DK2670751T3 - Fremgangsmåder til fremstilling af hiv- bindingsinhibitorprodrugforbindelse og mellemprodukter - Google Patents
Fremgangsmåder til fremstilling af hiv- bindingsinhibitorprodrugforbindelse og mellemprodukter Download PDFInfo
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- DK2670751T3 DK2670751T3 DK12704960.9T DK12704960T DK2670751T3 DK 2670751 T3 DK2670751 T3 DK 2670751T3 DK 12704960 T DK12704960 T DK 12704960T DK 2670751 T3 DK2670751 T3 DK 2670751T3
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- 238000000034 method Methods 0.000 title claims description 40
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 239000000543 intermediate Substances 0.000 title claims description 6
- 239000003112 inhibitor Substances 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 118
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 9
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 9
- 229940125797 compound 12 Drugs 0.000 claims description 9
- 229940125758 compound 15 Drugs 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 7
- 229940126543 compound 14 Drugs 0.000 claims description 7
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 5
- 229940125773 compound 10 Drugs 0.000 claims description 5
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 3
- 229960000281 trometamol Drugs 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 235000010288 sodium nitrite Nutrition 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 230000031709 bromination Effects 0.000 claims 1
- 238000005893 bromination reaction Methods 0.000 claims 1
- 238000006396 nitration reaction Methods 0.000 claims 1
- 230000007306 turnover Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000011261 inert gas Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 238000007792 addition Methods 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 239000002002 slurry Substances 0.000 description 8
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 239000012455 biphasic mixture Substances 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-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
- 230000029936 alkylation Effects 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 230000002051 biphasic effect Effects 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 238000009434 installation Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 1
- NPJMUNQBBLIMEM-UHFFFAOYSA-N 2-[chloromethyl-[(2-methylpropan-2-yl)oxy]phosphoryl]oxy-2-methylpropane Chemical compound CC(C)(C)OP(=O)(CCl)OC(C)(C)C NPJMUNQBBLIMEM-UHFFFAOYSA-N 0.000 description 1
- RRGJSMBMTOKHTE-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;[3-[2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl]-4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridin-1-yl]methyl dihydrogen phosphate Chemical compound OCC(N)(CO)CO.C1=2N(COP(O)(O)=O)C=C(C(=O)C(=O)N3CCN(CC3)C(=O)C=3C=CC=CC=3)C=2C(OC)=CN=C1N1C=NC(C)=N1 RRGJSMBMTOKHTE-UHFFFAOYSA-N 0.000 description 1
- VKWMGUNWDFIWNW-UHFFFAOYSA-N 2-chloro-1,1-dioxo-1,2-benzothiazol-3-one Chemical compound C1=CC=C2S(=O)(=O)N(Cl)C(=O)C2=C1 VKWMGUNWDFIWNW-UHFFFAOYSA-N 0.000 description 1
- WDRFYIPWHMGQPN-UHFFFAOYSA-N 2-chloroisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Cl)C(=O)C2=C1 WDRFYIPWHMGQPN-UHFFFAOYSA-N 0.000 description 1
- JYVLIDXNZAXMDK-UHFFFAOYSA-N 2-pentanol Substances CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- ASWXNYNXAOQCCD-UHFFFAOYSA-N dichloro(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Cl)(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 ASWXNYNXAOQCCD-UHFFFAOYSA-N 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- SWMDAPWAQQTBOG-UHFFFAOYSA-N fostemsavir Chemical compound C1=2N(COP(O)(O)=O)C=C(C(=O)C(=O)N3CCN(CC3)C(=O)C=3C=CC=CC=3)C=2C(OC)=CN=C1N1C=NC(C)=N1 SWMDAPWAQQTBOG-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- ARGDYOIRHYLIMT-UHFFFAOYSA-N n,n-dichloro-4-methylbenzenesulfonamide Chemical compound CC1=CC=C(S(=O)(=O)N(Cl)Cl)C=C1 ARGDYOIRHYLIMT-UHFFFAOYSA-N 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- VUNXBQRNMNVUMV-UHFFFAOYSA-N phenyl(piperazin-1-yl)methanone Chemical compound C=1C=CC=CC=1C(=O)N1CCNCC1 VUNXBQRNMNVUMV-UHFFFAOYSA-N 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 229950009390 symclosene Drugs 0.000 description 1
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- AIDS & HIV (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Claims (18)
1. Fremgangsmåde til fremstilling af forbindelsen med formlen I:
hvilken fremgangsmåde omfatter: (a) brominering af forbindelsen
m for at opnå forbindelsen
m Og (b) nitrering af forbindelse 2 for at opnå forbindelsen
m 9 Og (c) omdannelse af amingruppen på forbindelse 3 til en methoxygruppe for at opnå forbindelse
ΗΪ 9 Og (d) derefter omdannelse af forbindelse 4 til forbindelsen
2. Fremgangsmåde til fremstilling af forbindelsen med formlen I:
(I) hvilken fremgangsmåde omfatter: (i) omsætning af forbindelsen med
i nærvær af TMG, NMP og Nal eller K2C03 og MeCN for at opnå forbindelsen
og (ii) omsætning af forbindelse 11 med
for at fremstille forbindelsen
og (iii) derefter omdannelse af forbindelsen 12 til forbindelsen
(iv) derefter omdannelse af forbindelsen 13 til forbindelsen
Og (v) derefter omsætning af forbindelsen 14 for at fremstille forbindelsen
og (vi) derefter omdannelse af forbindelsen 15 til forbindelsen med formlen I.
3. Fremgangsmåde ifølge krav 1, hvor trin (a) udføres ved anvendelse af Ac20.
4. Fremgangsmåde ifølge krav 1, hvor trin (b) udføres under sure forhold.
5. Fremgangsmåde ifølge krav 4, hvor trin (b) udføres ved anvendelse af salpetersyre.
¢5) 9 Og (e) omdannelse af forbindelse 5 til forbindelsen
m 9 Og (1) dannelse af en bicyklisk struktur fra forbindelse 6 for at opnå
6. Fremgangsmåde ifølge krav 5, hvor trin (b) udføres ved anvendelse af salpetersyre og svovlsyre.
7. Fremgangsmåde ifølge krav 1, hvor trin (c) udføres ved anvendelse af NaN02 og TMS-C1 i alkohol.
8. Fremgangsmåde ifølge krav 7, hvor alkoholen er methanol.
9. Fremgangsmåde ifølge krav 1, hvor trin (d) udføres ved anvendelse af
9 Og (i) omdannelse af forbindelse 9 til strukturen
(?) 9 Og (g) derefter chlorering af forbindelse 7 for at fremstille
P5 9 Og (h) derefter tilstæning af en triazolyldel til forbindelsen 8 for at opnå
10. Fremgangsmåde ifølge krav 1, hvor trin (U) udtøres ved anvendelse af
(10} 9 Og (j) ændring af forbindelse 10 for at opnå forbindelsen
og (k) omsætning af forbindelse 11 for at fremstille forbindelsen
og (l) derefter omdannelse af forbindelsen 12 til forbindelsen
(m) derefter omdannelse af forbindelse 13 til forbindelsen
Og (n) derefter omsætning af forbindelsen 14 for at fremstille forbindelsen
og (o) derefter omdannelse af forbindelsen 15 til forbindelsen med formlen I.
11. Fremgangsmåde ifølge krav 1, hvor trin til udføres ved anvendelse af
12. Fremgangsmåde ifølge krav 1, hvor trin (j) udføres ved anvendelse af
13. Fremgangsmåde ifølge krav 2, hvor trin (ii) udføres ved anvendelse af
14. Fremgangsmåde ifølge krav 2, hvor trin (iv) udføres ved anvendelse af dichlormethan.
15. Fremgangsmåde ifølge krav 2, hvor trin (v) udføres ved anvendelse af
16. Fremgangsmåde ifølge krav 2, hvor trin (vi) udføres ved anvendelse af acetone i vand og tromethamin
17. Fremgangsmåde til fremstilling af forbindelsen med formlen (14):
(141 ·> hvilken forbindelse omfatter: (i) omsætning af forbindelsen med
for at opnå forbindelsen
Og (ii) omsætning af forbindelse 11 med
for at fremstille forbindelsen
og (iii) derefter omdannelse af forbindelsen 12 til forbindelsen
ved anvendelse af chlorgas; (iv) derefter fremstilling af forbindelsen 14
ved anvendelse af dichlormethan.
18. Forbindelse med følgende formel: eller
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161437821P | 2011-01-31 | 2011-01-31 | |
| PCT/US2012/022851 WO2012106189A1 (en) | 2011-01-31 | 2012-01-27 | Methods of making hiv attachment inhibitor prodrug compound and intermediates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2670751T3 true DK2670751T3 (da) | 2015-07-20 |
Family
ID=45688987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK12704960.9T DK2670751T3 (da) | 2011-01-31 | 2012-01-27 | Fremgangsmåder til fremstilling af hiv- bindingsinhibitorprodrugforbindelse og mellemprodukter |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US8436168B2 (da) |
| EP (1) | EP2670751B1 (da) |
| JP (1) | JP6006236B2 (da) |
| KR (1) | KR101848533B1 (da) |
| CN (1) | CN103339130B (da) |
| AR (1) | AR085052A1 (da) |
| AU (1) | AU2012212508B2 (da) |
| BR (1) | BR112013018159A2 (da) |
| CA (1) | CA2826260C (da) |
| CY (1) | CY1116505T1 (da) |
| DK (1) | DK2670751T3 (da) |
| EA (1) | EA021726B1 (da) |
| ES (1) | ES2539908T3 (da) |
| HR (1) | HRP20150616T1 (da) |
| HU (1) | HUE026880T2 (da) |
| IL (1) | IL227302A (da) |
| MX (1) | MX2013008371A (da) |
| PL (1) | PL2670751T3 (da) |
| PT (1) | PT2670751E (da) |
| RS (1) | RS54055B1 (da) |
| SG (1) | SG191841A1 (da) |
| SI (1) | SI2670751T1 (da) |
| SM (1) | SMT201500169B (da) |
| TW (1) | TW201309692A (da) |
| WO (1) | WO2012106189A1 (da) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7745625B2 (en) | 2004-03-15 | 2010-06-29 | Bristol-Myers Squibb Company | Prodrugs of piperazine and substituted piperidine antiviral agents |
| WO2010085456A1 (en) | 2009-01-20 | 2010-07-29 | Guided Delivery Systems Inc. | Anchor deployment devices and related methods |
| EA024872B1 (ru) | 2012-02-08 | 2016-10-31 | Бристол-Майерс Сквибб Компани | Способы получения пиперазинового пролекарства - ингибитора присоединения вич |
| EP3158563B1 (en) | 2014-06-23 | 2021-11-03 | Free Form Fibers LLC | A nuclear fuel structure containing fibers and a method of making the structure |
| CA2971104A1 (en) | 2014-12-18 | 2016-06-23 | ViiV Healthcare UK (No.4) Limited | A process for preparing halogenated azaindole compounds using boroxine |
| CA2971096A1 (en) | 2014-12-18 | 2016-06-23 | ViiV Healthcare UK (No.4) Limited | A process for preparing halogenated azaindole compounds using pybrop |
| WO2016141358A1 (en) * | 2015-03-05 | 2016-09-09 | Guided Delivery Systems Inc. | Devices and methods of visualizing and determining depth of penetration in cardiac tissue |
| JP6692542B2 (ja) * | 2016-05-13 | 2020-05-13 | 学校法人早稲田大学 | 簡便、迅速、高精度な皮膚ｐＨの測定法 |
| JP7429236B2 (ja) | 2019-01-17 | 2024-02-07 | ヴィーブ ヘルスケア ユーケー（ナンバー４）リミテッド | ホステムサビルの調製方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040110785A1 (en) | 2001-02-02 | 2004-06-10 | Tao Wang | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
| US7745625B2 (en) | 2004-03-15 | 2010-06-29 | Bristol-Myers Squibb Company | Prodrugs of piperazine and substituted piperidine antiviral agents |
| US7776863B2 (en) | 2004-03-24 | 2010-08-17 | Bristol-Myers Squibb Company | Methods of treating HIV infection |
| US7601715B2 (en) | 2005-06-22 | 2009-10-13 | Bristol-Myers Squibb Company | Process for preparing triazole substituted azaindoleoxoacetic piperazine derivatives and novel salt forms produced therein |
| US7851476B2 (en) * | 2005-12-14 | 2010-12-14 | Bristol-Myers Squibb Company | Crystalline forms of 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-YL)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-C]pyridin-3-YL]-1,2-dioxoethyl]-piperazine |
-
2012
- 2012-01-27 DK DK12704960.9T patent/DK2670751T3/da active
- 2012-01-27 EP EP20120704960 patent/EP2670751B1/en active Active
- 2012-01-27 SG SG2013051560A patent/SG191841A1/en unknown
- 2012-01-27 BR BR112013018159A patent/BR112013018159A2/pt not_active Application Discontinuation
- 2012-01-27 AU AU2012212508A patent/AU2012212508B2/en not_active Ceased
- 2012-01-27 MX MX2013008371A patent/MX2013008371A/es active IP Right Grant
- 2012-01-27 PT PT127049609T patent/PT2670751E/pt unknown
- 2012-01-27 PL PL12704960T patent/PL2670751T3/pl unknown
- 2012-01-27 CA CA2826260A patent/CA2826260C/en not_active Expired - Fee Related
- 2012-01-27 WO PCT/US2012/022851 patent/WO2012106189A1/en not_active Ceased
- 2012-01-27 US US13/359,708 patent/US8436168B2/en active Active
- 2012-01-27 KR KR1020137022709A patent/KR101848533B1/ko not_active Expired - Fee Related
- 2012-01-27 HU HUE12704960A patent/HUE026880T2/en unknown
- 2012-01-27 SI SI201230225T patent/SI2670751T1/sl unknown
- 2012-01-27 CN CN201280007153.8A patent/CN103339130B/zh not_active Expired - Fee Related
- 2012-01-27 EA EA201391123A patent/EA021726B1/ru not_active IP Right Cessation
- 2012-01-27 JP JP2013551361A patent/JP6006236B2/ja active Active
- 2012-01-27 ES ES12704960.9T patent/ES2539908T3/es active Active
- 2012-01-27 HR HRP20150616TT patent/HRP20150616T1/hr unknown
- 2012-01-27 RS RS20150388A patent/RS54055B1/sr unknown
- 2012-01-31 TW TW101103123A patent/TW201309692A/zh unknown
- 2012-01-31 AR ARP120100313A patent/AR085052A1/es not_active Application Discontinuation
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2013
- 2013-07-02 IL IL227302A patent/IL227302A/en active IP Right Grant
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2015
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- 2015-07-17 CY CY20151100631T patent/CY1116505T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP6006236B2 (ja) | 2016-10-12 |
| US8436168B2 (en) | 2013-05-07 |
| PL2670751T3 (pl) | 2015-09-30 |
| SMT201500169B (it) | 2015-09-07 |
| IL227302A (en) | 2016-10-31 |
| TW201309692A (zh) | 2013-03-01 |
| CN103339130B (zh) | 2015-05-06 |
| WO2012106189A1 (en) | 2012-08-09 |
| EA201391123A1 (ru) | 2013-12-30 |
| CY1116505T1 (el) | 2017-03-15 |
| AU2012212508A1 (en) | 2013-09-19 |
| MX2013008371A (es) | 2013-08-12 |
| SG191841A1 (en) | 2013-08-30 |
| EP2670751B1 (en) | 2015-04-22 |
| EP2670751A1 (en) | 2013-12-11 |
| US20130030178A1 (en) | 2013-01-31 |
| KR101848533B1 (ko) | 2018-04-12 |
| HUE026880T2 (en) | 2016-08-29 |
| ES2539908T3 (es) | 2015-07-07 |
| JP2014503594A (ja) | 2014-02-13 |
| HRP20150616T1 (hr) | 2015-07-03 |
| SI2670751T1 (sl) | 2015-07-31 |
| CA2826260A1 (en) | 2012-08-09 |
| BR112013018159A2 (pt) | 2018-09-11 |
| AR085052A1 (es) | 2013-08-07 |
| CA2826260C (en) | 2018-09-04 |
| CN103339130A (zh) | 2013-10-02 |
| IL227302A0 (en) | 2013-09-30 |
| AU2012212508B2 (en) | 2016-01-14 |
| EA021726B1 (ru) | 2015-08-31 |
| KR20140014154A (ko) | 2014-02-05 |
| RS54055B1 (sr) | 2015-10-30 |
| PT2670751E (pt) | 2015-07-29 |
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