RU2378252C2 - Новый способ получения промежуточных соединений, применяемых для синтеза аналогов витамина d - Google Patents
Новый способ получения промежуточных соединений, применяемых для синтеза аналогов витамина d Download PDFInfo
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- RU2378252C2 RU2378252C2 RU2006138613/04A RU2006138613A RU2378252C2 RU 2378252 C2 RU2378252 C2 RU 2378252C2 RU 2006138613/04 A RU2006138613/04 A RU 2006138613/04A RU 2006138613 A RU2006138613 A RU 2006138613A RU 2378252 C2 RU2378252 C2 RU 2378252C2
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- Russia
- Prior art keywords
- general structure
- compound
- compounds
- calcipotriol
- vii
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 278
- 238000000034 method Methods 0.000 title claims abstract description 73
- 230000015572 biosynthetic process Effects 0.000 title abstract description 25
- 238000003786 synthesis reaction Methods 0.000 title abstract description 24
- 229940046008 vitamin d Drugs 0.000 title description 24
- 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 79
- 229960002882 calcipotriol Drugs 0.000 claims abstract description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 94
- 239000001257 hydrogen Substances 0.000 claims description 94
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 90
- -1 triethylsilyl Chemical group 0.000 claims description 77
- 239000000203 mixture Substances 0.000 claims description 72
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 70
- 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 54
- 238000006243 chemical reaction Methods 0.000 claims description 53
- 125000006239 protecting group Chemical group 0.000 claims description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 239000003638 chemical reducing agent Substances 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 239000002585 base Substances 0.000 claims description 33
- 230000001681 protective effect Effects 0.000 claims description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 25
- 150000002431 hydrogen Chemical class 0.000 claims description 24
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 15
- 230000003993 interaction Effects 0.000 claims description 14
- 239000011541 reaction mixture Substances 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 238000007699 photoisomerization reaction Methods 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- JEVVXWTVBUFURF-UHFFFAOYSA-N (2-cyclopropyl-2-oxoethyl)phosphonic acid Chemical compound OP(O)(=O)CC(=O)C1CC1 JEVVXWTVBUFURF-UHFFFAOYSA-N 0.000 claims description 6
- MEOUMIDMNOIQIQ-UHFFFAOYSA-N 1-cyclopropyl-2-diethoxyphosphorylethanone Chemical compound CCOP(=O)(OCC)CC(=O)C1CC1 MEOUMIDMNOIQIQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 6
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 5
- 239000008096 xylene Substances 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 238000012546 transfer Methods 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 239000003444 phase transfer catalyst Substances 0.000 claims description 2
- 230000002441 reversible effect Effects 0.000 claims description 2
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 2
- XBKHACNRWFKJNC-MANNPBRJSA-N calcipotriol hydrate Chemical compound O.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 XBKHACNRWFKJNC-MANNPBRJSA-N 0.000 abstract 1
- 150000004682 monohydrates Chemical class 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 125000003710 aryl alkyl group Chemical group 0.000 description 37
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- 125000003342 alkenyl group Chemical group 0.000 description 26
- 125000000304 alkynyl group Chemical group 0.000 description 26
- 125000003118 aryl group Chemical group 0.000 description 26
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 25
- 150000003710 vitamin D derivatives Chemical class 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 229930003316 Vitamin D Natural products 0.000 description 23
- 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 23
- 235000019166 vitamin D Nutrition 0.000 description 23
- 239000011710 vitamin D Substances 0.000 description 23
- 125000001188 haloalkyl group Chemical group 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 238000004587 chromatography analysis Methods 0.000 description 17
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 16
- 239000003153 chemical reaction reagent Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 229910000085 borane Inorganic materials 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 13
- 125000000392 cycloalkenyl group Chemical group 0.000 description 13
- 125000000753 cycloalkyl group Chemical group 0.000 description 13
- 229910052736 halogen Inorganic materials 0.000 description 13
- 150000002367 halogens Chemical class 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- 229960001124 trientine Drugs 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 12
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 12
- 125000004043 oxo group Chemical group O=* 0.000 description 12
- 239000002243 precursor Substances 0.000 description 12
- 0 C[C@@]([C@@](CC1)[C@]2(C)[C@@]1[C@](*)CCC2)C=CC(C1CC1)=O Chemical compound C[C@@]([C@@](CC1)[C@]2(C)[C@@]1[C@](*)CCC2)C=CC(C1CC1)=O 0.000 description 11
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000012634 fragment Substances 0.000 description 11
- 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 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 238000006722 reduction reaction Methods 0.000 description 10
- 239000003223 protective agent Substances 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 230000033444 hydroxylation Effects 0.000 description 7
- 238000005805 hydroxylation reaction Methods 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 6
- 238000006742 Retro-Diels-Alder reaction Methods 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- LOPKSXMQWBYUOI-BDAKNGLRSA-N (1s,2r)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2[C@H](N)[C@H](O)CC2=C1 LOPKSXMQWBYUOI-BDAKNGLRSA-N 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000012552 review Methods 0.000 description 5
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 5
- LOPKSXMQWBYUOI-DTWKUNHWSA-N (1r,2s)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2[C@@H](N)[C@@H](O)CC2=C1 LOPKSXMQWBYUOI-DTWKUNHWSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 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
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 230000000640 hydroxylating effect Effects 0.000 description 4
- BDOLXPFAFMNDOK-UHFFFAOYSA-N oxazaborolidine Chemical class B1CCON1 BDOLXPFAFMNDOK-UHFFFAOYSA-N 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000008247 solid mixture Substances 0.000 description 4
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 4
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical group C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000001242 acetic acid derivatives Chemical class 0.000 description 3
- 150000001335 aliphatic alkanes Chemical group 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 150000005840 aryl radicals Chemical group 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000004679 hydroxides Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 3
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 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
- 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
- 238000004679 31P NMR spectroscopy Methods 0.000 description 2
- RGBXQYBYQPIFBW-UHFFFAOYSA-N 4-(7a-methyl-4-triethylsilyloxy-1,2,3,3a,4,5,6,7-octahydroinden-1-yl)-1-cyclopropylpent-2-en-1-one Chemical compound C1CC2C(O[Si](CC)(CC)CC)CCCC2(C)C1C(C)C=CC(=O)C1CC1 RGBXQYBYQPIFBW-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
- KZKNWJNMPADDRY-UHFFFAOYSA-N B1CCCO1 Chemical class B1CCCO1 KZKNWJNMPADDRY-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229910010082 LiAlH Inorganic materials 0.000 description 2
- 238000005654 Michaelis-Arbuzov synthesis reaction Methods 0.000 description 2
- FNJSWIPFHMKRAT-UHFFFAOYSA-N Monomethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(O)=O FNJSWIPFHMKRAT-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000003054 catalyst Substances 0.000 description 2
- 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
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
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- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- XDKQUSKHRIUJEO-UHFFFAOYSA-N magnesium;ethanolate Chemical class [Mg+2].CC[O-].CC[O-] XDKQUSKHRIUJEO-UHFFFAOYSA-N 0.000 description 1
- FMUNKBAIXLTEGC-UHFFFAOYSA-L magnesium;n,n-diethylethanamine;dichloride Chemical compound [Mg+2].[Cl-].[Cl-].CCN(CC)CC FMUNKBAIXLTEGC-UHFFFAOYSA-L 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- SIGOIUCRXKUEIG-UHFFFAOYSA-N methyl 2-dimethoxyphosphorylacetate Chemical compound COC(=O)CP(=O)(OC)OC SIGOIUCRXKUEIG-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 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
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 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
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 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 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US55854604P | 2004-04-02 | 2004-04-02 | |
| US60/558,546 | 2004-04-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2006138613A RU2006138613A (ru) | 2008-05-10 |
| RU2378252C2 true RU2378252C2 (ru) | 2010-01-10 |
Family
ID=34961754
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2006138613/04A RU2378252C2 (ru) | 2004-04-02 | 2005-03-23 | Новый способ получения промежуточных соединений, применяемых для синтеза аналогов витамина d |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US20070135395A1 (enExample) |
| EP (1) | EP1735276B1 (enExample) |
| JP (1) | JP4744507B2 (enExample) |
| KR (1) | KR20070056001A (enExample) |
| CN (1) | CN1938268B (enExample) |
| AR (1) | AR048462A1 (enExample) |
| AT (1) | ATE498609T1 (enExample) |
| BR (1) | BRPI0508704A (enExample) |
| CA (1) | CA2561590C (enExample) |
| DE (2) | DE602005026378D1 (enExample) |
| ES (1) | ES2361389T3 (enExample) |
| IL (1) | IL177357A (enExample) |
| MX (1) | MXPA06010824A (enExample) |
| MY (1) | MY146099A (enExample) |
| RU (1) | RU2378252C2 (enExample) |
| TW (1) | TWI322800B (enExample) |
| UA (1) | UA94568C2 (enExample) |
| WO (1) | WO2005095336A2 (enExample) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1948283B (zh) * | 2005-10-14 | 2010-12-29 | 台耀化学股份有限公司 | 维生素d衍生物的制备方法 |
| EP1844010B1 (en) | 2006-03-17 | 2013-02-13 | Leo Pharma A/S | Isomerisation of pharmaceutical intermediates |
| WO2009057136A2 (en) * | 2007-08-03 | 2009-05-07 | Glenmark Generics Limited | Epimerization by stereoselective synthesis of vitamin d analogues |
| EP2299809B1 (en) * | 2008-06-17 | 2018-10-17 | Ben Gurion University Of The Negev R&D Authority | Substituted cyclohexylidene-ethylidene-octahydro-indene compounds |
| US20120184514A1 (en) * | 2009-07-01 | 2012-07-19 | Vitamin Derivatives Inc. | Vitamin d compounds and methods for preparing same |
| CN101607932B (zh) * | 2009-07-23 | 2012-05-09 | 青岛正大海尔制药有限公司 | 一种光化学反应制备骨化三醇的方法及其装置 |
| CN103980172A (zh) * | 2014-04-26 | 2014-08-13 | 湖南华腾制药有限公司 | 一种1α,25-二羟基维生素D2的制备方法 |
| CN103980173A (zh) * | 2014-04-26 | 2014-08-13 | 湖南华腾制药有限公司 | 一种帕立骨化醇中间体的制备方法 |
| CN105624215B (zh) * | 2014-10-27 | 2020-10-27 | 天津金耀集团有限公司 | 一种卡泊三醇合成新方法 |
| CN104447211A (zh) * | 2014-12-12 | 2015-03-25 | 重庆华邦制药有限公司 | 维生素d类药物的中间体化合物及制备方法 |
| CN105777665B (zh) * | 2014-12-17 | 2018-11-06 | 上虞京新药业有限公司 | 卡泊三醇的中间体化合物及其制备方法 |
| ES2575744B1 (es) * | 2014-12-30 | 2017-02-09 | Laboratorios Viñas S.A. | Procedimiento para proteger derivados de vitamina D con SO2 y uso correspondiente |
| CN106905358B (zh) * | 2015-12-23 | 2020-12-01 | 重庆华邦胜凯制药有限公司 | 一种制备维生素d3类似物中间体的方法 |
| CN105717206B (zh) * | 2016-01-27 | 2018-02-06 | 重庆华邦制药有限公司 | 分离测定卡泊三醇中间体f及其杂质的方法 |
| 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 |
| ES2674336B1 (es) * | 2016-12-28 | 2019-04-11 | Laboratorios Vinas S A | Procedimiento para reducir derivados carbonilicos de vitamina d y uso correspondiente |
| CN113845541B (zh) * | 2021-10-19 | 2023-11-07 | 重庆华邦胜凯制药有限公司 | 一种制备维生素d3类似物的方法 |
| CN116396268A (zh) * | 2021-12-27 | 2023-07-07 | 上海信谊万象药业股份有限公司 | 一种阿法骨化醇中间体合成方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987000834A1 (en) * | 1985-08-02 | 1987-02-12 | Leo Pharmaceutical Products Ltd. A/S | Novel vitamin d analogues |
| US5244104A (en) * | 1992-01-02 | 1993-09-14 | Sias Equipment Company | Drying rack and spacer |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5247104A (en) * | 1992-11-04 | 1993-09-21 | Wisconsin Alumni Research Foundation | Preparation of 1α, 24-dihydroxyvitamin D analogs |
| JPH08325226A (ja) * | 1995-05-30 | 1996-12-10 | Teijin Ltd | ビタミンｄ３ 誘導体の製造法 |
| WO2004037781A1 (en) * | 2002-10-23 | 2004-05-06 | Leo Pharma A/S | Vitamin d analogues, compositions comprising said analogues and their use |
| ES2233209B1 (es) * | 2003-11-28 | 2006-04-01 | Laboratorios Viñas S.A. | Compuestos monohalogenovinilderivados de vitamina d. |
| JP4667450B2 (ja) * | 2004-03-18 | 2011-04-13 | レオ ファーマ アクティーゼルスカブ | ビタミンｄ類似体の立体選択的合成 |
-
2005
- 2005-03-23 RU RU2006138613/04A patent/RU2378252C2/ru active
- 2005-03-23 DE DE602005026378T patent/DE602005026378D1/de not_active Expired - Lifetime
- 2005-03-23 WO PCT/DK2005/000203 patent/WO2005095336A2/en not_active Ceased
- 2005-03-23 JP JP2007505379A patent/JP4744507B2/ja not_active Expired - Fee Related
- 2005-03-23 ES ES05715124T patent/ES2361389T3/es not_active Expired - Lifetime
- 2005-03-23 CN CN200580009943XA patent/CN1938268B/zh not_active Expired - Fee Related
- 2005-03-23 MX MXPA06010824A patent/MXPA06010824A/es active IP Right Grant
- 2005-03-23 CA CA002561590A patent/CA2561590C/en not_active Expired - Fee Related
- 2005-03-23 UA UAA200611527A patent/UA94568C2/ru unknown
- 2005-03-23 KR KR1020067022977A patent/KR20070056001A/ko not_active Abandoned
- 2005-03-23 DE DE05715124T patent/DE05715124T1/de active Pending
- 2005-03-23 US US10/588,800 patent/US20070135395A1/en not_active Abandoned
- 2005-03-23 BR BRPI0508704-0A patent/BRPI0508704A/pt not_active IP Right Cessation
- 2005-03-23 AT AT05715124T patent/ATE498609T1/de active
- 2005-03-23 EP EP05715124A patent/EP1735276B1/en not_active Expired - Lifetime
- 2005-03-25 MY MYPI20051315A patent/MY146099A/en unknown
- 2005-04-01 TW TW094110536A patent/TWI322800B/zh not_active IP Right Cessation
- 2005-04-01 AR ARP050101304A patent/AR048462A1/es unknown
-
2006
- 2006-08-08 IL IL177357A patent/IL177357A/en active IP Right Grant
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987000834A1 (en) * | 1985-08-02 | 1987-02-12 | Leo Pharmaceutical Products Ltd. A/S | Novel vitamin d analogues |
| US5244104A (en) * | 1992-01-02 | 1993-09-14 | Sias Equipment Company | Drying rack and spacer |
Non-Patent Citations (1)
| Title |
|---|
| CALVERLEY M.J. et al // Tetrahedron, v 43, #20, (1987), p.4609-4619 ANDREAS STEINMEYER et al // Steroids, 66 (2001) p.257-266. * |
Also Published As
| Publication number | Publication date |
|---|---|
| MY146099A (en) | 2012-06-29 |
| MXPA06010824A (es) | 2007-01-17 |
| WO2005095336A2 (en) | 2005-10-13 |
| IL177357A (en) | 2008-04-13 |
| WO2005095336A3 (en) | 2005-11-10 |
| UA94568C2 (ru) | 2011-05-25 |
| CN1938268B (zh) | 2010-06-02 |
| ES2361389T3 (es) | 2011-06-16 |
| KR20070056001A (ko) | 2007-05-31 |
| TW200613257A (en) | 2006-05-01 |
| CA2561590C (en) | 2008-11-18 |
| JP2007530602A (ja) | 2007-11-01 |
| JP4744507B2 (ja) | 2011-08-10 |
| US20070135395A1 (en) | 2007-06-14 |
| CA2561590A1 (en) | 2005-10-13 |
| ATE498609T1 (de) | 2011-03-15 |
| BRPI0508704A (pt) | 2007-08-07 |
| EP1735276B1 (en) | 2011-02-16 |
| AR048462A1 (es) | 2006-04-26 |
| TWI322800B (en) | 2010-04-01 |
| DE05715124T1 (de) | 2008-02-21 |
| RU2006138613A (ru) | 2008-05-10 |
| EP1735276A2 (en) | 2006-12-27 |
| HK1098124A1 (en) | 2007-07-13 |
| CN1938268A (zh) | 2007-03-28 |
| DE602005026378D1 (de) | 2011-03-31 |
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