CA2746428A1 - Synthese de morphine-6-glucuronide ou de l'un de ses derives - Google Patents
Synthese de morphine-6-glucuronide ou de l'un de ses derives Download PDFInfo
- Publication number
- CA2746428A1 CA2746428A1 CA2746428A CA2746428A CA2746428A1 CA 2746428 A1 CA2746428 A1 CA 2746428A1 CA 2746428 A CA2746428 A CA 2746428A CA 2746428 A CA2746428 A CA 2746428A CA 2746428 A1 CA2746428 A1 CA 2746428A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- dimorphin
- formula
- diyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- GNJCUHZOSOYIEC-GAROZEBRSA-N Morphine-6-glucuronide Chemical compound O([C@H]1C=C[C@H]2[C@H]3CC=4C5=C(C(=CC=4)O)O[C@@H]1[C@]52CCN3C)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O GNJCUHZOSOYIEC-GAROZEBRSA-N 0.000 title claims abstract description 26
- 230000015572 biosynthetic process Effects 0.000 title description 10
- 238000003786 synthesis reaction Methods 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 31
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- -1 isobutyryl Chemical group 0.000 claims abstract description 14
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical class O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 claims abstract description 10
- 239000003849 aromatic solvent Substances 0.000 claims abstract description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000005599 alkyl carboxylate group Chemical group 0.000 claims abstract description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 5
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 22
- 125000000732 arylene group Chemical group 0.000 claims description 21
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 229910001868 water Inorganic materials 0.000 claims description 16
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 229960005181 morphine Drugs 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 6
- QZCCVLMMVYJZTD-UHFFFAOYSA-N trimethyl(trifluoromethylsulfonyl)silane Chemical compound C[Si](C)(C)S(=O)(=O)C(F)(F)F QZCCVLMMVYJZTD-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 claims description 4
- NEQFBGHQPUXOFH-UHFFFAOYSA-N 4-(4-carboxyphenyl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=C(C(O)=O)C=C1 NEQFBGHQPUXOFH-UHFFFAOYSA-N 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- MIAUJDCQDVWHEV-UHFFFAOYSA-L benzene-1,2-disulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1S([O-])(=O)=O MIAUJDCQDVWHEV-UHFFFAOYSA-L 0.000 claims description 4
- WRUAHXANJKHFIL-UHFFFAOYSA-N benzene-1,3-disulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC(S(O)(=O)=O)=C1 WRUAHXANJKHFIL-UHFFFAOYSA-N 0.000 claims description 4
- QQVIHTHCMHWDBS-UHFFFAOYSA-L isophthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC(C([O-])=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-L 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- WPUMVKJOWWJPRK-UHFFFAOYSA-L naphthalene-2,7-dicarboxylate Chemical compound C1=CC(C([O-])=O)=CC2=CC(C(=O)[O-])=CC=C21 WPUMVKJOWWJPRK-UHFFFAOYSA-L 0.000 claims description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- YCGAZNXXGKTASZ-UHFFFAOYSA-L thiophene-2,5-dicarboxylate Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)S1 YCGAZNXXGKTASZ-UHFFFAOYSA-L 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 150000001336 alkenes Chemical class 0.000 claims description 3
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- JXUKFFRPLNTYIV-UHFFFAOYSA-N 1,3,5-trifluorobenzene Chemical compound FC1=CC(F)=CC(F)=C1 JXUKFFRPLNTYIV-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 238000000451 chemical ionisation Methods 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 230000013595 glycosylation Effects 0.000 description 6
- 238000006206 glycosylation reaction Methods 0.000 description 6
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000003637 basic solution Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 2
- 206010038678 Respiratory depression Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000011033 desalting Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000003147 glycosyl group Chemical group 0.000 description 2
- 239000008240 homogeneous mixture Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 125000005000 thioaryl group Chemical class 0.000 description 2
- IYXRQFVHZFEWSY-VYKNHSEDSA-N (4r,4ar,7s,7ar,12bs)-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol;hydrate Chemical compound O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O IYXRQFVHZFEWSY-VYKNHSEDSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 0 CC(CC1)(Cc(cc2)c(C3[C@]4*5)c5c2O*Oc2c5O[C@@]([C@@](C=CC6[C@@](C7)N(C)CC8)O)[C@]68c5c7cc2)C1C3C=C[C@@]4O Chemical compound CC(CC1)(Cc(cc2)c(C3[C@]4*5)c5c2O*Oc2c5O[C@@]([C@@](C=CC6[C@@](C7)N(C)CC8)O)[C@]68c5c7cc2)C1C3C=C[C@@]4O 0.000 description 1
- JUQFFVHLMGCQFQ-UHFFFAOYSA-N ClC1=CC=CC=C1Cl.FC1=CC(F)=CC(F)=C1 Chemical compound ClC1=CC=CC=C1Cl.FC1=CC(F)=CC(F)=C1 JUQFFVHLMGCQFQ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-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
- 238000006994 Koenigs-Knorr glycosidation reaction Methods 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 230000004989 O-glycosylation Effects 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical group [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- VIQSRHWJEKERKR-UHFFFAOYSA-L disodium;terephthalate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=C(C([O-])=O)C=C1 VIQSRHWJEKERKR-UHFFFAOYSA-L 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000000386 donor Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000000348 glycosyl donor Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- LXEJRKJRKIFVNY-UHFFFAOYSA-N terephthaloyl chloride Chemical compound ClC(=O)C1=CC=C(C(Cl)=O)C=C1 LXEJRKJRKIFVNY-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Pain & Pain Management (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0806948 | 2008-12-10 | ||
| FR0806948A FR2939436B1 (fr) | 2008-12-10 | 2008-12-10 | Synthese de morphine-6-glucuronide ou de l'un de ses derives |
| PCT/FR2009/052445 WO2010067007A2 (fr) | 2008-12-10 | 2009-12-08 | Synthese de morphine-6-glucuronide ou de l'un de ses derives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2746428A1 true CA2746428A1 (fr) | 2010-06-17 |
Family
ID=40996840
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2746428A Abandoned CA2746428A1 (fr) | 2008-12-10 | 2009-12-08 | Synthese de morphine-6-glucuronide ou de l'un de ses derives |
Country Status (30)
| Country | Link |
|---|---|
| US (1) | US8258298B2 (https=) |
| EP (1) | EP2376496B1 (https=) |
| JP (1) | JP5619768B2 (https=) |
| KR (1) | KR20110091534A (https=) |
| CN (1) | CN102307876B (https=) |
| AR (1) | AR074513A1 (https=) |
| AU (1) | AU2009326906B2 (https=) |
| BR (1) | BRPI0923238A2 (https=) |
| CA (1) | CA2746428A1 (https=) |
| CL (1) | CL2011001398A1 (https=) |
| CO (1) | CO6390060A2 (https=) |
| CR (1) | CR20110307A (https=) |
| EA (1) | EA201170790A1 (https=) |
| EC (1) | ECSP11011100A (https=) |
| ES (1) | ES2470666T3 (https=) |
| FR (1) | FR2939436B1 (https=) |
| HN (1) | HN2011001597A (https=) |
| IL (1) | IL213379A0 (https=) |
| MA (1) | MA32950B1 (https=) |
| MX (1) | MX337925B (https=) |
| MY (1) | MY152276A (https=) |
| NI (1) | NI201100116A (https=) |
| NZ (1) | NZ593342A (https=) |
| PE (1) | PE20110836A1 (https=) |
| SG (1) | SG172069A1 (https=) |
| TN (1) | TN2011000243A1 (https=) |
| TW (1) | TW201033218A (https=) |
| UA (1) | UA103643C2 (https=) |
| WO (1) | WO2010067007A2 (https=) |
| ZA (1) | ZA201104657B (https=) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10807995B2 (en) | 2018-07-13 | 2020-10-20 | Alkermes Pharma Ireland Limited | Thienothiophene compounds for long-acting injectable compositions and related methods |
| US10799496B2 (en) | 2018-07-13 | 2020-10-13 | Alkermes Pharma Ireland Limited | Naphthylenyl compounds for long-acting injectable compositions and related methods |
| US10975099B2 (en) | 2018-11-05 | 2021-04-13 | Alkermes Pharma Ireland Limited | Thiophene compounds for long-acting injectable compositions and related methods |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3766188A (en) * | 1971-06-28 | 1973-10-16 | Yamanouchi Pharma Co Ltd | Carbonyldioxymorphinan derivatives |
| GB9116909D0 (en) * | 1991-08-06 | 1991-09-18 | Salford Ultrafine Chem & Res | Morphine derivatives |
| GB2282758A (en) | 1993-08-23 | 1995-04-19 | Euro Celtique Sa | Oral morphine-6-glucuronide compositions |
| DE69815336T2 (de) | 1997-04-14 | 2004-05-06 | Ufc Ltd. | Morphin-derivate |
| PL194362B1 (pl) * | 1998-06-06 | 2007-05-31 | Cenes Ltd | Sposób syntezy beta-anomeru morfino-6-glukuronidui zastosowanie związków |
| GB9914382D0 (en) * | 1999-06-21 | 1999-08-18 | Ufc Limited | New process for the manufacture of morphine-6-glucuronide and its analogues and also to a manufacture of new intermediaries |
| KR20040014544A (ko) * | 2001-06-05 | 2004-02-14 | 컨트롤 딜리버리 시스템즈 인코포레이티드 | 서방 진통제 화합물 |
| US6740641B2 (en) * | 2001-07-27 | 2004-05-25 | Euro-Celtique, S.A. | Sugar derivatives of hydromorphone, dihydromorphine and dihydromorphine, compositions thereof and uses for treating or preventing pain |
| KR20050008658A (ko) * | 2002-03-19 | 2005-01-21 | 마이클 홀릭 | 아포모르핀의 글리코시드 및 오르토에스테르 글리코시드유도체들, 유사체들 및 그것의 용도 |
| FR2864082B1 (fr) | 2003-12-22 | 2006-03-10 | Synt Em | Nouveau derive de la morphine-6-glucuronide, composition pharmaceutique le contenant et son utilisation pour le traitement de la douleur |
-
2008
- 2008-12-10 FR FR0806948A patent/FR2939436B1/fr not_active Expired - Fee Related
-
2009
- 2009-12-08 SG SG2011042322A patent/SG172069A1/en unknown
- 2009-12-08 KR KR1020117013141A patent/KR20110091534A/ko not_active Abandoned
- 2009-12-08 EA EA201170790A patent/EA201170790A1/ru unknown
- 2009-12-08 MA MA33997A patent/MA32950B1/fr unknown
- 2009-12-08 MY MYPI20112601 patent/MY152276A/en unknown
- 2009-12-08 JP JP2011540161A patent/JP5619768B2/ja not_active Expired - Fee Related
- 2009-12-08 CN CN200980156211.1A patent/CN102307876B/zh not_active Expired - Fee Related
- 2009-12-08 BR BRPI0923238A patent/BRPI0923238A2/pt not_active IP Right Cessation
- 2009-12-08 AU AU2009326906A patent/AU2009326906B2/en not_active Ceased
- 2009-12-08 UA UAA201108590A patent/UA103643C2/ru unknown
- 2009-12-08 CA CA2746428A patent/CA2746428A1/fr not_active Abandoned
- 2009-12-08 PE PE2011001187A patent/PE20110836A1/es not_active Application Discontinuation
- 2009-12-08 WO PCT/FR2009/052445 patent/WO2010067007A2/fr not_active Ceased
- 2009-12-08 NZ NZ593342A patent/NZ593342A/xx not_active IP Right Cessation
- 2009-12-08 MX MX2011006264A patent/MX337925B/es active IP Right Grant
- 2009-12-08 EP EP09803824.3A patent/EP2376496B1/fr active Active
- 2009-12-08 ES ES09803824.3T patent/ES2470666T3/es active Active
- 2009-12-09 AR ARP090104751A patent/AR074513A1/es unknown
- 2009-12-09 TW TW098142093A patent/TW201033218A/zh unknown
-
2011
- 2011-05-17 TN TN2011000243A patent/TN2011000243A1/fr unknown
- 2011-06-03 EC EC2011011100A patent/ECSP11011100A/es unknown
- 2011-06-05 IL IL213379A patent/IL213379A0/en unknown
- 2011-06-06 CR CR20110307A patent/CR20110307A/es unknown
- 2011-06-08 NI NI201100116A patent/NI201100116A/es unknown
- 2011-06-08 US US13/155,646 patent/US8258298B2/en not_active Expired - Fee Related
- 2011-06-09 HN HN2011001597A patent/HN2011001597A/es unknown
- 2011-06-09 CL CL2011001398A patent/CL2011001398A1/es unknown
- 2011-06-10 CO CO11072135A patent/CO6390060A2/es active IP Right Grant
- 2011-06-23 ZA ZA2011/04657A patent/ZA201104657B/en unknown
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| BE484262A (https=) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20141008 |
|
| FZDE | Discontinued |
Effective date: 20171128 |