CN109369456A - A kind of preparation method of 2,4- dicyano trifluomethoxybenzene - Google Patents
A kind of preparation method of 2,4- dicyano trifluomethoxybenzene Download PDFInfo
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- CN109369456A CN109369456A CN201811422290.3A CN201811422290A CN109369456A CN 109369456 A CN109369456 A CN 109369456A CN 201811422290 A CN201811422290 A CN 201811422290A CN 109369456 A CN109369456 A CN 109369456A
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- trifluomethoxybenzene
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- dicyano
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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Abstract
The invention discloses a kind of industrialized process for preparing of 2,4- dicyano trifluomethoxybenzene.The industrialized process for preparing of 2, the 4- dicyano trifluomethoxybenzene, as initial feed, to synthesize 2,4- dicyano trifluomethoxybenzene by bromine, cyaniding three-step reaction in bromo, diazonium to amino trifluomethoxybenzene.2, the 4- dicyano trifluomethoxybenzene that this process obtains is off-white powder shape solid, and purity 98.5%, every step feed stock conversion respectively reaches 100%, and the total recovery of whole process reaches 39%.
Description
Technical field
The present invention relates to a kind of production methods of medicine intermediate, specifically, the present invention is 2,4- of one kind dicyano three
The preparation method of fluorine methoxyl group benzene.
Background technique
2,4- dicyano trifluomethoxybenzene is mainly used for pharmaceuticals industry at present.As can be used for: 1) synthesizing treating cancer
The derivative 2 of Mei Tanxinuo sum) synthesis p2x7 receptor antagonist indolecarboxamide derivative 3) synthesizing substituted and imidazoles
Compound treats the diseases 4 such as inflammation and cancer as tumour progression locus 2 inhibitor) synthesis thiadiazole compound as protein swash
Enzyme B regulator.
Currently, and having no the relevant report of 2,4- dicyano trifluomethoxybenzene synthetic method.Therefore, one is developed to be suitble to
The synthetic route of industrialized production is very necessary.
Summary of the invention
The object of the present invention is to provide methods and technique that one synthesizes 2,4- dicyano trifluomethoxybenzene, to meet work
Industry production needs.
The method of the present invention using to amino trifluomethoxybenzene as raw material, it is anti-by bromine in bromo, diazonium and three step of cyaniding
2,4- dicyano trifluomethoxybenzene should be synthesized, this method includes following reaction equation:
The preparation method of the present invention 2,4- dicyano trifluomethoxybenzene carries out as steps described below:
(1) bromo-reaction: being added to trifluoro-methoxyaniline, solvent sulfuric acid, 0~15 DEG C of temperature control into reaction vessel, excellent
Select 5~10 DEG C of temperature range.The ratio model of sulfuric acid volume (mL) used in it and the quality (g) to trifluoro-methoxyaniline
It encloses for 4.0~8.0:1, preferable ratio range is 5.0~6.0:1.Be slowly added under stirring brominated reagent bromate or bromine or
N- bromo-succinimide, it is preferential to select N- bromo-succinimide.Wherein N- bromo-succinimide with to trifluoromethoxy
The ratio range of the amount of the substance of aniline is 1.0~1.2:1, and optimum ratio range is 1.05~1.1:1.After reaction,
Enter in ice water, product is precipitated with solid, is filtered, is obtained the bromo- 4- amino trifluomethoxybenzene of 2-.
(2) diazo-reaction: the bromo- 4- amino trifluomethoxybenzene of 2- is added into reaction vessel, is added under stirring condition
Concentration is 40%HBr and H2The ratio range of the amount of the substance of the bromo- 4- amino trifluomethoxybenzene of O, HBr used and 2- is
The preferable ratio range of the amount of the substance of the bromo- 4- amino trifluomethoxybenzene of 1.0~5.0:1, HBr used and 2- be 1.1~
1.4.0:1.It is heated to 30 ~ 100 DEG C, 70 ~ 80 DEG C of preferred temperature range, 0.5 h of insulation reaction.20 ~ 100 DEG C are cooled to, compared with
Good temperature range is 40 ~ 50 DEG C, and the ratio of the amount of the substance of the bromo- 4- amino trifluomethoxybenzene of CuBr, CuBr and 2- is added
Range is 0.05~1.0:1, and preferable ratio range is 0.1~0.5:1.It is sufficiently stirred, NaNO is added dropwise2And H2The solution that O is made into,
NaNO2Ratio range with the amount of the substance of the bromo- 4- amino trifluomethoxybenzene of 2- is 1.0~2.5:1, and preferable ratio range is
1.0~1.3:1.Start decomposition reaction, 1 h is kept the temperature after dripping off.It is down to room temperature, pours into H2In O, organic layer is separated, is washed organic
Then it is molten to be subtracted each other pressure-off, obtains yellow liquid 2,4- dibromo trifluomethoxybenzene close to neutrality, liquid separation by layer for oil.
(3) product 2 of second step, 4- dibromo trifluomethoxybenzene, N, N- diformazan cyanogenation: are added into reaction vessel
The ratio range of the quality (g) of base formamide, DMF volume (mL) used and 2,4- bromine trifluomethoxybenzene is 4.0~8.0
(mL): 1(g), optimum ratio range is 5.0~6.0(mL): 1(g).Reaction temperature control is at 130~160 DEG C, preferable temperature
145~155 DEG C of range, 150~155 DEG C of optimum temperature range.After temperature reaches optimum temperature range, it is added with stirring cyaniding
Cuprous, cuprous cyanide used and 2, the ratio range of the amount of the substance of 4- dibromo trifluomethoxybenzene is 2.4~3.5:1, preferably
Ratio range is 2.4~3.0:1.After reaction, reaction product is poured into water, solid is precipitated, filtered, solvent extraction is added
It taking, then filters, liquid separation rotates, and it is dry, obtain off-white powder 2, bis- cyanophenyl trifluomethoxybenzene of 5-.
Specific embodiment 1
(1) bromo-reaction: 125 g are added into reaction vessel to trifluoro-methoxyaniline, 700 g of sulfuric acid, ice-water bath temperature control arrives
5 ℃.132 g N- bromo-succinimides are slowly added under stirring.In adition process, temperature does not exceed 15 DEG C.After adding
Insulation reaction 1 h, GC tracking, until reaction terminates.After the reaction was completed, reactant is poured into ice water, solid is precipitated, filtered,
It is dry, obtain bromo- 168 g of 4- amino trifluomethoxybenzene of brown solid 2-, yield 93%.
(2) 243 g of 40%HBr, 700 mL H diazo-reaction: are added into reaction vessel2The bromo- 4- ammonia of O, 256 g 2-
Base trifluomethoxybenzene is heated to 70 ~ 80 DEG C, 0.5 h of insulation reaction.40 ~ 50 DEG C are cooled to, 72 g CuBr are added, sufficiently
Stirring.83 g NaNO are added dropwise2, 250 mL H2The solution that O is made into keeps the temperature 1 h after dripping off.It is down to room temperature, pours into H2In O, point
Organic layer out, washed organic layer is close to neutrality, and liquid separation, then oily phase precipitation, obtains pale yellowish oil liquid 2, the bromo- fluoroform of 4- bis-
Oxygroup benzene o-fluorobenzyl bromide 272 g, 85 % of yield.
(3) 100 g 2,4- dibromo trifluomethoxybenzene, 500 mL DMF, control cyanogenation: are added into reaction vessel
Temperature is slowly added to 78 g cuprous cyanide solids to 150 DEG C under stirring, in adition process, temperature does not exceed 155 DEG C, adds
Afterwards, insulated and stirred is reacted, GC tracking, until reaction terminates.After the reaction was completed, cooling, reaction product is poured into water, is precipitated solid
Body filters, and the extraction of 1,2- dichloroethanes is added, then filters again, liquid separation, rotates, dry, obtains off-white powder shape solid 2,
4- dicyano trifluomethoxybenzene 33 g, 49 % of yield.
Specific embodiment 2
(1) 1250 g bromo-reaction: are added into reaction vessel to trifluoro-methoxyaniline, 6250 g of sulfuric acid, ice-water bath temperature control
To 5 DEG C.1307 g N- bromo-succinimides are slowly added under stirring.In adition process, temperature does not exceed 15 DEG C.Add
1 h of insulation reaction after complete, GC tracking, until reaction terminates.After the reaction was completed, reactant is poured into ice water, solid is precipitated, taken out
Filter, it is dry, obtain bromo- 1699 g of 4- amino trifluomethoxybenzene of brown solid 2-, yield 94%.
(2) 1208 g 40%HBr, 700 mL H diazo-reaction: are added into reaction vessel2O, the 1256 bromo- 4- of g 2-
Amino trifluomethoxybenzene is heated to 70 ~ 80 DEG C, 0.5 h of insulation reaction.40 ~ 50 DEG C are cooled to, 356 g CuBr are added,
It is sufficiently stirred.415 g NaNO are added dropwise2, 1200 mL H2The solution that O is made into keeps the temperature 1 h after dripping off.It is down to room temperature, is poured into
H2In O, organic layer is separated, washed organic layer is close to neutrality, and liquid separation, then oily phase precipitation, obtains pale yellowish oil liquid 2,4- bis-
Bromo- 1352 g of trifluomethoxybenzene o-fluorobenzyl bromide, 86 % of yield.
(3) cyanogenation: being added 1008 g 2 into reaction vessel, 4- dibromo trifluomethoxybenzene, 5200 mL DMF,
Temperature control is slowly added to 774 g cuprous cyanide solids to 150 DEG C under stirring, in adition process, temperature does not exceed 155 DEG C,
After adding, insulated and stirred reaction, GC tracking, until reaction terminates.After the reaction was completed, cooling, reaction product is poured into water, is analysed
Solid out filters, and the extraction of 1,2- dichloroethanes is added, then filters again, liquid separation, rotates, dry, and it is solid to obtain off-white powder shape
Body 2,4- dicyano trifluomethoxybenzene 326 g, 49 % of yield.
Claims (6)
- The preparation method of 1.2,4- dicyano trifluomethoxybenzenes, it is characterized in that, as raw material, to be passed through to amino trifluomethoxybenzene Cross bromo, bromine, cyaniding three-step reaction synthesis 2,4- dicyano trifluomethoxybenzene in diazonium.
- 2. the preparation method of 2,4- dicyano trifluomethoxybenzene as described in claim 1, it is characterised in that selection bromo examination When agent, select bromate, bromine, N- bromo-succinimide, C5H6Br2N2O2 etc. as brominated reagent, it is sub- with N- bromo succinyl Amine is best；N- bromo-succinimide used and the ratio range of the amount of the substance to two fluorine-based benzene are 1.0~1.2:1, Preferable ratio range is 1.05~1.1:1；The temperature range of bromo-reaction is 0~15 DEG C, and preferred temperature range is 5~10 ℃；Using the concentrated sulfuric acid as solvent when bromo, the ratio model of sulfuric acid volume (mL) used and the quality (g) to trifluoro-methoxyaniline Enclose is 4.0~8.0(mL): 1(g), preferable ratio range is 5.0~6.0(mL): 1(g).
- 3. the preparation method of 2,4- dicyano trifluomethoxybenzene as described in claim 1, it is characterised in that bromine is anti-in diazonium At once, raw material elder generation and HBr or HCl or H2SO4It at salt is best with raw material and HBr at salt；Temperature range at salt is 30 ~100 DEG C, preferred temperature range is 70~80 DEG C；The amount of the substance of HBr and the bromo- 4- amino trifluomethoxybenzene of 2- used Ratio range be 1.0~5.0:1, preferable ratio range be 1.1~1.4.0:1.
- 4. the preparation method of 2, the 4- dicyano trifluomethoxybenzene as described in claim 1,3, it is characterised in that bromine in diazonium When, the temperature range of decomposition reaction is 20~100 DEG C, and preferred temperature range is 40~50 DEG C；CuBr and the bromo- 4- of 2- used The ratio range of the amount of the substance of amino trifluomethoxybenzene is 0.05~1.0:1, and preferable ratio range is 0.1~0.5:1.
- 5. the preparation method of 2,4- dicyano trifluomethoxybenzene as described in claim 1, it is characterised in that in diazonium when bromine NaNO used2Ratio range with the amount of the substance of the bromo- 4- amino trifluomethoxybenzene of 2- is 1.0~2.5:1, preferable ratio Range is 1.0~1.3:1.
- 6. the preparation method of 2,4- dicyano trifluomethoxybenzene as described in claim 1, it is characterised in that used when cyaniding Solvent be mainly DMF, DMSO, NMP and o-dichlorohenzene etc., preferred solvents are DMF；DMF volume (mL) and 2,4- bromine used The ratio range of the quality (g) of trifluomethoxybenzene is 4.0~8.0(mL): 1(g), preferable ratio range is 5.0~6.0 (mL): 1(g)；Cyaniding replaces reagent selection cuprous cyanide or potassium ferrocyanide, and preferably cuprous cyanide replaces reagent as cyaniding； The ratio range of the amount of the substance of CuCN and 2,4- bromine trifluomethoxybenzene be 1.0~2.0:1, preferable ratio range be 1.1~ 1.5:1；130~160 DEG C of reaction temperature control range, 145~155 DEG C of preferred range, optimum temperature range 150~ 155 ℃。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115974705A (en) * | 2022-12-25 | 2023-04-18 | 阜新睿光氟化学有限公司 | Preparation method of 2-bromo-4-trifluoromethoxyaniline |
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- 2018-11-27 CN CN201811422290.3A patent/CN109369456A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115974705A (en) * | 2022-12-25 | 2023-04-18 | 阜新睿光氟化学有限公司 | Preparation method of 2-bromo-4-trifluoromethoxyaniline |
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