MXPA00010438A - Process for synthesizing cox-2 inhibitors - Google Patents
Process for synthesizing cox-2 inhibitorsInfo
- Publication number
- MXPA00010438A MXPA00010438A MXPA/A/2000/010438A MXPA00010438A MXPA00010438A MX PA00010438 A MXPA00010438 A MX PA00010438A MX PA00010438 A MXPA00010438 A MX PA00010438A MX PA00010438 A MXPA00010438 A MX PA00010438A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- further characterized
- aryl
- alkylamino
- process according
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 38
- 230000002194 synthesizing Effects 0.000 title claims description 11
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- 125000003118 aryl group Chemical group 0.000 claims description 40
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 22
- -1 nitro, amino Chemical group 0.000 claims description 20
- 125000003282 alkyl amino group Chemical group 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- VLTRZXGMWDSKGL-UHFFFAOYSA-M Perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 10
- LJQLCJWAZJINEB-UHFFFAOYSA-N Hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F LJQLCJWAZJINEB-UHFFFAOYSA-N 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 150000004820 halides Chemical class 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
- SVHQOIWIRUVWII-UHFFFAOYSA-N Tetraphenylborate Chemical compound C1=CC=CC=C1[B-](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 SVHQOIWIRUVWII-UHFFFAOYSA-N 0.000 claims description 5
- MBAKFIZHTUAVJN-UHFFFAOYSA-H hexafluoroantimony(1-) Chemical compound F[Sb-](F)(F)(F)(F)F MBAKFIZHTUAVJN-UHFFFAOYSA-H 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- ODGCEQLVLXJUCC-UHFFFAOYSA-N tetrafluoroborate Chemical compound F[B-](F)(F)F ODGCEQLVLXJUCC-UHFFFAOYSA-N 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 150000004703 alkoxides Chemical class 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 235000021317 phosphate Nutrition 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N Sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N Trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims 1
- 150000001642 boronic acid derivatives Chemical class 0.000 claims 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims 1
- 150000001768 cations Chemical class 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 150000004678 hydrides Chemical class 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 125000002346 iodo group Chemical group I* 0.000 claims 1
- HAUKUGBTJXWQMF-UHFFFAOYSA-N lithium;propan-2-olate Chemical compound [Li+].CC(C)[O-] HAUKUGBTJXWQMF-UHFFFAOYSA-N 0.000 claims 1
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 claims 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 abstract description 10
- 201000010099 disease Diseases 0.000 abstract description 4
- 230000001404 mediated Effects 0.000 abstract description 4
- 102000010907 Cyclooxygenase 2 Human genes 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 102100015381 PTGS2 Human genes 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- 108010037464 Cyclooxygenase 1 Proteins 0.000 description 7
- 102100006335 PTGS1 Human genes 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 150000003839 salts Chemical group 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 229940088597 Hormone Drugs 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 4
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 229940021182 non-steroidal anti-inflammatory drugs Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XEYBRNLFEZDVAW-ARSRFYASSA-N (5Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-5-oxocyclopentyl]hept-5-enoic acid Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- CZDYPVPMEAXLPK-UHFFFAOYSA-N Tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atoms Chemical group C* 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229960002986 dinoprostone Drugs 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000002829 reduced Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-Dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- 206010001897 Alzheimer's disease Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 229940117389 Dichlorobenzene Drugs 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010018987 Haemorrhage Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N Lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- KRKPYFLIYNGWTE-UHFFFAOYSA-N N,O-Dimethylhydroxylamine Chemical class CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N Potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-L Sulphite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 2
- 206010049975 Uterine contractions during pregnancy Diseases 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atoms Chemical group 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 231100000319 bleeding Toxicity 0.000 description 2
- 230000000740 bleeding Effects 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000002993 cycloalkylene group Chemical group 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
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- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
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- 239000003102 growth factor Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
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- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
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- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 2
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- 238000002844 melting Methods 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- VYPPZXZHYDSBSJ-UHFFFAOYSA-N methyl 6-methylpyridine-3-carboxylate Chemical compound COC(=O)C1=CC=C(C)N=C1 VYPPZXZHYDSBSJ-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
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- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
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Abstract
The invention encompasses a process for making compounds of Formula (I) useful in the treatment of cyclooxygenase-2 mediated diseases.
Description
PROCEDURE FOR SYNTHESIZING INHIBITORS OF CYCLOOXYGENASE-2
BACKGROUND OF THE INVENTION
The present invention relates to a process for synthesizing certain cyclooxygenase-2 inhibiting compounds. Additionally, certain intermediate compounds are included. Cyclooxygen-2 (COX-2) is an enzyme that is involved in pain, inflammation, uterine contractions induced by hormones and certain types of cancer growth. Recently, only one form of cyclooxygenase has been characterized, corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine semen vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is different from cyclooxygenase-1. COX-2 is rapidly and easily inducible by a number of agents including mitogenes, endotoxin, hormones, cytokines, and growth factors. Although the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of .prostoglandins and therefore is important in its physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow, the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostoglandins where rapid induction of the enzyme would occur in response to agents such as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective cyclooxygenase-2 inhibitor will reduce fever, inhibit the inflammatory process, counterattack hormone-induced uterine contractions and have potential anti-cancer effects, along with a decreased ability to induce some of the mechanism-based side effects. An object of the present invention is to provide a synthesis scheme for COX-2 inhibitor compounds that utilizes reduced temperatures in the synthesis. Another object of the present invention is to use a synthetic route that provides high yields. Another object of the present invention is to provide a synthesis scheme that uses a minimum of procedural steps. These and other objects will be evident to those of normal skill from the teachings contained herein.
BRIEF DESCRIPTION OF THE INVENTION
A method for synthesizing a compound of the formula I is described:
in which: 0-2 R groups are present; each R, R 'and R "independently represents alkyl of C-MO, aryl of Cβ-io, aralkyl, halo, -S (O) mH, -S (O) malkyl of C? -6, -S ( O) m aryl, nitro, amino, C -? - 6 alkylamino, di-alkylamino of d-β, -S (O) mNH2, -S (O) mNH C 1-6 alkyl, -S (O) mNHC (O) CF3 and cyano.
The alkyl and aryl groups, and the alkyl and aryl portions of aralkyl, -S (O) m C-? -6 alkyl, -S (O) m aryl, Ci-β alkylamino, C? Dial? 6 dialkylamino and -S (O) mNH-C-? -6 alkyl being optionally substituted with 1-3 groups selected from C-, aryl, halo, hydroxyl, -S (O) mH, -S (O) m alkyl of C? -6, -CN, C? -6 alkoxy. amino, C? -6 alkylamino, C? -6-alkylamino, -S (O) mNH2, -S (O) mNH C? -6 alkyl, -S (O) mNHC (O) CF3 and aryloxy;
And it is C or N;
and m is O, 1 or 2,
which comprises reacting a compound of formula II:
wherein R2 to R5 each independently represent C-? 6 alkyl, aryl or aralkyl, and X- represents a suitable counterion, with a compound of formula III:
wherein R, R 'and Y are as previously defined, in the presence of a base to produce a compound of formula Certain intermediate compounds are also included.
DETAILED DESCRIPTION OF THE INVENTION
The invention is described in detail using the terms -siF- are defined immediately unless otherwise specified. The term "alkyl" refers to a radical derived from monovalent alkane (hydrocarbon) containing from 1 to 15 carbon atoms unless otherwise defined. It can be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl. Alkyl also includes a straight or branched alkyl group that contains or is interrupted by a cycloalkylene moiety. Examples include the following:
in which: x plus y = from 0-10 and w plus z = from 0-9. The alkylene and monovalent alkyl portions of the alkyl group may be adhered at any available point of adhesion to the cycloalkylene portion. When substituted alkyl is present, it refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.
The term "alkoxy" refers to those groups of the designated length in either a straight or branched configuration. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like. The term "halogen" is designed to include fluorine, chlorine, bromine and iodine. Aryl refers to aromatic rings for example, phenyl, substituted phenyl and similar groups as well as rings that are fused, for example, naphthyl. Aryl therefore contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating double (resonant) bonds between adjacent carbon atoms. Preferred aryl groups are phenyl and naphthyl. Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups. X- represents a suitable counterion. Hence, the intermediates of formula II are in salt forms that may or may not be "pharmaceutically acceptable" as defined below. A subset of X- values which are of particular interest include the following: phosphates, for example hexafluorophosphate and the like; sulfates; sulfonates, for example, mesylate, tosylate, triflate and the like; acetates, for example, acetate, trifluoroacetate and the like; perchlorate; borate, for example, tetrafluoroborate, tetraphenylborate and the like; antimonate, for example, hexafluoroantimonate; halide, for example Cl, F, Br and I; benzoate and nafsylate.
The preferred values of X- which are used in the process described herein are selected from the group consisting of: hexafluorophosphate; the halides; sulfate; the sulfonates; trifluoroacetate; perchlorate; tetrafluoroborate; tetraphenylborate and hexafluoroantimonate. The salts encompassed within the term "pharmaceutically acceptable salts" refer to substantially non-toxic salts of the compounds that are prepared in general by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following: acetate, benzoate, the halides; napsylate and phosphate / diphosphate. Preferred X- values which refer to the novel intermediates described herein include: hexafluorophosphate, tetrafluoroborate, tetraphenylborate and hexafluoroantimonate. The compounds that are used in the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of those compounds are useful within the scope of the present invention. When a compound is chiral, the separated enantiomers, substantially free of the other, are included together with mixtures of the enantiomers. They are also polymorphs and hydrates of the compounds. The compounds of formula I can be administered in oral dosage forms such as tablets, capsules (including each time release and sustained release formulations), pills, powders, granules, elixirs, dyes, suspensions, syrups and emulsions. Likewise, they can also be administered parenterally, for example, by intravenous (bolus and infusion), intraperitoneal, subcutaneous or intramuscular injection. The following abbreviations are used: Me = methyl Et = ethyl n-Pr, Pr = normal propyl i-Pr = isoplopyl n-Bu, Bu = normal butyl i -Bu = isobutyl s-Bu = secondary butyl t-Bu = tertiary butyl c-Pr = cyclopropyl c-Bu = cyclobutyl r -Pen = cyclopentyl c-Hex = cyclohexyl Bn benzyl BOC,, Boc t-butyloxycarbonyl BBOOPP HHeexxaafflluuoorrooffoossffaattoo of Benzotriazol-1-yloxy tris / dimethylamino) -phosphonium cale. Calculated CBZ, Cbz Benzyloxycarbonyl CDI N, N'-carbonyldiimidazole DCC Dicyclohexylcarbodiimide DCM dichloromethane DIEA diisopropylethylamine DMF NN-dimethylformamide DMAP 4-Dimethylaminopyridine DSC N.N'-disuccinimidyl carbonate EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride MS Ion Mass Electron Spectroscopy
EtOAc ethyl acetate EtOH ethanol eq. equivalent (s) FAB-MS mass spectroscopy-fast atom bombardment HMDS bis (trimethylsilyl) amide HOAc acetic acid HOBT, HOBt Hydroxybenztriazole HPLC High-pressure liquid chromatography KHMDS potassium bis (trimethylsilyl) amide LAH Lithium aluminum hydride LDA diethylamide lithium LHMDS lithium bis (trimethylsilyl) amide MeOH methanol MF molecular formula MHz Megahertz MPLC medium pressure liquid chromatography NMM N-methylmorpholine NMR Nuclear magnetic resonance Ph phenyl prep. Prepared TFA trifluoroacetic acid 10 THF Tetrahydrofuran TLC thin layer chromatography TMS Trimethylsilane
In one aspect of the invention, a method for synthesizing a compound of the formula I is described:
In which:
0-2 R groups are present;
each R, R 'and R "independently represents C1-10 alkyl, C6-10 aryl, aralkyl, halo, -S (O) mH, -S (O) malkyl of C? -6, -S ( O) m aryl, nitro, amino, C? -6 alkylamino, di? Alkylamino of C? -6, -S (O) mNH2 > - ^ w - ^ S (O) mNHalkyl of C1-6, - S (O) mNHC (O) CF3 and cyano,
The alkyl and aryl groups, and the alkyl and aryl portions of aralkyl, -S (O) malkyl of C? -6, -S (O) maryl, C 1-6 alkylamino, di-C 1-6 alkylamino and -S (O) mNH-d-6 alkyl being optionally substituted with 1-3 groups selected from C 1 - alkyl, aryl, halo, hydroxyl, -S (O) m H, -S (O) m alkyl d -H.H. -CN, C1-6 alkoxy. amino, C? -6 alkylamino, di-alkylamino r? 10 of C1-6, -S (O) mNH2, -S (O) mNH C1-6 alkyl, -S (O) mNHC (O) CF3 and aryloxy;
And it is C or N;
and m is 0, 1 or 2,
which comprises reacting a compound of formula II:
wherein R 2 to R 5 each independently represent C 1-6 alkyl. aryl or aralkyl, and X- represents a suitable counterion, with a compound of formula
wherein R, R 'and Y are as previously defined, in the presence of a base to produce a compound of formula I. In a preferred aspect of the invention, a method is described for synthesizing a compound of formula I ':
in which: 0-2 R groups are present; each R, R 'and R "independently represents alkyl of C -? - 10, aryl of C? -io. aralkyl, halo, -S (O) mH, -S (O) malkyl of C? -6, - S (O) m aryl, nitro, amino, C 1-6 alkylamino, di-alkylamino of d-6, -S (O) mNH 2, -20 S (O) mNH C 1-6 alkyl, -S (O) mNHC (O) CF3 and cyano,
the alkyl and aryl groups, and the alkyl and aryl portions of aralkyl, -S (O) malkyls of d-6, -S (O) maryl, alkylamino of d-6, di-alkylamino of C? -6 and -S (O) mNH-C 1-6 alkyl being optionally substituted with 1-3 groups selected from C? -4 alkyl, aryl, halo, hydroxyl, -S (O) mH, -S (O) m C alkyl? -6, -CN, d-β alkoxy, amino, C 1-6 alkylamino, C 1-6 alkylamino, -S (O) mNH 2, -S (O) mNH C 1-6 alkyl, -S ( O) mNHC (O) CF3 and aryloxy;
And it is C or N;
and m is 0, 1 or 2, which comprises reacting a compound of formula
wherein R 2 to R 5 each independently represent d-β, aryl or aralkyl alkyl, and X- represents a suitable counter ion, with a compound of formula III:
wherein R, R 'and Y are as previously defined, in the presence of a base to produce a compound of formula I'. An aspect of the invention that is of particular interest relates to the process described above, in which a R group is present and is d-10 alkyl, C6-aryl or, aralkyl, halo, -S (O) mH , -S (O) malcyl of d-6, -S (O) maralkyl, -S (O) maryl, nitro or cyano. More particularly, the methods that are of particular interest relate to the procedures described above in which an R representing an alkyl group of d -.o- is present. Even more particularly, the procedures relate to the procedures described above. in which an R representing methyl is present. More preferred is the process described above in which an R is present and represents methyl adhering as follows:
Within this sub group, all other variables are as originally defined. In another aspect, the invention encompasses a process for making a compound of formula I in which Y represents N. Within this subgroup, all other variables are as originally defined.
In another aspect of the invention which is of particular interest, the method encompasses a compound wherein R 'is selected from the group consisting of C-6-10 aryl substituted with -S (O) m C? -6 alkyl. More particularly, the process encompasses a compound in which R 'represents phenyl substituted with methanesulfonyl at the 4' position as shown below:
Within this subgroup, all other variables are as originally defined. In another aspect of the invention that is of particular interest, the process encompasses a compound in which R "is selected from C1-10 alkyl, C-6-10 aryl, aralkyl, halo, -S (O) mH, -S (O) C 1-6 maltoyl, nitro and cyano More particularly, the invention which is of interest relates to a process in which R "is halo or aryl of Cβ-io- Even more particularly, R "represents halo, especially chlorine, Within this subgroup, all other variables are as originally defined In another aspect of the invention, the process uses a compound of formula II in which R2 to R5 represent d-β alkyl and in particular, methyl In this subgroup, all other variables are as originally defined In another aspect of the invention, the method uses a compound of formula II in which X represents a member selected from the group consisting of : hexafluorophosphate, halide, sulfate, sulfonate, borate, trifluoroaceta to or perchlorate. More particularly, X- represents a member selected from the group consisting of: hexafluorophosphate, chlorine, a sulfonate selected from methanesulfonate, toluenesulfonate and trifluoromethylsulfonate, tetrafluorobonate or trifluoroacetate. Within this subgroup, all other variables are as originally defined. As used herein, the term "base" refers to organic and inorganic bases, such as sodium or potassium hydroxide, cesium carbonate, Li, Na, or K alkoxide bases, such as sodium isopropoxide, potassium. or lithium, sodium, potassium or lithium t-butoxide and the like, Li, Na, or K amide bases, such as LHDMS, LDA and the like, and Na, K or Li hydride bases. For purposes of this specification, the reactions, unless otherwise specified, are generally carried out in a solvent such as benzene, chlorobenzene, dichlorobenzene, toluene and xylene; ether solvents such as diethyl ether, di-n-butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); halocarbon solvents including C mono-mono- or dihaloalkyl such as dichloromethane; linear, branched or cyclic CT-IO hydrocarbon solvents including hexane; and nitrogen containing solvents including N, N-dimethylacetamide, N, N-dimethylformamide (DMF), N-ethylpyrrolidinone, N-methylpyrrolidinone, and acetonitrile. The preferable solvents are alcohol, THF and DMF. Typically the reaction is conducted in a substantially non-reactive solvent, for example, tetrahydrofuran, dioxane, C-α-6 alkanol, chlorobenzene, dichlorobenzene or xylene. The reaction surprisingly can be conducted at substantially ambient temperatures. The compounds of formula I are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, lower back pain and neck, dysmenorrhea, headache , tooth pain, strains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, after surgical and dental procedures. In addition, said compound can inhibit neoplastic cell transformations and metastatic tumor growth and can therefore be used in the treatment of cancer. The compounds of formula I may also be useful for the treatment of dementia including pre-senile and senile dementia, and in particular, dementia associated with Alzheimer's disease (ie Alzheimer's dementia). By virtue of its high activity of cyclooxygenase-2 (COX-2) and / or its selectivity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1), the compounds of formula I are useful as an alternative for other non-steroidal anti-inflammatory drugs. (NSAID'S) particularly wherein said nonsteroidal anti-inflammatory drugs may be contraindicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions.; Bleeding Gl, coagulation disorders including anemia such as hypoprothrombinemia, hemophilia or other bleeding problems (including those related to impaired or reduced platelet function); kidney disease (for example impaired renal function); those before surgery or before taking anticoagulants; and those susceptible to asthma induced by NSAID. The compounds are cyclooxygenase-2 inhibitors and are therefore useful in the treatment of diseases mediated by cyclooxygenase-2 as listed above. This activity is illustrated by its ability to selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Accordingly, in a test, the ability of the compounds of this invention to treat cyclooxygenase mediated diseases can be demonstrated by measuring the amount of prostaglandin E2 (PGE2) synthesized in the presence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2 and a compound of formula I. The IC50 values represent the concentration of inhibitor that is required to return the synthesis of PGE2 to 50% of that obtained in comparison to the non-inhibited control. For the treatment of any of those cyclooxygenase mediated diseases, the compounds of formula I can be administered orally, topically, parenterally, by spray inhalation or rectally in unit dosage formulations containing conventional pharmaceutically acceptable non-toxic carriers, adjuvants and vehicles, . The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intrasternal injection, or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, dogs, cats, etc., the compound of the invention is effective in the treatment of humans. The procedure is described further in connection with the following scheme.
SCHEME 1
e 1. Base 2. Acid 3. Ammonia
The procedure described herein can be described in connection with the above generic description. The Grignard reagent at (0.1 -3 M, 0.8-2 equivalents) is prepared from the corresponding halide, for example Z equal to chlorine, and magnesium in a suitable solvent, such as THF, ether, toluene or mixtures thereof . The Grignard reagent is added to a cold solution (0 to -78 ° C, preferably -10 to -30 ° C) of amide b in a suitable solvent, leading to the formation of ketone III. The ketone III is isolated after aqueous manipulation by extraction and crystallization.
The treatment of ketone III (0.05-2 M) with a suitable base, eg, a metal alkoxide, in a suitable solvent at -78 ° C to 50 ° C, typically less than about 20 ° C, results in the formation of an intermediate enolate (not shown). The enolate is reacted with the trimethyium salt to form an intermediate (not shown) which is quenched in a suitable acid (0.05 - 10 M). An example is acetic acid. The ammonia is added to the mixture (typically as an aqueous solution) and the mixture is aged at room temperature at reflux for several hours. The product is isolated by extraction using, for example, ether, ethyl acetate or methylene chloride and crystallization to form a compound of formula I. The invention is further illustrated by the following non-limiting examples in which, unless otherwise stated: (i) all operations were carried out at room temperature, that is, at a temperature in the range of 18-25 ° C; solvent evaporation was carried out under reduced pressure (600-4000 pascais: 4.5-30 mm Hg) with a bath temperature of up to 60 ° C; the course of reactions was followed by thin layer chromatography (TLC) or high pressure liquid chromatography (HPLC) and the reaction times are given only for illustration; polymorphism can result in the isolation of materials with different melting points in some preparations; the structure and purity of all final products was ensured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data; when given, the NMR data are in the form of delta (d) values for major diagnostic protons, given in parts per million (ppm) in relation to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz or 400 MHz using the indicated solvent; Conventional abbreviations used for signal form are: s. singlet; d. doublet; t. triplet; m. multiplet; br. wide; etc.; also "Ar" means an aromatic signal; chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (bullying point), m.p. (melting point), L (liters), mL (milliliters), g (grams), mg (milligrams), mol (moles), mmol (millimoles), eq (equivalents).
PREPARED EXAMPLE 1
Weinreb
PE-1 Methyl 6-methylnicotinate 21.56 g (0.143 mol) N, O-Dimethylhydroxyamines 13.9 g (0.229 mol) Tetrahydrofuran 150 mL Isopropylmagnesium chloride 110 mL (0.220 mol) (2.0M in THF) "? • Toluene 180 ml
A solution of methyl 6-methylnicotinate (21.56 g), and N, O-dimethylhydroxylamine (13.9 g) in THF (150 ml) was cooled to 10 ° C. Chloride
Isopropylmagnesium (110 ml) was added over 2.5 h. The reaction mixture was poured into aqueous acetic acid (10 vol%, 126 ml) at 5 ° C. Toluene (60 mL) was added to the mixture, then the layers were separated. The aqueous layer was extracted
• 10 with toluene (2 x 60 ml) and the solvent was removed. The solid impurities were removed by filtration and the filtrate was concentrated to provide the Weinreb PE-1 amide as a light orange oil (24.2 g).
PREPARED EXAMPLE 2
Griqnard
Chloride of 4-thiomethylbenzyl 566g (3.28 mol) Magnesium 191 g (7.86 mol) Toluene 9L Tetrahydrofuran 0.545 L Amide Weinreb PE-1 300g (1.66 mol)
A mixture of magnesium (191 g, 7.86 mol) toluene (4L), 4-thiomethylbenzyl chloride (566 g, 3.28 mol) and tetrahydrofuran (0.545 L, 6.73 mol) were charged for 3-4 hours. An additional flask was charged with Weinreb PE-1 amide (300 g, 1.66 mol) and toluene (1.7L) and cooled to minus 20 ° C. The Grignard solution prepared above was added for 30 minutes and the mixture was aged for 1 hour. The reaction mixture was quenched by the addition of 50% aqueous acetic acid (0.5L). Toluene (1 L) and water (1 L) were added and the layers separated. The aqueous layer was extracted with toluene (2 x 2L). The combined organic extracts were extracted with dilute hydrochloric acid (1 x 2L). Ethyl acetate was added to the aqueous layer and the pH was adjusted with ammonia (0.6L). The phases were separated and the aqueous layer was extracted with ethyl acetate (2x 1.25L). The combined extracts were concentrated on a rotary evaporator to give PE-2 as a light yellow solid (326.5g).
PREPARED EXAMPLE 3
Oxidation
A mixture of ketosulfide PE-2 (270g, 1.05 mol), sulfuric acid
(2N) (20 ml) and methanol (2.70L) was heated to 55 ° C. An aqueous solution of sodium tungstate (6.0 g, 0.02 mol) was added, then hydrogen peroxide (380 ml) was added over 1 hour. Water (3L) was added and the mixture was cooled to room temperature, and then filtered. The solids were washed with water (2L) and dried under vacuum with a stream of nitrogen to give the ketosulfone PE-3 (250.2 g) as a colorless solid.
EXAMPLE 1
1 Chloroacetic acid (0.99 kg, 10.57 mmol) was added to dimethylformamide (4.37 kg, 59.78 mol) and the mixture was heated to 75 ° C.
Phosphorus oxychloride (3.36 kg, 21.91 mol) was added during 5 hours. The reaction mixture was aged for 3 hours, then cooled to room temperature. The reaction mixture and sodium hydroxide (19.7 kg) were added ?. concurrently for 2 hours to a mixture of water (12 kg), 60% by weight of aqueous hexafluorophosphoric acid (2.87 kg, 11.71 mol) and 4.7 N sodium hydroxide (2.3 kg) at < 9 ° C. The reaction flask was washed with dimethylformamide (0.36 kg) and added to the final mixture. The mixture was aged for 40 minutes and then filtered. The crude solid was washed with water (8.6 kg). The solid recrystallized from water (10.8 kg) and isopropanol (3.8 kg) by heating to 67 ° C. The mixture was cooled to 4 ° C and then filtered.
The solid was washed with water / isopropanol (11 kg, 26: 1) and dried to give the objective compound 1 as a yellow solid (2.28 kg).
EXAMPLE 2
To a suspension of compound 1-a (1.5 kg, 5.12 moles) in
THF (10 L) was added potassium butoxide (617 g, 5.5 moles) in THF (5.38 L, 5.38 moles) at < 15 ° C. Compound 1 (1.65 kg, 4.6 moles) was added and the reaction mixture was added at room temperature. The reaction mixture was converted to a solution of acetic acid (2.0 L) in THF (5 L) and the mixture was stirred for 1 hour. Concentrated aqueous ammonium hydroxide (4 L) was added and the mixture was heated to reflux for 3 hours. The mixture was cooled to 22 ° C and the layers separated. The organic layer was concentrated to 3 L and isopropyl acetate (5 L) was added. The resulting solution was again concentrated to 3-4 L and isopropyl acetate (19 L) added. The solution was washed with saturated sodium bicarbonate (2 x 9.5 L) and water (2 x 9.5 L), concentrated to dryness and purified to provide compound 2 as a solid (1.65 kg).
EXAMPLE 3
Chloroacetyl chloride (14.50 g, 0.112 mol) was added to dimethylformamide (50 mL) and the mixture was heated to 75 ° C to give a clear yellow solution. Phosphorus oxychloride (18.9 g, 0.123 mol) was added at 5 mL / h. The reaction mixture was added for 3 h then it was cooled to room temperature. The reaction mixture and 5N sodium hydroxide (70 mL) were added concurrently for 1 hour to a mixture of water (200 mL) and sodium hexafluorophosphate (21 g, 0.125 mol) at < 9 ° C. The reaction flask was washed with dimethylformamide (2 mL) and this is added to the final mixture. The mixture was aged for 40 minutes and then filtered. The crude solid was washed with water (100 mL). The solid was recrystallized from water (224 mL) and isopropanol (56 mL) by heating at 70 ° C. The mixture was cooled to 4 ° C and then filtered. The solid was washed with water / isopropanol (100 mL, 20: 1) and dried to give CDT-phosphate as a light yellow solid (26.8 g).
Claims (27)
- NOVELTY OF THE INVENTION CLAIMS 1. - A procedure for synthesizing a compound of the formula in which: 0-2 R groups are present; each R, R 'and R ", independently represents C1-10 alkyl, Cß-io aryl, aralkyl, halo, -S (O) mH, -S (O) malcly of Cr6, -S (O) maryl, nitro, amino, alkylamino of, dialkylamino of C 6, -S (O) mNH2, -S (O) mNHalkyl of Cß, -S (O) mNHC (O) CF3 and cyano, the alkyl and aryl groups , and the alkyl and aryl portions of aralkyl, -S (O) malkyls of d-6, -S (O) maryl, alkylamino of d-β, dialkylamino of C-rβ and -S (O) mNHalkyl of C 6 being optionally substituted with 1-3 groups selected from Cr4 alkyl, aryl, halo, hydroxyl, -S (O) mH, -S (O) malkyls of C? -6, -CN, d-6 alkoxy, amino, alkylamino of C? -6, dialkylamino of C -? - 6, -S (O) mNH2) -S (O) mNHalkyl of C? -6, -S (O) mNHC (O) CF3 and aryloxy; Y is C or N; and m is 0, 1 or 2, which comprises reacting a compound of formula II: < -H in which R to R each independently represent C 6 alkyl, aryl or aralkyl, and X "represents a suitable counterion, with a compound of formula III: wherein R, R 'and Y are as previously defined, in the presence of a base to produce a compound of formula I.
- 2. A process according to claim 1, further characterized in that a compound of the Formula I ': wherein R, R 'and R "are as originally defined, which comprises reacting a compound of formula II: wherein R > 2 L h-, a_s_lt.a, -. D RO and X "are as originally defined, with a compound of the formula MI ' in the presence of a base to produce a compound of formula I '.
- 3. A process according to claim 1, further characterized in that a group R is present and is C1-10 alkyl, -C1-ioyl, aralkyl, halo, -S (O) mH, - S (O) malqulo of C? -6, -S (O) marakyl, -S (O) maryl, nitro or cyano.
- 4. A process according to claim 3, further characterized in that an R is present and represents alkyl of 5. A process according to claim 4 further characterized in that an R is present which represents methyl. 6. - A method according to claim 2 further characterized in that an R is present and represents methyl < and 7. A process according to claim 1, further characterized in that Y represents N. 8. A process according to claim 1, further characterized R 'represents C ar-io aryl substituted with -S (O) malchyl of C -? - 6. 9. A process according to claim 8 further characterized in that R 'represents phenyl substituted with methanesulfcpyl at the 4' position. 10. A process according to claim 1 further characterized in that R "is selected from CMC alkyl, C & aryl, aralkyl, halo, -S (O) mH, -S (O) m alkyl 11. A process according to claim 10 further characterized in that R "is halo or aryl of C 1 -io- 12. A process according to claim 11 further characterized in that R "represents halo. 13. - A method according to claim 12 further characterized in that R "represents chlorine 14.- A method according to claim 1 • further characterized in that R2 to R5 represent d-β alkyl. 15. A process according to claim 14 further characterized in that R2 to R5 represent methyl. 16. A method according to claim 1 < • further characterized in that X- represents a member selected from the group consisting of: phosphates; sulfates; acetates; perchlorate; borates; 10 antimonatos; halides; benzoate and napsylate. 17. A process according to claim 16 further characterized in that X- represents a member selected from the group consisting of hexafluorophosphate; sulfate; mesylate; tosylate; triflate; acetate; trifluoroacetate; perchlorate; tetrafluoroborate; tetraphenylborate; Hexafluoroantimonate; chlorine; bromine; fluoro; iodo; benzoate and napsylate. 18. A process according to claim 17 further characterized in that X- represents hexafluorophosphate. 19. A process according to claim 17 further characterized in that X- represents a halide. 20. A process according to claim 19 further characterized in that the halide is chlorine. 21. A process according to claim 1 further characterized in that the base is selected from the group consisting of Na and K hydroxide; Cs carbonate; C 1-6 alkoxides of Li, Na and K; amides of Li, Na and K, and hydrides of Li, Na and K. 22. A process according to claim 21 further characterized in that the base is selected from the group consisting of: lithium isopropoxide, potassium t-butoxide, LHDMS, NaHMDS, LDA and NaH. 23.- A compound that has the structural formula: in which R to R5 each independently represent d-6 alkyl, aryl or aralkyl, R "independently represents C1-10 alkyl, Cß-io aryl, aralkyl, halo, -S (O) mH , -S (O) m alkyl of d-β, -S (O) m aryl, nitro, amino, alkylamino of d-β, di-alkylamino of C? -6. -S (O) mNH2, -S ( O) mNH alk, o of d-6, -S (O) mNHC (O) CF3 and cyano, the alkyl and aryl groups, and the alkyl and aryl portions of aralkyl, -S (O) m alkyl of C- ? -6, -S (O) maryl, C? -6 alkylamino, di-alkylamino of d-β and -S (O) mNH C 1-6 alkyl being optionally substituted with 1-3 groups selected from d-alkyl? -4, aryl, halo, hydroxyl, -S (O) mH, -S (O) m C 1-6 alkyl, -CN, C? -6 alkoxy, amino, d-β alkylamino, di-alkylamino d-β. -S (O) mNH 2, -S (O) mNH C 1-6 alkyl, -S (O) mNHC (O) CF 3 and aryloxy, and X- represents a counter ion selected from the group consisting of: hexafluorophosphate, tetrafluoroborate, tetraphenylborate and hexafluoroantimonate 24.- A compound of conformity in claim 23 represented by structural formula ll-a: ll-a wherein R "independently represents alkyl of C? -? or, aryl of C? -io. aralkyl, halo, -S (O) mH, -S (O) m alkyl of d-β. -S (O ) m aryl, nitro, amino, C? -6 alkylamino, C? -6 di-alkylamino, -S (O) mNH2, -S (O) mNH C? -6 alkyl, -S (O) mNHC (O) CF3 and cyano, the alkyl and aryl groups, and the alkyl and aryl portions of aralkyl, -S (O) malkyls of C? -6, -S (O) maryl, alkylamino of d-β, di-alkylamino of d-β and -S (O) mNHalkyl of d-β being optionally substituted with 1-3 selected groups of alkyl of d-4, aryl, halo, hydroxyl, -S (O) mH, -S (O) malkyl of C? -6, -CN, C? .6 alkoxy, amino, Ci-β alkylamino, C 1-6 alkylamino.-S (O) mNH2, -S (O) mNH alkyl of d-6 , -S (O) mNHC (O) CF3 and aryloxy, and X- represents a suitable cation 25. A compound according to claim 24 further characterized in that R "represents halo. 26. - A compound according to claim 25 further characterized in that halo is chlorine. 27. A compound according to claim 24 further characterized in that X- represents hexafluorophosphate.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/082,888 | 1998-04-24 | ||
US60/085,668 | 1998-05-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA00010438A true MXPA00010438A (en) | 2001-12-04 |
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