CA2555260C - Stereoselective synthesis of vitamin d analogues - Google Patents
Stereoselective synthesis of vitamin d analogues Download PDFInfo
- Publication number
- CA2555260C CA2555260C CA2555260A CA2555260A CA2555260C CA 2555260 C CA2555260 C CA 2555260C CA 2555260 A CA2555260 A CA 2555260A CA 2555260 A CA2555260 A CA 2555260A CA 2555260 C CA2555260 C CA 2555260C
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- CA
- Canada
- Prior art keywords
- general structure
- compound
- hydrogen
- mixture
- calcipotriol
- Prior art date
- 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.)
- Expired - Fee Related
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- 230000015572 biosynthetic process Effects 0.000 title abstract description 15
- 238000003786 synthesis reaction Methods 0.000 title abstract description 15
- 229940046008 vitamin d Drugs 0.000 title description 6
- 230000000707 stereoselective effect Effects 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 185
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 91
- 239000001257 hydrogen Substances 0.000 claims abstract description 91
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 claims abstract description 70
- 238000000034 method Methods 0.000 claims abstract description 61
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 44
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 43
- 229960002882 calcipotriol Drugs 0.000 claims abstract description 41
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 38
- 125000006239 protecting group Chemical group 0.000 claims abstract description 38
- 239000000203 mixture Substances 0.000 claims description 107
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 73
- 239000003638 chemical reducing agent Substances 0.000 claims description 56
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 51
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 51
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 23
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 239000012442 inert solvent Substances 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 235000010269 sulphur dioxide Nutrition 0.000 claims description 10
- 239000004291 sulphur dioxide Substances 0.000 claims description 10
- 230000000640 hydroxylating effect Effects 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical group [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000003125 aqueous solvent Substances 0.000 claims description 5
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical group [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 claims description 5
- LOPKSXMQWBYUOI-DTWKUNHWSA-N (1r,2s)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical class C1=CC=C2[C@@H](N)[C@@H](O)CC2=C1 LOPKSXMQWBYUOI-DTWKUNHWSA-N 0.000 claims description 3
- 150000000179 1,2-aminoalcohols Chemical class 0.000 claims description 3
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 3
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 3
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- LOPKSXMQWBYUOI-BDAKNGLRSA-N (1s,2r)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical group C1=CC=C2[C@H](N)[C@H](O)CC2=C1 LOPKSXMQWBYUOI-BDAKNGLRSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 20
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 229940093499 ethyl acetate Drugs 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
- 229910000085 borane Inorganic materials 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000006722 reduction reaction Methods 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- KMGCKSAIIHOKCX-UHFFFAOYSA-N 2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2CC(O)CC2=C1 KMGCKSAIIHOKCX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000006742 Retro-Diels-Alder reaction Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 239000003223 protective agent Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- -1 C-24 ketones Chemical class 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical group [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 238000011916 stereoselective reduction Methods 0.000 description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 5
- 229930003316 Vitamin D Natural products 0.000 description 5
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000011917 diastereoselective reduction Methods 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 235000019166 vitamin D Nutrition 0.000 description 5
- 239000011710 vitamin D Substances 0.000 description 5
- 150000003710 vitamin D derivatives Chemical group 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000005526 G1 to G0 transition Effects 0.000 description 4
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 4
- 238000006317 isomerization reaction Methods 0.000 description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000008247 solid mixture Substances 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 238000005698 Diels-Alder reaction Methods 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
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- 239000012299 nitrogen atmosphere Substances 0.000 description 3
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- 239000012071 phase Substances 0.000 description 3
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- 150000005671 trienes Chemical class 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VMKAFJQFKBASMU-QGZVFWFLSA-N (r)-2-methyl-cbs-oxazaborolidine Chemical compound C([C@@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-QGZVFWFLSA-N 0.000 description 2
- NXXNVJDXUHMAHU-UHFFFAOYSA-N 1-anthracen-9-ylethanone Chemical compound C1=CC=C2C(C(=O)C)=C(C=CC=C3)C3=CC2=C1 NXXNVJDXUHMAHU-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 0 C[C@@]([C@@](CC1)[C@@](C)(CCC2)[C@@]1C2=C[C@@](*C*(C1)=O)C(C2)=C1[C@](*)C[C@@]2O*)C=CC(C1CC1)O Chemical compound C[C@@]([C@@](CC1)[C@@](C)(CCC2)[C@@]1C2=C[C@@](*C*(C1)=O)C(C2)=C1[C@](*)C[C@@]2O*)C=CC(C1CC1)O 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
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- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 2
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 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
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- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
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- 229910004755 Cerium(III) bromide Inorganic materials 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
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- 229910002249 LaCl3 Inorganic materials 0.000 description 1
- 229930045534 Me ester-Cyclohexaneundecanoic acid Natural products 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- 229910020889 NaBH3 Inorganic materials 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 229910018162 SeO2 Inorganic materials 0.000 description 1
- 201000002380 X-linked amelogenesis imperfecta hypoplastic/hypomaturation 2 Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 238000005377 adsorption chromatography Methods 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- VCDGSBJCRYTLNU-AZWGFFAPSA-N alpine borane Chemical compound C1CCC2CCCC1B2[C@@H]1C[C@H](C2(C)C)C[C@H]2[C@H]1C VCDGSBJCRYTLNU-AZWGFFAPSA-N 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- FHCIILYMWWRNIZ-UHFFFAOYSA-N benzhydryl(chloro)silane Chemical compound C=1C=CC=CC=1C([SiH2]Cl)C1=CC=CC=C1 FHCIILYMWWRNIZ-UHFFFAOYSA-N 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 1
- MOOUSOJAOQPDEH-UHFFFAOYSA-K cerium(iii) bromide Chemical compound [Br-].[Br-].[Br-].[Ce+3] MOOUSOJAOQPDEH-UHFFFAOYSA-K 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical class Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000005175 epidermal keratinocyte Anatomy 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- ICAKDTKJOYSXGC-UHFFFAOYSA-K lanthanum(iii) chloride Chemical compound Cl[La](Cl)Cl ICAKDTKJOYSXGC-UHFFFAOYSA-K 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PHVXTQIROLEEDB-UHFFFAOYSA-N n-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-n-pyrrolidin-3-ylbenzamide Chemical compound CC1=CC=CC=C1C1CN(CC=2C=CC(=CC=2)C(=O)N(CCC=2C(=CC=CC=2)Cl)C2CNCC2)CCC1 PHVXTQIROLEEDB-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- GUFUWKKDHIABBW-UHFFFAOYSA-N pyrrolidin-1-ylmethanol Chemical compound OCN1CCCC1 GUFUWKKDHIABBW-UHFFFAOYSA-N 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229940082569 selenite Drugs 0.000 description 1
- MCAHWIHFGHIESP-UHFFFAOYSA-L selenite(2-) Chemical compound [O-][Se]([O-])=O MCAHWIHFGHIESP-UHFFFAOYSA-L 0.000 description 1
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Dermatology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US55396204P | 2004-03-18 | 2004-03-18 | |
| US60/553,962 | 2004-03-18 | ||
| DKPA200400454 | 2004-03-22 | ||
| DKPA200400454 | 2004-03-22 | ||
| PCT/DK2005/000161 WO2005087719A1 (en) | 2004-03-18 | 2005-03-10 | Stereoselective synthesis of vitamin d analogues |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2555260A1 CA2555260A1 (en) | 2005-09-22 |
| CA2555260C true CA2555260C (en) | 2011-12-06 |
Family
ID=34961016
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2555260A Expired - Fee Related CA2555260C (en) | 2004-03-18 | 2005-03-10 | Stereoselective synthesis of vitamin d analogues |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP1730108B1 (enExample) |
| JP (1) | JP4667450B2 (enExample) |
| KR (1) | KR100859277B1 (enExample) |
| CN (1) | CN1934078B (enExample) |
| AR (1) | AR048274A1 (enExample) |
| AT (1) | ATE390411T1 (enExample) |
| BR (1) | BRPI0507318A (enExample) |
| CA (1) | CA2555260C (enExample) |
| CY (1) | CY1108156T1 (enExample) |
| DE (2) | DE05706821T1 (enExample) |
| ES (1) | ES2304686T3 (enExample) |
| IL (1) | IL176718A (enExample) |
| PL (1) | PL1730108T3 (enExample) |
| RU (1) | RU2380359C2 (enExample) |
| SI (1) | SI1730108T1 (enExample) |
| TW (1) | TWI324063B (enExample) |
| WO (1) | WO2005087719A1 (enExample) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2378252C2 (ru) * | 2004-04-02 | 2010-01-10 | Лео Фарма А/С | Новый способ получения промежуточных соединений, применяемых для синтеза аналогов витамина d |
| EP1844010B1 (en) | 2006-03-17 | 2013-02-13 | Leo Pharma A/S | Isomerisation of pharmaceutical intermediates |
| US8013189B2 (en) * | 2007-09-21 | 2011-09-06 | Basf Se | Accelerated amide and ester reductions with amine boranes and additives |
| EP2299809B1 (en) * | 2008-06-17 | 2018-10-17 | Ben Gurion University Of The Negev R&D Authority | Substituted cyclohexylidene-ethylidene-octahydro-indene compounds |
| CN103265528B (zh) * | 2013-05-10 | 2015-05-06 | 湖南千金湘江药业股份有限公司 | 埃索美拉唑镁的制备方法 |
| CN106908524B (zh) * | 2015-12-23 | 2021-05-04 | 重庆华邦胜凯制药有限公司 | 卡泊三醇中间体l及其潜在基因毒性杂质的分离与测定方法 |
| CN107643354B (zh) * | 2016-07-22 | 2022-02-01 | 重庆华邦胜凯制药有限公司 | 卡泊三醇起始原料a及相关杂质的分离与测定方法 |
| ES2945426B2 (es) * | 2021-12-30 | 2024-01-22 | Laboratorios Vinas S A | Procedimiento para obtener epímeros 24S a partir de derivados de vitaminas D y procedimiento de obtención de vitaminas D relacionado |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4866048A (en) * | 1985-08-02 | 1989-09-12 | Leo Pharmaceutical Products Ltd. | Novel vitamin D analogues |
| JPH075542B2 (ja) * | 1988-09-14 | 1995-01-25 | 呉羽化学工業株式会社 | ビタミンｄ▲下３▼誘導体及びその製造方法 |
| US5247104A (en) * | 1992-11-04 | 1993-09-21 | Wisconsin Alumni Research Foundation | Preparation of 1α, 24-dihydroxyvitamin D analogs |
| GB9300763D0 (en) * | 1993-01-15 | 1993-03-03 | Leo Pharm Prod Ltd | Chemical compound |
| US5449668A (en) * | 1993-06-04 | 1995-09-12 | Duphar International Research B.V. | Vitamin D compounds and method of preparing these compounds |
| GB9524812D0 (en) * | 1995-12-05 | 1996-02-07 | Leo Pharm Prod Ltd | Chemical compounds |
| GB9622590D0 (en) * | 1996-10-30 | 1997-01-08 | Leo Pharm Prod Ltd | Chemical compounds |
| US6262283B1 (en) * | 1996-12-06 | 2001-07-17 | Magainin Pharmaceuticals Inc. | Stereoselective synthesis of 24-hydroxylated compounds useful for the preparation of aminosterols, vitamin D analogs, and other compounds |
| KR100676106B1 (ko) * | 1998-10-23 | 2007-02-28 | 데이진 가부시키가이샤 | 비타민 ｄ3 유도체 및 그것을 사용하는 염증성 호흡기질환 치료제 |
-
2005
- 2005-03-10 JP JP2007503195A patent/JP4667450B2/ja not_active Expired - Fee Related
- 2005-03-10 KR KR1020067015590A patent/KR100859277B1/ko not_active Expired - Fee Related
- 2005-03-10 DE DE05706821T patent/DE05706821T1/de active Pending
- 2005-03-10 RU RU2006129922/04A patent/RU2380359C2/ru active
- 2005-03-10 SI SI200530248T patent/SI1730108T1/sl unknown
- 2005-03-10 DE DE602005005645T patent/DE602005005645T2/de not_active Expired - Lifetime
- 2005-03-10 BR BRPI0507318-9A patent/BRPI0507318A/pt not_active IP Right Cessation
- 2005-03-10 EP EP05706821A patent/EP1730108B1/en not_active Expired - Lifetime
- 2005-03-10 PL PL05706821T patent/PL1730108T3/pl unknown
- 2005-03-10 WO PCT/DK2005/000161 patent/WO2005087719A1/en not_active Ceased
- 2005-03-10 CA CA2555260A patent/CA2555260C/en not_active Expired - Fee Related
- 2005-03-10 CN CN2005800086209A patent/CN1934078B/zh not_active Expired - Fee Related
- 2005-03-10 AT AT05706821T patent/ATE390411T1/de active
- 2005-03-10 ES ES05706821T patent/ES2304686T3/es not_active Expired - Lifetime
- 2005-03-16 TW TW094108053A patent/TWI324063B/zh not_active IP Right Cessation
- 2005-03-17 AR ARP050101046A patent/AR048274A1/es unknown
-
2006
- 2006-07-05 IL IL176718A patent/IL176718A/en active IP Right Grant
-
2008
- 2008-06-26 CY CY20081100667T patent/CY1108156T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TW200539866A (en) | 2005-12-16 |
| PL1730108T3 (pl) | 2008-09-30 |
| EP1730108A1 (en) | 2006-12-13 |
| DE602005005645T2 (de) | 2009-06-18 |
| CN1934078B (zh) | 2011-07-06 |
| CN1934078A (zh) | 2007-03-21 |
| RU2006129922A (ru) | 2008-02-27 |
| KR100859277B1 (ko) | 2008-09-19 |
| ATE390411T1 (de) | 2008-04-15 |
| TWI324063B (en) | 2010-05-01 |
| DE05706821T1 (de) | 2008-02-07 |
| JP2007529433A (ja) | 2007-10-25 |
| JP4667450B2 (ja) | 2011-04-13 |
| AR048274A1 (es) | 2006-04-12 |
| CA2555260A1 (en) | 2005-09-22 |
| DE602005005645D1 (de) | 2008-05-08 |
| EP1730108B1 (en) | 2008-03-26 |
| IL176718A (en) | 2007-07-04 |
| ES2304686T3 (es) | 2008-10-16 |
| KR20060134045A (ko) | 2006-12-27 |
| RU2380359C2 (ru) | 2010-01-27 |
| SI1730108T1 (sl) | 2008-08-31 |
| BRPI0507318A (pt) | 2007-06-26 |
| CY1108156T1 (el) | 2014-02-12 |
| WO2005087719A1 (en) | 2005-09-22 |
| HK1098122A1 (en) | 2007-07-13 |
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| EEER | Examination request | ||
| MKLA | Lapsed |
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