JP2011153140A - 融合二環式構造を異性化するための新規な方法、及びそれを含むビタミンd類似体の調製 - Google Patents
融合二環式構造を異性化するための新規な方法、及びそれを含むビタミンd類似体の調製 Download PDFInfo
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- JP2011153140A JP2011153140A JP2011012797A JP2011012797A JP2011153140A JP 2011153140 A JP2011153140 A JP 2011153140A JP 2011012797 A JP2011012797 A JP 2011012797A JP 2011012797 A JP2011012797 A JP 2011012797A JP 2011153140 A JP2011153140 A JP 2011153140A
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- 238000000034 method Methods 0.000 title claims abstract description 40
- 125000002619 bicyclic group Chemical group 0.000 title claims abstract description 27
- 229940046008 vitamin d Drugs 0.000 title claims description 18
- 238000002360 preparation method Methods 0.000 title description 2
- 150000004678 hydrides Chemical class 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 19
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 18
- 229930003316 Vitamin D Natural products 0.000 claims description 17
- 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 claims description 17
- 235000019166 vitamin D Nutrition 0.000 claims description 17
- 239000011710 vitamin D Substances 0.000 claims description 17
- 235000007164 Oryza sativa Nutrition 0.000 claims description 14
- 235000009566 rice Nutrition 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 150000003338 secosteroids Chemical class 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 125000000524 functional group Chemical group 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- -1 vinyl halide Chemical class 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 238000010168 coupling process Methods 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 238000006317 isomerization reaction Methods 0.000 claims description 5
- 150000003431 steroids Chemical class 0.000 claims description 5
- 238000007239 Wittig reaction Methods 0.000 claims description 4
- 125000005024 alkenyl aryl group Chemical group 0.000 claims description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 239000012156 elution solvent Substances 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 229910052805 deuterium Inorganic materials 0.000 claims description 2
- 125000004431 deuterium atom Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 240000007594 Oryza sativa Species 0.000 claims 1
- 150000001924 cycloalkanes Chemical class 0.000 claims 1
- 125000000113 cyclohexyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 20
- 241000209094 Oryza Species 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 150000002576 ketones Chemical class 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000006345 epimerization reaction Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 102000009310 vitamin D receptors Human genes 0.000 description 4
- 108050000156 vitamin D receptors Proteins 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical class C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- JHIVVAPYMSGYDF-PTQBSOBMSA-N cyclohexanone Chemical class O=[13C]1CCCCC1 JHIVVAPYMSGYDF-PTQBSOBMSA-N 0.000 description 3
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexyloxide Natural products O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 3
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- INLLPKCGLOXCIV-UHFFFAOYSA-N bromoethene Chemical compound BrC=C INLLPKCGLOXCIV-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 150000001934 cyclohexanes Chemical class 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical class O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Chemical class C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical class C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- YFTMLUSIDVFTKU-UHFFFAOYSA-M bromomethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CBr)C1=CC=CC=C1 YFTMLUSIDVFTKU-UHFFFAOYSA-M 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 150000001940 cyclopentanes Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002710 gonadal effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 208000018821 hormone-resistant prostate carcinoma Diseases 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 1
- 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 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 102000004217 thyroid hormone receptors Human genes 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical class 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
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/613—Unsaturated compounds containing a keto groups being part of a ring polycyclic
- C07C49/617—Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system
- C07C49/623—Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system having two rings
- C07C49/633—Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system having two rings the condensed ring system containing eight or nine carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
Abstract
【解決手段】シス融合二環式誘導体を対応するトランス融合二環式誘導体から調製する方法であって、前記トランス融合二環式誘導体を水素化物塩基と反応させる工程を含む方法。
【選択図】なし
Description
−R1はHまたはC1−C6アルキル基を表し;
−R2はHまたはDを表し、Dは重水素原子を表し;
−R3は任意に一つ以上の二重または三重結合を含み、及び/またはO、N、S、Siから選択される一つ以上のヘテロ原子により任意に中断されたC1−C20アルキルを表し;好ましくはR3は直鎖状または分枝状のC1−C20アルキル、C2−C20アルケニル、C2−C20アルキニルであり、前記アルキル、アルケニル、またはアルキニルは、OHまたはOH官能基の保護基から選択される一つ以上の基により任意に置換される。前記保護基は好ましくは、ケタールのような酸不安定基:エトキシエチル(EE)、またはトリアルキルシリル基のようなフッ素不安定基:トリメチルシリル(TMS)、トリエチルシリル(TES)、tert-ブチルジメチルシリル(TBS)、トリイソプリピルシリル(TIPS)、tert-ブチルジフェニルシリル(TBDPS)から選択される;
−mは0,1,2,3から選択される整数であり;
−nは0,1または2から選択される整数であり;
−存在する場合、Ri及びRjは同一でも異なってもよく、それぞれ1からnまたは1からm基を表し、同一でも互いに異なってもよく、ハロゲン原子、C1−C6アルキル、C2−C6アルケニル、OR、NRR’、CN、NO2、パーハロゲノ(C1−C6)アルキル、COR、COOR、CONRR’、アルキルアリール、アルケニルアリールから独立に選択され、ここでR及びR’は同一でも異なってもよく、H、アルキル、アリールから選択される]。
−m=n=0:
−R1=メチル;
−R2=H;及び/または
−R3は下式
溶出溶媒は更にTEAのような塩基を含んでも良い。
−ウィッティヒ反応を実施する工程;
−得られた化合物を対応するシクロヘキサン誘導体またはその前駆体とカップリングする工程;及び任意に
−得られた化合物を加水分解する工程。
実施例1を以下のようなスケールアップした量で繰り返した:
3.1.ビニルブロミド4の形成
テトラヒドロフラン(2.2L)中のカリウムビス(トリメチルシリル)アミド(484g, 2.42モル)の溶液を、テトラヒドロフラン(2.2L)中の(ブロモメチル)トリフェニルホスホニウムブロミド(1.124kg, 2.57モル)の溶液に-30℃でゆっくりと添加した。添加が終了してから、混合物を-30℃で1.5時間維持し、次いで0℃に温めた。次いでテトラヒドロフラン(0.5L)中のシスケトン3(340g, 0.945モル)の溶液を0℃で添加し、混合物を2.5時間攪拌した。次いで、20℃未満の温度を維持しながら。水をゆっくりと添加した。混合物をエチルアセテートで抽出した。有機相を塩水で洗浄し、乾かし、濃縮した。粗残余物をシリカゲル上でのフラッシュクロマトグラフィーにより精製し、純粋なビニルブロミド4(200g, 収率48%)を得た。
tert-ブチルリチウム(ペンタン中に1.7M、1.25L)の溶液を、テトラヒドロフラン(3.4L)中の4の溶液(431, 1.01モル)に-70℃で滴下した。添加が終了してから、混合物を-70℃で1.5時間攪拌し、テトラヒドロフラン(0.5L)中のアルデヒド5(253g, 1.05モル)の溶液を混合物を滴下した。次いで溶液を-70℃で1時間維持し、飽和塩化アンモニウム溶液の添加により停止した。溶液をエチルアセテートで抽出し、次いで有機相を塩水で洗浄し、乾燥して濃縮した。粗残余物をシリカゲル上でのフラッシュクロマトグラフィーにより精製し、純粋な化合物6(308g, 収率51%)を得た。
ジオキサン/水(120mL, 7/3)中のp-トルエンスルホン酸(57g, 0.299モル)の溶液を、ジオキサン/水(4L)中の化合物6(305g, 0.505モル)の溶液に添加した。混合物を60℃で4時間攪拌し、次いで室温に冷却した。エチルアセテートを添加し、溶液を炭酸水素ナトリウムの飽和水溶液と塩水で洗浄した。有機相を分離し、乾かし、濃縮した。粗残余物をシリカゲル上でのフラッシュクロマトグラフィーにより精製し、ジイソプロピルエーテル/エタノールから結晶化し、純粋なイネカルシトール1(145g, 収率71%)を得た。
実施例1で使用された370mgのトランス化合物の異性化を、室温で12時間、MeONa/MeOHの存在下で実施する。混合物を減圧下で蒸発させ、残余物をシリカゲルカラム(エチルアセテート/ヘキサン、2/8)で精製し、純粋なシスケトンをHPLC(エチルアセテート/ヘキサン、2:8)による分離によって65%の収率で得る。
比較例1をスケールアップした量で繰り返した。
実施例1で使用したトランス化合物の異性化を、以下の各種の条件で実施する。得られた比は以下の表に報告されている。
Claims (15)
- シス融合二環式誘導体を対応するトランス融合二環式誘導体から調製する方法であって、前記トランス融合二環式誘導体を水素化物塩基と反応させる工程を含む方法。
- 前記融合二環式誘導体が、任意に置換されたシクロアルカンで任意に置換されたシクロアルカノンを含む、請求項1に記載の方法。
- 前記トランス及びシス融合二環式構造が、それぞれ下式(I)及び(II)を有する、請求項1または2に記載の方法:
−R1はHまたはC1−C6アルキル基を表し;
−R2はHまたはDを表し、Dは重水素原子を表し;
−R3は任意に一つ以上の二重または三重結合を含み、及び/またはO、N、S、Siから選択される一つ以上のヘテロ原子を任意に含むC1−C20アルキルを表し;
−mは0,1,2,3から選択される整数であり;
−nは0,1または2から選択される整数であり;
−存在する場合、各Ri及びRjは同一でも異なってもよく、それぞれ1からnまたは1からm基を表し、同一でも互いに異なってもよく、ハロゲン原子、C1−C6アルキル、C2−C6アルケニル、OR、NRR’、CN、NO2、パーハロゲノ(C1−C6)アルキル、COR、COOR、CONRR’、アルキルアリール、アルケニルアリールから独立に選択され、ここでR及びR’は同一でも異なってもよく、H、アルキル、アリールから選択される]。 - 前記塩基が、式M−H(式中、MはIA族の原子である)を有する、請求項1から4のいずれか一項に記載の方法。
- 前記塩基がNaHである、請求項1から5のいずれか一項に記載の方法。。
- 前記工程が、THFまたはアルキル化THFから選択される溶媒で実施される、請求項1から6のいずれか一項に記載の方法。
- 更に加水分解工程を含み、前記異性化工程の後に実施される、請求項1から7のいずれか一項に記載の方法。
- 更に得られたシス融合二環式誘導体を精製する工程を含む、請求項1から8のいずれか一項に記載の方法。
- 前記精製がカラムクロマトグラフィーにより実施される、請求項9に記載の方法。
- 溶出溶媒がヘプタンとエチルアセテートとの混合物である、請求項10に記載の方法。
- シスC/D環接合を有するステロイドまたはセコステロイド誘導体の調製方法であって、請求項1から11のいずれか一項に記載のシス融合二環式誘導体を対応するトランス融合二環式誘導体から調製する方法を含む方法。
- −ウィッティヒ反応を実施して、ビニルハロゲン化物誘導体を導く工程;
−得られた化合物を対応するシクロヘキサン誘導体またはその前駆体とカップリングする工程;及び任意に
−得られた化合物を加水分解する工程。
を更に含む、請求項12から14のいずれか一項に記載の方法。
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