CN105646137A - Method for synthesizing 1-(1-chloromethylvinyl)-2,4-difluorobenzene - Google Patents
Method for synthesizing 1-(1-chloromethylvinyl)-2,4-difluorobenzene Download PDFInfo
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- CN105646137A CN105646137A CN201610022233.0A CN201610022233A CN105646137A CN 105646137 A CN105646137 A CN 105646137A CN 201610022233 A CN201610022233 A CN 201610022233A CN 105646137 A CN105646137 A CN 105646137A
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- difluorobenzene
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- 238000000034 method Methods 0.000 title claims abstract description 22
- GCMCDEDXHXWYCN-UHFFFAOYSA-N 1-(3-chloroprop-1-en-2-yl)-2,4-difluorobenzene Chemical compound FC1=CC=C(C(=C)CCl)C(F)=C1 GCMCDEDXHXWYCN-UHFFFAOYSA-N 0.000 title abstract 2
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 38
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims abstract description 34
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 22
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 238000003756 stirring Methods 0.000 claims abstract description 10
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 claims abstract description 8
- 229910000343 potassium bisulfate Inorganic materials 0.000 claims abstract description 8
- 239000007832 Na2SO4 Substances 0.000 claims abstract description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 5
- 238000010992 reflux Methods 0.000 claims abstract description 5
- SSZWWUDQMAHNAQ-UHFFFAOYSA-N 3-chloropropane-1,2-diol Chemical compound OCC(O)CCl SSZWWUDQMAHNAQ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000002585 base Substances 0.000 claims description 42
- 239000000047 product Substances 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 238000002390 rotary evaporation Methods 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 abstract description 3
- 238000005406 washing Methods 0.000 abstract description 3
- UHTPKEJQKFXVHC-UHFFFAOYSA-N 3-chloro-2-(2,4-difluorophenyl)propan-1-ol Chemical compound ClCC(CO)C1=C(C=C(C=C1)F)F UHTPKEJQKFXVHC-UHFFFAOYSA-N 0.000 abstract 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 abstract 2
- 238000001035 drying Methods 0.000 abstract 2
- 238000010438 heat treatment Methods 0.000 abstract 2
- 235000011152 sodium sulphate Nutrition 0.000 abstract 2
- 238000001704 evaporation Methods 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 230000007935 neutral effect Effects 0.000 abstract 1
- 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
- 229960001589 posaconazole Drugs 0.000 description 5
- 0 *C(c(ccc(F)c1)c1F)=C Chemical compound *C(c(ccc(F)c1)c1F)=C 0.000 description 3
- 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
- 238000012805 post-processing Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 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
- 150000004756 silanes Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- XFGDAPQOKJYPQP-UHFFFAOYSA-N 1-chloropropane-1,2-diol Chemical compound CC(O)C(O)Cl XFGDAPQOKJYPQP-UHFFFAOYSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- BPJGUCXOEXNMNZ-HVUXDCMCSA-N C/C(/F)=C\C(\F)=C/C#C Chemical compound C/C(/F)=C\C(\F)=C/C#C BPJGUCXOEXNMNZ-HVUXDCMCSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 208000032826 Ring chromosome 3 syndrome Diseases 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000007812 deficiency Effects 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
- 150000007517 lewis acids Chemical class 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
- 230000002265 prevention Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229910000077 silane Inorganic materials 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
- 238000010189 synthetic method Methods 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
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/32—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions without formation of -OH groups
- C07C29/34—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions without formation of -OH groups by condensation involving hydroxy groups or the mineral ester groups derived therefrom, e.g. Guerbet reaction
Abstract
The invention relates to a method for synthesizing 1-(1-chloromethylvinyl)-2,4-difluorobenzene. The method comprises the following steps: mixing 3-chloro-1,2-propanediol and 1,3-difluorobenzene, adding a catalyst, carrying out reaction at room temperature for 6-10 hours, heating to 50-70 DEG C, and carrying out reaction for 2-4 hours; adding the mixture into a hydrochloric acid solution at 5 to -5 DEG C, stirring uniformly, extracting 3-5 times by using dichloromethane as an extractant, and washing the extracting solution with a saturated NaHCO3 solution, water and a saturated saline solution; drying with anhydrous Na2SO4, filtering, and evaporating to remove the dichloromethane, thereby obtaining the 1-chloro-2-(2,4-difluorophenyl)-3-propanol; adding the 1-chloro-2-(2,4-difluorophenyl)-3-propanol and potassium hydrogen sulfate into chlorobenzene, and heating under reflux for 10-16 hours; and washing with water to a neutral state, drying with anhydrous Na2SO4, filtering, and distilling to obtain the target product. The synthesis route is disclosed in the specification.
Description
Technical field
The present invention relates to posaconazole intermediate synthesis technical field, the method for specific design one synthesis 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene.
Background technology
Posaconazole (chemical name: 4-[4-[4-[4-[[(3R, 5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-yl methyl) oxa-penta ring-3-base] methoxyl group] phenyl] piperazine-1-base] phenyl]-2-[(2S, 3S)-2-hydroxyl penta-3-base]-1,2,4-triazole-3-ketone, English name: Posaconazole), structural formula is shown below:
Being developed by Schering Plough company of the U.S., in JIUYUE, 2006 U.S. FDA approval listing, is a kind of highly lipophilic wide spectrum triazole antifungal agent. Commodity are called Noxafil (promise section flies), oral suspensions, it is mainly used in prevention 13 years old and above patient's intrusive mood aspergillosis and monilial infection, and treats pars oralis pharyngis monilial infection and the pars oralis pharyngis monilial infection to fluconazol and voriconazole drug resistance.
1-(1-chloromethyl vinyl base)-2,4 difluorobenzene is the intermediate of synthesis posaconazole, and its structural formula is shown below:
European patent EP 2789610 (A1), world patent WO2011144653 (A1), WO2011144656 (A1) and WO2011144657 (A1) all disclose by 1,3-difluorobenzene synthesizes the method for this intermediate, is shown below:
The method to use expensive trimethyl chloromethyl base silane class material, causes that 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene production cost is high. It addition, the method also to be used grignard reaction. This reaction needed anhydrous and oxygen-free condition, it is difficult to operation, not easily realizes industrialized production.
Summary of the invention
The present invention is directed to above-mentioned the deficiencies in the prior art, one is provided not use expensive trimethyl chloromethyl base silane, preparation cost low, do not adopt grignard reaction, without anhydrous and oxygen-free condition, easily operated, easily realize industrialized production, and post processing is simple, the method of synthesis 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene easy and simple to handle.
In order to solve above-mentioned technical problem, the technical solution used in the present invention is: a kind of method of synthesis 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene, and the step of this synthetic method includes:
(1) mix homogeneously at 5��-5 DEG C by 3-chlorine-1,2-propylene glycol and 1,3-difluorobenzene, is then dividedly in some parts catalyst while stirring, adds and reacts 6-10 hour under rear room temperature;Then reaction system is warmed up to 50-70 DEG C of continuation reaction 2-4 hour; After completion of the reaction, at 5��-5 DEG C, reaction system mixture is joined in hydrochloric acid solution, extract 3-5 time as extractant with dichloromethane after stirring, merge the dichloromethane layer every time extracted, then use saturated NaHCO successively3Solution, water, saturated aqueous common salt wash once respectively; The organic over anhydrous Na obtained2SO4Dried filtration, rotary evaporation obtains the chloro-2-of oil product 1-(2,4 difluorobenzene base)-3-propanol after removing dichloromethane;
(2) the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol step (1) prepared and potassium acid sulfate join in chlorobenzene, are heated to reflux 10-16 hour; Chlorobenzene layer is washed to neutrality after completion of the reaction, then uses anhydrous Na2SO4Dried filtration, filtrate decompression distillation obtains oily target product 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene after removing chlorobenzene.
The method of above-mentioned a kind of synthesis 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene, synthesis path is:
In step of the present invention (1), the mol ratio of 3-chlorine-1,2-propylene glycol, 1,3-difluorobenzene and catalyst is: 1��1.2:1:1��1.2; It is preferably 1:1:1; Catalyst can be the one in the lewis acids such as aluminum chloride, zinc chloride, ferric chloride, it is also possible to be concentrated sulphuric acid.
Step of the present invention (1) is dividedly in some parts catalyst and 4-6 can be divided into criticize addition, and this operation can effectively prevent reactant mixture excessively thickness, it is difficult to the appearance of the problems such as stirring.
In step of the present invention (1), hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration, the consumption of hydrochloric acid solution is with 3-chloro-1,2-propylene glycol meter, 3-chloro-1,2-propylene glycol molar concentration in hydrochloric acid solution is 0.05-0.2mol/100ml (the i.e. 3-of 100ml hydrochloric acid solution correspondence 0.05-0.2mol chloro-1,2-propylene glycol), it is preferred to 0.1mol/100ml.
In step of the present invention (1), each extraction quantity of dichloromethane and the volume ratio of hydrochloric acid solution are 1.5-2.5:3, it is preferably 2:3, such as, if having employed 300ml, the hydrochloric acid solution of 2mol/l concentration, then the extraction quantity that follow-up dichloromethane is each is 200ml.
In step of the present invention (2), the mol ratio of the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol and potassium acid sulfate is 1:1 1.5, it is preferred to 1:1.1.
In step of the present invention (2), the chloro-2-(2 of 1-, 4-difluorophenyl)-3-propanol molar concentration in chlorobenzene be 0.15-0.30mol/300ml (namely 300ml chlorobenzene correspondence add 0.15-0.30mol the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol); It is preferably 0.2mol/300ml.
Advantages of the present invention and beneficial effect:
1. the present invention adopts 3-chlorine-1,2-propylene glycol and 1,3-difluorobenzene first as raw material, prepares intermediate 1-(1-chloromethyl vinyl the base)-2,4 difluorobenzene of synthesis posaconazole in two steps; Preparation process neither adopts expensive trimethyl chloromethyl base silane class material, thus sufficiently lower production cost; And preparation technology is more gentle, easily operated, it does not have the anhydrous and oxygen-free condition that traditional handicraft grignard reaction needs, more easily operate, it is easy to realize industrialized production.
2. the product that prepared by the present invention, post processing is simple, it is thus only necessary to washing, dry, decompression distillation, can obtain end product, and yield is high.
Detailed description of the invention
The present invention is described in further detail by the examples below, but the present invention is not limited solely to following example.
Embodiment 1
1, by chloro-for 3-1,2-propylene glycol (33.16g, 0.30mol) with 1,3-difluorobenzene (34.23g, 0.30mol) at 0 DEG C, divide 5 batches after mix homogeneously while stirring and add aluminum chloride (40.00g altogether, 0.30mol), add and react 8 hours under rear room temperature, be then warmed up to 60 DEG C and continue reaction 3 hours.At 0 DEG C, mixture is carefully added into after completion of the reaction in the hydrochloric acid solution that 300ml concentration is 2mol/l, after stirring, uses dichloromethane extraction three times, each 200ml, combined dichloromethane layer, use saturated NaHCO3Solution, water, saturated aqueous common salt wash once respectively. Organic over anhydrous Na2SO4Dried filtration, rotary evaporation obtains the chloro-2-of oil product 1-(2,4 difluorobenzene base)-3-propanol 50.83g (0.25mol), productivity 82% after removing dichloromethane.
2, by chloro-for 1-2-(2,4 difluorobenzene base)-3-propanol 41.32g (0.20mol), potassium acid sulfate 29.96g (0.22mol) joins in 300ml chlorobenzene, is heated to reflux 14 hours. Chlorobenzene layer is washed to neutrality, anhydrous Na after completion of the reaction2SO4Dried filtration, decompression distillation obtains oil product 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene 32.06g (0.17mol), productivity 85% after removing chlorobenzene.
Embodiment 2
1, by chloro-for 3-1,2-propylene glycol (26.53g, 0.24mol) with 1,3-difluorobenzene (22.82g, 0.20mol) at 0 DEG C, after mix homogeneously, divide 4 batches while stirring and add ferric chloride (0.24mol) altogether, add and react 8 hours under rear room temperature, be then warmed up to 60 DEG C and continue reaction 3 hours. At 0 DEG C, mixture is carefully added into after completion of the reaction in the hydrochloric acid solution that 200ml concentration is 2mol/l, after stirring, uses dichloromethane extraction three times, each 130ml, combined dichloromethane layer, use saturated NaHCO3Solution, water, saturated aqueous common salt wash once respectively. Organic over anhydrous Na2SO4Dried filtration, rotary evaporation obtains the chloro-2-of oil product 1-(2,4 difluorobenzene base)-3-propanol 33.06g, (0.16mol), productivity 80% after removing dichloromethane.
2, by chloro-for 1-2-(2,4 difluorobenzene base)-3-propanol 41.32g (0.20mol), potassium acid sulfate 29.96g (0.22mol), join in 200ml chlorobenzene, be heated to reflux 14 hours. Chlorobenzene layer is washed to neutrality, anhydrous Na after completion of the reaction2SO4Dried filtration, decompression distillation obtains oil product 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene 31.68g (0.17mol), productivity 84% after removing chlorobenzene.
From the above it can be seen that the method product of the present invention is easily operated, post processing is simple, it is easy to industrialized production.
Claims (10)
1. the method for synthesis 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene, it is characterised in that: synthesis step includes:
(1) mix homogeneously at 5��-5 DEG C by 3-chlorine-1,2-propylene glycol and 1,3-difluorobenzene, is then dividedly in some parts catalyst while stirring, adds and reacts 6-10 hour under rear room temperature; Instead then answer system to be warmed up to 50-70 DEG C and continue reaction 2-4 hour; After completion of the reaction, at 5��-5 DEG C, reaction system mixture is joined in hydrochloric acid solution, extract 3-5 time as extractant with dichloromethane after stirring, merge the dichloromethane layer every time extracted, then use saturated NaHCO successively3Solution, water, saturated aqueous common salt wash once respectively; The organic over anhydrous Na obtained2SO4Dried filtration, rotary evaporation obtains the chloro-2-of oil product 1-(2,4 difluorobenzene base)-3-propanol after removing dichloromethane;
(2) the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol step (1) prepared and potassium acid sulfate join in chlorobenzene, are heated to reflux 10-16 hour; Chlorobenzene layer is washed to neutrality after completion of the reaction, then uses anhydrous Na2SO4Dried filtration, filtrate decompression distillation obtains oily target product 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene after removing chlorobenzene.
2. the method for synthesis 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene according to claim 1, it is characterised in that: synthesis path is:
3. synthesis 1-(1-chloromethyl vinyl base)-2 according to claim 1, the method of 4-difluorobenzene, it is characterized in that: in step (1), the mol ratio of 3-chlorine-1,2-propylene glycol, 1,3-difluorobenzene and catalyst is 1��1.2:1:1��1.2; Catalyst is divided into 4-6 to criticize addition.
4. synthesis 1-(1-chloromethyl vinyl base)-2 according to claim 1, the method of 4-difluorobenzene, it is characterized in that: in step (1), hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration, the consumption of hydrochloric acid solution is with 3-chloro-1,2-propylene glycol meter, 3-chlorine-1,2-propylene glycol molar concentration in hydrochloric acid solution is 0.05-0.2mol/100ml.
5. synthesis 1-(1-chloromethyl vinyl base)-2 according to claim 4, the method of 4-difluorobenzene, it is characterised in that: the consumption of hydrochloric acid solution is in 3-chlorine-1,2-propylene glycol, 3-chlorine-1,2-propylene glycol molar concentration in hydrochloric acid solution is 0.1mol/100ml.
6. the method for synthesis 1-(1-chloromethyl vinyl base)-2,4 difluorobenzene according to claim 1, it is characterised in that: the catalyst in step (1) is the one in aluminum chloride, zinc chloride, ferric chloride or concentrated sulphuric acid; The extraction quantity of each dichloromethane and the volume ratio of hydrochloric acid solution are 1.5-2.5:3.
7. synthesis 1-(1-chloromethyl vinyl base)-2 according to claim 1, the method of 4-difluorobenzene, it is characterized in that: in step (2), the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol is 1:1-1.5 with the mol ratio of potassium acid sulfate.
8. synthesis 1-(1-chloromethyl vinyl base)-2 according to claim 7, the method of 4-difluorobenzene, it is characterized in that: in step (2), the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol is 1:1.1 with the mol ratio of potassium acid sulfate.
9. synthesis 1-(1-chloromethyl vinyl base)-2 according to claim 1, the method of 4-difluorobenzene, it is characterized in that: in step (2), the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol molar concentration in chlorobenzene is 0.15-0.30mol/300ml.
10. synthesis 1-(1-chloromethyl vinyl base)-2 according to claim 9, the method of 4-difluorobenzene, it is characterized in that: in step (2), the chloro-2-of 1-(2,4 difluorobenzene base)-3-propanol molar concentration in chlorobenzene is 0.2mol/300ml.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101323600A (en) * | 2008-07-25 | 2008-12-17 | 西南大学 | Triadimefon and triadimenol compounds having antimicrobial activity, salts, synthetic methods and uses thereof |
| CN101817792A (en) * | 2008-07-25 | 2010-09-01 | 西南大学 | Bistriazolone, bistriadimenol compounds with antimicrobial activity, and salts, synthesis method and uses thereof |
| CN101824009A (en) * | 2010-05-27 | 2010-09-08 | 北京德众万全药物技术开发有限公司 | Simple preparation method for posaconazole and piperazine intermediate thereof |
| CN102643194A (en) * | 2012-03-27 | 2012-08-22 | 福州大学 | Preparation method of posaconazole intermediate |
| US20140343285A1 (en) * | 2011-09-19 | 2014-11-20 | Msn Laboratories Limited | Process for the Preparation of Triazole Antifungal Drug, Its Intermediates and Polymorphs Thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101323600A (en) * | 2008-07-25 | 2008-12-17 | 西南大学 | Triadimefon and triadimenol compounds having antimicrobial activity, salts, synthetic methods and uses thereof |
| CN101817792A (en) * | 2008-07-25 | 2010-09-01 | 西南大学 | Bistriazolone, bistriadimenol compounds with antimicrobial activity, and salts, synthesis method and uses thereof |
| CN101824009A (en) * | 2010-05-27 | 2010-09-08 | 北京德众万全药物技术开发有限公司 | Simple preparation method for posaconazole and piperazine intermediate thereof |
| US20140343285A1 (en) * | 2011-09-19 | 2014-11-20 | Msn Laboratories Limited | Process for the Preparation of Triazole Antifungal Drug, Its Intermediates and Polymorphs Thereof |
| CN102643194A (en) * | 2012-03-27 | 2012-08-22 | 福州大学 | Preparation method of posaconazole intermediate |
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