WO2009144961A1 - 環状リンカーを有する置換カルビノール化合物 - Google Patents
環状リンカーを有する置換カルビノール化合物 Download PDFInfo
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- WO2009144961A1 WO2009144961A1 PCT/JP2009/002406 JP2009002406W WO2009144961A1 WO 2009144961 A1 WO2009144961 A1 WO 2009144961A1 JP 2009002406 W JP2009002406 W JP 2009002406W WO 2009144961 A1 WO2009144961 A1 WO 2009144961A1
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- WIPO (PCT)
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- group
- dione
- hexafluoro
- methylimidazolidine
- nmr
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- 0 ***=*C(CC(F)(F)F)=I Chemical compound ***=*C(CC(F)(F)F)=I 0.000 description 4
- FEGYIIGUKYRXQP-GQCTYLIASA-N C/C=C/c1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)cnc1Oc1cccc(C(OC)=O)c1 Chemical compound C/C=C/c1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)cnc1Oc1cccc(C(OC)=O)c1 FEGYIIGUKYRXQP-GQCTYLIASA-N 0.000 description 1
- GLKKZRHEQNZWLB-UHFFFAOYSA-N CCC(C(N1CC2NC=CC(Oc3c(CC)cc(C(C(F)(F)F)(C(F)(F)F)O)cc3)=C2)=O)(c(cc2)cc3c2OCC3)NC1=O Chemical compound CCC(C(N1CC2NC=CC(Oc3c(CC)cc(C(C(F)(F)F)(C(F)(F)F)O)cc3)=C2)=O)(c(cc2)cc3c2OCC3)NC1=O GLKKZRHEQNZWLB-UHFFFAOYSA-N 0.000 description 1
- NQMBKLKYCXDNPI-YUSIFDCQSA-N CCC/C(/C)=C/C(/C(C(F)(F)F)(C(F)(F)F)O)=C\C[C@@H](C)COc1ccc(C(OC)=O)nc1 Chemical compound CCC/C(/C)=C/C(/C(C(F)(F)F)(C(F)(F)F)O)=C\C[C@@H](C)COc1ccc(C(OC)=O)nc1 NQMBKLKYCXDNPI-YUSIFDCQSA-N 0.000 description 1
- FPKGLCFXTWUVFW-BJFQTCHOSA-N CCCc(cc(C(C(F)(F)F)(C(F)(F)F)O)cc1)c1OC1=CCC(C[N-2]C(N[C@](C)(C(CC2)CC=C2OC(C)C)C=O)=O)C=C1 Chemical compound CCCc(cc(C(C(F)(F)F)(C(F)(F)F)O)cc1)c1OC1=CCC(C[N-2]C(N[C@](C)(C(CC2)CC=C2OC(C)C)C=O)=O)C=C1 FPKGLCFXTWUVFW-BJFQTCHOSA-N 0.000 description 1
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- SVPZMRDSXHKPKG-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)cc(CCC)c1Oc1ccnc(CN(C(C(C)(c(cc2)cc3c2OCO3)N2)=O)C2=O)c1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)cc(CCC)c1Oc1ccnc(CN(C(C(C)(c(cc2)cc3c2OCO3)N2)=O)C2=O)c1 SVPZMRDSXHKPKG-UHFFFAOYSA-N 0.000 description 1
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- PHSKCCSBNIJGQQ-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1cc(C(C)N(C(C(C)(c(cn2)ccc2OC)N2)=O)C2=O)ncc1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1cc(C(C)N(C(C(C)(c(cn2)ccc2OC)N2)=O)C2=O)ncc1 PHSKCCSBNIJGQQ-UHFFFAOYSA-N 0.000 description 1
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- CINWDGRLSZBYBJ-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1ccc(C(CN(C(C(C)(c(cc2)ccc2OC(C)C)N2)=O)C2=O)=O)c(O)c1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1ccc(C(CN(C(C(C)(c(cc2)ccc2OC(C)C)N2)=O)C2=O)=O)c(O)c1 CINWDGRLSZBYBJ-UHFFFAOYSA-N 0.000 description 1
- LNXNXWPTTVKOGC-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1ccc(CCN(C(C(C)(c(cc2)cc3c2OCCO3)N2)=O)C2=O)c(C#N)c1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1ccc(CCN(C(C(C)(c(cc2)cc3c2OCCO3)N2)=O)C2=O)c(C#N)c1 LNXNXWPTTVKOGC-UHFFFAOYSA-N 0.000 description 1
- WCNLYRROVZWKSN-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1ccc(CCN(C(C(CC)(c2ccc3OCCOc3c2)N2)=O)C2=O)cc1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1ccc(CCN(C(C(CC)(c2ccc3OCCOc3c2)N2)=O)C2=O)cc1 WCNLYRROVZWKSN-UHFFFAOYSA-N 0.000 description 1
- HTIJRQCMQICZOQ-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1ccnc(CN(C(C(C)(c(cc2)ccc2OC)N2)=O)C2=O)c1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1ccnc(CN(C(C(C)(c(cc2)ccc2OC)N2)=O)C2=O)c1 HTIJRQCMQICZOQ-UHFFFAOYSA-N 0.000 description 1
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- MISZBLFKTAZPEV-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1ccnc(CN(C(C(C)(c(cn2)ccc2S(C)(=O)=O)N2)=O)C2=O)c1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1ccnc(CN(C(C(C)(c(cn2)ccc2S(C)(=O)=O)N2)=O)C2=O)c1 MISZBLFKTAZPEV-UHFFFAOYSA-N 0.000 description 1
- NGUGIPDXAJNJJW-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1cnc(CCN(C(C(C)(c2ccc[o]2)N2)=O)C2=O)cc1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1cnc(CCN(C(C(C)(c2ccc[o]2)N2)=O)C2=O)cc1 NGUGIPDXAJNJJW-UHFFFAOYSA-N 0.000 description 1
- JLUKWKJZXLHLKJ-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1cnc(CN(C(C(C)(c(cc2)ccc2OC(C)C)N2)=O)C2=O)cc1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1cnc(CN(C(C(C)(c(cc2)ccc2OC(C)C)N2)=O)C2=O)cc1 JLUKWKJZXLHLKJ-UHFFFAOYSA-N 0.000 description 1
- KCNSWUMPUSEVMV-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1cncc(CN(C(C(C)(c(cc2)ccc2OC(C)C)N2)=O)C2=O)c1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1cncc(CN(C(C(C)(c(cc2)ccc2OC(C)C)N2)=O)C2=O)c1 KCNSWUMPUSEVMV-UHFFFAOYSA-N 0.000 description 1
- CAAKMXJAVBOVMG-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1ncc(CCN(C(C(C)(c2ccc3OCCc3c2)N2)=O)C2=O)cc1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1ncc(CCN(C(C(C)(c2ccc3OCCc3c2)N2)=O)C2=O)cc1 CAAKMXJAVBOVMG-UHFFFAOYSA-N 0.000 description 1
- XNAZLPIGQPSMHM-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1nccc(CN(C(C(C)(c(cc2)cc3c2OCC3)N2)=O)C2=O)c1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)O)ccc1Oc1nccc(CN(C(C(C)(c(cc2)cc3c2OCC3)N2)=O)C2=O)c1 XNAZLPIGQPSMHM-UHFFFAOYSA-N 0.000 description 1
- BUSAIKKYZGDNFB-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1-c(cc1)ccc1OCCCBr Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1-c(cc1)ccc1OCCCBr BUSAIKKYZGDNFB-UHFFFAOYSA-N 0.000 description 1
- GCOKKQQVKXTGJJ-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1OC1=CC=C(CCBr)CC1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1OC1=CC=C(CCBr)CC1 GCOKKQQVKXTGJJ-UHFFFAOYSA-N 0.000 description 1
- QTWDDDPSONDBST-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1Oc(nc1)cc(C(OC)=O)c1I Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1Oc(nc1)cc(C(OC)=O)c1I QTWDDDPSONDBST-UHFFFAOYSA-N 0.000 description 1
- VJDDKWVTOKLFFR-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1Oc1cc(CBr)ccc1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1Oc1cc(CBr)ccc1 VJDDKWVTOKLFFR-UHFFFAOYSA-N 0.000 description 1
- DHBQQVKHYJHALV-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1Oc1cccc(C=C)c1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1Oc1cccc(C=C)c1 DHBQQVKHYJHALV-UHFFFAOYSA-N 0.000 description 1
- UVSQNEDPAFKMLC-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1Oc1cccc(C=O)c1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1Oc1cccc(C=O)c1 UVSQNEDPAFKMLC-UHFFFAOYSA-N 0.000 description 1
- DLDSTEWUZYRHAO-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1Oc1nc(CO)ccc1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1Oc1nc(CO)ccc1 DLDSTEWUZYRHAO-UHFFFAOYSA-N 0.000 description 1
- YQQSOFDQGHMRPV-UHFFFAOYSA-N CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1Oc1nccc(CBr)c1 Chemical compound CCCc1cc(C(C(F)(F)F)(C(F)(F)F)OCOC)ccc1Oc1nccc(CBr)c1 YQQSOFDQGHMRPV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
-
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Definitions
- the present invention relates to atherosclerosis, arteriosclerosis such as arteriosclerosis caused by diabetes, dyslipidemia, hypercholesterolemia, lipid-related diseases, inflammatory diseases that are caused by inflammatory cytokines, allergies
- arteriosclerosis such as arteriosclerosis caused by diabetes, dyslipidemia, hypercholesterolemia, lipid-related diseases, inflammatory diseases that are caused by inflammatory cytokines, allergies
- the present invention relates to a substituted carbinol compound having a cyclic linker which is a novel LXR ⁇ agonist useful as a preventive and / or therapeutic agent for skin diseases such as sexual skin diseases, diabetes or Alzheimer's disease.
- LXR Liver X receptor
- RXR retinoid X receptor
- LXR subtypes the existence of two LXR genes ( ⁇ and ⁇ ) is known in mammals. LXR ⁇ and LXR ⁇ recognize similar sequences on DNA and activate transcription of nearby target genes, but their expression distributions differ greatly between the two genes. LXR ⁇ is a cholesterol metabolism in the liver, small intestine, adipose tissue, etc. LXR ⁇ is ubiquitously expressed in almost all tissues examined (Non-patent Documents 4 and 5).
- LXR target genes are genes (ApoE, CETP, and LPL) involved in reverse cholesterol transport (RCT) including ABC transporters (ABCA1, ABCG1, ABCG5, ABCG8). is there.
- RCT reverse cholesterol transport
- ABCA1, ABCG1, ABCG5, ABCG8 ABC transporters
- activation of LXR increases the expression of these genes and activates the reverse cholesterol transport pathway, thereby increasing cholesterol efflux from the periphery, increasing HDL cholesterol, and increasing the cholesterol content at the site of atherosclerotic lesions. It is expected to decrease (Non-patent Document 6).
- LXR plays an important role in regulating the expression of inflammatory mediators such as NO synthase, cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) through the suppression of NF- ⁇ B.
- Non-Patent Document 7 It is well known that inflammation is very important in arteriosclerotic lesions, and it is expected that deterioration of arteriosclerosis due to the expression of macrophage inflammatory mediators at the lesion site can be suppressed by LXR ligands or LXR agonists (non-patented). References 6 and 8).
- Non-Patent Documents 9 and 10 that is, it is strongly suggested that LXR plays an important role in cholesterol metabolism. Furthermore, by analyzing the symptoms of arteriosclerosis model mice that have normal LXR ⁇ and ⁇ functions in the liver, small intestine, etc., and LXR ⁇ and ⁇ in macrophages, the activity of LXR ⁇ and ⁇ in macrophages is affected by arteriosclerosis. It has been clarified that it has a strong influence on the rate (Non-patent Document 11). Therefore, activating reverse cholesterol transport by LXR activation, particularly in macrophages, is considered important for the treatment of arteriosclerosis.
- Non-patent Documents 1 and 2 As applications of LXR modulators or LXR agonists disclosed in the prior art, application to diseases such as hypercholesterolemia and atherosclerosis has been reported (Patent Documents 1 and 2). In addition, HDL cholesterol increased, VLDL and LDL cholesterol decreased, and atherosclerotic lesion site area decreased in high fat diet-loaded LDL receptor-deficient mice administered with LXR ligand (Non-patent Document 12). In addition, LXR ligands or LXR agonists are expected to control glucose metabolism in liver and adipose tissue and improve diabetes (Non-patent Documents 6 and 8).
- Non-patent Document 15 In recent years, it has been reported that insulin sensitivity and blood glucose level are improved by administering an LXR agonist to a diabetic model animal (Non-Patent Documents 13 and 14). Moreover, the possibility as a therapeutic agent for Alzheimer's disease, inflammatory disease, and skin disease has been pointed out (Non-patent Document 15).
- Non-patent Document 16 LXR agonists cause an increase in LDL cholesterol in animal species having cholesterol ester transfer protein (CETP) (Non-patent Document 16).
- CTP cholesterol ester transfer protein
- LXR ligands, LXR agonists and the like disclosed in the prior art there is no disclosure of LXR ⁇ / ⁇ selectivity.
- LXR agonists having a quinoline skeleton have been reported (Patent Document 11, Non-Patent Documents 20-22).
- the quinoline derivative WAY-254011 compound 4 of Non-Patent Document 22
- Patent Document 22 also reports a compound having an ⁇ / ⁇ ratio of 50 times maximum at the binding ability.
- the selectivity of ⁇ / ⁇ ratio is about 2.7 times at most, and it is selectively bound to LXR ⁇ . It can be seen that the effect of expressing the target gene of LXR is weak. Therefore, there is still a strong demand for compounds having an action of expressing a target gene selectively with LXR ⁇ .
- an object of the present invention is to create a novel compound exhibiting agonist activity with high selectivity for LXR ⁇ .
- R 1 represents a hydrogen atom, a C 1-8 alkyl group, a C 1-8 alkoxy C 1-8 alkyl group or a C 1-8 acyl group
- R 2 and R 3 each independently represents a hydrogen atom.
- Atom, C 1-8 alkyl group, C 3-8 cycloalkyl group, C 6-10 aryl group or 5-11 membered heterocyclic group (where C 6-10 aryl and 5-11 membered heterocyclic ring are Or may be substituted with 1 to 3 identical or different substituents selected from the following group A), or R 2 and R 3 together may form a 5- to 7-membered carbocyclic ring
- R 4 represents a hydrogen atom, a C 1-8 alkyl group, a halo C 1-8 alkyl group or a C 3-8 cycloalkyl group
- X 1 , X 2 , X 3 and X 4 each independently represent N or shows a CR 5
- R 5 is a hydrogen atom,
- halogen examples of the “halogen” atom in the halogen atom, halo C 1-8 alkyl group, and halo C 1-8 alkoxy group include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- the “C 1-8 alkyl group” means a linear or branched alkyl group having 1-8 carbon atoms.
- the “halo C 1-8 alkyl group” means a group in which one or more, preferably 1 to 9, halogen atoms are bonded to a C 1-8 alkyl group, such as a trifluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 3-fluoropropyl group, 3-chloropropyl group, 4-fluorobutyl group, 4-chlorobutyl group, 2,2,2-trifluoroethyl group, Examples include 3,3,3-trifluoropropyl group, pentafluoroethyl group, 2,2,2-trifluoro-1-trifluoromethylethyl group, and the like.
- the “C 2-8 alkenyl group” means a linear or branched alkenyl group having 2 to 8 carbon atoms and having a carbon-carbon double bond at any one or more positions on the alkyl chain.
- the “C 2-8 alkynyl group” means a linear or branched alkynyl group having 2 to 8 carbon atoms having a carbon-carbon triple bond at any one or more positions on the alkyl chain, For example, an ethynyl group, a prop-1-in-1-yl group, a prop-2-yn-1-yl group, a but-1-in-1-yl group, a but-3-in-1-yl group, -Methylprop-2-yn-1-yl group, penta-1-in-1-yl group, penta-4-in-1-yl group, hexa-1-in-1-yl group, hexa-5-in And a 1-yl group.
- C 1-8 alkoxy group examples include methoxy group, ethoxy group, n-propoxy group, 1-methylethoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert- Butoxy group, n-pentoxy group, isopentoxy group, neopentoxy group, 1-methylbutoxy group, 1-ethylpropoxy group, n-hexyloxy group, isohexyloxy group, 3-methylpentoxy group, 2-methylpentoxy group 1-methylpentoxy group, 3,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2, Examples include 3-dimethylbutoxy group, 1-ethylbutoxy group, 2-ethylbutoxy group and the like.
- the “C 1-8 alkoxy C 1-8 alkyl group” refers to a group in which the “C 1-8 alkoxy group” is bonded to the C 1-8 alkyl group, and includes, for example, a methoxymethyl group, a methoxyethyl group Ethoxymethyl group, ethoxyethyl group and the like.
- Specific examples of the “C 3-8 cycloalkyloxy group” of the present invention include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, and the like.
- the “halo C 1-8 alkoxy group” means a group in which the halo C 1-8 alkyl group is bonded to an oxygen atom, such as a trifluoromethoxy group, a 2-fluoroethoxy group, a 2-fluoroethoxy group, Chloroethoxy group, 2-bromoethoxy group, 3-fluoropropoxy group, 3-chloropropoxy group, 4-fluorobutoxy group, 4-chlorobutoxy group, 2,2,2-trifluoroethoxy group, 3,3,3 -Trifluoropropoxy group, pentafluoroethoxy group, 2,2,2-trifluoro-1-trifluoromethylethoxy group and the like.
- examples of the “C 1-8 acyl group” include an alkylcarbonyl group such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group and pivaloyl group, and alkenyl group such as acryloyl group.
- alkylcarbonyl group such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group and pivaloyl group
- alkenyl group such as acryloyl group.
- examples thereof include arylcarbonyl groups such as a carbonyl group and a benzoyl group.
- C 1-8 acyloxy group examples include alkylcarbonyl such as formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, and pivaloyloxy group.
- alkylcarbonyl such as formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, and pivaloyloxy group.
- alkenylcarbonyloxy groups such as oxy group and acryloyloxy group
- arylcarbonyloxy groups such as benzoyloxy group.
- the “C 6-10 aryl group” means a monocyclic or polycyclic aryl group having 6 to 10 carbon atoms.
- a partially saturated group is included in addition to the fully unsaturated group. Examples thereof include a phenyl group, a naphthyl group, an azulenyl group, an indenyl group, an indanyl group, and a tetralinyl group.
- examples of the “C 6-10 arylcarbonyl group” include a benzoyl group and a naphthoyl group.
- the “C 6-10 aryl C 1-8 alkyl group” means a group in which the following C 6-10 aryl group and the above C 1-8 alkyl group are bonded. Examples include a benzyl group, a phenethyl group, a 3-phenyl-n-propyl group, a 4-phenyl-n-butyl group, a 5-phenyl-n-pentyl group, an 8-phenyl-n-octyl group, and a naphthylmethyl group. It is done.
- the “C 3-8 cycloalkyl group” means a cyclic alkyl group having 3 to 8 carbon atoms.
- a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like can be given.
- it is a “C 3-6 cycloalkyl group” having 3 to 6 carbon atoms.
- the “5-11-membered heterocyclic group” means a 5- to 7-membered member containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms as atoms constituting the ring.
- the “mono C 1-8 alkylamino group” of the present invention include a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, a sec-butylamino group, tert-butylamino group, n-pentylamino group, isopentylamino group, neopentylamino group, 1-methylbutylamino group, 1-ethylpropylamino group, n-hexylamino group, isohexylamino group, 4-methyl Pentylamino group, 3-methylpentylamino group, 2-methylpentylamino group, 1-methylpentylamino group, 3,3-dimethylbutylamino group, 2,2-dimethylbutylamino group, 1,1-dimethylbutylamino Group, 1,2-dimethylbutylamino Group
- the “di-C 1-8 alkylamino group” of the present invention specifically includes a dimethylamino group, a methylethylamino group, a diethylamino group, a methyl-n-propylamino group, an ethyl-n-propylamino group, a di- n-propylamino group, methylisopropylamino group, ethylisopropylamino group, diisopropylamino group, methyl-n-butylamino group, ethyl-n-butylamino group, n-propyl-n-butylamino group, di-n- A butylamino group, a di-sec-butylamino group, a di-tert-butylamino group, a dipentylamino group, a dihexylamino group, and the like.
- C 1-8 alkylthio group examples include methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group.
- n-pentylthio group isopentylthio group, neopentylthio group, 1-methylbutylthio group, 1-ethylpropylthio group, n-hexylthio group, isohexylthio group, 4-methylpentylthio group, 3- Methylpentylthio group, 2-methylpentylthio group, 1-methylpentylthio group, 3,3-dimethylbutylthio group, 2,2-dimethylbutylthio group, 1,1-dimethylbutylthio group, 1,2- Dimethylbutylthio group, 1,3-dimethylbutylthio group, 2,3-dimethylbutylthio group, 1-ethylbutylthio group, 2- Examples thereof include an ethylbutylthio group, a trifluoromethylthio group, and a trichloromethylthio group.
- C 3-8 cycloalkylthio group examples include a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio group, and a cyclooctylthio group.
- C 1-8 alkylsulfinyl group examples include methylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group, isopropylsulfinyl group, n-butylsulfinyl group, isobutylsulfinyl group, sec-butyl.
- C 1-8 alkylsulfonyl group examples include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, sec-butyl.
- C 6-10 arylthio group examples include a phenylthio group, a p-tolylthio group, a p-chlorophenylthio group, a naphthylthio group, and an azulenylthio group.
- C 6-10 arylsulfinyl group examples include a benzenesulfinyl group, a p-toluenesulfinyl group, a p-chlorobenzenesulfinyl group, a naphthalen-1-ylsulfinyl group, and a naphthalen-2-ylsulfinyl group.
- C 6-10 arylsulfonyl group examples include a benzenesulfonyl group, p-toluenesulfonyl group, p-chlorobenzenesulfonyl group, naphthalen-1-yl-sulfonyl group, naphthalen-2-yl- A sulfonyl group etc. are mentioned.
- C 1-8 alkoxycarbonyl group examples include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, a 1-methylethoxycarbonyl group, an n-butoxycarbonyl group, and an isobutoxycarbonyl group.
- the “C 3-8 cycloalkenyl group” means a group having a carbon-carbon double bond at any one or more positions on the carbocyclic ring of the “C 3-8 cycloalkyl group”. Examples thereof include a cyclopropene group, a cyclobutene group, a cyclopentene group, a cyclohexene group, a cycloheptene group, a cyclooctene group, and a cyclohexadiene group.
- the “C 3-8 cycloalkenyl C 1-8 alkyl group” refers to a group in which a “C 3-8 cycloalkenyl group” is bonded to a C 1-8 alkyl group.
- the “5- to 7-membered carbocycle” means a hydrocarbon ring having 5 to 7 carbon atoms. Examples thereof include a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclopentene ring, a cyclohexene ring, and a cycloheptene ring.
- the “C 3-8 cycloalkyl C 1-8 alkyl group” means a group in which the “C 3-8 cycloalkyl group” is bonded to a C 1-8 alkyl group.
- a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, etc. are mentioned.
- the “C 3-8 cycloalkyl C 2-8 alkenyl group” means a group in which the “C 3-8 cycloalkyl group” is bonded to a C 2-8 alkenyl group. Examples thereof include a 2-cyclopropylethen-1-yl group, a 2-cyclobutylethen-1-yl group, a 2-cyclopentylethen-1-yl group, and a 2-cyclohexylethen-1-yl group.
- the “C 3-8 cycloalkyl C 2-8 alkynyl group” means a group in which the “C 3-8 cycloalkyl group” is bonded to a C 2-8 alkynyl group.
- Examples include 2-cyclopropylethynyl group, 2-cyclobutylethynyl group, 2-cyclopentylethynyl group, 2-cyclohexylethynyl group and the like.
- the “C 6-10 aryl C 2-8 alkenyl group” means a group in which the “C 6-10 aryl group” is bonded to C 2-8 alkenyl.
- Examples include a styryl group, cinnamyl group, 4-phenyl-3-buten-1-yl group, 5-phenyl-4-penten-1-yl group, 6-phenyl-6-hexen-1-yl group and the like. .
- C 6-10 aryl C 1-8 alkoxy group is a one to three C 1-8 on the ring
- the “C 6-10 aryl C 1-8 alkyl group” optionally substituted by an alkyl group means a group bonded to an oxygen atom. Examples include benzyloxy group, phenethyloxy group, naphthylmethyloxy group, 2-methylbenzyloxy group, 3-methylbenzyloxy group, 4-methylbenzyloxy group, 3,4-dimethylbenzyloxy group and the like.
- the “C 1-8 alkoxy C 1-8 alkyl group” means a group in which the C 1-8 alkoxy group is bonded to the C 1-8 alkyl group.
- the “C 1-8 alkyl chain” means a divalent hydrocarbon chain having a straight chain or branched chain having 1 to 8 carbon atoms, such as a methylene chain, an ethylene chain, a trimethylene chain, methylethylene.
- the “—O— (C 1-8 alkyl) chain” means a group in which the “C 1-8 alkyl chain” is bonded to an oxygen atom, such as —O— (methylene) chain, -O- (ethylene) chain, -O- (trimethylene) chain, -O- (1-methylethylene) chain, -O- (tetramethylene) chain, -O- (1-methylmethylene) chain, -O- (1,2-dimethylethylene) chain, -O- (pentamethylene) chain, -O- (1-methyltetramethylene) chain, -O- (2-methyltetramethylene) chain, -O- (hexamethylene) Chain, -O- (heptamethylene) chain, -O- (octamethylene) chain, and the like.
- the “C 2-8 alkenyl chain” has a straight chain or branched chain having 2 to 8 carbon atoms having a carbon-carbon double bond at one or more of “C 2-8 alkyl chain”.
- vinylene chain, propenylene chain, 1-methylvinylene chain, butenylene chain (for example, 1-butenylene chain, 2-butenylene chain, etc.), 1,2-dimethylvinylene chain examples include a pentenylene chain, a 1-methylbutenylene chain, a 2-methylbutenylene chain, a hexenylene chain, a heptenylene chain, an octenylene chain, and an isoprene chain.
- the “C 6-10 aryl chain” means a divalent aromatic hydrocarbon ring group, and examples thereof include an o-phenylene group, an m-phenylene group, and a p-phenylene group.
- the “5-11-membered heteroaryl chain” means a 5- to 7-membered member containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms as atoms constituting the ring.
- R 1 is preferably a hydrogen atom or a C 1-8 alkoxy C 1-8 alkyl group, more preferably a hydrogen atom or a methoxymethyl group, and particularly preferably a hydrogen atom.
- R 2 and R 3 are preferably a C 1-8 alkyl group, a C 6-10 aryl group, or a 5-11 membered heterocyclic group.
- the C 1-8 alkyl group of R 2 and R 3 is preferably a linear C 1-8 alkyl group, such as a methyl group, ethyl group, n-propyl, n-butyl group, etc.
- the linear alkyl group having 1 to 6 carbon atoms is more preferable, and a methyl group and an ethyl group are particularly preferable.
- the C 6-10 aryl group of R 2 and R 3 is preferably a phenyl group or a naphthyl group, more preferably a phenyl group.
- This phenyl group preferably has a substituent, such as a halogen atom such as a fluorine atom or a chlorine atom, a C 1-8 alkyl group such as a methyl group, a 1-methylethyl group or a 1,1-dimethylethyl group.
- C 1-8 alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, n-butoxy group, 1-methylethoxy group, cyclopropyloxy group, etc., C 1-8 alkylthio such as methylthio group, cyclopropylthio group, etc. group, C 1-8 alkylsulfinyl group such as methylsulfinyl group, C 1-8 alkylsulfonyl groups such as methylsulfonyl group, a nitro group, such as C 6-10 aryl C 1-8 alkoxy group such as a phenylmethoxy group is preferred Particularly preferred are C 1-8 alkoxy groups such as 1-methylethoxy group.
- the 5- to 11-membered heterocyclic group represented by R 2 and R 3 includes 1 to 2 heteroatoms selected from a nitrogen atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
- a 5- to 7-membered aromatic heterocyclic ring, an unsaturated heterocyclic ring, or a condensed heterocyclic ring obtained by condensing these heterocyclic rings with a benzene ring or a pyridine ring is preferable.
- These 5-11 membered heterocyclic groups may have a substituent, and examples of the substituent include C 1-8 such as a methoxy group, an ethoxy group, an n-propoxy group, a 1-methylethoxy group, and an n-butoxy group. Alkoxy groups are preferred.
- R 2 and R 3 are a C 1-8 alkyl group and the other is a C 6-10 aryl group or a 5-11 membered heterocyclic group is preferable.
- R 2 and R 3 together form a 5- to 7-membered carbon ring, a cyclopentane ring is preferable.
- R 4 is preferably a C 1-8 alkyl group such as a hydrogen atom or a methyl group.
- X 1 , X 2 , X 3 and X 4 are preferably N or CR 5 .
- R 5 is preferably a hydrogen atom or a C 1-8 alkyl group.
- the C 1-8 alkyl group for R 5 include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, neopentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, n-hexyl group, isohexyl group, n-heptyl group, n-octyl group, and the like.
- methyl group, n-propyl group, isopropyl group, C 1-8 alkyl groups such as an isobutyl group, an n-pentyl group, and an n-octyl group are preferred.
- Y is preferably a single bond or —O—.
- the C 6-10 aryl chain of Z is preferably an m-phenylene group or a p-phenylene group, and the 5-11 membered heteroaryl chain is a 2,3-pyridinediyl group, 2,4 -Pyridinediyl group, 2,6-pyridinediyl group, 3,5-pyridinediyl group are preferred.
- examples of the substituent substituted on the C 6-10 aryl chain and the 5-11 membered heteroaryl chain include a halogen atom such as a chlorine atom and an iodine atom, a C 1-8 alkyl group such as a methyl group, a cyano group, C 1-8 alkoxy group such as hydroxy group, methoxy group, ethoxy group, etc., C 6-10 aryl C 1-8 alkoxy group such as benzyloxy group, C 1-8 alkoxy C 1-8 alkyl group such as methoxymethyl group , Etc. are preferred.
- C 1-8 alkyl chain C 1-8 alkyl chain substituted with an oxo group, -O- (C 1-8 alkyl) chain are preferred, C 1-8 alkyl chain Is particularly preferred.
- alkyl chain portion a methylene chain, an ethylene chain, a trimethylene chain, a 1-methylmethylene chain, a tetramethylene chain, and a pentamethylene chain are preferable, and an ethylene chain is particularly preferable.
- addition salts of carbinol derivatives represented by the general formula (I) include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, trialkylamine salts, and the like.
- Examples of the solvate of the carbinol derivative represented by the general formula (I) include hydrates.
- geometrical isomers or optical isomers exist in the compound of the present invention these isomers are also included in the scope of the present invention.
- the (E) isomer is preferable.
- Compound (I) can be produced by various known methods, and is not particularly limited. For example, it can be produced according to the following reaction steps. That is, compound (I) can be produced by reacting a derivative represented by general formula (II) with an imidazolidine-2,4-dione compound represented by general formula (III). This reaction path is represented by the chemical reaction formula as follows.
- R 1A represents a protecting group for hydroxyl group or R 1 described above, and R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , Y, Z and L are the same as above.
- W 1 represents a halogen atom or a hydroxyl group.
- the protecting group R 1A can be converted to R 1 using commonly used methods (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
- the derivative represented by the general formula (II) is reacted with an imidazolidine-2,4-dione compound (III) in a solvent in the presence or absence of a base.
- the solvent is not particularly limited, but for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water, etc. are used alone or in combination. can do.
- the base is not particularly limited, but for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali hydroxide metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide, lithium carbonate Alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, t-butoxy sodium, t-butoxy potassium, lithium diisopropyl Amide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, n-butyllithium, s-butyllithium, t-butyllithium, etc. It is possible to use.
- the desired product can be obtained by reacting at -80 to 150 ° C
- compound (I) is produced by subjecting the derivative represented by general formula (II) and the imidazolidine-2,4-dione compound represented by general formula (III) to Mitsunobu reaction. Can do.
- a derivative represented by the general formula (II), an imide compound represented by the general formula (III), and a phosphine reagent are dissolved in a reaction solvent, an azo reagent or an ethylenedicarboxylic acid reagent is added thereto, and argon or
- the reaction can be carried out in a nitrogen atmosphere at 0 ° C. to 100 ° C., preferably at room temperature to 80 ° C. for 2 hours to 1 day.
- N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used.
- -Dimethylformamide, tetrahydrofuran, dioxane and acetonitrile are preferred, and N, N-dimethylformamide and tetrahydrofuran are particularly preferred.
- phosphine reagent examples include trialkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, tricyclohexylphosphine, and triarylphosphine, and triarylphosphine such as diphenylphosphinopolystyrene.
- trialkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, tricyclohexylphosphine, and triarylphosphine
- triarylphosphine such as diphenylphosphinopolystyrene.
- Examples include phosphine, among which trimethyl
- azo reagent examples include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate, 1,1′-azobis (N, N-dimethylformamide) (TMAD), 1,1 ′-(azodicarbonyl) dipiperidine ( ADDP), 1,1′-azobis (N, N-diisopropylformamide) (TIPA), 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazocine-2,5-dione (DHTD) and the like, and particularly preferred is diethyl azodicarboxylate.
- DEAD diethyl azodicarboxylate
- TMAD 1,1′-azobis (N, N-dimethylformamide)
- ADDP 1,1 ′-(azodicarbonyl) dipiperidine
- TIPA 1,1′-azobis (N, N-diisopropylformamide)
- DHTD 1,6-d
- the derivative represented by the general formula (II) can be produced by the following reaction route.
- R 1A represents a hydroxyl-protecting group or R 1 described above, X 1 , X 2 , X 3 , X 4 , Y, Z and L represent the same as above, and W 1 represents a halogen atom or A hydroxyl group, and W 2 represents a group derivable to -LW 1 )
- the solvent is not particularly limited, but for example, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, etc. alone or in combination Can be used.
- a base For example, a pyridine, a triethyleneamine etc. can be used.
- limiting in particular as a metal catalyst A palladium catalyst, a nickel catalyst, a copper oxide, a copper salt, etc. can be used.
- —W 2 represents a group that can be converted to —LW 1 (eg, —CH 3 , —CH ⁇ CH 2 , —CHO, —CN, —CO 2 Me, etc.), and —W 2 to —L
- the conversion to -W 1 can be performed by a known method.
- the derivative (IX) in which Y in the general formula (VI) is an oxygen atom can be produced by the following reaction route.
- R 1A represents a hydroxyl-protecting group or the above-mentioned R 1 , X 1 , X 3 , X 4 , X 4 , Z and W 2 are the same as described above, W 3 represents a halogen atom, Indicates a leaving group such as a methanesulfonyl group or a trifluoromethanesulfonyl group.
- a diaryl ether can be produced from a phenol derivative represented by general formula (VII) or general formula (XI) and an aryl derivative represented by general formula (VIII) or general formula (X) having a leaving group.
- the base is not particularly limited, but for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali hydroxide metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide, lithium carbonate Alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, t-butoxy sodium, t-butoxy potassium, lithium diisopropyl Amide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, n-butyllithium, s-butyllithium, t-butyllithium, etc.
- alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
- a metal catalyst preferably 0 to 100 ° C. for 1 minute to 5 days, preferably 1 hour to 3 days.
- the reaction is carried out at ⁇ 80 to 150 ° C., preferably 0 to 100 ° C. for 1 minute to 5 days, preferably 1 hour to 3 days to obtain the target derivative of the general formula (IX). .
- the derivative (IX ′) in which Y in the general formula (VI) is a single bond can be produced by the following reaction route by a condensation reaction generally known as the Suzuki reaction.
- R 1A represents a hydroxyl-protecting group or R 1 described above, and X 1 , X 2 , X 3 , X 4 , W 1 , W 2 , W 3 and Z are the same as described above.
- the derivative represented by the general formula (VII) was introduced into a derivative (X) into which a leaving group was introduced by a commonly used method (Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc.).
- a derivative of the general formula (IX ′) which is the target product can be obtained.
- the solvent is not particularly limited, but for example, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, etc. alone or in combination Can be used.
- the palladium catalyst is not particularly limited, but [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), bis (triphenylphosphine) palladium (II) diacetate, bis (triphenylphosphine) dichloro Palladium (II), palladium (II) diacetate, tetrakis (triphenylphosphine) palladium (0), etc. can be used.
- a preferable rate is achieved by using a base.
- Various inorganic or organic bases can be used as the base.
- the reaction is carried out at ⁇ 80 to 150 ° C., preferably 0 to 100 ° C. for 1 minute to 5 days, preferably 1 hour to 3 days to obtain the
- the derivative represented by the general formula (VII) can be produced by various methods, and is not particularly limited.
- the derivative can be produced according to the following reaction step.
- R 1A represents a protecting group or the above R 1 , X 1 , X 2 , X 3 , X 4 represent the same as above, W 4 represents a hydroxyl protecting group, and W 5 represents a halogen atom. Indicates an atom or a leaving residue.
- the introduction of the protecting group W 5 to the 4-hydroxybenzoic acid derivative (XII) was made with reference to a method generally used as a protecting condition for the protecting group (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.). Can be done.
- the induction from the carboxylic acid compound (XIII) obtained by the above method to the hexafluorocarbinol compound (XV) can be converted with reference to a known document (Tetrahedron 61 (2005) 1813-1819).
- the carboxylic acid compound (XIII) is converted into an acid halide, an acid anhydride, an ester or an amide (XIV) with reference to a generally used method (Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc.) (Trifluoromethyl) trimethylsilane and tetramethylammonium fluoride can be used to derive the hexafluorocarbinol compound (XV).
- (trifluoromethyl) trimethylsilane is used as a trifluoromethyl source, but is not limited thereto.
- Triethyl (trifluoromethyl) silane, triisopropyl (trifluoromethyl) silane, methyldiphenyl ( Trifluoromethyl) silane, dimethyl (diphenyl) trifluoromethylsilane, or the like may be used.
- perfluoroalkyl silanes such as (pentafluoroethyl) trimethylsilane and (heptafluoropropyl) trimethylsilane can be used for perfluoroalkylation.
- Tetramethylammonium fluoride is used as the fluorine compound, but is not limited thereto, and tetraalkylammonium salts such as tetraethylammonium fluoride and tetrabutylammonium fluoride, lithium fluoride, sodium fluoride, Metal salts such as potassium fluoride and cesium fluoride may be used.
- tetraalkylammonium salts such as tetraethylammonium fluoride and tetrabutylammonium fluoride, lithium fluoride, sodium fluoride, Metal salts such as potassium fluoride and cesium fluoride may be used.
- tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, tetramethylurea, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, etc. are used alone or in combination. be able to.
- the target product (XVI) can be produced by reacting the resulting hexafluorocarbinol compound (XV) with a halide of R 1A in a solvent in the presence or absence of a base.
- the solvent is not particularly limited, but for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, tetramethylurea, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water and the like alone Or they can be used in combination.
- R 1A halide may also be used as a solvent.
- the base is not particularly limited, but for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali hydroxide metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide, lithium carbonate Alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, t-butoxy sodium, t-butoxy potassium, lithium diisopropyl Amides, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, n-butyllithium, s-butyllithium, t-butyllithium, etc. It can be used machine metals.
- alkali metal hydrides such as lithium hydride, sodium
- R 1A can also be introduced as a protecting group into the hexafluorocarbinol compound (XV). It can be carried out with reference to a method generally used as a protecting condition for the protecting group (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
- the deprotection of the protecting group W 5 of the compound (XVI) obtained by the above method is not particularly limited, but a method generally used as deprotection conditions for the protecting group (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
- the derivative represented by the general formula (VII) can be produced using the following method.
- Compound (XVIII) can be synthesized by reacting aniline derivative (XVII) with hexafluoroacetone in a solvent or without solvent in the presence or absence of an acid.
- the solvent is not particularly limited, and for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, tetramethylurea, dimethyl sulfoxide, water and the like can be used alone or in combination.
- the acid is not particularly limited, but p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, formic acid, sulfuric acid, trifluoroacetic acid and the like can be used, but not limited thereto.
- the desired product can be obtained by reacting at 0 to 250 ° C., preferably 100 to 200 ° C. for 1 minute to 5 days, preferably 1 hour to 3 days.
- the method for converting the amino group of the compound (XVIII) into a hydroxyl group can be performed with reference to a commonly used method (Comprehensive® Organics Transformations Second Edition, John John Wiley & Sons, Inc.). That is, a diazonium salt obtained by diazotizing compound (XVIII) can be thermally decomposed in an acidic aqueous solution to be derived into a phenol derivative (XIX).
- R 1A can be introduced into the phenol derivative (XIX) as a protecting group. It can be carried out with reference to a method generally used as a protecting condition for the protecting group (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
- the 4-hydroxyphenylhexafluoropropyl derivative represented by the general formula (XXII) can be produced using a known method (International Publication WO2006 / 037480 Pamphlet, US Patent Publication No. 3396159).
- R 1A represents a protecting group or R 1 described above
- R 5 , X 1 , X 3 and X 4 represent the same as above
- W 6 represents halogen.
- tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, methanol, ethanol, isopropanol, water, etc. can be used alone or in combination.
- a halide agent or a base may be used as a solvent.
- the base is not particularly limited, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, lithium carbonate, Alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, t-butoxy sodium and t-butoxy potassium, lithium diisopropylamide Sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, n-butyllithium, s-butyllithium, t-butyllithium, etc.
- alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
- Metals pyridine, an organic base compound such as triethylamine can be used.
- the halogenating agent is not particularly limited, but for example, chlorine, bromine, iodine, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, N-chlorosuccinimide, N-bromosuccinimide, N-iodo Succinimide, carbon tetrabromide and the like can be used.
- halides such as potassium bromide, potassium iodide, sodium bromide and sodium iodide are oxidized with oxidizing agents such as aqueous hydrogen peroxide and aqueous sodium hypochlorite to generate halogenating agents in the system. You can also react. The reaction is carried out at ⁇ 80 to 150 ° C., preferably 0 to 100 ° C. for 1 minute to 5 days, preferably 1 hour to 3 days to obtain the target derivative of the general formula (XXII). .
- the derivative represented by the general formula (XXII) is obtained.
- the solvent is not particularly limited.
- tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, methanol, ethanol, isopropanol, water, etc. can be used alone or in combination.
- the base is not particularly limited, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, lithium carbonate, Alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, t-butoxy sodium and t-butoxy potassium, lithium diisopropylamide Sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, n-butyllithium, s-butyllithium, t-butyllithium, etc.
- alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
- Metals tetraethyl ammonium fluoride, tetrabutyl ammonium fluoride, lithium fluoride, sodium fluoride, potassium fluoride, can be used a fluoride salt such as cesium fluoride.
- the catalyst is not particularly limited.
- No particular restriction on the organic metal compound but can be used organic boron compound having R 5, organozinc compound, an organotin compound or the like.
- reaction can also be made to react after adding metal halides, such as copper bromide (I) and copper iodide (I), and performing a metal exchange reaction.
- the reaction is carried out at ⁇ 80 to 150 ° C., preferably 0 to 100 ° C. for 1 minute to 5 days, preferably 1 hour to 3 days to obtain the target derivative of the general formula (XX). .
- the carbinol compound represented by the general formula (I) of the present invention can be obtained by the above-described method, but may be further purified by a usual purification means such as a recrystallization method or column chromatography, if necessary. it can. If necessary, the desired salt or solvate can be obtained by a conventional method.
- the carbinol compound represented by the general formula (I) thus obtained, a salt thereof or a solvate thereof (hereinafter sometimes referred to as “compound represented by the general formula (I)”) is: As shown in the following test examples, it exhibits excellent LXR ⁇ agonist activity, diseases caused by abnormal cholesterol metabolism in animals including humans, such as arteriosclerosis such as atherosclerosis and arteriosclerosis caused by diabetes, lipid abnormalities Useful as an active ingredient in prophylactic and / or therapeutic agents for inflammation, hypercholesterolemia, lipid-related diseases, inflammatory diseases caused by inflammatory cytokines, skin diseases such as allergic skin diseases, diabetes or Alzheimer's disease It is.
- arteriosclerosis such as atherosclerosis and arteriosclerosis caused by diabetes
- lipid abnormalities Useful as an active ingredient in prophylactic and / or therapeutic agents for inflammation, hypercholesterolemia, lipid-related diseases, inflammatory diseases caused by inflammatory cytokines, skin diseases such as allergic skin diseases, diabetes or Alzheimer's disease It is.
- the pharmaceutical composition of the present invention contains a carbinol compound represented by the general formula (I), a salt thereof or a solvate thereof, and may be used alone, but is usually pharmaceutically acceptable. Used in combination with carriers, additives and the like.
- the administration form of the pharmaceutical composition is not particularly limited and can be appropriately selected depending on the purpose of treatment. For example, any of oral preparations, injections, suppositories, ointments, inhalants, eye drops, nasal drops, patches and the like may be used. Pharmaceutical compositions suitable for these dosage forms can be produced by known formulation methods.
- an excipient is added to the carbinol compound represented by the general formula (I), and further a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, and a corrigent as necessary.
- a binder e.g., a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, and a corrigent.
- binder examples include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone.
- disintegrant examples include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
- lubricant examples include purified talc, stearate, borax, and polyethylene glycol.
- corrigent examples include sucrose, orange peel, citric acid, and tartaric acid.
- oral liquids, syrups and elixirs are added by conventional methods by adding a flavoring agent, buffering agent, stabilizer, flavoring agent, etc. to the carbinol compound represented by the general formula (I).
- Etc. can be manufactured.
- the corrigent those mentioned above may be used.
- the buffer include sodium citrate
- examples of the stabilizer include tragacanth, gum arabic, and gelatin.
- a pH regulator, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. are added to the carbinol compound represented by the general formula (I).
- Muscle and intravenous injections can be manufactured.
- the pH adjusting agent and buffer include sodium citrate, sodium acetate, sodium phosphate and the like.
- the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
- local anesthetics include procaine hydrochloride and lidocaine hydrochloride.
- isotonic agents include sodium chloride and glucose.
- a known suppository carrier for the carbinol compound represented by the general formula (I) for example, polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride, etc. It can be produced by a conventional method after adding a surfactant such as a trademark.
- bases, stabilizers, wetting agents, preservatives, etc. that are usually used in the carbinol compound represented by the general formula (I) are blended as necessary, and mixed by a conventional method.
- the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like.
- the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate and the like.
- the carbinol compound represented by the general formula (I) can be converted into an inhalant, eye drop, or nasal drop by a conventional method.
- the dose of the carbinol compound represented by the general formula (I) varies depending on the age, body weight, symptom, dosage form, number of administrations, etc., but usually as a carbinol compound represented by the general formula (I) for adults It is preferable to administer 1 to 1000 mg per day orally or parenterally in 1 or several divided doses.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (benzo [d] [1,3] Dioxol-5-yl) -5-ethylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (2,3-dihydrobenzo [b] The reaction and treatment were carried out in the same manner using [1,4] dioxin-6-yl) -5-methylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (2,3-dihydrobenzo [b] The reaction and treatment were carried out in the same manner using [1,4] dioxin-6-yl) -5-ethylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 in place of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (2,3-dihydrobenzofuran-5- Yl) -5-methylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5-methyl-5- (quinoxalin-6-yl) ) The same reaction and treatment was performed using imidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 5- (4-methoxyphenyl) -5-methyl instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione
- the same reaction and treatment were conducted using imidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 5- (2-methoxyphenyl) -5-methyl instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione
- the same reaction and treatment were conducted using imidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (4- (1-methylethoxy) phenyl ) -5-Methylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 1 5- (4-butoxyphenyl) -5-methyl instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione
- the same reaction and treatment were conducted using imidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5-methyl-5- (4- (4- (4- Methylbenzyloxy) phenyl) imidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 1 5- (6-methoxypyridin-3-yl) instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione
- the reaction and treatment were conducted in a similar manner using -5-methylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- the obtained crude product was added to a solution of ethanol (10 mL) under ice cooling, 4N aqueous hydrochloric acid (4.0 mL) was added, and the mixture was stirred at 50 ° C. overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. Then, 4N sodium hydroxide aqueous solution was added and extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and concentrated under reduced pressure. Subsequently, the obtained crude product was dissolved in thionyl chloride (3.0 mL) and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (6-ethoxypyridin-3-yl) The reaction and treatment were conducted in a similar manner using -5-methylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- N-methyl-6-propoxynicotinamide was reacted and treated in the same manner as in Example 13-a) to obtain N-methoxy-N-methyl-6-propoxynicotinamide as white crystals.
- Example 1 in place of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5-methyl-5- (6-propoxypyridine- The reaction and treatment were conducted in a similar manner using 3-yl) imidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (3,4-dimethoxyphenyl) -5 The reaction and treatment were conducted in a similar manner using -methylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 in place of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5-methyl-5-p-tolylimidazolidine- The reaction and treatment were conducted in a similar manner using 2,4-dione to obtain the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5-methyl-5- (4-nitrophenyl) The same reaction and treatment were conducted using imidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (3,4-dichlorophenyl) -5- The same reaction and treatment were carried out using methylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5-methyl-5- (6- (methylthio) The same reaction and treatment were carried out using pyridin-3-yl) imidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (furan-2-yl) -5- The same reaction and treatment were carried out using methylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 1,5,5-trimethylimidazolidine-2, The reaction and treatment were conducted in a similar manner using 4-dione to obtain the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 1,3-diazaspiro [4.4] nonane-2, The reaction and treatment were conducted in a similar manner using 4-dione to obtain the title compound as a colorless oil.
- Example 27 3- (1- (3- (4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenoxy) phenyl) ethyl)- Preparation of 5- (4- (1-methylethoxy) phenyl) -5-methylimidazolidine-2,4-dione: a) Preparation of 1- (3- (4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylphenoxy) phenyl) ethanol:
- Example 30 5- (Benzo [d] [1,3] dioxol-5-yl) -3- (3- (4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropane) Preparation of -2-yl) -2-propylphenoxy) phenethyl) -5-methylimidazolidine-2,4-dione: a) Preparation of 4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propyl-1- (3-vinylphenoxy) benzene:
- Example 30d (4- (4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylphenoxy) phenyl) methanol as in Example 30d)
- the title compound was obtained as a colorless oil.
- Example 34c instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (benzo [d] [1,3 ] Dioxol-5-yl) -5-ethylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 34c instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (2,3-dihydrobenzo [b ] [1,4] dioxin-6-yl) -5-ethylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 34c instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (4- (1-methylethoxy) (Phenyl) -5-methylimidazolidine-2,4-dione was used for the same reaction and treatment to obtain the title compound as a colorless oil.
- Example 38 3- (4- (4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenoxy) phenethyl) -5- (4- Preparation of (1-methylethoxy) phenyl) -5-methylimidazolidine-2,4-dione: a) Preparation of 4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propyl-1- (4-vinylphenoxy) benzene:
- Example 9 Performed with 1- (4- (2-bromoethyl) phenoxy) -4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylbenzene The same operation as in Example 9 was performed to give the title compound as a colorless oil.
- Example 38d 5- (2,3-dihydrobenzo [b] [1,4 instead of 5- (4- (1-methylethoxy) phenyl) -5-methylimidazolidine-2,4-dione ] Dioxin-6-yl) -5-ethylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 40 5- (Benzo [d] [1,3] dioxol-5-yl) -3-((4- (4- (1,1,1,3,3,3-hexafluoro-2-hydroxy Propan-2-yl) -2-propylphenoxy) pyridin-2-yl) methyl) -5-methylimidazolidine-2,4-dione: a) Preparation of 2-chloro-4- (4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylphenoxy) pyridine:
- Acetic anhydride was added to the obtained residue and heated at an external temperature of 140 ° C. After completion of the reaction, methanol (4 mL) was added at room temperature, followed by neutralization with a saturated aqueous sodium hydrogen carbonate solution. After extraction with ethyl acetate, the mixture was concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate) to give the title compound (490 mg, yield 56%) as a colorless oil.
- Acetic acid (4- (4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylphenoxy) pyridin-2-yl) methyl (221 mg, 446 ⁇ mol) in methanol (3 mL) was added potassium carbonate (123 mg) at room temperature and stirred. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was neutralized with water and 2 mol / L hydrochloric acid at room temperature, extracted with ethyl acetate, and concentrated under reduced pressure.
- Example 56 3- (1- (4- (4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenoxy) pyridin-2-yl ) Ethyl) -5- (4- (1-methylethoxy) phenyl) -5-methylimidazolidine-2,4-dione: a) Preparation of 4- (4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylphenoxy) picolinaldehyde:
- Example 27b 1- (4- (4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylphenoxy) pyridin-2-yl) ethanol
- Example 27b The same operation as in Example 27b) was performed to give the title compound as a colorless oil.
- Example 56c 5- (2,3-dihydrobenzofuran-5-yl) -5 instead of 5- (4- (1-methylethoxy) phenyl) -5-methylimidazolidine-2,4-dione
- the same reaction was carried out using -methylimidazolidine-2,4-dione, and the same reaction and treatment were performed to obtain the title compound as a colorless oil.
- Example 56c 5- (6-methoxypyridin-3-yl) -5-methyl instead of 5- (4- (1-methylethoxy) phenyl) -5-methylimidazolidine-2,4-dione
- the same reaction was carried out using imidazolidine-2,4-dione, and the same reaction and treatment were carried out to obtain the title compound as a colorless oil.
- the title compound was obtained as a colorless oil.
- Methyl 2- (4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylphenoxy) -5-nitroisonicotinate (1.80 g , 3.41 mmol) in methanol (20 mL) was added 20 wt% palladium on carbon (300 mg), and the mixture was stirred at room temperature in a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered using celite, and the filtrate was concentrated under reduced pressure.
- Triphenylphosphine (50 mg) and carbon tetrabromide (67 mg) were added to a solution of the obtained residue in methylene chloride (1 mL) at 0 ° C. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate) to give the title compound (54 g, yield 99%) as a colorless oil.
- Example 1 with 4- (bromomethyl) -2- (4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylphenoxy) pyridine The title compound was obtained as a colorless oil.
- Example 64f 5- (2,3-dihydrobenzofuran-5 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione -Ill) -5-Methylimidazolidine-2,4-dione was used for the same reaction and treatment to obtain the title compound as a colorless oil.
- Example 64f 5- (3,4-dichlorophenyl) -5 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione
- the reaction and treatment were conducted in a similar manner using -methylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 64f 5- (furan-2-yl) -5 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione
- the reaction and treatment were conducted in a similar manner using -methylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 64f 1,5,5-trimethylimidazolidine-2 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione
- the title compound was obtained as a colorless oil by a similar reaction and treatment with 1,4-dione.
- Example 64f 1,3-diazaspiro [4.4] nonane-2 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione
- the title compound was obtained as a colorless oil by a similar reaction and treatment with 1,4-dione.
- Example 64c Performed with 6- (4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylphenoxy) -2-methyl-3-nitropyridine The same operation as in Example 64c) was performed to give the title compound as a colorless oil.
- Example 64d Performed with 6- (4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylphenoxy) -3-iodo-2-methylpyridine The same operation as in Example 64d) was performed to give the title compound as a colorless oil.
- the title compound was obtained as a colorless oil.
- Example 76g 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione instead of 5- (benzo [d] [1,3 ] Dioxol-5-yl) -5-ethylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 76g instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5-methyl-5- (4- (4 -Methylbenzyloxy) phenyl) imidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 76g 5- (3,4-dichlorophenyl) -5 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione
- the reaction and treatment were conducted in a similar manner using -methylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 76g instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 1,5,5-trimethylimidazolidine-2
- the title compound was obtained as a colorless oil by a similar reaction and treatment with 1,4-dione.
- Example 76g 1,3-diazaspiro [4.4] nonane-2 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione
- the title compound was obtained as a colorless oil by a similar reaction and treatment with 1,4-dione.
- Example 89e 5- (4- (1-methylethoxy) phenyl) -5 instead of 5- (2,3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2,4-dione
- the reaction and treatment were conducted in a similar manner using -methylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- Example 89e 5- (6-methoxypyridin-3-yl) -5- in place of 5- (2,3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2,4-dione
- the same reaction and treatment were carried out using methylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- potassium phosphate 401 mg
- 3-vinylphenylboronic acid 88 mg
- tetrakistriphenylphosphine palladium complex 57 mg
- the reaction mixture was neutralized with water and 2 mol / L hydrochloric acid at room temperature, extracted with ethyl acetate, and concentrated under reduced pressure.
- Example 30c with 2- (4 ′-(1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2′-propylbiphenyl-3-yl) oxirane ) To give the title compound as a colorless oil.
- Example 30d with 2- (4 ′-(1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2′-propylbiphenyl-3-yl) ethanol ) To give the title compound as a colorless oil.
- Example 96c instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (benzo [d] [1,3 ] Dioxol-5-yl) -5-ethylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 96c instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (2,3-dihydrobenzo [b ] [1,4] dioxin-6-yl) -5-ethylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 96c instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (4- (1-methylethoxy) (Phenyl) -5-methylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 100 5- (Benzo [d] [1,3] dioxol-5-yl) -3- (4- (4 '-(1,1,1,3,3,3-hexafluoro-2-hydroxy) Propan-2-yl) -2'-propylbiphenyl-3-yloxy) butyl) -5-methylimidazolidine-2,4-dione: a) Preparation of 3 '-(4-bromobutoxy) -4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylbiphenyl:
- Example 100b instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (benzo [d] [1,3 ] Dioxol-5-yl) -5-ethylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 100b instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (2,3-dihydrobenzo [b ] [1,4] dioxin-6-yl) -5-ethylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 100b 5- (4- (1-methylethoxy) instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione (Phenyl) -5-methylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 104 5- (Benzo [d] [1,3] dioxol-5-yl) -3- (5- (4 '-(1,1,1,3,3,3-hexafluoro-2-hydroxy) Propan-2-yl) -2'-propylbiphenyl-3-yloxy) pentyl) -5-methylimidazolidine-2,4-dione: a) Preparation of 3 '-(5-bromopentyloxy) -4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylbiphenyl :
- Example 104b instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (benzo [d] [1,3 ] Dioxol-5-yl) -5-ethylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 104b instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (2,3-dihydrobenzo [b ] [1,4] dioxin-6-yl) -5-ethylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 104b 5- (4- (1-methylethoxy) instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione (Phenyl) -5-methylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 108 5- (Benzo [d] [1,3] dioxol-5-yl) -3- (3- (4 '-(1,1,1,3,3,3-hexafluoro-2-hydroxy) Propan-2-yl) -2'-propylbiphenyl-4-yloxy) propyl) -5-methylimidazolidine-2,4-dione: a) Preparation of 4 '-(1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2'-propylbiphenyl-4-ol:
- Example 108c instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (benzo [d] [1,3 ] Dioxol-5-yl) -5-ethylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 108c instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (4- (1-methylethoxy) (Phenyl) -5-methylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (4- (1- (1-methyl Ethyl)) phenyl) -5-methylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (4- (1- (1,1 -Dimethylethyl)) phenyl) -5-methylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (2-naphthyl) -5-methylimidazole The same reaction and treatment were performed using lysine-2,4-dione to obtain the title compound as a colorless oil.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- [4- (1-methylethoxy)- The reaction and treatment were conducted in a similar manner using 3-fluorophenyl] -5-methylimidazolidine-2,4-dione to obtain the title compound as a colorless oil.
- reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate) to give 1- [5- (1-methylethoxy) pyridin-2-yl] ethanone 20 mg (yield 94%) as a yellow oil. Obtained as a thing.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- [5- (1-methylethoxy) pyridine -2-yl] -5-methylimidazolidine-2,4-dione was similarly reacted and treated to give the title compound as a colorless oil.
- reaction solution was returned to room temperature, 3N hydrochloric acid was added, and saturated aqueous sodium hydrogen carbonate was added to adjust the pH to 8.
- Example 1 instead of 5- (benzo [d] [1,3] dioxol-5-yl) -5-methylimidazolidine-2,4-dione, 5- (2- (benzyloxy) pyridine-5 -Ill) -5-Methylimidazolidine-2,4-dione was used for the same reaction and treatment to obtain the title compound as a colorless oil.
- N-methoxy-N-methyl-2-difluoromethoxynicotinamide 500 mg, 2.76 mmol
- sodium chlorodifluoroacetate 505 mg, 3.31 mmol
- sodium hydroxide 132 mg, 3.31 mmol
- the reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid and water were added, and the mixture was extracted with ethyl acetate.
- reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by preparative thin layer chromatography (hexane / ethyl acetate), and 5- (4- (1,1,1,3 , 3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylphenoxy) -2-nitrobenzaldehyde (576 mg, yield 89%) was obtained as a yellow oil.
- Phenylcarbamic acid 5- (4- (1,1,1,3,3,3-hexafluoro-2- (methoxymethoxy) propan-2-yl) -2-propylphenoxy) -2-nitrobenzyl
- Acetic acid (2.0 mL) and water (400 ⁇ L) were added to 0.424 mmol), and then iron powder (451 mg, 8.28 mmol) was added, followed by stirring at room temperature for 1 hour.
- N, N-dimethylformamide 300 ⁇ L was added, diethylazodicarboxylic acid in tetrahydrofuran (29 ⁇ L, 0.0635 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
- a mixed aqueous solution (100 ⁇ L of water) of potassium halide (77 mg, 0.465 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 5 minutes. Thereafter, the mixture was stirred overnight at room temperature.
- To the reaction solution were added an aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and concentrated under reduced pressure.
Abstract
Description
さらに、LXRはNF-κBの抑制を介して、NO合成酵素、シクロオキシゲナーゼ-2(COX-2)、インターロイキン-6(IL-6)のような炎症性メディエーターの発現調節において重要な役割を果たしていることが報告されている(非特許文献7)。動脈硬化病変において炎症が非常に重要であることはよく知られており、病変部位におけるマクロファージ炎症性メディエーターの発現による動脈硬化の悪化をLXRリガンド又はLXRアゴニストにより抑えられることが期待される(非特許文献6、8)。
また、LXRリガンド又はLXRアゴニストは肝臓、脂肪組織において糖代謝を制御し、糖尿病を改善することが期待される(非特許文献6、8)。近年、LXRアゴニストを糖尿病モデル動物に投与することにより、インスリン感受性や血糖値が改善されることが報告されている(非特許文献13、14)。また、アルツハイマー病、炎症性疾患、皮膚疾患治療薬としての可能性も指摘されている(非特許文献15)。
[1]次の一般式(I)
<グループA>
ハロゲン原子、C1-8アルキル基、ハロC1-8アルキル基、C2-8アルケニル基、C2-8アルキニル基、C3-8シクロアルキル基、シアノ基、ニトロ基、ヒドロキシ基、アミノ基、モノC1-8アルキルアミノ基、ジC1-8アルキルアミノ基、C1-8アルコキシ基、C3-8シクロアルキルオキシ基、ハロC1-8アルコキシ基、C1-8アシル基、カルボキシル基、C1-8アシルオキシ基、C1-8アルコキシカルボニル基、カルバモイル基、C6-10アリール基、5-11員ヘテロアリール基、(1乃至3のC1-8アルキル基で置換されていもよい)C6-10アリールC1-8アルコキシ基、C1-8アルキルチオ基、C3-8シクロアルキルチオ基、C1-8アルキルスルフィニル基、C1-8アルキルスルホニル基、C6-10アリールチオ基、C6-10アリールスルフィニル基、C6-10アリールスルホニル基〕
で表されるカルビノール化合物、若しくはその塩又はそれらの溶媒和物、
[2] 前記[1]に記載のカルビノール誘導体、若しくはその塩又はそれらの溶媒和物を有効成分とする医薬、
[3]アテローム性動脈硬化症、糖尿病に起因する動脈硬化症、脂質異常症、高コレステロール血症、脂質関連疾患、炎症性サイトカインにより引き起こされる疾患である炎症性疾患、皮膚疾患、糖尿病又はアルツハイマー病の予防及び/又は治療剤である前記[2]に記載の医薬、
[4]前記[1]に記載のカルビノール誘導体、若しくはその塩又はそれらの溶媒和物を有効成分とするLXR調節剤、
[5]前記[1]に記載のカルビノール誘導体、若しくはその塩又はそれらの溶媒和物、及び製薬上許容される担体からなる医薬組成物、
[6]治療を必要としている患者に、前記[1]に記載のカルビノール誘導体、若しくはその塩又はそれらの溶媒和物の有効量を投与することを特徴とする、アテローム性動脈硬化症、糖尿病に起因する動脈硬化症、脂質異常症、高コレステロール血症、脂質関連疾患、炎症性サイトカインにより引き起こされる疾患である炎症性疾患、皮膚疾患、糖尿病又はアルツハイマー病の予防及び/又は治療方法、
[7]アテローム性動脈硬化症、糖尿病に起因する動脈硬化症、脂質異常症、高コレステロール血症、脂質関連疾患、炎症性サイトカインにより引き起こされる疾患である炎症性疾患、皮膚疾患、糖尿病又はアルツハイマー病の予防及び/又は治療のための製剤を製造するための、前記[1]に記載のカルビノール誘導体、若しくはその塩又はそれらの溶媒和物の使用、
に関する。
本発明において、ハロゲン原子、ハロC1-8アルキル基、ハロC1-8アルコキシ基における「ハロゲン」原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子等が挙げられる。
また、本発明の「C3-8シクロアルキルオキシ基」としては、具体的には、シクロプロピルオキシ基、シクロブチルオキシ基、シクロペンチルオキシ基、シクロへキシルオキシ基等が挙げられる。
本発明の「C3-8シクロアルキルチオ基としては、具体的にはシクロプロピルチオ基、シクロブチルチオ基、シクロペンチルチオ基、シクロヘキシルチオ基、シクロヘプチルチオ基、シクロオクチルチオ基等が挙げられる。
本発明において、「C1-8アルコキシC1-8アルキル基」とは、 前記C1-8アルコキシ基が前記C1-8アルキル基に結合した基を意味する。例えば、エトキシメチル基、エトキシエチル基、エトキシへキシル基、エトキシオクチル基、n-プロポキシメチル基、1-メチルエトキシメチル基、n-ブトキシエチル基、t-ブトキシメチル基、t-ブトキプロピル基、n-ペントキシエチル基、ネオペントキシメチル基、イソヘキシルオキシエチル基、3-メチルペントキシメチル基、2-メチルペントキシプロピル基、1-メチルペントキシプロピル基、2-エチルブトキシヘキシル基等が挙げられる。
また、これらのC6-10アリール鎖、5-11員ヘテロアリール鎖に置換する置換基としては、塩素原子、ヨウ素原子等のハロゲン原子、メチル基等のC1-8アルキル基、シアノ基、ヒドロキシ基、メトキシ基、エトキシ基等のC1-8アルコキシ基、ベンジルオキシ基等のC6-10アリールC1-8アルコキシ基、メトキシメチル基等のC1-8アルコキシC1-8アルキル基、等が好ましい。
本発明化合物に幾何異性体又は光学異性体が存在する場合は、それらの異性体も本発明の範囲に含まれる。幾何異性体体が存在する場合、(E)体が好ましい。
一般式(IV)で示される誘導体を、塩基の存在下、金属触媒存在下でボロン酸誘導体(V)と溶媒中で反応させることによって目的物である一般式(VI)の誘導体が得られる。溶媒としては、特に制限は無いが、例えばジクロロメタン、クロロホルム、四塩化炭素、テトラヒドロフラン、トルエン、ジオキサン、N,N-ジメチルホルムアミド、N-メチルピロリドン、ジメチルスルホキシド、アセトニトリル、プロピオニトリル等を単独又は組み合わせて使用することができる。塩基は特に制限は無いが、例えばピリジン、トリエチレンアミン等を使用することができる。金属触媒としては特に制限はないが、パラジウム触媒、ニッケル触媒、銅酸化物や銅塩等を使用することができる。好ましくは酢酸銅(II)を使用することができる。本反応において形成される水を除去するための試薬、例えばモレキュラーシーブが反応混合物中に存在していてもよい。反応条件は、-80~150℃、好ましくは0~100℃にて、1分~5日間、好ましくは1時間~3日間反応させることによって目的物である一般式(IV)の誘導体が得られる。-W2は、-L-W1に変換可能な基(例えば、-CH3、-CH=CH2、-CHO、-CN、-CO2Me等)を示すが、-W2から-L-W1への変換は公知の方法で行うことができる。
一般式(VII)又は一般式(XI)で示されるフェノール誘導体と脱離基を有する一般式(VIII)又は一般式(X)示されるアリール誘導体からジアリールエーテルを製造することができる。ジアリールエーテル類の調製方法は、文献(Tetrahedron 56 (2000) pp5045-5065)等に記載されている。(VII)と(VIII)、または(X)と(XI)とを塩基の存在下、金属触媒下で溶媒中で反応させることによって目的物である一般式(IX)の誘導体が得られる。溶媒としては、特に制限は無いが、例えばジクロロメタン、クロロホルム、四塩化炭素、テトラヒドロフラン、トルエン、ジオキサン、N,N-ジメチルホルムアミド、N-メチルピロリドン、ジメチルスルホキシド、アセトニトリル、プロピオニトリル等を単独又は組み合わせて使用することができる。塩基は、特に制限はないが、例えば水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、ナトリウムメトキシド、カリウムメトキシド、ナトリウムエトキシド、カリウムエトキシド、t-ブトキシナトリウム、t-ブトキシカリウム等のアルコールの金属塩類、リチウムジイソプロピルアミド、ナトリウムジイソプロピルアミド、カリウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、n-ブチルリチウム、s-ブチルリチウム、t-ブチルリチウム等を使用することができる。金属触媒としては特に制限はないが、パラジウム触媒、ニッケル触媒、銅酸化物や銅塩等を使用することができる。反応条件は、-80~150℃、好ましくは0~100℃にて、1分~5日間、好ましくは1時間~3日間反応させることによって目的物である一般式(IX)の誘導体が得られる。
一般式(VII)で示される誘導体に、一般に用いられる方法(Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc.)で脱離基を導入した誘導体(X)に導いた後、塩基の存在下、パラジウム触媒下でボロン酸誘導体(V)と溶媒中で反応させることによって目的物である一般式(IX’)の誘導体が得られる。溶媒としては、特に制限は無いが、例えばジクロロメタン、クロロホルム、四塩化炭素、テトラヒドロフラン、トルエン、ジオキサン、N,N-ジメチルホルムアミド、N-メチルピロリドン、ジメチルスルホキシド、アセトニトリル、プロピオニトリル等を単独又は組み合わせて使用することができる。パラジウム触媒としては特に制限はないが、[1,1‘-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)、ビス(トリフェニルホスフィン)パラジウム(II) ジアセテート、ビス(トリフェニルホスフィン)ジクロロパラジウム(II) 、パラジウム(II) ジアセテート、テトラキス(トリフェニルホスフィン)パラジウム(0)等等を使用することができる。本反応においては、塩基を用いることにより好ましい速度が達成される。塩基としては種々の無機又は有機塩基を用いることができるが、例えば、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、酢酸リチウム、酢酸ナトリウム、酢酸カリウム、酸化マグネシウム、酸化カルシウム、水酸化バリウム、リン酸三リチウム、リン酸三ナトリウム、リン酸三カリウム、フッ化セシウム、炭酸セシウム、酸化アルミニウム、トリメチルアミン、トリエチルアミン、トルブチルアミン、N,N,N’,N’-テトラメチルエチレンジアミン、ジイソプロピルエチルアミン、N-メチルピペリジン、2,2,6,6-テトラメチル-N-メチルピペリジン、ピリジン、4-ジメチルアミノピリジン、N-メチルモルホリン、ナトリウムエトキシド、カリウムtert-ブトキシド等が使用できる。反応条件は、-80~150℃、好ましくは0~100℃にて、1分~5日間、好ましくは1時間~3日間反応させることによって目的物である一般式(IX’)の誘導体が得られる。
4-ヒドロキシ安息香酸誘導体(XII)への保護基W5の導入は、当該保護基の保護条件として一般に用いられる方法(Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.)を参考にして行うことができる。
文献では、トリフルオロメチル源として、(トリフルオロメチル)トリメチルシランを用いているがこれに限定されるものでなく、トリエチル(トリフルオロメチル)シラン、トリイソプロピル(トリフルオロメチル)シラン、メチルジフェニル(トリフルオロメチル)シラン、ジメチル(ジフェニル)トリフルオロメチルシラン等を使用しても良い。また(ペンタフルオロエチル)トリメチルシランや(ヘプタフルオロプロピル)トリメチルシラン等のペルフルオロアルキルシラン類を用いれば、ペルフルオロアルキル化することも出来る。
フッ素化合物として、テトラメチルアンモニウムフルオリドを用いているが、これに限定されるものでなく、テトラエチルアンモニウムフルオリド、テトラブチルアンモニウムフルオリド等のテトラアルキルアンモニウム塩や、フッ化リチウム、フッ化ナトリウム、フッ化カリウム、フッ化セシウム等の金属塩を用いても良い。溶媒はジメトキシエタンの他に、テトラヒドロフラン、トルエン、ジオキサン、N,N-ジメチルホルムアミド、N-メチルピロリドン、テトラメチルウレア、ジメチルスルホキシド、アセトニトリル、プロピオニトリル、アセトン、メチルエチルケトン等を単独又は組み合わせて使用することができる。
アニリン誘導体(XVII)に、溶媒中又は無溶媒にて、酸の存在下又は非存在下、ヘキサフルオロアセトンと反応させることにより化合物(XVIII)を合成することができる。溶媒としては特に制限はないが、例えば、テトラヒドロフラン、トルエン、ジオキサン、N,N-ジメチルホルムアミド、N-メチルピロリドン、テトラメチルウレア、ジメチルスルホキシド、水等を単独又は組み合わせて使用することができる。酸は特に制限はないが、p-トルエンスルホン酸やベンゼンスルホン酸、メタンスルホン酸、トリフルオロメタンスルホン酸、酢酸、ギ酸、硫酸、トリフルオロ酢酸等を使用することが出来るがこの限りではない。反応条件は、0~250℃、好ましくは100~200℃にて、1分~5日間、好ましくは1時間~3日間反応させることによって目的物が得られる。
一般式(XXI)で示される誘導体を、塩基の存在下又は非存在下、ハロゲン化剤と溶媒中で反応させることによって目的物である一般式(XXII)の誘導体が得られる。溶媒としては、特に制限は無いが、例えばテトラヒドロフラン、トルエン、ジオキサン、N,N-ジメチルホルムアミド、N-メチルピロリドン、ジメチルスルホキシド、アセトニトリル、プロピオニトリル、アセトン、メチルエチルケトン、メタノール、エタノール、イソプロパノール、水等を単独又は組み合わせて使用することができる。また、ハロゲン化物剤や塩基を溶媒として用いても良い。塩基は特に制限は無いが、例えば水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、ナトリウムメトキシド、カリウムメトキシド、ナトリウムエトキシド、カリウムエトキシド、t-ブトキシナトリウム、t-ブトキシカリウム等のアルコールの金属塩類、リチウムジイソプロピルアミド、ナトリウムジイソプロピルアミド、カリウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、n-ブチルリチウム、s-ブチルリチウム、t-ブチルリチウム等の有機金属類、ピリジン、トリエチルアミン等の有機塩基化合物を使用することができる。ハロゲン化剤は特に制限はないが、例えば塩素、臭素、ヨウ素、テトラブチルアンモニウムクロリド、テトラブチルアンモニウムブロミド、テトラブチルアンモニウムヨージド、N-クロロこはく酸イミド、N-ブロモこはく酸イミド、N-ヨードこはく酸イミド、四臭化炭素等を使用することができる。また、臭化カリウム、ヨウ化カリウム、臭化ナトリウム、ヨウ化ナトリウム等のハロゲン化物塩を過酸化水素水や次亜塩素酸ナトリウム水溶液等の酸化剤で酸化して系内でハロゲン化剤を発生させ反応することもできる。反応条件は、-80~150℃、好ましくは0~100℃にて、1分~5日間、好ましくは1時間~3日間反応させることによって目的物である一般式(XXII)の誘導体が得られる。
a) 4-(2-プロペン-1-イル)オキシ安息香酸メチルの製造:
1H-NMR (CDCl3) δ:3.86 (3H, s), 4.55 (2H, ddd, J = 1.6, 1.6, 5.3 Hz), 5.29 (1H, ddd, J = 1.6, 3.0, 10.6 Hz), 5.41 (1H, ddd, J = 1.6, 3.0, 17.5 Hz), 6.02 (1H, ddd, J = 5.3, 10.6, 17.5 Hz), 6.90 (2H, d, J = 8.9 Hz), 7.97 (2H, d, J = 8.9 Hz).
b) 4-ヒドロキシ-3-(2-プロペン-1-イル)安息香酸メチルの製造:
1H-NMR (CDCl3) δ:3.44 (2H, d, J = 6.2 Hz), 3.89 (3H, s), 5.13 (1H, d, J = 3.6 Hz), 5.18 (1H, s), 5.93-6.17 (2H, m), 6.85 (1H, d, J = 8.9 Hz), 7.78-7.88 (2H, m).
c) 4-ヒドロキシ-3-プロピル安息香酸メチルの製造:
1H-NMR (CDCl3) δ:0.96 (3H, t, J = 7.6 Hz), 1.65 (2H, qt, J = 7.6, 7.6 Hz), 2.61 (2H, t, J = 7.6 Hz), 3.89 (3H, s), 4.16 (1H, brs), 6.82 (1H, d, J = 8.6 Hz), 7.78 (1H, dd, J = 2.0, 8.6 Hz) 7.83 (1H, d, J = 2.0 Hz).
d) 4-ベンジルオキシ-3-プロピル安息香酸メチルの製造:
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.6 Hz), 1.66 (2H, qt, J = 7.6, 7.6 Hz), 2.67 (2H, t, J = 7.6 Hz), 3.86 (3H, s), 5.11 (2H, s), 6.88 (1H, d, J = 9.2 Hz), 7.27-7.43 (5H, m) 7.83-7.88 (2H, m).
e) 4-ベンジルオキシ-3-プロピル安息香酸の製造:
1H-NMR (CD3OD) δ:0.94 (3H, t, J = 7.6 Hz), 1.65 (2H, qt, J = 7.6, 7.6 Hz), 2.68 (2H, t, J = 7.6 Hz), 5.09 (2H, s), 6.93 (1H, d, J = 9.2 Hz), 7.31-7.49 (7H, m).
f) 2-(4-ベンジルオキシ-3-プロピルフェニル)-1,1,1,3,3,3-ヘキサフルオロプロパン-2-オールの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.6 Hz), 1.65 (2H, qt, J = 7.6, 7.6 Hz), 2.68 (2H, t, J = 7.6 Hz), 3.39 (1H, s), 5.10 (2H, s), 6.93 (1H, dd, J = 2.3, 7.3 Hz), 7.30-7.51 (7H, m).
g) 4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェニル(ベンジル)エーテルの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.6 Hz), 1.65 (2H, qt, J = 7.6, 7.6 Hz), 2.68 (2H, t, J = 7.6 Hz), 3.54 (3H, s), 4.83 (2H, s), 5.10 (2H, s), 6.93 (1H, d, J = 8.9 Hz), 7.29-7.44 (7H, m).
h) 4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノールの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.6 Hz), 1.62 (2H, qt, J = 7.6, 7.6 Hz), 2.60 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.84 (2H, s), 5.77 (1H, brs), 6.81 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.6 Hz) 7.33 (1H, s).
a)2-(4-アミノ-3-プロピルフェニル)-1,1,1,3,3,3-ヘキサフルオロ-2-プロパノールの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.6 Hz), 1.65 (2H, qt, J = 7.6, 7.6 Hz), 2.68 (2H, t, J = 7.6 Hz), 3.39 (1H, s), 5.10 (2H, s), 6.93 (1H, dd, J = 2.3, 7.3 Hz), 7.30-7.51 (7H, m).
b) 2-(4-ヒドロキシ-3-プロピルフェニル)-1,1,1,3,3,3-ヘキサフルオロ-2-プロパノ-ルの製造:
1H-NMR (CDCl3) δ:0.97 (3H, t, J = 7.3 Hz), 1.57-1.72 (2H, m), 2.61 (2H, t, J = 7.5 Hz), 3.39 (1H, s), 4.97 (1H, s), 6.82 (1H, d, J = 8.4 Hz), 7.39-7.44 (2H, m).
c)2-プロピル-4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)フェニルアセテートの製造:
1H-NMR (CDCl3) δ:0.96 (3H, t, J = 7.6 Hz), 1.59 (2H, qt, J = 7.6, 7.6 Hz), 2.33 (3H, s), 2.53 (2H, t, J = 7.6 Hz), 4.75 (1H, brs), 7.10 (1H, d, J = 8.6 Hz), 7.55 (1H, d, J = 8.6 Hz), 7.59 (1H, s).
d)4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノールの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.6 Hz), 1.62 (2H, qt, J = 7.6, 7.6 Hz), 2.60 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.84 (2H, s), 5.77 (1H, brs), 6.81 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.6 Hz) 7.33 (1H, s).
a) (3-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)フェニル)メタノールの製造:
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.6 Hz), 1.62-1.71 (2H, m), 2.68 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.70-4.71 (2H, m), 4.86 (2H, s), 6.83 (1H, d, J = 8.9 Hz), 6.90-6.92 (1H, m), 7.03-7.15 (2H, m), 7.31-7.47 (4H, m)
b) 1-(3-(ブロモメチル)フェノキシ)-4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルベンゼンの製造:
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.59-1.70 (2H, m), 2.67 (2H, t, J = 7.3 Hz), 3.56 (3H, s), 4.47 (2H, s), 4.86 (2H, s), 6.84 (1H, d, J = 8.9 Hz), 6.90 (1H, ddd, J = 1.0, 2.0, 8.0 Hz), 7.05 (1H, dd, J = 1.0, 1.5 Hz), 7.16 (1H, ddd, J = 1.5, 2.0 Hz), 7.30-7.48 (3H, m).
製造例4 (3-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)フェニル)メタノールの製造:
a) 3-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ベンズアルデヒドの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.6 Hz), 1.63-1.69 (2H, m), 2.64 (2H, t, J = 7.3 Hz), 3.56 (3H, s), 4.87 (2H, s), 6.87 (1H, d, J = 8.9 Hz), 7.24-7.66 (5H, m), 7.89 (1H, d, J = 8.4 Hz), 9.99 (1H, s).
b) (3-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)フェニル)メタノールの製造:
1H-NMR (CDCl3) δ: 0.95 (3H, t, J = 7.6 Hz), 1.62-1.71 (2H, m), 2.68 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.70-4.71 (2H, m), 4.86 (2H, s), 6.83 (1H, d, J = 8.9 Hz), 6.90-6.92 (1H, m), 7.03-7.15 (2H, m), 7.31-7.47 (4H, m).
1-(ベンゾ[d][1,3]ジオキソール-5-イル)エタノン(446 mg, 2.72 mmol)をエタノール(200 mL)、水(200 mL)に溶解させ、シアン化ナトリウム(200 mg, 4.08 mmol)、炭酸アンモ二ウム(918 mg, 9.55 mmol)を加え、70℃にて終夜撹拌した。反応液をろ過し水、ヘキサン/酢酸エチルで洗浄し、無水硫酸ナトリウムを用いて乾燥し、5-(ベンゾ[d][1,3]ジオキソール-5-イル)-5-メチルイミダゾリジン-2,4-ジオン 326 mg (収率51.2%)を白色結晶として得た。
1H-NMR (CDCl3) δ:1.83 (3H, s), 5.99 (2H, s), 6.81 (1H, d, J = 8.3 Hz), 6.95 (1H, dd, J = 2.2, 8.3 Hz), 6.99 (1H, d, J = 2.2 Hz).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.58-1.68 (2H, m), 1.76 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 3.60 (1H, s), 4.64 (2H, s), 5.73 (2H, s), 6.73-7.56 (10H, m).
1-(ベンゾ[d][1,3]ジオキソール-5-イル)ニトリル(20 g、 136 mmol)のテトラヒドロフラン(680 mL)溶液に氷冷下、エチルマグネシウムブロマイド(204 mL)を加え、氷冷下2時間攪拌した。その後、室温にて終夜攪拌した。反応液に氷冷下水、1M硫酸を加え、酢酸エチルで抽出した後、有機層を飽和炭酸水素ナトリウム、飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣を薄層シリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、1-(ベンゾ[d][1,3]ジオキソール-5-イル)プロパン-1-オン 17.7 g(収率73 %)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.21 (3H, t, J = 7.3 Hz), 2.93 (2H, q, J = 7.3 Hz), 6.04 (2H, s), 6.85 (1H, d, J = 8.1 Hz), 7.45 (1H, d, J = 1.7 Hz), 7.57 (1H, dd, J = 1.7, 8.1 Hz).
1-(ベンゾ[d][1,3]ジオキソール-5-イル)プロパン-1-オンを用いて実施例1-a)と同様に反応・処理し、5-(ベンゾ[d][1,3]ジオキソール-5-イル)-5-エチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.69 (3H, s), 4.21 (4H, s), 6.81 (1H, d, J = 8.1 Hz), 6.93 (1H, dd, J = 2.2, 8.1 Hz), 6.95 (1H, d, J = 2.2 Hz).
1H-NMR (CDCl3) δ:0.80 (3H, t, J = 7.3 Hz), 0.92 (3H, t, J = 7.3 Hz), 1.57-1.66 (2H, m), 1.97-2.21 (2H, m), 2.63 (2H, t, J = 7.6 Hz), 3.84 (1H, s), 4.63 (2H, s), 5.95 (1H, s), 6.16 ‘1H, s), 6.73-7.55 (10H, m).
1,4-ベンゾジオキサン-6-イルメチルケトンを用いて実施例1-a)と同様に反応・処理し、5-(2,3-ジヒドロベンゾ[b][1,4]ジオキシン-6-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.73 (3H, s), 4.26-4.30 (2H, m), 4.43-4.47 (2H, m), 7.43 (1H, d, J = 2.7 Hz), 7.84 (1H, d, J= 2.7 Hz).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.56-1.70 (2H, m), 1.74 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 4.21-4.30 (4H, m), 4.63 (2H, s), 5.86 (1H,s), 6.75-6.96 (5H, m), 7.05-7.08 (1H, m), 7.14-7.29 (2H, m), 7.39-7.44 (1H, m), 7.54-7.56 (1H, m).
1-(2,3-ジヒドロベンゾ[b][1,4]ジオキシン-6-イル)ニトリルを用いて実施例2-a)と同様に反応・処理し、1-(2,3-ジヒドロベンゾ[b][1,4]ジオキシン-6-イル)プロパン-1-オンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.21 (3H, t, J = 7.3 Hz), 2.93 (2H, q, J = 7.3 Hz), 5.64 (4H, s), 6.45 (1H, d, J = 8.1 Hz), 7.05 (1H, d, J = 1.7 Hz), 7.17 (1H, dd, J = 1.7, 8.1 Hz).
11-(2,3-ジヒドロベンゾ[b][1,4]ジオキシン-6-イル)プロパン-1-オンを用いて実施例1-a)と同様に反応・処理し、5-(2,3-ジヒドロベンゾ[b][1,4]ジオキシン-6-イル)-5-エチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.69 (3H, s), 4.21 (4H, s), 6.81 (1H, d, J = 8.1 Hz), 6.93 (1H, dd, J = 2.2, 8.1 Hz), 6.95 (1H, d, J = 2.2 Hz).
1H-NMR (CDCl3) δ:0.80 (3H, t, J = 7.3 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.59-1.68 (2H, m), 1.98-2.22 (2H, m), 2.64 (2H, t, J = 7.6 Hz), 3.83 (1H, s), 4.23-4.24 (4H, m), 4.62 (2H, s), 5.71 (1H, s), 6.73-7.55 (10H, m).
2,3-ジヒドロベンゾフラン(10 g, 83.2 mmol)をジクロロメタン(400 mL)に溶解させ、-10℃にてアセチルクロライド(11.8 mL, 167 mmol)、塩化アルミニウム(33.3 g, 250 mmol)を順に加え、-10℃にて30分間撹拌した。反応液に5%塩酸水溶液を加え、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮し、1-(2,3-ジヒドロベンゾフラン-5-イル)エタノン 13.4 g(収率99%)を無色油状物として得た。
1H-NMR (CDCl3) δ:2.55 (3H, s), 3.25 (2H, t, J = 8.6 Hz), 4.67 (2H, t, J = 8.6 Hz), 6.80 (1H, d, J = 8.1 Hz), 7.80 (1H, dd, J = 1.9, 8.1 Hz), 7.85 (1H, d, J = 1.9 Hz).
1H-NMR (CDCl3) δ:2.62 (3H, s), 3.32 (2H, t, J = 8.6 Hz), 4.74 (2H, t, J = 8.6 Hz), 6.87 (1H, d, J = 8.8 Hz), 7.22 (1H, dd, J = 2.2, 8.8 Hz), 7.34 (1H, d, J = 2.2 Hz).
1H-NMR (CDCl3) δ: 0.93 (3H, t, J = 7.3 Hz), 1.58-1.69 (2H, m), 1.77 (3H, s), 2.65 (2H, t, J = 7.6 Hz), 3.12 (2H, t, J = 8.3 Hz), 3.81 (1H, s), 4.56 (2H, t, J = 8.3 Hz), 4.65 (2H, s), 5.83 (1H, s), 6.69-7.27 (8H, m), 7.39 (1H, d, J = 8.6 Hz), 7.55 (1H, s).
特開昭63-280080 に記載の方法に準じて5-メチル-5-(キノキサリン-6-イル)イミダゾリジン-2,4-ジオンを得た。
1H-NMR (CDCl3) δ:1.91 (3H, s), 8.07(1H, dd, J = 2.2, 8.8 Hz), 8.15 (1H, d, J = 8.8 Hz), 8.25 (1H, d, J = 2.2 Hz), 8.90 (1H, d, J = 2.0 Hz), 8.92 (1H, d, J = 2.0 Hz).
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.3 Hz), 1.43-1.53 (2H, m), 1.93 (3H, s), 2.55 (2H, t, J = 7.6 Hz), 4.67 (2H, s), 5.03 (1H, s), 6.67-7.30 (6H, m), 7.40-7.55 (2H, m), 7.90-8.30 (3H, m), 8.88-8.90 (1H, m).
1-(1-メトキシフェニル-4-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(4-メトキシフェニル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (DMSO) δ:0.80 (3H, t, J = 7.3 Hz), 1.78-2.07 (2H, m), 3.69 (3H, s), 6.95 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.4 Hz), 8.58 (1H, s), 10.71 (1H, s).
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.56-1.67 (2H, m), 1.78 (3H, s), 2.63 (2H, t, J = 7.6 Hz), 3.77 (3H, s), 3.78 (1H, s), 4.64 (2H, s), 6.74-7.56 (11H, m).
1-(1-メトキシフェニル-2-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(2-メトキシフェニル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.69 (3H, s), 4.21 (4H, s), 6.81 (1H, d, J = 8.1 Hz), 6.93 (1H, dd, J = 2.2, 8.1 Hz), 6.95 (1H, d, J = 2.2 Hz).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.57-1.71 (2H, m), 1.75 (3H, s), 2.65 (2H, t, J = 7.6 Hz), 3.70 (3H, s), 3.79 (1H, s), 4.71 (2H, s), 6.20 (1H, s), 6.79 (1H, d, J = 8.6 Hz), 6.81-7.57 (10H, m).
1-(4-ヒドロキシフェニル)エタノン(15.0 g、110 mmol)をアセトン(125 mL)に溶解させ、炭酸カリウム(30.4 g, 220 mmol)、ヨウ化1-メチルエチル(16.5 mL, 165 mmol)を順に加え、70℃にて8時間撹拌した。反応液をろ過し、アセトンで洗浄し減圧濃縮した。得られた残渣に水、酢酸エチルを加え、酢酸エチルで抽出し、有機層を1N-水酸化ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮し、1-[4-(1-メチルエトキシ)フェニル]エタノン 18.2 g(収率93%)を白色結晶として得た。
1H-NMR (CDCl3) δ:1.37 (6H, d, J = 5.9 Hz), 2.56 (3H, s), 4.65 (1H, quint, J = 5.9 Hz), 6.90 (2H, d, J = 8.9 Hz). 7.92 (2H, d, J = 8.9 Hz).
1-[4-(1-メチルエトキシ)フェニル]エタノンを用いて実施例1-a)と同様に反応・処理し、5-(4-(1-メチルエトキシ)フェニル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.28 (6H, d, J = 5.9 Hz), 1.72 (3H, s), 4.59 (1H, quint, J = 5.9 Hz), 6.89 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.31 (6H, d, J = 5.4 Hz), 1.56-1.68 (2H, m), 1.78 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 3.67 (1H, s), 4.52 (1H, q, J = 5.4 Hz), 4.64 (2H, s), 5.71 (1H, s), 6.74-7.40 (11H, m).
ヨウ化1-ブチルを用いて実施例9-a-1)と同様に反応・処理し、1-(4-ブトキシフェニル)エタノンを白色結晶として得た。
1H-NMR (CDCl3) δ:0.97 (3H, t, J = 7.3 Hz), 1.41-1.49 (2H, m), 1.70-1.81 (2H, m), 2.50 (3H, s), 3.97 (3H, s), 6.88 (2H, d, J = 8.9 Hz), 7.88 (2H, d, J = 8.9 Hz).
1-[4-(1-ブトキシ)フェニル]エタノンを用いて実施例1-a)と同様に反応・処理し、5-(4-ブトキシフェニル)- 5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (DMSO) δ: 0.92 (3H, t, J = 7.3 Hz), 1.35-1.73 (4H, m), 3.95 (2H, t, J = 7.3 Hz), 6.93 (2H, d, J = 8.9 Hz), 7.34 (2H, d, J = 8.9 Hz), 8.52 (1H, s), 10.69 (1H,s).
1H-NMR (CDCl3) δ: 0.89-0.99 (6H, m), 1.40-1.80 (6H, m), 1.77 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 3.74 (1H, s), 3.93 (2H, t, J = 6.5 Hz), 4.64 (2H, s), 5.80 (1H, s), 6.76 (1H, d, J = 8.6 Hz), 6.82-6.88 (3H, m), 6.93 (1H, dd, J = 1.0, 1.0 Hz), 7.04-7.08 (1H, m), 7.15-7.55 (5H, m).
臭化4-メチルベンジルを用いて実施例9-a-1)と同様に反応・処理し、表題化合物を白色結晶として得た。
1H-NMR (CDCl3) δ:1.37 (6H, d, J = 5.9 Hz), 2.56 (3H, s), 4.65 (1H, quint, J = 5.9 Hz), 6.90 (2H, d, J = 8.9 Hz). 7.92 (2H, d, J = 8.9 Hz).
1-[4-(1-(4-メチルフェニルメトキシ))フェニル]エタノンを用いて実施例1-a)と同様に反応・処理し、5-メチル-5-(4-(4-メチルベンジルオキシ)フェニル)イミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.28 (6H, d, J = 5.9 Hz), 1.72 (3H, s), 4.59 (1H, quint, J = 5.9 Hz), 6.89 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.56-1.70 (2H, m), 1.76 (3H, s), 2.34 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 3.70 (1H, s), 4.63 (2H, s), 4.99 (2H, s), 5.80 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 6.83-7.55 (14H, m).
1-(6-メトキシピリジン-3-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(6-メトキシピリジン-3-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.74 (3H, s), 3.90 (3H, s), 6.81 (1H, d, J = 8.6 Hz), 7.81 (1H, dd, J = 2.7, 8.6 Hz), 8.23 (1H, d, J = 2.7 Hz).
1H-NMR (CDCl3) δ:0.86 (3H, t, J = 7.3 Hz), 1.51-1.59 (2H, m), 1.76 (3H, s), 2.57 (2H, t, J = 7.6 Hz), 4.10 (3H, s), 4.64 (2H, s), 6.70-7.30 (6H, m), 7.40-7.56 (2H, m), 7.83-7.84 (1H, m), 8.10-8.20 (1H, m).
6-クロロ-N-メチルニコチン酸クロライド(7.39 g, 42.0 mmol)のテトラヒドロフラン(50 mL)溶液に氷冷下、メチルアミン(42 mL, 84.0 mmol)、トリエチルアミン(6.4 mL, 46.2 mmol)を加え、室温にて3時間攪拌した。反応終了後、減圧濃縮した。その後、ろ過しテトラヒドロフランで洗浄した。得られた残渣を再結晶(酢酸エチル/ヘキサン)し、6-クロロ-N-メチルニコチンアミド(6.52 g, 収率 91%)を白色結晶として得た。
1H-NMR (CDCl3) δ:3.04 (3H, d, J = 4.9 Hz), 6.39 (1H, brs), 7.41(1H, d, J = 8.6 Hz), 8.10 (1H, dd, J = 2.4, 8.6 Hz), 8.74 (1H, d, J = 2.4 Hz).
6-クロロ-N-メチルニコチンアミド(500 mg, 2.93 mmol)のエタノール(10 mL)溶液に氷冷下、水素化ナトリウム(純度50%)(176 mg, 7.33 mmol)を加え、8時間加熱還流した。反応終了後、減圧濃縮した。その後、ろ過し水、酢酸エチルで洗浄し、乾燥し、6-エトキシ-N-メチルニコチンアミド(556 mg, 収率 >100%)を白色結晶として得た。
1H-NMR (CDCl3) δ:1.41 (3H, t, J = 7.3 Hz), 3.02 (3H, d, J = 4.9 Hz), 4.40 (2H, q, J = 7.3 Hz), 6.01 (1H, brs), 6.75 (1H, d, J = 8.6 Hz), 7.99 (1H, dd, J = 2.4, 8.6 Hz), 8.53 (1H, d, J = 2.4 Hz).
6-エトキシ-N-メチルニコチンアミド (556 mg, 3.09 mmol)のエタノール(10 mL)溶液に氷冷下、4N 水酸化ナトリウム水溶液(4.0 mL)を加え、50℃にて終夜攪拌した。反応終了後、減圧濃縮した。その後、4N 塩酸水溶液を加え、クロロホルムで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、減圧濃縮した。得られた粗生成物をエタノール(10 mL)溶液に氷冷下、4N 塩酸水溶液(4.0 mL)を加え、50℃にて終夜攪拌した。反応終了後、減圧濃縮した。その後、4N水酸化ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、減圧濃縮した。
続いて得られた粗生成物を塩化チオニル(3.0 mL)に溶解させて、室温にて1時間攪拌した。反応終了後、反応液を減圧濃縮した。得られた残渣をジクロロメタン(3.0 mL)に溶解させ、氷冷下N,O-ジメチルヒドロキシアミン塩酸塩(643 mg, 6.60 mmol)、ジイソプロピルエチルアミン(223 μL, 1.28 mmol)を加えて、室温にて終夜攪拌した。反応終了後、反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、6-エトキシ-N-メトキシ-N-メチルニコチンアミド(493 mg, 2.35 mmol)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.41 (3H, t, J = 7.3 Hz), 3.38 (3H, s), 3.58 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 6.73 (1H, d, J = 8.6 Hz), 7.99 (1H, dd, J = 2.2, 8.6 Hz), 8.63 (1H, d, J = 2.2 Hz).
6-エトキシ-N-メトキシ-N-メチルニコチンアミドを用いて実施例2-a) と同様に反応・処理し、1-(6-エトキシピリジン-3-イル)エタノン表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ:1.42 (3H, t, J = 7.3 Hz), 2.57 (3H, s), 4.44 (2H, q, J = 7.3 Hz), 6.76 (1H, d, J = 8.6 Hz), 8.14 (1H, dd, J = 2.4, 8.6 Hz), 8.76 (1H, d, J = 2.4 Hz).
1-(6-エトキシピリジン-3-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(6-エトキシピリジン-3-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.28 (6H, d, J = 5.9 Hz), 1.72 (3H, s), 4.59 (1H, quint, J = 5.9 Hz), 6.89 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.19-1.61 (5H, m), 1.76 (3H, s), 2.59 (2H, t, J = 7.6 Hz), 4.35-4.50 (2H, m), 4.63 (2H, s), 6.70-7.57 (8H, m), 8.00-8.29 (2H, m).
6-クロロ-N-メチルニコチンアミドに実施例13-a)のエタノールの代わりに1-プロパノールを用いてと同様に反応・処理し、N-メチル-6-プロポキシニコチンアミドを無色油状物として得た。
1H-NMR (CDCl3) δ:1.03 (3H, t, J = 7.3 Hz), 1.81 (2H, tq, J = 7.0, 7.3 Hz), 3.02 (3H, d, J = 4.9 Hz), 4.29 (2H, t, J = 7.0 Hz), 6.05 (1H, brs), 6.76 (1H, d, J = 8.6 Hz), 7.99 (1H, dd, J = 2.4, 8.6 Hz), 8.53 (1H, d, J = 2.4 Hz).
N-メチル-6-プロポキシニコチンアミドを実施例13-a) と同様に反応・処理し、N-メトキシ-N-メチル-6-プロポキシニコチンアミドを白色結晶として得た。
1H-NMR (CDCl3) δ:1.03 (3H, t, J = 7.3 Hz), 1.82 (2H, tq, J = 6.8, 7.3 Hz), 3.37 (3H, s), 3.58 (3H, s), 4.30 (2H, t, J = 6.8 Hz), 6.74 (1H, d, J = 8.6 Hz), 7.99 (1H, dd, J = 1.9, 8.6 Hz), 8.63 (1H, d, J = 1.9 Hz).
N-メトキシ-N-メチル-6-プロポキシニコチンアミドを実施例2-a)と同様に反応・処理し、1-(6-プロポキシピリジン-3-イル)エタノンを黄色油状物として得た。
1H-NMR (CDCl3) δ:1.03 (3H, t, J = 7.3 Hz), 1.82 (2H, tq, J = 7.0, 7.3 Hz), 2.57 (3H, s), 4.33 (2H, t, J = 7.0 Hz), 6.78 (1H, d, J = 8.9 Hz), 8.14 (1H, dd, J = 2.2, 8.9 Hz), 8.76 (1H, d, J = 2.2 Hz).
1-(6-プロポキシピリジン-3-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-メチル-5-(6-プロポキシピリジン-3-イル)イミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.28 (6H, d, J = 5.9 Hz), 1.72 (3H, s), 4.59 (1H, quint, J = 5.9 Hz), 6.89 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz).
1H-NMR (CDCl3) δ:0.87 (3H, t, J = 7.3 Hz), 1.04 (3H, t, J = 7.6 Hz), 1.51-1.91 (4H, m), 1.75 (3H, s), 2.57 (2H, t, J = 7.6 Hz), 4.11-4.60 (6H, m), 6.70-7.49 (8H, m), 7.80-8.20 (2H, m).
1-[4-(1,2-ジメトキシ)フェニル]エタノンを用いて実施例1-a)と同様に反応・処理し、5-(3,4-ジメトキシフェニル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (DMSO) δ:1.62 (3H, s), 3.74 (3H, s), 3.76 (3H, s), 6.93-7.01 (3H, m), 8.58 (1H, s), 10.73 (1H, s).
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.56-1.70 (2H, m), 1.79 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 3.79 (3H, s), 3.84 (1H, s), 3.85 (3H, s), 4.65 (2H, s), 5.92 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 6.81-7.56 (9H, m).
1-[4-(1-メチル)フェニル]エタノンを用いて実施例1-a)と同様に反応・処理し、5-メチル-5-p-トリルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.28 (6H, d, J = 5.9 Hz), 1.72 (3H, s), 4.59 (1H, quint, J = 5.9 Hz), 6.89 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.59-1.70 (2H, m), 1.78 (3H, s), 2.33 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 3.62 (1H, s), 4.64 (2H, s), 5.73 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 6.83-6.88 (1H, m), 6.93-6.95 (1H, m), 7.04-7.35 (6H, m), 7.38-7.56 (2H, m).
1-[4-(1-ニトロ)フェニル]エタノンを用いて実施例1-a)と同様に反応・処理し、5-メチル-5-(4-ニトロフェニル)イミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.71 (3H, s), 7.78 (2H, d, J = 8.6 Hz), 8.27 (2H, d, J = 8.6 Hz), 8.82 (1H, s), 10.98 (1H, s).
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.55-1.69 (2H, m), 1.84 (3H, s), 2.62 (2H, t, J = 7.6 Hz), 3.85 (1H, s), 4.65 (2H, s), 6.48 (1H, s), 6.79 (1H, d, J = 8.3 Hz), 6.84-6.91 (1H, m), 7.02-7.06 (1H, m), 7.30-7.32 (2H, m), 7.40-7.44 (1H, m), 7.55-7.57 (1H, m), 7.68-7.72 (2H, m), 8.18-8.23 (2H, m).
1-[4-(3,4-ジクロロ)フェニル]エタノンを用いて実施例1-a)と同様に反応・処理し、5-(3,4-ジクロロフェニル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.28 (6H, d, J = 5.9 Hz), 1.72 (3H, s), 4.59 (1H, quint, J = 5.9 Hz), 6.89 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.59-1.70 (2H, m), 1.78 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 3.61 (1H, s), 4.64 (2H, s), 5.84 (1H, s), 6.79 (1H, d, J = 8.6 Hz), 6.84-7.58 (9H, m).
6-クロロニコチン酸メチル(100mg,0.583mmol)をN,N’-ジメチルホルムアミド(1。5mL)中、氷冷下ナトリウムチオメトキシド(41mg)を加えた後、室温で3時間攪拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、6-(メチルチオ)ニコチン酸メチル120mg(収率>100%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:2.61 (3H, s), 3.93 (3H, s), 7.23 (1H, d, J = 8.1 Hz), 8.05 (1H, dd, J = 1.6, 8.1 Hz), 9.02 (1H, d, J = 1.6 Hz).
6-チオメトキシニコチン酸エチル(120mg,0.583mmol)をメタノール(3.0mL)中、氷冷下水酸化ナトリウム水溶液(5mL)を加えた後、室温で1時間攪拌した。反応溶液を減圧濃縮した。4N 塩酸水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、6-(メチルチオ)ニコチン酸78mg(収率79%)を白色結晶として得た。
1H-NMR (CDCl3) δ:2.62 (3H, s), 7.27 (1H, d, J = 8.4 Hz), 8.09 (1H, dd, J = 1.6, 8.4 Hz), 9.09 (1H, d, J = 1.6 Hz).
6-(メチルチオ)ニコチン酸を実施例13-a)と 同様に反応・処理し、N-メトキシ-N-メチル-6-(メチルチオ)ニコチンアミドを白色結晶として得た。
1H-NMR (CDCl3) δ:2.60 (3H, s), 3.38 (3H, s), 3.57 (3H, s), 7.23 (1H, d, J = 8.6 Hz), 7.88 (1H, dd, J = 1.6, 8.6 Hz), 8.84 (1H, d, J = 1.6 Hz).
N-メトキシ-N-メチル-6-(メチルチオ)ニコチンアミドを用いて実施例13-a)と同様に反応・処理し、1-(6-(メチルチオ)ピリジン-3-イル)エタノンを白色結晶として得た。
1H-NMR (CDCl3) δ:2.59 (3H, s), 2.61 (3H, s), 7.25 (1H, d, J = 8.4 Hz), 8.02 (1H, dd, J = 2.4, 8.4 Hz), 8.98 (1H, d, J = 2.4 Hz).
1-(6-(メチルチオ)ピリジン-3-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-メチル-5-(6-(メチルチオ)ピリジン-3-イル)イミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.75 (3H, s), 2.53 (3H, s), 7.28 (1H, d, J = 8.6 Hz), 7.76 (1H, dd, J = 1.9, 8.6 Hz), 8.50 (1H, d, J = 1.9 Hz).
1H-NMR (CDCl3) δ:0.76 (3H, t, J = 7.3 Hz), 1.36-1.47 (2H, m), 1.70 (3H, s), 2.43-2.48 (2H, m), 2.49 (3H, s), 4.52-4.60 (2H, m), 5.52 (1H, brs), 6.43 (1H, s), 6.53 (1H, s), 6.73 (1H, d, J = 8.5 Hz), 6.85-6.94 (2H, m), 7.09 (1H, d, J = 8.5 Hz), 7.18-7.22 (1H, m), 7.37-7.40 (1H, m), 7.52 (1H, d, J = 1.5 Hz), 7.57 (1H, dd, J = 2.4, 8.5 Hz), 8.21 (1H, d, J = 1.7 Hz).
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.56-1.65 (2H, m), 1.88 (3H, s), 2.62-2.65 (2H, m), 2.81-2.83 (3H, m), 4.64-4.74 (2H, m), 5.74 (1H, brs), 6.36 (1H, d, J = 8.1 Hz), 6.51 (1H, dd, J = 7.4, 8.1 Hz), 6.73-6.78 (1H, m), 6.95 (1H, d, J = 8.3 Hz), 7.14 (1H, d, J = 7.3 Hz), 7.30-7.38 (2H, m), 7.57 (1H, s), 7.70 (1H, d, J = 8.3 Hz), 7.87-7.92 (1H, m), 8.71 (1H, d, J = 2.2, 10.1 Hz).
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.56-1.65 (2H, m), 1.85 (3H, s), 2.62 (2H, t, J = 7.8 Hz), 3.21 (3H, s), 4.31 (1H, brs), 4.66 (2H, s), 6.61 (1H, s), 6.75 (1H, d, J = 8.5 Hz), 6.87-6.92 (2H, m), 7.07 (1H, d, J = 7.8 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.44 (1H, dd, J = 2.0, 8.5 Hz), 7.58 (1H, s), 8.02 (1H, d, J = 8.3 Hz), 8.10 (1H, dd, J = 2.2, 8.3 Hz), 8.84 (1H, d, J = 2.0 Hz).
1-[フラン-2-イル]エタノンを用いて実施例1-a)と同様に反応・処理し、5-(フラン-2-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (DMSO) δ:1.62 (3H, s), 6.43 (1H, s), 7.63 (1H, s), 8.38 (1H, s), 10.78 (1H, s).
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.58-1.72 (2H, m), 1.77 (3H, s), 2.66 (2H, t, J = 7.3 Hz), 3.66 (1H, s), 4.70 (2H, s), 5.65 (1H, s), 6.30-6.35 (2H, m), 6.79 (1H, d, J = 1.5 Hz), 6.84-6.90 (1H, m), 6.98 (1H, dd, J = 2.0, 2.0 Hz), 7.07-7.56 (5H, m).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.34 (6H, s), 1.57-1.69 (2H, m), 2.65 (2H, t, J = 7.6 Hz), 2.87 (3H, s), 4.00 (1H, s), 4.63 (2H, s), 5.03 (1H, s), 6.80-7.57 (7H, m).
シクロペンタノンを用いて実施例1-a)と同様に反応・処理し、1,3-ジアザスピロ[4.4]ノナン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.78-2.09 (8H, m).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.57-2.20 (10H, m), 2.65 (2H, t, J = 7.6 Hz), 3.92 (1H, s), 4.64 (2H, s), 5.90 (1H, s), 6.81 (1H, d, J = 8.6 Hz), 6.84-6.95 (2H, m), 7.07-7.31 (2H, m), 7.43 (1H, dd, J = 1.5, 8.6 Hz), 7.56 (1H, d, J = 1.5 Hz).
a) 2-クロロ-5-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)ピリジンの製造:
1H-NMR (CDCl3) δ:3.57 (3H, s), 4.90 (2H, s), 7.46 (1H, d, J = 8.6 Hz), 7.93 (1H, dd, J = 2.9, 8.6 Hz), 8.67 (1H, d, J = 2.9 Hz).
b) 3-アリル-2-クロロ-5-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)ピリジンの製造:
1H-NMR (CDCl3) δ:3.54-3.57 (5H, m), 4.88 (2H, s), 5.12-5.25 (2H, m), 5.88-5.98 (1H, s), 7.81 (1H, d, J = 2.2 Hz), 8.52 (1H, d, J = 2.2 Hz).
c) (E)-3-(5-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-3-(プロパ-1-エニル)ピリジン-2-イルオキシ)安息香酸メチルの製造:
1H-NMR (CDCl3) δ:1.98 (3H, dd, J = 1.7, 6,6 Hz), 3.55 (3H, s), 3.92 (3H, s), 4.87 (2H, s), 6.46 (1H, qd, J = 6.6, 15.6 Hz), 6.71 (1H, dd, J = 1.7, 15.6 Hz), 7.36-7.39 (1H, m), 7.49-7.53 (1H, m), 7.83 (1H, t, J = 2.0 Hz), 7.92-7.95 (1H, m), 7.97 (1H, d, J = 2.2 Hz), 8.18 (1H, d, J = 2.2 Hz).
1H-NMR (CDCl3) δ:1.97 (3H, dd, J = 1.7, 6.6 Hz), 3.55 (3H, s), 4.68 (1H, s), 4.74 (2H, s), 4.87 (2H, s), 6.45 (1H, qd, J = 6.6, 15.3 Hz), 6.70 (1H, dd, J = 1.7, 15.3 Hz), 6.95-7.10 (2H, m), 7.19-7.30 (1H, m), 7.41-7.44 (1H, m), 7.95 (1H, s), 8.19 (1H, s).
e) (E)-3-(3-(5-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-3-(プロパ-1-エニル)ピリジン-2-イルオキシ)ベンジル)-5-(4-(1-メチルエトキシ)フェニル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 5.9 Hz), 1.77 (3H, s), 1.96 (3H, dd ,J = 1.4, 6.8 Hz), 4.25 (1H, s), 4.51 (1H, q, J = 5.9 Hz), 4.66 (2H, s), 5.91 (1H, s), 6.44 (1H, dd, J = 6.8, 15.9 Hz), 6.68 (1H, dd, J = 1.4, 15.9 Hz), 6.83 (2H, d, J = 8.9 Hz), 7.05-7.38 (6H, m), 8.02 (1H, d, J = 2.2 Hz), 8.23 (1H, d, J = 2.2 Hz).
1H-NMR (CDCl3) δ:0.99 (3H, t, J = 7.3 Hz), 1.31 (6H, d, J = 6.5 Hz), 1.64-1.78 (5H, m), 2.71 (2H, t ,J = 7.6 Hz), 4.51 (1H, q, J = 6.5 Hz), 4.65-4.66 (2H, m), 6.11 (1H, s), 6.81-6.87 (3H, m), 7.02-7.20 (3H, m), 7.26-7.37 (3H, m), 7.79 (1H, d, J = 2.2 Hz), 8.25 (1H, d, J = 2.2 Hz).
a) 1-(3-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)フェニル)エタノールの製造:
1H-NMR (CDCl3) δ: 0.95 (3H, t, J = 7.3 Hz), 1.50 (6H, d, J = 6.8 Hz), 1.59-1.71 (2H, m), 2.69 (2H, t, J = 7.6 Hz), 3.55 (3H, s), 4.85-4.90 (3H, m), 6.80-6.88 (2H, m), 7.06-7.16 (2H, m), 7.30-7.46 (3H, m).
1H-NMR (CDCl3) δ: 0.93 (3H, t, J = 7.3 Hz), 1.31 (6H, d, J = 5.9 Hz), 1.56-1.84 (8H, m), 2.66 (2H, t, J = 7.6 Hz), 3.68 (1H, s), 4.51 (1H, q, J = 5.9 Hz), 5.31 (1H, q, J = 7.0 Hz), 5.66 (1H, s), 6.68-7.55 (11H, m).
1H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.3 Hz), 1.60-1.84 (8H, m), 2.66 (2H, t, J = 7.6 Hz), 3.13-3.20 (2H, m), 3.82 (1H, s), 4.51-4.60 (2H, m), 5.30 (1H, q, J = 6.5 Hz), 5.80 (1H, s), 6.65-7.55 (10H, m).
1H-NMR (CDCl3) δ: 0.88 (3H, t, J = 7.3 Hz), 1.54-1.80 (8H, m), 2.58 (2H, t, J = 7.6 Hz), 4.09 (3H, s), 4.16-4.24 (2H, m), 5.23 (1H, s), 6.72-7.57 (8H, m), 8.02-8.34 (2H, m).
a) 4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピル-1-(3-ビニルフェノキシ)ベンゼンの製造:
1H-NMR (CDCl3) δ:0.96 (3H, t, J = 7.3 Hz), 1.61-1.74 (2H, m), 2.70 (2H, t, J = 7.3 Hz), 3.56 (3H, s), 4.86 (2H, s), 5.28 (1H, dd, J = 0.5, 10.8 Hz), 5.74 (1H, dd, J = 0.5, 17.6 Hz), 6.69 (1H, dd, J = 10.8, 17.6 Hz), 6.83 (1H, d, J = 8.6 Hz), 6.87 (1H, ddd, J = 1.4 Hz, 2.4, 8.1 Hz), 7.07 (1H, dd, J = 1.9, 2.4 Hz), 7.19 (1H, ddd, J = 1.4, 1.9, 8.1 Hz), 7.31 (1H, dd, J = 8.1, 8.1 Hz), 7.30-7.50 (2H, m).
b)2-(3-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)フェニル)オキシランの製造:
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.59-1.70 (2H, m), 2.68 (2H, t, J = 7.6 Hz), 2.78 (1H, dd, J = 2.7, 5.7 Hz), 3.15 (1H, dd, J = 4.1, 5.7 Hz), 3.56 (3H, s), 3.85 (1H, dd, J = 2.7 , 4.1 Hz), 4.85 (2H, s), 6.81 (1H, d, J = 8.9 Hz), 6.89-6.96 (2H, m), 7.07 (1H, ddd, J = 1.4 Hz, 1.4, 8.1 Hz), 7.30-7.40 (2H, m), 7.48 (1H, d, J = 1.4 Hz).
c)2-(3-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)フェニル)エタノールの製造:
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.62-1.71 (2H, m), 2.68 (2H, t, J = 7.3 Hz), 2.87 (1H, t, J = 6.5 Hz), 3.41-4.57 (4H, m), 3.88 (1H, dt, J = 6.5 , 6.5 Hz), 4.86 (2H, s), 6.81-7.08 (4H, m), 7.27-7.46 (3H, m).
d) 5-(ベンゾ[d][1,3]ジオキソール-5-イル)-3-(3-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)フェネチル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ: 0.95 (3H, t, J = 7.3 Hz), 1.57-1.70 (2H, m), 1.69 (3H, s), 2.67 (2H, t, J = 7.6 Hz), 2.93 (2H, t, J = 7.3 Hz), 3.70-3.79 (3H, m), 5.77 (1H, s), 5.94 (2H, s), 6.73-6.95 (7H, m), 7.17 (1H, d, J = 8.6 Hz), 7.43 (1H, d, J = 8.6 Hz), 7.55 (1H, s).
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.3 Hz), 0.95 (3H, t, J = 7.3 Hz), 1.58-1.71 (2H, m), 1.98-2.13 (2H, m), 2.67 (2H, t, J = 7.6 Hz), 2.91 (2H, t, J = 7.3 Hz), 3.62 (1H, s), 3.74 (2H, t, J = 7.3 Hz), 5.85 (1H, s), 5.94 (2H, s), 6.74-6.96 (7H, m), 7.18 (1H, d, J = 8.6 Hz), 7.43 (1H, d, J = 8.6 Hz), 7.55 (1H, s).
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.3 Hz), 0.95 (3H, t, J = 7.3 Hz), 1.58-1.70 (2H, m), 1.98-2.13 (2H, m), 2.67 (2H, t, J = 7.6 Hz), 2.91 (2H, t, J = 7.8 Hz), 3.70 (1H, s), 3.73 (2H, t, J = 7.6 Hz), 4.22-4.25 (4H, m), 5.77 (1H, s), 6.73-7.29 (8H, m), 7.43 (1H, d, J = 8.6 Hz), 7.55 (1H, s).
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.31 (6H, d, J = 6.5 Hz), 1.59-1.69 (2H, m), 1.71 (3H, s), 2.67 (2H, t, J = 7.6 Hz), 2.93 (2H, t, J = 7.0 Hz), 3.69 (1H, s), 3.76 (2H, t, J = 7.0 Hz), 4.51 (1H, q, J = 6.5 Hz), 5.70 (1H, s), 6.74-6.86 (6H, m), 6.93 (1H, d, J = 7.8 Hz), 7.16-7.27 (3H, m), 7.42 (1H, d, J = 8.6 Hz), 7.55 (1H, s).
a) 4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ベンズアルデヒドの製造:
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.54-1.66 (2H, m), 2.61 (2H, t, J = 7.6 Hz), 3.57 (3H, s), 4.88 (2H, s), 7.01 (1H, d, J = 8.6 Hz), 7.02-7.07 (2H, m), 7.44-7.55 (2H, m), 7.85-7.91 (2H, m) , 9.95 (1H, s).
b) (4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)フェニル)メタノールの製造:
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.53-1.70 (3H, m), 2.68 (2H, t, J = 7.6 Hz), 3.55 (3H, s), 4.69 (2H, d, J = 5.9 Hz), 4.85 (2H, s), 6.83 (1H, d, J = 8.6 Hz), 6.96-7.01 (2H, m), 7.30-7.47 (4H, m).
c) 5-(ベンゾ[d][1,3]ジオキソール-5-イル)-3-(4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ベンジル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ: 0.93 (3H, t, J = 7.3 Hz), 1.57-1.71 (2H, m), 1.78 (3H, s), 2.65 (2H, t, J = 7.6 Hz), 3.62 (1H, s), 4.63 (2H, s), 5.85 (1H, s), 5.95 (2H, s), 6.75-7.00 (6H, m), 7.32 (2H, d, J = 8.6 Hz), 7.43 (1H, d, J = 8.6 Hz), 7.55 (1H, s).
1H-NMR (CDCl3) δ: 0.95 (3H, t, J = 7.3 Hz), 1.57-1.70 (2H, m), 1.69 (3H, s), 2.67 (2H, t, J = 7.6 Hz), 2.93 (2H, t, J = 7.3 Hz), 3.70-3.79 (3H, m), 5.77 (1H, s), 5.94 (2H, s), 6.73-6.95 (7H, m), 7.17 (1H, d, J = 8.6 Hz), 7.43 (1H, d, J = 8.6 Hz), 7.55 (1H, s).
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.3 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.58-1.68 (2H, m), 2.01-2.25 (2H, m), 2.65 (2H, t, J = 7.6 Hz), 3.57 (1H, s), 4.20-4.24 (4H, m), 4.61 (2H, s), 5.83 (1H, s), 6.78-7.00 (6H, m), 7.33 (2H, d, J = 8.6 Hz), 7.43 (1H, d, J = 8.6 Hz), 7.55 (1H, s).
1H-NMR (CDCl3) δ:1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.32 (6H, d, J = 5.9 Hz), 1.59-1.68 (2H, m), 1.79 (3H, s), 2.65 (2H, t, J = 7.6 Hz), 3.56 (1H, s), 4.53 (1H, d, J = 5.9 Hz), 4.63 (2H, s), 5.71 (1H, s), 6.80-6.91 (5H, m), 7.30-7.35 (2H, m), 7.43 (1H, d, J = 8.6 Hz), 7.56 (2H, s).
a) 4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピル-1-(4-ビニルフェノキシ)ベンゼンの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.61-1.70 (2H, m), 2.68 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.86 (2H, s), 5.21 (1H, dd, J = 1.5, 10.8 Hz), 5.68 (1H, dd, J = 1.5, 17.6 Hz), 6.70 (1H, dd, J = 10.8, 17.6 Hz), 6.85(1H, d, J = 8.6 Hz), 6.92-6.99 (2H, m), 7.34-7.48 (4H, m).
b) 2-(4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)フェニル)エタノールの製造:
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.59-1.71 (2H, m), 2.69 (2H, t, J = 7.6 Hz), 2.87 (1H, t, J = 6.5 Hz), 3.55 (3H, s), 3.88 (2H, t, J = 6.5 Hz), 4.85 (2H, s), 6.82 (1H, d, J = 8.6 Hz), 6.93-6.98 (2H, m), 7.20-7.23 (2H, m), 7.30-7.47 (2H, m).
c) 1-(4-(2-ブロモエチル)フェノキシ)-4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルベンゼンの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.59-1.71 (2H, m), 2.68 (2H, t, J = 7.6 Hz), 3.15 (2H, t, J = 7.6 Hz), 3.55 (3H, s), 3.56 (2H, t, J = 7.6 Hz), 4.85 (2H, s), 6.83 (1H, d, J = 8.6 Hz), 6.91-6.97 (2H, m), 7.18-7.21 (2H, m), 7.43 (1H, d, J = 8.6 Hz), 7.56 (2H, s).
d) 3-(4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)フェネチル)-5-(4-(1-メチルエトキシ)フェニル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.29 (6H, d, J = 6.2 Hz), 1.62-1.71 (2H, m), 1.72 (3H, s), 2.67 (2H, t, J = 7.6 Hz), 2.92 (2H, t, J = 6.2 Hz), 3.75 (2H, t, J = 6.2 Hz), 3.77 (1H, s), 4.49 (1H, q, J = 6.2 Hz), 5.73 (1H, s), 6.73 (1H, d, J = 8.6 Hz), 6.81-6.91 (4H, m), 7.10-7.14 (2H, m), 7.42 (1H, d, J = 8.6 Hz), 7.55 (2H, s).
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.3 Hz), 0.94 (3H, t, J = 7.3 Hz), 1.59-1.70 (2H, m), 1.96-2.16 (2H, m), 2.67 (2H, t, J = 7.6 Hz), 2.91 (2H, t, J = 7.3 Hz), 3.73 (2H, t, J = 7.3 Hz), 3.78 (1H, s), 4.11-4.18 (4H, m), 5.88 (1H, s), 6.70-7.12 (8H, m), 7.42 (1H, d, J = 8.6 Hz), 7.54 (1H, s).
a) 2-クロロ-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジンの製造:
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.52-1.66 (2H, m), 2.55 (2H, t, J = 7.3 Hz), 3.58 (3H, s), 4.89 (2H, s), 6.76 (1H, dd, J = 2.2, 5.4 Hz), 7.07 (1H, d, J = 8.6 Hz), 7.50-7.57 (3H, m), 8.26 (1H, d, J = 5.4 Hz).
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.53-1.64 (2H, m), 2.52 (3H, s), 2.57 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 4.89 (2H, s), 6.30 (1H, dd, J = 2.2, 5.7 Hz), 7.03 (1H, d, J = 8.6 Hz), 7.46-7.55 (3H, m), 8.36 (1H, d, J = 5.7 Hz).
c) 酢酸(4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)メチルの製造:
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.6 Hz), 1.56-1.66 (2H, m), 2.14 (3H, s), 2.57 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 4.89 (2H, s), 5.20 (2H, s), 6.71 (1H, dd, J = 2.4, 5.7 Hz), 6.89 (1H, d, J = 2.4 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.50-7.57 (2H, m), 8.47 (1H, d, J = 5.7 Hz).
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.55-1.63 (2H, m), 2.56 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 4.71 (2H, s), 4.89 (2H, s), 6.74 (1H, dd, J = 2.4, 5.7 Hz), 6.78 (1H, d, J = 2.4 Hz), 7.04 (1H, d, J = 8.6 Hz), 7.48-7.56 (2H, m), 8.43 (1H, d, J = 5.7 Hz).
e) 2-(ブロモメチル)-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジンの製造:
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.50-1.64 (2H, m), 2.57 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 4.50 (2H, s), 4.89 (2H, s), 6.70 (1H, dd, J = 2.4, 5.7 Hz), 6.99 (1H, d, J = 2.4 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.49-7.57 (2H, m), 8.45 (1H, d, J = 5.7 Hz).
f) 5-(ベンゾ[d][1,3]ジオキソール-5-イル)-3-((4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)メチル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CD3OD) δ:0.89 (3H, t, J = 7.3 Hz), 1.52-1.61 (2H, m), 1.75 (3H, s), 2.48 (2H, t, J = 7.6 Hz), 5.02 (2H, s), 5.98 (2H, s), 6.77-7.28 (6H, m), 7.72 (1H, d, J = 8.6 Hz), 7.79 (1H, s), 8.68 (1H, d, J = 6.5 Hz).
実施例42 5-(2,3-ジヒドロベンゾ[b][1,4]ジオキシン-6-イル)-5-エチル-3-((4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)メチル)イミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ:0.80-0.92 (6H, m), 1.50-1.70 (2H, m), 1.90-2.20 (2H, m), 2.46 (2H, t, J = 7.6 Hz), 4.00-4.30 (4H, m), 4.63 (2H, s), 5.86 (1H,s), 6.78-7.26 (6H, m), 7.70-7.80 (2H, m), 7.72-7.78 (1H, m).
1H-NMR (CD3OD) δ:0.89 (3H, t, J = 7.3 Hz), 1.50-1.61 (2H, m), 1.76 (3H, s), 2.46 (2H, t, J = 7.6 Hz), 3.23 (2H, t, J = 8.1 Hz), 3.39 (1H, s), 4.59 (2H, t, J = 8.1 Hz), 5.11 (2H, s), 6.77 (1H, d, 8.6 Hz), 6.91 (1H, s), 7.06-7.28 (4H, m), 7.71(1H, d, J = 8.6 Hz), 7.77 (1H, s), 8.71 (1H, d, J = 5.9 Hz).
1H-NMR (CD3OD) δ:0.91 (3H, t, J = 7.3 Hz), 1.55-1.65 (2H, m), 1.80 (3H, s), 2.51 (2H, t, J = 7.6 Hz), 3.81 (3H, s), 5.14 (2H, s), 6.95-7.44 (7H, m), 7.72 (1H, d, J = 8.6 Hz), 7.80 (1H, s), 8.68 (1H, d, J = 6.5 Hz).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.31 (6H, d, J = 5.9 Hz), 1.34-1.58 (2H, m), 1.73 (3H, s), 2.53 (2H, t, J = 7.6 Hz), 3.57 (1H, s), 4.49-4.60 (1H, m), 4.77 (2H, s), 4.88 (1H, s), 6.48 (1H, s), 6.65-6.99 (3H, m), 7.00 (1H, d, J = 8.6 Hz), 7.36 (2H, d, J = 8.6 Hz), 7.43-7.54 (2H, m), 8.37 (1H, d, J = 5.9 Hz).
1H-NMR (CD3OD) δ: 0.88 (3H, t, J = 7.0 Hz), 0.96 (3H, t, J = 7.3 Hz), 1.37-1.59 (4H, m), 1.70-1.81 (5H, m), 2.46 (2H, t, J = 7.6 Hz), 3.96 (2H, t, J = 6.5 Hz), 5.03 (2H, s), 6.91 (2H, d, J = 8.6 Hz), 6.95 (1H, d, J = 1.5 Hz), 7.08 (1H, d, J = 8.6 Hz), 7.17 (1H, d, J = 6.5 Hz), 7.40 (2H, d, J = 8.6 Hz), 7.71 (1H, d, J = 8.6 Hz), 7.78 (1H, s), 8.68 (1H, d, J = 6.5 Hz).
1H-NMR (CD3OD) δ:0.88 (3H, t, J = 7.3 Hz), 1.50-1.59 (5H, m), 2.35 (3H, s), 2.46 (2H, t, J = 7.6 Hz), 5.01 (2H, s), 5.02 (2H, s), 6.97-7.39 (11H, s), 7.71 (1H, d, J = 8.6 Hz), 7.78 (1H, s), 8.67 (1H, d, J = 6.5 Hz).
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.53-1.62 (2H, m), 1.81 (3H, s), 2.49 (2H, t, J = 7.6 Hz), 3.38 (1H, s), 4.18 (3H, s), 5.08 (2H, s), 7.08-7.33 (5H, m), 7.00 (1H, d, J = 8.6 Hz), 7.73 (2H, d, J = 8.6 Hz), 7.79 (1H, s), 8.69 (1H, d, J = 6.8 Hz).
1H-NMR (CD3OD) δ:0.89 (3H, t, J = 7.3 Hz), 1.52-1.60 (2H, m), 1.77 (3H, s), 2.36 (3H, s), 2.46 (2H, t, J = 7.6 Hz), 5.00 (2H, s), 7.01-7.45 (7H, m), 7.72 (1H, d, J = 8.6 Hz), 7.80 (1H, s), 8.68 (1H, d, J = 6.5 Hz).
1H-NMR (CD3OD) δ:0.88 (3H, t, J = 7.3 Hz), 1.51-1.60 (2H, m), 1.83 (3H, s), 2.47 (2H, t, J = 7.6 Hz), 5.03 (2H, s), 7.03-7.25 (7H, m), 7.70-7.81 (4H, m), 8.27 (2H, d, J = 8.6 Hz), 8.68 (1H, d, J = 6.5 Hz).
1H-NMR (CDCl3) δ:0.76 (3H, t, J = 7.3 Hz), 1.37 (2H, qt, J = 7.3, 7.6 Hz), 1.82 (3H, s), 2.40 (2H, t, 7.6 Hz), 2.59 (3H, s), 4.76-4.79 (2H, m), 5.65 (1H, s), 6.19 (1H, s), 6.43 (1H, s), 6.82-6.86 (1H, m), 6.96 (1H, d, J = 8.1 Hz), 7.21 (1H, d, J = 8.1 Hz), 7.59 (1H, d, J = 8.6 Hz), 7.68 (1H, d, J = 2.2 Hz), 7.77 (1H, dd, J = 2.7, 8.6 Hz), 8.12 (1H, d, J = 2.2 Hz), 8.39 (1H, d, J = 5.4 Hz).
1H-NMR (CDCl3) δ:0.86 (3H, t, J = 7.3 Hz), 1.53 (2H, qt, J = 7.3, 7.6 Hz), 1.89 (3H, s), 2.50 (2H, t, 7.6 Hz), 3.22 (3H, s), 4.73-4.82 (2H, m), 5.30 (1H, s), 6.65 (1H, d, J = 2.2 Hz), 6.75 (1H, dd, J = 2.2, 5.7 Hz), 7.01 (1H, d, J = 8.6 Hz), 7.19 (1H, s), 7.59 (1H, d, J = 5.7, 8.6 Hz), 7.67 (1H, s), 8.06 (1H, d, J = 8.3 Hz), 8.21 (1H, dd, J = 2.2, 8.3 Hz), 8.33 (1H, d, J = 5.7 Hz), 8.91 (1H, d, J = 2.2 Hz).
1H-NMR (CD3OD) δ:0.91 (3H, t, J = 7.3 Hz), 1.55-1.64 (2H, m), 1.80 (3H, s), 2.52 (2H, t, J = 7.3 Hz), 5.10 (2H, s), 6.36-6.45 (2H, m), 7.10-7.25 (3H, m), 7.40 (1H, s), 7.72 (1H, d, J = 8.6 Hz), 7.79 (1H, s), 8.69 (1H, d, J = 5.4 Hz).
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.4 Hz), 1.39 (6H, s), 1.52-1.64 (2H, m), 2.52 (2H, t, J = 7.6 Hz), 2.90 (3H, s), 5.02 (2H, s), 5.96 (2H, s), 6.95 (1H, s), 7.13 (1H, d, J = 8.6 Hz), 7.30 (d, J = 7.3 Hz), 7.72 (1H, d, J = 8.6 Hz), 7.79 (1H, s), 8.69 (1H, d, J = 7.3 Hz).
1H-NMR (CD3OD) δ:0.91 (3H, t, J = 7.3 Hz), 1.27-2.36 (10H, m), 2.52 (2H, t, J = 7.6 Hz), 5.01 (2H, s), 7.02 (1H, s), 7.13 (1H, d, J = 8.6 Hz), 7.27 (d, J = 7.3 Hz), 7.73 (1H, d, J = 8.6 Hz), 7.80 (1H, s), 8.70 (1H, d, J = 7.3 Hz).
a)4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピコリンアルデヒドの製造:
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.6 Hz), 1.52-1.66 (2H, m), 2.55 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 4.90 (2H, s), 7.02-7.08 (2H, m), 7.46 (1H, d = 2.7 Hz), 7.50-7.58 (2H, m), 8.66 (1H, d, J = 5.4 Hz), 10.05 (1H, s).
b)1-(4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)エタノールの製造:
1H-NMR (CDCl3) δ: 0.90 (3H, t, J = 7.3 Hz), 1.40 (6H, d, J = 6.5 Hz), 1.53-1.67 (2H, m), 2.57 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 4.00-4.15 (1H, m), 4.80-4.89 (3H, m), 6.68 (1H, dd, J = 2.3, 5.7 Hz), 6.83 (1h, d, J = 2.3 Hz), 7.03 (1H, d, J = 8.6 Hz), 7.47-7.56 (2H, m), 8.40 (1H, d, J = 5.7 Hz).
c) 3-(1-(4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)エチル)-5-(4-(1-メチルエトキシ)フェニル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ: 0.93 (3H, t, J = 7.3 Hz), 1.31 (6H, d, J = 5.9 Hz), 1.52-1.85 (8H, m), 2.55 (2H, t, J = 7.6 Hz), 4.48-4.54 (1H, m), 4.69 (1H, s), 5.32-5.36 (1H, m), 6.32 (1H, s), 6.86-6.92 (1H, m), 6.78-6.88 (3H, m), 6.98-7.04 (1H, m), 7.34-7.40 (2H, m), 7.57 (1H, d, J = 8.6 Hz), 7.63 (1H, s), 8.36 (1H, d, J = 6.5 Hz).
1H-NMR (CDCl3) δ: 0.90 (3H, t, J = 7.3 Hz), 1.53-1.85 (8H, m), 2.55 (2H, t, J = 7.6 Hz), 3.20 (2H, t, d = 8.1 Hz), 3.82 (1H, s), 4.52-4.60 (2H, m), 4.78 (1H, s), 5.32-5.36 (1H, m), 6.12 (1H, s), 6.44-7.36 (6H, m), 7.57 (1H, d, 8.6 Hz), 7.64 (1H, s), 8.35 (1H, t, J = 5.9 Hz).
1H-NMR (CDCl3) δ:0.83 (3H, t, J = 7.3 Hz), 1.42-1.84 (8H, m), 2.48 (2H, t, J = 7.6 Hz), 3.97 (3H, s), 4.64 (2H, s), 6.70-7.30 (6H, m), 7.40-7.56 (2H, m), 7.83-7.84 (1H, m), 8.10-8.20 (1H, m).
a) 3-ブロモ-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジンの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.60-1.68 (2H, m), 2.65 (2H, t, J = 7.3 Hz), 3.51 (3H, s), 4.88 (2H, s), 6.20 (1H, d, J = 8.4 Hz), 7.45-7.48 (2H, m), 7.55 (1H, d, J = 2.2 Hz), 8.32 (1H, dd, J = 1.4, 2.2 Hz), 8.46 (1H, d, J = 1.4 Hz).
b) 5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ニコチノニトリルの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.58-1.68 (2H, m), 2.62 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 4.89 (2H, s), 6.95 (1H, d, J = 8.6 Hz), 7.45 (1H, dd, J = 1.6, 2.4 Hz), 7.49-7.59 (2H, m), 8.59 (1H, d, J = 2.4 Hz), 8.63 (1H, d, J = 1.4 Hz).
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.6 Hz), 1.58-1.72 (2H, m), 2.65 (2H, t, J = 7.3 Hz), 3.95 (3H, s), 4.74 (1H, s), 6.88 (1H, d, J = 8.9 Hz), 7.55 (1H, dd, J = 2.0, 8.9 Hz), 7.66 (2H, d, J = 2.0 Hz), 7.66 (1H, dd, J = 1.6, 2.7 Hz), 8.48 (1H, d, J = 2.7 Hz), 8.96 (1H, d, J = 1.6 Hz).
d) 3-(ブロモメチル)-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジンの製造:
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.6 Hz), 1.57-1.72 (2H, m), 2.67 (2H, t, J = 7.3 Hz), 3.66 (3H, s), 4.46 (2H, s), 4.87 (2H, s),6.87 (1H, d, J = 8.4 Hz), 7.33 (1H, dd, J = 2.0, 2.7 Hz), 7.43 (1H, dd, J = 2.0, 8.4 Hz), 7.52 (2H, d, J = 2.0 Hz), 8.30 (1H, d, J = 2.7 Hz), 8.41 (1H, d, J = 2.0 Hz).
e) 5-(ベンゾ[d][1,3]ジオキソール-5-イル)-3-((5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ピリジン-3-イル)メチル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CD3OD) δ:0.90 (3H, t, J = 7.3 Hz), 1.48-1.71 (2H, m), 1.77 (3H, s), 2.53 (2H, t, J = 7.6 Hz), 4.78 (2H, s), 5.95 (2H, s), 6.76-7.85 (7H, m), 8.31 (1H, s), 8.70 (1H, s).
1H-NMR (CDCl3) δ:0.82-0.93 (6H, m), 1.45-1.65 (2H, m), 1.90-2.20 (2H, m), 2.52 (2H, t, J = 7.6 Hz), 4.02-4.30 (4H, m), 4.76 (2H, s), 6.83-7.26 (4H, m), 7.50-7.90 (3H, m), 8.33 (1H, s), 8.78 (1H, s).
1H-NMR (CD3OD) δ:0.91 (3H, t, J = 7.3 Hz), 1.47-1.70 (2H, m), 1.79 (3H, s), 2.55 (2H, t, J = 7.6 Hz), 3.20 (2H, t, J = 7.3 Hz), 4.57 (2H, t, J = 7.3 Hz), 4.77 (2H, s), 6.77-7.83 (7H, m), 8.30 (1H, s), 8.71 (1H, s).
1H-NMR (CD3OD) δ:1H-NMR (CDCl3) δ:0.89 (3H, t, J = 7.6 Hz), 1.30 (6H, d, J = 6.5 Hz), 1.40-1.90 (5H, m), 2.52 (2H, t, J = 7.6 Hz), 4.40-4.60 (1H, m), 4.78 (2H, s), 6.83-7.82 (8H, m), 8.30 (1H, s), 8.74 (1H, s).
1H-NMR (CD3OD) δ:0.91 (3H, t, J = 7.3 Hz), 1.50-1.70 (2H, m), 1.80 (3H, s), 2.55 (2H, t, J = 7.6 Hz), 3.37 (3H, s), 4.11 (2H, s), 7.00-7.20 (3H, m), 7.60-7.75 (2H, m), 7.96 (1H, s), 8.22-8.53 (3H, m).
a)2-クロロ-5-ニトロイソニコチン酸メチルの製造:
1H-NMR (CDCl3) δ:3.99 (3H, s), 7.61 (1H, s), 9.06 (1H, s).
b) 2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-5-ニトロイソニコチン酸メチルの製造:
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.52-1.64 (2H, m), 2.53 (2H, t, J = 7.3 Hz), 3.58 (3H, s), 4.01 (3H, s), 4.89 (2H, s), 7.13 (1H, d, J = 8.6 Hz), 7.14 (1H, s), 7.50-7.56 (2H, m), 8.88 (1H, s).
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.56-1.70 (2H, m), 2.56 (2H, t, J = 7.3 Hz), 3.57 (3H, s), 3.99 (3H, s), 4.88 (2H, s), 7.08 (1H, d, J = 8.6 Hz), 7.45 (1H, s), 7.47-7.51 (2H, m), 8.59 (1H, s).
d) 2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)イソニコチン酸メチルの製造:
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.54-1.68 (2H, m), 2.59 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 3.97 (3H, s), 4.88 (2H, s), 7.11 (1H, d, J = 8.9 Hz), 7.45-7.52 (3H, m), 7.57 (1H, d, J = 5.4 Hz) 8.30 (1H, d, J = 5.4 Hz).
e) 4-(ブロモメチル)-2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジンの製造:
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.54-1.68 (2H, m), 2.59 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.40 (2H, s), 4.88 (2H, s), 6.96 (1H, d, J = 0.8 Hz), 7.05 (1H, dd, J = 0.8, 5.4 Hz), 7.09 (1H, d, J = 8.6 Hz), 7.43-7.51 (2H, m), 8.15 (1H, d, J = 5.4 Hz).
f) 5-(ベンゾ[d][1,3]ジオキソール-5-イル)-3-((2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ピリジン-4-イル)メチル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CD3OD) δ:0.89 (3H, t, J = 7.3 Hz), 1.53-1.66 (2H, m), 1.74 (3H, s), 2.53 (2H, t, J = 7.6 Hz), 4.73 (2H, s), 5.97 (2H, s), 6.55-7.28 (6H, m), 7.61 (1H, d, J = 8.6 Hz), 7.68 (1H, s), 8.22 (1H, d, J = 5.1 Hz).
1H-NMR (CD3OD)δ:0.81-0.92 (6H, m), 1.51-1.1.62 (2H, m), 2.00-2.20 (2H, m), 2.52 (2H, t, J = 7.6 Hz), 4.65 (2H, s), 5.98 (2H, s), 6.79-6.84 (2H, m), 6.96 (1H, dd, J = 1.9, 8.1 Hz), 7.02-7.06 (3H, m), 7.59 (1H, d, J = 8.6 Hz), 7.67 (1H, s), 8.16 (1H, d, J = 5.7 Hz).
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.52-1.66 (2H, m), 1.74 (2H, m), 2.54 (2H, t, J = 7.6 Hz), 4.00-4.30 (4H, m), 4.67 (2H, s), 6.81-7.26 (6H, m), 7.57-7.68 (2H, m), 8.19 (1H, d, J = 5.4 Hz).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.54-1.63 (2H, m), 1.68 (3H, s), 2.55 (2H, t, J = 7.6 Hz), 3.20 (2H, t, J = 8.8 Hz), 4.00 (1H, s), 4.13 (2H, t, J = 8.8 Hz), 4.70 (2H, s), 5.98 (1H, s), 6.75-6.80 (2H, m), 6.90 (1H, dd, J = 1.2, 5.1 Hz), 7.01 (1H, J = 8.6 Hz), 7.18 (1H, dd, J = 2.2, 8.3 Hz), 7.29 (1H, s), 7.51 (1H, dd, J = 1.9, 8.6 Hz), 7.60 (1H, d, J = 1.9 Hz), 8.08 (1H, d, J = 5.1 Hz).
1H-NMR (CD3OD) δ:0.90 (3H, t, J = 7.3 Hz), 1.53-1.67 (2H, m), 1.80 (3H, s), 2.55 (2H, t, J = 7.6 Hz), 3.72 (3H, s), 4.76 (2H, s), 6.91-7.45 (7H, m), 7.58 (1H, d, J = 8.6 Hz), 7.67 (1H, s), 8.19 (1H, d, J = 5.4 Hz).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.31 (6H, d, J = 5.9 Hz), 1.51-1.65 (2H, m), 1.73 (3H, s), 2.55 (2H, t, J = 7.6 Hz), 4.01 (1H, s), 4.48-4.60 (1H, m), 4.75 (2H, s), 5.93 (1H, s), 6.77 (1H, s), 6.86-6.91 (2H, m), 7.02 (1H, d, J = 8.6 Hz), 7.34 (2H, J = 8.6 Hz), 7.51 (1H, d, J = 8.6 Hz), 7.59 (1H, s), 8.09 (1H, d, J = 5.1 Hz).
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.3 Hz), 1.44-1.54 (2H, m), 1.80 (3H, s), 2.50 (2H, t, J = 7.6 Hz), 3.96 (3H, s), 4.48 (1H, d, J = 10.8 Hz), 4.69 (1H, d, J = 10.8 Hz), 5.28 (1H, s), 6.27 (1H, s), 6.53 (1H, d, J = 1.2 Hz), 6.78 (1H, d, J = 8.8 Hz), 6.91 (1H, dd, J = 1.2, 5.1 Hz), 7.02 (1H, J = 8.6 Hz), 7.55 (1H, d, J = 8.6 Hz), 7.62 (1H, s), 7.72 (1H, dd, J = 2.7, 8.8 Hz), 8.05 (1H, d, J = 2.7 Hz), 8.14 (1H, d, J = 5.1 Hz).
1H-NMR (CD3OD) δ:0.89 (3H, t, J = 7.3 Hz), 1.51-1.65 (2H, m), 1.78 (3H, s), 2.34 (3H, s), 2.52 (2H, t, J = 7.6 Hz), 4.67 (2H, s), 6.80 (1H, s), 7.01-7.06 (2H, m), 7.16-7.38 (4H, m), 7.58 (1H, d, J = 8.6 Hz), 7.66 (1H, s), 8.16 (1H, d, J = 5.4 Hz).
1H-NMR (CDCl3) δ:0.89 (3H, t, J = 7.3 Hz), 1.53-1.62 (2H, m), 1.76 (3H, s), 2.53 (2H, t, J = 7.6 Hz), 4.67 (2H, s), 6.81 (1H, s), 7.01-7.67 (7H, m), 8.17 (1H, d, J = 5.4 Hz).
1H-NMR (CD3OD) δ:0.90 (3H, t, J = 7.3 Hz), 1.53-1.67 (2H, m), 1.79 (3H, s), 2.56 (2H, t, J = 7.3 Hz), 4.74 (2H, s), 6.36-6.41 (2H, m), 6.88 (1H, s), 7.05-7.28 (2H, m), 7.39 (1H, d, J = 1.6 Hz), 7.60 (1H, d, J = 8.6 Hz), 7.68 (1H, s), 8.20 (1H, d, J = 5.4 Hz).
1H-NMR (CD3OD) δ:0.90 (3H, t, J = 7.3 Hz), 1.40 (6H, s), 1.52-1.64 (2H, m), 2.55 (2H, t, J = 7.6 Hz), 2.91 (3H, s), 4.68 (2H, s), 6.77 (1H, s), 6.95 (1H, s), 7.00-7.06 (2H, m), 7.57 (d, J = 8.6 Hz), 7.65 (1H, s), 8.19 (1H, d, J = 5.1 Hz).
1H-NMR (CD3OD) δ:0.90 (3H, t, J = 7.3 Hz), 1.53-2.14 (10H, m), 2.55 (2H, t, J = 7.6 Hz), 4.68 (2H, s), 6.79 (1H, s), 7.05-7.08 (2H, m), 7.60 (1H, d, J = 8.6 Hz), 7.67 (1H, s), 8.20 (d, J = 5.9 Hz).
a) 6-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-メチル-3-ニトロピリジンの製造:
1H-NMR (CDCl3) δ:0.89 (3H, t, J = 7.3 Hz), 1.52-1.66 (2H, m), 2.55 (2H, t, J = 7.6 Hz), 2.74 (3H, s), 3.58 (3H, s), 4.88 (2H, s), 6.82 (1H, d, J = 8.6 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.47-7.55 (2H, m), 8.38 (1H, d, J = 8.6 Hz).
b) 6-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-3-ヨード-2-メチルピリジンの製造:
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.56-1.68 (2H, m), 2.56-2.61 (5H, m), 3.56 (3H, s), 4.87 (2H, s), 6.39 (1H, d, J = 8.6 Hz), 7.07 (1H, d, J = 8.6 Hz), 7.39-7.50 (2H, m), 7.96 (1H, d, J = 8.6 Hz).
c) 2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-6-メチルピリジンの製造:
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.56-1.70 (2H, m), 2.47 (3H, s), 2.63 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.87 (2H, s), 6.55 (1H, d, J = 8.1 Hz), 6.90 (1H, d, J = 7.3 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.38-7.50 (2H, m), 7.57 (1H, dd, J = 7.3, 8.1 Hz).
d) 酢酸(6-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)メチルの製造:
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.56-1.65 (2H, m), 2.08 (3H, s), 2.60 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.87 (2H, s), 5.10 (2H, s), 6.75 (1H, d, J = 8.0 Hz), 7.05 (1H, d, J = 8.0 Hz), 7.09 (1H, d, J = 8.6 Hz), 7.40-7.50 (2H, m), 7.70 (1H, dd, J = 8.0, 8.0 Hz).
e) (6-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)メタノールの製造:
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.57-1.77 (2H, m), 2.60 (2H, t, J = 7.6 Hz), 3.57 (3H, s), 4.65 (2H, s), 5.10 (2H, s), 6.75 (1H, d, J = 7.6 Hz), 6.98 (1H, d, J = 7.6 Hz), 7.08 (1H, d, J = 8.6 Hz), 7.40-7.52 (2H, m), 7.71 (1H, dd, J = 7.6, 7.6 Hz).
f) 2-(ブロモメチル)-6-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジンの製造:
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.56-1.65 (2H, m), 2.61 (2H, t, J = 7.4 Hz), 3.57 (3H, s), 4.74 (2H, s), 4.89 (2H, s), 6.74 (1H, d, J = 8.3 Hz), 7.12 (1H, d, J = 7.8 Hz), 7.19 (1H, d, J = 7.8 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.52 (1H, s), 7.70 (1H, dd, J = 7.8, 7.8 Hz).
g) 5-(ベンゾ[d][1,3]ジオキソール-5-イル)-3-((6-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)メチル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CD3OD) δ:0.90 (3H, t, J = 7.3 Hz), 1.51 (3H, s), 1.52-1.67 (2H, m), 2.59 (2H, t, J = 7.6 Hz), 4.76 (2H, s), 5.95 (2H, s), 6.76 (1H, dd, J = 7.3, 7.3 Hz), 6.89-7.08 (5H, m), 7.53-7.72 (3H, m).
1H-NMR (CD3OD)δ:0.82 (3H, t, J = 7.3 Hz), 0.91 (3H, t, J = 7.3 Hz), 1.55-1.64 (2H, m), 1.94-2.12 (2H, m), 2.58 (2H, t, J = 7.6 Hz), 4.67 (2H, s), 5.96 (2H, s), 6.68 (1H, d, J = 8.4 Hz), 6.79 (1H, d, J = 8.1 Hz), 6.86 (1H, d, J = 7.8 Hz), 7.00 (1H, dd, J = 1.9, 8.4 Hz), 7.03-7.27 (2H, m), 7.50-7.69 (3H, m).
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.53-1.63 (2H, m), 1.62 (3H, s), 2.55 (2H, t, J = 7.6 Hz), 3.18 (2H, t, J = 8.9 Hz), 4.56 (2H, t, J = 8.9 Hz), 4.67 (2H, s), 6.72 (1H, d, J = 8.1 Hz), 6.84 (1H, d, J = 8.3 Hz), 6.94 (1H, d, J = 7.3 Hz), 7.04-7.12 (2H, m), 7.52 (1H, d, J = 8.6 Hz), 7.55 (1H, s), 7.67 (1H, dd, J = 8.1, 8.3 Hz).
1H-NMR (CD3OD) δ:0.89 (3H, t, J = 7.3 Hz), 1.48 (3H, s), 1.49-1.63 (2H, m), 2.55 (2H, t, J = 7.6 Hz), 3.82 (3H, s), 4.70 (1H, d, J = 16.2 Hz), 4.80 (1H, d, J = 16.2 Hz), 6.80 (1H, d, J = 8.6 Hz), 6.91-7.73 (9H, m).
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.30 (6H, d, J = 5.9 Hz), 1.36 (3H, s), 1.51-1.62 (2H, m), 2.55 (2H, t, J = 7.6 Hz), 3.41 (1H, s), 4.46-4.56 (1H, m), 4.67 (2H, s), 6.83-6.89 (3H, m), 6.93 (1H, d, J = 7.3 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.51-7.55 (2H, m), 7.67 (1H, dd, J = 7.3, 7.8 Hz).
1H-NMR (CD3OD) δ: 0.90 (3H, t, J = 7.3 Hz), 0.97 (3H, t, J = 7.3 Hz), 1.43-1.80 (9H, m), 2.58 (2H, t, J = 7.6 Hz), 3.91 (2H, t, J = 6.2 Hz), 4.70 (2H, s), 6.76 (2H, d, J = 7.8 Hz), 6.84-6.91 (2H, m), 7.07 (1H, d, J = 8.6 Hz), 7.35 (1H, d, J = 8.6 Hz), 7.54 (1H, d, J = 8.6 Hz), 7.59 (1H, s), 7.67 (1H, dd, J = 7.8, 7.8 Hz).
1H-NMR (CD3OD) δ:0.90 (3H, t, J = 7.3 Hz), 1.50 (3H, s), 1.54-1.64 (2H, m), 2.36 (3H, s), 2.58 (2H, t, J = 7.6 Hz), 4.70 (2H, s), 5.00 (2H, s), 6.73-7.42 (11H, m), 7.55 (1H, d, J = 8.6 Hz), 7.60 (1H, s), 7.67 (1H, dd, J = 7.8, 7.8 Hz).
1H-NMR (CDCl3) δ:0.73 (3H, t, J = 7.3 Hz), 1.33-1.44 (2H, m), 1.48 (3H, s), 2.50 (2H, t, J = 7.6 Hz), 3.93 (1H, s), 3.96 (3H, s), 4.68 (1H, d, J = 16.7 Hz), 4.76 (1H, d, J = 16.7 Hz), 5.85 (1H, s), 6.70 (1H, d, J = 8.6 Hz), 6.84 (1H, d, J = 8.1 Hz), 6.94 (1H, d, J = 7.3 Hz), 7.07 (1H, d, J = 8.6 Hz), 7.54 (1H, d, J = 8.6 Hz), 7.58 (1H, s), 7.63-7.76 (3H, m).
1H-NMR (CD3OD) δ:0.90 (3H, t, J = 7.3 Hz), 1.47(3H, s), 1.53-1.63 (2H, m), 2.32 (3H, s), 2.58 (2H, t, J = 7.6 Hz), 4.69 (2H, s), 6.77 (1H, d, J = 7.8 Hz), 6.90 (1H, d, J = 7.3 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.16 (2H, d, J = 7.8 Hz), 7.33 (2H, d, J = 7.8 Hz), 7.52-7.58 (2H, m), 7.67 (1H, dd, J = 7.3, 7.8 Hz).
1H-NMR (CD3OD) δ:0.90 (3H, t, J = 7.3 Hz), 1.44 (3H, s), 1.51-1.65 (2H, m), 2.54-2.64 (2H, m), 4.71 (2H, s), 6.81 (1H, d, J = 8.1 Hz), 6.94 (1H, d, J = 7.3 Hz), 7.10 (1H, d, J = 8.6 Hz), 7.18-7.72 (5H, m), 8.18 (2H, d, J = 8.6 Hz).
1H-NMR (CD3OD) δ:0.90 (3H, t, J = 7.3 Hz), 1.44 (3H, s), 1.51-1.64 (2H, m), 2.58 (2H, t, J = 7.6 Hz), 4.70 (2H, s), 6.77 (1H, d, J = 8.1 Hz), 6.92 (1H, d, J = 7.3 Hz), 7.06 (8.6 Hz), 7.15-7.60 (5H, m), 7.69 (1H, dd, J = 7.3, 8.1 Hz).
1H-NMR (CDCl3) δ:0.89 (3H, t, J = 7.3 Hz), 1.15 (6H, s), 1.50-1.63 (2H, m), 2.57 (2H, t, J = 7.6 Hz), 2.79 (3H, s), 4.71 (2H, s), 6.79 (1H, d, J = 7.8 Hz), 6.95 (1H, d, J = 7.8 Hz), 7.00 (d, J = 8.6 Hz), 7.51 (d, J = 8.6 Hz), 7.56 (1H, s), 7.69 (1H, dd, J = 7.8, 7.8 Hz).
1H-NMR (CD3OD) δ:0.90 (3H, t, J = 7.3 Hz), 1.50-2.00 (10H, m), 2.57 (2H, t, J = 7.6 Hz), 4.69 (2H, s), 6.78 (1H, d, J = 8.1 Hz), 6.93 (1H, d, J = 8.6 Hz), 7.04 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 8.6 Hz), 7.58 (1H, s), 7.69 (1H, dd, J = 7.8, 8.1 Hz).
a) 2-ブロモ-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジンの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.56-1.71 (2H, m), 2.65 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.86 (2H, s), 6.87 (1H, d, J = 8.6 Hz), 7.16 (1H, dd, J = 3.0, 8.6 Hz), 7.40-7.54 (3H, m) , 8.16 (1H, d, 3.0 Hz).
b) 5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピコリノニトリルの製造:
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.58-1.68 (2H, m), 2.59 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 4.88 (2H, s), 7.01 (1H, d, J = 8.6 Hz), 7.20-7.26 (1H, m), 7.49-7.69 (3H, m), 8.45 (1H, d, J = 2.4 Hz).
c) 5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ピコリン酸メチルの製造:
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.58-1.66 (2H, m), 2.61 (2H, t, J = 7.6 Hz), 4.00 (3H, s), 6.99 (1H, d, J = 8.6 Hz), 7.21-7.26 (1H, m), 7.50-7.66 (2H, m), 8.11 (1H, d, J = 8.9 Hz), 8.47 (1H, d, J = 2.7 Hz).
d) 2-(ブロモメチル)-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジンの製造:
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.60-1.71 (2H, m), 2.66 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.57 (2H,s), 4.86 (2H,s), 6.89 (1H, d, J = 8.6 Hz), 7.22-7.26 (1H, m), 7.40-7.52 (3H, m), 8.33 (1H, d, J = 2.7 Hz).
e) 5-(2,3-ジヒドロベンゾフラン-5-イル)-3-((5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)メチル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ: 0.92 (3H, t, J = 7.3 Hz), 1.56-1.69 (2H, m), 1.86 (3H, s), 2.63 (2H, t, J = 7.6 Hz), 3.18 (2H, t, J = 8.5 Hz), 4.16 (1H, s), 4.57 (2H, t, J = 8.6 Hz), 4.82 (2H, s), 5.92 (1H, s), 6.75 (1H, d, J = 8.3 Hz), 6.83 (1H, d, J = 8.6 Hz), 7.15-7.26 (3H, m), 7.39 (1H, s), 7.47 (2H, d, J = 8.6 Hz), 7.63 (1H, s), 8.21 (1H, d, J = 1.6 Hz).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.32 (6H, d, J = 5.9 Hz), 1.56-1.70 (2H, m), 1.80 (3H, s), 2.63 (2H, t, J = 7.6 Hz), 3.93 (1H, s), 4.40-4.58 (1H, m), 4.82 (2H,s), 5.82 (1H,s), 6.81-6.89 (3H, m), 7.14-7.49 (6H, m), 8.24 (1H, s).
1H-NMR (CDCl3) δ: 0.92 (3H, t, J = 7.3 Hz), 1.55-1.69 (2H, m), 1.88 (3H, s), 2.63 (2H, t, J = 7.6 Hz), 3.92 (3H, s), 4.22 (1H, s), 4.82 (2H, s), 6.25 (1H, s), 6.45 (1H, d, J = 8.9 Hz), 6.83 (1H, d, J = 8.6 Hz), 7.16-7.23 (1H, m), 7.48 (2H, d, J = 8.6 Hz), 7.60 (1H, s), 7.77 (1H,dd, J =1.6, 3.5 Hz), 8.22 (H, s), 8.30 (1H, d, J = 1.6 Hz).
a) トリフルオロメタンスルホン酸4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェニルの製造:
MS (EI) :478
b) 4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピル-3'-ビニルビフェニルの製造:
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.3 Hz), 1.53-1.64 (2H, m), 2.57 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 4.89 (2H, s), 5.30 (1H, dd, J = 0.5, 10.8 Hz), 5.76 (1H, dd, J = 0.5, 17.6 Hz), 6.70 (1H, dd, J = 10.8, 17.6 Hz),6.30-7.55 (7H, m).
c) 2-(4'-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2'-プロピルビフェニル-3-イル)オキシランの製造:
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.3 Hz), 1.41-1.52 (2H, m), 2.56 (2H, t, J = 7.6 Hz), 2.83 (1H, dd, J = 2.4, 5.7 Hz), 3.18 (1H, dd, J = 4.1, 5.7 Hz), 3.57 (3H, s), 3.85 (1H, dd, J = 2.4 , 4.1 Hz), 4.89, (2H, s), 7.21-7.51 (7H, m).
d) 2-(4'-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2'-プロピルビフェニル-3-イル)エタノールの製造:
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.3 Hz), 1.45-1.54 (2H, m), 2.58 (2H, t, J = 7.8 Hz), 2.93 (1H, t, J = 6.6 Hz), 3.58 (3H, s), 3.91 (1H, d, J = 6.6 Hz), 4.89, (2H, s), 7.17-7.40 (5H, m), 7.46 (1H, d, J = 8.6 Hz), 7.51 (1H, s).
e) 5-(ベンゾ[d][1,3]ジオキソール-5-イル)-3-(2-(4'-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2'-プロピルビフェニル-3-イル)エチル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ: 0.80 (3H, t, J = 7.3 Hz), 1.43-1.52 (2H, m), 1.67 (3H, s), 2.56 (2H, t, J = 7.6 Hz), 2.99 (2H, t, J = 7.3 Hz), 3.72 (1H, s), 3.79 (2H, t, J = 7.3 Hz), 5.77 (1H, s), 5.93 (2H, s), 6.79 (1H, d, J = 8.1 Hz), 6.81 (1H, dd, J = 1.9, 8.1 Hz), 6.87 (1H, d, J = 1.9 Hz), 7.13-7.29 (5H, m), 7.52 (1H, d, J = 8.6 Hz), 7.59 (1H, s).
1H-NMR (CDCl3) δ: 0.78-0.83 (6H, m), 1.43-1.52 (2H, m), 1.95-2.20 (2H, m), 2.56 (2H, t, J = 7.6 Hz), 2.97 (2H, t, J = 7.3 Hz), 3.70 (1H, s), 3.77 (2H, t, J = 7.3 Hz), 5.86 (1H, s), 5.94 (2H, s), 6.71 (1H, d, J = 8.1 Hz), 6.85 (1H, dd, J = 1.9, 8.1 Hz), 6.95 (1H, d, J = 1.9 Hz), 7.11-7.27 (5H, m), 7.52 (1H, d, J = 8.6 Hz), 7.59 (1H, s).
1H-NMR (CDCl3) δ: 0.77-0.83 (6H, m), 1.43-1.52 (2H, m), 1.93-2.12 (2H, m), 2.56 (2H, t, J = 7.6 Hz), 2.97 (2H, t, J = 7.3 Hz), 3.77 (2H, t, J = 7.3 Hz), 3.79 (1H, s), 4.20-4.29 (4H, m), 5.86 (1H, s), 6.77 (1H, d, J = 8.1 Hz), 6.85 (1H, dd, J = 1.9, 8.1 Hz), 6.97 (1H, d, J = 1.9 Hz), 7.12-7.27 (5H, m), 7.52 (1H, d, J = 8.6 Hz), 7.59 (1H, s).
1H-NMR (CDCl3) δ: 0.80 (3H, t, J = 7.3 Hz), 1.30 (6H, d, J = 5.9 Hz), 1.42-1.51 (2H, m), 1.69 (3H, s), 2.55 (2H, t, J = 7.6 Hz), 2.99 (2H, t, J = 7.3 Hz), 3.74 (1H, s), 3.80 (2H, t, J = 7.3 Hz), 4.50 (1H, q, J = 5.9 Hz), 5.69 (1H, s), 6.79 (2H, d, 8.6 Hz), 7.13-7.31 (7H, m), 7.51 (1H, d, J = 8.6 Hz), 7.59 (1H, s).
a) 4'-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2'-プロピルビフェニル-3-オールの製造:
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.3 Hz), 1.41-1.57 (2H, m), 2.59 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 4.90 (2H, s), 6.76-6.78 (1H, m), 6.82-6.85 (2H, m), 7.22-7.32 (2H, m), 7.44 (1H, d, J = 8.6 Hz), 7.50 (1H, s).
b) 3'-(3-ブロモプロポキシ)-4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルビフェニルの製造:
1H-NMR (CDCl3) δ:0.83 (3H, t, J = 7.3 Hz), 1.42-1.57 (2H, m), 2.29-2.38 (2H, m), 2.59 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 3.62 (2H, t, J = 6.5 Hz), 4.13 (2H, t, J = 5.7 Hz), 4.90 (2H, s), 6.84-6.91 (3H, m), 7.29-7.38 (2H, m), 7.45 (1H, d, J = 8.6 Hz), 7.50 (1H, s).
c) 5-(ベンゾ[d][1,3]ジオキソール-5-イル)-3-(3-(4'-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2'-プロピルビフェニル-3-イルオキシ)プロピル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.3 Hz), 1.42-1.55 (2H, m), 1.76 (3H, s), 2.09-2.18 (2H, m), 2.58 (2H, t, J = 7.6 Hz), 3.73 (2H, t, J = 6.8 Hz), 3.78 (1H, bs), 3.99 (2H, t, J = 5.9 Hz), 5.93 (2H, s), 5.96 (1H, bs), 6.72-6.98 (6H, m), 7.16-7.31 (2H, m), 7.53 (1H, d, J = 8.1 Hz), 7.59 (1H, bs).
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.6 Hz), 0.87 (3H, t, J = 7.3 Hz), 1.42-1.55 (2H, m), 2.02-2.18 (4H, m), 2.58 (2H, t, J = 7.6 Hz), 3.72 (2H, t, J = 6.8 Hz), 3.74 (1H, bs), 3.97 (2H, t, J = 6.2 Hz), 5.93 (2H, s), 6.12 (1H, bs), 6.73 (1H, d, J = 8.1 Hz), 6.76-6.87 (3H, m), 6.93 (1H, dd, J = 8.1, 1.9 Hz), 7.03 (1H, d, J = 1.9 Hz), 7.16-7.30 (2H, m), 7.53 (1H, d, J = 8.1 Hz), 7.59 (1H, bs).
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.0 Hz), 0.87 (3H, t, J = 7.3 Hz), 1.42-1.55 (2H, m), 2.02-2.18 (4H, m), 2.58 (2H, t, J = 7.6 Hz), 3.71 (2H, t, J = 6.8 Hz), 3.77 (1H, bs), 3.97 (2H, t, J = 6.2 Hz), 4.22 (4H, s), 5.98 (1H, bs), 6.77-6.87 (3H, m), 6.81(1H, d, J = 8.6 Hz), 6.94 (1H, dd, J = 8.6, 1.9 Hz), 7.03 (1H, d, J = 1.9 Hz), 7.16-7.30 (2H, m), 7.53 (1H, d, J = 7.8 Hz), 7.59 (1H, bs).
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.3 Hz), 1.31 (6H, d, J = 5.9 Hz), 1.42-1.55 (2H, m), 1.78 (3H, s), 2.09-2.18 (2H, m), 2.58 (2H, t, J = 7.6 Hz), 3.73 (1H, bs), 3.73 (2H, t, J = 6.8 Hz), 3.99 (2H, t, J = 6.5 Hz), 4.47-4.56 (1H, m), 5.82 (1H, bs), 6.79-6.87 (5H, m), 7.16-7.36 (4H, m), 7.53 (1H, d, J = 7.6 Hz), 7.59 (1H, bs).
a) 3'-(4-ブロモブトキシ)-4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルビフェニルの製造:
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.3 Hz), 1.45-1.57 (2H, m), 1.96-2.11 (4H, m), 2.59 (2H, t, J = 7.6 Hz), 3.53 (2H, t, J = 6.2 Hz), 3.58 (3H, s), 4.02 (2H, t, J = 5.5 Hz), 4.89 (2H, s), 6.81-6.91 (3H, m), 7.25-7.35 (2H, m), 7.45 (1H, d, J = 8.6 Hz), 7.50 (1H, s).
b) 5-(ベンゾ[d][1,3]ジオキソール-5-イル)-3-(4-(4'-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2'-プロピルビフェニル-3-イルオキシ)ブチル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.6 Hz), 1.42-1.55 (2H, m), 1.78 (7H, bs), 2.59 (2H, t, J = 7.6 Hz), 3.59 (2H, t, J = 6.8 Hz), 3.65 (1H, bs), 3.97 (2H, t, J = 5.9 Hz), 5.79 (1H, bs), 5.95 (2H, s), 6.77-6.97 (6H, m), 7.16-7.32 (2H, m), 7.53 (1H, d, J = 8.4 Hz), 7.59 (1H, bs).
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.3 Hz), 0.89 (3H, t, J = 7.3 Hz), 1.42-1.56 (2H, m), 1.78-1.80 (4H, m), 2.00-2.23 (2H, m), 2.58 (2H, t, J = 7.6 Hz), 3.57 (2H, t, J = 5.9 Hz), 3.74 (1H, bs), 3.96 (2H, t, J = 5.1 Hz), 5.95 (2H, s), 6.08 (1H, bs), 6.78 (1H, d, J = 8.4 Hz), 6.79-6.87 (3H, m), 6.94 (1H, dd, J = 8.4, 1.9 Hz), 7.03 (1H, d, J = 1.9 Hz), 7.16-7.32 (2H, m), 7.53 (1H, d, J = 7.8 Hz), 7.59 (1H, s).
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.3 Hz), 0.89 (3H, t, J = 7.3 Hz), 1.42-1.56 (2H, m), 1.78-1.80 (4H, m), 1.99-2.24 (2H, m), 2.58 (2H, t, J = 8.1 Hz), 3.56 (2H, t, J = 5.9 Hz), 3.80 (1H, bs), 3.96 (2H, t, J = 5.1 Hz), 4.22 (4H, s), 6.02 (1H, bs), 6.79-6.88 (3H, m), 6.85 (1H, d, J = 8.6 Hz), 6.95 (1H, dd, J = 8.6, 1.9 Hz), 7.02 (1H, d, J = 1.9 Hz), 7.16-7.32 (2H, m), 7.53 (1H, d, J = 7.6 Hz), 7.59 (1H, s).
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.3 Hz), 1.31 (6H, d, J = 5.9 Hz), 1.43-1.56 (2H, m), 1.80 (7H, bs), 2.59 (2H, t, J = 7.6 Hz), 3.59 (2H, t, J = 6.8 Hz), 3.68 (1H, bs), 3.97 (2H, t, J = 5.7 Hz), 4.48-4.57 (1H, m), 5.73 (1H, bs), 6.80-6.89 (5H, m), 7.19-7.37 (4H, m), 7.53 (1H, d, J = 7.6 Hz), 7.59 (1H, bs).
a) 3'-(5-ブロモペンチルオキシ)-4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルビフェニルの製造:
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.3 Hz), 1.45-1.98 (8H, m), 2.60 (2H, t, J = 7.6 Hz), 3.44 (2H, t, J = 6.8 Hz), 3.58 (3H, s), 4.00 (2H, t, J = 6.3 Hz), 4.90 (2H, s), 6.81-6.91 (3H, m), 7.29-7.35 (2H, m), 7.45 (1H, d, J = 8.6 Hz), 7.50 (1H, s).
b) 5-(ベンゾ[d][1,3]ジオキソール-5-イル)-3-(5-(4'-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2'-プロピルビフェニル-3-イルオキシ)ペンチル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.0 Hz), 1.43-1.54 (4H, m), 1.62-1.83 (4H, m), 1.78 (3H, s), 2.59 (2H, t, J = 7.6 Hz), 3.53 (2H, t, J = 7.3 Hz), 3.69 (1H, bs), 3.93 (2H, t, J = 6.2 Hz), 5.80 (1H, bs), 5.93 (2H, s), 6.76-6.96 (6H, m), 7.16-7.32 (2H, m), 7.53 (1H, d, J = 8.6 Hz), 7.60 (1H, bs).
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.6 Hz), 0.88 (3H, t, J = 7.0 Hz), 1.43-1.54 (4H, m), 1.62-1.82 (4H, m), 1.99-2.23 (2H, m), 2.59 (2H, t, J = 7.6 Hz), 3.52 (2H, t, J = 7.3 Hz), 3.67 (1H, bs), 3.92 (2H, t, J = 6.2 Hz), 5.90 (1H, bs), 5.93-5.95 (2H, m), 6.76-7.02 (6H, m), 7.16-7.33 (2H, m), 7.53 (1H, d, J = 8.6 Hz), 7.60 (1H, bs).
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.6 Hz), 0.88 (3H, t, J = 7.3 Hz), 1.43-1.56 (4H, m), 1.62-1.84 (4H, m), 1.98-2.24 (2H, m), 2.59 (2H, t, J = 7.8 Hz), 3.51 (2H, t, J = 7.3 Hz), 3.85 (1H, bs), 3.92 (2H, t, J = 6.2 Hz), 4.21 (4H, s), 6.01 (1H, bs), 6.79-7.02 (6H, m), 7.16-7.31 (2H, m), 7.53 (1H, d, J = 8.4 Hz), 7.60 (1H, bs).
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.0 Hz), 1.31 (6H, d, J = 5.9 Hz), 1.43-1.54 (4H, m), 1.59-1.83 (4H, m), 1.79 (3H, s), 2.59 (2H, t, J = 7.6 Hz), 3.53 (2H, t, J = 7.3 Hz), 3.70 (1H, bs), 3.93 (2H, t, J = 6.5 Hz), 4.48-4.57 (1H, m), 5.73 (1H, bs), 6.79-6.88 (5H, m), 7.19-7.36 (4H, m), 7.51- 7.60 (2H, m).
a) 4'-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2'-プロピルビフェニル-4-オールの製造:
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.3 Hz), 1.44-1.64 (2H, m), 2.60 (2H, t, J = 7.6 Hz), 3.60 (3H, s), 4.89 (2H, s), 6.94-6.98 (3H, m), 7.20-7.26 (2H, m), 7.43 (1H, d, J = 8.6 Hz), 7.49 (1H, s).
b) 4'-(3-ブロモプロポキシ)-4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルビフェニルの製造:
1H-NMR (CDCl3) δ:0.82 (3H, t, J = 7.3 Hz), 1.44-1.64 (2H, m), 2.31-2.40 (2H, m), 2.60 (2H, t, J = 7.6 Hz), 3.60 (3H, s), 3.64 (2H, t, J = 6.5 Hz), 4.52 (2H, t, J = 6.2 Hz), 4.89 (2H, s), 6.94-6.98 (3H, m), 7.20-7.26 (2H, m), 7.43 (1H, d, J = 8.6 Hz), 7.49 (1H, s).
c) 5-(ベンゾ[d][1,3]ジオキソール-5-イル)-3-(3-(4'-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2'-プロピルビフェニル-4-イルオキシ)プロピル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ:0.79-0.96 (3H, m), 1.44-1.64 (2H, m), 1.78-1.79 (3H, m), 2.12-2.17 (2H, m), 2.55-2.64 (2H, m), 3.65 (1H, brs), 3.70-3.78 (2H, m), 3.94-4.04 (2H, m), 5.93 (1H, brs), 5.94-5.96 (2H, m), 6.74-7.00 (5H, m), 7.16-7.26 (3H, m), 7.42-7.59 (2H, m).
1H-NMR (CDCl3) δ:0.79-0.96 (6H, m), 1.44-1.61 (2H, m), 2.06-2.18 (4H, m), 2.55-2.64 (2H, m), 3.69-3.76 (2H, m), 3.93-4.02 (2H, m), 5.82-5.84 (1H, m), 5.94-5.96 (2H, m), 6.75-7.04 (5H, m), 7.16-7.30 (3H, m), 7.42-7.58 (2H, m).
実施例110 5-(2,3-ジヒドロベンゾ[b][1,4]ジオキシン-6-イル)-5-エチル-3-(3-(4'-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2'-プロピルビフェニル-4-イルオキシ)プロピル)イミダゾリジン-2,4-ジオンの製造:
1H-NMR (CDCl3) δ: 0.79-0.93 (6H, m), 1.44-1.64 (2H, m), 2.00-2.22 (4H, m), 2.56-2.63 (2H, m), 3.58-3.65 (1H, m), 3.69-3.76 (2H, m), 3.92-4.02 (2H, m), 4.22-4.23 (4H, m), 5.89-5.94 (1H, m), 6.81-7.03 (5H, m), 7.15-7.27 (3H, m), 7.42-7.58 (2H, m).
1H-NMR (CDCl3) δ: 0.79-0.95 (3H, m), 1.29-1.33 (6H, m), 1.44-1.64 (2H, m), 1.78-1.80 (3H, m), 2.12-2.17 (2H, m), 2.56-2.61 (2H, m), 3.64 (1H, brs), 3.73-3.78 (2H, m), 3.94-4.04 (2H, m), 4.49-4.54 (1H, m), 5.77 (1H, brs), 6.82-6.88 (3H, m), 7.16-7.58 (8H, m).
1(4-(1-(1-メチルエチル))フェニル)-エタノンを用いて実施例1-a)と同様に反応・処理し、5-(4-(1-(1-メチルエチル))フェニル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (270 MHz, DMSO) δ:1.18 (6H, d, J = 7.0 Hz), 1.63 (3H, s), 2.87 (1H, quint, 7.0 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.37 (2H, d, J = 8.4 Hz), 8.54 (1H, s), 10.73 (1H, s).
1H-NMR (270 MHz, CDCl3) δ:0.92 (3H, t, J = 7.4 Hz), 1.22 (6H, d, J = 7.0 Hz), 1.62 (2H, qt, J = 7.4, 7.6 Hz), 1.78 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 2.88 (1H, sept, J = 7.0 Hz), 3.82 (1H, br-s), 4.63 (2H, s), 5.82 (1H, br-s), 6.78 (1H, d, J = 8.9 Hz), 6.86 (1H, dd, J = 7.6, 1.9 Hz), 6.94 (1H, s), 7.07 (1H, d, J = 7.6 Hz), 7.16-7.30 (3H, m), 7.34 (2H, d, J = 8.4 Hz), 7.42 (1H, d, J = 8.4 Hz), 7.56 (1H, s).
1(4-(1-(1,1-ジメチルエチル))フェニル)-エタノンを用いて実施例1-a)と同様に反応・処理し、5-(4-(1-(1,1-ジメチルエチル))フェニル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (270 MHz, DMSO) δ: 1.26 (9H, s), 1.63 (3H, s), 7.35-7.43 (4H, m), 8.56 (1H, s), 10.73 (1H, s).
1H-NMR (270 MHz, CDCl3) δ:0.92 (3H, t, J = 7.4 Hz), 1.29 (9H, s), 1.62 (2H, qt, J = 7.4, 7.6 Hz), 1.78 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 3.89 (1H, br-s), 4.63 (2H, s), 5.91 (1H, br-s), 6.79 (1H, d, J = 8.7 Hz), 6.86 (1H, dd, J = 7.6, 1.9 Hz), 6.94 (1H, t, J = 1.9 Hz), 7.07 (1H, d, J = 7.6 Hz), 7.17 (1H, d, J = 7.6 Hz), 7.23-7.30 (2H, m), 7.36 (2H, d, J = 1.4 Hz), 7.42 (1H, d, J = 8.7 Hz), 7.56 (1H, s).
1(2-ナフチル)-エタノンを用いて実施例1-a)と同様に反応・処理し、5-(2-ナフチル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (270 MHz, DMSO) δ:1.77 (3H, s), 7.51-7.62 (3H, m), 7.62-8.00 (4H, m), 8.73 (1H, s), 10.86 (1H, s).
1H-NMR (270 MHz, CDCl3) δ:0.90 (3H, t, J = 7.4 Hz), 1.59 (2H, qt, J = 7.0, 7.6 Hz), 1.89 (3H, s), 2.61 (2H, t, J = 7.6 Hz), 3.85 (1H, br-s), 4.66 (2H, s), 6.08 (1H, br s), 6.76 (1H, d, J = 8.9 Hz), 6.85 (1H, dd, J = 8.1, 1.9 Hz), 6.96 (1H, t, J = 1.9 Hz), 7.07 (1H, d, J = 8.1 Hz), 7.17 (1H, d, J = 7.8 Hz), 7.22-7.28 (2H, m), 7.38 (1H, d, J = 8.6 Hz), 7.47-7.52 (2H, m), 7.55 (1H, d, J = 1.9 Hz), 7.79-7.84 (2H, m), 7.89 (1H, d, J = 1.6 Hz).
3-フルオロ-4-ヒドロキシ安息香酸(500 mg、3.20 mmol)をN,N-ジメチルホルムアミド(16 mL)に溶解させ、氷冷下水素化ナトリウム(純度50%)(384 mg, 8.01 mmol)、ヨウ化1-メチルエチル(959 μL, 9.61 mmol)を順に加え、60℃にて3時間撹拌した。その後さらに室温にて3日間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)にて精製し、3-フルオロ-4-(1-メチルエトキシ)安息香酸イソプロピル 618 mg(収率80%)を無色油状物として得た。
1H-NMR (CDCl3) δ:1.35 (6H, d, J = 6.4 Hz), 1.39 (6H, d, J = 6.0 Hz), 4.61-4.70 (1H, m), 5.17-5.26 (1H, m), 6.97 (1H, dd, J = 8.3, 8.6 Hz), 7.73 (1H, dd, J = 2.2, 11.5 Hz), 7.78 (1H, ddd, J = 1.2, 2.2, 8.6 Hz).
3-フルオロ-4-(1-メチルエトキシ)安息香酸イソプロピル(618 mg、2.57 mmol)をメタノール(13 mL)に溶解させ、氷冷下1N 水酸化ナトリウム水溶液(13 mL)加え、60℃にて1時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮し、3-フルオロ-4-(1-メチルエトキシ)安息香酸505 mg(収率99%)を白色結晶として得た。
1H-NMR (CDCl3) δ:1.42 (6H, d, J = 6.1 Hz), 4.65-4.74 (1H, m), 7.00 (1H, dd, J = 8.3, 8.6 Hz), 7.80 (1H, dd, J = 2.0, 11.5 Hz), 7.85 (1H, ddd, J = 1.2, 2.0, 8.6 Hz).
3-フルオロ-4-(1-メチルエトキシ)安息香酸(100 mg、0.505 mmol)をジクロロメタン(2.5 mL)に溶解させ、メトキシメチルアミン塩酸塩(99 mg, 1.01 mmol)、WSC-HCl(106 mg, 0.555 mmol)、トリエチルアミン(422 μL, 3.03 mmol)、HOBt-H2O(34 mg, 0.252 mmol)を順に加え、室温にて終夜撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を5%塩酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮し、3-フルオロ-4-(1-メチルエトキシ)-N-メトキシ-N-メチルベンズアミド 117 mg(収率96%)を無色油状物として得た。
1H-NMR (CDCl3) δ:1.39 (6H, d, J = 6.1 Hz), 3.36 (3H, s), 3.57 (3H, s), 4.58-4.67 (1H, m), 6.97 (1H, dd, J = 8.3, 8.8 Hz), 7.52 (1H, ddd, J = 1.0, 2.0, 8.3 Hz), 7.55 (1H, dd, J = 2.0, 12.2 Hz).
3-フルオロ-4-(1-メチルエトキシ)-N-メトキシ-N-メチルベンズアミド(117 mg、 0.485 mmol)のテトラヒドロフラン(2.4 mL)溶液に氷冷下、メチルマグネシウムブロマイド(750 μL, 0.728 mmol)を加え、氷冷下1時間攪拌した。反応液に氷冷下水、5%塩酸水溶液を加え、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮し、1-(3-フルオロ-4-(1-メチルエトキシ)フェニル)エタノン 94 mg(収率99 %)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.41 (6H, d, J = 6.1 Hz), 2.55 (3H, s), 4.64-4.73 (1H, m), 6.99 (1H, dd, J = 8.0, 8.8 Hz), 7.69 (1H, dd, J = 2.2, 12.0 Hz), 7.71 (1H, ddd, J = 1.0, 2.2, 8.0 Hz).
1-(3-フルオロ-4-(1-メチルエトキシ)フェニル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-[4-(1-メチルエトキシ)-3-フルオロフェニル]-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.32 (6H, d, J = 6.1 Hz), 1.72 (3H, s), 4.55-4.64 (1H, m), 7.09 (1H, dd, J = 8.6, 9.0 Hz), 7.22 (1H, ddd, J = 1.0, 2.2, 8.6 Hz), 7.24 (1H, dd, J = 2.2, 10.7 Hz).
1H-NMR (270 MHz, CDCl3) δ:0.93 (3H, t, J = 7.4 Hz), 1.34 (6H, d, J = 6.2 Hz), 1.62 (2H, qt, J = 7.4, 7.6 Hz), 1.76 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 3.85 (1H, br-s), 4.52 (1H, sept, 6.2 Hz), 4.64 (2H, s), 5.87 (1H, br-s), 6.77 (1H, d, J = 8.5 Hz), 6.86 (1H, dd, J = 7.8, 1.6 Hz), 6.93 (1H, t, J = 8.5 Hz), 7.05-7.12 (2H, m), 7.15 (1H, d, J = 2.6 Hz), 7.20 (1H, d, J = 2.6 Hz), 7.23-7.30 (1H, m), 7.41 (1H, d, J = 8.4 Hz), 7.55 (1H, s).
5-ヒドロキシ-2-メチルピリジン(11.0 g, 100 mmol)をN,N’-ジメチルホルムアミド(100 mL)に溶解させ、氷冷下水素化ナトリウム(7.2 g, 150 mmol)、ヨウ化1-メチルエタン(12 mL, 121 mmol)を加え、室温にて終夜撹拌した。その後ヨウ化1-メチルエタン(4 mL) を加え、60℃にて4時間撹拌した。反応液に水を加え、ジエチルエーテルで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、5-(1-メチルエトキシ)-2-メチルピリジン 12.7 g (収率84%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.34 (6H, d, J -= 6.0 Hz), 2.48 (3H, s), 4.52 (1H, sept, J -= 6.0 Hz), 7.03-7.10 (2H, m), 8.17 (1H, d, J -= 2.4 Hz).
5-(1-メチルエトキシ)-2-メチルピリジン(227 mg, 0.661 mmol)をジクロロメタン(7.5 mL)に溶解させ、氷冷下3-クロロパーオキシ安息香酸(408 mg, 0.733 mmol)を加え、0℃にて45分間撹拌した。反応液に酢酸エチル、飽和メタ重亜硫酸ナトリウム水溶液、炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)を用いて精製し、5-(1-メチルエトキシ)-2-メチルピリジン 1-酸化物 240 mg (収率6%)を無色油状物として得た。
1H-NMR (CDCl3) δ:1.35 (6H, d, J -= 6.2 Hz), 2.46 (3H, s), 4.47 (1H, sept, J -= 6.2 Hz), 6.82 (1H, dd, J -= 2.2, 8.9 Hz), 7.11 (1H, d, J -= 8.9 Hz), 8.05 (1H, d, J -= 2.2 Hz).
5-(1-メチルエトキシ)-2-メチルピリジン 1-酸化物(234 mg, 1.40 mmol)を酢酸無水物(3.0 mL)に溶解させ、140℃にて1時間撹拌した。室温にて反応液にメタノールを加え攪拌後減圧濃縮した。酢酸エチルで抽出し、有機層を炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、酢酸 [5-(1-メチルエトキシ)ピリジン-2-イル]メチル 209 mg (収率71%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.36 (6H, d, J -= 6.2 Hz), 2.13 (3H, s), 4.58 (1H, sept, J -= 6.2 Hz), 5.13 (2H, s), 7.17 (1H, dd, J -= 2.4, 8.1 Hz), 7.26-7.30 (1H, m), 8.27 (1H, d, J-= 2.4 Hz).
酢酸[5-(1-メチルエトキシ)ピリジン-2-イル]メチル(209 mg)をメタノール(2.0 mL)に溶解させ、炭酸カリウム(276 mg, 2.0 mmol)を加え、室温にて1時間撹拌した。反応液を減圧濃縮し、反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、[5-(1-メチルエトキシ)ピリジン-2-イル]メタノール 137 mg (収率83%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.36 (6H, d, J -= 6.0 Hz), 4.57 (1H, sept, J -= 6.0 Hz), 4.69 (2H, s), 7.15-7.22 (2H, m), 8.23 (1H, s).
[5-(1-メチルエトキシ)ピリジン-2-イル]メタノール(30 mg, 0.198 mmol)をアセトン(2.0 mL)に溶解させ、氷冷下2,2,6,6-テトラメチルピペリジン 1-オキシル(3.1 mg, 0.020 mmol)、トリクロロイソシアヌル酸(50 mg, 0.218 mmol)を加え、0℃にて5分間撹拌した。反応液を減圧濃縮し、反応液に炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、5-(1-メチルエトキシ)ピコリンアルデヒド 25 mg (収率85%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.41 (6H, d, J -= 6.4 Hz), 4.71 (1H, sept, J -= 6.4 Hz), 7.25-7.27 (1H, m), 7.95 (1H, d, J -= 8.4 Hz), 8.39 (1H, d, J -= 2.8 Hz), 9.98 (1H, s).
5-(1-メチルエトキシ)ピコリンアルデヒド(24 mg, 0.145 mmol)をテトラヒドロフラン(1.5 mL)に溶解させ、氷冷下メチルマグネシウムブロマイド(230 μL, 0.218 mmol)を加え、0℃にて30分間撹拌した。さらに室温にて30分間攪拌した。反応液に1N-塩酸水溶液、炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、1-[5-(1-メチルエトキシ)ピリジン-2-イル]エタノール 27 mg (収率98%)を茶色油状物として得た。
1H-NMR (CDCl3) δ:1.36 (6H, d, J -= 6.0 Hz), 1.48 (3H, d, J -= 6.4 Hz), 4.57 (1H, sept, J -= 6.0 Hz), 4.85 (1H, q, 6.4 Hz), 7.17-7.21 (2H, m), 8.19-8.20 (1H, m).
1-[5-(1-メチルエトキシ)ピリジン-2-イル]エタノール(22 mg, 0.119 mmol)をアセトン(1.2 mL)に溶解させ、氷冷下下2,2,6,6-テトラメチルピペリジン 1-オキシル(2.0 mg, 0.012 mmol)、トリクロロイソシアヌル酸(30 mg, 0.131 mmol)を加え、0℃にて10分間撹拌した。反応液を減圧濃縮し、反応液に炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、1-[5-(1-メチルエトキシ)ピリジン-2-イル]エタノン 20 mg (収率94%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.40 (6H, d, J -= 6.2 Hz), 2.68 (3H, s), 4.68 (1H, sept, J -= 6.2 Hz), 7.22 (1H, dd, J -= 2.7, 8.6 Hz), 8.03 (1H, d, J -= 8.6 Hz), 8.28 (1H, d, J -= 2.7 Hz).
1-[5-(1-メチルエトキシ)ピリジン-2-イル]エタノンを用いて実施例1-a)と同様に反応・処理し、5-[5-(1-メチルエトキシ)ピリジン-2-イル]-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.33 (6H, d, J -= 6.2 Hz), 1.79 (3H, s), 4.67 (1H, sept, J -= 6.2 Hz), 7.36 (1H, dd, J -= 2.7, 8.9 Hz), 7.46 (1H, d, J -= 8.9 Hz), 8.18 (1H, d, J -= 2.7 Hz).
1H-NMR (270 MHz, CD3OD) δ:0.91 (3H, t, J = 7.3 Hz), 1.36 (6H, d, J = 5.8 Hz), 1.63 (2H, qt, J = 7.3, 7.6 Hz), 1.83 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 4.52 (2H, s), 4.77 (1H, sept, J = 5.8 Hz), 6.82-6.89 (2H, m), 6.95 (1H, s), 7.08 (1H, d, J = 8.0 Hz), 7.31 (1H, t, J = 8.0 Hz), 7.50 (1H, d, J = 8.0 Hz), 7.61 (1H, s), 7.74-7.80 (2H, m), 8.26 (1H, s).
2-ヒドロキシ-5-ブロモピリジン(1.00 g, 5.75 mmol)をN,N’-ジメチルホルムアミド(23 mL)に溶解し、アルゴン雰囲気中氷冷下にて水素化ナトリウム(純度50%) (253 mg, 6.32 mmol) を加えた。5分後ベンジルブロミド (6.82 mL, 6.90 mmol) を同温にて加えた後、室温にて1時間撹拌した。氷冷下にて反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、シリカゲルカラムクロマトグラフィー(n-ヘキサン/ 酢酸エチル=1/1) で精製し、5-ブロモ-2-(ベンジルオキシ)ピリジン 1.51 g (収率99%) を淡黄色固体として得た。
1H-NMR (CDCl3) δ:5.10 (2H, s), 6.54 (1H, d, J = 9.5 Hz), 7.28-7.39 (7H, m).
アルゴン雰囲気下、5-ブロモ-2-(ベンジルオキシ)ピリジン(100 mg, 0.38 mmol)とテトラキストリフェニルホスフィンパラジウム (46 mg, 0.04 mmol) をトルエン(1.5 mL)に溶解し、1-エトキシエテニルトリn-ブチルスズ (140 mL, 0.42 mmol) を加え、100℃にて一晩中撹拌した。反応液を室温に戻し、3N 塩酸を加えた後、飽和重曹水を加え、pH8とした。反応液をセライトろ過し、反応液に酢酸エチルを加えて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、分取薄層クロマトグラフィー (n-ヘキサン/ 酢酸エチル=1/1) で精製し、1-(2-(ベンジルオキシ)ピリジン-5-イル)エタノン 51 mg (収率59%) を淡黄色油状物として得た。
1H-NMR (CDCl3) δ:2.39 (3H, s), 5.19 (2H, s), 6.61 (1H, d, J= 9.7 Hz), 7.30-7.39 (5H, m), 7.86 (1H, dd, J= 2.7, 9.7 Hz), 8.09 (1H, d, J = 2.7 Hz).
1-(2-(ベンジルオキシ)ピリジン-5-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(2-(ベンジルオキシ)ピリジン-5-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CD3OD) δ:1.67 (3H, s), 5.19 (1H, d, J = 14.6 Hz), 5.23 (1H, d, J = 14.6 Hz), 6.61 (1H, d, J = 9.5 Hz), 7.29-7.34 (5H, m), 7.67 (1H, dd, J = 2.7, 9.5 Hz), 7.78 (1H, d, J = 2.7 Hz).
1H-NMR (400 MHz, CD3OD) δ:0.90 (3H, t, J = 7.5 Hz), 1.58-1.62 (2H, m), 1.64 (3H, s), 2.62 (2H, t, J = 7.5 Hz), 4.60 (2H, s), 5.17 (1H, d, J = 14.4 Hz), 5.22 (1H, d, J = 14.4 Hz), 6.59 (1H, d, J = 9.0 Hz), 6.82 (1H, d, J = 8.8 Hz), 6.84-6.88 (1H, m ), 7.02 (1H, d, J = 8.0 Hz), 7.10-7.31 (7H, m), 7.49 (1H, d, J = 7.7 Hz), 7.61 (1H, s), 7.62 (1H, d, J = 9.5 Hz), 7.79 (1H, s).
2-ヒドロキシニコチン酸(2.00 g, 14.4 mmol)とメトキシメチルアミン (2.80 g, 28.8mmol) 塩化メチレン(70 mL)に溶解し、0℃にてジシクロヘキシルカルボジイミド (5.90 g, 28.8 mmol)、トリエチルアミン (4.00 mL)、および4-N,N-ジメチルアミノピリジン (176 mg, 1.44 mmol) を加えた。室温にて一晩中撹拌後、反応液に少量の水を加え、減圧濃縮した。酢酸エチルを加え、生じた結晶をろ去し、さらに酢酸エチルを加え同様に生じた結晶をろ去した。得られた残渣を、シリカゲルカラムクロマトグラフィー(n-ヘキサン/ 酢酸エチル=1/1) で精製し、N-メトキシ-N-メチル-2-ヒドロキシニコチンアミド 2.18 g (収率84%) を無色固体として得た。
1H-NMR (CDCl3) δ:3.35 (3H,s), 3.63 (3H, s), 6.58 (1H, d, J= 9.4 Hz), 8.00 (1H, dd, J = 2.4, 9.4 Hz), 8.15 (1H, d, J = 2.4 Hz).
N-メトキシ-N-メチル-2-ヒドロキシニコチンアミド(500 mg, 2.76 mmol)、クロロジフルオロ酢酸ナトリウム (505mg, 3.31 mmol)、および水酸化ナトリウム (132 mg, 3.31 mmol) をN, N-ジメチルホルムアミド (1.4 mL) に加え、アルゴン雰囲気下125℃にて一晩中撹拌した。反応液を室温に戻し、1N 塩酸、水を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、分取薄層クロマトグラフィー (クロロホルム/ メタノール=9/1) で精製し、N-メトキシ-N-メチル-2-ジフルオロメトキシニコチンアミド 341 mg (収率53%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:3.39 (3H, s), 3.57 (3H, s), 6.93 (1H, dd, J= 8.6 Hz), 7.51 (1H, t, J = 72.5 Hz), 8.14 (1H, dd, J = 2.4, 8.6 Hz), 8.63 (1H, d, J = 2.4 Hz).
N-メトキシ-N-メチル-2-ジフルオロメトキシニコチンアミド(336 mg, 1.45 mmol) をテトラヒドロフラン (7.3 mL) に溶解し、アルゴン雰囲気下0℃にて0.93 M臭化メチルマグネシウム (2.4 mL, 2.18 mmol) を滴下した。10分間撹拌した後、同温にて反応液に1N 塩酸を加えた。次に、反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、シリカゲルカラムクロマトグラフィー (n-ヘキサン/ 酢酸エチル=4/1) で精製し、1-(2-(ジフルオロメトキシ)ピリジン-5-イル)エタノン 264 mg (収率98%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:2.61 (3H, s), 6.98 (1H, d, J = 8.5 Hz), 7.54 (1H, t, J = 72.2 Hz), 8.30 (1H, dd, J = 2.0, 8.5 Hz), 8.78 (1H, d, J = 2.0 Hz).
1-(2-(ジフルオロメトキシ)ピリジン-5-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(2-ジフルオロメトキシピリジン-5-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CD3OD) δ:1.77 (3H, s), 7.00 (1H, d, J = 8.5 Hz), 7.55 (1H, t, J = 73.0 Hz), 8.01 (1H, dd, J = 2.7, 8.5 Hz), 8.35 (1H, d, J = 2.7 Hz).
1H-NMR (270 MHz, CD3OD) δ:0.90 (3H, t, J = 7.5 Hz), 1.55-1.64 (2H, m), 1.72 (3H, s), 2.57 (2H, t, J = 7.5 Hz), 4.60 (2H, s), 6.80-6.87 (2H, m), 6.95 (1H, d, J = 8.6 Hz), 7.03 (1H, d, J = 7.6 Hz), 7.04-7.29 (3H, m), 7.47-7.53 (1H, m), 7.60 (1H, s), 7.94 (1H, d, J = 8.4 Hz), 8.29 (1H, s).
4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノール(500 mg, 1.44 mmol)のN, N-ジメチルホルムアミド (7.2 mL) 溶液に、炭酸カリウム (300 mg, 2.17 mmol)を加え、氷冷下5-フルオロ-2-ニトロベンズアルデヒド (220 mg, 1.30 mmol) を加え、60℃にて1時間撹拌した。反応液を室温に戻し、水を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、分取薄層クロマトグラフィー (ヘキサン/酢酸エチル) で精製し、5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-ニトロベンズアルデヒド 576 mg (収率89%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.60 (2H, qt, J = 7.3, 7.8 Hz), 2.58 (2H, t, J = 7.8 Hz), 3.58 (3H, s), 4.89 (2H, s), 7.03 (1H, d, J = 8.6 Hz), 7.17 (1H, dd, J = 2.7, 8.6 Hz), 7.40 (1H, d, J = 2.7 Hz), 7.52 (1H, d, J = 8.6 Hz), 7.59 (1H, s), 8.18 (1H, d, J = 8.6 Hz), 10.45 (1H, s).
5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-ニトロベンズアルデヒド(576 mg, 1.16 mmol)のメタノール (5.8 mL) 溶液に、氷冷下水素化ホウ素ナトリウム(46 mg, 1.22 mmol)を加え、氷冷下にて20分間撹拌した。反応液に、水、5%塩酸水溶液を加えた後、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、(5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-ニトロフェニル)メタノール 575 mg (収率99%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.61 (2H, qt, J = 7.3, 7.3 Hz), 2.60 (2H, t, J = 7.3 Hz), 3.57 (3H, s), 4.88 (2H, s), 5.00 (2H, s), 6.84 (1H, dd, J = 2.7, 8.9 Hz), 7.02 (1H, d, J = 8.6 Hz), 7.32 (1H, d, J = 2.7 Hz), 7.49 (1H, d, J = 8.6 Hz), 7.56 (1H, s), 8.18 (1H, d, J = 8.9 Hz).
(5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-ニトロフェニル)メタノール(221 mg, 0.444 mmol)のジクロロメタン (2.2 mL) 溶液に、ピリジン (72 μL, 0.889 mmol)を加え、氷冷下フェニルイソシアネート(97 μL, 0.889 mmol)を加え、室温にて終夜撹拌した。反応液に水、5%塩酸水溶液を加えた後、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、分取薄層クロマトグラフィー (ヘキサン/酢酸エチル) で精製し、フェニルカルバミン酸 5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-ニトロベンジル 249 mg (収率91%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.59 (2H, qt, J = 7.3, 7.6 Hz), 2.58 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.84 (2H, s), 5.65 (2H, s), 6.74 (1H, s), 6.88 (1H, dd, J = 2.7, 8.9 Hz), 7.01 (1H, d, J = 8.9 Hz), 7.07-7.13 (1H, m), 7.20 (1H, d, J = 2.7 Hz), 7.29-7.39 (4H, m), 7.47 (1H, d, J = 8.9 Hz), 7.55 (1H, s), 8.20 (1H, d, J = 8.9 Hz).
フェニルカルバミン酸 5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-ニトロベンジル(249 mg, 0.424 mmol)に酢酸 (2.0 mL)、水(400 μL) を加えた後、鉄粉末 (451 mg, 8.28 mmol)を加え、室温にて1時間撹拌した。反応液に1N 水酸化ナトリウム水溶液を加え、セライトろ過し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、フェニルカルバミン酸 2-アミノ-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ベンジル 218 mg (収率92%) を黄色アモルファスとして得た。
1H-NMR (CDCl3) δ:0.97 (3H, t, J = 7.3 Hz), 1.69 (2H, qt, J = 7.3, 7.3 Hz), 2.72 (2H, t, J = 7.3 Hz), 3.55 (3H, s), 4.84 (2H, s), 5.16 (2H, s), 6.71 (1H, d, J = 8.4 Hz), 6.72 (1H, d, J = 8.6 Hz), 6.87 (1H, dd, J = 2.7, 8.4 Hz), 6.97 (1H, d, J = 2.7 Hz), 7.05-7.11 (1H, m), 7.26-7.42 (6H, m).
フェニルカルバミン酸 2-アミノ-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ベンジル(215 mg, 0.367 mmol)のジオキサン (1.8 mL) 溶液に、濃塩酸 (180 μL)を加え、5℃にて亜硝酸ナトリウム(38 mg, 0.550 mmol)水溶液を加え、5℃にて10分間撹拌した。その後、5℃にて塩化銅(73 mg, 0.733 mmol)の塩酸溶液を加え、50℃にて終夜攪拌した。反応液に3N 水酸化ナトリウム水溶液を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、分取薄層クロマトグラフィー (ヘキサン/酢酸エチル) で精製し、フェニルカルバミン酸 2-クロロ-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ベンジル 97 mg (収率47%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.64 (2H, qt, J = 7.3, 7.3 Hz), 2.65 (2H, t, J = 7.3 Hz), 5.28 (2H, s), 6.84-6.87 (2H, m), 7.06-7.10 (1H, m), 7.12 (1H, d, J = 2.7 Hz), 7.29-7.39 (5H, m), 7.46 (1H, d, J = 7.1 Hz), 7.58 (1H, s).
フェニルカルバミン酸 2-クロロ-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ベンジル(97 mg, 0.173 mmol)のジクロロメタン(870 μL)溶液に氷冷下、ジイソプロピルエチルアミン(121μL, 0.692 mmol)を加えた後、クロロメチルメチルエーテル(26μL, 0.346 mmol)を加え40℃にて2時間撹拌した。反応液にメタノールを加え、室温にて3時間攪拌し、反応液を減圧濃縮した。得られた残渣をシリカゲル分取薄層クロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製しフェニルカルバミン酸 2-クロロ-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ベンジル 60 mg (収率57%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.64 (2H, qt, J = 7.3, 7.6 Hz), 2.66 (2H, t, J = 7.6 Hz), 3.55 (3H, s), 4.84 (2H, s), 5.29 (2H, s), 6.71 (1H, s), 6.83 (1H, d, J = 8.9 Hz), 6.87 (1H, dd, J = 2.4, 8.9 Hz), 7.05-7.11 (1H, m), 7.15 (1H, d, J = 2.4 Hz), 7.28-7.40 (6H, m), 7.48 (1H, s).
フェニルカルバミン酸 2-クロロ-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ベンジル(60 mg, 0.367 mmol)のメタノール (1.0 mL) 溶液に、ナトリウムメトキシド(32 mg, 0.590 mmol)水溶液を加え、3時間加熱還流した。反応液に水を加え、メタノールを減圧除去し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、分取薄層クロマトグラフィー (ヘキサン/酢酸エチル) で精製し、(2-クロロ-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)フェニル)メタノール 56 mg (収率>100%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.6 Hz), 1.65 (2H, qt, J = 7.6, 7.6 Hz), 2.67 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.77 (2H, s), 4.86 (2H, s), 6.83 (1H, d, J = 8.5 Hz), 6.85 (1H, dd, J = 2.9, 8.8 Hz), 7.19 (1H, d, J = 2.9 Hz), 7.33 (1H, d, J = 8.8 Hz), 7.37 (1H, d, J = 8.5 Hz), 7.48 (1H, s).
(2-クロロ-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)フェニル)メタノール(10 mg, 0.0212 mmol)、5-メチル-5-(4-(1-メチルエトキシ)フェニル)イミダゾリジン-2,4-ジオン(16 mg, 0.0635 mmol)、トリフェニルホスフィン(16 mg, 0.0635 mmol)を加え減圧下乾燥した。N, N-ジメチルホルムアミド(300 μL)を加え、氷冷下ジエチルアゾジカルボン酸のテトラヒドロフラン溶液(29 μL, 0.0635 mmol)を加え、室温にて4時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、分取薄層クロマトグラフィー (ヘキサン/酢酸エチル) で精製し、3-(2-クロロ-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ベンジル)-5-(4-(1-メチルエトキシ)フェニル)-5-メチルイミダゾリジン-2,4-ジオン 7.6 mg (収率>100%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.1 Hz), 1.30 (6H, d, J = 6.1 Hz), 1.60 (2H, qt, J = 7.1, 7.6 Hz), 1.74 (3H, s), 2.60 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.51 (1H, sept, J = 6.1 Hz), 4.76 (2H, s), 4.86 (2H, s), 5.82 (1H, s), 6.70 (1H, d, J = 2.4 Hz), 6.81-6.85 (4H, m), 7.32 (1H, d, J = 8.6 Hz), 7.33 (2H, d, J = 8.8 Hz), 7.38 (1H, d, J = 9.0 Hz), 7.47 (1H, s).
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.6 Hz), 1.30 (3H, d, J = 6.0 Hz), 1.31 (3H, d, J = 6.0 Hz), 1.60 (2H, qt, J = 7.6, 7.6 Hz), 1.73 (3H, s), 2.61 (2H, t, J = 7.6 Hz), 4.51 (1H, sept, J = 6.0 Hz), 4.77 (2H, s), 5.75 (1H, s), 6.68 (1H, d, J = 2.4 Hz), 6.78-6.83 (4H, m), 7.31 (1H, d, J = 8.8 Hz), 7.32 (2H, d, J = 8.8 Hz), 7.43 (1H, d, J = 8.0 Hz), 7.56 (1H, s).
4-ヒドロキシ-3-プロピル安息香酸メチルを製造例1-a)からc)を用いてプロピル化し、3,5-ジプロピル-4-ヒドロキシ安息香酸メチルを得た後、製造例1-d)からh)の方法を用いて、2,6-ジプロピル-4-[1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル]フェノールを白色粉末として得た。
1H-NMR (CDCl3) δ:0.97 (6H, t, J = 7.6 Hz), 1.64 (4H, qt, J = 7.6, 7.6 Hz), 2.59 (4H, t, J = 7.6 Hz), 3.54 (3H, s), 4.83 (2H, s), 4.88 (1H, s), 7.19 (2H, s).
4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノールの代わりに2,6-ジプロピル-4-[1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル]フェノールを用いて119-a-1) と同様に反応・処理し、5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2,6-ジプロピルフェノキシ)-2-ニトロベンズアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.86 (6H, t, J = 7.3 Hz), 1.56 (4H, qt, J = 7.3, 7.3 Hz), 2.40 (4H, t, J = 7.3 Hz), 3.58 (2H, s), 4.90 (3H, s), 6.96 (1H, dd, J = 3.0, 9.2 Hz), 7.29 (1H, d, J = 3.0 Hz), 7.42 (2H, s), 8.16 (1H, d, J = 9.2 Hz), 10.46 (1H, s).
5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2,6-ジプロピルフェノキシ)-2-ニトロベンズアルデヒド(100 mg, 0.186 mmol)のジオキサン/水(2:1, 1.7 mL)溶液に氷冷下、鉄粉末(26 mg, 0.465 mmol)、酢酸(290 μL)を順に加え、室温にて終夜攪拌した。反応終了後、氷冷下水、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリムで乾燥後、減圧濃縮した。得られた粗生成物(98 mg)のアセトニトリル(0.744 mL)溶液に、p-トルエンスルホン酸一水和物(106 mg, 0.558 mmol)を加え、亜硝酸ナトリウム (26 mg, 0.372 mmol)とヨウ化カリウム(77 mg, 0.465 mmol)の混合水溶液(水100 μL)を氷冷下で加え、同温にて5分間攪拌した。その後室温にて終夜攪拌した。反応液にチオ硫酸ナトリウム水溶液、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、(2-ヨード-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2,6-ジプロピルフェノキシ)ベンズアルデヒド 8.0 mg(収率7.0 %)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.85 (6H, t, J = 7.3 Hz), 1.50-1.59 (4H, m), 2.41 (4H, t, J = 7.6 Hz), 3.57 (3H, s), 4.89 (2H, s), 6.74 (1H, dd, J = 3.0, 8.6 Hz), 7.31 (1H, d, J = 3.0 Hz), 7.38 (2H, s), 7.82 (1H, d, J = 8.6 Hz), 10.01 (1H, s).
(2-ヨード-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2,6-ジプロピルフェノキシ)ベンズアルデヒド(25 mg, 0.0404 mmol)のメタノール(2.0 mL)溶液に氷冷下水素化ホウ素ナトリウム(1.7 mg, 0.445 mmol)を加え、30分間攪拌した。反応終了後、氷冷下水を加え、クロロホルムで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し、(2-ヨード-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2,6-ジプロピルフェノキシ)フェニル)メタノール(27 mg, 収率>100%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.85 (6H, t, J = 7.3 Hz), 1.51-1.60 (4H, m), 1.96 (1H, t, J = 6.3 Hz), 2.43 (4H, t, J = 7.6 Hz), 3.57 (3H, s), 4.62 (2H, d, J = 6.3 Hz), 4.88 (2H, s), 6.34 (1H, dd, J = 2.9, 8.6 Hz), 7.00 (1H, d, J = 2.9 Hz), 7.36 (2H, s), 7.64 (1H, d, J = 8.6 Hz).
(2-クロロ-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)フェニル)メタノールの代わりに(2-ヨード-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2,6-ジプロピルフェノキシ)フェニル)メタノールを用いて119-a-8)と同様に反応・処理し、3-(2-ヨード-5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2,6-ジプロピルフェノキシ)ベンジル)-5-(4-(1-メチルエトキシ)フェニル)-5-メチルイミダゾリジン-2,4-ジオンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.83 (6H, t, J = 7.3 Hz), 1.30 (3H, d, J = 5.8 Hz), 1.31 (3H, d, J = 5.8 Hz), 1.46-1.55 (4H, m), 1.68 (3H, s), 2.36 (4H, t, J = 7.1 Hz), 3.57 (3H, s), 4.49-4.55 (1H, m), 4.61 (2H, s), 4.88-4.92 (2H, m), 5.74 (1H, s), 6.36 (1H, d, J = 2.4 Hz), 6.46 (1H, dd, J = 2.4, 8.8 Hz), 6.87 (2H, d, J = 8.8 Hz), 7.34 (2H, s), 7.35 (2H, d, J = 8.8 Hz), 7.67 (1H, d, J = 8.8 Hz).
1H-NMR (CDCl3) δ:0.83 (6H, t, J = 7.3 Hz), 1.30 (3H, d, J = 6.1 Hz), 1.31 (3H, d, J = 6.1 Hz), 1.46-1.55 (4H, m), 1.67 (3H, s), 2.37 (4H, t, J = 7.6 Hz), 4.47-4.55 (1H, m), 4.62 (2H, s), 5.61 (1H, s), 6.37 (1H, d, J = 2.7 Hz), 6.43 (1H, dd, J = 2.7, 8.8 Hz), 6.87 (2H, d, J = 8.8 Hz), 7.35 (2H, d, J = 8.8 Hz), 7.43 (2H, s), 7.67 (1H, d, J = 8.8 Hz).
1H-NMR (CDCl3) δ:0.82 (6H, t, J = 7.3 Hz), 1.32 (6H, d, J = 6.1 Hz), 1.48-1.57 (4H, m), 1.74 (3H, s), 2.40 (4H, t, J = 7.6 Hz), 4.48-4.55 (1H, m), 4.60 (2H, s), 5.69 (1H, s), 6.59 (1H, dd, J = 2.2, 8.8 Hz), 6.72 (1H, d, J = 2.2 Hz), 6.86 (2H, d, J = 9.0 Hz), 6.92 (1H, d, J = 7.8 Hz), 7.32 (2H, d, J = 8.8 Hz), 7.43 (2H, s).
1H-NMR (270 MHz, CD3OD) δ:0.93 (3H, t, J = 7.4 Hz), 1.61-1.63 (2H, m), 1.68 (3H, s), 2.65 (2H, t, J = 7.4 Hz), 2.91 (2H, t, J = 6.1 Hz), 3.73 (2H, t, J = 6.1 Hz), 4.04 (3H, s), 6.72 (1H, d, J = 8.8 Hz), 6.77 (2H, d, J = 7.2 Hz), 7.11 (2H, d, J = 7.2 Hz), 7.14-7.24 (1H, m), 7.47 (1H, d, J = 8.8 Hz), 7.59 (1H, s), 8.17 (1H, d, J = 6.2 Hz), 8.27 (1H, d, J = 2.4 Hz).
1H-NMR (400 MHz, CD3OD) δ:0.93 (3H, t, J = 7.3 Hz), 1.56 (3H, s), 1.65 (2H, qt, J = 7.3, 7.5 Hz), 2.65 (2H, t, J = 7.5 Hz), 2.89 (2H, dt, J = 2.0, 6.7 Hz), 3.72 (2H, t, J = 6.7 Hz), 5.17 (2H, s), 6.53 (1H, d, J = 9.2 Hz), 6.72 (2H, d, J = 8.6 Hz), 6.73 (1H, d, J = 9.2 Hz), 7.07 (2H, d, J = 8.6 Hz), 7.25-7.30 (5H, m), 7.47 (1H, d, J = 9.5 Hz), 7.48 (1H, d, J = 9.5 Hz), 7.60 (1H, s), 7.69 (1H, d, J = 2.2 Hz).
4-フルオロ-2-メチル-1-ニトロベンゼンを用いて実施例119-a-1)と同様に反応・処理し、2-メチル-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-1-ニトロベンゼンを白色結晶として得た。
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.8 Hz), 2.60 (2H, t, J = 7.8 Hz), 2.62 (3H, s), 3.57 (3H, s), 4.88 (2H, s), 6.81 (1H, dd, J = 2.2, 9.0 Hz), 6.87 (1H, d, J = 2.2 Hz), 6.99 (1H, d, J = 8.8 Hz), 7.48 (1H, d, J = 8.8 Hz), 7.55 (1H, s), 8.07 (1H, d, J = 9.0 Hz).
2-メチル-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-1-ニトロベンゼン(293 mg、0.609 mmol)のメタノール溶液(3.0 mL)に、パラジウム炭素(29 mg)を加え,水素雰囲気下3時間攪拌した。反応液をセライトろ過後、減圧濃縮し、2-メチル-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニルアミン 274 mg(収率>100 %)を赤紫色油状物として得た。
1H-NMR (CDCl3) δ:0.97 (3H, t, J = 7.4 Hz), 1.68 (2H, qt, J = 7.4, 7.8 Hz), 2.17 (3H, s), 2.71 (2H, t, J = 7.8 Hz), 3.54 (3H, s), 4.84 (2H, s), 6.68 (1H, d, J = 8.3 Hz), 6.70 (1H, d, J = 8.8 Hz), 6.73 (1H, dd, J = 2.4, 8.3 Hz), 6.78 (1H, d, J = 2.4 Hz), 7.27 (1H, d, J = 8.8 Hz), 7.40 (1H, s).
2-メチル-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニルアミン(271 mg、0.600 mmol)のアセトニトリル(3.0 mL)溶液に、p-トルエンスルホン酸一水和物(342 mg, 1.80 mmol)を加え、亜硝酸ナトリウム (83 mg, 1.20 mmol)とヨウ化カリウム(249 mg, 1.50 mmol)の混合水溶液(水400 μL)を10℃で加え、同温にて10分間攪拌した。その後室温にて終夜攪拌した。反応液にチオ硫酸ナトリウム水溶液、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(4-ヨード-3-メチルフェノキシ)-2-プロピルベンゼン 226 mg(収率67 %)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.6 Hz), 1.64 (2H, qt, J = 7.6, 7.6 Hz), 2.41 (3H, s), 2.66 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.86 (2H, s), 6.54 (1H, dd, J = 2.4, 8.6 Hz), 6.83 (1H, d, J = 8.6 Hz), 6.91 (1H, d, J = 2.4 Hz), 7.37 (1H, d, J = 8.6 Hz), 7.47 (1H, s), 7.74 (1H, d, J = 8.6 Hz).
4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(4-ヨード-3-メチルフェノキシ)-2-プロピルベンゼン(265 mg, 0.471 mmol)をN,N-ジメチルホルムアミド(4.7 mL)、水(0.9 mL)に溶解させて、ビニルボロン酸ピナコールエステル(280 μL, 1.65 mmol)、テトラキストリフェニルホスフィンパラジウム(54 mg, 0.0471 mmol)、炭酸ナトリウム(300 mg, 2.83 mmol)を順に加え、80℃にて1時間攪拌した。反応終了後、反応溶液をセライトろ過し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(ヘキサン/クロロホルム)にて精製し、4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(3-メチル-4-ビニルフェノキシ)-2-プロピルベンゼン(218 mg, 収率>100%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.66 (2H, qt, J = 7.3, 7.3 Hz), 2.34 (3H, s), 2.68 (2H, t, J = 7.3 Hz), 3.55 (3H, s), 4.85 (2H, s), 5.26 (1H, dd, J = 1.4, 11.1 Hz), 5.59 (1H, dd, J = 1.4, 17.3 Hz), 6.77-6.81 (2H, m), 6.83 (1H, d, J = 8.9 Hz), 6.89 (1H, dd, J = 11.1, 17.3 Hz), 7.34 (1H, d, J = 8.9 Hz), 7.45 (1H, s), 7.46 (1H, d, J = 8.9 Hz).
4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(3-メチル-4-ビニルフェノキシ)-2-プロピルベンゼンを用いて実施例38-b)と同様に反応・処理し、2-{2-メチル-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノールを無色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.67 (2H, qt, J = 7.3, 7.3 Hz), 2.33 (3H, s), 2.69 (2H, t, J = 7.3 Hz), 2.89 (2H, t, J = 6.8 Hz), 3.55 (3H, s), 3.82-3.88 (2H, m), 4.85 (2H, s), 6.78 (1H, dd, J = 2.7, 8.4 Hz), 6.80 (1H, d, J = 8.6 Hz), 6.85 (1H, d, J = 2.7 Hz), 7.15 (1H, d, J = 8.4 Hz), 7.34 (1H, d, J = 8.6 Hz), 7.45 (1H, s).
2-{2-メチル-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノール(189 mg, 0.0393 mmol)のジクロロメタン (300 μL) 溶液に、ピリジン (16 μL, 0.197 mmol)を加え、0℃にて塩化 p-トルエンスルホン酸(11 mg, 0.059 mmol)水溶液を加え、室温にて7時間撹拌した。ピリジン (8.0 μL, 0.0985 mmol)を加え、0℃にて塩化 p-トルエンスルホン酸(5.5 mg, 0.030 mmol)水溶液を加え、室温にて3時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出した。有機層を5%塩酸水溶液、飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、分取薄層クロマトグラフィー (ヘキサン//酢酸エチル) で精製し、トルエン-4-スルホン酸 2-{2-メチル-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エチル エステル 13 mg (収率50%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.67 (2H, qt, J = 7.3, 7.3 Hz), 2.22 (3H, s), 2.45 (3H, s), 2.68 (2H, t, J = 7.3 Hz), 2.96 (2H, t, J = 7.3 Hz), 3.56 (3H, s), 4.17 (2H, t, J = 7.3 Hz), 4.85 (2H, s), 6.71 (1H, dd, J = 2.7, 8.4 Hz), 6.77 (1H, d, J = 8.4 Hz), 6.78 (1H, d, J = 2.7 Hz), 7.02 (1H, d, J = 8.4 Hz), 7.30-7.34 (1H, m), 7.31 (2H, d, J = 7.8 Hz), 7.46 (1H, s), 7.73 (2H, d, J = 7.8 Hz).
4-フルオロ-2-ヒドロキシ-1-ニトロベンゼン(100 mg, 0.637 mmol)のN, N-ジメチルホルムアミド (3.2 mL) 溶液に、炭酸カリウム (132 mg, 0.955 mmol)を加え、氷冷下ヨウ化メチル (48 μL, 0.764 mmol)を加え 室温にて一時間撹拌した。さらに炭酸カリウム (132 mg, 0.955 mmol)を加え、氷冷下ヨウ化メチル (48 μL, 0.764 mmol)を加え反応液を60℃にて一時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、4-フルオロ-2-メトキシ-1-ニトロ-ベンゼン 118 mg (収率>100%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:3.97 (3H, s), 6.74 (1H, ddd, J = 2.4, 7.8, 9.0 Hz), 6.80 (1H, dd, J = 2.4, 10.2 Hz), 7.97 (1H, dd, J = 6.1, 9.0 Hz).
4-フルオロ-2-メトキシニトロベンゼンを用いて実施例119-a-1)と同様に反応・処理し、4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(3-メトキシ-4-ニトロフェノキシ)-2-プロピルベンゼンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.3 Hz), 2.61 (2H, t, J = 7.3 Hz), 3.57 (3H, s), 3.93 (3H, s), 4.88 (2H, s), 6.43 (1H, dd, J = 2.4, 9.0), 6.69 (1H, d, J = 2.4 Hz), 7.02 (1H, d, J = 8.5 Hz), 7.49 (1H, d, J = 8.5 Hz), 7.56 (1H, s), 7.95 (1H, d, J = 9.0 Hz).
4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(3-メトキシ-4-ニトロフェノキシ)-2-プロピルベンゼンを用いて実施例126-a-2)、126-a-3)と同様に反応・処理し、4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(4-ヨード-3-メトキシフェノキシ)-2-プロピルベンゼンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.98 (3H, t, J = 7.3 Hz), 1.70 (2H, qt, J = 7.3, 7.8 Hz), 2.73 (2H, t, J = 7.8 Hz), 3.54 (3H, s), 3.83 (3H, s), 4.84 (2H, s), 6.47 (1H, dd, J = 2.0, 8.8), 6.56 (1H, d, J = 2.0 Hz), 6.70 (1H, d, J = 8.6 Hz), 6.72 (1H, d, J = 8.8 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.42 (1H, s).
4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(4-ヨード-3-メトキシフェノキシ)-2-プロピルベンゼンを用いて実施例126-a-4)と同様に反応・処理し、4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(3-メトキシ-4-ビニルフェノキシ)-2-プロピルベンゼンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.67 (2H, qt, J = 7.3, 7.8 Hz), 2.69 (2H, t, J = 7.8 Hz), 3.56 (3H, s), 3.82 (3H, s), 4.86 (2H, s), 5.23 (1H, dd, J = 1.7, 11.2 Hz), 5.68 (1H, dd, J = 1.7, 17.8 Hz), 6.50 (1H, dd, J = 2.2, 8.5), 6.58 (1H, d, J = 2.2 Hz), 6.87 (1H, d, J = 8.8 Hz), 6.99 (1H, dd, J = 11.2, 17.8 Hz), 7.36 (1H, d, J = 8.8 Hz), 7.42 (1H, d, J = 8.5 Hz), 7.47 (1H, s).
4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(3-メトキシ-4-ビニルフェノキシ)-2-プロピルベンゼンを用いて実施例38b)と同様に反応・処理し、2-{2-メトキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノールを無色油状物として得た。
1H-NMR (CDCl3) δ:0.96 (3H, t, J = 7.3 Hz), 1.68 (2H, qt, J = 7.3, 7.8 Hz), 2.69 (2H, t, J = 7.8 Hz), 2.89 (2H, t, J = 6.4 Hz), 3.55 (3H, s), 3.80 (3H, s), 3.83 (2H, t, J = 6.4 Hz), 4.85 (2H, s), 6.48 (1H, dd, J = 2.2, 8.3 Hz), 6.59 (1H, d, J = 2.2 Hz), 6.84 (1H, d, J = 8.6 Hz), 7.12 (1H, d, J = 8.3 Hz), 7.35 (1H, d, J = 8.6 Hz), 7.46 (1H, s).
2-{2-メトキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノールを用いて実施例38-c)と同様に反応・処理し、1-(2-ブロモエチル)-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-メトキシベンゼンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.96 (3H, t, J = 7.3 Hz), 1.67 (2H, qt, J = 7.3, 7.8 Hz), 2.69 (2H, t, J = 7.8 Hz), 3.15 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 3.57 (2H, t, J = 7.6 Hz), 3.80 (3H, s), 4.86 (2H, s), 6.47 (1H, dd, J = 2.4, 8.1), 6.58 (1H, d, J = 2.4 Hz), 6.84 (1H, d, J = 8.9 Hz), 7.10 (1H, d, J = 8.1 Hz), 7.36 (1H, d, J = 8.9 Hz), 7.47 (1H, s).
1H-NMR (400 MHz, CD3OD) δ:0.96 (3H, t, J = 7.5 Hz), 1.23 (6H, d, J = 6.1 Hz), 1.61 (3H, s), 1.63-1.72 (2H, m), 2.68 (2H, t, J = 7.5 Hz), 2.88 (2H, t, J = 6.5 Hz), 3.72 (3H, s), 3.74 (2H, t, J = 6.5 Hz), 4.47-4.51 (1H, m), 6.19 (1H, dd, J = 2.2, 8.0 Hz), 6.52 (1H, d, J = 2.2 Hz), 6.74 (1H, d, J = 8.8 Hz), 6.80 (2H, d, J = 8.8 Hz), 7.25-7.29 (3H, m), 7.49 (1H, d, J = 8.8 Hz), 7.60 (1H, s).
ヨウ化メチルの代わりにヨウ化ベンジルを用いて実施例127-a-1)と同様に反応・処理し、2-ベンジルオキシ-4-フルオロ-1-ニトロ-ベンゼンを無色油状物として得た。
1H-NMR (CDCl3) δ:5.23 (2H, s), 6.74 (1H, ddd, J = 2.4, 7.3, 9.0 Hz), 6.83 (1H, dd, J = 2.4, 10.2 Hz), 7.33-7.47 (5H, m), 7.97 (1H, dd, J = 6.1, 9.0 Hz).
2-ベンジルオキシ-4-フルオロ-1-ニトロ-ベンゼンを用いて実施例119-a-1)と同様に反応・処理し、2-(ベンジルオキシ)-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-1-ニトロベンゼンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.89 (3H, t, J = 7.1 Hz), 1.55 (2H, qt, J = 7.1, 7.8 Hz), 2.50 (2H, t, J = 7.8 Hz), 3.58 (3H, s), 4.89 (2H, s), 5.18 (2H, s), 6.50 (1H, dd, J = 2.2, 8.6 Hz), 6.58 (1H, d, J = 2.2 Hz), 6.92 (1H, d, J = 8.8 Hz), 7.31-7.39 (5H, m), 7.46 (1H, d, J = 8.8 Hz), 7.54 (1H, s), 7.97 (1H, d, J = 8.6 Hz).
2-(ベンジルオキシ)-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-1-ニトロベンゼンを用いて実施例126-a-2)と同様に反応・処理し、2-ベンジルオキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニルアミンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.97 (3H, t, J = 7.3 Hz), 1.68 (2H, qt, J = 7.3, 7.3 Hz), 2.70 (2H, t, J = 7.3 Hz), 3.55 (3H, s), 4.84 (2H, s), 5.04 (2H, s), 6.50 (1H, dd, J = 2.4, 8.3 Hz), 6.61 (1H, d, J = 2.4 Hz), 6.67 (1H, d, J = 8.8 Hz), 6.72 (1H, d, J = 8.3 Hz), 7.33-7.40 (7H, m).
2-ベンジルオキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニルアミンを用いて実施例126-a-3)と同様に反応・処理し、2-(ベンジルオキシ)-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-1-ヨードベンゼンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.61 (2H, qt, J = 7.3, 7.6 Hz), 2.60 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.86 (2H, s), 5.11 (2H, s), 6.36 (1H, dd, J = 2.4, 8.6 Hz), 6.52 (1H, d, J = 2.4 Hz), 6.78 (1H, d, J = 8.9 Hz), 7.31-7.43 (6H, m), 7.47 (1H, s), 7.70 (1H, d, J = 8.6 Hz).
2-(ベンジルオキシ)-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-1-ヨードベンゼンを用いて実施例126-a-4)と同様に反応・処理し、2-(ベンジルオキシ)-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-1-ビニルベンゼンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.6 Hz), 1.64 (2H, qt, J = 7.6, 7.6 Hz), 2.64 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.86 (2H, s), 5.05 (2H, s), 5.23 (1H, dd, J = 1.5, 11.2 Hz), 5.70 (1H, dd, J = 1.5, 17.8 Hz), 6.54 (1H, dd, J = 2.2, 8.3 Hz), 6.58 (1H, d, J = 2.2 Hz), 6.81 (1H, d, J = 8.5 Hz), 7.07 (1H, dd, J = 11.2, 17.8 Hz), 7.32-7.38 (6H, m), 7.46 (1H, d, J = 8.3 Hz), 7.42 (1H, d, J = 8.5 Hz), 7.47 (1H, s).
2-(ベンジルオキシ)-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-1-ビニルベンゼンを用いて実施例38-b)と同様に反応・処理し、2-{2-ベンジルオキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノールを無色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.6 Hz), 1.65 (2H, qt, J = 7.6, 7.8 Hz), 2.66 (2H, t, J = 7.8 Hz), 2.94 (2H, t, J = 6.4 Hz), 3.56 (3H, s), 3.86 (2H, t, J = 6.4 Hz), 4.86 (2H, s), 5.04 (2H, s), 6.52 (1H, dd, J = 2.2, 8.3 Hz), 6.61 (1H, d, J = 2.2 Hz), 6.79 (1H, d, J = 8.8 Hz), 7.15 (1H, d, J = 8.3 Hz), 7.31-7.37 (6H, m), 7.46 (1H, s).
2-{2-ベンジルオキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノールを用いて実施例38-c)と同様に反応・処理し、2-(ベンジルオキシ)-1-(2-ブロモエチル)-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ベンゼンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.64 (2H, qt, J = 7.3, 7.8 Hz), 2.65 (2H, t, J = 7.8 Hz), 3.21 (2H, t, J = 7.3 Hz), 3.56 (3H, s), 3.61 (2H, t, J = 7.3 Hz), 4.86 (2H, s), 5.05 (2H, s), 6.51 (1H, dd, J = 2.4, 8.1 Hz), 6.60 (1H, d, J = 2.4 Hz), 6.79 (1H, d, J = 8.6 Hz), 7.13 (1H, d, J = 8.1 Hz), 7.31-7.42 (6H, m), 7.46 (1H, s).
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.1 Hz), 1.28 (6H, d, J = 5.9 Hz), 1.61-1.69 (2H, m), 1.69 (3H, s), 2.65 (2H, t, J = 7.3 Hz), 2.99 (2H, brs), 3.83 (2H, brs), 4.44-4.52 (1H, m), 5.02 (2H, s), 6.33 (1H, d, J = 8.5 Hz), 6.54 (1H, s), 6.71 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 6.6 Hz), 6.92 (1H, d, J = 8.0 Hz), 7.17-7.44 (8H, m), 7.54 (1H, s).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.29 (6H, d, J = 6.1 Hz), 1.60-1.68 (2H, m), 1.70 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 2.90 (2H, t, J = 7.3 Hz), 3.75 (2H, t, J = 7.3 Hz), 4.45-4.51 (1H, m), 5.87 (1H, s), 6.38 (1H, dd, J = 1.9, 8.3 Hz), 6.44 (1H, d, J = 1.9 Hz), 6.79 (1H, d, J = 8.6 Hz), 6.82 (2H, d, J = 8.5 Hz), 6.92 (1H, d, J = 8.3 Hz), 7.26 (2H, d, J = 8.5 Hz), 7.41 (1H, d, J = 8.6 Hz), 7.54 (1H, s).
(5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-ニトロフェニル)メタノールを用いて実施例119-a)と同様に反応・処理し、{2-アミノ-5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-メタノールを無色油状物として得た。
1H-NMR (CDCl3) δ:0.97 (3H, t, J = 7.0 Hz), 1.68 (2H, qt, J = 7.0, 7.3 Hz), 2.71 (2H, t, J = 7.3 Hz), 3.54 (3H, s), 4.66 (2H, s), 4.83 (2H, s), 6.69 (1H, d, J = 8.6 Hz), 6.71 (1H, d, J = 8.1 Hz), 6.82-6.86 (2H, m), 7.28 (1H, d, J = 8.6 Hz), 7.41 (1H, s).
{2-アミノ-5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-メタノールを用いて実施例119-a)と同様に反応・処理し、4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-3-ヨードフェニルメタノールを無色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.0 Hz), 1.64 (2H, qt, J = 7.0, 7.8 Hz), 2.66 (2H, t, J = 7.8 Hz), 3.56 (3H, s), 4.65 (2H, d, J = 5.9 Hz), 4.86 (2H, s), 6.65 (1H, dd, J = 2.4, 8.6 Hz), 6.85 (1H, d, J = 8.9 Hz), 7.17 (1H, d, J = 2.4 Hz), 7.37 (1H, d, J = 8.9 Hz), 7.48 (1H, s), 7.75 (1H, d, J = 8.6 Hz).
4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-3-ヨードフェニルメタノールを用いて実施例127-a-3)と同様に反応・処理し、4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(4-ヨード-3-(メトキシメチル)フェノキシ)-2-プロピルベンゼンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.64 (2H, qt, J = 7.3, 7.8 Hz), 2.66 (2H, t, J = 7.8 Hz), 3.47 (3H, s), 3.55 (3H, s), 4.40 (2H, s), 4.85 (2H, s), 6.64 (1H, dd, J = 2.7, 8.6 Hz), 6.83 (1H, d, J = 8.6 Hz), 7.13 (1H, d, J = 2.7 Hz), 7.36 (1H, d, J = 8.6 Hz), 7.47 (1H, s), 7.75 (1H, d, J = 8.6 Hz).
実施例127-a-4)と同様に反応・処理し、4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(3-(メトキシメチル)-4-ビニルフェノキシ)-2-プロピルベンゼンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.0 Hz), 1.66 (2H, qt, J = 7.0, 7.8 Hz), 2.68 (2H, t, J = 7.8 Hz), 3.42 (3H, s), 3.56 (3H, s), 4.49 (2H, s), 4.86 (2H, s), 5.31 (1H, dd, J = 1.4, 10.8 Hz), 5.64 (1H, d, J = 1.4, 17.3 Hz), 6.83 (1H, d, J = 8.6 Hz), 6.90 (1H, dd, J = 2.4, 7.8 Hz), 6.93 (1H, dd, J = 10.8, 17.3 Hz), 7.03 (1H, d, J = 2.4 Hz), 7.35 (1H, d, J = 8.6 Hz), 7.47 (1H, s), 7.52 (1H, d, J = 7.8 Hz).
4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(3-(メトキシメチル)-4-ビニルフェノキシ)-2-プロピルベンゼンを用いて実施例38b)と同様に反応・処理し、2-{2-メトキシメチル-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノールを無色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.66 (2H, qt, J = 7.3, 7.3 Hz), 2.39 (1H, t, J = 5.4 Hz), 2.69 (2H, t, J = 7.3 Hz), 2.92 (2H, t, J = 6.5 Hz), 3.44 (3H, s), 3.55 (3H, s), 3.86 (2H, dt, J = 5.4, 6.5 Hz), 4.45 (2H, s), 4.85 (2H, s), 6.81 (1H, d, J = 8.1 Hz), 6.92 (1H, dd, J = 2.4, 8.1 Hz), 7.01 (1H, d, J = 2.4 Hz), 7.24 (1H, d, J = 8.1 Hz), 7.34 (1H, d, J = 8.1 Hz), 7.46 (1H, s).
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.30 (6H, d, J = 5.7 Hz), 1.66 (2H, qt, J = 7.3, 7.8 Hz), 1.75 (3H, s), 2.67 (2H, t, J = 7.8 Hz), 2.90-3.00 (2H, m), 3.41 (3H, s), 3.73 (2H, t, J = 7.6 Hz), 4.46 (2H, s), 4.50 (1H, sept, J = 5.7 Hz), 5.78 (1H, s), 6.74 (1H, dd, J = 2.4, 8.4 Hz), 6.74 (1H, d, J = 8.9 Hz), 6.84 (2H, d, J = 8.9 Hz), 7.00 (1H, d, J = 2.4 Hz), 7.08 (1H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.9 Hz), 7.42 (1H, d, J = 8.9 Hz), 7.54 (1H, s).
5-フルオロ-2-ニトロベンゾニトリルを用いて実施例119-a-1) と同様に反応・処理し、2-ニトロ-5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-ベンゾニトリルを無色油状物として得た。
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.60 (2H, qt, J = 7.3, 7.8 Hz), 2.56 (2H, t, J = 7.6 Hz), 3.59 (3H, s), 4.91 (2H, s), 7.06 (1H, d, J = 8.4 Hz), 7.24 (1H, dd, J = 2.4, 9.2 Hz), 7.37 (1H, d, J = 2.4 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.63 (1H, s), 8.34 (1H, d, J = 9.2 Hz).
2-ニトロ-5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-ベンゾニトリルを用いて実施例119-a)と同様に反応・処理し、2-アミノ-5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-ベンゾニトリルを無色油状物として得た。
1H-NMR (CDCl3) δ:0.96 (3H, t, J = 7.0 Hz), 1.66 (2H, qt, J = 7.0, 7.8 Hz), 2.68 (2H, t, J = 7.8 Hz), 3.55 (3H, s), 4.85 (2H, s), 6.61 (1H, d, J = 8.9 Hz), 6.77 (1H, d, J = 8.6 Hz), 7.05-7.10 (2H, m), 7.34 (1H, d, J = 8.6 Hz), 7.45 (1H, s).
2-アミノ-5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-ベンゾニトリルを用いて実施例120-a) と同様に反応・処理し、2-ヨード-5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-ベンゾニトリルを無色油状物として得た。
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.6 Hz), 1.61 (2H, qt, J = 7.6, 7.8 Hz), 2.60 (2H, t, J = 7.8 Hz), 3.57 (3H, s), 4.87 (2H, s), 6.91 (1H, d, J = 8.6 Hz), 6.93 (1H, dd, J = 2.4, 8.9 Hz), 7.19 (1H, d, J = 2.4 Hz), 7.46 (1H, d, J = 8.6 Hz), 7.54 (1H, s), 7.83 (1H, d, J = 8.9 Hz).
2-ヨード-5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-ベンゾニトリルを用いて実施例126-a-4) と同様に反応・処理し、5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-2-ビニル-ベンゾニトリルを無色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.63 (2H, qt, J = 7.3, 7.3 Hz), 2.63 (2H, t, J = 7.3 Hz), 3.57 (3H, s), 4.88 (2H, s), 5.50 (1H, d, J = 10.8 Hz), 5.87 (1H, d, J = 17.6 Hz), 6.90 (1H, d, J = 8.9 Hz), 7.04 (1H, dd, J = 10.8, 17.6 Hz), 7.17 (1H, d, J = 2.2 Hz), 7.19 (1H, dd, J = 2.2, 7.6 Hz), 7.44 (1H, d, J = 8.9 Hz), 7.53 (1H, s), 7.66 (1H, d, J = 7.6 Hz).
5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-2-ビニル-ベンゾニトリル(14 mg, 0.030 mmol)をジクロロメタン(300 μL)に溶解させ、氷冷下炭酸水素ナトリウム(7.5 mg, 0.089 mmol)、3-クロロパーオキシ安息香酸(8.5 mg, 0.030 mmol)を加え、室温にて1時間30分撹拌した。その後、さらに氷冷下炭酸水素ナトリウム(7.5 mg, 0.089 mmol)、3-クロロパーオキシ安息香酸(8.5 mg, 0.030 mmol)を加え、室温にて終夜攪拌した。反応液に飽和亜硫酸ナトリウム水溶液、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、2-オキシラニル-5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-ベンゾニトリル 5.5 mg (収率38%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.6 Hz), 1.62 (2H, qt, J = 7.6, 7.8 Hz), 2.62 (2H, t, J = 7.8 Hz), 2.77 (1H, dd, J = 2.2, 5.7 Hz), 3.27 (1H, dd, J = 3.8, 5.7 Hz), 3.57 (3H, s), 4.23 (1H, dd, J = 2.2, 3.8 Hz), 4.88 (2H, s), 6.89 (1H, d, J = 8.6 Hz), 7.18-7.22 (2H, m), 7.30 (1H, d, J = 8.6 Hz), 7.45 (1H, d, J = 8.6 Hz), 7.53 (1H, s).
2-オキシラニル-5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-ベンゾニトリル(5.0 mg, 0.0102 mmol)のテトラヒドロフラン(200 μL)溶液に氷冷下三フッ化ホウ素ジエチルエーテル(2.5 μL, 0.0204 mmol)、シアノ水素化ホウ素ナトリウム(2.6 mg, 0.0409 mmol)を順に加え、室温にて2時間攪拌した。その後、さらに氷冷下三フッ化ホウ素ジエチルエーテル(2.5 μL, 0.0204 mmol)、シアノ水素化ホウ素ナトリウム(2.6 mg, 0.0409 mmol)を順に加え、室温にて終夜攪拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリム水溶液、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)にて精製し、2-(2-ヒドロキシ-エチル)-5-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-ベンゾニトリル(2.2 mg, 収率44%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.6 Hz), 1.63 (2H, qt, J = 7.6, 7.8 Hz), 2.63 (2H, t, J = 7.8 Hz), 3.09 (2H, t, J = 5.9 Hz), 3.57 (3H, s), 3.92-3.98 (2H, m), 4.87 (2H, s), 6.87 (1H, d, J = 8.6 Hz), 7.16 (1H, dd, J = 2.4, 8.1 Hz), 7.22 (1H, d, J = 2.4 Hz), 7.38 (1H, d, J = 8.1 Hz), 7.42 (1H, d, J = 8.6 Hz), 7.52 (1H, s).
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.28 (6H, d, J = 5.7 Hz), 1.63 (2H, qt, J = 7.3, 7.8 Hz), 1.73 (3H, s), 2.61 (2H, t, J = 7.8 Hz), 3.14 (2H, t, J = 5.7 Hz), 3.86 (2H, t, J = 5.7 Hz), 4.47 (1H, sept, J = 5.7 Hz), 5.86 (1H, s), 6.75 (1H, d, J = 8.6 Hz), 6.83 (2H, d, J = 8.9 Hz), 6.93 (1H, dd, J = 2.2, 8.6 Hz), 7.09 (1H, d, J = 7.3 Hz), 7.11 (1H, d, J = 2.2 Hz), 7.30 (2H, d, J = 8.9 Hz), 7.51 (1H, d, J = 7.3 Hz), 7.60 (1H, s).
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.63 (2H, qt, J = 7.3, 7.8 Hz), 1.71 (3H, s), 2.62 (2H, t, J = 7.8 Hz), 3.14 (2H, t, J = 6.5 Hz), 3.86 (2H, t, J = 6.5 Hz), 4.14-4.18 (4H, m), 5.86 (1H, s), 6.75 (1H, d, J = 8.4 Hz), 6.83 (1H, d, J = 8.1 Hz), 6.88 (1H, dd, J = 1.9, 8.1 Hz), 6.92 (1H, d, J = 1.9 Hz), 6.95 (1H, dd, J = 2.4, 8.4 Hz), 7.10 (1H, d, J = 8.6 Hz), 7.12 (1H, d, J = 2.4 Hz), 7.51 (1H, d, J = 8.6 Hz), 7.60 (1H, s).
1 1H-NMR (CDCl3) δ:0.87 (3H, t, J = 7.3 Hz), 1.30 (3H, d, J = 5.9 Hz), 1.31 (3H, d, J = 5.9 Hz), 1.51-1.65 (2H, m), 1.79 (3H, s), 2.56 (2H, t, J = 7.3 Hz), 4.60-4.69 (1H, m), 4.76 (2H, s), 6.75 (1H, dd, J = 2.4, 5.9 Hz), 7.04 (1H, d, J = 2.4 Hz), 7.13 (1H, d, J = 8.6 Hz), 7.35 (1H, dd, J = 3.0, 8.9 Hz), 7.51 (1H, d, J = 8.9 Hz), 7.64 (1H, d, J = 8.6 Hz), 7.71 (1H, s), 8.17 (1H, d, J = 3.0 Hz), 8.34 (1H, d, J = 5.9 Hz).
1-(4-ヒドロキシフェニル)エタノン(1.36 g、10 mmol)をアセトン(50 mL)に溶解させ、ヨウ化テトラブチルアンモニウム(370 mg, 1.0 mmol)、炭酸カリウム(2.76 g, 20 mmol)、3-クロロ-2-メチル-1-プロペン(1.5 mL, 15 mmol)を順に加え、70℃にて終夜撹拌した。反応液をろ過し、アセトンで洗浄し減圧濃縮した。得られた残渣に水、酢酸エチルを加え、酢酸エチルで抽出し、有機層を1N-水酸化ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮し、1-(4-(2-メチルアリルオキシ)フェニル)エタノン 1.71 g(収率90%)を無色油状物として得た。
1H-NMR (CDCl3) δ:1.84 (3H, s), 2.56 (3H., s), 4.50 (2H, s), 4.95-5.15 (2H, m ), 6.95 (2H, d, J = 8.9 Hz), 7.93 (2H, d, J = 8.9 Hz).
1-(4-(2-メチルアリルオキシ)フェニル)エタノン(85 mg, 0.450 mmol)をPEG400(0.3 mL)に溶解させ、マイクロ波照射下250℃にて2時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、1-(2,2-ジメチル-2,3-ジヒドロベンゾフラン-5-イル)エタノン 42 mg (収率50%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.50 (6H, s), 2.54 (3H, s), 3.04 (2H, s), 6.74 (1H, d, J = 9.2 Hz), 7.78-7.81 (2H, m).
1-(2,2-ジメチル-2,3-ジヒドロベンゾフラン-5-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(2,2-ジメチル-2,3-ジヒドロベンゾフラン-5-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.43 (6H, s), 1.72 (3H, s), 3.02 (2H, s), 6.64 (1H, d, J = 8.4 Hz), 7.21 (1H, d, J= 8.4 Hz), 7.28 (1H, s).
1H-NMR (CDCl3) δ:0.80-0.87 (3H, m), 0.95 (3H, t, J = 7.3 Hz), 1.46 (6H, s), 1.62 (2H, qt, J = 7.3, 7.6 Hz), 1.90 (3H, s), 2.60-2.80 (2H, m), 2.90-3.48 (3H, m), 3.02 (2H, s), 3.64-3.70 (2H, m), 3.90-3.94 (2H, m), 4.27-4.44 (2H, m), 5.86 (1H, s), 6.72 (1H, d, J = 8.4 Hz), 7.10-7.15 (1H, m), 7.26-7.30 (1H, m), 7.34 (1H, s), 7.49-7.54 (1H, m), 7.54 (1H, s).
1-(3-ヒドロキシフェニル)エタノン(1.36 g、10 mmol)をアセトン(50 mL)に溶解させ、炭酸カリウム(2.76 g, 20 mmol)、ヨウ化1-メチルエチル(1.5 mL, 15 mmol)を順に加え、70℃にて終夜撹拌した。反応液をろ過し、アセトンで洗浄し減圧濃縮した。得られた残渣に水、酢酸エチルを加え、酢酸エチルで抽出し、有機層を1N-水酸化ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮し、1-(3-(1-メチルエトキシ)フェニル)エタノン 1.67 g(収率94%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.35 (6H, d, J = 6.0 Hz), 2.55 (3H, s), 4.63 (1H, quint, J = 6.0 Hz), 7.09 (1H, dd, J = 2.4, 8.3 Hz). 7.35 (1H, t, J = 8.0 Hz), 7.48-7.52 (2H, m).
1-[3-(1-メチルエトキシ)フェニル]エタノンを用いて実施例1-a)と同様に反応・処理し、5-[3-(1-メチルエトキシ)フェニル]-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CD3OD) δ:1.30 (6H, d, J = 6.0 Hz), 1.73 (3H, s), 4.60 (1H, sept, J = 6.0 Hz), 6.85 (1H, dd, J = 1.6, 8.3 Hz), 7.03-7.10 (2H, m), 7.27 (1H, t, J = 8.3 Hz).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.32 (6H, d, J = 5.9 Hz), 1.56 (2H, qt, J = 7.3, 7.8 Hz), 1.82 (3H, s), 2.52 (2H, t, J = 7.8 Hz), 4.55 (1H, sept, J = 5.9 Hz), 4.77 (2H, s), 6.00 (1H, s), 6.65-6.68 (2H, m), 6.83-6.87 (1H, m), 7.01 (1H, d, J = 8.6 Hz), 7.04-7.08 (2H, m), 7.24-7.30 (1H, m), 7.57 (1H, d, J = 8.6 Hz), 7.64 (1H, s), 8.33 (1H, d, J = 6.2 Hz).
ジクロロメタン(6.7mL)に0℃にてアセチルクロライド(189 μL, 2.66 mmol)、塩化アルミニウム(267 mg, 2.0 mmol)を順に加え、0℃にて10分間撹拌した。その後、シクロプロピル(フェニル)スルファン(200 mg, 1.33 mmol)のジクロロメタン(890 μL)溶液を加え、0℃にて30分間撹拌した。反応液に5%塩酸水溶液を加え、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、1-(4-(シクロプロピルチオ)フェニル)エタノン 181 mg(収率71%)を無色油状物として得た。
1H-NMR (CDCl3) δ:0.69-0.75 (2H, m), 1.12-1.19 (2H, m), 2.16-2.25 (1H, m), 2.58 (3H, s), 7.41 (2H, d, J = 8.9 Hz), 7.87 (2H, d, J = 8.9 Hz).
1H-NMR (CDCl3) δ:0.56-0.62 (2H, m), 1.05-1.12 (2H, m), 1.74 (3H, s), 2.18-2.26 (1H, m), 7.34-7.44 (4H, m).
1H-NMR (CDCl3) δ:0.65-0.69 (2H, m), 0.88 (3H, t, J = 7.3 Hz), 1.04-1.11 (2H, m), 1.57 (2H, qt, J = 7.3, 7.6 Hz), 1.82 (3H, s), 2.12-2.20 (1H, m), 2.52 (2H, t, J = 7.6 Hz), 4.77 (2H, s), 6.09 (1H, s), 6.66 (1H, s), 6.67 (1H, d, J = 5.4 Hz), 7.01 (1H, d, J = 8.9 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.9 Hz), 7.64 (1H, s), 8.34 (1H, d, J = 5.4 Hz).
1H-NMR (270 MHz, CD3OD) δ:0.86 (3H, t, J = 7.3 Hz), 1.22 (6H, d, J = 6.7 Hz), 1.54 (2H, qt, J = 7.3, 7.6 Hz), 1.72 (3H, s), 2.50 (2H, t, J = 7.6 Hz), 2.89 (1H, sept, J = 6.7 Hz), 4.70 (2H, s), 6.66 (1H, d, J = 2.2 Hz), 6.80 (1H, dd, J = 2.6, 5.8 Hz), 7.09 (1H, d, J = 9.0 Hz), 7.25 (2H, d, J = 8.5 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.63 (1H, d, J = 9.0 Hz), 7.70 (1H, s), 8.33 (1H, d, J = 5.8 Hz).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.4 Hz), 1.30 (9H, s), 1.56 (2H, qt, J = 7.6, 7.4 Hz), 2.36 (3H, s), 2.45 (2H, t, J = 7.6 Hz), 5.03 (1H, d, J = 17.2 Hz), 5.13 (1H, d, J = 17.2 Hz), 6.92 (1H, s), 7.06 (1H, d, J = 8.5 Hz), 7.13-7.28 (1H, m), 7.41 (4H, s), 7.70 (1H, d, J = 8.5 Hz), 7.76 (1H, s), 8.71 (1H, d, J = 6.8 Hz).
1H-NMR (CD3OD) δ:0.86 (3H, t, J = 7.3 Hz), 1.31 (6H, d, J = 5.9 Hz), 1.56 (2H, qt, J = 7.6, 7.3 Hz), 1.71 (3H, s), 2.52 (2H, t, J = 7.6 Hz), 4.59 (1H, sept, J = 5.9 Hz), 4.89 (2H, s), 6.68 (1H, d, J = 2.2 Hz), 6.79 (1H, dd, J = 2.6, 5.9 Hz), 7.08-7.13 (1H, m), 7.21-7.32 (3H, m), 7.64 (1H, d, J = 8.6 Hz), 7.70 (1H, s), 8.33 (1H, d, J = 5.9 Hz).
1H-NMR (270 MHz, CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.56 (2H, qt, J = 7.8, 7.3 Hz), 1.78 (3H, s), 2.44 (2H, t, J = 7.8 Hz), 2.48 (3H, s), 5.09 (2H, s), 6.87 (1H, s), 7.17 (1H, d, J = 6.8 Hz), 7.23 (1H, d, J = 2.4 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.68-7.76 (2H, m), 8.70 (1H, d, J = 6.8 Hz).
4-(3-メトキシ)フェニル)-1-エタノンを用いて実施例1-a)と同様に反応、処理し、5-(4-(3-メトキシ)フェニル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (270 MHz, DMSO ) δ:1.62 (3H, s), 3.58 (3H, s), 6.88-7.05 (3H, m), 7.28-7.34 (1H, m), 8.59 (1H, s).
1H-NMR (270 MHz, CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.56 (2H, qt, J = 7.8, 7.3 Hz), 1.78 (3H, s), 2.45 (2H, t, J = 7.8 Hz), 3.82 (3H, s), 5.05 (1H, d, J = 16.9 Hz), 5.23 (1H, d, J = 16.9 Hz), 6.88 (1H, dd, J = 2.2, 8.6 Hz), 6.92 (1H, s), 7.05-7.34 (5H, m), 7.70 (1H, d, J = 8.1 Hz), 7.76 (1H, s), 8.71 (1H, d, J = 6.5 Hz).
1H-NMR (270 MHz, CD3OD) δ:0.88 (3H, t, J = 7.3 Hz), 1.58 (2H, qt, J = 7.4, 7.3 Hz), 1.93 (3H, s), 2.56 (2H, t, J = 7.4 Hz), 4.87 (1H, d, J = 17.6 Hz), 5.00 (1H, d, J = 17.6 Hz), 7.31 (1H, d, J = 5.9 Hz), 7.32 (1H, d, J = 6.9 Hz), 7.64-7.76 (3H, m), 7.82 (1H, s), 7.92 (1H, d, J = 8.4 Hz), 8.23 (1H, t, J = 7.8 Hz), 8.64 (1H, d, J = 6.9 Hz), 8.68 (1H, d, J = 7.8 Hz).
1H-NMR (270 MHz, CD3OD) δ:0.89 (3H, t, J = 7.3 Hz), 1.51-1.64 (2H, m), 1.89 (3H, s), 2.56 (2H, t, J = 7.6 Hz), 4.85 (1H, d, J = 18.4 Hz), 4.93 (1H, d, J = 18.4 Hz), 7.27-7.35 (3H, m), 7.73 (1H, d, J = 8.4 Hz), 7.81 (1H, s), 8.10-8.19 (1H, m), 8.59-8.62 (1H, m), 8.81-8.88 (2H, m), 9.04 (1H, s).
1H-NMR (270 MHz, CD3OD) δ:0.87 (3H, t, J = 7.3 Hz), 1.57 (2H, qt, J = 7.6, 7.3 Hz), 1.76 (3H, s), 2.51 (2H, t, J = 7.6 Hz), 4.83-4.94 (4H, m), 6.94 (1H, d, J = 8.4 Hz), 7.20 (1H, s), 7.27 (1H, d, J = 8.4 Hz), 7.37 (1H, d, J = 8.4 Hz), 7.75 (1H, d, J = 8.4 Hz), 7.80 (1H, s), 7.91 (1H, dd, J = 2.6, 8.4 Hz), 8.27 (1H, d, J = 2.2 Hz), 8.63 (1H, d, J = 8.4 Hz).
1H-NMR (400 MHz, CD3OD) δ:0.77 (3H, t, J = 7.3 Hz), 1.44 (2H, qt, J = 7.3, 7.6 Hz), 1.83 (3H, s), 2.37 (2H, t, J = 7.6 Hz), 4.94 (2H, s), 7.10 (1H, d, J = 2.6 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.29 (1H, dd, J = 6.8, 2.6 Hz), 7.51-7.53 (2H, m), 7.64 (1H, dd, J = 8.8, 2.0 Hz), 7.68 (1H, d, J = 8.3 Hz), 7.74 (1H, s), 7.88-7.92 (3H, m), 7.99 (1H, s), 8.59 (1H, d, J = 6.8 Hz).
1H-NMR (400 MHz, CD3OD) δ:0.89 (3H, t, J = 7.3 Hz), 1.59 (2H, qt, J = 7.3, 7.6 Hz), 1.89 (3H, s), 2.56 (2H, t, J = 7.6 Hz), 4.98 (2H, s), 7.30 (1H, d, J = 8.7 Hz), 7.33 (1H, dd, J = 6.8. 2.4 Hz), 7.35 (1H, s), 7.74 (1H, d, J = 8.7 Hz), 7.81 (1H, s), 8.32 (2H, d, J = 6.8 Hz), 8.62 (1H, d, J = 6.8 Hz), 8.93 (2H, d, J = 6.8 Hz).
1H-NMR (400 MHz, CD3OD) δ:0.88 (3H, t, J = 7.3 Hz), 1.60 (2H, qt, J = 7.3, 7.6 Hz), 1.90 (3H, s), 2.56 (2H, t, J = 7.6 Hz), 5.04 (2H, s), 7.27 (1H, dd, J = 2.4, 6.7 Hz), 7.29 (1H, d, J = 8.8 Hz), 7.43 (1H, d, J = 2.4 Hz), 7.74 (1H, d, J = 8.6 Hz), 7.82 (1H, s), 8.61-8.63 (3H, m), 8.87 (1H, s).
実施例148 5-(フロ[2,3-b]ピリジン-5-イル)-3-((4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)メチル)-5-メチルイミダゾリジン-2,4-ジオンの製造:
6-ヒドロキシニコチン酸(5.0 g, 35.9 mmol)のエタノール(180 mL)溶液に硫酸(1.0 mL)を加え、60℃にて20分間攪拌した。その後、硫酸(33.0 mL)を加え、加熱還流下6時間30分攪拌した。氷冷下飽和炭酸水素ナトリウム水溶液を加え、エタノールを減圧濃縮した。酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し、減圧濃縮し、6-ヒドロキシニコチン酸エチル 5.33 g(収率89 %)を白色結晶として得た。
1H-NMR (CDCl3) δ:1.36 (3H, t, J = 7.1 Hz), 4.33 (2H, q, J = 7.1 Hz), 6.58 (1H, d, J = 9.5 Hz), 8.01 (1H, dd, J = 2.4, 9.5 Hz), 8.19 (1H, d, J = 2.4 Hz), 12.43 (1H, brs).
6-ヒドロキシニコチン酸エチル(2.0 g, 12.0 mmol)をピリジン (60 mL)に溶解させた後、ヨウ素(6.07 g, 23.9 mmol)を加え、60℃にて終夜攪拌した。その後、室温にて水を加え、酢酸エチルで抽出した後、有機層を飽和亜硫酸ナトリウム水溶液、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。得られた残渣をカラムクロマトグラフィー(クロロホルム/メタノール)で精製し、減圧濃縮し、6-ヒドロキシ-5-ヨードニコチン酸エチル 2.9 g(収率83 %)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.37 (3H, t, J = 7.1 Hz), 4.34 (2H, q, J = 7.1 Hz), 8.30 (1H, d, J = 2.2 Hz), 8.64 (1H, d, J = 2.2 Hz), 12.75 (1H, brs).
6-ヒドロキシ-5-ヨードニコチン酸エチル(200 mg, 0.682 mmol)にN,N‘-ジメチルホルムアミド (4.1 mL)、水(1.4 mL)を加えた。その後、テトラキストリフェニルホスフィンパラジウム(79 mg, 0.0682 mmol)、ビニルボロン酸(417 μL, 2.46 mmol)、炭酸ナトリウム(433 mg, 4.09 mmol)を加え、80℃にて20分間攪拌した。その後、さらにテトラキストリフェニルホスフィンパラジウム(79 mg, 0.0682 mmol)、ビニルボロン酸(417 μL, 2.46 mmol)を加え、80℃にて20分間攪拌した。反応液をセライトろ過し、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(クロロホルム/アセトン)で精製し、減圧濃縮し、6-ヒドロキシ-5-ビニルニコチン酸エチル 95 mg(収率72 %)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.38 (3H, t, J = 7.3 Hz), 4.35 (2H, q, J = 7.3 Hz), 5.45 (1H, d, J = 11.2 Hz), 6.15 (1H, d, J = 17.8 Hz), 6.80 (1H, dd, J = 11.2, 17.8 Hz), 8.08 (1H, d, J = 2.2 Hz), 8.14 (1H, d, J = 2.2 Hz), 12.49 (1H, brs).
6-ヒドロキシ-5-ビニルニコチン酸エチル(439 mg, 2.27 mmol)にテトラヒドロフラン (5.7 mL)、水(5.7 mL)を加えた。その後、氷冷下N-クロロスクシンイミド(607 mg, 4.55 mmol)を加え、室温にて終夜攪拌した。その後、トリエチルアミン(1.26 mL, 9.09 mmol)、60℃にて2時間攪拌した。反応液を減圧濃縮した。得られた残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、減圧濃縮し、3-ヒドロキシ-2,3-ジヒドロフロ[2,3-b]ピリジン-5-カルボン酸エチル 577 mg(収率>100 %)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.39 (3H, t, J = 7.3 Hz), 2.92 (1H, brs), 4.37 (2H, q, J = 7.3 Hz), 4.58 (1H, dd, J = 3.0, 10.8 Hz), 4.75 (1H, dd, J = 7.0, 10.8 Hz), 5.48 (1H, brs), 8.34 (1H, d, J = 2.2 Hz), 8.82 (1H, d, J = 2.2 Hz).
3-ヒドロキシ-2,3-ジヒドロフロ[2,3-b]ピリジン-5-カルボン酸エチル(577 mg, 2.27 mmol)のジクロロメタン(11 mL)溶液に トリエチルアミン(1.89 mL, 13.6 mmol)を加え、氷冷下メタンスルホン酸無水物(951 mg, 5.46 mmol)を加え、室温にて1時間攪拌した。反応液に水を加え、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(ヘキサン/アセトン)で精製し、減圧濃縮し、フロ[2,3-b]ピリジン-5-カルボン酸エチル 114 mg(収率26 %)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.44 (3H, t, J = 7.3 Hz), 4.44 (2H, q, J = 7.3 Hz), 6.87 (1H, d, J = 2.7 Hz), 7.78 (1H, d, J = 2.7 Hz), 8.60 (1H, d, J = 1.9 Hz), 9.02 (1H, d, J = 1.9 Hz).
フロ[2,3-b]ピリジン-5-カルボン酸エチル(114 mg, 0.597 mmol)のメタノール(3.0 mL)溶液に 氷冷下1N-水酸化ナトリウム水溶液(3.0 mL)を加え、室温にて1時間攪拌した。反応液に5%塩酸水溶液を加え、トルエンを加えた後、減圧濃縮し、フロ[2,3-b]ピリジン-5-カルボン酸259 mg(収率>100 %)を黄色油状物として得た。
1H-NMR (CDCl3) δ:7.04 (1H, d, J = 2.4 Hz), 7.99 (1H, d, J = 2.4 Hz), 8.69 (1H, d, J = 2.0 Hz), 8.92 (1H, d, J = 2.0 Hz).
フロ[2,3-b]ピリジン-5-カルボン酸を用いて実施例13-a)と同様に反応・処理し、N-メトキシ-N-メチルフロ[2,3-b]ピリジン-5-カルボキサミドを黄色油状物として得た。
1H-NMR (CDCl3) δ:3.42 (3H, s), 3.55 (3H, s), 6.84 (1H, d, J = 2.7 Hz), 7.76 (1H, d, J = 2.7 Hz), 8.34 (1H, d, J = 2.2 Hz), 8.74 (1H, d, J = 2.2 Hz).
N-メトキシ-N-メチルフロ[2,3-b]ピリジン-5-カルボキサミドを用いて実施例1-a)と同様に反応・処理し、1-(フロ[2,3-b]ピリジン-5-イル)エタノンを黄色油状物として得た。
1H-NMR (CDCl3) δ:2.71 (3H, s), 6.90 (1H, d, J = 2.7 Hz), 7.80 (1H, d, J = 2.7 Hz), 8.56 (1H, d, J = 2.2 Hz), 8.97 (1H, d, J = 2.2 Hz).
1-(フロ[2,3-b]ピリジン-5-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(フロ[2,3-b]ピリジン-5-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.85 (3H, s), 6.97 (1H, d, J = 2.4 Hz), 7.93 (1H, d, J = 2.4 Hz), 8.29 (1H, d, J = 2.2 Hz), 8.44 (1H, d, J = 2.2 Hz).
1H-NMR (400 MHz, CD3OD) δ:0.83 (3H, t, J = 7.6 Hz), 1.51 (2H, qt, J = 7.3, 7.6 Hz), 1.84 (3H, s), 2.47 ( 2H, t, J = 7.6 Hz), 4.96 (2H, s), 6.98 (1H, d, J = 2.4 Hz), 7.21 (1H, d, J = 2.7 Hz), 7.26 (1H, d, J = 8.6 Hz), 7.37 (1H, dd, J = 2.4, 6.8 Hz), 7.73 (1H, d, J = 8.6 Hz), 7.79 (1H, s), 7.96 (1H, d, J = 2.4 Hz), 8.30 (1H, d, J = 2.4 Hz), 8.42 (1H, d, J = 2.4 Hz), 8.63 (1H, d, J = 6.8 Hz).
5-(フロ[2,3-b]ピリジン-5-イル)-5-メチルイミダゾリジン-2,4-ジオン(22.5 mg, 0.097 mmol)のメタノール(500μL)溶液にパラジウムカーボン(2.3 mg)を加えて、水素雰囲気下、室温にて9時間攪拌した。反応液をセライトろ過し、減圧濃縮し、5-(2,3-ジヒドロフロ[2,3-b]ピリジン-5-イル)-5-メチルイミダゾリジン-2,4-ジオンを淡黄色油状物として得た。
1H-NMR (CDCl3) δ:1.75 (3H, s), 3.30 (2H, t, J = 8.8 Hz), 4.66 (2H, t, J = 8.8 Hz), 7.80 (1H, d, J = 2.4 Hz), 7.98 (1H, d, J = 2.4 Hz).
1H-NMR (400 MHz, CD3OD) δ:0.86 (3H, t, J = 7.3 Hz), 1.55 (2H, qt, J = 7.3, 7.5 Hz), 1.73 (3H, s), 2.53 ( 2H, t, J = 7.5 Hz), 3.27-3.31 (2H, m), 4.66 (2H, t, J = 8.7 Hz), 4.71 (2H, s), 6.69 (1H, d, J = 2.4 Hz), 6.81 (1H, dd, J = 2.4, 5.9 Hz), 7.12 (1H, d, J = 8.6 Hz), 7.64 (1H, d, J = 8.6 Hz), 7.71 (1H, s), 7.85 (1H, s), 7.97 (1H, d, J = 2.2 Hz), 8.33 (1H, d, J = 5.9 Hz).
1H-NMR (CDCl3) δ:0.86 (3H, t, J = 7.3 Hz), 1.49-1.59 (2H, m), 1.72 (3H, s), 2.48 (2H, t, J = 7.3 Hz), 3.97 (3H, s), 4.92 (2H, s), 6.92-6.96 (2H, m), 7.12 (1H, d, J = 2.7 Hz), 7.25 (1H, d, J = 8.6 Hz), 7.37 (1H, dd, J = 2.7, 6.6 Hz), 7.38-7.42 (2H, m), 7.73 (1H, d, J = 8.6 Hz), 7.80 (1H, s), 8.64 (1H, d, J = 6.6 Hz).
1H-NMR (270 MHz, CD3OD) δ:0.87 (3H, t, J = 7.0 Hz), 1.49-1.59 (2H, m), 1.75 (3H, s), 2.51 (2H, t, J = 7.0 Hz), 4.92 (2H, s), 7.00 (1H, d, J = 8.8 Hz), 7.10-7.28 (3H, m), 7.35-7.40 (1H, m), 7.68-7.82 (2H, m), 7.98-8.04 (1H, m), 8.32 (1H, d, J = 5.9 Hz), 8.61 (1H, d, J = 7.0 Hz).
1H-NMR (270 MHz, CD3OD) δ:0.87 (3H, t, J = 7.5 Hz), 1.52-1.60 (2H, m), 1.67 (3H, s), 2.52 (2H, t, J = 7.5 Hz), 4.93 (2H, s), 5.14 (1H, d, J = 14.4 Hz), 5.26 (1H, d, J = 14.4 Hz), 6.60 (1H, d, J = 9.3 Hz), 7.12-7.31 (7H, m), 7.37 (1H, d, J = 7.0 Hz), 7.65 (1H, d, J = 9.3 Hz), 7.73 (1H, d, J = 8.4 Hz), 7.79-7.82 (2H, m), 8.63 (1H, d, J = 6.8 Hz).
2-ヒドロキシアセトフェノン(1.36 g, 10.0 mmol)をアセトン (50 mL) に溶解し、室温にて炭酸カリウム (2.76 g, 20.0 mmol) とアリルブロミド (1.27 mL, 15.0 mmol) を加えた後、3時間加熱還流した。反応液を室温に戻し、酢酸エチルを加え、水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣を、シリカゲルカラムクロマトグラフィー(n-ヘキサン/酢酸エチル=10/1) で精製し、1-(4-(アリルオキシ)フェニル)エタノン 1.76 g (100%) を無色油状物として得た。
1H-NMR (CDCl3) δ:2.56 (3H, s), 4.60-4.62 (2H, m), 5.31-5.45 (2H, m), 6.00-6.09 (1H, m), 6.93-6.97 (2H, m), 7.92-7.95 (2H, m).
1-(4-(アリルオキシ)フェニル)エタノン(80.0 mg, 0.45 mmol)をポリエチレングリコール400 (0.3 mL) に加え、マイクロウェーブ波照射下250℃にて1時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣を分取薄層クロマトグラフィー(n-ヘキサン/酢酸エチル=2/1) で精製し、1-(3-アリル-4-ヒドロキシフェニル)エタノン 63 mg (収率79%) を淡赤褐色固体として得た。
1H-NMR (CDCl3) δ:2.54 (3H, s), 3.46 (2H, d, J = 6.2 Hz), 5.16-5.23 (2H, m), 6.85 (1H, d, J = 8.9 Hz), 7.00-7.12 (1H, m), 7.78-7.81 (2H, m).
1-(3-アリル-4-ヒドロキシフェニル)エタノン(56 mg, 0.32 mmol) を塩化メチレン (1.6 mL) に溶解し、アルゴン雰囲気下室温にて塩化ジルコニウム(IV) (90 mg, 0.38 mmol) を加え、一晩中撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、分取薄層クロマトグラフィー (n-ヘキサン/酢酸エチル=4/1) で精製し、1-(2-メチル-2,3-ジヒドロベンゾフラン-5-イル)エタノン 24 mg (収率43%) を無色油状物として得た。
1H-NMR (CDCl3) δ:1.49 (3H, d, J = 6.2 Hz), 2.54 (3H, s), 2.84 (1H, dd, J = 7.0, 15.4 Hz), 3.36 (1H, dd, J = 8.9, 15.4 Hz), 4.98-5.07 (1H, m), 6.77 (1H, d, J = 7.8 Hz), 7.77-7.82 (2H, m).
1-(2-メチル-2,3-ジヒドロベンゾフラン-5-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(2-メチル-2,3-ジヒドロベンゾフラン-5-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CD3OD) δ:1.40 (3H, d, J = 6.4 Hz), 1.72 (3H, s), 2.80 (1H, dd, J = 7.6, 15.6 Hz), 3.30-3.35 (1H, m), 4.86-4.91 (1H, m), 6.67 (1H, dd, J = 8.4 Hz), 7.20 (1H, d, J= 8.4 Hz), 7.30 (1H, s).
3-ヒドロキシアセトフェノン(1.36 g, 10.0 mmol)をアセトン (50 mL) に溶解し、室温にて炭酸カリウム (2.76 g, 20.0 mmol) とアリルブロミド (1.27 mL, 15.0 mmol) を加えた後、2時間加熱還流した。反応液を室温に戻し、酢酸エチルを加え、水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣を、シリカゲルカラムクロマトグラフィー(n-ヘキサン/ 酢酸エチル=10/1) で精製し、1-(3-(アリルオキシ)フェニル)エタノン 1.76 g (100%) を淡黄色油状物として得た。
1H-NMR (CDCl3) δ:2.59 (3H, s), 4.60 (2H, d, J = 5.4 Hz), 5.31 (1H, dd, J = 1.5, 10.5 Hz), 5.43 (1H, dd, J = 1.5, 17.3 Hz), 6.02-6.11 (1H, m), 7.13 (1H, d, J = 8.3 Hz), 7.37 (1H, t, J = 7.8 Hz), 7.50-7.55 (1H, m).
1-(3-(アリルオキシ)フェニル)エタノン(240 mg, 13.5 mmol)をポリエチレングリコール400 (0.9 mL) に加え、マイクロウェーブ波照射下250℃にて1時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣を分取薄層クロマトグラフィー(n-ヘキサン/酢酸エチル=2/1) で精製し、1-(4-アリル-3-ヒドロキシフェニル)エタノン 22 mg (9%) を無色固体として得た。
1H-NMR (CDCl3) δ:2.59 (3H, s), 3.47 (2H, d, J = 6.5 Hz), 5.10-5.18 (2H, m), 5.94-6.09 (1H, m), 7.21 (1H, d, J = 8.1 Hz), 7.47 (1H, dd, J= 1.9, 8.1 Hz), 7.57 (1H, d, J = 1.9 Hz).
1-(4-アリル-3-ヒドロキシフェニル)エタノン(863 mg, 4.90 mmol) を塩化メチレン (25 mL) に溶解し、アルゴン雰囲気下室温にて塩化ジルコニウム(IV) (1.37g, 5.88 mmol) を加え、一晩中撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、シリカゲルカラムクロマトグラフィー (n-ヘキサン/酢酸エチル=6/1) で精製し、1-(2-メチル-2,3-ジヒドロベンゾフラン-6-イル)エタノン 167 mg (収率19%) を黄色油状物として得た。
1H-NMR (CD3OD) δ:1.48 (3H, d, J = 6.4 Hz), 2.56 (3H, s), 2.85 (1H, dd, J = 8.8, 16.0 Hz), 3.36 (1H, dd, J = 8.8, 16.0 Hz), 4.94-5.03 (1H, m), 7.22 (1H, d, J = 7.6 Hz), 7.31 (1H, s), 7.47 (1H, d, J= 7.6 Hz).
1-(2-メチル-2,3-ジヒドロベンゾフラン-6-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、表題化合物を白色結晶として得た。
1H-NMR (CD3OD) δ:1.40 (3H, d, J = 6.0 Hz), 1.71 (3H, s), 2.77 (1H, dd, J = 7.2, 15.6 Hz), 3.26-3.33 (1H, m), 4.85-4.93 (1H, m), 6.83 (1H, d, J = 2.0 Hz), 6.95 (1H, dd, J= 2.0, 8.0 Hz), 7.15 (1H, d, J = 8.0 Hz).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.45 (3H, d, J = 6.2 Hz), 1.57 (2H, qt, J = 7.3, 7.6 Hz), 1.79 (3H, s), 2.51 (2H, t, J = 7.6 Hz), 2.79 (1H, dd, J = 7.6, 15.1 Hz), 3.29 (1H, dd, J = 8.6, 15.1 Hz), 4.76 (2H, s), 4.87-5.01 (1H, m), 5.99 (1H, s), 6.62 (1H, d, J = 2.4 Hz), 6.68 (1H, dd, J = 2.4, 5.4 Hz), 6.90 (1H, d, J = 1.9 Hz), 6.97 (1H, dd, J = 1.9, 7.8 Hz), 7.01 (1H, d, J = 8.6 Hz), 7.13 (1H, d, J = 7.8 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.64 (1H, s), 8.34 (1H, d, J = 5.4 Hz).
アルゴン雰囲気下0℃にてプロピオニルクロリド (0.72 mL, 8.30 mmol) のジクロロメタン (10 mL) 溶液に塩化アルミニウム (835 mg, 6.25 mmol) を加え10分間撹拌後、同温にて1,2-ジヒドロベンゾフラン(500 mg, 4.15 mmol) のジクロロメタン (11 mL) 溶液を滴下した。5分間撹拌後、0℃にて1N HClを加え、酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー (n-ヘキサン/酢酸エチル) で精製し、1-(2,3-ジヒドロベンゾフラン-5-イル)プロパン-1-オン 716 mg (収率98%) を白色固体として得た。
1H-NMR (CD3OD) δ:1.21 (3H, t, J = 7.6 Hz), 2.94 (2H, q, J = 7.6 Hz), 3.25 (2H, t, J = 8.8 Hz), 4.66 (2H, t, J = 8.8 Hz), 6.80 (1H, d, J = 8.4 Hz), 7.81 (1H, d, J = 8.4 Hz), 7.86 (1H, s).
1-(2,3-ジヒドロベンゾフラン-5-イル)プロパン-1-オンを用いて実施例1-a)と同様に反応・処理し、5-(2,3-ジヒドロベンゾフラン-5-イル)-5-エチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CD3OD) δ:0.91 (3H, t, J = 7.2 Hz), 1.95-2.01 (1H, m), 2.14-2.20 (1H, m), 3.20 (2H, t, J= 8.4 Hz), 4.54 (2H, t, J = 8.8 Hz), 6.71 (1H, d, J = 8.4 Hz), 7.23 (1H, d, J = 8.4 Hz), 7.37 (1H, s).
1H-NMR (CDCl3) δ:0.88 (6H, t, J = 7.3 Hz), 1.56 (2H, qt, J = 7.3, 7.6 Hz), 2.03-2.33 (2H, m), 2.51 (2H, t, J = 7.6 Hz), 3.20 (2H, t, J = 8.6 Hz), 4.57 (2H, t, J = 8.6 Hz), 4.76 (2H, s), 6.08 (1H, s), 6.64 (1H, dd, J = 2.2, 5.7 Hz), 6.70 (1H, d, J = 2.2 Hz), 6.75 (1H, d, J = 8.6 Hz), 6.99 (1H, d, J = 8.6 Hz), 7.24 (1H, dd, J = 2.2, 8.6 Hz), 7.40 (1H, d, J = 2.2 Hz), 7.57 (1H, d, J = 8.6 Hz), 7.63 (1H, s), 8.32 (1H, d, J = 5.7 Hz).
3-ヒドロキシアセトフェノン(1.36 g, 10.0 mmol)をN,N-ジメチルホルムアミド (50 mL) に溶解し、室温にて炭酸カリウム (2.76 g, 20.0 mmol)、2-メチル-2-プロペニルクロリド (1.5 mL, 15.0 mmol)、及びヨウ化テトラn-ブチルアンモニウム (370 mg, 1.00 mmol) を加えた後、80℃にて2時間撹拌した。反応液に水を加え、エーテルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した後、得られた残渣を、シリカゲルカラムクロマトグラフィー(n-ヘキサン/酢酸エチル=10/1) で精製し、1-(3-(2-メチル-3-プロペニルオキシ)フェニル)エタノン 1.93 g (100%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.83 (3H, s), 2.60 (3H, s), 4.49 (2H, s), 5.06 (2H, d, J = 27.8 Hz), 7.01-7.16 (1H, m), 7.37 (1H, t, J = 8.1 Hz), 7.49-7.55 (1H, m).
1-(3-(2-メチル-3-プロペニルオキシ)フェニル)エタノン(765 mg, 13.5 mmol)をポリエチレングリコール400 (0.9 mL) に加え、マイクロウェーブ波照射下250℃にて1時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣を分取薄層クロマトグラフィー(n-ヘキサン/酢酸エチル=10/1) で精製し、1-(3-ヒドロキシ-4-(2-メチル-3-プロペニル)フェニル)エタノン 32 mg (13%) を無色固体として得た。
1H-NMR (CDCl3) δ:1.75 (3H, s), 2.58 (3H, s), 3.43 (2H, s), 4.90 (2H, d, J = 28.6 Hz), 7.19 (1H, d, J= 7.6 Hz), 7.43-7.50 (2H, m).
1-(3-ヒドロキシ-4-(2-メチル-3-プロペニル)フェニル)エタノン(1.15 g, 6.04 mmol) をメタノール (30 mL) に溶解し、室温にて塩酸 (8 mL) を加え、70℃にて4.5時間撹拌した。氷冷下にて反応液に飽和重曹水を加えて中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、シリカゲルカラムクロマトグラフィー (n-ヘキサン/ 酢酸エチル=10/1) で精製し、1-(2,2-ジメチル-2,3-ジヒドロベンゾフラン-6-イル)エタノン 961 mg (収率84%) を赤褐色油状物として得た。
1H-NMR (CDCl3) δ:1.49 (6H, s), 2.56 (3H, s), 3.04 (2H, s), 7.20 (1H, d, J = 7.8 Hz), 7.28 (1H, d, J= 1.4 Hz), 7.46 (1H, dd, J = 1.4, 7.8 Hz).
1-(2,2-ジメチル-2,3-ジヒドロベンゾフラン-6-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(2,2-ジメチル-2,3-ジヒドロベンゾフラン-6-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CD3OD) δ:1.43 (6H, s), 1.72 (3H, s), 3.00 (2H, s), 6.80 (1H, d, J = 2.0 Hz), 6.94 (1H, dd, J= 2.0, 8.0 Hz), 7.14 (1H, d, J = 8.0 Hz).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.0 Hz), 1.46 (6H, s), 1.55 (2H, qt, J = 7.0, 7.3 Hz), 1.80 (3H, s), 2.52 (2H, t, J = 7.3 Hz), 2,98 (2H, s), 4.77 (2H, s), 5.93 (1H, s), 6.62 (1H, d, J = 2.4 Hz), 6.68 (1H, dd, J = 2.4, 5.4 Hz), 6.87 (1H, d, J = 1.6 Hz), 6.96 (1H, dd, J = 1.6, 7.8 Hz), 7.02 (1H, d, J = 8.4 Hz), 7.12 (1H, d, J = 7.8 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.64 (1H, s), 8.34 (1H, d, J = 5.4 Hz).
1H-NMR (CDCl3) δ:0.89 (3H, t, J = 7.6 Hz), 1.45 (6H, s), 1.57 (2H, qt, J = 7.6, 7.8 Hz), 1.81 (3H, s), 2.53 (2H, t, J = 7.8 Hz), 2,99 (2H, s), 4.77 (2H, s), 5.92 (1H, s), 6.65-6.70 (3H, m), 7.01 (1H, d, J = 8.9 Hz), 7.22 (1H, dd, J = 1.9, 8.6 Hz), 7.32 (1H, d, J = 1.9 Hz), 7.58 (1H, d, J = 8.9 Hz), 7.64 (1H, s), 8.33 (1H, d, J = 6.8 Hz).
(2-ヒドロキシピリジン-5-イル)エタノン(100 mg, 0.55 mmol)をテトラヒドロフラン (3 mL)に溶解し、ヨードトリジウテリウムメタン (86 mL, 1.38 mmol) を加え、0℃にて水素化アルミニウム (27 mg, 0.61 mmol) を加え室温にて撹拌した。30分後、ヨードトリジウテリウムメタン (86 mL, 1.38 mmol) を追加し、更に30分間撹拌した。0℃にて反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、シリカゲルカラムクロマトグラフィー (n-ヘキサン/ 酢酸エチル=1/1) で精製し、N-メトキシ-N-メチル-6-トリジウテリウムメトキシニコチンアミド 94 mg (収率86%) を白色固体として得た。
1H-NMR (CD3OD) δ:3.34 (3H, s), 3.63 (3H, s), 6.53 (1H, d, J= 9.5 Hz), 7.85 (1H, dd, J = 2.4, 9.5 Hz), 8.09 (1H, d, J = 2.4 Hz).
N-メトキシ-N-メチル-6-トリジウテリウムメトキシニコチンアミド(93 mg, 0.47 mmol) をテトラヒドロフラン (2.4 mL) に溶解し、アルゴン雰囲気下0℃にて0.93 M臭化メチルマグネシウム (0.76 mL, 0.70 mmol) を滴下した。1時間撹拌した後、同温にて反応液に1N 塩酸を加えた。次に、反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルム/メタノール混合液 (=95/5) で抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、シリカゲルカラムクロマトグラフィー (クロロホルム/メタノール=10/1) で精製し、1-(2-(トリジウテリウムメチルオキシ)ピリジン-5-イル)エタノン を含む混合物62 mg (収率98%) を得た。
1H-NMR (CD3OD) δ:2.46 (3H, s), 6.57 (1H, d, J = 9.7 Hz), 7.88 (1H, dd, J = 2.7, 9.7 Hz), 8.13 (1H, d, J = 2.7 Hz).
1-(2-(トリジウテリウムメチルオキシ)ピリジン-5-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、表題化合物を白色結晶として得た。
1H-NMR (CD3OD) δ:1.70 (3H, s), 6.57 (1H, d, J = 9.5 Hz), 7.66 (1H, dd, J = 2.2, 9.5 Hz), 7.74 (1H, d, J = 2.2 Hz).
1H-NMR (CDCl3) δ:0.89 (3H, t, J = 7.3 Hz), 1.58 (2H, qt, J = 7.3, 7.3 Hz), 1.77 (3H, s), 2.54 (2H, t, J = 7.3 Hz), 4.78 (2H, s), 6.21 (1H, s), 6.52 (1H, d, J = 9.5 Hz), 6.63 (1H, d, J = 2.2 Hz), 6.74 (1H, dd, J = 2.2, 5.7 Hz), 6.94 (1H, d, J = 8.6 Hz), 7.48-7.56 (3H, m), 7.65 (1H, s), 8.36 (1H, d, J = 5.7 Hz).
1H-NMR (CDCl3) δ:0.89 (3H, t, J = 7.3 Hz), 1.56 (2H, qt, J = 7.3, 7.6 Hz), 1.79 (3H, s), 2.52 (2H, t, J = 7.6 Hz), 4.24 (4H, s), 4.77 (2H, s), 5.97 (1H, s), 6.64 (1H, d, J = 2.7 Hz), 6.67 (1H, dd, J = 2.7, 5.4 Hz), 6.85 (1H, d, J = 8.4 Hz), 6.97 (1H, dd, J = 2.4, 8.4 Hz), 7.01 (1H, d, J = 8.4 Hz), 7.07 (1H, d, J = 2.4 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.64 (1H, s), 8.34 (1H, d, J = 5.4 Hz).
シクロプロピルフェニルチオエーテル(5.0 g, 33.3 mmol) をテトラヒドロフラン (50 mL) に溶解し、アルゴン雰囲気下0℃にてn-ブチルリチウム(25.1 mL, 39.9 mmol) を5分間にて滴下した。その後―78℃にてN-ヨウ化スクシンイミド(8.99 g, 39.9 mmol)のテトラヒドロフラン (100 mL)溶液を滴下した。終夜攪拌し、室温まで徐々に昇温させた。反応液に飽和炭酸水素ナトリウム水溶液を加え、ヘキサンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、シリカゲルカラムクロマトグラフィー (ヘキサン) で精製し、粗生成物 5.64 g ((1-ヨードシクロプロピル)(フェニル)スルファン:シクロプロピルフェニルチオエーテル=2.4:1) を得た。次に、5-ヒドロキシ-2-メチルピリジン(1.82 g, 16.7 mmol) をトルエン (150 mL) に溶解し、炭酸銀(9.19 g, 33.3 mmol)、1-ヨードシクロプロピル)(フェニル)スルファン:シクロプロピルフェニルチオエーテル(=2.4:1)混合物 (5.64 g, 16.7 mmol(*1-ヨードシクロプロピル)(フェニル)スルファンの量で換算)) を加え、室温にて終夜攪拌した。その後、酢酸(200 mL)を加え、10分間攪拌した。反応液をセライトろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製し、2-メチル-5-(1-(フェニルチオ)シクロプロポキシ)ピリジン 1.88 g (収率44%) を黄色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ:1.34-1.37 (2H, m), 1.44-1.50 (2H, m), 2.51 (3H, s), 7.09 (1H, d, J = 8.6 Hz), 7.22-7.35 (4H, m), 7.46-7.52 (2H, m), 8.31 (1H, d, J = 2.9 Hz).
2-メチル-5-(1-(フェニルチオ)シクロプロポキシ)ピリジン(2.04 g, 7.93 mmol) をクロロホルム (15 mL) に溶解し、アルミナ(5.0 g)、オクソン (3.79 g, 6.18 mmol) を加え、80℃にて1時間攪拌した。その後、さらにオクソン (1.36 g, 2.22 mmol) を加え、1時間攪拌した。反応液をセライトろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製し、2-メチル-5-(1-(フェニルスルホニル)シクロプロポキシ)ピリジン 542 mg (収率24%) を黄色油状物として得た。
1H-NMR (400 MHz, CD3OD) δ:1.42-1.46 (2H, m), 1.91-1.94 (2H, m), 2.47 (3H, s), 7.22 (1H, d, J = 8.6 Hz), 7.55 (1H, dd, J = 2.8, 8.6 Hz), 7.64 (2H, tt, J = 1.7, 7.0 Hz), 7.76 (1H, tt, J = 1.7, 7.0 Hz), 7.88 (2H, td, J = 1.7, 7.0 Hz), 8.16 (1H, d, J = 2.8 Hz).
2-メチル-5-(1-(フェニルスルホニル)シクロプロポキシ)ピリジン(540 mg, 1.87 mmol) をメタノール (5.5 mL) に溶解し、亜リン酸ナトリウム(671 mg, 5.598 mmol)、氷冷下ナトリウムアマルガム(3.58 g, 7.47 mmol)を加え、同温にて30分間攪拌した後、室温にて3時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣を蒸留精製し、5-シクロプロポキシ-2-メチルピリジン 240 m g (収率86%) を黄色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ:0.77-0.83 (4H, m), 2.49 (3H, s), 3.76 (1H, tt, J = 3.0, 5.7 Hz), 7.06 (1H, d, J = 8.3 Hz), 7.25 (1H, dd, J = 2.9, 8.6 Hz), 8.31 (1H, d, J = 2.9 Hz).
5-シクロプロポキシ-2-メチルピリジンを用いて116-a)と同様に反応・処理し、5-シクロプロポキシ-2-メチルピリジン 1-酸化物を白色結晶として得た。
1H-NMR (400 MHz, CDCl3) δ:0.77-0.86 (4H, m), 2.47 (3H, s), 3.74 (1H, tt, J = 3.0, 5.7 Hz), 6.91 (1H, dd, J = 2.2, 8.8 Hz), 7.12 (1H, d, J = 8.8 Hz), 8.27 (1H, d, J = 2.2 Hz).
5-シクロプロポキシ-2-メチルピリジン 1-酸化物を用いて116-a)と同様に反応・処理し、(5-シクロプロポキシピリジン-2-イル)メタノールを白色結晶として得た。
1H-NMR (400 MHz, CDCl3) δ:0.80-0.83 (4H, m), 3.39 (1H, br s), 3.80 (1H, tt, J = 3.0, 5.9 Hz), 4.71 (2H, s), 7.18 (1H, d, J = 8.5 Hz), 7.36 (1H, dd, J = 2.7, 8.5 Hz), 8.37 (1H, d, J = 2.7 Hz).
(5-シクロプロポキシピリジン-2-イル)メタノールを用いて116-a)と同様に反応・処理し、5-シクロプロポキシピコリンアルデヒドを白色結晶として得た。
1H-NMR (270 MHz, CDCl3) δ:0.82-0.92 (4H, m), 3.89 (1H, tt, J = 3.0, 5.8 Hz), 7.50 (1H, dd, J = 2.8, 8.8 Hz), 7.98 (1H, d, J = 8.8 Hz), 8.53 (1H, d, J = 2.8 Hz), 10.00 (1H, s).
5-シクロプロポキシピコリンアルデヒドを用いて116-a)と同様に反応・処理し、1-(5-シクロプロポキシピリジン-2-イル)エタノールを白色結晶として得た。
1H-NMR (400 MHz, CDCl3) δ:0.79-0.83 (4H, m), 1.49 (3H, d, J = 6.6 Hz), 3.79 (1H, tt, J = 3.0, 5.6 Hz), 3.94 (1H, d, J = 4.4 Hz), 4.85 (1H, dq, J = 4.4, 6.6 Hz), 7.20 (1H, d, J = 8.6 Hz), 7.36 (1H, dd, J = 2.8, 8.8 Hz), 8.34 (1H, d, J = 2.8 Hz).
1-(5-シクロプロポキシピリジン-2-イル)エタノールを用いて116-a)と同様に反応・処理し、1-(5-シクロプロポキシピリジン-2-イル)エタノンを白色結晶として得た。
1H-NMR (400 MHz, CDCl3) δ:0.81-0.91 (4H, m), 2.68 (3H, s), 3.86 (1H, tt, J = 3.0, 6.0 Hz), 7.44 (1H, dd, J = 2.7, 8.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.42 (1H, d, J = 2.7 Hz).
1-(5-シクロプロポキシピリジン-2-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(5-シクロプロポキシピリジン-2-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (400 MHz, CDCl3) δ:0.79-0.84 (4H, m), 1.80 (3H, s), 3.80 (1H, tt, J = 3.0, 5.9 Hz), 6.27 (1H, br-s), 7.38 (1H, dd, J = 2.9, 8.8 Hz), 7.51 (1H, br-s), 7.58 (1H, d, J = 8.8 Hz), 8.35 (1H, d, J = 2.9 Hz).
1H-NMR (CDCl3) δ:0.77-0.83 (4H, m), 0.88 (3H, t, J = 7.3 Hz), 1.56 (2H, qt, J = 7.3, 7.6 Hz), 2.05 (3H, s), 2.53 (2H, t, J = 7.6 Hz), 3.74-3.80 (1H, m), 4.82 (2H, s), 6.35 (1H, s), 6.62 (1H, dd, J = 1.9, 5.7 Hz), 6.78 (1H, d, J = 1.9 Hz), 7.01 (1H, d, J = 8.6 Hz), 7.36 (1H, dd, J = 2.4, 8.1 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.1 Hz), 7.64 (1H, s), 8.29 (1H, d, J = 5.7 Hz), 8.32 (1H, d, J = 2.4 Hz).
実施例160において2-ヒドロキシ-5-メチルピリジンの代わりに4-ヒドロキシアセトフェノンを用いて同様に反応・処理し、1-(4-(1-(フェニルスルホニル)シクロプロポキシ)フェニル)エタノンを黄色油状物として得た。
1H-NMR (CDCl3) δ:1.38-1.42 (2H, m), 1.45-1.49 (2H, m), 2.57 (3H, s), 7.13 (2H, d, J = 8.8 Hz), 7.28-7.36 (3H, m), 7.46-7.49 (2H, m), 7.96 (2H, d, J = 8.8 Hz).
1-(4-(1-(フェニルスルホニル)シクロプロポキシ)フェニル)エタノンを用いて実施例160と同様に反応・処理し、1-(4-(1-(フェニルスルホニル)シクロプロポキシ)フェニル)エタノンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.37-1.41 (2H, m), 1.96-2.00 (2H, m), 2.57 (3H, s), 7.17 (2H, d, J = 8.8 Hz), 7.55-7.59 (2H, m), 7.68-7.71 (1H, m), 7.86-7.90 (2H, m), 7.91 (2H, d, J = 8.8 Hz).
1-(4-(1-(フェニルスルホニル)シクロプロポキシ)フェニル)エタノンを用いて実施例1-a)と同様に反応・処理し、表題化合物を白色結晶として得た。
1H-NMR (CDCl3) δ:1.36-1.41 (2H, m), 1.72 (3H, s), 1.87-1.92 (2H, m), 7.08 (2H, d, J = 8.9 Hz), 7.39 (2H, d, J = 8.9 Hz), 7.55-7.62 (2H, m), 7.68-7.74 (1H, m), 7.82-7.86 (2H, m).
5-メチル-5-(4-(1-(フェニルスルホニル)シクロプロポキシ)フェニル)イミダゾリジン-2,4-ジオンを用いて実施例160と同様に反応・処理し、表題化合物を白色結晶として得た。
1H-NMR (CDCl3) δ:0.62-0.70 (2H, m), 0.72-0.81 (2H, m), 1.73 (3H, s), 3.73-3.79 (1H, m), 7.04 (2H, d, J = 8.9 Hz), 7.34 (2H, d, J = 8.9 Hz).
1H-NMR (CDCl3) δ:0.74-0.79 (4H, m), 0.89 (3H, t, J = 7.3 Hz), 1.56 (2H, qt, J = 7.3, 7.3 Hz), 1.82 (3H, s), 2.52 (2H, t, J = 7.3 Hz), 3.68-3.75 (1H, m), 4.77 (2H, s), 5.98 (1H, s), 6.66-6.69 (2H, m), 7.00 (1H, d, J = 8.1 Hz), 7.04 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.57 (1H, d, J = 8.1 Hz), 7.64 (1H, s), 8.34 (1H, d, J = 6.5 Hz).
3-ブロモフェノール(1.68 g, 9.77 mmol)のN,N‘-ジメチルホルムアミド (32 mL)溶液に、氷冷下水素化ナトリウム(純度50%) (516 mg, 10.7 mmol)、0℃にて臭化アセトアルデヒドジエチルアセタール(1.76 mL, 11.7 mmol) を加え、120℃にて終夜撹拌した。室温にて反応液に水を加え、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、シリカゲルカラムクロマトグラフィー (ヘキサン) で精製し、1-ブロモ-3-(2,2-ジエトキシエトキシ)ベンゼン2.69 g (収率>100%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.25 (6H, t, J -= 7.2 Hz), 3.57-3.70 (2H, m), 3.72-3.80 (2H, m), 3.98 (2H, d, J -= 5.2 Hz), 4.82 (1H, t, J -= 5.2 Hz), 6.84-6.87 (1H, m), 7.07-7.15 (3H, m).
1-ブロモ-3-(2,2-ジエトキシエトキシ)ベンゼン(2.3 g, 8.35 mmol)のトルエン(28 mL)溶液に、PPA (5.0 mL)、加熱還流下終夜攪拌した。室温にて反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、シリカゲルカラムクロマトグラフィー (ヘキサン) で精製し、6-ブロモベンゾフラン1.2 g (収率68%、7-ブロモベンゾフランとの混合物) を黄色油状物として得た。
1H-NMR (CDCl3) δ:6.75 (1H, dd, J -= 1.1, 2.4 Hz), 7.36 (1H, dd, J -= 1.6, 8.1 Hz), 7.46 (1H, d, J -= 8.1 Hz), 7.60 (1H, d, J -= 2.4 Hz), 7.68 (1H, s).
6-ブロモベンゾフランと7-ブロモベンゾフランの混合物(1.12 g, 5.68 mmol)のトルエン(19 mL)溶液に、テトラキストリフェニルホスフィンパラジウム (650 mg, 0.57 mmol)、トリブチル(1-エトキシビニル)スズ (2.11 mL, 6.25 mmol)を加え100℃にて終夜攪拌した。室温にて反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、シリカゲルカラムクロマトグラフィー (ヘキサン) で精製し、1-(ベンゾフラン-6-イル)エタノン (280 mg) を黄色結晶として得た。
1H-NMR (CDCl3) δ:2.67 (3H, s), 6.83 (1H, d, J -= 1.1 Hz), 7.65 (1H, d, J -= 8.4 Hz), 7.78 (1H, d, J -= 1.9 Hz), 7.89 (1H, dd, J -= 1.1, 8.4 Hz), 8.12 (1H, s).
1-(ベンゾフラン-6-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(ベンゾフラン-6-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.82 (3H, s), 6.83 (1H, dd, J -= 0.8, 1.6 Hz), 7.32 (1H, dd, J -= 1.6, 8.4 Hz), 7.63 (1H, d, J -= 8.4 Hz), 7.67 (1H, s), 7.78 (1H, d, J -= 2.2 Hz).
1H-NMR (CDCl3) δ:0.87 (3H, t, J = 7.3 Hz), 1.55 (2H, qt, J = 7.3, 7.8 Hz), 1.91 (3H, s), 2.50 (2H, t, J = 7.8 Hz), 4.79 (2H, s), 6.13 (1H, s), 6.66-6.68 (2H, m), 6.75-6.76 (1H, m), 7.00 (1H, d, J = 8.6 Hz), 7.42 (1H, dd, J = 1.6, 8.1 Hz), 7.57 (1H, d, J = 8.6 Hz), 7.60 (1H, d, J = 8.1 Hz), 7.64 (1H, s), 7.65 (1H, d, J = 1.9 Hz), 7.73 (1H, d, J = 1.6 Hz), 8.35 (1H, d, J = 6.5 Hz).
5-(ベンゾフラン-6-イル)-5-メチルイミダゾリジン-2,4-ジオンを用いて実施例149と同様に反応・処理し、5-(2,3-ジヒドロベンゾフラン-6-イル)-5-メチルイミダゾリジン-2,4-ジオンを白色結晶として得た。
1H-NMR (CDCl3) δ:1.72 (3H, s), 3.18 (2H, t, J -= 8.6 Hz), 4.54 (2H, t, J = 8.6 Hz), 6.87 (1H, d, J -= 1.4 Hz), 6.96 (1H, dd, J -= 2.2, 7.6 Hz), 7.19 (1H, d, J -= 7.6 Hz)
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.55 (2H, qt, J = 7.3, 7.8 Hz), 1.80 (3H, s), 2.51 (2H, t, J = 7.8 Hz), 3.18 (2H, t, J = 8.9 Hz), 4.58 (2H, t, J = 8.9 Hz), 4.76 (2H, s), 6.03 (1H, s), 6.62 (1H, d, J = 2.4 Hz), 6.68 (1H, dd, J = 2.4, 5.9 Hz), 6.95 (1H, d, J = 1.9 Hz), 6.99 (1H, dd, J = 1.9, 7.6 Hz), 7.01 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 7.6 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.64 (1H, s), 8.34 (1H, d, J = 5.9 Hz).
クロロメチルメトキシエーテルを用いて実施例9-a)と同様に反応・処理し、5-(メトキシメトキシ)-2-メチルピリジンを無色油状物として得た。
1H-NMR (CDCl3) δ: 2.50 (3H, s), 3.48 (3H, s), 5.17 (2H, s), 7.07 (1H, d, J= 8.4 Hz), 7.27 (1H, dd, J = 3.0, 8.4 Hz), 8.29 (1H, d, J = 3.0 Hz).
5-メトキシメトキシ-2-メチルピリジン(3.0 g, 19.6 mmol)のテトラヒドロフラン (100 mL) 溶液に、-78℃にてn-ブチルリチウム (18.4 mL, 29.4 mmol)を加え、-78℃にて40分間攪拌した。その後、(1-メチルエトキシ)ボラン酸エステル(6.8 mL, 29.4 mmol)を加え、-78℃にて45分間攪拌した。反応液に1N 塩酸水溶液を加えた後、昇温させた。反応液を酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をジエチルエーテルで洗浄ろ過し、5-(メトキシメトキシ)-2-メチルピリジン-4-イルボロン酸2.08 g (収率54%) を白色結晶として得た。
1H-NMR (CDCl3) δ: 2.53 (3H, s), 3.52 (3H, s), 5.31 (2H, s), 5.80 (2H, s), 7.54 (1H, s), 8.41 (1H, s).
5-(メトキシメトキシ)-2-メチルピリジン-4-イルボロン酸(500 mg, 2.54 mmol)のテトラヒドロフラン (12.7 mL) 溶液に、室温にて過酸化水素水溶液(純度30%) (2.9 mL, 25.4 mmol)を加え、室温にて4時間攪拌した。反応液に飽和過硫酸ナトリウム水溶液を加えた後、減圧濃縮した。得られた残渣をクロロホルム/メタノールで洗浄ろ過し、5-(メトキシメトキシ)-2-メチルピリジン-4(1H)-オン 440 mg (収率>100%) を黄色アモルファスとして得た。
1H-NMR (CDCl3) 2.37 (3H, s), 3.44 (3H,s ), 5.11 (2H, s), 6.40 (1H, s), 7.66 (1H, s).
5-(メトキシメトキシ)-2-メチルピリジン-4(1H)-オン(1.28 g, 7.56 mmol)のN,N’-ジメチルホルムアミド(19 mL)溶液に炭酸カリウム(2.10 g, 15.1 mmol)、2-ブロモエタノール(804 μL, 11.3 mmol)を順に加え、90℃にて終夜攪拌した。反応終了後、反応溶液を減圧濃縮した。得られた残渣をクロロホルム/メタノールに溶解させ、固形物をろ過し、ろ液を減圧濃縮した。得られた残渣をカラムクロマトグラフィー(ヘキサン/アセトン)にて精製し、2-(5-(メトキシメトキシ)-2-メチルピリジン-4-イルオキシ)エタノール(900 mg, 収率56%)を橙色油状物にて得た。
1H-NMR (CDCl3) 2.48 (3H, s), 3.54 (3H, s), 3.99 (2H, t, J = 4.4 Hz), 4.16 (2H, t, J = 4.4 Hz), 5.16 (2H, s), 6.70 (1H, s), 8.21 (1H, s).
2-(5-(メトキシメトキシ)-2-メチルピリジン-4-イルオキシ)エタノール(900 mg, 4.22 mmol)を酢酸エチル(10 mL)に溶解させ、4N 塩酸-酢酸エチル溶液(10 mL)を加え、室温にて5時間攪拌した。反応終了後、氷冷下4N 水酸化ナトリウム水溶液を用いて反応溶液をpH=8 にした。反応溶液を減圧濃縮した。得られた残渣をクロロホルム/メタノールにて洗浄し、乾燥し、粗生成物として4-(2-ヒドロキシエトキシ)-6-メチルピリジン-3-オール(1.2 g)を白色固形物として得た。
1H-NMR (CDCl3) δ: 2.44 (3H, s), 3.93 (2H, t, J = 4.4 Hz), 4.18 (2H, s), 6.95 (1H, s), 7.76 (1H, s).
4-(2-ヒドロキシエトキシ)-6-メチルピリジン-3-オールを用いて実施例27-b)と同様に反応・処理し、7-メチル-2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジンを無色油状物として得た。
1H-NMR (CDCl3) 2.42 (3H, s), 4.23-4.31 (4H, m), 6.64 (1H, s), 8.04 (1H, s).
7-メチル-2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジンを用いて実施例116と同様に反応・処理し、7-メチル-2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジン 6-酸化物を黄色固形物として得た。
1H-NMR (CDCl3) 2.45 (3H, s), 4.28-4.35 (4H, m), 6.75 (1H, s), 8.09 (1H, s).
7-メチル-2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジン 6-酸化物を用いて実施例16)と同様に反応・処理し、酢酸 (2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジン-7-イル)メチルを黄色油状物として得た。
1H-NMR (CDCl3) 2.14 (3H, s), 4.29-4.35 (4H, m), 5.09 (2H, s), 6.88 (1H, s), 8.16 (1H, s).
酢酸 (2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジン-7-イル)メチルを用いて実施例116と同様に反応・処理し、(2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジン-7-イル)メタノールを黄色油状物として得た。
1H-NMR (CDCl3) 4.29-4.35 (4H, m), 4.62 (2H, s), 6.76 (1H, s), 8.12 (1H, s).
(2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジン-7-イル)メタノールを用いて実施例116)と同様に反応・処理し、2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジン-7-カルバルデヒドを黄色固体として得た。
1H-NMR (CDCl3) 4.39 (4H, s), 7.51 (1H, s), 8.31 (1H, s), 9.93 (1H, s).
2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジン-7-カルバルデヒドを用いて実施例116と同様に反応・処理し、1-(2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジン-7-イル)エタノンを黄色油状物として得た。
1H-NMR (CDCl3) 2.66 (3H, s), 4.36 (4H, s), 7.60 (1H, s), 8.20 (1H, s).
1-(2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジン-7-イル)エタノンを用いて実施例1-a)と同様に反応・処理し、5-(2,3-ジヒドロ-[1,4]ジオキシノ[2,3-c]ピリジン-7-イル)-5-メチルイミダゾリジン-2,4-ジオンを無色油状物として得た。
1H-NMR (CDCl3) 1.73 (3H, s), 4.29-4.37 (4H, m), 7.06 (1H, s), 8.05 (1H,s).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.56 (2H, qt, J = 7.3, 7.8 Hz), 1.75 (3H, s), 2.52 (2H, t, J = 7.8 Hz), 4.25-4.33 (4H, m), 4.81 (2H, s), 6.55 (1H, s), 6.62 (1H, dd, J = 2.4, 5.7 Hz), 6.80 (1H, d, J = 2.4 Hz), 7.01 (1H, d, J = 8.6 Hz), 7.20 (1H, s), 7.60 (1H, d, J = 8.6 Hz), 8.06 (1H, s), 8.27 (1H, d, J = 5.7 Hz).
1H-NMR (CDCl3) δ:0.84 (6H, t, J = 7.3 Hz), 1.32 (6H, d, J = 5.7 Hz), 1.53 (4H, qt, J = 7.3, 7.8 Hz), 1.80 (3H, s), 2.36 (4H, t, J = 7.8 Hz), 4.53 (1H, sept, J = 5.7 Hz), 4.76 (2H, s), 5.72 (1H, s), 6.51-6.54 (2H, ,m), 6.87 (2H, d, J = 8.9 Hz), 7.41 (2H, d, J = 8.9 Hz), 7.47 (2H, s), 8.28 (1H, d, J = 5.1 Hz).
1H-NMR (CDCl3) δ:0.84 (6H, t, J = 7.6 Hz), 1.52-1.63 (4H, m), 1.68 (3H, s), 2.38 (4H, t, J = 7.6 Hz), 5.25 (2H, s), 5.96 (2H, s), 6.82 (1H, d, J = 8.1 Hz), 6.94-7.00 (3H, m), 7.20-7.30 (1H, m), 7.60 (2H, s), 8.59 (1H, d, J = 6.5 Hz).
1H-NMR (CDCl3) δ:0.85 (6H, t, J = 7.3 Hz), 1.47-1.60 (4H, m), 1.73 (3H, s), 2.38 (4H, t, J = 7.6 Hz), 3.96 (3H, s), 4.52 (2H, s), 6.94 (1H, d, J = 8.9 Hz), 7.09 (1H, s), 7.38 (1H, s), 7.62 (2H, s), 7.90 (1H, s), 8.24 (1H, d, J = 2.7 Hz), 8.65 (1H, d, J = 6.8 Hz).
1H-NMR (CDCl3) δ:0.83 (6H, t, J = 7.4 Hz), 1.23 (6H, d, J = 7.1 Hz), 1.47-1.60 (4H, m), 1.71 (3H, s), 2.35 (4H, t, J= 7.8 Hz), 2.91 (1H, sept, J = 4.0 Hz), 4.77 (2H, s), 6.65-6.68 (2H, m), 7.28 (2H, d, J = 8.5 Hz), 7.41 (2H, t, J= 8.5 Hz), 7.59 (2H, s), 8.24 (1H, d, J = 2.7 Hz), 8.58 (1H, d, J = 6.6 Hz).
1H-NMR (CD3OD) δ:0.83 (6H, t, J = 7.3 Hz), 1.31 (9H, s), 1.50 (4H, qt, J = 7.3, 7.3 Hz), 1.71 (3H, s), 2.35 (4H, t, J = 7.3 Hz), 4.88 (2H, s), 6.88 (1H, s), 7.22 (1H, d, J = 6.5 Hz), 7.38-7.47 (4H, s), 7.59 (2H, s), 8.56 (1H, d, J = 6.5 Hz).
1H-NMR (CD3OD) δ:0.84 (6H, t, J = 7.3 Hz), 1.32 (6H, d, J = 5.9 Hz), 1.52 (4H, qt, J = 7.3, 7.6 Hz), 1.69 (3H ,s), 2.37 (4H, t, J = 7.6 Hz), 4.60 (1H, sept, J = 5.9 Hz), 4.88 (2H, s), 6.92 (1H, s), 7.06-7.14 (1H, m), 7.19-7.28 (3H, m), 7.60 (2H, s), 8.58 (1H, d, J = 6.5 Hz).
以下に記載する化合物を順次製造した。
ビニルボロン酸ピナコールエステルの代わりにcis-プロペンボロン酸(trans-体が10%以下で混合しているものを使用している)を用いて実施例126と同様に反応・処理し、(Z)-3-ニトロ-2-(プロパ-1-エニル)ピリジンを無色油状物として得た。
1H-NMR (CDCl3) δ:2.03 (3H, dd, J = 1.7, 7.3 Hz), 6.20-6.27 (1H, m), 6.80 (1H, qd, J = 1.7, 11.7 Hz), 7.34 (1H, dd, J = 4.6, 8.1 Hz), 8.24 (1H, dd, J = 1.4, 8.1 Hz), 8.82 (1H, dd, J = 1.4, 4.6 Hz).
1H-NMR (CDCl3) δ:2.02 (3H, dd, J = 1.4, 6.8 Hz), 7.03 (1H, qd, J = 1.4, 15.1 Hz), 7.18-7.29 (2H, m), 8.16 (1H, dd, J = 1.7, 8.3 Hz), 8.72 (1H, dd, J = 1.7, 4.6 Hz).
実施例121)と同様に反応・処理し、2-プロピルピリジン-3-アミンを無色油状物として得た。
1H-NMR (CDCl3) δ:1.02 (3H, t, J = 7.4 Hz), 1.78 (2H, qt, J = 7.4, 7.8 Hz), 2.67 (2H, t, J = 7.8 Hz), 6.89-6.97 (2H, m), 7.99 (1H, dd, J = 1.7, 4.4 Hz).
実施例119-a))と同様に反応・処理し、2-プロピルピリジン-3-オールを無色油状物として得た。
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.64 (2H, qt, J = 7.3, 7.6 Hz), 2.66 (2H, t, J = 7.6 Hz), 7.01 (1H, dd, J = 4.6, 8.1 Hz), 7.09 (1H, dd, J = 1.4, 8.1 Hz), 7.92 (1H, dd, J = 1.4, 4.6 Hz).
2-プロピルピリジン-3-オール(2.42 g, 17.7 mmol)をエタノール(40 mL)、水(10 mL)に溶解させた。氷冷下ヨウ素(4.71 g, 18.6 mmol)を加え、2時間攪拌した。その後、室温にて4時間攪拌した。反応終了後、エタノールを減圧濃縮した。酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)にて精製し、6-ヨード-2-プロピルピリジン-3-オール(2.80 g, 収率60%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.6 Hz), 1.65 (2H, qt, J = 7.6, 7.6 Hz), 2.69 (2H, t, J = 7.6 Hz), 6.84 (1H, d, J = 8.3 Hz), 7.41 (1H, d, J = 8.3 Hz).
6-ヨード-2-プロピルピリジン-3-オール(2.0 g, 7.60 mmol)をN,N’-ジメチルホルムアミド(30 mL)に溶解させた。室温にてジニトリル亜鉛(1.34 g, 11.4 mmol)、テトラキストリフェニルホスフィンパラジウム(878 mg, 0.760 mmol)を加え、マイクロ波照射下20分間攪拌した。反応終了後、反応溶液をセライトろ過し、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)にて精製し、5-ヒドロキシ-6-プロピルピコリノニトリル(1.75 g, 収率>100%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.99 (3H, t, J = 7.3 Hz), 1.76 (2H, qt, J = 7.3, 7.6 Hz), 2.82 (2H, t, J = 7.6 Hz), 7.15 (1H, d, J = 8.4 Hz), 7.46 (1H, d, J = 8.4 Hz).
5-ヒドロキシ-6-プロピルピコリノニトリル(1.73 g, 10.7 mmol)をメタノール(80 mL)に溶解させた。氷冷下濃硫酸(20 mL)を加え、室温にて5分間攪拌した。その後、100℃にて終夜攪拌した。反応終了後、反応溶液に4N 水酸化ナトリウム水溶液にて中和させ、飽和炭酸水素ナトリウム水溶液を加えた。その後、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)にて精製し、5-ヒドロキシ-6-プロピルピコリン酸メチル(980 mg, 収率47%)を無色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.72 (2H, qt, J = 7.3, 7.8 Hz), 2.88 (2H, t, J = 7.8 Hz), 3.90 (3H, s), 7.25 (1H, d, J = 8.3 Hz), 7.89 (1H, d, J = 8.3 Hz).
実施例127)と同様に反応・処理し、5-(ベンジルオキシ)-6-プロピルピコリン酸メチルを無色油状物として得た。
1H-NMR (CDCl3) δ:0.99 (3H, t, J = 7.6 Hz), 1.76 (2H, qt, J = 7.6, 7.8 Hz), 2.94 (2H, t, J = 7.8 Hz), 3.96 (3H, s), 5.16 (2H, s), 7.19 (1H, d, J = 8.6 Hz), 7.34-7.45 (5H, m), 7.97 (1H, d, J = 8.6 Hz).
5-(ベンジルオキシ)-6-プロピルピコリン酸メチル(2.0 g, 5.02 mmol)をメタノール(6 mL)に溶解させた。氷冷下4N 水酸化ナトリウム水溶液(2.0 mL)を加え、室温にて1時間攪拌した。その後、さらに氷冷下4N 水酸化ナトリウム水溶液(1.0 mL)を加え、室温にて1時間攪拌した。反応終了後、反応溶液に4N 塩酸水溶液にてpH4~5付近にさせた。その後、酢酸エチル/テトラヒドロフランで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をジエチルエーテルにて洗浄し、5-(ベンジルオキシ)-6-プロピルピコリン酸(943 mg, 収率69%)を無色油状物として得た。
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.64 (2H, qt, J = 7.3, 7.3 Hz), 2.77 (2H, t, J = 7.3 Hz), 5.20 (2H, s), 7.32-7.47 (6H, m), 7.82 (1H, d, J = 8.3 Hz).
5-(ベンジルオキシ)-6-プロピルピコリン酸(1.23 g, 4.53 mmol)を酢酸エチル(150 mL)に溶解させた。氷冷下、ペンタフルオロフェノール(1.0 g, 5.44 mmol)、N, N’-ジシクロヘキシルカルボジイミド(1.12 g, 5.44 mmol)を順に加え、室温にて終夜撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/アセトン)を用いて精製し、5-(ベンジルオキシ)-6-プロピルピコリン酸ペルフルオロフェニル (1.56g, 収率79%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:1.01 (3H, t, J = 7.3 Hz), 1.80 (2H, qt, J = 7.3, 7.8 Hz), 2.98 (2H, t, J = 7.8 Hz), 5.22 (2H, s), 7.25 (1H, d, J = 8.5 Hz), 7.35-7.45 (5H, m), 8.12 (1H, d, J = 8.5 Hz).
5-(ベンジルオキシ)-6-プロピルピコリン酸ペルフルオロフェニル(1.0 g, 2.29 mmol)テトラメチルアンモニウムフルオライド(1.06 g, 11.4 mmol)を真空ポンプ化乾燥し、エチレングリコールジメチルエーテル(26 mL)に溶解させた。氷冷下、トリフルオロメチルトリメチルシラン (1.69 mL, 11.4 mmol)、を加え、氷冷下1時間攪拌した。その後、室温にて2時間撹拌した。反応終了後、反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、2-(5-(ベンジルオキシ)-6-プロピルピリジン-2-イル)-1,1,1,3,3,3-ヘキサフルオロプロパン-2-オール(372 mg, 収率41%)を茶色油状物として得た。
1H-NMR (CDCl3) δ:0.98 (3H, t, J = 7.3 Hz), 1.80 (2H, qt, J = 7.3, 7.6 Hz), 2.92 (2H, t, J = 7.6 Hz), 5.15 (2H, s), 7.28-7.51 (7H, m).
2-(5-(ベンジルオキシ)-6-プロピルピリジン-2-イル)-1,1,1,3,3,3-ヘキサフルオロプロパン-2-オール(537 mg, 1.37 mmol)をN,N’-ジメチルホルムアミド(2.5 mL)に溶解させ、氷冷下水素化ナトリウム(純度50%)(79 mg, 1.64 mmol)、塩化メトキシメチルエーテル(113 μL, 1.50 mmol)を加え、氷冷下1時間30分間攪拌した。その後、さらに室温にて45分間攪拌した。反応終了後、反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、3-(ベンジルオキシ)-6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジン (407 mg, 収率68%)を無色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.78 (2H, qt, J = 7.3, 7.3 Hz), 2.86 (2H, t, J = 7.3 Hz), 3.55 (3H, s), 4.90 (2H, s), 5.11 (2H, s), 7.17 (1H, d, J = 8.5 Hz), 7.34-7.42 (5H, m), 7.46 (1H, d, J = 8.5 Hz).
3-(ベンジルオキシ)-6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジン(407 mg, 0.931 mmol)をエタノール(2.0 mL)に溶解させ、パラジウム炭素(40 mg)を加え、水素雰囲気下2時間間攪拌した。反応終了後、反応液をセライトろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)を用いて精製し、6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジン-3-オール (304 mg, 収率94%)を茶色油状物として得た。
1H-NMR (CDCl3) δ:0.97 (3H, t, J = 7.3 Hz), 1.80 (2H, qt, J = 7.3, 7.6 Hz), 2.78 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.90 (2H, s), 7.12 (1H, d, J = 8.5 Hz), 7.43 (1H, d, J = 8.5 Hz).
4-ヒドロキシ-6-メチル-2H-ピラン-2-オン (11.1 g, 88.0 mmol)をエタノール (5.0 mL)に懸濁し、28 % アンモニア水 (55 mL)を加え、100 ℃にて1時間攪拌した。反応液を室温まで冷却後、クロロホルム (25 mL) 、エーテル (25 mL)を加えて固化物を濾取し、これをクロロホルム (10 mL)、エーテル(10 mL)、テトラヒドロフラン(30 mL)で 順に洗浄し、減圧濃縮した。その後、さらに得られた残渣をクロロホルム (10 mL)、エーテル(10 mL)、テトラヒドロフラン(30 mL)で 順に洗浄し、4-ヒドロキシ-6-メチルピリジン-2(1H)-オン(9.70 g, 収率88%)を淡黄色結晶として得た。
1HNMR(DMSO) d: 2.06 (3H, s), 5.31 (1H, d, J = 1.4 Hz), 5.57 (1H, d, J = 1.4 Hz), 10.28 (1H, br.), 10.87 (1H, br.).
70 % 硝酸 30 mL)に氷冷下、4-ヒドロキシ-6-メチルピリジン-2(1H)-オン(10.5 g、83.9 mmol)を加え、70 ℃にて 1時間30分攪拌した。反応液を氷冷下、氷水(70 mL) に加えた。反応溶液をろ過し、冷水、テトラヒドロフラン、ジエチルエーテルで順に洗浄し、乾燥させ、4-ヒドロキシ-6-メチル-3-ニトロピリジン-2(1H)-オン(11.5 g、収率80%)を黄色結晶として得た。
1HNMR(DMSO) d: 2.15 (3H, s), 5.82 (1H, s), 11.84 (1H, br.), 12.25 (1H, br.).
ヒドロキシ-6-メチル-3-ニトロピリジン-2(1H)-オン(8.77 g, 51.6 mmol)を 0 ℃ にて ホスホリルクロライド(30 mL, 320 mmol)に懸濁し、50℃にて攪拌しながらN,N-ジエチルアニリン (17 mL, 108 mmol)を加えた。その後、100℃ にて 終夜攪拌した。反応終了後、室温にて水を加え、ろ過した。ろ過物を水で洗浄後、乾燥し、2,4-ジクロロ-6-メチル-3-ニトロピリジン(9.04 g, 収率84%)を黒茶色結晶として得た。
1HNMR(CDCl3) d: 2.06 (3H, s), 7.63 (1H, s).
2,4-ジクロロ-6-メチル-3-ニトロピリジン(15.0 g, 72.5 mmol)を 氷冷下濃硫酸(73 mL)に溶解し、クロム酸(21.7 g, 217 mmol)を加え、徐々に室温まで昇温させながら終夜攪拌した。反応終了後、氷冷下、氷水を加え、ろ過した。 テトラヒドロフランを加えた後、減圧濃縮し、粗生成物(15.7 g)を得た。得られた粗生成物(15.7 g)をテトラヒドロフラン(180 mL)、メタノール(180 mL)に溶解させた。反応溶液に氷冷下、トリエチルアミン(90 mL, 652 mmol)、クロロギ酸メチルエステル(34 mL, 435 mmol)を加え、10分間攪拌した。反応終了後、水を加え、酢酸エチルで抽出し、有機層を飽和塩化アンモニウム水溶液で洗浄し、硫酸ナトリウムにて乾燥し、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(クロロホルム/メタノール)にて精製し、4,6-ジクロロ-5-ニトロピコリン酸メチル(12.6 g, 収率69%)を黄色結晶として得た。
1HNMR(CDCl3) d: 4.09 (3H, s), 8.25 (1H, s).
実施例25-c)と同様に反応・処理し、6-クロロ-4-(6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジン-3-イルオキシ)-5-ニトロピコリン酸メチルを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.75 (2H, qt, J = 7.3, 7.3 Hz), 2.71 (2H, t, J = 7.3 Hz), 3.59 (3H, s), 3.99 (3H, s), 4.97 (2H, s), 7.43 (1H, s), 7.51 (1H, d, J = 8.1 Hz), 7.72 (1H, d, J = 8.1 Hz).
実施例171)と同様に反応・処理し、5-アミノ-4-(6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジン-3-イルオキシ)ピコリン酸メチルを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.6 Hz), 1.80 (2H, qt, J = 7.6, 7.6 Hz), 2.82 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 3.93 (3H, s), 4.96 (2H, s), 7.30 (1H, d, J = 8.6 Hz), 7.42 (1H, s), 7.59 (1H, d, J = 8.6 Hz), 8.26 (1H, s).
実施例119-a)と同様に反応・処理し、4-(6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジン-3-イルオキシ)-5-ヨードピコリン酸メチルを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.80 (2H, qt, J = 7.3, 7.3 Hz), 2.76 (2H, t, J = 7.3 Hz), 3.58 (3H, s), 3.96 (3H, s), 4.97 (2H, s), 7.33 (1H, s), 7.38 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 8.6 Hz), 9.04 (1H, s).
4-(6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジン-3-イルオキシ)-5-ヨードピコリン酸メチル(500 mg, 0.823 mmol)のテトラヒドロフラン(8.2 mL)溶液に氷冷下水素化アルミニウムリチウム(63 mg, 1.65 mmol)を加え、室温にて1時間攪拌した。反応終了後、氷冷下水を加え、室温にて30分間攪拌した。その後、反応溶液をセライトろ過し、クロロホルムにて抽出し、有機層を飽和食塩水にて洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(ヘキサン/アセトン)にて精製し、(4-(6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジン-3-イルオキシ)ピリジン-2-イル)メタノール(141 mg, 収率38%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.76 (2H, qt, J = 7.3, 7.6 Hz), 2.75 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 4.73 (2H, s), 4.95 (2H, s), 6.73 (1H, dd, J = 2.4, 5.7 Hz), 6.82 (1H, d, J = 2.4 Hz), 7.37 (1H, d, J = 8.6 Hz), 7.61 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 5.7 Hz).
実施例38-c)と同様に反応・処理し、3-(2-(ブロモメチル)ピリジン-4-イルオキシ)-6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.0 Hz), 1.77 (2H, qt, J = 7.0, 7.6 Hz), 2.76 (2H, t, J = 7.6 Hz), 3.59 (3H, s), 4.51 (2H, s), 4.96 (2H, s), 6.71 (1H, dd, J = 2.2, 5.7 Hz), 7.01 (1H, d, J = 2.2 Hz), 7.39 (1H, d, J = 8.6 Hz), 7.62 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 5.7 Hz).
実施例1において、5-(ベンゾ[d][1,3]ジオキソール-5-イル)-5-メチルイミダゾリジン-2,4-ジオンの代わりに5-メチル-5-(4-(1-メチルエトキシ)フェニル)イミダゾリジン-2,4-ジオンを用いて同様に反応・処理し、3-((4-(6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジン-3-イルオキシ)ピリジン-2-イル)メチル)-5-(4-(1-メチルエトキシ)フェニル)-5-メチルイミダゾリジン-2,4-ジオンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.0 Hz), 1.32 (6H, d, J = 5.7 Hz), 1.74 (2H, qt, J = 7.0, 7.6 Hz), 1.84 (3H, s), 2.73 (2H, t, J = 7.6 Hz), 3.58 (3H, s), 4.54 (1H, sept, J = 5.7 Hz), 4.79 (2H, s), 4.95 (2H, s), 5.72 (1H, s), 6.67 (1H , dd, J = 1.9, 5.9 Hz), 6.71 (1H, d, J = 1.9 Hz), 6.88 (2H, d, J = 8.9 Hz), 7.34 (1H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.9 Hz), 7.59 (1H, d, J = 8.4 Hz), 8.42 (1H, d, J = 5.9 Hz).
1H-NMR (CDCl3) δ:0.89 (3H, t, J = 7.3 Hz), 1.28 (6H, d, J = 5.9 Hz), 1.74 (2H, qt, J = 7.3, 7.3 Hz), 1.74 (3H, s), 2.73 (2H, t, J = 7.3 Hz), 4.59 (1H, sept, J = 5.9 Hz), 4.84 (2H, s), 6.90 (2H , d, J = 8.9 Hz), 7.03 (1H, d, J = 2.2 Hz), 7.17 (1H, dd, J = 2.2, 6.5 Hz), 7.39 (2H, d, J = 8.9 Hz), 7.73 (1H, d, J = 8.6 Hz), 7.80 (1H, d, J = 8.6 Hz), 8.54 (1H, d, J = 6.5 Hz).
2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-5-ヨードイソニコチン酸メチル(450 mg, 0.741 mmol)のメタノール(3.5 mL)溶液に3N-水酸化ナトリウム水溶液(3.5 mL)を加え、室温にて1時間攪拌した。反応終了後、5%塩酸水溶液、飽和炭酸水素ナトリウム水溶液を加え、クロロホルム/メタノールで抽出した後、有機層を硫酸ナトリウムを用いて乾燥させた。ろ過後、ろ液を減圧濃縮し、2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-5-ヨードイソニコチン酸441 mg (収率>100 %)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.59 (2H, qt, J = 7.3, 7.8 Hz), 2.57 (2H, t, J = 7.8 Hz), 3.53 (3H, s), 4.88 (2H, s), 6.91 (1H, s), 7.15 (1H, d, J = 8.9 Hz), 7.49 (1H, d, J = 8.9 Hz), 7.54 (1H, s), 8.34 (1H, s).
2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-5-ヨードイソニコチン酸(441 mg, 0.741 mmol)のテトラヒドロフラン(3.7 mL)溶液に氷冷下ボラン-テトラヒドロフラン溶液(2.97 mL, 1M in THF 溶液)を加え、室温にて1時間30分攪拌した。反応終了後、水、1N-水酸化ナトリウム水溶液、5%塩酸水溶液を加え、酢酸エチルで抽出した後、有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、硫酸ナトリウムを用いて乾燥させた。有機層を減圧濃縮し、得られた残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)にて精製し、(2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-5-ヨードピリジン-4-イル)メタノール 391 mg (収率91 %)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.61 (2H, qt, J = 7.3, 7.6 Hz), 2.58 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.65 (2H, s), 4.88 (2H, s), 7.08 (1H, d, J = 8.5 Hz), 7.18 (1H, s), 7.45 (1H, d, J = 8.5 Hz), 7.51 (1H, s), 8.37 (1H, s).
(2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-5-ヨードピリジン-4-イル)メタノールを用いて実施例38-c)と同様に反応・処理し、4-(ブロモメチル)-2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-5-ヨードピリジンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.60 (2H, qt, J = 7.3, 7.3 Hz), 2.57 (2H, t, J = 7.3 Hz), 3.56 (3H, s), 4.46 (2H, s), 4.88 (2H, s), 7.08 (1H, d, J = 8.4 Hz), 7.12 (1H, s), 7.46 (1H, d, J = 8.4 Hz), 7.51 (1H, s), 8.45 (1H, s).
1H-NMR (CDCl3) δ:0.88 (3H, d, J = 7.3 Hz), 1.22 (6H, d, J = 6.8 Hz), 1.52-1.60 (2H, m), 1.83 (3H, s), 2.52 (2H, t, J= 7.0 Hz), 2.90 (1H, sept, J = 6.8 Hz), 3.86 (1H, s), 4.63 (2H, s), 6.01 (1H, s), 6.46 (1H, s), 7.00-7.60 (6H, m), 8.40 (1H, s).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.52-1.63 (2H, m), 1.79 (3H, s), 2.52 (2H, J= 7.8 Hz), 3.91 (1H, s), 4.22 (4H, s), 4.62 (2H, s), 5.98 (1H, s), 6.44 (1H, s), 6.85-7.23 (3H, m), 7.52-7.59 (2H, m), 8.40 (1H, s).
1H-NMR (CDCl3) δ:0.81 (3H, t, J = 7.0 Hz), 1.52-1.63 (2H, m), 1.95 (3H, s), 2.45 (2H, t, J = 7.3 Hz), 3.90 (1H, s), 4.66 (2H, s), 6.23 (1H, s), 6.49 (1H, s), 6.98 (1H. d, J = 8.4 Hz), 7.48-7.63 (5H, m), 7.81-7.90 (4H, m), 8.39 (1H, s).
1H-NMR (CDCl3) δ:0.89 (3H, J = 7.3 Hz), 1.55-1.64 (2H, m), 1.84 (3H, s), 2.36 (1H, s), 2.55 (2H, t, J = 8.1 Hz), 3.83 (1H, s), 4.69 (2H, s), 5.83 (1H, s), 6.36-6.44 (2H, m), 6.71 (1H, s), 7.03-7.60 (4H, m), 8.40 (1H, s).
1H-NMR (CDCl3) δ:0.89 (3H, t, J = 6.8 Hz), 1.39 (6H, s), 1.55-1.64 (2H, m), 2.55 (3H, t, J = 8.1 Hz), 2.91 (3H, s), 3.77 (1H, s), 4.62 (2H, s), 6.41 (1H, s), 7.02-7.59 (4H, m), 8.45 (1H, s).
1H-NMR (CDCl3) δ:0.87 (3H, t, J = 7.3 Hz), 1.52-1.63 (2H, m), 1.81 (3H, s), 2.35 (3H, s), 2.51 (2H, t, J = 7.8 Hz), 3.92 (1H, s), 4.62 (2H, s), 5.00 (2H, s), 6.03 (1H, s), 6.44 (1H, s), 6.96-7.59 (10H, m), 8.40 (1H, s).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.32 (3H, d, J = 6.2 Hz), 1.33 (3H, d, J = 6.2 Hz),, 1.49-1.62 (2H, m), 1.81 (3H, s), 2.52 (2H, t, J = 7.6 Hz), 2.74 (1H, s), 3.81 (1H, s), 4.53 (1H, sept, J= 6.2 Hz), 4.63 (2H, s), 6.02 (1H, s), 6.43 (1H, s), 6.94-7.28 (4H, m), 7.53 (1H, d, J = 8.1 Hz), 7.59 (1H, s), 8.41 (1H, s).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.30 (3H, d, J = 6.0 Hz), 1.31 (3H, d, J = 6.0 Hz), 1.52-1.62 (2H, m), 1.82 (3H, s), 2.52 (2H, t, J = 8.4 Hz), 2.73 (1H, s), 3.82 (1H, s), 4.52 (1H, sept, J= 6.0 Hz), 4.63 (2H, s), 5.93 (1H, s), 6.45 (1H, s), 6.87-7.59 (6H, m), 8.40 (1H, s).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.49-1.62 (2H, m), 1.81 (3H, s), 2.52 (2H, t, J = 8.1 Hz), 3.80 (1H, s), 4.63 (2H, s), 5.92 (1H, s), 5.96 (2H, s), 6.44 (1H, s), 6.79-7.23 (4H, m), 7.53 (1H, d, J = 8.1 Hz), 7.59 (1H, s), 8.40 (1H, s).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.52-1.63 (2H, m), 1.82 (3H, s), 2.52 (2H, t, J = 8.1 Hz), 3.20 (2H, t, J= 8.6 Hz), 3.86 (1H, s), 4.56 (2H, t, J= 8.6 Hz), 4.63 (2H, s), 6.46 (1H, s), 6.77 (1H, d, J = 8.1 Hz), 7.01 (1H, d, J= 8.6 Hz), 7.16-7.28 (2H, m), 7.34 (1H, s), 7.53 (1H, d, J = 8.6 Hz), 7.59 (1H, s), 8.40 (1H, s).
1H-NMR (CDCl3) δ:0.79 (3H, t, J = 7.3 Hz), 1.42-1.48 (2H, m), 1.72 (3H, s), 2.49 (2H, t, J = 7.3 Hz), 4.17 (3H, s), 4.55 (1H, d, J = 17.4 Hz), 4.58 (1H, d, J = 17.4 Hz), 6.17 (1H, s), 7.02 (2H, d, J= 8.5 Hz), 7.16-7.27 (2H, m), 7.60 (1H, d, J= 8.8 Hz), 7.63 (1H, s), 8.51 (1H, s).
1H-NMR (CDCl3) δ:0.87 (3H, t, J = 7.3 Hz), 1.30 (3H, d, J = 5.7 Hz), 1.31 (3H, d, J = 5.7 Hz), 1.55 (2H, qt, J = 7.3, 7.8 Hz), 1.87 (3H, s), 2.48 (2H, t, J = 7.8 Hz), 4.53 (1H, sept, J = 5.7 Hz), 4.88 (2H, s), 5.93 (1H, s), 6.67 (1H, s), 6.91 (2H, d, J = 8.9 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.40 (2H, d, J = 8.9 Hz), 7.57 (1H, d, J = 8.6 Hz), 7.62 (1H, s), 8.39 (1H, s).
5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-ビニルピリジンの製造:
実施例126と同様に反応・処理し、5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-ビニルピリジンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.66 (2H, qt, J = 7.3, 7.8 Hz), 2.68 (2H, t, J = 7.8 Hz), 3.56 (3H, s), 4.86 (2H, s), 5.45 (1H, dd, J = 1.2, 12.0 Hz), 6.12 (1H , dd, J = 1.2, 17.6 Hz), 6.82 (1H, dd, J = 12.0, 17.6 Hz), 6.86 (1H, d, J = 8.8 Hz), 7.24 (1H, dd, J = 2.7, 8.6 Hz), 7.35 (1H, d, J = 8.6 Hz), 7.40 (1H, d, J = 8.8 Hz), 7.51 (1H, s), 8.34 (1H, d, J = 2.7 Hz).
実施例30-b)と同様に反応・処理し、5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-(オキシラン-2-イル)ピリジン 1-酸化物を無色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.6 Hz), 2.60 (2H, t, J = 7.6 Hz), 2.73 (1H, dd, J = 2.7, 5.9 Hz), 3.30 (1H , dd, J = 4.3, 5.9 Hz), 3.57 (3H, s), 4.50 (1H, dd, J = 2.7, 4.3 Hz), 4.87 (2H, s), 6.93 (1H, dd, J = 2.2, 8.9 Hz), 6.99 (1H, d, J = 8.4 Hz), 7.21 (1H, d, J = 8.9 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.54 (1H, s), 7.99 (1H, d, J = 2.2 Hz).
実施例30-b)と同様に反応・処理し、5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-(2-ヒドロキシエチル)ピリジン 1-酸化物を無色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.64 (2H, qt, J = 7.3, 7.6 Hz), 2.67 (2H, t, J = 7.6 Hz), 3.11 (2H, t, J = 5.7 Hz), 3.53 (3H, s), 3.91 (2H , t, J = 5.7 Hz), 4.88 (2H, s), 7.13 (1H, d, J = 8.6 Hz), 7.19 (1H, dd, J = 2.2, 8.6 Hz), 7.50 (1H, d, J = 8.6 Hz), 7.53 (1H, d, J = 8.6 Hz), 7.60 (1H, s), 8.11 (1H, d, J = 2.2 Hz).
5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-2-(2-ヒドロキシエチル)ピリジン 1-酸化物(2.29 g, 4.74 mmol)の酢酸(24 mL)溶液に亜鉛粉末 (6.2 g, 94.7 mmol)を加え、室温にて4時間攪拌した。反応終了後、反応液をセライトろ過し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、硫酸ナトリウムを用いて乾燥させた。ろ過後、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/アセトン)を用いて精製し、2-(5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)エタノール 2.0 g (収率90 %)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.6 Hz), 1.67 (2H, qt, J = 7.6, 7.8 Hz), 2.69 (2H, t, J = 7.8 Hz), 3.02 (2H, t, J = 5.6 Hz), 3.56 (3H, s), 4.03 (2H , t, J = 5.6 Hz), 4.86 (2H, s), 6.83 (1H, d, J = 8.8 Hz), 7.17 (1H, d, J = 8.3 Hz), 7.26 (1H, dd, J = 3.0, 8.8 Hz), 7.40 (1H, d, J = 8.3 Hz), 7.51 (1H, s), 8.28 (1H, d, J = 3.0 Hz).
1H-NMR (CDCl3) δ:0.96 (3H, t, J = 7.3 Hz), 1.67 (2H, qt, J = 7.3, 7.6 Hz), 2.69 (2H, t, J = 7.6 Hz), 3.35 (2H, t, J = 6.8 Hz), 3.57 (3H, s), 3.79 (2H , t, J = 6.8 Hz), 4.87 (2H, s), 6.85 (1H, d, J = 8.6 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.26 (1H, dd, J = 2.4, 8.6 Hz), 7.41 (1H, d, J = 8.4 Hz), 7.51 (1H, s), 8.35 (1H, d, J = 2.4 Hz).
1H-NMR (270 MHz, CDCl3) δ:0.94 (3H, t, J = 7.2 Hz), 1.30 (6H, dd, J = 1.4, 5.9 Hz), 1.62 (2H, qt, J = 7.2, 7.6 Hz), 1.70 (3H, s), 2.58 (2H, t, J = 7.6 Hz), 3.16 (2H, t, J = 6.4 Hz), 3.98 (2H, t, J = 6.4 Hz), 4.52 (1H, sept, J = 5.9 Hz), 6.85 (2H, d, J = 8.9 Hz), 6.96 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.33 (2H, d, J = 8.9 Hz), 7.48 (1H, d, J = 8.6 Hz), 7.68 (1H, d, J = 8.6 Hz), 7.72 (1H, s), 8.23 (1H, d, J = 2.2 Hz).
1H-NMR (270 MHz, CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.63 (2H, qt, J = 7.3, 7.4 Hz), 1.77 (3H, s), 2.58 (2H, t, J = 7.4 Hz), 3.42 (2H, t, J = 6.4 Hz), 3.99 (2H, t, J = 6.4 Hz), 4.10 (3H, s), 7.03 (1H, d, J = 8.5 Hz), 7.10-7.19 (1H, m), 7.66-7.72 (3H, m), 7.83 (1H, d, J = 8.5 Hz), 8.19-8.30 (2H, m), 8.37 (1H, s).
1H-NMR (270 MHz, CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.63 (2H, qt, J = 7.3, 7.6 Hz), 1.71 (3H, s), 2.58 (2H, t, J = 7.6 Hz), 3.10-3.20 (4H,m), 3.98 (2H, t, J = 6.4 Hz), 4.56 (2H, t, J = 8.6 Hz), 6.73 (1H, d, J = 8.6 Hz), 6.98 (1H, d, J = 8.4 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.29-7.34 (2H, m), 7.53 (1H, d, J = 7.0 Hz), 7.67 (1H, d, J = 8.4 Hz), 7.72 (1H, s), 8.24 (1H, s).
1H-NMR (CDCl3) δ:0.96 (3H, t, J = 7.3 Hz), 1.16 (6H, d, J = 1.7 Hz), 1.63-1.69 (5H, m), 2.68 (2H, t, J = 8.0 Hz), 2.82-2.86 (1H, m), 3.25-3.30 (2H, m), 3.87-3.93 (2H, m), 6.92 (1H, J = 8.8 Hz), 7.20 (2H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.5 Hz), 7.54-7.75 (4H, m), 8.36 (1H, s).
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.24 (9H, s), 1.63-1.67 (5H, m), 2.66-2.69 (2H, m), 3.19-3.28 (2H, m), 3.83-3.94 (2H, m), 6.87 (1H, d, J = 8.6 Hz), 7.36-7.73 (8H, m), 8.29 (1H, s).
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.63-1.68 (5H, m), 2.64-2.69 (2H, m), 3.23-3.30 (2H, m), 3.91 (2H, t, J = 6.3 Hz), 4.14-4.16 (4H, m), 6.79-6.87 (3H, m), 6.99 (1H, d, J = 8.8 Hz), 7.61-7.75 (4H, m), 8.42 (1H, d, J = 2.7 Hz).
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.56-1.62 (2H, m), 1.81 (3H, s), 2.52-2.57 (2H, m), 2.70 (1H, s), 3.25-3.30 (2H, m), 3.95 (2H, t, J = 6.4 Hz), 6.88 (1H, d, J = 8.8 Hz), 7.48-7.92 (11H, m), 8.37 (1H, s).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.59-1.67 (5H, m), 2.62 (2H, t, J = 8.3 Hz), 2.70 (1H, s), 3.30-3.32 (2H, m), 3.94-3.97 (2H, m), 6.35-6.37 (1H, m), 6.43 (1H, d, J = 3.4 Hz), 7.02 (1H, d, J = 8.8 Hz), 7.44 (1H, s), 7.63 (1H, d, J = 8.8 Hz), 7.74 (1H, s), 7.82 (1H, d, J = 8.8 Hz), 7.91 (1H, dd, J = 2.7, 8.8 Hz), 8.57 (1H, d, J = 2.8 Hz).
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.6 Hz), 1.30 (6H, s), 1.63-1.68 (2H, m), 2.67 (2H, t, J = 7.8 Hz), 2.85 (3H, s), 3.23 (2H, t, J = 6.1 Hz), 3.89 (2H, t, J = 6.8 Hz), 7.07 (1H, d, J = 8.8 Hz), 7.63 (1H, d, J = 8.5 Hz), 7.70-7.72 (2H, m), 7.84 (1H, d, J = 6.4 Hz), 8.49 (1H, d, J = 2.4 Hz).
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.60-1.67 (5H, m), 2.29 (3H, s), 2.65 (2H, t, J = 7.8 Hz), 2.70 (1H, s), 3.20-3.26 (2H, m), 3.90 (2H, t, J = 6.6 Hz), 4.98 (1H, d, J = 14.6 Hz), 5.02 (1H, d, J = 14.6 Hz), 6.95-7.32 (9H, m), 7.54-7.74 (4H, m), 8.40 (1H, d, J = 2.9 Hz).
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.28 (6H, d, J = 5.8 Hz), 1.61-1.68 (5H, m), 2.64-2.70 (2H, m), 3.15-3.29 (2H, m), 3.92 (2H, t, J = 6.4 Hz), 4.55 (1H, sept, J= 5.8 Hz), 6.97-7.16 (4H, m), 7.64-7.74 (4H, m), 8.43 (1H, d, J = 2.2 Hz).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.33 (6H, d, J = 5.9 Hz), 1.57-1.68 (2H, m), 1.80 (3H, s), 2.65 (2H, t, J = 7.6 Hz), 3.30-3.36 (2H, m), 3.92-3.98 (2H, m), 4.68-4.77 (1H, m), 7.04 (1H, d, J = 8.9 Hz), 7.63-7.74 (4H, m), 7.92 (1H, d, J = 8.9 Hz), 8.00 (1H, dd, J = 2.7, 8.9 Hz), 8.25 (1H, s), 8.59 (1H, d, J = 2.7 Hz).
1H-NMR (400 MHz, CD3OD) δ:0.95 (3H, t, J = 7.4 Hz), 1.61-1.68 (2H, m), 1.70 (3H, s), 2.67 (2H, t, J = 7.4 Hz), 3.05 (2H, t, J = 6.5 Hz), 3.84 (2H, t, J = 6.5 Hz), 6.78 (1H, d, J = 8.8 Hz), 6.89 (1H, d, J = 8.8 Hz), 7.18 (2H, brs), 7.30-7.35 (1H, m), 7.54 (1H, d, J = 8.8 Hz), 7.65 (1H, d, J = 2.4 Hz), 7.91 (1H, dd, J = 2.4, 8.8 Hz), 8.00 (1H, s), 8.27 (1H, d, J = 2.4 Hz).
1H-NMR (400 MHz, CD3OD) δ:0.93 (3H, t, J = 7.4 Hz), 1.59 (3H, s), 1.61-1.67 (2H, m), 2.65 (2H, t, J = 7.4 Hz), 3.03 (2H, t, J = 6.4 Hz), 3.82 (2H, t, J = 6.4 Hz), 5.15 (1H, d, J = 14.4 Hz), 5.21 (1H, d, J = 14.4 Hz), 6.52 (1H, d, J = 9.8 Hz), 6.80 (1H, d, J = 8.5 Hz), 7.07 (1H, dd, J = 2.5, 8.5 Hz), 7.13 (1H, d, J = 8.1 Hz), 7.26-7.30 (5H, m), 7.54-7.58 (2H, m), 7.65 (1H, s), 7.74 (1H, d, J = 2.5 Hz), 8.02 (1H, d, J = 2.2 Hz).
6-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-3-アミンの製造:
実施例119-a)と同様に反応・処理し、6-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-3-アミンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.65 (2H, qt, J = 7.3, 7.8 Hz), 2.66 (2H, t, J = 7.8 Hz), 3.55 (3H, s), 4.85 (2H, s), 6.78 (1H, d, J = 8.1 Hz), 6.93 (1H, d, J = 8.6 Hz), 7.11 (1H, dd, J = 3.0, 8.1 Hz), 7.38 (1H, d, J = 8.6 Hz), 7.46 (1H, s), 7.74 (1H, d, J = 3.0 Hz).
実施例119-a)と同様に反応・処理し、2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-5-ヨードピリジンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.0 Hz), 1.59 (2H, qt, J = 7.0, 7.3 Hz), 2.57 (2H, t, J = 7.3 Hz), 3.56 (3H, s), 4.88 (2H, s), 6.78 (1H, d, J = 8.6 Hz), 7.08 (1H, d, J = 8.6 Hz), 7.45 (1H, d, J = 8.6 Hz), 7.51 (1H, s), 7.95 (1H, dd, J = 2.4, 8.6 Hz), 8.35 (1H, d, J = 2.4 Hz).
実施例126)と同様に反応・処理し、2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-5-ビニルピリジンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.8 Hz), 2.61 (2H, t, J = 7.8 Hz), 3.56 (3H, s), 4.88 (2H, s), 5.30 (1H, d, J = 11.3 Hz), 5.72 (1H , d, J = 17.8 Hz), 6.68 (1H, dd, J = 11.3, 17.8 Hz), 6.90 (1H, d, J = 8.6 Hz), 7.09 (1H, d, J = 8.9 Hz), 7.45 (1H, d, J = 8.9 Hz), 7.51 (1H, s), 7.81 (1H, dd, J = 2.2, 8.6 Hz), 8.17 (1H, d, J = 2.2 Hz).
実施例185と同様に反応・処理し、2-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-5-(オキシラン-2-イル)ピリジンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.61 (2H, qt, J = 7.3, 7.6 Hz), 2.59 (2H, t, J = 7.6 Hz), 2.84 (1H, dd, J = 2.7, 5.1 Hz), 3.19 (1H , dd, J = 4.1, 5.1 Hz), 3.56 (3H, s), 3.88 (1H, dd, J = 2.7, 4.1 Hz), 4.88 (2H, s), 6.91 (1H, d, J = 8.6 Hz), 7.08 (1H, d, J = 8.6 Hz), 7.45 (1H, d, J = 8.6 Hz), 7.51 (1H, s), 7.56 (1H, d, J = 2.4, 8.6 Hz), 8.17(1H, d, J = 2.4 Hz).
実施例38-b)と同様に反応・処理し、2-(6-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-3-イル)エタノールを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.64 (2H, qt, J = 7.3, 7.6 Hz), 2.62 (2H, t, J = 7.6 Hz), 2.91 (2H, t, J = 5.7 Hz), 3.57 (3H, s), 3.90 (2H , t, J = 5.7 Hz), 4.86 (2H, s), 6.75 (1H, d, J = 8.6 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.6 Hz), 7.62 (1H, s), 7.92 (1H, dd, J = 2.4, 8.6 Hz), 8.39 (1H, d, J = 2.4 Hz).
実施例126と同様に反応・処理し、4-メチルベンゼンスルホン酸 2-(6-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-3-イル)エチルを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.3 Hz), 2.44 (3H, s), 2.60 (2H, t, J = 7.3 Hz), 2.93 (2H, t, J = 6.5 Hz), 3.56 (3H, s), 4.20 (2H , t, J = 6.5 Hz), 4.88 (2H, s), 6.83 (1H, d, J = 8.4 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.50 (1H, s), 7.52 (1H, dd, J = 2.4, 8.4 Hz), 7.72 (2H, d, J = 8.1 Hz), 7.94 (1H, d, J = 2.4 Hz).
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.3 Hz), 1.26 (6H, dd, J = 2.0, 5.8 Hz), 1.56-1.63 (5H, m), 2.57 (2H, t, J = 7.8 Hz), 2.92 (2H, t, J = 6.6 Hz), 3.74 (2H, t, J = 6.6 Hz), 4.55 (1H, sept,J = 5.8 Hz), 6.85 (2H, d, J = 8.8 Hz), 6.95 (1H, d, J = 8.6 Hz), 7.26 (2H, d, J = 9.0 Hz), 7.56-7.64 (4H, m), 7.90 (1H, s).
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.6 Hz), 1.58-1.63 (5H, m), 2.56 (2H, t, J = 7.8 Hz), 2.93-2.96 (2H, m), 3.13 (2H, t, J= 8.8 Hz), 3.74-3.76 (2H, m), 4.49 (2H., t, J= 8.8 Hz), 6.66-6.80 (2H, m), 7.02-7.23 (3H, m), 7.60-7.74 (3H, m), 7.99 (1H, s).
1H-NMR (CDCl3) δ:0.99 (3H, t, J = 7.3 Hz), 1.20 (3H, d, J = 6.0 Hz), 1.21 (3H, d, J = 6.0 Hz), 1.64 (3H, s), 1.78-1.87 (2H, m), 2.88-2.96 (4H, m), 3.73 (2H, t, J = 6.4 Hz), 4.48 (1H, sept, J= 6.0 Hz), 6.79 (4H, dd, J = 3.2, 8.3 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.28 (2H, J = 8.6 Hz), 7.56 (1H, d, J = 8.6 Hz).
1H-NMR (CDCl3) δ:0.99 (3H, t, J = 7.3 Hz), 1.63 (3H, s), 1.78-1.87 (2H, m), 2.91-2.96 (2H, m), 3.08-3.13 (2H, m), 3.19 (2H, t, J = 8.6 Hz), 3.73 (2H, t, J = 6.6 Hz), 4.47 (2H, t, J = 8.6 Hz), 6.64 (1H, d, J = 8.6 Hz), 6.83 (1H, d, J = 8.3 Hz), 7.08-7.21 (5H, m), 7.56 (1H, d, J = 8.5 Hz).
1H-NMR (CDCl3) δ:0.99 (3H, t, J = 7.3 Hz), 1.65 (3H, s), 1.78-1.87 (2H, m), 2.92-2.96 (4H, m), 3.75 (2H, t, J = 6.8 Hz), 3.82 (3H, s), 6.73 (1H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.11-7.15 (3H, m), 7.56 (1H, d, J = 8.6 Hz), 7.68 (1H, dd, J = 2.7, 8.8 Hz), 8.14 (1H, d, J = 2.2 Hz).
3-(6-ブロモピリジン-3-イルオキシ)-6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジンの製造:
実施例3と同様に反応・処理し、3-(6-ブロモピリジン-3-イルオキシ)-6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.80 (2H, qt, J = 7.3, 7.6 Hz), 2.85 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.92 (2H, s), 7.15 (1H, d, J = 8.4 Hz), 7.19 (1H, dd, J = 3.2, 8.4 Hz), 7.49 (1H, d, J = 8.4 Hz), 7.53 (1H, d, J = 8.4 Hz), 8.18 (1H, d, J = 3.2 Hz).
実施例126と同様に反応・処理し、-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピル-3-(6-ビニルピリジン-3-イルオキシ)ピリジンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.97 (3H, t, J = 7.0 Hz), 1.82 (2H, qt, J = 7.0, 7.6 Hz), 2.89 (2H, t, J = 7.6 Hz), 3.56 (3H, s), 4.92 (2H, s), 5.48 (1H, dd, J = 1.4, 10.8 Hz), 6.15 (1H , dd, J = 1.4, 17.6 Hz), 6.83 (1H, dd, J = 10.8, 17.6 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.27 (1H, dd, J = 2.7, 8.6 Hz), 7.38 (1H, d, J = 8.6 Hz), 7.49 (1H, d, J = 8.6 Hz), 8.35 (1H, d, J = 2.7 Hz).
実施例185と同様に反応・処理し、5-(6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジン-3-イルオキシ)-2-(オキシラン-2-イル)ピリジン 1-酸化物を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.0 Hz), 1.78 (2H, qt, J = 7.0, 7.3 Hz), 2.73 (1H, dd, J = 2.7, 5.4 Hz), 2.79 (2H, t, J = 7.3 Hz), 3.30 (1H , dd, J = 4.1, 5.4 Hz), 3.56 (3H, s), 4.49 (1H, dd, J = 2.7, 4.1 Hz), 4.92 (2H, s), 6.94 (1H, dd, J = 2.2, 8.4 Hz), 7.24 (1H, d, J = 8.4 Hz), 7.30 (1H, d, J = 8.4 Hz), 7.58 (1H, d, J = 8.4 Hz), 8.04 (1H, d, J = 2.2 Hz).
実施例185と同様に反応・処理し、5-(6-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルピリジン-3-イルオキシ)-2-(2-ヒドロキシエチル)ピリジン 1-酸化物を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.79 (2H, qt, J = 7.3, 7.6 Hz), 2.81 (2H, t, J = 7.6 Hz), 3.24 (2H, t, J = 7.0 Hz), 3.57 (3H, s), 4.02 (2H , t, J = 7.0 Hz), 4.93 (2H, s), 6.96 (1H, dd, J = 2.2, 8.6 Hz), 7.29 (1H, d, J = 8.6 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.58 (1H, d, J = 8.4 Hz), 8.07 (1H, d, J = 2.2 Hz).
実施例185と同様に反応・処理し、1,1,1,3,3,3-ヘキサフルオロ-2-(5-(6-(2-ヒドロキシエチル)ピリジン-3-イルオキシ)-6-プロピルピリジン-2-イル)プロパン-2-オールを黄色油状物として得た。
1H-NMR (CDCl3) δ:1.00 (3H, t, J = 7.0 Hz), 1.83 (2H, qt, J = 7.0, 7.6 Hz), 2.96 (2H, t, J = 7.6 Hz), 3.06 (2H, t, J = 5.9 Hz), 4.04 (2H , t, J = 5.9 Hz), 7.23 (1H, d, J = 8.6 Hz), 7.24 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 2.7, 8.6 Hz), 7.50 (1H, d, J = 8.4 Hz), 8.32 (1H, d, J = 2.7 Hz).
実施例185と同様に反応・処理し、4-メチルベンゼンスルホン酸 2-(5-(6-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルピリジン-3-イルオキシ)ピリジン-2-イル)エチルを黄色油状物として得た。
1H-NMR (CDCl3) δ:1.01 (3H, t, J = 7.3 Hz), 1.83 (2H, qt, J = 7.3, 7.8 Hz), 2.44 (3H, s), 2.95 (2H, t, J = 7.8 Hz), 3.15 (2H, t, J = 6.2 Hz), 4.43 (2H , t, J = 6.2 Hz), 7.18-7.33 (6H, m), 7.50 (1H, d, J = 8.4 Hz), 7.73 (1H, d, J = 8.1 Hz), 8.25 (1H, d, J = 2.4 Hz).
1H-NMR (CDCl3) δ:1.01 (3H, t, J = 7.3 Hz), 1.28 (6H, d, J = 5.7 Hz), 1.76 (3H, s), 1.83 (2H, qt, J = 7.3, 7.6 Hz), 2.95 (2H, t, J = 7.6 Hz), 3.12 (2H, t, J = 6.8 Hz), 3.90 (2H, t, J = 6.8 Hz), 4.47 (1H, sept, J = 5.7 Hz), 5.54 (1H, s), 6.81 (2H , t, J = 8.9 Hz), 7.04-7.10 (2H, m), 7.24 (1H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.9 Hz), 7.48 (1H, d, J = 8.4 Hz), 8.18 (1H, d, J = 3.2 Hz).
4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-3-ヨードベンズアルデヒドの製造:
実施例119-a)と同様に反応・処理し、4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-3-ヨードベンズアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.62-1.71 (2H, m), 2.61 (2H, t, J = 7.1 Hz), 3.57 (3H, s), 4.88 (2H, s), 6.78 (1H, d, J = 8.3 Hz), 6.97 (1H, d, J = 8.8 Hz), 7.49 (1H, d, J = 8.8 Hz), 7.57 (1H, s), 7.78 (1H, dd, J = 2.0, 8.3 Hz), 8.41 (1H, d, J = 2.0 Hz), 9.88 (1H, s).
実施例27)と同様に反応・処理し、1-(4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-3-ヨードフェニル)エタノールを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.97 (3H, t, J = 7.3 Hz), 1.50 (3H, d, J = 6.8 Hz), 1.65-1.79 (2H, m), 2.71 (2H, t, J = 7.3 Hz), 3.55 (3H, s), 4.85 (2H, s), 4.83-4.92 (1H, m), 6.71 (1H, d, J = 8.9 Hz), 6.83 (1H, d, J = 8.6 Hz), 7.31 (1H, dd, J = 1.9, 8.9 Hz), 7.35 (1H, d, J = 8.6 Hz), 7.48 (1H, s), 7.90 (1H, d, J = 1.9 Hz).
1-(4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-3-ヨードフェニル)エタノール(26 mg, 0.0446 mmol)をジクロロメタン(3 mL)に溶解させた。室温にて二酸化マンガン(78 mg, 0.891 mmol)を加え、室温にて終夜攪拌した。反応終了後、反応溶液をセライトろ過し、減圧濃縮し、1-(4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-3-ヨードフェニル)エタノン(16 mg, 収率60%)を無色油状物として得た。
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.3 Hz), 1.60-1.74 (2H, m), 2.58 (3H, s), 2.62 (2H, t, J = 7.3 Hz), 3.57 (3H, s), 4.87 (2H, s), 6.74 (1H, d, J = 8.6 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.55 (1H, s), 7.87 (1H, dd, J = 1.9, 8.6 Hz), 8.48 (1H, d, J = 1.9 Hz).
1-(4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-3-ヨードフェニル)エタノン(16 mg, 0.0268 mmol)のアセトニトリル(268 μL)溶液にヒドロキシ p-トルエンスルホキシヨードベンゼン(11 mg, 0.0268 mmol)を加え、加熱還流下終夜攪拌した。その後、さらにヒドロキシ p-トルエンスルホキシヨードベンゼン(11 mg, 0.0268 mmol)を加え、加熱還流下終夜攪拌した。反応終了後、反応液を減圧濃縮し、得られた残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)にて精製し、トルエン-4-スルホン酸 2-{3-ヨード-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-ヒドロキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-2-オキソ-エチル エステル 5.4 mg (収率28 %)を無色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.6 Hz), 1.61-1.70 (2H, m), 2.46 (3H, s), 2.58 (2H, t, J = 7.6 Hz), 5.16 (2H, s), 6.67 (1H, d, J = 8.6 Hz), 6.97 (1H, d, J = 8.6 Hz), 7.36 (2H, d, J = 8.3 Hz), 7.57 (1H, d, J = 8.6 Hz), 7.66 (1H, s), 7.75 (1H, dd, J = 2.0, 8.6 Hz), 7.85 (2H, d, J = 8.3 Hz), 8.34 (1H, d, J = 2.0 Hz).
1H-NMR (CDCl3) δ:0.94 (3H, t, J = 7.4 Hz), 1.33 (6H, d, J = 6.1 Hz), 1.61-1.70 (2H, m), 1.93 (3H, s), 2.59 (2H, t, J = 7.1 Hz), 4.51-4.58 (1H, m), 4.85 (1H, d, J = 17.6 Hz), 4.88 (1H, d, J = 17.6 Hz), 5.63 (1H, s), 6.70 (1H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 6.99 (1H, d, J = 8.8 Hz), 7.46 (2H, d, J = 8.8 Hz), 7.57 (1H, d, J = 8.8 Hz), 7.66 (1H, s), 7.85 (1H, dd, J = 2.0, 8.8 Hz), 8.49 (1H, d, J = 2.0 Hz).
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.33 (6H, d, J = 5.9 Hz), 1.54-1.68 (2H, m), 1.93 (3H, s), 2.58 (2H, t, J = 7.6 Hz), 4.48-4.62 (1H, m), 4.89 (1H, d, J = 17.8 Hz), 4.90 (1H, d, J = 17.8 Hz), 5.84 (1H, s), 6.91 (2H, d, J = 8.9 Hz), 6.98 (2H, d, J = 8.9 Hz), 6.99 (1H, d, J = 8.6 Hz), 7.47 (2H, d, J = 8.9 Hz), 7.54 (1H, d, J = 8.6 Hz), 7.63 (1H, s), 7.95 (2H, d, J = 8.9 Hz).
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.54-1.67 (2H, m), 1.91 (3H, s), 2.59 (2H, t, J = 7.8 Hz), 4.26 (4H, s), 4.88 (1H, d, J = 17.6 Hz), 4.89 (1H, d, J = 17.6 Hz), 5.91 (1H, s), 6.89 (1H, d, J = 8.6 Hz), 6.98 (2H, d, J = 8.9 Hz), 6.99 (1H, d, J = 8.6 Hz), 7.04 (1H, dd, J = 2.4, 8.6 Hz), 7.09 (1H, d, J = 2.4 Hz), 7.54 (1H, d, J = 8.6 Hz), 7.63 (1H, s), 7.95 (2H, d, J = 8.9 Hz).
1-{2-メトキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノンの製造:
実施例119-a)と同様に反応・処理し、1-{2-メトキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.63 (2H, qt, J = 7.3, 7.6 Hz), 2.60 (3H, s), 2.63 (2H, t, J = 7.6 Hz), 3.57 (3H, s), 3.88 (3H, s), 4.87 (2H, s), 6.46 (1H, dd, J = 2.4, 8.4 Hz), 6.61 (1H, d, J = 2.4 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 8.4 Hz), 7.52 (1H, s), 7.79 (1H, d, J = 8.4 Hz).
実施例205と同様に反応・処理し、トルエン-4-スルホン酸 2-{2-メトキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-ヒドロキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-2-オキソ-エチル エステルを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.6 Hz), 1.62 (2H, qt, J = 7.6, 7.8 Hz), 2.45 (3H, s), 2.59 (2H, t, J = 7.8 Hz), 3.89 (3H, s), 5.24 (2H, s), 6.46 (1H, dd, J = 2.2, 8.6 Hz), 6.56 (1H, d, J = 2.2 Hz), 6.99 (1H, d, J = 8.4 Hz), 7.35 (2H, d, J = 7.8 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.63 (1H, s), 7.87 (1H, d, J = 8.6 Hz), 7.88 (2H, d, J = 7.8 Hz).
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.33 (6H, d, J = 5.9 Hz), 1.54-1.65 (2H, m), 1.92 (3H, s), 2.60 (2H, t, J = 7.8 Hz), 3.89 (3H, s), 4.50-4.59 (1H, m), 4.93 (2H, s), 5.82 (1H, s), 6.45 (1H, dd, J = 2.4, 8.9 Hz), 6.58 (1H, d, J = 2.4 Hz), 6.89-6.92 (2H, m), 6.99 (1H, d, J = 8.6 Hz), 7.45-7.49 (2H, m), 7.53 (1H, d, J = 8.6 Hz), 7.62 (1H, s), 7.94 (1H, d, J = 8.9 Hz).
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.6 Hz), 1.54-1.65 (2H, m), 1.92 (3H, s), 2.62 (2H, t, J = 7.3 Hz), 3.23 (2H, t, J = 8.6 Hz), 3.89 (3H, s), 4.59 (2H, t, J = 8.6 Hz), 4.93 (2H, s), 5.88 (1H, s), 6.45 (1H, dd, J = 2.4, 8.6 Hz), 6.58 (1H, d, J = 2.4 Hz), 6.79 (1H, d, J = 8.4 Hz), 6.99 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.4 Hz), 7.43 (1H, s), 7.54 (1H, d, J = 8.6 Hz), 7.63 (1H, s), 7.94 (1H, d, J = 8.6 Hz).
2-エトキシ-4-フルオロ-1-ニトロ-ベンゼンの製造:
実施例127と同様に反応・処理し、2-エトキシ-4-フルオロ-1-ニトロ-ベンゼンを黄色油状物として得た。
1H-NMR (CDCl3) δ:1.50 (3H, t, J = 6.8 Hz), 4.17 (2H, q, J = 6.8 Hz), 6.70 (1H, dd, J = 2.7, 7.3 Hz), 6.76 (1H, ddd, J = 2.7, 8.9, 9.7 Hz), 7.93 (1H, dd, J = 5.9, 8.9 Hz).
実施例119-a)と同様に反応・処理し、2-エトキシ-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-1-ニトロベンゼンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.6 Hz), 1.48 (3H, t, J = 7.0 Hz), 1.61 (2H, qt, J = 7.6, 7.8 Hz), 2.61 (2H, t, J = 7.8 Hz), 3.57 (3H, s), 4.13 (2H, q, J = 7.0 Hz), 4.88 (2H, s), 6.42 (1H, dd, J = 2.2, 9.2 Hz), 6.65 (1H, d, J = 2.2 Hz), 7.00 (1H, d, J = 8.6 Hz), 7.48 (1H, d, J = 8.6 Hz), 7.55 (1H, s), 7.92 (1H, d, J = 9.2 Hz).
2-エトキシ-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-1-ニトロベンゼンを用いて実施例))119-a)と同様に反応・処理し、-エトキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニルアミンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.98 (3H, t, J = 7.0 Hz), 1.44 (3H, t, J = 7.0 Hz), 1.71 (2H, qt, J = 7.0, 7.6 Hz), 2.73 (2H, t, J = 7.6 Hz), 3.55 (3H, s), 4.03 (2H, q, J = 7.0 Hz), 4.84 (2H, s), 6.47 (1H, dd, J = 2.4, 8.1 Hz), 6.55 (1H, d, J = 2.4 Hz), 6.71 (1H, d, J = 8.1 Hz), 6.72 (1H, d, J = 8.9 Hz), 7.28 (1H, d, J = 8.9 Hz), 7.41 (1H, s).
実施例119-a)と同様に反応・処理し、2-エトキシ-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-1-ヨードベンゼンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.49 (3H, t, J = 7.6 Hz), 1.65 (2H, qt, J = 7.3, 7.6 Hz), 2.67 (2H, t, J = 7.6 Hz), 3.57 (3H, s), 4.05 (2H, q, J = 7.6 Hz), 4.86 (2H, s), 6.33 (1H, dd, J = 2.2, 8.6 Hz), 6.53 (1H, d, J = 2.2 Hz), 6.86 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 8.6 Hz), 7.48 (1H, s), 7.69 (1H, d, J = 8.6 Hz).
実施例126)と同様に反応・処理し、2-エトキシ-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-1-ビニルベンゼンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.96 (3H, t, J = 7.0 Hz), 1.44 (3H, t, J = 7.0 Hz), 1.67 (2H, qt, J = 7.0, 7.8 Hz), 2.69 (2H, t, J = 7.8 Hz), 3.56 (3H, s), 4.01 (2H, q, J = 7.0 Hz), 4.86 (2H, s), 5.22 (1H, dd, J = 1.4, 11.1 Hz), 5.71 (1H, dd, J = 1.4, 18.1 Hz), 6.49 (1H, dd, J = 2.2, 8.4 Hz), 6.56 (1H, d, J = 2.2 Hz), 6.86 (1H, d, J = 8.9 Hz), 7.01 (1H, dd, J = 11.1, 18.1 Hz), 7.36 (1H, d, J = 8.9 Hz), 7.43 (1H, d, J = 8.4 Hz), 7.46 (1H, s).
2-エトキシ-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)-1-ビニルベンゼン(53 mg, 0.108 mmol)をジオキサン (100 μL)に溶解し、室温にて臭化ナトリウム (16 mg, 0.151 mmol)と臭素酸ナトリウム (11 mg, 0.0753 mmol)の混合水溶液(水200 μL)を加え、濃硫酸 (6.4 μL, 0.118 mmol) を加えた。室温にて3時間30分撹拌した。クロロホルムで抽出し、有機層を飽和チオ硫酸ナトリウム水溶液、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(n-ヘキサン/ 酢酸エチル) で精製し、2-ブロモ-1-{5-ブロモ-2-エトキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノール 49 mg (収率68%) を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.98 (3H, t, J = 7.3 Hz), 1.39 (3H, t, J = 7.0 Hz), 1.72 (2H, qt, J = 7.3, 7.8 Hz), 2.74 (2H, t, J = 7.8 Hz), 2.83 (1H, d, J = 5.1 Hz), 3.51 (1H, dd, J = 8.1, 10.3 Hz), 3.55 (3H, s), 3.77 (1H, dd, J = 3.2, 10.3 Hz), 3.89-4.00 (2H, m), 4.85 (2H, s), 5.11-5.17 (1H, m), 6.50 (1H, s), 6.63 (1H, d, J = 8.9 Hz), 7.33 (1H, d, J = 8.9 Hz), 7.47 (1H, s), 7.71 (1H, s).
実施例205と同様に反応・処理し、2-ブロモ-1-{5-ブロモ-2-エトキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.95 (3H, t, J = 7.3 Hz), 1.46 (3H, t, J = 6.8 Hz), 1.68 (2H, qt, J = 7.3, 7.8 Hz), 2.66 (2H, t, J = 7.8 Hz), 3.57 (3H, s), 3.97 (2H, q, J = 6.8 Hz), 4.54 (2H, s), 4.87 (2H, s), 6.38 (1H, s), 6.86 (1H, d, J = 8.6 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.54 (1H, s), 8.18 (1H, s).
実施例1において、5-(ベンゾ[d][1,3]ジオキソール-5-イル)-5-メチルイミダゾリジン-2,4-ジオンの代わりに5-(5-(1-メチルエトキシ)ピリジン-2-イル)5-メチルイミダゾリジン-2,4-ジオンを用いて同様に反応・処理し、3-(2-(5-ブロモ-2-エトキシ-4-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)フェニル)-2-オキソエチル)-5-(5-(1-メチルエトキシ)ピリジン-2-イル)-5-メチルイミダゾリジン-2,4-ジオンを無色油状物として得た。
1H-NMR (CDCl3) δ:0.97 (3H, t, J = 7.3 Hz), 1.38 (6H, d, J = 5.7 Hz), 1.48 (3H, t, J = 7.0 Hz), 1.70 (2H, qt, J = 7.3, 7.8 Hz), 1.91 (3H, s), 2.67 (2H, t, J = 7.8 Hz), 3.59 (3H, s), 3.98 (2H, q, J = 7.0 Hz), 4.60 (1H, sept, J = 5.7 Hz), 4.88 (2H, s), 4.89 (2H, s), 6.34 (1H, s), 6.39 (1H, s), 6.88 (1H, d, J = 8.6 Hz), 7.23 (1H, dd, J = 2.8, 8.6 Hz), 7.47 (1H, d, J = 8.6 Hz), 7.54 (1H, s), 7.66 (1H, d, J = 8.6 Hz), 8.24 (1H, d, J = 2.8 Hz), 8.28 (1H, s).
実施例121と同様に反応・処理し、3-(2-{2-エトキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-2-オキソ-エチル)-5-(5-(1-メチルエトキシ)ピリジン-2-イル)-5-メチル-イミダゾリジン-2,4-ジオンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.39 (6H, d, J = 5.7 Hz), 1.53 (3H, t, J = 7.0 Hz), 1.61 (2H, qt, J = 7.3, 7.6 Hz), 2.00 (3H, s), 2.60 (2H, t, J = 7.6 Hz), 3.57 (3H, s), 4.13 (2H, q, J = 7.0 Hz), 4.66 (1H, sept, J = 5.7 Hz), 4.87 (2H, s), 4.91 (2H, s), 6.45 (1H, dd, J = 2.2, 8.6 Hz), 6.57 (1H, d, J = 2.2 Hz), 6.98 (1H, d, J = 8.4 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.45 (1H, d, J = 8.4 Hz), 7.52 (1H, s), 7.90 (1H, d, J = 8.4 Hz), 7.93 (1H, d, J = 8.6 Hz), 8.30 (1H, s).
4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-1-(4-ヨード-3-メチルフェノキシ)-2-プロピルベンゼン(393 mg, 0.699 mmol)のトルエン(7.0 mL)溶液にエトキシビニルトリブチルスズ(473 μL, 1.40 mmol)、テトラキストリフェニルホスフィンパラジウム(162 mg, 0.140 mmol)を順に加え、1時間加熱還流した。その後、さらにエトキシビニルトリブチルスズ(946 μL, 2.80 mmol)を加えて1時間30分加熱還流した。反応終了後、氷冷下5%塩酸水溶液を加え、室温にて終夜攪拌した。反応溶液をセライトろ過し、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水にて洗浄し、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)にて精製し、1-{2-メチル-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノン(291 mg, 収率80%)を黄色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.0 Hz), 1.63 (2H, qt, J = 7.0, 7.6 Hz), 2.55 (3H, s), 2.57 (3H, s), 2.63 (2H, t, J = 7.6 Hz), 3.57 (3H, s), 4.87 (2H, s), 6.78 (1H, dd, J = 2.4, 8.6 Hz), 6.84 (1H, d, J = 2.4 Hz), 6.94 (1H, d, J = 8.9 Hz), 7.42 (1H, d, J = 8.9 Hz), 7.51 (1H, s), 7.75 (1H, d, J = 8.6 Hz).
1-{2-メチル-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノンを用いて実施例205と同様に反応・処理し、トルエン-4-スルホン酸 2-{2-メチル-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-ヒドロキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-2-オキソ-エチル エステルを黄色結晶として得た。
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.3 Hz), 2.45 (3H, s), 2.46 (3H, s), 2.60 (2H, t, J = 7.3 Hz), 5.10 (2H, s), 6.74 (1H, dd, J = 1.9, 7.6 Hz), 6.83 (1H, d, J = 1.9 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.35 (2H, d, J = 7.8 Hz), 7.54 (1H, d, J = 7.8 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.63 (1H, s), 7.83 (2H, d, J = 7.6 Hz).
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.33 (6H, d, J = 5.9 Hz), 1.55-1.66 (2H, m), 1.92 (3H, s), 2.53 (3H, s), 2.59 (2H, t, J = 7.0 Hz), 4.50-4.59 (1H, m), 4.78 (1H, d, J = 17.6 Hz), 4.80 (1H, d, J = 17.6 Hz), 5.94 (1H, s), 6.77 (1H, dd, J = 2.4, 8.9 Hz), 6.83 (1H, d, J = 2.4 Hz), 6.90 (2H, d, J = 8.6 Hz), 6.96 (1H, d, J = 8.9 Hz), 7.45 (2H, d, J = 8.6 Hz), 7.53 (1H, d, J = 8.9 Hz), 7.63 (1H, s), 7.74 (1H, d, J = 8.9 Hz).
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.55-1.66 (2H, m), 1.92 (3H, s), 2.53 (3H, s), 2.59 (2H, t, J = 7.0 Hz), 3.23 (2H, t, J = 8.6 Hz), 4.59 (2H, t, J = 8.9 Hz), 4.78 (1H, d, J = 17.6 Hz), 4.80 (1H, d, J = 17.6 Hz), 5.97 (1H, s), 6.76 (1H, dd, J = 2.2, 8.6 Hz), 6.78 (1H, d, J = 8.6 Hz), 6.84 (1H, d, J = 2.2 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.28 (1H, dd, J = 1.9, 8.6 Hz), 7.41 (1H, d, J = 1.9 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.63 (1H, s), 7.74 (1H, d, J = 8.6 Hz).
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.6 Hz), 1.36 (6H, d, J = 5.9 Hz), 1.55-1.68 (2H, m), 1.88 (3H, s), 2.53 (3H, s), 2.60 (2H, t, J = 7.6 Hz), 4.54-4.62 (1H, m), 4.82 (2H, s), 6.42 (1H, s), 6.77 (1H, dd, J = 2.2, 8.9 Hz), 6.84 (1H, d, J = 2.2 Hz), 6.96 (1H, d, J = 8.6 Hz), 7.20 (1H, dd, J = 2.4, 8.9 Hz), 7.54 (1H, d, J = 8.6 Hz), 7.61 (1H, d, J = 8.9 Hz), 7.63 (1H, s), 7.75 (1H, d, J = 8.9 Hz), 8.21 (1H, d, J = 2.4 Hz).
1-エチル-2-(3-メチル-4-ニトロ-フェノキシ)-3-プロピル-5-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-ベンゼンの製造:
実施例119-a)と同様に反応・処理し、1-エチル-2-(3-メチル-4-ニトロ-フェノキシ)-3-プロピル-5-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-ベンゼンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.87 (3H, t, J = 7.3 Hz), 1.14 (3H, t, J = 7.3 Hz), 1.56 (2H, qt, J = 7.3, 7.8 Hz), 2.43 (2H, t, J = 7.8 Hz), 2.48 (2H, q, J = 7.3 Hz), 2.61 (3H, s), 3.58 (3H, s), 4.90 (2H, s), 6.60 (1H, dd, J = 2.7, 9.2 Hz), 6.73 (1H, d, J = 2.7 Hz), 7.40 (1H, s), 7.42 (1H, s), 8.04 (1H, d, J = 9.2 Hz).
1-エチル-2-(3-メチル-4-ニトロ-フェノキシ)-3-プロピル-5-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-ベンゼンを用いて実施例)))))119-a)と同様に反応・処理し、4-[2-エチル-6-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-2-メチル-フェニルアミンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.86 (3H, t, J = 7.3 Hz), 1.12 (3H, t, J = 7.6 Hz), 1.55 (2H, qt, J = 7.3, 7.6 Hz), 2.25 (3H, s), 2.45 (2H, t, J = 7.6 Hz), 2.49 (2H, q, J = 7.6 Hz), 3.57 (3H, s), 4.88 (2H, s), 6.41 (1H, d, J = 8.6 Hz), 6.59 (1H, s), 6.83 (1H, d, J = 8.6 Hz), 7.33 (1H, s), 7.35 (1H, s).
実施例119-a)と同様に反応・処理し、1-エチル-2-(4-ヨード-3-メチル-フェノキシ)-3-プロピル-5-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-ベンゼンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.87 (3H, t, J = 7.3 Hz), 1.14 (3H, t, J = 7.6 Hz), 1.57 (2H, qt, J = 7.3, 7.8 Hz), 2.39 (3H, s), 2.45 (2H, t, J = 7.8 Hz), 2.50 (2H, q, J = 7.6 Hz), 3.59 (3H, s), 4.90 (2H, s), 6.26 (1H, dd, J = 2.7, 7.6 Hz), 6.73 (1H, d, J = 2.7 Hz), 7.37 (1H, s), 7.38 (1H, s), 7.63 (1H, d, J = 7.6 Hz).
実施例212と同様に反応・処理し、1-{4-[2-エチル-6-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-2-メチル-フェニル}-エタノンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.87 (3H, t, J = 7.0 Hz), 1.14 (3H, t, J = 7.6 Hz), 1.57 (2H, qt, J = 7.0, 7.3 Hz), 2.44 (2H, t, J = 7.3 Hz), 2.49 (2H, q, J = 7.6 Hz), 2.55 (6H, s), 3.58 (3H, s), 4.90 (2H, s), 6.51 (1H, dd, J = 2.7, 8.9 Hz), 6.69 (1H, d, J = 2.7 Hz), 7.38 (1H, s), 7.40 (1H, s), 7.71 (1H, d, J = 8.9 Hz).
1-{4-[2-エチル-6-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-2-メチル-フェニル}-エタノンを用いて実施例205と同様に反応・処理し、表題化合物を白色結晶として得た。
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.16 (3H, t, J = 7.6 Hz), 1.59 (2H, qt, J = 7.3, 7.6 Hz), 2.41-2.53 (4H, m), 2.46 (3H, s), 2.47 (3H, s), 5.10 (2H, s), 6.53 (1H, dd, J = 2.2, 8.4 Hz), 6.71 (1H, d, J = 2.2 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.49 (1H, s), 7.50 (1H, s), 7.51 (1H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz).
1H-NMR (CDCl3) δ:0.86 (3H, t, J = 7.3 Hz), 1.14 (3H, t, J = 7.6 Hz), 1.33 (6H, d, J = 5.9 Hz), 1.49-1.63 (2H, m), 1.91 (3H, s), 2.40-2.52 (4H, m), 2.52 (3H, s), 4.48-4.61 (1H, m), 4.77 (1H, d, J = 17.3 Hz), 4.79 (1H, d, J = 17.3 Hz), 5.96 (1H, s), 6.55 (1H, dd, J = 2.7, 8.9 Hz), 6.71 (1H, d, J = 2.7 Hz), 6.90 (2H, d, J = 8.9 Hz), 7.45 (2H, d, J = 8.9 Hz), 7.49 (2H, s), 7.71 (1H, d, J = 8.9 Hz).
1H-NMR (CDCl3) δ:0.86 (3H, t, J = 7.3 Hz), 1.14 (3H, t, J = 7.6 Hz), 1.35 (6H, d, J = 6.2 Hz), 1.56 (2H, qt, J = 7.3, 7.6 Hz), 1.87 (3H, s), 2.42-2.52 (4H, m), 2.52 (3H, s), 4.51-4.64 (1H, m), 4.81 (2H, s), 6.41 (1H, s), 6.56 (1H, dd, J = 2.7, 8.4 Hz), 6.71 (1H, d, J = 2.7 Hz), 7.19 (1H, dd, J = 2.4, 8.6 Hz), 7.48 (1H, s), 7.50 (1H, s), 7.62 (1H, d, J = 8.6 Hz), 7.72 (1H, d, J = 8.4 Hz), 8.20 (1H, d, J = 2.4 Hz).
1-{2-ベンジルオキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノンの製造:
実施例212と同様に反応・処理し、1-{2-ベンジルオキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-メトキシメトキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-エタノンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.61 (2H, qt, J = 7.3, 7.8 Hz), 2.59 (2H, t, J = 7.8 Hz), 2.62 (3H, s), 3.60 (3H, s), 4.90 (2H, s), 5.13 (2H, s), 6.54 (1H, dd, J = 2.4, 8.6 Hz), 6.60 (1H, d, J = 2.4 Hz), 6.93 (1H, d, J = 8.9 Hz), 7.34-7.45 (6H, m), 7.53 (1H, s), 7.83 (1H, d, J = 8.6 Hz).
実施例205)と同様に反応・処理し、トルエン-4-スルホン酸 2-{2-ベンジルオキシ-4-[2-プロピル-4-(2,2,2-トリフルオロ-1-ヒドロキシ-1-トリフルオロメチル-エチル)-フェノキシ]-フェニル}-2-オキソ-エチル エステルを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.89 (3H, t, J = 7.3 Hz), 1.57 (2H, qt, J = 7.3, 7.3 Hz), 2.43 (3H, s), 2.52 (2H, t, J = 7.3 Hz), 5.07 (2H, s), 5.14 (2H, s), 6.50-6.54 (2H, m), 6.94 (1H, d, J = 8.6 Hz), 7.24-7.43 (7H, m), 7.54 (1H, d, J = 8.6 Hz), 7.62 (1H, s), 7.67 (2H, d, J = 8.6 Hz), 7.92 (1H, d, J = 9.2 Hz).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.33 (6H, d, J = 5.7 Hz), 1.54 (2H, qt, J = 7.3, 7.8 Hz), 1.92 (3H, s), 2.49 (2H, t, J = 7.8 Hz), 4.55 (1H, sept, J = 5.7 Hz), 4.84 (1H, d, J = 18.1 Hz), 4.85 (1H, d, J = 18.1 Hz), 5.12 (2H, s), 5.72 (1H, s), 6.48 (1H, d, J = 1.9 Hz), 6.53 (1H, dd, J = 1.9, 8.9 Hz), 6.89-6.93 (3H, m), 7.28-7.37 (5H, m), 7.45-7.50 (3H, m), 7.61 (1H, s), 7.98 (1H, d, J = 8.9 Hz).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.3 Hz), 1.54 (2H, qt, J = 7.3, 7.6 Hz), 1.89 (3H, s), 2.49 (2H, t, J = 7.6 Hz), 4.25 (4H, s), 4.83 (1H, d, J = 18.6 Hz), 4.84 (1H, d, J = 18.6 Hz), 5.12 (2H, s), 5.67 (1H, s), 6.48 (1H, d, J = 2.4 Hz), 6.53 (1H, dd, J = 2.4, 8.6 Hz), 6.89 (1H, d, J = 8.6 Hz), 6.93 (1H, d, J = 8.9 Hz), 7.04 (1H, dd, J = 2.2, 8.9 Hz), 7.09 (1H, d, J = 2.2 Hz), 7.28-7.37 (5H, m), 7.52 (1H, d, J = 8.6 Hz), 7.61 (1H, s), 7.99 (1H, d, J = 8.6 Hz).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.6 Hz), 1.36 (6H, d, J = 6.5 Hz), 1.54 (2H, qt, J = 7.6, 7.8 Hz), 1.87 (3H, s), 2.49 (2H, t, J = 7.8 Hz), 4.58 (1H, sept, J = 6.5 Hz), 4.87 (2H, s), 5.13 (2H, s), 6.29 (1H, s), 6.48 (1H, d, J = 2.4 Hz), 6.53 (1H, dd, J = 2.4, 8.9 Hz), 6.92 (1H, d, J = 8.9 Hz), 7.29-7.36 (5H, m), 7.52 (1H, d, J = 8.9 Hz), 7.61 (1H, s), 7.64 (1H, d, J = 8.9 Hz), 7.97 (1H, d, J = 8.9 Hz), 8.21 (1H, d, J = 2.7 Hz).
1H-NMR (CDCl3) δ:0.87 (3H, t, J = 7.3 Hz), 1.54 (2H, qt, J = 7.3, 7.8 Hz), 1.91 (3H, s), 2.48 (2H, t, J = 7.8 Hz), 3.22 (2H, t, J = 8.9 Hz), 4.58 (2H, t, J = 8.9 Hz), 4.83 (1H, d, J = 18.1 Hz), 4.85 (1H, d, J = 18.1 Hz), 5.11 (2H, s), 5.85 (1H, s), 6.48 (1H, d, J = 2.2 Hz), 6.52 (1H, dd, J = 2.2, 8.4 Hz), 6.79 (1H, d, J = 8.6 Hz), 6.91 (1H, d, J = 8.9 Hz), 7.27-7.36 (6H, m), 7.43 (1H, s), 7.51 (1H, d, J = 8.9 Hz), 7.61 (1H, s), 7.97 (1H, d, J = 8.4 Hz).
1H-NMR (CDCl3) δ:0.88 (3H, t, J = 7.6 Hz), 1.54 (2H, qt, J = 7.6, 7.8 Hz), 1.84 (3H, s), 2.49 (2H, t, J = 7.8 Hz), 4.28-4.34 (4H, m), 4.86 (2H, s), 5.13 (2H, s), 6.35 (1H, s), 6.48 (1H, d, J = 2.2 Hz), 6.52 (1H, dd, J = 2.2, 8.9 Hz), 6.92 (1H, d, J = 8.6 Hz), 7.26-7.40 (6H, m), 7.52 (1H, d, J = 8.6 Hz), 7.61 (1H, s), 7.97 (1H, d, J = 8.9 Hz), 8.09 (1H, s).
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.60 (2H, qt, J = 7.3, 7.8 Hz), 1.91 (3H, s), 2.56 (2H, t, J = 7.8 Hz), 4.27 (4H, s), 4.89 (1H, d, J = 17.8 Hz), 4.91 (1H, d, J = 17.8 Hz), 5.79 (1H, s), 6.37 (1H, d, J = 2.2 Hz), 6.55 (1H, dd, J = 2.2, 8.9 Hz), 6.91 (1H, d, J = 8.6 Hz), 7.03 (1H, dd, J = 2.2, 8.6 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.09 (1H, d, J = 2.2 Hz), 7.57 (1H, d, J = 8.6 Hz), 7.63 (1H, s), 7.68 (1H, d, J = 8.9 Hz), 11.87 (1H, s).
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.37 (6H, d, J = 5.7 Hz), 1.60 (2H, qt, J = 7.3, 7.3 Hz), 1.89 (3H, s), 2.56 (2H, t, J = 7.3 Hz), 4.59 (1H, sept, J = 5.7 Hz), 4.93 (2H, s), 6.34 (1H, s), 6.37 (1H, d, J = 2.2 Hz), 6.55 (1H, dd, J = 2.2, 9.2 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.21 (1H, dd, J = 2.7, 7.3 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.62 (1H, d, J = 7.3 Hz), 7.63 (1H, s), 7.69 (1H, d, J = 9.2 Hz), 8.22 (1H, d, J = 2.7 Hz), 11.87 (1H, s).
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.59 (2H, qt, J = 7.3, 7.6 Hz), 1.93 (3H, s), 2.55 (2H, t, J = 7.6 Hz), 3.24 (2H, t, J = 8.9 Hz), 4.60 (2H, t, J = 8.9 Hz), 4.90 (1H, d, J = 17.6 Hz), 4.92 (1H, d, J = 17.6 Hz), 5.88 (1H, s), 6.37 (1H, d, J = 2.4 Hz), 6.55 (1H, dd, J = 2.4, 8.9 Hz), 6.80 (1H, d, J = 8.4 Hz), 7.05 (1H, d, J = 8.4 Hz), 7.29 (1H, dd, J = 1.9, 8.4 Hz), 7.41 (1H, d, J = 1.9 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.63 (1H, s), 7.68 (1H, d, J = 8.9 Hz), 11.88 (1H, s).
1H-NMR (CDCl3) δ:0.90 (3H, t, J = 7.6 Hz), 1.59 (2H, qt, J = 7.6, 7.8 Hz), 1.86 (3H, s), 2.55 (2H, t, J = 7.8 Hz), 4.28-4.36 (4H, m), 4.92 (2H, s), 6.37 (1H, d, J = 2.7 Hz), 6.48 (1H, s), 6.55 (1H, dd, J = 2.7, 8.9 Hz), 7.05 (1H, d, J = 8.4 Hz), 7.23 (1H, s), 7.56 (1H, d, J = 8.4 Hz), 7.63 (1H, s), 7.68 (1H, d, J = 8.9 Hz), 8.11 (1H, s), 11.87 (1H, s).
1-(5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)エタノンの製造:
5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピコリノニトリルに実施例2-a)と同様に反応・処理し、1-(5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)エタノンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.6 Hz), 1.63 (2H, qt, J = 7.6, 7.6 Hz), 2.63 (2H, t, J = 7.6 Hz), 2.70 (3H, s), 3.57 (3H, s), 4.88 (2H, s), 6.98 (1H, d, J = 8.6 Hz), 7.29 (1H, dd, J = 2.7, 8.6 Hz), 7.49 (1H, d, J = 8.6 Hz), 7.56 (1H, s), 8.06 (1H, d, J = 8.6 Hz), 8.37 (1H, d, J = 2.7 Hz).
実施例205と同様に反応・処理し、4-メチルベンゼンスルホン酸2-(5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)-2-オキソエチルを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.91 (3H, t, J = 7.3 Hz), 1.61 (2H, qt, J = 7.3, 7.6 Hz), 2.45 (3H, s), 2.59 (2H, t, J = 7.6 Hz), 5.58 (2H, s), 7.00 (1H, d, J = 8.6 Hz), 7.26 (1H, dd, J = 1.9, 8.8 Hz), 7.36 (1H, d, J = 8.3 Hz), 7.59 (1H, d, J = 8.6 Hz), 7.67 (1H, s), 7.90 (2H, d, J = 8.3 Hz), 8.02 (1H, d, J = 8.8 Hz), 8.29 (1H, d, J = 1.9 Hz).
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.34 (6H, d, J = 6.1 Hz), 1.60 (2H, qt, J = 7.3, 7.6 Hz), 1.93 (3H, s), 2.60 (2H, t, J = 7.6 Hz), 4.55 (1H, sept, J = 6.1 Hz), 5.16 (1H, d, J = 18.5 Hz), 5.18 (1H, d, J = 18.5 Hz), 5.67 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 7.02 (1H, d, J = 8.6 Hz), 7.26 (1H, dd, J = 2.4, 8.8 Hz), 7.48 (2H, d, J = 9.0 Hz), 7.59 (1H, d, J = 8.6 Hz), 7.67 (1H, s), 8.03 (1H, d, J = 8.8 Hz), 8.37 (1H, d, J = 2.4 Hz).
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.6 Hz), 1.56 (2H, qt, J = 7.6, 7.8 Hz), 1.92 (3H, s), 2.61 (2H, t, J = 7.8 Hz), 5.17 (2H, s), 5.99 (2H, s), 6.84 (1H, d, J = 7.8 Hz), 7.00 (1H, d, J = 8.6 Hz), 7.05 (1H, d, J = 7.8 Hz), 7.10 (1H, s), 7.25 (1H, dd, J = 2.9, 8.8 Hz), 7.60 (1H, d, J = 8.6 Hz), 7.67 (1H, s), 8.02 (1H, d, J = 8.8 Hz), 8.38 (1H, d, J = 2.9 Hz).
1-(5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)プロパン-1-オンの製造:
5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピコリノニトリルに実施例2-a) においてメチルマグネシウムブロマイドの代わりにエチルマグネシウムブロマイドを用いて同様に反応・処理し、1-(5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)プロパン-1-オンを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.22 (3H, t, J = 7.3 Hz), 1.63 (2H, qt, J = 7.3, 7.6 Hz), 2.63 (2H, t, J = 7.6 Hz), 3.21 (2H, q, J = 7.3 Hz), 3.57 (3H, s), 4.88 (2H, s), 6.99 (1H, d, J = 8.8 Hz), 7.30 (1H, dd, J = 2.7, 8.6 Hz), 7.48 (1H, d, J = 8.8 Hz), 7.56 (1H, s), 8.06 (1H, d, J = 8.6 Hz), 8.36 (1H, d, J = 2.7 Hz).
1-(5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-(メトキシメトキシ)プロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)プロパン-1-オンを用いて実施例205と同様に反応・処理し、4-メチルベンゼンスルホン酸 1-(5-(4-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)-2-プロピルフェノキシ)ピリジン-2-イル)-1-オキソプロパン-2-イルを黄色油状物として得た。
1H-NMR (CDCl3) δ:0.93 (3H, t, J = 7.3 Hz), 1.59 (3H, d, J = 7.1 Hz), 1.63 (2H, qt, J = 7.3, 7.3 Hz), 2.43 (3H, s), 2.61 (2H, t, J = 7.3 Hz), 5.34 (1H, q, J = 7.1 Hz), 7.02 (1H, d, J = 8.6 Hz), 7.20 (1H, dd, J = 2.4, 8.3 Hz), 7.31 (1H, d, J = 7.8 Hz), 7.60 (1H, d, J = 8.6 Hz), 7.68 (1H, s), 7.84 (2H, d, J = 7.8 Hz), 8.07 (1H, d, J = 8.3 Hz), 8.32 (1H, d, J = 2.4 Hz).
1H-NMR (CDCl3) δ:0.92 (3H, t, J = 7.3 Hz), 1.33 (6H, d, J = 5.9 Hz), 1.52-1.65 (2H, m), 1.70-1.79 (3H, m), 1.84 (3H, s), 2.52-2.62 (2H, m), 4.48-4.59 (1H, m), 5.62-5.76 (1H, m), 5.82 (1H, s), 6.82-6.86 (1H, m), 6.89 (2H, d, J = 8.9 Hz), 6.93-6.98 (1H, m), 7.31-7.35 (1H, m), 7.37 (2H, d, J = 8.9 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.65 (1H, s), 8.01-8.10 (1H, m).J = 8.6 Hz).
<プラスミドの構築>
ヒトLXRα及びLXRβ cDNAのリガンド結合ドメイン(LBD)を哺乳類発現
ベクターpBIND(Promega)の酵母GAL4転写因子DNA結合ドメイン(DBD)に隣接して挿入することによって発現構築物を調製し、それぞれpBIND-LXRα/GAL4及びpBIND-LXRβ/GAL4を作製した。GAL4応答性リポーター構築物、pG5lucは、Promega社から入手できる公知のベクターであり、プロモーターに隣接して位置する5コピーのGAL4応答エレメントとルシフェラーゼリポーター遺伝子を含む。
<アッセイ>
LXRα/GAL4又はLXRβ/GAL4ハイブリッド及びGAL4応答性リポーターベクターpG5luc安定発現CHOK-1細胞を、5%CO2の湿潤雰囲気下、37℃で、10%非働化処理ウシ胎児血清、100単位/mlペニシリンG及び100μg/ml硫酸ストレプトマイシンを含有するHAM-F12培地を入れた96ウェルプレートに20,000細胞/ウェルで播種した。24時間後、被検化合物を試験濃度範囲(0.01μM、0.1μM、1μM、10μM)にわたって溶解した培地を添加し、細胞とともに24時間インキュベーションした。ルシフェラーゼアッセイ基質としてBright-Glo(Promega)を用い、発光強度をルミノメーターLB960(Berthold Technologies)で測定することにより、試験化合物がLXRα又はβのLBDを介してルシフェラーゼ転写の活性化に及ぼす作用を測定した。比較化合物としてT0901317(国際公開WO2000/54759パンフレットの実施例12の化合物)を同時に評価した。ルシフェラーゼ活性の結果はT0901317の10μMにおける発光強度を100とした時の試験化合物の各濃度における活性値(%eff)として表1に示した。
<結果>
表1に示す通り、本発明のカルビノール化合物は対照薬であるT0901317よりもLXRβに高い選択性を有するLXRアゴニストであることが実験的に確認された。
Claims (7)
- 次の一般式(I)
<グループA>
ハロゲン原子、C1-8アルキル基、ハロC1-8アルキル基、C2-8アルケニル基、C2-8アルキニル基、C3-8シクロアルキル基、シアノ基、ニトロ基、ヒドロキシ基、アミノ基、モノC1-8アルキルアミノ基、ジC1-8アルキルアミノ基、C1-8アルコキシ基、C3-8シクロアルキルオキシ基、ハロC1-8アルコキシ基、C1-8アシル基、カルボキシル基、C1-8アシルオキシ基、C1-8アルコキシカルボニル基、カルバモイル基、C6-10アリール基、5-11員ヘテロ環基、(1乃至3のC1-8アルキル基で置換されていてもよい)C6-10アリールC1-8アルコキシ基、C1-8アルキルチオ基、C3-8シクロアルキルチオ基、C1-8アルキルスルフィニル基、C1-8アルキルスルホニル基、C6-10アリールチオ基、C6-10アリールスルフィニル基、C6-10アリールスルホニル基、C1-8アルコキシC1-8アルキル基〕
で表されるカルビノール化合物、若しくはその塩又はそれらの溶媒和物。 - 請求項1に記載のカルビノール誘導体、若しくはその塩又はそれらの溶媒和物を有効成分とする医薬。
- アテローム性動脈硬化症、糖尿病に起因する動脈硬化症、脂質異常症、高コレステロール血症、脂質関連疾患、炎症性サイトカインにより引き起こされる疾患である炎症性疾患、皮膚疾患、糖尿病又はアルツハイマー病の予防及び/又は治療剤である請求項2記載の医薬。
- 請求項1に記載のカルビノール誘導体、若しくはその塩又はそれらの溶媒和物を有効成分とするLXR調節剤。
- 請求項1に記載のカルビノール誘導体、若しくはその塩又はそれらの溶媒和物、及び製薬上許容される担体からなる医薬組成物。
- 治療を必要としている患者に、請求項1に記載のカルビノール誘導体、若しくはその塩又はそれらの溶媒和物の有効量を投与することを特徴とする、アテローム性動脈硬化症、糖尿病に起因する動脈硬化症、脂質異常症、高コレステロール血症、脂質関連疾患、炎症性サイトカインにより引き起こされる疾患である炎症性疾患、皮膚疾患、糖尿病又はアルツハイマー病の予防及び/又は治療方法。
- アテローム性動脈硬化症、糖尿病に起因する動脈硬化症、脂質異常症、高コレステロール血症、脂質関連疾患、炎症性サイトカインにより引き起こされる疾患である炎症性疾患、皮膚疾患、糖尿病又はアルツハイマー病の予防及び/又は治療のための製剤を製造するための、請求項1に記載のカルビノール誘導体、若しくはその塩又はそれらの溶媒和物の使用。
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Also Published As
Publication number | Publication date |
---|---|
AU2009252615A1 (en) | 2009-12-03 |
EP2281817A1 (en) | 2011-02-09 |
EA201071238A1 (ru) | 2011-06-30 |
ZA201008424B (en) | 2011-11-30 |
AU2009252615B2 (en) | 2013-08-15 |
JPWO2009144961A1 (ja) | 2011-10-06 |
EA018584B1 (ru) | 2013-09-30 |
NZ589504A (en) | 2012-07-27 |
MX2010012882A (es) | 2010-12-14 |
IL209489A0 (en) | 2011-01-31 |
CN102105452A (zh) | 2011-06-22 |
US8153634B2 (en) | 2012-04-10 |
KR20110025899A (ko) | 2011-03-14 |
TW201010983A (en) | 2010-03-16 |
CA2725111A1 (en) | 2009-12-03 |
JP5541803B2 (ja) | 2014-07-09 |
US20100048610A1 (en) | 2010-02-25 |
EP2281817A4 (en) | 2011-10-05 |
BRPI0913212A2 (pt) | 2019-09-24 |
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