PT826680E

PT826680E - Compostos di-hidronaftaleno e naftaleno intermediarios formulacoes e metodos para a sua preparacao

Compostos di-hidronaftaleno e naftaleno intermediarios formulacoes e metodos para a sua preparacao Download PDF

Info

Publication number: PT826680E
Authority: PT; Portugal
Prior art keywords: formula; compound; alkyl; methanone; phenyl
Prior art date: 1996-08-29

Application number

PT97306545T

Other languages

English (en)

Portuguese (pt)

Inventor

Thomas Alan Crowell

Henry Uhlman Bryant

Charles David Jones

Original Assignee

Lilly Co Eli

Priority date

1996-08-29

Filing date

1997-08-27

Publication date

2002-03-28

1997-08-27 Application filed by Lilly Co Eli filed Critical Lilly Co Eli

2002-03-28 Publication of PT826680E publication Critical patent/PT826680E/pt

Links

239000000203 mixture Substances 0.000 title abstract description 35
238000000034 method Methods 0.000 title abstract description 33
238000002360 preparation method Methods 0.000 title description 18
-1 methyl-1-pyrrolidinyl Chemical group 0.000 claims abstract description 94
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 45
150000003839 salts Chemical class 0.000 claims abstract description 19
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 11
239000001257 hydrogen Substances 0.000 claims abstract description 10
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
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 abstract description 7
239000012453 solvate Substances 0.000 claims abstract description 6
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 5
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 3
XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims abstract 3
150000001875 compounds Chemical class 0.000 claims description 120
239000000262 estrogen Substances 0.000 claims description 32
229940011871 estrogen Drugs 0.000 claims description 30
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
125000006239 protecting group Chemical group 0.000 claims description 17
239000003795 chemical substances by application Substances 0.000 claims description 15
208000024891 symptom Diseases 0.000 claims description 15
239000004480 active ingredient Substances 0.000 claims description 12
125000001309 chloro group Chemical group Cl* 0.000 claims description 12
RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 11
239000000583 progesterone congener Substances 0.000 claims description 11
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
125000000217 alkyl group Chemical group 0.000 claims description 8
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
208000024172 Cardiovascular disease Diseases 0.000 claims description 5
208000031226 Hyperlipidaemia Diseases 0.000 claims description 5
229910052799 carbon Inorganic materials 0.000 claims description 5
239000003085 diluting agent Substances 0.000 claims description 5
239000000546 pharmaceutical excipient Substances 0.000 claims description 5
206010027304 Menopausal symptoms Diseases 0.000 claims description 4
206010028980 Neoplasm Diseases 0.000 claims description 4
239000000969 carrier Substances 0.000 claims description 4
229910052731 fluorine Inorganic materials 0.000 claims description 4
125000001153 fluoro group Chemical group F* 0.000 claims description 4
208000001685 postmenopausal osteoporosis Diseases 0.000 claims description 4
239000008194 pharmaceutical composition Substances 0.000 claims description 3
208000037803 restenosis Diseases 0.000 claims description 3
201000009273 Endometriosis Diseases 0.000 claims description 2
125000003545 alkoxy group Chemical group 0.000 claims description 2
210000003433 aortic smooth muscle cell Anatomy 0.000 claims description 2
201000011510 cancer Diseases 0.000 claims description 2
230000001419 dependent effect Effects 0.000 claims description 2
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
230000035755 proliferation Effects 0.000 claims description 2
230000001575 pathological effect Effects 0.000 claims 3
206010006187 Breast cancer Diseases 0.000 claims 1
208000026310 Breast neoplasm Diseases 0.000 claims 1
208000002495 Uterine Neoplasms Diseases 0.000 claims 1
206010046798 Uterine leiomyoma Diseases 0.000 claims 1
210000000481 breast Anatomy 0.000 claims 1
201000010260 leiomyoma Diseases 0.000 claims 1
208000011580 syndromic disease Diseases 0.000 claims 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 claims 1
206010046766 uterine cancer Diseases 0.000 claims 1
208000010579 uterine corpus leiomyoma Diseases 0.000 claims 1
201000007954 uterine fibroid Diseases 0.000 claims 1
238000009472 formulation Methods 0.000 abstract description 20
239000000543 intermediate Substances 0.000 abstract description 10
125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 6
KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 abstract description 6
125000006528 (C2-C6) alkyl group Chemical group 0.000 abstract description 5
208000006386 Bone Resorption Diseases 0.000 abstract description 2
206010065687 Bone loss Diseases 0.000 abstract description 2
230000024279 bone resorption Effects 0.000 abstract description 2
150000002790 naphthalenes Chemical class 0.000 abstract description 2
238000006243 chemical reaction Methods 0.000 description 42
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 27
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 20
239000000243 solution Substances 0.000 description 20
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
239000002904 solvent Substances 0.000 description 18
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
239000003921 oil Substances 0.000 description 16
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 15
235000019439 ethyl acetate Nutrition 0.000 description 15
239000002253 acid Substances 0.000 description 14
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
239000000047 product Substances 0.000 description 13
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
FDGCNGPUZIIRQI-UHFFFAOYSA-N (4-methoxyphenyl)methanone Chemical compound O(C1=CC=C([C-]=O)C=C1)C FDGCNGPUZIIRQI-UHFFFAOYSA-N 0.000 description 12
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
239000011541 reaction mixture Substances 0.000 description 12
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 11
230000017858 demethylation Effects 0.000 description 11
238000010520 demethylation reaction Methods 0.000 description 11
HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 10
125000003870 2-(1-piperidinyl)ethoxy group Chemical group [*]OC([H])([H])C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 10
239000003153 chemical reaction reagent Substances 0.000 description 10
238000005481 NMR spectroscopy Methods 0.000 description 9
230000015572 biosynthetic process Effects 0.000 description 9
210000000988 bone and bone Anatomy 0.000 description 9
QRPUVEAHEMVOOG-UHFFFAOYSA-O (4-hydroxyphenyl)methanone Chemical compound OC1=CC=C([C+]=O)C=C1 QRPUVEAHEMVOOG-UHFFFAOYSA-O 0.000 description 8
BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 8
208000001132 Osteoporosis Diseases 0.000 description 8
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
238000004458 analytical method Methods 0.000 description 8
210000002966 serum Anatomy 0.000 description 8
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
239000012267 brine Substances 0.000 description 7
238000004587 chromatography analysis Methods 0.000 description 7
239000004615 ingredient Substances 0.000 description 7
150000002632 lipids Chemical class 0.000 description 7
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
238000002560 therapeutic procedure Methods 0.000 description 7
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 6
201000010099 disease Diseases 0.000 description 6
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
239000000463 material Substances 0.000 description 6
239000012299 nitrogen atmosphere Substances 0.000 description 6
239000007858 starting material Substances 0.000 description 6
125000006016 2-bromoethoxy group Chemical group 0.000 description 5
125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 5
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical class C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 5
150000008064 anhydrides Chemical class 0.000 description 5
125000003118 aryl group Chemical group 0.000 description 5
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
239000001768 carboxy methyl cellulose Substances 0.000 description 5
230000000694 effects Effects 0.000 description 5
239000012442 inert solvent Substances 0.000 description 5
238000006366 phosphorylation reaction Methods 0.000 description 5
230000008569 process Effects 0.000 description 5
210000004291 uterus Anatomy 0.000 description 5
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
VFLQQZCRHPIGJU-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine;hydron;chloride Chemical compound Cl.ClCCN1CCCCC1 VFLQQZCRHPIGJU-UHFFFAOYSA-N 0.000 description 4
125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 4
238000005160 1H NMR spectroscopy Methods 0.000 description 4
WCLJTEXCGGSJJN-UHFFFAOYSA-N 4-(2-piperidin-1-ylethoxy)benzaldehyde Chemical compound C1=CC(C=O)=CC=C1OCCN1CCCCC1 WCLJTEXCGGSJJN-UHFFFAOYSA-N 0.000 description 4
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
241000124008 Mammalia Species 0.000 description 4
229910019142 PO4 Inorganic materials 0.000 description 4
241000700159 Rattus Species 0.000 description 4
229920002472 Starch Polymers 0.000 description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
239000012298 atmosphere Substances 0.000 description 4
239000000460 chlorine Substances 0.000 description 4
238000009164 estrogen replacement therapy Methods 0.000 description 4
239000012458 free base Substances 0.000 description 4
239000010452 phosphate 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
230000002829 reductive effect Effects 0.000 description 4
239000000741 silica gel Substances 0.000 description 4
229910002027 silica gel Inorganic materials 0.000 description 4
235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 4
229920001027 sodium carboxymethylcellulose Polymers 0.000 description 4
239000007787 solid Substances 0.000 description 4
239000008107 starch Substances 0.000 description 4
235000019698 starch Nutrition 0.000 description 4
239000000126 substance Substances 0.000 description 4
239000000725 suspension Substances 0.000 description 4
DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 3
DKLBIQFPQRSEQG-UHFFFAOYSA-N (4-hydroxyphenyl)-[6-methoxy-2-(3-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]methanone Chemical compound COC1=CC=CC(C=2CCC3=CC(OC)=CC=C3C=2C(=O)C=2C=CC(O)=CC=2)=C1 DKLBIQFPQRSEQG-UHFFFAOYSA-N 0.000 description 3
BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 3
125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 3
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 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
229940122361 Bisphosphonate Drugs 0.000 description 3
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 3
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
102000003982 Parathyroid hormone Human genes 0.000 description 3
108090000445 Parathyroid hormone Proteins 0.000 description 3
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
ZJAMMHNGLLKZRM-UHFFFAOYSA-N [6-methoxy-2-(3-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-(4-methoxyphenyl)methanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=C(C=2C=C(OC)C=CC=2)CCC2=CC(OC)=CC=C12 ZJAMMHNGLLKZRM-UHFFFAOYSA-N 0.000 description 3
229910052783 alkali metal Inorganic materials 0.000 description 3
239000012670 alkaline solution Substances 0.000 description 3
238000005804 alkylation reaction Methods 0.000 description 3
239000002585 base Substances 0.000 description 3
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
239000006227 byproduct Substances 0.000 description 3
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
239000003054 catalyst Substances 0.000 description 3
235000012000 cholesterol Nutrition 0.000 description 3
239000012043 crude product Substances 0.000 description 3
210000003979 eosinophil Anatomy 0.000 description 3
230000001076 estrogenic effect Effects 0.000 description 3
238000001914 filtration Methods 0.000 description 3
229910052736 halogen Inorganic materials 0.000 description 3
150000002367 halogens Chemical class 0.000 description 3
230000002401 inhibitory effect Effects 0.000 description 3
230000000670 limiting effect Effects 0.000 description 3
229910052744 lithium Inorganic materials 0.000 description 3
235000019359 magnesium stearate Nutrition 0.000 description 3
FKUUDDGRDRPAQQ-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=C[C-]=C1 FKUUDDGRDRPAQQ-UHFFFAOYSA-M 0.000 description 3
230000009245 menopause Effects 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
229940053934 norethindrone Drugs 0.000 description 3
VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 3
230000000269 nucleophilic effect Effects 0.000 description 3
239000012044 organic layer Substances 0.000 description 3
239000007800 oxidant agent Substances 0.000 description 3
239000000199 parathyroid hormone Substances 0.000 description 3
229960001319 parathyroid hormone Drugs 0.000 description 3
230000026731 phosphorylation Effects 0.000 description 3
239000001267 polyvinylpyrrolidone Substances 0.000 description 3
229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
239000000843 powder Substances 0.000 description 3
125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 3
230000004044 response Effects 0.000 description 3
238000010898 silica gel chromatography Methods 0.000 description 3
239000012312 sodium hydride Substances 0.000 description 3
229910000104 sodium hydride Inorganic materials 0.000 description 3
238000010561 standard procedure Methods 0.000 description 3
230000000638 stimulation Effects 0.000 description 3
239000000758 substrate Substances 0.000 description 3
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
239000000829 suppository Substances 0.000 description 3
238000003786 synthesis reaction Methods 0.000 description 3
239000006188 syrup Substances 0.000 description 3
235000020357 syrup Nutrition 0.000 description 3
239000000454 talc Substances 0.000 description 3
229910052623 talc Inorganic materials 0.000 description 3
235000012222 talc Nutrition 0.000 description 3
150000003512 tertiary amines Chemical class 0.000 description 3
238000012360 testing method Methods 0.000 description 3
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
OBOBUDMMFXRNDO-UHFFFAOYSA-N 1-(3-chloropropyl)piperidine;hydron;chloride Chemical compound Cl.ClCCCN1CCCCC1 OBOBUDMMFXRNDO-UHFFFAOYSA-N 0.000 description 2
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