KR102647670B1 - 방법 - Google Patents
방법 Download PDFInfo
- Publication number
- KR102647670B1 KR102647670B1 KR1020197021499A KR20197021499A KR102647670B1 KR 102647670 B1 KR102647670 B1 KR 102647670B1 KR 1020197021499 A KR1020197021499 A KR 1020197021499A KR 20197021499 A KR20197021499 A KR 20197021499A KR 102647670 B1 KR102647670 B1 KR 102647670B1
- Authority
- KR
- South Korea
- Prior art keywords
- complex alcohol
- reaction mixture
- phosphorylating
- complex
- alcohol
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 43
- 230000000865 phosphorylative effect Effects 0.000 claims abstract description 15
- -1 3-[2-carboxyethyl(dodecyl)amino]propanoic acid (3-[2-carboxyethyl(dodecyl)amino] propanoic acid) Chemical group 0.000 claims description 168
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 81
- 239000011541 reaction mixture Substances 0.000 claims description 61
- 238000006243 chemical reaction Methods 0.000 claims description 48
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 22
- 230000007062 hydrolysis Effects 0.000 claims description 21
- 238000006460 hydrolysis reaction Methods 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 12
- 229930003799 tocopherol Natural products 0.000 claims description 12
- 239000011732 tocopherol Substances 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 235000010384 tocopherol Nutrition 0.000 claims description 9
- 229960001295 tocopherol Drugs 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- XYYUAOIALFMRGY-UHFFFAOYSA-N 3-[2-carboxyethyl(dodecyl)amino]propanoic acid Chemical compound CCCCCCCCCCCCN(CCC(O)=O)CCC(O)=O XYYUAOIALFMRGY-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- 150000003512 tertiary amines Chemical group 0.000 claims description 5
- SEBPXHSZHLFWRL-UHFFFAOYSA-N 3,4-dihydro-2,2,5,7,8-pentamethyl-2h-1-benzopyran-6-ol Chemical compound O1C(C)(C)CCC2=C1C(C)=C(C)C(O)=C2C SEBPXHSZHLFWRL-UHFFFAOYSA-N 0.000 claims description 4
- 239000002280 amphoteric surfactant Substances 0.000 claims description 4
- 125000003367 polycyclic group Chemical group 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 235000006708 antioxidants Nutrition 0.000 claims description 3
- 125000002837 carbocyclic group Chemical group 0.000 claims description 3
- GJJVAFUKOBZPCB-UHFFFAOYSA-N 2-methyl-2-(4,8,12-trimethyltrideca-3,7,11-trienyl)-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-UHFFFAOYSA-N 0.000 claims description 2
- 230000003444 anaesthetic effect Effects 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- KSDGSKVLUHKDAL-UHFFFAOYSA-L disodium;3-[2-carboxylatoethyl(dodecyl)amino]propanoate Chemical compound [Na+].[Na+].CCCCCCCCCCCCN(CCC([O-])=O)CCC([O-])=O KSDGSKVLUHKDAL-UHFFFAOYSA-L 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- 229930003802 tocotrienol Natural products 0.000 claims description 2
- 239000011731 tocotrienol Substances 0.000 claims description 2
- 235000019148 tocotrienols Nutrition 0.000 claims description 2
- LLKGTXLYJMUQJX-UHFFFAOYSA-M sodium;3-[2-carboxyethyl(dodecyl)amino]propanoate Chemical compound [Na+].CCCCCCCCCCCCN(CCC(O)=O)CCC([O-])=O LLKGTXLYJMUQJX-UHFFFAOYSA-M 0.000 claims 2
- 125000005210 alkyl ammonium group Chemical group 0.000 claims 1
- 230000003078 antioxidant effect Effects 0.000 claims 1
- 150000001298 alcohols Chemical class 0.000 abstract description 22
- 150000003333 secondary alcohols Chemical class 0.000 abstract description 3
- 150000003509 tertiary alcohols Chemical class 0.000 abstract description 2
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 15
- 229960000984 tocofersolan Drugs 0.000 description 15
- 235000004835 α-tocopherol Nutrition 0.000 description 15
- 239000002076 α-tocopherol Substances 0.000 description 15
- 229940087168 alpha tocopherol Drugs 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 230000026731 phosphorylation Effects 0.000 description 8
- 238000006366 phosphorylation reaction Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 5
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 5
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 4
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 4
- WNEUGJMZHVUVLF-UHFFFAOYSA-N CCC(CCCCCC)O.CCC(CCCCCC)O Chemical compound CCC(CCCCCC)O.CCC(CCCCCC)O WNEUGJMZHVUVLF-UHFFFAOYSA-N 0.000 description 4
- DBTKUGNCCKNCFN-UHFFFAOYSA-N CCCCCC(O)CC.CCCCCC(O)CC Chemical compound CCCCCC(O)CC.CCCCCC(O)CC DBTKUGNCCKNCFN-UHFFFAOYSA-N 0.000 description 4
- 125000005189 alkyl hydroxy group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- XTWKEHYBXVTTQC-UHFFFAOYSA-N octan-4-ol Chemical compound CCCC(CCCC)O.C(CC)C(CCCC)O XTWKEHYBXVTTQC-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 229930182558 Sterol Natural products 0.000 description 3
- 125000003302 alkenyloxy group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- URMYFQFQMJBCNT-UHFFFAOYSA-N nonan-2-ol Chemical compound CCCCCCCC(C)O.CCCCCCCC(C)O URMYFQFQMJBCNT-UHFFFAOYSA-N 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- ATKIGFUAOXHQMV-UHFFFAOYSA-N octan-1-ol Chemical compound CCCCCCCCO.CCCCCCCCO ATKIGFUAOXHQMV-UHFFFAOYSA-N 0.000 description 3
- XAQDNRLCLMAVQN-UHFFFAOYSA-N octan-2-ol Chemical compound CCCCCCC(C)O.CCCCCCC(C)O XAQDNRLCLMAVQN-UHFFFAOYSA-N 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 3
- 229960004134 propofol Drugs 0.000 description 3
- 230000000241 respiratory effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 150000003432 sterols Chemical class 0.000 description 3
- 235000003702 sterols Nutrition 0.000 description 3
- 235000019149 tocopherols Nutrition 0.000 description 3
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 3
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 2
- YNZQSDTXBBBFQH-UHFFFAOYSA-N 4-ethylheptan-2-ol Chemical compound CCCC(CC)CC(C)O YNZQSDTXBBBFQH-UHFFFAOYSA-N 0.000 description 2
- LLUQZGDMUIMPTC-UHFFFAOYSA-N 4-methylheptan-1-ol Chemical compound CCCC(C)CCCO LLUQZGDMUIMPTC-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- CDCSAKUZPCFKSQ-UHFFFAOYSA-N CC(CC)(CCCCC)O.CC(CC)(CCCCC)O Chemical compound CC(CC)(CCCCC)O.CC(CC)(CCCCC)O CDCSAKUZPCFKSQ-UHFFFAOYSA-N 0.000 description 2
- DGOKNKCPHIAXHM-UHFFFAOYSA-N CCCCCC(C)O.CCCCCC(C)O Chemical compound CCCCCC(C)O.CCCCCC(C)O DGOKNKCPHIAXHM-UHFFFAOYSA-N 0.000 description 2
- TTXLOJOULWGAPC-UHFFFAOYSA-N CCCCCCCCC(C)O.CCCCCCCCC(C)O Chemical compound CCCCCCCCC(C)O.CCCCCCCCC(C)O TTXLOJOULWGAPC-UHFFFAOYSA-N 0.000 description 2
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 102000018997 Growth Hormone Human genes 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 2
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 2
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 2
- 229940079156 Proteasome inhibitor Drugs 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- JUIUXBHZFNHITF-IEOSBIPESA-N [(2r)-2,5,7,8-tetramethyl-2-[(4r,8r)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] dihydrogen phosphate Chemical compound OP(=O)(O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C JUIUXBHZFNHITF-IEOSBIPESA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000006323 alkenyl amino group Chemical group 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- 229940035674 anesthetics Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- FMABSXTZZMCAFE-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO.CCCCCCCCCCO FMABSXTZZMCAFE-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 125000004986 diarylamino group Chemical group 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 235000010382 gamma-tocopherol Nutrition 0.000 description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 2
- 239000003193 general anesthetic agent Substances 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- IHXVXCBURCKKCV-UHFFFAOYSA-N heptan-3-ol Chemical compound CCC(CCCC)O.CCC(CCCC)O IHXVXCBURCKKCV-UHFFFAOYSA-N 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 239000011872 intimate mixture Substances 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 229960005127 montelukast Drugs 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 description 2
- 229960000801 nelarabine Drugs 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- IYNICVMVZDAJFD-UHFFFAOYSA-N nonan-1-ol Chemical compound CCCCCCCCCO.CCCCCCCCCO IYNICVMVZDAJFD-UHFFFAOYSA-N 0.000 description 2
- LWSSSMZSSDBJQL-UHFFFAOYSA-N nonan-5-ol Chemical compound CCCCC(O)CCCC.CCCCC(O)CCCC LWSSSMZSSDBJQL-UHFFFAOYSA-N 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000000014 opioid analgesic Substances 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- REIUXOLGHVXAEO-UHFFFAOYSA-N pentadecan-1-ol Chemical compound CCCCCCCCCCCCCCCO REIUXOLGHVXAEO-UHFFFAOYSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 239000003207 proteasome inhibitor Substances 0.000 description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- KJIOQYGWTQBHNH-UHFFFAOYSA-N undecanol Chemical compound CCCCCCCCCCCO KJIOQYGWTQBHNH-UHFFFAOYSA-N 0.000 description 2
- WGVKWNUPNGFDFJ-DQCZWYHMSA-N β-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C WGVKWNUPNGFDFJ-DQCZWYHMSA-N 0.000 description 2
- 239000002478 γ-tocopherol Substances 0.000 description 2
- QUEDXNHFTDJVIY-DQCZWYHMSA-N γ-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-DQCZWYHMSA-N 0.000 description 2
- GZIFEOYASATJEH-VHFRWLAGSA-N δ-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-VHFRWLAGSA-N 0.000 description 2
- CRDAMVZIKSXKFV-FBXUGWQNSA-N (2-cis,6-cis)-farnesol Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C/CO CRDAMVZIKSXKFV-FBXUGWQNSA-N 0.000 description 1
- 239000000260 (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol Substances 0.000 description 1
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 1
- JVLBPIPGETUEET-WIXLDOGYSA-O (3r,4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one Chemical compound C([N@+]1(C)[C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)C1CC1 JVLBPIPGETUEET-WIXLDOGYSA-O 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
- C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/095—Compounds containing the structure P(=O)-O-acyl, P(=O)-O-heteroatom, P(=O)-O-CN
-
- C—CHEMISTRY; METALLURGY
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Abstract
본 발명은 고온에서 2차 및 3차 알코올과 같은 복합 알코올과 P4O10의 효율적이고 경제적인 인산화 방법, 및 이로 인해 얻어진 생성물에 관한 것이다.
Description
본 발명은 복합 알코올의 인산화 방법, 및 상기 방법에 의해 얻어진 생성물에 관한 것이다.
선행 기술 문헌이 본 명세서에서 언급되는 경우, 그러한 참고 문헌은 그 출판물이 호주 또는 다른 국가에서 당업계의 통상적인 지식의 일부를 형성한다는 것을 인정하는 것으로 간주되지 않는다는 것을 이해해야 한다.
인산화 방법 및 시약은 인산화되는 화합물이 현저히 분해되는 것을 방지하고 원하는 수율을 산출하도록 선택된다.
몇몇 인산화 방법에서, 2:2:2-트리클로로에틸 디클로로포스페이트(2:2:2-trichloroethyl dichlorophosphate), 디-이미다졸라이드 클로로포스페이트(di-imidazolide chlorophosphate) 및 디-아닐리드 클로로포스페이트(di-analide chlorophosphate)와 같은 시약이 인산화되는 화합물의 분해를 방지하기 위해 완만한 조건 하에서 사용되었다. 그러나, 이러한 방법은 경제적이지 않거나 상업적인 목적에 적합하지 않은 제한된 수율을 생성하는 것으로 밝혀졌다.
다른 인산화 방법에서는 시약으로 옥시 염화인(phosphorous oxychloride)을 사용하였으나, 반응은 일반적으로 다양한 부산물과 염화수소를 생성하였다. 이러한 방법은 시약 옥시 염화인이 취급하기 어렵기 때문에 상업적으로 실행 가능하지 않을 수 있다.
일반적으로 오산화인(phosphorus pentoxide)으로 알려져있지만 산화인(V), 무수인산(phosphoric anhydride) 및 오산화이인(diphosphorus pentoxide)과 같은 다른 이름을 갖는 시약 P4O10은 흰색의 결정성 고형물(crystalline solid)이다. 이 시약은 에탄올 및 다른 단사슬 1차 알코올(즉, 6개 미만의 탄소 원자)의 인산화를 위해 사용되었으며, 1차 지방 알코올, 2차 알코올 및 방향족 알코올과 같은 알코올의 인산화에 적합하다는 것이 발견되었다. 호주 특허 문헌 200043870은 80℃ 이하의 온도에서 이러한 알코올들 및 P4O10, 부분적으로 수소화된 P4O10 또는 이의 혼합물 중 하나 이상의 친밀 혼합물(intimate mixture)을 포함하며 인산화된 알코올이 실질적으로 형성될 때까지 상기 온도, 즉 80℃ 이하에서 일정한 시간 동안 반응하는 것을 허용하는 방법을 개시하고 있다.
고온에서 2차 알코올 및 3차 알코올과 같은 복합 알코올과 P4O10의 인산화는 탈수(dehydration) 및 이중 결합 형성과 같은 부반응 및/또는 분해를 일으키는 것으로 여겨졌다. 이러한 문제점은 고온에서 복합 알코올의 효율적이고 경제적인 인산화를 위한 P4O10의 사용을 배제한다.
본 발명은 복합 알코올이 고온에서 인산화될 수 있고, 이러한 온도에서 복합 알코올의 분해를 최소화하여 원하는 수율을 얻을 수 있는 것을 발견하였다.
따라서, 본 발명은 복합 알코올을 인산화하는 방법을 제공하며, 상기 방법은:
(a) 발열 반응 온도에 도달할 때까지 복합 알코올과 P4O10를 혼합하는 단계;
(b) 발열 반응이 완료될 때까지 상기 단계 (a)의 반응 혼합물을 반응시키고, 필요에 따라 적어도 약 90℃ 내지 140℃로 상기 단계 (a)의 상기 반응 혼합물을 가열하는 단계;
(c) 상기 단계 (b)의 반응 혼합물을 적어도 약 80℃로 냉각시키는 단계; 및
(d) 상기 단계 (c)의 반응 혼합물을 약 30분 내지 약 90분 동안 가수분해하는 단계;를 포함한다.
또한, 본 발명은 이러한 방법에 의해 얻어진 생성물을 제공한다.
본 발명은 복합 알코올을 인산화하는 방법에 관한 것이며, 상기 방법은:
(a) 발열 반응 온도에 도달할 때까지 복합 알코올과 P4O10를 혼합하는 단계;
(b) 발열 반응이 완료될 때까지 상기 단계 (a)의 반응 혼합물을 반응시키고, 필요에 따라 적어도 약 90℃ 내지 140℃로 상기 단계 (a)의 상기 반응 혼합물을 가열하는 단계;
(c) 상기 단계 (b)의 반응 혼합물을 적어도 약 80℃로 냉각시키는 단계; 및
(d) 상기 단계 (c)의 반응 혼합물을 약 30분 내지 약 90분 동안 가수분해하는 단계;를 포함한다.
복합 알코올
복합 알코올은 적어도 6개의 탄소 원자(즉, 6개 이상의 탄소 원자)를 포함하는 선형 또는 분지형 알코올일 수 있다. 몇몇 실시예에 따르면, 복합 알코올은 적어도 7개의 탄소 원자를 포함한다. 다른 실시예에 따르면, 복합 알코올은 적어도 8개의 탄소 원자를 포함한다. 특정 실시예에 따르면, 복합 알코올은 적어도 10개의 탄소 원자를 포함한다. 여기에서 언급된 탄소 원자의 수는 선형 또는 분지형 복합 알코올의 백본(backbone) 또는 고리형 복합 알코올의 고리 시스템(ring system)을 구성하는 탄소 원자 수를 나타낸다.
선형 또는 분지형 복합 알코올의 예로서, 헥산올(hexanol), 헥산-1-올(hexan-1-ol), 헵탄올(heptanol), 헵탄-1-올(heptan-1-ol), 옥탄올(octanol), 옥탄-1-올(octan-1-ol), 데칸올(decanol), 데칸-1-올(decan-1-ol), 운데칸올(undecanol), 도데칸올(dodecanol), 1-도데칸올(1-dodecanol), 트리데칸올(tridecanol), 1-테트라데칸올(1-tetradecanol), 펜타데칸올(pentadecanol), 세틸 알코올(cetyl alcohol), 스테아릴 알코올(stearyl alcohol), 1-메틸헥산-1-올(1-methylhexan-1-ol), 2-메틸헥산-1-올(2-methylhexan-1-ol), 3-메틸-헵탄-1-올(3-methyl-hexan-1-ol), 4-메틸헥산-1-올(4-methylhexan-1-ol), 1-메틸헥산-2-올(1-methylhexan-2-ol), 2-메틸헥산-2-올(2-methylhexan-2-ol), 3-메틸-헥산-2-올(3-methylhexan-2-ol), 4-메틸헥산-2-올(4-methylhexan-2-ol), 1-메틸헥산-3-올(1-methylhexan-3-ol), 2-메틸헥산-3-올(2-methylhexan-3-ol), 3-메틸-헥산-3-올(3-methyl-hexan-3-ol), 4-메틸헥산-3-올(4-methylhexan-3-ol), 1-메틸헥산-4-올(1-methylhexan-4-ol), 2-메틸헥산-4-올(2-methylhexan-4-ol), 3-메틸-헥산-4-올(3-methyl-hexan-4-ol), 4-메틸헥산-4-올(4-methylhexan-4-ol), 1-메틸헥산-5-올(1-methylhexan-5-ol), 2-메틸헥산-5-올(2-methylhexan-5-ol), 3-메틸-헥산-5-올(3-methyl-hexan-5-ol), 4-메틸헥산-5-올(4-methylhexan-5-ol), 1-메틸헥산-6-올(1-methylhexan-6-ol), 2-메틸헥산-6-올(2-methylhexan-6-ol), 3-메틸-헥산-6-올(3-methyl-hexan-6-ol), 4-메틸헥산-6-올(4-methylhexan-6-ol), 1-에틸헥산-1-올(1-ethylhexan-1-ol), 2-에틸헥산-1-올(2-ethylhexan-1-ol), 3-에틸-헥산-1-올(3-ethyl-hexan-1-ol), 4-메틸헥산-1-올(4-ethylhexan-1-ol), 1-에틸헥산-2-올(1-ethylhexan-2-ol), 2-에틸헥산-2-올(2-ethylhexan-2-ol), 3-에틸-헥산-2-올(3-ethyl-hexan-2-ol), 4-에틸헥산-2-올(4-ethylhexan-2-ol), 1-에틸헥산-3-올(1-ethylhexan-3-ol), 2-에틸헥산-3-올(2-ethylhexan-3-ol), 3-에틸-헥산-3-올(3-ethyl-hexan-3-ol), 4-에틸헥산-3-올(4-ethylhexan-3-ol), 1-에틸헥산-4-올(1-ethylhexan-4-ol), 2-에틸헥산-4-올(2-ethylhexan-4-ol), 3-에틸-헥산-4-올(3-ethyl-hexan-4-ol), 4-에틸헥산-4-올(4-ethylhexan-4-ol), 1-에틸헥산-5-올(1-ethylhexan-5-ol), 2-에틸헥산-5-올(2-ethylhexan-5-ol), 3-에틸-헥산-5-올(3-ethyl-hexan-5-ol), 4-에틸헥산-5-올(4-ethylhexan-5-ol), 1-에틸헥산-6-올(1-ethylhexan-6-ol), 2-에틸헥산-6-올(2-ethylhexan-6-ol), 3-에틸-헥산-6-올(3-ethyl-hexan-6-ol), 4-에틸헥산-6-올(4-ethylhexan-6-ol), 1-메틸헵탄-1-올(1-methylheptan-1-ol), 2-메틸헵탄-1-올(2-methylheptan-1-ol), 3-메틸-헵탄-1-올(3-methyl-heptan-1-ol), 4-메틸헵탄-1-올(4-methylheptan-1-ol), 1-메틸헵탄-2-올(1-methylheptan-2-ol), 2-메틸헵탄-2-올(2-methylheptan-2-ol), 3-메틸-헵탄-2-올(3-methyl-heptan-2-ol), 4-메틸헵탄-2-올(4-methylheptan-2-ol), 1-메틸헵탄-3-올(1-methylheptan-3-ol), 2-메틸헵탄-3-올(2-methylheptan-3-ol), 3-메틸-헵탄-3-올(3-methyl-heptan-3-ol), 4-메틸헵탄-3-올(4-methylheptan-3-ol), 1-메틸헵탄-4-올(1-methylheptan-4-ol), 2-메틸헵탄-4-올(2-methylheptan-4-ol), 3-메틸-헵탄-4-올(3-methyl-heptan-4-ol), 4-메틸헵탄-4-올(4-methylheptan-4-ol), 1-메틸헵탄-5-올(1-methylheptan-5-ol), 2-메틸헵탄-5-올(2-methylheptan-5-ol), 3-메틸-헵탄-5-올(3-methyl-heptan-5-ol), 4-메틸헵탄-5-올(4-methylheptan-5-ol), 1-메틸헵탄-6-올(1-methylheptan-6-ol), 2-메틸헵탄-6-올(2-methylheptan-6-ol), 3-메틸-헵탄-6-올(3-methyl-heptan-6-ol), 4-메틸헵탄-6-올(4-methylheptan-6-ol), 1-메틸헵탄-7-올(1-methylheptan-7-ol), 2-메틸헵탄-7-올(2-methylheptan-7-ol), 3-메틸-헵탄-7-올(3-methyl-heptan-7-ol), 4-메틸헵탄-7-올(4-methylheptan-7-ol), 1-에틸헵탄-1-올(1-ethylheptan-1-ol), 2-에틸헵탄-1-올(2-ethylheptan-1-ol), 3-에틸-헵탄-1-올(3-ethyl-heptan-1-ol), 4-메틸헵탄-1-올(4-ethylheptan-1-ol), 1-에틸헵탄-2-올(1-ethylheptan-2-ol), 2-에틸헵탄-2-올(2-ethylheptan-2-ol), 3-에틸-헵탄-2-올(3-ethyl-heptan-2-ol), 4-에틸헵탄-2-올(4-ethylheptan-2-ol), 1-에틸헵탄-3-올(1-ethylheptan-3-ol), 2-에틸헵탄-3-올(2-ethylheptan-3-ol), 3-에틸-헵탄-3-올(3-ethyl-heptan-3-ol), 4-에틸헵탄-3-올(4-ethylheptan-3-ol), 1-에틸헵탄-4-올(1-ethylheptan-4-ol), 2-에틸헵탄-4-올(2-ethylheptan-4-ol), 3-에틸-헵탄-4-올(3-ethyl-heptan-4-ol), 4-에틸헵탄-4-올(4-ethylheptan-4-ol), 1-에틸헵탄-5-올(1-ethylheptan-5-ol), 2-에틸헵탄-5-올(2-ethylheptan-5-ol), 3-에틸-헵탄-5-올(3-ethyl-heptan-5-ol), 4-에틸헵탄-5-올(4-ethylheptan-5-ol), 1-에틸헵탄-6-올(1-ethylheptan-6-ol), 2-에틸헵탄-6-올(2-ethylheptan-6-ol), 3-에틸-헵탄-6-올(3-ethyl-heptan-6-ol), 4-에틸헵탄-6-올(4-ethylheptan-6-ol), 1-에틸헵탄-7-올(1-ethylheptan-7-ol), 2-에틸헵탄-7-올(2-ethylheptan-7-ol), 3-에틸-헵탄-7-올(3-ethyl-heptan-7-ol), 4-에틸헵탄-7-올(4-ethylheptan-7-ol), 1-메틸옥탄-1-올(1-methyloctan-1-ol), 2-메틸옥탄-1-올(2-methyloctan-1-ol), 3-메틸-옥탄-1-올(3-methyl-octan-1-ol), 4-메틸옥탄-1-올(4-methyloctan-1-ol), 1-메틸옥탄-2-올(1-methyloctan-2-ol), 2-메틸옥탄-2-올(2-methyloctan-2-ol), 3-메틸-옥탄-2-올(3-methyl-octan-2-ol), 4-메틸옥탄-2-올(4-methyloctan-2-ol), 1-메틸옥탄-3-올(1-methyloctan-3-ol), 2-메틸옥탄-3-올(2-methyloctan-3-ol), 3-메틸-옥탄-3-올(3-methyl-octan-3-ol), 4-메틸옥탄-3-올(4-methyloctan-3-ol), 1-메틸옥탄-4-올(1-methyloctan-4-ol), 2-메틸옥탄-4-올(2-methyloctan-4-ol), 3-메틸-옥탄-4-올(3-methyl-octan-4-ol), 4-메틸옥탄-4-올(4-methyloctan-4-ol), 1-메틸옥탄-5-올(1-methyloctan-5-ol), 2-메틸옥탄-5-올(2-methyloctan-5-ol), 3-메틸-옥탄-5-올(3-methyl-octan-5-ol), 4-메틸옥탄-5-올(4-methyloctan-5-ol), 1-메틸옥탄-6-올(1-methyloctan-6-ol), 2-메틸옥탄-6-올(2-methyloctan-6-ol), 3-메틸-옥탄-6-올(3-methyl-octan-6-ol), 4-메틸옥탄-6-올(4-methyloctan-6-ol), 1-메틸옥탄-7-올(1-methyloctan-7-ol), 2-메틸옥탄-7-올(2-methyloctan-7-ol), 3-메틸-옥탄-7-올(3-methyl-octan-7-ol), 4-메틸옥탄-7-올(4-methyloctan-7-ol), 1-메틸옥탄-8-올(1-methyloctan-8-ol), 2-메틸옥탄-8-올(2-methyloctan-8-ol), 3-메틸-옥탄-8-올(3-methyl-octan-8-ol), 4-메틸옥탄-8-올(4-methyloctan-8-ol), 1-에틸옥탄-1-올(1-ethyloctan-1-ol), 2-에틸옥탄-1-올(2-ethyloctan-1-ol), 3-에틸-옥탄-1-올(3-ethyl-octan-1-ol), 4-메틸옥탄-1-올(4-ethyloctan-1-ol), 1-에틸옥탄-2-올(1-ethyloctan-2-ol), 2-에틸옥탄-2-올(2-ethyloctan-2-ol), 3-에틸-옥탄-2-올(3-ethyl-octan-2-ol), 4-에틸옥탄-2-올(4-ethyloctan-2-ol), 1-에틸옥탄-3-올(1-ethyloctan-3-ol), 2-에틸옥탄-3-올(2-ethyloctan-3-ol), 3-에틸-옥탄-3-올(3-ethyl-octan-3-ol), 4-에틸옥탄-3-올(4-ethyloctan-3-ol), 1-에틸옥탄-4-올(1-ethyloctan-4-ol), 2-에틸옥탄-4-올(2-ethyloctan-4-ol), 3-에틸-옥탄-4-올(3-ethyl-octan-4-ol), 4-에틸옥탄-4-올(4-ethyloctan-4-ol), 1-에틸옥탄-5-올(1-ethyloctan-5-ol), 2-에틸옥탄-5-올(2-ethyloctan-5-ol), 3-에틸-옥탄-5-올(3-ethyl-octan-5-ol), 4-에틸옥탄-5-올(4-ethyloctan-5-ol), 1-에틸옥탄-6-올(1-ethyloctan-6-ol), 2-에틸옥탄-6-올(2-ethyloctan-6-ol), 3-에틸-옥탄-6-올(3-ethyl-octan-6-ol), 4-에틸옥탄-6-올(4-ethyloctan-6-ol), 1-에틸옥탄-7-올(1-ethyloctan-7-ol), 2-에틸옥탄-7-올(2-ethyloctan-7-ol), 3-에틸-옥탄-7-올(3-ethyl-octan-7-ol), 4-에틸옥탄-7-올(4-ethyloctan-7-ol), 1-에틸옥탄-8-올(1-ethyl-octan-8-ol), 2-에틸옥탄-8-올(2-ethyloctan-8-ol), 3-에틸-옥탄-8-올(3-ethyl-octan-8-ol), 4-에틸옥탄-8-올(4-ethyloctan-8-ol), 1-메틸노난-1-올(1-methylnonan-1-ol), 2-메틸노난-1-올(2-methylnonan-1-ol), 3-메틸-노난-1-올(3-methyl-nonan-1-ol), 4-메틸노난-1-올(4-methylnonan-1-ol), 1-메틸노난-2-올(1-methylnonan-2-ol), 2-메틸노난-2-올(2-methylnonan-1-ol), 3-메틸-노난-2-올(3-methyl-nonan-1-ol), 4-메틸노난-2-올(4-methylnonan-1-ol), 1-메틸노난-3-올(1-methylnonan-3-ol), 2-메틸노난-3-올(2-methylnonan-3-ol), 3-메틸-노난-3-올(3-methyl-nonan-3-ol), 4-메틸노난-3-올(4-methylnonan-3-ol), 1-메틸노난-4-올(1-methylnonan-4-ol), 2-메틸노난-4-올(2-methylnonan-4-ol), 3-메틸-노난-4-올(3-methyl-nonan-4-ol), 4-메틸노난-4-올(4-methylnonan-4-ol), 1-메틸노난-5-올(1-methylnonan-5-ol), 2-메틸노난-5-올(2-methylnonan-5-ol), 3-메틸-노난-5-올(3-methyl-nonan-5-ol), 4-메틸노난-5-올(4-methylnonan-5-ol), 1-메틸노난-6-올(1-methylnonan-6-ol), 2-메틸노난-6-올(2-methylnonan-6-ol), 3-메틸-노난-6-올(3-methylnonan-6-ol), 4-메틸노난-6-올(4-methylnonan-6-ol), 1-메틸노난-7-올(1-methylnonan-7-ol), 2-메틸노난-7-올(2-methylnonan-7-ol), 3-메틸-노난-7-올(3-methylnonan-7-ol), 4-메틸노난-7-올(4-methylnonan-7-ol), 1-메틸노난-8-올(1-methylnonan-8-ol), 2-메틸노난-8-올(2-methylnonan-8-ol), 3-메틸-노난-8-올(3-methylnonan-8-ol), 4-메틸노난-8-올(4-methylnonan-8-ol), 1-메틸노난-9-올(1-methylnonan-9-ol), 2-메틸노난-9-올(2-methylnonan-9-ol), 3-메틸-노난-9-올(3-methylnonan-9-ol), 4-메틸노난-9-올(4-methylnonan-9-ol), 1-에틸노난-1-올(1-ethylnonan-1-ol), 2-에틸노난-1-올(2-ethylnonan-1-ol), 3-에틸-노난-1-올(3-ethyl-nonan-1-ol), 4-메틸노난-1-올(4-ethylnonan-1-ol), 1-에틸노난-2-올(1-ethylnonan-2-ol), 2-에틸노난-2-올(2-ethylnonan-2-ol), 3-에틸-노난-2-올(3-ethyl-nonan-2-ol), 4-에틸노난-2-올(4-ethylnonan-2-ol), 1-에틸노난-3-올(1-ethylnonan-3-ol), 2-에틸노난-3-올(2-ethylnonan-2-ol), 3-에틸-노난-3-올(3-ethyl-nonan-2-ol), 4-에틸노난-3-올(4-ethylnonan-2-ol), 1-에틸노난-4-올(1-ethylnonan-4-ol), 2-에틸노난-4-올(2-ethylnonan-4-ol), 3-에틸-노난-4-올(3-ethyl-nonan-4-ol), 4-에틸노난-4-올(4-ethylnonan-4-ol), 1-에틸노난-5-올(1-ethylnonan-5-ol), 2-에틸노난-5-올(2-ethylnonan-5-ol), 3-에틸-노난-5-올(3-ethyl-nonan-5-ol), 4-에틸노난-5-올(4-ethylnonan-5-ol), 1-에틸노난-6-올(1-ethylnonan-6-ol), 2-에틸노난-6-올(2-ethylnonan-6-ol), 3-에틸-노난-6-올(3-ethyl-nonan-6-ol), 4-에틸노난-6-올(4-ethylnonan-6-ol), 1-에틸노난-7-올(1-ethylnonan-7-ol), 2-에틸노난-7-올(2-ethylnonan-7-ol), 3-에틸-노난-7-올(3-ethyl-nonan-7-ol), 4-에틸노난-7-올(4-ethylnonan-7-ol), 1-에틸노난-8-올(1-ethylnonan-8-ol), 2-에틸노난-8-올(2-ethylnonan-8-ol), 3-에틸-노난-8-올(3-ethyl-nonan-8-ol), 4-에틸노난-8-올(4-ethylnonan-8-ol), 1-에틸노난-9-올(1-ethylnonan-9-ol), 2-에틸노난-9-올(2-ethylnonan-9-ol), 3-에틸-노난-9-올(3-ethyl-nonan-9-ol), 및 4-에틸노난-9-올(4-ethylnonan-9-ol)을 포함하지만, 이에 한정되지 않는다.
복합 알코올은 고리형 복합 알코올일 수 있으며, 탄소고리형(carbocyclic) 또는 헤테로고리형(heterocyclic)일 수 있다. 또한, 탄소고리 또는 헤테로고리 복합 알코올은 방향족 또는 비-방향족일 수 있다. 몇몇 실시예에서, 헤테로고리 복합 알코올은 하나 이상의 헤테로원자를 포함한다. 일 실시예에 따르면, 헤테로고리 복합 알코올은 하나의 헤테로원자를 포함한다. 다른 실시예에 따르면, 헤테로고리 복합 알코올은 2개의 헤테로원자를 포함한다. 헤테로원자는 N, O, S 및 P로 이루어진 군으로부터 선택될 수 있다.
고리형 복합 알코올은 또한, 단환 또는 다환일 수 있다. 다환 복합 알코올은 둘 이상의 고리를 포함할 수 있다. 몇몇 실시예에 따르면, 다환 복합 알코올은 둘 이상의 고리를 포함하며, 여기에서 둘 이상의 고리는 융합된다.
특정 실시예에 따르면, 복합 알코올은 스테롤(sterol)이다. 스테롤은 피토스테롤(phytosterol)일 수 있다. 특정 일 실시예에 따르면, 스테롤은 콜레스테롤이다.
다른 특정 실시예에 따르면, 복합 알코올은 크로마놀(chromanol)이다. 몇몇 실시예에 따르면, 크로마놀은 토코페롤(tocopherol) 또는 토코트리에놀(tocotrienol)이다.
몇몇 실시예에 따르면, 토코페롤은 천연 또는 합성 또는 이들의 조합물이다. 천연 토코페롤은 일반적으로 약 95%의 α-토코페롤 및 소량의 γ-토코페롤을 포함한다. 반면에, 합성 토코페롤은 일반적으로 약 99~98%의 α-토코페롤을 포함한다. 또한, 합성 토코페롤은 8개의 가능한 입체 이성질체(stereoisomers)의 혼합물을 포함하며, 여기에서 단지 1개만 자연 발생한다.
다른 실시예에 따르면, 토코페롤은 α-토코페롤, β-토코페롤, γ-토코페롤, δ-토코페롤 또는 이의 조합물이다. 특정 실시예에 따르면, 토코페롤은 α-토코페롤이다. 일 실시예에 따르면, 토코페롤은 약 90% 이상의 α-토코페롤을 포함한다. 다른 실시예에 따르면, 토코페롤은 α-토코페롤(즉, 100% α-토코페롤)이다.
또한, 복합 알코올은 약제학적 화합물, 마취제 또는 항산화제일 수 있다.
몇몇 실시예에 따르면, 약제학적 화합물은 탁산(taxane), 뉴클레오시드(nucleoside) 또는 활성효소 억제제(kinase inhibitor)와 같은 항 종양 약물(oncology drug), 스테로이드(steroid), 오피오이드 진통제(opioid analgesic), 호흡 기관용 약제(respiratory drug), 중추 신경계(central nervous system, CNS)용 약제, 고콜레스테롤혈증 치료제(hypercholesterolemia drug), 항고혈압제(antihypertensive drug), 면역 억제성 약제(immunosuppressive drug), 항생제(antibiotic), 황체 형성 호르몬 방출 호르몬(luteinising hormone releasing hormone, LHRH) 작용제, LHRH 길항제, 항바이러스제(antiviral drug), 항레트로바이러스제 (antiretroviral drug), 에스트로겐 수용체 조절제(estrogen receptor modulator), 성장 호르몬 방출 억제 인자 유사 물질(somatostatin mimic), 소염제(anti-inflammatory drug), 비타민 D2 유사 물질(vitamin D2 analogue), 합성 티록신(synthetic thyroxine), 항히스타민제(antihistamine), 항진균제(antifungal agent), 비스테로이드 항염증제(nonsteroidal anti-inflammatory drug, NSAID) 또는 마취제(anesthetic)이다.
적합한 항 종양 약물은 파크리탁셀(paclitaxel), 카바지탁셀(cabazitaxel) 및 도세탁셀(docetaxel)과 같은 탁산(taxanes); 이리노테칸(irinotecan) 및 토포테칸(topotecan)과 같은 캄토테신(camptothecin) 및 이의 유사 물질; 빈플루닌(vinflunine)과 같은 항미세관 약제(antimicrotubule agent); 젬시타빈(gemcitabine), 클라드리빈(cladribine), 플루다라빈(fludarabine), 카페시타빈(capecitabine), 데시타빈(decitabine), 아자시티딘(azacitidine), 클로파라빈(clofarabine) 및 넬라라빈(nelarabine)과 같은 뉴클레오시드(nucleosides); 스프라이셀(sprycel), 템시로리무스(temisirolimus), 다사티닙(dasatinib), AZD6244, AZD1152, PI-103, R-로스코비틴(R-roscovitine), 올로모우신(olomoucine) 및 푸르발라놀 A(purvalanol A)와 같은 활성효소 억제제(kinase inhibitor); 익사베필론(ixabepilone)과 같은 에포틸론 B(epothilone B) 유사 물질; 암루비신(amrubicin), 독소루비신(doxorubicin), 에피루비신(epirubicin) 및 발루비신(valrubicin)과 같은 안트라사이클린(anthrocyclines); 트라벡테딘(trabectecin)과 같은 과산화물 유발 인자(super oxide inducers); 보르테조마이브(bortezomib)와 같은 프로테아솜 억제제(proteosome inhibitors) 및 다른 프로테아솜 억제제, 삽입성 물질(intercalating agents) 및 알킬화제(alkylating agents)를 포함한다.
적합한 스테로이드는 디하이드로테스토스테론(dihydrotestosterone), 에스트라디올(estradiol) 및 에티닐 에스트라디올(ethynylestradiol)과 같은 동화성 스테로이드(anabolic steroids), 및 코르티손(cortisone), 프레드니실론(prednisilone), 부데소니드(budesonide), 트리암시놀론(triamcinolone), 플루티카손(fluticasone), 모메타손(mometasone), 암시노나이드(amcinonide), 플루오시놀론(flucinolone), 데소나이드(desonide), 할시노라이드(halcinonide), 프레드니카르베이트(prednicarbate), 플로코르토론(fluocortolone), 덱사메타손(dexamethasone), 베타메타손(betamethasone) 및 플루프레드니딘(fluprednidine)과 같은 코르티코스테로이드(corticosteroids)를 포함한다.
적합한 오피오이드 진통제는 모르핀(morphine), 옥시모르폰(oxymorphone), 날록손(naloxone), 코데인(codeine), 옥시코돈(oxycodone), 메틸날트렉손(methylnaltrexone), 하이드로모르폰(hydromorphone), 부프레노르핀(buprenorphine) 및 에토르핀(etorphine)을 포함한다.
적합한 호흡 기관용 약제는 기관지 확장제(bronchodilators), 호흡기 스테로이드(inhaled steroids), 및 충혈 완화제(decongestants)를 포함하며, 보다 구체적으로는 살부타몰(salbutamol), 이프라트로피움 브로마이드(ipratropium bromide), 몬테루카스트(montelukast) 및 포르모테롤(formoterol)을 포함한다. 적합한 CNS 약제는 쿠에티아핀(quetiapine)과 같은 항정신병제(antipsychotic), 및 벤라팍신(venlafaxine)과 같은 항우울제(antidepressants)를 포함한다.
고콜레스테롤혈증을 제어하는 치료제는 에제티미브(ezetimibe); 및 심바스타틴(simvastatin), 로바스타틴(lovastatin), 아토르바스타틴(atorvastatin), 플루바스타틴(fluvastatin), 피타바스타틴(pitavastatin), 프라바스타틴(pravastatin) 및 로수바스타틴(rosuvastatin)과 같은 스타틴(statins);을 포함한다.
적합한 항고혈압제는 로자탄(losartan), 올메살탄(olmesartan), 메독소밀(medoxomil), 메트로롤(metrolol), 트라보프로스트(travoprost) 및 보센탄(bosentan)을 포함한다.
적합한 면역 억제성 약제는 글루코코티코이드(glucocorticoids), 세포 증식 억제제(cytostatics), 항체 단편(antibody fragments), 항이뮤노필린(anti-immunophilins), 인터페론(interferons), TNF 결합 단백질(TNF binding proteins)을 포함하며, 보다 구체적으로는 타크로리무스(tacrolimus)와 같은 칼시뉴린 억제제(cacineurin inhibitors); 마이코페놀레이트 모페틸(mycophenolate mofetil)과 같은 마이코페놀산(mycophenolic acid) 및 이의 유도체; 및 사이클로스포린(cyclosporine)을 포함한다.
적합한 항세균제는 아목시실린(amoxicillin), 메로페넴(meropenem) 및 클라블라산(clavulanic acid)과 같은 항생제를 포함한다.
적합한 LHRH 작용제는 고세렐린 아세테이트(goserelin acetate), 데스로렐린(deslorelin) 및 류프로렐린(leuprorelin)을 포함한다.
적합한 LHRH 길항제는 세트로레릭스(cetrorelix), 가니렐릭스(ganirelix), 아바렐릭스(abarelix) 및 데가렐릭스(degarelix)를 포함한다.
항바이러스제는 라미브딘(lamivudine), 지도부딘(zidovudine), 아바카비어(abacavir) 및 엔테카비어(entecavir)와 같은 뉴클레오사이드 유사 물질을 포함하며, 적합한 항레트로바이러스제는 아타자나비어(atazanavir), 로피나비어(lapinavir) 및 리토나비르(ritonavir)와 같은 프로테아제 억제제(protease inhibitors)를 포함한다. 적합한 선택적 에스트로겐 수용체 조절제는 랄록시펜(raloxifene) 및 풀베스트란트(fulvestrant)를 포함한다.
적합한 성장 호르몬 방출 억제 인자 유사 물질은 옥트레오타이드(octreotide)를 포함한다.
적합한 소염제는 메살라진(mesalazine)을 포함하며, 적합한 NSAID는 아세트아미노펜(acetaminophen)(파라세타몰(paracetamol))을 포함한다.
적합한 비타민 D2 유사 물질은 파리칼시톨(paricalcitol)을 포함한다.
적합한 합성 티록신은 레보티록신(levothyroxine)을 포함한다.
적합한 항히스타민제는 펙소페나딘(fexofenadine)을 포함한다.
적합한 항진균제는 보리코나졸(viriconazole)과 같은 아졸(azoles)을 포함한다.
적합한 항산화제는 아스코르브산(ascorbic acid); 레티놀과 같은 하이드록시 카로티노이드(hydroxy carotenoid); 및 칼시페롤(calciferol)을 포함한다.
적합한 마취제는 프로포폴(propofol)을 포함한다.
또한, 복합 알코올은 예를 들어 테트라글리콜(tetraglycol) 및 라우릴 알코올(lauryl alcohol)과 같은 용매일 수 있다.
몇몇 실시예에 따르면, 복합 알코올은 수용액에 용해되거나 용해되지 않는다. 복합 알코올은 파르네솔(farnesol)일 수 있다.
몇몇 실시예에 따르면, 복합 알코올은 둘 이상의 복합 알코올의 혼합물일 수 있다.
전술한 실시예에 따르면, 선형, 분지형 또는 고리형 복합 알코올은 모노하이드록시(monohydroxy) 또는 폴리하이드록시(polyhydroxy)이다. 몇몇 실시예에 따르면, 폴리하이드록시 복합 알코올은 2개의 하이드록시기를 포함한다. 다른 실시예에 따르면, 폴리하이드록시 복합 알코올은 둘 이상의 하이드록시기를 포함한다. 예를 들어, 폴리하이드록시 복합 알코올은 3, 4 또는 5개의 하이드록시기를 포함할 수 있다. 특정 실시예에 따르면, 복합 알코올은 모노하이드록시 복합 알코올이다.
전술한 실시예에 따르면, 선형, 분지형 또는 고리형 복합 알코올은 치환되지 않거나 하나 이상의 치환기로 치환될 수 있다. 달리 정의하지 않는 한, 본 명세서에서 사용된 용어 "치환된(substituted)" 또는 "치환기(substituent)"는 C1- 6알킬(C1-6alkyl), C1- 6알케닐(C1- 6alkenyl), C1- 6알키닐(C1- 6alkynyl), 아릴(aryl), 알데히드(aldehyde), 할로겐(halogen), 할로C1 - 6alkyl(haloC1 - 6alkyl), 할로C1 - 6알케닐(haloC1-6alkenyl), 할로C1 - 6알키닐(haloC1 - 6alkynyl), 할로아릴(haloaryl), 하이드록시(hydroxy), C1- 6알킬하이드록시(C1- 6alkylhydroxy), C1- 6알콕시(C1- 6alkoxy), -OC1- 6알킬하이드록시(-OC1-6alkylhydroxy), -OC1- 6알킬 C1- 6알콕시(-OC1- 6alkylC1 - 6alkoxy), C1-6알케닐옥시(C1-6alkenyloxy), 아릴옥시(aryloxy), 벤질옥시(benzyloxy), 할로C1 - 6알콕시(haloC1-6alkoxy), 할로C1 - 6알케닐옥시(haloC1 - 6alkenyloxy), 할로아릴옥시(haloaryloxy), 니트로(nitro), 니트로C1 - 6알킬(nitroC1 - 6alkyl), 니트로C1 - 6알케닐(nitroC1-6alkenyl), 니트로C1 - 6알키닐(nitroC1 - 6alkynyl), 니트로아릴(nitroaryl), 니트로헤테로사이클릴(nitroheterocyclyl), 아미노(amino), C1- 6알킬 아미노(C1-6alkylamino), C1- 6디알킬아미노(C1- 6dialkylamino), C1- 6알케닐 아미노(C1-6alkenylamino), C1- 6알키닐아미노(C1- 6alkynylamino), 아릴아미노(arylamino), 디아릴아미노(diarylamino), 벤질아미노(benzylamino), 디벤질아미노(dibenzylamino), 아실(acyl), C1- 6알케닐 아실(C1- 6alkenylacyl), C1- 6알키닐아실(C1- 6alkynylacyl), 아릴아실(arylacyl), 아실아미노(acylamino), 디아실아미노(diacylamino), 아실옥시(acyloxy), 알킬술포닐옥시(alkylsulphonyloxy), 아릴술페닐옥시(arylsulphenyloxy), 헤테로사이클릴(heterocyclyl), 헤테로사이클옥시(heterocycloxy), 헤테로사이클아미노, 할로헤테로사이클릴(haloheterocyclyl), 알킬술페닐(alkylsulphenyl), 아릴술페닐(arylsulphenyl), 카보알콕시(carboalkoxy), 카보아릴옥시(carboaryloxy), 메르캅토(mercapto), C1- 6알킬티오, 벤질티오(benzylthio), 아실티오(acylthio), 및 인 함유기(phosphorus-containing groups)로부터 선택된 하나 이상의 군으로 치환되거나 치환되지 않은 군을 나타낸다.
인산화 시약
복합 알코올은 P4O10와 혼합된다. 몇몇 실시예에 따르면, P4O10는 부분적으로 수소화된다(또는 폴리인산(polyphosphoric acid)).
하이드록실기(복합알코올) 대 하이드록실기의 몰 비는 약 3:1 내지 약 1:3일 수 있다. 몇몇 실시예에 따르면, 몰 비는 약 2:1 내지 약 1:2이다. 일 실시예에 따르면, 몰 비는 2:1이다.
다른 실시예에 따르면, 몰비는 약 1:1이거나 대체로 동몰(equimolar)이다. 이러한 특정 실시예에 따르면, 하이드록실기(복합알코올) 대 P4O10의 몰 비는 약 1:0.25일 것이다.
방법
본 발명의 방법은 복합 알코올을 인산화하기 위한 것이며,
(a) 발열 반응 온도에 도달할 때까지 복합 알코올과 P4O10를 혼합하는 단계;
(b) 발열 반응이 완료될 때까지 상기 단계 (a)의 반응 혼합물을 반응시키고, 필요에 따라 적어도 약 90℃ 내지 140℃로 상기 단계(a)의 상기 반응 혼합물을 가열하는 단계;
(c) 상기 단계 (b)의 반응 혼합물을 적어도 약 80℃로 냉각시키는 단계; 및
(d) 상기 단계 (c)의 반응 혼합물을 약 30분 내지 약 90분 동안 가수분해하는 단계;를 포함한다.
단계 (a)
단계 (a)는 발열 반응 온도에 도달할 때까지 복합 알코올과 P4O10를 혼합시키는 단계를 포함한다.
"발열 반응"의 의미는 관련 분야에서 잘 알려져 있다. 발열 반응은 빛에 의해 또는 본 발명에서와 같이 열에 의해 에너지를 방출하는 화학 반응을 나타낸다. 용어 "발열 반응 온도"는 본 명세서에서 복합 알코올과 P4O10 사이의 화학 반응이 열을 방출하기 시작하는 온도를 나타낸다.
복합 알코올과 P4O10는 발열 반응 온도에 도달할 때까지 혼합되며, 친밀 혼합물을 형성하도록 혼합될 수 있다. 혼합 단계는 (수동 또는 기계적) 교반을 포함하여 가능한 모든 수단에 의해 달성될 수 있다. 몇몇 실시예에 따르면, 혼합 단계는 고전단 믹서(high-shear mixer)를 사용하는 것을 포함한다.
몇몇 실시예에 따르면, 상기 단계는 또한 복합 알코올과 P4O10를 가열하여 복합 알코올과 P4O10 사이의 화학 반응을 발열 반응 온도로 진행시키는 것을 포함할 수 있다. 예를 들어, 복합 알코올과 P4O10는 이들의 발열 반응 온도에 짧은 시간 내에 도달하도록 가열될 수 있다. 예를 들어, 복합 알코올과 P4O10는 복합 알코올과 P4O10 사이의 화학 반응을 약 15 내지 30분 내에 발열 반응 온도로 진행시키기 위해 가열될 수 있다.
다른 실시예에 따르면, 복합 알코올과 P4O10 사이의 화학 반응이 이 온도에 도달하는데 필요한 시간에 걸쳐 발열 반응 온도를 달성하도록 가열하지 않는다.
단계 (b)
단계 (b)는 발열 반응이 완료될 때까지 단계 (a)의 반응 혼합물을 반응시키는 단계를 포함한다. 몇몇 실시예에 따르면, 반응이 진행됨에 따라, 발열 반응 공정에 의해 열이 발생하며, 외부 가열 없이 반응 온도가 상승한다.
발열 반응은 복합 알코올과 P4O10 사이의 화학 반응 온도가 떨어지기 시작할 때 완료된다.
필요에 따라, 단계 (b)는 복합 알코올과 P4O10 사이의 발열 반응이 완료된 후 단계 (a)의 반응 혼합물의 온도가 약 90℃ 미만인 경우 가열하는 단계를 포함할 수 있다. 일 실시예에 따르면, 단계 (a)의 반응 혼합물은 적어도 약 90℃ 내지 140℃로 가열될 수 있다. 다른 실시예에 따르면, 단계 (a)의 반응 혼합물은 약 90℃, 약 100℃, 또는 약 110℃로 가열될 수 있다.
단계 (a)의 반응 혼합물의 온도는 약 30분 내지 약 180분 동안 적절한 온도를 유지할 수 있다. 몇몇 실시예에 따르면, 단계 (a)의 반응 혼합물은 이 온도에서 약 60분 내지 약 180분 동안 유지될 수 있다. 다른 실시예에 따르면, 단계 (a)의 반응 혼합물은 이 온도에서 약 60분 동안 유지될 수 있다.
필요에 따라, 단계 (b)는 복합 알코올과 P4O10 사이의 발열 반응이 완료된 후 단계 (a)의 반응 혼합물의 온도가 약 90℃ 미만인 경우 가열하는 단계를 포함할 수 있다. 일 실시예에 따르면, 단계 (a)의 반응 혼합물은 적어도 약 90℃ 내지 140℃로 가열될 수 있다. 다른 실시예에 따르면, 단계 (a)의 반응 혼합물은 약 90℃, 약 100℃, 또는 약 110℃로 가열될 수 있다.
단계 (a)의 반응 혼합물의 온도는 약 30분 내지 약 180분 동안 적절한 온도를 유지할 수 있다. 몇몇 실시예에 따르면, 단계 (a)의 반응 혼합물은 이 온도에서 약 60분 내지 약 180분 동안 유지될 수 있다. 다른 실시예에 따르면, 단계 (a)의 반응 혼합물은 이 온도에서 약 60분 동안 유지될 수 있다.
몇몇 실시예에 따르면, 단계 (b)는 혼합하는 단계를 포함하지 않는다. 다른 실시예에서, 이 단계는 혼합하는 단계를 포함한다. 전술한 바와 같이, 혼합 단계는 (수동 또는 기계적) 교반을 포함하여 가능한 모든 수단에 의해 달성될 수 있으며, 고전단 믹서(high-shear mixer)를 사용하는 것을 포함한다.
단계 (c)
단계 (c)는 단계 (b)의 반응 혼합물을 적어도 80℃로 냉각시키는 단계를 포함한다.
이 단계에서, 온도는 적어도 80℃이다. 용어 "적어도 80℃(at least 80℃)"는 본 명세서에서 80℃ 이상의 온도를 나타낸다. 몇몇 실시예에 따르면, 온도는 적어도 80℃ 내지 약 160℃이다. 다른 실시예에 따르면, 온도는 약 90℃ 내지 140℃이다. 일 실시예에 따르면, 온도는 약 90℃이다. 다른 실시예에 따르면, 온도는 약 100℃이다. 다른 실시예에 따르면, 온도는 약 110℃이다.
단계 (b)의 반응 혼합물은 단계 (b)의 반응 혼합물의 온도가 복합 알코올과 P4O10 사이의 발열 반응이 완료된 후의 온도 보다 높은 경우 적절한 온도로 냉각될 것이다.
몇몇 실시예에 따르면, 단계 (b)의 반응 혼합물을 냉각하는 것은 시간이 경과함에 따라 점진적으로 진행시킬 수 있다. 다른 실시예에 따르면, 시간은 특정 기간으로 제한될 수 있다. 예를 들어, 그 기간은 약 30분 내지 약 90분으로 제한될 수 있으며, 그 후 외부 수단을 사용하여 단계 (b)의 반응 혼합물을 추가로 냉각시킬 수 있다.
일단 냉각된 온도에서, 단계 (b)의 반응 혼합물은 이 온도에서 약 30분 내지 약 180분 동안 유지될 수 있다. 몇몇 실시예에 따르면, 단계 (b)의 반응 혼합물은 약 60 내지 약 180분 동안 유지될 수 있다. 일 실시예에 따르면, 단계 (b)의 반응 혼합물은 약 60 내지 약 120분 동안 유지될 수 있다. 다른 실시예에 따르면, 단계 (b)의 반응 혼합물은 약 60분 동안 유지될 수 있다.
단계 (d)
단계 (d)는 단계 (c)의 반응 혼합물을 가수 분해하는 단계를 포함한다.
가수 분해 단계는 수용액을 첨가하는 단계를 포함한다. 수용액은 물(예를 들어, 탈이온수)일 수 있다. 몇몇 실시예에 따르면, 과량의 물이 가수 분해 단계 중에 첨가된다. 가수 분해 중에, 단계 (c)의 반응 혼합물은 적어도 80℃의 가수 분해 온도로 유지될 수 있다. 용어 "적어도 80℃"는 전술한 바와 같은 의미를 갖는다. 몇몇 실시예에 따르면, 가수 분해 온도는 적어도 80℃ 내지 약 150℃이다. 일 실시예에 따르면, 가수 분해 온도는 약 90℃ 내지 110℃이다. 다른 실시예에 따르면, 가수 분해 온도는 약 90℃ 내지 100℃이다. 다른 실시예에 따르면, 가수 분해 온도는 약 100℃ 내지 110℃이다.
가수 분해는 약 30 내지 약 180분 동안 수행될 수 있다. 몇몇 실시예에 따르면, 가수 분해는 약 30 내지 약 120분 동안 수행된다. 몇몇 실시예에 따르면, 가수분해는 약 30 내지 약 90분 동안 수행된다. 일 실시예에 따르면, 가수 분해는 약 60 내지 약 120분 동안 수행된다. 다른 실시예에 따르면, 가수 분해는 약 90 내지 약 120분 동안 수행된다. 일 실시예에 따르면, 가수 분해는 약 60 내지 약 90분 동안 수행된다.
선택적 용매
상기 방법은 추가 용매가 없는 상태에서 수행될 수 있다. 용어 "추가 용매(additional solvent)"는 본 명세서에서 가수 분해 단계 중에 사용된 물과 같은 수용액과 다른 용매를 나타낸다. 몇몇 실시예에 따르면, 반응은 복합 알코올과 P4O10가 니트 형태(neat form)로 혼합되도록 추가 용매 없이 수행된다.
생성물
본 발명은 또한 상기 방법에 의해 얻어진 생성물에 관한 것이다.
상기 방법에 의해 생성된 생성물은 인산화된 모노-복합알코올, 인산화된 디-복합 알코올 또는 이의 혼합물일 수 있다. 특정 실시예에 따르면, 생성물은 인산화된 모노-복합 알코올 및 인산화된 디-복합 알코올의 혼합물이다. 이러한 실시예에 따르면, 인산화된 모노-복합 알코올과 인산화된 디-복합 알코올의 혼합물의 몰 비는 적어도 약 2:1, 약 2:1, 약 6:4 또는 약 8:2일 수 있거나, 약 4:1 내지 약 1:4 또는 약 6:4 내지 약 8:2일 수 있다.
몇몇 실시예에 따르면, 상기 방법에 의해 얻어진 생성물은 교차 결합된 포스페이트 디에스테르(cross-coupled phosphate diester)일 수 있다.
상기 방법에 의해 얻어진 생성물이 반응되지 않은 복합 알코올 및/또는 관련 물질의 잔량 또한 포함하는 것을 이해해야 한다. 몇몇 실시예에 따르면, 상기 방법에 의해 얻어진 생성물은 약 2% w/w 이하의 반응되지 않은 복합 알코올을 포함한다. 몇몇 실시예에 따르면, 상기 방법에 의해 얻어진 생성물은 약 1% w/w 이하의 반응되지 않은 복합 알코올을 포함한다. 이러한 실시예에 따르면, 상기 방법은 정제 단계를 추가로 포함할 수 있다.
추가 생성물을 얻기 위한 추가 방법 단계
상기 방법에 의해 얻어진 생성물은 양쪽성 계면 활성제(amphoteric surfactant)와 더 반응할 수 있다.
이러한 실시예에 따르면, 복합 알코올은 토코페롤(tocopherol)이며, 인산화된 복합 알코올은 토코페릴 포스페이트(tocopheryl phosphate )이다. 토코페릴 포스페이트는 모노-토코페릴 포스페이트(mono-tocopheryl phosphate), 디-토코페릴 포스페이트(di-tocopheryl phosphate) 또는 이의 혼합물일 수 있다.
일 실시예에 따르면, 양쪽성 계면 활성제는 화학식 NR1R2R3의 3차 아민이며, 상기 화학식에서 R1은 C6-22 알킬로 이루어진 군으로부터 선택되며, R2 및 R3는 H, (CH2)nCOOX, (CH2)nCHOHCH2SO3X, (CH2)nCHOHCH2OPO3X(X는 H이거나 나트륨, 칼륨, 리튬, 칼슘, 마그네슘, 암모늄, 알킬암모늄 및 알칸올아민으로 이루어진 군으로부터 선택된 양이온과 염을 형성함)로 이루어진 군으로부터 선택되며, n은 1 또는 2이다.
용어 "C6-22 알킬"은 직쇄(straight chain) 또는 분지쇄(branched chain)이거나 6 내지 22개의 탄소 원자를 갖는 고리형 탄화수소기를 나타낸다. 그 예로서 헥실(hexyl), 사이클로헥실(cyclohexyl), 데실(decyl), 도데실(dodecyl), 트리데실(tridecyl), 테트라데실(tetradecyl), 펜타데실(pentadecyl), 헥사데실(hexadecyl), 헵타데실(heptadecyl) 및 옥타데실(octadecyl)을 포함하지만 이에 한정되는 것을 아니다.
몇몇 실시예에 따르면, R1은 C12 알킬(도데실)이며, R2 및 R3는 개별적으로 CH2CH2COOH 및 CH2CH2COONa로부터 선택된다.
특정 실시예에 따르면, 3차 아민은 3-[2-카르복시에틸(도데실)아미노] 프로판산(3-[2-carboxyethyl(dodecyl)amino] propanoic acid)이다. 다른 실시예에 따르면, 3차 아민은 3,3'-도데실이미노)디프로피온산 모노나트륨염(3,3'-dodecylimino)dipropionic acid monosodium salt)(또는 라우릴이미노디프로피온산(lauryliminodipropionic acid), 나트륨 라우릴이미노디프로피오네이트(sodium lauryliminodipropionate) 또는 N-라우릴 이미노디프로피오네이트(N-lauryl iminodipropionate))이다.
추가 방법에 의해 얻어진 생성물은 라우릴이미노디프로피온산 토코페릴 포스페이트(lauryliminodipropionic acid tocopheryl phosphates) 또는 이의 염일 수 있다. 몇몇 실시예에 따르면, 상기 염은 나트륨 염이다.
실시예
본 발명의 다양한 실시예/양태가 하기의 비제한적 실시예를 참조하여 설명될 것이다.
실시예 1
합성 α-토코페롤 및 P4O10를 혼합(질량 비 0.170)하고, 가열하여 발열 반응 온도에 약 15분 내에 도달하였다. 반응 혼합물의 온도가 약 120℃에 도달할 때까지 가열을 지속한 다음 정지시켰다. 반응 혼합물의 온도는 단기간 동안 계속 상승하였다. 발열 반응이 완료되면, 반응 혼합물을 약 60분 동안 어떠한 외부 제어 없이 냉각시켰다. 그 다음, 가수 분해가 약 60분 동안 탈이온수로 수행되기 전 반응 혼합물을 약 90℃의 온도로 더 냉각시켰다.
상기 방법은 약 58.52% w/w의 모노-토코페릴 포스페이트와 약 30.49% w/w의 디-토코페릴 포스페이트를 생성하였다.
또한, 약 0.21% w/w의 미반응된 합성 α-토코페롤이 있는 것으로 나타났다.
실시예 2
합성 α-토코페롤 및 P4O10를 혼합(질량 비 0.170)하고, 가열하여 발열 반응 온도에 약 15분 내에 도달하였다. 반응 혼합물의 온도가 약 120℃에 도달할 때까지 가열을 지속한 다음 정지시켰다. 반응 혼합물의 온도는 단기간 동안 계속 상승하였다. 발열 반응이 완료되면, 반응 혼합물을 약 60분 동안 어떠한 외부 제어 없이 냉각시켰다. 그 다음, 가수 분해가 약 60분 동안 탈이온수로 수행되기 전 반응 혼합물을 약 90℃의 온도로 더 냉각시켰다.
상기 방법은 약 59.26% w/w의 모노-토코페릴 포스페이트와 약 30.91% w/w의 디-토코페릴 포스페이트를 생성하였다.
또한, 약 0.20% w/w의 미반응된 합성 α-토코페롤이 있는 것으로 나타났다.
실시예 3
천연 α-토코페롤(0.07 %w/w)와 P4O10를 혼합(질량 비 0.170)하고, 가열하여 발열 반응 온도에 약 15분 내에 도달하였다. 반응 혼합물의 온도가 약 120℃에 도달할 때까지 가열을 지속한 다음 정지시켰다. 반응 혼합물의 온도는 단기간 동안 계속 상승하였다. 발열 반응이 완료되면, 반응 혼합물을 약 60분 동안 어떠한 외부 제어 없이 냉각시켰다. 그 다음, 가수 분해가 약 60분 동안 탈이온수로 수행되기 전 반응 혼합물을 약 90℃의 온도로 더 냉각시켰다.
상기 방법은 약 55.79% w/w의 모노-토코페릴 포스페이트와 약 27.68% w/w의 디-토코페릴 포스페이트를 생성하였다.
또한, 약 0.07% w/w의 미반응된 합성 α-토코페롤이 있는 것으로 나타났다.
실시예 4
프로포폴(1.07 g, 6.00 mmol)과 P4O10를 반응 튜브에서 혼합하고, 강하게 교반시켰다. 발열 반응이 완료되도록 반응 혼합물을 120분 이상 H2O 배스(50~90℃)로 가열한 다음, 60분 동안 90℃에서 H2O(0.260 g)로 가수 분해시켰다.
실온으로 냉각시킨 후, 반응 혼합물을 EtOH(30 mL)에 용해시키고, 100 mL의 RBF로 옮기고 진공 하에 농축시켰다(60℃ H2O 배스). 잔류하는 붉은색 유성 고체를 뜨거운 헥산(90 mL)에 현탁시키고 고온에서 여과시켰다. 헥산 여과액을 진공 하에 농축시켜(60℃ H2O 배스) 약 25 mL로 만든 다음, 얼음 배스에서 약 120분 동안 냉각시켰다. 차가운 현탁액을 진공 하에 여과하고, 필터 케이크(filter cake)를 차가운 헥산(3 x 15 mL)으로 세척하고 진공 오븐 (55 ℃)에서 건조시켜 백색 분말을 얻었다.
최종 생성물의 질량 분광 분석은 원하는 프로포폴의 모노포스페이트 유도체가 형성된 것을 나타냈다.
실시예 5
프로포폴(0.565 g, 3.17 mmol), D-α-토코페롤(1.35 g, 3.13 mmol)과 P4O10를 래들리 12 스테이션 캐러셀(Radleys 12 Station Carousel) 반응 튜브에서 혼합하였다. 반응 혼합물을 100℃에서 120분 동안 가열하여 각각의 발열 반응을 완료시켰다. 그 후, 반응 혼합물을 90℃로 냉각시킨 후, 그 온도에서 H2O(0.360g)로 60분 동안 가수 분해시켰다.
실온으로 냉각시킨 후, 반응 혼합물을 EtOH(30 mL)로 희석하고, 여과하고, 진공 하에 농축하여 (60℃의 H2O 배스) 갈색 오일 물질을 수득하였다.
최종 생성물의 질량 분광 분석은 교차 결합된 포스페이트 디에스테르 뿐만 아니라 프로포폴 및 D-α-토코페롤의 모노포스페이트 유도체가 형성되었음을 나타내었다.
실시예 6
라우릴 알코올(0.990 g, 5.31 mmol)과 P4O10(0.530 g, 1.87 mmol)를 래들리 12 스테이션 캐러셀(Radleys 12 Station Carousel) 반응 튜브에서 혼합하고, 강하게 교반시켰다. 반응 혼합물을 100℃에서 60분 동안 가열하여 각각의 발열 반응을 완료시켰다. 그 후, 반응 혼합물을 90℃로 냉각시킨 후, 그 온도에서 H2O(0.140g)로 60분 동안 가수 분해시켰다.
실온으로 냉각시킨 후, 반응 혼합물을 Et2O(6 mL)와 H2O(6 mL) 사이에 분배시켰다. Et2O상을 진공 하에 농축하여(60℃의 H2O 배스) 노란 액체를 수득하였다.
최종 생성물의 질량 분광 분석은 원하는 라우릴 알코올의 모노포스페이트 유도체가 형성되었음을 나타내었다.
실시예 7
β-에스트라디올(0.490 g, 1.80 mmol)과 P4O10 (0.140 g, 0.493 mmol)를 래들리 12 스테이션 캐러셀(Radleys 12 Station Carousel) 반응 튜브에서 혼합하고 트리아세틴(triacetin)(2 mL)에서 현탁시켰다. 반응 혼합물을 100℃에서 60분 동안 가열하여 각각의 발열 반응을 완료시켰다. 그 후, 반응 혼합물을 90℃로 냉각시킨 후, 그 온도에서 H2O(1.00g)로 60분 동안 가수 분해시켰다.
실온으로 냉각시킨 후, 반응 혼합물을 헥산(2 x 25 mL)으로 세척하였다. 생성된 현탁액을 THF(30 mL)에 용해시키고 진공 하에 농축하여(60℃ H2O 배스) 유성의 베이지색 고체를 수득하였다.
최종 생성물의 질량 분광 분석은 원하는 모노포스페이트 유도체가 형성되었음을 나타내었다.
이하의 청구 범위 및 본 발명의 전술한 설명에서, 명시적인 언어 또는 필요한 의미로 인해 문맥이 다른 것을 요구하는 경우를 제외하고, 단어 "포함한다(comprise)" 또는 "포함한다(comprises)" 또는 "포함하는(comprising)"과 같은 변형은 포괄적인 의미로 사용되며, 즉 명시된 특징의 존재를 명확히 하지만 본 발명의 다양한 실시예에서의 다른 특징의 존재 또는 추가를 배제하는 것은 아니다.
Claims (20)
- 복합 알코올을 인산화하는 방법으로서,
(a) 발열 반응이 시작되고 상기 발열 반응에 의해 생성된 열이 외부 가열 없이 반응 혼합물의 온도를 상승시키는 조건 하에서 상기 복합 알코올과 P4O10을 혼합하는 단계;
(b) 외부 가열 없이 상기 반응 혼합물의 온도가 떨어지기 시작하면 상기 단계 (a)의 반응 혼합물의 반응을 완료시키는 단계;
(c) 상기 단계 (b)의 상기 반응 혼합물을 적어도 80℃로 가열 또는 냉각하는 단계; 및
(d) 상기 단계 (c)의 상기 반응 혼합물을 30분 내지 90분 동안 가수분해하는 단계;를 포함하고,
상기 복합 알코올은 탄소고리형(carbocyclic), 헤테로고리형 (heterocyclic), 단환(monocyclic) 또는 다환(polycyclic)인 고리형 복합 알코올이거나, 상기 복합 알코올은 크로마놀(chromanol)인, 복합 알코올을 인산화하는 방법. - 제1항에 있어서,
상기 크로마놀은 토코페롤(tocopherol) 또는 토코트리에놀(tocotrienol)인, 복합 알코올을 인산화하는 방법. - 제1항 또는 제2항에 있어서,
상기 복합 알코올은 약제학적 화합물, 마취제, 항산화제 또는 용매인, 복합 알코올을 인산화하는 방법. - 제1항에 있어서,
상기 복합 알코올은 모노하이드록시(monohydroxy) 또는 폴리하이드록시(polyhydroxy)인, 복합 알코올을 인산화하는 방법. - 제1항에 있어서,
상기 단계 (d)는 수용액을 첨가하는 단계를 포함하는, 복합 알코올을 인산화하는 방법. - 제1항에 있어서,
상기 단계 (c)의 반응 혼합물은 80℃ 내지 150℃의 가수분해 온도에서 유지되는, 복합 알코올을 인산화하는 방법. - 제1항에 있어서,
상기 가수분해는 60분 내지 90분 동안 수행되는, 복합 알코올을 인산화하는 방법. - 제1항에 있어서,
상기 가수분해 단계 (d)의 생성물은 인산화된 모노-복합 알코올 및 인산화된 디-복합 알코올의 혼합물인, 복합 알코올을 인산화하는 방법. - 제8항에 있어서,
상기 인산화된 모노-복합 알코올과 상기 인산화된 디-복합 알코올의 혼합물의 몰비는 6:4 내지 8:2인, 복합 알코올을 인산화하는 방법. - 제1항에 있어서,
상기 복합 알코올은 토코페롤이고,
상기 방법은 상기 단계 (d)의 가수분해된 반응 혼합물과 양쪽성 계면 활성제(amphoteric surfactant)를 반응시키는 단계를 추가로 포함하며,
상기 양쪽성 계면 활성제는 화학식 NR1R2R3의 3차 아민이며, R1은 C6-22 알킬로 이루어진 군으로부터 선택되며, R2 및 R3는 H, (CH2)nCOOX, (CH2)nCHOHCH2SO3X, (CH2)nCHOHCH2OPO3X로 이루어진 군으로부터 선택되며, n은 1 또는 2이고, X는 H이거나 나트륨, 칼륨, 리튬, 칼슘, 마그네슘, 암모늄, 알킬암모늄 및 알칸올아민으로 이루어진 군으로부터 선택된 양이온과 염을 형성하는, 복합 알코올을 인산화하는 방법. - 제10항에 있어서,
상기 3차 아민은 3-[2-카르복시에틸(도데실)아미노]프로판산(3-[2-carboxyethyl(dodecyl)amino] propanoic acid), 3,3'-(도데실이미노)디프로피온산 모노나트륨염(3,3'-(dodecylimino)dipropionic acid monosodium salt), 라우릴이미노디프로피온산(lauryliminodipropionic acid), 나트륨 라우릴이미노디프로피오네이트(sodium lauryliminodipropionate) 및 N-라우릴 이미노디프로피오네이트(N-lauryl iminodipropionate)로 이루어진 군으로부터 선택된, 복합 알코올을 인산화하는 방법. - 삭제
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EP3558903B1 (en) | 2024-07-03 |
JP2020502193A (ja) | 2020-01-23 |
RU2019119347A (ru) | 2021-01-22 |
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EP3558903A1 (en) | 2019-10-30 |
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WO2018112512A1 (en) | 2018-06-28 |
KR20190100298A (ko) | 2019-08-28 |
EP3558903A4 (en) | 2019-11-27 |
JP7198754B2 (ja) | 2023-01-04 |
US20190330260A1 (en) | 2019-10-31 |
AU2022201954B2 (en) | 2023-12-21 |
MX2019006845A (es) | 2019-10-15 |
RU2019119347A3 (ko) | 2021-04-16 |
AU2022201954A1 (en) | 2022-04-14 |
IL267006A (en) | 2019-07-31 |
CN110662733A (zh) | 2020-01-07 |
IL267006B1 (en) | 2024-07-01 |
US20220106353A1 (en) | 2022-04-07 |
AU2017381395A1 (en) | 2019-06-20 |
CA3045702A1 (en) | 2018-06-28 |
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