromo-3-benzo-isoxazolone to obtain the 3-chloro-5-bromo-benzo-isoxazole. The method is low in raw material price and cost, fewer in reaction steps, simple in post treatment, high in total recovery and capable of reducing environment pollution.
Description
Technical field
The present invention relates to technical field of organic synthesis, especially relate to the synthetic method of a kind of 3-chloro-7-bromobenzene and isoxzzole and isomers 3-chloro-5-bromobenzene and isoxzzole.
Background technology
The synthetic skeleton structure that needs novelty of modern new drug.The most of chemical new drug of having reported at present, its molecular skeleton is all heterocycle structure, such as the main component of s-generation Antipsychotic Drug Risperidone is the benzo isoxazole class.The basic framework of benzisoxa oxazole analog derivative is the benzisoxa oxazole, and this skeleton structure has obvious constitutional features, on one side it is hydrophilic-structure, the other side is the oleophylic structure, can successfully enter in cytolemma, in vivo effect; Also have two hydrogen bonded to be subjected to the site on its structure, can be well and receptors bind; Benzisoxa oxazole or the bioisostere of benzamide, and benzamide is the most common structure of functional groups in the chemical small molecules of known report; By introduce different types of functional group on the skeleton structure of benzisoxa oxazole feature, can also increase the molecular structures diversity.Therefore fast simple synthetic compound with benzisoxa oxazole skeleton has very important significance.
Publication number CN101245065A, in the Chinese patent in open day on August 20th, 2008, a kind of method for preparing benzisoxa oxazole analog derivative is disclosed, it is first with 2, the 3-of 4-difluorophenyl-4-piperidyl-ketoxime or acid salt and replacement (2-chloroethyl)-2-methyl-4H pyrido [1,2-A] the pyrimidin-4-one reaction, generate the Pyridopyrimidinone derivatives of new replacement, then through closed loop, hydrogenation reduction, produce the benzisoxa oxazole derivatives.Expensive raw material price in the method, cost is high, the most important thing is that the method will just can obtain having the derivative of benzisoxa oxazole skeleton by closed loop and hydrogenation at last, and reactions steps is loaded down with trivial details, and severe reaction conditions, and efficiency of pcr product is low.
The invention provides a kind of 3-chloro-7(5)-the fast simple synthetic method of bromobenzene and isoxzzole, the method is used cheap raw material, and process is easily controlled, and reactions steps is few, and aftertreatment is simple, and total recovery is high, has reduced simultaneously environmental pollution.
Summary of the invention
The object of the present invention is to provide a kind of 3-chloro-7(5)-synthetic method of bromobenzene and isoxzzole, can obtain fast the compound of the benzisoxa oxazole skeleton that has by the present invention, and method cost of material of the present invention is cheap, process is easily controlled, reactions steps is few, aftertreatment is simple, and total recovery is high, has added the H of catalytic amount when chlorination
3PO
4, reduced POCl
3Consumption, hot sherwood oil extracting is directly adopted in aftertreatment, sherwood oil can reclaim, and further reduces costs, and has reduced simultaneously environmental pollution.
To achieve these goals, the present invention is by the following technical solutions:
The synthetic method of a kind of 3-chloro-7-bromobenzene and isoxzzole, described synthetic method comprises the following steps:
(1) 2-fluoro-3-bromo-benzoic acid is synthetic
the adjacent bromofluorobenzene of 13.5～14.5g is dissolved in 140～150mL anhydrous tetrahydro furan and is cooled to-65～-70 ℃, drip the LDA that 102～105mL concentration is 1.0～1.3mol/L under nitrogen protection, LDA dropwises in 30min, constantly stir during this time, continue to stir 30～40min after dropwising under the constant temperature of-65～-70 ℃, then reaction solution is poured in the reaction vessel that 200～210g dry ice is housed, be stirred to without being spin-dried for after Bubble formation, add 200～210mL water to dilute to get diluent in reaction vessel, regulate diluent pH to 4～5 rear filtrations, the frozen water washing leaching cake, in 50～60 ℃ of lower vacuum-dryings, get white solid, it is 2-fluoro-3-bromo-benzoic acid.The reaction formula of this step is:
(2) 2-fluoro-3-methyl-bromobenzoate is synthetic
The 2-fluoro-3-bromo-benzoic acid that 10～10.5g step (1) is obtained joins the SOCl of 80～85mL
2In, after reflux stirs 12～14h, SOCl is reclaimed in air distillation
2, residuum is splashed in 20～30mL anhydrous methanol, during constantly stir, dropwise rear continuation and stir 30～40min, be concentrated into driedly, get brown solid, i.e. 2-fluoro-3-methyl-bromobenzoate.The reaction formula of this step is:
(3) 7-bromo-3-benzisoxa oxazolone is synthetic
Add 38～39g potassium tert.-butoxide after 25～26gN-ethanoyl azanol being dissolved in the DMF of 600～650mL drying; stir the 2-fluoro-3-methyl-bromobenzoate that adds 40～42g step (2) to obtain after 30～40min; stir 24～30h after being heated to 85～87 ℃; underpressure distillation is diluted with water to 500～600mL after reclaiming DMF; and use ethyl acetate extraction; lower water saving phase pH to 4～5 rear stirring 30～60min at-1～0 ℃; filter; filtrate is rear in 50～60 ℃ of lower vacuum-dryings with the frozen water washing; get field gray solid, i.e. 7-bromo-3-benzisoxa oxazolone.The reaction formula of this step is:
(4) 3-chloro-7-bromobenzene and isoxzzole is synthetic
POCl with 19～20mL
3H with 1.9～2.1mL
3PO
4Join in the 7-bromo-3-benzisoxa oxazolone that 22.5～23g step (3) obtains, at room temperature drip 7.9～8g pyridine post-heating to 90～95 ℃ and isothermal reaction 24～30h, add 200～210mL sherwood oil after being cooled to 50～55 ℃, pour out petroleum ether layer after stirring 30～35min, petroleum ether layer is dry, filter, be concentrated into dried, get white solid, i.e. 3-chloro-7-bromobenzene and isoxzzole.The reaction formula of this step is:
As preferably, in step (3), potassium tert.-butoxide by etc. quality divide 3～4 times to add.Potassium tert.-butoxide by etc. quality divide the stability that adds to control reaction for 3～4 times.
As preferably, in step (3), during extraction, the add-on of ethyl acetate is 100～110mL, and extraction times is 3～4 times, merges water after extraction.
As preferably, in step (4), after petroleum ether layer is poured out, add again 200～210mL sherwood oil in residuum, pour out petroleum ether layer after stirring 30～35min, so repeat to extract 2～3 times, merge petroleum ether layer.
As preferably, in step (4), petroleum ether layer adopts anhydrous sodium sulfate drying.
The synthetic method of a kind of 3-chloro-5-bromobenzene and isoxzzole, described synthetic method comprises the following steps:
Synthesizing of (I) 2-fluoro-5-methyl-bromobenzoate
20～21g2-fluoro-5-bromo-benzoic acid is joined 150～160mL SOCl
2In, after reflux stirs 12～14h, SOCl is reclaimed in air distillation
2, residuum is splashed in 50～60mL anhydrous methanol, during constantly stir, dropwise rear continuation and stir 30～40min, be concentrated into driedly, get faint yellow oily thing, i.e. 2-fluoro-5-methyl-bromobenzoate.The reaction formula of this step is:
Synthesizing of (II) 5-bromo-3-benzisoxa oxazolone
Add 38～39g potassium tert.-butoxide after 25～26gN-ethanoyl azanol being dissolved in the DMF of 600～650mL drying; stir the 2-fluoro-3-methyl-bromobenzoate that adds 40～42g step (II) to obtain after 30～40min; stir 24～30h after being heated to 85～87 ℃; underpressure distillation is diluted with water to 500～600mL after reclaiming DMF; and use ethyl acetate extraction; lower water saving phase pH to 4～5 rear stirring 30～60min at-1～0 ℃; filter; filtrate is rear in 50～60 ℃ of lower vacuum-dryings with the frozen water washing; get beige solid, i.e. 5-bromo-3-benzisoxa oxazolone.The reaction formula of this step is:
Synthesizing of (III) 3-chloro-5-bromobenzene and isoxzzole
POCl with 19～20mL
3H with 1.9～2.1mL
3PO
4Join in the 5-bromo-3-benzisoxa oxazolone that 21.2～21.6g step (II) obtains, at room temperature drip 7.9～8g pyridine post-heating to 90～95 ℃ and isothermal reaction 24～30h, add 200～210mL sherwood oil after being cooled to 50～55 ℃, pour out petroleum ether layer after stirring 30～35min, petroleum ether layer is dry, filter, be concentrated into dried, get white solid, i.e. 3-chloro-5-bromobenzene and isoxzzole.The reaction formula of this step is:
As preferably, in step (II), potassium tert.-butoxide by etc. quality divide 3～4 times to add.
As preferably, in step (II), during extraction, the add-on of ethyl acetate is 100～110mL, and extraction times is 3～4 times, merges water after extraction.
As preferably, in step (III), after petroleum ether layer is poured out, add again 200～210mL sherwood oil in residuum, pour out petroleum ether layer after stirring 30～35min, so repeat to extract 2～3 times, merge petroleum ether layer.
As preferably, in step (III), petroleum ether layer adopts anhydrous sodium sulfate drying.
Therefore, the present invention has following beneficial effect:
(1) each reaction raw materials is all commercially available, and cost of material is low, is conducive to control cost;
(2) reactions steps is few, the stable easily control of reaction process, and aftertreatment is simple, and total recovery is high;
(3) added the H of catalytic amount during chlorination
3PO
4, reduced POCl
3Consumption, hot sherwood oil extracting is directly adopted in aftertreatment, sherwood oil can reclaim, and further reduces costs, and has reduced simultaneously environmental pollution.
Embodiment
The present invention will be further described below by embodiment.
In the present invention, if not refer in particular to, all per-cents are weight unit, and all devices and raw material all can be buied from market or the industry is commonly used, and the method in following embodiment if no special instructions, is this area ordinary method.
Embodiment 1
One, 3-chloro-7-bromobenzene and isoxzzole is synthetic
(1) 2-fluoro-3-bromo-benzoic acid is synthetic
the adjacent bromofluorobenzene of 13.5g is dissolved in the 140mL anhydrous tetrahydro furan and is cooled to-70 ℃, dripping 105mL concentration under nitrogen protection is the LDA of 1.0mol/L, LDA dropwises in 30min, constantly stir during this time, continue to stir 30min after dropwising under the constant temperature of-70 ℃, then reaction solution is poured in the reaction vessel that 200g dry ice is housed, be stirred to without being spin-dried for after Bubble formation, add 200mL water to dilute to get diluent in reaction vessel, regulate the rear filtration of diluent pH to 5, the frozen water washing leaching cake, in 50 ℃ of lower vacuum-dryings, get 16.2 white solids, it is 2-fluoro-3-bromo-benzoic acid, yield is 95.9%.
LC-MS[ESI，m/z]：[M+1]
+=218.9/220.8(1/1)。
1H?NMR(400MHz,DMSO-d
6)δ13.60(s,1H),7.94(ddd,J=8.0,6.4,1.7Hz,1H),7.86(ddd,J=8.3,6.8,1.7Hz,1H),7.26(t,J=8.0,1H)。
(2) 2-fluoro-3-methyl-bromobenzoate is synthetic
The 2-fluoro-3-bromo-benzoic acid that 10g step (1) is obtained joins the SOCl of 80mL
2In, after reflux stirs 12h, SOCl is reclaimed in air distillation
2, residuum is splashed in the 20mL anhydrous methanol, during constantly stir, dropwise rear continuation and stir 30min, be concentrated into driedly, get the 10.01g brown solid, i.e. 2-fluoro-3-methyl-bromobenzoate, yield is 94.1%.
LC-MS[ESI，m/z]：[M+1]
+=232.8/234.8(1/1)。
1H-NMR(400MHz,DMSO-d
6)δ7.86(ddd,J=7.9,6.6,1.6Hz,1H),7.73(ddd,J=7.9,6.2,1.6Hz,1H),7.09(t,J=7.9Hz,1H),3.94(s,3H)。
(3) 7-bromo-3-benzisoxa oxazolone is synthetic
add the 38g potassium tert.-butoxide after 25gN-ethanoyl azanol being dissolved in the DMF of 600mL drying, potassium tert.-butoxide by etc. quality divide 3 times to add, stir the 2-fluoro-3-methyl-bromobenzoate that adds 40g step (2) to obtain after 30min, stir 30h after being heated to 85 ℃, underpressure distillation is diluted with water to 500mL after reclaiming DMF, and with 100mL ethyl acetate extraction 3 times, merge water after extraction, lower the rear stirring of water saving phase pH to 4 30min at 0 ℃, filter, filtrate is rear in 50 ℃ of lower vacuum-dryings with the frozen water washing, get 29.57g field gray solid, it is 7-bromo-3-benzisoxa oxazolone, yield is 80.5%.
LC-MS[ESI，m/z]：[M+1]
+=213.9/215.9(1/1)。
1H-NMR(400MHz,DMSO-d
6)δ12.44(br,s,1H),7.82(dd,J=7.9,0.8Hz,1H),7.80(dd,J=7.9,0.8Hz,1H),6.87(t,J=7.9Hz,1H)。
(4) 3-chloro-7-bromobenzene and isoxzzole is synthetic
POCl with 19mL
3H with 1.9mL
3PO
4Join in the 7-bromo-3-benzisoxa oxazolone that 22.5g step (3) obtains, at room temperature drip 7.9g pyridine post-heating to 90 ℃ and isothermal reaction 30h, add the 200mL sherwood oil after being cooled to 50 ℃, pour out petroleum ether layer after stirring 30min, so repeat to extract 2 times, merge petroleum ether layer, petroleum ether layer is adopted anhydrous sodium sulfate drying, filter, be concentrated into dried, the 18.6g white solid, i.e. 3-chloro-7-bromobenzene and isoxzzole, yield is 76%.
1H-NMR(400MHz,CDCl
3)δ7.80(dd,J=7.7,0.7Hz,1H),7.65(dd,J=7.9,0.7Hz,1H),7.30(t,J=7.8Hz,1H)。
Two, 3-chloro-5-bromobenzene and isoxzzole is synthetic
Synthesizing of (I) 2-fluoro-5-methyl-bromobenzoate
20g2-fluoro-5-bromo-benzoic acid is joined 150mL SOCl
2In, after reflux stirs 12h, SOCl is reclaimed in air distillation
2, residuum is splashed in the 50mL anhydrous methanol, during constantly stir, dropwise rear continuation and stir 30min, be concentrated into driedly, get the faint yellow oily thing of 20.53g, i.e. 2-fluoro-5-methyl-bromobenzoate, yield is 96.5%.
LC-MS[ESI，m/z]：[M+1]
+=232.8/234.8(1/1)。
1H-NMR(400MHz,DMSO-d
6)δ8.05(dd,J=6.4,2.6Hz,1H),7.64-7.57(m,1H),7.03(dd,J=10.1,8.8Hz,1H),3.93(s,3H).。
Synthesizing of (II) 5-bromo-3-benzisoxa oxazolone
Add the 38g potassium tert.-butoxide after 25gN-ethanoyl azanol being dissolved in the DMF of 600mL drying, potassium tert.-butoxide by etc. quality divide 3 times to add.Stir the 2-fluoro-5-methyl-bromobenzoate that adds 40g step (I) to obtain after 30min, stir 24h after being heated to 85 ℃, underpressure distillation is diluted with water to 500mL after reclaiming DMF, and with 100mL ethyl acetate extraction 3 times, merging water, lower the rear stirring of water saving phase pH to 5 30min at 0 ℃, filter, filtrate is rear in 50～60 ℃ of lower vacuum-dryings with the frozen water washing, gets 32.04g beige solid, be 5-bromo-3-benzisoxa oxazolone, yield is 87.2%.
LC-MS[ESI，m/z]：[M+1]
+=213.9/215.9(1/1)。
1H-NMR(400MHz,DMSO-d
6)δ12.88(br,s,1H),7.96(d,J=1.8Hz,1H),7.72(dd,J=8.9,1.8Hz,1H),7.54(d,J=8.9Hz,1H)。
1H-NMR(400MHz,CDCl
3)δ7.92(d,J=1.9Hz,1H),7.69(dd,J=8.9,1.9Hz,1H),7.33(d,J=8.9Hz,1H)。
Synthesizing of (III) 3-chloro-5-bromobenzene and isoxzzole
POCl with 19mL
3H with 1.9mL
3PO
4Join in the 5-bromo-3-benzisoxa oxazolone that 21.2g step (II) obtains, at room temperature drip 7.9g pyridine post-heating to 90 ℃ and isothermal reaction 24h, add the 200mL sherwood oil after being cooled to 50 ℃, pour out petroleum ether layer after stirring 30min, so repeat to extract 2 times, merge petroleum ether layer, petroleum ether layer is adopted anhydrous sodium sulfate drying, filter, be concentrated into dried, the 19.00g white solid, i.e. 3-chloro-5-bromobenzene and isoxzzole, yield is 82.5%.
1H-NMR(400MHz,CDCl
3)δ7.85(d,J=1.9Hz,1H),7.72(dd,J=8.9,1.9Hz,1H),7.50(d,J=8.9Hz,1H)。
Embodiment 2
One, 3-chloro-7-bromobenzene and isoxzzole is synthetic
(1) 2-fluoro-3-bromo-benzoic acid is synthetic
the adjacent bromofluorobenzene of 14g is dissolved in the 145mL anhydrous tetrahydro furan and is cooled to-67 ℃, dripping 102mL concentration under nitrogen protection is the LDA of 1.1mol/L, LDA dropwises in 30min, constantly stir during this time, continue to stir 35min after dropwising under the constant temperature of-67 ℃, then reaction solution is poured in the reaction vessel that 205g dry ice is housed, be stirred to without being spin-dried for after Bubble formation, add 205mL water to dilute to get diluent in reaction vessel, regulate the rear filtration of diluent pH to 4.5, the frozen water washing leaching cake, in 55 ℃ of lower vacuum-dryings, get 16.95 white solids, it is 2-fluoro-3-bromo-benzoic acid, yield is 96.8%.
LC-MS[ESI，m/z]：[M+1]
+=218.9/220.8(1/1)。
1H?NMR(400MHz,DMSO-d
6)δ13.60(s,1H),7.94(ddd,J=8.0,6.4,1.7Hz,1H),7.86(ddd,J=8.3,6.8,1.7Hz,1H),7.26(t,J=8.0,1H)。
(2) 2-fluoro-3-methyl-bromobenzoate is synthetic
The 2-fluoro-3-bromo-benzoic acid that 10.3g step (1) is obtained joins the SOCl of 82mL
2In, after reflux stirs 13h, SOCl is reclaimed in air distillation
2, residuum is splashed in the 25mL anhydrous methanol, during constantly stir, dropwise rear continuation and stir 35min, be concentrated into driedly, get the 10.33g brown solid, i.e. 2-fluoro-3-methyl-bromobenzoate, yield is 94.3%.
LC-MS[ESI，m/z]：[M+1]
+=232.8/234.8(1/1)。
1H-NMR(400MHz,DMSO-d
6)δ7.86(ddd,J=7.9,6.6,1.6Hz,1H),7.73(ddd,J=7.9,6.2,1.6Hz,1H),7.09(t,J=7.9Hz,1H),3.94(s,3H)。
(3) 7-bromo-3-benzisoxa oxazolone is synthetic
add the 38.4g potassium tert.-butoxide after 25.5gN-ethanoyl azanol being dissolved in the DMF of 630mL drying, potassium tert.-butoxide by etc. quality divide 3 times to add, stir the 2-fluoro-3-methyl-bromobenzoate that adds 41g step (2) to obtain after 30～40min, stir 25h after being heated to 86 ℃, underpressure distillation is diluted with water to 550mL after reclaiming DMF, and with 105mL ethyl acetate extraction 3 times, merge water after extraction, lower the rear stirring of water saving phase pH to 4.5 45min at-0.5 ℃, filter, filtrate is rear in 55 ℃ of lower vacuum-dryings with the frozen water washing, get 30.5g field gray solid, it is 7-bromo-3-benzisoxa oxazolone, yield is 81%.
LC-MS[ESI，m/z]：[M+1]
+=213.9/215.9(1/1)。
1H-NMR(400MHz,DMSO-d
6)δ12.44(br,s,1H),7.82(dd,J=7.9,0.8Hz,1H),7.80(dd,J=7.9,0.8Hz,1H),6.87(t,J=7.9Hz,1H)。
(4) 3-chloro-7-bromobenzene and isoxzzole is synthetic
POCl with 20mL
3H with 2mL
3PO
4Join in the 7-bromo-3-benzisoxa oxazolone that 22.7g step (3) obtains, at room temperature drip 7.95g pyridine post-heating to 92 ℃ and isothermal reaction 26h, add the 205mL sherwood oil after being cooled to 52 ℃, pour out petroleum ether layer after stirring 32min, so repeat to extract 2 times, merge petroleum ether layer, petroleum ether layer is adopted anhydrous sodium sulfate drying, filter, be concentrated into dried, the 18.8g white solid, i.e. 3-chloro-7-bromobenzene and isoxzzole, yield is 76.3%.
1H-NMR(400MHz,CDCl
3)δ7.80(dd,J=7.7,0.7Hz,1H),7.65(dd,J=7.9,0.7Hz,1H),7.30(t,J=7.8Hz,1H)。
Two, 3-chloro-5-bromobenzene and isoxzzole is synthetic
Synthesizing of (I) 2-fluoro-5-methyl-bromobenzoate
20.5g2-fluoro-5-bromo-benzoic acid is joined 155mL SOCl
2In, after reflux stirs 13h, SOCl is reclaimed in air distillation
2, residuum is splashed in the 55mL anhydrous methanol, during constantly stir, dropwise rear continuation and stir 35min, be concentrated into driedly, get the faint yellow oily thing of 21.09g, i.e. 2-fluoro-5-methyl-bromobenzoate, yield is 96.7%.
LC-MS[ESI，m/z]：[M+1]
+=232.8/234.8(1/1)。
1H-NMR(400MHz,DMSO-d
6)δ8.05(dd,J=6.4,2.6Hz,1H),7.64-7.57(m,1H),7.03(dd,J=10.1,8.8Hz,1H),3.93(s,3H).。
Synthesizing of (II) 5-bromo-3-benzisoxa oxazolone
add the 38.5g potassium tert.-butoxide after 25～26gN-ethanoyl azanol being dissolved in the DMF of 630mL drying, potassium tert.-butoxide by etc. quality divide 3 times to add, stir the 2-fluoro-5-methyl-bromobenzoate that adds 41g step (I) to obtain after 35min, stir 25h after being heated to 86 ℃, underpressure distillation is diluted with water to 550mL after reclaiming DMF, and with 105mL ethyl acetate extraction 3 times, merge water, lower the rear stirring of water saving phase pH to 4.5 35min at-0.5 ℃, filter, filtrate is rear in 55 ℃ of lower vacuum-dryings with the frozen water washing, get 32.99g beige solid, it is 5-bromo-3-benzisoxa oxazolone, yield is 87.6%.
LC-MS[ESI，m/z]：[M+1]
+=213.9/215.9(1/1)。
1H-NMR(400MHz,DMSO-d
6)δ12.88(br,s,1H),7.96(d,J=1.8Hz,1H),7.72(dd,J=8.9,1.8Hz,1H),7.54(d,J=8.9Hz,1H)。
1H-NMR(400MHz,CDCl
3)δ7.92(d,J=1.9Hz,1H),7.69(dd,J=8.9,1.9Hz,1H),7.33(d,J=8.9Hz,1H)。
Synthesizing of (III) 3-chloro-5-bromobenzene and isoxzzole
POCl with 19.5mL
3H with 1.9mL
3PO
4Join in the 5-bromo-3-benzisoxa oxazolone that 21.4g step (II) obtains, at room temperature drip 7.95g pyridine post-heating to 93 ℃ and isothermal reaction 26h, add the 205mL sherwood oil after being cooled to 52 ℃, pour out petroleum ether layer after stirring 30～35min, so repeat to extract 3 times, merge petroleum ether layer, petroleum ether layer is adopted anhydrous sodium sulfate drying, filter, be concentrated into dried, the 19.25g white solid, i.e. 3-chloro-5-bromobenzene and isoxzzole, yield is 82.8%.
1H-NMR(400MHz,CDCl
3)δ7.85(d,J=1.9Hz,1H),7.72(dd,J=8.9,1.9Hz,1H),7.50(d,J=8.9Hz,1H)。
Embodiment 3
One, 3-chloro-7-bromobenzene and isoxzzole is synthetic
(1) 2-fluoro-3-bromo-benzoic acid is synthetic
the adjacent bromofluorobenzene of 14.5g is dissolved in the 150mL anhydrous tetrahydro furan and is cooled to-65～-70 ℃, dripping 105mL concentration under nitrogen protection is the LDA of 1.0mol/L, LDA dropwises in 30min, constantly stir during this time, continue to stir 40min after dropwising under the constant temperature of-65 ℃, then reaction solution is poured in the reaction vessel that 210g dry ice is housed, be stirred to without being spin-dried for after Bubble formation, add 210mL water to dilute to get diluent in reaction vessel, regulate the rear filtration of diluent pH to 4, the frozen water washing leaching cake, in 60 ℃ of lower vacuum-dryings, get the 17.32g white solid, it is 2-fluoro-3-bromo-benzoic acid, yield is 95.4%.
LC-MS[ESI，m/z]：[M+1]
+=218.9/220.8(1/1)。
1H?NMR(400MHz,DMSO-d
6)δ13.60(s,1H),7.94(ddd,J=8.0,6.4,1.7Hz,1H),7.86(ddd,J=8.3,6.8,1.7Hz,1H),7.26(t,J=8.0,1H)。
(2) 2-fluoro-3-methyl-bromobenzoate is synthetic
The 2-fluoro-3-bromo-benzoic acid that 10.5g step (1) is obtained joins the SOCl of 85mL
2In, after reflux stirs 14h, SOCl is reclaimed in air distillation
2, residuum is splashed in the 30mL anhydrous methanol, during constantly stir, dropwise rear continuation and stir 40min, be concentrated into driedly, get the 10.52g brown solid, i.e. 2-fluoro-3-methyl-bromobenzoate, yield is 94.2%.
LC-MS[ESI，m/z]：[M+1]
+=232.8/234.8(1/1)。
1H-NMR(400MHz,DMSO-d
6)δ7.86(ddd,J=7.9,6.6,1.6Hz,1H),7.73(ddd,J=7.9,6.2,1.6Hz,1H),7.09(t,J=7.9Hz,1H),3.94(s,3H)。
(3) 7-bromo-3-benzisoxa oxazolone is synthetic
Add the 39g potassium tert.-butoxide after 26gN-ethanoyl azanol being dissolved in the DMF of 650mL drying; potassium tert.-butoxide by etc. quality divide 4 times to add; stir the 2-fluoro-3-methyl-bromobenzoate that adds 42g step (2) to obtain after 40min; stir 30h after being heated to 87 ℃; underpressure distillation is diluted with water to 600mL after reclaiming DMF; and with 110mL ethyl acetate extraction 4 times; lower the rear stirring of water saving phase pH to 4 60min at-1 ℃; filter; filtrate is rear in 60 ℃ of lower vacuum-dryings with the frozen water washing; 30.9g field gray solid, i.e. 7-bromo-3-benzisoxa oxazolone, yield is 80.1%.
LC-MS[ESI，m/z]：[M+1]
+=213.9/215.9(1/1)。
1H-NMR(400MHz,DMSO-d
6)δ12.44(br,s,1H),7.82(dd,J=7.9,0.8Hz,1H),7.80(dd,J=7.9,0.8Hz,1H),6.87(t,J=7.9Hz,1H)。
(4) 3-chloro-7-bromobenzene and isoxzzole is synthetic
POCl with 21mL
3H with 2.1mL
3PO
4Join in the 7-bromo-3-benzisoxa oxazolone that 23g step (3) obtains, at room temperature drip 8g pyridine post-heating to 95 ℃ and isothermal reaction 24h, add the 210mL sherwood oil after being cooled to 55 ℃, pour out petroleum ether layer after stirring 35min, so repeat to extract 2 times, merge petroleum ether layer, petroleum ether layer is adopted anhydrous sodium sulfate drying, filter, be concentrated into dried, the 19.0g white solid, i.e. 3-chloro-7-bromobenzene and isoxzzole, yield is 76.2%.
1H-NMR(400MHz,CDCl
3)δ7.80(dd,J=7.7,0.7Hz,1H),7.65(dd,J=7.9,0.7Hz,1H),7.30(t,J=7.8Hz,1H)。
Two, 3-chloro-5-bromobenzene and isoxzzole is synthetic
Synthesizing of (I) 2-fluoro-5-methyl-bromobenzoate
21g2-fluoro-5-bromo-benzoic acid is joined 160mL SOCl
2In, after reflux stirs 14h, SOCl is reclaimed in air distillation
2, residuum is splashed in the 60mL anhydrous methanol, during constantly stir, dropwise rear continuation and stir 40min, be concentrated into driedly, get the faint yellow oily thing of 21.52g, i.e. 2-fluoro-5-methyl-bromobenzoate, yield is 96.3%.
LC-MS[ESI，m/z]：[M+1]
+=232.8/234.8(1/1)。
1H-NMR(400MHz,DMSO-d
6)δ8.05(dd,J=6.4,2.6Hz,1H),7.64-7.57(m,1H),7.03(dd,J=10.1,8.8Hz,1H),3.93(s,3H).。
Synthesizing of (II) 5-bromo-3-benzisoxa oxazolone
add the 39g potassium tert.-butoxide after 26gN-ethanoyl azanol being dissolved in the DMF of 650mL drying, potassium tert.-butoxide by etc. quality divide 4 times to add, stir the 2-fluoro-5-methyl-bromobenzoate that adds 42g step (I) to obtain after 40min, stir 30h after being heated to 87 ℃, underpressure distillation is diluted with water to 600mL after reclaiming DMF, and with 110mL ethyl acetate extraction 4 times, merge water, lower the rear stirring of water saving phase pH to 4 60min at-1 ℃, filter, filtrate is rear in 60 ℃ of lower vacuum-dryings with the frozen water washing, get 33.98g beige solid, it is 5-bromo-3-benzisoxa oxazolone, yield is 88.1%.
LC-MS[ESI，m/z]：[M+1]
+=213.9/215.9(1/1)。
1H-NMR(400MHz,DMSO-d
6)δ12.88(br,s,1H),7.96(d,J=1.8Hz,1H),7.72(dd,J=8.9,1.8Hz,1H),7.54(d,J=8.9Hz,1H)。
1H-NMR(400MHz,CDCl
3)δ7.92(d,J=1.9Hz,1H),7.69(dd,J=8.9,1.9Hz,1H),7.33(d,J=8.9Hz,1H)。
Synthesizing of (III) 3-chloro-5-bromobenzene and isoxzzole
POCl with 20mL
3H with 1.9mL
3PO
4Join in the 5-bromo-3-benzisoxa oxazolone that 21.6g step (II) obtains, at room temperature drip 8g pyridine post-heating to 95 ℃ and isothermal reaction 30h, add the 210mL sherwood oil after being cooled to 55 ℃, pour out petroleum ether layer after stirring 35min, so repeat to extract 3 times, merge petroleum ether layer, petroleum ether layer is adopted anhydrous sodium sulfate drying, filter, be concentrated into dried, the 19.34g white solid, i.e. 3-chloro-5-bromobenzene and isoxzzole, yield is 82.4%.
1H-NMR(400MHz,CDCl
3)δ7.85(d,J=1.9Hz,1H),7.72(dd,J=8.9,1.9Hz,1H),7.50(d,J=8.9Hz,1H)。
Above-described embodiment is a kind of better scheme of the present invention, is not that the present invention is done any pro forma restriction, also has other variant and remodeling under the prerequisite that does not exceed the technical scheme that claim puts down in writing.
Claims (10)
1. the synthetic method of a 3-chloro-7-bromobenzene and isoxzzole, is characterized in that, described synthetic method comprises the following steps:
(1) 2-fluoro-3-bromo-benzoic acid is synthetic
the adjacent bromofluorobenzene of 13.5～14.5g is dissolved in 140～150mL anhydrous tetrahydro furan and is cooled to-65～-70 ℃, drip the LDA that 102～105mL concentration is 1.0～1.3mol/L under nitrogen protection, LDA dropwises in 30min, constantly stir during this time, continue to stir 30～40min after dropwising under the constant temperature of-65～-70 ℃, then reaction solution is poured in the reaction vessel that 200～210g dry ice is housed, be stirred to without being spin-dried for after Bubble formation, add 200～210mL water to dilute to get diluent in reaction vessel, regulate diluent pH to 4～5 rear filtrations, the frozen water washing leaching cake, in 50～60 ℃ of lower vacuum-dryings, get white solid, it is 2-fluoro-3-bromo-benzoic acid,
(2) 2-fluoro-3-methyl-bromobenzoate is synthetic
The 2-fluoro-3-bromo-benzoic acid that 10～10.5g step (1) is obtained joins the SOCl of 80～85mL
2In, after reflux stirs 12～14h, SOCl is reclaimed in air distillation
2, residuum is splashed in 20～30mL anhydrous methanol, during constantly stir, dropwise rear continuation and stir 30～40min, be concentrated into driedly, get brown solid, i.e. 2-fluoro-3-methyl-bromobenzoate;
(3) 7-bromo-3-benzisoxa oxazolone is synthetic
Add 38～39g potassium tert.-butoxide after 25～26gN-ethanoyl azanol being dissolved in the DMF of 600～650mL drying, stir the 2-fluoro-3-methyl-bromobenzoate that adds 40～42g step (2) to obtain after 30～40min, stir 24～30h after being heated to 85～87 ℃, underpressure distillation is diluted with water to 500～600mL after reclaiming DMF, and use ethyl acetate extraction, lower water saving phase pH to 4～5 rear stirring 30～60min at-1～0 ℃, filter, filtrate is rear in 50～60 ℃ of lower vacuum-dryings with the frozen water washing, get field gray solid, i.e. 7-bromo-3-benzisoxa oxazolone;
(4) 3-chloro-7-bromobenzene and isoxzzole is synthetic
POCl with 19～20mL
3H with 1.9～2.1mL
3PO
4Join in the 7-bromo-3-benzisoxa oxazolone that 22.5～23g step (3) obtains, at room temperature drip 7.9～8g pyridine post-heating to 90～95 ℃ and isothermal reaction 24～30h, add 200～210mL sherwood oil after being cooled to 50～55 ℃, pour out petroleum ether layer after stirring 30～35min, petroleum ether layer is dry, filter, be concentrated into dried, get white solid, i.e. 3-chloro-7-bromobenzene and isoxzzole.
2. the synthetic method of a kind of 3-chloro-7-bromobenzene according to claim 1 and isoxzzole, is characterized in that, in step (3), potassium tert.-butoxide by etc. quality divide 3～4 times to add.
3. the synthetic method of a kind of 3-chloro-7-bromobenzene according to claim 1 and isoxzzole, is characterized in that, when extracting in step (3), the add-on of ethyl acetate is 100～110mL, and extraction times is 3～4 times, merges water after extraction.
4. the synthetic method of a kind of 3-chloro-7-bromobenzene according to claim 1 and isoxzzole, it is characterized in that, in step (4), after petroleum ether layer is poured out, add again 200～210mL sherwood oil in residuum, pour out petroleum ether layer after stirring 30～35min, so repeat to extract 2～3 times, merge petroleum ether layer.
5. the synthetic method of according to claim 1 or 4 described a kind of 3-chloro-7-bromobenzenes and isoxzzole, is characterized in that, in step (4), petroleum ether layer adopts anhydrous sodium sulfate drying.
6. the synthetic method of a 3-chloro-5-bromobenzene and isoxzzole, is characterized in that, described synthetic method comprises the following steps:
Synthesizing of (I) 2-fluoro-5-methyl-bromobenzoate
20～21g2-fluoro-5-bromo-benzoic acid is joined 150～160mL SOCl
2In, after reflux stirs 12～14h, SOCl is reclaimed in air distillation
2, residuum is splashed in 50～60mL anhydrous methanol, during constantly stir, dropwise rear continuation and stir 30～40min, be concentrated into driedly, get faint yellow oily thing, i.e. 2-fluoro-5-methyl-bromobenzoate;
Synthesizing of (II) 5-bromo-3-benzisoxa oxazolone
Add 38～39g potassium tert.-butoxide after 25～26gN-ethanoyl azanol being dissolved in the DMF of 600～650mL drying, stir the 2-fluoro-5-methyl-bromobenzoate that adds 40～42g step (I) to obtain after 30～40min, stir 24～30h after being heated to 85～87 ℃, underpressure distillation is diluted with water to 500～600mL after reclaiming DMF, and use ethyl acetate extraction, lower water saving phase pH to 4～5 rear stirring 30～60min at-1～0 ℃, filter, filtrate is rear in 50～60 ℃ of lower vacuum-dryings with the frozen water washing, get beige solid, i.e. 5-bromo-3-benzisoxa oxazolone;
Synthesizing of (III) 3-chloro-5-bromobenzene and isoxzzole
POCl with 19～20mL
3H with 1.9～2.1mL
3PO
4Join in the 5-bromo-3-benzisoxa oxazolone that 21.2～21.6g step (II) obtains, at room temperature drip 7.9～8g pyridine post-heating to 90～95 ℃ and isothermal reaction 24～30h, add 200～210mL sherwood oil after being cooled to 50～55 ℃, pour out petroleum ether layer after stirring 30～35min, petroleum ether layer is dry, filter, be concentrated into dried, get white solid, i.e. 3-chloro-5-bromobenzene and isoxzzole.
7. the synthetic method of a kind of 3-chloro-5-bromobenzene according to claim 6 and isoxzzole, is characterized in that, in step (II), potassium tert.-butoxide by etc. quality divide 3～4 times to add.
8. the synthetic method of according to claim 6 or 7 described a kind of 3-chloro-5-bromobenzenes and isoxzzole, is characterized in that, when extracting in step (II), the add-on of ethyl acetate is 100～110mL, and extraction times is 3～4 times, merges water after extraction.
9. the synthetic method of a kind of 3-chloro-5-bromobenzene according to claim 6 and isoxzzole, it is characterized in that, in step (III), after petroleum ether layer is poured out, add again 200～210mL sherwood oil in residuum, pour out petroleum ether layer after stirring 30～35min, so repeat to extract 2～3 times, merge petroleum ether layer.
10. the synthetic method of according to claim 6 or 9 described a kind of 3-chloro-5-bromobenzenes and isoxzzole, is characterized in that, in step (III), petroleum ether layer adopts anhydrous sodium sulfate drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310341708.9A CN103382187B (en) | 2013-08-06 | 2013-08-06 | 3-chloro-7(5)-bromo-benzo-isoxazole compounding method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310341708.9A CN103382187B (en) | 2013-08-06 | 2013-08-06 | 3-chloro-7(5)-bromo-benzo-isoxazole compounding method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103382187A true CN103382187A (en) | 2013-11-06 |
| CN103382187B CN103382187B (en) | 2015-06-03 |
Family
ID=49490139
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310341708.9A Expired - Fee Related CN103382187B (en) | 2013-08-06 | 2013-08-06 | 3-chloro-7(5)-bromo-benzo-isoxazole compounding method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103382187B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848446A (en) * | 2020-08-21 | 2020-10-30 | 阿里生物新材料（常州）有限公司 | Synthesis method of 2-bromo-5-cyano-4-fluorobenzoic acid methyl ester |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1997630A (en) * | 2004-06-08 | 2007-07-11 | A.卡尔松研究股份公司 | New disubstituted phenylpiperidines as modulators of dopamine neurotransmission |
| CN101305010A (en) * | 2005-09-01 | 2008-11-12 | 阿雷生物药品公司 | Raf inhibitor compounds and methods of use thereof |
| WO2012142237A1 (en) * | 2011-04-15 | 2012-10-18 | Newlink Geneticks Corporation | Fused imidazole derivatives useful as ido inhibitors |
-
2013
- 2013-08-06 CN CN201310341708.9A patent/CN103382187B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1997630A (en) * | 2004-06-08 | 2007-07-11 | A.卡尔松研究股份公司 | New disubstituted phenylpiperidines as modulators of dopamine neurotransmission |
| CN101305010A (en) * | 2005-09-01 | 2008-11-12 | 阿雷生物药品公司 | Raf inhibitor compounds and methods of use thereof |
| WO2012142237A1 (en) * | 2011-04-15 | 2012-10-18 | Newlink Geneticks Corporation | Fused imidazole derivatives useful as ido inhibitors |
Non-Patent Citations (4)
| Title |
|---|
| DAI KUBOTA ET AL: "Tricyclic pharmacophore-based molecules as novel integrin avb3 antagonists.PartIV:Preliminary control of avb3 selectivity by meta-oriented substitution", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 14, no. 12, 28 February 2006 (2006-02-28), pages 4177 * |
| JANICE E. SIESER ET AL: "Synthesis of a Bicyclic Piperazine from L-Aspartic Acid and Application of a Fluoride-Promoted SNAr Coupling", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》, vol. 15, no. 6, 4 September 2011 (2011-09-04), pages 1332 - 1334 * |
| THIERRY RAUSIS ET AL: "The Basicity Gradient-Driven Migration of Iodine:Conferring Regioflexibility on the Substitution of Fluoroarenes", 《EUR.J.ORG.CHEM.》, vol. 2002, no. 19, 20 September 2002 (2002-09-20), pages 3351 - 3355 * |
| 齐传民 等: "新型异恶唑类化合物的合成及其生物活性的研究", 《北京师范大学学报(自然科学版)》, vol. 37, no. 6, 30 December 2001 (2001-12-30) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848446A (en) * | 2020-08-21 | 2020-10-30 | 阿里生物新材料（常州）有限公司 | Synthesis method of 2-bromo-5-cyano-4-fluorobenzoic acid methyl ester |
| CN111848446B (en) * | 2020-08-21 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthesis method of 2-bromo-5-cyano-4-fluorobenzoic acid methyl ester |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103382187B (en) | 2015-06-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108047261B (en) | Preparation method of clitorium | |
| CN103524440B (en) | The preparation method of gout therapertics Lesinurad and Lesinurad intermediate | |
| CN103980263B (en) | The synthesis technique of canagliflozin | |
| CN102702191B (en) | Synthesis method of vinpocetine | |
| CN106946887B (en) | A kind of preparation method introducing catalyst optimization synthesis Dipyridamole | |
| CN103382187B (en) | 3-chloro-7(5)-bromo-benzo-isoxazole compounding method | |
| CN102850347A (en) | Resolution method for pyrazole derivative or salt thereof | |
| CN103772189B (en) | Synthesis method of diethylstilbestrol compound methyl pigeon pea ketonic acid A | |
| CN102558042B (en) | 4-bromine-6-methylnicotinicacid and preparation method thereof | |
| CN104140402B (en) | A kind of benzothiazole compound and preparation method thereof | |
| CN106892863A (en) | The preparation method of vismodegib and its intermediate | |
| CN104387790B (en) | A kind of benzindole salt dyestuff of thienyl-containing group and its production and use | |
| CN103408487B (en) | Refining method of gimeracil | |
| CN102911109B (en) | Preparation method of 6-amino-5-fluorine-1-isoindolinone | |
| CN103804187B (en) | Synthesis method of diethylstilbestrol compound pigeon pea ketonic acid A | |
| CN103058950A (en) | Preparation method of febuxostat | |
| CN107162983B (en) | Synthesis and refining method of methimazole | |
| CN102633683B (en) | Synthesis method of 1-hydroxymethyl cyclopropylacetonitrile | |
| CN103664885A (en) | Preparation method of benzimidazole proton pump inhibitor intermediate | |
| JPWO2015012271A1 (en) | Method for producing heterocyclic compound | |
| CN105061421A (en) | Method for preparing 2-chloro-1, 8-naphthyridine derivative | |
| CN108976198A (en) | A kind of synthetic method of 3- (4- pyridine) Benzazole compounds | |
| CN102964411B (en) | Synthesis method of androstane-4,6-diene-17 alpha-methyl-17 beta-alcohol-3-ketone | |
| CN104725301A (en) | Preparation method of 1,2-dihydropyridin-2-one derivative | |
| CN103086818A (en) | Method for synthesizing alpha-oxyamide with 2-hydroxy propylene cyanide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150603 Termination date: 20210806 |