WO2002050009A1 - Process for the synthesis of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one - Google Patents
Process for the synthesis of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one Download PDFInfo
- Publication number
- WO2002050009A1 WO2002050009A1 PCT/US2001/048800 US0148800W WO0250009A1 WO 2002050009 A1 WO2002050009 A1 WO 2002050009A1 US 0148800 W US0148800 W US 0148800W WO 0250009 A1 WO0250009 A1 WO 0250009A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bis
- trifluoromethyl
- phenyl
- magnesium bromide
- acetic anhydride
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 44
- 230000008569 process Effects 0.000 title claims abstract description 40
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 13
- MCYCSIKSZLARBD-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 MCYCSIKSZLARBD-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000003786 synthesis reaction Methods 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 93
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 56
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 28
- 239000007818 Grignard reagent Substances 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 150000004795 grignard reagents Chemical class 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 21
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- CSVCVIHEBDJTCJ-UHFFFAOYSA-N 1-bromo-3,5-bis(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(Br)=CC(C(F)(F)F)=C1 CSVCVIHEBDJTCJ-UHFFFAOYSA-N 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 6
- SJBBXFLOLUTGCW-UHFFFAOYSA-N 1,3-bis(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(C(F)(F)F)=C1 SJBBXFLOLUTGCW-UHFFFAOYSA-N 0.000 claims description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 4
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-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
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 3
- 239000011541 reaction mixture Substances 0.000 description 14
- 238000007792 addition Methods 0.000 description 13
- 239000011777 magnesium Substances 0.000 description 10
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 9
- 229910052749 magnesium Inorganic materials 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 4
- 102100024304 Protachykinin-1 Human genes 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- -1 magnesium halide Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 101800003906 Substance P Proteins 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 150000004791 alkyl magnesium halides Chemical class 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000008570 general process Effects 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 2
- 0 *c1cc(C(F)(F)F)cc(C(F)(F)F)c1 Chemical compound *c1cc(C(F)(F)F)cc(C(F)(F)F)c1 0.000 description 1
- HVFQJWGYVXKLTE-UHFFFAOYSA-N 3,5-bis(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 HVFQJWGYVXKLTE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000005841 biaryl group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000007514 turning Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
Definitions
- the present invention relates to processes for the preparation of l-(3,5- bis(trifluoromethyl)phenyl)ethan-l-one (CAS 30071-93-3) which is useful as an intermediate in the preparation of therapeutic agents.
- the present invention provides a process for the preparation of l-(3,5-bis(trifluoromethyl)- phenyl)ethan-l-one which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
- the subject invention provides a process for the preparation of l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one via a very simple, short and highly efficient synthesis.
- novel process of this invention involves the synthesis of l-(3,5- bis(trifluoromethyl)phenyl)ethan-l-one.
- present invention is concerned with novel processes for the preparation of a compound of the formula:
- This compound is an intermediate in the synthesis of compounds which possess pharmacological activity.
- such compounds are substance P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment of inflammatory diseases, psychiatric disorders, and emesis.
- the present invention is directed to processes for the preparation of 1- (3,5-bis(trifluoromethyl)phenyl)ethan-l-one of the formula:
- X is selected from chloro, bromo and iodo; and R is Ci-8alkyl.
- the treatment of acetic anhydride with the Grignard reagent prepared by an exchange reaction between 3,5-bis(trifluoromethyl)bromobenzene and a C ⁇ _8 alkyl magnesium halide provides l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one in higher yields and in a safer, more efficient route than the processes disclosed in the art.
- C ⁇ _8 as in Ci-salkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branched arrangement, such that Ci-8alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl.
- halo or halide is intended to include chloro, bromo and iodo.
- the present invention is directed to a process for the preparation of l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one which comprises the exchange reaction of 3,5-bis(trifluoromethyl)bromobenzene with a Ci-8alkyl magnesium halide in THF to form a Grignard reagent followed by addition of the Grignard reagent to acetic anhydride to give l-(3,5-bis(trifluoromethyl)phenyl)- ethan-1-one.
- Another embodiment of the present invention is directed to a process for the preparation of l-(3,5-bis(trifluoromethyl)-phenyl)ethan-l-one which comprises the reaction of 3,5-bis(trifluoromethyl)bromobenzene with ethyl magnesium bromide in tetrahydrofuran to form l-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide followed by addition of the Grignard reagent to an excess of acetic anhydride to give l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one.
- a specific embodiment of the present invention concerns a process for the preparation of l-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide of the formula:
- Grignard reagent selected from: ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide, in an organic solvent to form l-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide.
- Another specific embodiment of the present invention concerns a process for the preparation of l-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide of the formula:
- Another specific embodiment of the present invention concerns a process for the preparation of l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one of the formula:
- Grignard reagent selected from: ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide, in an organic solvent to form a Grignard reagent of the formula:
- Another specific embodiment of the present invention concerns a process for the preparation of l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one of the formula:
- Grignard reagent selected from: ethyl magnesium bromide and isopropyl magnesium chloride, in an organic solvent to form a Grignard reagent of the formula:
- the Grignard reagent is added to the acetic anhydride.
- step (b) excess acetic anhydride is removed by the addition of an aqeueous solution of a base, such as sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, and the like.
- a base such as sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, and the like.
- Preferred solvents for conducting the instant process comprise an organic solvent which is selected from toluene, tetrahydrofuran (THF), diethyl ether, diglyme, and methyl t-butyl ether.
- the most preferred organic solvent is tetrahydrofuran.
- tetrahydrofuran or diethyl ether are the more preferred organic solvents and tetrahydrofuran is the most preferred organic solvent.
- the Ci-8 alkyl magnesium halide is preferably selected from ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide, more preferably selected from ethyl magnesium bromide and isopropyl magnesium chloride, and even more preferably ethyl magnesium bromide.
- the magnesium employed to prepare the alkyl Grignard reagent may be in the form of magnesium granules, magnseium turnings, magnesium dust, magnesium powder, suspension of magnesium in oil, and the like. To mimimize safety risks, the use of magnesium granules is preferred.
- Formation of the Grignard of l-(3,5-bis(trifluoromethyl)phenyl)- bromide may be performed in tetrahydrofuran at between about 30 and 35°C. .
- the reaction is exothermic and the reaction may be controlled by the rate of addition of the bromide to the magnesium slurry.
- the reaction mixture may be aged at reflux until ⁇ 1 mol % of bromide remains.
- Grignard formation is usually complete within 2 hours, however reaction times of up to 5 hours give comparable yields of l-(3,5- bis(trifluoromethyl)phenyl)ethan- 1 -one.
- the Grignard formation may be performed in tetrahydrofuran at a temperature range between about 0 and 20°C, and preferably a reaction temperature range between about 0 and 10°C.
- the Grignard reagent be added to the acetic anhydride.
- an excess of acetic anhydride be present when reacting the Grignard reagent.
- the Grignard reagent be added to an excess of acetic anhydride.
- the Grignard reagent is added to cooled acetic anhydride.
- the Grignard reagent is added slowly (over a period of 1-2 hr, for example) to a cooled mixture of acetic anhydride in either tetrahydrofuran or tert-butyl methylether, maintaining the temperature at below about 5°C, or alternatively between about -10 to -15 °C.
- the temperature of the acetic anhydride upon addition of the Grignard reagent be less than about 5°C, more preferrably, less than about -10°C, it is even more preferrably less than about -15°C.
- the temperature of the reaction mixture may be raised to about 5°C.
- isolation of l-(3,5-bis(trifluoro- methyl)phenyl)ethan-l-one may be achieved by adding cold water to the reaction mixture followed by the slow addition of aqueous solution of a base to hydrolyze the excess acetic anhydride.
- the base may be an inorganic base selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, and the like.
- a preferred base is sodium hydroxide.
- the pH of the aqueous layer is preferably brought to greater than 10. When the pH is greater than 10, the mixture is extracted with tert-butyl methylether. The extracts are washed with aqueous sodium bicarbonate and aqueous sodium chloride and the solvents are removed by distillation. The l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one obtained in accordance with the present invention may be used as starting material in further reactions directly or following distillation.
- the assay yield of l,3-bis(trifluoromethyl)bromobenzene was 93.7% (137.3 g, 469 mmol), which contained 0.6% l,3-bis(trifluoromethyl)benzene, 1.0% l,2-dibromo-3,5-bis(trifluoromethyl)benzene, and 0.3% l,4-dibromo-3,5-bis-
- Step B Preparation of l-(3.5-Bis(trifluoromethyl)phenyl)magnesium Bromide
- Step C Coupling Reaction To a solution of acetic anhydride (97.6 kg) in THF (207.9 kg) in a
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention is concerned with a novel process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one (CAS 30071-93-3). This compound is useful as an intermediate in the synthesis of therapeutic agents.
Description
PROCESS FOR THE SYNTHESIS OF l-(3,5-BIS(TRIFLUOROMETHYL)- PHEN YL)ETHAN- 1 -ONE
BACKGROUND OF THE INVENTION
The present invention relates to processes for the preparation of l-(3,5- bis(trifluoromethyl)phenyl)ethan-l-one (CAS 30071-93-3) which is useful as an intermediate in the preparation of therapeutic agents. In particular, the present invention provides a process for the preparation of l-(3,5-bis(trifluoromethyl)- phenyl)ethan-l-one which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The general processes disclosed in the art for the preparation of l-(3,5- bis(trifluoromethyl)phenyl)ethan-l-one result in relatively low and inconsistent yields of the desired product. In contrast to the previously known processes, the present invention provides effective methodology for the preparation of l-(3,5-bis(trifluoro- methyl)phenyl)ethan-l-one in relatively high yield and with a lower degree of exothermicity and, hence, a greater degree of safety.
It will be appreciated that l-(3,5-bis(trifluoromethyl)phenyl)ethan-l- one is an important intermediate for a particularly useful class of therapeutic agents. As such, there is a need for the development of a process for the preparation of l-(3,5- bis(trifluoromethyl)phenyl)ethan-l-one which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
Accordingly, the subject invention provides a process for the preparation of l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one via a very simple, short and highly efficient synthesis.
SUMMARY OF THE INVENTION
The novel process of this invention involves the synthesis of l-(3,5- bis(trifluoromethyl)phenyl)ethan-l-one. In particular, the present invention is concerned with novel processes for the preparation of a compound of the formula:
This compound is an intermediate in the synthesis of compounds which possess pharmacological activity. In particular, such compounds are substance P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment of inflammatory diseases, psychiatric disorders, and emesis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to processes for the preparation of 1- (3,5-bis(trifluoromethyl)phenyl)ethan-l-one of the formula:
An embodiment of the general process for the preparation of 3,5-bis(trifluoromethyl)-benzoic acid is as follows:
X is selected from chloro, bromo and iodo; and R is Ci-8alkyl.
In accordance with the present invention, the treatment of acetic anhydride with the Grignard reagent prepared by an exchange reaction between 3,5-bis(trifluoromethyl)bromobenzene and a Cι_8 alkyl magnesium halide provides l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one in higher yields and in a safer, more efficient route than the processes disclosed in the art.
In the present invention, C ι_8 as in Ci-salkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branched arrangement, such that Ci-8alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl. In the present invention halo or halide is intended to include chloro, bromo and iodo.
In a preferred embodiment, the present invention is directed to a process for the preparation of l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one which comprises the exchange reaction of 3,5-bis(trifluoromethyl)bromobenzene with a Ci-8alkyl magnesium halide in THF to form a Grignard reagent followed by addition of the Grignard reagent to acetic anhydride to give l-(3,5-bis(trifluoromethyl)phenyl)- ethan-1-one.
Another embodiment of the present invention is directed to a process for the preparation of l-(3,5-bis(trifluoromethyl)-phenyl)ethan-l-one which comprises the reaction of 3,5-bis(trifluoromethyl)bromobenzene with ethyl magnesium bromide in tetrahydrofuran to form l-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide followed by addition of the Grignard reagent to an excess of acetic anhydride to give l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one.
A specific embodiment of the present invention concerns a process for the preparation of l-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide of the formula:
which comprises: treating 3,5-bis(trifluoromethyl)bromobenzene of the formula:
with a Grignard reagent selected from: ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide, in an organic solvent to form l-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide.
Another specific embodiment of the present invention concerns a process for the preparation of l-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide of the formula:
which comprises: treating 3,5-bis(trifluoromethyl)bromobenzene of the formula:
with ethyl magnesium bromide or isopropyl magnesium chloride in an organic solvent to form l-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide. Another specific embodiment of the present invention concerns a process for the preparation of l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one of the formula:
which comprises: a) treating 3,5-bis(trifluoromethyl)benzene of the formula:
with a Grignard reagent selected from: ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide, in an organic solvent to form a Grignard reagent of the formula:
b) followed by contacting the Grignard reagent with acetic anhydride in an organic solvent to give l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one of the formula:
which comprises: a) treating 3,5-bis(trifluoromethyl)benzene of the formula:
with a Grignard reagent selected from: ethyl magnesium bromide and isopropyl magnesium chloride, in an organic solvent to form a Grignard reagent of the formula:
b) followed by contacting the Grignard reagent with acetic anhydride in an organic solvent to give l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one of the formula:
In a more preferred embodiment, following step (b) excess acetic anhydride is removed by the addition of an aqeueous solution of a base, such as sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, and the like.
Preferred solvents for conducting the instant process comprise an organic solvent which is selected from toluene, tetrahydrofuran (THF), diethyl ether, diglyme, and methyl t-butyl ether. The most preferred organic solvent is tetrahydrofuran. In the formation of the Grignard reagent, tetrahydrofuran or diethyl ether are the more preferred organic solvents and tetrahydrofuran is the most preferred organic solvent.
The Ci-8 alkyl magnesium halide is preferably selected from ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide, more preferably selected from ethyl magnesium bromide and isopropyl magnesium chloride, and even more preferably ethyl magnesium bromide. The magnesium employed to prepare the alkyl Grignard reagent may be in the form of magnesium granules, magnseium turnings, magnesium dust, magnesium powder, suspension of magnesium in oil, and the like. To mimimize safety risks, the use of magnesium granules is preferred.
Formation of the Grignard of l-(3,5-bis(trifluoromethyl)phenyl)- bromide may be performed in tetrahydrofuran at between about 30 and 35°C. . The reaction is exothermic and the reaction may be controlled by the rate of addition of the bromide to the magnesium slurry. The reaction mixture may be aged at reflux until <1 mol % of bromide remains. Grignard formation is usually complete within 2 hours, however reaction times of up to 5 hours give comparable yields of l-(3,5- bis(trifluoromethyl)phenyl)ethan- 1 -one.
Alternatively, to minimize solvent loss, the Grignard formation may be performed in tetrahydrofuran at a temperature range between about 0 and 20°C, and preferably a reaction temperature range between about 0 and 10°C.
In the present invention, it is preferred that the Grignard reagent be added to the acetic anhydride. In the present invention, it is also preferred that an excess of acetic anhydride be present when reacting the Grignard reagent. In the present invention, it is more preferred that the Grignard reagent be added to an excess of acetic anhydride.
Surprisingly, the presence of an excess of acetic anhydride (i.e. greater than a 1 : 1 molar ratio) is important to providing high yields of the desired product. When the acetic anhydride was added to the Grignard reagent at 20°C an exothermic reaction resulted which produced a bis-adduct of the formula:
Surprisingly, however, when the Grignard reagent was added to acetic anhydride, little byproduct was formed and l-(3,5-bis(trifluoromethyl)phenyl)ethan-l- one was obtained in 85-90% yield.
In the present invention, it is preferred that the Grignard reagent is added to cooled acetic anhydride. In the present invention, it is more preferred that the Grignard reagent is added slowly (over a period of 1-2 hr, for example) to a cooled mixture of acetic anhydride in either tetrahydrofuran or tert-butyl methylether, maintaining the temperature at below about 5°C, or alternatively between about -10 to -15 °C. In the addition of the Grignard reagent with acetic anhydride, it is preferred that the temperature of the acetic anhydride upon addition of the Grignard reagent be less than about 5°C, more preferrably, less than about -10°C, it is even more preferrably less than about -15°C. Upon addition of the Grignard reagent, the temperature of the reaction mixture may be raised to about 5°C. In a preferred additional embodiment, isolation of l-(3,5-bis(trifluoro- methyl)phenyl)ethan-l-one may be achieved by adding cold water to the reaction mixture followed by the slow addition of aqueous solution of a base to hydrolyze the excess acetic anhydride. The base may be an inorganic base selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, and the like. A preferred base is sodium hydroxide. The pH of the aqueous layer is preferably brought to greater than 10. When the pH is greater than 10, the mixture is extracted with tert-butyl methylether. The extracts are washed with aqueous sodium bicarbonate and aqueous sodium chloride and the solvents are removed by distillation. The l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one obtained in accordance with the present invention may be used as starting material in further
reactions directly or following distillation. The isolated product can be distilled at atmospheric or reduced pressure to provide a clear colorless oil with BP = 185-189°C.
Many of the starting materials are either commercially available or known in the literature and others can be prepared following literature methods described for analogous compounds. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, distillation, normal phase or reverse phase chromatography.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.
EXAMPLE 1
3,5-Bis(trifluoromethyObromobenzene
To glacial acetic acid (22.0 mL), cooled to 15 °C in a 1 L 3-n RB flask (equipped with mechanical stirrer, thermocouple, and addition funnel), was added concentrated (96%) sulfuric acid (142 mL) in one portion. An exothermic heat of solution raised the temperature to 35 °C. After cooling to 25 °C, l,3-bis(trifluoro- methyl)benzene (107 g, 500 mmol) was added. With the acid mixture rapidly stirring, l,3-dibromo-5,5-dimethylhydantoin (77.25 g; 270 mmol) was added over 2 min to
give a multiple phase mixture (solid and two liquid). An exothermic reaction occured that raised the internal temperature to -40 °C (jacket cooling at 15 °C). After the reaction temperature began to drop (after 5 min) the reaction mixture was maintained at 45 °C for 4.5 hr. The rate and selectivity of the bromination is highly dependent on the agitation of the two phase reaction. Slower stirring increases the amount of bis- bromination and slows the overall rate of reaction. The reaction mixture remains heterogeneous throughout the reaction and the organic phase separates when agitation is interrupted. At the end of the reaction, the phases separate slowly (bromide density = 1.699). The rate of bromination is also dependent on the ratio of acetic to sulfuric acid. Progress of the reaction is monitored by GC analysis, as follows.
Sample: -50 μl of mixed phase, dilute with cyclohexane (1.5 mL), wash with water (1 mL), then 2N NaOH (1 mL), separate and inject.
Resteck RTX-1701 [60 meter x 0.320 mm]: 100 °C; ramp: 5 °C/min to 200 °C; 200 °C for 10 min; Flow 1.15 mlJmin
Rt:l,3-bis(trifluoromethyl)benzene: 7.0 min
3,5-bis(trifIuoromethyl)bromobenzene: 9.4 min
Biaryl: 19.2 min
The mixture was cooled to 2 °C and poured slowly into cold water (250 mL). The mixture was stirred vigorously for 10 min, allowed to settle, and the lower organic layer was separated and washed with 5N NaOH (75 mL) to give 145.1 g of a clear, colorless organic layer.
The assay yield of l,3-bis(trifluoromethyl)bromobenzene was 93.7% (137.3 g, 469 mmol), which contained 0.6% l,3-bis(trifluoromethyl)benzene, 1.0% l,2-dibromo-3,5-bis(trifluoromethyl)benzene, and 0.3% l,4-dibromo-3,5-bis-
(trifluoromethyl)benzene. Total isomer byproducts measured by GC were 2.0 mol %.
EXAMPLE 2
1 -(3.5-Bis(trifluoromethyl)phenyl)ethan- 1 -one
Mg
BrCH2CH3 *- BrMgCH2CH3
THF
Step A: Preparation of Seeds of Ethyl Magnesium Bromide
To a 20 L reactor equipped with stirring apparatus and under N2 was added magnesium granules (0.33 kg), THF and a small amount of iodine flakes. A small amount of ethylbromide was added dropwise followed by THF (9.37 kg). To the stirred reaction mixture was added dropwise a solution of ethylbromide (1.56 kg) in THF (2.34 kg) such that the reaction temperature was maintained below 35 °C. Upon completion of addition, the reaction mixture was stirred at 30-35 °C for 1 hour.
Step B: Preparation of l-(3.5-Bis(trifluoromethyl)phenyl)magnesium Bromide
By Grignard Exchange Reaction To a 500 L reactor equipped with stirring apparatus and under N2 was
added magnesium granules (7.0 kg) and THF (200 kg) and the suspension of ethyl magnesium bromide in THF from Step A. To the stirred reaction mixture was added dropwise a solution of ethylbromide (32.7 kg) in THF (49.1 kg) such that the reaction temperature was maintained below 35 °C. Upon completion of addition, the reaction mixture was stirred at 30-35 °C for 1 hour. A portion of the suspension of ethyl magnesium bromide in THF was reserved as seeds for later batches.
To the stirred reaction mixture was added dropwise a solution of 3,5-bis(trifluoromethyl)bromobenzene (120kg) in THF (120 kg) such that the reaction temperature was maintained below 30 °C. The reaction mixture was held below 30 °C until conversion was more than 95 %. The reaction was monitored by HPLC (sample preparation: 100 μL sample quenched into 3.5 mL of 1: 1 THF:2N HC1, then diluted to 100 mL in 65:35 acetonitrile:pH 6 buffer).
Step C: Coupling Reaction To a solution of acetic anhydride (97.6 kg) in THF (207.9 kg) in a
1500 L reactor was added dropwise with stirring the solution of l-(3,5-bis(trifluoro- methyl)phenyl)magnesium bromide from Step B such that the reaction temperature was maintained below 5 °C and then the reaction mixture was kept at below 5 °C for 0.5 hour.
Step D: Hydrolysis
To the reaction mixture from Step C water (195.1 kg) was added dropwise such that the reaction temperature was maintained below 5 °C. The reaction mixture was heated at 55-65 °C for 0.5 hour with stirring, then cooled to below 15 °C and the phases were allowed to separate. Methyl tert-butyl ether (120 kg) was added and the mixture was neutralized by the addition with stirring of 5N NaOH (98.9 kg) [25% NaOH (67.3kg, 0.44 eq/acetic anhydride) and water (31.6 kg)] was added dropwise over 1 hr, until a pH of greater than 10. The organic phase was separated and washed with 5% NaHCO3 (80 kg) [NaHCO3 (90.75 kg) and water (76 kg)]. The organic phase was separated and concentrated at a temperature below 95 °C. The concentrate was then distilled at reduced pressure at a temperature below 125 °C to give l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, reaction conditions other than the particular conditions as. set forth herein above may be applicable as a consequence of variations in the reagents or methodology to prepare the compounds from the processes of the invention indicated above. Likewise, the specific reactivity of starting materials may vary according to and depending upon the particular substituents present or the conditions of manufacture, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
Claims
WHAT IS CLAIMED IS:
1. A process for the preparation of a compound of the formula:
CF,
A process for the preparation of a compound of the formula:
CF3
CF,
with a Grignard reagent selected from: ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide; in an organic solvent to form l-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide of the formula:
b) followed by contacting the l-(3,5-bis(trifluoromethyl)- phenyl)magnesium bromide with acetic anhydride in an organic solvent to give the compound of the formula:
which comprises: a) treating 3,5-bis(trifluoromethyl)benzene of the formula:
CF3
CF3
with a Grignard reagent selected from: ethyl magnesium bromide and isopropyl magnesium chloride; in an organic solvent to form l-(3,5-bis(trifluoro-methyl)phenyl)magnesium bromide of the formula:
b) followed by contacting the l-(3,5-bis(trifluoromethyl)phenyl)- magnesium bromide with acetic anhydride in an organic solvent to give the compound of the formula:
4. The process of Claim 1 wherein the organic solvent comprises a solvent which is selected from: tetrahydrofuran, toluene, diethyl ether, diglyme, and methyl t-butyl ether.
5. The process of Claim 1 wherein the organic solvent comprises tetrahydrofuran.
6. The process of Claim 2 wherein the organic solvent comprises a solvent which is selected from: tetrahydrofuran, toluene, diethyl ether, diglyme, and methyl t-butyl ether.
7. The process of Claim 2 wherein the organic solvent comprises tetrahydrofuran.
8. The process of Claim 3 wherein the organic solvent comprises a solvent which is selected from: tetrahydrofuran, toluene, diethyl ether, diglyme, and methyl t-butyl ether.
9. The process of Claim 3 wherein the organic solvent comprises tetrahydrofuran.
10. The process of Claim 2 wherein the formation of the l-(3,5- bis(trifluoromethyl)phenyl)magnesium bromide is conducted at a temperature range below about 30°C.
11. The process of Claim 3 wherein the formation of the l-(3,5- bis(trifluoromethyl)phenyl)magnesium bromide is conducted at a temperature range below about 30°C.
12. The process of Claim 2 wherein the l-(3,5-bis(trifluoro- methyl)phenyl)magnesium bromide is added to acetic anhydride.
13. The process of Claim 3 wherein the l-(3,5-bis(trifluoro- methyl)phenyl)magnesium bromide is added to acetic anhydride.
14. The process of Claim 2 wherein the l-(3,5-bis(trifluoro- methyl)phenyl)magnesium bromide is added to an excess of acetic anhydride.
15. The process of Claim 3 wherein the l-(3,5-bis(trifluoro- methyl)phenyl)magnesium bromide is added to an excess of acetic anhydride.
16. The process of Claim 2 wherein the temperature of the acetic anhydride upon addition of the l-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide is less than about 5°C.
17. The process of Claim 3 wherein the temperature of the acetic anhydride upon addition of the l-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide is less than about 5°C.
18. The process of Claim 2 wherein following step (b), excess acetic anhydride is removed by the addition of an aqeueous solution of a base.
19. The process of Claim 3 wherein following step (b), excess acetic anhydride is removed by the addition of an aqeueous solution of sodium hydroxide.
20. A process for the preparation of l-(3,5-bis(trifluoromethyl)- phenyl)ethan-l-one which comprises the reaction of 3,5-bis(trifluoromethyl)- bromobenzene with ethyl magnesium bromide in tetrahydrofuran to form l-(3,5- bis(trifluoromethyl)phenyl)magnesium bromide followed by addition of the Grignard reagent to an excess of acetic anhydride to give l-(3,5-bis(trifluoromethyl)- phenyl)ethan- 1 -one.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2002230961A AU2002230961A1 (en) | 2000-12-20 | 2001-12-18 | Process for the synthesis of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one |
| CA002431457A CA2431457A1 (en) | 2000-12-20 | 2001-12-18 | Process for the synthesis of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one |
| US10/451,293 US6814895B2 (en) | 2000-12-20 | 2001-12-18 | Process for the synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one |
| EP01991219A EP1345878A4 (en) | 2000-12-20 | 2001-12-18 | Process for the synthesis of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25679000P | 2000-12-20 | 2000-12-20 | |
| US60/256,790 | 2000-12-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2002050009A1 true WO2002050009A1 (en) | 2002-06-27 |
Family
ID=22973590
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2001/048800 WO2002050009A1 (en) | 2000-12-20 | 2001-12-18 | Process for the synthesis of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US6814895B2 (en) |
| EP (1) | EP1345878A4 (en) |
| AU (1) | AU2002230961A1 (en) |
| CA (1) | CA2431457A1 (en) |
| WO (1) | WO2002050009A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016043079A1 (en) * | 2014-09-19 | 2016-03-24 | 東レ・ファインケミカル株式会社 | Method for producing 2'-trifluoromethyl group-substituted aromatic ketone |
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|---|---|---|---|---|
| US4450296A (en) * | 1980-09-18 | 1984-05-22 | International Flavors & Fragrances Inc. | Process for the production of arylalkanone and intermediate |
| US5142092A (en) * | 1988-10-24 | 1992-08-25 | Bayer Aktiengesellschaft | Fluorine-containing acetophenones optionally halogenated on the CH3 -group and their precurser fluorine-containing benzonitriles |
| US5235068A (en) * | 1988-04-28 | 1993-08-10 | Sumitomo Chemical Company, Limited | Process for producing acylaromatic compounds |
| US5510507A (en) * | 1994-01-11 | 1996-04-23 | E. I. Du Pont De Nemours And Company | Selective asymmetric hydrogenation of dehydroamino acid derivatives using rhodium and iridium diphosphinite carbohydrate catalyst compositions |
| US6248265B1 (en) * | 1998-12-18 | 2001-06-19 | Albemarle Corporation | Clean generation of a fluoroaryl grignard reagent |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL132490A (en) * | 1998-10-23 | 2004-09-27 | Nippon Catalytic Chem Ind | Method for manufacturing fluoroaryl magnesium halide |
| JP2003502300A (en) | 1999-06-11 | 2003-01-21 | メルク エンド カムパニー インコーポレーテッド | Synthesis process of 1- (3,5-bis (trifluoromethyl) -phenyl) ethan-1-one |
| US6255545B1 (en) | 1999-06-11 | 2001-07-03 | Merck & Co., Inc. | Process for the synthesis of 3,5-bis(trifluoromethyl)-bromobenzene |
| EP1192116A4 (en) | 1999-06-11 | 2002-10-24 | Merck & Co Inc | Process for the synthesis of 3,5-bis(trifluoromethyl)-bromobenzene |
| CN1358163A (en) | 1999-07-01 | 2002-07-10 | 麦克公司 | Process for the synthesis (R)-1-(3.5-bis (trifluoromethyl)-phenyl) ethan-1-ol by asymmetric transfer hydrogenation |
-
2001
- 2001-12-18 EP EP01991219A patent/EP1345878A4/en not_active Withdrawn
- 2001-12-18 WO PCT/US2001/048800 patent/WO2002050009A1/en not_active Application Discontinuation
- 2001-12-18 US US10/451,293 patent/US6814895B2/en not_active Expired - Fee Related
- 2001-12-18 CA CA002431457A patent/CA2431457A1/en not_active Abandoned
- 2001-12-18 AU AU2002230961A patent/AU2002230961A1/en not_active Abandoned
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4450296A (en) * | 1980-09-18 | 1984-05-22 | International Flavors & Fragrances Inc. | Process for the production of arylalkanone and intermediate |
| US5235068A (en) * | 1988-04-28 | 1993-08-10 | Sumitomo Chemical Company, Limited | Process for producing acylaromatic compounds |
| US5142092A (en) * | 1988-10-24 | 1992-08-25 | Bayer Aktiengesellschaft | Fluorine-containing acetophenones optionally halogenated on the CH3 -group and their precurser fluorine-containing benzonitriles |
| US5510507A (en) * | 1994-01-11 | 1996-04-23 | E. I. Du Pont De Nemours And Company | Selective asymmetric hydrogenation of dehydroamino acid derivatives using rhodium and iridium diphosphinite carbohydrate catalyst compositions |
| US6248265B1 (en) * | 1998-12-18 | 2001-06-19 | Albemarle Corporation | Clean generation of a fluoroaryl grignard reagent |
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|---|
| MARCH J.: "Advanched organic chemistry: reactions, mechanisms and structure", MCGRAW-HILL BOOK COMPANY, 1968, NEW YORK, pages 475 - 476, XP002909562 * |
| See also references of EP1345878A4 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016043079A1 (en) * | 2014-09-19 | 2016-03-24 | 東レ・ファインケミカル株式会社 | Method for producing 2'-trifluoromethyl group-substituted aromatic ketone |
| JP6086163B2 (en) * | 2014-09-19 | 2017-03-01 | 東レ・ファインケミカル株式会社 | Method for producing 2'-trifluoromethyl group-substituted aromatic ketone |
| US9783476B2 (en) | 2014-09-19 | 2017-10-10 | Toray Fine Chemicals Co., Ltd. | Method of producing 2′-trifluoromethyl group-substituted aromatic ketone |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2431457A1 (en) | 2002-06-27 |
| US6814895B2 (en) | 2004-11-09 |
| EP1345878A1 (en) | 2003-09-24 |
| AU2002230961A1 (en) | 2002-07-01 |
| US20040108603A1 (en) | 2004-06-10 |
| EP1345878A4 (en) | 2005-12-14 |
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