CN102020587A - Method for synthesizing 2-methoxy-4-cyano benzaldehyde - Google Patents
Method for synthesizing 2-methoxy-4-cyano benzaldehyde Download PDFInfo
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- 238000000034 method Methods 0.000 title abstract description 7
- ZXENVSJZOHXCKL-UHFFFAOYSA-N 4-formyl-3-methoxybenzonitrile Chemical compound COC1=CC(C#N)=CC=C1C=O ZXENVSJZOHXCKL-UHFFFAOYSA-N 0.000 title abstract 3
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 32
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 150000001649 bromium compounds Chemical class 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 25
- 150000001408 amides Chemical class 0.000 claims description 17
- 238000006460 hydrolysis reaction Methods 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- -1 xylylene bromide Chemical compound 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 238000010189 synthetic method Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- 230000018044 dehydration Effects 0.000 claims description 6
- 238000006297 dehydration reaction Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 238000005660 chlorination reaction Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 abstract description 8
- 238000010438 heat treatment Methods 0.000 abstract description 2
- PRSZIONFUSZSGJ-UHFFFAOYSA-N 3-methoxy-4-methylbenzamide Chemical compound COC1=CC(C(N)=O)=CC=C1C PRSZIONFUSZSGJ-UHFFFAOYSA-N 0.000 abstract 2
- QLJZMAGXHHXXMS-UHFFFAOYSA-N 3-methoxy-4-methylbenzonitrile Chemical compound COC1=CC(C#N)=CC=C1C QLJZMAGXHHXXMS-UHFFFAOYSA-N 0.000 abstract 2
- BQJLTBKKFLTXKO-UHFFFAOYSA-N 3-methoxy-4-methylbenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=CC=C1C BQJLTBKKFLTXKO-UHFFFAOYSA-N 0.000 abstract 2
- MRAHIVCBBZNVHV-UHFFFAOYSA-N benzonitrile;hydrobromide Chemical compound Br.N#CC1=CC=CC=C1 MRAHIVCBBZNVHV-UHFFFAOYSA-N 0.000 abstract 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 17
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 239000002253 acid Substances 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 208000005156 Dehydration Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000007603 infrared drying Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000014347 soups Nutrition 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
Abstract
The invention relates to a method for synthesizing 2-methoxy-4-cyano benzaldehyde which servers as an important medicinal intermediate. The method comprises the following steps: causing 3-methoxy-4-methyl benzoate to react with thionyl chloride react under the heating condition to generate 3-methoxy-4-methyl benzoyl chloride; causing the 3-methoxy-4-methyl benzoyl chloride to react with aqueous ammonia to generate 3-methoxy-4-methyl benzoyl amide; dehydrating the 3-methoxy-4-methyl benzoyl amide to generate 3-methoxy-4-methyl benzonitrile; brominating the 3-methoxy-4-methyl benzonitrile by N-bromosuccinimide (NBS) to generate 3-methoxy-4-benzylene bromide benzonitrile; and hydrolyzing the 3-methoxy-4-benzylene bromide benzonitrile to obtain the target product of 2-methoxy-4-cyano benzaldehyde. The method provided by the invention has the outstanding advantages that the reaction condition is mild, the reactions are rapid, the process is simple, and the operation is easy, thereby being suitable for industrial production.
Description
Technical field
The invention belongs to the organic compound field of six carbon aromatic rings, relate to the technology of preparing that phenyl ring has alkoxyl group, cyano group and aldehyde compound.
Background technology
2-methoxyl group-4-cyanobenzaldehyde is a very important pharmaceutical intermediate, does not see that so far it is the synthetic method of raw material Synthetic 2-methoxyl group-4-cyanobenzaldehyde with 3-methoxyl group-4-tolyl acid that bibliographical information is arranged.That the preparation method that this invention is reported has in actual production is simple to operate, the yield advantages of higher, be easy to advantages such as suitability for industrialized production.Key of the present invention is the synthetic of cyano group and aldehyde radical on the phenyl ring, the synthetic of cyano group realized by using prussiate to replace halogen mostly on the phenyl ring, but prussiate is Poisons, and we have adopted from the carboxylic acid that relatively is easy to get and have synthesized cyano group efficiently by steps such as ammonification dehydrations for fear of the use Poisons.And aldehyde radical synthetic also be used monobromomethane generation then hydrolysis realize, the hydrolysing agent of this compound must be weak base or DMSO (dimethyl sulfoxide (DMSO)), strong acid or highly basic all can cause the hydrolysis of cyano group, document Journal of Medicinal Chemistry, 2007.Vol.50, the No.10 report is hydrolyzed with Silver Nitrate, but Silver Nitrate price comparison costliness is not suitable for suitability for industrialized production.
Summary of the invention
The objective of the invention is to overcome the shortcoming and defect of aforesaid method, designed a synthetic route that efficiently is converted into 2-methoxyl group-4-cyanobenzaldehyde by 3-methoxyl group-4-tolyl acid.
Technical scheme of the present invention is as follows: add generation 3-methoxyl group-4-methyl benzoyl chloride under the thionyl chloride heating condition by 3-methoxyl group-4-tolyl acid, generate 3-methoxyl group-4-methyl benzamide with the ammoniacal liquor reaction again, acid amides generates 3-methoxyl group-4-methyl benzonitrile through dehydration, use NBS (N-bromosuccinimide again, Bromosuccinimide) make monobromomethane for generating 3-methoxyl group-4-two bromo methyl benzonitriles, generate target product 2-methoxyl group-4-cyanobenzaldehyde by hydrolysis.Its concrete operations step is as follows:
(1) 3-methoxyl group-4-methyl benzamide is synthetic: carboxylic acyloxy chlorination, aminating reaction compound (1) are 1: 1.2～1.5: 1.3～1.7 with the molar ratio of thionyl chloride, ammoniacal liquor, preferred 1: 1.2: 1.3; Reaction is at 80～90 ℃ of thermotonus 2～4h, preferred 2h.Its reaction equation is as follows:
(2) 2-methoxyl group-4-cyano group toluene is synthetic: acid amides (2) is 1: 1.2～1.6 with the molar ratio of thionyl chloride in the dehydration of amide reaction, preferred 1: 1.5.Temperature of reaction is 60～80 ℃, preferred 60 ℃, and reaction 0.5～4h.Its reaction equation is as follows:
(3) 2-methoxyl group-4-cyano group xylylene bromide is synthetic: the solvent of use can be tetracol phenixin, chloroform, toluene or 1,2-ethylene dichloride, preferred tetracol phenixin.Raw material (3) is 1: 2.1～2.5 with the consumption mol ratio of NBS, preferred 1: 2.3.60～90 ℃ of temperature of reaction, the reaction times is 3～5h.Preferred 78 ℃, the reaction times is 3～5h.Its reaction equation is as follows:
(4) product 2-methoxyl group-4-cyanobenzaldehyde is synthetic: the organic solvent that uses in the hydrolysis reaction of two bromo-derivatives can be methylene dichloride, tetracol phenixin, DMSO or ethanol, and preferred solvent is an ethanol.The consumption of organic solvent is 1～10 times of two bromo-derivatives (4) by weight, preferred 2 times.The hydrolysing agent that uses has ammoniacal liquor, triethylamine aqueous solution, dimethylamine agueous solution, pyrrole
Pyridine, sodium bicarbonate, DMSO (dimethyl sulfoxide (DMSO)) etc., preferred pyridine and DMSO.Two bromo-derivatives (4) are 1: 2～1: 5 with the mol ratio of organic bases, preferred 1: 4.Hydrolysising reacting temperature is controlled at 10 ℃～60 ℃, preferred 60 ℃.Reaction times is 2～24h, preferred 2h.After hydrolysis reaction finished, extracting method was extraction, can adopt methylene dichloride, tetracol phenixin, toluene, benzene, ethyl acetate etc., preferred methylene dichloride.With saturated aqueous common salt and water organic phase is washed respectively then, last anhydrous magnesium sulfate drying, precipitation, it is as follows to get its reaction equation of light yellow product (5):
In the above-mentioned reaction of the present invention, the final step hydrolysis reaction is a committed step of the present invention, though the bibliographical information hydrolysising condition is a lot, but also be easy to the character restriction of hydrolysis in view of the special construction contraposition cyano group of this compound, the present invention has adopted the organic weak base condition to be hydrolyzed, effectively prevent the hydrolysis of cyano group, obtained target product efficiently.Organic bases nearly all among the present invention can be realized hydrolysis, ammoniacal liquor for example, diethylamine aqueous solution, dimethylamine agueous solution, triethylamine aqueous solution, pyridine etc.Sodium bicarbonate aqueous solution and DMSO (dimethyl sulfoxide (DMSO)) can realize that equally two bromo-derivatives are hydrolyzed into aldehyde radical simultaneously, and cyano group is unaffected.
The advantage that the present invention gives prominence to is: the reaction conditions gentleness, be swift in response, and technology is simple, and is easy to operate, is fit to suitability for industrialized production.
Below with specific embodiment this aspect is described further.
Embodiment
Embodiment 1
(1) 3-methoxyl group-4-methyl benzamide is synthetic: 3-methoxyl group-4-tolyl acid 900g (5.42mol) is added in the 2L four-hole reaction flask, adding thionyl chloride 496ml (6.83mol) stirs, beginning slowly is warming up to 80 ℃, reaction solution adularescent soup compound gradually becomes brown liquid state, become brownish black at last, about 2h reaction finishes, and adds the underpressure distillation of 150ml toluene, steams reaction residue thionyl chloride.Then reaction solution is joined in the beaker or reaction flask of the ammoniacal liquor that 2.5L (7.3mol) 25% is housed, stir, have faint yellow solid to separate out while dripping, suction filtration, infrared drying gets 850g product (2), and yield is 95%.
(2) the cyaniding body is synthetic: add acid amides (2) 82.5g (0.5mol) with 1L four-hole reaction flask, drip thionyl chloride 89.3g (0.75mol) in reaction flask, about 45min dropwises.Temperature is controlled at 60 ℃, reaction 2h.Reaction solution is poured in the 800g frozen water, and the limit bevelling stirs, and has yellow solid to separate out, suction filtration, and drying obtains 71.5g product (3), yield 97%.
(3) bromination reaction: get the said products (3) 50g (0.31mol) and be dissolved in the 100ml carbon tetrachloride solvent, heated and stirred, temperature in the kettle is controlled at 75 ℃ as far as possible, in reactor, add AIBN (Diisopropyl azodicarboxylate, azodiisobutyronitrile) 1.5g (0.01mol) and NBS125g (0.7mol) in batches.Behind the reinforced reaction 3h that finishes, sampling is GC and is analyzed, and raw material reaction is complete.Begin to be cooled to 20 ℃, suction filtration.The organic layer anhydrous magnesium sulfate drying filters, and the filtrate precipitation obtains the product (4) of 95g, yield 95%.
The hydrolysis reaction of (four) two bromo-derivatives: two bromo-derivatives (4) 91g (0.3mol) are dissolved among the 500mlDMSO, are heated to 100 ℃, insulation reaction 3h.Sampling is GC and is analyzed, raw material＜0.1%.Reaction solution is poured in the 500ml water, uses the 2*200ml dichloromethane extraction, with 400ml saturated aqueous common salt and 400ml water organic phase is washed respectively then, last anhydrous magnesium sulfate drying, and precipitation gets light yellow product (5) 43g, and yield is 90%
Embodiment 2
(1) 3-methoxyl group-4-methyl benzamide is synthetic: 3-methoxyl group-4-tolyl acid 900g (5.42mol) is added in the 2L four-hole reaction flask, adding thionyl chloride 496ml (6.83mol) stirs, beginning slowly is warming up to 90 ℃, reaction solution adularescent soup compound gradually becomes brown liquid state, become brownish black at last, about 2h reaction finishes, and adds the underpressure distillation of 150ml toluene, steams reaction residue thionyl chloride.Then reaction solution is joined in the beaker or reaction flask of the ammoniacal liquor that 2.5L (7.3mol) 25% is housed, stir, have faint yellow solid to separate out while dripping, suction filtration, infrared drying gets 769g product (2), and yield is 86%.
Embodiment 3
Reaction (one) and embodiment 1 are together.
(2) the cyaniding body is synthetic: add acid amides (2) 82.5g (0.5mol) with 1L four-hole reaction flask, drip thionyl chloride 89.3g (0.75mol) in reaction flask, about 45min dropwises.Temperature is controlled at 80 ℃, reaction 0.5h.Pour reaction solution in 800g frozen water limit bevelling stirring, have yellow solid to separate out, suction filtration, drying obtains 65g product (3), yield 89%.
Embodiment 4
Reaction (one) and (two) and embodiment 1 are together.
(3) bromination reaction: get the said products (3) 50g (0.31mol) and be dissolved in 100ml1, in the 2-ethylene dichloride solvent, heated and stirred, temperature in the kettle is controlled at 80 ℃ as far as possible, in reactor, add AIBN (Diisopropyl azodicarboxylate, azodiisobutyronitrile) 1.5g (0.01mol) and NBS125g (0.7mol) in batches.Behind the reinforced reaction 3h that finishes, sampling is GC and is analyzed, and raw material reaction is complete.Begin to be cooled to 20 ℃, suction filtration.The organic layer anhydrous magnesium sulfate drying filters, and the filtrate precipitation obtains the product (4) of 89g, yield 89%.
Embodiment 5
Reaction (one), (two) and (three) and embodiment 1 are together.
The hydrolysis reaction of (four) two bromo-derivatives: get dibrominated product (4) 91g (0.3mol) product and be dissolved in the 200ml alcohol solvent, in the pyridine adding reaction flask with 47.4g (0.6mol), be warming up to 100 ℃, insulation reaction 2h.Sampling is GC and is analyzed, raw material＜0.1%.Be cooled to 20 ℃, add the 200ml dichloromethane extraction.Tell organic layer.Dilute hydrochloric acid with 5% adds above-mentioned organic layer, regulates the pH value and is approximately 3.Standing demix is told organic phase, and water carries out a washing again.The organic phase anhydrous magnesium sulfate drying, obtaining pure light yellow product (5) 41g yield behind the precipitation is 85%.
Embodiment 6
Reaction (one), (two) and (three) and embodiment 1 are together.
The hydrolysis reaction of (four) two bromo-derivatives: get two bromo compound (4) 91g (0.3mol) and be dissolved in the 200ml ethanol, sodium bicarbonate 100.8g (1.2mol) is added in the reaction flask, controlled temperature is at 65～70 ℃.Insulation reaction 1h.Sampling is GC and is analyzed, raw material＜0.1%.Be cooled to 20 ℃, add the 200ml dichloromethane extraction.Tell organic layer.Wash with the 200ml saturated aqueous common salt, standing demix is told organic phase, and water carries out a washing again, the organic phase anhydrous magnesium sulfate drying, and precipitation obtains pure light yellow product (5) 29g, and yield is 60%.
Claims (6)
1.2-the synthetic method of methoxyl group-4-cyanobenzaldehyde is characterized in that the concrete operations step is as follows:
(1) 3-methoxyl group-4-methyl benzamide is synthetic:
Carboxylic acyloxy chlorination, aminating reaction compound (1) are 1: 1.2～1.5: 1.3～1.7 with the molar ratio of thionyl chloride, ammoniacal liquor, and reaction is at 80～90 ℃ of reaction 2～4h;
(2) 2-methoxyl group-4-cyano group toluene is synthetic:
Acid amides (2) is 1: 1.2～1.6 with the molar ratio of thionyl chloride in the dehydration of amide reaction, at 60～80 ℃ of reaction 0.5～4h;
(3) 2-methoxyl group-4-cyano group xylylene bromide is synthetic:
Solvent is tetracol phenixin, chloroform, toluene or 1, the 2-ethylene dichloride, and raw material (3) is 1: 2.1～2.5 with the consumption mol ratio of NBS, is 3～5h 60～90 ℃ of reaction times;
(4) product 2-methoxyl group-4-cyanobenzaldehyde is synthetic:
Organic solvent is selected from methylene dichloride, tetracol phenixin, DMSO or ethanol, and consumption is 1～10 times of two bromo-derivatives (4) by weight; The organic bases that hydrolysing agent uses is selected from a kind of among ammoniacal liquor, triethylamine aqueous solution, dimethylamine agueous solution, pyridine, sodium bicarbonate, the DMSO; Two bromo-derivatives (4) are 1: 2～1: 5 with the mol ratio of organic bases; Hydrolysis reaction is at 10～60 ℃ of reaction 2～24h; Reaction finishes the back and uses methylene dichloride, tetracol phenixin, and toluene, benzene or ethyl acetate extraction, organic phase are washed organic phase with saturated aqueous common salt and water respectively, and through anhydrous magnesium sulfate drying, precipitation gets light yellow product (5).
2. according to the synthetic method of the described 2-methoxyl group of claim 1-4-cyanobenzaldehyde, it is characterized in that (one) 3-methoxyl group-4-methyl benzamide synthetic described in carboxylic acyloxy chlorination, aminating reaction compound (1) be 1: 1.2: 1.3 with the molar ratio of thionyl chloride, ammoniacal liquor; Reaction is at 80～90 ℃ of thermotonus 2h.
3. according to the synthetic method of the described 2-methoxyl group of claim 1-4-cyanobenzaldehyde, it is characterized in that in (two) 2-methoxyl group-4-cyano group toluene synthetic that the molar ratio of acid amides (2) and thionyl chloride is 1: 1.5 in the dehydration of amide reaction; Temperature of reaction is 60 ℃.
4. according to the synthetic method of the described 2-methoxyl group of claim 1-4-cyanobenzaldehyde, it is characterized in that the synthetic middle solvent that uses of (three) 2-methoxyl group-4-cyano group xylylene bromide is tetracol phenixin; Raw material (3) is 1: 2.3 with the consumption mol ratio of NBS; 78 ℃ of temperature of reaction.
5. according to the synthetic method of the described 2-methoxyl group of claim 1-4-cyanobenzaldehyde, it is characterized in that organic solvent is an ethanol described in (four) product 2-methoxyl group-4-cyanobenzaldehyde synthetic, its consumption is 2 times of two bromo-derivatives (4) by weight; The hydrolysing agent organic bases that uses is pyridine or DMSO; Two bromo-derivatives (4) are 1: 4 with the mol ratio of organic bases; At 60 ℃ of reaction 2h; Hydrolysis reaction is used dichloromethane extraction after finishing.
6. according to the synthetic method of the described 2-methoxyl group of claim 1-4-cyanobenzaldehyde, it is characterized in that in the concrete operations step:
(1) carboxylic acyloxy chlorination described in 3-methoxyl group-4-methyl benzamide synthesizes, aminating reaction compound (1) are 1: 1.2: 1.3 with the molar ratio of thionyl chloride, ammoniacal liquor; Reaction is at 80～90 ℃ of thermotonus 2h;
(2) molar ratio of acid amides (2) and thionyl chloride is 1: 1.5 in the synthetic middle dehydration of amide reaction of 2-methoxyl group-4-cyano group toluene; Temperature of reaction is 60;
(3) the synthetic middle solvent that uses of 2-methoxyl group-4-cyano group xylylene bromide is tetracol phenixin; Raw material (3) is 1: 2.3 with the consumption mol ratio of NBS; 78 ℃ of temperature of reaction;
(4) organic solvent described in product 2-methoxyl group-4-cyanobenzaldehyde synthetic is an ethanol, and its consumption is 2 times of two bromo-derivatives (4) by weight; The hydrolysing agent organic bases that uses is pyridine or DMSO; Two bromo-derivatives (4) are 1: 4 with the mol ratio of organic bases; At 60 ℃ of reaction 2h; Hydrolysis reaction is used dichloromethane extraction after finishing.
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| CN102924346A (en) * | 2012-11-07 | 2013-02-13 | 山东润科化工股份有限公司 | Method for synthesizing methyl sulfone base dibromo toluene |
| CN107721869A (en) * | 2017-03-30 | 2018-02-23 | 上海雅本化学有限公司 | A kind of synthetic method of the cyanobenzaldehyde of 2 methoxyl group 4 |
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| CN115010621B (en) * | 2022-07-21 | 2023-11-03 | 山东百启生物医药有限公司 | Synthesis method of 4-bromo-3-methylbenzonitrile |
| CN115010621A (en) * | 2022-07-21 | 2022-09-06 | 山东百启生物医药有限公司 | Synthetic method of 4-bromo-3-methylbenzonitrile |
| CN115368272A (en) * | 2022-08-31 | 2022-11-22 | 汉瑞药业(荆门)有限公司 | Preparation method of 4-cyano-2-methoxybenzaldehyde |
| CN115991661A (en) * | 2023-01-06 | 2023-04-21 | 浙江科聚生物医药有限公司 | Preparation method of high-purity non-neridone key intermediate |
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