WO2010010150A1 - Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 - Google Patents
Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 Download PDFInfo
- Publication number
- WO2010010150A1 WO2010010150A1 PCT/EP2009/059496 EP2009059496W WO2010010150A1 WO 2010010150 A1 WO2010010150 A1 WO 2010010150A1 EP 2009059496 W EP2009059496 W EP 2009059496W WO 2010010150 A1 WO2010010150 A1 WO 2010010150A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- optionally substituted
- alkyl
- protected
- phenyl
- cycloalkyl
- Prior art date
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- 238000003786 synthesis reaction Methods 0.000 title abstract description 22
- 239000003112 inhibitor Substances 0.000 title abstract description 14
- 102000008645 11-beta-Hydroxysteroid Dehydrogenase Type 1 Human genes 0.000 title abstract description 4
- 108010088011 11-beta-Hydroxysteroid Dehydrogenase Type 1 Proteins 0.000 title abstract description 4
- 230000015572 biosynthetic process Effects 0.000 title description 13
- -1 epoxide compound Chemical class 0.000 claims description 247
- 125000000217 alkyl group Chemical group 0.000 claims description 143
- 238000000034 method Methods 0.000 claims description 80
- 125000003545 alkoxy group Chemical group 0.000 claims description 68
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 64
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 53
- 150000001875 compounds Chemical class 0.000 claims description 52
- 125000001424 substituent group Chemical group 0.000 claims description 51
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 43
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
- 125000004076 pyridyl group Chemical group 0.000 claims description 25
- 239000000460 chlorine Substances 0.000 claims description 23
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 22
- 125000002947 alkylene group Chemical group 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 125000003386 piperidinyl group Chemical group 0.000 claims description 21
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000003107 substituted aryl group Chemical group 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000004043 oxo group Chemical group O=* 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 15
- 125000000335 thiazolyl group Chemical group 0.000 claims description 15
- 125000001544 thienyl group Chemical group 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 229910052740 iodine Inorganic materials 0.000 claims description 13
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
- 229910014585 C2-Ce Inorganic materials 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 10
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 10
- 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 10
- 238000006735 epoxidation reaction Methods 0.000 claims description 10
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 10
- 125000005479 oxodihydropyridyl group Chemical group 0.000 claims description 10
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 10
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 10
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 10
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 9
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 5
- 125000003725 azepanyl group Chemical group 0.000 claims description 5
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 4
- 125000003700 epoxy group Chemical group 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 2
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002978 peroxides Chemical group 0.000 claims description 2
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 claims description 2
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004633 N-oxo-pyridyl group Chemical group 0.000 claims 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 239000000543 intermediate Substances 0.000 abstract description 15
- 208000002705 Glucose Intolerance Diseases 0.000 abstract description 4
- 206010020772 Hypertension Diseases 0.000 abstract description 4
- 206010024229 Leprosy Diseases 0.000 abstract description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 4
- 208000020084 Bone disease Diseases 0.000 abstract description 2
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- 208000028698 Cognitive impairment Diseases 0.000 abstract description 2
- 206010012289 Dementia Diseases 0.000 abstract description 2
- 206010018429 Glucose tolerance impaired Diseases 0.000 abstract description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 abstract description 2
- 206010022489 Insulin Resistance Diseases 0.000 abstract description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 abstract description 2
- 208000008589 Obesity Diseases 0.000 abstract description 2
- 208000001132 Osteoporosis Diseases 0.000 abstract description 2
- 201000004681 Psoriasis Diseases 0.000 abstract description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 abstract description 2
- 208000010877 cognitive disease Diseases 0.000 abstract description 2
- 230000002939 deleterious effect Effects 0.000 abstract description 2
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- 230000000694 effects Effects 0.000 abstract description 2
- 230000004406 elevated intraocular pressure Effects 0.000 abstract description 2
- 239000003862 glucocorticoid Substances 0.000 abstract description 2
- 201000001421 hyperglycemia Diseases 0.000 abstract description 2
- 230000001771 impaired effect Effects 0.000 abstract description 2
- 230000003955 neuronal function Effects 0.000 abstract description 2
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- 201000008827 tuberculosis Diseases 0.000 abstract description 2
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- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 100
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
- 239000000203 mixture Substances 0.000 description 85
- 239000000243 solution Substances 0.000 description 85
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- 235000019439 ethyl acetate Nutrition 0.000 description 46
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 45
- 238000005160 1H NMR spectroscopy Methods 0.000 description 44
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- 238000006243 chemical reaction Methods 0.000 description 37
- 229910052938 sodium sulfate Inorganic materials 0.000 description 36
- 239000007832 Na2SO4 Substances 0.000 description 35
- 239000002904 solvent Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
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- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 31
- 125000006239 protecting group Chemical group 0.000 description 30
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 239000012043 crude product Substances 0.000 description 26
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 23
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 20
- 239000012267 brine Substances 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
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- 238000004440 column chromatography Methods 0.000 description 12
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 7
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- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- UVLMUJDRINTYOT-WRONEBCDSA-N methyl 6-[4-[(1s)-1-[(6s)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl]ethyl]phenyl]pyridine-3-carboxylate Chemical compound N1=CC(C(=O)OC)=CC=C1C1=CC=C([C@H](C)N2C(O[C@](CC(C)(C)O)(CC2)C=2C=CC=CC=2)=O)C=C1 UVLMUJDRINTYOT-WRONEBCDSA-N 0.000 description 2
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
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- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
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- 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
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- QFYXSLAAXZTRLG-UHFFFAOYSA-N pyrrolidine-2,3-dione Chemical compound O=C1CCNC1=O QFYXSLAAXZTRLG-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 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
- 239000000523 sample Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- CGRKYEALWSRNJS-UHFFFAOYSA-N sodium;2-methylbutan-2-olate Chemical compound [Na+].CCC(C)(C)[O-] CGRKYEALWSRNJS-UHFFFAOYSA-N 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- PHICBFWUYUCFKS-UHFFFAOYSA-N spiro[4.4]nonane Chemical compound C1CCCC21CCCC2 PHICBFWUYUCFKS-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 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 description 1
- 229950002757 teoclate Drugs 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- XJPKDRJZNZMJQM-UHFFFAOYSA-N tetrakis(prop-2-enyl)stannane Chemical compound C=CC[Sn](CC=C)(CC=C)CC=C XJPKDRJZNZMJQM-UHFFFAOYSA-N 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical group C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- PFURGBBHAOXLIO-PHDIDXHHSA-N trans-cyclohexane-1,2-diol Chemical compound O[C@@H]1CCCC[C@H]1O PFURGBBHAOXLIO-PHDIDXHHSA-N 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- YOIAWAIKYVEKMF-UHFFFAOYSA-N trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F.OS(=O)(=O)C(F)(F)F YOIAWAIKYVEKMF-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
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- C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
- C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Definitions
- 1 l ⁇ -HSDl inhibitors are promising for the treatment of diabetes, metabolic syndrome, obesity, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hypertension-related cardiovascular disorders, hyperlipidemia, deleterious gluco-corticoid effects on neuronal function (e.g. cognitive impairment, dementia, and/or depression), elevated intra-ocular pressure, various forms of bone disease (e.g., osteoporosis), tuberculosis, leprosy (Hansen's disease), psoriasis, and impaired wound healing (e.g., in patients that exhibit impaired glucose tolerance and/or type 2 diabetes).
- neuronal function e.g. cognitive impairment, dementia, and/or depression
- various forms of bone disease e.g., osteoporosis
- tuberculosis e.g., leprosy (Hansen's disease)
- psoriasis e.g., in patients that exhibit impaired glucose tolerance and/or type 2 diabetes.
- the present invention provides economical and efficient methods for the synthesis of 1 l ⁇ -HSDl inhibitors, for example, oxazinone compounds and tertiary alcohol oxazinone compounds as disclosed herein.
- One embodiment of the present invention is a method of preparing an oxazinone compound represented by structural formula (I):
- R 1 is (a) absent or (b) is selected from optionally substituted (Ci-Ce)alkyl, optionally substituted (C 2 -Ce)alkenyl, optionally substituted (C 2 -Ce)alkynyl, optionally substituted (Ci-C3)alkoxy(Ci-C3)alkoxy, and optionally substituted (C 1 - C 3 )alkoxy(C 1 -C 3 )alkyl;
- E is (a) a bond or (b) (Ci-C3)alkylene or (Ci-C2)alkoxy, wherein the O is attached to R 2 , each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl and oxo;
- R 2 is selected from optionally substituted (Ci-Ce)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl;
- R 3 is selected from optionally substituted (Ci-Ce)alkyl, optionally substituted (C 2 -Ce)alkenyl, optionally substituted (C 2 -Ce)alkynyl, optionally substituted (C 3 - C5)cycloalkyl(Ci -Chalky 1, optionally substituted (Ci-C3)alkoxy(Ci-C3)alkoxy and optionally substituted (Ci-C 3 )alkoxy(Ci-C 3 )alkyl;
- a 1 is (a) a bond, or (b) (Ci-C3)alkylene, CH 2 CH 2 O, wherein the oxygen is attached to Cy 1 ;
- Cy 1 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted monocyclic cycloalkyl or optionally substituted monocyclic heterocyclyl;
- a 2 is (a) a bond, O, S or NR 4 , wherein R 4 is (Ci-C 3 )alkyl or (C 3 - Ce)cycloalkyl; or (b) (Ci-C 3 )alkylene or (Ci-C 2 )alkoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, or trifluoromethyl.
- Cy 2 is (a) hydrogen or (b) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl.
- the method comprises the step of reacting a ⁇ -haolalcohol compound, for example a ⁇ -haloalcohol compound represented by structural formula (II) with an isocyanate compound represented by structural formula (III)
- a ⁇ -haolalcohol compound for example a ⁇ -haloalcohol compound represented by structural formula (II)
- X is a leaving group
- Another embodiment of the present invention is a method of preparing an epoxide compound represented by structural formula (IV):
- the method comprises the step of oxidizing with an epoxidation reagent a 2-methyl- 3-propenyl intermediate represented by the following structural formula:
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 and E in structural formulas (IV) and (V) are as defined in structural formula (I).
- Another embodiment of the present invention is a method of preparing tertiary alcohol oxazinone compound represented by structural formula (VI):
- the method comprises the step of reducing the epoxide group of the epoxide compound represented by structural formula (IV) with a reducing agent.
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 and E in structural formula (VI) are as defined in structural formula
- the tertiary alcohol oxazinone compound represented by structural formula (VI) can be prepared using the compound of structural formula VII:
- Example 22 provides details of the synthetic steps of FIG. 2 for the preparation of (S)-3-((S)- ⁇ - (4-bromophenyl) ethyl)-6- (2- hydroxy-2-methylpropyl)- 6- phenyl-1,3- oxazinan-2- one.
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 and E in structural formula (VII) are as defined in structural formula (I).
- Another embodiment of the present invention is an epoxide compound represented by structural formula (IV) or a salt thereof.
- Yet another embodiment of the present invention is a 2-methyl-3-propenyl intermendiate represented by structural formula (V) or a salt thereof.
- inventions of the present invention are the epoxide compounds and salts thereof, and 2-methyl-3-propenyl intermediates and salts thereof as prepared with the methods of the present invention, in particular, the epoxide compounds and 2-methyl-3-propenyl intermediates corresponding to the above described embodiments.
- FIG. 1 is a schematic, showing the synthesis of a specific tertiary alcohol oxazinone compound, a 1 l ⁇ -HSDl inhibitor, using the methods disclosed herein.
- FIG. 2 is a schematic, showing the synthesis of a specific tertiary alcohol oxazinone compound, a 1 l ⁇ -HSDl inhibitor, using the methods disclosed herein.
- the present invention provides methods for synthesizing 1 l ⁇ -HSDl inhibitors, for example, oxazinone compounds and tertiary alcohol oxazinone compounds as disclosed herein.
- the oxazinone compound represented by structural formula (I), for example, compounds 5 and 6 (see Figure), can be prepared by reacting a ⁇ -haloalcohol compound represented by structural formula (II) with an isocyanate compound represented by structural formula (III). Both, the ⁇ -haloalcohol compound and the isocyanate compound can be prepared from commercially available compounds using methods known in the art (see, Exemplification section).
- the tertiary alcohol oxazinone compound represented by structural formula (VI) such as, for example, compound 8 (see Figure 1) is prepared by first oxidizing 2-methyl-3-propenyl intermediate represented by structural formula (V) with an epoxidation reagent to obtain the epoxide compound represented by structural formula (IV).
- the 2-methyl-3-propenyl intermediate is an oxazinone compound that can be prepared using the method described in the previous paragraph, wherein R is 2-methyl-3-propenyl.
- the epoxide group of the epoxide compound is reduced with a reducing agent to form the tertiary alcohol oxazinone compound.
- Oxazinone compounds and tertiary alcohol oxazinone compounds represented by structural formulas (I) and (VI), respectively, for which Cy 1 is phenyl substituted with a leaving group (e.g., -Br) and optionally substituted with one or more additional substituents, can be used to prepare biaryl group containing 11 ⁇ - HSDl inhibitors, for example, by using a "Suzuki” coupling reaction as described in Example 111 of U.S. Provisional Patent Application No. 60/962,058, filed July 26, 2007.
- oxazinone compounds represented by structural formulas (I) and (VI), respectively, for which Cy 1 is phenyl substituted with a leaving group (e.g., -Br) and optionally substituted with one or more additional substituents can be used to prepare biaryl group containing 1 l ⁇ -HSDl inhibitors, by conversion of the leaving group (e.g. -Br) to a boronic acid or boronate ester, followed by using a "Suzuki” coupling reaction with Cy 2 -Cl or Cy 2 -Br (see EXAMPLE 23).
- biaryl group containing 1 l ⁇ -HSDl inhibitors can be obtained from isocyanate compounds that already contain the biaryl group using the methods of the present invention.
- the synthesis of a variety of biaryl compounds is provided in the Exemplification section.
- protected refers to the chemical group with its functional groups that may interfere with a desired reaction having been reacted with a protective group, e.g., the ring nitrogen atom in the case piperidine.
- the oxazinone compound represented by structural formula (I) is prepared by reacting a ⁇ -haloalcohol compound represented by structural formula (II) with an isocyanate compound represented by structural formula (III) as shown above.
- the reaction of the a ⁇ -haloalcohol with the isocyanate compound is carried out in the presence of a base. More typically, the reaction is carried out in the presence of a non-nucleophilic base. Most typically, the reaction is carried out in the presence of a non-nucleophilic amine base.
- Suitable non-nucleophilic amide bases include, but are not limited to as lithium amide (LiNH 2 ), sodium amide (NaNH 2 ), lithium dimethylamide, lithium diethylamide, lithium diisopropylamide, lithium dicyclohexylamide, silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, lithium tetramethylpiperidide, and lithium tetramethylpiperidine.
- Other non-nucleophilic bases include but are not limited to sodium hydride, sodium tert-pentoxide and sodium tert-butoxide.
- non-nucleophilic amine bases include, but are not limited to, diisopropylethylamine, 2,2,6, 6-tetramethylpiperidine, 4-dimethylaminopyridine, 2,6- di-tert-butyl-4-methylpyridine, l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2,8,9-trimethyl-2,5,8,9-tetraaza-l-phosphabicyclo[3.3.3]undecane and the like.
- the base is l,8-diazabicyclo[5.4.0]undec-7-ene.
- the isocyanate compound is more commonly used in excess.
- from about one to about ten equivalents of base relative to ⁇ -haloalcohol are used, more typically from about one to about six equivalents, and, even more typically, from one to about 5 equivalents.
- the reaction is carried out in an anhydrous aprotic, non- nucleophilic solvent at ⁇ -haloalcohol compound concentrations between about 0.01 M and 5 M.
- ⁇ -Haloalcohol compound concentrations are more typically, however, between about 0.05 M and 2 M.
- Suitable solvents include, but are not limited to ethereal solvents such as diethyl ether, tetrahydrofuran (THF), tert-butyl-methyl ether and 1,4-dioxane, and non-ethereal solvents such as dimethyl formamide and dimethyl sulfoxide and the like.
- ethereal solvents such as diethyl ether, tetrahydrofuran (THF), tert-butyl-methyl ether and 1,4-dioxane
- non-ethereal solvents such as dimethyl formamide and dimethyl sulfoxide and the like.
- Suitable reaction temperatures generally range from about 0 °C to about the boiling point of the solvent. More typically, temperatures are sufficiently high to allow refluxing, for example, about 68°C for tetrahydrofuran.
- the epoxide compound represented by structural formula (IV) is prepared by oxidizing the propenyl group of the 2-methyl-3-propenyl intermediate represented by structural formula (V) with an epoxidation reagent.
- the 2-methyl-3-propenyl intermediate is an oxazinone compound that can be prepared using the method described in the previous paragraphs (e.g., the reaction of a compound of Formula II with a compound of Formula III).
- Suitable epoxidation reagents include, but are not limited to peroxides (e.g., hydrogen peroxide, t-butyl hydroperoxide), peroxycarboxylic acids (e.g., 3-chloroperbenzoic acid (MCPBA), peracetic acid, pertrifluoroacetic acid), magnesium bis(monoperoxyphthalate) hexahydrate, potassium monoperoxysulfate optionally in the presence of 1,2:4, 5-di-O- isopropylidene- ⁇ -D-erythro-2,3-hexodiulo-2,6-pyranose, dimethyldioxirane and the like.
- peroxides e.g., hydrogen peroxide, t-butyl hydroperoxide
- peroxycarboxylic acids e.g., 3-chloroperbenzoic acid (MCPBA), peracetic acid, pertrifluoroacetic acid
- MCPBA 3-chloroperbenzoic acid
- the epoxidation reagent is a peroxycarboxylic acid, and, most typically, it is 3-chloroperbenzoic acid.
- the reaction is carried out in an aprotic, non-nucleophilic solvent at 2-methyl-3-propenyl intermediate concentrations between about 0.01 M and 5 M.
- 2-Methyl-3-propenyl intermediate concentrations are more typically, however, between about 0.05 M and 2 M.
- Suitable solvents include, but are not limited to, halogenated solvents (e.g., chloroform, dichloromethane and 1 ,2-dichloroethane, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), or hexamethylphosphorus triamide and ethereal solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4- dioxane.
- the solvent is a halogenated solvent. More typically, the solvent is dichloromethane or 1,2-dichloroethane. Most typically, the solvent is dichloromethane.
- Suitable reaction temperatures generally range from about 0°C to about the boiling point of the solvent used. Most typically, the reaction is carried out at ambient temperature.
- the tertiary alcohol oxazinone compound represented by structural formula (VI) is prepared by reducing the epoxide group of the epoxide compound represented by structural formula (IV) with a reducing agent.
- Suitable reducing agents include, but are not limited to hydride reducing agents such as lithium triethylborohydride, LiAlH 4 , LiBH 4 , lithium tri-t-butoxyaluminum hydride in the presence of triethylborane, potassium tri-sec-butylboro hydride or sodium bis(2- methoxyethoxy)aluminum hydride and the like.
- Suitable reducing agents include, but are not limited to BH 3 .Et 3 N-LiC10 4 , lithium di-tert-butylbiphenyl, or hydrogen or sodium formate in the presence of palladium on charcoal. Most typically, the reducing agent is lithium triethylborohydride (super hydride).
- reducing agent relative to the epoxide compound
- reaction is carried out in an anhydrous aprotic, non-nucleophilic solvent at epoxide compound concentrations between about 0.01 M and 5 M.
- Epoxide compound concentrations are more typically, however, between about 0.05 M and 2 M.
- Suitable solvents include, but are not limited to ethereal solvents such as diethyl ether, tetrahydrofuran (THF), tert-butyl-methyl ether and 1,4-dioxane, and non-ethereal solvents such as dimethyl formamide and dimethyl sulfoxide and the like.
- the solvent is an ethereal solvent.
- the solvent is anhydrous tetrahydrofuran.
- Suitable reaction temperatures generally range from about 0°C to about ambient temperature.
- Cy 1 , Cy 2 , R 2 , R 3 and X are as defined in structural formulas (I) to (VI) (see summary of invention) and R 1 is absent or is (C 1 - C 6 )alkyl;
- a 1 is a bond, CH 2 , or CH 2 CH 2 , or CH when R 1 is present;
- a 2 is a bond, O, OCH 2 CO or CH 2 ;
- X is a Cl, Br, I or -OSO 2 R, wherein R is (Ci-C 4 )alkyl optionally substituted with one or more F, or phenyl optionally substituted with halogen, (C 1 - C4)alkyl or NO 2 ; and
- E is a bond or (Ci-C3)alkylene.
- R 1 , R 2 , R 3 , X and E are as defined in the first preferred embodiment and A 1 is a bond or CH when R 1 is present; A 2 is a bond; Cy 2 is hydrogen; Cy 1 is phenyl substituted with Cl, Br, I or OSO 2 CF 3 , and optionally substituted with one or more additional substituents.
- a 2 , Cy 2 , R 1 , R 2 , R 3 , X and E are as defined in the second preferred embodiment and A 1 is -CH, R 1 is present and Cy 1 is represented by the following structural formula:
- Z is a Cl, Br, I, OSO 2 CF 3 , OSO 2 Me, or OSO 2 C 6 H 4 Me, r is O, 1, 2 or 3; and each G 1 is independently selected from the group consisting Of (Ci-C 4 )alkyl, 1IaIo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halogen, cyano and nitro.
- a 1 , A 2 , Cy 1 , Cy 2 , R 2 , R 3 , X, E, r, G 1 and Z are defined as in the third preferred embodiment and R 1 is methyl or ethyl.
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , X, E, r, G 1 and Z are defined as in the fourth preferred embodiment and R 2 is phenyl, thienyl, or pyridyl, each optionally substituted with halogen, nitro, cyano, (Ci-Ce)alkyl, protected hydroxy(Ci-C3)alkyl, (Ci-C3)alkoxy, protected CONH 2 , protected carboxylic acid and SO 2 Me; and with regard to the preparation of an oxazinone compound, R 3 is methyl, ethyl, propyl, butyl, vinyl, allyl, 2-methyl-3-propenyl, or ethoxyethyl, each optionally substituted with up to two groups independently selected from (Ci- C 4 )alkyl, (Ci-C 4 )alkoxy, (Ci-C 4 )alkoxycarbonyl, benzyloxy
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 3 , X, E, r, G 1 and Z are defined as in the sixths preferred embodiment and R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, protected CONH 2 , (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy and SO 2 Me.
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X, E, r, G 1 and Z are defined as in the seventh preferred embodiment and, with regard to the preparation of an oxazinone compound, R 3 is 2-methyl-3-propenyl or 2-cyano-2- methylpropyl.
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 3 , X, E, r, G 1 and Z are defined as in the ninth preferred embodiment and R 2 is phenyl or fluorophenyl.
- a 1 , A 2 , R 1 , R 2 , R 3 , X and E are defined as in the first preferred embodiment and Cy 1 is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, azepanyl, pyridyl, thiazolyl, pyrimidinyl, each optionally substituted with 1 to 4 groups; and Cy 2 is phenyl, thienyl, pyridyl, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, S,S-dioxothiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benztriazolyl, oxodihydropyridyl
- a 1 , A 2 , Cy 1 , Cy 2 , R 2 , R 3 , X and E are defined as in the eleventh preferred embodiment and R 1 is methyl or ethyl.
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , X and E are defined as in the twelfth preferred embodiment and R 2 is phenyl, thienyl, or pyridyl, each optionally substituted with halogen, nitro, cyano, (Ci-Ce)alkyl, protected hydroxy(Ci-C3)alkyl, (Ci-C3)alkoxy, protected CONH 2 , protected carboxylic acid and SO 2 Me; and, with regard to the preparation of an oxazinone compound, R 3 is methyl, ethyl, propyl, butyl, vinyl, allyl, 2-methyl-3-propenyl, or ethoxyethy
- a 1 , A 2 , Cy 1 , R 1 , R 2 , R 3 , X and E are defined as in the thirteenth preferred embodiment and Cy 2 is optionally substituted and selected from the group consisting of benzimidazolyl, benzotriazolyl, oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl, oxodihydropyrazinyl, piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl and thiadiazolyl.
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 3 , X and E are defined as in the fifteenth preferred embodiment and R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, protected CONH 2 , (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy and SO 2 Me.
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X and E are defined as in the seventeenth preferred embodiment and, with regard to the preparation of an oxazinone compound, R 3 is 3-propenyl-2-methyl, or 2-cyano-2- methylpropyl.
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 3 , X and E are defined as in the eighteenth preferred embodiment and R 2 is phenyl or fluorophenyl.
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , R 3 , X and E are defined as in the nineteenth preferred embodiment and suitable substituents for a substitutable ring nitrogen atom in the group represented by Cy 2 are selected from the group consisting of (Ci-C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci- C 2 )alkyl, (Ci-C 4 )alkoxycarbonyl and (Ci-C 4 )alkylcarbonyl; and suitable substituents for a substitutable ring carbon atom in the Cy 2 is selected from the group consisting fluorine, chlorine, cyano, protected hydroxy, protected amino, (Ci-C4)alkyl, (C3- C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci-C 2 )alkyl, (C
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X and E are as defined in any one of the above preferred embodiments and R 3 is 2-methyl-3-propenyl.
- a 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X and E are as defined in any one of the above preferred embodiments and R is 3-propenyl.
- a 1 , A 2 , Cy 1 , R 1 , R 2 , X and E are as defined in any one of the above preferred embodiments and Cy 2 is represented by one of the following structural formulas:
- G 2a is (Ci-C 4 )alkyl, (C 3 -C 4 )cycloalkyl or (Ci-C 4 )haloalkyl;
- G 2b is hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (Ci-C 4 )alkyl, (C3-C 4 )cycloalkyl, (C 3 - C 4 )cycloalkyl(Ci-C 2 )alkyl, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, (Ci-C 4 )haloalkoxy, CONH 2 , (Ci-C 4 )alkylaminocarbonyl, di(Ci-C 4 )alkylaminocarbonyl or (C 1 - C 4 )alkylcarbonylamino .
- inventions of the present invention are the epoxide compounds and salts thereof, and 2-methyl-3-propenyl intermediates and salts thereof as prepared with the methods of the present invention, in particular, the epoxide compounds and 2-methyl-3-propenyl intermediates corresponding to the above described preferred embodiments.
- ⁇ -haloalcohol compound refers to compound represented by structural formula (II)
- X includes any suitable leaving group as described herein, not just halogen.
- Suitable leaving groups include, but are not limited to halides, alkylsulfonates, trifluoromethanesulfonate (triflate) and phenylsulfonates which are optionally substituted with a methyl, halogen, nitro and the like, for example, methanesulfonate (mesylate), p-toluenesulfonate (tosylate), p- bromobenzenesulfonate (brosylate), p-nitrobenzenesulfonate (nosylate) and the like.
- leaving groups are Cl, Br, I or -OSO 2 R, wherein R is (Ci-C4)alkyl optionally substituted with one or more F, or phenyl optionally substituted with halogen, (Ci-C 4 )alkyl or NO 2 .
- leaving groups are Cl, Br, I or - OSO 2 R.
- bias group refers to a group where an optionally substituted aryl or optionally substituted heteroaryl is bonded to another optionally substituted aryl or optionally substituted heteroaryl (e.g., biphenyl).
- alkyl refers to a straight chain or branched saturated hydrocarbyl group having 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
- cycloalkyl means a monocyclic, bicyclic or tricyclic, saturated hydrocarbon ring having 3-10 carbon atoms and includes, for example, cyclopropyl (c-Pr), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, spiro [4.4]nonane, adamantyl and the like.
- cyclopropyl c-Pr
- cyclobutyl cyclopentyl
- cyclohexyl cycloheptyl
- cyclooctyl bicyclo[2.2.2]octyl
- bicyclo[2.2.1]heptyl bicyclo[2.2.1]heptyl
- spiro [4.4]nonane adamantyl and the like.
- aryl means an aromatic radical which is a phenyl group, a naphthyl group, an indanyl group or a tetrahydronaphthalene group.
- An aryl group is optionally substituted with 1-4 substituents.
- substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido.
- heteroaryl means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a saturated or unsaturated ring containing 0-4 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3- pyrrolyl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 2-, A-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, lH-indol-6-yl, lH-indol-5- yl, lH-benzimidazol-6-yl, lH-benzimidazol-5-yl, 2-, A-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, A-, 5-, 6-, 7- or 8-quinoliny
- a heteroaryl is optionally substituted.
- substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido, or by oxo to form an N-oxide.
- heterocyclyl means a A-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
- exemplary heterocyclyls include pyrrolidine, pyrrolidin- 2-one, l-methylpyrrolidin-2-one, piperidine, piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine, l-(2,2,2-trifluoroethyl)piperazine, l,2-dihydro-2- oxopyridine, l,4-dihydro-4-oxopyridine, piperazin-2-one, 3,4,5,6-tetrahydro-4- oxopyrimidine, 3,4-dihydro-4-oxopyrimidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran,
- alkoxy group refers to an alkyl-O- group or a cycloalkyl-O- group, where the preferred alkyl and cycloalkyl groups and optional substituents thereon are those given above.
- An alkoxy group can be unsubstituted or substituted with one or more substituents.
- alkenyl group refers to a straight chain or branched hydrocarbyl group which includes one or more double bonds.
- an alkenyl group includes between 2 and 12 carbon atoms (i.e., (C 2 -C i 2 )-alkenyl).
- Suitable alkenyl groups include but are not limited to n-butenyl, cyclooctenyl and the like.
- An alkenyl group can be unsubstituted or substituted with one or more substituents.
- alkynyl group (also herein referred to as "alkynyl”) as used herein, refers to a straight chain or branched hydrocarbyl group which includes one or more triple bonds. The triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
- Suitable alkynyl groups include, but are not limited to, (C 2 -Cs)-alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l-butynyl,4-propyl-2-pentynyl- , and 4-butyl-2- hexynyl.
- An alkynyl group can be unsubstituted or substituted with one or more substituents.
- alkylene group refers to a group represented by -[CH 2 ]Z-, wherein z is a positive integer, preferably from one to eight, more preferably from one to four.
- cycloalkyl alkyl alkoxy alkyl
- alkoxy alkyl alkoxy alkyl
- a (C a -Cb)alkoxy(C c -Cd)alkyl is a group that includes an alkoxy group with between a and b carbon atoms that is covalently bonded to an alkyl group with between c and d carbon atoms.
- Suitable substituents are those which do not substantially interfere with the reactions described herein, that is, that do not substantially decrease the yield (e.g., a decrease of greater than 50%) or cause a substantial amount of by-product formation (e.g., where by-products represent at least 50% of the theoretical yield).
- "interfering" substituents can be used, provided that they are first converted to a protected form. Suitable protecting groups are known in the art and are disclosed, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (2007).
- Solvate may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. Solvates, wherein water is the solvent molecule incorporated into the crystal lattice, are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. Certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.
- Enantiomer means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms.
- the symbol “*” in a structural formula represents the presence of a chiral carbon center.
- R and “S” represent the configuration of substituents around one or more chiral carbon atoms.
- R* and “S*” denote the relative configurations of substituents around one or more chiral carbon atoms.
- the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
- Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
- the stereochemistry of a disclosed compound is named or depicted by structure
- the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers.
- the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
- the compounds of the invention may be present in the form of pharmaceutically acceptable salts.
- the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts.”
- Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
- Pharmaceutically acceptable basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.
- Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, s
- Protecting groups for an hydroxyl group -OH and reactions and conditions for protecting and deprotecting the hydroxyl group are well known in the art and are disclosed, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (2007), Chapter 2 and references cited therein.
- a protecting group may protect a hydroxyl group as ether.
- Such protecting groups include, but are not limited to methyl, methoxymethyl, methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p- methoxybenzyloxymethyl, [3,4-dimethoxybenzyl)oxy]methyl, p- nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, [(R)-I -(2- nitrophenyl)ethoxy]methyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, [(p- phenylphenyl)oxy]methyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2-cyanoethoxymethyl, bis(2-chloroethoxy)methyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, menthoxymethyl, O-bis(2-acetoxyethoxy)methyl, tetrahydropyranyl
- suitable protecting groups protect the hydroxyl group as esters, for example, formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trichloroacetamidate, trifluoroacetate, methoxy acetate, triphenylmethoxyacetate, phenoxyacetate, /?-chlorophenoxyacetate, phenylacetate, /?-P-phenylacetate, diphenylacetate, 3-phenylpropionate, bisfluorous chain type propanoyl (Bfp-OR), A- pentenoate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate, 5-[3-Bis(4- methoxyphenyl)hydroxymethylphenoxy]levulinate, pivaloate, 1-adamantoate, crotonate, 4-methoxycrotonate, benzoate, /?-phenylbenzoate
- Protecting groups for a carbonyl group and reactions and conditions for protecting and deprotecting the carbonyl group are well known in the art and are disclosed, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (2007), Chapter 4 and references cited therein.
- a protecting group may protect a carbonyl group as acetal or ketal.
- acetals and ketals include acyclic acetals and ketals (e.g., dimethyl, diisopropyl, bis(2,2,2-trichloroethyl), cyclic acetals and ketals (e.g., 1,3-dioxanes, 1,3- dio xo lanes, 1,3-dioxapane and the like), chiral acetals and ketals (e.g., (4R, 5R)- diphenyl- 1 ,3-dioxolane, 4,5-dimethyl- 1 ,3-dioxolane, trans- 1 ,2-cyclohexanediol ketal and the like), dithio acetals and ketals (e.g., S,S' -dimethyl, S,S' -diethyl, S,S'- dipropyl, 1,3-dithiane and the like), and monothio acetals and
- Protecting groups for a carboxyl group and reactions and conditions for protecting and deprotecting the carboxyl group are well known in the art and are disclosed, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (2007), Chapter 5 and references cited therein.
- a protecting group may protect a carboxyl group as ester.
- esters include, but are not limited to substituted methyl esters (e.g., 9-fluorenylmethyl, methoxymethyl, methoxyethoxymethyl and the like), 2-substituted ethyl esters (e.g., 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilyl)ethyl and the like), 2,6- dialkylphenyl esters (e.g., 2,6-dimethylphenyl, 2,6-di-t-butyl-4-methylphenyl, pentafluorophenyl and the like), substituted benzyl esters (e.g., triphenylmethyl, diphenylmethyl, 9-anthrylmethyl and the like), silyl esters (e.g., trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and the like.
- substituted methyl esters e.g., 9-flu
- a protecting group may protect a carboxyl group as amide (e.g., N,N-dimethyl, pyrrolidinyl, piperidinyl and the like) or hydrazide (e.g., N-phenyl).
- amide e.g., N,N-dimethyl, pyrrolidinyl, piperidinyl and the like
- hydrazide e.g., N-phenyl
- a protecting group may protect an amino group as carbamate (e.g., 9- fluorenylmethyl, 2,2,2-trichloroethyl, 4-phenylacetoxybenzyl, 2-methylthioethyl, m- nitrophenyl, and the like) or amide (e.g., formamide, acetamide, 3- phenylpropanamide).
- carbamate e.g., 9- fluorenylmethyl, 2,2,2-trichloroethyl, 4-phenylacetoxybenzyl, 2-methylthioethyl, m- nitrophenyl, and the like
- amide e.g., formamide, acetamide, 3- phenylpropanamide
- a protecting group may protect an aromatic heterocycle as N-sulfonyl derivative (e.g., N,N-dimethylsulfonamide, methanesulfoneamide, mesitylenesulfonamide and the like), carbamate (e.g., benzyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl and the like), N-alkyl and N-aryl derivatives, N-trialkylsilyl, N-allyl, N-benzyl, amino acetal derivative, or amide.
- N-sulfonyl derivative e.g., N,N-dimethylsulfonamide, methanesulfoneamide, mesitylenesulfonamide and the like
- carbamate e.g., benzyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl and the like
- a protecting group may protect an amide group as N-methylamide, N- allylamide, N-t-butylamide and the like.
- Protecting groups for a sulfonamide group, and reactions and conditions for protecting and deprotecting the sulfonamide group are well known in the art and are disclosed, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (2007), Chapter 7 and references cited therein.
- a protecting group may protect a sulfonamide group as N-t- butylsulfonamide, N-diphenylmethylsulfonamide, N-benzylsulfonamide and the like.
- FIG. 1 shows a preferred synthesis of a specific tertiary alcohol oxazinone compound (compound 8) known to be a 1 l ⁇ -HSDl inhibitor.
- Compounds 3 to 8 of FIG. 1 were synthesized as described in Examples 1 to 4.
- the dichloromethane layer was cut and dried with anhydrous sulfate.
- the resulting solution was passed through a celite plug and concentrated to ⁇ 1.5 L which fine particles of a white solid developed.
- the solution was filtered and concentrated to a thick oil via reduced pressure to produce 239 g of product (93.7 wt%, 79.4 % yield).
- the material was used in the following coupling without further purification.
- the aqueous solution was cut and the remaining organic solution was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure.
- the resulting material was subjected to flash silica chromatography (5-30 % ethyl acetate/hexanes, 1.74 kg of silica) to produce 137.8 g of material (59 wt%, 3.1 :1 diastereomeric ratio favoring the desired diastereomer 6, 32.3 % yield).
- the material was used in the following epoxidation without further purification.
- the resulting solution was diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with 1x500 mL of 30 wt% solution of sodium thiosulfate and 1x500 mL of saturated aqueous solution of sodium bicarbonate.
- the wash sequence were repeated until the peak on an HPLC trace of the organic solution that corresponds to a HPLC sample peak of MCPBA is ⁇ 2.5 A% (220 nm), which in this example the wash sequence was repeated 3 times.
- To the agitated solution was charged a solution of hydrogen peroxide (95.7 rnL of a 35 wt% aqueous solution diluted with 400 rnL of water, 1.08 mol, 5.60 equiv).
- the resulting solution was diluted with 1.00 L of methyl tert-butyl ether (MTBE) and washed with 1.00 L of water followed by 500 mL of a ⁇ 30 wt% solution of sodium thiosulfate.
- the organic solution was dried with anhydrous sodium sulfate, filtered, and then concentrated via reduced pressure.
- the resulting material was subjected to flash silica chromatography (10-60% ethyl acetate, 600 g of silica) to produce 68 g of material consisting of both diastereomers (1.98:1 dr) and 41 g of the desired diastereomer (>99:1 dr).
- the material consisting of the mixed fractions was recrystallized from 250 mL of isopropyl acetate (IPAC) and 200 mL of heptane (anti- solvent) to produce upon filtration 31.3 g of product (95.7 A% at 220 nm, 74:1 dr). The two samples were combined to produce 72.3 g of product (83.6 % yield for the two step operation).
- IPAC isopropyl acetate
- heptane anti- solvent
- Step 1 l-Chloro-3-(4-fluorophenyl)hex-5-en-3-ol.
- Step 2 6-Allyl-6-(4-fiuorophenyl)-3-((5)-l-phenylethyl)-l,3-oxazinan-2-one.
- Step 2 (i?)-6-allyl-3-((5)- 1 -(4-bromophenyl)ethyl)-6-(4-fluorophenyl)- 1 ,3-oxazinan- 2-one and (5)-6-allyl-3-((5)- 1 -(4-bromophenyl)ethyl)-6-(4-fluorophenyl)- 1 ,3- oxazinan-2-one
- Step 5 Enantiomers of 6-methyl-6-phenyl-3-m-tolyl-l,3-oxazinan-2-one.
- the mixture was diluted with EtOAc (50 mL) and washed with 1% aq HCl (2 x 15 mL), satd aq NaHCO 3 (10 mL) and brine (10 mL), and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by chromatography on a 12-g silica cartridge eluted with a 10-45% EtOAc in hexanes gradient to afford two isomeric products.
- Step 1 To a solution of 2-phenylcyclopropanecarboxylic acid (1.0 g, 6.17 mmol) in dry toluene (20 mL) was added triethylamine (934 mg, 9.26 mmol) and DPPA (2.0 g, 7.41 mmol) under N 2 , and the reaction mixture was refluxed for 3 h. The solution was concentrated to give (2-isocyanatocyclopropyl)benzene (800 mg), which was used for the next step without further purification.
- Isomer 1 (7?)-6-allyl-3-((7?) -l-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)- l,3-oxazinan-2-one (334 mg, 7%).
- Isomer 2 (5)-6-allyl-3-((i?) -l-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-
- Step 3 The title compound was prepared from (R)-6-allyl-3-((S)- 1 -(4- bromophenyl)ethyl)-6-phenyl-l,3-oxazinan-2-one following a procedure analogous to that described in Example 78.
- Step 1 3-(2',4'-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl- 1 ,3-oxazinan-2- one
- Step 3 6-(2-azidoethyl)-3-(2',4'-difluorobiphenyl-3-yl)-6-phenyl- 1 ,3-oxazinan-2- one
- 2-(3-(2',4'-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-l,3- oxazinan-6-yl)ethyl methanesulfonate 230 mg, 0.47 mmol
- anhydrous DMF 5 rnL
- NaN 3 92 mg, 1.42 mmol
- Step l 6-allyl-3-((5)-l-(2 > ,4 > -difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-l,3- oxazinan-2-one
- Step 2 To a solution of (R)-6-allyl-3-((S)- 1 -(4'-fluorobiphenyl-4-yl)ethyl)-6-phenyl- l,3-oxazinan-2-one (3 g, 7.23 mmol) in acetone (20 rnL) was added a solution of KMnO 4 (685 mg, 4.34 mmol) and NaIO 4 (5.6 g, 26 mmol) in H 2 O (15 mL) dropwise at 0 °C. The mixture was stirred for 4 h. When TLC showed that the starting material had disappeared, the precipitate was removed by filtration, and the acetone was removed under reduced pressure.
- the mixture was stirred for 2-3 h at rt and diluted with water (8 mL). The pH was adjusted to 6-7 with 0.5 N HCl. The layers were separated, and the aqueous phase was extracted with EtOAc (3 ⁇ 10 mL).
- Step 2 A mixture of (i?)-3-((5)-l-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3- hydroxypropyl)-l,3-oxazinan-2-one (250 mg, 0.6 mmol), 5- (methoxycarbonyl)pyridin-3-ylboronic acid (163 mg, 0.9 mmol), PdCl 2 (PPlIs) 2 (50 mg, 20%) and aqueous CS2CO3 solution (2 M, 2 mL) in 1,4-dioxane (6 mL) was heated to reflux at 100 °C overnight under N 2 . The mixture was filtered, and the filtrate was extracted with EtOAc for 3 times.
- Methyl 5-(4-((S)- 1 -((R)-6-(4-fiuorophenyl)-6-(3-hydroxypropyl)-2-oxo- 1 ,3- oxazinan-3-yl)ethyl)phenyl)nicotinate (30 mg, 0.1 mmol) was dissolved in anhydrous NH3 in EtOH (5 mL). Then the mixture was stirred at rt overnight.
- Step 1 (S)- 1 -bromo-4-( 1 -isocyanatoethyl)benzene
- Step 4 (5)-3-((5)-l-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-l,3-oxazinan- 2-one and 3-((R)-3-((S)- 1 -(4-bromophenyl)ethyl)-2-oxo-6-phenyl- 1 ,3-oxazinan-6- yl)propanal
- Step 5 (S)-3-((S)- 1 -(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl- 1 ,3-oxazinan- 2-one
- Step 6 (S)-3-((S)- ⁇ - (4-bromophenyl) ethyl)-6- (2- hydroxy-2-methylpropyl)- 6- phenyl-1,3- oxazinan-2- one
- 1,4-dioxane (5 mL) was added CsCO 3 (1 mL, 2 mmol) and Pd(PPh 3 ) 2 Cl 2 (50 mg).
- Methyl 6-(4-((S)-l-((S)-6-(2-hydroxy-2- methylpropyl)-2- oxo- 6- phenyl- 1,3- oxazinan-3-yl)ethyl)phenyl)nicotinate 150 mg, 0.307 mmol was dissolved in NH 2 MeZMeOH (IO mL). The mixture was stirred at rt overnight.
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US13/054,959 US8487094B2 (en) | 2008-07-25 | 2009-07-23 | Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 |
EP09780984A EP2323994A1 (en) | 2008-07-25 | 2009-07-23 | Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 |
JP2011519172A JP5390610B2 (en) | 2008-07-25 | 2009-07-23 | Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 |
CN2009801288831A CN102105454A (en) | 2008-07-25 | 2009-07-23 | Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 |
CA2729993A CA2729993A1 (en) | 2008-07-25 | 2009-07-23 | Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 |
IL208896A IL208896A (en) | 2008-07-25 | 2010-10-24 | Derivatives of 6-(2-methyl-oxiranylmethyl)-[1,3] oxazinan-2-one and a process for their preparation |
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2009
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- 2009-07-23 WO PCT/EP2009/059496 patent/WO2010010150A1/en active Application Filing
- 2009-07-23 CN CN2009801288831A patent/CN102105454A/en active Pending
- 2009-07-23 EP EP09780984A patent/EP2323994A1/en not_active Withdrawn
- 2009-07-23 JP JP2011519172A patent/JP5390610B2/en not_active Expired - Fee Related
- 2009-07-23 US US13/054,959 patent/US8487094B2/en active Active
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Also Published As
Publication number | Publication date |
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IL208896A (en) | 2015-03-31 |
US8487094B2 (en) | 2013-07-16 |
CN102105454A (en) | 2011-06-22 |
EP2323994A1 (en) | 2011-05-25 |
JP5390610B2 (en) | 2014-01-15 |
CA2729993A1 (en) | 2010-01-28 |
IL208896A0 (en) | 2011-01-31 |
JP2011528697A (en) | 2011-11-24 |
US20110269957A1 (en) | 2011-11-03 |
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