CN103626791B - A kind of method of synthesizing 3-amino-4-fluorobenzoic boric acid - Google Patents
A kind of method of synthesizing 3-amino-4-fluorobenzoic boric acid Download PDFInfo
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- CN103626791B CN103626791B CN201310605655.7A CN201310605655A CN103626791B CN 103626791 B CN103626791 B CN 103626791B CN 201310605655 A CN201310605655 A CN 201310605655A CN 103626791 B CN103626791 B CN 103626791B
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Abstract
The invention belongs to organic chemistry material synthesis field.Synthesize a method for 3-amino-4-fluorobenzoic boric acid, comprise following three steps: p-Fluoro bromo benzene is made Grignard reagent by the first step, be then obtained by reacting intermediate with trimethyl borate to fluorobenzoic boric acid A; Second step intermediate A and nitrosonitric acid react and generate intermediate 3-nitro-4-fluorobenzoic boric acid B; 3rd step intermediate B hydrogenation under the catalysis of palladium carbon generates product 3-amino-4-fluorobenzoic boric acid C.Synthetic method raw material of the present invention is easy to get, simple to operate, cost is lower, provides a kind of suitable route preparing 3-amino-4-fluorobenzoic boric acid.
Description
technical field:
The invention belongs to organic compound synthesis field, relate to the preparation method of 3-amino-4-fluorobenzoic boric acid.
background technology:
Current literature search does not find the synthetic method of 3-amino-4-fluorobenzoic boric acid.3-amino-4-fluorobenzoic boric acid the pinacol ester the most close with 3-amino-4-fluorobenzoic boric acid structure is adopt the fluoro-5-bromaniline of 2-and tetramethyl ethylene ketone two boron at PdCl substantially
2(dppf) obtained under catalysis.Taking off tetramethyl ethylene ketone by 3-amino-4-fluorobenzoic boric acid pinacol ester, to prepare 3-amino-4-fluorobenzoic boric acid be possible in theory, but so just many single step reactions, and this route another one shortcoming is that 2-fluoro-5-bromaniline is expensive, is not easy to obtain.
summary of the invention:
The object of the invention is to overcome above-mentioned not enough problem, a kind of method of synthesizing 3-amino-4-fluorobenzoic boric acid is provided, adopt fluorophenyl Grignard reagent, react with trimethyl borate and generate fluorobenzoic boric acid, more further with fluorobenzoic boric acid being carried out to nitrated, reduction generation product.This method raw material is easy to get, simple to operate, cost is lower, provides a kind of suitable route preparing 3-amino-4-fluorobenzoic boric acid.
The technical scheme that the present invention is adopted for achieving the above object is: comprise following three steps:
The first step boronation: p-Fluoro bromo benzene is made Grignard reagent, is then obtained by reacting with trimethyl borate fluorobenzoic boric acid intermediate A;
Second step is nitrated: intermediate A and nitrosonitric acid nitration reaction generate 3-nitro-4-fluorobenzoic boric acid intermediate B;
3rd step hydro-reduction: intermediate B hydrogenation under the catalysis of palladium carbon generates product 3-amino-4-fluorobenzoic boric acid.
Described the first step boronation: first the mixed solution of p-Fluoro bromo benzene and tetrahydrofuran (THF) is instilled in magnesium, add thermal initiation, drip off rear 50
oc is incubated 1 hour, is cooled to-30
ounder C, instillation trimethyl borate, react after 3 hours, uses aqueous hydrochloric acid cancellation, then be extracted with ethyl acetate, saturated common salt water washing organic phase, and concentrated organic phase is to not flow liquid, and with normal heptane making beating, filtration, drying obtains intermediate A.
Described second step is nitrated: nitrosonitric acid is cooled to-20
oc ~-55
oc, vigorous stirring, slowly will add in nitrosonitric acid fluorobenzoic boric acid more in batches, insulation reaction 2 hours after reinforced, reaction solution is poured in previously prepd trash ice fast after completion of the reaction, vigorous stirring, is 3 ~ 6 with sodium carbonate adjust pH, be extracted with ethyl acetate, dried over mgso, concentrated, normal heptane making beating, filter, drying obtains intermediate B.
Described 3rd step hydro-reduction: intermediate B and methyl alcohol, palladium carbon are placed in hydrogenation still, are warming up to 55
oc does hydrogenation reaction, and after completion of the reaction by reaction solution Büchner funnel suction filtration removing palladium carbon, be concentrated into not flow liquid, with organic solvent making beating, vacuum-drying, product recrystallization obtains light grey solid, and vacuum-drying obtains the finished product.
In the described the first step, p-Fluoro bromo benzene, magnesium and trimethyl borate mol ratio are 1.0:1.05-1.2:1.1-1.2.
Be 1.0:16.7-23.4 to fluorobenzoic boric acid and nitrosonitric acid mol ratio in described second step.
Described the first step Raw p-Fluoro bromo benzene purity is greater than 98%.
Described second step Raw nitrosonitric acid purity is greater than 98%.
Described organic solvent can for ethyl acetate, ethanol and normal heptane etc. not only can easily reclaim but also not with the inert solvent of reaction raw materials and product generation chemical reaction.
Reaction mechanism of the present invention is as follows:
Synthetic route of the present invention is simple, and raw material is easy to get, simple to operate, and cost is lower, often walks yield higher, provides a kind of suitable route preparing 3-amino-4-fluorobenzoic boric acid, meet the widespread demand at present to product of the present invention.
embodiment:
Elaborate to the present invention below in conjunction with specific embodiment, but the present invention is not limited to specific embodiment, all technical schemes in concept of the present invention are all in scope.
embodiment 1
Prepare a method for 3-amino-4-fluorobenzoic boric acid, with to fluorophenyl Grignard reagent, react with trimethyl borate and generate fluorobenzoic boric acid, more further with fluorobenzoic boric acid being carried out to nitrated, reduction generation product.
Reaction mechanism of the present invention is as follows:
concrete technology:
The first step boronation: by magnesium chips 14.59g(1.05eq) and 50mlTHF join in 1000ml four-hole boiling flask, logical nitrogen.Raw material p-Fluoro bromo benzene 100g(1.0eq will be dissolved with) THF solution in bottle, drip 1/10th, 50 DEG C of initiation reactions, dropwise post-heating and reflux 2 hours.-5
ounder C by Grignard reagent dropwise to trimethyl borate 65.31g(1.1eq) in.Drip off rear stirring 3 hours.PH=4-5 is regulated with the HCl of concentration 2M/L, separatory after stirring 0.5h, aqueous phase ethyl acetate (EA) extraction, each 200ml at 0 DEG C.Organic phase with the sodium chloride solution washing that 300ml is saturated, is separated organic phase, organic phase is spin-dried for again, and with the making beating of 250ml normal heptane, obtain off-white color solid 50g, yield is 56%, nuclear-magnetism
1hNMR content>=97%.
Second step is nitrated: nitrosonitric acid (140mL) is placed in 250mL four-hole bottle, with ethanol the dry ice bath temperature control-35
oc is to-45
oc, rapid stirring.Slowly being added in four-hole bottle grinding fluorobenzoic boric acid (20g) finish-drying in batches, keeping temperature of reaction to be-35
oc ~-45
oc.After fluorobenzoic boric acid is added, react complete to TLC detection raw material reaction.Poured into by reaction solution in 200g trash ice, quick vigorous stirring, have yellow solid to separate out, Büchner funnel suction filtration, frozen water 20mL washs 2 times, drains.It is 6 that the filtrate obtained is added sodium bicarbonate adjust pH, is extracted with ethyl acetate, and merges oil phase, dried over mgso, and be spin-dried for not flow liquid, normal heptane is pulled an oar, and obtains faint yellow solid 8.3g, yield 31.5%.
3rd step hydro-reduction is placed in 500mL single port bottle 3-nitro-4-fluorobenzoic boric acid (63g), adds methyl alcohol (100mL), palladium carbon (6.3g, 10%) magneton, seals with plug.Vacuumize with water pump, syringe needle passes into hydrogen.Reaction flask is placed in 55
ostirring reaction in C oil bath.Hydrogen balloon has reacted rear replacing until no longer absorb hydrogen.By reaction solution Büchner funnel suction filtration removing palladium carbon, be spin-dried for not flow liquid, with normal heptane making beating, vacuum-drying.Gained solid is dissolved in methyl alcohol (30mL), adds water 150mL, have a large amount of solid to separate out, evaporating methyl alcohol and a part of water with revolving steaming, being cooled to 5
oc, Büchner funnel suction filtration obtains light grey solid, vacuum-drying, obtains the finished product 42.6g, through 1HNMR, yield 80.7% determines that structure meets, and HPLC is 99.1%.3-amino-4-fluorobenzoic boric acid
1hNMR (400MHz, DMSO-d
6, D
2o) δ ppm:7.19 (1H, d, J=9.6), 6.96 (2H, q, J=5.2), 3.15(2H, S).
embodiment 2
Prepare a method for 3-amino-4-fluorobenzoic boric acid, identical with embodiment 1 method and reaction mechanism, concrete technology:
The first step boronation is by magnesium chips 14.59g(1.05eq) and 50mlTHF join in 1000ml four-hole boiling flask, logical nitrogen.Raw material p-Fluoro bromo benzene 100g(1.0eq will be dissolved with) THF solution in bottle, drip 1/10th, 50 DEG C of initiation reactions, dropwise post-heating and reflux 2 hours.-5
ounder C by Grignard reagent dropwise to trimethyl borate 65.31g(1.1eq) in.Drip off rear stirring 3 hours.At 0 DEG C, regulate pH=2-3 with 2M/LHCl, separatory after stirring 0.5h, aqueous phase EA extracts, each 200ml.Organic phase with the sodium chloride solution washing that 300ml is saturated, is separated organic phase, organic phase is spin-dried for again, and with the making beating of 250ml normal heptane, obtain off-white color solid 45g, yield is 50.4%, nuclear-magnetism
1hNMR content>=97%.
Second step is nitrated is placed in 250mL four-hole bottle by nitrosonitric acid (140mL), with ethanol the dry ice bath temperature control-35
oc is to-45
oc, rapid stirring.Slowly being added in four-hole bottle grinding fluorobenzoic boric acid (20g) finish-drying in batches, keeping temperature of reaction to be-35
oc ~-40
oc.After fluorobenzoic boric acid is added, react complete to TLC detection raw material reaction.Poured into by reaction solution in 200g trash ice, quick vigorous stirring, have yellow solid to separate out, Büchner funnel suction filtration, frozen water 20mL washs 2 times, drains.It is 6 that the filtrate obtained is added sodium bicarbonate adjust pH, is extracted with ethyl acetate, and merges oil phase, dried over mgso, and be spin-dried for not flow liquid, normal heptane is pulled an oar, and obtains faint yellow solid 10.6g, yield 40.0%.
3rd step hydro-reduction is placed in 500mL single port bottle 3-nitro-4-fluorobenzoic boric acid (6.3g), adds methyl alcohol (10mL), palladium carbon (0.63g, 10%) magneton, seals with plug.Vacuumize with water pump, syringe needle passes into hydrogen.Reaction flask is placed in 55
ostirring reaction in C oil bath.Hydrogen balloon has reacted rear replacing until no longer absorb hydrogen.By reaction solution Büchner funnel suction filtration removing palladium carbon, be spin-dried for not flow liquid, with normal heptane making beating, vacuum-drying.Gained solid is dissolved in methyl alcohol (3mL), adds water 15mL, have a large amount of solid to separate out, evaporating methyl alcohol and a part of water with revolving steaming, being cooled to 5
oc, Büchner funnel suction filtration obtains light grey solid, vacuum-drying, obtains the finished product 4.26g, yield 80.7%, warp
1hNMR determines that structure meets, and HPLC is 99.1%.
embodiment 3
Prepare a method for 3-amino-4-fluorobenzoic boric acid, identical with embodiment 1 method and reaction mechanism, concrete technology:
The first step boronation is by magnesium chips 14.59g(1.05eq) and 50mlTHF join in 1000ml four-hole boiling flask, logical nitrogen.Raw material p-Fluoro bromo benzene 100g(1.0eq will be dissolved with) THF solution in bottle, drip 1/10th, 50 DEG C of initiation reactions, dropwise post-heating and reflux 2 hours.-5
ounder C by Grignard reagent dropwise to trimethyl borate 71.24g(1.2eq) in.Drip off rear stirring 3 hours.At 0 DEG C, regulate pH=2-3 with 2M/LHCl, separatory after stirring 0.5h, aqueous phase EA extracts, each 200ml.Organic phase with the sodium chloride solution washing that 300ml is saturated, is separated organic phase, organic phase is spin-dried for again, and with the making beating of 250ml normal heptane, obtain off-white color solid 55.4g, yield is 62%, nuclear-magnetism
1hNMR content>=97%.
Second step is nitrated is placed in 250mL four-hole bottle by nitrosonitric acid (120mL), with ethanol the dry ice bath temperature control-35
oc is to-45
oc, rapid stirring.Slowly being added in four-hole bottle grinding fluorobenzoic boric acid (20g) finish-drying in batches, keeping temperature of reaction to be-35
oc ~-40
oc.After fluorobenzoic boric acid is added, react complete to TLC detection raw material reaction.Poured into by reaction solution in 200g trash ice, quick vigorous stirring, have yellow solid to separate out, Büchner funnel suction filtration, frozen water 20mL washs 2 times, drains.It is 6 that the filtrate obtained is added sodium bicarbonate adjust pH, is extracted with ethyl acetate, and merges oil phase, dried over mgso, and be spin-dried for not flow liquid, normal heptane is pulled an oar, and obtains faint yellow solid 10.1g, yield 38.0%.
3rd step hydro-reduction is placed in 500mL single port bottle 3-nitro-4-fluorobenzoic boric acid (6.3g), adds methyl alcohol (10mL), palladium carbon (0.63g, 10%) magneton, seals with plug.Vacuumize with water pump, syringe needle passes into hydrogen.Reaction flask is placed in 55
ostirring reaction in C oil bath.Hydrogen balloon has reacted rear replacing until no longer absorb hydrogen.By reaction solution Büchner funnel suction filtration removing palladium carbon, be spin-dried for not flow liquid, with normal heptane making beating, vacuum-drying.Gained solid is dissolved in methyl alcohol (3mL), adds water 15mL, have a large amount of solid to separate out, evaporating methyl alcohol and a part of water with revolving steaming, being cooled to 5
oc, Büchner funnel suction filtration obtains light grey solid, vacuum-drying, obtains the finished product 4.26g, yield 80.7%, warp
1hNMR determines that structure meets, and HPLC is 99.1%.
Claims (9)
1. synthesize a method for 3-amino-4-fluorobenzoic boric acid, it is characterized in that: comprise following three steps:
The first step boronation: p-Fluoro bromo benzene is made Grignard reagent, is then obtained by reacting with trimethyl borate fluorobenzoic boric acid intermediate A;
Second step is nitrated: intermediate A and nitrosonitric acid nitration reaction generate 3-nitro-4-fluorobenzoic boric acid intermediate B;
3rd step hydro-reduction: intermediate B hydrogenation under the catalysis of palladium carbon generates product 3-amino-4-fluorobenzoic boric acid.
2. a kind of method of synthesizing 3-amino-4-fluorobenzoic boric acid according to claim 1, is characterized in that: the first step boronation: first instilled in magnesium by the mixed solution of p-Fluoro bromo benzene and tetrahydrofuran (THF), add thermal initiation, drip off rear 50
oc is incubated 1 hour, is cooled to-30
ounder C, instillation trimethyl borate, react after 3 hours, uses aqueous hydrochloric acid cancellation, then be extracted with ethyl acetate, saturated common salt water washing organic phase, and concentrated organic phase is to not flow liquid, and with normal heptane making beating, filtration, drying obtains intermediate A, and yield is 65 ~ 70%.
3. a kind of method of synthesizing 3-amino-4-fluorobenzoic boric acid according to claim 1, is characterized in that: second step is nitrated: nitrosonitric acid is cooled to-20
oc ~-55
oc, vigorous stirring, slowly will add in nitrosonitric acid fluorobenzoic boric acid more in batches, insulation reaction 2 hours after reinforced, reaction solution is poured in previously prepd trash ice fast after completion of the reaction, vigorous stirring, be 3 ~ 6 with sodium carbonate adjust pH, be extracted with ethyl acetate, dried over mgso, concentrated, normal heptane making beating, filter, drying obtains intermediate B, and yield is 40%.
4. a kind of method of synthesizing 3-amino-4-fluorobenzoic boric acid according to claim 1, is characterized in that: the 3rd step hydro-reduction: intermediate B and methyl alcohol, palladium carbon are placed in hydrogenation still, are warming up to 55
oc does hydrogenation reaction, and after completion of the reaction by reaction solution Büchner funnel suction filtration removing palladium carbon, be concentrated into not flow liquid, with organic solvent making beating, vacuum-drying, product recrystallization obtains light grey solid, and vacuum-drying obtains the finished product, yield 80.7%.
5., according to the arbitrary a kind of described method of synthesizing 3-amino-4-fluorobenzoic boric acid of claim 1-4, it is characterized in that: in the described the first step, p-Fluoro bromo benzene, magnesium and trimethyl borate mol ratio are 1.0:1.05-1.2:1.1-1.2.
6. according to the arbitrary a kind of described method of synthesizing 3-amino-4-fluorobenzoic boric acid of claim 1-4, it is characterized in that: be 1.0:16.7-23.4 to fluorobenzoic boric acid and nitrosonitric acid mol ratio in described second step.
7., according to the arbitrary a kind of described method of synthesizing 3-amino-4-fluorobenzoic boric acid of claim 1-4, it is characterized in that: described the first step Raw p-Fluoro bromo benzene purity is greater than 98%.
8. a kind of method of synthesizing 3-amino-4-fluorobenzoic boric acid according to claim 4, is characterized in that: described organic solvent adopt not only can easily reclaim but also not with the inert solvent of reaction raw materials and product generation chemical reaction.
9. a kind of method of synthesizing 3-amino-4-fluorobenzoic boric acid according to claim 8, is characterized in that: described organic solvent is ethyl acetate, ethanol or normal heptane.
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Citations (3)
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| EP1988095A2 (en) * | 2007-04-27 | 2008-11-05 | Archimica GmbH | Method for manufacturing aminoaryl or heteroaryl boronic acid and their derivatives |
| CN102367260A (en) * | 2011-12-12 | 2012-03-07 | 南京药石药物研发有限公司 | Synthesis method of 2-aminopyrimidine-5-boric acid |
| CN103044471A (en) * | 2012-12-20 | 2013-04-17 | 大连联化化学有限公司 | Method for preparing 4-amino benzene boric acid hydrochloride |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1988095A2 (en) * | 2007-04-27 | 2008-11-05 | Archimica GmbH | Method for manufacturing aminoaryl or heteroaryl boronic acid and their derivatives |
| CN102367260A (en) * | 2011-12-12 | 2012-03-07 | 南京药石药物研发有限公司 | Synthesis method of 2-aminopyrimidine-5-boric acid |
| CN103044471A (en) * | 2012-12-20 | 2013-04-17 | 大连联化化学有限公司 | Method for preparing 4-amino benzene boric acid hydrochloride |
Non-Patent Citations (1)
| Title |
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| "Synthesis and crystal structure of 4-amino-3-fluorophenylboronic acid";Sasmita Das,et al.;《Tetrahedron Letters》;20031231;第44卷;第7719-7722页 * |
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