CA2774215A1 - Bicyclic heterocycles and their use as ccr2 receptor antagonists - Google Patents

Info

Publication number

CA2774215A1

CA2774215A1 CA2774215A CA2774215A CA2774215A1 CA 2774215 A1 CA2774215 A1 CA 2774215A1 CA 2774215 A CA2774215 A CA 2774215A CA 2774215 A CA2774215 A CA 2774215A CA 2774215 A1 CA2774215 A1 CA 2774215A1

Authority

CA

Canada

Prior art keywords

hydroxy

spiro

alkyl

oxo

methyl

Prior art date

2009-10-07

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 239000002464 receptor antagonist Substances 0.000 title claims description 5
• 229940044551 receptor antagonist Drugs 0.000 title claims description 5
• 102000004497 CCR2 Receptors Human genes 0.000 title abstract description 6
• 108010017312 CCR2 Receptors Proteins 0.000 title abstract description 6
• 125000002618 bicyclic heterocycle group Chemical group 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 293
• 229910052720 vanadium Inorganic materials 0.000 claims abstract description 20
• 229910052721 tungsten Inorganic materials 0.000 claims abstract description 13
• 150000003839 salts Chemical class 0.000 claims abstract description 9
• 239000003814 drug Substances 0.000 claims abstract description 7
• 102000004499 CCR3 Receptors Human genes 0.000 claims abstract description 4
• 108010017316 CCR3 Receptors Proteins 0.000 claims abstract description 4
• 125000000217 alkyl group Chemical group 0.000 claims description 149
• -1 halo C1-6 alkyl Chemical group 0.000 claims description 140
• 125000001424 substituent group Chemical group 0.000 claims description 62
• 125000000623 heterocyclic group Chemical group 0.000 claims description 39
• 125000005843 halogen group Chemical group 0.000 claims description 37
• 229910052739 hydrogen Inorganic materials 0.000 claims description 37
• 239000001257 hydrogen Substances 0.000 claims description 36
• 125000001072 heteroaryl group Chemical group 0.000 claims description 32
• 125000004432 carbon atom Chemical group C* 0.000 claims description 31
• 125000003545 alkoxy group Chemical group 0.000 claims description 29
• 238000000034 method Methods 0.000 claims description 29
• 229910052736 halogen Inorganic materials 0.000 claims description 27
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
• 229910052757 nitrogen Inorganic materials 0.000 claims description 22
• 125000003118 aryl group Chemical group 0.000 claims description 21
• 229910052799 carbon Inorganic materials 0.000 claims description 21
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 20
• 239000000543 intermediate Substances 0.000 claims description 19
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 13
• 150000002367 halogens Chemical class 0.000 claims description 12
• 208000032064 Chronic Limb-Threatening Ischemia Diseases 0.000 claims description 10
• 206010034576 Peripheral ischaemia Diseases 0.000 claims description 10
• 125000002947 alkylene group Chemical group 0.000 claims description 10
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
• 150000002431 hydrogen Chemical group 0.000 claims description 9
• 125000005936 piperidyl group Chemical group 0.000 claims description 9
• 238000011282 treatment Methods 0.000 claims description 9
• 201000010099 disease Diseases 0.000 claims description 8
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
• 125000002252 acyl group Chemical group 0.000 claims description 7
• 125000003342 alkenyl group Chemical group 0.000 claims description 7
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
• 238000004519 manufacturing process Methods 0.000 claims description 7
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
• 125000000304 alkynyl group Chemical group 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 6
• 230000008569 process Effects 0.000 claims description 6
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
• HXBJAWLXMQBPEE-CQSHLORDSA-N (3s,6r,8as)-n-(3,4-dichlorophenyl)-6-[2-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]ethyl]-3-methyl-4-oxo-1,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-2-carboxamide Chemical compound C([C@H]1CC[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(Cl)=CC=1)CN(C[C@H]1O)CCC21CC2 HXBJAWLXMQBPEE-CQSHLORDSA-N 0.000 claims description 5
• 206010003178 Arterial thrombosis Diseases 0.000 claims description 5
• 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 5
• 206010063837 Reperfusion injury Diseases 0.000 claims description 5
• 239000013543 active substance Substances 0.000 claims description 5
• 208000006673 asthma Diseases 0.000 claims description 5
• 230000007214 atherothrombosis Effects 0.000 claims description 5
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
• 206010012601 diabetes mellitus Diseases 0.000 claims description 5
• 125000001153 fluoro group Chemical group F* 0.000 claims description 5
• 208000012947 ischemia reperfusion injury Diseases 0.000 claims description 5
• 201000006417 multiple sclerosis Diseases 0.000 claims description 5
• 125000001624 naphthyl group Chemical group 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 238000011321 prophylaxis Methods 0.000 claims description 5
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
• FEWPOFNLPZBZRQ-RYQLBKOJSA-N (4s,7s,9ar)-n-(3,4-dichlorophenyl)-4-[2-(8,8-difluoro-6-azaspiro[2.5]octan-6-yl)ethyl]-7-methyl-6-oxo-1,3,4,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxamide Chemical compound C([C@H]1COC[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(Cl)=CC=1)CN(CC1(F)F)CCC21CC2 FEWPOFNLPZBZRQ-RYQLBKOJSA-N 0.000 claims description 4
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 4
• 206010002388 Angina unstable Diseases 0.000 claims description 4
• 208000037260 Atherosclerotic Plaque Diseases 0.000 claims description 4
• 206010007559 Cardiac failure congestive Diseases 0.000 claims description 4
• 208000031229 Cardiomyopathies Diseases 0.000 claims description 4
• 208000011231 Crohn disease Diseases 0.000 claims description 4
• 208000002249 Diabetes Complications Diseases 0.000 claims description 4
• 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
• 206010019280 Heart failures Diseases 0.000 claims description 4
• 208000007177 Left Ventricular Hypertrophy Diseases 0.000 claims description 4
• 208000006011 Stroke Diseases 0.000 claims description 4
• 208000025865 Ulcer Diseases 0.000 claims description 4
• 208000007814 Unstable Angina Diseases 0.000 claims description 4
• 125000005002 aryl methyl group Chemical group 0.000 claims description 4
• 150000001602 bicycloalkyls Chemical group 0.000 claims description 4
• 208000033679 diabetic kidney disease Diseases 0.000 claims description 4
• 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 4
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
• 208000004296 neuralgia Diseases 0.000 claims description 4
• 208000021722 neuropathic pain Diseases 0.000 claims description 4
• BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical class NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 claims description 4
• 208000037803 restenosis Diseases 0.000 claims description 4
• 230000001225 therapeutic effect Effects 0.000 claims description 4
• 231100000397 ulcer Toxicity 0.000 claims description 4
• SCTLTHNKDNXIKO-CQSHLORDSA-N (3s,6r,8as)-n-[3-chloro-4-(trifluoromethyl)phenyl]-6-[3-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]-3-oxopropyl]-3-methyl-4-oxo-1,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-2-carboxamide Chemical compound C([C@H]1CC[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(=CC=1)C(F)(F)F)CC(=O)N(C[C@H]1O)CCC21CC2 SCTLTHNKDNXIKO-CQSHLORDSA-N 0.000 claims description 3
• FXEIQKQXQQPXNN-YNFBMLRVSA-N (3s,6r,9as)-n-(3,4-dichlorophenyl)-6-[2-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]ethyl]-3-methyl-4-oxo-3,6,7,8,9,9a-hexahydro-1h-pyrido[1,2-a]pyrazine-2-carboxamide Chemical compound C([C@H]1CCC[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(Cl)=CC=1)CN(C[C@H]1O)CCC21CC2 FXEIQKQXQQPXNN-YNFBMLRVSA-N 0.000 claims description 3
• OLFWZXCKXARENZ-YNFBMLRVSA-N (3s,6r,9as)-n-(3,4-dichlorophenyl)-6-[3-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]-3-oxopropyl]-3-methyl-4-oxo-3,6,7,8,9,9a-hexahydro-1h-pyrido[1,2-a]pyrazine-2-carboxamide Chemical compound C([C@H]1CCC[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(Cl)=CC=1)CC(=O)N(C[C@H]1O)CCC21CC2 OLFWZXCKXARENZ-YNFBMLRVSA-N 0.000 claims description 3
• JQCIUOQXYPKXPD-KVJIRVJXSA-N (3s,6r,9as)-n-(3-chlorophenyl)-6-[2-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]ethyl]-3-methyl-4-oxo-3,6,7,8,9,9a-hexahydro-1h-pyrido[1,2-a]pyrazine-2-carboxamide Chemical compound C([C@H]1CCC[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C=CC=1)CN(C[C@H]1O)CCC21CC2 JQCIUOQXYPKXPD-KVJIRVJXSA-N 0.000 claims description 3
• KRANRITWUBKTIK-KVJIRVJXSA-N (3s,6r,9as)-n-(3-fluorophenyl)-6-[2-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]ethyl]-3-methyl-4-oxo-3,6,7,8,9,9a-hexahydro-1h-pyrido[1,2-a]pyrazine-2-carboxamide Chemical compound C([C@H]1CCC[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(F)C=CC=1)CN(C[C@H]1O)CCC21CC2 KRANRITWUBKTIK-KVJIRVJXSA-N 0.000 claims description 3
• NSRPAFABUMMXJN-YNFBMLRVSA-N (3s,6r,9as)-n-[3-chloro-4-(trifluoromethyl)phenyl]-6-[3-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]-3-oxopropyl]-3-methyl-4-oxo-3,6,7,8,9,9a-hexahydro-1h-pyrido[1,2-a]pyrazine-2-carboxamide Chemical compound C([C@H]1CCC[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(=CC=1)C(F)(F)F)CC(=O)N(C[C@H]1O)CCC21CC2 NSRPAFABUMMXJN-YNFBMLRVSA-N 0.000 claims description 3
• OOYPIJHNKGDTMC-QTLCSOKXSA-N (3s,6s,8ar)-n-(3,4-dichlorophenyl)-3-[2-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]ethyl]-6-methyl-5-oxo-3,6,8,8a-tetrahydro-2h-[1,3]oxazolo[3,2-a]pyrazine-7-carboxamide Chemical compound C([C@H]1CO[C@@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(Cl)=CC=1)CN(C[C@H]1O)CCC21CC2 OOYPIJHNKGDTMC-QTLCSOKXSA-N 0.000 claims description 3
• OOYPIJHNKGDTMC-UQOODKLHSA-N (3s,6s,8as)-n-(3,4-dichlorophenyl)-3-[2-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]ethyl]-6-methyl-5-oxo-3,6,8,8a-tetrahydro-2h-[1,3]oxazolo[3,2-a]pyrazine-7-carboxamide Chemical compound C([C@H]1CO[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(Cl)=CC=1)CN(C[C@H]1O)CCC21CC2 OOYPIJHNKGDTMC-UQOODKLHSA-N 0.000 claims description 3
• FZWMNZSUXRCVBW-GJGKJRLISA-N (4s,7s)-n-(3,4-dichlorophenyl)-4-[[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]methyl]-7-methyl-6-oxo-2,3,4,7,9,9a-hexahydropyrazino[2,1-b][1,3]oxazine-8-carboxamide Chemical compound C([C@@H]1CCOC2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(Cl)=CC=1)N(C[C@H]1O)CCC21CC2 FZWMNZSUXRCVBW-GJGKJRLISA-N 0.000 claims description 3
• QHKNQXLAQKWKKZ-DZKDUJFISA-N (4s,7s,9ar)-n-(3,4-dichlorophenyl)-4-[2-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]ethyl]-7-methyl-6-oxo-1,3,4,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxamide Chemical compound C([C@H]1COC[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(Cl)=CC=1)CN(C[C@H]1O)CCC21CC2 QHKNQXLAQKWKKZ-DZKDUJFISA-N 0.000 claims description 3
• NWSZWHLEQJCCRT-DZKDUJFISA-N (4s,7s,9ar)-n-(3,4-dichlorophenyl)-4-[3-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]-3-oxopropyl]-7-methyl-6-oxo-1,3,4,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxamide Chemical compound C([C@H]1COC[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(Cl)=CC=1)CC(=O)N(C[C@H]1O)CCC21CC2 NWSZWHLEQJCCRT-DZKDUJFISA-N 0.000 claims description 3
• GCTHRTJBORKLIG-DZKDUJFISA-N (4s,7s,9ar)-n-[3-chloro-4-(trifluoromethyl)phenyl]-4-[2-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]ethyl]-7-methyl-6-oxo-1,3,4,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxamide Chemical compound C([C@H]1COC[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(=CC=1)C(F)(F)F)CN(C[C@H]1O)CCC21CC2 GCTHRTJBORKLIG-DZKDUJFISA-N 0.000 claims description 3
• HDGZNBAZKHMHLV-DZKDUJFISA-N (4s,7s,9ar)-n-[3-chloro-4-(trifluoromethyl)phenyl]-4-[3-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]-3-oxopropyl]-7-methyl-6-oxo-1,3,4,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxamide Chemical compound C([C@H]1COC[C@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(=CC=1)C(F)(F)F)CC(=O)N(C[C@H]1O)CCC21CC2 HDGZNBAZKHMHLV-DZKDUJFISA-N 0.000 claims description 3
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
• 239000002604 chemokine receptor CCR2 antagonist Substances 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
• 239000011737 fluorine Chemical group 0.000 claims description 3
• 239000000651 prodrug Substances 0.000 claims description 3
• 229940002612 prodrug Drugs 0.000 claims description 3
• MTADGFQXQUVZFX-QBKABZPQSA-N (3s,6s,8ar)-n-(3,4-dichlorophenyl)-3-[3-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]-3-oxopropyl]-6-methyl-5-oxo-3,6,8,8a-tetrahydro-2h-[1,3]oxazolo[3,2-a]pyrazine-7-carboxamide Chemical compound C([C@H]1CO[C@@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(Cl)=CC=1)CC(=O)N(C[C@H]1O)CCC21CC2 MTADGFQXQUVZFX-QBKABZPQSA-N 0.000 claims description 2
• DLDGJGVYNQDEFQ-QBKABZPQSA-N (3s,6s,8ar)-n-[3-chloro-4-(trifluoromethyl)phenyl]-3-[3-[(8s)-8-hydroxy-6-azaspiro[2.5]octan-6-yl]-3-oxopropyl]-6-methyl-5-oxo-3,6,8,8a-tetrahydro-2h-[1,3]oxazolo[3,2-a]pyrazine-7-carboxamide Chemical compound C([C@H]1CO[C@@H]2CN([C@H](C(N21)=O)C)C(=O)NC=1C=C(Cl)C(=CC=1)C(F)(F)F)CC(=O)N(C[C@H]1O)CCC21CC2 DLDGJGVYNQDEFQ-QBKABZPQSA-N 0.000 claims description 2
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
• 206010012655 Diabetic complications Diseases 0.000 claims description 2
• 125000004043 oxo group Chemical group O=* 0.000 claims description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 21
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 7
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 4
• 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims 2
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 2
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 2
• 239000003067 chemokine receptor CCR5 antagonist Substances 0.000 claims 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
• 229910052717 sulfur Inorganic materials 0.000 claims 1
• 239000005557 antagonist Substances 0.000 abstract description 8
• 102000004274 CCR5 Receptors Human genes 0.000 abstract description 2
• 108010017088 CCR5 Receptors Proteins 0.000 abstract description 2
• 125000002619 bicyclic group Chemical group 0.000 abstract description 2
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 165
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
• 239000000243 solution Substances 0.000 description 82
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 67
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 67
• 239000000203 mixture Substances 0.000 description 61
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
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• 238000006243 chemical reaction Methods 0.000 description 55
• 239000002904 solvent Substances 0.000 description 44
• 239000006260 foam Substances 0.000 description 39
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
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• 239000003921 oil Substances 0.000 description 37
• 235000019198 oils Nutrition 0.000 description 37
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 35
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
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• VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 34
• 235000019341 magnesium sulphate Nutrition 0.000 description 33
• 235000019439 ethyl acetate Nutrition 0.000 description 31
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
• 239000003153 chemical reaction reagent Substances 0.000 description 30
• 239000007787 solid Substances 0.000 description 30
• MFUVCHZWGSJKEQ-UHFFFAOYSA-N 3,4-dichlorphenylisocyanate Chemical compound ClC1=CC=C(N=C=O)C=C1Cl MFUVCHZWGSJKEQ-UHFFFAOYSA-N 0.000 description 28
• 239000012044 organic layer Substances 0.000 description 28
• BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 description 28
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
• 239000012267 brine Substances 0.000 description 22
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
• 244000166102 Eucalyptus leucoxylon Species 0.000 description 21
• 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 21
• 238000004587 chromatography analysis Methods 0.000 description 21
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 21
• 125000006239 protecting group Chemical group 0.000 description 19
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
• 235000017557 sodium bicarbonate Nutrition 0.000 description 19
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 18
• JKPUKCNQAPZRSS-UHFFFAOYSA-N benzyl pyrazine-2-carboxylate Chemical compound C=1N=CC=NC=1C(=O)OCC1=CC=CC=C1 JKPUKCNQAPZRSS-UHFFFAOYSA-N 0.000 description 18
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