WO2009121989A1 - Method for obtaining polysubstituted pyrrolidines with hepatitis c inhibiting activity - Google Patents
Method for obtaining polysubstituted pyrrolidines with hepatitis c inhibiting activity Download PDFInfo
- Publication number
- WO2009121989A1 WO2009121989A1 PCT/ES2009/000179 ES2009000179W WO2009121989A1 WO 2009121989 A1 WO2009121989 A1 WO 2009121989A1 ES 2009000179 W ES2009000179 W ES 2009000179W WO 2009121989 A1 WO2009121989 A1 WO 2009121989A1
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- WIPO (PCT)
- Prior art keywords
- general formula
- chiral
- alkyl
- compound
- metal complex
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 28
- 150000003235 pyrrolidines Chemical class 0.000 title abstract description 7
- 230000002401 inhibitory effect Effects 0.000 title description 4
- 208000006454 hepatitis Diseases 0.000 title 1
- 231100000283 hepatitis Toxicity 0.000 title 1
- 125000002091 cationic group Chemical group 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 150000001875 compounds Chemical class 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 150000008300 phosphoramidites Chemical class 0.000 claims description 20
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 19
- -1 tetrafluoroborate Chemical compound 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- 150000004696 coordination complex Chemical class 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000003435 aroyl group Chemical group 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 125000001769 aryl amino group Chemical group 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 7
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 6
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 229910002651 NO3 Inorganic materials 0.000 claims description 4
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 4
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- OXZYBOLWRXENKT-UHFFFAOYSA-N 4-(trifluoromethyl)benzoyl chloride Chemical group FC(F)(F)C1=CC=C(C(Cl)=O)C=C1 OXZYBOLWRXENKT-UHFFFAOYSA-N 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 229910052709 silver Inorganic materials 0.000 abstract description 10
- 239000004332 silver Substances 0.000 abstract description 10
- 125000001424 substituent group Chemical group 0.000 abstract description 5
- 238000005070 sampling Methods 0.000 abstract description 2
- 238000006257 total synthesis reaction Methods 0.000 abstract description 2
- 235000013930 proline Nutrition 0.000 abstract 1
- 150000003148 prolines Chemical class 0.000 abstract 1
- 239000000047 product Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 241000711549 Hepacivirus C Species 0.000 description 7
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000004296 chiral HPLC Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 0 *C(C1)C(*)*(*)C1(*)O Chemical compound *C(C1)C(*)*(*)C1(*)O 0.000 description 3
- RBWNDBNSJFCLBZ-UHFFFAOYSA-N 7-methyl-5,6,7,8-tetrahydro-3h-[1]benzothiolo[2,3-d]pyrimidine-4-thione Chemical compound N1=CNC(=S)C2=C1SC1=C2CCC(C)C1 RBWNDBNSJFCLBZ-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000006352 cycloaddition reaction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000002222 fluorine compounds Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 201000004384 Alopecia Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010049565 Muscle fatigue Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 229940052810 complex b Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011894 semi-preparative HPLC Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- 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
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/10—Silver compounds
-
- 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
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
Definitions
- the present invention relates to a highly enantioselective process catalyzed by small amounts of a chiral complex of cationic silver that allows to generate polysubstituted pyrrolidines, which give rise to substituted proline derivatives after a three-step synthetic sequence.
- the invention also relates to a broad sampling of chiral complexes of cationic silver and the use of different substituents in one of the key step components of this total synthesis.
- the hepatitis C virus whose strand of RNA belongs to the family Flaviridae, is the major causative agent of a chronic liver infection not classified in hepatitis A and B and that affects approximately 2% to 3% of Ia world population. This type of infection often leads to cirrhosis, hepatocellular carcinoma, and liver failure in later stages. It has been estimated that, of the entire infected population, 20%, 4% may develop liver cirrhosis and liver cancer, respectively, in the following decade. The therapy currently used, and which is more successful, is based on the combination of pegylated interferon ⁇ with the antiviral agent ribavirin.
- the hepatitis C virus has a genome, which is a single strand of RNA, which encodes a large protein that contains between 3010 and 3030 amino acids.
- This polyprotein is processed and provides the structural proteins of the virus, the so-called NS2 and NS3 being responsible of the production of its RNA polymerase.
- This polymerase vital for virus replication, is an enzyme that is very well characterized and active domains that must be blocked by inhibitors have been identified. In this way, the profiles of these inhibitory substances can be designed and even detect their efficacy against possible mutations (F. Pauwels et al., J. Virol. 2007, 81, 6909) (GL Warren, et al. Med Chem. 2006, 49, 5912).
- the present invention provides a process for preparing cationic silver complexes with chiral phosphoramidite (III) and (IV) ligands and characterizing them as much as possible in both solution and solid state.
- a first aspect of the present invention refers to a chiral metal complex of general formula A:
- R 6 is hydrogen or a radical selected from the group comprising a (Ci-C 6 ) alkyl, an aryl (C 5 -C 1 4 ) or an arylalkyl
- R 7 is hydrogen or a radical selected from the group comprising an alkyl (CrC 6 ), aryl (C5-C 14 ) or arylalkyl
- R 8 is hydrogen or a radical selected from the group comprising alkyl (CrC 6 ), alkoxyalkyl, (dialkylamino) alkyl (CrC 6 ) or aryl
- X is selected from the list comprising fluoride, acetate, perchlorate, trifuoromethanesulfonate, tetrafluoroborate, nitrate, hexafluorophosphate or hexafluoroantimoniate;
- the chiral metal complex has any of the following general formulas (S a ) - (lll) or (R 3 H 111 ) ° (Sa) - (IV) or (f? A ) - (IV):
- Another aspect of the present invention relates to the chiral metal complex that has the general formula B:
- the chiral metal complex of general formula B has any of the following general formulas 2 (S a ) - (lll), 2 (f? A ) - (IH),
- the chiral metal complexes of the invention have the following particularities, the radicals R 6 and R 7 are alkyl (CrC 6 ) or arylalkyl and / or R 8 is hydrogen and / or X is perchlorate. More preferably R 6 and R 7 are an arialkyl of the formula -CH (Me) Ph, R 8 is hydrogen and X is perchlorate.
- These complexes are prepared by contacting an equivalent of chiral phosphoramidite (a) and an equivalent of cationic silver salt (b) in presence of an organic solvent and in the absence of light. More preferably, the organic solvent is toluene and the reaction is carried out at room temperature.
- radicals R 1 to R 5 can be: R 1 a hydrogen or an aroyl, R 2 a hydrogen or an alkyl (Ci-C 6 ), R 3 an alkyl (CrC 6 ) or arylalkyl, R 4 a radical that selected from the list consisting of hydroxy, alkoxy, alkylamino, arylamino, dialkylamino or heteroaryl and R5.
- Chiral phosphoramidites derived from 1,1'-binaft-2,2'-ol have a typical structure (III) or (IV) with a binary symmetry axis capable of coordinating with silver cations, from the corresponding commercially available salts , to give rise to chiral complexes of cationic silver.
- the cycloaddition reactions are very attractive from the point of view of asymmetric synthesis since at the same reaction step it is possible to generate, at most, four stereogenic centers with a determined absolute configuration.
- the enantioselective 1,3-dipolar cycloaddition reactions take place through metallo-dipoles generated with small amounts of base and a chiral Lewis acid, which in this invention will be the chiral phosphoramidite complex.
- cationic silver In this way, highly enantioselective processes are achieved being able to use low reaction temperatures up to -60 0 C.
- the invention also relates to the optimization of the 1,3-dipolar enantioselective reaction of azomethine ilides derived from iminoesters (V) with acrylic systems (Vl) catalyzed by sub-stoichiometric amounts of said chiral silver complexes .
- R 2 is a (Ci-C 6 ) alkyl
- R 3 is an alkyl (CrCe) or arylalkyl
- R 4 is a radical selected from the list comprising alkoxy, alkylamino, arylamino, or dialkylamino
- R 5 is heteroaryl .
- the product thus obtained has a very high conversion and a high enantiomeric excess.
- the invention After purifying the intermediate pyrrolidine, the invention also provides a process with the synthetic steps necessary to obtain the antiviral agents with structure (I) or (II) starting from the enantiomerically enriched pyrrolidines obtained in the previous object, by means of said reaction of cycloaddition, which comprises properly using two or three sequential steps that include an amidation reaction.
- the enantiomerically pure intermediate pyrrolidines (I) and (II) will be distinguished from the final antiviral products (I) and (II), since these two structures satisfy both types of molecules at different stages of the synthesis.
- the enantiomerically enriched intermediate pyrrolidines are compounds with general formula (I) or (II), where:
- R 1 is hydrogen, R 2 is (Ci-C 6 ) alkyl, R 3 is (Ci-C 6 ) alkyl or arylalkyl, R 4 is alkoxy, alkylamino, arylamino, or dialkylamino and R 5 is heteroaryl, while the antiviral compounds proline derivatives, enantiomerically enriched, have a general formula (I) or (II), where R 1 is aroyl, R 2 is hydrogen, R 3 it is alkyl (CrC 6 ) or arylalkyl, R 4 is hydroxy, alkylamino, arylamino, or dialkylamino and R 5 is heteroaryl.
- the aroyl group which has the antiviral compounds, can have a crucial importance in the inhibitory activity of the hepatitis C virus since it is the part of the molecule that facilitates the permeability through the cell membranes.
- a third aspect of the present invention refers to a process for the preparation of a compound of general formula (C):
- R 2 is an alkyl (CrC 6 )
- R 3 is an alkyl (Ci-C 6 ) or arylalkyl
- R 4 is a radical selected from the list comprising alkoxy, alkylamino, arylamino, or dialkylamino
- R 5 is heteroaryl.
- this procedure is used for the preparation of a compound of general formula C with the absolute configuration (2S, 4S, 5R) or (2R, 4R, 5S) as represented in formulas C (I) or C (II):
- R 2 is an alkyl (CrC 6 )
- R 3 is an alkyl (Ci-C 6 ) or arylalkyl
- R 4 is a radical selected from the list comprising alkoxy, alkylamino, arylamino, or dialkylamino
- R 5 is heteroaryl.
- the method further comprises adding sub-stoichiometric amounts of a base and where the reaction is carried out in the absence of light and at temperatures below 0 0 C.
- R 2 is (Ci-C 3 ) alkyl
- R 3 is isobutyl
- R 4 is alkoxy
- R 5 is thienyl. More preferably R 2 is methyl, R 3 is isobutyl, R 4 is tert-butoxy and R 5 is 2-thienyl
- this step can be carried out as follows: to an equimolar mixture of the iminoester (V) (precursor of the dipole) and the corresponding acrylic system (Vl) with 8 mol% of the aforementioned chiral phosphoramidite complex (lll) / cationic silver or phosphoramidite (IV) / cationic silver between 0 and -20 0 C using toluene as a solvent, is treated with 8 mol% of a base.
- the product thus obtained has a very high conversion and a high enantiomeric excess.
- R 1 is aroyl, and R 2 to R 5 as described above; which comprises the reaction of a compound of general formula C, described above, with an acryloyl chloride.
- the acryloyl chloride is 4-trifluoromethylbenzoyl chloride.
- the compound of general formula D has the absolute configuration (2S, 4S, 5R) or (2R, 4R, 5S) as represented in the following formulas D (I) or D (II):
- R 2 is alkyl (Cr C 3 )
- R 3 is isobutyl
- R 4 is alkoxy
- R 5 is thienyl More preferably R 2 is methyl, R 4 is ferc-butoxy and R 5 is 2-thienyl.
- Another aspect of the present invention relates to the preparation, from a compound of general formula (D), of a compound of general formula (E):
- R 1 , R 3 and R 5 have been described above; which comprises the treatment of a compound of general formula D, with trifluoroacetic acid followed by a reaction of hydrolysis of the ester in basic medium.
- the compound of general formula E has the absolute configuration (2S, 4S, 5 /?) Or (2R, 4R, 5S) as represented in the following formulas:
- alkyl (o) refers to a monovalent straight or branched chain radical, of a saturated hydrocarbon of 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, / -propyl, n-butyl, fe ⁇ f-butyl, sec-butyl, n-pentyl, etc.
- the alkyl has between 1 and 3 carbon atoms.
- aryl (o) refers to a radical derived from an aromatic hydrocarbon by loss of a hydrogen atom in a carbon atom of the nucleus and includes aromatic mono-, bi- or polycyclic radicals and heteroaromatic of between 5 to 14 carbons, optionally substituted with one or more groups selected from halo, alkyl (as previously defined), methoxy or nitro groups.
- arylalkyl (o) alone or in combination, refers to an alkyl group, as defined above, which contains an aryl group, as previously defined, as a substituent.
- alkoxyalkyl (o) refers to an alkyl group (described previously) containing an alkoxy group.
- alkoxy alone or in combination, refers to an "alkyl-oxy” radical, where the term “alkyl” is as defined above.
- dialkylamino alkyl (o) refers to an alkyl group (described previously) containing a dialkylamino group.
- This "dialkylamino” group alone or in combination, refers to a radical of the formula -NRR ', where R and R', independently of each other, are hydrogen or an alkyl or arylalkyl group as previously defined.
- alkylamino or arylamino refer to a substituent with structure -NHR, where R is an alkyl or aryl group, respectively, as defined above.
- heteroaryl (o) refers to an aromatic (or non-aromatic) ring of four, five, six or seven links containing one or more heteroatoms.
- heteroatom refers to an atom other than carbon, the most frequent being nitrogen, oxygen, and sulfur.
- hydroxy refers to a group whose formula is -OH.
- the resulting product was recrystallized from a mixture of hexane / ethyl acetate to obtain the antiviral product with a 79% yield, a purity of 97% and an enantiomeric ratio of 96 to 4 (according to analysis performed by chiral HPLC, Chiralpak AD).
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Abstract
The invention relates to a highly enantioselective method catalysed by small quantities of a chiral complex of cationic silver, which can be used to generate polysubstituted pyrrolidines which give rise to derivatives of substituted prolines following a three-step synthetic sequence. The invention also relates to a broad sampling of chiral complexes of cationic silver and to the use of different substituents in one of the components of the key step of the total synthesis.
Description
PROCEDIMIENTO PARA LA OBTENCIÓN DE PIRROLID1NAS POLISUSTITUIDAS INHIBIDORAS DEL VIRUS DE LA HEPATITIS C PROCEDURE FOR OBTAINING INHIBITING POLYUSTITUTED PIRROLID1NAS OF HEPATITIS C VIRUS
La presente invención se refiere a un proceso altamente enantioselectivo catalizado por pequeñas cantidades de un complejo quiral de plata catiónica que permite generar pirrolidinas polisustituidas, las cuales dan lugar a derivados de prolinas sustituidas tras una secuencia sintética de tres pasos. La invención también se refiere a un amplio muestreo de complejos quirales de plata catiónica y a Ia utilización de distintos sustituyentes en uno de los componentes del paso clave de esta síntesis total.The present invention relates to a highly enantioselective process catalyzed by small amounts of a chiral complex of cationic silver that allows to generate polysubstituted pyrrolidines, which give rise to substituted proline derivatives after a three-step synthetic sequence. The invention also relates to a broad sampling of chiral complexes of cationic silver and the use of different substituents in one of the key step components of this total synthesis.
ESTADO DE LATÉCNICA ANTERIORSTATE OF PREVIOUS LATÉCNICA
El virus de Ia hepatitis C, cuya hebra de ARN pertenece a Ia familia Flaviridae, es el mayor agente causante de una infección crónica hepática no encasillada dentro de las hepatitis A y B y que afecta aproximadamente entre un 2% y un 3% de Ia población mundial. Este tipo de infecciones conduce, a menudo, a cirrosis, carcinoma hepatocelular, y fallos del hígado en etapas posteriores. Se ha estimado que, de toda Ia población infectada, un 20%, un 4% pueden desarrollar cirrosis hepática y cáncer de hígado, respectivamente, en Ia década siguiente. La terapia utilizada actualmente, y que más éxitos está cosechando, está basada en Ia combinación del interferón α pegilado con el agente antiviral ribavirina. El 50% de los pacientes sometidos a este tratamiento han sido capaces de combatir eficazmente a este virus, aunque con Ia desventaja de padecer efectos secundarios agudos como anemia, neutropenia, trombocitopenia, dolor muscular y fatiga, cefaleas, alteraciones psiquiátricas, insomnio, alopecia, anorexia, alergias, etc. Por estas razones el desarrollo de nuevas terapias para tratar y combatir esta infección es de importancia capital y en estos momentos Ia intensidad de las investigaciones en este área son un fiel reflejo de toda Ia inversión económica destinada a este fin. Otro inconveniente añadido a este tratamiento es Ia elevada cantidad de fármaco suministrado por kg de peso, Io cual acentúa mucho más estos efectos adversos.The hepatitis C virus, whose strand of RNA belongs to the family Flaviridae, is the major causative agent of a chronic liver infection not classified in hepatitis A and B and that affects approximately 2% to 3% of Ia world population. This type of infection often leads to cirrhosis, hepatocellular carcinoma, and liver failure in later stages. It has been estimated that, of the entire infected population, 20%, 4% may develop liver cirrhosis and liver cancer, respectively, in the following decade. The therapy currently used, and which is more successful, is based on the combination of pegylated interferon α with the antiviral agent ribavirin. 50% of patients undergoing this treatment have been able to effectively combat this virus, although with the disadvantage of suffering from acute side effects such as anemia, neutropenia, thrombocytopenia, muscle pain and fatigue, headaches, psychiatric disorders, insomnia, alopecia, anorexia, allergies, etc. For these reasons the development of new therapies to treat and combat this infection is of paramount importance and at this time the intensity of research in this area is a true reflection of all the economic investment destined for this purpose. Another drawback added to this treatment is the high amount of drug supplied per kg of weight, which greatly accentuates these adverse effects.
El virus de Ia hepatitis C presenta un genoma, el cual es una mono-hebra de ARN, que codifica a una proteína grande que contiene entre 3010 y 3030 aminoácidos. Esta poliproteína es procesada y proporciona las proteínas estructurales del virus, siendo las denominadas NS2 y NS3 las responsables
de Ia producción de su polimerasa de ARN. Esta polimerasa, vital para Ia replicación del virus, es un enzima que se encuentra muy bien caracterizado y se han identificado los dominios activos que deben ser bloqueados por los inhibidores. De esta manera, los perfiles de estas sustancias inhibidoras pueden ser diseñados e incluso detectar Ia eficacia de éstas frente a posibles mutaciones (F. Pauwels et al., J. Virol. 2007, 81, 6909) (G. L. Warren, et al. Med. Chem. 2006, 49, 5912).The hepatitis C virus has a genome, which is a single strand of RNA, which encodes a large protein that contains between 3010 and 3030 amino acids. This polyprotein is processed and provides the structural proteins of the virus, the so-called NS2 and NS3 being responsible of the production of its RNA polymerase. This polymerase, vital for virus replication, is an enzyme that is very well characterized and active domains that must be blocked by inhibitors have been identified. In this way, the profiles of these inhibitory substances can be designed and even detect their efficacy against possible mutations (F. Pauwels et al., J. Virol. 2007, 81, 6909) (GL Warren, et al. Med Chem. 2006, 49, 5912).
Uno de los mejores y más eficaces inhibidores descubiertos corresponde a Ia familia de pirrolidinas sustituidas como las que se describen en las estructuras generales (I) y (II) (G. Burton, T., et al., Bioorg. Med. Chem. Lett. 2005, 15,One of the best and most effective inhibitors discovered corresponds to the family of substituted pyrrolidines such as those described in the general structures (I) and (II) (G. Burton, T., et al., Bioorg. Med. Chem. Lett. 2005, 15,
1553). Aunque su nivel de ensayos no se ha realizado todavía en humanos, las pruebas realizadas a ratones infectados proporcionaron resultados espectaculares conociéndose que concentraciones de IC50 0.3-0.5 μM son muy efectivas contra el virus de Ia hepatitis C.1553). Although its level of trials has not yet been performed in humans, the tests performed on infected mice provided spectacular results knowing that concentrations of IC 50 0.3-0.5 μM are very effective against the hepatitis C virus.
Hasta ahora todas las síntesis realizadas de las mencionadas estructuras pirrolidínicas se basan en reacciones de cicloadición 1,3 dipolares (C. Nájera, J. M. Sansano, Angew. Chem., Int. Ed. 2005, 44, 6272) a temperaturas más o menos elevadas utilizando metalo-dipolos derivados de metales alcalinos y metales de transición. En todos los casos los productos obtenidos son mezclas racémicas (M. J. Slater, et al. J. Med. Chem. 2007, 50, 897) (G. Burton, et al. Bioorg. Med. Chem. Lett. 2007, 17, 1930) o una mezcla de diastereoisómeros en Ia que posteriormente se aisló por separado cada enantiómero aplicando las reacciones de hidrólisis correspondientes (C. Nájera, M. G. Retamosa, J. M. Sansano, A. de Cózar, F. P. Cossío, Eur. J. Org. Chem. 2007, 5038) y en ningún caso se ha documentado hasta ahora una metodología capaz de obtener estos compuestos enantioselectivamente. En las publicaciones o patentes donde se ha precisado aislar cada enantiómero por separado se ha recurrido a Ia técnica de HPLC quiral semi-preparativa o a Ia resolución del racemato empleando el ácido fosfórico derivado del 1 ,1'-binaft-2,2'-ol (D. Haigh, et al, PCT Int. Appl. 2007, WO 2007039143; Chem. Abstr. 2007, 146, 401814), (R. Guidetti, et al, S. A. Smith, PCT Int. Appl. 2006, WO 2006045615; Chem. Abstr. 2006, 144, 433104) y otras.So far all the syntheses made of the aforementioned pyrrolidine structures are based on 1,3 dipolar cycloaddition reactions (C. Nájera, JM Sansano, Angew. Chem., Int. Ed. 2005, 44, 6272) at more or less elevated temperatures using metallo-dipoles derived from alkali metals and transition metals. In all cases the products obtained are racemic mixtures (MJ Slater, et al. J. Med. Chem. 2007, 50, 897) (G. Burton, et al. Bioorg. Med. Chem. Lett. 2007, 17, 1930 ) or a mixture of diastereoisomers in which each enantiomer was subsequently isolated separately by applying the corresponding hydrolysis reactions (C. Nájera, MG Retamosa, JM Sansano, A. de Cózar, FP Cossío, Eur. J. Org. Chem. 2007 , 5038) and in no case has a methodology so far been able to obtain these compounds enantioselectively. In publications or patents where it has been necessary to isolate each enantiomer separately, the semi-preparative chiral HPLC technique or the racemate resolution has been used using the phosphoric acid derived from 1,1'-binaft-2,2'-ol (D. Haigh, et al, PCT Int. Appl. 2007, WO 2007039143; Chem. Abstr. 2007, 146, 401814), (R. Guidetti, et al, SA Smith, PCT Int. Appl. 2006, WO 2006045615; Chem. Abstr. 2006, 144, 433104) and others.
Este conjunto de moléculas ha representado desde hace unos años una esperanzadora alternativa para frenar el desarrollo del virus de Ia hepatitis C,
sin embargo en los procesos de obtención de los mismos se obtienen mezclas racémicas, o resuelven estos inconvenientes con otras moléculas quirales o bien empleando Ia técnica de HPLC semi-preparativa.This group of molecules has represented for some years a hopeful alternative to stop the development of the hepatitis C virus, However, in the process of obtaining them, racemic mixtures are obtained, or they solve these problems with other chiral molecules or using the semi-preparative HPLC technique.
EXPLICACIÓN DE LA INVENCIÓNEXPLANATION OF THE INVENTION
La presente invención proporciona un procedimiento para preparar complejos de plata catiónica con ligandos del tipo fosforamidito quirales (III) y (IV) y caracterizarlos en Ia medida que sea posible tanto en disolución como en estado sólido.The present invention provides a process for preparing cationic silver complexes with chiral phosphoramidite (III) and (IV) ligands and characterizing them as much as possible in both solution and solid state.
Así, un primer aspecto de Ia presente invención se refiere a un complejo metálico quiral de fórmula general A:Thus, a first aspect of the present invention refers to a chiral metal complex of general formula A:
(a) (b) caracterizado por Ia coordinación de fosforamidito quiral (a) y de sai de plata catiónica (b); donde R6 es hidrógeno o un radical seleccionado del grupo que comprende un alquilo (Ci-C6), un arilo (C5-C14) o un arilalquilo; R7 es hidrógeno o un radical seleccionado del grupo que comprende un alquilo (CrC6), arilo (C5-C14) o arilalquilo; R8 es hidrógeno o un radical seleccionado del grupo que comprende alquilo (CrC6), alcoxialquilo, (dialquilamino)alquilo (CrC6) o arilo; X se selecciona de Ia lista que comprende fluoruro, acetato, perclorato, trifuorometanosulfonato, tetrafluoroborato, nitrato, hexafluorofosfato o hexafluoroantimoniato; y ( — ) representa un enlace que puede existir o no.(a) (b) characterized by the coordination of chiral phosphoramidite (a) and cationic silver sai (b); wherein R 6 is hydrogen or a radical selected from the group comprising a (Ci-C 6 ) alkyl, an aryl (C 5 -C 1 4 ) or an arylalkyl; R 7 is hydrogen or a radical selected from the group comprising an alkyl (CrC 6 ), aryl (C5-C 14 ) or arylalkyl; R 8 is hydrogen or a radical selected from the group comprising alkyl (CrC 6 ), alkoxyalkyl, (dialkylamino) alkyl (CrC 6 ) or aryl; X is selected from the list comprising fluoride, acetate, perchlorate, trifuoromethanesulfonate, tetrafluoroborate, nitrate, hexafluorophosphate or hexafluoroantimoniate; and (-) represents a link that may or may not exist.
Que el enlace ( — ) exista o no, da lugar a un fosforamidito quiral (a) de fórmula general (III) ó (IV):
Whether the (-) link exists or not, results in a chiral phosphoramidite (a) of general formula (III) or (IV):
En una realización preferida el complejo metálico quiral presenta cualquiera de las fórmulas generales siguientes (Sa)-(lll) o (R3H111) ° (Sa)-(IV) o (f?a)-(IV):In a preferred embodiment the chiral metal complex has any of the following general formulas (S a ) - (lll) or (R 3 H 111 ) ° (Sa) - (IV) or (f? A ) - (IV):
Otro aspecto de Ia presente invención se refiere al complejo metálico quiral que presenta Ia fórmula general B:Another aspect of the present invention relates to the chiral metal complex that has the general formula B:
En una realización preferida el complejo metálico quiral de fórmula general B, presenta cualquiera de las fórmulas generales siguientes 2(Sa)-(lll), 2(f?a)-(IH),In a preferred embodiment the chiral metal complex of general formula B has any of the following general formulas 2 (S a ) - (lll), 2 (f? A ) - (IH),
y donde los radicales R6 a R8 y X se han definido anteriormente.and where the radicals R 6 to R 8 and X have been defined above.
A partir de ahora, se entenderá por complejo metálico quiral de Ia invención aquellos con estructuras englobadas en cualquiera de las formulas generales A V B.From now on, chiral metal complex of the invention will be understood as those with structures encompassed in any of the general formulas A V B.
Así, en una realización más preferida, los complejos metálicos quirales de Ia invención presentan las siguientes particularidades, los radicales R6 y R7 son alquilo (CrC6) o arilalquilo y/o R8 es hidrógeno y/o X es perclorato. Más preferiblemente R6 y R7 son un arialquilo de fórmula -CH(Me)Ph, R8 es hidrógeno y X es perclorato.Thus, in a more preferred embodiment, the chiral metal complexes of the invention have the following particularities, the radicals R 6 and R 7 are alkyl (CrC 6 ) or arylalkyl and / or R 8 is hydrogen and / or X is perchlorate. More preferably R 6 and R 7 are an arialkyl of the formula -CH (Me) Ph, R 8 is hydrogen and X is perchlorate.
Estos complejos se preparan poniendo en contacto un equivalente de fosforamidito quiral (a) y un equivalente de sal de plata catiónica (b) en
presencia de un disolvente orgánico y en ausencia de luz. Más preferiblemente el disolvente orgánico es tolueno y Ia reacción se lleva a cabo a temperatura ambiente.These complexes are prepared by contacting an equivalent of chiral phosphoramidite (a) and an equivalent of cationic silver salt (b) in presence of an organic solvent and in the absence of light. More preferably, the organic solvent is toluene and the reaction is carried out at room temperature.
Estos complejos se utilizan, bajo unas determinadas condiciones, en Ia reacción 1 ,3-dipolar enantioselectiva de iluros de azometino y alquenos electrofílicos. El conjunto de pasos sintéticos optimizados dan lugar a una serie de intermedios y productos finales que comparten las fórmulas generales (I) oThese complexes are used, under certain conditions, in the 1,3-dipolar reaction enantioselective of azomethine ilides and electrophilic alkenes. The set of optimized synthetic steps give rise to a series of intermediates and final products that share the general formulas (I) or
(II):(II):
Donde los radicales R1 a R5 puede ser: R1 un hidrógeno ó un aroílo, R2 un hidrógeno o un alquilo (Ci-C6), R3 un alquilo (CrC6) o arilalquilo, R4 un radical que se selecciona de Ia lista que comprende hidroxi, alcoxi, alquilamino, arilamino, o dialquilamino y R5 un heteroarilo.Where the radicals R 1 to R 5 can be: R 1 a hydrogen or an aroyl, R 2 a hydrogen or an alkyl (Ci-C 6 ), R 3 an alkyl (CrC 6 ) or arylalkyl, R 4 a radical that selected from the list consisting of hydroxy, alkoxy, alkylamino, arylamino, dialkylamino or heteroaryl and R5.
Los fosforamiditos quirales derivados de 1 ,1'-binaft-2,2'-ol presentan una estructura típica (III) o (IV) con un eje de simetría binario capaz de coordinarse con cationes de plata, procedentes de las correspondientes sales comercialmente asequibles, para dar lugar así a complejos quirales de plata catiónica.Chiral phosphoramidites derived from 1,1'-binaft-2,2'-ol have a typical structure (III) or (IV) with a binary symmetry axis capable of coordinating with silver cations, from the corresponding commercially available salts , to give rise to chiral complexes of cationic silver.
Generalmente, las reacciones de cicloadición son muy atractivas desde el punto de vista de Ia síntesis asimétrica ya que en un mismo paso de reacción se consigue, como máximo, generar cuatro centros estereogénicos con una configuración absoluta determinada. Como una parte de las reacciones de cicloadición, las reacciones de cicloadición 1 ,3-dipolares enantioselectivas tienen lugar a través de metalo-dipolos generados con pequeñas cantidades de base y un ácido de Lewis quiral, que en esta invención será el complejo fosforamidito quiral/plata catiónica. De esta manera, se consiguen procesos altamente enantioselectivos pudiéndose utilizar bajas temperaturas de reacción hasta -60 0C. Otro dato a tener en cuenta son las restricciones estructurales y
electrónicas de este tipo de transformaciones químicas puesto que una pequeña modificación en cualquiera de estos dos supuestos los resultados pueden variar de una manera extraordinaria. Por ejemplo, no es muy habitual en este tipo de reacciones que los dipolos derivados de aminoácidos distintos a Ia glicina proporcionen buenos rendimientos y elevados excesos enantioméricos.Generally, the cycloaddition reactions are very attractive from the point of view of asymmetric synthesis since at the same reaction step it is possible to generate, at most, four stereogenic centers with a determined absolute configuration. As a part of the cycloaddition reactions, the enantioselective 1,3-dipolar cycloaddition reactions take place through metallo-dipoles generated with small amounts of base and a chiral Lewis acid, which in this invention will be the chiral phosphoramidite complex. cationic silver In this way, highly enantioselective processes are achieved being able to use low reaction temperatures up to -60 0 C. Another data to be taken into account are the structural restrictions and electronic of this type of chemical transformations since a small modification in any of these two assumptions the results can vary in an extraordinary way. For example, it is not very common in this type of reaction that the dipoles derived from amino acids other than glycine provide good yields and high enantiomeric excesses.
Como se describe a continuación, Ia invención también se refiere a Ia optimización de Ia reacción 1 ,3-dipolar enantioselectiva de iluros de azometino derivados de iminoésteres (V) con sistemas acrílicos (Vl) catalizada por cantidades subestequiométricas de los citados complejos de plata quirales.As described below, the invention also relates to the optimization of the 1,3-dipolar enantioselective reaction of azomethine ilides derived from iminoesters (V) with acrylic systems (Vl) catalyzed by sub-stoichiometric amounts of said chiral silver complexes .
Donde R2 es un alquilo (Ci-C6), R3 es un alquilo (CrCe) o arilalquilo, R4 es un radical que se selecciona de Ia lista que comprende alcoxi, alquilamino, arilamino, o dialquilamino y R5 es heteroarilo. El producto así obtenido presenta una conversión muy elevada y un elevado exceso enantiomérico.Where R 2 is a (Ci-C 6 ) alkyl, R 3 is an alkyl (CrCe) or arylalkyl, R 4 is a radical selected from the list comprising alkoxy, alkylamino, arylamino, or dialkylamino and R 5 is heteroaryl . The product thus obtained has a very high conversion and a high enantiomeric excess.
Tras purificar Ia pirrolidina intermedia, Ia invención también proporciona un procedimiento con los pasos sintéticos necesarios para obtener los agentes antivirales con estructura (I) ó (II) partiendo de las pirrolidinas enantioméricamente enriquecidas obtenidas en el objeto previo, por medio de la citada reacción de cicloadición, que comprende utilizar adecuadamente dos o tres pasos secuenciales que incluyen una reacción de amidación.After purifying the intermediate pyrrolidine, the invention also provides a process with the synthetic steps necessary to obtain the antiviral agents with structure (I) or (II) starting from the enantiomerically enriched pyrrolidines obtained in the previous object, by means of said reaction of cycloaddition, which comprises properly using two or three sequential steps that include an amidation reaction.
A continuación se distinguirán las pirrolidinas intermedias enantioméricamente puras (I) y (II) de los productos finales antivirales (I) y (II), ya que estas dos estructuras satisfacen ambos tipos de moléculas en distintas etapas de Ia síntesis. Las pirrolidinas intermedias enriquecidas enantioméricamente son compuestos con fórmula general (I) o (II), donde:Next, the enantiomerically pure intermediate pyrrolidines (I) and (II) will be distinguished from the final antiviral products (I) and (II), since these two structures satisfy both types of molecules at different stages of the synthesis. The enantiomerically enriched intermediate pyrrolidines are compounds with general formula (I) or (II), where:
R1 es hidrógeno, R2 es alquilo (Ci-C6), R3 es alquilo (Ci-C6) o arilalquilo, R4 es alcoxi, alquilamino, arilamino, o dialquilamino y R5 es heteroarilo, mientras los compuestos antivirales derivados de prolina, enriquecidos enantioméricamente, presentan una fórmula general (I) o (II), donde R1 es aroílo, R2 es hidrógeno, R3
es alquilo (CrC6) o arilalquilo, R4 es hidroxi, alquilamino, arilamino, o dialquilamino y R5 es heteroarilo.R 1 is hydrogen, R 2 is (Ci-C 6 ) alkyl, R 3 is (Ci-C 6 ) alkyl or arylalkyl, R 4 is alkoxy, alkylamino, arylamino, or dialkylamino and R 5 is heteroaryl, while the antiviral compounds proline derivatives, enantiomerically enriched, have a general formula (I) or (II), where R 1 is aroyl, R 2 is hydrogen, R 3 it is alkyl (CrC 6 ) or arylalkyl, R 4 is hydroxy, alkylamino, arylamino, or dialkylamino and R 5 is heteroaryl.
El grupo aroílo, que presentan los compuestos antivirales, puede tener una importancia crucial en la actividad inhibidora del virus de Ia hepatitis C puesto que es Ia parte de Ia molécula que facilita Ia permeabilidad a través de las membranas celulares.The aroyl group, which has the antiviral compounds, can have a crucial importance in the inhibitory activity of the hepatitis C virus since it is the part of the molecule that facilitates the permeability through the cell membranes.
Por todo ello, un tercer aspecto de Ia presente invención se refiere a un procedimiento para Ia preparación de un compuesto de fórmula general (C):Therefore, a third aspect of the present invention refers to a process for the preparation of a compound of general formula (C):
donde R2 es un alquilo (CrC6), R3 es un alquilo (Ci-C6) o arilalquilo, R4 es un radical que se selecciona de la lista que comprende alcoxi, alquilamino, arilamino, o dialquilamino y R5 es heteroarilo.where R 2 is an alkyl (CrC 6 ), R 3 is an alkyl (Ci-C 6 ) or arylalkyl, R 4 is a radical selected from the list comprising alkoxy, alkylamino, arylamino, or dialkylamino and R 5 is heteroaryl.
En una realización preferida, este procedimiento se utiliza para Ia preparación de un compuesto de fórmula general C con Ia configuración absoluta (2S,4S,5R) o (2R,4R,5S) tal y como se representa en las fórmulas C(I) ó C(II):
In a preferred embodiment, this procedure is used for the preparation of a compound of general formula C with the absolute configuration (2S, 4S, 5R) or (2R, 4R, 5S) as represented in formulas C (I) or C (II):
donde R2 es un alquilo (CrC6), R3 es un alquilo (Ci-C6) o arilalquilo, R4 es un radical que se selecciona de Ia lista que comprende alcoxi, alquilamino, arilamino, o dialquilamino y R5 es heteroarilo.where R 2 is an alkyl (CrC 6 ), R 3 is an alkyl (Ci-C 6 ) or arylalkyl, R 4 is a radical selected from the list comprising alkoxy, alkylamino, arylamino, or dialkylamino and R 5 is heteroaryl.
En una realización más preferida el procedimiento además comprende Ia adición de cantidades subestequiométricas de una base y donde Ia reacción se lleva a cabo en ausencia de luz y a temperaturas por debajo de los 0 0C.In a more preferred embodiment, the method further comprises adding sub-stoichiometric amounts of a base and where the reaction is carried out in the absence of light and at temperatures below 0 0 C.
En una realización aún más preferida R2 es alquilo (Ci-C3), R3 es isobutilo, R4 es alcoxi y R5 es tienilo. Más preferiblemente R2 es metilo, R3 es isobutilo, R4 es terc-butoxi y R5 es 2-tieniloIn an even more preferred embodiment R 2 is (Ci-C 3 ) alkyl, R 3 is isobutyl, R 4 is alkoxy and R 5 is thienyl. More preferably R 2 is methyl, R 3 is isobutyl, R 4 is tert-butoxy and R 5 is 2-thienyl
De forma concreta, este paso se puede efectuar del siguiente modo: a una mezcla equimolar del iminoéster (V) (precursor del dipolo) y del correspondiente sistema acrílico (Vl) con un 8% en moles del citado complejo quiral de fosforamidito (lll)/plata catiónica o fosforamidito (IV)/plata catiónica entre 0 y -20 0C usando tolueno como disolvente, se trata con un 8% en moles de una base. El producto así obtenido presenta una conversión muy elevada y un elevado exceso enantiomérico.Specifically, this step can be carried out as follows: to an equimolar mixture of the iminoester (V) (precursor of the dipole) and the corresponding acrylic system (Vl) with 8 mol% of the aforementioned chiral phosphoramidite complex (lll) / cationic silver or phosphoramidite (IV) / cationic silver between 0 and -20 0 C using toluene as a solvent, is treated with 8 mol% of a base. The product thus obtained has a very high conversion and a high enantiomeric excess.
Como se especifica más adelante, tras purificar Ia pirrolidina intermedia, se deben completar dos o tres pasos secuenciales que incluyen Ia reacción de amidación con distintos cloruros de aroílo, realizada en diclorometano a reflujo y en presencia de un exceso de una base, Ia hidrólisis de los esteres (o del éster) ferc-butílicos en presencia de ácido trifluoroacético y, finalmente, una hidrólisis de los esteres residuales (metílicos, etílicos o isopropílicos) en presencia de hidróxido de potasio en metanol/agua. La purificación de los inhibidores del virus de Ia hepatitis C re realiza por recristalización en Ia mezcla de disolventes adecuado, obteniéndose los productos finales con purezas superiores al 98%.
Por tanto, otro aspecto de Ia presente invención se refiere a Ia preparación de un compuesto de fórmula general (D) a partir del compuesto (C):As specified below, after purifying the intermediate pyrrolidine, two or three sequential steps must be completed that include the amidation reaction with different aroyl chlorides, performed in dichloromethane at reflux and in the presence of an excess of a base, the hydrolysis of the esters (or of the ester) ferc-butyl in the presence of trifluoroacetic acid and, finally, a hydrolysis of the residual esters (methyl, ethyl or isopropyl) in the presence of potassium hydroxide in methanol / water. The purification of hepatitis C virus inhibitors is carried out by recrystallization in the appropriate solvent mixture, obtaining the final products with purities greater than 98%. Therefore, another aspect of the present invention relates to the preparation of a compound of general formula (D) from the compound (C):
D donde R1 es aroílo, y R2 a R5 como se han descrito anteriormente; que comprende Ia reacción de un compuesto de fórmula general C, descrito anteriormente, con un cloruro de acriloílo. Preferiblemente el cloruro de acriloílo es el cloruro de 4-trifluorometilbenzoílo.D where R 1 is aroyl, and R 2 to R 5 as described above; which comprises the reaction of a compound of general formula C, described above, with an acryloyl chloride. Preferably the acryloyl chloride is 4-trifluoromethylbenzoyl chloride.
En otra realización preferida, el compuesto de fórmula general D presenta Ia configuración absoluta (2S,4S,5R) o (2R,4R,5S) tal y como se representa en las siguientes fórmulas D(I) o D(II):In another preferred embodiment, the compound of general formula D has the absolute configuration (2S, 4S, 5R) or (2R, 4R, 5S) as represented in the following formulas D (I) or D (II):
R1 a R5 se han descrito anteriormente.R 1 to R 5 have been described above.
En una realización más preferida R1 es 4-[(CF3)C6H4C(=O)]-, R2 es alquilo (Cr C3), R3 es isobutilo, R4 es alcoxi y R5 es tienilo. Más preferiblemente R2 es metilo, R4 es ferc-butoxi y R5 es 2-tienilo.In a more preferred embodiment R 1 is 4 - [(CF 3 ) C 6 H 4 C (= O)] -, R 2 is alkyl (Cr C 3 ), R 3 is isobutyl, R 4 is alkoxy and R 5 is thienyl More preferably R 2 is methyl, R 4 is ferc-butoxy and R 5 is 2-thienyl.
Por último, otro aspecto de Ia presente invención de refiere a Ia preparación, a partir de un compuesto de fórmula general (D), de un compuesto de fórmula general (E):
Finally, another aspect of the present invention relates to the preparation, from a compound of general formula (D), of a compound of general formula (E):
EAND
Donde R1, R3 y R5 se han descrito anteriormente; que comprende el tratamiento de un compuesto de fórmula general D, con ácido trifluoroacético seguido de una reacción de hidrólisis del éster en medio básico.Where R 1 , R 3 and R 5 have been described above; which comprises the treatment of a compound of general formula D, with trifluoroacetic acid followed by a reaction of hydrolysis of the ester in basic medium.
En una realización preferida, el compuesto de fórmula general E presenta Ia configuración absoluta (2S,4S,5/?) o (2R,4R,5S) tal y como se representa en las siguientes fórmulas:In a preferred embodiment, the compound of general formula E has the absolute configuration (2S, 4S, 5 /?) Or (2R, 4R, 5S) as represented in the following formulas:
Donde R1, R3 y R5 se han descrito anteriormente. Más preferiblemente R1 es 4- (CF3)C6H4C(=O)-, R3 es isobutilo y R5 es 2-tienilo.Where R 1 , R 3 and R 5 have been described above. More preferably R 1 is 4- (CF3) C6H4C (= O) -, R 3 is isobutyl and R 5 is 2-thienyl.
Tal y como se utiliza en esta descripción, el término "alquil(o)", solo o en combinación, se refiere a un radical monovalente de cadena lineal o ramificada, de un hidrocarburo saturado de 1 a 6 átomos de carbono, por ejemplo, metilo, etilo, n-propilo, /-propilo, n-butilo, feπf-butilo, sec-butilo, n-pentilo, etc. Preferiblemente el alquilo tiene entre 1 y 3 átomos de carbono.As used in this description, the term "alkyl (o)", alone or in combination, refers to a monovalent straight or branched chain radical, of a saturated hydrocarbon of 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, / -propyl, n-butyl, feπf-butyl, sec-butyl, n-pentyl, etc. Preferably the alkyl has between 1 and 3 carbon atoms.
El término "aril(o)", solo o en combinación, se refiere a un radical derivado de un hidrocarburo aromático por pérdida de un átomo de hidrógeno en un átomo de carbono del núcleo e incluye radicales mono-, bi- o policíclicos aromáticos y heteroaromáticos de entre 5 a 14 carbonos, opcionalmente sustituidos con uno o más grupos seleccionados entre grupos halo, alquilo (tal y como se ha definido previamente), metoxilo o nitro.
El término "arilalquil(o)", solo o en combinación, se refiere a un grupo alquilo, tal y como se ha definido con anterioridad, que contiene un grupo arilo, tal y como se ha definido previamente, como sustituyente.The term "aryl (o)", alone or in combination, refers to a radical derived from an aromatic hydrocarbon by loss of a hydrogen atom in a carbon atom of the nucleus and includes aromatic mono-, bi- or polycyclic radicals and heteroaromatic of between 5 to 14 carbons, optionally substituted with one or more groups selected from halo, alkyl (as previously defined), methoxy or nitro groups. The term "arylalkyl (o)", alone or in combination, refers to an alkyl group, as defined above, which contains an aryl group, as previously defined, as a substituent.
El término "alcoxialquil(o)", solo o en combinación, se refiere a un grupo alquilo (descrito previamente) que contiene un grupo alcoxi. Este término "alcoxi", solo o en combinación, se refiere a un radical "alquil-oxi", donde el término alquil es el definido con anterioridad.The term "alkoxyalkyl (o)", alone or in combination, refers to an alkyl group (described previously) containing an alkoxy group. This term "alkoxy", alone or in combination, refers to an "alkyl-oxy" radical, where the term "alkyl" is as defined above.
El término "(dialquilamino)alquil(o)", solo o en combinación, se refiere a un grupo alquilo (descrito previamente) que contiene un grupo dialquilamino. Este grupo "dialquilamino", solo o en combinación, se refiere a un radical de fórmula -NRR', donde R y R', independientemente entre sí, son hidrógeno o un grupo alquilo o arilalquilo tal y como se ha definido previamente.The term "(dialkylamino) alkyl (o)", alone or in combination, refers to an alkyl group (described previously) containing a dialkylamino group. This "dialkylamino" group, alone or in combination, refers to a radical of the formula -NRR ', where R and R', independently of each other, are hydrogen or an alkyl or arylalkyl group as previously defined.
Los términos "alquilamino" o "arilamino" hacen referencia a un sustituyente con estructura -NHR, donde R es un grupo alquilo o arilo, respectivamente, tal y como se han definido anteriormente.The terms "alkylamino" or "arylamino" refer to a substituent with structure -NHR, where R is an alkyl or aryl group, respectively, as defined above.
El término "heteroaril(o)", solo o en combinación se refiere a un anillo aromático (o no aromático) de cuatro, cinco, seis o siete eslabones que contiene uno o varios heteroátomos. El término heteroátomo hace referencia a un átomo distinto al carbono, siendo los más frecuentes nitrógeno, oxígeno, y azufre.The term "heteroaryl (o)", alone or in combination, refers to an aromatic (or non-aromatic) ring of four, five, six or seven links containing one or more heteroatoms. The term heteroatom refers to an atom other than carbon, the most frequent being nitrogen, oxygen, and sulfur.
El término "aroíl(o)", solo o en combinación, se refiere a un grupo arilo con uno o varios sustituyentes seleccionados entre grupos alquilo, alcoxi, halo y nitro (definidos previamente), unido a un grupo carbonilo C=O. Este término aroílo estaría representado por Ia fórmula arilo-C(=O)-.The term "aroyl (o)", alone or in combination, refers to an aryl group with one or more substituents selected from alkyl, alkoxy, halo and nitro groups (previously defined), attached to a C = O carbonyl group. This aroyl term would be represented by the aryl-C formula (= O) -.
El término "hidroxi", solo o en combinación, se refiere a un grupo cuya fórmula es -OH.The term "hydroxy", alone or in combination, refers to a group whose formula is -OH.
A Io largo de Ia descripción y las reivindicaciones Ia palabra "comprende" y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Para los expertos en Ia materia, otros objetos, ventajas y características de Ia invención se desprenderán en parte de Ia descripción y en parte de Ia práctica de Ia invención. Los siguientes ejemplos se
proporcionan a modo de ilustración, y no se pretende que sean limitativos de Ia presente invención.Throughout the description and the claims, the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and characteristics of the invention will emerge partly from the description and partly from the practice of the invention. The following examples are They are provided by way of illustration, and are not intended to be limiting of the present invention.
EJEMPLOSEXAMPLES
A continuación se ¡lustrará Ia invención mediante unos ensayos realizados por los inventores, que ponen de manifiesto Ia efectividad del procedimiento descrito.The invention will now be illustrated by tests carried out by the inventors, which show the effectiveness of the described procedure.
EJEMPL0 1EXAMPLE 1
Complejos equimolares quirales de fosforamidito (lll)/sal de plata catiónica [R6 = H, alquilo, arilo o arilalquilo; R7 = H, alquilo, arilo o arilalquilo; R8 = H, alquilo, alcoxialquilo, (dialquilamino) alquilo o arilo; X = fluoruro, acetato, perclorato, trifuorometanosulfonato, tetrafluoroborato, nitrato, hexafluorofosfato o hexafluoroantimoniato].Chiral equimolar phosphoramidite complexes (lll) / cationic silver salt [R 6 = H, alkyl, aryl or arylalkyl; R 7 = H, alkyl, aryl or arylalkyl; R 8 = H, alkyl, alkoxyalkyl, (dialkylamino) alkyl or aryl; X = fluoride, acetate, perchlorate, trifuoromethanesulfonate, tetrafluoroborate, nitrate, hexafluorophosphate or hexafluoroantimoniate].
A una suspensión de perclorato de plata (0,2 mmol, 41 mg) en tolueno (2 ml_) se Ie añadió el fosforamidito quiral (Sa)-(lll) [R6, R7 = (R)-CH(Me)Ph, R8 = H] (0,2 mmol, 110 mg) y Ia mezcla se agitó a temperatura ambiente durante una hora en ausencia de luz. Al cabo de este tiempo el disolvente se evaporó a vacío (15 torr) obteniendo el complejo deseado.To a suspension of silver perchlorate (0.2 mmol, 41 mg) in toluene (2 ml_) was added chiral phosphoramidite (S a ) - (lll) [R 6 , R 7 = (R) -CH (Me ) Ph, R 8 = H] (0.2 mmol, 110 mg) and the mixture was stirred at room temperature for one hour in the absence of light. After this time the solvent was evaporated in vacuo (15 torr) to obtain the desired complex.
EJEMPLO 2EXAMPLE 2
Complejos equimolares quirales de fosforamidito (IV)/sal de plata catiónica [R6 = H, alquilo, arilo o arilalquilo; R7 = H, alquilo, arilo o arilalquilo; R8 = H, alquilo, alcoxialquilo, (dialquilamino)alquilo o arilo; X = fluoruro, acetato, perclorato, trifuorometanosulfonato, tetrafluoroborato, nitrato, hexafluorofosfato o hexafluoroantimoniato].Chiral equimolar phosphoramidite (IV) / cationic silver salt complexes [R 6 = H, alkyl, aryl or arylalkyl; R 7 = H, alkyl, aryl or arylalkyl; R 8 = H, alkyl, alkoxyalkyl, (dialkylamino) alkyl or aryl; X = fluoride, acetate, perchlorate, trifuoromethanesulfonate, tetrafluoroborate, nitrate, hexafluorophosphate or hexafluoroantimoniate].
A una suspensión de perclorato de plata (0,2 mmol, 41 mg) en tolueno (2 mL) se Ie añadió el fosforamidito quiral (Sa)-(HI) [R6, R7 = (R)-CH(Me)Ph, R8 = H] (0,4 mmol, 220 mg) y Ia mezcla se agitó a temperatura ambiente durante una hora en ausencia de luz. Al cabo de este tiempo el disolvente se evaporó a vacío (15 torr) obteniendo el complejo deseado. Estos complejos resultaron ser algo más inestables que los obtenidos siguiendo el mismo método descrito en el ejemplo 1.
EJEMPLO 3To a suspension of silver perchlorate (0.2 mmol, 41 mg) in toluene (2 mL) was added chiral phosphoramidite (S a ) - (HI) [R 6 , R 7 = (R) -CH (Me ) Ph, R 8 = H] (0.4 mmol, 220 mg) and the mixture was stirred at room temperature for one hour in the absence of light. After this time the solvent was evaporated in vacuo (15 torr) to obtain the desired complex. These complexes turned out to be somewhat more unstable than those obtained following the same method described in example 1. EXAMPLE 3
Compuesto intermedio (C) [R1 = H, R2 = metilo, R3 = isobutilo, R4 = tere- butoxi, R5 = 2-tienilo]Intermediate compound (C) [R 1 = H, R 2 = methyl, R 3 = isobutyl, R 4 = tere-butoxy, R 5 = 2-thienyl]
A una suspensión de perclorato de plata (0,02 mmol, 4,1 mg) en tolueno (2 ml_) se Ie añadió el fosforamidito quiral (Sa)-(lll) [R6, R7 = (R)-CH(Me)Ph, H8 = H] (0,02 mmol, 11 mg) y Ia mezcla se agitó a temperatura ambiente durante una hora en ausencia de luz. A continuación se adicionó a -20 0C el iminoéster (V) [R2 = metilo, R3 = isobutilo, R5 = 2-tienilo] (0,25 mmol, 60 mg), el sistema acrílico (Vl) [R4 = terc-butoxi] (0,25 mmol, 37 μl_) y trietilamina (0,02 mmol, 3 μl_). La mezcla resultante se mantuvo con agitación a -20 0C durante dos días y, transcurrido este periodo, el disolvente se evaporó a vacío (15 torr) Ia mezcla se purificó por cromatografía de columna utilizando gel de sílice, y el producto resultante (C) [R1 = H, R2 = metilo, R3 = isobutilo, R4 = terc-butoxi, R5 = 2- tienilo] se obtuvo con una pureza del 98%, un rendimiento del 72% y una relación enantiomérica de 91 a 9 (según análisis realizado por HPLC quiral Chiralpak AD). En este paso es muy importante obtener el producto puro puesto que cualquier impureza afecta negativamente tanto al rendimiento como al aislamiento del producto antiviral final.To a suspension of silver perchlorate (0.02 mmol, 4.1 mg) in toluene (2 ml_) was added chiral phosphoramidite (S a ) - (lll) [R 6 , R 7 = (R) -CH (Me) Ph, H 8 = H] (0.02 mmol, 11 mg) and the mixture was stirred at room temperature for one hour in the absence of light. Then it was added at -20 0 C the imino ester (V) [R 2 = methyl, R 3 = isobutyl, R 5 = 2-thienyl] (0.25 mmol, 60 mg), acrylic system (Vl) [R 4 = tert-butoxy] (0.25 mmol, 37 μl_) and triethylamine (0.02 mmol, 3 μl_). The resulting mixture was allowed to stir at -20 0 C for two days and, after this period, the solvent was evaporated in vacuo (15 torr) the mixture was purified by column chromatography using silica gel, and the resulting product (C ) [R 1 = H, R 2 = methyl, R 3 = isobutyl, R 4 = tert-butoxy, R 5 = 2- thienyl] was obtained with a purity of 98%, a yield of 72% and an enantiomeric ratio of 91 to 9 (according to analysis performed by Chiralpak AD chiral HPLC). In this step it is very important to obtain the pure product since any impurity negatively affects both the performance and the isolation of the final antiviral product.
EJEMPLO 4EXAMPLE 4
Compuesto intermedio (D) [R1 = 4-(CF3)C6H4C(=O)-, R2 = metilo, R3 = isobutilo, R4 = ferc-butoxi, R5 = 2-tienilo]Intermediate compound (D) [R 1 = 4- (CF 3 ) C 6 H 4 C (= O) -, R 2 = methyl, R 3 = isobutyl, R 4 = ferc-butoxy, R 5 = 2-thienyl]
A una disolución del compuesto (C) [R1 = H, R2 = metilo, R3 = isobutilo, R4 = ferc-butoxi, R5 = 2-tienilo] (0,5 mmol, 184 mg) y trietilamina (0,7 mmol, 97 μL) en diclorometano (5 mL) se Ie añadió a 0 0C cloruro de 4-trifuorometilbenzoílo (0,55 mmol, 81 μL). Finalizada Ia adición Ia mezcla de reacción se mantuvo a reflujo durante 19 h. La fase orgánica se lavó con una disolución acuosa de cloruro de amonio (1M), se separó, se secó sobre sulfato de magnesio anhidro y se evaporó a vacío (15 torr). El crudo resultante se purificó por cromatogafía de columna obteniendo el producto deseado (C) [R1 = 4-(CF3)C6H4C(=O)-, R2 = metilo, R3 = isobutilo, R4 = terc-butoxi, R5 = 2-tienilo] con un rendimiento del 86%, una pureza del 97% y una relación enantiomérica de 94 a 6 (según análisis realizado por HPLC quiral, Chiralpak AD).
EJEMPLO 5To a solution of compound (C) [R 1 = H, R 2 = methyl, R 3 = isobutyl, R 4 = ferc-butoxy, R 5 = 2-thienyl] (0.5 mmol, 184 mg) and triethylamine ( 0.7 mmol, 97 µL) in dichloromethane (5 mL) 4-trifuoromethylbenzoyl chloride (0.55 mmol, 81 µL) was added at 0 ° C. After the addition, the reaction mixture was refluxed for 19 h. The organic phase was washed with an aqueous solution of ammonium chloride (1M), separated, dried over anhydrous magnesium sulfate and evaporated in vacuo (15 torr). The resulting crude was purified by column chromatography to obtain the desired product (C) [R 1 = 4- (CF 3 ) C 6 H 4 C (= O) -, R 2 = methyl, R 3 = isobutyl, R 4 = tert-butoxy, R 5 = 2-thienyl] with a yield of 86%, a purity of 97% and an enantiomeric ratio of 94 to 6 (according to analysis by chiral HPLC, Chiralpak AD). EXAMPLE 5
Compuesto final antiviral (E) [R1 = 4-(CF3)C6H4C(=O)-, R2 = H5 R3 = isobutilo, R4 = H, R5 = 2-tienilo]Final antiviral compound (E) [R 1 = 4- (CF 3 ) C 6 H 4 C (= O) -, R 2 = H 5 R 3 = isobutyl, R 4 = H, R 5 = 2-thienyl]
Una disolución del producto (D) (obtenido en el ejemplo 4) (0,5 mmol, 270 mg) en una mezcla de diclorometano/ácido trifluoroacético (5 mL/2,5 rriL) se mantuvo agitando a temperatura ambiente durante 17 h. Finalizado este periodo el disolvente se evaporó a vacío (15 torr) y Ia mezcla resultante se disolvió de nuevo en acetato de etilo y Ia nueva fase orgánica se lavó con una disolución de cloruro de sodio (1M). La fase orgánica se secó sobre sulfato de magnesio anhidro y se evaporó a vacío (15 torr) resultando un producto crudo que fue disuelto en una mezcla de disolventes formada por cuatro partes (en volumen) de metanol y una parte en(en volumen) de una disolución acuosa 1M de hidróxido de potasio (20 mL). La disolución resultante se calentó a reflujo durante 17 h evaporando el metanol al finalizar dicho periodo. Se añadió diclorometano y se aciduló Ia mezcla hasta pH = 1 aproximadamente con ácido clorhídrico (1M). La fase orgánica se lavó con una disolución acuosa de cloruro de sodio (1M), se secó sobre sulfato de magnesio anhidro y se evaporó a vacío (15 torr). El producto resultante se recristalizó en una mezcla de hexano/acetato de etilo obteniéndose el producto antiviral con un 79% de rendimiento, una pureza del 97% y una relación enantiomérica de 96 a 4 (según análisis realizado por HPLC quiral, Chiralpak AD). El producto cristaliza en forma de láminas incoloras (p. f. 126-127 0C descompone), [α]o20 = +95 (c 1 , MeOH).
A solution of the product (D) (obtained in example 4) (0.5 mmol, 270 mg) in a dichloromethane / trifluoroacetic acid mixture (5 mL / 2.5 rriL) was kept stirring at room temperature for 17 h. After this period, the solvent was evaporated in vacuo (15 torr) and the resulting mixture was dissolved again in ethyl acetate and the new organic phase was washed with a solution of sodium chloride (1M). The organic phase was dried over anhydrous magnesium sulfate and evaporated in vacuo (15 torr) resulting in a crude product that was dissolved in a solvent mixture consisting of four parts (by volume) of methanol and one part by (by volume) of a 1M aqueous solution of potassium hydroxide (20 mL). The resulting solution was heated at reflux for 17 h, evaporating the methanol at the end of said period. Dichloromethane was added and the mixture was acidified to approximately pH = 1 with hydrochloric acid (1M). The organic phase was washed with an aqueous solution of sodium chloride (1M), dried over anhydrous magnesium sulfate and evaporated in vacuo (15 torr). The resulting product was recrystallized from a mixture of hexane / ethyl acetate to obtain the antiviral product with a 79% yield, a purity of 97% and an enantiomeric ratio of 96 to 4 (according to analysis performed by chiral HPLC, Chiralpak AD). The product crystallizes in the form of colorless sheets (mp 126-127 0 C decomposes), [α] or 20 = +95 (c 1, MeOH).
Claims
1. Complejo metálico quiral de fórmula general A:1. Chiral metallic complex of general formula A:
AgX 
AgX
(a) (b) caracterizado por Ia coordinación de fosforamidito quiral (a) y de sal de plata catiónica (b); donde:(a) (b) characterized by the coordination of chiral phosphoramidite (a) and cationic silver salt (b); where:
R6 es hidrógeno o un radical seleccionado del grupo que comprende un alquilo (Ci-C6), un arilo (C5-C14) o un arilalquilo;R 6 is hydrogen or a radical selected from the group comprising an alkyl (Ci-C 6 ), an aryl (C 5 -C 1 4) or an arylalkyl;
R7 es hidrógeno o un radical seleccionado del grupo que comprende un alquilo (Ci-C6), arilo (C5-C14) o arilalquilo;R 7 is hydrogen or a radical selected from the group comprising a (Ci-C 6 ) alkyl, (C 5 -C 14 ) aryl or arylalkyl;
R8 es hidrógeno o un radical seleccionado del grupo que comprende alquilo (Ci-C6), alcoxialquilo, (dialquilamino)alquilo (Ci-C6) o arilo;R 8 is hydrogen or a radical selected from the group comprising (Ci-C 6 ) alkyl, alkoxyalkyl, (dialkylamino) (Ci-C 6 ) alkyl or aryl;
X se selecciona de Ia lista que comprende fluoruro, acetato, perclorato, trifuorometanosulfonato, tetrafluoroborato, nitrato, hexafluorofosfato o hexafluoroantimoniato; y ( — ) representa un enlace que puede existir o no.X is selected from the list comprising fluoride, acetate, perchlorate, trifuoromethanesulfonate, tetrafluoroborate, nitrate, hexafluorophosphate or hexafluoroantimoniate; and (-) represents a link that may or may not exist.
2. Complejo metálico quiral según reivindicación 1 donde el enlace ( — ) existe y cuya fórmula general es (Sa)-(lll) o (Ra)-(W):2. Chiral metal complex according to claim 1 wherein the (-) bond exists and whose general formula is (S a ) - (lll) or (Ra) - (W):
R6 a R8 y X están descritos en Ia reivindicación 1. R 6 to R 8 and X are described in claim 1.
3. Complejo metálico quiral según reivindicación 1 , donde el enlace (---) no existe y cuya fórmula general es (Sa)-(IV) o (Ra)-( IV):3. Chiral metal complex according to claim 1, wherein the link (---) does not exist and whose general formula is (S a ) - (IV) or (R a ) - (IV):
R >6 a,, DR8y X están descritos en Ia reivindicación 1.R> 6 a ,, D R8 and X are described in claim 1.
4. Complejo metálico quiral de fórmula general B:4. Chiral metallic complex of general formula B:
caracterizado por Ia coordinación de dos equivalentes fosforamidito quiral (a) y un equivalente de sal de plata catiónica (b), donde R6 a R8 y X se describen en Ia reivindicación 1.characterized by the coordination of two chiral phosphoramidite equivalents (a) and an equivalent cationic silver salt (b), wherein R 6 to R 8 and X are described in claim 1.
5. Complejo metálico quiral según reivindicación 4 donde el enlace ( — ) existe y cuya fórmula general es 2(Sa)-(11O ° 2(Ka)-(IH):5. Chiral metal complex according to claim 4 wherein the (-) bond exists and whose general formula is 2 (Sa) - ( 11 O ° 2 (Ka) - (IH):
6. Complejo metálico quiral según reivindicación 4 donde el enlace (--) no existe y cuya fórmula general es 2(Sa)-(IV) o 2(Ra)-{ IV):6. Chiral metal complex according to claim 4 wherein the (-) bond does not exist and whose general formula is 2 (S a ) - (IV) or 2 (R a ) - {IV):
7. Complejo metálico quiral según cualquiera de las reivindicaciones 1-6 donde R6 y R7 son arilalquilos.7. Chiral metal complex according to any of claims 1-6 wherein R 6 and R 7 are arylalkyl.
8. Complejo metálico quiral según cualquiera de las reivindicaciones 1-7 donde R8 es hidrógeno.8. Chiral metal complex according to any of claims 1-7 wherein R 8 is hydrogen.
9. Complejo metálico quiral según cualquiera de las reivindicaciones 1-8 donde X es perclorato.9. Chiral metal complex according to any of claims 1-8 wherein X is perchlorate.
10. Procedimiento para Ia preparación de un complejo metálico según cualquiera de las reivindicaciones 1-9 que comprende poner en contacto un equivalente de fosforamidito quiral (a) y un equivalente de sal de plata catiónica (b) en presencia de un disolvente orgánico y en ausencia de luz.10. Process for the preparation of a metal complex according to any of claims 1-9 which comprises contacting an equivalent of chiral phosphoramidite (a) and an equivalent of cationic silver salt (b) in the presence of an organic solvent and in absence of light
11. Procedimiento según reivindicación 10 donde el disolvente orgánico es tolueno y Ia reacción se lleva a cabo a temperatura ambiente.11. Method according to claim 10 wherein the organic solvent is toluene and the reaction is carried out at room temperature.
12. Procedimiento para Ia preparación de un compuesto de fórmula general (C):12. Procedure for the preparation of a compound of general formula (C):
R3 R^NΛCO2R2 W R4°C\= <VI) donde R2 es un alquilo (C-I-CΘ), R3 es un alquilo (Ci-C6) o arilalquilo, R4 es un radical que se selecciona de Ia lista que comprende alcoxi, alquilamino, arilamino, o dialquilamino y R5 es heteroarilo.R 3 R ^ N Λ CO 2 R 2 W R4 ° C \ = < VI) where R 2 is a (CI-CΘ) alkyl, R 3 is a (Ci-C 6 ) alkyl or arylalkyl, R 4 is a radical which is selected from the list comprising alkoxy, alkylamino, arylamino, or dialkylamino and R 5 is heteroaryl.
13. Procedimiento según reivindicación 12 para Ia preparación de un compuesto de fórmula general C con Ia configuración absoluta (2S,4S,5f?) o (2R4R.5S) tal y como se representa en las siguientes fórmulas:13. Method according to claim 12 for the preparation of a compound of general formula C with the absolute configuration (2S, 4S, 5f?) Or (2R4R.5S) as represented in the following formulas:
R2 a R5 como se han descrito en Ia reivindicación 12.R 2 to R 5 as described in claim 12.
14. Procedimiento según cualquiera de las reivindicaciones 12 o 13 que además comprende Ia adición de cantidades subestequiométricas de una base y donde Ia reacción se lleva a cabo en ausencia de luz y a temperaturas por debajo de los 0 0C.14. Method according to any of claims 12 or 13, which further comprises adding sub-stoichiometric amounts of a base and wherein the reaction is carried out in the absence of light and at temperatures below 0 0 C.
15. Procedimiento según cualquiera de las reivindicaciones 12 a 14 donde R2 es alquilo (C1-C3), R3 es isobutilo, R4 es alcoxi y R5 es tienilo. 15. Process according to any of claims 12 to 14 wherein R 2 is (C 1 -C 3 ) alkyl, R 3 is isobutyl, R 4 is alkoxy and R 5 is thienyl.
16. Procedimiento para Ia preparación de un compuesto de fórmula general (D):16. Procedure for the preparation of a compound of general formula (D):
17. Procedimiento según reivindicación 16 para Ia preparación de un compuesto de fórmula general D con Ia configuración absoluta (2S,4S,5R) o (2R,4R,5S) tal y como se representa en las siguientes fórmulas:17. Method according to claim 16 for the preparation of a compound of general formula D with the absolute configuration (2S, 4S, 5R) or (2R, 4R, 5S) as represented in the following formulas:
R1 a R5 como se han descrito en Ia reivindicación 16.R 1 to R 5 as described in claim 16.
18. Procedimiento según cualquiera de las reivindicaciones 16 o 17 donde el cloruro de acriloílo es cloruro de 4-trifluorometilbenzoílo.18. A process according to any of claims 16 or 17 wherein the acryloyl chloride is 4-trifluoromethylbenzoyl chloride.
19. Procedimiento según cualquiera de las reivindicaciones 16 a 18 donde R1 es 4-(CF3)C6H4C(=O)-, R2 es alquilo (C1-C3), R3 es ¡sobutilo, R4 es alcoxi y R5 es tienilo.19. A method according to any of claims 16 to 18 wherein R 1 is 4- (CF 3 ) C 6 H 4 C (= O) -, R 2 is alkyl (C 1 -C 3 ), R 3 is butyl, R 4 is alkoxy and R 5 is thienyl.
20. Procedimiento para Ia preparación de un compuesto de fórmula general (E): 
E donde R1 es aroílo, y R3 y R5 como se han descrito en Ia reivindicación 16; que comprende el tratamiento de un compuesto de fórmula general D, como se ha descrito anteriormente, con ácido trifluoroacético seguido de una reacción de hidrólisis del éster en medio básico.20. Procedure for the preparation of a compound of general formula (E): E where R 1 is aroyl, and R 3 and R 5 as described in claim 16; which comprises the treatment of a compound of general formula D, as described above, with trifluoroacetic acid followed by a hydrolysis reaction of the ester in basic medium.
21. Procedimiento según reivindicación 20 para Ia preparación de un compuesto de fórmula general E con Ia configuración absoluta (2S,4S,5R) o (2R,4R,5S) tal y como se representa en las siguientes fórmulas:21. Method according to claim 20 for the preparation of a compound of general formula E with the absolute configuration (2S, 4S, 5R) or (2R, 4R, 5S) as represented in the following formulas:
R1 es aroílo, R3 y R5 como se han descrito en Ia reivindicación 16.R 1 is aroyl, R 3 and R 5 as described in claim 16.
22. Procedimiento según cualquiera de las reivindicaciones 20 o 21 donde R1 es 4-(CF3)C6H4C(=O)-, R3 es isobutilo y R5 es tienilo. 22. Method according to any of claims 20 or 21 wherein R 1 is 4- (CF 3 ) C 6 H 4 C (= O) -, R 3 is isobutyl and R 5 is thienyl.
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| ESP200800908 | 2008-04-02 | ||
| ES200800908A ES2326253B2 (en) | 2008-04-02 | 2008-04-02 | PROCEDURE FOR OBTAINING POLYUSTITUTED PIRROLIDINES INHIBITING OF HEPATITIS VIRUS C. |
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|---|---|---|---|---|
| WO2006045615A1 (en) * | 2004-10-25 | 2006-05-04 | Glaxo Group Limited | 4- (pyrazine-2-yl) -pyrrolidine-2-carboxylic acid compounds and derivatives thereof as hepatitis c virus inhibitors |
| WO2007039143A1 (en) * | 2005-09-23 | 2007-04-12 | Glaxo Group Limited | C (2) -heteroarylmethyl-c (4) -pyrazin-2-yl acyl pyrrolidine compounds and their user for treating viral infections, especially hepatitics c (hcv) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006045615A1 (en) * | 2004-10-25 | 2006-05-04 | Glaxo Group Limited | 4- (pyrazine-2-yl) -pyrrolidine-2-carboxylic acid compounds and derivatives thereof as hepatitis c virus inhibitors |
| WO2007039143A1 (en) * | 2005-09-23 | 2007-04-12 | Glaxo Group Limited | C (2) -heteroarylmethyl-c (4) -pyrazin-2-yl acyl pyrrolidine compounds and their user for treating viral infections, especially hepatitics c (hcv) |
Non-Patent Citations (3)
| Title |
|---|
| LONGMIRE J. ET AL.: "Highly enantioselective Ag(I)-catalyzed [3+2] cycloaddition of azomethine ylides", JOURNAL OF AMERICAN CHEMICAL SOCIETY, vol. 124, 2002, pages 13400 - 13401 * |
| NAJERA C. ET AL.: "Diastereoselective 1,3-dipolar cycloaddition reactions between azomethine ylides and chiral acrylates. Synthesis of hepatitis C virus RNA- dependent RNA polymerase inhibitors", EUROPEAN JOURNAL ORGANIC CHEMISTRY, 2007, pages 5038 - 5049 * |
| POLET D. ET AL.: "Phosphoramidite ligands in iridium-catalyzed allylic substitution", CHEMISTRY A EUROPEAN JOURNAL, vol. 12, 2006, pages 3596 - 3609 * |
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| ES2326253B2 (en) | 2010-04-21 |
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