WO2022264172A1 - Novel process for the preparation of 2-chloro-4-fluorotoluene - Google Patents
Novel process for the preparation of 2-chloro-4-fluorotoluene Download PDFInfo
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- WO2022264172A1 WO2022264172A1 PCT/IN2022/050553 IN2022050553W WO2022264172A1 WO 2022264172 A1 WO2022264172 A1 WO 2022264172A1 IN 2022050553 W IN2022050553 W IN 2022050553W WO 2022264172 A1 WO2022264172 A1 WO 2022264172A1
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- chloro
- formula
- aminotoluene
- fluorotoluene
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- CSARJIQZOSVYHA-UHFFFAOYSA-N 2-chloro-4-fluoro-1-methylbenzene Chemical compound CC1=CC=C(F)C=C1Cl CSARJIQZOSVYHA-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- RQKFYFNZSHWXAW-UHFFFAOYSA-N 3-chloro-p-toluidine Chemical compound CC1=CC=C(N)C=C1Cl RQKFYFNZSHWXAW-UHFFFAOYSA-N 0.000 claims abstract description 60
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 6
- 239000012954 diazonium Substances 0.000 claims description 37
- 150000001989 diazonium salts Chemical class 0.000 claims description 36
- 239000003153 chemical reaction reagent Substances 0.000 claims description 35
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 22
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 20
- 238000010438 heat treatment Methods 0.000 claims description 19
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 13
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- -1 alkyl pyridine Chemical compound 0.000 claims description 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 12
- 235000010288 sodium nitrite Nutrition 0.000 claims description 11
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 4
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229940043279 diisopropylamine Drugs 0.000 claims description 4
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 4
- 235000010289 potassium nitrite Nutrition 0.000 claims description 4
- 239000004304 potassium nitrite Substances 0.000 claims description 4
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims description 4
- 239000012414 tert-butyl nitrite Substances 0.000 claims description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims 2
- 239000000203 mixture Substances 0.000 description 31
- 239000012044 organic layer Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000005260 corrosion Methods 0.000 description 5
- 230000007797 corrosion Effects 0.000 description 5
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 4
- 229910000856 hastalloy Inorganic materials 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012025 fluorinating agent Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000197 pyrolysis Methods 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 1
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 description 1
- MIMUSZHMZBJBPO-UHFFFAOYSA-N 6-methoxy-8-nitroquinoline Chemical compound N1=CC=CC2=CC(OC)=CC([N+]([O-])=O)=C21 MIMUSZHMZBJBPO-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 229960001602 ceritinib Drugs 0.000 description 1
- VERWOWGGCGHDQE-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 VERWOWGGCGHDQE-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 125000001752 diazonium salt group Chemical group 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- GNHDVXLWBQYPJE-UHFFFAOYSA-N saflufenacil Chemical compound C1=C(Cl)C(C(=O)NS(=O)(=O)N(C)C(C)C)=CC(N2C(N(C)C(=CC2=O)C(F)(F)F)=O)=C1F GNHDVXLWBQYPJE-UHFFFAOYSA-N 0.000 description 1
- 229910001495 sodium tetrafluoroborate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
Definitions
- the present invention relates to a novel process for the preparation of 2-chloro-4-fluorotoluene of formula I.
- saflufenacil a herbicide
- 2-chloro-4-fluorotoluene of formula I is a crucial intermediate in the synthesis of ceritinib, an antineoplastic drug.
- 2-chloro-4-fluorotoluene of formula I is also useful for the various drugs which are currently at various stages of development.
- US4912268 discloses a process for the preparation of 2-chloro-4-fluorotoluene of formula I, which consists of reacting 2-chloro-4-aminotoluene of formula III using ammonium bifluoride in anhydrous hydrogen fluoride, dodecane and a gas mixture of nitric oxide, nitrogen, and oxygen at 80°C to 96°C resulting diazonium salt of 2-chloro-4-aminotoluene of formula II which further decomposes to form 2-chloro-4-fluorotoluene of formula I.
- US’268 employs f!uoropolymer-lined steel tubular reactor fitted with internal tetrafluoroethylene polymer baffles, thermocouple, bottom-inlet gas sparger and an external pump-fed recirculation loop.
- CN108569948B discloses a process for the preparation of 2-chl oro-4-fluorotoluene of formula I, which consists of reacting 2-chl oro-4-anunotoluene of formula III using anhydrous hydrogen fluoride, sodium nitrite at temperature -5°C to 15°C to obtain the diazonium salt, wherein the ratio of diazonium salt to hydrogen fluoride is 1 : 8 to 1:18, followed by thermal decomposition of the diazonium salt in a steps; in first step when the temperature is within the range of 0°C to 20°C, then the temperature is increased by 0.5°C to 1°C per hour, when the temperature is within the range of 20°C to 80°C, then the temperature is increased by 1°C to 2°C per hour, and the temperature is increased to 80°C and kept for 2 hours at 80°C.
- CN110759806A discloses a process for the preparation of 2-chloro-4-fluorotoluene of formula I, which consists of reacting 2-chloro-4-aminotoluene of formula III using anhydrous hydrogen fluoride, sodium nitrite at 0°C followed by pyrolysis in two stages; the first stage is to raise the temperature to 30°C wherein the heating time needs to be controlled between 1.5 hour at a constant rate; and the second stage is to raise temperature from 30°C to 50°C, and the heating time is controlled between 2.5 hour at a constant rate. After pyrolysis, the reaction mixture is kept for 19 hours.
- IN201811046158 discloses a process for the preparation of 2-chloro-4-fluorotoluene of formula I, which consists of reacting 2-chloro-4-aminotoluene of formula III using aqueous hydrochloric acid, aqueous sodium tetrafluoroborate or aqueous potassium hexafluorophosphate or aqueous fluoroboric acid, and aqueous sodium nitrite at -5°C to 0°C to obtain diazonium salt of 2-chloro- 4-aminotoluene of formula II. The resulting diazonium salt is heated slowly at 110°C to obtain 2- chloro-4-fluorotoluene of formula I.
- the inventors of the present invention provide a novel process for preparing 2-chloro-4- fluorotoluene of formula I, which is simple, requires non-expensive assets and is industrially amenable.
- An object of the present invention is to provide a process for the preparation of 2-chloro-4- fluorotoluene of formula I from 2-chloro-4-aminotoluene of formula III, which employs inexpensive/economic reagents suitable for large scale batch production which avoids the corrosion of the reactor.
- Another object of the present invention is to provide a process for the preparation of 2-chloro-4- fluorotoluene of formula I which is simple and requires non-expensive assets.
- Yet another object of the present invention is to provide a process for the preparation of 2-chloro- 4-fluorotoluene of formula I at a controlled temperature.
- the present invention relates to a novel, efficient and industrially advantageous process for the preparation of 2-chloro-4-fluorotoluene of formula I.
- a first aspect of the present invention provides a process for the preparation of 2-chloro-4- fluorotoluene of formula I comprising the steps of: a) diazotizing 2-chloro-4-aminotoluene of formula IP using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II; and b) heating the reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II to obtain 2-chloro-4-fluorotoluene of formula I.
- a second aspect of the present invention provides a process for the preparation of 2-chloro-4- fluorotoluene of formula I comprising the steps of: a) diazotizing 2-chloro-4-aminotoluene of formula IP using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II; b) isolating diazonium salt of 2-chloro-4-aminotoluene of formula II from the reaction mixture; and c) heating isolated diazonium salt of 2-chloro-4-aminotoluene of formula II to obtain 2- chloro-4-fluorotoluene of formula I.
- a third aspect of the present invention provides a process for the preparation of 2-chloro-4- fluorotoluene of formula I comprising the steps of: a) mixing 2-chloro-4-aminotoluene of formula III with a fluorinating reagent in the presence of at least one base to obtain a mixture; b) adding a diazotizing reagent to the mixture obtained in step a) at a temperature in the range of 20°C to 140°C to obtain 2-chloro-4-fluorotoluene of formula I.
- the present invention discloses a process for the preparation of 2-chloro-4-fluorotoluene of formula I.
- a process for the preparation of 2-chloro-4-fluorotoluene of formula I is described herein after:
- step (a) 2-chloro-4-aminotoluene of formula IP is diazotized using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II, and
- step (b) the reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II is heated to obtain 2-chloro-4-fluorotoluene of formula I.
- the diazotizing reagent suitable for the reaction used in the step (a) is selected from the group consisting of sodium nitrite, potassium nitrite, tert-butyl nitrite and isoamyl nitrite.
- the fluorinating reagent suitable for the reaction used in the step (a) is selected from the group consisting of anhydrous hydrogen fluoride and tetrafluoroboric acid.
- the base suitable for the reaction used in the step (a) is selected from the group consisting of pyridine, Ci to C4 alkyl pyridine, triethylamine, diisopropylamine, piperidine, /V-methylpiperidine, piperazine, pyrrolidine, imidazole, benzimidazole, and Ci to C4 alkyl imidazole.
- the molar ratio of 2-chloro-4-aminotoluene of formula III to the diazotizing reagent used in the step (a) is in the range of 1 : 1 to 1 :2.
- the molar ratio of 2-chloro-4-aminotoluene of formula III to the fluorinating reagent used in the step (a) is in the range of 1 :2 to 1 :20.
- the molar ratio of 2-chloro-4-aminotoluene of formula III to the base used in the step (a) is in the range of 1:0.8 to 1:10.0.
- the molar ratio of 2-chloro-4-aminotoluene of formula III to the base used in the step (a) is in the range of 1 : 1 to 1:5.
- the diazotization reaction of the step (a) is carried out at a temperature in the range of -10°C to 40°C.
- 2-chloro-4-aminotoluene of formula III is first mixed with a fluorinating reagent in the presence of at least one base to obtain a mixture.
- the mixture thus obtained is mixed lot wise or slowly with the diazotizing reagent at a temperature in the range of -10°C to 40°C.
- reaction mixture comprising diazonium salt is heated to obtain 2-chloro-4-fluorotoluene of formula I.
- step (b) is carried out by heating the diazonium salt of 2- chloro-4-aminotoluene of formula II in two steps:
- step (b) is carried out by heating the diazonium salt of 2-chloro-4-aminotoluene of formula II at a rate of 5°C to 10.5°C or more per hour to achieve the temperature in the range of 60°C to 140°C.
- the excess fluorinating agent may be isolated and recovered.
- the inorganic base suitable for washing the organic layer is selected from a group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
- step (a) 2-chloro-4-aminotoluene of formula IP is diazotized using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II.
- step (b) diazonium salt of 2-chloro-4-aminotoluene of formula II is isolated from the reaction mixture.
- step (c) isolated diazonium salt of 2-chloro-4-aminotoluene of formula II is heated to obtain 2- chloro-4-fluorotoluene of formula I.
- the diazotizing reagents suitable for the reaction used in the step (a) is selected from the group consisting of sodium nitrite, potassium nitrite, tert-butyl nitrite and isoamyl nitrite.
- the fluorinating reagents suitable for the reaction used in the step (a) is selected from the group consisting of anhydrous hydrogen fluoride and tetrafluoroboric acid.
- the base suitable for the reaction used in the step (a) is selected from the group consisting of pyridine, Ci to C4 alkyl pyridine, triethylamine, diisopropylamine, piperidine, /V-methylpiperidine, piperazine, pyrrolidine, imidazole, benzimidazole, and Ci to C4 alkyl imidazole.
- the molar ratio of 2-chloro-4-aminotoluene of formula III to the diazotizing reagent is in the range of 1:1 to 1:2.
- the molar ratio of 2-chloro-4-aminotoluene of formula IP to the fluorinating reagent is in the range of 1:2 to 1:20.
- the molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1 : 0.8 to 1 : 100
- the molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1:1 to 1:5.
- the diazotization reaction is carried out at a temperature in the range of -10°C to 40°C.
- 2-chloro-4-aminotoluene of formula III is first mixed with a fluorinating reagent in the presence of at least one base to obtain a mixture.
- the mixture thus obtained is mixed lot wise or slowly with the diazotizing reagent at a temperature in the range of -10°C to 40°C.
- diazonium salt of 2-chloro-4-aminotoluene of formula II is isolated by filtration.
- the isolated diazonium salt of 2-chloro-4-aminotoluene of formula II is heated to obtain 2-chloro-4-fluorotoluene of formula I.
- the step (b) is carried out by heating the diazonium salt of 2-chloro-4-aminotoluene of formula II in two steps:
- the step (b) is carried out by heating the diazonium salt of 2-chloro-4-aminotoluene of formula II at a rate of 5°C to 10°C or more per hour to achieve the temperature in the range of 60°C to 140°C.
- the excess fluorinating agent may be isolated and recovered.
- the inorganic base suitable for washing the organic layer is selected from a group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
- step (a) 2-chloro-4-aminotoluene of formula IP is mixed with a fluorinating reagent in the presence of at least one base to obtain a mixture.
- step (b) a diazotizing reagent is added to the mixture of the step (a) at a temperature in the range of 20°C to 140°C to obtain 2-chloro-4-fluorotoluene of formula I.
- the diazotizing reagents suitable for the reaction used in the step (a) is selected from the group consisting of sodium nitrite, potassium nitrite, tert-butyl nitrite and isoamyl nitrite.
- the fluorinating reagents suitable for the reaction used in the step (a) is selected from the group consisting of anhydrous hydrogen fluoride and tetrafluoroboric acid.
- the base suitable for the reaction used in the step (a) is selected from the group consisting of pyridine, Ci to C 4 alkyl pyridine, triethylamine, diisopropylamine, piperidine, /V-methylpiperidine, piperazine, pyrrolidine, imidazole, benzimidazole and Ci to C 4 alkyl imidazole.
- the molar ratio of 2-chloro-4-aminotoluene of formula III to the diazotizing reagent is in the range of 1:1 to 1:2.
- the molar ratio of 2-chloro-4-aminotoluene of formula IP to the fluorinating reagent is in the range of 1:2 to 1:20.
- the molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1 : 0.8 to 1 : 100
- the molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1:1 to 1:5.
- the excess fluorinating agent may be isolated and recovered.
- the inorganic base suitable for washing the organic layer is selected from a group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
Abstract
The present invention relates to a process for the preparation of 2-chloro-4-fluorotoluene of formula I from diazotization of 2-chloro-4-aminotoluene of formula III.
Description
NOVEL PROCESS FOR THE PREPARATION OF 2-CHLORO-4-FLUOROTOLUENE
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of 2-chloro-4-fluorotoluene of formula I.
BACKGROUND: 2-chloro-4-fluorotoluene of formula I is a key intermediate for the synthesis of several pharmaceutical, agrochemical, and other important fine chemical products.
For example, saflufenacil, a herbicide, can be prepared using 2-chloro-4-fluorotoluene of formula I. 2-chloro-4-fluorotoluene of formula I is a crucial intermediate in the synthesis of ceritinib, an antineoplastic drug.
2-chloro-4-fluorotoluene of formula I is also useful for the various drugs which are currently at various stages of development.
Several synthetic methods have been reported in literature to prepare 2-chloro-4-fluorotoluene of formula I.
US4912268 discloses a process for the preparation of 2-chloro-4-fluorotoluene of formula I, which consists of reacting 2-chloro-4-aminotoluene of formula III using ammonium bifluoride in anhydrous hydrogen fluoride, dodecane and a gas mixture of nitric oxide, nitrogen, and oxygen at 80°C to 96°C resulting diazonium salt of 2-chloro-4-aminotoluene of formula II which further decomposes to form 2-chloro-4-fluorotoluene of formula I. The process of US’268 employs
f!uoropolymer-lined steel tubular reactor fitted with internal tetrafluoroethylene polymer baffles, thermocouple, bottom-inlet gas sparger and an external pump-fed recirculation loop.
CN108569948B discloses a process for the preparation of 2-chl oro-4-fluorotoluene of formula I, which consists of reacting 2-chl oro-4-anunotoluene of formula III using anhydrous hydrogen fluoride, sodium nitrite at temperature -5°C to 15°C to obtain the diazonium salt, wherein the ratio of diazonium salt to hydrogen fluoride is 1 : 8 to 1:18, followed by thermal decomposition of the diazonium salt in a steps; in first step when the temperature is within the range of 0°C to 20°C, then the temperature is increased by 0.5°C to 1°C per hour, when the temperature is within the range of 20°C to 80°C, then the temperature is increased by 1°C to 2°C per hour, and the temperature is increased to 80°C and kept for 2 hours at 80°C.
CN110759806A discloses a process for the preparation of 2-chloro-4-fluorotoluene of formula I, which consists of reacting 2-chloro-4-aminotoluene of formula III using anhydrous hydrogen fluoride, sodium nitrite at 0°C followed by pyrolysis in two stages; the first stage is to raise the temperature to 30°C wherein the heating time needs to be controlled between 1.5 hour at a constant rate; and the second stage is to raise temperature from 30°C to 50°C, and the heating time is controlled between 2.5 hour at a constant rate. After pyrolysis, the reaction mixture is kept for 19 hours.
IN201811046158 discloses a process for the preparation of 2-chloro-4-fluorotoluene of formula I, which consists of reacting 2-chloro-4-aminotoluene of formula III using aqueous hydrochloric acid, aqueous sodium tetrafluoroborate or aqueous potassium hexafluorophosphate or aqueous fluoroboric acid, and aqueous sodium nitrite at -5°C to 0°C to obtain diazonium salt of 2-chloro- 4-aminotoluene of formula II. The resulting diazonium salt is heated slowly at 110°C to obtain 2- chloro-4-fluorotoluene of formula I.
Thus these are numerous processes available in the literature for the preparation of 2-chloro-4- fluorotoluene of formula I.
However, these processes are associated with certain drawbacks.
The process of US4912268 employs dodecane and nitric oxide gas for the preparation of 2-chloro- 4-fluorotoluene of formula I making the process operation tedious and expensive. Further, the use
of specific reactor such as fluoropolymer-lined steel tubular reactor makes the process expensive and industrially not feasible.
The processes of CN108569948B and CN110759806A employ anhydrous hydrogen fluoride which is highly corrosive and requires expensive assets.
Considering the challenges faced, there is a need to develop an alternative process for the manufacture of 2-chloro-4-fluorotoluene of formula I.
The inventors of the present invention provide a novel process for preparing 2-chloro-4- fluorotoluene of formula I, which is simple, requires non-expensive assets and is industrially amenable.
OBJECTS OF THE INVENTION
Some of the objects of the present invention are described herein below:
It is an object of the present invention to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
An object of the present invention is to provide a process for the preparation of 2-chloro-4- fluorotoluene of formula I from 2-chloro-4-aminotoluene of formula III, which employs inexpensive/economic reagents suitable for large scale batch production which avoids the corrosion of the reactor.
Another object of the present invention is to provide a process for the preparation of 2-chloro-4- fluorotoluene of formula I which is simple and requires non-expensive assets.
Yet another object of the present invention is to provide a process for the preparation of 2-chloro- 4-fluorotoluene of formula I at a controlled temperature.
Other objects and advantages of the present invention will be more apparent from the following description which is not intended to limit the scope of the present invention.
SUMMARY OF THE INVENTION
The present invention relates to a novel, efficient and industrially advantageous process for the preparation of 2-chloro-4-fluorotoluene of formula I.
A first aspect of the present invention provides a process for the preparation of 2-chloro-4- fluorotoluene of formula I comprising the steps of: a) diazotizing 2-chloro-4-aminotoluene of formula IP using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II; and b) heating the reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II to obtain 2-chloro-4-fluorotoluene of formula I.
Scheme - 1
A second aspect of the present invention provides a process for the preparation of 2-chloro-4- fluorotoluene of formula I comprising the steps of: a) diazotizing 2-chloro-4-aminotoluene of formula IP using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II; b) isolating diazonium salt of 2-chloro-4-aminotoluene of formula II from the reaction mixture; and
c) heating isolated diazonium salt of 2-chloro-4-aminotoluene of formula II to obtain 2- chloro-4-fluorotoluene of formula I.
A third aspect of the present invention provides a process for the preparation of 2-chloro-4- fluorotoluene of formula I comprising the steps of: a) mixing 2-chloro-4-aminotoluene of formula III with a fluorinating reagent in the presence of at least one base to obtain a mixture; b) adding a diazotizing reagent to the mixture obtained in step a) at a temperature in the range of 20°C to 140°C to obtain 2-chloro-4-fluorotoluene of formula I.
Scheme - II
DETAILED DESCRIPTION OF THE INVENTION
The present invention discloses a process for the preparation of 2-chloro-4-fluorotoluene of formula I.
In accordance with the first aspect of the present invention there is provided a process for the preparation of 2-chloro-4-fluorotoluene of formula I. The process is described herein after:
In step (a) 2-chloro-4-aminotoluene of formula IP is diazotized using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II, and
In step (b), the reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II is heated to obtain 2-chloro-4-fluorotoluene of formula I.
The diazotizing reagent suitable for the reaction used in the step (a) is selected from the group consisting of sodium nitrite, potassium nitrite, tert-butyl nitrite and isoamyl nitrite.
The fluorinating reagent suitable for the reaction used in the step (a) is selected from the group consisting of anhydrous hydrogen fluoride and tetrafluoroboric acid.
The base suitable for the reaction used in the step (a) is selected from the group consisting of pyridine, Ci to C4 alkyl pyridine, triethylamine, diisopropylamine, piperidine, /V-methylpiperidine, piperazine, pyrrolidine, imidazole, benzimidazole, and Ci to C4 alkyl imidazole.
The molar ratio of 2-chloro-4-aminotoluene of formula III to the diazotizing reagent used in the step (a) is in the range of 1 : 1 to 1 :2.
The molar ratio of 2-chloro-4-aminotoluene of formula III to the fluorinating reagent used in the step (a) is in the range of 1 :2 to 1 :20.
The molar ratio of 2-chloro-4-aminotoluene of formula III to the base used in the step (a) is in the range of 1:0.8 to 1:10.0.
Specifically, the molar ratio of 2-chloro-4-aminotoluene of formula III to the base used in the step (a) is in the range of 1 : 1 to 1:5.
The diazotization reaction of the step (a) is carried out at a temperature in the range of -10°C to 40°C.
In an exemplary embodiment of the first aspect of the invention, 2-chloro-4-aminotoluene of formula III is first mixed with a fluorinating reagent in the presence of at least one base to obtain
a mixture. The mixture thus obtained is mixed lot wise or slowly with the diazotizing reagent at a temperature in the range of -10°C to 40°C.
After completion of the diazotization reaction, the reaction mixture comprising diazonium salt is heated to obtain 2-chloro-4-fluorotoluene of formula I.
In one embodiment of the first aspect, step (b) is carried out by heating the diazonium salt of 2- chloro-4-aminotoluene of formula II in two steps:
1) heating diazonium salt at a rate of 0.5°C to 5.0°C per hour to achieve the temperature in the range of 0°C to 60°C; and
2) heating diazonium salt further at a rate of 1.0°C to 5.0°C per hour to achieve the temperature in the range of 60°C to 140°C.
In the second embodiment of the first aspect, step (b) is carried out by heating the diazonium salt of 2-chloro-4-aminotoluene of formula II at a rate of 5°C to 10.5°C or more per hour to achieve the temperature in the range of 60°C to 140°C.
After completion of heating, the resulting mixture is cooled. The aqueous and organic layers are separated. The resulting organic layer is washed with an aqueous solution of inorganic base and subjected to distillation to obtain 2-chloro-4-fluorotoluene of formula I.
The excess fluorinating agent may be isolated and recovered.
The inorganic base suitable for washing the organic layer is selected from a group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
In accordance with the second aspect of the present invention there is provided a process for the preparation of 2-chloro-4-fluorotoluene of formula I. The process is described herein after:
In step (a) 2-chloro-4-aminotoluene of formula IP is diazotized using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II.
In step (b) diazonium salt of 2-chloro-4-aminotoluene of formula II is isolated from the reaction mixture.
In step (c) isolated diazonium salt of 2-chloro-4-aminotoluene of formula II is heated to obtain 2- chloro-4-fluorotoluene of formula I.
The diazotizing reagents suitable for the reaction used in the step (a) is selected from the group consisting of sodium nitrite, potassium nitrite, tert-butyl nitrite and isoamyl nitrite.
The fluorinating reagents suitable for the reaction used in the step (a) is selected from the group consisting of anhydrous hydrogen fluoride and tetrafluoroboric acid.
The base suitable for the reaction used in the step (a) is selected from the group consisting of pyridine, Ci to C4 alkyl pyridine, triethylamine, diisopropylamine, piperidine, /V-methylpiperidine, piperazine, pyrrolidine, imidazole, benzimidazole, and Ci to C4 alkyl imidazole.
The molar ratio of 2-chloro-4-aminotoluene of formula III to the diazotizing reagent is in the range of 1:1 to 1:2.
The molar ratio of 2-chloro-4-aminotoluene of formula IP to the fluorinating reagent is in the range of 1:2 to 1:20.
The molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1 : 0.8 to 1 : 100
Specifically, the molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1:1 to 1:5.
The diazotization reaction is carried out at a temperature in the range of -10°C to 40°C.
In an exemplary embodiment of the second aspect, 2-chloro-4-aminotoluene of formula III is first mixed with a fluorinating reagent in the presence of at least one base to obtain a mixture. The mixture thus obtained is mixed lot wise or slowly with the diazotizing reagent at a temperature in the range of -10°C to 40°C.
After completion of the diazotization reaction, diazonium salt of 2-chloro-4-aminotoluene of formula II is isolated by filtration.
In the subsequent step, the isolated diazonium salt of 2-chloro-4-aminotoluene of formula II is heated to obtain 2-chloro-4-fluorotoluene of formula I.
In one embodiment of the second aspect, the step (b) is carried out by heating the diazonium salt of 2-chloro-4-aminotoluene of formula II in two steps:
1) heating diazonium salt at a rate of 0.5°C to 5.0°C per hour to achieve the temperature in the range of 0°C to 60°C; and
2) heating diazonium salt further at a rate of 1.0°C to 5.0°C per hour to achieve the temperature in the range of 60°C to 140°C.
In the second embodiment of the second aspect, the step (b) is carried out by heating the diazonium salt of 2-chloro-4-aminotoluene of formula II at a rate of 5°C to 10°C or more per hour to achieve the temperature in the range of 60°C to 140°C.
After completion of heating, the resulting mixture is cooled to 20°C to 35°C. The aqueous and organic layers are separated. The resulting organic layer is washed with an aqueous solution of inorganic base and subjected to distillation to obtain 2-chloro-4-fluorotoluene of formula I.
The excess fluorinating agent may be isolated and recovered.
The inorganic base suitable for washing the organic layer is selected from a group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
In accordance with the third aspect of the present invention there is provided a process for the preparation of 2-chloro-4-fluorotoluene of formula I. The process is described herein after:
In step (a) 2-chloro-4-aminotoluene of formula IP is mixed with a fluorinating reagent in the presence of at least one base to obtain a mixture.
In step (b) a diazotizing reagent is added to the mixture of the step (a) at a temperature in the range of 20°C to 140°C to obtain 2-chloro-4-fluorotoluene of formula I.
The diazotizing reagents suitable for the reaction used in the step (a) is selected from the group consisting of sodium nitrite, potassium nitrite, tert-butyl nitrite and isoamyl nitrite.
The fluorinating reagents suitable for the reaction used in the step (a) is selected from the group consisting of anhydrous hydrogen fluoride and tetrafluoroboric acid.
The base suitable for the reaction used in the step (a) is selected from the group consisting of pyridine, Ci to C4 alkyl pyridine, triethylamine, diisopropylamine, piperidine, /V-methylpiperidine, piperazine, pyrrolidine, imidazole, benzimidazole and Ci to C4 alkyl imidazole.
The molar ratio of 2-chloro-4-aminotoluene of formula III to the diazotizing reagent is in the range of 1:1 to 1:2.
The molar ratio of 2-chloro-4-aminotoluene of formula IP to the fluorinating reagent is in the range of 1:2 to 1:20.
The molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1 : 0.8 to 1 : 100
Specifically, the molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1:1 to 1:5.
After completion of reaction, the resulting mixture is cool to 20°C to 35°C. The aqueous and organic layers are separated. The resulting organic layer is washed with an aqueous solution of inorganic base and subjected to distillation for obtaining 2-chloro-4-fluorotoluene of formula I.
The excess fluorinating agent may be isolated and recovered.
The inorganic base suitable for washing the organic layer is selected from a group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
Various features and embodiments of the present invention are illustrated in the following representative examples, which are intended to be illustrative and non-limiting.
EXAMPLES:
Example 1: Preparation of 2-chloro-4-fluorotoluene of formula I
To a stirred solution of anhydrous hydrogen fluoride (70. Og) and pyridine (30. Og), 2-chloro-4- aminotoluene (50.0g) of formula III was added drop wise at -5°C to 15°C. The resulting mixture was then stirred for 3 hours at the same temperature. Sodium nitrite (32. Og) was then added to the resulting mixture lot wise at -5°C to 35°C and stirred for 1 hour to obtain a mixture having diazonium salt of 2-chloro-4-aminotoluene of formula II.
The resulting mixture was then heated slowly to achieve the temperature of 90°C. The resulting mixture was cooled to 30°C to 35°C. The layers were then separated and pH of the organic layer was adjusted to neutral pH followed by distillation to obtain 2-chloro-4-fluorotoluene of formula I. Yield: 79.89%, Purity: 98.30%.
Observations: No Corrosion of the Hastelloy C276 reactor observed. Further no tar material was observed.
Example 2: Preparation of 2-chloro-4-fluorotoluene of formula I
To a stirred solution of anhydrous hydrogen fluoride (70. Og) and pyridine (30. Og), 2-chloro-4- aminotoluene (50.0g) of formula III was added drop wise at -5°C to 15°C. The resulting mixture was then stirred for 3 hours at the same temperature. Sodium nitrite (32. Og) was then added to the resulting mixture lot wise at -5°C to 35°C and stirred for 1 hour to obtain a mixture having diazonium salt of 2-chloro-4-aminotoluene of formula II.
The resulting mixture was then heated slowly at a rate of more than 6°C per hour to achieve the temperature of 80°C followed by stirring at 70°C to 80°C to obtain 2-chloro-4-fluorotoluene of formula I. Yield: 72%. Purity: 98.79%.
Observations: No Corrosion of the Hastelloy C276 reactor observed. Further no tar material was observed.
Example 3: Preparation of 2-chloro-4-fluorotoluene of formula I
To a stirred solution of anhydrous hydrogen fluoride (70. Og) and pyridine (30. Og), 2-chloro-4- aminotoluene (50.0g) of formula III was added drop wise at -5°C to 15°C. The resulting mixture was then stirred for 3 hours at the same temperature. Sodium nitrite (32. Og) was then added to the resulting mixture lot wise at -5°C to 35°C and stirred for 1 hour to obtain a mixture having diazonium salt of 2-chloro-4-aminotoluene of formula II.
The resulting mixture was then heated slowly to achieve the temperature of 70°C to 80°C. The resulting mixture was cooled to 30°C to 35°C. The layers were then separated and pH of the organic layer was adjusted to neutral pH followed by distillation to obtain 2-chloro-4-fluorotoluene of formula I. Yield: 64.0% Purity: 98.65%.
Observations: No Corrosion of the Hastelloy C276 reactor observed. Further no tar material was observed.
Comparative Example 1: Preparation of 2-chloro-4-fluorotoluene of formula I
To a stirred solution of anhydrous hydrogen fluoride (70. Og), and pyridine (lg), 2-chloro-4- aminotoluene (50.0g) of formula III was added drop wise at -5°C to 15°C. The resulting mixture was then stirred for 3 hours at the same temperature. Sodium nitrite (26. Og) was then added to the resulting mixture lot wise at -5°C to 35°C and stirred for 1 hour to obtain a mixture having diazonium salt of 2-chloro-4-aminotoluene of formula II.
The resulting mixture was then heated slowly to achieve the temperature of 60°C. The resulting mixture was cooled to 30°C to 35°C. The layers were then separated and pH of the organic layer was adjusted to neutral pH followed by distillation to obtain 2-chloro-4-fluorotoluene of formula I. Yield: 57.8%, Purity: 83.84%.
Observations: Heavy Corrosion of the Hastelloy C276 reactor observed when lg (2% w/w) pyridine is used. Further heavy tar material inside the reactor was observed.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred
embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
While considerable emphasis has been placed herein on the particular features of this invention, it will be appreciated that various modifications can be made, and that many changes can be made in the preferred embodiments without departing from the principles of the invention. These and other modifications in the nature of the invention or the preferred embodiments will be apparent to those skilled in the art from the invention herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.
Claims
1. A process for the preparation of 2-chloro-4-fluorotoluene of formula I;
said process comprising the steps of: a) diazotizing 2-chloro-4-aminotoluene of formula III,
using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II; and b) heating the reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II to obtain 2-chloro-4-fluorotoluene of formula I.
2. The process as claimed in the claim 1 ; wherein diazotizing reagent selected from a group consisting of sodium nitrite, potassium nitrite, tert-butyl nitrite and isoamyl nitrite.
3. The process as claimed in the claim 1 ; wherein the molar ratio of 2-chloro-4-aminotoluene of formula III to the diazotizing reagent is in the range of 1 : 1 to 1:2.
4. The process as claimed in the claim 1 ; wherein fluorinating reagent selected from a group consisting of anhydrous hydrogen fluoride and tetrafluoroboric acid.
5. The process as claimed in the claim 1 ; wherein the molar ratio of 2-chloro-4-aminotoluene of formula III to the fluorinating reagent used is in the range of 1 :2 to 1 :20.
6. The process as claimed in the claim 1 ; wherein base selected from a group consisting of pyridine, Ci to C4 alkyl pyridine, triethylamine, diisopropylamine, piperidine, N- methylpiperidine, piperazine, pyrrolidine, imidazole, benzimidazole, and Ci to C4 alkyl imidazole.
7. The process as claimed in the claim 1 ; wherein the molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1 : 0.8 to 1 : 10.0.
8. The process as claimed in the claim 1 ; wherein the molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1 : 1 to 1:5.
9. The process as claimed in the claim 1 ; wherein diazotization reaction is carried out at a temperature in the range of -10°C to 40°C.
10. The process as claimed in the claim 1; wherein the step (b) is carried out by heating the diazonium salt of 2-chloro-4-aminotoluene of formula II in two steps: a) heating diazonium salt at a rate of 0.5°C to 5.0°C per hour to achieve the temperature in the range of 0°C to 60°C; and b) heating diazonium salt further at a rate of 1.0°C to 5.0°C per hour to achieve the temperature in the range of 60°C to 140°C.
11. The process as claimed in the claim 1 ; wherein the step (b) is carried out by heating the diazonium salt of 2-chloro-4-aminotoluene of formula II at a rate of 5°C to 10°C per hour to achieve the temperature in the range of 60°C to 140°C.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US4096196A (en) * | 1975-10-31 | 1978-06-20 | Olin Corporation | Diazotization-fluorination in a medium of hydrogen fluoride containing tertiary amine compounds |
CN110759806A (en) * | 2019-10-25 | 2020-02-07 | 阜新宇泽化工有限公司 | Preparation method of 2-chloro-4-fluorotoluene |
CN108569948B (en) * | 2017-03-09 | 2021-06-04 | 辽宁天予化工有限公司 | Preparation method of 2-chloro-4-fluorotoluene |
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2022
- 2022-06-17 WO PCT/IN2022/050553 patent/WO2022264172A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4096196A (en) * | 1975-10-31 | 1978-06-20 | Olin Corporation | Diazotization-fluorination in a medium of hydrogen fluoride containing tertiary amine compounds |
CN108569948B (en) * | 2017-03-09 | 2021-06-04 | 辽宁天予化工有限公司 | Preparation method of 2-chloro-4-fluorotoluene |
CN110759806A (en) * | 2019-10-25 | 2020-02-07 | 阜新宇泽化工有限公司 | Preparation method of 2-chloro-4-fluorotoluene |
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