WO2014140318A1 - Procédé amélioré pour réactions de transfert d'acyle - Google Patents
Procédé amélioré pour réactions de transfert d'acyle Download PDFInfo
- Publication number
- WO2014140318A1 WO2014140318A1 PCT/EP2014/055174 EP2014055174W WO2014140318A1 WO 2014140318 A1 WO2014140318 A1 WO 2014140318A1 EP 2014055174 W EP2014055174 W EP 2014055174W WO 2014140318 A1 WO2014140318 A1 WO 2014140318A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- preparation
- alkyl group
- ester
- methyl
- thienyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 93
- 125000002252 acyl group Chemical group 0.000 title claims abstract description 56
- 238000006276 transfer reaction Methods 0.000 title abstract description 8
- -1 Glycopyrroniunn Chemical compound 0.000 claims abstract description 84
- 238000002360 preparation method Methods 0.000 claims abstract description 73
- 229940110309 tiotropium Drugs 0.000 claims abstract description 25
- 150000002148 esters Chemical class 0.000 claims abstract description 22
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 claims abstract description 19
- 229940019903 aclidinium Drugs 0.000 claims abstract description 12
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960001491 trospium Drugs 0.000 claims abstract description 10
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 claims abstract description 9
- 229960000396 atropine Drugs 0.000 claims abstract description 9
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 claims description 55
- FIMXSEMBHGTNKT-RZVDLVGDSA-N scopine Chemical compound C([C@@H]1N2C)[C@H](O)C[C@@H]2[C@@H]2[C@H]1O2 FIMXSEMBHGTNKT-RZVDLVGDSA-N 0.000 claims description 50
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 claims description 40
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 claims description 40
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 claims description 40
- 239000003795 chemical substances by application Substances 0.000 claims description 40
- 229960002646 scopolamine Drugs 0.000 claims description 40
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 229960002462 glycopyrronium bromide Drugs 0.000 claims description 18
- SYHWYWHVEQQDMO-UHFFFAOYSA-N methyl 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C=1C=CSC=1C(O)(C(=O)OC)C1=CC=CS1 SYHWYWHVEQQDMO-UHFFFAOYSA-N 0.000 claims description 14
- FVEJUHUCFCAYRP-UHFFFAOYSA-N 2-hydroxy-2,2-dithiophen-2-ylacetic acid Chemical compound C=1C=CSC=1C(O)(C(=O)O)C1=CC=CS1 FVEJUHUCFCAYRP-UHFFFAOYSA-N 0.000 claims description 12
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 claims description 12
- GYDFTKNRHZMENP-ZDUSSCGKSA-N [(3r)-1-azabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound O([C@@H]1C2CCN(CC2)C1)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 GYDFTKNRHZMENP-ZDUSSCGKSA-N 0.000 claims description 10
- OVGMKPGXRHJNKJ-UHFFFAOYSA-N (1-methylpyrrolidin-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate Chemical compound C1N(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 OVGMKPGXRHJNKJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 5
- 229960000257 tiotropium bromide Drugs 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- ANGKOCUUWGHLCE-UHFFFAOYSA-N 2-cyclopentyl-2-hydroxy-2-phenylacetic acid (1,1-dimethyl-3-pyrrolidin-1-iumyl) ester Chemical compound C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 ANGKOCUUWGHLCE-UHFFFAOYSA-N 0.000 claims description 2
- RVCSYOQWLPPAOA-CVPHZBIISA-M [(5s)-spiro[8-azoniabicyclo[3.2.1]octane-8,1'-azolidin-1-ium]-3-yl] 2-hydroxy-2,2-diphenylacetate;chloride Chemical compound [Cl-].[N+]12([C@H]3CCC2CC(C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 RVCSYOQWLPPAOA-CVPHZBIISA-M 0.000 claims description 2
- XLAKJQPTOJHYDR-QTQXQZBYSA-M aclidinium bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=CC=C1 XLAKJQPTOJHYDR-QTQXQZBYSA-M 0.000 claims description 2
- 229960005012 aclidinium bromide Drugs 0.000 claims description 2
- UPTVHSCRWQCIOS-UHFFFAOYSA-N ethyl 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C=1C=CSC=1C(O)(C(=O)OCC)C1=CC=CS1 UPTVHSCRWQCIOS-UHFFFAOYSA-N 0.000 claims description 2
- XVPLJTBUQPYCJR-UHFFFAOYSA-N propyl 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C=1C=CSC=1C(O)(C(=O)OCCC)C1=CC=CS1 XVPLJTBUQPYCJR-UHFFFAOYSA-N 0.000 claims description 2
- 229960001530 trospium chloride Drugs 0.000 claims description 2
- ASMXXROZKSBQIH-VITNCHFBSA-N aclidinium Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=CC=C1 ASMXXROZKSBQIH-VITNCHFBSA-N 0.000 abstract description 7
- 239000002243 precursor Substances 0.000 abstract description 6
- OYYDSUSKLWTMMQ-JKHIJQBDSA-N trospium Chemical compound [N+]12([C@@H]3CC[C@H]2C[C@H](C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 OYYDSUSKLWTMMQ-JKHIJQBDSA-N 0.000 abstract description 6
- 238000006243 chemical reaction Methods 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 16
- 239000002585 base Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- ANGKOCUUWGHLCE-HKUYNNGSSA-N [(3s)-1,1-dimethylpyrrolidin-1-ium-3-yl] (2r)-2-cyclopentyl-2-hydroxy-2-phenylacetate Chemical compound C1[N+](C)(C)CC[C@@H]1OC(=O)[C@](O)(C=1C=CC=CC=1)C1CCCC1 ANGKOCUUWGHLCE-HKUYNNGSSA-N 0.000 description 6
- 150000004703 alkoxides Chemical class 0.000 description 6
- WRJPSSPFHGNBMG-VIFPVBQESA-N [(3r)-1-azabicyclo[2.2.2]octan-3-yl] acetate Chemical compound C1CC2[C@@H](OC(=O)C)CN1CC2 WRJPSSPFHGNBMG-VIFPVBQESA-N 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 238000003760 magnetic stirring Methods 0.000 description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N methyl bromide Substances BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 150000003462 sulfoxides Chemical class 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- MEGPURSNXMUDAE-UHFFFAOYSA-N Scopoline Natural products C1C(O2)CC3N(C)C1C2C3O MEGPURSNXMUDAE-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 229940102396 methyl bromide Drugs 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- MEGPURSNXMUDAE-RLMOJYMMSA-N scopoline Chemical compound C([C@H](O1)C2)[C@@H]3N(C)[C@H]2[C@H]1[C@H]3O MEGPURSNXMUDAE-RLMOJYMMSA-N 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000003944 tolyl group Chemical group 0.000 description 3
- 0 *OC(C(c1ccc[s]1)(c1ccc[s]1)O)=O Chemical compound *OC(C(c1ccc[s]1)(c1ccc[s]1)O)=O 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000003700 epoxy group Chemical group 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000002050 international nonproprietary name Substances 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- CXYRUNPLKGGUJF-RAFJPFSSSA-M scopolamine methobromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)C)=CC=CC=C1 CXYRUNPLKGGUJF-RAFJPFSSSA-M 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- ANGKOCUUWGHLCE-NNBQYGFHSA-N (1,1-dimethylpyrrolidin-1-ium-3-yl) (2r)-2-cyclopentyl-2-hydroxy-2-phenylacetate Chemical compound C1[N+](C)(C)CCC1OC(=O)[C@](O)(C=1C=CC=CC=1)C1CCCC1 ANGKOCUUWGHLCE-NNBQYGFHSA-N 0.000 description 1
- ANGKOCUUWGHLCE-WHCXFUJUSA-N (1,1-dimethylpyrrolidin-1-ium-3-yl) (2s)-2-cyclopentyl-2-hydroxy-2-phenylacetate Chemical compound C1[N+](C)(C)CCC1OC(=O)[C@@](O)(C=1C=CC=CC=1)C1CCCC1 ANGKOCUUWGHLCE-WHCXFUJUSA-N 0.000 description 1
- FSNYTEYOTCTPSO-SSDOTTSWSA-N (2r)-1-azabicyclo[2.2.2]octan-2-ol Chemical compound C1CN2[C@H](O)CC1CC2 FSNYTEYOTCTPSO-SSDOTTSWSA-N 0.000 description 1
- YGCWPCVAVSIFLO-LBPRGKRZSA-N (2r)-2-phenyl-1,2-dihydroimidazo[2,1-b][1,3]benzothiazole Chemical compound C1([C@@H]2CN3C4=CC=CC=C4SC3=N2)=CC=CC=C1 YGCWPCVAVSIFLO-LBPRGKRZSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- ISNICOKBNZOJQG-UHFFFAOYSA-N 1,1,2,3,3-pentamethylguanidine Chemical compound CN=C(N(C)C)N(C)C ISNICOKBNZOJQG-UHFFFAOYSA-N 0.000 description 1
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
- ZROILLPDIUNLSE-UHFFFAOYSA-N 1-phenyl-1h-pyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1C1=CC=CC=C1 ZROILLPDIUNLSE-UHFFFAOYSA-N 0.000 description 1
- KVIBIKHDCMNIST-UHFFFAOYSA-N 2-methoxy-2,2-dithiophen-2-ylacetic acid methyl 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound COC(C(=O)O)(C=1SC=CC1)C=1SC=CC1.COC(C(C=1SC=CC1)(C=1SC=CC1)O)=O KVIBIKHDCMNIST-UHFFFAOYSA-N 0.000 description 1
- OYYDSUSKLWTMMQ-UHFFFAOYSA-N 3-[(2-hydroxy-2,2-diphenylacetyl)oxy]-8lambda^{5}-azaspiro[bicyclo[3.2.1]octane-8,1'-pyrrolidin]-8-ylium Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C(=O)OC(C1)CC2CCC1[N+]21CCCC1 OYYDSUSKLWTMMQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- QMQPIPZIDOPSHZ-YSLLJANASA-N C(C)(=O)O[C@H]1CN2CCC1CC2.OC(C(=O)O[C@H]2CN1CCC2CC1)(C=1SC=CC1)C=1SC=CC1 Chemical compound C(C)(=O)O[C@H]1CN2CCC1CC2.OC(C(=O)O[C@H]2CN1CCC2CC1)(C=1SC=CC1)C=1SC=CC1 QMQPIPZIDOPSHZ-YSLLJANASA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- IMNYADDODFQLBS-BGMSHATGSA-N OC(C(O[C@@H]1C(C2)C2(CC2)N2C1)=O)(c1ccc[s]1)c1ccc[s]1 Chemical compound OC(C(O[C@@H]1C(C2)C2(CC2)N2C1)=O)(c1ccc[s]1)c1ccc[s]1 IMNYADDODFQLBS-BGMSHATGSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108050008598 Phosphoesterases Proteins 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DQHNAVOVODVIMG-UHFFFAOYSA-M Tiotropium bromide Chemical compound [Br-].C1C(C2C3O2)[N+](C)(C)C3CC1OC(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 DQHNAVOVODVIMG-UHFFFAOYSA-M 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- AWYTZWASKWHFCH-FVGYRXGTSA-N [(3R)-1-azabicyclo[2.2.2]octan-3-yl] acetate 1-(2-hydroxy-1-azabicyclo[2.2.2]octan-2-yl)ethanone Chemical compound C(C)(=O)C1(N2CCC(C1)CC2)O.C(C)(=O)O[C@H]2CN1CCC2CC1 AWYTZWASKWHFCH-FVGYRXGTSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- IXQKXEUSCPEQRD-DKRGWESNSA-N cucurbitacin B Chemical compound C([C@H]1[C@]2(C)C[C@@H](O)[C@@H]([C@]2(CC(=O)[C@]11C)C)[C@@](C)(O)C(=O)/C=C/C(C)(C)OC(=O)C)C=C2[C@H]1C[C@H](O)C(=O)C2(C)C IXQKXEUSCPEQRD-DKRGWESNSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical class CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229910052735 hafnium Inorganic materials 0.000 description 1
- VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940046810 spiriva Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
-
- 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
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- 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
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Definitions
- the present invention relates to a novel process for the preparation of esters like Aclidinium, Atropin, Glycopyrronium, Tiotropium, Trospium and their respective precursors and derivatives, based on direct acyl transfer reactions.
- Tiotropium is the international non-proprietary name (INN) for the quaternary ammonium derivative of di-(2- thienyl)glycolic acid Scopine ester with the chemical name (1 a,2 ,4 ,7 )-7-[(hydroxy-di(2-thienyl)acetyl)oxy]-9,9-dimethyl-3-oxa-9- azoniatricyclo[3.3.1 .0 2,4 ]nonane and is a highly effective anticholinergic agent with a specificity for muscarinic receptors.
- INN international non-proprietary name
- Tiotropium bromide currently marketed under the brand name SPIRIVA® is presently approved for the treatment of respiratory disorders, such as asthma or chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
- COPD chronic obstructive pulmonary disease
- Scopine base also referred to as Scopine
- Scopine ester also referred to as Scopine Dithienylglycolate
- Scopine Dithienylglycolate has to be isolated and purified before quaternization, leading to further reduction of the Tiotropium yield.
- Scopolamine or its salts into Scopine Dithienylglycolate and/or Tiotropium halide salts can be performed in a single reaction step by the use of an acyl transfer agent.
- esters including, but not limited to Aclidinium, Atropin, Glycopyrronium, Tiotropium, Trospium and their respective precursors and derivatives, in particular their salts, involving the reaction of an acyl transfer agent that is capable to promote the transfer of an acyl group, is described hereinafter.
- R1 is pyrrolidine or a azapolycycle based compound, optionally substituted
- R2 is a Ci-C 4 -alkyl group or 1 -phenyl 2-hydroxy ethyl
- R3 is a Ci-C 4 -alkyl group, preferably methyl
- R4 is selected from hydrogen, aryl or heteroaryl
- R5 is selected from aryl or heteroaryl
- n 0 or 1
- the acyl transfer agent may be chosen among agents such as: - Azapolycycles, preferably cyclic and bicyclic guanidines having ring sizes of 5 to 8 atoms, optionally substituted with a C1-C10 alkyl substituent on one of the non-bridgehead nitrogen atoms such as tetramethylguanidine, pentamethylguanidine or 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD)
- agents such as: - Azapolycycles, preferably cyclic and bicyclic guanidines having ring sizes of 5 to 8 atoms, optionally substituted with a C1-C10 alkyl substituent on one of the non-bridgehead nitrogen atoms such as tetramethylguanidine, pentamethylguanidine or 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD)
- DMAP Dimethylaminopyridine
- Isothiourea-based organocatalysts such as tetramisole and benzotetramisole - Azoles such as imidazole, pyrazole, 1 ,2,3-triazole, 1 ,2,4-triazole, tetrazole and the areno-fused and hetareno-fused derivatives of these heterocycles;
- Tin derivatives such distannoxanes, dialkyltindicarboxylat.es, dialkyltin oxides, dialkyltin dihalides, hexaalkyldistannoxanes, trialkyltin halides, trialkyltin ethers and trialkyltin carboxylates;
- Hydrolytic enzymes such as lipases and protease and phosphoesterases
- Inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid and phosphoric acids
- Sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and camphorsulfonic acid
- acyl transfer agents Any combination of the acyl transfer agents listed above Preferred acyl transfer agents are those operating in neutral or slightly basic/slightly acidic conditions.
- acyl transfer agents are azapolycycles, preferably 1 ,5,7- Triazabicyclo[4.4.0]dec-5-ene (TBD).
- TBD Triazabicyclo[4.4.0]dec-5-ene
- Scopine Dithienylglycolate obtained by this process may be converted into Tiotropium salt involving but not limited to its quaternary ammonium salts, I methods known in the art, described in EP 0 418 716.
- the improved process may also be applied for the preparation of Aclidinium ((3R)- [(2-Hydroxy-2,2-di-2-thienylacetyl)oxy]-1 -(3-phenoxypropyl)-1 - azoniabicyclo[2.2.2]octane) halide salts, preferably Aclidinium Bromide.
- the improved process may be applied for the preparation of the Aclidinium precursor (R)-Quinuclidin-3-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetate.
- (R)-Quinuclidin-3-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetate obtained by this process may be converted into an Aclidinium halide salt by processes known in the art, e.g. as described in WO 2001/0041 18.
- the improved process may also be applied for the preparation of Glycopyrronium (3- [[(2R)-2-cyclopentyl-2-hydroxy- 2-phenylacetyl]oxy]-1 ,1 -dimethyl- pyrrolidinium (3S)) and 3-[[(2S)-2-cyclopentyl-2-hydroxy-2-phenylacetyl]oxy]-1 ,1 -dimethyl-pyrrolidinium (3R)) halide salts, preferably Glycopyrronium bromide.
- the improved process may be applied for the preparation of the Glycopyrronium precursor 3-[[-2-cyclopentyl-2-hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium.
- the Ester ⁇ obtained by this process may be converted into an Glycopyrronium halide salt by processes known in the art, i.e. crystallization, as described in US 2,956,062.
- the improved process may also be applied for the preparation of Atropin ((8-methyl- 8-azabicyclo[3.2.1 ]oct-3-yl) 3-hydroxy-2-phenylpropanoate).
- Scopine base and Scopine methyl halide salts obtained by the process described above may be converted into Tiotropium or its derivatives by methods known in the art, e.g. as described in EP 0 418 716 or WO 2006/ 021559, respectively.
- Scopolamine and its quaternary ammonium salts may be obtained using commercially available sources or may be synthesized by using methods well known in the art.
- esters I and esters II may be obtained by using commercially available sources or may be synthesized by using methods well known in the art.
- Scopolamine methyl halide salt may derive from any commonly used halide, most preferably bromine.
- the counterion (X " ) may derive from any commonly used halide, most preferably bromine. In the case of Trospium halide salt synthesis, the counterion (X " ) may derive from any commonly used halide, most preferably chlorine.
- the ester of Di-(2-thienyl)glycolic acid is an alkyl eater, more preferably one selected from the methyl ester, ethyl ester, n-propyl ester or the isopropyl ester.
- the most preferred ester is Di-(2-thienyl)glycolic acid methyl ester.
- the solvent involved in the process for the preparation of Tiotropium, Scopine Dithienylglycolate or Scopine free base or their respective derivatives is selected from the group consisting of aromatic hydrocarbons, sulfoxides, alcohols, nitriles, amides and mixtures thereof.
- the solvent involved in the process for the preparation of Atropin, Glycopyrronium, Aclidinium, Trospium and their respective derivatives is selected from the group consisting of aromatic hydrocarbons, sulfoxides, alcohols, nitriles, amides and mixtures thereof.
- a preferred aromatic hydrocarbon is toluene.
- a preferred sulfoxide is dimethylsulfoxide (DMSO).
- a preferred alcohol is n-butanol.
- a preferred nitrile is acetonitrile.
- a preferred amide is dimethylformamide (DMF).
- the amount of acyl transfer agent is from 1 .2 to 2.5 equivalents, preferably from 1 .5 to 2.0 equivalents, compared to the molar quantity of Scopolamine.
- the amount of Di-(2- thienyl)glycolic acid ester is from 0.8 to 1 .1 equivalents, preferable from 0.9 to 1 .0 equivalents, compared to the molar quantity of Scopolamine.
- the preferred solvent is toluene.
- the amount of acyl transfer agent is from 0.8 to 1 .5 equivalents, preferably from 1 .0 to 1 .2 equivalents, compared to the molar quantity of the Scopolamine N-methyl halide salt.
- the amount of Di-(2-thienyl)glycolic acid ester is from 0.8 to 1 .1 equivalents, preferable from 0.9 to 1 .0 equivalents, compared to the molar quantity of the Scopolamine N-methyl halide salt.
- the preferred solvent is DMSO.
- the preferred Tiotropium halide salt is the bromine salt, resulting from Scopolamine N-methyl bromide as the preferred Scopolamine methyl halide.
- the amount of acyl transfer agent is from 1 .0 to 1 .2 equivalents, compared to the molar quantity of Scopolamine.
- the preferred solvent is toluene.
- the preferred corresponding Scopolamine derivatives are Scopolamine base (resulting in the final product Scopine base) or Scopolamine N-methyl bromide (resulting in the final product Scopine methyl bromide), respectively.
- the preferred amount of acyl transfer agent is from 1 .0 to 2.0 equivalents, compared to the molar quantity of (R)-Quinuclidin-3-yl acetate.
- the preferred solvent is toluene.
- Scopine (or corresponding quaternary ammonium derivatives) does not have to be isolated, avoiding the well known losses in its recovery described above.
- neutral reaction conditions can be maintained during the whole process by the use of acyl transfer agents, resulting in a further reduction of the formation of byproducts such as Scopoline and its derivatives which are generated by using acid and/or basic conditions.
- the present process requires fewer synthetic steps, milder reaction conditions (up to ambient temperature and pressure) resulting in reduced energy consumption, higher total yields, selectivity and purity of the desired reaction products and again less formation of byproducts.
- the acyl transfer agent is only applied in stoichiometric or even sub- stoichiometric amounts, not only reagent costs and the amount of generated waste are reduced compared to prior art processes, but also the isolation procedures are simplified.
- the acyl transfer reaction is very flexible since it can be run with both scopolamine and derivatives thereof, giving a direct access to Scopine and its derivatives, Di-(2- thienyl)glycolic acid Scopine alkyl esters as well as Tiotropium and its derivatives.
- the acyl transfer reaction may be applied to a broad range of other esters as indicated above.
- Scopolamine free base (1 .50 g; 4,94 mmol, 1 eq) and TBD (0.207 g; 7.42 mmol, 1 .5 eq) were dissolved in 2 mL of toluene at 30 °C. After stirring for 24 h at 30°C, Methyl Dithienylglycolate (1 .26 g; 4,94 mmol, 1 eq) was added to the reaction mixture. After stirring for an additional 2.5 h at 30°C under nitrogen atmosphere, a 10% solution of citric acid was added. After layer separation, the aqueous layer was washed with CH2CI2 and then basified with 10% Na2CO3 solution until a pH of 8.5 was reached.
- Scopolamine methyl bromide (0.100 g; 0.25 mmol, 1 eq) and TBD (0.035 g; 0.25 mmol, 1 eq) were dissolved in 1 mL of dimethylsulfoxide at 25 °C under magnetic stirring; after 24 h Methyl Dithienylglycolate (0.063 g; 0.25 mmol, 1 eq) was added and the reaction mixture was stirred at 25 °C for additional 2h. The solvent was distilled off to yield 0.190g of a residue with a Tiotropium bromide assay of 14% (0.017g).
- Preparative example 3 Preparation of Scopine base
- Scopolamine (0.100 g; 0.33 mmol) and TBD (0.046 g; 0.40 mmol, 1 .2 eq) were charged into a round bottom flask (5 mL) and were dissolved in 0.7 mL of toluene at 25 °C. After 48 h under magnetic stirring, a suspension is formed and the reaction was found to be complete. After separating from the solid by centrifugation and subsequent concentrating under vacuum, 0.051 g (99.3%) of Scopine free base was obtained.
- Preparative example 4 Preparation of (R)-Quinuclidin-3-yl 2-hvdroxy-2,2- di(thiophen-2-yl)acetate i. Preparation of (R)-Quinuclidin-3-yl acetate
- Acetyl chloride (2.5 ml_, 4.5 eq) was added to a solution of (R) Quinuclidinol (1 .0 g, 1 eq) in CHCI3 at 0 °C. The formed suspension was stirred at 25°C for 30 minutes, then the mixture of reaction was heated at 50 °C under magnetic stirring. After 30 minutes a solution formed. After adding Na 2 CO 3 and H 2 O and subsequent separation of the phases, the aqueous phase was extracted with EtOAC (3x 15 ml_) and solvent was removed at reduced pressure to yield 0,95g of (R)-Quinuclidin-3-yl acetate. ii.
- R1 is pyrrolidine or a azapolycycle, optionally substituted
- R2 is a C1 -C4-alkyl group or 1 -phenyl 2-hydroxy ethyl
- R3 is a C1 -C4-alkyl group, preferably methyl
- R4 is selected from hydrogen, aryl or heteroaryl
- R5 is selected from aryl or heteroaryl
- n 0 or 1
- the present invention also provides a process for the preparation of Scopine Dithienylglycolate wherein
- R1 is 9-Methyl-3-oxa-9-azoniatricyclo[3.3.1 .0 2,4 ]nonan-7-yl
- R2 is a C1 -C4-alkyl group or 1 -phenyl 2-hydroxy ethyl, preferably 1 -phenyl 2-Hydroxy ethyl
- R3 is a C1 -C4-alkyl group, preferably methyl
- R4 and R5 are 2-thienyl
- n 0.
- the present invention also provides a process for the preparation of a Tiotropium halide salt comprising the step of preparing Scopine Dithienylglycolate according to the process described above:
- Scopine Dithienylglycolate produced according to a process of the invention for the preparation of a Tiotropium halide salt.
- the present invention also provides a process for the preparation of a Tiotropium halide salt wherein
- R1 is a 9,9-Dimethyl-3-oxa-9-azoniatricyclo[3.3.1 .0 2,4 ]nonan-7-yl halide salt
- R2 is a C1 -C4-alkyl group or 1 -phenyl 2-hydroxy ethyl, preferably 1 -phenyl 2- hydroxy ethyl
- R3 is a C1 -C4-alkyl group, preferably methyl
- R4 and R5 are 2-thienyl
- the present invention also provides a process for the preparation of (R)-Quinuclidin- 3-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetate wherein
- R1 is 1 -Azabicyclo[2.2.2]octan-3-yl
- R2 is a C1 -C4-alkyl group, preferably methyl
- R3 is a C1 -C4-alkyl group, preferably methyl
- R4 and R5 are 2-thienyl
- n 0.
- the present invention also provides a process for the preparation of an Aclidinium halide salt comprising the step of preparing (R)-Quinuclidin-3-yl 2-hydroxy-2,2- di(thiophen-2-yl)acetate as described above.
- the processes above may further be characterized in that Ester II selected from the group consisting of Di-(2-thienyl)glycolic acid methyl ester, the Di-(2-thienyl)glycolic acid ethyl ester or Di-(2-thienyl)glycolic acid propyl ester, preferably Di-(2- thienyl)glycolic acid methyl ester.
- the present invention also provides a process for the preparation of 3-[[-2- cyclopentyl-2-hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium wherein
- R1 is 1 -Methylpyrrolidinium-3-yl halide salt
- R2 is a C1 -C4-alkyl group, preferably methyl
- R3 is a C1 -C4-alkyl group, preferably methyl
- R4 is phenyl
- R5 is cyclopentyl
- n 0.
- the present invention also provides a process for the preparation of a Glycopyrronium halide salt comprising the step of preparing 3-[[-2-cyclopentyl-2- hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium as described above.
- a process for the preparation of a Glycopyrronium halide salt comprising the step of preparing 3-[[-2-cyclopentyl-2- hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium as described above.
- Use of 3-[[- 2-cyclopentyl-2-hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium produced according to a process of the invention for the preparation of a Glycopyrronium halide salt.
- the present invention also provides a process for the preparation of a Glycopyrronium halide salt according wherein
- R1 is a 1 ,1 -Dimethylpyrrolidinium-3-yl halide salt
- R2 is a C1 -C4-alkyl group, preferably methyl
- R3 is a C1 -C4-alkyl group, preferably methyl
- R4 is phenyl
- R5 is cyclopentyl
- n 0.
- the present invention also provides a process for the preparation of Atropin wherein R1 is 8-Methylazabicyclo[3.2.1 ]octan-3-yl
- R2 is a C1 -C4-alkyl group, preferably methyl
- R3 is a C1 -C4-alkyl group, preferably methyl
- R4 is hydrogen
- R5 is phenyl
- n 1 .
- the present invention also provides a process for the preparation of a Trospium halide salt wherein
- R1 is Spiro[8-azoniabicyclo[3.2.1 ]octane-8,1 '-pyrrolidinium]-3-yl halide salt
- R2 is a C1 -C4-alkyl group, preferably methyl
- R3 is a C1 -C4-alkyl group, preferably methyl
- R4 and R5 are phenyl
- n 0
- acyl transfer agent is a azapolycycle, preferably 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD).
- the present invention also provides a process for the preparation of a Tiotropium salt comprising the step of reacting Scopine with an ester of Di-(2-thienyl)glycolic acid, characterized in that Scopine or one of its quaternary ammonium salts is prepared from Scopolamine in the presence of an acyl transfer agent, preferably 1 ,5,7- Triazabicyclo[4.4.0]dec-5-ene.
- the present invention also provides a process for the preparation of Scopine Dithienylglycolate comprising the step of reacting Scopolamine with Di-(2- thienyl)glycolic acid methyl ester in the presence of an acyl transfer agent, preferably 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene.
- the present invention provides a process for the preparation of Scopine Dithienylglycolate or a Tiotropium salt comprising the step of reacting Scopolamine or any of its methyl halide salts with an ester of Di-(2-thienyl)glycolic acid in the presence of an acyl transfer agent.
- acyl transfer agent is 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD).
- ester of ester of Di-(2- thienyl)glycolic acid is one of the methyl ester, the ethyl ester or the propyl ester, preferably Di-(2-thienyl)glycolic acid methyl ester.
- the solvent is selected from a group consisting of aromatic hydrocarbons such as toluene, sulfoxides such as dimethylsulfoxide (DMSO), nitriles such as acetonitrile, amides such as dimethylformamide (DMF), alcohols such as n-butanol and mixtures thereof.
- aromatic hydrocarbons such as toluene
- sulfoxides such as dimethylsulfoxide (DMSO)
- nitriles such as acetonitrile
- amides such as dimethylformamide (DMF)
- alcohols such as n-butanol and mixtures thereof.
- the process may be further characterized in that the amount of acyl transfer agent is from 0.8 to 1 .5 equivalents, preferably from 1 .0 to 1 .2 equivalents, compared to the molar quantity of the corresponding Scopolamine methyl halide salt.
- the process for the preparation of a Tiotropium halide salt above may be further characterized in that the amount of Di-(2-thienyl)glycolic acid ester is from 0.8 to 1 .1 equivalents, preferably from 0.9 to 1 .0 equivalents, compared to the molar quantity of the Scopolamine methyl halide salt.
- the process for the preparation of a Tiotropium halide salt above may be further characterized in that the reaction is carried out in DMSO as the solvent.
- the process for the preparation of a Tiotropium halide salt above may be further characterized in that the Tiotropium salt is the bromide salt that is prepared from Scopolamine methyl bromide.
- the process may be further characterized in that in that the amount of acyl transfer agent is from 1 .2 to 2.5 equivalents, preferably from 1 .5 to 2.0 equivalents, compared to the molar quantity of Scopolamine.
- the process for the preparation of Scopine Dithienylglycolate above may be further characterized in that the amount of Di-(2-thienyl)glycolic acid ester is from 0.8 to 1 .1 equivalents, preferably from 0.9 to 1 .0 equivalents, compared to the molar quantity of Scopolamine.
- the present invention also provides a process for the preparation of Scopine Base, comprising the step of reacting of Scopolamine in the presence of an acyl transfer agent.
- the process for the preparation of Scopine Base above may be further characterized in that the amount of acyl transfer agent is from 1 .0 to 1 .2 equivalents, compared to the molar quantity of Scopolamine.
- the process may be further characterized in that the reaction is carried out in toluene as the solvent.
- an acyl transfer agent preferably 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene.
- the present invention also provides a process for the preparation of a Tiotropium salt comprising the step of reacting Scopine with an ester of Di-(2-thienyl)glycolic acid, characterized in that Scopine or one of its quaternary ammonium salts is prepared from Scopolamine in the presence of an acyl transfer agent, preferably 1 ,5,7- Triazabicyclo[4.4.0]dec-5-ene.
- the present invention also provides a process for the preparation of a Tiotropium salt comprising the step of preparing Scopine Dithienylglycolate by reacting Scopolamine with an ester of Di-(2-thienyl)glycolic acid in the presence of an acyl transfer agent, preferably 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene.
- an acyl transfer agent preferably 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene.
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Abstract
L'invention concerne un nouveau procédé pour préparer des esters du type aclidinium, atropine, glycopyrroniunn, tiotropium, prospium et leurs précurseurs et dérivés respectifs en fonction des réactions de transfert d'acyle.
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EP13001306 | 2013-03-14 | ||
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104478871A (zh) * | 2014-12-26 | 2015-04-01 | 东华大学 | 一种胆碱m受体拮抗剂阿地溴铵及其制备方法 |
Citations (3)
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US20070123557A1 (en) * | 2005-11-10 | 2007-05-31 | Bodor Nicholas S | Soft anticholinergic esters |
EP1953156A1 (fr) * | 2007-01-29 | 2008-08-06 | Boehringer Ingelheim Pharma GmbH & Co. KG | Procédé de fabrication de sels de scopinium |
WO2009087419A1 (fr) * | 2008-01-10 | 2009-07-16 | Generics [Uk] Limited | Nouveau procédé de préparation d'esters de scopine |
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2014
- 2014-03-14 WO PCT/EP2014/055174 patent/WO2014140318A1/fr active Application Filing
Patent Citations (3)
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US20070123557A1 (en) * | 2005-11-10 | 2007-05-31 | Bodor Nicholas S | Soft anticholinergic esters |
EP1953156A1 (fr) * | 2007-01-29 | 2008-08-06 | Boehringer Ingelheim Pharma GmbH & Co. KG | Procédé de fabrication de sels de scopinium |
WO2009087419A1 (fr) * | 2008-01-10 | 2009-07-16 | Generics [Uk] Limited | Nouveau procédé de préparation d'esters de scopine |
Non-Patent Citations (1)
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T. ALLMENDINGER ET. AL.: "Carry Over of Impurities. A Detailed Exemplification for Glycopyrrolate.", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 16, 8 October 2012 (2012-10-08), pages 1754 - 1769, XP002723240, DOI: 10.1021/op3001788 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104478871A (zh) * | 2014-12-26 | 2015-04-01 | 东华大学 | 一种胆碱m受体拮抗剂阿地溴铵及其制备方法 |
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