GB2427193A - Process for 2-amino-5-aryl-5-arylsulfonylcyclohexylmethanol derivatives - Google Patents
Process for 2-amino-5-aryl-5-arylsulfonylcyclohexylmethanol derivatives Download PDFInfo
- Publication number
- GB2427193A GB2427193A GB0611721A GB0611721A GB2427193A GB 2427193 A GB2427193 A GB 2427193A GB 0611721 A GB0611721 A GB 0611721A GB 0611721 A GB0611721 A GB 0611721A GB 2427193 A GB2427193 A GB 2427193A
- Authority
- GB
- United Kingdom
- Prior art keywords
- formula
- compound
- difluorophenyl
- hal
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 27
- -1 6- trifluoromethylpyridin-3-yl Chemical group 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 14
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 10
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 3
- 108010081348 HRT1 protein Hairy Chemical group 0.000 claims description 3
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 229960001479 tosylchloramide sodium Drugs 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 7
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000003540 gamma secretase inhibitor Substances 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 239000000243 solution Substances 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000002585 base Substances 0.000 description 14
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 12
- 238000005804 alkylation reaction Methods 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000029936 alkylation Effects 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 6
- 229940011051 isopropyl acetate Drugs 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 150000001414 amino alcohols Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 4
- YPAUWRYBCPNEPA-YWZIUSIVSA-N (3r,4as,6s,8ar)-6-(2,5-difluorophenyl)-3-ethyl-1-[(4-methoxyphenyl)methyl]-6-[4-(trifluoromethyl)phenyl]sulfonyl-4,4a,5,7,8,8a-hexahydro-3h-benzo[c]thiazine 2,2-dioxide Chemical compound N1([C@@H]2CC[C@](C[C@@H]2C[C@H](S1(=O)=O)CC)(C=1C(=CC=C(F)C=1)F)S(=O)(=O)C=1C=CC(=CC=1)C(F)(F)F)CC1=CC=C(OC)C=C1 YPAUWRYBCPNEPA-YWZIUSIVSA-N 0.000 description 3
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 3
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 3
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000002923 oximes Chemical class 0.000 description 3
- 239000011369 resultant mixture Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 238000007126 N-alkylation reaction Methods 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000002547 isoxazolines Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- OCQAXYHNMWVLRH-QZTJIDSGSA-N (2r,3r)-2,3-dibenzoyl-2,3-dihydroxybutanedioic acid Chemical compound O=C([C@@](O)(C(=O)O)[C@](O)(C(O)=O)C(=O)C=1C=CC=CC=1)C1=CC=CC=C1 OCQAXYHNMWVLRH-QZTJIDSGSA-N 0.000 description 1
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 1
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000031124 Dementia Alzheimer type Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- JQGGAELIYHNDQS-UHFFFAOYSA-N Nic 12 Natural products CC(C=CC(=O)C)c1ccc2C3C4OC4C5(O)CC=CC(=O)C5(C)C3CCc2c1 JQGGAELIYHNDQS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 1
- 125000004036 acetal group Chemical group 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical group 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229940090047 auto-injector Drugs 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- VSSAZBXXNIABDN-UHFFFAOYSA-N cyclohexylmethanol Chemical class OCC1CCCCC1 VSSAZBXXNIABDN-UHFFFAOYSA-N 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- LFPLOYLKHHNDLO-UHFFFAOYSA-N disodium;trimethylsilylazanide Chemical compound [Na+].[Na+].C[Si](C)(C)[NH-].C[Si](C)(C)[NH-] LFPLOYLKHHNDLO-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 235000020375 flavoured syrup Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000006142 intramolecular cycloaddition reaction Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- BXSDMMPOQRECKB-UHFFFAOYSA-N sodium;chloro-(4-methylphenyl)sulfonylazanide;hydrate Chemical compound O.[Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 BXSDMMPOQRECKB-UHFFFAOYSA-N 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/30—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a convenient route to compounds of formula I: <EMI ID=1.1 HE=50 WI=44 LX=840 LY=823 TI=CF> <PC>which are intermediates in the synthesis of gamma-secretase inhibitors VII: <EMI ID=1.2 HE=65 WI=42 LX=867 LY=1487 TI=CF> <PC>useful in treatment of Alzheimer's disease.
Description
PROCESS FOR
DERIVATIVES
This invention is in the field of synthetic organic chemistry, and in particular concerns a novel route to a particular class of 2-amino-5-aryl5-arylsulfonylcyclohexylmethanol derivatives, and to processes using said cyclohexylmethanol derivatives for the synthesis of compounds useful in treatment of Alzheimer's disease and related conditions.
International Patent Publication No. WO 2004/10 1539 discloses that compounds in accordance with formula: R' Ar2 SO2 Ar'SOj \__/ inhibit the processing of amyloid precursor protein (APP) by y-secretase into the amy1oid peptide.
Since said processing is believed to play a primary role in the onset and progression of Alzheimer's disease and other conditions involving deposition of 3-amyloid in the brain, the said compounds are of considerable interest for the treatment and/or prevention of such conditions.
In the above formula Ar' and Ar2 are optionally-substituted phenyl or heteroaryl, R' is H or an optionally-substituted hydrocarbon group, and the wavy lines indicate bonds which are mutually cis with respect to the cyclohexane ring.
It has subsequently been found that enantiopure compounds having the stereochemical configuration shown below: R1 1-IN 0% ol Ar are particularly potent. Therefore there is a need for an efficient synthesis of the relevant enantiopure compounds, suitable for execution on a large (eg. multikilogram) scale.
The present invention provides an efficient route to 2-amino-5,5disubstituted- cyclohexylmethanol intermediates incorporating the desired stereochemistry, and further provides methods for converting said intermediates into the end products indicated above. Certain intermediates in the above processes are novel compounds, and constitute further aspects of the invention.
According to a first aspect of the invention, there is provided a process for preparing a compound of formula 1:
OH
comprising the sequential steps of: (a) reacting a compound of formula II: O3 rac-1I firstly with hydroxylamine hydrochloride and then with an oxidising agent to form an isoxazoline of formula III:
AI Ar1
rac-III (b) reducing said isoxazoline to form the compound of formula I as a racemate; and (c) optionally resolving the racemic mixture formed in step (b) and isolating the enantiomer depicted in formula I; wherein, throughout, rac indicates a compound existing as a racemic mixture; bonds indicated by wavy lines are mutually cis with respect to the cyclohexane ring; =X represents =0, or -0-(CH2)-O- where n is 2 or 3, or -(OR2)2 where R2 is C,4alkyl; Ar' represents 4-chlorophenyl, 4-trifluoromethyiphenyl or 6- trifluoromethylpyridin-3-yl; and Ar2 represents 2,5-difluorophenyl, 2,6- difluorophenyl or 2,3,6-trifluorophenyl.
In formula II, =X represents =0, -(OR2)2 where R2 represents C,4alkyl, OCH2CH2O- or - OCH2CH2CH2O-. Thus, X completes a carbonyl group or a cyclic or acyclic acetal group. The two groups may be the same or different, but are typically the same, and suitable identities for R2 include methyl and ethyl. Most conveniently, =X represents -OCH2CH2O-.
In step (a) of the inventive process, a compound of formula 11 is treated firstly with hydroxylamine hydrochloride and secondly with an oxidising agent to form an isoxazoline Ill in racemic form. Treatment with hydroxylamine hydrochloride is typically carried out in an alcoholic or aqueous- alcoholic medium at moderately elevated temperature (eg about 70 C) using an excess of the reagent, and serves to convert the group =X to the corresponding oxime =N-OH. It is unnecessary to isolate said oxime, and the oxidising agent may simply be added to the reaction mixture after a few hours (eg. about 2 hours) at the elevated temperature, and preferably after cooling to about 50 C.
The oxidising agent serves to oxidise the oxime functionality to the corresponding nitnle oxide, typically via the corresponding hydroxamoyl chloride or bromide. A preferred oxidising agent is chloramine-T (Nchloro-p-toluenesulfonamide, sodium salt), which may be added to the reaction mixture in approximately 50% molar excess. Alternative oxidising agents include N- chlorosuccinimide, N- bromosuccinimide and sodium hypochiorite, which are preferably added in combination with a tertiary amine such as triethylamine. The oxidation is typically carried out over a period of a few hours (eg 2 hours) at moderately elevated temperature (eg about 50 C). Under the conditions described above, the initially-formed nitrile oxide undergoes intramolecular cycloaddition with the olefin functionality in 11 to form isoxazolines III. The cycloaddition is highly diastereoselective, and provides the desired cis stereochemistry relative to the Ar' SO2- subsitutent. However, the isoxazolines III are formed as a mixture of enantiomers 111(a) and 111(b): Ar-Ar' Ar 111(a) 111(b) The racemic isoxazoline III may be isolated by cooling the reaction mixture, filtering the resulting slurry and washing the solid product with aqueous ethanol. The dried product may be used in the next step without further purification.
In step (b) of the inventive process, racemic isoxazoline III is reduced to form racemic amino alcohol I. Reducing agents suitable for this purpose include diisobutylaluminium hydride (LIBALH), lithium borohydride, sodium bis(2-methoxyethoxy)aluminium hydride (RedA1TM), and borane- methyl sulfide complex, of which DIBALH is preferred. In a typical procedure, excess (eg 2-fold) DIBALH as a wt% solution in toluene is added to a slurry or solution of the isoxazoline in an aprotic solvent (such as THF), cooled to about -5 C. The mixture is heated to about 50 C for 1-2 hours, recooled to 0 C, quenched with methanol, then stirred with 2M aqueous soldium hydroxide for several hours (eg.
overnight). Thereafter, the layers are separated, and the product isolated from the organic layer. A preferred method of isolation comprises distillation of the solvent with simultaneous addition of toluene, so that subsequent cooling causes precipitation of the solid product which is collected by filtration.
In optional step (c) of the inventive process, the racemic aminoalcohol is resolved, and the enantiomer corresponding to formula 1 retained. Step (c) is optional in that it is possible, in principle, to use the racemic aminoalcohol in subsequent processes and to postpone the resolution to a later stage, e.g. to a final step. However, it is usually more efficient and economical to resolve at an early rather than a later stage in a multi-step synthesis, and it is seen as an advantage of the present invention that it enables the absolute stereochemistry of the ring junction of the ultimate product to be established at an early stage of the overall process. Any of the known methods of resolution may be employed, such as chiral HPLC or formation of diastereomeric salts or amides with a chiral acid. In a preferred embodiment, a solution of the racemic aminoalcohol (eg in THF) is treated with a solution of dibenzoylD-tartaric acid or ditoluoyl-D-tartaric acid (0.5 molar equivalents) (eg. in isopropyl acetate), causing selective crystallisation of the desired enantiomer in the form of the D-dibenzoyl- or D-ditoluoyl hemitartrate. If desired, the enantiopure aminoalcohol of formula I may be isolated as the free base by treating the above- described hemitartrate salt with excess alkali, but it is more conveniently stored (and used in subsequent processes) as the hemitartrate salt.
According to a second aspect of the invention, there is provided an enantiopure compound of formula I: NH2 OH wherein Ar1 and Ar2 are as defined above, optionally in the form of an acid addition salt. In a particular embodiment, said compound is in the form of the D-dibenzoyl hemitartrate or the D-ditoluoyl hemitartrate.
According to a third aspect of the invention, there is provided a racemate comprising the enantiomers 111(a) and 111(b) in any proportion: S02 111(a) 111(b) where Ar' and Ar2 are as defined previously.
According to a fourth aspect of the invention, there is provided a compound of formula II: x H o wherein Ar', Ar2 and X are as defined previously.
Compounds of formula II are readily prepared by alkylation of sulfones IV: Ar' -S02-CH2-Ar2
IV
with a compound of formula V and with a compound of formula VI: Y' H wherein Y' and Y2 are leaving groups and Ar', Ar2 and X are as defined previously. In principle, Y' and can be any leaving group such as halide, alkylsulfonate, arylsulfonate or triflate, but in practice Y' and are typically independently selected from Cl, Br and I. Both alkylations may be carried out via a one- pot process, eg. in DMSO solution at ambient temperature in the presence of strong base such as potassium t-butoxide. In this process, =X is preferably not =0. The synthesis of sulfones IV is described in WO 2004/013090.
A variety of processes may be used to convert the aminoalcohols I into compounds useful in the treatment of Alzheimer's disease and related conditions, including processes disclosed in the aforementioned International Publication No. WO 2004/101539.
Therefore, according to a fifth aspect of the invention there is provided a process for preparing an enantiopure compound of formula Vii: 0% R' IIN" \r2 Ar1
VII
wherein R' represents H or a hydrocarbon group of up to 10 carbon atoms, optionally substituted with CF3, CHF2, halogen, CN, C14alkoxy or di(C1alkyl)amino; and and Ar2 are as defined previously; comprising the sequential steps of: (1) providing an enantiopure compound of formula I as defined previously; (2) converting the compound of formula! into a compound of formula VIII: 0 0 Z%I Y3 Ar1
VIII
where Y3 represents a leaving group, Z represents H or a protecting group; (3) treating the compound of formula VIII with strong base to form a compound of formula LX: o o R' S Ar 0H Ar' Ix and (4) when R1 is other than H, isolating the dcsired enantiomer, and when Z represents a protecting group, removing said protecting group.
When Z represents a protecting group, said protecting group must be able to prevent N-alkylation taking place in competition with the desired ring closure in step (3) above, but must be readily cleavable under mild conditions when required. Such groups are well known in the art, and examples include benzyl, p-methoxybenzyl and allyl.
In one embodiment of this aspect of the invention, no protecting group is used (i.e. Z'H), and Y3 is R'CH2SO2-O, step (2) being carried out by treatment of the compound of formula I with 2 or more equivalents of (R'CH2SO2-O-)2 or R'CH2SO2C1 in the presence of base. In this embodiment, treatment with strong base in step (3) results in ring closure, leading directly to the product of formula VII.
However, unless R' is H, the product is formed as a diastereomeric mixture from which the desired diastereomer must be separated (eg by chiral HPLC). Alternatively, the mixture may be aged (eg for about 5 hours) with potassium t-butoxide in t-butanol at 85 C. Under these conditions, the solution becomes enriched with the desired (more thermodynamically stable) diastereomer. The cyclisation is typically carried out in an aprotic solvent such as THF at low temperature in the presence of strong base such as an alkyl lithium, an alkyl metal bis(trimcthylsilyl)amidc, or lithium diisopropylamide (LDA).
LDA is preferred.
In the absence of an N-protecting group (i.e. where Z is H), the product of the cyclisation step may be contaminated with an azetidine by-product arising from N- alkylation competing with C- alkylation. This may be prevented by appropriate use of N-protection, and in a second embodiment of this aspect of the invention, Z represents a protecting group, and step (2) comprises the following sub- steps: (i) treatment of the compound of formula I with R3SiCI and base, where each R is independently a Ci6alkyl group, to convert the -OH group into - OSiR3; (ii) treatment of the product of sub-step (i) with (R'CH2SO2-O)2 or R'CH2SO2-Cl in the presence of base to convert the -NH2 group to - NHSO2CH2R'; (iii) treatment of the product of sub-step (ii) with Z - Hal and strong base, where Hal represents Cl, Br or I, to convert the -NHSO2CH2R' group to -N(Z)SO2CH2Rt; (iv) treatment of the product of the previous sub-step with acid to regenerate the -OH group, sub-step (iv) optionally being carried out prior to sub-step (iii); and (v) conversion of the OH group to a leaving group Y3.
In the first of said sub-steps, the OH group is protected as a silyl ether -OSiR3 (where each R is independently C16 alkyl), eg. the tbutyldimethylsilyl ether. In the second sub-step, the amino group is converted to -NHSO2CH2R' by treatment with the relevant sulfonyl chloride or sulfonic anhydride as before. In the third sub-step, the -NHSO2CH2R1 group is converted to -N(Z)SO2CH2R', where Z is a protecting group, by Nalkylation with Z-Hal where Hal is Br, Cl or I. This takes place under standard alkylation conditions, e.g. in DMF in the presence of a strong base such as sodium hydride. If necessary, the silyl ether group is cleaved by treatment with acid to regenerate the -OH group, but in practice this sub-step may conveniently be combined with sub-step (ii) by including an acid-wash as part of an aqueous extractive work-up in that sub-step. In the final sub-step the OH group is converted to a leaving group Y3. In principle, Y3 can be any leaving group, but is most conveniently a sulfonate ester RaSO2O, where R is Ci6alkyl, optionally bearing up to 3 halogen substituents, or phcnyl, optionally bearing up to 3 substituents selected from halogen and C16alkyl, formed by reaction with (RaSO2O)2 or r-sO2Cl as before. Typically R is methyl, and Y3 is mesylate.
A variation of the second embodiment comprises use of methanesulfonyl chloride or methanesulfonic anhydride in sub-step (ii) (i.e. R' is H), and an additional step, prior to the removal of the protecting group, of alkylating the product IX (R'=H) with R'-Y4 to form a compound of formula IX(a): 0 0 s Ai 0;iri IX(a) where Y4 is a leaving group and R represents R' that is other than H. The alkylation takes place under standard conditions, eg, in THF at about 0 C in the presence of a base such as an alkali metal bis(trimethylsilyl)amide, and proceeds with a high degree of stereoselectivity, producing the desired diastereomer in high yield. In principle, Y4 can be any suitable leaving group, but typically Y4 is Cl, Br on.
In a preferred route to compounds of formula VII in which R' is other than H, ring closure and N- protection are carried out sequentially in a one-pot process, and are followed by alkylation with R-Y4 as described above. Therefore, according to a sixth aspect of the invention there is provided a process for preparing an enantiopure compound of formula VII(a): % R1 I-ll'T 0% ol Ar1 VII(a) wherein R1" represents a hydrocarbon group of up to 10 carbon atoms, optionally substituted with CF3.
CHF2, halogen, CN, C 1alkoxy or di(Ci4alkyl)amino; and and Ar2 are as defined previously; comprising the sequential steps of: (a) reacting an enantiopure compound of formula I as defined previously with at least two equivalents of methanesulfonyl chloride or methanesulfonic anhydride in the presence of base to form a compound of formula X(a): /SO2MC Y (a) Y = McSO2-0 (b) Y = Hal OS Ar Ar'
X
(b) optionally reacting the compound of formula X(a) with M-Hal to form a compound of formula X(b), where M is a cation and Hal is Cl, Br or I; (c) treating the compound of formula X(a) or X(b) with strong base and then with Z-Hal to form a compound of formula XI: \\ oI Ar Ar1
XI
where Z is a protecting group; (d) reacting the compound of formula XI with R1aY4, where Y4 is a leaving group, and strong base; and (c) removing the protecting group Z. In step (a) of the process according to said sixth aspect of the invention, an enantiopure aminoalcohol of formula I is treated with at least two equivalents of MeSO2C1 or (MeSO2-O- )2 to form the bis-mesylate X(a). This intermediate may be cyclised directly as described previously, but in a preferred embodiment it is treated in situ with M-Hal so as to replace the mesylate ester leaving group with Hal, where Hal is Cl, Br or I, and M is a cation such as lithium, sodium, potassium, ammonium or mono-, di-, tn- or tetrailcylammonium. The resulting compound of formula X(b) may be cyclised in the subsequent step with less risk of N-alkylation competing with the desired C-alkylation. In a typical procedure, step (a) is carried out in dichloromethane at about 10 C in the presence of triethylamine. -11 -
Thereafter, DMF is added, dichioromethanc is distilled off, sodium bromide is added, the mixture heated at about 85 C for about 7 hours, then the intermediate X(b) (Y=Br) isolated by precipitation following dilution with water.
In step (c) of the process according to the sixth aspect of the invention, the intermediate of formula X(a) or X(b) is treated with strong base so as to effect ring-closure via C-alkylation in the same manner as the conversion of VIII to IX described previously. However, as part of the same procedure, an N-protecting group Z is attached by adding Z-Hal to the reaction mixture. in a preferred procedure, the compound of formula X(a) or X(b) in THF is added to a 2 to 3-fold excess of LDA in THF while maintaining a low temperature (eg. below -45 C). After several hours at this temperature, the mixture is treated with excess Z-Hal, preferably in combination with sodium iodide and dimethylacetamide and after addition of water to the mixture, and warmed to ambient temperature to complete the reaction. The resulting compound of formula Xl is typically isolated by aqueous extractive work-up, e.g. by diluting the mixture with aqueous HC1 and toluene, separating and washing the organic layer, distilling off the THF with addition of further toluene, and addition of heptane to precipitate the product.
In subsequent steps of the process according to the sixth aspect of the invention, alkylation with RhY4 is carried out in the same manner as described previously for the synthesis of compounds IX(a), then the protecting group Z is removed, to generate the compound of formula VII(a).
In all of the above-described processes involving an N-protecting group represented by Z, the preferred identities for Z are allyl, benzyl and pmethoxybenzyl, of which p-methoxybenzyl is most preferred. These groups may be removed when required by well-known procedures. For example, an allyl group may be cleaved by treatment with DIBALH in the presence of [Ph2PCH2CH2CH2PPh2]NiC12; a bcnzyl group may be removed by hydrogenation over a Pd/C or a Pd(OH)2/C catalyst; and a p- methoxybenzyl group may be removed by similar hydrogenation, or by treatment with acid, eg. a mixture of thioglycolic acid and methanesulfonic acid.
In all the above-described processes, Ar' preferably represents 4chiorophenyl or 4- trifluoromethyiphenyl, most preferably 4-trifluoromethylphenyl, and Ar2 preferably represents 2,5difluorophenyl.
In the processes involving alkylation with RIaY4, Y4 is preferably Cl, Br or 1, and R is preferably an unsubstituted C,6allcyl group such as methyl, ethyl, or n-propyl or isopropyl, or a C2.
6alkenyl group such as allyl. In a preferred embodiment, Ria represents ethyl.
It will be appreciated that the processes described above, constituting the fifth and sixth aspects of the invention, may also be carried out on the racemic aminoalcohols of formula I, provided that an additional resolution step is carried out at some point during the said processes, eg. as a final step.
However, use of the enantiopure aminoalcohols is preferred.
Those skilled in the art will appreciate that although the term "enantiopure" in its strictest sense would imply the presence of one enantiomer to the total exclusion of the other, such a high degree of purity is rarely, if ever, achievable in practice. Thus, as used herein, the term "enantiopure" will be understood to mean a high excess of the indicated enantiomer, without excluding minor amounts of the alternative enantiomer.
The compounds of fonnulac VII and VII(a) have an activity as inhibitors of the processing of APP by y secretase, and are therefore useful in the treatment or prevention of disorders involving excessive secretion andlor deposition of -amyloid, in particular Alzheimer's disease.
The said compounds may be used to prepare pharmaceutical compositions comprising one or more of the said products or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a phannaceutical carrier, such as the conventional tableting ingredients known to those skilled in the art, e.g. as described in WO 01/70677, and formed into unit dosage forms. Typical unit dosage forms contain from I to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. Tablets or pills of the composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, as described, for example, in WO 0 1/70677.
The liquid forms in which the compositions may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils, as described in WO 01/70677.
For treating or preventing Alzheimer's disease, a suitable dosage level of the active ingredient is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.1 to mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day. In some cases, however, dosage outside these limits may be used.
Assays for determining the level of activity of the relevant compounds towards y-secretase are disclosed in WO 0 1/70677 and in Biochemistry, 2000, 39(30), 8698-8704. See also, J. Neuroscience Methods, 2000, 102, 6 1-68.
EXAMPLES
Example I
2-(3-(2,5-difluorophenyl)-3- { [4-trifluoromethyl)phenvllsulfonvl} hex-Sen-i -VI)- I.3-dioxolane To a solution of 1,4-difluoro-2-( { [4trifluoromethyl)phenyl]sulfonyl}methyl)benzene (WO 2004/013090) (12.70 kg, 37.8 mol) in DMSO (33.8 L) was added a solution of potassium tert-butoxide (4.66 kg, 41.5 mol) in DMSO (17 L) maintaining the temperature below 25 C. The resultant mixture was cooled to 15 C and 2-(2-bromoethyl)-i,3-dioxolane (7.85 kg, 43.4 mol) added maintaining the temperature below 20 C. The reaction mixture was aged at ambient temperature for 105 minutes and then cooled to 15 C and a solution of potassium tert-butoxide (6.77 kg, 60.3 mol) in DMSO (23.8 L) added. The mixture was aged for 30 minutes and then added to a solution of allyl bromide (16.0 kg, 132 mol) in DMSO (34.8 L) maintaining the internal temperature below 25 C. Water (36.0 L) was added at ambient temperature, the resultant slurry was filtered and the solid washed with a 2:1 mixture of DMSO:water (16 kg) and then water (2 x 15 kg). Drying in vacuo afforded 2-(3-(2,5-difluorophenyl)-3- {[4trifluoromethyl)phenyl]sulfonyl}hex-5-en-1-yl)-1,3-dioxolane (14.2 kg, 79%). H NMR (400 MHz, CDC13) 6 7.67 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz), 7.07 (2H, m), 6.82 (1H, ddd, J = 4.8, 9.0, 12.2 Hz), 5.92 (1H, m) , 5.28 (lH, dq, J = 1.6, 17.0 Hz), 5.20 (IH, dq, J = 1.4, 10.2 Hz), 4.91 (IH, t, J = 4.4 Hz), 3.93 (4H, m), 3.30 (1H, m), 3.12 (1H, m), 2.51 (2H, m), 2.02 (IH, m), 1.58 (1H, m).
Example 2
Cis-5-(2,5-difluorophenyl)-5- { [4-trifluoromethyl)phenyllsulfonyl I -3, 3a,4.5.6.7-hexahydro-2, 1- benzisoxazole 2-(3-(2,5-Difluorophenyl)-3 - { [4-trifluoromethyl)phenyl]sulfonyl} hex-5- en- l-yl)-l,3-dioxolane (Example 1) (28.0 kg, 58.8 mol) and hydroxylamine hydrochloride (5.31 kg, 76.0 mol) in ethanol (140 L) and water (28 L) was aged at 70 C for 2 hours and then cooled to 50 C. A solution of chloramine-T hydrate (20.1 kg, 88.2 mol) in water (56 L) and ethanol (196 L) was then added and the mixture aged at 50 C for 2 hours before cooling to ambient. The resultant slurry was filtered and the solid washed with a 4:1 mixture of ethanol:water (20 L). Drying in vacuo furnished cis-5-(2,5difluorophenyl)-5-{[4- trifluoromethyl)phenyl]sulfonyl} -3,3a,4,5,6,7-hexahydro-2, 1 - benzisoxazole (21.4 kg, 84%). H NMR (400 MHz, CDC13) 6 7.73-7.70 (2H, m), 7.61-7.55 (2H, m), 7.23-7.10 (2H, m) , 6.95-6.85 (1H, m), 4.60 (1H, app t, J = 8.4 Hz), 3.92 (1H, dd, J = 8.4, 10. 4 Hz), 3.25-2.90 (4H, m), 2.40-2.06 (3H, m).
Example 3
((1K. 2S. 5R)- and ((18. 2R, 58)-2-amino-5-(2,5-difluorophenyl)-5-114(trifluoromethyl)phenyllsulfonyll cyclohexyllmethanol cis-5-(2,5-Difluorophenyl)-5- { [4-trifluoromethyl)phenyl]sulfonyl} -3,3a, 4,5,6,7-hexahydro-2, 1- benzisoxazole (Example 2) (50.0 g, 112 mmol) was slurried in tetrahydrofuran (300 mL) and cooled to -5 C. Diisobutylaluminum hydride (2Owt% in toluenc, 212 mL, 252 mmol) was added maintaining the temperature below -3 C. The resultant solution was aged for 1.5 hours, warmed to 50 C for 1.5 hours and then recooled to 0 C. Methanol (10 mL) was added maintaining the temperature below 15 C and then aqueous sodium hydroxide (2M, 300 mL) was added. The mixture was stirred for 14 hours and then the layers separated. The organic layer was distilled to a volume of 250 mL whilst toluene (250 mL) was added. The mixture was allowed to cool and the resultant slurry was filtered and the solids washed with toluene (50 mL). Drying in vacuo furnished ((1R, 2S, 5R)- and ((is, 2R, 58)-2-amino-5-(2,5- difluorophenyl)-5- { [4-(trifluoromethyl)phenyl]sulfonyl} cyclohexyl) methanol (40.9 g, 82%).
- 14 - H NMR (400 MHz, d6-DMSO, 80 C) 6 7.88 (2H, d, J = 8.3 Hz), 7.67 (2H, d, J = 8.3 Hz), 7.26 (1H, m), 7.08 (2H, m), 3.40 (2H, m), 3.08 (1H, m), 2.47 (2H, m), 2.40 (1H, d, J = 12.8 Hz), 2.25 (1H, t, J = 12.8 Hz), 1.69 (1H, m), 1.36 (211, m).
Example 4
((iS, 2R, 58)-2-amino-5 -(2,5-difluorophenyi)-5- { [4trifluoromethvi)phenyilsuifonyii cyclohexyi)methanol D-dibenzoyl hemitartrate To a solution of ((1R, 2S, 5R)- and ((iS, 2R, 55)-2-amino-5-(2,5- difluorophenyl)-5-{[4(trifluoromethyl)phenyl]sulfonyl}cyciohexyl)methanoi (Example 3) (7.5 kg, 16.7 mol) in tetrahydrofuran (56.3 L) was added a solution of dibenzoyl-D-tartaric acid (2.99 kg, 8.34 mol) in isopropyl acetate (56.3 L) maintaining the temperature below 25 C. The resultant mixture was aged overnight, filtered and the solids washed with tetrahydrofuran/isopropyl acetate (1:1, 22.5 L), followed by tetrahydrofuran (22.5 L).
Drying in vacuo afforded ((15, 2R, 5S)-2-amino-5-(2,5-difluorophenyl)-5- { [4- trifluoromethyl)phenyl]sulfonyl} cyclohexyl)methanol D-dibenzoyl hemitartrate (4.05 kg, 39%, 96.1% enantiomeric excess). 1H NMR (400 MHz, cL,-MeOH) 68.18-8.13 (2H, m), 7.83-7.80 (2H, m), 7.63-7.60 (2H, m), 7.59-7.51 (lH, m), 7.45-7.42 (2H, m), 7.25-6.95 (3H, m), 5.89 (1H, s), 3.75-3.52 (2H, m) 3.49- 3.42 (111, m), 2.85-2.80 (1H, m), 2.58-2.45 (1H, m), 2.40-2.30 (2H, m), 2. 08-1.98 (1H, m), 1.73-1.53 (2H, m).
Example 5
N-(( 1R. 2S. 48)-2-bromomethyl-4-(2,5-difluorophenyl)-4- 114(trifluoromethyl)pheny11sulfonyl cyclohexyl)methanesulfonamide To a slurry of((1S, 2R, 5S)-2-amino-5-(2,5-difluorophenyl)-5-{[4trifluoromethyl)phenyl]sulfonyl} cyclohexyl)methanol D-dibenzoyl hemitartrate (Example 4) (4.10 kg, 3.3 mol) in dichloromethane (76.0 kg) was added 0.4 N NaOH (23.5 kg, 9.4 mol) and the resultant mixture aged for 45 minutes. The lower organic layer was separated and washed with water (13 kg) and then reduced in volume to 12 L by distillation. Triethylamine (1.67 kg, 16.5 mol) was added followed by a solution of methanesulfonic anhydride (2.83 kg, 16.3 mol) in methylene chloride (11 kg) maintaining the temperature below 10 C. Dimethylformamide (30 kg) was then added andthe mixture distilled to remove the dichloromethane and reach a volume of 34 L. Sodium bromide (1. 34 kg, mol) was added and the batch heated to 85 C for 7 hours. Dimethylformamide (7 kg) was added followed by water (35 L) to crystallise the product. The resultant slurry was filtered and the solid washed with water (2 x 5 L).
Drying in vacuo furnished N-(( 1 R, 2S, 45)-2-bromomethyl-4-(2,5difluorophenyl)-4- { [4- (trifluoromethyl)phenyl]sulfonyl} cyclohexyl)methanesulfonamide (3.49 kg, 91%). H NMR (400 MHz, d6-DMSO, 80 C) 6 7.89 (2H, d, J = 8.4 Hz), 7.67 (2H, d, J = 8.4 Hz), 7.28 (1H, m), 7.15 (IH, d, J 7.3 Hz), 7.10 (2H, m), 3.68 (1H, m), 3.62 (IH, dd, J = 6.6, 10.1 Hz), 3.52 (1H, bt, J = 8.2 Hz), 2.97 (3H, s), 2.79 (IH, bm), 2.60 (1H, bm), 2.45 (IH, m), 2.22 (IH, t, J = 13.5 Hz), 2. 03 (1H, m), 1.82 (1H, m), 1.43 (IH, m).
- 15 -
Example 6
(4aS. 6S, 8aTh-6-(2,5-difluorophenyl)- 1 -(4-methoxybenzyl)-6- [4trifluoromethyl)phenyl]sulfonyl I octahydro- 1H-2, 1 -benzothiazinc 2.2dioxide Tetrahydrofuran (14.7 kg) was cooled to below -60 C and hexyllithium (5.2 kg of a 2.28 M solution in hexane, 16.8 mol) was added maintaining the temperature below -20 C. Diisopropylamine (1.78 kg, 17.6 moles) was then added maintaining the temperature below -20 C. The resultant solution was cooled to -60 C and then a solution of N-(( I R, 2S, 45)-2-bromomethyl-4-(2,5- difluorophenyl)-4- { [4(trifluoromethyl)phenyl]sulfonyl} cyclohexyl)methanesulfonamide (Example 5) (3.22 kg, 5.45 mol) in tetrahydrofuran (4.8 kg) added maintaining the temperature below -45 C. The resultant solution was aged for 3 h and then water (0.11 kg, 6.15 mol) was added maintaining the temperature below -40 C. The solution was allowed to warm to -20 C and a solution of sodium iodide (0.42 kg, 2.80 mol) in N,N-dimethylacetamide (8.66 kg) was added, followed bypara- methoxybenzylchloride (1.58 kg, 10.1 mol). The mixture was warmed to room temperature and aged to reach full conversion. A solution of HC1 [1.64 L of cone. HCI (specific gravity 1.18) diluted with 17 L water, 19.4 mol] was added maintaining the temperature below 50 C. Toluene (44.3 kg) was added and the layers were separated. The organic was washed with water (3 x 8.9 kg) and then distilled to reach a volume of 22.5 L, adding toluene as necessary to reach a residual tetrahydrofuran content of <2 mol%.
Heptane (12.6 kg) was added and the resultant slurry was filtered, and washed with a 1:1 mixture of toluene and heptane (2.8 kg of each), followed by heptane (2.8 kg). Drying in vacuo furnished (4aS, 6S, 8aR)-6-(2,5-difluorophenyl)- 1 -(4-methoxybenzyl)-6- { [4-trifluoromethyl) phenyl}sulfonyl} octahydro- 1 H- 2,1-benzothiazine 2,2-dioxide (3.05 kg, 89%). H NMR (400 MHz, d6-DMSO, 85 C) 6 7.85 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.1 Hz), 7.37 (2H, d, J = 8.4 Hz), 7.30-7.23 (lH, m), 7.13-7.05 (2H, m), 6.92 (2H, d, J = 8.5 Hz), 4.53 (1H, d, J = 16.6 Hz), 4.11 (1H, d, J = 16.6 Hz), 3.82 (3H, s), 3.50 (1H, br s), 3.35 (1H, dt, J = 3.7, 13.7 Hz), 3.25-3.18 (1H, m), 2.69-2.60 (1H, m), 2.48-2. 40 (1H, m), 2.38-2.25 (1H, m), 2.21-2.11 (2H, m), 2.10-2.01 (1H, m), 1.79-1.68 (2H, m), 1.40-1.28 (IH, m) .
Example 7
(3R. 4aS, 6S, 8aR)-6-(2,5-difluoroyhenyl)-3-ethyl- I -(4-methoxybenzvl)-6[4- (trifluoromethyl)phenyllsulfonyl} octahydro- 1H-2, 1 -benzothiazine 2,2- dioxide A solution of (4aS, 6S, 8aR)-6-(2,5-difluorophenyl)- 1 -(4-methoxybenzyl)- 6- { [4- trifluoromethyl)phenyl]sulfonyl} octahydro- I H-2, 1 -benzothiazine 2,2- dioxide (Example 6) (2.97 kg, 4.7 mol) and ethyl iodide (1.03 kg, 6.60 mol) in tetrahydrofuran (26.3 kg) was cooled to -5 C. Sodium bis(trimethylsilylamide) (1.OM in THF, 5.97 kg, 6.60 mol) was then added maintaining the temperature below 1 C. The mixture was aged for 80 minutes and then an aqueous citric acid solution (0.55 kg citric acid, 2. 84 mel in 28.3 kg water) was added maintaining the temperature below 8 C. Methyl tert-butyl ether (22 kg) was added and the layers were allowed to settle. The organic layer was washed with water (8.91 kg) and then distilled to a volume of 34 L. The mixture was further distilled adding isopropanol (80.2 kg) to reach a final volume of 34 L. The resultant slurry was cooled and filtered and the solid washed with isopropanol (2.70 kg). Drying in vacuo furnished (3R, 4aS, 6S, 8aR)-6-(2,5-difluorophenyl)- 3-ethyl-I -(4-methoxybenzyl)-6- { [4-(trifluoromethyl)phenyl]sulfonyl} octahydro- 1 H-2, 1 -ben.zothiazine 2,2-dioxide (2.74 kg, 88%). H NMR (400 MHz, d6-DMSO, 85 C) 8 7.87 (2H, d, J = 8.0 Hz), 7.56 (2H, d, J = 7.2 Hz), 7.40 (2H, d, J = 8.0 Hz), 7.3 1-7. 25 (1H, m), 7.18-7.03 (2H, m), 6.94-6.90 (2H, d, J 8.0 Hz), 4.55 (1H, d, J = 17.2 Hz), 4.17 (IH, d, J = 16.8 Hz), 3.81 (3H, s), 3.49-3.48 (1H, m), 3.28-3.19 (1H, m), 2.70-2.61 (1H, m), 2.52-2.43 (1H, m), 2.20-1.92 (5H, m), 1.75-1.67 (2H, m), 1.60-1.49 (1H, m), 1.38- 1.28 (lH, m), 1.10 (3H, t, J = 7.2 Hz).
Example 8
(3R. 4aS, 6S. 8aR)-6-(2,5-difluorohenyl)-3-ethyl-6- [4-(trifluoromethyl) phenyllsulfonyl} octahydro- 1H- 2.1 -benzothiazine 2,2-dioxide To a stirred solution of (3R, 4aS, 6S, 8aR)-6-(2,5-difluorophenyl)-3 - ethyl-i -(4-methoxybenzyl)-6- { [4- (trifluoromethyl)phenyl]sulfonyl} octahydro1H-2, 1 -benzothiazine 2,2- dioxide (Example 7) (2.74 kg, 4.16 mol) in dichloromethane (18 L) at 0 C was added thioglycolic acid (1.53 kg,16.6 mol). A solution of methanesulfonic acid (1.21 kg, 12.5 mol) in dichloromethane (2 L) was added maintaining the temperature below 5 C. The reaction was then aged 30 minutes and then 2M NaOH solution (18 L, 36 mol) added maintaining the internal temperature below 10 C. The lower organic layer was diluted with isopropyl acetate (35 L) and the combined organics washed sequentially with 2M NaOH (18 L, 36 mol) and then water (17 L). The organic layer was distilled to a volume of 15 Land further isopropyl acetate (20 L) added. The solution was again distilled to a volume of 15 L and then heptane (12.5 L) added to crystallise the product. The solid was isolated by filtration and washed with 2:1 heptane:isopropyl acetate (5 L). Drying in vacuo furnished (3R, 4aS, 6S, 8aR)-6-(2,5-difluorophenyl) -3-ethyl-6-{[4(trifluoromethyl)phenyl]sulfonyl} octahydro- I H-2, 1 -benzothiazine 2,2dioxide (1.97 kg, 89%). H NMR (400 MHz, d6-DMSO, 85 C) 6 7.88 (2H, d, J = 7.9 Hz), 7.65 (2H, d, J = 7. 6 Hz, 7.30-7.23 (1H, m), 7.22- 7.05 (2H, m), 7.00-6.95 (1H, m), 3.48-3.40 (IH, m), 2.96-2.89 (1H, m), 2. 63-2.38 (4H, m), 2.10-1.95 (1 m), 1.90-1.79 (3H, m), 1.65-1.35 (3H, m), 1. 05 (3H, t, J = 7.6 Hz).
Claims (11)
1. A process for preparing a compound of formula I: NH2 OH comprising the sequential steps of: (a) reacting a compound of formula II: os rac-Il firstly with hydroxylamine hydrochloride and then with an oxidising agent to form an isoxazoline of formula III:
O Ar2 Ar1
rac-Ill (b) reducing said isoxazoline to form the compound of formula I as a racemate; and (c) optionally resolving the racemic mixture formed in step (b) and isolating the cnantiomer depicted in formula 1; wherein, throughout, rac indicates a compound existing as a racemic mixture; bonds indicated by wavy lines are mutually cis with respect to the cyclohexane ring; =X represents =0, or -0-(CH2)-0- where n is 2 or 3, or -(OR2)2 where R2 is C,4alkyl; Ar' represents 4-chiorophenyl, 4-trifluoromethyiphenyl or 6- trifluoromethylpyridin-3-yl; and Ar2 represents 2,5-difluorophenyl, 2,6- difluorophenyl or 2,3,6-trifluorophenyl.
2. The process of claim 1 wherein =X represents -CH2CH2O-.
3. The process of claim I or claim 2 wherein the oxidising agent in step (a) is chloramine-T.
4. A process according to any previous claim wherein the reducing agent used in step (b) is DIBALH.
5. A process according to any previous claim wherein step (c) is carried out by formation and selective crystallisation of the D-dibenzoyl hemitartrate or D-ditoluoyl hemitartrate salt.
6. A process for preparing an enantiopure compound of formula V1I(a): O% R1' HN" \ O*I Ar1 VII(a) wherein R' represents a hydrocarbon group of up to 10 carbon atoms, optionally substituted with CF3, CHF2, halogen, CN, C,alkoxy or di(C,4alkyl)amino; and Ar1 and Ar2 are as defined previously; comprising the sequential steps of: (a) providing an enantiopurc compound of formula I by the process of any previous claim and reacting same with at least two equivalents of methanesulfonyl chloride or methanesulfonic anhydride in the presence of base to form a compound of formula X(a): /SO2Me Fll Y (a) Y = MeSO2-0 (b)Y= Hal 0'S Ar Ar1 x (b) optionally reacting the compound of formula X(a) with M-Hal to form a compound of formula X(b), where M is a cation and Hal is Cl, Br or 1; (c) treating the compound of formula X(a) or X(b) with strong base and then with Z-Hal to form a compound of formula XI: \\ Z,,..S 0 \, Ai2 Ar1
XI
where Z is a protecting group; (d) reacting the compound of formula XI with RlaY4, where Y4 is a leaving group, and strong base; and (e) removing the protecting group Z.
7. A process according to claim 6 wherein Z represents p-methoxybenzyl and is removed in the final step by treatment with acid or by hydrogenation.
8. A process according to claim 6 or claim 7 wherein Ria represents ethyl.
9. A process according to any previous claim wherein Ar' represents 4trifluoromethylphenyl and Ar2 represents 2,5-difluorophenyl..
10. An enantiopure compound of formula I:
OH Art (I)
or the D-dibcnzoyl hemitartrate or D-ditoluoyl hemitartratc salt thereof, wherein Ar' and Ar2 are as defined in claim 1.
11. The enantiopure compound of claim 10 wherein Ar' is 4trifluoromethylphenyl and Ar2 is 2,5-difluorophenyl.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0512049.8A GB0512049D0 (en) | 2005-06-14 | 2005-06-14 | Chemical process |
Publications (2)
Publication Number | Publication Date |
---|---|
GB0611721D0 GB0611721D0 (en) | 2006-07-26 |
GB2427193A true GB2427193A (en) | 2006-12-20 |
Family
ID=34855475
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GBGB0512049.8A Ceased GB0512049D0 (en) | 2005-06-14 | 2005-06-14 | Chemical process |
GB0611721A Withdrawn GB2427193A (en) | 2005-06-14 | 2006-06-14 | Process for 2-amino-5-aryl-5-arylsulfonylcyclohexylmethanol derivatives |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GBGB0512049.8A Ceased GB0512049D0 (en) | 2005-06-14 | 2005-06-14 | Chemical process |
Country Status (1)
Country | Link |
---|---|
GB (2) | GB0512049D0 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004101538A1 (en) * | 2003-05-16 | 2004-11-25 | Merck Sharp & Dohme Limited | Cyclohexyl sulphones as gamma-secretase inhibitors |
-
2005
- 2005-06-14 GB GBGB0512049.8A patent/GB0512049D0/en not_active Ceased
-
2006
- 2006-06-14 GB GB0611721A patent/GB2427193A/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004101538A1 (en) * | 2003-05-16 | 2004-11-25 | Merck Sharp & Dohme Limited | Cyclohexyl sulphones as gamma-secretase inhibitors |
WO2004101539A1 (en) * | 2003-05-16 | 2004-11-25 | Merck Sharp & Dohme Limited | Cyclic sulfonamides for inhibition of gamma-secretase |
Non-Patent Citations (2)
Title |
---|
"3,4-Fused cyclohexyl sulfones as gamma-secretase inhibitors" * |
"Practical asymmetric synthesis of a gamma secretase exploiting substrate-controlled intramolecular nitrile oxide-olefin cycloaddition" * |
Also Published As
Publication number | Publication date |
---|---|
GB0611721D0 (en) | 2006-07-26 |
GB0512049D0 (en) | 2005-07-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8877798B2 (en) | 1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders | |
US20070259854A1 (en) | Triazole Derivative or Salt Thereof | |
FR2783246A1 (en) | 3-Alkyl sulfonyl methylene azetidine derivatives with strong affinity for cannabinoid receptors, and useful for treatment of e.g. central nervous system or immune system | |
WO2006084975A1 (en) | Derivatives of n-[(4,5-diphenyl-3-alkyl-2-thienyl) methyl] amine (amide, thiourea and urea) as cannabinoid cb1 receptor antagonists | |
JP2002530276A (en) | New piperazine and piperidine compounds | |
WO2010059922A1 (en) | Pyrrolidine carboxamide compounds | |
KR20080089413A (en) | 4,5-dihydro-(1h)-pyrazole derivatives as cannabinoid cb1 receptor modulators | |
US6878732B2 (en) | NK1 antagonists | |
WO2011002103A2 (en) | A cycloalkane derivative | |
US20030144270A1 (en) | NK1 antagonists | |
PL192561B1 (en) | Substituted benzylamines and their application in treating depressions | |
FR2906251A1 (en) | PYRROLIZINE, INDOLIZINE AND QUINOLIZINE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF | |
FR2880023A1 (en) | New N-((4,5-diphenyl-3-alkyl-2-thienyl)methyl)methyl amine derivatives are cannabinoids receptor inhibitor useful to treat or prevent e.g. gastro-intestinal disorders, inflammatory phenomena and diseases of the immune system | |
MX2010010446A (en) | (hetero-)aryl cyclohexane derivatives. | |
KR20120101711A (en) | Tricyclic antibiotics | |
US4925867A (en) | Hydrocarbon substituted pyrrolidinones, intermediates therefor, and anti-convulsant use thereof | |
EP3350173B1 (en) | Stereoselective process | |
GB2427193A (en) | Process for 2-amino-5-aryl-5-arylsulfonylcyclohexylmethanol derivatives | |
WO2012171248A1 (en) | 1,3-oxazolidine-2-one-like compound, preparation method and uses thereof | |
JP2008088057A (en) | N-substituted-n-(4-piperidinyl)amide derivative | |
CA2738041A1 (en) | Oxopiperidinyl and pyranyl sulfonamides as ampa potentiators | |
WO2015081920A1 (en) | Process for preparing lurasidone and intermediate thereof | |
WO2006030931A1 (en) | N-substituted n-(4-piperidinyl)amide derivative | |
JP2010535716A (en) | Renin inhibitor | |
LACI et al. | NK1 ANTAGONISTS |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |