JP5219368B2 - (1r,2s,5s)−3−アザビシクロ[3,1,0]ヘキサン−2−カルボキサミド,n−[3−アミノ−1−(シクロブチルメチル)−2,3−ジオキソプロピル]]−3−[(2s)−2−[[[1,1−ジメチルエチル]アミノ]カルボニルアミノ]−3,3−ジメチル−1−オキソブチル]−6,6−ジメチルの調製のためのプロセスおよび中間体 - Google Patents
(1r,2s,5s)−3−アザビシクロ[3,1,0]ヘキサン−2−カルボキサミド,n−[3−アミノ−1−(シクロブチルメチル)−2,3−ジオキソプロピル]]−3−[(2s)−2−[[[1,1−ジメチルエチル]アミノ]カルボニルアミノ]−3,3−ジメチル−1−オキソブチル]−6,6−ジメチルの調製のためのプロセスおよび中間体 Download PDFInfo
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- JP5219368B2 JP5219368B2 JP2006517263A JP2006517263A JP5219368B2 JP 5219368 B2 JP5219368 B2 JP 5219368B2 JP 2006517263 A JP2006517263 A JP 2006517263A JP 2006517263 A JP2006517263 A JP 2006517263A JP 5219368 B2 JP5219368 B2 JP 5219368B2
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- carbamate
- acid
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- 238000000034 method Methods 0.000 title claims description 53
- 230000008569 process Effects 0.000 title claims description 16
- 239000000543 intermediate Substances 0.000 title description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 title description 3
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 title description 3
- 238000002360 preparation method Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 89
- -1 H 2 SO 4 Inorganic materials 0.000 claims description 65
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 23
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 20
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 238000005859 coupling reaction Methods 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 230000008878 coupling Effects 0.000 claims description 10
- 238000010168 coupling process Methods 0.000 claims description 10
- 229910052751 metal Inorganic materials 0.000 claims description 10
- 239000002184 metal Substances 0.000 claims description 10
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 10
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 230000003647 oxidation Effects 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 5
- 230000000996 additive effect Effects 0.000 claims description 5
- 150000008064 anhydrides Chemical class 0.000 claims description 5
- 150000001718 carbodiimides Chemical class 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 4
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- 239000012190 activator Substances 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 4
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 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 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- UCZSGRLQZLKLCQ-UHFFFAOYSA-N 2-phenylpropan-2-yl carbamate Chemical compound NC(=O)OC(C)(C)C1=CC=CC=C1 UCZSGRLQZLKLCQ-UHFFFAOYSA-N 0.000 claims description 3
- QWYTUBPAXJYCTH-UHFFFAOYSA-N 2-trimethylsilylethyl carbamate Chemical compound C[Si](C)(C)CCOC(N)=O QWYTUBPAXJYCTH-UHFFFAOYSA-N 0.000 claims description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 230000003213 activating effect Effects 0.000 claims description 3
- DQEFBVRIBYYPLE-UHFFFAOYSA-N anthracen-9-ylmethyl carbamate Chemical compound C1=CC=C2C(COC(=O)N)=C(C=CC=C3)C3=CC2=C1 DQEFBVRIBYYPLE-UHFFFAOYSA-N 0.000 claims description 3
- DUXANUSOCMOJSI-UHFFFAOYSA-N benzhydryl carbamate Chemical compound C=1C=CC=CC=1C(OC(=O)N)C1=CC=CC=C1 DUXANUSOCMOJSI-UHFFFAOYSA-N 0.000 claims description 3
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 claims description 3
- LWABFMLTBBNLTA-UHFFFAOYSA-N cyclobutyl carbamate Chemical compound NC(=O)OC1CCC1 LWABFMLTBBNLTA-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 150000004714 phosphonium salts Chemical class 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- OCAAZRFBJBEVPS-UHFFFAOYSA-N prop-2-enyl carbamate Chemical compound NC(=O)OCC=C OCAAZRFBJBEVPS-UHFFFAOYSA-N 0.000 claims description 3
- FLCPORVHXQFBHT-UHFFFAOYSA-N quinolin-8-yl carbamate Chemical compound C1=CN=C2C(OC(=O)N)=CC=CC2=C1 FLCPORVHXQFBHT-UHFFFAOYSA-N 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 claims description 3
- LVLANIHJQRZTPY-UHFFFAOYSA-N vinyl carbamate Chemical compound NC(=O)OC=C LVLANIHJQRZTPY-UHFFFAOYSA-N 0.000 claims description 3
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 2
- BHUXAQIVYLDUQV-UHFFFAOYSA-N 1-(diethylamino)propan-2-ol Chemical compound CCN(CC)CC(C)O BHUXAQIVYLDUQV-UHFFFAOYSA-N 0.000 claims description 2
- UCYJVNBJCIZMTJ-UHFFFAOYSA-N 1-(ethylamino)propan-2-ol Chemical compound CCNCC(C)O UCYJVNBJCIZMTJ-UHFFFAOYSA-N 0.000 claims description 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 2
- OZGSEIVTQLXWRO-UHFFFAOYSA-N 2,4,6-trichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=C(Cl)C=C1Cl OZGSEIVTQLXWRO-UHFFFAOYSA-N 0.000 claims description 2
- HVHZEKKZMFRULH-UHFFFAOYSA-N 2,6-ditert-butyl-4-methylpyridine Chemical compound CC1=CC(C(C)(C)C)=NC(C(C)(C)C)=C1 HVHZEKKZMFRULH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- UBARRNXCKBFUEN-UHFFFAOYSA-N 4,5-diphenyl-5h-1,3-oxazol-2-one Chemical compound N=1C(=O)OC(C=2C=CC=CC=2)C=1C1=CC=CC=C1 UBARRNXCKBFUEN-UHFFFAOYSA-N 0.000 claims description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 claims description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- 241000872931 Myoporum sandwicense Species 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 2
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 claims description 2
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 2
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 2
- 150000004692 metal hydroxides Chemical class 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- MXHTZQSKTCCMFG-UHFFFAOYSA-N n,n-dibenzyl-1-phenylmethanamine Chemical compound C=1C=CC=CC=1CN(CC=1C=CC=CC=1)CC1=CC=CC=C1 MXHTZQSKTCCMFG-UHFFFAOYSA-N 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 2
- AMMGCGVWJMRTQI-UHFFFAOYSA-N prop-1-en-2-yl carbonochloridate Chemical compound CC(=C)OC(Cl)=O AMMGCGVWJMRTQI-UHFFFAOYSA-N 0.000 claims description 2
- 229910001927 ruthenium tetroxide Inorganic materials 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 2
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 claims 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 claims 2
- 150000003141 primary amines Chemical class 0.000 claims 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- LXKLUWFIBVXFGX-QPJJXVBHSA-N [(e)-3-phenylprop-2-enyl] carbamate Chemical compound NC(=O)OC\C=C\C1=CC=CC=C1 LXKLUWFIBVXFGX-QPJJXVBHSA-N 0.000 claims 1
- HUXULLJDEXUMOP-UHFFFAOYSA-N carbamimidoyl fluoride Chemical compound NC(F)=N HUXULLJDEXUMOP-UHFFFAOYSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 claims 1
- DWYMPOCYEZONEA-UHFFFAOYSA-L fluoridophosphate Chemical compound [O-]P([O-])(F)=O DWYMPOCYEZONEA-UHFFFAOYSA-L 0.000 claims 1
- 239000007800 oxidant agent Substances 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 125000006413 ring segment Chemical group 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 125000003342 alkenyl group Chemical group 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 239000001301 oxygen Substances 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 125000004434 sulfur atom Chemical group 0.000 description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000002877 alkyl aryl group Chemical group 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
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- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 4
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Virology (AREA)
- Genetics & Genomics (AREA)
- Crystallography & Structural Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本出願は、2003年7月17日に出願された米国仮特許出願番号60/479,517からの優先権の利益を主張する。
本発明は、以下の式I:
(1R,2S,5S)−3−アザビシクロ[3,1,0]ヘキサン−2−カルボキサミド,N−[3−アミノ−1−(シクロブチルメチル)−2,3−ジオキソプロピル]−3−[(2S)−2−[[[1,1−ジメチルエチル]アミノ]カルボニルアミノ]−3,3−ジメチル−1−オキソブチル]−6,6−ジメチルは、2001年7月19日に出願された米国特許出願番号09/908,955および2002年1月18日に出願された米国特許出願番号10/052,386(各々が参考として本明細書中に援用される)に開示されている。
1つの実施形態において、本願は、式Iの化合物
(1)式IIの化合物を式IIIの化合物とカップリングさせて、式IVの化合物を得る工程
(2)式Vの化合物のヒドロキシル基を酸化して、式VIの化合物を得る工程
上記および本明細書中全体にわたって使用される場合、以下の用語は、特に示されない限り、以下の意味を有すると理解されるべきである。
式IIの化合物を、適切な溶媒中で式IIIの化合物とカップリングさせ、式IVの化合物を得、ここで、RおよびZは上で定義された通りである。
式Vの化合物を適切な溶媒中で酸化して、式VIの化合物を形成する。化合物Vの調製は、本願と同日に出願された同時係属中の特許出願CD06068US01(2003年6月17日に出願された、仮出願番号60/479487に基づく)に開示される。簡単には、化合物Vの調製は、以下のスキームに表される:
工程2からの式VIの化合物を適切な溶媒中で酸を使用して脱保護して、式VIIの化合物を生じる。工程3の反応は、約0℃〜約80℃の範囲、好ましくは、約10℃〜約50℃の範囲、より好ましくは約15℃〜約30℃の範囲の温度で実施され得る。工程3において使用され得る酸の非限定的な例としては、無機塩(好ましくは、H3PO4、H2SO4、HClおよびHBr、より好ましくは、HCl)が挙げられる。適切な溶媒の非限定的な例としては、2−イソプロパノール、メタノール、エタノール、アセトニトリル、THF、トルエン、EtOAc、iPrOAc、DMFおよびNMPが挙げられる。工程3の反応は、約20℃〜約90℃の範囲、好ましくは、約30℃〜約60℃の範囲、より好ましくは、約40℃〜約50℃の範囲の温度で、約4時間もしくは反応が完了するまで実施され得る。式VIIの化合物は、好ましくは、結晶化により精製される。
式IVの化合物を適切な溶媒中で酸を用いて処理し、式VIIIの化合物を生じる。適切な酸の非限定的な例としては、任意の有機塩もしくは無機塩、好ましくは、無機塩(例えば、H3PO4、H2SO4、HClおよびHBr、より好ましくは、HCl)が挙げられる。適切な溶媒の非限定的な例としては、水混和性溶媒、好ましくは、EtOAcもしくはMTBE、メチレンクロライドまたはイソプロピル酢酸、より好ましくは、EtOAcもしくはMTBEが挙げられる。
式VIIの化合物を、適切な溶媒中で式VIIIの化合物とカップリングさせて、式Iの化合物を生じる。このペプチドカップリングにおいて使用される代表的な方法は、工程1において上で議論したものと同じである。好ましい活性化試薬は、EDClであり、好ましい添加物は、HOBtであり、好ましい塩基は、N−メチルモルホリンであり、そして、好ましい溶媒は、メチルtert−ブチルエーテル(MTBE)であり、これら3つ全ては、例えば、アセトニトリルのような溶媒中にある。より好ましくは、工程5のカップリング工程は、活性化試薬としてイソブチルクロロホルメートを用いる混合無水物手順である。
MHz=メガヘルツ
NMR=核磁気共鳴分光法
DMSO=ジメチルスルホキシド
EDCl=1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩
MTBE=メチルtert−ブチルエーテル
NMM=N−メチルモルホリン
Equiv=当量
IPA=イソプロピルアルコール
(工程1)
1.0当量の式IIの化合物を容器Aに充填し、その後、温度を20℃と30℃との間に維持しながら、3容量のアセトニトリルおよび2.25当量の2,6−ルチジンを充填した。次いで、2.0当量の式IIIの化合物、0.5当量の1−ヒドロキシベンゾトリアゾール水和物、1.2当量のEDCl塩酸塩および4容量のアセトニトリルを、10℃と20℃との間で、容器Bに充填した。次いで、式IIの化合物を含有する溶液を、式IIIの化合物を含有するスラリーに直ぐに添加した。反応は、約3〜5時間で完了した。
1H−NMR(400MHz,CD3OD):δ7.45(m,5H),4.92(s,ブロード,5H),4.39(q,3H),4.33(dd,1H),4.28(s,1H),4.03(d,1H),3.96(dd,1H),1.63(d,3H),1.45(m,2H),1.28(s,9H),1.05(s,3H),1.04(s,9H),0.91(s,3H);13C−NMR(100.6MHz,CD3OD):δ179.3,173.3,160.1,140.7,130.6,130.4,128.0,63.9,59.2,52.6,51.1,49.3,36.4,33.3,30.1,28.8,27.5,27.2,21.5,20.5,13.6。
1当量の式Vの化合物の撹拌混合物に、4容量のイソプロパノールを充填し、そして6容量の酢酸エチル中の2.5当量のEDClを2容量のメチルスルホキシドに添加した。次いで、この混合物を−5℃まで冷却した。この冷却した混合物に、約1.5当量のジクロロ酢酸を約1時間にわたってゆっくり添加した。添加した後、この混合物を−5℃にて約21時間撹拌し、水(5容量)を添加した。次いで、この混合物を20℃まで暖めた。分離した後、この水層を酢酸エチル(3容量)で抽出した。合せた有機層を水(5容量)で洗浄した。有機層中の酢酸エチルを、蒸留によりヘプタンで置き換えた。溶媒を置き換えた後、この混合物を20℃にて2時間撹拌して、濾過した。湿ったケーキを、ヘプタン(2.5容量を2回)で洗浄し、40℃にて12時間、乾燥して、80%モル収率の式VIの化合物を生じた。
1H NMR(DMSO):δ8.00(s,1H),7.72(s,1H),7.20-7.08(m,1H),4.75-4.62(m,1H),3.35(s,1H),2.48-2.30(m,1H),2.10-1.48(m,8H),1.41-1.22(m,9H)。
1当量の式VIの化合物および6容量のイソプロピルアルコールの撹拌混合物に、イソプロパノール中の2容量の5〜6N HClを添加した。このバッチを、40〜50℃で約4時間加熱し、反応の完了についてサンプル採取した。この混合物を約2容量まで濃縮し、25〜35℃まで冷却した。次いで、10容量のメチルtert−ブチルエーテルを充填し、このバッチを0〜5℃まで冷却した。1時間後、この沈殿した固体を濾過し、多くのメチルtert−ブチルエーテルで洗浄した。湿った生成物を40℃にて12時間、真空下で乾燥させ、91%モル収率の式VIIの化合物を生じた。
1H NMR(DMSO):δ8.55(s,3H),8.32(s,1H),8.06(s,1H),4.55-4.62(m,1H),2.21-1.44(m,9H)。
水(2.5容量)中の1N HClの溶液を、メチルtert−ブチルエーテル(4容量、MTBE)中の1当量の式IVの化合物に充填し、次いで、20〜25℃にて1時間撹拌した。この有機層を分離して、水層をMTBE(2容量)で抽出した。合せた有機層を乾燥させ、蒸発させて、固体を生じたか、または、次の工程に使用した(か、または、溶媒であるMTBEを蒸留によりアセトニトリルもしくはEtOAcで置き換え、次いで、次の工程で使用した)。
アセトニトリル(10容量)中の式VIIIの化合物(1当量、上で得られたもの)の溶液に、式VIIの化合物(1.3当量)およびEDCl(1.5当量)および1−ヒドロキシベンゾトリアゾール(0.3当量)を添加した。この懸濁液を撹拌し、次いで、N−メチルモルホリン(1.1当量)を1時間にわたって15〜20℃にて添加した。この反応混合物を、減圧下で約3容量まで濃縮し、次いで、MEBE(4容量)および1N HCl(4容量)で希釈した。この混合物を撹拌し、有機層を分離し、5%NaHCO3水溶液(3容量を2回)で処理した。この有機層を濃縮して、約85〜90%モル収率で式Iの化合物を得た。
1H NMR(500MHz,DMSO−d6)δ8.20-8.30(dd,1H),7.76-8.04(ブロード,2H),5.97(s,1H),5.86(dd,1H),4.85(m,1H),4.26(s,1H),4.11(d,1H),3.74-3.96(m,2H),2.40(m,1H),1.80(m,4H),1.73(m,2H),1.60-1.70(m,2H),1.43(m,1H),1.26(dd,1H),1.17(s,9H),0.82-1.00(m,6H),0.89(m,9H)。
13C NMR(75MHz,DMSO−d6)δ197.9,197.2,174.4,173.7,171.6,171.5,171.1,171.0,170.8,163.1,162.8,157.5,157.4,157.3,157.2,94.4,94.3,60.8,59.8,59.4,59.2,56.9,56.8,53.7,52.3,52.1,51.8,49.0,48.9,48.8,47.5,40.1,40.0,39.5,39.2,39.0,36.8,36.6,35.8,35.7,34.2,34.1,34.0,32.4,32.2,32.1,31.9,30.7,30.6,30.4,29.4,29.1,28.0,27.9,27.8,27.7,27.4,27.2,27.1,26.9,26.4,26.2,26.1,26.0,18.7,18.6,18.5,18.4,18.0,17.9,17.8,17.7,12.6,12.5。
酢酸エチル(10容量)中の化合物式VIII(1当量、上で得られたもの)の溶液に、式VIIの化合物(1.2当量)およびイソブチルクロロホルメート(1.5当量)を添加した。この懸濁液を0〜10℃まで冷却し、次いで、N−メチルモルホリン(1.1当量、NMM)を1時間にわたって添加した。この反応混合物を、MTBE(5容量)で希釈し、次いで、NMMを沈殿させた。HCl塩を濾過した。この濾液を、1N HCl(2容量)で洗浄し、次いで、有機層を5%NaHCO3水溶液(3容量)で洗浄した。この有機層を濃縮して、約90〜95%モル収率で式Iの化合物を得た。
1H NMR(500MHz,DMSO−d6)δ8.20-8.30(dd,1H),7.76-8.04(ブロード,2H),5.97(s,1H),5.86(dd,1H),4.85(m,1H),4.26(s,1H),4.11(d,1H),3.74-3.96(m,2H),2.40(m,1H),1.80(m,4H),1.73(m,2H),1.60-1.70(m,2H),1.43(m,1H),1.26(dd,1H),1.17(s,9H),0.82-1.00(m,6H),0.89(m,9H)。
13C NMR(75MHz,DMSO−d6)δ197.9,197.2,174.4,173.7,171.6,171.5,171.1,171.0,170.8,163.1,162.8,157.5,157.4,157.3,157.2,94.4,94.3,60.8,59.8,59.4,59.2,56.9,56.8,53.7,52.3,52.1,51.8,49.0,48.9,48.8,47.5,40.1,40.0,39.5,39.2,39.0,36.8,36.6,35.8,35.7,34.2,34.1,34.0,32.4,32.2,32.1,31.9,30.7,30.6,30.4,29.4,29.1,28.0,27.9,27.8,27.7,27.4,27.2,27.1,26.9,26.4,26.2,26.1,26.0,18.7,18.6,18.5,18.4,18.0,17.9,17.8,17.7,12.6,12.5。
Claims (24)
- 式Iの化合物:
(1)式IIの化合物を式IIIの化合物とカップリングさせて、式IVの化合物を得る工程
(2)式Vの化合物のヒドロキシル基を酸化して、式VIの化合物を得る工程
(3)式VIの化合物を脱保護して、式VIIの化合物を得る工程;
- Z+が、第一級アミン塩基または第二級アミン塩基を表す、請求項1に記載の方法。
- 前記第一級アミン塩基または第二級アミン塩基が、N(H)(R)2またはN(H)2(R)であり、ここで、Rは、一つより多くのRが存在する場合には同じであっても異なっていてもよく、そして独立して選択され、そして、H、アリール、アラルキル、アルキル、シクロアルキルおよびヘテロシクロアルキルからなる群より選択される、請求項2に記載の方法。
- 請求項1に記載の方法であって、工程1の前記カップリングする工程が、前記式IIの化合物のカルボン酸基を、活性化剤で活性化する工程を包含し、該活性化剤は、炭酸もしくはカルボン酸混合の無水物、N,N’−カルボニルジイミダゾール、エチルクロロホルメート、2−エトキシ1−エトキシカルボニル−1,2−ジヒドロキノリン(EEDQ)、エチルクロロホルメート、イソブチルクロロホルメート、イソプロペニルクロロホルメート、トリメチルアセチルクロライド、2,4,6−トリクロロベンゾイルクロライド、イソブチルクロロホルメート、4−ニトロフェニルクロロホルメート、シアヌルクロライド、オキサリルクロライド、三フッ化ジエチルアミノ硫黄、ビス(テトラメチレン)フルオロホルムアミジニウムヘキサフルオロホスフェート(BPTFFH)、ジメチルホルムアミド/POCl3(Vilsmeier試薬)、リン試薬、硫黄試薬、カルボジイミド、ピリジニウム塩およびホスホニウム塩からなる群より選択される、方法。
- 前記活性化剤が、ジシクロヘキシルジカルボジイミド(DCC)、1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩(EDCl)およびジイソプロピルカルボジイミドからなる群より選択されるカルボジイミドである、請求項5に記載の方法。
- 前記カルボジイミドはEDClである、請求項6に記載の方法。
- 工程1はさらに、2,4,6−コリジン、2,6−ジtert−ブチル−4−メチルピリジン、1−ジエチルアミノ−2−プロパノール、N−エチルアミノ−2−プロパノール、N−エチルジイソプロピルアミン、4−エチルモルホリン、1−エチルピペリジン、2,6−ルチジン、4−メチルモルホリン、1−メチルピペリジン、トリベンジルアミン、トリエチルアミン、金属水酸化物、金属アルコキシド、金属重炭酸塩、および金属炭酸塩からなる群より選択される塩基を添加する工程を包含する、請求項1に記載の方法。
- 前記塩基が2,6−ルチジンである、請求項8に記載の方法。
- 工程1は、4−ジメチルアミノピリジン、1−メチルイミダゾール、1,2,4−トリアゾール、4−(1−ピロリジノ)ピリジン、N−ヒドロキシスクシンイミド、イミダゾール、および1−ヒドロキシベンゾトリアゾールからなる群より選択される添加物を添加する工程をさらに包含する、請求項1に記載の方法。
- 前記添加物が、1−ヒドロキシベンゾトリアゾールである、請求項10に記載の方法。
- Rがメチルであり、かつ前記酸がHClである、請求項12に記載の方法。
- 前記式IVの化合物の形成を触媒するために酸が添加される、請求項1に記載の方法。
- 請求項1に記載の方法であって、工程2における前記式Vおよび式VIの化合物のN保護基が、アリル、メトキシメチル、ベンジルオキシメチル、CY3COからなる群より選択され、ここで、各Yは、同じであっても異なっていてもよく、独立して、ハロゲン、ベンジルオキシカルボニル、トリチル、ピバロイルオキシメチル、テトラヒドラニル、ベンジル、ジ(p−メトキシフェニル)メチル、トリフェニルメチル、(p−メトキシフェニル)ジフェニルメチル、ジフェニルホスフィニル、ベンゼンスルフェニル、メチルカルバメート、2−トリメチルシリルエチルカルバメート、1−メチル−1−フェニルエチルカルバメート、t−ブチルカルバメート(「t−Boc」)、シクロブチルカルバメート、1−メチルシクロブチルカルバメート、アダマンチルカルバメート、ビニルカルバメート、アリルカルバメート、シナミルカルバメート、8−キノリルカルバメート、4,5−ジフェニル−3−オキサゾリン−2−オン、ベンジルカルバメート、9−アントリルメチルカルバメート、ジフェニルメチルカルバメート、S−ベンジルカルバメート、および
- 工程2における前記酸化法が、DMSOベースの酸化、KMNO4、Br2、MnO2、四酸化ルテニウム/NaIO4、塩化クロム酸ピリジニウム(PCC)、二クロム酸ピリジニウム、酢酸中の次亜塩素酸ナトリウム、BaBrO3および硝酸セリウムアンモニウムからなる群より選択される酸化剤によって触媒される、請求項1に記載の方法。
- 工程2における前記酸化が、DMSOベースの酸化である、請求項16に記載の方法。
- 工程2における前記式VIの化合物が、結晶化により精製される、請求項1に記載の方法。
- 工程3における前記式VIの化合物が、H3PO4、H2SO4、HClおよびHBrからなる群より選択される酸で脱保護される、請求項1に記載の方法。
- 工程3における前記式VIIの化合物が、結晶化により精製される、請求項1に記載の方法。
- 工程4における前記式IVの化合物が、H3PO4、H2SO4、HClおよびHBrからなる群より選択される酸で処理される、請求項1に記載の方法。
- 工程5における前記カップリングする工程が、イソブチルクロロホルメートを用いる混合無水物手順である、請求項1に記載の方法。
- 工程5における前記式VIIの化合物が、カップリングの間にインサイチュで生成される、請求項1に記載の方法。
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PCT/US2004/018914 WO2004113294A1 (en) | 2003-06-17 | 2004-06-15 | Process and intermediates for the preparation of (1r, 2s, 5s)-3-azabicyclo[3, 1, 0]hexane-2-carboxamide, n-[3-amino-1-(cyclobutylmethyl)-2, 3-dioxopropyl] ]-3-[(2s)-2-[[[1, 1-dimethylethyl]amino]carbonylamino]-3, 3-dimethyl-1-oxobutyl]-6, 6-dimethyl |
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CN102199111A (zh) | 2011-09-28 |
US20050059800A1 (en) | 2005-03-17 |
MXPA05013753A (es) | 2006-03-08 |
WO2004113294A1 (en) | 2004-12-29 |
CN1805932A (zh) | 2006-07-19 |
CN1805932B (zh) | 2011-05-18 |
ZA200509100B (en) | 2011-06-29 |
DE602004012746T2 (de) | 2009-04-09 |
ES2299850T3 (es) | 2008-06-01 |
CA2526629A1 (en) | 2004-12-29 |
JP2006528133A (ja) | 2006-12-14 |
CN102199111B (zh) | 2012-07-04 |
HK1084387A1 (en) | 2006-07-28 |
EP1641754B1 (en) | 2008-03-26 |
ATE390412T1 (de) | 2008-04-15 |
CA2526629C (en) | 2012-10-02 |
AR044694A1 (es) | 2005-09-21 |
US7326795B2 (en) | 2008-02-05 |
EP1641754A1 (en) | 2006-04-05 |
DE602004012746D1 (de) | 2008-05-08 |
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