CN105601469B - The synthetic method of 1 (1 chloromethyl vinyl base) 2,4 difluorobenzenes - Google Patents
The synthetic method of 1 (1 chloromethyl vinyl base) 2,4 difluorobenzenes Download PDFInfo
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- CN105601469B CN105601469B CN201610022190.6A CN201610022190A CN105601469B CN 105601469 B CN105601469 B CN 105601469B CN 201610022190 A CN201610022190 A CN 201610022190A CN 105601469 B CN105601469 B CN 105601469B
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- difluorobenzene
- hydrochloric acid
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- -1 chloromethyl vinyl Chemical group 0.000 title claims abstract description 31
- 238000010189 synthetic method Methods 0.000 title claims abstract description 18
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical class FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 title claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 70
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 50
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 21
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 21
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- CFXQEHVMCRXUSD-UHFFFAOYSA-N 1,2,3-Trichloropropane Chemical compound ClCC(Cl)CCl CFXQEHVMCRXUSD-UHFFFAOYSA-N 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 10
- 239000001294 propane Substances 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 239000007832 Na2SO4 Substances 0.000 claims abstract description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 claims abstract description 8
- 239000000284 extract Substances 0.000 claims abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- 239000012044 organic layer Substances 0.000 claims description 8
- 238000002390 rotary evaporation Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 238000007792 addition Methods 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- 238000005292 vacuum distillation Methods 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 239000010410 layer Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 8
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- 239000004411 aluminium Substances 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 239000012266 salt solution Substances 0.000 claims 1
- GXSGGPZZNIICCS-UHFFFAOYSA-N 1-(1,3-dichloropropan-2-yl)-2,4-difluorobenzene Chemical compound ClCC(CCl)C1=C(C=C(C=C1)F)F GXSGGPZZNIICCS-UHFFFAOYSA-N 0.000 abstract description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract description 4
- 229920006395 saturated elastomer Polymers 0.000 abstract description 4
- 239000011780 sodium chloride Substances 0.000 abstract description 4
- 235000002639 sodium chloride Nutrition 0.000 abstract description 4
- 125000003963 dichloro group Chemical group Cl* 0.000 abstract description 3
- 238000010792 warming Methods 0.000 abstract description 2
- 125000004212 difluorophenyl group Chemical group 0.000 abstract 1
- 238000001704 evaporation Methods 0.000 abstract 1
- 230000008020 evaporation Effects 0.000 abstract 1
- 239000011435 rock Substances 0.000 abstract 1
- 238000000935 solvent evaporation Methods 0.000 abstract 1
- 229920002554 vinyl polymer Polymers 0.000 description 10
- 239000000047 product Substances 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 6
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 5
- 229960001589 posaconazole Drugs 0.000 description 5
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 206010007134 Candida infections Diseases 0.000 description 3
- 238000003747 Grignard reaction Methods 0.000 description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 150000004756 silanes Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000000178 1,2,4-triazoles Chemical class 0.000 description 1
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 208000032826 Ring chromosome 3 syndrome Diseases 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 229940099075 noxafil Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/32—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by introduction of halogenated alkyl groups into ring compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/25—Preparation of halogenated hydrocarbons by splitting-off hydrogen halides from halogenated hydrocarbons
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A kind of synthetic method of 1 (1 chloromethyl vinyl base) 2,4 difluorobenzenes, step includes：1,2,3 trichloropropane is added drop-wise in 1,3 difluorobenzenes, alchlor is added after 20 40min；0.5 1.5h at 5~5 DEG C, is warming up to 20 45 DEG C of 1.5 3h of reaction；It is added in hydrochloric acid solution and extracts, uses saturation NaHCO successively3Solution, water, saturated aqueous common salt washed once respectively；Use anhydrous Na2SO4Filtered after drying, solvent evaporation obtains 1,3 dichloro 2 (2,4 difluorophenyl) propane；(2, the 4 difluorophenyl) propane of 1,3 dichloro 2 and potassium hydroxide are added in the tert-butyl alcohol, flow back 3.5 6h；Remove the tert-butyl alcohol, water on the rocks is neutralized with hydrochloric acid neutrality at 5~5 DEG C, is extracted in three times with dichloromethane, use anhydrous Na2SO4Filtered after drying, evaporation, which is removed, obtains target product after dichloromethane.Path is：
Description
Technical field
Field is synthesized the present invention relates to posaconazole intermediate, and in particular to a kind of 1- (1- chloromethyl vinyls base) -2,4-
The synthetic method of difluorobenzene.
Background technology
Posaconazole (chemical name：4- [4- [4- [4- [[(3R, 5R) -5- (2,4 difluorobenzene base) -5- (1,2,4- triazoles -
1- ylmethyls) penta ring -3- bases of oxa-] methoxyl group] phenyl] piperazine -1- bases] phenyl] -2- [the amyl- 3- yls of (2S, 3S) -2- hydroxyls] -
1,2,4- triazole -3- ketone, English name：Posaconazole), structural formula is shown below：
Developed by Schering Plough company of the U.S., the U.S. FDA of in September, 2006 approval listing, is a kind of highly lipophilic wide spectrum three
Triazole antifungal agent.Trade name Noxafil (promise section flies), oral suspensions is mainly used in preventing 13 years old and above patient
Intrusive mood Aspergillus and monilial infection, and treatment pars oralis pharyngis monilial infection and to Fluconazole and the mouth of voriconazole resistance
Pharyngeal monilial infection.
1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes are the intermediate for synthesizing posaconazole, its structural formula such as following formula institute
Show：
European patent EP 2789610 (A1), world patent WO 2011144653 (A1), WO 2011144656 (A1) with
And WO 2011144657 (A1) discloses the method that the intermediate is synthesized by 1,3- difluorobenzenes, is shown below：
This method will use expensive trimethyl chloromethyl base silane class material, cause 1- (1- chloromethyl vinyls base)-
2,4- difluorobenzene production costs are high.In addition, also to use grignard reaction in this method.The reaction needs anhydrous and oxygen-free condition, difficult
In operation, it is difficult to realize industrialized production.
The content of the invention
The present invention is for above-mentioned the deficiencies in the prior art there is provided one kind without using expensive trimethyl chloromethyl base silicon
Alkane, to prepare cost low, do not use grignard reaction, without anhydrous and oxygen-free condition, it is easily operated, easily realize industrialized production, and after
Processing is simple, the synthetic method of 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes easy to operate.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention is：A kind of 1- (1- chloromethyl vinyls base) -2,
The step of synthetic method of 4- difluorobenzenes, synthetic method, includes：
(1) by 1,2,3- trichloropropanes are added drop-wise in 5~-5 DEG C of 1,3- difluorobenzenes dropwise, reactant mixture stirring 20-
Alchlor is added portionwise after 40min, has gas releasing after addition；Reacted 0.5-1.5 hours at 5~-5 DEG C after adding,
Then 20-45 DEG C is warming up to continue to react 1.5-8 hours；Hydrochloric acid to be added mixture at 5~-5 DEG C molten after completion of the reaction
In liquid, extracted 3-5 times with dichloromethane after stirring, then combined dichloromethane layer uses saturation NaHCO successively3Solution,
Water, saturated aqueous common salt washed once respectively；The organic layer anhydrous Na of acquisition2SO4Filtered after drying, rotary evaporation removes dichloro
Oil product 1,3- bis- chloro- 2- (2,4- difluorophenyl) propane are obtained after methane；
(2) the chloro- 2- of 1,3- bis- (2, the 4- difluorophenyl) propane for preparing step (1) method and potassium hydroxide or hydroxide
Sodium is added in alcohol compound, is heated to reflux 3.5-6 hours；Alcohol compound, gained are removed in vacuum distillation after completion of the reaction
Added in the mixture for removing alcohol compound at frozen water, 5~-5 DEG C and neutrality is neutralized with hydrochloric acid, extracted in three times with dichloromethane
Take, merge organic layer, then use anhydrous Na2SO4Filtered after drying, rotary evaporation, which is removed, obtains oily target product after dichloromethane
1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes.
A kind of above-mentioned synthetic method of 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes of the present invention, synthesis path is：
The mol ratio of 1,2,3- trichloropropanes in step (1) of the present invention, 1,3- difluorobenzene and alchlor is 1~1.2:
1:1~1.2, preferably 1:1:1.
Alchlor is divided into 4-6 batches of additions in step (1) of the present invention, and the operation can effectively prevent reactant mixture excessively
It is sticky, it is difficult to the appearance for the problems such as stirring.
Hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration in step (1) of the present invention, and the consumption of hydrochloric acid solution is with 1,2,3-
Trichloropropane meter, concentration of 1,2, the 3- trichloropropane in hydrochloric acid solution is 0.05-0.2mol/100ml (i.e. using 0.05-
The 1 of 0.2mol, 2,3- trichloropropanes, correspondence uses the hydrochloric acid solution 100ml of 2mol/l concentration)；Preferably 0.1mol/100ml.
The dichloromethane and the volume ratio of hydrochloric acid solution extracted every time in step (1) of the present invention is 1:1, such as, if adopted
With the hydrochloric acid solution 200ml of 2mol/l concentration, then it is 200ml to extract the dichloromethane used every time.
The chloro- 2- of 1,3- bis- (2,4- difluorophenyl) propane and potassium hydroxide or sodium hydroxide rubs in step (2) of the present invention
You are than being 1:1-2, preferably 1:1.1.
The use ratio of the chloro- 2- of 1,3- bis- (2,4- difluorophenyl) propane and alcohol compound is in step (2) of the present invention
0.15-0.25mol：150ml；Preferably 0.20mol：150ml.
The use ratio of the chloro- 2- of 1,3- bis- (2,4- difluorophenyl) propane and frozen water is 0.15- in step (2) of the present invention
0.25mol：150ml；Preferably 0.20mol：150ml.
Concentration of hydrochloric acid is 5mol/l in step (2) of the present invention.
The use ratio of the chloro- 2- of 1,3- bis- (2,4- difluorophenyl) propane and dichloromethane in step (2) of the present invention is
0.15-0.25mol：450ml；Preferably 0.20mol：450ml.
The alcohol compound of step (2) of the present invention is the tert-butyl alcohol, ethanol, propyl alcohol or isopropanol.
The advantages of the present invention：
1. the present invention is used 1,2,3- trichloropropane and 1,3- difluorobenzene as raw material first, synthesis is prepared in two steps
The intermediate of posaconazole --- 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes；Preparation process is neither using expensive
Trimethyl chloromethyl base silane class material, the chloracetyl chloride of severe toxicity is not used yet, so as to sufficiently lower production cost, behaviour is added
Make security；And preparation technology is more gentle, easily operated, the anhydrous and oxygen-free bar needed without traditional handicraft grignard reaction
Part, easily realizes industrialized production.
2. product prepared by the present invention, post processing is simple, it is thus only necessary to washs, dry, vacuum distillation, you can obtain finally
Product, high income.
Embodiment
The present invention is described in further detail below by embodiment, but the present invention is not limited solely to following examples.
Embodiment 1
1st, by 1,2,3- trichloropropanes (29.40g, 0.20mol) be added drop-wise to dropwise 0 DEG C 1,3- difluorobenzenes (22.82g,
In 0.20mol), reactant mixture continues to stir divides 5 batches to add alchlor (26.66g, 0.20mol) altogether after 30min, adds
There is gas releasing afterwards.Reacted after adding at 0 DEG C 1 hour, then (20-35 degrees Celsius) continuation is reacted 6 hours at room temperature.Reaction
Mixture is carefully added into the hydrochloric acid solution that 200ml concentration is 2mol/l at 0 DEG C after finishing, dichloro is used after stirring
Methane is extracted three times, each 200ml, combined dichloromethane layer, uses saturation NaHCO3Solution, water, saturated aqueous common salt are washed respectively
Once.Organic layer anhydrous Na2SO4Filtered after drying, rotary evaporation, which is removed, obtains oil product 1, the chloro- 2- of 3- bis- after dichloromethane
(2,4- difluorophenyl) propane 38.26g (0.17mol), yield 85%.
2nd, by chloro- 2- (2,4- difluorophenyl) propane 45.01g (0.20mol) potassium hydroxide of 1,3- bis- 12.34g
(0.22mol) is added in the 150ml tert-butyl alcohols, is heated to reflux 5 hours.The tert-butyl alcohol, gained are removed in vacuum distillation after completion of the reaction
Add to be neutralized with 5mol/l hydrochloric acid at 150ml frozen water, 0 DEG C in mixture and arrive neutrality, extracted in three times with 450ml dichloromethane
Take, merge organic layer, anhydrous Na2SO4Filtered after drying, rotary evaporation, which is removed, obtains oil product 1- (1- chloromethyls after dichloromethane
Vinyl) -2,4- difluorobenzenes 33.95g (0.18mol), yield 90%.
Embodiment 2
1st, by 1,2,3- trichloropropanes (26.54g, 0.18mol) be added drop-wise to dropwise 0 DEG C 1,3- difluorobenzenes (17.11g,
In 0.15mol), reactant mixture continues to stir divides 4 batches to add alchlor (24.00g, 0.18) altogether after 30min, after addition i.e.
There is gas releasing.Reacted after adding at 0 DEG C 1 hour, then continue to react 6 hours at room temperature.After completion of the reaction will be mixed at 0 DEG C
Compound is carefully added into the hydrochloric acid solution that 150ml concentration is 2mol/l, with dichloromethane extraction three times after stirring, every time
150ml, combined dichloromethane layer, uses saturation NaHCO3Solution, water, saturated aqueous common salt washed once respectively.Organic layer is with anhydrous
Na2SO4Filtered after drying, rotary evaporation, which is removed, obtains oil product 1,3- bis- chloro- 2- (2,4- difluorophenyl) propane after dichloromethane
29.37g (0.13mol), yield 87%.
2nd, by 1,3- bis- chloro- 2- (2,4- difluorophenyl) propane (33.76g, 0.15mol), sodium hydroxide (6.8g,
0.17mol) it is added in 100ml isopropanols, is heated to reflux 5 hours.The tert-butyl alcohol is removed in vacuum distillation after completion of the reaction, and gained is mixed
Add to be neutralized with 5mol/l hydrochloric acid at 100ml frozen water, 0 DEG C in compound and arrive neutrality, extracted in three times with 300ml dichloromethane,
Merge organic layer, anhydrous Na2SO4Filtered after drying, rotary evaporation, which is removed, obtains oil product 1- (1- chloromethyl second after dichloromethane
Alkenyl) -2,4- difluorobenzenes 24.05g (0.13mol), yield 85%.
It was found from above-described embodiment, method reaction product of the invention is easily operated, and post processing is simple, it is easy to industrial metaplasia
Production.
Claims (10)
1. a kind of 1-（1- chloromethyl vinyl bases）The synthetic method of -2,4- difluorobenzene, it is characterised in that：Synthesis step includes：
（1）1,2,3- trichloropropane is added drop-wise in 5 ~ -5 DEG C of 1,3- difluorobenzenes dropwise, reactant mixture stirring 20-40min
After alchlor is added portionwise, after addition i.e. have gas releasing；Reacted 0.5-1.5 hours at 5 ~ -5 DEG C after adding, Ran Housheng
Temperature continues to react 1.5-8 hours to 20-45 DEG C；Add mixture in hydrochloric acid solution, stir at 5 ~ -5 DEG C after completion of the reaction
Extracted 3-5 times with dichloromethane after mixing uniformly, then combined dichloromethane layer uses saturation NaHCO successively3Solution, water, saturation food
Salt solution washed once respectively；The organic layer anhydrous Na of acquisition2SO4Filtered after drying, rotary evaporation, which is removed, obtains oily after dichloromethane
Shape product 1, the chloro- 2- of 3- bis-（2,4- difluorophenyls）Propane；
（2）By step（1）The chloro- 2- of 1,3- bis- prepared by method（2,4- difluorophenyls）Propane adds with potassium hydroxide or sodium hydroxide
Enter into alcohol compound, be heated to reflux 3.5-6 hours；Alcohol compound is removed in vacuum distillation after completion of the reaction, and gained is removed
Added in the mixture of alcohol compound at frozen water, 5 ~ -5 DEG C and neutrality is neutralized with hydrochloric acid, extracted in three times with dichloromethane, closed
And organic layer, then use anhydrous Na2SO4Filtered after drying, rotary evaporation, which is removed, obtains oily target product 1- after dichloromethane（1-
Chloromethyl vinyl base）- 2,4- difluorobenzene.
2. 1- according to claim 1（1- chloromethyl vinyl bases）The synthetic method of -2,4- difluorobenzene, it is characterised in that：
Synthesis path is：
。
3. 1- according to claim 1（1- chloromethyl vinyl bases）The synthetic method of -2,4- difluorobenzene, it is characterised in that：
Step（1）In 1,2,3- trichloropropanes, the mol ratio of 1,3- difluorobenzene and alchlor is 1 ~ 1.2:1:1~1.2；Tri-chlorination
Aluminium is divided into 4-6 batches of additions.
4. 1- according to claim 1（1- chloromethyl vinyl bases）The synthetic method of -2,4- difluorobenzene, it is characterised in that：
Step（1）Middle hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration, and the consumption of hydrochloric acid solution is with 1,2,3- trichloropropane meter, 1,2,
Concentration of the 3- trichloropropanes in hydrochloric acid solution is 0.05-0.2mol/100ml.
5. 1- according to claim 4（1- chloromethyl vinyl bases）The synthetic method of -2,4- difluorobenzene, it is characterised in that：
Step（1）In concentration of 1,2, the 3- trichloropropanes in hydrochloric acid solution be 0.1mol/100ml.
6. 1- according to claim 1（1- chloromethyl vinyl bases）The synthetic method of -2,4- difluorobenzene, it is characterised in that：
Step（1）In the volume ratio of the dichloromethane that extracts every time and hydrochloric acid solution be 1:1.
7. 1- according to claim 1（1- chloromethyl vinyl bases）The synthetic method of -2,4- difluorobenzene, it is characterised in that：
Step（2）In the chloro- 2- of 1,3- bis-（2,4- difluorophenyls）The mol ratio of propane and potassium hydroxide or sodium hydroxide is 1:1-2；1,
The chloro- 2- of 3- bis-（2,4- difluorophenyls）The use ratio of propane and alcohol compound is 0.15-0.25mol：150ml；3- bis- is chloro-
2-（2,4- difluorophenyls）The use ratio of propane and frozen water is 0.15-0.25mol：150ml.
8. 1- according to claim 7（1- chloromethyl vinyl bases）The synthetic method of -2,4- difluorobenzene, it is characterised in that：
Step（2）In the chloro- 2- of 1,3- bis-（2,4- difluorophenyls）The mol ratio of propane and potassium hydroxide is 1:1.1；1,3- bis- chloro- 2-
（2,4- difluorophenyls）The use ratio of propane and the tert-butyl alcohol is 0.2mol：150ml；The chloro- 2- of 3- bis-（2,4- difluorophenyls）Third
The use ratio of alkane and frozen water is 0.2mol：150ml.
9. 1- according to claim 1（1- chloromethyl vinyl bases）The synthetic method of -2,4- difluorobenzene, it is characterised in that：
Step（2）Middle concentration of hydrochloric acid is 5mol/l；Alcohol compound is the tert-butyl alcohol, ethanol, propyl alcohol or isopropanol.
10. 1- according to claim 1（1- chloromethyl vinyl bases）The synthetic method of -2,4- difluorobenzene, it is characterised in that：
Step（2）In the chloro- 2- of 1,3- bis-（2,4- difluorophenyls）The use ratio of propane and dichloromethane is 0.15-0.25mol：
450ml。
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