CN115010622B - Preparation method of 2-bromo-5-cyanobenzaldehyde - Google Patents
Preparation method of 2-bromo-5-cyanobenzaldehyde Download PDFInfo
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- CN115010622B CN115010622B CN202210699036.8A CN202210699036A CN115010622B CN 115010622 B CN115010622 B CN 115010622B CN 202210699036 A CN202210699036 A CN 202210699036A CN 115010622 B CN115010622 B CN 115010622B
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- cyanobenzaldehyde
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- bromoxynil
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- BFXZVSRDZFPABM-UHFFFAOYSA-N 4-bromo-3-formylbenzonitrile Chemical compound BrC1=CC=C(C#N)C=C1C=O BFXZVSRDZFPABM-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 10
- SKXUZFJOLNNWIG-UHFFFAOYSA-N 4-bromo-3-methylbenzonitrile Chemical compound CC1=CC(C#N)=CC=C1Br SKXUZFJOLNNWIG-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- 239000000706 filtrate Substances 0.000 claims description 15
- MKEWOMLQLUYQPK-UHFFFAOYSA-N 4-bromo-3-(hydroxymethyl)benzonitrile Chemical compound OCC1=CC(C#N)=CC=C1Br MKEWOMLQLUYQPK-UHFFFAOYSA-N 0.000 claims description 14
- 239000005489 Bromoxynil Substances 0.000 claims description 14
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 14
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 14
- 125000005997 bromomethyl group Chemical group 0.000 claims description 14
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 10
- 238000001704 evaporation Methods 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 5
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- 238000002386 leaching Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000031709 bromination Effects 0.000 abstract 1
- 238000005893 bromination reaction Methods 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 description 9
- 238000001514 detection method Methods 0.000 description 6
- 102000012195 Fructose-1,6-bisphosphatases Human genes 0.000 description 3
- 108010017464 Fructose-Bisphosphatase Proteins 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- SCLFNIOYFAYJST-UHFFFAOYSA-N 3-methylbenzonitrile Chemical compound [CH2]C1=CC=CC(C#N)=C1 SCLFNIOYFAYJST-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229940053202 antiepileptics carboxamide derivative Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 2-bromo-5-cyanobenzaldehyde, which takes 4-bromo-3-methylbenzonitrile as a raw material to obtain 2-bromo-5-cyanobenzaldehyde through bromination and oxidation.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 2-bromo-5-cyanobenzaldehyde.
Background
Liver fructose-1, 6-bisphosphatase (FBPase) is a key enzyme gluconeogenesis pathway in the liver. N-arylsulfonyl-4-arylaminoindole-2-carboxamide derivatives have been disclosed as FBPase inhibitors having therapeutic effects on diabetes. And 2-bromo-5-cyanobenzaldehyde is widely focused as a key intermediate for the synthesis of therapeutic diabetes. In addition, 2-bromo-5-cyanobenzaldehyde is also a key intermediate for synthesizing anticancer drugs and antiviral drugs, and is widely applied to the market.
At present, the patent WO2018/156554 and the patent US2002/143024 respectively disclose a synthetic method of 2-bromo-5-cyanobenzaldehyde, but the methods generally have the problems of longer reaction time, lower yield, higher material cost and more complex post-treatment and purification.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of 2-bromo-5-cyanobenzaldehyde, which has the advantages of shorter reaction period, lower synthesis cost, simple post-treatment operation and purification method and higher yield. The invention ensures the supply requirement of the 2-bromo-5-cyanobenzaldehyde in the market and also provides ideas and directions for the technological production of the 2-bromo-5-cyanobenzaldehyde.
The invention relates to a synthetic method of 2-bromo-5-cyanobenzaldehyde, which comprises the following reaction routes:
the method comprises the following specific steps:
(1) Synthesis of 3- (bromomethyl) -4-bromoxynil
Under Ar protection, CCl is added into a reaction bottle 4 4-bromo-3-methylbenzonitrile, stirring and dissolving; sequentially adding benzoyl peroxide and N-bromosuccinimide, carrying out reflux reaction for 1-1.5h, and naturally cooling to 25 ℃; suction filtering, concentrating and evaporating filtrate to dryness to obtain a solid crude product I; recrystallizing the solid crude product I by using a mixed solvent of ethyl acetate and n-heptane to obtain an off-white solid 3- (bromomethyl) -4-bromoxynil;
(2) Synthesis of 4-bromo-3-hydroxymethylbenzonitrile
Under the protection of Ar, THF is added into a reaction bottle, and then 3- (bromomethyl) -4-bromoxynil is added into the reaction bottle, stirred and dissolved; sequentially adding water and calcium carbonate, carrying out reflux reaction for 6-6.5h, and naturally cooling to 25 ℃; suction filtering, leaching a filter cake by using THF, concentrating and evaporating filtrate to dryness to obtain 4-bromo-3-hydroxymethylbenzonitrile;
(3) Synthesis of 2-bromo-5-cyanobenzaldehyde
Under the protection of Ar, methylene dichloride and 4-bromo-3-hydroxymethyl benzonitrile are sequentially added into a reaction bottle, and stirred for dissolution; manganese dioxide is then added; reacting for 5-5.5h at room temperature, filtering by diatomite, eluting a filter cake by methylene dichloride, and concentrating the filtrate under reduced pressure to obtain the 2-bromo-5-cyanobenzaldehyde.
4-bromo-3-methylbenzonitrile in molar ratio: n-bromosuccinimide=1: 1-1.2.
3- (bromomethyl) -4-bromoxynil: calcium carbonate = 1:1-5.
4-bromo-3-hydroxymethylbenzonitrile in molar ratio: manganese dioxide = 1:3-7.
Compared with the prior art, the invention adopts a brand new synthetic route, has shorter reaction period, lower synthetic cost, simple post-treatment operation and purification method and higher yield. The invention ensures the supply requirement of the 2-bromo-5-cyanobenzaldehyde in the market and also provides ideas and directions for the technological production of the 2-bromo-5-cyanobenzaldehyde.
Drawings
FIG. 1 is a nuclear magnetic spectrum of a target product 2-bromo-5-cyanobenzaldehyde.
Detailed Description
Example 1
Under Ar protection, 500mLCCl is added into a reaction bottle in sequence 4 4-bromo-3-methylbenzonitrile (125 g,0.64 mol), dissolved by stirring; BPO (15.5 g,0.063 mol), NBS (113.9 g,0.64 mol) were added in this order to start the heating reflux reaction; after the reaction is carried out for 1.5 hours, the heating is stopped after the detection reaction is finished, and the temperature is naturally reduced to 25 ℃; suction filtering, concentrating and evaporating filtrate to dryness to obtain a solid crude product I; ethyl acetate: n-heptane=1: 5, recrystallizing the solid crude product I by using a mixed solvent to obtain 147.5g of off-white solid 3- (bromomethyl) -4-bromoxynil with the yield: 85%.
Under Ar protection, 500ml of LTHF and 3- (bromomethyl) -4-bromoxynil (100 g,0.36 mol) were added to the flask and dissolved with stirring; 218mL of water and calcium carbonate (36.37 g,0.36 mol) were then added in sequence to begin heating reflux; after 6 hours, the residue of the detected raw materials is basically unchanged, the reaction is stopped, and the raw materials are naturally cooled to 25 ℃; suction filtration, leaching of filter cake with 100mLTHF, concentration and evaporation of filtrate to dryness, obtaining pure white solid 4-bromo-3-hydroxymethylbenzonitrile 60g, yield: 78%.
1000mL of dichloromethane and 4-bromo-3-hydroxymethylbenzonitrile (100 g,0.47 mol) are sequentially added into a reaction bottle under the protection of Ar, and stirred for dissolution; manganese dioxide (122.6 g,1.41 mol) was then added; reacting for 5.5 hours at room temperature, and finishing the detection reaction; the mixture is filtered through diatomite, the filter cake is rinsed with 250mL of methylene dichloride, and the filtrate is concentrated under reduced pressure to obtain 85.5g of pale yellow solid pure 2-bromo-5-cyanobenzaldehyde, and the yield is: 86.4%.
Example 2
Under Ar protection, 500mLCCl is added into a reaction bottle in sequence 4 4-bromo-)3-methylbenzonitrile (125 g,0.64 mol), dissolved by stirring; BPO (15.5 g,0.063 mol) and NBS (135 g,0.75 mol) were added in this order to start the heating reflux reaction; after the reaction is carried out for 1 hour, after the detection reaction is finished, stopping heating, and naturally cooling to 25 ℃; suction filtering, concentrating and evaporating filtrate to dryness to obtain a solid crude product I; ethyl acetate: n-heptane=1: 5, recrystallizing the solid crude product I by using a mixed solvent to obtain 140.6g of off-white solid 3- (bromomethyl) -4-bromoxynil with the yield: 80.2%.
Under Ar protection, 500ml of LTHF and 3- (bromomethyl) -4-bromoxynil (100 g,0.36 mol) were added to the flask and dissolved with stirring; 900mL of water and calcium carbonate (180 g,1.80 mol) are added in sequence, and heating reflux is started; after 6.5 hours, detecting that the raw materials are reacted, stopping the reaction, and naturally cooling to 25 ℃; suction filtration, leaching of filter cake with 100mL THF, concentration of filtrate and evaporation to dryness, obtaining pure white solid of 72g of 4-bromo-3-hydroxymethylbenzonitrile, yield: 93.4%.
1000mL of dichloromethane and 4-bromo-3-hydroxymethylbenzonitrile (100 g,0.47 mol) are sequentially added into a reaction bottle under the protection of Ar, and stirred for dissolution; manganese dioxide (284 g,3.29 mol) was then added; reacting for 5 hours at room temperature, and finishing the detection reaction; the mixture is filtered through diatomite, the filter cake is rinsed with 250mL of methylene dichloride, and the filtrate is concentrated under reduced pressure to obtain 95g of pale yellow solid pure 2-bromo-5-cyanobenzaldehyde, and the yield is: 96%.
Example 3
Under Ar protection, 500mLCCl is added into a reaction bottle in sequence 4 4-bromo-3-methylbenzonitrile (125 g,0.64 mol), dissolved by stirring; BPO (15.5 g,0.063 mol) and NBS (124.6 g,0.70 mol) were added in this order to start the heating reflux reaction; after the reaction is carried out for 1 hour, after the detection reaction is finished, stopping heating, and naturally cooling to 25 ℃; suction filtering, concentrating and evaporating filtrate to dryness to obtain a solid crude product I; ethyl acetate: n-heptane=1: 5, recrystallizing the solid crude product I by using the mixed solvent to obtain 144.8g of white solid 3- (bromomethyl) -4-bromoxynil with yield: 82.3%.
Under Ar protection, 500ml of LTHF and 3- (bromomethyl) -4-bromoxynil (100 g,0.36 mol) were added to the flask and dissolved with stirring; 900mL of water and calcium carbonate (90 g,0.9 mol) are added in sequence, and heating reflux is started; after 6.h, the reaction of the detected raw materials is finished, the reaction is stopped, and the raw materials are naturally cooled to 25 ℃; suction filtration, leaching of filter cake with 100mLTHF, concentration and evaporation of filtrate to dryness, obtaining pure white solid of 65.3g of 4-bromo-3-hydroxymethylbenzonitrile, yield: 85.6%.
1000mL of dichloromethane and 4-bromo-3-hydroxymethylbenzonitrile (100 g,0.47 mol) are sequentially added into a reaction bottle under the protection of Ar, and stirred for dissolution; manganese dioxide (204.3 g,2.35 mol) was then added; reacting for 5.5 hours at room temperature, and finishing the detection reaction; the mixture is filtered through diatomite, the filter cake is rinsed with 250mL of methylene dichloride, and the filtrate is concentrated under reduced pressure to obtain 90.8g of pale yellow solid pure 2-bromo-5-cyanobenzaldehyde, and the yield is: 92%.
Claims (1)
1. The synthesis method of the 2-bromo-5-cyanobenzaldehyde is characterized by comprising the following reaction routes:
the method comprises the following specific steps:
(1) Synthesis of 3- (bromomethyl) -4-bromoxynil
Under Ar protection, CCl is added into a reaction bottle 4 4-bromo-3-methylbenzonitrile, stirring and dissolving; sequentially adding benzoyl peroxide and N-bromosuccinimide, carrying out reflux reaction for 1-1.5h, and naturally cooling to 25 ℃; suction filtering, concentrating and evaporating filtrate to dryness to obtain a solid crude product I; recrystallizing the solid crude product I by using a mixed solvent of ethyl acetate and n-heptane to obtain an off-white solid 3- (bromomethyl) -4-bromoxynil;
(2) Synthesis of 4-bromo-3-hydroxymethylbenzonitrile
Under the protection of Ar, THF is added into a reaction bottle, and then 3- (bromomethyl) -4-bromoxynil is added into the reaction bottle, stirred and dissolved; sequentially adding water and calcium carbonate, carrying out reflux reaction for 6-6.5h, and naturally cooling to 25 ℃; suction filtering, leaching a filter cake by using THF, concentrating and evaporating filtrate to dryness to obtain 4-bromo-3-hydroxymethylbenzonitrile;
(3) Synthesis of 2-bromo-5-cyanobenzaldehyde
Under the protection of Ar, methylene dichloride and 4-bromo-3-hydroxymethyl benzonitrile are sequentially added into a reaction bottle, and stirred for dissolution; manganese dioxide is then added; reacting at room temperature for 5-5.5h, filtering with diatomite, eluting a filter cake with dichloromethane, and concentrating the filtrate under reduced pressure to obtain 2-bromo-5-cyanobenzaldehyde;
4-bromo-3-methylbenzonitrile: n-bromosuccinimide=1: 1-1.2;
3- (bromomethyl) -4-bromoxynil: calcium carbonate = 1:1-5;
4-bromo-3-hydroxymethylbenzonitrile in molar ratio: manganese dioxide = 1:3-7.
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