WO2015111004A2 - Improved process for the preparation of chlorophenyl trifluoroethanone - Google Patents
Improved process for the preparation of chlorophenyl trifluoroethanone Download PDFInfo
- Publication number
- WO2015111004A2 WO2015111004A2 PCT/IB2015/050533 IB2015050533W WO2015111004A2 WO 2015111004 A2 WO2015111004 A2 WO 2015111004A2 IB 2015050533 W IB2015050533 W IB 2015050533W WO 2015111004 A2 WO2015111004 A2 WO 2015111004A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- chlorophenyl
- process according
- trifluoroethanone
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 35
- RAOQEOLDFDHACL-UHFFFAOYSA-N 1-(2-chlorophenyl)-2,2,2-trifluoroethanone Chemical compound FC(F)(F)C(=O)C1=CC=CC=C1Cl RAOQEOLDFDHACL-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 claims abstract description 9
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960003804 efavirenz Drugs 0.000 claims abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 63
- 150000001875 compounds Chemical class 0.000 claims description 52
- 238000006243 chemical reaction Methods 0.000 claims description 44
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- -1 trichloroethoxycarbonyl Chemical group 0.000 claims description 11
- 229940093499 ethyl acetate Drugs 0.000 claims description 9
- 235000019439 ethyl acetate Nutrition 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 230000000397 acetylating effect Effects 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 150000004795 grignard reagents Chemical class 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 239000007818 Grignard reagent Substances 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 238000006640 acetylation reaction Methods 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229960004132 diethyl ether Drugs 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 4
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 230000021736 acetylation Effects 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 230000026030 halogenation Effects 0.000 claims description 3
- 238000005658 halogenation reaction Methods 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- JVTSHOJDBRTPHD-UHFFFAOYSA-N 2,2,2-trifluoroacetaldehyde Chemical compound FC(F)(F)C=O JVTSHOJDBRTPHD-UHFFFAOYSA-N 0.000 claims description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 claims description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 229940052303 ethers for general anesthesia Drugs 0.000 claims description 2
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- LWLPYZUDBNFNAH-UHFFFAOYSA-M magnesium;butane;bromide Chemical compound [Mg+2].[Br-].CCC[CH2-] LWLPYZUDBNFNAH-UHFFFAOYSA-M 0.000 claims description 2
- WSHFRLGXCNEKRX-UHFFFAOYSA-M magnesium;butane;bromide Chemical compound [Mg+2].[Br-].CC[CH-]C WSHFRLGXCNEKRX-UHFFFAOYSA-M 0.000 claims description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical group [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 2
- QGEFGPVWRJCFQP-UHFFFAOYSA-M magnesium;methanidylbenzene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C1=CC=CC=C1 QGEFGPVWRJCFQP-UHFFFAOYSA-M 0.000 claims description 2
- VMVNZNXAVJHNDJ-UHFFFAOYSA-N methyl 2,2,2-trifluoroacetate Chemical group COC(=O)C(F)(F)F VMVNZNXAVJHNDJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 102000001324 CD59 Antigens Human genes 0.000 claims 3
- 108010055167 CD59 Antigens Proteins 0.000 claims 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 150000008064 anhydrides Chemical class 0.000 claims 1
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 description 39
- XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 20
- 238000003786 synthesis reaction Methods 0.000 description 20
- IZISMXMXCLUHGI-UHFFFAOYSA-N n-(4-chlorophenyl)-2,2-dimethylpropanamide Chemical compound CC(C)(C)C(=O)NC1=CC=C(Cl)C=C1 IZISMXMXCLUHGI-UHFFFAOYSA-N 0.000 description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000012298 atmosphere Substances 0.000 description 6
- 238000006138 lithiation reaction Methods 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- ZVDDJPSHRNMSKV-UHFFFAOYSA-N acetaldehyde;hydrochloride Chemical compound Cl.CC=O ZVDDJPSHRNMSKV-UHFFFAOYSA-N 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- YQZVDKHNBCIHCR-UHFFFAOYSA-N n-(2-bromo-4-chlorophenyl)-2,2-dimethylpropanamide Chemical compound CC(C)(C)C(=O)NC1=CC=C(Cl)C=C1Br YQZVDKHNBCIHCR-UHFFFAOYSA-N 0.000 description 2
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 0 *Nc(c(C(C(F)(F)F)=O)c1)ccc1Cl Chemical compound *Nc(c(C(C(F)(F)F)=O)c1)ccc1Cl 0.000 description 1
- LWJNWXYSLBGWDU-UHFFFAOYSA-N 2,2-dimethyl-n-phenylpropanamide Chemical compound CC(C)(C)C(=O)NC1=CC=CC=C1 LWJNWXYSLBGWDU-UHFFFAOYSA-N 0.000 description 1
- LBWMQVOHFPLVBY-UHFFFAOYSA-N 3,3,3-trifluoro-1-phenylpropan-1-one Chemical class FC(F)(F)CC(=O)C1=CC=CC=C1 LBWMQVOHFPLVBY-UHFFFAOYSA-N 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical class C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000022561 Cyclopis Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 235000014435 Mentha Nutrition 0.000 description 1
- 241001072983 Mentha Species 0.000 description 1
- 239000012345 acetylating agent Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000011021 bench scale process Methods 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000003487 electrochemical reaction Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000014569 mints Nutrition 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940054565 sustiva Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Definitions
- the present invention relates to an improved process for the preparation of chlorophenyl trifluoroethanone of formula I. an intermediate used in the preparation of Efavirenz.
- Efavirenz is an HIV-1 specific, non-nucleoside. reverse transcriptase inhibitor (NNRTI) which is used to treat human immunodeficiency virus (HIV ) infection.
- NRTI reverse transcriptase inhibitor
- Efavirenz has been marketed under the brand name SUSTIVA by Bristol Myers Squibb.
- Efavirenz is chemically described as (4S )-6-chloiO-4-(cyclopi pylethynyl )- 1.4-dihydiO-4-(trifluoiOmethyl)-2H-3.1 - benzoxazin-2-one and is structurally below.
- Efavirenz is first disclosed in US patent 5.519.021 and in EP patent 582 455.
- R is halogenated 0,. 6 alkyl
- X is a halogen
- trifluoromethylated compounds like trifluoroacetyl group become high synthetic interest due to their exceptional properties and applicability as building blocks, hi recent times, trifluoromethyl-acetophenones with an additional amino substituent in ortho- position have become useful precursors for selective colorimetric sensing of anions, fluorinated benzoxazinones and quinolines. These molecules can also be used in anion recognition, which is stabilized by hydrogen bonding.
- a well established method to form trifluoroacetyl group is the nucleophilic addition of TMS- CF 3 (Ruppert' s reagent) to esters or aldehydes, whereas the second reaction requires the oxidation of the intermediate trifluoromethylated alcohol.
- the main objective of the present invention is to provide a process which is safe on industrial scale for the preparation of chlorophenyl trifluoroethanone of formula I.
- Another objective of the present invention is to provide a commercially viable process for the preparation of chlorophenyl trifluoroethanone of formula I.
- the present invention provides an improved process for the preparation of chlorophenyl trifluoroethanone of fomiula I which comprises the steps:
- R H or X conventional amino protecting groups to provide compound of fomiula 3.
- R H or X
- PG amino-protecting grop ii. acetylating the compound of fomiula 3 to provide compound 4.
- the present invention provides a process for the preparation of chlorophenyl trifluoroethanone of formula I. which comprises the steps:
- PG amino-protecting group
- X is halogen atom iii. acetylating the compound of fomiula 6 to provide compound 4.
- the present invention provides a process for the preparation of chlorophenyl trifluoroethanone of formula I, which comprises the steps:
- reaction of acetylation and deprotection can be carried out in one step.
- reaction in another embodiment of the present invention can be carried in the presence or absence of basic ligands such as sodium, magnesium and lithium.
- Suitable X represents a halogen selected from chlorine, bromine, fluorine and iodine.
- Suitable amino protecting groups are trichloroethoxycarbonyl. benzyloxycarbonyl (Cbz), chloroacetyl. trifluoroacetyl. phenylacetyl. formyl. acetyl, benzoyl, tert-butoxycarbonyl (BOC). para-methoxybenzyloxycarbonyl. para-methoxybenzyl. para-nitrobenzyl diphenylmethoxycarbonyl. phthaloyl. succinyl, benzyl, diphenylmethyl. triphenylmethyl (trityl ). methanesulfonyl. para-toluenesulfonyl. pivaloyl. trimethylsilyl, triethylsilyl, triphenylsilyl and the like.
- the protection is carried out in the presence or absence of a base and in a solvent.
- the base is selected from sodium hydroxide, potassium hydroxide and carbonates such as potassium carbonates.
- the organic solvent used in the reaction is selected from alcohols such as methanol, ethanol. butanol; hydrocarbons such as heptane; aromatic hydrocarbons such as toluene, xylene: halogenated solvents such as dichloromethane. chloroform. 1 ,2- dichloroethane; ethers such as diethyl ether. MTBE. 1.4 dioxane. THF; nit iles such as acetonitrile; esters such as ethylacetate; sulfoxides such as DMSO; amides such as DMF and water or mixtures thereof.
- Acetylation is carried out using a acetylating agent which is selected from the group consisting of methyltrifluoroacetate. ethyltrifluoroacetate. trifluoroacetylchloride. trifluoroacetic anhydride and mixtures thereof.
- the reaction is carried out in the presence of Grignard reagent in a solvent.
- the Grignard reagent is selected from methyl magnesium bromide/chloride, ethyl magnesium bromide/chloride. isopropyl magnesium bromide/chloride. n-butyl magnesium bromide/chloride.
- the solvent is selected from toluene, xylene, diethylether. diisopropylether. MTBE. tetrahydrofuran. and the like.
- the deprotection step comprises the single-step removal of the protecting groups.
- the deprotection is carried out either by using an acid or a base or by catalytic hydrogenation in the presence of a hydrogenation catalyst, optionally in the presence of an acid, under high pressure or by catalytic transfer hydrogenation (CTH ) in the presence of a catalytic transfer hydrogenation reagent, and optionally in the presence of an acid.
- CTH catalytic transfer hydrogenation
- Suitable acids used for deprotection are selected from mineral acids such as hydrochloric acid, viz. methanolic HC1. Ethanolic HC1. 1.4-dioxane HC1. IPA HC1; sulphuric acid; acetic acid and the like.
- the reaction is carried out in a solvent selected from methanol, ethanol. isopropanol or any other suitable solvent.
- Halogenation is carried out using suitable halogenating reagents for the preparation of corresponding bromides, chlorides, iodides or fluorides include for example NBS. Bi acetic acid. HBr/acetic acid. aqueous HBr. l,3-dibi mo-5.5-dimethylhydantoin, tetrabutylammonium bromide. N-bromoacetamide. NCS. SO 2 CK hydrogen fluoride, tetra- butylammonium fluoride, pyridinium hydrofluoride. potassium iodide, sodium iodide or lithium iodide and the like.
- the reaction is carried out in a solvent selected from dichloromethane. dichloroehtane, chloroform, carbon tetrachloride, MTBE. acetonitrile, toluene, acetic acid, sulfuric acid, hydrochloric acid or water and the like.
- Step 1 Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:
- Step 3 Synthesis of l -(2-amino-5-chlorophenyl)-2,2.2-trifluoi ethanone hydrochloride from N-(2-bromo-4-chloiOphenyl)pivalamide:
- the crude compound was added to a mixture of acetic acid (4 vol. ) and HC1 (2 vol. ) and slowly heated to 75°C and stirred for 4 h at the same temperature.
- the reaction mixture was cooled to 0-5°C and filtered, washed with ethyl acetate ( 1 vol. ) to afford 40 of the title compound.
- Step 1 Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:
- Step 3 Synthesis of l -(2-amino-5-chlorophenyl)-2,2.2-trifluoiOethanone hydrochloride from N-(2-bromo-4-chloiOphenyl)pivalamide:
- Step 1 Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:
- Step 2 Synthesis of N-(2-bromo-4-chloiOphenyl (pivalamide from N-(4- chlorophenyl )pivalamide: Bromine ( 1.2 mmol) was added dropwise to a solution of N-(4-chlorophenyl )pivalamide ( 1 mmol ) in acetic acid (2 vol. ) at room temperature. The reaction was stirred at the same temperature for lh. After completion of the reaction the reaction mixture was poured into crushed ice to get precipitate. The precipitate was filtered and washed with water to yield 90% N-(2-biOmo-4-chlorophenyl)pivalamide.
- Step 3 Synthesis of l -(2-amino-5-chlorophenyl)-2,2.2-trifluoi ethanone hydrochloride from N-(2-biOmo-4-chlorophenyl)pivalamide:
- Step 1 Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:
- Step 3 Synthesis of l -(2-amino-5-chloi'ophenyl)-2.2.2-trifluoi'oethanone hydrochloride from N-(2-biOmo-4-chlorophenyl)pivalamide:
- Step 1 Synthesis of N-(4-chlorophenyl (pivalamide 2 from p-chloroaniline:
- Step 2 Synthesis of N-(2-bromo-4-chloiOphenyl (pivalamide from N-(4- chlorophenyl )pivalamide:
- Step 3 Synthesis of l -(2-amino-5-chloi phenyl)-2,2.2-trifluoiOethanone hydrochloride from N-(2-biOmo-4-chlorophenyl)pivalamide:
- Sodamide (3.2 mmol ) was added to a solution of N-(2-bromo-4-chloiOphenyl) pivalamide ( 1 mmol ) & lithium chloride (0.25mmol) in THF (4 vol. ) at 20°C under inert atmosphere.
- the reaction mixture was maintained at 25°C for 6hrs and cooled to - 15°C.
- ethyltrifluoroacetate ( 1.4 mmol) was added at - 15°C.
- the reaction mixture was warmed to room temperature and stirred for another 30 min. After completion of the starting material the reaction was quenched with aqueous ammonium chloride solution (50 ml ) and extracted with MTBE (2X50 nil ).
- Step 1 Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:
- Step 2 Synthesis of N-(2-biOmo-4-chlorophenyl )pivalamide from N-(4- chlorophenyl)pivalamide:
- Step 3 Synthesis of l -(2-aniino-5-chloi phenyl)-2,2.2-trifluoiOethanone hydrochloride from N-(2-biOnio-4-chlorophenyl)pivalamide: Magnesium (2.3 mmol ) was added to a solution of N-(2-bromo-4-chloiOphenyl ) pivalamide ( 1 mmol ) & lithium chloride (0.25mmol) in THF (4 vol. ) at 20°C under inert atmosphere. The reaction mixture was maintained at 25°C for 6hrs and cooled to - 15°C.
- Step 1 Synthesis of 4-chloi -2-bromo phenyl pivalamide
- Step 2 Synthesis of l-(2-amino-5-chloi phenyl )-2.2.2.-trifluoroethanone hydrochloride from 4-chloro-2-biomo phenyl pivalamide.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN304/CHE/2014 | 2014-01-24 | ||
| IN304CH2014 IN2014CH00304A (enrdf_load_stackoverflow) | 2014-01-24 | 2015-01-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2015111004A2 true WO2015111004A2 (en) | 2015-07-30 |
| WO2015111004A3 WO2015111004A3 (en) | 2017-05-11 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2015/050533 WO2015111004A2 (en) | 2014-01-24 | 2015-01-24 | Improved process for the preparation of chlorophenyl trifluoroethanone |
Country Status (2)
| Country | Link |
|---|---|
| IN (1) | IN2014CH00304A (enrdf_load_stackoverflow) |
| WO (1) | WO2015111004A2 (enrdf_load_stackoverflow) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777610A (zh) * | 2015-10-16 | 2016-07-20 | 浙江沙星医药化工有限公司 | 一种制备4-氯-2-(三氟乙酰基)苯胺盐酸盐水合物的方法 |
| CN106518636A (zh) * | 2016-10-18 | 2017-03-22 | 浙江天宇药业股份有限公司 | 4‑氯‑2‑（三氟乙酰基）苯胺盐酸盐水合物及其游离碱的制备方法 |
| CN108821938A (zh) * | 2018-08-06 | 2018-11-16 | 江苏沙星化工有限公司 | 一种制备4-氯-2-（三氟乙酰）-苯胺盐酸盐副产物的分离方法 |
| CN108997150A (zh) * | 2018-08-31 | 2018-12-14 | 江苏沙星化工有限公司 | 一种依法韦仑中间体的制备方法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2006223469A1 (en) * | 2005-03-09 | 2006-09-21 | Merck Sharp & Dohme Corp. | Quinazolinone T-type calcium channel antagonists |
-
2015
- 2015-01-24 IN IN304CH2014 patent/IN2014CH00304A/en unknown
- 2015-01-24 WO PCT/IB2015/050533 patent/WO2015111004A2/en active Application Filing
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777610A (zh) * | 2015-10-16 | 2016-07-20 | 浙江沙星医药化工有限公司 | 一种制备4-氯-2-(三氟乙酰基)苯胺盐酸盐水合物的方法 |
| CN105777610B (zh) * | 2015-10-16 | 2018-10-09 | 浙江沙星科技有限公司 | 一种制备4-氯-2-(三氟乙酰基)苯胺盐酸盐水合物的方法 |
| CN106518636A (zh) * | 2016-10-18 | 2017-03-22 | 浙江天宇药业股份有限公司 | 4‑氯‑2‑（三氟乙酰基）苯胺盐酸盐水合物及其游离碱的制备方法 |
| CN108821938A (zh) * | 2018-08-06 | 2018-11-16 | 江苏沙星化工有限公司 | 一种制备4-氯-2-（三氟乙酰）-苯胺盐酸盐副产物的分离方法 |
| CN108997150A (zh) * | 2018-08-31 | 2018-12-14 | 江苏沙星化工有限公司 | 一种依法韦仑中间体的制备方法 |
| CN108997150B (zh) * | 2018-08-31 | 2021-01-12 | 江苏沙星化工有限公司 | 一种依法韦仑中间体的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| IN2014CH00304A (enrdf_load_stackoverflow) | 2015-09-04 |
| WO2015111004A3 (en) | 2017-05-11 |
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