BE468914A

BE468914A -

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Publication number: BE468914A
Authority: BE; Belgium
Prior art keywords: cholesterol; process according; imide; unsaturated; acid
Prior art date

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English (en)

French (fr)

Publication of BE468914A publication Critical patent/BE468914A/fr

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238000000034 method Methods 0.000 claims description 38
HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 35
PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 28
230000008569 process Effects 0.000 claims description 27
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 25
LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 17
150000003431 steroids Chemical class 0.000 claims description 16
239000002904 solvent Substances 0.000 claims description 15
239000002253 acid Substances 0.000 claims description 14
AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 13
239000000920 calcium hydroxide Substances 0.000 claims description 13
229910001861 calcium hydroxide Inorganic materials 0.000 claims description 13
XUGISPSHIFXEHZ-UHFFFAOYSA-N 3beta-acetoxy-cholest-5-ene Natural products C1C=C2CC(OC(C)=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XUGISPSHIFXEHZ-UHFFFAOYSA-N 0.000 claims description 12
XUGISPSHIFXEHZ-VEVYEIKRSA-N cholesteryl acetate Chemical group C1C=C2C[C@@H](OC(C)=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 XUGISPSHIFXEHZ-VEVYEIKRSA-N 0.000 claims description 12
150000007529 inorganic bases Chemical class 0.000 claims description 11
150000003949 imides Chemical class 0.000 claims description 10
UCTLRSWJYQTBFZ-UHFFFAOYSA-N Dehydrocholesterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)CCCC(C)C)CCC33)C)C3=CC=C21 UCTLRSWJYQTBFZ-UHFFFAOYSA-N 0.000 claims description 9
150000002148 esters Chemical class 0.000 claims description 9
239000003208 petroleum Substances 0.000 claims description 9
QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound 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-YRZJJWOYSA-N 0.000 claims description 9
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 7
229910052784 alkaline earth metal Inorganic materials 0.000 claims description 7
150000001342 alkaline earth metals Chemical class 0.000 claims description 7
238000002360 preparation method Methods 0.000 claims description 7
239000008096 xylene Substances 0.000 claims description 7
230000031709 bromination Effects 0.000 claims description 6
238000005893 bromination reaction Methods 0.000 claims description 6
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
229910052794 bromium Inorganic materials 0.000 claims description 6
239000003795 chemical substances by application Substances 0.000 claims description 6
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 claims description 6
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 6
239000003463 adsorbent Substances 0.000 claims description 5
239000012190 activator Substances 0.000 claims description 4
239000003701 inert diluent Substances 0.000 claims description 4
239000012442 inert solvent Substances 0.000 claims description 4
MARXMDRWROUXMD-UHFFFAOYSA-N 2-bromoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Br)C(=O)C2=C1 MARXMDRWROUXMD-UHFFFAOYSA-N 0.000 claims description 3
230000003213 activating effect Effects 0.000 claims description 3
235000012000 cholesterol Nutrition 0.000 claims description 3
238000010438 heat treatment Methods 0.000 claims description 3
239000011541 reaction mixture Substances 0.000 claims description 3
VEXBOSOAFMUEPC-UOQFGJKXSA-N (3s,8s,9s,10r,13r,14s,17r)-7-bromo-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-ol Chemical compound BrC1C=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 VEXBOSOAFMUEPC-UOQFGJKXSA-N 0.000 claims description 2
150000001408 amides Chemical class 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims description 2
238000007865 diluting Methods 0.000 claims 2
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims 1
LQNUZADURLCDLV-IDEBNGHGSA-N nitrobenzene Chemical group [O-][N+](=O)[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 LQNUZADURLCDLV-IDEBNGHGSA-N 0.000 claims 1
238000007127 saponification reaction Methods 0.000 claims 1
238000006243 chemical reaction Methods 0.000 description 29
239000000243 solution Substances 0.000 description 20
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
-1 4 -bromocholesterol Chemical compound 0.000 description 12
239000000203 mixture Substances 0.000 description 12
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
229930182558 Sterol Natural products 0.000 description 10
239000000047 product Substances 0.000 description 10
235000003702 sterols Nutrition 0.000 description 10
238000007269 dehydrobromination reaction Methods 0.000 description 9
230000026030 halogenation Effects 0.000 description 9
238000005658 halogenation reaction Methods 0.000 description 9
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
VPJVBRBCTRHWHP-KVBUMPSKSA-N [(3s,8s,9s,10r,13r,14s,17r)-7-bromo-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound BrC1C=C2C[C@@H](OC(C)=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 VPJVBRBCTRHWHP-KVBUMPSKSA-N 0.000 description 8
150000001875 compounds Chemical class 0.000 description 8
229910052736 halogen Inorganic materials 0.000 description 7
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
150000002367 halogens Chemical class 0.000 description 6
150000003432 sterols Chemical class 0.000 description 6
238000003756 stirring Methods 0.000 description 6
230000015572 biosynthetic process Effects 0.000 description 5
BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 5
239000000292 calcium oxide Substances 0.000 description 5
ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 5
150000001840 cholesterol esters Chemical class 0.000 description 5
235000019441 ethanol Nutrition 0.000 description 5
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
229930003316 Vitamin D Natural products 0.000 description 4
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 4
229910052799 carbon Inorganic materials 0.000 description 4
125000004432 carbon atom Chemical group C* 0.000 description 4
150000007530 organic bases Chemical group 0.000 description 4
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
230000008707 rearrangement Effects 0.000 description 4
238000010992 reflux Methods 0.000 description 4
229910000029 sodium carbonate Inorganic materials 0.000 description 4
238000001256 steam distillation Methods 0.000 description 4
238000006467 substitution reaction Methods 0.000 description 4
235000019166 vitamin D Nutrition 0.000 description 4
239000011710 vitamin D Substances 0.000 description 4
150000003710 vitamin D derivatives Chemical class 0.000 description 4
229940046008 vitamin d Drugs 0.000 description 4
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
150000007513 acids Chemical class 0.000 description 3
230000004913 activation Effects 0.000 description 3
125000000746 allylic group Chemical group 0.000 description 3
RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 3
229910001863 barium hydroxide Inorganic materials 0.000 description 3
238000009835 boiling Methods 0.000 description 3
239000006227 byproduct Substances 0.000 description 3
238000001816 cooling Methods 0.000 description 3
239000013078 crystal Substances 0.000 description 3
GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 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
238000002803 maceration Methods 0.000 description 3
238000007086 side reaction Methods 0.000 description 3
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
LWGFSMMVVHGBFX-XGRWYXQASA-N C(C)(=O)O[C@@H]1CC2=C(C[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@]2(CC1)C)C)[C@H](C)CCCC(C)C)Br Chemical compound C(C)(=O)O[C@@H]1CC2=C(C[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@]2(CC1)C)C)[C@H](C)CCCC(C)C)Br LWGFSMMVVHGBFX-XGRWYXQASA-N 0.000 description 2
VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
ZDJNZMUXYIZDLQ-ZNUCKLRSSA-N [(3S,8S,9S,10R,13S,14S,17R)-16-bromo-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C(C)(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC([C@@H]([C@]4(CC[C@@H]3[C@]2(CC1)C)C)[C@H](C)CCCC(C)C)Br ZDJNZMUXYIZDLQ-ZNUCKLRSSA-N 0.000 description 2
CCORPVHYPHHRKB-NXUCFJMCSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] propanoate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CC)C1 CCORPVHYPHHRKB-NXUCFJMCSA-N 0.000 description 2
ACGNVBRAISEVDK-RPIQFHTISA-N [(3s,9s,10r,13r,14r,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,9,11,12,14,15,16,17-decahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C1[C@@H](OC(C)=O)CC[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@H](C)CCCC(C)C)CC[C@H]33)C)C3=CC=C21 ACGNVBRAISEVDK-RPIQFHTISA-N 0.000 description 2
229910000287 alkaline earth metal oxide Inorganic materials 0.000 description 2
QVQLCTNNEUAWMS-UHFFFAOYSA-N barium oxide Chemical compound [Ba]=O QVQLCTNNEUAWMS-UHFFFAOYSA-N 0.000 description 2
150000004649 carbonic acid derivatives Chemical class 0.000 description 2
150000001768 cations Chemical class 0.000 description 2
238000001311 chemical methods and process Methods 0.000 description 2
239000007795 chemical reaction product Substances 0.000 description 2
238000002425 crystallisation Methods 0.000 description 2
230000008025 crystallization Effects 0.000 description 2
230000006378 damage Effects 0.000 description 2
238000006704 dehydrohalogenation reaction Methods 0.000 description 2
239000003085 diluting agent Substances 0.000 description 2
238000010790 dilution Methods 0.000 description 2
239000012895 dilution Substances 0.000 description 2
230000008030 elimination Effects 0.000 description 2
238000003379 elimination reaction Methods 0.000 description 2
230000007062 hydrolysis Effects 0.000 description 2
238000006460 hydrolysis reaction Methods 0.000 description 2
150000004679 hydroxides Chemical class 0.000 description 2
238000002844 melting Methods 0.000 description 2
230000008018 melting Effects 0.000 description 2
150000002894 organic compounds Chemical class 0.000 description 2
230000000717 retained effect Effects 0.000 description 2
239000007858 starting material Substances 0.000 description 2
150000003512 tertiary amines Chemical class 0.000 description 2
238000012360 testing method Methods 0.000 description 2
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical class [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
239000004215 Carbon black (E152) Substances 0.000 description 1
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
239000005155 Cholesterol Propionate Substances 0.000 description 1
241001465754 Metazoa Species 0.000 description 1
241000251539 Vertebrata <Metazoa> Species 0.000 description 1
238000013019 agitation Methods 0.000 description 1
230000001476 alcoholic effect Effects 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
229910052788 barium Inorganic materials 0.000 description 1
DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
230000008901 benefit Effects 0.000 description 1
229910052791 calcium Inorganic materials 0.000 description 1
239000011575 calcium Substances 0.000 description 1
229910000019 calcium carbonate Inorganic materials 0.000 description 1
125000002091 cationic group Chemical group 0.000 description 1
229910052801 chlorine Inorganic materials 0.000 description 1
239000000460 chlorine Substances 0.000 description 1
150000001841 cholesterols Chemical class 0.000 description 1
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
238000004090 dissolution Methods 0.000 description 1
238000001035 drying Methods 0.000 description 1
230000000694 effects Effects 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
238000001914 filtration Methods 0.000 description 1
235000013305 food Nutrition 0.000 description 1
150000002366 halogen compounds Chemical class 0.000 description 1
230000002140 halogenating effect Effects 0.000 description 1
TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical group [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
239000012535 impurity Substances 0.000 description 1
238000011835 investigation Methods 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
230000001788 irregular Effects 0.000 description 1
239000000463 material Substances 0.000 description 1
230000007246 mechanism Effects 0.000 description 1
229910052751 metal Inorganic materials 0.000 description 1
239000002184 metal Substances 0.000 description 1
150000002828 nitro derivatives Chemical class 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
239000002245 particle Substances 0.000 description 1
239000002243 precursor Substances 0.000 description 1
239000003223 protective agent Substances 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
230000009257 reactivity Effects 0.000 description 1
238000011084 recovery Methods 0.000 description 1
230000005070 ripening Effects 0.000 description 1
239000007787 solid Substances 0.000 description 1
241000894007 species Species 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000000126 substance Substances 0.000 description 1
125000001424 substituent group Chemical group 0.000 description 1
KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
238000005406 washing Methods 0.000 description 1
239000013585 weight reducing agent Substances 0.000 description 1