CN108059590A - A kind of preparation method of 3- trifluoromethoxies -4- chlorobenzaldehydes - Google Patents
A kind of preparation method of 3- trifluoromethoxies -4- chlorobenzaldehydes Download PDFInfo
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- CN108059590A CN108059590A CN201711335108.6A CN201711335108A CN108059590A CN 108059590 A CN108059590 A CN 108059590A CN 201711335108 A CN201711335108 A CN 201711335108A CN 108059590 A CN108059590 A CN 108059590A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 14
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000011777 magnesium Substances 0.000 claims abstract description 12
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 12
- GQHWSLKNULCZGI-UHFFFAOYSA-N trifluoromethoxybenzene Chemical compound FC(F)(F)OC1=CC=CC=C1 GQHWSLKNULCZGI-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 9
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims abstract description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006170 formylation reaction Methods 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 230000000536 complexating effect Effects 0.000 claims abstract description 6
- QUXHCILOWRXCEO-UHFFFAOYSA-M magnesium;butane;chloride Chemical compound [Mg+2].[Cl-].CCC[CH2-] QUXHCILOWRXCEO-UHFFFAOYSA-M 0.000 claims abstract description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006138 lithiation reaction Methods 0.000 claims abstract description 3
- XOHOCMBXDFQWDF-UHFFFAOYSA-N 4-chloro-3-(trifluoromethoxy)benzaldehyde Chemical class FC(F)(F)OC1=CC(C=O)=CC=C1Cl XOHOCMBXDFQWDF-UHFFFAOYSA-N 0.000 claims description 21
- 238000009413 insulation Methods 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- OLDJEKBXICPMAS-UHFFFAOYSA-N 1-chloro-3-(trifluoromethoxy)benzene Chemical compound FC(F)(F)OC1=CC=CC(Cl)=C1 OLDJEKBXICPMAS-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- -1 lithium halogen Chemical class 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 5
- NZRLCYJRHKUVCV-UHFFFAOYSA-N 1-chloro-2-(trifluoromethoxy)benzene Chemical compound FC(F)(F)OC1=CC=CC=C1Cl NZRLCYJRHKUVCV-UHFFFAOYSA-N 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000013517 stratification Methods 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims 2
- MXQYNJUHAZVMAX-UHFFFAOYSA-N C(CCC)[Mg]CCCC.[Li] Chemical compound C(CCC)[Mg]CCCC.[Li] MXQYNJUHAZVMAX-UHFFFAOYSA-N 0.000 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 229910001629 magnesium chloride Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000012805 post-processing Methods 0.000 abstract description 2
- SONFEJGLHKNKEF-UHFFFAOYSA-N 4-chloro-2-(trifluoromethoxy)benzaldehyde Chemical compound FC(F)(F)OC1=CC(Cl)=CC=C1C=O SONFEJGLHKNKEF-UHFFFAOYSA-N 0.000 abstract 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 abstract 1
- 239000002904 solvent Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 14
- 230000008569 process Effects 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- UUNGXYVLXYGZKH-UHFFFAOYSA-M [Cl-].CCCC[Mg+] Chemical class [Cl-].CCCC[Mg+] UUNGXYVLXYGZKH-UHFFFAOYSA-M 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/02—Lithium compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to technical field of organic synthesis; more particularly to a kind of preparation method of 3 trifluoromethoxy, 4 chlorobenzaldehyde; the preparation method is using 4 bromine, 1 chlorine, 2 (trifluoromethoxy) benzene as raw material; with complexing lithiumation object lithium halogen exchange reaction occurs for raw material; then again with N, 3 trifluoromethoxy, 4 chlorobenzaldehyde is made by formylation reaction in N dimethylformamides；The complexing lithiumation object of tributyl magnesium reason is made for butylmagnesium chloride and n-BuLi generation lithiation for the complexing lithiumation object, and the solvent which uses is reaction dissolvent for tetrahydrofuran and toluene.The advantages of 3 trifluoromethoxy, 4 chlorobenzaldehyde preparation method of the invention, is cheap and easy to get using raw material, and reaction condition is mild, and post-processing operation is simple, and production cost is relatively low, high income, reduces reaction cost, is suitble to industrialized production.
Description
Technical field：
The present invention relates to technical field of organic synthesis, and in particular to a kind of preparation of 3- trifluoromethoxies -4- chlorobenzaldehydes
Method.
Background technology：
The character of 3- trifluoromethoxy -4- chlorobenzaldehydes is colourless transparent liquid, is a kind of very extensive chemical industry of purposes
Intermediate is widely used in medicine and the synthesis of other fine chemical products, such as can prepare in terms of medicine antitumor
Drug and Cyclooxygenase-2 (COX2) inhibitor.
The content of the invention：
The technical problems to be solved by the invention are to provide the 3- fluoroforms that a kind of purity is high, simple for process and at low cost
The preparation method of oxygroup -4- chlorobenzaldehydes.
The technical problems to be solved by the invention are realized using following technical solution：
Using the bromo- 1- of 4- chloro- 2- (trifluoromethoxy) benzene as raw material, tetrahydrofuran and toluene are reaction dissolvent, butyl chlorination
The complexing lithiumation object that tributyl magnesium reason is made in lithiation occurs for magnesium and n-BuLi, and gained complexing lithiumation object and the bromo- 1- of 4- are chloro-
2- (trifluoromethoxy) benzene occurs lithium halogen exchange reaction and is made, and then passes through formylation reaction system with n,N-Dimethylformamide again
Obtain 3- trifluoromethoxy -4- chlorobenzaldehydes.
A kind of preparation method of 3- trifluoromethoxies -4- chlorobenzaldehydes, comprises the following steps：
(1) under nitrogen protection, first butylmagnesium chloride is put into reaction vessel, toluene is added in, is cooled to -30~-20 DEG C,
Then n-BuLi is added dropwise, mixing control dropping temperature carries out insulation reaction at -30~-20 DEG C after being added dropwise, and three fourths are made
Base magnesium is managed；
(2) the bromo- 1- of 4- chloro- 2- (trifluoromethoxy) benzene is dissolved in tetrahydrofuran and toluene, then by the 4- of dissolving
The bromo- chloro- 2- of 1- (trifluoromethoxy) benzene is added dropwise in the solution of tributyl magnesium reason obtained above, is kept the temperature after being added dropwise
Reaction；
(3) n,N-Dimethylformamide is added dropwise after the reaction was complete for raw material, and insulation reaction, raw material reaction are carried out after being added dropwise
Stop reaction after completely, the hydrochloric acid stirring of mass concentration 10% is added in into reaction system after reaction, by the PH of reaction solution
Value is transferred to 7, then stratification, through extraction, merges organic layer, precipitation obtains 3- trifluoromethoxy -4- chlorobenzaldehyde crude products；
(4) that 3- trifluoromethoxy -4- chlorobenzaldehydes crude products are obtained 3- trifluoromethoxy -4- chlorobenzaldehydes by rectifying is pure
Product.
The molar ratio of butylmagnesium chloride and n-BuLi is in the step (1)：1:(1.5-2.0), butyl chlorination
The concentration of magnesium is 1.75mol/L, and the concentration of n-BuLi is 2.5mol/L.
The bromo- 1- of 4- chloro- 2- (trifluoromethoxy) benzene dropping temperature is -50~-10 DEG C in the step (2), insulation reaction
Temperature is -50~-10 DEG C.
The molar ratio of the chloro- 2- of the bromo- 1- of 4- (trifluoromethoxy) benzene and n-BuLi is described in the step (2)：
1:(0.6-1.3)。
The dropping temperature of n,N-Dimethylformamide is -20~20 DEG C in the step (3), and insulation reaction temperature is -20
~20 DEG C.
The molar ratio of the chloro- 2- of the bromo- 1- of 4- (trifluoromethoxy) benzene and N,N-dimethylformamide in the step (3)
For：1:(1.0-1.5).
The beneficial effects of the invention are as follows：The present invention is anti-through lithiumation using the bromo- 1- of 4- chloro- 2- (trifluoromethoxy) benzene as raw material
It answers, 3- trifluoromethoxy -4- chlorobenzaldehydes is made after the exchange of lithium halogen, formylation reaction and hydrolysis, it is raw materials used cheap easy
, reaction condition is mild, and post-processing operation is simple, and production cost is relatively low, high income, is suitble to industrialized production.
Specific embodiment：
In order to be easy to understand the technical means, the creative features, the aims and the efficiencies achieved by the present invention, tie below
Specific embodiment is closed, the present invention is further explained.
Embodiment 1
(1) lithiumation：Under nitrogen protection, first in 1000mL three-necked flasks, 59mL butylmagnesium chlorides are added in, are cooled to -30
~-20 DEG C, 66mL n-BuLis are then added dropwise, process is added dropwise and maintains -30~-20 DEG C, rear insulation reaction is added dropwise.
(2) lithium halogen exchanges：The bromo- 1- of 52g 4- chloro- 2- (trifluoromethoxy) benzene is dissolved in 100ml tetrahydrofurans and 50ml
The in the mixed solvent of toluene.The above-mentioned tributyl magnesium reason solution prepared is cooled to -30~-20 DEG C, it is chloro- that the bromo- 1- of 4- are added dropwise
2- (trifluoromethoxy) benzene raw materials, be added dropwise process maintain -30~-20 DEG C, be added dropwise rear insulation reaction 2 it is small when.
(3) formylation reaction：Above-mentioned reaction solution is raised to temperature to 0~10 DEG C, and 16.5g N, N- dimethyl is slowly added dropwise
Formamide, be added dropwise process maintain 0~10 DEG C, be added dropwise rear insulation reaction 2 it is small when, after reaction be added dropwise 10% hydrochloric acid extremely
Reaction solution pH value is 7, adds in 100mL ethyl acetate liquid separations, and with organic phase is separated after saturated common salt water washing, dry, precipitation obtains
To 3- trifluoromethoxy -4- chlorobenzaldehyde crude products.
(4) purify：By 3- trifluoromethoxy -4- chlorobenzaldehyde crude product rectifying, the fraction of 100 DEG C of collection obtains 33.9g
3- trifluoromethoxy -4- chlorobenzaldehyde products, yield 80%.
Embodiment 2
(1) lithiumation：Under nitrogen protection, first in 1000mL three-necked flasks, 59mL butylmagnesium chlorides are added in, are cooled to -30
~-20 DEG C, 66mL n-BuLis are then added dropwise, process is added dropwise and maintains -30~-20 DEG C, rear insulation reaction is added dropwise.
(2) lithium halogen exchanges：The bromo- 1- of 52g 4- chloro- 2- (trifluoromethoxy) benzene is dissolved in 100ml tetrahydrofurans and 50ml
The in the mixed solvent of toluene.The above-mentioned tributyl magnesium reason solution prepared is cooled to -50~-30 DEG C, it is chloro- that the bromo- 1- of 4- are added dropwise
2- (trifluoromethoxy) benzene raw materials, be added dropwise process maintain -50~-30 DEG C, be added dropwise rear insulation reaction 2 it is small when.
(3) formylation reaction：Above-mentioned reaction solution is raised to temperature to -10~0 DEG C, and 16.5g N, N- dimethyl is slowly added dropwise
Formamide, be added dropwise process maintain -10~0 DEG C DEG C, be added dropwise rear insulation reaction 2 it is small when, after reaction be added dropwise 10% salt
Acid to reaction solution pH value is 7, adds in 100mL ethyl acetate liquid separations, and with organic phase is separated after saturated common salt water washing, drying takes off
It is molten, obtain 3- trifluoromethoxy -4- chlorobenzaldehyde crude products.
(4) purify：By 3- trifluoromethoxy -4- chlorobenzaldehyde crude product rectifying, the fraction of 100 DEG C of collection obtains 25.4g
3- trifluoromethoxy -4- chlorobenzaldehyde products, yield 60%.
Embodiment 3
(1) lithiumation：Under nitrogen protection, first in 1000mL three-necked flasks, 59mL butylmagnesium chlorides are added in, are cooled to -30
~-20 DEG C, 82.6mL n-BuLis are then added dropwise, process is added dropwise and maintains -30~-20 DEG C, rear insulation reaction is added dropwise.
(2) lithium halogen exchanges：The bromo- 1- of 52g 4- chloro- 2- (trifluoromethoxy) benzene is dissolved in 100mL tetrahydrofurans and 50ml
The in the mixed solvent of toluene.The above-mentioned tributyl magnesium reason solution prepared is cooled to -30~-20 DEG C, it is chloro- that the bromo- 1- of 4- are added dropwise
2- (trifluoromethoxy) benzene raw materials, be added dropwise process maintain -30~-20 DEG C, be added dropwise rear insulation reaction 2 it is small when.
(3) formylation reaction：Above-mentioned reaction solution is raised to temperature to -10~0 DEG C, and 21g N, N- dimethyl methyls is slowly added dropwise
Amide, be added dropwise process maintain -10~0 DEG C, be added dropwise rear insulation reaction 2 it is small when, after reaction be added dropwise 10% hydrochloric acid extremely
Reaction solution pH value is 7, adds in 100mL ethyl acetate liquid separations, and with organic phase is separated after saturated common salt water washing, dry, precipitation obtains
To 3- trifluoromethoxy -4- chlorobenzaldehyde crude products.
(4) purify：By 3- trifluoromethoxy -4- chlorobenzaldehyde crude product rectifying, the fraction of 100 DEG C of collection obtains 3- trifluoros
Methoxyl group -4- chlorobenzaldehyde products, yield 80%.
Embodiment 4
(1) lithiumation：Under nitrogen protection, first in 1000mL three-necked flasks, 40.4mL butylmagnesium chlorides are added in, be cooled to-
30~-20 DEG C, 45mL n-BuLis are then added dropwise, process is added dropwise and maintains -30~-20 DEG C, rear insulation reaction is added dropwise.
(2) lithium halogen exchanges：The bromo- 1- of 52g 4- chloro- 2- (trifluoromethoxy) benzene is dissolved in 100mL tetrahydrofurans and 50mL
The in the mixed solvent of toluene.The above-mentioned tributyl magnesium reason solution prepared is cooled to -20~-10 DEG C, it is chloro- that the bromo- 1- of 4- are added dropwise
2- (trifluoromethoxy) benzene raw materials, be added dropwise process maintain -20~-10 DEG C, be added dropwise rear insulation reaction 2 it is small when.
(3) formylation reaction：Above-mentioned reaction solution is raised to temperature to 10~20 DEG C, and 13.7g N, N- dimethyl is slowly added dropwise
Formamide, be added dropwise process maintain 10~20 DEG C, be added dropwise rear insulation reaction 2 it is small when, after reaction be added dropwise 10% hydrochloric acid
It is 7 to reaction solution pH value, adds in 100mL ethyl acetate liquid separations, with organic phase is separated after saturated common salt water washing, dries, precipitation,
Obtain 3- trifluoromethoxy -4- chlorobenzaldehyde crude products.
(4) purify：By 3- trifluoromethoxy -4- chlorobenzaldehyde crude product rectifying, the fraction of 100 DEG C of collection obtains 23.3g
3- trifluoromethoxy -4- chlorobenzaldehyde products, yield 55%.
The basic principles, main features and the advantages of the invention have been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (7)
1. a kind of preparation method of 3- trifluoromethoxies -4- chlorobenzaldehydes, it is characterised in that：With the chloro- 2- (fluoroforms of the bromo- 1- of 4-
Oxygroup) benzene is raw material, tetrahydrofuran and toluene are reaction dissolvent, and butylmagnesium chloride and n-BuLi occur lithiation and be made three
The complexing lithiumation object of dibutyl magnesium lithium, gained are complexed lithiumation object and are exchanged instead with the bromo- 1- of 4- chloro- 2- (trifluoromethoxy) benzene generation lithium halogen
It should be made, 3- trifluoromethoxy -4- chlorobenzaldehydes then are made by formylation reaction with n,N-Dimethylformamide again.
2. a kind of preparation method of 3- trifluoromethoxies -4- chlorobenzaldehydes, which is characterized in that comprise the following steps：
(1) under nitrogen protection, first butylmagnesium chloride is put into reaction vessel, toluene is added in, is cooled to -30~-20 DEG C, then
N-BuLi is added dropwise, mixing control dropping temperature carries out insulation reaction at -30~-20 DEG C after being added dropwise, and tributyl magnesium is made
Reason；
(2) the bromo- 1- of 4- chloro- 2- (trifluoromethoxy) benzene is dissolved in tetrahydrofuran and toluene, then by the bromo- 1- of the 4- of dissolving
Chloro- 2- (trifluoromethoxy) benzene is added dropwise in the solution of tributyl magnesium reason obtained above, and insulation reaction is carried out after being added dropwise；
(3) n,N-Dimethylformamide is added dropwise after the reaction was complete for raw material, insulation reaction is carried out after being added dropwise, the reaction was complete for raw material
Stop reaction afterwards, the hydrochloric acid stirring of mass concentration 10% is added in into reaction system after reaction, by the pH value tune of reaction solution
To 7, then stratification, through extraction, merges organic layer, precipitation obtains 3- trifluoromethoxy -4- chlorobenzaldehyde crude products；
(4) 3- trifluoromethoxy -4- chlorobenzaldehydes crude products are obtained into 3- trifluoromethoxy -4- chlorobenzaldehyde sterlings by rectifying.
3. the preparation method of 3- trifluoromethoxies -4- chlorobenzaldehydes according to claim 2, it is characterised in that：The fourth
The molar ratio of base magnesium chloride and n-BuLi is：1:(1.5-2.0), the concentration of butylmagnesium chloride are 1.75mol/L, positive fourth
The concentration of base lithium is 2.5mol/L.
4. the preparation method of 3- trifluoromethoxies -4- chlorobenzaldehydes according to claim 2, it is characterised in that：The 4-
The bromo- chloro- 2- of 1- (trifluoromethoxy) benzene dropping temperature is -50~-10 DEG C, and insulation reaction temperature is -50~-10 DEG C.
5. the preparation method of 3- trifluoromethoxies -4- chlorobenzaldehydes according to claim 2, it is characterised in that：The 4-
The molar ratio of the bromo- chloro- 2- of 1- (trifluoromethoxy) benzene and n-BuLi is：1:(0.6-1.3).
6. the preparation method of 3- trifluoromethoxies -4- chlorobenzaldehydes according to claim 2, it is characterised in that：The N,
The dropping temperature of dinethylformamide is -20~20 DEG C, and insulation reaction temperature is -20~-0 DEG C.
7. the preparation method of 3- trifluoromethoxies -4- chlorobenzaldehydes according to claim 2, it is characterised in that：The 4-
The molar ratio of the bromo- chloro- 2- of 1- (trifluoromethoxy) benzene and N,N-dimethylformamide is：1:(1.0-1.5).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108892616A (en) * | 2018-08-31 | 2018-11-27 | 凯莱英生命科学技术(天津)有限公司 | Prepare continuous device and its application of benzaldehydes intermediate |
| CN114163316A (en) * | 2021-11-19 | 2022-03-11 | 爱斯特（成都）生物制药股份有限公司 | Method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1608071A (en) * | 2000-02-02 | 2005-04-20 | 万有制药株式会社 | Method of converting functional group through halogen-metal exchange reaction |
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| CN108892616B (en) * | 2018-08-31 | 2024-06-07 | 凯莱英生命科学技术(天津)有限公司 | Continuous device for preparing benzaldehyde intermediate and application thereof |
| CN114163316A (en) * | 2021-11-19 | 2022-03-11 | 爱斯特（成都）生物制药股份有限公司 | Method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde |
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