NL1001194C2 - Synthese van 3-£4-(2-aminoethoxy)-benzoyl|-2-aryl-6-hydroxybenzo£b|thio- fenen. - Google Patents

Synthese van 3-£4-(2-aminoethoxy)-benzoyl|-2-aryl-6-hydroxybenzo£b|thio- fenen. Download PDF

Info

Publication number: NL1001194C2
Authority: NL; Netherlands
Prior art keywords: formula; hydroxy; chlorine; benzoyl; crystalline
Prior art date: 1994-09-19

Application number

NL1001194A

Other languages

English (en)

Dutch (nl)

Other versions

NL1001194A1 (nl

Inventor

Wayne Douglas Luke

Randal Scot Miller

John Mcneill Mcgill Iii

Elizabeth Smit Labell

Original Assignee

Lilly Co Eli

Priority date (The priority date 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 date listed.)

1994-09-19

Filing date

1995-09-14

Publication date

1997-04-04

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26976194&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=NL1001194(C2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1994-09-19 Priority claimed from US08/308,325 external-priority patent/US5629425A/en

1995-09-14 Application filed by Lilly Co Eli filed Critical Lilly Co Eli

1996-03-19 Publication of NL1001194A1 publication Critical patent/NL1001194A1/xx

1997-04-04 Application granted granted Critical

1997-04-04 Publication of NL1001194C2 publication Critical patent/NL1001194C2/nl

Links

-1 2-aminoethoxy Chemical group 0.000 title claims description 44
230000015572 biosynthetic process Effects 0.000 title description 11
238000003786 synthesis reaction Methods 0.000 title description 11
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 145
150000001875 compounds Chemical class 0.000 claims description 80
FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 56
239000000203 mixture Substances 0.000 claims description 49
238000000034 method Methods 0.000 claims description 46
239000012453 solvate Substances 0.000 claims description 46
238000005917 acylation reaction Methods 0.000 claims description 45
239000002904 solvent Substances 0.000 claims description 41
230000010933 acylation Effects 0.000 claims description 39
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 37
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 34
238000006900 dealkylation reaction Methods 0.000 claims description 30
239000000460 chlorine Substances 0.000 claims description 25
229910052801 chlorine Inorganic materials 0.000 claims description 25
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 23
230000020335 dealkylation Effects 0.000 claims description 21
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
CFXQEHVMCRXUSD-UHFFFAOYSA-N 1,2,3-Trichloropropane Chemical compound ClCC(Cl)CCl CFXQEHVMCRXUSD-UHFFFAOYSA-N 0.000 claims description 18
238000002441 X-ray diffraction Methods 0.000 claims description 16
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 14
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 14
229910052794 bromium Inorganic materials 0.000 claims description 14
125000001309 chloro group Chemical group Cl* 0.000 claims description 13
125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 11
239000003795 chemical substances by application Substances 0.000 claims description 9
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
238000001914 filtration Methods 0.000 claims description 7
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 6
229910052802 copper Inorganic materials 0.000 claims description 6
239000010949 copper Substances 0.000 claims description 6
229910052739 hydrogen Inorganic materials 0.000 claims description 6
239000001257 hydrogen Substances 0.000 claims description 6
230000005855 radiation Effects 0.000 claims description 6
OFHAGSNEHHNRSV-UHFFFAOYSA-N 1-benzothiophene;hydrochloride Chemical compound Cl.C1=CC=C2SC=CC2=C1 OFHAGSNEHHNRSV-UHFFFAOYSA-N 0.000 claims description 5
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
125000000217 alkyl group Chemical group 0.000 claims description 5
238000004821 distillation Methods 0.000 claims description 5
238000004519 manufacturing process Methods 0.000 claims description 4
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
229910052757 nitrogen Inorganic materials 0.000 claims description 3
125000000623 heterocyclic group Chemical group 0.000 claims description 2
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
230000001747 exhibiting effect Effects 0.000 claims 2
WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims 1
QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims 1
125000003545 alkoxy group Chemical group 0.000 claims 1
229940125846 compound 25 Drugs 0.000 claims 1
125000004122 cyclic group Chemical group 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
238000006243 chemical reaction Methods 0.000 description 46
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
239000000243 solution Substances 0.000 description 41
239000013078 crystal Substances 0.000 description 26
FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 25
ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 22
238000002360 preparation method Methods 0.000 description 22
239000000047 product Substances 0.000 description 21
RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 20
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 17
239000011541 reaction mixture Substances 0.000 description 17
239000002178 crystalline material Substances 0.000 description 16
238000002844 melting Methods 0.000 description 14
230000008018 melting Effects 0.000 description 14
229910052796 boron Inorganic materials 0.000 description 13
238000004128 high performance liquid chromatography Methods 0.000 description 13
ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 12
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
238000007792 addition Methods 0.000 description 9
239000002002 slurry Substances 0.000 description 9
239000007787 solid Substances 0.000 description 9
238000000634 powder X-ray diffraction Methods 0.000 description 8
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 7
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
238000010992 reflux Methods 0.000 description 7
QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 6
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
239000002585 base Substances 0.000 description 6
BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
239000000706 filtrate Substances 0.000 description 6
239000012535 impurity Substances 0.000 description 6
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
125000006239 protecting group Chemical group 0.000 description 6
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
238000005481 NMR spectroscopy Methods 0.000 description 5
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
229910052782 aluminium Inorganic materials 0.000 description 5
XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 5
125000005605 benzo group Chemical group 0.000 description 5
239000006227 byproduct Substances 0.000 description 5
238000002425 crystallisation Methods 0.000 description 5
230000008025 crystallization Effects 0.000 description 5
239000000463 material Substances 0.000 description 5
PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 5
239000003960 organic solvent Substances 0.000 description 5
GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 5
BKXVVCILCIUCLG-UHFFFAOYSA-N raloxifene hydrochloride Chemical compound [H+].[Cl-].C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 BKXVVCILCIUCLG-UHFFFAOYSA-N 0.000 description 5
238000001953 recrystallisation Methods 0.000 description 5
239000007858 starting material Substances 0.000 description 5
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 5
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 4
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
239000003054 catalyst Substances 0.000 description 4
239000003153 chemical reaction reagent Substances 0.000 description 4
238000004817 gas chromatography Methods 0.000 description 4
239000002245 particle Substances 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
238000010791 quenching Methods 0.000 description 4
230000000171 quenching effect Effects 0.000 description 4
239000000126 substance Substances 0.000 description 4
VFLQQZCRHPIGJU-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine;hydron;chloride Chemical compound Cl.ClCCN1CCCCC1 VFLQQZCRHPIGJU-UHFFFAOYSA-N 0.000 description 3
125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 3
238000005727 Friedel-Crafts reaction Methods 0.000 description 3
JLERVPBPJHKRBJ-UHFFFAOYSA-N LY 117018 Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCC3)=CC=2)C2=CC=C(O)C=C2S1 JLERVPBPJHKRBJ-UHFFFAOYSA-N 0.000 description 3
LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
238000003776 cleavage reaction Methods 0.000 description 3
238000010438 heat treatment Methods 0.000 description 3
238000005580 one pot reaction Methods 0.000 description 3
150000008379 phenol ethers Chemical class 0.000 description 3
238000007363 ring formation reaction Methods 0.000 description 3
230000007017 scission Effects 0.000 description 3
238000003756 stirring Methods 0.000 description 3
238000004809 thin layer chromatography Methods 0.000 description 3
150000003568 thioethers Chemical class 0.000 description 3
229930192474 thiophene Natural products 0.000 description 3
APMJBTGDXWLDED-UHFFFAOYSA-N 1,2-dichloroethane;[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone;hydrochloride Chemical compound Cl.ClCCCl.C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 APMJBTGDXWLDED-UHFFFAOYSA-N 0.000 description 2
238000005160 1H NMR spectroscopy Methods 0.000 description 2
VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical compound NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 description 2
229910015900 BF3 Inorganic materials 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
KHKWHMPEDILGEQ-UHFFFAOYSA-N ClCCCl.Cl.S1C2=C(C=C1)C=CC=C2 Chemical compound ClCCCl.Cl.S1C2=C(C=C1)C=CC=C2 KHKWHMPEDILGEQ-UHFFFAOYSA-N 0.000 description 2
RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
101150101537 Olah gene Proteins 0.000 description 2
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 2
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
230000002378 acidificating effect Effects 0.000 description 2
150000001298 alcohols Chemical class 0.000 description 2
AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 2
230000001833 anti-estrogenic effect Effects 0.000 description 2
150000008365 aromatic ketones Chemical class 0.000 description 2
239000003849 aromatic solvent Substances 0.000 description 2
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
238000006555 catalytic reaction Methods 0.000 description 2
238000005660 chlorination reaction Methods 0.000 description 2
MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
239000012043 crude product Substances 0.000 description 2
LJSQFQKUNVCTIA-UHFFFAOYSA-N diethyl sulfide Chemical compound CCSCC LJSQFQKUNVCTIA-UHFFFAOYSA-N 0.000 description 2
238000004090 dissolution Methods 0.000 description 2
239000000328 estrogen antagonist Substances 0.000 description 2
DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 2
239000012065 filter cake Substances 0.000 description 2
239000012467 final product Substances 0.000 description 2
239000012458 free base Substances 0.000 description 2
239000007789 gas Substances 0.000 description 2
238000005658 halogenation reaction Methods 0.000 description 2
125000004464 hydroxyphenyl group Chemical group 0.000 description 2
150000007529 inorganic bases Chemical class 0.000 description 2
RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
239000011968 lewis acid catalyst Substances 0.000 description 2
229910001507 metal halide Inorganic materials 0.000 description 2
150000005309 metal halides Chemical class 0.000 description 2
239000012074 organic phase Substances 0.000 description 2
239000008194 pharmaceutical composition Substances 0.000 description 2
229920000137 polyphosphoric acid Polymers 0.000 description 2
229910000027 potassium carbonate Inorganic materials 0.000 description 2
239000000843 powder Substances 0.000 description 2
239000002244 precipitate Substances 0.000 description 2
238000012545 processing Methods 0.000 description 2
AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
238000001228 spectrum Methods 0.000 description 2
125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 description 2
238000012360 testing method Methods 0.000 description 2
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
150000003577 thiophenes Chemical class 0.000 description 2
ZSUXOVNWDZTCFN-UHFFFAOYSA-L tin(ii) bromide Chemical compound Br[Sn]Br ZSUXOVNWDZTCFN-UHFFFAOYSA-L 0.000 description 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
WNRWEBKEQARBKV-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine Chemical compound ClCCN1CCCCC1 WNRWEBKEQARBKV-UHFFFAOYSA-N 0.000 description 1
RMGFLMXDCGQKPS-UHFFFAOYSA-N 1-(2-chloroethyl)pyrrolidine Chemical compound ClCCN1CCCC1 RMGFLMXDCGQKPS-UHFFFAOYSA-N 0.000 description 1
125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
XQJAHBHCLXUGEP-UHFFFAOYSA-N 2-bromo-1-(4-methoxyphenyl)ethanone Chemical compound COC1=CC=C(C(=O)CBr)C=C1 XQJAHBHCLXUGEP-UHFFFAOYSA-N 0.000 description 1
125000000872 2-diethylaminoethoxy group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 description 1
NHIKMAPYSZXBRO-UHFFFAOYSA-N 3-methoxy-2-(4-methoxyphenyl)-1-benzothiophene Chemical compound S1C2=CC=CC=C2C(OC)=C1C1=CC=C(OC)C=C1 NHIKMAPYSZXBRO-UHFFFAOYSA-N 0.000 description 1
QMVAZEHZOPDGHA-UHFFFAOYSA-N 3-methoxybenzenethiol Chemical compound COC1=CC=CC(S)=C1 QMVAZEHZOPDGHA-UHFFFAOYSA-N 0.000 description 1
ZAPMTSHEXFEPSD-UHFFFAOYSA-N 4-(2-chloroethyl)morpholine Chemical compound ClCCN1CCOCC1 ZAPMTSHEXFEPSD-UHFFFAOYSA-N 0.000 description 1
WHKJLXLFQNXNNR-UHFFFAOYSA-N 4-(2-piperidin-1-ylethoxy)benzoyl chloride;hydrochloride Chemical compound Cl.C1=CC(C(=O)Cl)=CC=C1OCCN1CCCCC1 WHKJLXLFQNXNNR-UHFFFAOYSA-N 0.000 description 1
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
HRWAGCVMOGWQJF-UHFFFAOYSA-N 6-methoxy-2-(4-methoxyphenyl)-1-benzothiophene Chemical compound C1=CC(OC)=CC=C1C1=CC2=CC=C(OC)C=C2S1 HRWAGCVMOGWQJF-UHFFFAOYSA-N 0.000 description 1
229910015845 BBr3 Inorganic materials 0.000 description 1
239000005711 Benzoic acid Substances 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
DOZGMAMSPUQBNI-UHFFFAOYSA-N ClCCl.Cl.S1C2=C(C=C1)C=CC=C2 Chemical compound ClCCl.Cl.S1C2=C(C=C1)C=CC=C2 DOZGMAMSPUQBNI-UHFFFAOYSA-N 0.000 description 1
238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
239000007836 KH2PO4 Substances 0.000 description 1
239000005909 Kieselgur Substances 0.000 description 1
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
LJHLDZQXTQNFBP-UHFFFAOYSA-N [4-(2-aminoethoxy)phenyl]-[4-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone Chemical class OC1=CC=CC=2SC(=C(C=21)C(C1=CC=C(C=C1)OCCN)=O)C1=CC=C(C=C1)O LJHLDZQXTQNFBP-UHFFFAOYSA-N 0.000 description 1
FUYHPEFCMUFNLQ-UHFFFAOYSA-N [4-(2-aminoethoxy)phenyl]-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone Chemical class C1=CC(OCCN)=CC=C1C(=O)C1=C(C=2C=CC(O)=CC=2)SC2=CC(O)=CC=C12 FUYHPEFCMUFNLQ-UHFFFAOYSA-N 0.000 description 1
KGSLUOGYYWUPCO-UHFFFAOYSA-N [4-[2-(dimethylamino)ethoxy]phenyl]-(6-hydroxy-2-phenyl-1-benzothiophen-3-yl)methanone Chemical compound C1=CC(OCCN(C)C)=CC=C1C(=O)C1=C(C=2C=CC=CC=2)SC2=CC(O)=CC=C12 KGSLUOGYYWUPCO-UHFFFAOYSA-N 0.000 description 1
GVHFVTLDHBPKOF-UHFFFAOYSA-N [4-[2-(dimethylamino)ethoxy]phenyl]-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone Chemical compound C1=CC(OCCN(C)C)=CC=C1C(=O)C1=C(C=2C=CC(O)=CC=2)SC2=CC(O)=CC=C12 GVHFVTLDHBPKOF-UHFFFAOYSA-N 0.000 description 1
MSRYQTKAUSVEDP-UHFFFAOYSA-N [6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(OC)C=C2S1 MSRYQTKAUSVEDP-UHFFFAOYSA-N 0.000 description 1
MPPNHHUKVJDWQV-UHFFFAOYSA-N [6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(OC)C=C2S1 MPPNHHUKVJDWQV-UHFFFAOYSA-N 0.000 description 1
238000010521 absorption reaction Methods 0.000 description 1
239000002253 acid Substances 0.000 description 1
125000002252 acyl group Chemical group 0.000 description 1
150000001346 alkyl aryl ethers Chemical class 0.000 description 1
125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
230000029936 alkylation Effects 0.000 description 1
238000005804 alkylation reaction Methods 0.000 description 1
RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
230000002280 anti-androgenic effect Effects 0.000 description 1
229940046836 anti-estrogen Drugs 0.000 description 1
239000011260 aqueous acid Substances 0.000 description 1
125000003118 aryl group Chemical group 0.000 description 1
125000005002 aryl methyl group Chemical group 0.000 description 1
125000004391 aryl sulfonyl group Chemical group 0.000 description 1
239000012298 atmosphere Substances 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
UIJGNTRUPZPVNG-UHFFFAOYSA-N benzenecarbothioic s-acid Chemical compound SC(=O)C1=CC=CC=C1 UIJGNTRUPZPVNG-UHFFFAOYSA-N 0.000 description 1
235000010233 benzoic acid Nutrition 0.000 description 1
JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 description 1
238000009835 boiling Methods 0.000 description 1
239000000872 buffer Substances 0.000 description 1
238000011088 calibration curve Methods 0.000 description 1
125000004432 carbon atom Chemical group C* 0.000 description 1
150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
239000007795 chemical reaction product Substances 0.000 description 1
239000007805 chemical reaction reactant Substances 0.000 description 1
239000007810 chemical reaction solvent Substances 0.000 description 1
KWVPLQSWXYDXSP-UHFFFAOYSA-N chloroform;[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone;hydrochloride Chemical compound Cl.ClC(Cl)Cl.C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 KWVPLQSWXYDXSP-UHFFFAOYSA-N 0.000 description 1
238000010520 demethylation reaction Methods 0.000 description 1
229940075894 denatured ethanol Drugs 0.000 description 1
230000001419 dependent effect Effects 0.000 description 1
238000001514 detection method Methods 0.000 description 1
238000000113 differential scanning calorimetry Methods 0.000 description 1
238000007865 diluting Methods 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
238000001035 drying Methods 0.000 description 1
239000003480 eluent Substances 0.000 description 1
230000002124 endocrine Effects 0.000 description 1
125000004185 ester group Chemical group 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
229940011871 estrogen Drugs 0.000 description 1
239000000262 estrogen Substances 0.000 description 1
GEBZGEGHFMUFJA-UHFFFAOYSA-N ethyl 4-(2-piperidin-1-ylethoxy)benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1OCCN1CCCCC1 GEBZGEGHFMUFJA-UHFFFAOYSA-N 0.000 description 1
125000004494 ethyl ester group Chemical group 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
238000000605 extraction Methods 0.000 description 1
239000011521 glass Substances 0.000 description 1
230000002140 halogenating effect Effects 0.000 description 1
230000026030 halogenation Effects 0.000 description 1
229910000856 hastalloy Inorganic materials 0.000 description 1
CMVTYSMYHSVDIU-UHFFFAOYSA-N hydron;4-(2-piperidin-1-ylethoxy)benzoic acid;chloride Chemical compound Cl.C1=CC(C(=O)O)=CC=C1OCCN1CCCCC1 CMVTYSMYHSVDIU-UHFFFAOYSA-N 0.000 description 1
238000011065 in-situ storage Methods 0.000 description 1
238000002955 isolation Methods 0.000 description 1
239000010410 layer Substances 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
239000011159 matrix material Substances 0.000 description 1
229930182817 methionine Natural products 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
235000019796 monopotassium phosphate Nutrition 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
125000006606 n-butoxy group Chemical group 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
WLGDAKIJYPIYLR-UHFFFAOYSA-M octane-1-sulfonate Chemical compound CCCCCCCCS([O-])(=O)=O WLGDAKIJYPIYLR-UHFFFAOYSA-M 0.000 description 1
210000000056 organ Anatomy 0.000 description 1
239000012044 organic layer Substances 0.000 description 1
230000020477 pH reduction Effects 0.000 description 1
230000001575 pathological effect Effects 0.000 description 1
239000012071 phase Substances 0.000 description 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
239000010452 phosphate Substances 0.000 description 1
239000003495 polar organic solvent Substances 0.000 description 1
GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
239000008057 potassium phosphate buffer Substances 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
238000010926 purge Methods 0.000 description 1
238000000746 purification Methods 0.000 description 1
125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
MDGWZLQPNOETLH-UHFFFAOYSA-N raloxifene core Chemical compound C1=CC(O)=CC=C1C1=CC2=CC=C(O)C=C2S1 MDGWZLQPNOETLH-UHFFFAOYSA-N 0.000 description 1
150000003839 salts Chemical class 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
239000012047 saturated solution Substances 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
239000011343 solid material Substances 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
230000003637 steroidlike Effects 0.000 description 1
239000000758 substrate Substances 0.000 description 1
238000010189 synthetic method Methods 0.000 description 1
150000007970 thio esters Chemical class 0.000 description 1
150000003573 thiols Chemical class 0.000 description 1
HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
UBZYKBZMAMTNKW-UHFFFAOYSA-J titanium tetrabromide Chemical compound Br[Ti](Br)(Br)Br UBZYKBZMAMTNKW-UHFFFAOYSA-J 0.000 description 1
XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 description 1
238000000825 ultraviolet detection Methods 0.000 description 1
238000005292 vacuum distillation Methods 0.000 description 1
238000001291 vacuum drying Methods 0.000 description 1
239000002699 waste material Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/56—Radicals substituted by oxygen atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Engineering & Computer Science (AREA)
Public Health (AREA)
Chemical Kinetics & Catalysis (AREA)
Endocrinology (AREA)
Diabetes (AREA)
Gynecology & Obstetrics (AREA)
Reproductive Health (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

NL1001194A 1994-09-19 1995-09-14 Synthese van 3-£4-(2-aminoethoxy)-benzoyl|-2-aryl-6-hydroxybenzo£b|thio- fenen. NL1001194C2 (nl)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
US30832594		1994-09-19
US08/308,325 US5629425A (en)	1994-09-19	1994-09-19	Haloalkyl hemisolvates of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-piperidinoethoxy)-benzoyl]benzo[b]thiophene
US42791495A	1995-04-26	1995-04-26
US42791495		1995-04-26

Publications (2)

Publication Number	Publication Date
NL1001194A1 NL1001194A1 (nl)	1996-03-19
NL1001194C2 true NL1001194C2 (nl)	1997-04-04

Family

ID=26976194

Family Applications (2)

Application Number	Title	Priority Date	Filing Date
NL1001194A NL1001194C2 (nl)	1994-09-19	1995-09-14	Synthese van 3-£4-(2-aminoethoxy)-benzoyl\|-2-aryl-6-hydroxybenzo£b\|thio- fenen.
NL1001196A NL1001196C2 (nl)	1994-09-19	1995-09-14	Nieuw farmaceutisch produkt.

Family Applications After (1)

Application Number	Title	Priority Date	Filing Date
NL1001196A NL1001196C2 (nl)	1994-09-19	1995-09-14	Nieuw farmaceutisch produkt.

Country Status (50)

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US (4)	US6472531B1 (it)
JP (2)	JPH08193081A (it)
KR (2)	KR100381346B1 (it)
CN (2)	CN1068324C (it)
AP (1)	AP754A (it)
AT (2)	AT407988B (it)
AU (3)	AU692907B2 (it)
BE (2)	BE1009626A3 (it)
BG (1)	BG62793B1 (it)
BR (2)	BR9504059A (it)
CA (2)	CA2158399C (it)
CH (3)	CH691478A5 (it)
CO (2)	CO4410190A1 (it)
CZ (2)	CZ292007B6 (it)
DE (3)	DE19534744A1 (it)
DK (4)	DK175903B1 (it)
EE (1)	EE03386B1 (it)
EG (1)	EG23763A (it)
ES (2)	ES2109882B1 (it)
FI (2)	FI121424B (it)
FR (2)	FR2732020B1 (it)
GB (2)	GB2293602B (it)
GE (1)	GEP19991821B (it)
GR (2)	GR1002709B (it)
HR (2)	HRP950483B1 (it)
HU (2)	HU227683B1 (it)
IE (2)	IE950722A1 (it)
IL (3)	IL115314A (it)
IS (1)	IS1788B (it)
IT (2)	IT1277602B1 (it)
LU (2)	LU88661A1 (it)
LV (2)	LV11177B (it)
MY (1)	MY116371A (it)
NL (2)	NL1001194C2 (it)
NO (2)	NO308107B1 (it)
NZ (2)	NZ280027A (it)
OA (1)	OA10406A (it)
PE (2)	PE14796A1 (it)
PL (2)	PL187686B1 (it)
PT (2)	PT101771B (it)
RO (2)	RO115260B1 (it)
RS (2)	RS49513B (it)
SE (2)	SE509265C2 (it)
SI (2)	SI9500293A (it)
SK (1)	SK283502B6 (it)
TR (1)	TR199501136A2 (it)
TW (1)	TW412534B (it)
UA (2)	UA44240C2 (it)
UY (1)	UY24040A1 (it)
WO (1)	WO1996009045A1 (it)

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USRE38968E1 (en)	1992-07-28	2006-02-07	Eli Lilly And Company	Methods for inhibiting bone loss using 6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thien-3-yl-4-[2-(piperidin-1-yl) ethoxyphenylimethanone hydrochloride
USRE39049E1 (en)	1992-07-28	2006-03-28	Eli Lilly And Company	Methods for inhibiting bone loss
TW366342B (en) *	1992-07-28	1999-08-11	Lilly Co Eli	The use of 2-phenyl-3-aroylbenzothiophenes in inhibiting bone loss
US5478847A (en)	1994-03-02	1995-12-26	Eli Lilly And Company	Methods of use for inhibiting bone loss and lowering serum cholesterol
CO4410190A1 (es) *	1994-09-19	1997-01-09	Lilly Co Eli	3-[4-(2-AMINOETOXI)-BENZOIL]-2-ARIL-6-HIDROXIBENZO [b] TIOFENO CRISTALINO
EA001257B1 (ru) *	1996-03-26	2000-12-25	Эли Лилли Энд Компани	Бензотиофены, содержащие их фармацевтические композиции и способы лечения патологических состояний с их использованием
US6458811B1 (en) *	1996-03-26	2002-10-01	Eli Lilly And Company	Benzothiophenes formulations containing same and methods
ZA992858B (en)	1996-10-30	1999-07-29	Lilly Co Eli	Methods of preventing breast cancer.
CA2236254A1 (en) *	1997-04-30	1998-10-30	David Warren Hoard	Process for preparing benzo¬b\|thiophenes
CN1250563C (zh)	1999-05-04	2006-04-12	斯特拉坎有限公司	雄激素糖苷及其产生雄性征的活性
AU2002230409A1 (en) *	2000-11-27	2002-06-03	Eli Lilly And Company	Process for preparing 3-aryl-benzo(b)thiophenes
EP2316468A1 (en)	2002-02-22	2011-05-04	Shire LLC	Delivery system and methods for protecting and administering dextroamphetamine
US7407955B2 (en)	2002-08-21	2008-08-05	Boehringer Ingelheim Pharma Gmbh & Co., Kg	8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
EP1832583A1 (en)	2002-09-30	2007-09-12	A/S GEA Farmaceutisk Fabrik	Novel raloxifene sulphuric acid addition salts and/or solvates thereof, and pharmaceutical compositions comprising these
US6861422B2 (en)	2003-02-26	2005-03-01	Boehringer Ingelheim Pharma Gmbh & Co. Kg	Dihydropteridinones, processes for preparing them and their use as pharmaceutical compositions
US20060106010A1 (en) *	2003-05-27	2006-05-18	Black Larry J	Methods for inhibiting bone loss
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Publication number	Publication date
BE1009625A3 (fr)	1997-06-03
DK175886B1 (da)	2005-05-23
LV11177A (lv)	1996-04-20
LV11177B (en)	1996-08-20
ITMI951936A1 (it)	1997-03-15
ITMI951935A0 (it)	1995-09-15
GB2293382B (en)	1998-08-19
LV11178B (en)	1996-08-20
AT502957A1 (de)	2007-06-15
IL115315A (en)	1999-09-22
NO953657L (no)	1996-03-20
DE19534744A1 (de)	1996-03-21
CZ240295A3 (en)	1996-04-17
HUT74178A (en)	1996-11-28
SE9503213D0 (sv)	1995-09-15
PE32796A1 (es)	1996-08-07
GB2293382A (en)	1996-03-27
CO4410190A1 (es)	1997-01-09
DE19534745A1 (de)	1996-04-04
PE14796A1 (es)	1996-05-19
FI954402L (fi)	1996-03-20
IL115314A (en)	2000-02-29
JPH08176147A (ja)	1996-07-09
CZ290343B6 (cs)	2002-07-17
NO953658L (no)	1996-03-20
KR960010634A (ko)	1996-04-20
SE509265C2 (sv)	1998-12-21
YU61395A (sh)	1998-09-18
LU88660A1 (fr)	1996-07-15
CA2158400C (en)	2006-10-24
IL115314A0 (en)	1996-05-14
WO1996009045A1 (en)	1996-03-28
JPH08193081A (ja)	1996-07-30
CH691594A5 (de)	2001-08-31
HRP950482B1 (en)	2007-04-30
CN1127253A (zh)	1996-07-24
HU9502723D0 (en)	1995-11-28
NZ280027A (en)	1997-05-26
CN1068324C (zh)	2001-07-11
AU3173195A (en)	1996-04-04
JP2860071B2 (ja)	1999-02-24
DK2797A (da)	1997-01-09
ES2109882A1 (es)	1998-01-16
NL1001194A1 (nl)	1996-03-19
ES2109882B1 (es)	1998-08-16
GB2293602B (en)	1998-05-06
FR2724655B1 (fr)	1997-11-14
GR1002709B (el)	1997-06-04
BR9504059A (pt)	1996-09-24
PT101770B (pt)	1997-04-30
CH691125A5 (de)	2001-04-30
MY116371A (en)	2004-01-31
US20020173645A1 (en)	2002-11-21
NO953657D0 (no)	1995-09-15
SI9500293A (en)	1996-06-30
CA2158399A1 (en)	1996-03-20
RS49578B (sr)	2007-04-10
US6399778B1 (en)	2002-06-04
SI9500292A (en)	1996-06-30
FI954403A0 (fi)	1995-09-18
PT101771B (pt)	1997-04-30
TR199501136A2 (tr)	1996-06-21
CN1075069C (zh)	2001-11-21
UA44240C2 (uk)	2002-02-15
SK283502B6 (sk)	2003-08-05
DE19534745B4 (de)	2004-06-09
DK175887B1 (da)	2005-05-23
NL1001196C2 (nl)	1997-04-04
EE03386B1 (et)	2001-04-16
GR1002697B (el)	1997-05-22
GEP19991821B (en)	1999-11-05
CZ292007B6 (cs)	2003-07-16
GB9519032D0 (en)	1995-11-15
BG62793B1 (bg)	2000-08-31
ES2129293A1 (es)	1999-06-01
AU3718695A (en)	1996-04-09
CA2158399C (en)	2001-03-20
PL310517A1 (en)	1996-04-01
US6472531B1 (en)	2002-10-29
PT101771A (pt)	1996-04-30
CO4410191A1 (es)	1997-01-09
CH691478A5 (de)	2001-07-31
ES2129293B1 (es)	2000-01-16
NO313996B1 (no)	2003-01-13
AP754A (en)	1999-07-22
IT1277601B1 (it)	1997-11-11
OA10406A (en)	2001-12-05
KR100367376B1 (ko)	2003-03-06
HRP950483B1 (en)	2003-02-28
EE9700055A (et)	1997-08-15
SE520721C2 (sv)	2003-08-12
AP9700938A0 (en)	1997-04-30
IE950721A1 (en)	1996-03-20
CA2158400A1 (en)	1996-03-20
BG101242A (en)	1998-03-31
CZ240395A3 (en)	1996-04-17
CN1132205A (zh)	1996-10-02
GB9519028D0 (en)	1995-11-15
PL310518A1 (en)	1996-04-01
TW412534B (en)	2000-11-21
HUT75033A (en)	1997-03-28
HK1019009A1 (en)	2000-01-14
FR2724655A1 (fr)	1996-03-22
RS49513B (sr)	2006-10-27
KR960010637A (ko)	1996-04-20
IE80883B1 (en)	1999-05-19
RO115260B1 (ro)	1999-12-30
GB2293602A (en)	1996-04-03
DE19549755B4 (de)	2005-05-04
ITMI951935A1 (it)	1997-03-15
ITMI951936A0 (it)	1995-09-15
FI954402A0 (fi)	1995-09-18
AU692907B2 (en)	1998-06-18
AU691955B2 (en)	1998-05-28
IT1277602B1 (it)	1997-11-11
HRP950482A2 (en)	1998-02-28
UY24040A1 (es)	1996-03-07
FI121424B (fi)	2010-11-15
FI112226B (fi)	2003-11-14
LV11178A (lv)	1996-04-20
IL125283A (en)	2001-06-14
DK102895A (da)	1996-03-20
SE9503213L (sv)	1996-03-20
HU227683B1 (en)	2011-11-28
HRP950483A2 (en)	1997-10-31
DK102795A (da)	1996-03-20
UA42716C2 (uk)	2001-11-15
US5731327A (en)	1998-03-24
ATA154295A (de)	2000-12-15
IE950722A1 (en)	1996-03-20
BR9504060A (pt)	1996-09-24
PL182450B1 (pl)	2002-01-31
PT101770A (pt)	1996-04-30
BE1009626A3 (fr)	1997-06-03
NO308107B1 (no)	2000-07-24
AT407988B (de)	2001-07-25
NZ280028A (en)	1997-05-26
HU9502721D0 (en)	1995-11-28
SE9503214D0 (sv)	1995-09-15
IS4446A (is)	1997-03-18
HU225417B1 (en)	2006-11-28
FR2732020A1 (fr)	1996-09-27
EG23763A (en)	2007-08-08
IS1788B (is)	2001-11-28
YU61495A (sh)	1998-05-15
SK23397A3 (en)	1997-08-06
DK175897B1 (da)	2005-05-30
KR100381346B1 (ko)	2004-04-13
NO953658D0 (no)	1995-09-15
DK2897A (da)	1997-01-09
FR2732020B1 (fr)	1997-11-14
DK175903B1 (da)	2005-06-06
IL115315A0 (en)	1995-12-31
SE9503214L (sv)	1996-03-20
LU88661A1 (fr)	1996-07-15
AU3173095A (en)	1996-04-04
RO115259B1 (ro)	1999-12-30
NL1001196A1 (nl)	1996-03-19
FI954403A7 (fi)	1996-03-20
PL187686B1 (pl)	2004-09-30

Legal Events

Date	Code	Title	Description
1996-06-03	AD1A	A request for search or an international type search has been filed
1997-02-03	RD2N	Patents in respect of which a decision has been taken or a report has been made (novelty report)	Effective date: 19961202
1997-06-02	PD2B	A search report has been drawn up

Publication	Publication Date	Title
NL1001194C2 (nl)	1997-04-04	Synthese van 3-£4-(2-aminoethoxy)-benzoyl\|-2-aryl-6-hydroxybenzo£b\|thio- fenen.
RU2108331C1 (ru)	1998-04-10	Способ получения кристаллического сольвата, кристаллический сольват 6-гидрокси-2-(4-гидроксифенил)-3-[4-(2-пиперидиноэтокси)бензоил]бензо(b)тиофенгидрохлорида и способ получения несольватированного кристаллического 6-гидрокси-2-(4-гидроксифенил)-3-[4-(2-пиперидиноэтокси)бензоил]бензо(b)тиофенгидрохлорида