CA2056063A1 - Aminodiol derivatives - Google Patents
Aminodiol derivativesInfo
- Publication number
- CA2056063A1 CA2056063A1 CA002056063A CA2056063A CA2056063A1 CA 2056063 A1 CA2056063 A1 CA 2056063A1 CA 002056063 A CA002056063 A CA 002056063A CA 2056063 A CA2056063 A CA 2056063A CA 2056063 A1 CA2056063 A1 CA 2056063A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- cycloalkyl
- aryl
- radicals
- hydrogen
- 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.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 4
- 108010010369 HIV Protease Proteins 0.000 claims abstract description 3
- 108090000783 Renin Proteins 0.000 claims abstract description 3
- 102100028255 Renin Human genes 0.000 claims abstract description 3
- 239000003112 inhibitor Substances 0.000 claims abstract description 3
- 150000003254 radicals Chemical class 0.000 claims description 31
- -1 (C1-C7)-alkoxy Chemical group 0.000 claims description 23
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000006622 cycloheptylmethyl group Chemical group 0.000 claims description 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 2
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 150000005840 aryl radicals Chemical class 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 7
- 125000006621 (C3-C8) cycloalkyl-(C1-C6) alkyl group Chemical group 0.000 claims 3
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
- 125000002619 bicyclic group Chemical group 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 150000001721 carbon Chemical group 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- VJCHUDDPWPQOLH-UHFFFAOYSA-N trimethyl(1,3-thiazol-2-yl)silane Chemical compound C[Si](C)(C)C1=NC=CS1 VJCHUDDPWPQOLH-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 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
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 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
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- QFFVPLLCYGOFPU-UHFFFAOYSA-N barium chromate Chemical compound [Ba+2].[O-][Cr]([O-])(=O)=O QFFVPLLCYGOFPU-UHFFFAOYSA-N 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 238000000451 chemical ionisation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- XPYGGHVSFMUHLH-UUSULHAXSA-N falecalcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(O)(C(F)(F)F)C(F)(F)F)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C XPYGGHVSFMUHLH-UUSULHAXSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000007871 hydride transfer reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- IUKIKGAICKWMEB-JTQLQIEISA-N tert-butyl n-[(2s)-1-cyclohexyl-1-oxopropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C)C(=O)C1CCCCC1 IUKIKGAICKWMEB-JTQLQIEISA-N 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003555 thioacetals Chemical class 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IUNXOGIHFLDANL-UHFFFAOYSA-M triphenyl(pyridin-2-ylmethyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CC1=CC=CC=N1 IUNXOGIHFLDANL-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
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Abstract
Abstract of the disclosure Aminodiol derivatives The invention relates to compounds of the formula
Description
20a61~
HOECHST ARTIENGE5ELLSCHAFT HOE 90JF 353 Dr. JA/AP
Description Aminodiol derivatives The invention relates to compounds of the formula Ia or Ib R 3 (S) ~ R S
R - N ~ C~R
~ (Ia) 6/\
R 3 ~ R 5 R--N"" (R~--~0 R2 ~ O (Ib) ,~
and their salts, in which R1 is R -W-;
W is -CO-, -O-CO-, -SO2- or -NH-CO-;
R~ is hydrogen, (C1-C10)-alkyl which is optionally mono- or diunsaturated and which is optionally ~ubstituted by up ; '' ' 2~5B~
to 3 identical or different radicals from the series comprising hydroxyl, (Cl-C7)-alkoxy, (C1-C7)-alkanoylo y, carboxyl, (Cl-C7)-alkoxycarbonyl, halogen, amino, (C1-C7)-alkylamino, di-(Cl-C7)-alkylamino, (C1-C5)-alko ycarbonyl-amino and (C7-CIs)-aralko ycarbonylamino, (C3-C8)-cyclo-alkyl, (C3-C8)-cycloalXyl-(Cl-C6)-alkyl, (C6-Cl~)-arylwhich is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (cl-c7)-alko y, (Cl-C7)-alkyl, (Cl-C7)-alkoxy-carbonyl, amino, and anilino and trifluoromethyl whichare optionally ~ubstituted by up to two halogens, (C6-Cl4)-aryl-(Cl-C6)-alkyl, in which the aryl moiety is optionally substituted by one or two identical or dif-ferent radicals from the series comprising F, Cl, Br, I, hydro yl, (C1-C7)-alXoxy, (C1-C7)-alkyl, (C1-C7)-alkoxy-carbonyl,amino,(C1-C,)-alkylamino,di-(C1-C,)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C,)-alkyl, (Cl-C,)-alkylamino-(cl-c7)-alkyl~ di-(C1-C7)-alkylamino-(Cl-C7)-alkyl, (C1-C,)-alkoxycarbonylmethoxy, carbamoyl, sulfa-moyl, (Cl-C,)-alkoxysulfonyl and sulfo, or is the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle having at least one carbon atom, 1 to 4 nitroqen atoms and/or 1 sulfur or oxygen atom ac ring members, and which is optionally mono-, di- or trisubstituted by one or more radicals from the ~eries comprising F, Cl, Br, hydroxyl, (C1-C,)-alkoxy, (Cl-C,)-alkyl, (C1-C8)-alkoxycarbonyl, amino and trifluoromethyl.
R2 is H or a hydroxyl protective group, such as are de~cribed, for example, in T.W. Greene, ~Protective Groups in Organic Synthesis"; A. Wiley-Interscience Publications; New York-Chiche~ter-Bri~bane-Toronto-Singapore, 1981. Of these, benzyl, p-metho ybenzyl, methoxymethyl, metho yethyl, benzyloxymethyl, acetyl, trimethylsilyl, tert.-butyldimethylsilyl and tert.-butyldiphenylsilyl are particularly suitable.
R3 is (cl-cl2)-alkyl~ mono-, bi- or tricyclic (C3-Cl8)-cycloalkyl or mono-, bi- or tricyclic (c3-cl8)-cycloalkyl-:
. ~
:
, 2~G~6~
(C,-C6)-alkyl, where the cycloalkyl moiety is in each case optionally substituted by (Cl-C6)-alkyl.
R4 and R5 are identical or different and are hydrogen, (cl-cl2)-alkyl~ (C3-C,2)-cycloalkyl, (C3-Cl2)-cycloalkyl-(cl-c6)-alkyl~ (C6-Clj)-aryl-(Cl-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (Cl-C6)-alkyl and halogen, Het or Het-(Cl-C6)-alkyl, where Het i8 a S-, 6- or 7-membered heterocyclic ring which is optionally fused to benzene and can be aromatic, partial-ly hydrogenated or completely hydrogenated and which as a hetero element contains one or two identical or dif-ferent radicals from the group comprising N, 0, S, N0, S0 and S02 and which can be substituted by one or two iden-tical or different radicals from the group comprising(Cl-C6)-alkyl, (cl-c4)-alkoxy and halogen.
R6 and R7 are identical or different and are hydrogen, (C1-C12)-alkyl~ (C3-C~2)-cycloalkyl, (C3-C,2)-cycloalkyl-(C,-C6)-alkyl, (C6-C,4)-aryl-(C,-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (C~-C6)-alkyl, (C,-C4)-alkoxy and halogen; or R~ and R7, together with the carbon atom carrying them, are (C3-Cl2)-cycloalkyl.
The compounds of the formulae Ia and Ib are enantiomers.
The invention relates both to the optically pure com-pounds and to their stereoisomer mixtures, such as racemates.
Alkyl can be straight-chain or branched. The same applies to radicals derived therefrom such as alkoxy.
Cycloalkyl is understood as meaning, for exa~ple, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
A Het radical preferably has one of the following meaningss pyridyl, thiazolyl, thienyl, pyranyl, benzo-furyl, isobenzofuryl, furyl, pyrrolyl, imidazolyl, pyrazinyl, indazolyl, guinolyl, isoquinolyl, phthal-azinyl, pyrimidinyl, pyrazinyl, indolizinyl, isoindolyl, indolyl, quinoxalinyl, quinazolinyl, cinnolinyl, oxazo-ly', isoxazolyl or isothiazolyl. The radicals can be aromatic, partially hydrogenated or completely hydrogen-ated. They can be substituted by one or two identical or different radicals from the group comprising (Cl-C6)-alkyl, (C,-C4)-alkoxy and halogen.
(C6-C14)-Aryl i8 understood as meaning, for example, phenyl, naphthyl or biphenylyl; phenyl is preferred.
Halogen i8 fluorine, chlorine, bromine or iodine.
Suitable salts are in particular salts with mineral acids, such as HCl, H2S04 or H3P04, into which the com-pounds of the formula Ia or Ib are converted, for example for the purposes of storage.
Preferred compounds of the formula Ia or Ib are those in which W is as defined above, R^ is hydrogen, (C,-C10)-alkyl which is optionally mono- or diunsaturated, (C3-CB)-cycloalkyl, (C3-C8)-cycloalkyl-(C,-C6)-alkyl, (C6-C,4)-aryl, (C6-C,4)-aryl-(C,-C8)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle additionally having atleast 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members, R2 is as defined above, R3 is (C1-C6)-alkyl, mono-, bi- or tricyclic (C3-Cl~)-cycloalkyl or mono-, bi- or tricyclic (C3-Cla)-cycloalkyl-(C1-C3)-alkyl;
.
R4 and R5 are aY defined above; and R6 and R7 are identical or different and are hydrogen, (C1-C~z)-alkyl, (C3-Cl2)-cycloalkyl or (C3-C12)-cycloalkyl-(cl-c6)-alkyl; or, together with the carbon atom carrying them, are (C3-C12)-cycloalkyl;
and their salts.
Particularly preferred compounds of the formula Ia or Ib are those in which W is -CO-, -O-CO- and R~ is hydrogen, (cl-clo)-alkyl which is optionally mono- or diunsaturated, (C3-CB)-cycloalkyl, (c3-c8)-cycloa~ l-c6)-a~ (C6-Cl4)-aryl, (C6-Cl4)-aryl-(Cl-C6)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle having at least l carbon atom, l to 4 nitrogen atoms and/or 1 sulfur or oxgen atom as ring member~;
R2 is as defined above; and R3 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl;
R4 and R5 are as defined above; and RB and R7 are identiGal and are hydrogen or (C1-C4)-alkyl, or, together with the carbon atom carrying them, are (Cs~c7)~cYcloalkyl;
and their ~alts.
Very particularly preferred compounds of the formula Ia or Ib are those in which R1 and R2 are as defined above, 2 ~
R9 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl;
R~ and R5 are identical or different and are hydrogen, (Cl-C~)-alkyl, (C5-C,)-cycloalkyl, (C5-C,)-cycloalkyl-(Cl-C3)-alkyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thi-enyl, 3-thienyl, 1-methylimidazol-2-yl, l-methylimidazol-4-yl or 1-methylimidazol-5-yl; and R6 and R7 are identical and are hydrogen, (C1-C4)-alkyl or, together with the carbon atom carrying them, are a (C5-C~)-cycloalkyl, and their salts.
~ he invention furthermore relates to a process for the preparation of compounds of the formula Ia or Ib, which comprises reacting a compound of the formula IIa or IIb ,, , -..
h O ~
R - N ~ ~R
~ (IIa) -~\
R CHO
R--N ~ OR
~ (IIb ~/\ ' . :
in which the radicals R1, R2, R3, R6 and R7 are as defined above, with a phosphorane of the formula III
R ~ R 4 p ~ (III) R l10 R5 in which R4 and R5 are a8 defined above and R8, R~ and Rl are identical or different aryl radical~, preferably phenyl.
To prepare a compound of the formula ITa or IIb, sultably protected amino acid dQrivativQs can be used as stsrting materials. ThesQ yield IIa or IIb as a result of double reaction with the nucleophilic formyl equivalent 2-trimethylsilylthiazole TST (Scheme 1) (A. Dondoni et al., J. Org. Chem. 1990, 55, 1439) in a solvent which is inert .
- . . .. ....
. , .. . ~. :
.
,:
~a69~
to this nucleophile such as diethyl ether, di-n-butyl ether, MTB, dichloromethane, DIP, THF, tetrahydropyran or DME at a temperature between -40C and the boiling point of the solvent, preferably between -40-C and +25-C. The first addition of TST take~ place with high syn selec-tion, the second with high anti selection. The resultant hydroxyl function is protected in the next reaction step using methods known from the literature. The liberation of the formyl group can be carried out by the following reaction sequence:
1) N-Alkylation with a suitable alkylating reagent such as, for example, dimethyl sulfate or methyl iodide without solvent or in a suitable inert solvent such as, for example, acetonitrile, THF, MTB, DIP or EA
at temperatures between 25C and the boiling point of the appropriate solvent.
2) Reduction using a hydride transfer reagent ~uch as, for example, NaBH4 in a solvent suitable for these types of reaction such as, for example, methanol or ethanol at temperatures between -30C and 25C, preferably between -20C and 0C.
HOECHST ARTIENGE5ELLSCHAFT HOE 90JF 353 Dr. JA/AP
Description Aminodiol derivatives The invention relates to compounds of the formula Ia or Ib R 3 (S) ~ R S
R - N ~ C~R
~ (Ia) 6/\
R 3 ~ R 5 R--N"" (R~--~0 R2 ~ O (Ib) ,~
and their salts, in which R1 is R -W-;
W is -CO-, -O-CO-, -SO2- or -NH-CO-;
R~ is hydrogen, (C1-C10)-alkyl which is optionally mono- or diunsaturated and which is optionally ~ubstituted by up ; '' ' 2~5B~
to 3 identical or different radicals from the series comprising hydroxyl, (Cl-C7)-alkoxy, (C1-C7)-alkanoylo y, carboxyl, (Cl-C7)-alkoxycarbonyl, halogen, amino, (C1-C7)-alkylamino, di-(Cl-C7)-alkylamino, (C1-C5)-alko ycarbonyl-amino and (C7-CIs)-aralko ycarbonylamino, (C3-C8)-cyclo-alkyl, (C3-C8)-cycloalXyl-(Cl-C6)-alkyl, (C6-Cl~)-arylwhich is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (cl-c7)-alko y, (Cl-C7)-alkyl, (Cl-C7)-alkoxy-carbonyl, amino, and anilino and trifluoromethyl whichare optionally ~ubstituted by up to two halogens, (C6-Cl4)-aryl-(Cl-C6)-alkyl, in which the aryl moiety is optionally substituted by one or two identical or dif-ferent radicals from the series comprising F, Cl, Br, I, hydro yl, (C1-C7)-alXoxy, (C1-C7)-alkyl, (C1-C7)-alkoxy-carbonyl,amino,(C1-C,)-alkylamino,di-(C1-C,)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C,)-alkyl, (Cl-C,)-alkylamino-(cl-c7)-alkyl~ di-(C1-C7)-alkylamino-(Cl-C7)-alkyl, (C1-C,)-alkoxycarbonylmethoxy, carbamoyl, sulfa-moyl, (Cl-C,)-alkoxysulfonyl and sulfo, or is the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle having at least one carbon atom, 1 to 4 nitroqen atoms and/or 1 sulfur or oxygen atom ac ring members, and which is optionally mono-, di- or trisubstituted by one or more radicals from the ~eries comprising F, Cl, Br, hydroxyl, (C1-C,)-alkoxy, (Cl-C,)-alkyl, (C1-C8)-alkoxycarbonyl, amino and trifluoromethyl.
R2 is H or a hydroxyl protective group, such as are de~cribed, for example, in T.W. Greene, ~Protective Groups in Organic Synthesis"; A. Wiley-Interscience Publications; New York-Chiche~ter-Bri~bane-Toronto-Singapore, 1981. Of these, benzyl, p-metho ybenzyl, methoxymethyl, metho yethyl, benzyloxymethyl, acetyl, trimethylsilyl, tert.-butyldimethylsilyl and tert.-butyldiphenylsilyl are particularly suitable.
R3 is (cl-cl2)-alkyl~ mono-, bi- or tricyclic (C3-Cl8)-cycloalkyl or mono-, bi- or tricyclic (c3-cl8)-cycloalkyl-:
. ~
:
, 2~G~6~
(C,-C6)-alkyl, where the cycloalkyl moiety is in each case optionally substituted by (Cl-C6)-alkyl.
R4 and R5 are identical or different and are hydrogen, (cl-cl2)-alkyl~ (C3-C,2)-cycloalkyl, (C3-Cl2)-cycloalkyl-(cl-c6)-alkyl~ (C6-Clj)-aryl-(Cl-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (Cl-C6)-alkyl and halogen, Het or Het-(Cl-C6)-alkyl, where Het i8 a S-, 6- or 7-membered heterocyclic ring which is optionally fused to benzene and can be aromatic, partial-ly hydrogenated or completely hydrogenated and which as a hetero element contains one or two identical or dif-ferent radicals from the group comprising N, 0, S, N0, S0 and S02 and which can be substituted by one or two iden-tical or different radicals from the group comprising(Cl-C6)-alkyl, (cl-c4)-alkoxy and halogen.
R6 and R7 are identical or different and are hydrogen, (C1-C12)-alkyl~ (C3-C~2)-cycloalkyl, (C3-C,2)-cycloalkyl-(C,-C6)-alkyl, (C6-C,4)-aryl-(C,-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (C~-C6)-alkyl, (C,-C4)-alkoxy and halogen; or R~ and R7, together with the carbon atom carrying them, are (C3-Cl2)-cycloalkyl.
The compounds of the formulae Ia and Ib are enantiomers.
The invention relates both to the optically pure com-pounds and to their stereoisomer mixtures, such as racemates.
Alkyl can be straight-chain or branched. The same applies to radicals derived therefrom such as alkoxy.
Cycloalkyl is understood as meaning, for exa~ple, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
A Het radical preferably has one of the following meaningss pyridyl, thiazolyl, thienyl, pyranyl, benzo-furyl, isobenzofuryl, furyl, pyrrolyl, imidazolyl, pyrazinyl, indazolyl, guinolyl, isoquinolyl, phthal-azinyl, pyrimidinyl, pyrazinyl, indolizinyl, isoindolyl, indolyl, quinoxalinyl, quinazolinyl, cinnolinyl, oxazo-ly', isoxazolyl or isothiazolyl. The radicals can be aromatic, partially hydrogenated or completely hydrogen-ated. They can be substituted by one or two identical or different radicals from the group comprising (Cl-C6)-alkyl, (C,-C4)-alkoxy and halogen.
(C6-C14)-Aryl i8 understood as meaning, for example, phenyl, naphthyl or biphenylyl; phenyl is preferred.
Halogen i8 fluorine, chlorine, bromine or iodine.
Suitable salts are in particular salts with mineral acids, such as HCl, H2S04 or H3P04, into which the com-pounds of the formula Ia or Ib are converted, for example for the purposes of storage.
Preferred compounds of the formula Ia or Ib are those in which W is as defined above, R^ is hydrogen, (C,-C10)-alkyl which is optionally mono- or diunsaturated, (C3-CB)-cycloalkyl, (C3-C8)-cycloalkyl-(C,-C6)-alkyl, (C6-C,4)-aryl, (C6-C,4)-aryl-(C,-C8)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle additionally having atleast 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members, R2 is as defined above, R3 is (C1-C6)-alkyl, mono-, bi- or tricyclic (C3-Cl~)-cycloalkyl or mono-, bi- or tricyclic (C3-Cla)-cycloalkyl-(C1-C3)-alkyl;
.
R4 and R5 are aY defined above; and R6 and R7 are identical or different and are hydrogen, (C1-C~z)-alkyl, (C3-Cl2)-cycloalkyl or (C3-C12)-cycloalkyl-(cl-c6)-alkyl; or, together with the carbon atom carrying them, are (C3-C12)-cycloalkyl;
and their salts.
Particularly preferred compounds of the formula Ia or Ib are those in which W is -CO-, -O-CO- and R~ is hydrogen, (cl-clo)-alkyl which is optionally mono- or diunsaturated, (C3-CB)-cycloalkyl, (c3-c8)-cycloa~ l-c6)-a~ (C6-Cl4)-aryl, (C6-Cl4)-aryl-(Cl-C6)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle having at least l carbon atom, l to 4 nitrogen atoms and/or 1 sulfur or oxgen atom as ring member~;
R2 is as defined above; and R3 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl;
R4 and R5 are as defined above; and RB and R7 are identiGal and are hydrogen or (C1-C4)-alkyl, or, together with the carbon atom carrying them, are (Cs~c7)~cYcloalkyl;
and their ~alts.
Very particularly preferred compounds of the formula Ia or Ib are those in which R1 and R2 are as defined above, 2 ~
R9 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl;
R~ and R5 are identical or different and are hydrogen, (Cl-C~)-alkyl, (C5-C,)-cycloalkyl, (C5-C,)-cycloalkyl-(Cl-C3)-alkyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thi-enyl, 3-thienyl, 1-methylimidazol-2-yl, l-methylimidazol-4-yl or 1-methylimidazol-5-yl; and R6 and R7 are identical and are hydrogen, (C1-C4)-alkyl or, together with the carbon atom carrying them, are a (C5-C~)-cycloalkyl, and their salts.
~ he invention furthermore relates to a process for the preparation of compounds of the formula Ia or Ib, which comprises reacting a compound of the formula IIa or IIb ,, , -..
h O ~
R - N ~ ~R
~ (IIa) -~\
R CHO
R--N ~ OR
~ (IIb ~/\ ' . :
in which the radicals R1, R2, R3, R6 and R7 are as defined above, with a phosphorane of the formula III
R ~ R 4 p ~ (III) R l10 R5 in which R4 and R5 are a8 defined above and R8, R~ and Rl are identical or different aryl radical~, preferably phenyl.
To prepare a compound of the formula ITa or IIb, sultably protected amino acid dQrivativQs can be used as stsrting materials. ThesQ yield IIa or IIb as a result of double reaction with the nucleophilic formyl equivalent 2-trimethylsilylthiazole TST (Scheme 1) (A. Dondoni et al., J. Org. Chem. 1990, 55, 1439) in a solvent which is inert .
- . . .. ....
. , .. . ~. :
.
,:
~a69~
to this nucleophile such as diethyl ether, di-n-butyl ether, MTB, dichloromethane, DIP, THF, tetrahydropyran or DME at a temperature between -40C and the boiling point of the solvent, preferably between -40-C and +25-C. The first addition of TST take~ place with high syn selec-tion, the second with high anti selection. The resultant hydroxyl function is protected in the next reaction step using methods known from the literature. The liberation of the formyl group can be carried out by the following reaction sequence:
1) N-Alkylation with a suitable alkylating reagent such as, for example, dimethyl sulfate or methyl iodide without solvent or in a suitable inert solvent such as, for example, acetonitrile, THF, MTB, DIP or EA
at temperatures between 25C and the boiling point of the appropriate solvent.
2) Reduction using a hydride transfer reagent ~uch as, for example, NaBH4 in a solvent suitable for these types of reaction such as, for example, methanol or ethanol at temperatures between -30C and 25C, preferably between -20C and 0C.
3) Liberation of the aldehyde group by action of reagents for the cleavage of thioacetals (see Tamura et al., Synthesis 312 (1973), Seebach et al., ibid. 357 (1977) and literature cited therein), preferably by means of N-bromosuccinimide in a mixture of acetone and water, preferably at O-C to 30-C.
. .. .
' ~ ' ` ~ , . ;
,. :. !
:- ' ~ .
_ 9 _ 2 3~ t~
Scheme 1 Rl N~H > R--N~S
H OH
protection 1 ,~<N 3 "Me+"
>R--N S >
\~o R 6~\R 7 3 Me Rl N~s3 R R
2~6~6t, R3 HN_ R--N~S
e.a. NBS
\~0 R \ 7 R
Rl N ~ H 3 'Me-l'' > ~b ~ 4."H ~"
R 6-\ 7 6 ~. e . g NBS
R
The Wittig reaction with a suitable phosphorane in an inert solvent such as diethyl ether, di-n-butyl ether, MTB, DIP, THF, DNE or dioxane at -30-C up to the boiling point of the solvent, preferably between 0C and 30C, yields the title compounds of the formula Ia or Ib. The aldehyde of the formula IIa or IIb can also be reacted with the anion of a suitable phosphine oxide with the formation of the title compound (Horner; see Krauch, Kunz, Reaktionen der Organischen Chemie (Reactions of Organic Chemistry), H~thig Verlag Heidelberg 1976, page 241).
The compoundc of the formulae Ia and Ib according to the invention are valuable intermediates for the preparation of pharmaceuticals, in particular of inhib~tors of renin and of HIV protease. Inhibitors in whose synthesis these compounds can advantageously be used are described, for example, in FEBS Lett. Vol. 230, 38 (1988), J. Med. Chem.
Vol. 31, 2264 (1988), ibid. 2277, Biochem. Biophys. Res.
.. ; ~ . , .
20a6~63 Commun. Vol. 146, 959 (1987) and EP-A-370,454.
List of the abbreviations used:
TLC thin-layer chromatography DCI desorption chemical ionization DIP diisopropyl ether DNE 1,2-dimethoxyethane EA ethyl acetate -FAB fa~t atom bombardment Hep n-heptane ~ molecular peak MeOH methanol NS mass spectrum MTB methyl tert.-butyl ether Et20 diethyl ether R.T. room temperature m.p. melting point THF tetrahydrofuran NBS N-bromosuccinimide TST trimethylsilylthiazole 20 Red-Al sodium bis(2-methoxyethoxy)dihydroaluminate CH2Cl2 dichloromethane The examples below are used to illustrate the present invention, without restricting it theretos Example 1 (2S,lRS)-2-t-Butyloxycarbonylamino-3-cyclohexyl-1-(2-thiazolyl)propanol 3.14 g (10 mmol) of N-Boc-L-cyclohexylalanine-N,O-di-methylamide are dissolved in 30 ml of dry THF and cooled to 0C. 5.7 ml (20 mmol) of Red-Al (70 % in toluene) are added dropwise. After ~tirring at ODC for 2 hours, the mixture i8 poured into 200 ml of ice-water and extracted 3 x with ethyl acetate. The combined organic pha~es are washed with saturated NaCl solution, dried with Na2SO~
~, ~ ~ ' ' ; ,. --, - . . .
and concentrated. 2.6 g of N-Boc-L-cyclohexylalaninal are obtained, which is dissolved as the crude product in 30 ml of dry CH2C12 and treated dropwise at -30C with 3.13 g (20 mmol) of 2-trimethylsilylthiazole. The mixture is kept in a deep-freeze at -25-C for 14 hours. After concentrating, the re~idue i8 dissolved in 30 ml of THF/5 ml of H20 and treated with 3 g (20 mmol) of cesium fluoride. After refluxing for 7 hours, the mixture iB
diluted with ethyl acetate and washed twice with satd.
NaCl solution. It i8 concentrated after drying over Na2SO4 .
The product is separated from small amounts of unreacted aldehyde on silica gel (eluent EA/Hep 1 : 2). 1.83 g (54 %) of the title compound are obtained. According to NMR, it is a 5 : 1 mixture (R- or S-configuration on carbon C-1).
R (EA/Hep 1:1) = 0.21; MS (DCI) = 341 (M + 1) Example la (4S,5R)-3-t-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-(2-thiazolyl)oxa~olidine 23 g of the title compound 1 (67.6 mmol) in 250 ml of toluene are heated to reflux for 48 hours with 40 ml of 2,2-dimethoxypropane and 2.5 g of p-toluenesulfonic acid.
After cooling, the mixture is washed with 1 N NaHC03 solution, dried with MgS04 and concentrated. The crude product is purified on SiOz using EA/cyclohexane (1 s 4).
12.5 g of the title compound are obtained.
Rr (EA/Hep 1:1) = 0.55; MS (DCI) = 381 (M + l); m.p.
= 89 - 91C, [~]DZ = -67.9 (c = 1, CH30H).
Example lb (4S,5R,lR)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-tl'-hydroxy-1'-(2-thiazolyl)methyl~oxazolidine , ~ .
- 13 _ 2~36~
12.S g (32.8 mmol) of the title compound la are dissolved in 70 ml of acetonitrile. 3.9 ml (1.25 equivalents) of dimethyl sulfate are added and the mixture is heated to boiling for 7 hours. After standing overnight at RT, it is concentrated to dryness. The solid re~idue iB dis-solved in 150 ml of methanol. 4.3 g (0.013 mol) of ~odium borohydride are added in portions with efficient cooling, during which the temperature should not rise above -lO-C.
After subsequently stirring at 0C for 30 minutes, 40 ml of acetone are added. After concentrating, the residue is taken up in 500 ml of EA and washed with 200 ml of satd.
NaCl solution. After drying with Na2S04, the solution is concentrated and the crude product is sub~ected to coarse purificstion by filtration through a little silica gel, 14 g being obtained (Compound 5, Scheme 1). This product is dissolved in 250 ml of acetone/H20 (95 s 5) and 16.5 g of NBS are added with cooling (s 25C) in the course of 10 min. After the end of the addition, the mixture i8 strongly cooled and treated in small portions with 500 ml of satd. Na2S03 solution (s 25-C, strongly exothermic~).
After diluting with 500 ml of H20, the mixture is ex-tracted 3 x with Et20. The combined extracts are washed twice with H20 and once with saturated NaCl solution, dried with Na2S04 and concentrated. Water residues are removed by azeotropic di~tillation with toluene on a ^Rotavapor. 5.9 g of aldehyde (Compound 6, Scheme 1) are obtained, which is immediately dissolved in 80 ml of CH2Cl2 and cooled to -40C. 5.88 g (37.4 mmol) of tri-methylsilylthiazole are in~ected. The mixture is ~lowly warmed to RT overnight. After concentrating, it i~ t~ken up in 80 ml of THF nnd treated with 11.8 g (37.4 mmol) of tetrabutylammonium fluoride trihydrate. After 2 hour~, the mixture is diluted with EA, wa~hed twice with H20 and once with satd. NaCl ~olution, dried with Na2S0~ and concentrated. The crystalline crude product is recry~tal-lized from acetonitrile, 4.7 g of the title compound being obtained.
R~ (DIP) = 0.4; NS (DCI) = 411 (M + l); m.p. = 176 -178C;
1~]2 = +35.7o (c = 1, CH30H)-2 ~ 3 Example lc (4S,5R,1'R)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-[1'-benzyloxy-1'-(2-thiazolyl)methyl]-oxazolidine 5.4 g (13.2 mmol) of the title compound lb are dissolved in 100 ml of THF and added dropwise to 0.7 g of sodium hydride (50 % in oil, washed twice with Hep) in 20 ml of THF. After 20 min at reflux, the mixture is cooled to 50C and 0.5 g of tetrabutylammonium iodide and 1.76 ml of benzyl bromide are added. After stirring at RT for 3 hours, the mixture is taken up in about 500 ml of satd.
NaCl solution. After extracting twice with ethyl acetate, the extract is dried with Na2S0~ and concentrated, 5 g of the title compound being obtained, which can be further reacted without further purification.
Rf (DIP) = 0.45; NS (DCI) = 500 (M + l); m.p. = 96C;
t~]DO = +46.3 (c = 1, CH30H).
Example ld (4S,5R,l'R)-3-t.Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-(1'-benzyloxy-l'-formyl)oxazolidine 2.1 g (4.2 mmol) of the title compound lc are dissolved in 10 ml of acetonitrile and 0.55 ml of dimethyl sulfate are added. After refluxing for 8 hours and standing overnight at RT, the mixture i8 concentrated to drynes#.
The crude product is dissolved in 15 ml of CH30H, and 0.5 g of NaBH4 is added in small portlon~ at -10C and the solution is concentrated. The residue is taken up in EA, and the solution is washed with satd. NaCl solution and dried with Na2S04. After concentrating, the crude product is di~solved in 23 ml of acetone/HzO (95 s 5) and added dropwi6e (15 min, -10C) to 2.25 q of NBS in 22 ml of acetone~H20 (95 s 5). 80 ml of satd. Na2S04 solution are added in small portions such that the temperature does not rise above +20C. After diluting with 100 ml of . .
- 1S ~3~3 H20, the mixture i8 extracted 3 x with Et20. The combined extracts are washed twice with H20, dried with MgSO~ and concentrated, 1.75 g (95 ~) of the title compound being obtained, which are reused a8 a crude product.
Rs (DIP) = 0.4; NS (DCI) = 446 (M + 1).
Example le (4S,SR,l'S)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-~1~-benzyloxy-3~-(2-pyridyl)-prop-2'-enyl]-oxazolidine 1.72 g (4 mmol) of 2-picolyltriphenylphosphonium chloride are suspended in 30 ml of dry THF. 0.43 g of potassium t.-butylate are added under argon. After 2 hours at RT, 0.85 g of the title compound ld in 5 ml of THF is added dropwise (-15C) to the lemon-yellow solution. After standing at RT overnight, the mixture is diluted with H20, extracted (3 x) with EA, washed with satd. NaCl solution, dried (Na2SO4) and concentrated. Chromatography on SiO2 yields 0.11 g of cis-isomer and 0.4 g of trans-isomer of the title compound as an oil.
R~ (DIP) = 0.45 (ci8) 0.3 (trans);
NS (DCI) = 521 (N + l);
1~]D = +26.8 (c = 1, NeOH, trans)
. .. .
' ~ ' ` ~ , . ;
,. :. !
:- ' ~ .
_ 9 _ 2 3~ t~
Scheme 1 Rl N~H > R--N~S
H OH
protection 1 ,~<N 3 "Me+"
>R--N S >
\~o R 6~\R 7 3 Me Rl N~s3 R R
2~6~6t, R3 HN_ R--N~S
e.a. NBS
\~0 R \ 7 R
Rl N ~ H 3 'Me-l'' > ~b ~ 4."H ~"
R 6-\ 7 6 ~. e . g NBS
R
The Wittig reaction with a suitable phosphorane in an inert solvent such as diethyl ether, di-n-butyl ether, MTB, DIP, THF, DNE or dioxane at -30-C up to the boiling point of the solvent, preferably between 0C and 30C, yields the title compounds of the formula Ia or Ib. The aldehyde of the formula IIa or IIb can also be reacted with the anion of a suitable phosphine oxide with the formation of the title compound (Horner; see Krauch, Kunz, Reaktionen der Organischen Chemie (Reactions of Organic Chemistry), H~thig Verlag Heidelberg 1976, page 241).
The compoundc of the formulae Ia and Ib according to the invention are valuable intermediates for the preparation of pharmaceuticals, in particular of inhib~tors of renin and of HIV protease. Inhibitors in whose synthesis these compounds can advantageously be used are described, for example, in FEBS Lett. Vol. 230, 38 (1988), J. Med. Chem.
Vol. 31, 2264 (1988), ibid. 2277, Biochem. Biophys. Res.
.. ; ~ . , .
20a6~63 Commun. Vol. 146, 959 (1987) and EP-A-370,454.
List of the abbreviations used:
TLC thin-layer chromatography DCI desorption chemical ionization DIP diisopropyl ether DNE 1,2-dimethoxyethane EA ethyl acetate -FAB fa~t atom bombardment Hep n-heptane ~ molecular peak MeOH methanol NS mass spectrum MTB methyl tert.-butyl ether Et20 diethyl ether R.T. room temperature m.p. melting point THF tetrahydrofuran NBS N-bromosuccinimide TST trimethylsilylthiazole 20 Red-Al sodium bis(2-methoxyethoxy)dihydroaluminate CH2Cl2 dichloromethane The examples below are used to illustrate the present invention, without restricting it theretos Example 1 (2S,lRS)-2-t-Butyloxycarbonylamino-3-cyclohexyl-1-(2-thiazolyl)propanol 3.14 g (10 mmol) of N-Boc-L-cyclohexylalanine-N,O-di-methylamide are dissolved in 30 ml of dry THF and cooled to 0C. 5.7 ml (20 mmol) of Red-Al (70 % in toluene) are added dropwise. After ~tirring at ODC for 2 hours, the mixture i8 poured into 200 ml of ice-water and extracted 3 x with ethyl acetate. The combined organic pha~es are washed with saturated NaCl solution, dried with Na2SO~
~, ~ ~ ' ' ; ,. --, - . . .
and concentrated. 2.6 g of N-Boc-L-cyclohexylalaninal are obtained, which is dissolved as the crude product in 30 ml of dry CH2C12 and treated dropwise at -30C with 3.13 g (20 mmol) of 2-trimethylsilylthiazole. The mixture is kept in a deep-freeze at -25-C for 14 hours. After concentrating, the re~idue i8 dissolved in 30 ml of THF/5 ml of H20 and treated with 3 g (20 mmol) of cesium fluoride. After refluxing for 7 hours, the mixture iB
diluted with ethyl acetate and washed twice with satd.
NaCl solution. It i8 concentrated after drying over Na2SO4 .
The product is separated from small amounts of unreacted aldehyde on silica gel (eluent EA/Hep 1 : 2). 1.83 g (54 %) of the title compound are obtained. According to NMR, it is a 5 : 1 mixture (R- or S-configuration on carbon C-1).
R (EA/Hep 1:1) = 0.21; MS (DCI) = 341 (M + 1) Example la (4S,5R)-3-t-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-(2-thiazolyl)oxa~olidine 23 g of the title compound 1 (67.6 mmol) in 250 ml of toluene are heated to reflux for 48 hours with 40 ml of 2,2-dimethoxypropane and 2.5 g of p-toluenesulfonic acid.
After cooling, the mixture is washed with 1 N NaHC03 solution, dried with MgS04 and concentrated. The crude product is purified on SiOz using EA/cyclohexane (1 s 4).
12.5 g of the title compound are obtained.
Rr (EA/Hep 1:1) = 0.55; MS (DCI) = 381 (M + l); m.p.
= 89 - 91C, [~]DZ = -67.9 (c = 1, CH30H).
Example lb (4S,5R,lR)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-tl'-hydroxy-1'-(2-thiazolyl)methyl~oxazolidine , ~ .
- 13 _ 2~36~
12.S g (32.8 mmol) of the title compound la are dissolved in 70 ml of acetonitrile. 3.9 ml (1.25 equivalents) of dimethyl sulfate are added and the mixture is heated to boiling for 7 hours. After standing overnight at RT, it is concentrated to dryness. The solid re~idue iB dis-solved in 150 ml of methanol. 4.3 g (0.013 mol) of ~odium borohydride are added in portions with efficient cooling, during which the temperature should not rise above -lO-C.
After subsequently stirring at 0C for 30 minutes, 40 ml of acetone are added. After concentrating, the residue is taken up in 500 ml of EA and washed with 200 ml of satd.
NaCl solution. After drying with Na2S04, the solution is concentrated and the crude product is sub~ected to coarse purificstion by filtration through a little silica gel, 14 g being obtained (Compound 5, Scheme 1). This product is dissolved in 250 ml of acetone/H20 (95 s 5) and 16.5 g of NBS are added with cooling (s 25C) in the course of 10 min. After the end of the addition, the mixture i8 strongly cooled and treated in small portions with 500 ml of satd. Na2S03 solution (s 25-C, strongly exothermic~).
After diluting with 500 ml of H20, the mixture is ex-tracted 3 x with Et20. The combined extracts are washed twice with H20 and once with saturated NaCl solution, dried with Na2S04 and concentrated. Water residues are removed by azeotropic di~tillation with toluene on a ^Rotavapor. 5.9 g of aldehyde (Compound 6, Scheme 1) are obtained, which is immediately dissolved in 80 ml of CH2Cl2 and cooled to -40C. 5.88 g (37.4 mmol) of tri-methylsilylthiazole are in~ected. The mixture is ~lowly warmed to RT overnight. After concentrating, it i~ t~ken up in 80 ml of THF nnd treated with 11.8 g (37.4 mmol) of tetrabutylammonium fluoride trihydrate. After 2 hour~, the mixture is diluted with EA, wa~hed twice with H20 and once with satd. NaCl ~olution, dried with Na2S0~ and concentrated. The crystalline crude product is recry~tal-lized from acetonitrile, 4.7 g of the title compound being obtained.
R~ (DIP) = 0.4; NS (DCI) = 411 (M + l); m.p. = 176 -178C;
1~]2 = +35.7o (c = 1, CH30H)-2 ~ 3 Example lc (4S,5R,1'R)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-[1'-benzyloxy-1'-(2-thiazolyl)methyl]-oxazolidine 5.4 g (13.2 mmol) of the title compound lb are dissolved in 100 ml of THF and added dropwise to 0.7 g of sodium hydride (50 % in oil, washed twice with Hep) in 20 ml of THF. After 20 min at reflux, the mixture is cooled to 50C and 0.5 g of tetrabutylammonium iodide and 1.76 ml of benzyl bromide are added. After stirring at RT for 3 hours, the mixture is taken up in about 500 ml of satd.
NaCl solution. After extracting twice with ethyl acetate, the extract is dried with Na2S0~ and concentrated, 5 g of the title compound being obtained, which can be further reacted without further purification.
Rf (DIP) = 0.45; NS (DCI) = 500 (M + l); m.p. = 96C;
t~]DO = +46.3 (c = 1, CH30H).
Example ld (4S,5R,l'R)-3-t.Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-(1'-benzyloxy-l'-formyl)oxazolidine 2.1 g (4.2 mmol) of the title compound lc are dissolved in 10 ml of acetonitrile and 0.55 ml of dimethyl sulfate are added. After refluxing for 8 hours and standing overnight at RT, the mixture i8 concentrated to drynes#.
The crude product is dissolved in 15 ml of CH30H, and 0.5 g of NaBH4 is added in small portlon~ at -10C and the solution is concentrated. The residue is taken up in EA, and the solution is washed with satd. NaCl solution and dried with Na2S04. After concentrating, the crude product is di~solved in 23 ml of acetone/HzO (95 s 5) and added dropwi6e (15 min, -10C) to 2.25 q of NBS in 22 ml of acetone~H20 (95 s 5). 80 ml of satd. Na2S04 solution are added in small portions such that the temperature does not rise above +20C. After diluting with 100 ml of . .
- 1S ~3~3 H20, the mixture i8 extracted 3 x with Et20. The combined extracts are washed twice with H20, dried with MgSO~ and concentrated, 1.75 g (95 ~) of the title compound being obtained, which are reused a8 a crude product.
Rs (DIP) = 0.4; NS (DCI) = 446 (M + 1).
Example le (4S,SR,l'S)-3-t.-Butyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-~1~-benzyloxy-3~-(2-pyridyl)-prop-2'-enyl]-oxazolidine 1.72 g (4 mmol) of 2-picolyltriphenylphosphonium chloride are suspended in 30 ml of dry THF. 0.43 g of potassium t.-butylate are added under argon. After 2 hours at RT, 0.85 g of the title compound ld in 5 ml of THF is added dropwise (-15C) to the lemon-yellow solution. After standing at RT overnight, the mixture is diluted with H20, extracted (3 x) with EA, washed with satd. NaCl solution, dried (Na2SO4) and concentrated. Chromatography on SiO2 yields 0.11 g of cis-isomer and 0.4 g of trans-isomer of the title compound as an oil.
R~ (DIP) = 0.45 (ci8) 0.3 (trans);
NS (DCI) = 521 (N + l);
1~]D = +26.8 (c = 1, NeOH, trans)
Claims (7)
1. A compound of the formula Ia or Ib (Ia) (Ib) in which R1 is R4-W-;
W is -CO-, -O-CO-, -SO2- or -NH-CO-;
Ra is hydrogen, (C1-C10)-alkyl which is optionally mono- or diunsaturated and which is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkanoyloxy, carboxyl, (C1-C7)-alkoxycarbonyl, halogen, amino, (C1-C7)-alkylamino, di-(C1-C7)-alkylamino, (C1-C5)-alkoxycarbonyl-amino and (C7-C15)-aralkoxycarbonylamino, (C3-C8)-cyclo-alkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl,(C6-C14)-aryl which is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C7)-alkoxy-carbonyl, amino, and anilino and trifluoromethyl which are optionally substituted by up to two halogens, (C6-C14)-aryl-(C1-C6)-alkyl, in which the aryl moiety is optionally substituted by one or two identical or dif-ferent radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C7)-alkoxy-carbonyl,amino,(C1-C7)-alkylamino,di-(C1-C7)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, (C1-C7)-alkoxycarbonylmethoxy, carbamoyl, sulfa-moyl, (C1-C7)-alkoxysulfonyl and sulfo, or is the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle having at least 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members, and which is optionally mono-, di- or trisub-stituted by one or more radicals from the series com-prising F, Cl, Br, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C6)-alkoxycarbonyl, amino and trifluoromethyl, R2 is H or a hydroxyl protective group;
R3 is (C1-C12)-alkyl, mono-, bi- or tricyclic (C3-C16)-cycloalkyl or mono-, bi- or tricyclic (C3-C16)-cycloalkyl-(C1-C6)-alkyl, where the cycloalkyl moiety is in each case optionally substituted by (C1-C6)-alkyl;
R4 and R5 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12) -Cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (C1-C6)-alkyl and halogen, Het or Het-(C1-C6)-alkyl, where Het is a 5-, 6- or 7-membered heterocyclic ring which is optionally fused to benzene and can be aromatic, partial-ly hydrogenated or completely hydrogenated and which as a hetero element contains one or two identical or dif-ferent radicals from the group comprising N, O, S, NO, SO
and SO2 and which can be substituted by one or two iden-tical or different radicals from the group comprising (C1-C6)-alkyl, (C1-C4)-alkoxy and halogen; and R6 and R7 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (C1-C6)-alkyl, (C1-C4)-alkoxy and halogen; or R6 and R7, together with the carbon atom carrying them, are (C3-C12)-cycloalkyl;
and its salts.
W is -CO-, -O-CO-, -SO2- or -NH-CO-;
Ra is hydrogen, (C1-C10)-alkyl which is optionally mono- or diunsaturated and which is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkanoyloxy, carboxyl, (C1-C7)-alkoxycarbonyl, halogen, amino, (C1-C7)-alkylamino, di-(C1-C7)-alkylamino, (C1-C5)-alkoxycarbonyl-amino and (C7-C15)-aralkoxycarbonylamino, (C3-C8)-cyclo-alkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl,(C6-C14)-aryl which is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C7)-alkoxy-carbonyl, amino, and anilino and trifluoromethyl which are optionally substituted by up to two halogens, (C6-C14)-aryl-(C1-C6)-alkyl, in which the aryl moiety is optionally substituted by one or two identical or dif-ferent radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C7)-alkoxy-carbonyl,amino,(C1-C7)-alkylamino,di-(C1-C7)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, (C1-C7)-alkoxycarbonylmethoxy, carbamoyl, sulfa-moyl, (C1-C7)-alkoxysulfonyl and sulfo, or is the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle having at least 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members, and which is optionally mono-, di- or trisub-stituted by one or more radicals from the series com-prising F, Cl, Br, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C6)-alkoxycarbonyl, amino and trifluoromethyl, R2 is H or a hydroxyl protective group;
R3 is (C1-C12)-alkyl, mono-, bi- or tricyclic (C3-C16)-cycloalkyl or mono-, bi- or tricyclic (C3-C16)-cycloalkyl-(C1-C6)-alkyl, where the cycloalkyl moiety is in each case optionally substituted by (C1-C6)-alkyl;
R4 and R5 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12) -Cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (C1-C6)-alkyl and halogen, Het or Het-(C1-C6)-alkyl, where Het is a 5-, 6- or 7-membered heterocyclic ring which is optionally fused to benzene and can be aromatic, partial-ly hydrogenated or completely hydrogenated and which as a hetero element contains one or two identical or dif-ferent radicals from the group comprising N, O, S, NO, SO
and SO2 and which can be substituted by one or two iden-tical or different radicals from the group comprising (C1-C6)-alkyl, (C1-C4)-alkoxy and halogen; and R6 and R7 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C6)-alkyl, where aryl can in each case be substituted by one, two or three identi-cal or different radicals from the group comprising (C1-C6)-alkyl, (C1-C4)-alkoxy and halogen; or R6 and R7, together with the carbon atom carrying them, are (C3-C12)-cycloalkyl;
and its salts.
2. A compound of the formula Ia or Ib, in which Ra is hydrogen, (C1-C10)-alkyl which is optionally mono- or diunsaturated, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heterocycle additionally having at least 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members, R3 is (C1-C6)-alkyl, mono-, bi- or tricyclic (C3-C18)-cycloalkyl or mono-, bi- or tricyclic (C3-C12)-cycloalkyl-(C1-C3)-alkyl;
R6 and R7 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12)-cycloalkyl or (C3-C12)-cycloalkyl-(C1-C6)-alkyl; or, together with the carbon atom carrying them, are ( C3-C12) -cycloalkyl;
and the other radicals are as defined in claim 1;
and its salts.
R6 and R7 are identical or different and are hydrogen, (C1-C12)-alkyl, (C3-C12)-cycloalkyl or (C3-C12)-cycloalkyl-(C1-C6)-alkyl; or, together with the carbon atom carrying them, are ( C3-C12) -cycloalkyl;
and the other radicals are as defined in claim 1;
and its salts.
3. A compound of the formula Ia or Ib as claimed in claim 1 or 2, in which W is -CO-, -O-CO-;
Ra is hydrogen, (C1-C10)-alkyl which is optionally mono- or diunsaturated, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic hsterocycle having at least 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxgen atom as ring members;
R3 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl;
R6 and R7 are identical and are hydrogen, (C1-C4)-alkyl or, together with the carbon atom carrying them, are a (C5-C7)-cycloalkyl;
and the other radicals are as defined in claim 1;
and its salts
Ra is hydrogen, (C1-C10)-alkyl which is optionally mono- or diunsaturated, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl, or the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic hsterocycle having at least 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxgen atom as ring members;
R3 is methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-ethylbutyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl;
R6 and R7 are identical and are hydrogen, (C1-C4)-alkyl or, together with the carbon atom carrying them, are a (C5-C7)-cycloalkyl;
and the other radicals are as defined in claim 1;
and its salts
4. A compound of the formula Ia or Ib as claimed in one of claims 1 to 3, in which R1 and R3 are as defined in claim 3;
R4 and R5 are identical or different and are hydrogen, (C1-C4)-alkyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkyl-(C1-C3)-alkyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thi-enyl, 3-thienyl, 1-methylimidazol-2-yl, 1-methylimidazol-4-yl or 1-methylimidazol-5-yl;
R6 and R7 are identical and are hydrogen, (C1-C4)-alkyl or, together with the carbon atom carrying them, are a (C5-C7)-cycloalkyl;
and the other radicals are as defined in claim 1;
and its salts.
R4 and R5 are identical or different and are hydrogen, (C1-C4)-alkyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkyl-(C1-C3)-alkyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thi-enyl, 3-thienyl, 1-methylimidazol-2-yl, 1-methylimidazol-4-yl or 1-methylimidazol-5-yl;
R6 and R7 are identical and are hydrogen, (C1-C4)-alkyl or, together with the carbon atom carrying them, are a (C5-C7)-cycloalkyl;
and the other radicals are as defined in claim 1;
and its salts.
5. A process for the preparation of a compound of the formula Ia or Ib as claimed in one of claims 1 to 4, which comprises reacting a compound of the formula IIa or IIb (IIa) (IIb) in which the radicals R1, R2, R3, R6 and R7 are as defined in claim 1, with a phosphorane of the formula III
(III) in which R4 and R5 are as defined in claim 1 and R8, R9 and R10 are identical or different aryl radicals;
and converting the compound obtained, if appropriate, into its salt.
(III) in which R4 and R5 are as defined in claim 1 and R8, R9 and R10 are identical or different aryl radicals;
and converting the compound obtained, if appropriate, into its salt.
6. A compound of the formula IIa or IIb (IIa) (IIb) in which R1, R2, R3, R6 and R7 are as defined in claim 1.
7. The use of a compound as claimed in one of claims 1 to 4 for the preparation of inhibitors of renin and of HIV protease.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4037437.8 | 1990-11-24 | ||
DE4037437A DE4037437A1 (en) | 1990-11-24 | 1990-11-24 | Amino diol DERIVATIVES |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2056063A1 true CA2056063A1 (en) | 1992-05-25 |
Family
ID=6418858
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002056063A Abandoned CA2056063A1 (en) | 1990-11-24 | 1991-11-22 | Aminodiol derivatives |
Country Status (18)
Country | Link |
---|---|
EP (1) | EP0487980A1 (en) |
JP (1) | JPH04266877A (en) |
KR (1) | KR920009806A (en) |
CN (1) | CN1061778A (en) |
AU (1) | AU8808691A (en) |
CA (1) | CA2056063A1 (en) |
CS (1) | CS354591A3 (en) |
DE (1) | DE4037437A1 (en) |
FI (1) | FI915495A (en) |
HU (1) | HU208964B (en) |
IE (1) | IE914081A1 (en) |
MX (1) | MX9102186A (en) |
NO (1) | NO914584L (en) |
NZ (1) | NZ240693A (en) |
PL (1) | PL292498A1 (en) |
PT (1) | PT99585A (en) |
TW (1) | TW206218B (en) |
ZA (1) | ZA919245B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102822152A (en) * | 2009-11-09 | 2012-12-12 | 诺瓦德克斯制药股份有限公司 | Novel 1,3-oxazolidine compounds and their use as renin inhibitors |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6071895A (en) * | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
US5888992A (en) * | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
RU2126794C1 (en) * | 1992-03-11 | 1999-02-27 | Нархекс Лимитед | Amino-derivatives of oxo- or hydroxy-substituted hydrazines, method of their synthesis and pharmaceutical compositions for inhibition of retrovirus protease |
ATE253050T1 (en) | 1992-03-11 | 2003-11-15 | Narhex Ltd | AMINE DERIVATIVES OF OXO- AND HYDROXY-SUBSTITUTED HYDROCARBONS |
US5691368A (en) * | 1995-01-11 | 1997-11-25 | Hoechst Marion Roussel, Inc. | Substituted oxazolidine calpain and/or cathepsin B inhibitors |
KR100709257B1 (en) * | 2005-08-30 | 2007-04-19 | 삼성에스디아이 주식회사 | Fuel supply apparatus and fuel cell system with the same |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989007109A1 (en) * | 1988-02-01 | 1989-08-10 | The Upjohn Company | Renin inhibiting peptides with polar end groups |
-
1990
- 1990-11-24 DE DE4037437A patent/DE4037437A1/en not_active Withdrawn
-
1991
- 1991-06-29 TW TW080105058A patent/TW206218B/zh active
- 1991-11-14 EP EP91119397A patent/EP0487980A1/en not_active Withdrawn
- 1991-11-21 FI FI915495A patent/FI915495A/en unknown
- 1991-11-22 PL PL29249891A patent/PL292498A1/en unknown
- 1991-11-22 NO NO91914584A patent/NO914584L/en unknown
- 1991-11-22 PT PT99585A patent/PT99585A/en not_active Application Discontinuation
- 1991-11-22 CN CN91110931A patent/CN1061778A/en active Pending
- 1991-11-22 HU HU913654A patent/HU208964B/en not_active IP Right Cessation
- 1991-11-22 CS CS913545A patent/CS354591A3/en unknown
- 1991-11-22 NZ NZ240693A patent/NZ240693A/en unknown
- 1991-11-22 AU AU88086/91A patent/AU8808691A/en not_active Abandoned
- 1991-11-22 ZA ZA919245A patent/ZA919245B/en unknown
- 1991-11-22 CA CA002056063A patent/CA2056063A1/en not_active Abandoned
- 1991-11-22 KR KR1019910020895A patent/KR920009806A/en not_active Application Discontinuation
- 1991-11-22 IE IE408191A patent/IE914081A1/en not_active Application Discontinuation
- 1991-11-22 JP JP3307398A patent/JPH04266877A/en active Pending
- 1991-11-22 MX MX9102186A patent/MX9102186A/en unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102822152A (en) * | 2009-11-09 | 2012-12-12 | 诺瓦德克斯制药股份有限公司 | Novel 1,3-oxazolidine compounds and their use as renin inhibitors |
Also Published As
Publication number | Publication date |
---|---|
TW206218B (en) | 1993-05-21 |
HU208964B (en) | 1994-02-28 |
HU913654D0 (en) | 1992-02-28 |
NO914584D0 (en) | 1991-11-22 |
NZ240693A (en) | 1993-07-27 |
HUT63621A (en) | 1993-09-28 |
PT99585A (en) | 1992-10-30 |
ZA919245B (en) | 1992-07-29 |
AU8808691A (en) | 1992-05-28 |
MX9102186A (en) | 1992-07-08 |
CS354591A3 (en) | 1992-06-17 |
NO914584L (en) | 1992-05-25 |
PL292498A1 (en) | 1992-11-16 |
KR920009806A (en) | 1992-06-25 |
FI915495A0 (en) | 1991-11-21 |
EP0487980A1 (en) | 1992-06-03 |
DE4037437A1 (en) | 1992-05-27 |
CN1061778A (en) | 1992-06-10 |
IE914081A1 (en) | 1992-06-03 |
FI915495A (en) | 1992-05-25 |
JPH04266877A (en) | 1992-09-22 |
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