AU2006251138C1 - Tricyclic spiro derivatives as CRTH2 modulators - Google Patents

Info

Publication number

AU2006251138C1

AU2006251138C1 AU2006251138A AU2006251138A AU2006251138C1 AU 2006251138 C1 AU2006251138 C1 AU 2006251138C1 AU 2006251138 A AU2006251138 A AU 2006251138A AU 2006251138 A AU2006251138 A AU 2006251138A AU 2006251138 C1 AU2006251138 C1 AU 2006251138C1

Authority

AU

Australia

Prior art keywords

chloro

indole

pyrrolidin

trioxospiro

acetic acid

Prior art date

2005-05-24

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.)

Ceased

Links

• Espacenet
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• 125000003003 spiro group Chemical group 0.000 title claims abstract description 101
• 102000009389 Prostaglandin D receptors Human genes 0.000 title claims abstract description 6
• 108050000258 Prostaglandin D receptors Proteins 0.000 title claims abstract description 6
• 230000002757 inflammatory effect Effects 0.000 claims abstract description 22
• 208000026935 allergic disease Diseases 0.000 claims abstract description 19
• 230000000694 effects Effects 0.000 claims abstract description 15
• 208000017520 skin disease Diseases 0.000 claims abstract description 15
• 230000002265 prevention Effects 0.000 claims abstract description 7
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 561
• 150000001875 compounds Chemical class 0.000 claims description 269
• 239000002253 acid Substances 0.000 claims description 181
• -1 hydroxy, amino, aminocarbonyl Chemical group 0.000 claims description 130
• 238000000034 method Methods 0.000 claims description 116
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 107
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 85
• 125000003118 aryl group Chemical group 0.000 claims description 57
• 125000001072 heteroaryl group Chemical group 0.000 claims description 52
• FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 30
• 229910052736 halogen Inorganic materials 0.000 claims description 26
• 239000001257 hydrogen Substances 0.000 claims description 25
• 229910052739 hydrogen Inorganic materials 0.000 claims description 25
• 150000002367 halogens Chemical class 0.000 claims description 22
• 208000024376 chronic urticaria Diseases 0.000 claims description 21
• 150000003839 salts Chemical class 0.000 claims description 20
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 19
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 19
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 17
• 230000029936 alkylation Effects 0.000 claims description 15
• 238000005804 alkylation reaction Methods 0.000 claims description 15
• 239000003814 drug Substances 0.000 claims description 15
• 230000008569 process Effects 0.000 claims description 15
• 239000008194 pharmaceutical composition Substances 0.000 claims description 14
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 12
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 12
• 125000003545 alkoxy group Chemical group 0.000 claims description 12
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
• 208000017983 photosensitivity disease Diseases 0.000 claims description 12
• 208000006673 asthma Diseases 0.000 claims description 11
• 150000002431 hydrogen Chemical group 0.000 claims description 11
• 206010012438 Dermatitis atopic Diseases 0.000 claims description 10
• 201000008937 atopic dermatitis Diseases 0.000 claims description 10
• 206010052568 Urticaria chronic Diseases 0.000 claims description 9
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 9
• 238000002360 preparation method Methods 0.000 claims description 9
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
• 206010012442 Dermatitis contact Diseases 0.000 claims description 8
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
• 208000002029 allergic contact dermatitis Diseases 0.000 claims description 8
• 208000010247 contact dermatitis Diseases 0.000 claims description 8
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 8
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 8
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
• 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 7
• 208000010201 Exanthema Diseases 0.000 claims description 7
• 201000002481 Myositis Diseases 0.000 claims description 7
• QECVIPBZOPUTRD-UHFFFAOYSA-N N=S(=O)=O Chemical compound N=S(=O)=O QECVIPBZOPUTRD-UHFFFAOYSA-N 0.000 claims description 7
• 206010051246 Photodermatosis Diseases 0.000 claims description 7
• 206010036087 Polymorphic light eruption Diseases 0.000 claims description 7
• 206010039085 Rhinitis allergic Diseases 0.000 claims description 7
• 125000004442 acylamino group Chemical group 0.000 claims description 7
• 201000009961 allergic asthma Diseases 0.000 claims description 7
• 208000002205 allergic conjunctivitis Diseases 0.000 claims description 7
• 201000010105 allergic rhinitis Diseases 0.000 claims description 7
• 229910052782 aluminium Inorganic materials 0.000 claims description 7
• 150000001412 amines Chemical class 0.000 claims description 7
• 208000024998 atopic conjunctivitis Diseases 0.000 claims description 7
• 208000029407 autoimmune urticaria Diseases 0.000 claims description 7
• 229940079593 drug Drugs 0.000 claims description 7
• 201000005884 exanthem Diseases 0.000 claims description 7
• 201000006417 multiple sclerosis Diseases 0.000 claims description 7
• 201000008482 osteoarthritis Diseases 0.000 claims description 7
• 206010037844 rash Diseases 0.000 claims description 7
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 230000007062 hydrolysis Effects 0.000 claims description 5
• 238000006460 hydrolysis reaction Methods 0.000 claims description 5
• 208000027866 inflammatory disease Diseases 0.000 claims description 5
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
• 230000001684 chronic effect Effects 0.000 claims description 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
• 229940124530 sulfonamide Drugs 0.000 claims description 4
• 150000003456 sulfonamides Chemical class 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000006516 2-(benzyloxy)ethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
• SYZBWTOXLKZZNP-UHFFFAOYSA-N 2-[1'-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl]-5-chloro-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound O1C(C(C)(C)C)=NC(CN2C(C3(CC2=O)C2=CC(Cl)=CC=C2N(CC(O)=O)C3=O)=O)=N1 SYZBWTOXLKZZNP-UHFFFAOYSA-N 0.000 claims description 2
• WBTUGPRALHNURF-UHFFFAOYSA-N 2-[5-chloro-1'-[(4-methoxy-3-methylpyridin-2-yl)methyl]-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound COC1=CC=NC(CN2C(C3(CC2=O)C2=CC(Cl)=CC=C2N(CC(O)=O)C3=O)=O)=C1C WBTUGPRALHNURF-UHFFFAOYSA-N 0.000 claims description 2
• 229910052799 carbon Inorganic materials 0.000 claims description 2
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 7
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 5
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 3
• 206010002198 Anaphylactic reaction Diseases 0.000 claims 2
• 206010048768 Dermatosis Diseases 0.000 claims 2
• 208000003455 anaphylaxis Diseases 0.000 claims 2
• 230000009610 hypersensitivity Effects 0.000 claims 2
• 206010021247 idiopathic urticaria Diseases 0.000 claims 2
• 238000004519 manufacturing process Methods 0.000 claims 2
• BDWQUHFLKUXBHZ-UHFFFAOYSA-N 2-(1'-benzyl-5-chloro-2,2'-dioxospiro[indole-3,4'-pyrrolidine]-1-yl)acetic acid Chemical compound C12=CC(Cl)=CC=C2N(CC(=O)O)C(=O)C1(CC1=O)CN1CC1=CC=CC=C1 BDWQUHFLKUXBHZ-UHFFFAOYSA-N 0.000 claims 1
• IXKFWNVFUXXEFY-FQEVSTJZSA-N 2-[(3s)-5-chloro-1'-[(5-chloro-2-fluorophenyl)methyl]-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C([C@]1(C(=O)N(C2=CC=C(Cl)C=C21)CC(=O)O)C1=O)C(=O)N1CC1=CC(Cl)=CC=C1F IXKFWNVFUXXEFY-FQEVSTJZSA-N 0.000 claims 1
• MIZGYGQQDQJKQN-UHFFFAOYSA-N 2-[1'-[(2-fluorophenyl)methyl]-2,2',5'-trioxo-5-(trifluoromethoxy)spiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C12=CC(OC(F)(F)F)=CC=C2N(CC(=O)O)C(=O)C1(C1=O)CC(=O)N1CC1=CC=CC=C1F MIZGYGQQDQJKQN-UHFFFAOYSA-N 0.000 claims 1
• HLKOBRAMJFIEGK-UHFFFAOYSA-N 2-[1'-[(4-acetamidophenyl)methyl]-5-chloro-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C1=CC(NC(=O)C)=CC=C1CN1C(=O)C2(C3=CC(Cl)=CC=C3N(CC(O)=O)C2=O)CC1=O HLKOBRAMJFIEGK-UHFFFAOYSA-N 0.000 claims 1
• FRNKZMPGRLAFSU-UHFFFAOYSA-N 2-[1'-[(4-carbamoylphenyl)methyl]-5-chloro-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C1=CC(C(=O)N)=CC=C1CN1C(=O)C2(C3=CC(Cl)=CC=C3N(CC(O)=O)C2=O)CC1=O FRNKZMPGRLAFSU-UHFFFAOYSA-N 0.000 claims 1
• OMZNSFXGTFCYFB-UHFFFAOYSA-N 2-[1'-[(4-fluorophenyl)methyl]-2,2',5'-trioxo-5-(trifluoromethoxy)spiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C12=CC(OC(F)(F)F)=CC=C2N(CC(=O)O)C(=O)C1(C1=O)CC(=O)N1CC1=CC=C(F)C=C1 OMZNSFXGTFCYFB-UHFFFAOYSA-N 0.000 claims 1
• VEEDEOIGYMFLIJ-UHFFFAOYSA-N 2-[5-chloro-1'-(1,3-oxazol-2-ylmethyl)-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C12=CC(Cl)=CC=C2N(CC(=O)O)C(=O)C1(C1=O)CC(=O)N1CC1=NC=CO1 VEEDEOIGYMFLIJ-UHFFFAOYSA-N 0.000 claims 1
• WNEFBNBADIHNTR-UHFFFAOYSA-N 2-[5-chloro-1'-[(2-chloro-5-fluorophenyl)methyl]-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C12=CC(Cl)=CC=C2N(CC(=O)O)C(=O)C1(C1=O)CC(=O)N1CC1=CC(F)=CC=C1Cl WNEFBNBADIHNTR-UHFFFAOYSA-N 0.000 claims 1
• AYLVIBHVUIINDQ-UHFFFAOYSA-N 2-[5-chloro-1'-[(2-fluorophenyl)methyl]-2,2'-dioxospiro[indole-3,4'-pyrrolidine]-1-yl]acetic acid Chemical compound C12=CC(Cl)=CC=C2N(CC(=O)O)C(=O)C1(CC1=O)CN1CC1=CC=CC=C1F AYLVIBHVUIINDQ-UHFFFAOYSA-N 0.000 claims 1
• VFEFRCZEARGBHS-UHFFFAOYSA-N 2-[5-chloro-1'-[(2-methyl-1,3-thiazol-4-yl)methyl]-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound S1C(C)=NC(CN2C(C3(CC2=O)C2=CC(Cl)=CC=C2N(CC(O)=O)C3=O)=O)=C1 VFEFRCZEARGBHS-UHFFFAOYSA-N 0.000 claims 1
• PTGHDUZXAIHWGN-UHFFFAOYSA-N 2-[5-chloro-1'-[(3-chlorophenyl)methyl]-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C12=CC(Cl)=CC=C2N(CC(=O)O)C(=O)C1(C1=O)CC(=O)N1CC1=CC=CC(Cl)=C1 PTGHDUZXAIHWGN-UHFFFAOYSA-N 0.000 claims 1
• UJYVUWBBXAPUDC-UHFFFAOYSA-N 2-[5-chloro-1'-[(3-methyl-5-phenyl-1,2-oxazol-4-yl)methyl]-2,2'-dioxospiro[indole-3,4'-pyrrolidine]-1-yl]acetic acid Chemical compound C1C2(C3=CC(Cl)=CC=C3N(CC(O)=O)C2=O)CC(=O)N1CC=1C(C)=NOC=1C1=CC=CC=C1 UJYVUWBBXAPUDC-UHFFFAOYSA-N 0.000 claims 1
• VJYXHXGNMCGAMT-UHFFFAOYSA-N 2-[5-chloro-1'-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl]-2,2',5'-trioxospiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C12=CC(Cl)=CC=C2N(CC(=O)O)C(=O)C1(C1=O)CC(=O)N1CC(N=1)=CSC=1C1=CC=C(Cl)C=C1 VJYXHXGNMCGAMT-UHFFFAOYSA-N 0.000 claims 1
• XGABWFHBDDEURD-UHFFFAOYSA-N 4-[5-chloro-2,2',5'-trioxo-1'-[[4-(trifluoromethyl)phenyl]methyl]spiro[indole-3,3'-pyrrolidine]-1-yl]butanoic acid Chemical compound C12=CC(Cl)=CC=C2N(CCCC(=O)O)C(=O)C1(C1=O)CC(=O)N1CC1=CC=C(C(F)(F)F)C=C1 XGABWFHBDDEURD-UHFFFAOYSA-N 0.000 claims 1
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 14
• 201000010099 disease Diseases 0.000 abstract description 12
• 239000000543 intermediate Substances 0.000 description 199
• 238000004949 mass spectrometry Methods 0.000 description 194
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 174
• 229960000583 acetic acid Drugs 0.000 description 124
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 123
• 235000011054 acetic acid Nutrition 0.000 description 121
• 239000007787 solid Substances 0.000 description 103
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
• 238000004128 high performance liquid chromatography Methods 0.000 description 71
• 238000007429 general method Methods 0.000 description 68
• 239000002904 solvent Substances 0.000 description 59
• 235000019439 ethyl acetate Nutrition 0.000 description 58
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 53
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 52
• 239000000203 mixture Substances 0.000 description 52
• 239000000243 solution Substances 0.000 description 48
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 45
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 45
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 44
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 44
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 38
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
• 238000003756 stirring Methods 0.000 description 31
• ACCRRLVDDBQSKQ-UHFFFAOYSA-N 5-chlorospiro[1h-indole-3,3'-pyrrolidine]-2,2',5'-trione Chemical compound C12=CC(Cl)=CC=C2NC(=O)C21CC(=O)NC2=O ACCRRLVDDBQSKQ-UHFFFAOYSA-N 0.000 description 30
• 239000002585 base Substances 0.000 description 29
• 229910000104 sodium hydride Inorganic materials 0.000 description 29
• 238000006243 chemical reaction Methods 0.000 description 28
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• 239000000377 silicon dioxide Substances 0.000 description 25
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
• 238000005481 NMR spectroscopy Methods 0.000 description 23
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
• 229910000027 potassium carbonate Inorganic materials 0.000 description 22
• 239000002168 alkylating agent Substances 0.000 description 21
• 229940100198 alkylating agent Drugs 0.000 description 21
• 235000011181 potassium carbonates Nutrition 0.000 description 21
• 239000000725 suspension Substances 0.000 description 21
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 19
• 239000000284 extract Substances 0.000 description 19
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 19
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 19
• 229910052740 iodine Inorganic materials 0.000 description 19
• 238000000746 purification Methods 0.000 description 19
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 18
• 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 18
• BHMBVRSPMRCCGG-UHFFFAOYSA-N prostaglandine D2 Natural products CCCCCC(O)C=CC1C(CC=CCCCC(O)=O)C(O)CC1=O BHMBVRSPMRCCGG-UHFFFAOYSA-N 0.000 description 18
• 239000011541 reaction mixture Substances 0.000 description 18
• 239000012312 sodium hydride Substances 0.000 description 18
• 229910052794 bromium Inorganic materials 0.000 description 17
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 16
• 150000001649 bromium compounds Chemical class 0.000 description 16
• 150000004694 iodide salts Chemical class 0.000 description 16
• 238000010992 reflux Methods 0.000 description 16
• 150000001348 alkyl chlorides Chemical class 0.000 description 15
• 125000000217 alkyl group Chemical group 0.000 description 15
• 230000015572 biosynthetic process Effects 0.000 description 15
• 238000001704 evaporation Methods 0.000 description 15
• 230000008020 evaporation Effects 0.000 description 15
• NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 15
• 206010042033 Stevens-Johnson syndrome Diseases 0.000 description 14
• 239000012267 brine Substances 0.000 description 14
• 238000003818 flash chromatography Methods 0.000 description 14
• 239000003208 petroleum Substances 0.000 description 14
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
• 238000004587 chromatography analysis Methods 0.000 description 13
• JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 13
• LOTKRQAVGJMPNV-UHFFFAOYSA-N 1-fluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C([N+]([O-])=O)=C1 LOTKRQAVGJMPNV-UHFFFAOYSA-N 0.000 description 12
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
• 230000027455 binding Effects 0.000 description 12
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 11
• 210000004027 cell Anatomy 0.000 description 11
• 235000019341 magnesium sulphate Nutrition 0.000 description 11
• 239000000047 product Substances 0.000 description 11
• 125000001424 substituent group Chemical group 0.000 description 11
• BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 11
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
• 206010044223 Toxic epidermal necrolysis Diseases 0.000 description 10
• 231100000087 Toxic epidermal necrolysis Toxicity 0.000 description 10
• 125000000304 alkynyl group Chemical group 0.000 description 10
• 230000000875 corresponding effect Effects 0.000 description 10
• JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 10
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