Hexafluoroxylenes: Fluorine Chemistry and ... - Chemspec Events

Hexafluoroxylenes:Fluorine Chemistry and BeyondAndrea MissioR&D DirectorChemsource Symposium 2006Geneva, June 14 & 15, 20061

HISTORY (1)1960 RIMARThe production of fluorinated intermediates starts in Trissino.1988 MITENIMITENI (“MIT”-”ENI”) joint ventureEniChem Synthesis – Italy - & Mitsubishi Corporation – Japan.Headquarters in Milan – Production plant in Trissino.1996 MITENIMITENI becomes an affiliated Company of Mitsubishi Corporation(91% Mitsubishi Corporation – 9% Jemco)2

HISTORY (3)2nd TechnologyDuring the 70’s benzotrifluorides are producedby the halogen exchange technology.The aim is to produce PCBTF(p-chlorobenzotrifluoride)which is the basic intermediatefor the synthesis of the herbicide “Trifluralin”FF FCl3rd TechnologyFluoroaromatics production also begins in the 70’sand the first advanced intermediates(fluorobenzene derivatives)are produced through a diazotization process.5

A BROAD RANGE OF TECHNOLOGIES,NOT JUST FLUORINATIONRIMAR (1960 -1987)HALOGEN EXCHANGE – DIAZOTIZATION - ELECTROFLUORINATIONMITENI (Joint venture; 1988 - 1995)NitrationRing chlorinationBrominationPhoto-chlorinationAmidationMITENI (100% Mitsubishi; 1996 -)SandmeyerAminationFriedel-CraftsGrignard reactionsHydrogenationOxidation6

m-HexafluoroxylenesRepresentative structures of compounds containing the HFX coreFF FFlupropadine(May & Baker)RodenticidewithdrawnFFFN7

m-HexafluoroxylenesRepresentative structures of compounds containing the HFX coreOHNHNFAprepitant(Merck)NK-1 antagonistlaunchedNOOFFFFFF8

m-HexafluoroxylenesRepresentative structures of compounds containing the HFX coreN H 2SSR-240600(SanofiAventis)NK-1 antagonistPhase IONClOClNOFFFFFF9

m-HexafluoroxylenesRepresentative structures of compounds containing the HFX coreBistrifluron(DongbuHannong)InsecticideDevelopmentFFOHNOHNClFFFFFF11

m-HexafluoroxylenesRepresentative structures of compounds containing the HFX coreCO 2EtNTorcetrapib(Pfizer)CETP inhibitorPhase IIIFFFNCO 2MeFFFFFF12

Preparation of m-HFXCH 3CCl 3h; Cl 2; 48 hrs;CH 3CCl 3CCl 3CF 3HF; ; P8 hrs;CCl 3CF 314

Photochlorination – (1)Mechanism of PhotochlorinationCH 3CH 3CH 2ClCH 3h; Cl 2; h; Cl 2; h; Cl 2;+CH 3CH 2ClCH 2ClCHCl 2CH 2Clh; Cl 2; h; Cl 2; h; Cl 2;CHCl 2CHCl 2CHCl 2CHCl 2CCl 3CCl 3CCl 315

Photochlorination – (2)What you get in …… is what you get out …… at least for impuritiesSpecs for purchased material:m-xylenep-xyleneo-xilene98.5% min0.6% max0.6% maxSpecs (Miteni) for m-HFX:m-HFXp-HFX99% min0.6% max16

Halogen Exchange – (1)Mechanism of Halogen ExchangeCCl 3CClF 2CCl 3CCl 3HF; HF; HF; CClCCl 3CCl 2F2FCCl 3CF 3CCl 2FCCl 2FHF; HF; HF; CF 3CClF 2CF 3CF 3CF 3CCl 2FCClF 2CClF 2CClF 217

Halogen Exchange – (2)GC @ 10 h m-HFX F 5 Cl F4Cl2 F3Cl3 F2Cl4 FCl5 m-HCXRT (min) 2,37 4,68 9,82 17,58 24,95 32,47 40,2618

Halogen Exchange – (3)CF 3CCl 319

Halogen Exchange – (4)(7)(6)(5)CF 3(1)(2)(3)(4)(8)CCl 3(3) (8)20

Halogen Exchange – (5)CF 3CCl 321

Bromination (1)CF 3CF 3BrominationF 3CF 3CBrBrominating Agent Conditions CommentsBr 2FeCl 3 ; SbCl 3 ; SbCl 5 ;70°C; 7-24 hYield: max 5.2%NBSH 2 SO 4 ; 4°C; 4 h;then RT; 17 hYield: 93.5%HDBH2 SO 4 ;-5 35°C; 6 h;M + - HBrO2 SO 4 ;3RT 50°C; 7 hYield: 90.8%May contain 1,3-DCHYield: 71%K + salt is carcinogen22

Bromination (3)CF 3BrominationCF 3F 3CF 3CBrNBSDBHPM 177,98 285,92Bromine content % 44,9 55,9Price $$ $Selectivity % > 98 90Specificity % 99,4 99,524

Grignard ReagentCF 3GrignardCF 3F 3CBrF 3CMgBrT: 45 °C; no initiator necessary; t: 6-8 hrsSafety is Mandatory:Solvent Choice is Critical(Flash Point; Peroxides)Et 2 O THF n-Hexane Toluene m-XyleneFlash-Point (°C) - 45 - 14 - 22 4 27Boiling Point (°C) 34 66 68 110 13825

Benzyl AlcoholFFFCO 2EtNNONONFFFYield: 70%FFFFFFNCO 2MeFFFCF 3CH 2OCF 3F 3CMgBrF 3COHSafety is Mandatory:Source of CH 2 O is CriticalParaformaldehyde: crystalline powderWO 05/035472 Miteni, Italy26

Benzyl HalidesFFFCO 2EtNNONONFFFYield: 80%FFFFFFNCO 2MeFFFCF 3CF 3HBr 48%F 3COHH 2SO 4conc.;100°C; 8 h;F 3CBrCF 3CF 3SOCl 2;F 3COHDMF; RT; 2 h;F 3CClYield: 86%WO 05/035472 Miteni, Italy27

PhenylacetyleneFF FFFFNCF 3CF 3F 3COHP 2O 5Br 2Y: 52.5% Y: 84.1%F 3CCF 3KOt-BuCF 3F 3CBrBrY: 64.8%F 3CCHOverall yield: 29%28

BenzaldehydeOHNHNFNOOFFFFFFCF 3CF 3CF 3MgDMFF 3CBrF 3CMgBrF 3CCHOSolvent: Et 2 O; yield: 53%THF; yield: 72%THF/xylene; yield: 55%29

AcetophenoneOHNHNFNOOFFFFFFCF 3CF 3CF 3CF 3MgCH 3CHO H 2O 2F 3CBrF 3CMgBrT: 0 °CF 3COHcatalystsT: 75 °CF 3COYield: 95% Yield: 91%Overall yield: 86.5%WO 04/094353 & WO 04/094358 Miteni, Italy30

ACKNOWLEDGEMENTSAlessandro NardelloMarisa PrettoAndrea FaccinSimonetta MondiniMirco Dall’Ava31

THANK YOU32

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