CA2776457A1 - Spiro-condensed cyclohexane derivatives as hsl inhibitors useful for the treatment of diabetes - Google Patents

Info

Publication number

CA2776457A1

CA2776457A1 CA2776457A CA2776457A CA2776457A1 CA 2776457 A1 CA2776457 A1 CA 2776457A1 CA 2776457 A CA2776457 A CA 2776457A CA 2776457 A CA2776457 A CA 2776457A CA 2776457 A1 CA2776457 A1 CA 2776457A1

Authority

CA

Canada

Prior art keywords

alpha

aza

spiro

hydroxy

decan

Prior art date

2009-10-15

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

• 238000011282 treatment Methods 0.000 title claims abstract description 105
• 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 20
• 239000003112 inhibitor Substances 0.000 title abstract description 6
• 125000000113 cyclohexyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 title description 4
• 150000001875 compounds Chemical class 0.000 claims abstract description 575
• 150000003839 salts Chemical class 0.000 claims abstract description 26
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
• -1 pyridinylalkyl Chemical group 0.000 claims description 241
• 238000006243 chemical reaction Methods 0.000 claims description 148
• 125000000217 alkyl group Chemical group 0.000 claims description 114
• 238000000034 method Methods 0.000 claims description 88
• 150000002148 esters Chemical class 0.000 claims description 84
• 229910052739 hydrogen Inorganic materials 0.000 claims description 80
• 239000001257 hydrogen Substances 0.000 claims description 79
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 76
• 125000003884 phenylalkyl group Chemical group 0.000 claims description 73
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 61
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 60
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 59
• 229910052799 carbon Inorganic materials 0.000 claims description 52
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 50
• CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical group C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 48
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 48
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 43
• 125000001425 triazolyl group Chemical group 0.000 claims description 42
• 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 40
• 125000001188 haloalkyl group Chemical group 0.000 claims description 38
• 125000004076 pyridyl group Chemical group 0.000 claims description 38
• 229910052736 halogen Inorganic materials 0.000 claims description 37
• 150000002367 halogens Chemical class 0.000 claims description 37
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 34
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 34
• 125000003545 alkoxy group Chemical group 0.000 claims description 32
• 125000002883 imidazolyl group Chemical group 0.000 claims description 30
• 125000001424 substituent group Chemical group 0.000 claims description 30
• 125000003342 alkenyl group Chemical group 0.000 claims description 28
• WLDBKDYSWDAYMZ-UHFFFAOYSA-N decan-1-one Chemical compound CCCCCCCCC[C]=O WLDBKDYSWDAYMZ-UHFFFAOYSA-N 0.000 claims description 28
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 27
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 25
• XSYIKVDGHYPASC-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]-2-azaspiro[4.5]decane-1,8-dione Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2(CCC(=O)CC2)CC1 XSYIKVDGHYPASC-UHFFFAOYSA-N 0.000 claims description 24
• 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 24
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 20
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 20
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 15
• 238000002360 preparation method Methods 0.000 claims description 14
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
• 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 13
• 125000005081 alkoxyalkoxyalkyl group Chemical group 0.000 claims description 12
• 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 12
• 125000005347 halocycloalkyl group Chemical group 0.000 claims description 12
• 208000008589 Obesity Diseases 0.000 claims description 11
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
• 235000020824 obesity Nutrition 0.000 claims description 11
• 125000005359 phenoxyalkyl group Chemical group 0.000 claims description 11
• 230000008569 process Effects 0.000 claims description 11
• KBJXDTIYSSQJAI-UHFFFAOYSA-N propylcarbamic acid Chemical compound CCCNC(O)=O KBJXDTIYSSQJAI-UHFFFAOYSA-N 0.000 claims description 11
• 201000001320 Atherosclerosis Diseases 0.000 claims description 10
• 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 10
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 10
• 229940098779 methanesulfonic acid Drugs 0.000 claims description 10
• YXBLRHFBCIYRIK-UHFFFAOYSA-N phenyl cyclopropanesulfonate Chemical compound C1CC1S(=O)(=O)OC1=CC=CC=C1 YXBLRHFBCIYRIK-UHFFFAOYSA-N 0.000 claims description 10
• 208000032928 Dyslipidaemia Diseases 0.000 claims description 9
• 208000017170 Lipid metabolism disease Diseases 0.000 claims description 9
• 208000001145 Metabolic Syndrome Diseases 0.000 claims description 9
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 9
• 125000000304 alkynyl group Chemical group 0.000 claims description 9
• 125000005144 cycloalkylsulfonyl group Chemical group 0.000 claims description 8
• 125000001544 thienyl group Chemical group 0.000 claims description 8
• MXNSDPGLSJLLCE-UHFFFAOYSA-N (3-fluorophenyl)methylcarbamic acid Chemical compound OC(=O)NCC1=CC=CC(F)=C1 MXNSDPGLSJLLCE-UHFFFAOYSA-N 0.000 claims description 7
• 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 7
• 125000005120 alkyl cycloalkyl alkyl group Chemical group 0.000 claims description 7
• 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 7
• 125000004461 halocycloalkylalkyl group Chemical group 0.000 claims description 7
• 125000004689 alkyl amino carbonyl alkyl group Chemical group 0.000 claims description 6
• 125000005016 hydroxyalkynyl group Chemical group 0.000 claims description 6
• 125000005082 alkoxyalkenyl group Chemical group 0.000 claims description 5
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
• 125000004686 alkyl sulfanyl alkyl group Chemical group 0.000 claims description 5
• 125000004687 alkyl sulfinyl alkyl group Chemical group 0.000 claims description 5
• 125000006515 benzyloxy alkyl group Chemical group 0.000 claims description 5
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 5
• 125000006348 halo alkyl alkoxy alkyl group Chemical group 0.000 claims description 5
• 125000005020 hydroxyalkenyl group Chemical group 0.000 claims description 5
• UFEJKYYYVXYMMS-UHFFFAOYSA-N methylcarbamic acid Chemical compound CNC(O)=O UFEJKYYYVXYMMS-UHFFFAOYSA-N 0.000 claims description 5
• PKFVPEFGVGHPHC-UHFFFAOYSA-N 2-(4-methoxyphenyl)-2-azaspiro[4.5]dec-7-en-1-one Chemical compound C1=CC(OC)=CC=C1N1C(=O)C2(CC=CCC2)CC1 PKFVPEFGVGHPHC-UHFFFAOYSA-N 0.000 claims description 4
• UDKQLMUIXOHPNM-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]-2-azaspiro[4.5]dec-7-en-1-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2(CC=CCC2)CC1 UDKQLMUIXOHPNM-UHFFFAOYSA-N 0.000 claims description 4
• RHVNLQFFFNALIE-UHFFFAOYSA-N 8-hydroxy-2-[4-(1,1,1-trifluoropropan-2-yloxy)phenyl]-2-azaspiro[4.5]decan-1-one Chemical compound C1=CC(OC(C)C(F)(F)F)=CC=C1N1C(=O)C2(CCC(O)CC2)CC1 RHVNLQFFFNALIE-UHFFFAOYSA-N 0.000 claims description 4
• YXXDVGBOHPPQFQ-UHFFFAOYSA-N 8-methyl-2-[4-(trifluoromethoxy)phenyl]-2-azaspiro[4.5]dec-7-en-1-one Chemical compound C1CC(C)=CCC11C(=O)N(C=2C=CC(OC(F)(F)F)=CC=2)CC1 YXXDVGBOHPPQFQ-UHFFFAOYSA-N 0.000 claims description 4
• KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 4
• NIXKBAZVOQAHGC-UHFFFAOYSA-M phenylmethanesulfonate Chemical compound [O-]S(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-M 0.000 claims description 4
• KDFJROLWEFNMSN-UHFFFAOYSA-N (2-hydroxy-2-methylpropyl)carbamic acid Chemical compound CC(C)(O)CNC(O)=O KDFJROLWEFNMSN-UHFFFAOYSA-N 0.000 claims description 3
• FQCDZURCBARRDO-UHFFFAOYSA-N 2-phenylethylcarbamic acid Chemical compound OC(=O)NCCC1=CC=CC=C1 FQCDZURCBARRDO-UHFFFAOYSA-N 0.000 claims description 3
• HFACNFBAGXEJFH-UHFFFAOYSA-N 8-hydroxy-8-propyl-2-[4-(2,2,2-trifluoroethoxy)phenyl]-2-azaspiro[4.5]decan-1-one Chemical compound C1CC(CCC)(O)CCC11C(=O)N(C=2C=CC(OCC(F)(F)F)=CC=2)CC1 HFACNFBAGXEJFH-UHFFFAOYSA-N 0.000 claims description 3
• JHFINHOBWIGQHJ-UHFFFAOYSA-N cyclopropylcarbamic acid Chemical compound OC(=O)NC1CC1 JHFINHOBWIGQHJ-UHFFFAOYSA-N 0.000 claims description 3
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• PWXJULSLLONQHY-UHFFFAOYSA-N phenylcarbamic acid Chemical compound OC(=O)NC1=CC=CC=C1 PWXJULSLLONQHY-UHFFFAOYSA-N 0.000 claims description 3
• KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims description 3
• FUCWTKJJFDLHEX-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-8-(2,2,2-trifluoro-1,1-dihydroxyethyl)-2-azaspiro[4.5]decan-1-one Chemical compound C1=CC(C(C)(C)C)=CC=C1N1C(=O)C2(CCC(CC2)C(O)(O)C(F)(F)F)CC1 FUCWTKJJFDLHEX-UHFFFAOYSA-N 0.000 claims description 2
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
• 239000013543 active substance Substances 0.000 claims description 2
• 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims 2
• 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
• 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims 1
• 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims 1
• 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims 1
• FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 349
• KSMVZQYAVGTKIV-UHFFFAOYSA-N decanal Chemical compound CCCCCCCCCC=O KSMVZQYAVGTKIV-UHFFFAOYSA-N 0.000 description 273
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 218
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 150
• 239000007787 solid Substances 0.000 description 146
• 239000000203 mixture Substances 0.000 description 145
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 116
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 115
• 235000019439 ethyl acetate Nutrition 0.000 description 113
• 239000000243 solution Substances 0.000 description 107
• 239000002904 solvent Substances 0.000 description 107
• 239000011541 reaction mixture Substances 0.000 description 106
• 229910001868 water Inorganic materials 0.000 description 103
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 80
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
• 239000000741 silica gel Substances 0.000 description 69
• 229910002027 silica gel Inorganic materials 0.000 description 69
• 229960004132 diethyl ether Drugs 0.000 description 68
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 66
• 238000003818 flash chromatography Methods 0.000 description 66
• 239000012044 organic layer Substances 0.000 description 66
• 239000007832 Na2SO4 Substances 0.000 description 65
• 239000012267 brine Substances 0.000 description 65
• 229910052938 sodium sulfate Inorganic materials 0.000 description 65
• 235000011152 sodium sulphate Nutrition 0.000 description 65
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 65
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
• 230000015572 biosynthetic process Effects 0.000 description 60
• 238000003786 synthesis reaction Methods 0.000 description 60
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
• 238000003756 stirring Methods 0.000 description 52
• VJPPLCNBDLZIFG-ZDUSSCGKSA-N 4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Chemical compound C(C#CC)(=O)N[C@@H]1CN(CCC1)C1=C2C(=C(NC2=C(C=C1F)C(=O)N)C)C VJPPLCNBDLZIFG-ZDUSSCGKSA-N 0.000 description 48
• 102000000019 Sterol Esterase Human genes 0.000 description 44
• 108010055297 Sterol Esterase Proteins 0.000 description 44
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 42
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
• 239000000047 product Substances 0.000 description 31
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 29
• CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 28
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
• RYEXTBOQKFUPOE-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].CC[CH2-] RYEXTBOQKFUPOE-UHFFFAOYSA-M 0.000 description 27
• LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 26
• 239000000463 material Substances 0.000 description 26
• 150000002431 hydrogen Chemical group 0.000 description 25
• 238000010992 reflux Methods 0.000 description 25
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 24
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
• IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 22
• 230000003647 oxidation Effects 0.000 description 22
• 238000007254 oxidation reaction Methods 0.000 description 22
• XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 22
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• 239000007788 liquid Substances 0.000 description 21
• 238000011321 prophylaxis Methods 0.000 description 21
• KFTAVWZBCJFRFM-UHFFFAOYSA-N 8-[4-(2,2,2-trifluoroethoxy)phenyl]-2-oxa-8-azadispiro[2.2.4^{6}.2^{3}]dodecan-7-one Chemical compound C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)C2(CCC3(OC3)CC2)CC1 KFTAVWZBCJFRFM-UHFFFAOYSA-N 0.000 description 20
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 20
• VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 19
• 229910000104 sodium hydride Inorganic materials 0.000 description 19
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
• 239000000543 intermediate Substances 0.000 description 18
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 18
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
• FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 17
• 238000005984 hydrogenation reaction Methods 0.000 description 16
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 15
• JNBMWZIPQZRIFM-UHFFFAOYSA-N ethyl 4-hydroxy-1-(2-methoxyethyl)cyclohexane-1-carboxylate Chemical compound CCOC(=O)C1(CCOC)CCC(O)CC1 JNBMWZIPQZRIFM-UHFFFAOYSA-N 0.000 description 15
• 239000012312 sodium hydride Substances 0.000 description 15
• 239000008346 aqueous phase Substances 0.000 description 14
• 210000004027 cell Anatomy 0.000 description 14
• 238000011097 chromatography purification Methods 0.000 description 14
• ZAQZICGOYPRHCK-UHFFFAOYSA-N dodecan-6-one Chemical compound CCCCCCC(=O)CCCCC ZAQZICGOYPRHCK-UHFFFAOYSA-N 0.000 description 14
• 235000021588 free fatty acids Nutrition 0.000 description 14
• 239000010410 layer Substances 0.000 description 14
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