WO2004065347A1 - Esters d'allyle substitue par un groupe difluoromethylene, leur procede de synthese et leur utilisation - Google Patents
Esters d'allyle substitue par un groupe difluoromethylene, leur procede de synthese et leur utilisation Download PDFInfo
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- WO2004065347A1 WO2004065347A1 PCT/FR2003/003780 FR0303780W WO2004065347A1 WO 2004065347 A1 WO2004065347 A1 WO 2004065347A1 FR 0303780 W FR0303780 W FR 0303780W WO 2004065347 A1 WO2004065347 A1 WO 2004065347A1
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- -1 difluoromethylene group Chemical group 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims description 21
- 230000015572 biosynthetic process Effects 0.000 title abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title abstract description 10
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 title 1
- 150000002148 esters Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 239000001257 hydrogen Substances 0.000 claims abstract description 25
- 150000003254 radicals Chemical class 0.000 claims abstract description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 150000005840 aryl radicals Chemical class 0.000 claims abstract 2
- 239000002585 base Substances 0.000 claims description 58
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 55
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000002798 polar solvent Substances 0.000 claims description 10
- 239000002243 precursor Substances 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 8
- 150000002466 imines Chemical class 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 239000004215 Carbon black (E152) Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 125000000129 anionic group Chemical group 0.000 claims description 7
- 229930195733 hydrocarbon Natural products 0.000 claims description 7
- 239000000758 substrate Substances 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 6
- 150000002430 hydrocarbons Chemical class 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 150000001450 anions Chemical class 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical class [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 150000002894 organic compounds Chemical class 0.000 claims description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 2
- 235000017168 chlorine Nutrition 0.000 claims 3
- 230000002378 acidificating effect Effects 0.000 claims 1
- 125000001309 chloro group Chemical class Cl* 0.000 claims 1
- 125000004429 atom Chemical group 0.000 description 21
- 150000002738 metalloids Chemical group 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 12
- 229910052752 metalloid Inorganic materials 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 8
- 238000006352 cycloaddition reaction Methods 0.000 description 7
- 239000012429 reaction media Substances 0.000 description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910052798 chalcogen Inorganic materials 0.000 description 4
- 150000001787 chalcogens Chemical class 0.000 description 4
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- HIFUSLDGVWKSOA-UHFFFAOYSA-N CC(=O)OC=CCC(F)(F)F Chemical compound CC(=O)OC=CCC(F)(F)F HIFUSLDGVWKSOA-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 150000001723 carbon free-radicals Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 2
- 101150065749 Churc1 gene Proteins 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 102100038239 Protein Churchill Human genes 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000007033 dehydrochlorination reaction Methods 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 230000003071 parasitic effect Effects 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- FBIQLWHBSXTVCJ-UHFFFAOYSA-N (2-chloro-4,4,4-trifluorobutyl) acetate Chemical compound CC(=O)OCC(Cl)CC(F)(F)F FBIQLWHBSXTVCJ-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- QDFXRVAOBHEBGJ-UHFFFAOYSA-N 3-(cyclononen-1-yl)-4,5,6,7,8,9-hexahydro-1h-diazonine Chemical compound C1CCCCCCC=C1C1=NNCCCCCC1 QDFXRVAOBHEBGJ-UHFFFAOYSA-N 0.000 description 1
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010056740 Genital discharge Diseases 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- XRNKOIHIBUKMQP-NSCUHMNNSA-N [(e)-4,4,4-trifluorobut-2-enyl] acetate Chemical compound CC(=O)OC\C=C\C(F)(F)F XRNKOIHIBUKMQP-NSCUHMNNSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 229910000095 alkaline earth hydride Inorganic materials 0.000 description 1
- 150000001409 amidines Chemical group 0.000 description 1
- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001804 chlorine Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- ZEAUJQWDPKRESH-KAMYIIQDSA-N n,1-diphenylmethanimine oxide Chemical compound C=1C=CC=CC=1[N+](/[O-])=C/C1=CC=CC=C1 ZEAUJQWDPKRESH-KAMYIIQDSA-N 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 150000003017 phosphorus Chemical class 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 125000002577 pseudohalo group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- TWPVZKPFIMFABN-UHFFFAOYSA-N sulfuryl diiodide Chemical compound IS(I)(=O)=O TWPVZKPFIMFABN-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
Definitions
- the subject of the present invention is compounds forming an allyl ester substituted with a difluoromethylene group.
- heterocycles in particular nitrogen-containing and in particular 5-membered, have become relatively frequent when they carry groups (-CF 2 ).
- -CF 2 groups
- one of the aims of the present invention is to provide a family of precursors for these nitrogen heterocycles.
- the use of these precursors should be easy, should not require many steps.
- Another object of the present invention is to provide a process for the synthesis of said precursors.
- Another object of the present invention is to provide a technique for using these precursors.
- R f is a radical carrying a perfluoromethylene group which group ensures the bond with the rest of the molecule: *> R 1 and R 3> which may be the same or different, are chosen from hydrogen and the radicals alcohols or aryls; ⁇ is an electron-withdrawing group such that ⁇ -OH is an acid whose pKa (in water) is at most equal to 8, advantageously 6, preferably 5.
- the ⁇ -OH group constitutes an acid whose pKa is at least equal to 1, advantageously to 2.
- the ⁇ -O "group does not constitute a good group therefore, both for use as a precursor of cycloaddition and for its synthesis.
- R, and R 3 do not clutter the molecule too much, so it is advisable to avoid that Ri and / or R 3 are attached to the double bond by a tertiary or even secondary carbon.
- At least one of Ri and R 3 is a light alkyl (light, that is to say at most 4 carbons) or better still, hydrogen.
- R is hydrogen; it is also preferred that R 3 is hydrogen; and it is even more preferred that R 1 and R 3 are hydrogen.
- R f is of formula (II)
- the X similar (that is to say that they are identical) or different, represent a chlorine, a fluorine or a radical of formula C n F 2n + ⁇ with n integer at most equal to 5, preferably to 2, with the condition that the Xs of the methylene group carrying the open bond are not chlorine and that at least one of them is a fluorine atom, advantageously the Xs of methylene carrying the open bond are either fluorine atoms or else a fluorine atom and a radical of formula C n F 2n + ⁇ (such radicals are indeed considered to be electronically close to fluorine atoms),
- - GEA is a hydrocarbon or electro-attractor group (that is to say that the Hammett constant ⁇ p (sigma p) is> 0, advantageously at least equal à, 0,2), preferably inert, advantageously, when p is equal to 1, an electron-withdrawing group (cf. preceding lines); - p is a positive integer, that is, it cannot understand the value 0.
- GEA is advantageously fluorine especially when p is less than or equal to 2.
- the X's are advantageously all fluors, especially when p is less than or equal to 2.
- GEA electron-withdrawing group
- p represents an integer advantageously at most equal to 4, preferably to 2;
- GEA advantageously represents an electron-withdrawing group the possible functions of which are inert under the conditions of the reaction, advantageously fluorine or a perfluorinated residue of formula C n F 2n + ⁇ , with n integer at most equal to 8, advantageously 5,
- the total number of carbons of R f is advantageously between 1 and 15, preferably between 1 and 10.
- R f has the formula C r F 2r + 1 with r positive integer ranging from 1 to 10, advantageously from 1 to 5, preferably from 1 to 3.
- the present invention is particularly advantageous for Rf of low molecular weight, that is to say those which are relatively volatile (that is to say corresponding to an R f H whose boiling point under atmospheric pressure is at most equal to 100 ° C).
- the technique is particularly interesting for Rf having a radical having an odd number of carbons and a particular mention must be made for the Rf in Ci, C 2 and C 3 .
- the trifluoromethyl, pentafluoroethyl and heptafluoropropyl radicals are among the preferred values of R f .
- ⁇ represents an acyl, advantageously such that the pKa (measured or reduced to a value in water) is at least equal to approximately 2 (the expression approximately is used here to underline that the number which follows corresponds to a mathematical rounding), advantageously to around 3.
- ⁇ -OH is an alkanoic acid, advantageously from 1 to 8 carbon atoms, preferably from 2 to 5. Economically, the value of ⁇ equal to acetyl is the most interesting.
- Another object of the present invention is to provide an easy access route to the molecules mentioned above.
- ⁇ (xi) represents a halogen leaving group (heavier than fluorine, chlorine or bromine) or pseudohalogen such that ⁇ H has a Hammett constant at least equal to that of trifluoroacetic acid, advantageously at least equal to that mesylic acid) with a base chosen from strong nitrogenous bases whose associated acid has a pKa at least equal to 12 among anionic bases with the condition that when the base is a non-nitrogenous anionic base the latter is present of a solvent or a mixture of polar solvents.
- the compounds of formula (III) are fragile compounds whose purification is often difficult, or almost impossible, due to the instability, in particular thermal, of the compounds of formula (III), especially when ⁇ represents a halogen forming a good group leaving as bromine or iodine.
- the chlorine derivative is a little more stable.
- Z representing a methylene group (optionally substituted but preferably unsubstituted) carrying ⁇ -O- and ⁇ limited here to Cl and Br, or even I (but the sulfonyl iodide is not stable; its existence which could not be transient, has not been demonstrated and cannot be implemented, except to do so in situ).
- bases can give good results: - non-anionic bases in which a nitrogen doublet is conjugated with a carbon-nitrogen double bond; these bases can be used, either alone in stoichiometric or over-stoichiometric quantities, or can be used in quantitative quantities with another base, preferably more basic than these said non-anionic bases; in particular these bases can be used with the bases below, which they are in principle used in stoichiometric or super-stoichiometric amounts; - Anionic nitrogen bases which give good results, but are generally expensive, and the effect of which is all the better when polar aprotic solvents are used as solvents; - non-nitrogenous anionic bases, advantageously not derived from an alcohol or water (hydroxide ions and alcoholates are respectively to be avoided and preferably to be avoided).
- a polar solvent the donor index of which is at least equal to 10, advantageously 15, preferably 20.
- these polar solvents have a dielectric constant ⁇ (epsilon) at least equal to 7.
- ⁇ epsilon
- this basicity is relatively low in the sense of the basicity of Bronsted, that is to say that the pKa of the associated acid of said solvent is greater than 5, advantageously 6, more preferably 7.
- said reaction medium is aprotic and anhydrous.
- this aprotic and anhydrous medium is such that the strongest acid present in the medium, without taking into account the substrate, has a pKa at least equal to 20, better to 25, advantageously to 30, preferably 35.
- This constraint aims to avoid parasitic reactions during the tearing of the proton from the substrate by the base; in fact the anions resulting from the tearing of a proton by a base are nucleophiles which can lead to a nucleophilic substitution reaction which is not desired.
- anions are not formed. More generally, it is preferable that the constituents of the reaction mixture are not, in contact with the base used, capable of giving nucleophyte anions. Strong acids (pKa ⁇ 2), or even medium acids (2 ⁇ pKa ⁇ 4.5) do not, strictly speaking, interfere with the reaction because they consume base, giving only anions with little or no nucleophilicity, and therefore little or no parasitic reaction (s). The acids associated with the bases according to the present invention, or resulting from them, obviously do not harm the present invention. This is the reason why the hydroxide ions, or even alcoholates, are not suitable for the processes according to the present invention. Indeed, they lead to molecules which are to be avoided as solvents.
- the content of labile hydrogen atoms (that is to say those not corresponding to the pKa specified above) is at most equal to 1/3, advantageously 1 / 4, preferably at 10% (in moles), relative to the initial content in that of said base or of said compound of formula (III) which is not in excess.
- One of the advantages of encryptors is that it makes it possible to at least partially overcome solvents with a high donor index.
- donor index or donor number: "donor number”
- donor number the donor index
- enthalpy 2 - ⁇ H expressed in kilocaloriemol
- the donor index will be calculated by donor function by multiplying the donor index of each of the solvents by the molar fraction which it represents and by summing these products .
- anionic nitrogen bases mention should be made of the salts, in particular alkali or noteworthy alkali, of amines, silylated or not, as well as silylamines.
- the salts giving the best results mention should be made of the salified disilylamines and in particular the salts, in particular alkali or alkaline earth, of hexamethyldisilazane (HMDZ).
- HMDZ hexamethyldisilazane
- non-nitrogenous anionic bases mention should be made of non-oxygenated bases such as, for example, alkali or alkaline earth hydrides, and alkane salts such as butyllithium and alkali carbonates. It should be remembered that the bases of this family must be used in the presence of polar solvents.
- the bases giving the best results are the bases comprising 2 nitrogen atoms conjugated as already mentioned and as detailed below.
- said base is nitrogenous and not anionic and corresponds to formula (IV): ° - -A-R2
- A is a metalloid atom in column VB (column of nitrogen, and advantageously the latter) (the periodic classification of the elements used in this application is that of the supplement to the Bulletin of the departments Chimique de France, January 1966, n ° 1).
- chalcogens advantageously monosubstituted by a monovalent radical R 6 (in which case the chalcogens constitute said metalloid carrying a doublet),
- the metalloids of column VB are preferably nitrogen, whether for A "or for A 1 .
- D is chosen from those described above and whose single bond ensuring the link with the rest of the molecule is carried by an atom chosen from sp 2 hybridization carbon atoms substituted by a function or by a bivalent radical R 7 carrying a hydrogen or optionally substituted by a carbon radical R 6 to give a formula of D specified below:
- the base of formula (IV) comprises a metalloid atom (saturated, that is to say not carrying a double bond), having a resonance (or conjugation) with a bond ⁇ connecting two atoms, at least one of which is a disubstituted and positively charged atom from the column VB; advantageously an organic base comprising a trivalent atom from column VB (column of nitrogen in Mendeleev's table), advantageously nitrogen, an atom whose doublet is directly or indirectly conjugated to a ⁇ bond connecting two atoms, including minus one is an atom from column VB (i.e. A).
- the radical R is chosen from hydrogen, the values of D and from hydrocarbon radicals, advantageously aryls and especially alkyls.
- the radical D and this imine function are arranged in such a way that the atoms of nitrogen and of said metalloid are as far apart as possible, in other words and for example, that the nitrogen of the imine function is that of the two atoms linked by the ⁇ bond which is the farthest from the trivalent atom of column V.
- the imine function is general for all the atoms of column VB linked by the bond ⁇ in the case where the bond ⁇ has a carbon atom and an atom from column V.
- the previous sequence corresponds to the formula:
- said trivalent atom of the VB column forms or constitutes a tertiary amine.
- said organic base comprising a trivalent atom from column VB, the doublet of which is conjugated to a ⁇ bond, constitutes a molecule of the following formula:
- the potentiation effect of the base is particularly marked when said ⁇ bond connecting two atoms is intracyclic (or a mesomeric form is intracyclic), even when it is intracyclic in an aromatic cycle.
- organic base comprising a saturated metalloid atom, having a resonance with a ⁇ bond can be advantageously chosen from dialkoyiaminopyridines, in particular in the para or ortho position (that is to say in the position 2 of pyridine or 4 see formula above).
- said base carrying at least 2 trivalent nitrogen is advantageously such that said 2 trivalent nitrogen form a binding system comprising an imine conjugated with the doublet of an amine.
- Amines which, like DBU (DiazaBicycloUndecene, which has 9 carbon atoms) or DBN (DiazaBicycloNonene which has 7 carbon atoms), form with the imine function a substituted amidine function, advantageously intracyclic with 1 or even 2 rings, constitute also particularly interesting bases for implementing the present invention. Examples of such bases are to be found in diazabicycloalkenes of 6 to 15 carbon atoms:
- R 6 'and R 6 "have the same value as Rs. It is possible to substitute the free aryl vertices (engaged in an aromatic) or aliphatic (whose attachment point is a sp 3 carbon). But this is of little interest and the disadvantage of weighing down the base.
- Another object of the present invention is to find a cycloaddition technique capable of working with the compounds of formula (I).
- one of the main interests of the present invention is to provide easy access to heterocycles by a 3 + 2 type addition, and in particular 1, 3 dipolar cycloadditions.
- the co-substrate is an organic compound carrying a pentavalent nitrogen itself carrying 2 double bonds (including the donor-acceptor type bonds) of which at least one double bond connects said nitrogen to a carbon.
- the co-substrates providing the part of 3 atoms correspond to the canonical dipolar forms as follows:
- b can be a nitrogen, optionally substituted, a and c can be oxygen, nitrogen or carbon, these last two atoms can carry a hydrocarbon radical or a hydrogen.
- R f is trifluoromethyl
- Ri and R 3 are hydrogen and ⁇ is chlorine.
- Test 02JGR910 test in RPAS 100 ml with double envelope, agitation: 4 inclined blades (600 rpm): 2a (10 g at 96% by weight, 38.5 mmol), DMF (35 g), K 2 C0 3 (18 g, 0.130 mol), b)% CPG area
- the reaction medium is left overnight at room temperature before treatment. After filtration (filtered glass No. 4) and washing of the cake with 10 ml of DMF, the filtrate is poured into 20 ml of water and this aqueous phase is extracted with MTBE (3 * 25 ml). The organic layer is assayed by 19 F NMR with internal standard:
- 2-chloro-4,4,4-trifluorobutyl acetate is charged into a 250 ml three-necked flask fitted with a condenser, a thermometer, an addition funnel and a magnetic stirrer (3a) (12 g 58.9 mmol) and diisopropyl ether (135 ml 0.95 mol). 1, 8-diazabicyclo [5.4.0] undec-7-ene (8.98 g 59 mmol) is added dropwise over 25 minutes. The reaction medium is heated at 70 ° C for 4 hours. The evolution is followed by CPG injections. At the end of the reaction, a yield of product formed of 77.5% is determined by GC assay with internal standard.
- the reaction medium is poured into 200 ml of water. Extraction is carried out with 3 times 100 ml of diisopropyl ether and the organic phases, previously grouped together, are dried over magnesium sulfate. After concentration at atmospheric pressure of the diisopropyl ether, 7 g (Yield: 71%) of the trifluorobutenol acetate are isolated by conventional distillation.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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JP2004567023A JP2006511592A (ja) | 2002-12-20 | 2003-12-17 | ジフルオロメチレン基で置換されたアリルのエステル、その合成方法およびその使用 |
EP03799615A EP1631539A1 (fr) | 2002-12-20 | 2003-12-17 | Esters d'allyle substitue par un groupe difluoromethylene, leur procede de synthese et leur utilisation |
AU2003299334A AU2003299334A1 (en) | 2002-12-20 | 2003-12-17 | Esters of allyl substituted by a difluoromethylene group, method for the synthesis thereof and use thereof |
US10/539,639 US20060069284A1 (en) | 2002-12-20 | 2003-12-17 | Esters of allyl substituted by a difluoromethylene group, method for the synthesis thereof and use thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR02/16308 | 2002-12-20 | ||
FR0216308A FR2849025B1 (fr) | 2002-12-20 | 2002-12-20 | Esters d'allyle substitue par un groupe difluoromethylene, leur procede de synthese et leur utilisation |
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WO2004065347A1 true WO2004065347A1 (fr) | 2004-08-05 |
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PCT/FR2003/003780 WO2004065347A1 (fr) | 2002-12-20 | 2003-12-17 | Esters d'allyle substitue par un groupe difluoromethylene, leur procede de synthese et leur utilisation |
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US (1) | US20060069284A1 (fr) |
EP (1) | EP1631539A1 (fr) |
JP (1) | JP2006511592A (fr) |
AU (1) | AU2003299334A1 (fr) |
FR (1) | FR2849025B1 (fr) |
WO (1) | WO2004065347A1 (fr) |
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2002
- 2002-12-20 FR FR0216308A patent/FR2849025B1/fr not_active Expired - Fee Related
-
2003
- 2003-12-17 US US10/539,639 patent/US20060069284A1/en not_active Abandoned
- 2003-12-17 WO PCT/FR2003/003780 patent/WO2004065347A1/fr active Application Filing
- 2003-12-17 AU AU2003299334A patent/AU2003299334A1/en not_active Abandoned
- 2003-12-17 JP JP2004567023A patent/JP2006511592A/ja not_active Withdrawn
- 2003-12-17 EP EP03799615A patent/EP1631539A1/fr not_active Withdrawn
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Also Published As
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US20060069284A1 (en) | 2006-03-30 |
AU2003299334A1 (en) | 2004-08-13 |
JP2006511592A (ja) | 2006-04-06 |
FR2849025B1 (fr) | 2005-10-14 |
FR2849025A1 (fr) | 2004-06-25 |
EP1631539A1 (fr) | 2006-03-08 |
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