NZ335212A - Process for the preparation of 14- alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinans - Google Patents
Process for the preparation of 14- alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinansInfo
- Publication number
- NZ335212A NZ335212A NZ335212A NZ33521296A NZ335212A NZ 335212 A NZ335212 A NZ 335212A NZ 335212 A NZ335212 A NZ 335212A NZ 33521296 A NZ33521296 A NZ 33521296A NZ 335212 A NZ335212 A NZ 335212A
- Authority
- NZ
- New Zealand
- Prior art keywords
- formula
- aryl
- compound
- methoxymethyl
- cyclopropylmethyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 26
- 238000002360 preparation method Methods 0.000 title claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 66
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 31
- -1 alkenyl halides Chemical class 0.000 claims abstract description 29
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 20
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 19
- 125000003302 alkenyloxy group Chemical group 0.000 claims abstract description 18
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 15
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 14
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 11
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims abstract description 10
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims abstract description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 9
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims abstract description 9
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 claims abstract description 9
- 229960004127 naloxone Drugs 0.000 claims abstract description 9
- 229960003086 naltrexone Drugs 0.000 claims abstract description 9
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 9
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 claims abstract description 8
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 claims abstract description 7
- YQNZUKAKYJMEFE-LMDOGRNLSA-N oxymorphindole Chemical compound N1C2=CC=CC=C2C(C[C@]23O)=C1[C@H](O1)[C@]42CCN(C)[C@@H]3CC2=CC=C(O)C1=C42 YQNZUKAKYJMEFE-LMDOGRNLSA-N 0.000 claims abstract description 7
- 229960005118 oxymorphone Drugs 0.000 claims abstract description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000029936 alkylation Effects 0.000 claims abstract description 4
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical class C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000007513 acids Chemical class 0.000 claims abstract description 3
- 150000001350 alkyl halides Chemical class 0.000 claims abstract description 3
- CYYWAXVARNZFBI-UHFFFAOYSA-N bromomethoxyethane Chemical compound CCOCBr CYYWAXVARNZFBI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 150000004820 halides Chemical class 0.000 claims abstract description 3
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 claims abstract description 3
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims abstract description 3
- DBTXKJJSFWZJNS-UHFFFAOYSA-N o-phenylhydroxylamine;hydrochloride Chemical compound Cl.NOC1=CC=CC=C1 DBTXKJJSFWZJNS-UHFFFAOYSA-N 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 132
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 109
- 239000000243 solution Substances 0.000 claims description 66
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 55
- 125000003118 aryl group Chemical group 0.000 claims description 54
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 46
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 44
- 239000012312 sodium hydride Substances 0.000 claims description 44
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 37
- 235000011468 Albizia julibrissin Nutrition 0.000 claims description 31
- 241001070944 Mimosa Species 0.000 claims description 31
- 239000012267 brine Substances 0.000 claims description 27
- 239000003921 oil Substances 0.000 claims description 27
- 239000012044 organic layer Substances 0.000 claims description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 27
- 230000015572 biosynthetic process Effects 0.000 claims description 26
- 238000003786 synthesis reaction Methods 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 238000004458 analytical method Methods 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 239000012458 free base Substances 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 9
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 239000012230 colorless oil Substances 0.000 claims description 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
- XRRFZOCDAWPIBB-IDRHMUJXSA-N chembl1257082 Chemical compound CS(O)(=O)=O.N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC=2C3=CC=CC=C3OC=25)O)CC1)O)CC1CC1 XRRFZOCDAWPIBB-IDRHMUJXSA-N 0.000 claims description 7
- 238000002955 isolation Methods 0.000 claims description 7
- DKJCUVXSBOMWAV-PCWWUVHHSA-N naltrindole Chemical compound N1([C@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC2=C3[CH]C=CC=C3N=C25)O)CC1)O)CC1CC1 DKJCUVXSBOMWAV-PCWWUVHHSA-N 0.000 claims description 7
- 239000002244 precipitate Substances 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- 238000010898 silica gel chromatography Methods 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 7
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 claims description 6
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 4
- SFSURLOVKBVPAD-UHFFFAOYSA-N chloro-dimethyl-(2-methylpropyl)silane Chemical compound CC(C)C[Si](C)(C)Cl SFSURLOVKBVPAD-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- ACTAPAGNZPZLEF-UHFFFAOYSA-N chloro(tripropyl)silane Chemical compound CCC[Si](Cl)(CCC)CCC ACTAPAGNZPZLEF-UHFFFAOYSA-N 0.000 claims description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 2
- 150000008050 dialkyl sulfates Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims 3
- ZHVWWEYETMPAMX-PCWWUVHHSA-N naltriben Chemical compound N1([C@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC=2C3=CC=CC=C3OC=25)O)CC1)O)CC1CC1 ZHVWWEYETMPAMX-PCWWUVHHSA-N 0.000 claims 3
- AVMHMVJVHYGDOO-NSCUHMNNSA-N (e)-1-bromobut-2-ene Chemical compound C\C=C\CBr AVMHMVJVHYGDOO-NSCUHMNNSA-N 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims 1
- ZHVWWEYETMPAMX-IFKAHUTRSA-N naltriben Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC=2C3=CC=CC=C3OC=25)O)CC1)O)CC1CC1 ZHVWWEYETMPAMX-IFKAHUTRSA-N 0.000 abstract description 5
- WIYUZYBFCWCCQJ-IFKAHUTRSA-N Naltrindole Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC=2C3=CC=CC=C3NC=25)O)CC1)O)CC1CC1 WIYUZYBFCWCCQJ-IFKAHUTRSA-N 0.000 abstract 2
- 230000002152 alkylating effect Effects 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 abstract 1
- 235000019439 ethyl acetate Nutrition 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- 239000006185 dispersion Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 14
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 10
- 239000006260 foam Substances 0.000 description 8
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 239000003887 narcotic antagonist Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 3
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 3
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940125833 compound 23 Drugs 0.000 description 3
- 229940125961 compound 24 Drugs 0.000 description 3
- 229940125846 compound 25 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical compound C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- PURSZYWBIQIANP-UHFFFAOYSA-N 1-(bromomethyl)-2-chlorobenzene Chemical compound ClC1=CC=CC=C1CBr PURSZYWBIQIANP-UHFFFAOYSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- SCSSXJVRZMQUKA-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-pyridin-4-ylpropanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)NC(C(=O)O)CC1=CC=NC=C1 SCSSXJVRZMQUKA-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- LZIYAIRGDHSVED-UHFFFAOYSA-N 1-(bromomethyl)-3-chlorobenzene Chemical compound ClC1=CC=CC(CBr)=C1 LZIYAIRGDHSVED-UHFFFAOYSA-N 0.000 description 1
- LNWXALCHPJANMJ-UHFFFAOYSA-N 1-(bromomethyl)-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(CBr)=C1 LNWXALCHPJANMJ-UHFFFAOYSA-N 0.000 description 1
- PDFGFQUSSYSWNI-UHFFFAOYSA-N 2-(bromomethyl)-1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1CBr PDFGFQUSSYSWNI-UHFFFAOYSA-N 0.000 description 1
- RUHJZSZTSCSTCC-UHFFFAOYSA-N 2-(bromomethyl)naphthalene Chemical compound C1=CC=CC2=CC(CBr)=CC=C21 RUHJZSZTSCSTCC-UHFFFAOYSA-N 0.000 description 1
- RUROFEVDCUGKHD-UHFFFAOYSA-N 3-bromoprop-1-enylbenzene Chemical compound BrCC=CC1=CC=CC=C1 RUROFEVDCUGKHD-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N hydroxylamine hydrochloride Substances Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A process for preparing a compound of the formula (I) comprises: ia) reacting naloxone of formula (II), naltrexone of formula (III) or oxymorphone of formula (IIIa) with phenylhydrazine hydrochloride in the presence of acid producing naloxindole of formula (NLI), naltrindole of formula (NTI) or oxymorphindole of formula (OMI) or ib) naloxone of formula (II), naltrexone of formula (III) or oxymorphone of formula (IIIa) is reacted with O-phenyl- hydroxyl amine hydrochloride in the presence of acid, producing the benzofurane derivatives of formula (NLB), naltriben of formula (NTB) or OMB of the formula (OMB); ii) protecting the 3-hydroxy group present in the products of step ia) or ib) by alkylation with benzyl bromide, methoxymethyl bromide, ethoxymethyl bromide, trityl chloride, or a silylating agent, in the presence of a solvent and a base, producing a compound of the formula (IV) iii) treating a compound of the formula (IV) with dialkyl sulphates, alkyl halides, alkenyl halides, aralkyl halides, arylalkenyl halides, alkanoyl halides, or arylalkanoyl halides in a solvent such as N,N dimethyl formamide or tetrahydrofurane, using a base, producing a compound of the formula (V) or iv) optionally hydrolyzing in diluted acids a compound of formula (V) optionally in the presence of a solvent, producing a compound of the formula (VI) and v) alkylating or acylating the compound of the formula (VI) to produce a compound of the formula (I) wherein: R1 is allyl, cyclopropylmethyl or methyl; R2 is alkoxy, alkenyloxy, arylalkyloxy, arylalkenyloxy alkanoyloxy or arylalkanoyloxy; R3 is hydroxy, alkoxy, arylalkyloxy, alkenyloxy, alkanoyloxy, arylalkanoyloxy or alkyloxyalkoxy; X is O, NH or NR4 and R4 is alkoxy, alkenyloxy, arylalkyloxy, arylalkenyloxy, alkanoyloxy or arylalkanoyloxy provided that when R1 is cyclopropylmethyl and R2 is methoxymethyl X is not O or N-methoxymethyl. In formula (IV) R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl; and X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl or N-silyl. In formula (V) R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl and X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl or N-silyl. In formula (VI) X is NH, O or N-benzyl.
Description
New Zealand Paient Spedficaiion for Paient Number 335212
6212
WO 98/22467 PCT/SE96/01497 _
NEW PROCESS FOR THE PREPARATION OF MORPHINANS
Field of the invention
The present invention is directed to a new process for the preparation of 14-alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinans.
Background of the invention
Opioid antagonists have been indispensable as tools in opioid research. For example, the chief criterion for the classification of an agonist effect as being opioid receptor mediated is the ability of known opioid antagonists naloxone or naltrexone to reversibly antagonize this cffect in a competitive fashion. The usefulness of naloxone and naltrexone for this purpose stems from the fact that they are universal opioid antagonists; that is, they are capable of antagonizing the agonist effects mediated by multiple opioid receptor types.
In addition to their uses as pharmacological tools, selective, non-peptide opioid antagonists have been described as having potential clinical applications in the treatment of a variety of disorders where endogenous opioids play a modulatory role. These include for instance disorders of food intake, shock, constipation, mental disorders, CNS injury, alcoholism, and immune function (P.S. Portoghese at al., J. Med. Chem., Vol. 34: 1757-1762, 1991).
Non-peptide, competitive, 5-selective opioid antagonists have been found to have immunosuppressive potency and less toxicity than the presently used immunosuppressive compound cyclosporin (EP 456 833; EP 485 636; EP 614 898; K. Arakawa et al., Transplantation, Vol. 53: 951-953,1992; K. Arakawa et al., Transplant Proc., Vol. 24: 696-697,1992; K. Arakawa et al., Transplant Proc., Vol. 25: 738-740, 1993). Such immunosuppressive agents can be used after organ transplantation to suppress the rejection
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
2
PGT/SE96/01497 _
of the foreign organ and also in the treatment of autoimmune diseases (e.g. rheumatoid arthritis).
In US 5 223 507 and US 5 225 417 the synthesis of 14-O-substituted indolomorphinans and benzofuranomorphinans have been disclosed. According to the process used for preparing the compounds claimed and disclosed in US 5 223 507, only a 3,14-dimethoxy substituted benzofuranomorphinan was prepared. According to the process used for preparing compounds claimed and disclosed in US 5 225 417, two 14-O-alkyl substituted benzofuranomorphinans have been prepared. According to the methods used for preparing the compounds of both the two mentioned prior art documents, the 3-hydroxy group was protected by a methyl group which is not easily removed without having a loss in yield.
According to the processes known from the prior art, the variations of the substituents at the oxygen in position 14 are very much limited when a 3-hydroxy group is supposed to be present in the molecule. It is for instance not possible to prepare compounds with a substituent at the oxygen in 14-position, as this position is labile to the conditions used for the cleavage of the 3-methoxy group.
Thus, the object of the present invention was to find a new process which would facilitate the preparation of 14-O-substituted indolomorphinans and benzofuranomorphinans.
The present patent application discloses a process whereby naloxone, naltrexone or oxymorphone is used as the starting material, whereby the 14-aIkoxy group is introduced after the protection of the oxygen in 3-position with an easily removable protecting group, preferably benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, thereby providing a process enabling the synthesis of compounds involving 14-O-substitution.
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
PCT/SE96/01497 _
3
Outline of the invention
The present invention is directed to a new process for the preparation of compounds of the general formula (I)
wherein
Rl represents allyl, cyclopropylmethyl or methyl;
R2 represents C]-C6 alkoxy, Cj-Cg alkenyloxy, C7-C16 arylalkyloxy wherein aryl is C6-C10 aryl and alkyloxy is Cj-C6 alkyloxy, C7-C16 arylalkenyloxy wherein aryl is Cg-Cjo aryl and alkenyloxy is Cj-Cg alkenyloxy, Cj-Cg alkanoyloxy, C7-C16 arylalkanoyloxy wherein aryl is C6-C10 aryl and alkanoyloxy is Ci-Cg alkanoyloxy;
R3 represents hydroxy, C[-Q alkoxy, C7-C16 arylalkyloxy wherein aryl is C6-C10 aryl and alkyloxy is C1-C6 alkyloxy, Cj-Cg alkenyloxy, C4-C6 alkanoyloxy, C7-C16 arylalkanoyloxy wherein the aryl is Cg-Cjo aryl and the alkanoyloxy is C\-C(, alkanoyloxy, C2-C]o alkyloxyalkoxy wherein alkyloxy is C1-C4 alkyloxy and alkoxy is Cj-Cg alkoxy; and
X represents O, NH or NR4 wherein R4 is Cj-Cg alkoxy, Cj-Cg alkenyloxy, C7-C16 arylalkyloxy wherein aryl is C6-C10 aryl and alkyloxy is Ci -C(, alkyloxy, C7-C16 arylalkenyloxy wherein the aryl is C6-C10 aryl and alkenyloxy is Cj-Cg alkenyloxy, Cj-Cg alkanoyloxy, C7-C16 arylalkanoyloxy wherein aryl is C6-C10 aryl and alkanoyoloxy is Cj-Cg alkanoyloxy.
R3
(I)
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
WO 98/22467 PCT/SE96/01497 _
The process for the preparation of the compounds of the general formula (I) comprises the following steps:
(i) Naloxone (II), naltrexone (III) or oxymorphone (Ilia) of the formula
(II): R = ally!
(III): R = cyclopropylmethyl (Ilia): R = methyl is reacted with phenylhydrazine hydrochloride in the presence of an acid, preferably methanesulfonic acid, sulfuric acid or hydrochloric acid, giving naloxindole (NLI), naltrindole (NTI) or oxymorphindole (OMI), PS. Portoghese et al., J. Med. Chem. Vol. 31: 281-282, 1988, of the following formula:
NLI: R = allyl, X = NH NTI: R = cyclopropylmethyl, X = NH OMI: R = methyl, X = NH
or;
naloxone (II), naltrexone(m) or oxymorphone is reacted with O-phcnyl-hydroxyl amine hydrochloride in the presence of an acid, preferably methanesulfonic acid, sulfuric acid or hydrochloric acid, giving the benzofurane derivatives NLB, naltriben (NTB; P. S.
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
PCT/SE96/01497 _
Portoghese et al., J. Med. Chem., Vol. 34: 1715-1720,1991) or OMB (US 5 223 507) of the formula
NLB: R = ally!, X = O NTB: R = cyclopropylmethyl, X = O OMB: R - methyl, X = O
(ii) the 3-hydroxy group is protected by alkylation with benzyl bromide, methoxymethyl bromide, ethoxymethyl bromide, trityl chloride or a silylating agent, preferably dimethyl isobutyl-silyl chloride, trimethylsilyl chloride, triethylsilyl chloride, t-butyldimcthylsilyl chloride or tri-i-propylsilyl chloride, in a solvent, preferably N,N-dimethylformamide, dichloromethane or tetrahydrofurane, in the presence of a base which may not be a weak base, preferably potassium carbonate, potassium hydroxide, sodium hydride, sodium amide or diisopropyl ethylamine, giving a compound of the formula (IV)
(IV)
wherein
Rj is allyl, cyclopropylmethyl or methyl;
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
PCT/SE96/01497 _
6
X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl or N-silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; (iii) the compound of the formula (IV) is treated with C1-C2 dialkyl sulfates, Ci-Cfc alkyl halides, C\-C(, alkenyl halides, C7-C16 aralkyl halides wherein the aryl is Cg-Cjo aryl and the alkyl is Cj-Q alkyl, C7-C16 arylalkenyl halides wherein the aryl is Cg-Cjo aryl and the alkenyl is C2-C6 alkenyl, C2-C6 alkanoyl halides, C7-C16 arylalkanoyl halides wherein the aryl is C6-C10 aryl and the alkanoyl is C2-C6 alkanoyl, in a solvent, preferably N,N-dimethyl formamide or tetrahydrofurane, using a strong base, preferably sodium hydride, potassium hydride or sodium amide, giving a compound of the formula (V)
wherein
Rj is allyl or cyclopropylmethyl;
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and
R3 is C1-C6 alkyl, Cj-Cg alkenyl; C7-C16 arylalkyl wherein the aryl is C^-Cjq aryl and the alkyl is Ci-Cg alkyl; C7-C16 arylalkenyl wherein the aryl C(j-Cio aryl and the alkenyl is Cj-C6 alkenyl; Q-C6 alkanoyl, C7-C16 arylalkanoyl wherein the aryl is Cg-Cjo aryl and the alkyl is C1-C6 alkyl;
X is as defined in the formula (IV) above; and
,/Ri
(v)
r2o
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
7
PCT/SE96/01497 _
optionally the following step (iv) whereby
(iv) the compound of the formula (V) wherein X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl or silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl;
is hydrolized in diluted acids, preferably hydrochloric acid or sulfuric acid, optionally in the presence of a solvent, preferably an alcohol, and in particular methanol, ethanol or n-propanol, giving a compound of the formula (VI)
wherein Rj, and R3 are as defined above in formula (V), and X is NH, O or N-benzyl; and
(v) the compound of the formula (VI) is alkylated or acylated, giving a compound of the formula (I).
Detailed description of the invention
The invention will now be described in more detail by the following examples.
HC
(VI)
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
PCT/SE96/01497 _
8
EXAMPLES Example 1
Synthesis of 17-(CycIopropylmethyl)-6,7-dehydro-4,5a-epoxy- 14-hydroxy-3-(methoxymethoxy)-6,7-2\3'-benzo[b]furanomorphinan (compound 1).
Sodium hydride (426 mg, 17.7 mmol; obtained from 710 mg of sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of naltriben methanesulfonate (2.0 g, 3.9 mmol) in 30 ml of anhydrous N,N-dimethyl formamide at 0° C. The resulting mixture was stirred at 0° C for 20 min and then at room temperature for another 60 min. After cooling to 0° C, methoxymethyl bromide (653 (J.I, 8 mmol) was added and stirring was continued for 15 min at 0° C and then for additional 120 min at room temperature. Excess sodium hydride was destroyed by addition of methanol and H2O. The resulting mixture was extracted with ethyl acetate (4 x 50 ml), the combined organic layers were washed with H2O (2 x 50 ml) and brine, dried over Na2SC>4 and evaporated to give an oil which was crystallized from MeOH to yield 1.0 g (56%) of compound 1. M. p. 129-130° C.
'H-NMR (CDCI3): 5 7.45 (d, J = 8.3 Hz, 1 arom. H), 7.37 (d, J = 8.3 Hz, 1 arom. H), 7.25 (m, 1 arom.H), 7.16 (m, 1 arom.), 6.86 (d, J = 8.3 Hz, 1 arom. H), 6.60 (d, J = 8.3 Hz, 1 arom. H), 5.63 (s, H-C(5)), 5.17 and 5.06 (2 d, J = 6.6, 6.6 Hz, 0CH20), 3.42 (s, CH3O).
Analysis calculated for C28H29NO5. 0.2 MeOH (465.95): C 72.69, H 6.45, N 3.01; found: 72.58, H 6.28, N 3.00.
Example 2
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-hydroxy-3-(methoxymethoxy)-6,7-2' ,3'-(N-methoxymethylindolo)morphinan (compound 2).
Sodium hydride (492 mg, 20.5 mmol; obtained from 820 mg of 60% dispersion in oil by washings with n-hexane) was added to a solution of naltrindole hydrochloride (1.5 g, 3.3
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
9
PCT/SE96/01497 _
mmol) in 30 ml of anhydrous N,N-dimethyl formamide at 0° C. After stirring at 0° C for 15 min and additional 30 min at room temperature, the mixture was cooled again to 0° C and methoxymethyl bromide (1.27 g, 10.2 mmol) was added. After stirring at 0° C for 30 min, stirring was continued for another 120 min at room temperature. Methanol and H2O were added to destroy excess of sodium hydride. The mixture was extracted with ehtyl acetate (3 x 60 ml), the combined organic layers were washed with H2O (2 x 50 ml) and brine (2 x 50 ml) and evaporated to give a yellowish oil which was purified by column chromatography (silica gel, elution with Ct^CVMeOH/conc. NH4OH 245:10:1) to afford 500 mg (30%) pure compound 2 as a colorless foam.
'h NMR (CDCI3): S 7.44 (m, 2 arom. H), 7.20 (m, 1 arom. H), 7.07 (m, 1 arom. H), 6.82 (d, J = 8 Hz, 1 arom. H), 6.58 (J = 8 Hz), 5.81 (s, H-C(5)), 5.79 and 5.50 (2 d, J = 10.8, 10.8 Hz, NCH20) 5.12 and 5.50 (2 d, J = 6.4, 6.4 Hz, 0CH20), 3.41 and 3.33 (2 s, CH3O).
Analysis calculated for C30H34N2O5 (502.61): C 71.69, H 6.82, N 5.57; found: C 71.92, H 6.94, N 5.34.
Example 3
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-14-(2' ,6'-dichlorobenzyloxy)-4,5a-epoxy-3-(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 3).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 8 ml of anhydrous N,N-dimethylformamide at 0° C. After stirring at 0° C for 15 min, stirring was continued for another 30 min at room temperature and the mixture was cooled again to 0° C. 2,6-Dichlorobenzyl bromide (240 g, 1 mmol) was added at once and stirring was continued for 15 min at 0° C and then for 3 h at room temperature. Excess sodium hydride was destroyed with MeOH and H2O and the mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with H2O (2 x 30 ml)
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
and brine (2 x 30 ml), dried over Na2S04 and evaporated. The residue (400 mg colorless oil) was crystallized from MeOH to yield 300 mg (75%) of compound 3. M. p. 180-182° C.
JH NMR (CDC13): 8 7.41 (d, J = 8.3 Hz, 1 arom. H), 7.33 (d, J = 8.3 Hz, 1 arom. H), 7.23 (m, 1 arom. H), 7.14 (m, 2 arom. H), 7.03 and 7.01 (2 d, J = 7.3, 7.3 Hz, 2 arom. H), 6.84 (d, J = 8.3 Hz, 1 arom. H), 6.59 (d, J = 8.3 Hz, 1 arom. H), 5.56 (s, H-C(5)), 5.32 and 4.68 (2 d, J = 8.7, 8.7 Hz, OCH2Ph), 5.16 and 5.05 (2 d, J = 6.6, 6.6 Hz, 0CH20), 3.41 (s, CH3O).
Example 4
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-14-(2\6'-dichlorobenzyloxy)-4,5a-epoxy-3-hydroxy-6,7-2\3'-benzo[b]furanomorphinan (compound 4).
A solution of compound 3 (150 mg, 0.24 mmol) in MeOH (4 ml) and IN HC1 (2 ml) was refluxed for 1 h. After cooling, the solution was alkalized with conc. NH4OH, extracted wiht ethyl acetate (3x15 ml), the combined organic layers were washed with H20 (2x15 ml) and brine (10 ml), dried over Na2S04 and evaporated to give an oily residue which was crystallized from MeOH to yield 70 mg (51%) of compound 4. M. p. 193-195° C (dec.).
]H NMR (CDCI3): 5 7.42 (d, J = 8.3 Hz, 1 arom. H), 7.33 (d, J = 8 Hz, 1 arom. H), 7.24 (m, 1 arom. H), 7.14 (m, 2 arom. H), 7.03 and 7.01 (2 d, J = 7.3 Hz, 1 arom. H), 6.64 (d, J = 8.1 Hz, 1 arom. H), 6.56 (d, J = 8.1 Hz, 1 arom. H), 5.58 (s, H-C(5)), 5.32 and 4.68 (2 d, J = 8.6 Hz, OCH2Ph).
Analysis calculated for C33H29CI2NO4 (574.51): C 68.79, H 5.09, N 2.44; found: C 68.97, H 5.05, N 2.44.
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
11
Example 5
Synthesis of 17-(Cyclopropylmethyl) -6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-14-(3' -nitrobenzyloxy)-6,7-2' ,3' -benzo[b]furanomoiphinan (compound 5).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 6 ml of anhydrous N,N-dimethylformamide at 0° C. The resulting mixture was stirred at 0° C for 15 min and then at room temperature for another 30 min. After cooling to 0° C, 3-nitrobenzyl bromide (216 mg, 1 mmol) was added and stirring was continued first at 0° C for 15 min and then at room temperature for 3 h. Excess sodium hydride was destroyed by addition of MeOH and H2O. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H2O (2 x 20 ml) and brine (2 x 20 ml), dried over Na2S04 and evaporated to give 380 mg of a brown oil which was purified by column chromatography (silica gel, elution with CH2Cl2/MeOH/conc. NH4OH 240:10:1) to afford 100 mg (26%) of compound 5 as colorless foam.
'h NMR (CDCI3): 5 8.25 (s, 1 arom. H), 7.99 (m, 1 arom. H), 7.55 (d, J = 7.8 Hz, 1 arom. H), 7.47 (d, J = 8.3 Hz, 1 arom. H), 7.28 (m, 4 arom. H), 7.15 (m, 1 arom. H), 6.87 (d, J = 8.3 Hz, 1 arom. H), 6.62 (d, J = 8.3 Hz, 1 arom. H), 5.66 (s, H-C(5)), 5.17 and 5.07 (2 d, J = 6.6 Hz, 0CH20,4.92 and 4.44 (2 d, J = 11.5 Hz, OCH2Ph), 3.42 (s, CH3O).
Example 6
Synthesis of 17-(Cyclopropylmethyl)-6,7-dchydro-4,5cc-epoxy-3-hydroxy-14-(3 nitrobenzyloxy)-6,7-2\3'-benzo[b]furanomorphinan Hydrochloride (compound 6).
A solution of compound 5 (80 mg, 0.13 mmol) in MeOH (4 ml) and IN HC1 (2 ml) was refluxed for 1 h. After cooling, the solution was alkalized with conc. NH4OH, extracted with ethyl acetate (3 x 20 ml), the combined organic layers were washed with H2O (2x15 ml) and brine (15 ml), dried over Na2S04 and evaporated. The oily residue was dissolved in
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
12
PCT/SE96/01497 _
acetone and transformed into the hydrochloride salt (compound 6) by addition of ethereal HC1. Yield 50 mg (66%). M. p. > 230° C (dec.).
JH NMR (DMSO-d6): 5 9.40 (s, OH), 9.15 (broad s, +NH), 7.84 (s, 1 arom. H), 7.60 (d, J = 8.8 Hz, 1 arom. H), 7.53 (d, J = 7.6 Hz, 1 arom. H), 7.45 (d, J = 8 Hz, 1 arom. H), 7.23 (d, J = 7.6 Hz, 1 arom. H), 7.19 (d, J = 7.6 Hz, 1 arom. H), 6.98 (m, 1 arom. H), 6.88 (d, J = 7.6 Hz, 1 arom. H), 6.69 (d, J = 8.3 Hz, 1 arom. H), 6.66 (d, J = 8.3 Hz, 1 arom. H), 6.03 (s, H-C(5)), 4.98 and 4.87 (2 d, J = 14, 14 Hz, OCH2Ph).
Analysis calculated for C33H30N2O6 x HC1 (587.08): C 67.52, H 5.32, N. 4.77; found: C 67.78, H 5.25, N 4. 76.
Example 7
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-14-(2-naphthylmethoxy)-6,7-2',3,-benzo[b]furanomorphinan (compound 7).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 5 ml of anhydrous N,N-dimethylformamidc at 0° C. The resulting mixture was stirred at 0° C for 15 min and then at room temperature for another 30 min. After cooling to 0° C, 2-(bromomethyl)naphthalene (221 mg, 1 mmol) was added and stirring was continued at first at 0° C for 15 min and then at room temperature for 2 h. Excess sodium hydride was destroyed by addition of MeOH and H2O. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20 ml) and brine (2x10 ml), dried over Na2S04 and evaporated to give a crystalline residue which was recrystallized to yield 285 mg (73%) of compound 7. M. p. 198-201° C.
*H NMR (CDCI3): 8 7.72-7.08 (m, 11 arom. H), 6.86 (d, J = 8.3 Hz, 1 arom. H), 6.62 (d, J = 8.3 Hz, 1 arom. H), 5.68 (s, H-C(5)), 5.17 and 5.07 (2 d, J = 6.6, 6.6 Hz, 0CH20), 5.01 and 4.57 (2 d, J = 11.2, 11.2 Hz, OCH2Ar), 3.42 (s, CH3O).
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
13
Analysis calculated for C39H37NO5 x 0.2 EtOAc (C4H8O2) (617.35): C77.43, H 6.30, N 2.27; found: C 77.40, H 6.27, N 2.27.
Example 8
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(2'-naphthylmethoxy)-6,7-2',3'-benzo[b]furanomorphinan hydrochloride(compound 8).
A solution of compound 7 (180 mg, 0.3 mmol) in MeOH (5 ml) and IN HCl (3 ml) was refluxed for 30 min, coolcd and kept in the refrigerator overnight. The crystals formed were isolated and washed with small amounts of MeOH and ether to yield 150 mg (84%) of compound 8. M. p. >215° C.
]H NMR (DMSO-d6): 5 9.42 (s, OH), 9.00 (broad s, +NH), 7.68-6.85 (m, 11 arom. H), 6.71 (d, J = 8 Hz, 1 arom. H), 6.67 (d, J = 8 Hz, 1 arom. H), 6.04 (s, H-C(5)), 4.92 (s, OCH2Ar).
Analysis calculated for C37H33NO4 x HCl. 0.3 MeOH (601.75): C74.45, H 5.90, N 2.33; found: C 74.47, H 5.76, N 2.35.
Example 9
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-(2'-fluorobenzyloxy)-3-(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 9).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 5 ml of anhydrous N,N-dimethylformamide at 0° C. The resulting mixture was stirred at 0° C for 10 min and the at room temperature for another 30 min. After cooling to 0° C, 2-flourobenzyl bromide (120 |il, 1 mmol) was added and stirring was continued at first at 0° C for 15 min and then at room temperature for 2 h. Excess sodium hydride was destroyed by addition of MeOH and H2O. The resulting mixture was extracted with ethyl
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
14
acetate (3 x 30 ml), the combined organic layers were washed with H2O (2 x 20 ml) and brine (2 x 20 ml), dried over Na2SC>4 and evaporated to give an oil which purified by column chromatography (silica gel, elution with ethyl acetate/n-hexane 1) 1:3 2) 1:1) to afford 215 mg (58%) of compound 9 as colorless foam.
*H NMR (DMSO-dg): 8 7.56 (d, J = 8 Hz, 1 arom. H), 7.49 (d, J = 8 Hz, 1 arom. H), 7.31 (m, 1 arom. H), 7.21 (m, 1 arom. H), 6.81 (d, 3 = 8.4 Hz, 1 arom. H), 6.67 (d, J = 8.4 Hz), 5.72 (s, H-C(5)), 5.06 and 5.01 (2 d, J = 6.4, 6.4 Hz, 0CH20), 4.89 and 4.57 (2 d, J = 11.6, 11.6 Hz, OCH2Ph), 3.33 (s, CH3O).
Analysis calculated forC35H34N05 (567.66): C 74.06, H 6.04, N 2.47; found: C 73.71, H 5.92, N 2.42.
Example 10
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-(2'-fluorobenzyloxy)-3-hydroxy-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound 10).
A solution of compound 9 (160 mg, 0.28 mmol) in MeOH (3 ml) and IN HCl (3 ml) was refluxed for 20 min, then cooled and kept in the refrigerator overnight. The crystals formed were isolated and washed with small amounts of MeOH and ether to yield 110 mg (70%) of compound 10. M. p. > 215° C.
!H NMR (CDCI3): 6 9.45 (s, OH), 9.04 (broad s, +NH), 7.54 (d, J = 8.4 Hz, 1 arom. H, 7.31-6.73 (m, 7 arom. H), 6.71 (d, J = 8.2 Hz, 1 arom. H), 6.66 (d, J = 8.2 Hz, 1 arom. H), 5.98 (s, H-C(5)), 4.81 and 4.84 (2 d, J = 12 Hz, OCH2Ph).
Analysis calculated for C33H30FNO4 x HCl. 1.4 H20 (585.29): C 67.72, H 5.82, N 2.39; found: C 67.63, H 5.56, N 2.51.
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
Example 11
Synthesis of 14-(Cinnamyloxy)-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-(methoxymcthoxy)-6,7-2\3'-benzo[b]furanomorphinan (compound 11).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 5 ml of anhydrous N,N-dimethylformamide at 0° C. The resulting mixture was stirred at 0° C for 15 min and then at room temperature for another 30 min. After cooling to 0° C, cinnamyl bromide (197 mg, 1 mmol) was added and stirring was continued first at 0° C for 10 min and then at room temperature for 2 h. Excess sodium hydride was destroyed by addition of MeOH and H2O. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20 ml) and brine (1 x 20 ml), dried over Na2S04 and evaporated to give a crystalline residue which was treated with boiling methanol to afford 200 mg (53%) of compound 11. M. p. 156-159° C.
*H NMR (CDCI3): 8 7.47 (d, J = 8 Hz, 1 arom. H), 7.33 (d, J = 8 Hz, 1 arom. H), 7.28-7.07 (m, 7 arom. H), 6.84 (d, J, 8.4 Hz, 1 arom. H), 6.59 (d, J = 8.4 Hz, 1 arom. H), 6.38 (d, J = 16 Hz, 1 olef. H), 6.13 (m, 1 olef. H), 5.68 (s, H-C(5)), 5.16 and 5.06 (2 d, J = 6.4, 6.4 Hz, 0CH20), 4.46 and 4.11 (2 m, CH20-C(14)), 3.42 (s, CH3O).
Analysis calculated for C37H37N05. 0.1 EtOAc (584.52): C 76.85, H 6.52, N 2.40; found: C 76.70, H 6.48, N 2.41.
Example 12
Synthesis of 14-(Cinnamyloxy)-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-6,7-2\3'-benzo[b]furanomorphinan Salicylate (compound 12).
A solution of compound 11 (160 mg, 0.28 mmol) in MeOH (3 ml) and IN HCl (3 ml) was refluxed for 1 h. After cooling, the solution was alkalized with conc. NH40H, extracted with ethyl acetate (3 x 15 ml), the combined organic layers were washed with H20 (2x15
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
16
ml) and brine (10 ml), dried over Na2SC>4 and evaporated to give a colorless foam (100 mg). To a solution of this foam in a small amount of methanol 30 mg of salicyclic acid were added, the crystals formed collected and washed with cold methanol to yield 100 mg (53%)
O
of compound 12. M. p. > 170 C.
'h NMR (CDC13): 5 7.94 (d, J = 8 Hz, 1 arom. H), 7.35 (d, J = 8 Hz, 1 arom. H), 7.30-6.73 (m, 12 arom. H), 6.56 (d, J = 8 Hz, 1 arom. H), 5.96 (s, 2 olef. H), 5.55 (s, H-C(5)), 4.33-4.02 (m, CH20-C(14)).
Analysis calculated for C35H33NO4. Salicyclic acid (C7H5O3). 1 MeOH (701.82): C 73.57, H 6.18, N 2.00; found: C 73.56, H 5.96, N 2.06.
Example 13
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy- 14-methoxy-3-(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 13).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 5 ml of anhydrous N,N-dimethylformamide at 0° C. The resulting mixture was stirred at 0° C for 15 min and the at room temperature for another 30 min. After cooling to 0° C, dimethyl sulfate (100 |il, 1 mmol) was added and stirring was continued at first at 0° C for 15 min and then at room temperature for 2 h. Excess sodium hydride was destroyed by addition of MeOH and H2O. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H2O (2 x 20 ml) and brine (2 x 20 ml), dried over Na2S04 and evaporated to give a colorless foam (280 mg) of compound 13 which was pure by TLC and NMR.
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
17
1H NMR (DMSO-ds): 8 7.56 (d, J = 8 Hz, 1 arom. H), 7.52 (d, J = 8 Hz, 1 arom. H), 7.32 (dd, J = 8, 8 Hz, 1 arom. H), 7.23 (dd, J = 8, 8 Hz, 1 arom. H), 6.79 (d, J = 8.2 Hz, 1 arom. H), 6.64 (d, J = 8.2 Hz, 1 arom. H), 5.64 (s, H-C(5», 5.05 and 5.00 (2 d, J = 6.4, 6.4 Hz, OCH20), 3.32 (CH30).
Analysis calculated for C29H31NO5. 0.2 MeOH (479.98): C 73.07, H 6.68, N 2.92; found: C 72.94, H 6.60, N 2.92.
Example 14
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy- 14-methoxy-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound 14).
A solution of compound 13 (160 mg, 0.28 mmol) in MeOH (3 ml) and IN HCl (2 ml) was refluxed for 20 min, then cooled and kept in the refrigerator overnight. The crystals formed were isolated and washed with small amounts of MeOH and ether to yield 70 mg (36%) of compound 14. M. p. > 240° C.
!H NMR (DMSO-d6): 5 9.47 (s, OH), 9.17 (broad s, "NH), 7.61 (d, J = 8 Hz, 1 arom. H), 7.53 (d, J = 8 Hz, 1 arom. H), 7.36 (dd, J = 8, 8 Hz, 1 arom. H), 7.27 (dd, J = 8, 8 Hz, 1 arom. H), 6.72 (d, J = 8.4 Hz, 1 arom. H), 6.65 (d, J = 8.4 Hz, 1 arom. H), 5.90 (s, H-C(5)), 3.35 (s, CH3O).
Analysis calculated for C27H27NO4 x HCl. 1.5 H20 (493.00): C 65.78, H 6.34, N 2.84; found: C 65.89, H 6.20, N 2.85.
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
18
Example 15
Synthesis of 17-(Cyclopropylmethyl)-14-(2' -chlorobenzyloxy)-6,7-dehydro-4,5 a-epoxy-3 -(methoxymethoxy)-6,7-2' ,3' -(N-methoxymethylindolo)morphinan (compound 15).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 2 (327 mg, 0.65 mmol) in 5 ml of anhydrous N,N-dimethylformamide at 0° C. The resulting mixture was stirred at 0° C for 15 min and then at room temperature for another 30 min. After cooling to 0° C, 2-chlorobenzyl bromide (205 mg, 1 mmol) was added and stirring was continued first at 0° C for 15 min and then at room temperature for 3 h. Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 40 ml) and brine (2 x 30 ml), dried over Na2S04 and evaporated to give 370 mg of compound 15 as colorless foam which was pure by TLC and NMR.
!H NMR (CDC13): 5 7.56 (m, 1 arom. H), 7.44 (m, 1 arom. H), 7.37-7.17 (m, 3 arom. H), 7.01 (m, 1 arom. H), 6.91 (m, 1 arom. H), 6.83 (d, J = 8.2 Hz, 1 arom. H), 6.59 (d, J = 8.2 Hz, 1 arom. H), 5.90 (s, H-C(5)), 5.82 and 5.55 (2 d, J = 11.2, 11.2 Hz, NCH20), 5.13 and 5.03 (2 d, J = 6.4, 6.4 Hz, 0CH20), 4.98 and 4.56 (2 d, J = 13, 13 Hz, OCH2Ph), 3.40 and 3.26 (2 s, 2 CH30).
Example 16
Synthesis of 17-(Cyclopropylmethyl)-14-(2'-chlorobenzyloxy)-6,7-dehydro-4,5a-epoxy-3-hydroxy-6,7-2',3'-indolomorphinan Hydrochloride (compound 16).
A solution of compound 15 (300 mg, 0.48 mmol) in MeOH (5 ml) and IN HCl (3 ml) was refluxed for 1 h. After cooling, the solution was alkalized with conc. NH4OH, extracted with ethyl acetate (3 x 20 ml), the combined organic layers were washed with H20 (2 x 20 ml) and brine (20 ml), dried over Na2S04 and evaporated to give a colorless oil. To a solution of this foam in a small amount of methanol ethereal HCl was added, the crystals
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
19
formed collected and washed with cold methanol to yield 120 mg (43%) of compound 16. M. p. > 250° C (dec.).
JH NMR (DMSO-d6): 5 11.38 (s, NH), 9.38 (s, OH), 8.76 (broad s, ±NH), 7.34-6.85 (m, 8 arom. H), 6.72 (d, J = 8 Hz, 1 arom. H), 6.64 (d, J = 8 Hz, 1 arom. H), 5.93 (s, H-C(5)), 4.80 and 4.67 (2 d, J = 13, 13 Hz, OCH2Ph).
Analysis calculated for C33H31N2O3 x HCl. (575.54): C 68.87, H 5.60, N 4.87; found: C 68.81, H 5.59, H 4.77.
Example 17
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-3,14-dimethoxy-4,5a-epoxy-6,7-2',3'-benzo[b]furanomorphinan (compound 17).
Sodium hydride (144 mg, 6 mmol; obtained from 240 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of naltriben methane-sulfonate (500 mg, 0.97 mmol) in 10 ml of anhydrous N,N-dimethylformamide at 0° C. The resulting mixture was stirred at 0° C for 15 min and then at room temperature for another 30 min. After cooling to 0° C, dimethyl sulfate (380 (J.1, 4 mmol) was added and stirring was continued first at 0° C for 30 min and then at room temperature for 3 h. Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 40 ml), the combined organic layers were washed with H20 (2 x 30 ml) and brine (2 x 30 ml), dried over Na2S04 and evaporated to give a crystalline residue which was recrystallized from MeOH to afford 320 mg (74%) of compound 17. M. p. 221-224° C (dec.).
*H NMR (CDCI3): 5 7.47-7.14 (m, 4 arom. H), 6.64 (d, J = 8.4 Hz, 1 arom. H), 6.59 (d, J = 8.4 Hz, 1 arom. H), 5.62 (s, H-C(5)), 3.78 (s, CH30-C(3)), 3.31 (s, CH30-C(14)).
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
Analysis calculated for C28H29NO4. 0.3 MeOH (453.16): C 75.01, H 6.72, N 3.09; found: C 74.97, H 6.68, N 3.05.
Example 18
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5oc-epoxy-3-hydroxy-14-(3'-chlorobenzyloxy)-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound 19).
To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) in anhydrous N,N-dimethyl formamide (10 ml) was added sodium hydride (60% dispersion in oil, 60 mg, 1.5 mmol) at 0° C. The solution was stirred for 1 h at 20° C and then cooled to 0° C prior to addition of bromomethyl methyl ether (125 mg, 1.0 mmol). The mixture was warmed up to room temperature during 1 h and cooled again to 0° C before sodium hydride (60% dispersion in oil, 100 mg, 2.5 mmol) was added. After 1 h, 3-chlorobenzyl bromide (308 mg, 1.5 mmol) was added to the solution and the resulting mixture was stirred for 4 h at 20° C, and then 5 ml of methanol and 5 ml ethyl acetate were slowly added at 0° C, followed by addition of saturated aqueous NH4CI solution (20 ml). The mixture was extracted with ethyl acetate (3 x 50 ml), the combined organic layers were washed with brine, dried over MgSC>4, and evaporated to give crude 17-(cyclopropylmethyl)-6,7-dehydro-4,5ot-epoxy-3-(methoxymethoxy)-14-(3'-chlorobenzyloxy)-6,7-2\ 3'-benzo[b]furanomorphinan (compound 18). This crude product was dissolved in 5 ml of ethanol and 1.5 ml of IN hydrochloric acid and refluxed for 1 h. The reaction mixture was alkalized with IN aqueous NH4OH solution, extracted with ethyl acetate (3 x 50 ml), the combined organic layers were washed with brine, dried over MgSC>4, and concentrated to give a crude product which was purified by silica gel column chromatography (hexane: CHCI3 (75:25—>50:50->25:75100:0) ->CHCl3:AcOEt (80:20-»50:50->0:100) to afford the title compound as the free base (colorless oil; 232 mg, 86%). ^H NMR (CDCI3): 6 7.50-7.05 (m, 8 arom. H), 6.69 (d, J = 8.4 Hz, 1 arom. H), 6.58 (d, J = 8.4 Hz, 1 arom. H), 5.68 (s, H-C(5)), 4.81 and 4.35 (2 d, J = 11.6, 11.6 Hz, OCH2(3'-ClPh)). A solution of this free base in anhydrous diethyl ether (5 ml) was treated with HCl/ether solution (1M, 2 ml) at 0° C. Isolation of the precipitate provided the title compound 19 as a solid. M. p. >230° C
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
21
PCT/SE96/01497 _
(dec.). *H NMR (DMSO-d6): 5 9.40 (s, OH), 8.59 (broad s, +NH), 7.53-6.90 (m, 8 arom. H), 6.65 (s, 2 arom. H) 6.03 (s, H-C(5)), 4.74 and 4.62 (2 d, J = 13.6, 13.6 Hz, OCH2(3'-C1PH)). Analysis calculated for C33H30CINO4. HCl. 1.5 H20: C 65.67, H 5.68, N 2.32; found: C 65.31, H 5.37, N 2.33.
Example 19
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-l4-(2'-chlorobenzyloxy)-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound 21).
To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) in anhydrous N,N-dimethyl formamide (10 ml) was added sodium hydride (60% dispersion in oil, 100 mg, 2.5 mmol) at 0° C. The solution was stirred for 1 h at 20° C and then cooled to 0° C prior to addition of bromomethyl methyl ether (125 mg, 1.0 mmol). The mixture was warmed up to room temperature during 1 h and cooled again to 0° C before sodium hydride (60% dispersion in oil, 100 mg, 2.5 mmol) was added. After 1 h, 2-chlorobenzyl bromide (205 mg, 1.0 mmol) was added to the solution and the resulting mixture was stirred for 12 h at 20° C, and then 5 ml of methanol and 5 ml ethyl acetate were slowly added at 0° C, followed by addition of saturated aqueous NH4CI solution (20 ml). The mixture was extracted with ethyl acetate (3 x 50 ml), the combined organic layers were washed with brine, dried over MgS04, and concentrated to give crude 17-(cyclopropylmethyl)-'6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-14-(2'-chlorobenzyloxy)-6,7-2', 3'-benzo[b]furanomorphinan (compound 20). This crude product was dissolved in 5 ml of ethanol and 2 ml of IN hydrochloric acid and refluxed for 2 h. The reaction mixture was alkalized with IN aqueous NH4OH solution, extracted with ethyl acetate (3 x 50 ml), the combined organic layers were washed with brine, dried over MgS04, and evaporated to give a crude product which was purified by silica gel column chromatography (hexane: CHCI3 (75:25—>50:50—>25:75—>100:0) to afford the title compound as the free base (colorless oil; 236 mg, 87%). *H NMR (CDCI3): 5 7.45-6.90 (m, 8 arom. H), 6.72 (d, J = 8.4 Hz, 1 arom. H), 6.68 (d, J = 8.4 Hz, 1 arom. H), 5.72 (s, H-C(5)), 4.96 and 4.55 (2 d, J = 11.6, 11.6 Hz, OCH2(2'-ClPh)). A solution of this free base in (5 ml) of anhydrous
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
PCT/SE96/01497 _
22
diethyl ether was treated with HCl/ether solution (1M, 2 ml) at 0° C. Isolation of the precipitate provided the title compound as a solid. M. p. >220° C.
]H NMR (DMSO-d6): 5 9.40 (s, OH), 8.59 (broad s, "NH), 7.56-6.90 (m, 8 arom. H), 6.66 (s, 2 arom. H) 6.03 (s, H-C(5)), 4.74 (s, OCH2(2'-ClPh)).
Analysis calculated for C33H30CINO4 x HCl. 1.5 H20: C 65.67, H 5.68, N 2.32; found: C 65.72, H 5.48, N 2.25.
Example 20
Synthesis of 14-Allyloxy-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-l allyl-6,7-2',3'-indolomorphinan Hydrochloride (compound 22).
Dimethyl isobutylsilyl chloride (114 mg, 0.75 mmol) was added at 0° C to a stirred solution of naltrindole methanesulfonate (255 mg, 0.5 mmol) and diisopropyl ethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide (10 ml). The resulting solution was stirred at 20° C for 1 h and then cooled to 0° C prior to the addition of sodium hydride (60% dispersion in oil, 120 mg, 3.0 mmol). After 1 h, dimethyl isobutylsilyl chloride (114 mg, 0.75 mmol) was added to the mixture. The resulting mixture was stirred for 1 h at 20° C and then cooled to 0° C before adding sodium hydride (60% dispersion in oil, 120 mg, 3.00 mmol). After 1 h allyl bromide (1.51 mg, 1.25 mmol) was added. The reaction mixture was stirred for 2 h at 20° C and then quenched with saturated aqueous NH4CI solution and extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with brine, dried over MgS04, and evaporated to give a yellow oil which was dissolved in methanol (6 ml) and 1 N hydrochloric acid (2 ml) and refluxed for 6 h. The reaction mixture was alkalized with IN NH4OH solution, extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with brine, dried over MgS04, and evaporated. This crude product was purified by silica gel column chromatography (hexane: CHCI3 (75:25—>50:50) —>CHCl3:AcOEt—> (75:25—>50:50—>AcOEt) to give the title compound as the free base (colorless oil; 106 mg).
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
WO 98/22467 PCT/SE96/01497 _
23
*H NMR (CDCI3): 5 7.40 (d, J = 8.4 Hz, 1 arom. H), 7.24 (m, 1 arom. H), 7.15 (m, 1 arom. H), 7.03 (m, 1 arom. H), 6.57 (d, J = 8.4 Hz, 1 arom. H), 6.50 (d,J = 8.4 Hz, 1 arom. H), 6.08 (m, 1 olef. H), 5.76 (m, 1 olef. H), 5.72 (s, H-C(5)), 5.15-4.75 (m, 6 H, CH2N, 2 CH2 = C), 4.24 and 3.92 (2 dd, J = 12.4,4.8 Hz, CH20).
The free base was dissolved in diethyl ether (5 ml) and treated with HCl/ether solution (1M, 2 ml) at 0° C. Isolation of the precipitate provided the title compound 22 as a solid.
Example 21
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-aIlyloxy-6,7,2',3'-indolomorphinan Hydrochloride (compound 23)
To a stirred solution of naltrindole hydrochloride (220 mg, 0.5 mmol) in anhydrous N,N-dimethyl formamide (10 ml) was added sodium hydride (60% dispersion in oil, 160 mg, 4.0 mmol) at 0°C. The solution was stirred for 1 h at 20° C, and then cooled to 0° C prior to addition of bromomethyl methyl ether (250 mg, 2.0 mmol). The mixture was warmed up to r.t. during one hour and cooled again to 0° C before sodium hydride (60%, 100 mg, 2.5 mmol) was added. After 1 h allyl bromide (242 mg, 2.0 mmol) was added to the solution and the resulting mixture was stirred for 4 h at 20° C, and then 5 ml methanol and 5 ml ethyl acetate were slowly added at 0° C, followed by addition of saturated aqueous NH4CI solution (20 ml). The mixture was extracted with ethyl acetate (3x50 ml), the combined organic layers were washed with brine, dried over MgSC>4, and evaporated to give crude product, which was dissolved in 5 ml ethanol/1 ml 6N hydrochloric acid and refluxed for 2 hrs. The reaction mixture was alkalized with IN aqueous NH4OH solution, extracted with ethyl acetate (3.50 ml), the combined organic layers were washed with brine, dried over MgS04, and concentrated to give a crude product, which was purified by silica gel column chromatography (Hexane: CHCI3 (75:25—>50:50—>25:75—>0:100) —>CHCl3i AcOEt (75:25—>50:50—>0:100)) to afford compound 23 (53 mg, 23%) as the free base (colorless
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
PCT/SE96/01497 _
24
oil). NMR (CDCI3): 8 7.50-7.00 (m, 4 arom. H), 6.65-6.45 (m, 2 arom. H), 5.80 (m, 1H, CH=C), 5.75 (s, H-C(5)), 5.18-4.85 (m, C=CH2), 4.25 & 3.95 (m, OCH2).
A solution of this free base (53 mg) in anhydrous ethyl ether (5 ml) was treated with HCl/ether solution (1M, 1 ml) at 0° C. Isolation of the precipitate provided the title compound 23 as a solid (hydrochloride salt). M.p. 270-285° C (dec.). IR (HCl salt, KBr) 3087 (m), 2846 (m), 1623 (s), 1505 (s), 1462 (s), 1330 (s), 1166 (s), 922 (s) cm"1.
Example 22
Synthesis of 17-Cyclopropylmethyl-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-benzyloxy-6,7,2\3'-benzo[b]foranomorphinan Hydrochloride (compound 24):
To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) and N,N-diisopropylethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide (10 ml) was added triisopropylsilyl chloride (145 mg, 0.75 mmol) at 0°C. The solution was stirred for 1 h at 20° C, and then cooled to 0° C prior to addition of sodium hydride (60%, 120 mg, 3.0 mmol) was added. After 1 h, benzyl bromide (171 mg, 1.0 mmol) was dropwise added to the solution. The resulting mixture was stirred for 2 h at 20° C, and then 5 ml methanol and 5 ml ethyl acetate were slowly added at 0° C. After 30 min the mixture was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgSC>4, and concentrated to a yellow oil, which was purified by silica gel column chromatography (Hexane: CHCI3 (75:25—>60:40)—>Hexane: AcOEt (75:25-»50:50)) to afford compound 24 (206 mg, 82%) as the free base (colorless oil). *H NMR (CDCI3): 87.60-7.05 (m, 9 arom. H), 6.80-6.60 (m, 2 arom. H), 5.72 (s, H-C(5)), 4.95 and 4.52 (2 d, 1=11.6,11.6 Hz, OCH2Ph).
A solution of this free base in anhydrous ethyl ether (5 ml) was treated with HCl/ether solution (1M, 1 ml) at 0° C. Isolation of the precipitate provided the title compound 24 as a solid (hydrochloride salt). M.p. 255-270° C (dec.). IR (HCl salt, KBr) 3642 (m), 3174 (s), 2936 (s), 1616 (s), 1500 (s), 1457 (s), 1309 (s), 1068 (s), 932 (s) cm"1. Analysis calculated
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
PCT/SE96/01497 _
for C33H31NO4. HCl. 0.80 H20: C 71.23, H 6.09, N, 2.52. Found: C 71.32, H 5.78, N 2.35.
Example 23
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-allyloxy-6,7,2',3'-benzo[b]foranomoiphinan Hydrochloride (compound 25)
To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) and N,N-diisopropylethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide (10 ml) was added triisopropylsilyl chloride (145 mg, 0.75 mmol) at 0°C. The solution was stirred for 1 h at 20° C, and then cooled to 0° C prior to addition of sodium hydride (60%, 120 mg, 3.0 mmol) was added. After 1 h, allyl bromide (363 mg, 3.0 mmol) was dropwise added to the solution. The resulting mixture was stirred for 2 h at 20° C, and then 5 ml methanol and 5 ml ethyl acetate were slowly added at 0° C. After 30 min the mixture was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgSC>4, and concentrated to a yellow oil, which was dissolved in MgSC>4, and concentrated to a yellow oil, which was dissolved in 10 ml ethanol/2.0 ml IN hydrochloric acid and refluxed for 5 hrs. The reaction mixture was alkalized with IN aqueous NH4OH solution, extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgSC>4, and concentrated to give a crude product, which was purified by silica gel column chromatography (Hexane: CHCI3 (75:25—>50:50)—>CHCl3: AcOEt (75:25—>50:50—>AcOEt)) to afford compound 25 (106 mg, 46%) as the free base (colorless oil), 'h NMR (CDCI3): 5 7.50-7.08 (m, 4 arom. H), 6.70-6.45 (m, 2 arom. H), 5.75 (m, 1H, CH=C) 5.65 (s, H-C(5)), 5.18-4.82 (m, 2H), 4.81 (br s, OH), 4.25 and 3.90 (m, OCH2).
A solution of this free base in anhydrous ethyl ether (5 ml) was treated with HCl/ether solution (1M, 1 ml) at 0° C. Isolation of the precipitate provided the title compound 25 as a solid (hydrochloride salt). M.p. 280-290° C (dec.). IR (HCl salt, KBr) 3642 (m), 2948 (s),
SUBSTITUTE SHEET (RULE 26)
Printed from Mimosa
Claims (15)
1. A process for the preparation of a compound of the formula (I) Ra (D wherein Rl represents allyl, cyclopropylmethyl or methyl; R2 represents C\-C(, alkoxy, Cj-Cg alkenyloxy, C7-C16 arylalkyloxy wherein aryl is Cg-Cjo aryl and alkyloxy is Cj-Cg alkyloxy, C7-C16 arylalkenyloxy wherein aryl is Cg-Cjo aryl and alkenyloxy is Cj-Cg alkenyloxy, Cj-Cg alkanoyloxy, C7-C16 arylalkanoyloxy wherein aryl is C^-Cio aryl and alkanoyloxy is C| -C^ alkanoyloxy; R3 represents hydroxy, C\-C(, alkoxy, C7-C16 arylalkyloxy wherein aryl is C^-Cjo aryl and alkyloxy is Cj-C6 alkyloxy, Ci-Cg alkenyloxy, Q-Cfc alkanoyloxy, C7-C16 arylalkanoyloxy wherein the aryl is Cg-Cio aryl and the alkanoyloxy is Ci-Cf, alkanoyloxy, C2-Cio alkyloxyalkoxy wherein alkyloxy is Q-C4 alkyloxy and alkoxy is Cj-Cg alkoxy; and X represents O, NH or NR4 wherein R4 is C]-Q alkoxy, Cj-Cg alkenyloxy, C7-C16 arylalkyloxy wherein aryl is C6-C10 aryl and alkyloxy is C)-C6 alkyloxy, C7-C16 arylalkenyloxy wherein the aryl is Cg-Cio aryl and alkenyloxy is Cj-Cg alkenyloxy, C1-Q5 alkanoyloxy, C7-C16 arylalkanoyloxy wherein aryl is Cfi-Cjo aryl and alkanoyoloxy is C\-C(, alkanoyloxy; SUBSTITUTE SHEET (RULE 26) Printed from Mimosa WO 98/22467 PCT/SE96/01497 - 28 comprising the following steps: (i) naloxone (II), naltrexone (III) or oxymorphone (Ilia) of the formula (II): R = allyl (III): R = cyclopropylmethyl (Ilia): R = methyl is reacted with phenylhydrazine hydrochloride in the presence of acid, giving naloxindole (NLI), naltrindole (NTI) or oxymorphindole (OMI), of the formula NLI: R = allyl, X = NH NTI: R = cyclopropylmethyl, X = NH OMI: R = methyl, X = NH or naloxone (II), naltrexone (III) or oxymorphone (Ilia) is reacted with O-phenyl-hydroxyl amine hydrochloride in the presence of acid, giving the benzofurane derivatives NLB, naltriben (NTB) or OMB of the formula SUBSTITUTE SHEET (RULE 26) Printed from Mimosa WO 98/22467 PCT/SE96/01497 - 29 HC OMB: R = methyl, X = O NLB: R = allyl, X = O NTB: R = cyclopropylmethyl, X = O (ii) the 3-hydroxy group is protected by alkylation with benzyl bromide, methoxymethyl bromide, ethoxymethyl bromide, trityl chloride, or a silylating agent, in the presence of a solvent and a base, giving a compound of the formula (IV) wherein R[ is allyl, cyclopropylmethyl or methyl; R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl; and X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl or N-silyl; (iii) the compound of the formula (IV) is treated with C1-C2 dialkyl sulfates, C]-Cg alkyl halides, Cj-Cg alkenyl halides, C7-C16 aralkyl halides wherein the aryl is Cg-Cjo aryl and the alkyl is Cj-Cg alkyl, C7-C16 arylalkenyl halides wherein the aryl is Cfi-CjQ aryl and the alkenyl is C2-C6 alkenyl, C2-C6 alkanoyl halides, or C7-C16 arylalkanoyl halides wherein the aryl is Cg-Cio aryl and the alkanoyl is C2-C6 alkanoyl, in a solvent, preferably N,N- R2C (IV) SUBSTITUTE SHEET (RULE 26) Printed from Mimosa WO 98/22467 PCT/SE96/01497 - 30 dimethyl formamide or tetrahydrofurane, using a base, giving a compound of the formula wherein Rj is allyl, cyclopropylmethyl or methyl; R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl; and R3 is C\-Cf, alkyl, Cj-C6 alkenyl; C7-C16 arylalkyl wherein the aryl is Cg-Cjo aryl and the alkyl is C]-C6 alkyl; C7-C16 arylalkenyl wherein the aryl Cg-Cjo aryl and the alkenyl is Cj-Cg alkenyl; Cj-Cg alkanoyl, C7-C16 arylalkanoyl wherein the aryl is Cg-Cjo aryl and the alkyl is Ci-Cg alkyl; X is as defined in the formula (IV) above; and optionally the following step (iv) whereby (iv) the compound of the formula (V) wherein X is as defined in formula (IV) above, is hydrolized in diluted acids, optionally in the presence of a solvent, giving a compound of the formula (VI) (V) <r < PR3 (v) r2o SUBSTITUTE SHEET (RULE 26) Printed from Mimosa WO 98/22467 PCT/SE96/01497 _ 31 (v) the compound of the formula (VI) is alkylated or acylated, giving a compound of the formula (I).
2. A process according to claim 1, wherein Rj is allyl or cyclopropylmethyl; R2 is C]-C6 alkoxy, Cj-Cg alkenyloxy, C7-C16 arylalkyloxy, C7-C16 arylalkenyloxy; R3 is hydroxy, C]-C6 alkoxy, Cj-C6 alkanoyloxy.
3. A process according to claim 1, whereby the acid used in step (i) is selected from methanesulfonic acid, sulfuric acid and hydrochloric acid.
4. A process according to claim 1, whereby the protection of the 3-hydroxy group in step (ii) is performed by alkylation with dimethyl isobutyl-silyl chloride, trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride and tri-i-propylsilyl chloride.
5. A process according to claim 1, whereby the solvent in step (ii) is selected from N,N-dimethylformamide, dichloromethane and tetrahydrofurane.
6. A process according to claim 1, whereby the base in step (ii) is selected from potassium carbonate, potassium hydroxide, sodium hydride, sodium amide and diisopropyl ethylamine. SUBSTITUTE SHEET (RULE 26) Printed from Mimosa WO 98/22467 PCT/S /01497 _ * sT*. n - ' 'i 32 T T
7. A process according to claim 1, whereby the solvent in step (iii) is selected from N,N-dimethylformamide and tetrahydrofurane.
8. A process according to claim 1, whereby the strong base in step (iii) is selected from sodium hydride, potassium hydride and sodium amide.
9. A process according to claim 1, whereby the diluted acid in step (iv) is hydrochloric acid or sulfuric acid.
10. A process according to claim 1, whereby step (iv) is performed in the presence of a solvent.
11. A process according to claim 10, whereby the solvent is an alcohol.
12. A process according to claim 11, whereby the solvent is selected from methanol, ethanol and propanol.
13. A compound according to formula (I) produced by the process of claim 1. substitute sheet (rule 26) 1 PCT/SE96 /O 1 4 0 2 "12-1998 AMENDED CLAIMS:
14. A compound according tcTformula (IV) wherein 10 R1 is allyl, cyclopropylmethyl or methyl; R2 is benzyl, methoxymethyl, ethoxymethyl, trityl, silyl, dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and 15 X is NH, 0, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl, N-silyl, dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and with the proviso that: 20 (i) when R| is cyclopropylmethyl and R2 is methoxymethyl, X is not 0 or N-methoxymethyl. December 2, 1998/HE amended sheet PCT/SE9 6 / O 1 4 5 7 2 0 2 -12-1998
15. A compound according to the formula (V) R2C (V) wherein Rj is allyl or cyclopropylmethyl; R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl; and r3 is C[-C6 alkyl, Cj-Q alkenyl; C7-C16 arylalkyl wherein the aryl is Q-Cjo aryl and the alkyl is Cj-Cg alkyl; C7-C16 arylalkenyl wherein the aryl Q-Cjq aryl and the alkenyl is Cj-C6 alkenyl; C|-C6 alkanoyl, C7-C16 arylalkanoyl wherein the aryl is Q-Cjo aryl and the alkyl is C1-C6 alkyl; X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl, N-silyl, dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and with the proviso that: (j) when R\ is cyclopropylmethyl, R2 is methoxymethyl and r3 is methyl, X is not 0. ■0*- December 2, 1998 / EE amended sheet 35 A process according to claim 1 substantially as herein described or exemplified. A compound according to claim 13 substantially as herein described or exemplified A compound according to claim 14 substantially as herein described or exemplified A compound according to claim 15 substantially as herein described or exemplified
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ335212A NZ335212A (en) | 1996-11-19 | 1996-11-19 | Process for the preparation of 14- alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinans |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ335212A NZ335212A (en) | 1996-11-19 | 1996-11-19 | Process for the preparation of 14- alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinans |
| PCT/SE1996/001497 WO1998022467A1 (en) | 1996-11-19 | 1996-11-19 | New process for the preparation of morphinans |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ335212A true NZ335212A (en) | 2003-12-19 |
Family
ID=34797899
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ335212A NZ335212A (en) | 1996-11-19 | 1996-11-19 | Process for the preparation of 14- alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinans |
Country Status (1)
| Country | Link |
|---|---|
| NZ (1) | NZ335212A (en) |
-
1996
- 1996-11-19 NZ NZ335212A patent/NZ335212A/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8252808B2 (en) | Process and compounds for the production of (+)opiates | |
| US4089855A (en) | Process for the stereoselective reduction of 6- and 8-keto morphine and morphinan derivatives with formamidinesulfinic acid and compounds obtained thereby | |
| EP1562953B1 (en) | Process for the preparation of quaternary n-alkyl morphinan alkaloid salts | |
| ES2540534T3 (en) | Procedure for the preparation of quaternary salts of N-alkyl morphinan alkaloids | |
| EP0759922B1 (en) | New antagonist compounds | |
| US8853401B2 (en) | Processes for the preparation of morphinane and morphinone compounds | |
| US20040082526A1 (en) | Macrolide antibiotics | |
| NO171209B (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE MORPHINAN ESTERS | |
| US4161597A (en) | N-alkyl-14-hydroxymorphinans and derivatives | |
| JP4879740B2 (en) | Synthetic methods of morphinan compounds and intermediates thereof | |
| RU2297419C2 (en) | Derivative of 14-hydroxynjrmorphinone, derivative of morphinone, derivative of morphine, methods for preparing derivative of 14-hydroxynormorphinone, derivative of morphinone, noroxymorphone | |
| CA2319627A1 (en) | Therapeutic compounds | |
| PL125548B1 (en) | Process for preparing novel derivatives of acylated homotaurine | |
| AU1402497A (en) | New process for the preparation of morphinans | |
| NZ335212A (en) | Process for the preparation of 14- alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinans | |
| US5994327A (en) | Process for the preparation of morphinans | |
| FI81583B (en) | FOERFARANDE FOER N-DEMETYLERING AV MORFINANALKALOIDER. | |
| MXPA06013128A (en) | Use of opioid receptor antagonist compounds for the prevention and/or treatment of diseases associated with the target calcineurin. | |
| KR20140047609A (en) | Process for the preparation of morphine analogs via metal catalyzed n-demethylation/functionalization and intramolecular group transfer | |
| EP2019105A1 (en) | Process for the preparation of quaternary n-alkyl morphine or morphinane alkaloid derivatives | |
| WO2012013671A1 (en) | Processes for the production of 14 - oxygenated morphinan - 6 - ones | |
| Schmidhammer et al. | Synthesis and biological evaluation of 14‐alkoxymorphinans. Part 7. 14, 14′‐dimethoxy analogues of norbinaltorphimine: Synthesis and determination of their χ opioid antagonist selectivity | |
| AU757975B2 (en) | Therapeutic compounds | |
| CA2189140C (en) | New antagonist compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PSEA | Patent sealed |