CN109053443A - The bromo- 3- aldehyde radical-phenoxy group of 4-(4-)-benzonitrile synthetic method - Google Patents
The bromo- 3- aldehyde radical-phenoxy group of 4-(4-)-benzonitrile synthetic method Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- 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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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/42—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis
- C07C45/43—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis of >CX2 groups, X being halogen
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/287—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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Abstract
The present invention provides a kind of synthetic methods of 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile, using 3- methylphenol as starting material, 3- methyl-phenyl ester compound is prepared with anhydride reaction, 3- methyl-phenyl ester compound is reacted with sulfonic acid chloride prepares 3- chloromethyl-phenyl ester compound and 3- dichloromethyl-phenyl ester compound mixture, 3- hydroxy-benzaldehyde is obtained after adding methenamine to hydrolyze, the bromo- 3- hydroxy-benzaldehyde of 4- is obtained through bromination reaction, adds 4- fluorobenzonitrile that 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile is made after condensation reaction.Reaction raw materials of the present invention are cheap and easy to get, and reaction step is few, and production cost is low, simple process, and product purity is high, up to 99.0% or more, are advantageously implemented industrialized production.
Description
(1) technical field: the present invention relates to a kind of medicine intermediate 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitriles
Synthetic method.
(2) background technique: 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile is synthesis allergic dermatitis kind new medicine
The important intermediate of Crisaborole.Crisaborole is non-steroid therapeutic agent, is a kind of boracic anti-inflammatory agent, can inhibit
PDE4 activity and TNF α, IL-12, IL-23 and other cytokine release, curative effect determines, highly-safe, is positioned as slightly extremely
The steroids alternative medicine of moderate eczema (also known as allergic dermatitis).
Currently, this is a new drug, the clinical three phases test of children and adults is just completed, document there is no disclosure to report.
(3) summary of the invention: the present invention provides a kind of synthesis side of new 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile
Method, it is simple process, low cost, high-quality, and product purity is high.
Technical scheme is as follows:
The present invention prepares 3- methyl-phenyl ester compound, 3- methyl-benzene using 3- methylphenol as starting material, with anhydride reaction
Carboxylate is reacted with sulfonic acid chloride prepares 3- chloromethyl-phenyl ester compound and 3- dichloromethyl-phenyl ester compound mixture, abbreviation chlorination
Liquid obtains 3- hydroxy-benzaldehyde in chlorated liquid plus after methenamine hydrolysis, obtains the bromo- 3- hydroxyl-benzene first of 4- through bromination reaction
Aldehyde, then with after 4- fluorobenzonitrile condensation reaction be made 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile, product purity >=
99.0%.It elaborates below to specific steps of the present invention.
(1) esterification: raw material 3- methylphenol and acid anhydrides carry out esterification, and reaction vessel needs anhydrous condition, i.e.,
Vacuum, nitrogen are replaced three times, and reaction temperature controls 70~85 DEG C, after fully reacting, is collected by vacuum distillation, obtains 3- methyl-
Phenyl ester compound, wherein 3- methylphenol and anhydride weight ratio g/g are 1:0.9-2.0.
The acid anhydrides is selected from formic anhydride or one of acetic anhydride or propionic andydride, preferably acetic anhydride.
(2) chlorination reaction: in dry reaction flask, 3- methyl-phenyl ester compound that esterification is obtained initiator,
It reacts in the presence of organic solvent with sulfonic acid chloride, is first heated to back 3- methyl-phenyl ester compound, organic solvent and part initiator
Stream, then it is slowly added dropwise to raw material sulfonic acid chloride and remaining initiator under reflux, the reaction was continued, is steamed after fully reacting by decompression
It is dry, chlorated liquid is obtained, the substance in this chlorated liquid is 3- chloromethyl-phenyl ester compound and the mixing of 3- dichloromethyl-phenyl ester compound
Object；3- methyl-phenyl ester the compound: initiator: sulfonic acid chloride: the w/v g/g/g/ml of organic solvent is 1:0.02-
0.2:1.5-2.5:4.0-7.0.
The reaction organic solvent is selected from one of dichloromethane or chloroform, preferably chloroform.
The initiator is selected from azodiisobutyronitrile.
(3) hydrolysis: divide two step method, first step reaction: in above-mentioned reaction product chlorated liquid, be directly added into Wu Luotuo
Product, organic solvent alcohols and water, heating, heat preservation, then depressurize and boil off organic solvent alcohols, wherein with raw material 3- methyl-phenyl ester
On the basis of object, 3- methyl-phenyl ester compound: methenamine: water: the w/v g/g/ml/ml of alcohols is 1:0.6-1.0:
1.5-2.5:2.5-3.5；Second step reaction: it after decompression boils off organic solvent alcohols, adds water and hydrolyst, heating is protected
Temperature is extracted and is refined with organic solvent after fully reacting, obtain 3- hydroxy-benzaldehyde, wherein 3- methyl-phenyl ester compound: hydrolysis
Catalyst: for the second time plus the w/v g/g/ml of water is 1:0.45-2.0:5.0-7.0.
The hydrolysis, point two steps carry out, and the first step is 3- chloromethyl-phenyl ester compound and 3- dichloromethyl-phenyl ester
Compound is first reacted with methenamine, could be hydrolyzed into aldehyde with acid later；Under the action of an acid, while ester hydrolysis is carried out.
The organic solvent alcohols is selected from methanol or one of ethyl alcohol or isopropanol, preferably ethyl alcohol, most preferably
95% ethyl alcohol.
The hydrolyst is selected from one of hydrochloric acid or sulfuric acid.Hydrolyst is preferably hydrochloric acid, and additive amount is excellent
Be selected as 3- methyl-phenyl ester compound: the weight ratio g/g of hydrochloric acid is 1.0:0.8~2.0.When hydrolyst selects sulfuric acid, sulfuric acid
Additive amount is preferably 3- methyl-phenyl ester compound: the weight ratio g/g of sulfuric acid is 1.0:0.45~1.13.
The hydrolysis product is extracted and is refined with organic solvent, wherein extracting organic solvent selects methyl tertbutyl
Ether, purification organic solvent are selected from one of water or toluene and need to add active carbon in subtractive process, it is therefore an objective to remove big
The coloring matter of amount.
(4) bromination reaction: in dry reaction flask, hydrolysis product 3- hydroxy-benzaldehyde exists in organic solvent
It is lower to be reacted with bromine, then after organic solvent refines, obtain the bromo- 3- hydroxy-benzaldehyde wet product of 4-.
The weight ratio g/g of the 3- hydroxy-benzaldehyde and bromine be 1.0:1.0-2.0,3- hydroxy-benzaldehyde with react
The w/v g/ml of organic solvent is 1.0:5.0-7.0；The reaction organic solvent is selected from methylene chloride or three chloromethanes
One of alkane, purification organic solvent are selected from toluene.
(5) condensation reaction: in clean reaction flask, the bromo- 3- hydroxy-benzaldehyde wet product of reaction product 4-, organic molten
With 4- fluorobenzonitrile condensation reaction in the presence of agent, catalyst, heated, heat preservation obtains reaction product, then through organic solvent purification,
Filtering, drying obtain 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile product；The wherein bromo- 3- hydroxy-benzaldehyde of 4-: reaction has
Solvent: 4- fluorobenzonitrile: the weight ratio g/g/g/g of catalyst is 1.0:10.0-12.0:1.0-2.5:1.0-2.5.
In the condensation reaction, reaction organic solvent is selected from one of dimethyl acetamide or dimethylformamide,
Preferably dimethyl acetamide.
In the condensation reaction, catalyst choice potassium carbonate, due to that can generate HF in reaction process, potassium carbonate is as suction
Sour agent and catalyst promote reaction to carry out to positive direction.
In the condensation reaction, reaction product is refined through organic solvent, purification organic solvent be selected from methanol or ethyl alcohol or
One of isopropanol, preferably isopropanol.
Reaction route chemical equation is as follows in the method for the present invention:
Synthetic method of the present invention, using 3- methylphenol as starting material, through esterification, chlorination, hydrolysis, bromination and condensation reaction
4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile is obtained, product purity >=99.0% in product purity, process flow, is produced into
This etc. all obtains unexpected effect, and the present invention has outstanding feature and progress:
(1) raw material of the present invention is easy to get, cheap, and synthesis technology process is short, greatly reduces production cost.
(2) in second step chlorination reaction, using the lower solvent chloroform of toxicity or methylene chloride, four chlorinations are not used
Carbon reduces toxicity, reduces environmental pollution, improve the safety of personnel, convenient for operation, is advantageously implemented industrialized production.
(3) discharge such as sewage is reduced, reacts used solvent, majority can multiple recovery.
(4) hydrolysis uses two-step method, is conducive to the conversion of raw material, further increases reaction yield.
(5) HF can be generated in condensation reaction, the present invention uses potassium carbonate, i.e., as acid absorbent again as catalyst,
While promoting reaction to carry out to positive direction, also it is conducive to the conversion of raw material, improves reaction yield.
(6) purpose of the present invention product purity is high, and postprocessing working procedures greatly simplify, and product purity is up to 99.0% or more.
(4) specific embodiment
The present invention is further illustrated below by the specific embodiment of embodiment form, is convenient for those skilled in the art
The present invention is further understood, without constituting the limitation to its right, any specific number of range described in the claims in the present invention
Value and carrier, are implementable.
Embodiment 1
The present embodiment reacts preparation 3- methyl-benzeneacetic acid ester, 3- first with anhydride esterifying using 3- methylphenol as starting material
Base-phenylacetate and sulfonic acid chloride raw material carry out chlorination reaction preparation 3- chloromethyl-phenylacetate and 3- dichloromethyl-phenylacetate
Mixture, abbreviation chlorated liquid, in chlorated liquid plus methenamine and organic solvent and catalyst reaction is hydrolyzed after obtain
3- hydroxy-benzaldehyde, 3- hydroxy-benzaldehyde carry out bromination reaction with bromine in the presence of an organic and obtain the bromo- 3- hydroxyl-of 4-
Benzaldehyde, the bromo- 3- hydroxy-benzaldehyde of 4- are made after condensation reaction in the presence of organic solvent and catalyst with 4- fluorobenzonitrile
4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile, directly obtains product purity >=99.0%.Specific step is as follows.
(1) esterification
Raw material: 3- methylphenol 320g, acetic anhydride 288g；
Reaction vessel: vacuum, nitrogen displacement are three times (anhydrous)；
Reaction step: reaction vessel puts into acetic anhydride 288g under nitrogen protection, is heated to 70~85 DEG C, closes nitrogen, drop
Add 3- methylphenol 320g, time for adding 0.5~1 hour, keep the temperature 1 hour after adding, cool to 55 DEG C or so, GC is qualified, subtracts
Pressure distillation, first recycle acetic acid, acetic anhydride, interception end cuts be intermediate 3- methyl-benzeneacetic acid ester 422g, colourless liquid,
GC >=98.0%.
(2) chlorination reaction
Raw material: 3- methyl-benzeneacetic acid ester 128g, sulfonic acid chloride 192g, initiator azodiisobutyronitrile 2.56g, organic solvent
Chloroform 512ml；
Reaction vessel: vacuum, nitrogen displacement are three times (anhydrous)；
Reaction step: in the reaction vessel, 3- methyl-benzeneacetic acid ester 128g, initiator azo are added under nitrogen protection
Chloroform 512ml is added in bis-isobutyronitrile 1.28g, closes nitrogen, is heated to flow back under stirring, is slowly added dropwise to sulfonic acid chloride 192g
With remaining initiator azodiisobutyronitrile 1.28g, dropwise addition 3 hours or more, the reaction was continued 0.5 hour or more after dripping off, GC inspection
It is qualified to survey, and evaporated under reduced pressure obtains chlorated liquid.
(3) hydrolysis
Raw material: chlorated liquid (using 3- methyl-benzeneacetic acid ester raw material as standard, 128g), methenamine 76.8g, 95% ethyl alcohol
320ml and water 192ml, second plus water 768ml, hydrolyst hydrochloric acid 151g, extracts and uses organic solvent methyl tertiary butyl ether(MTBE),
Conventional amount used；Purification is toluene, conventional amount used with organic solvent；
Reaction vessel: for the reaction vessel of step (2)；
Reaction step: methenamine 76.8g, 95% ethyl alcohol 320ml and water are added in the chlorated liquid of step (2) preparation
192ml heats 70~80 DEG C, and decompression boils off ethyl alcohol after heat preservation 2 hours, and second plus water 768ml, hydrochloric acid 151g are heated to 70
After~80 DEG C, heat preservation 2 hours, TLC tracking, after fully reacting, reaction product cools to 40 DEG C or less；
The extraction and purification step of reaction product:
It is extracted first with organic solvent methyl tertiary butyl ether(MTBE): methyl tertiary butyl ether(MTBE) 96ml is added, it is 20~35 DEG C cooling, point
Layer, water layer use methyl tertiary butyl ether(MTBE) 96ml x2 to extract again, merge organic layer；NaHCO will be saturated3Aqueous solution is added in organic layer,
It adjusts pH and is greater than 7, layering, water layer extracts 96ml with methyl tertiary butyl ether(MTBE) and is stripped again once, merges organic layer, and evaporated under reduced pressure obtains
3- hydroxy-benzaldehyde crude product, faint yellow solid about 75g；
It is refined again with organic solvent toluene: being extracted in upper step and add toluene 300ml or so, active carbon in the solid 75g obtained
15g, is heated to 70~80 DEG C, and heat filtering after heat preservation 2 hours is washed with 75ml or so toluene, is slow cooling to 10 DEG C hereinafter, 0
~10 DEG C keep the temperature 1 hour, and filtering, 75ml toluene is washed；For filter cake at 50~60 DEG C, vacuum drying obtains 3- hydroxy-benzaldehyde about 69g,
Off-white color crystalline powder, purity >=99.0%.
(4) bromination reaction
Raw material: 3- hydroxy-benzaldehyde 35.4g, bromine 35.4g, organic solvent dichloromethane 212ml；It refines with organic molten
Agent toluene, conventional amount used；
Reaction vessel: vacuum, nitrogen displacement are three times；
Reaction step: in clean reaction vessel, 3- hydroxy-benzaldehyde 35.4g and methylene chloride 212ml is added, very
Three times, stirring cools to 0 DEG C hereinafter, dropwise addition bromine 35.4g, adds water 250ml, adjusted with liquid alkaline after fully reacting for empty nitrogen displacement
PH is to neutrality, and cool down filtering, and wet product adds toluene 354ml to be heated to dissolve, and branch vibration layer, organic phase is warming up to reflux, cools down
Filter, drying, obtains the bromo- 3- hydroxy-benzaldehyde 35.5g of 4-.
(5) condensation reaction
Raw material: 4- bromo- 3- hydroxy-benzaldehyde 35.5g, 4- fluorobenzonitrile 35.5g, potassium carbonate 35.5g react organic solvent
Dimethyl acetamide 355g；Purification organic solvent isopropanol, conventional amount used；
Reaction vessel: vacuum, nitrogen displacement are three times；
Reaction step: in reaction flask, the bromo- 3- hydroxy-benzaldehyde 35.5g of 4-, dimethyl acetamide 355g, 4- fluorine is added
Benzonitrile 35.5g, potassium carbonate 35.5g, vacuum nitrogen are replaced three times, are stirred and heated to 60~70 DEG C, heat preservation 2 hours or more, are dropped
Temperature is to 15~25 DEG C, filtering, and 888ml washing obtains 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile wet product 44.6g；Add isopropyl
Alcohol 142ml is dissolved by heating, and cooling filtering drying obtains 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile 41.8g, and purity >=
99.0%.
Embodiment 2
The present embodiment obtains 4- using 3- methylphenol as starting material, through esterification, chlorination, hydrolysis, bromination and condensation reaction
(the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile, product purity >=99.0%, the specific steps are as follows:
(1) esterification
Raw material: 3- methylphenol 320g, propionic andydride 330g；
Reaction vessel: vacuum, nitrogen displacement are three times (anhydrous)；
Reaction step: reaction vessel three times (anhydrous), puts into propionic andydride through vacuum, nitrogen displacement under nitrogen protection
330g is heated to 70~85 DEG C, closes nitrogen, and 3- methylphenol 320g is added dropwise, time for adding 0.5~1 hour, adds 1 hour afterwards,
55 DEG C or so are cooled to, GC is qualified, vacuum distillation, first recycles propionic acid, propionic andydride, and interception end cuts is 3- methyl-phenylpropyl alcohol
Acid esters 432g, colourless liquid, GC >=98.0%.
(2) chlorination reaction
Raw material: 3- methyl-Phenpropionate 32g, sulfonic acid chloride 80g, azodiisobutyronitrile 6.4g, organic solvent chloroform
160ml；
Reaction vessel: vacuum, nitrogen displacement are three times (anhydrous)；
Reaction step: in dry reaction flask, 3- methyl-Phenpropionate 32g, initiator azodiisobutyronitrile is added
3.2g；Vacuum, nitrogen displacement three times, are added chloroform 160ml, are heated to flow back under stirring, slowly be added dropwise under nitrogen protection
Enter sulfonic acid chloride 80g and remaining initiator azodiisobutyronitrile 3.2g, be added dropwise 3 hours or more, the reaction was continued 0.5 hour after dripping off
More than, GC detection is qualified, and evaporated under reduced pressure obtains chlorated liquid.
(3) hydrolysis
Raw material: chlorated liquid (using 3- methyl-Phenpropionate raw material as standard, 32g), methenamine 32g, methanol 112ml and
Water 80ml, second plus water 224ml, hydrolyst sulfuric acid 35.2g, extracts organic solvent methyl tertiary butyl ether(MTBE), conventional amount used；
Purification organic solvent is toluene, conventional amount used；
Reaction vessel: for the reaction vessel of step (2)；
Reaction step: methenamine 32g, methanol 112ml and water are added in the chlorated liquid of above-mentioned steps (2) preparation
80ml heats 70~80 DEG C, and decompression boils off methanol after heat preservation 2 hours, and second plus water 224ml, sulfuric acid 35.2g are heated to 70
After~80 DEG C, heat preservation 2 hours, TLC tracking after fully reacting, cools to 40 DEG C hereinafter, extracting technique: being added organic molten
Agent methyl tertiary butyl ether(MTBE) 48ml, 20~35 DEG C cooling, layering, water layer uses methyl tertiary butyl ether(MTBE) 48ml x2 to extract again, merges organic
Layer；NaHCO will be saturated3Aqueous solution is added in organic layer, and pH is greater than 7, and layering, it is anti-again that water layer methyl tertiary butyl ether(MTBE) extracts 48ml
Extraction is primary, merges organic layer, and evaporated under reduced pressure obtains 3- hydroxy-benzaldehyde crude product, faint yellow solid about 18.5g；
It is refined with organic solvent toluene: adding toluene 192ml, active carbon 4.5g in solid 15g, be heated to 70~80 DEG C, protected
Temperature 2 hours after heat filtering, washed with 15ml toluene, be slow cooling to 10 hereinafter, 0~10 DEG C keep the temperature 1 hour, filtering, 15ml toluene
It washes.Filter cake is at 50~60 DEG C, vacuum drying, obtains 3- hydroxy-benzaldehyde 13.5g, off-white color crystalline powder, and purity >=
99.0%.
(4) bromination reaction
Raw material: 3- hydroxy-benzaldehyde 35.4g, bromine 70g, organic solvent chloroform 247ml；Refine organic solvent first
Benzene, conventional amount used；
Reaction vessel: vacuum, nitrogen displacement are three times；
Reaction step: in clean reaction flask, 3- hydroxy-benzaldehyde 35.4g and chloroform 247ml, vacuum is added
Nitrogen is replaced three times, and stirring cools to 0 DEG C hereinafter, bromine 70g is added dropwise, and after fully reacting plus water 250ml, is adjusted pH with liquid alkaline and is arrived
Neutrality, cooling filtering, wet product add toluene 460ml or so to be heated to dissolve, and branch vibration layer, organic phase is warming up to reflux, cools down
Filter, drying, obtains the bromo- 3- hydroxy-benzaldehyde 36g of 4-.
(5) condensation reaction
Raw material: 4- bromo- 3- hydroxy-benzaldehyde 36g, 4- fluorobenzonitrile 90g, potassium carbonate 90g, organic solvent dimethylacetamide
Amine 432g；Refine organic solvent ethyl alcohol, conventional amount used；
Reaction vessel: vacuum, nitrogen displacement are three times；
Reaction step: in reaction flask, the bromo- 3- hydroxy-benzaldehyde 36g of 4-, dimethyl acetamide 432g, 4- fluorobenzene is added
Formonitrile HCN 90g, potassium carbonate 90g, vacuum nitrogen are replaced three times, are stirred and heated to 60~70 DEG C, heat preservation 2 hours or more, are cooled to 15
~25 DEG C, filtering 888ml washing obtains 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile wet product 44.6g, adds ethyl alcohol 216ml smart
System dissolves by heating, and cooling filtering drying obtains 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile 42g, purity >=99.0%.
Embodiment 3
The present embodiment obtains 4- using 3- methylphenol as starting material, through esterification, chlorination, hydrolysis, bromination and condensation reaction
(the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile, product purity >=99.0%, the specific steps are as follows:
(1) esterification
Raw material: 3- methylphenol 160g, acetic anhydride 165g；
Reaction vessel: vacuum, nitrogen displacement are three times (anhydrous)；
Reaction step: reaction vessel vacuum, nitrogen displacement three times (anhydrous), put into acetic anhydride 165g under nitrogen protection,
70~85 DEG C are heated to, nitrogen is closed, 3- methylphenol 160g is added dropwise, time for adding 0.5~1 hour, 1 hour after adding, cools down
To 55 DEG C or so, GC is qualified, vacuum distillation, first recycles acetic acid, acetic anhydride, and interception end cuts is 3- methyl-benzeneacetic acid ester
213g, colourless liquid, GC >=98.0%.
(2) chlorination reaction
Raw material: 3- methyl-benzeneacetic acid ester 32g, sulfonic acid chloride 64g, initiator azodiisobutyronitrile 2.3g, organic solvent trichlorine
Methane 160ml；
Reaction vessel: vacuum, nitrogen displacement are three times (anhydrous)；
Reaction step: in dry reaction flask, 3- methyl-benzeneacetic acid ester 32g, azodiisobutyronitrile 1.5g is added；Very
Empty, nitrogen displacement three times, is added chloroform 160ml, is heated to flow back under stirring, is slowly added dropwise to sulfonic acid chloride under nitrogen protection
64g and azodiisobutyronitrile 0.8g, dropwise addition 3 hours or more, the reaction was continued after dripping off 0.5h or more, GC detection qualification, decompression steaming
It is dry, obtain chlorated liquid.
(3) hydrolysis
Raw material: chlorated liquid (using 3- methyl-benzeneacetic acid ester raw material as standard, 32g), methenamine 24g, 95% ethyl alcohol
100ml and first step water 65ml, second step add water 224ml, hydrolyst hydrochloric acid 47g, extract organic solvent methyl- tert fourth
Base ether, conventional amount used；Purification organic solvent is toluene, conventional amount used；
Reaction vessel: for the reaction vessel of step (2)；
Reaction step: methenamine 24g, 95% ethyl alcohol 100ml and water are added in the chlorated liquid of step (2) preparation
65ml heats 70~80 DEG C, and decompression boils off ethyl alcohol after heat preservation 2 hours, and second plus water 224ml, hydrochloric acid 47g, it is heated to 70~
After 80 DEG C, heat preservation 2 hours, TLC tracking after fully reacting, cools to 40 DEG C hereinafter, methyl tertiary butyl ether(MTBE) 40ml or so is added,
20~35 DEG C cooling, layering, water layer uses methyl tertiary butyl ether(MTBE) 40ml x2 to extract again, merges organic layer；NaHCO will be saturated3It is water-soluble
Liquid is added in organic layer, and pH is greater than 7, and layering, water layer extracts 40ml with methyl tertiary butyl ether(MTBE) and is stripped again once, merges organic layer,
Evaporated under reduced pressure obtains 3- hydroxy-benzaldehyde crude product, faint yellow solid about 18.5g；
It is refined with organic solvent toluene: adding toluene 75ml or so, active carbon 3.7g in solid 15g, be heated to 70~80 DEG C,
Heat preservation 2 hours after heat filtering, washed with 15ml or so toluene, be slow cooling to 10 hereinafter, 0~10 DEG C keep the temperature 1 hour, filtering,
15ml or so toluene is washed, and filter cake is at 50~60 DEG C, vacuum drying, obtains 3- hydroxy-benzaldehyde 13.5g, off-white color crystalline powder,
Purity >=99.0%.
(4) bromination reaction
Raw material: 3- hydroxy-benzaldehyde 35.4g, bromine 53.1g, organic solvent dichloromethane 247ml；Refine organic solvent
Toluene, conventional amount used；
Reaction vessel: vacuum, nitrogen displacement are three times；
Reaction step: in clean reaction flask, 3- hydroxy-benzaldehyde 35.4g and methylene chloride 247ml, vacuum is added
Nitrogen is replaced three times, and stirring cools to 0 DEG C hereinafter, dropwise addition bromine 53.1g, adds water 250ml after fully reacting, with liquid alkaline adjusting pH
To neutrality, cooling filtering, wet product adds toluene 410ml or so, is heated to dissolve, branch vibration layer, and organic phase is warming up to reflux, cooling
Filtering, drying, obtains the bromo- 3- hydroxy-benzaldehyde 36g of 4-.
(5) condensation reaction
Raw material: 4- bromo- 3- hydroxy-benzaldehyde 36g, 4- fluorobenzonitrile 64.3g, potassium carbonate 61.1g, organic solvent dimethyl
Acetamide 390g；Refine organic solvent isopropanol, conventional amount used；
Reaction vessel: vacuum, nitrogen displacement are three times；
Reaction step: in reaction flask, the bromo- 3- hydroxy-benzaldehyde 36g of 4-, dimethyl acetamide 390g, 4- fluorobenzene is added
Formonitrile HCN 64.3g, potassium carbonate 61.1g, vacuum nitrogen are replaced three times, are stirred and heated to 60~70 DEG C, heat preservation 2 hours or more, are cooled down
To 15~25 DEG C, filtering 888ml washing obtains 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile wet product 44.6g, adds isopropanol
178ml is dissolved by heating, and cooling filtering drying obtains 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile 42g, purity >=99.0%.
Claims (10)
1. a kind of synthetic method of 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile, which is characterized in that this method is with 3- methylbenzene
Phenol is starting material, obtains 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzene first through esterification, chlorination, hydrolysis, bromination and condensation reaction
Nitrile, product purity >=99.0%, comprising the following steps:
(1) esterification: 3- methylphenol and anhydride reaction obtain intermediate 3- methyl-phenyl ester compound, 3- methylphenol and acid
Acid anhydride weight ratio g/g is 1:0.9-2.0；
(2) chlorination reaction: intermediate 3- methyl-phenyl ester compound is reacted in the presence of organic solvent and initiator with sulfonic acid chloride, is obtained
To intermediate 3- chloromethyl-phenyl ester compound and 3- dichloromethyl-phenyl ester compound mixture, abbreviation chlorated liquid, 3- methyl-phenyl ester
Compound: initiator: sulfonic acid chloride: the w/v g/g/g/ml of organic solvent is 1:0.02-0.2:1.5-2.5:4.0-7.0；
Initiator selects azodiisobutyronitrile, and organic solvent is selected from one of dichloromethane or chloroform；
(3) hydrolysis: chlorated liquid reacts in the presence of organic solvent alcohols, water and hydrolyst with methenamine, reaction
Product extracts through organic solvent, is refining to obtain intermediate 3- hydroxy-benzaldehyde；Organic solvent alcohols is selected from methanol or ethyl alcohol or isopropyl
One of alcohol, hydrolyst are selected from one of hydrochloric acid or sulfuric acid, extract organic solvent and are selected from methyl tertiary butyl ether(MTBE)；
(4) bromination reaction: intermediate 3- hydroxy-benzaldehyde is reacted with bromine in the presence of an organic, and reaction product is through organic
Solvent refining obtains the bromo- 3- hydroxy-benzaldehyde of intermediate 4-, and 3- hydroxy-benzaldehyde and bromine weight ratio g/g are 1.0:1.0-
2.0,3- hydroxy-benzaldehydes are 1.0:5.0-7.0 with organic solvent w/v g/ml is reacted, and reaction organic solvent is selected from two
One of chloromethanes or chloroform；
(5) condensation reaction: the bromo- 3- hydroxy-benzaldehyde of intermediate 4- in the presence of organic solvent, catalyst and 4- fluorobenzonitrile into
Row condensation reaction, reaction product are refining to obtain finished product 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile through organic solvent, wherein 4-
Bromo- 3- hydroxy-benzaldehyde: reaction organic solvent: 4- fluorobenzonitrile: the weight ratio g/g/g/g of catalyst is 1.0:10.0-
12.0:1.0-2.5:1.0-2.5；It refines organic solvent and is selected from methanol or one of ethyl alcohol or isopropanol；React organic solvent
Selected from one of dimethyl acetamide or dimethylformamide, catalyst is potassium carbonate.
2. the synthetic method of 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile according to claim 1, it is characterised in that step
Suddenly in (1), 3- methylphenol is starting material and anhydride reaction, and the acid anhydrides is in formic anhydride or acetic anhydride or propionic andydride
One kind, reaction temperature be 70~85 DEG C.
3. the synthetic method of 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile according to claim 1, it is characterised in that step
Suddenly the organic solvent in (2) is preferably chloroform.
4. the synthetic method of 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile according to claim 1, it is characterised in that step
Suddenly in (3), using two-step hydrolysis reaction method, first step hydrolysis, chlorated liquid first adds in the presence of organic solvent alcohols and water
After pyrohydrolysis, then warm, decompression removal ethyl alcohol, adds water and carry out second step hydrolysis with hydrolyst, wherein raw material
On the basis of 3- methyl-phenyl ester compound, first step hydrolysis, 3- methyl-phenyl ester compound: methenamine: water: the weight of alcohols
Volume ratio g/g/ml/ml is 1:0.6-1.0:1.5-2.5:2.5-3.5；Second one-step hydrolysis, 3- methyl-phenyl ester compound: hydrolysis is urged
Agent: the w/v g/g/ml of second of water is 1:0.45-2.0:5.0-7.0.
5. the synthetic method of 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile according to claim 1 or 4, feature exist
In step (3), organic solvent alcohols is preferably 95% ethyl alcohol.
6. the synthetic method of 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile according to claim 1 or 4, feature exist
In step (3), hydrolyst is preferably hydrochloric acid, and the additive amount of hydrochloric acid is 3- methyl-phenyl ester compound: hydrochloric acid in hydrolysis
Weight ratio g/g be 1.0:0.8~2.0.
7. the synthetic method of 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile according to claim 1 or 4, feature exist
In step (3), hydrolyst is selected as sulfuric acid, and the additive amount of sulfuric acid is preferably 3- methyl-phenyl ester compound in hydrolysis:
The weight ratio g/g of sulfuric acid is 1.0:0.45~1.13.
8. the synthetic method of 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile according to claim 1, it is characterised in that step
Suddenly in (4), organic solvent is preferably methylene chloride, and purification organic solvent is toluene.
9. the synthetic method of 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile according to claim 1, it is characterised in that step
Suddenly in (5), reaction organic solvent is preferably dimethyl acetamide.
10. the synthetic method of 4- (the bromo- 3- aldehyde radical-phenoxy group of 4-)-benzonitrile according to claim 1, it is characterised in that
In step (5), purification organic solvent is preferably isopropanol.
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