JP2017509638A - 抗真菌化合物の調製方法 - Google Patents
抗真菌化合物の調製方法 Download PDFInfo
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- JP2017509638A JP2017509638A JP2016557623A JP2016557623A JP2017509638A JP 2017509638 A JP2017509638 A JP 2017509638A JP 2016557623 A JP2016557623 A JP 2016557623A JP 2016557623 A JP2016557623 A JP 2016557623A JP 2017509638 A JP2017509638 A JP 2017509638A
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- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- 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
- C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
Abstract
Description
本出願は、2014年3月19日に出願された米国仮特許出願第61/955,565号の優先権を主張するものであり、その内容が参照により本明細書に明示的に組み込まれる。
2−(2,4−ジフルオロフェニル)−1,1−ジフルオロ−3−(1H−テトラゾール−1−イル)−1−(5−(4−(2,2,2−トリフルオロエトキシ)フェニル)ピリジン−2−イル)プロパン−2−オール(1または1a)。
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
ケトン8:
と反応させて化合物1または1a:
を含む方法を提供する。
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
をさらに含む方法を提供する。
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
と反応させてケトン8:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールであり、
R3およびR4はそれぞれ独立して、アルキル、置換アルキル、アリール、置換アリール、アルコキシ、置換アルコキシ、OH、アリールオキシまたは置換アリールオキシであり、かつ
R5、R6、R7およびR8はそれぞれ独立して、H、アルキル、置換アルキル、アリール、置換アリール、アルコキシ、置換アルコキシ、アリールオキシまたは置換アリールオキシである)
を含む方法を提供する。
またはそれらの混合物の調製方法であって、式6の化合物:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
またはそれらの混合物を化合物1に変換する工程
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
(式中、R2は、
を含む方法を提供する。
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールであり、かつ
R’はトリメチルシリルまたはHである)
を含む方法を提供する。
(式中、R’はトリメチルシリルまたはHである)
を含む方法を提供する。
i.式15の化合物:
ii.式17または17aの化合物:
iii.式19または19aの化合物:
iv.式9または9aの化合物:
またはそれらの混合物をアリール化して化合物1または1a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
i.式15の化合物:
ii.ケトン16:
iii.ニトロアルコール18または18a:
iv.アミノアルコール20または20a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
i.式15の化合物:
ii.式17または17aの化合物:
iii.ニトロアルコール18または18a:
iv.アミノアルコール20または20a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
ii.式17または17aの化合物:
iii.式19または19aの化合物:
iv.アミノアルコール20または20a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールであり、かつ
R’はHまたはTMSである)
を含む方法を提供する。
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールであり、かつ
R’はHまたはTMSである)
を含む方法を提供する。
i.式15の化合物:
ii.ケトン16:
iii.ニトリル24または24a:
iv.アミノアルコール20または20a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールであり、かつ
R’はHまたはTMSである)
を含む方法を提供する。
i.式15の化合物:
ii.式23または23aの化合物:
iii.ニトリル24または24a:
iv.アミノアルコール20または20a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールであり、かつ
R’はHまたはTMSである)
を含む方法を提供する。
i.式15の化合物:
ii.式23または23aの化合物:
iii.式19または19aの化合物:
iv.アミノアルコール20または20a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールであり、かつ
R’はHまたはTMSである)
を含む方法を提供する。
i.式15の化合物:
ii.式23または23aの化合物:
iii.式19または19aの化合物:
iv.式9または9aの化合物:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールであり、かつ
R’はHまたはTMSである)
を含む方法を提供する。
i.式19または19aの化合物:
ii.アミノアルコール20または20a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
i.式19または19aの化合物:
ii.アミノアルコール9または9a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む方法を提供する。
R’’’はCNまたは−CH2NH2であり、
YはBr、Iまたは
あるいはR’’およびR’’’は一緒になってカルボニルを形成していてもよいが、
R’’およびR’’’が一緒になってカルボニルを形成している場合、YはBrではない)
を提供する。
「キラル」という用語は、鏡像相手と重ね合わせることができないという特性を有する分子を指し、「アキラル」という用語は、それらの鏡像相手に重ね合わせることができる分子を指す。
一態様では、本発明は、本明細書中の式のいずれか(例えば、式1または1a)の化合物および薬学的に許容される担体を含む医薬組成物を提供する。
本明細書中の化合物および組成物は、本明細書中の化合物(または組成物)を植物(例えば、種子、苗、草、雑草、穀物)に接触させる工程を含む植物の表面にいる微生物における金属酵素活性の調整方法で使用することができる。本明細書中の化合物または組成物を、対象の植物、圃場または他の農業領域に投与する(例えば、接触させる、塗布する、噴霧する、霧吹きする、散布するなど)ことによって、本化合物および組成物を(例えば、除草剤、殺虫剤、成長調整剤などとして)使用して、植物、圃場または他の農業領域を治療することができる。この投与は出芽前または出芽後であってもよい。この投与は治療もしくは予防投与計画のいずれかであってもよい。
本明細書中のスキームにおける構造の可変部分に関する定義は、本明細書に詳述されている式の中の対応する位置の可変部分の定義に対応している。
1H NMR (500 MHz, CDCl3): δ 8.76 (s, 1 H), 8.70 (s, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.70 (s, 1 H), 7.64 (d, J = 8.5 Hz, 1 H), 7.54 (d, J = 8.5 Hz, 2 H), 7.42- 7.37 (m, 1 H), 7.08 (d, J = 8.5 Hz, 2 H), 6.79- 6.75 (m, 1 H), 6.69- 6.66 (m, 1 H), 5.58 (d, J = 14.0 Hz, 1 H), 5.14 (d, J = 14.0 Hz, 1 H), 4.44 - 4.39 (m, 2 H). HPLC: 99.1%. MS (ESI): m/z 528 [M++1].
1のためのキラル分取HPLC仕様:
カラム:Chiralpak IA、250×4.6mm、5u
移動相:A)n−ヘキサン、B)IPA
定組成:A:B(65:35)
流速:1.00mL/分
旋光度[α]D:+24°(C=0.1%、MeOH)
綺麗で乾燥したジャケット付きの100Lの反応器に銅粉末(1375g、2.05当量、10ミクロン、楕円体、SAFC Cat#326453)およびDMSO(17.5L、7体積)を添加した。次に、ブロモジフルオロ酢酸エチル(2.25kg、1.05当量、Apollo社ロット#102956)を添加し、得られたスラリーを20〜25℃で1〜2時間撹拌した。次いで、2,5−ジブロモピリジン(2−Br、2.5kg、1.0当量、Alfa Aesar社ロット#F14P38)をこのバッチに添加し、混合物を(グリコールジャケットを用いて)35℃に直ちに加熱した。35℃で70時間後、CG/MS分析のために混合物から試料を採取した。反応スラリーの試料を1/1のCH3CN/水で希釈し、濾過し(0.45ミクロン)、濾液を直接分析した。理想的には、2,5−ジブロモピリジンの残りが5%未満(AUC)であれば反応が完了しているとみなす。この特定のバッチでは、10%(AUC)の2,5−ジブロモピリジンが残っていた。しかし、既に反応時間が長いために、本発明者らは、そのバッチを延長してもこれ以上の変換は促進されないと感じた。そこで反応が完了しているものとみなし、EtOAc(35L)で希釈した。反応混合物を20〜35℃で1時間撹拌し、次いで、固体(銅塩)をセライトパッドに通して濾過で除去した。反応器内の残留する固体をEtOAc(2×10L)を用いて順方向に洗い流し、次いで、これをセライトで濾過した。濾過ケークをさらなるEtOAc(3×10L)で洗浄し、EtOAc濾液を1つにまとめた。NH4Cl(10kg)をDI水(100L)に溶解し、次いで28%NH4OH水溶液(2.0L)を添加してpHを9に到達させて、緩衝液を調製した。次いで、1つにまとめたEtOAc濾液を、温度を30℃未満に維持しながら予め冷却した(0〜15℃の)NH4Cl溶液およびNH4OH(35L、pH=9)緩衝液にゆっくりと添加した。次いで、混合物を15〜30分間撹拌し、相を分離した。水層(青色)を除去し、水層中の青色が識別不可能になるまで有機層を緩衝液で洗浄した。この実験では3×17.5Lの洗浄液が必要であった。次いで、有機層を塩水(12.5L)およびpH9のNH4Cl緩衝液(12.5L)の1/1混合物で洗浄し、MgSO4で乾燥し、濾過し、濃縮乾固した。これにより粗製化合物3−Br[2.29kg、77%の収率、GC/MSで88%(AUC)]を黄色の油として得た。粗製の3−Br中に存在する主要な不純物は未反応の2,5−ジブロモピリジン[GC/MSで10%(AUC)]であった。1H NMR(CDCl3)は粗製化合物3−Brの前のロットと一貫していた。次いで、粗製化合物3−Brを同様の純度のロットと1つにまとめ、カラムクロマトグラフィ(SiO2ゲル上で5/95のEtOAc/ヘプタン)で精製した。
綺麗で乾燥した72Lの丸底フラスコに、1−ブロモ−2,4−ジフルオロベンゼン(1586g、1.15当量、Oakwood社ロット#H4460)およびMTBE(20L、12.6体積)を添加した。この溶液を−70〜−75℃に冷却し、n−BuLi(3286mL、1.15当量、2.5Mのヘキサン溶液、SAFCロット#32799MJ)で処理し、−75〜−55℃に維持しながら可能な限り素早く添加した。この添加は完了するのに典型的に35〜45分を要した(注記:n−BuLiをゆっくりと添加した場合、白色のスラリーが形成され、これにより典型的に乏しい結果が生じる)。−70〜−65℃で45分間撹拌した後、化合物3−Br(2000g、1.0当量、AMRIロット#15CL049A)のMTBE(3体積)溶液を−75〜−55℃に維持しながら、添加漏斗により素早く(20〜30分)アリールリチウム溶液に添加した。−75〜−55℃で30〜60分間撹拌した後、GC/MSで反応系を分析し、微量(0.5%AUC)の1−ブロモ−2,4−ジフルオロベンゼンのみが存在することを確認した。反応系を2MのHCl(3.6L)水溶液でゆっくりと失活させ、室温に温めた。NaHCO3(4L)を用いて混合物のpHを6.5〜8.5に調整し、有機層を分離した。MTBE層を塩水(5%NaCl水溶液、4L)で洗浄し、MgSO4で乾燥し、濾過し、濃縮した。中間体ヘミアセタールを4に変換するために、粗製の混合物を20Lのロータリーエバポレーター(rotovap)フラスコ内で60〜65℃で3時間(真空下で)加熱し、この時点で1H NMR(CDCl3)によれば全てのヘミアセタールが所望のケトン4−Brに変換されていた。これにより粗製化合物4−Br[2.36kg、HPLCで75%(AUC)]が褐色の油として得られ、これを放置すると固化した。次いで、この材料をさらに精製することなく次の工程で「そのまま」使用することができる。
本出願の全体にわたって引用されている全ての参考文献(文献、取得済特許、公開特許出願および同時係属中の特許出願を含む)の内容全体が参照により本明細書に明示的に組み込まれる。
当業者であれば、本明細書に記載されている本発明の具体的な実施形態の多くの均等物を知っているか、日常の実験のみを用いて確認することができるであろう。そのような均等物は、以下の特許請求の範囲によって包含されるものとする。
Claims (30)
- 請求項1の化合物および薬学的に許容される担体を含む組成物。
- さらなる治療薬をさらに含む、請求項2に記載の組成物。
- 抗真菌薬であるさらなる治療薬および抗感染症薬をさらに含む、請求項3に記載の組成物。
- i.式15の化合物:
ii.式17または17aの化合物:
iii.式19または19aの化合物:
iv.式9または9aの化合物:
またはそれらの混合物を得る工程と
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む、請求項15に記載の方法。 - i.式15の化合物:
をアリール化してケトン16:
ii.ケトン16:
iii.ニトロアルコール18または18a:
iv.アミノアルコール20または20a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む、請求項15に記載の方法。 - i.式15の化合物:
をニトロメチル化して式17または17aの化合物:
ii.式17または17aの化合物:
iii.ニトロアルコール18または18a:
iv.アミノアルコール20または20a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む、請求項15に記載の方法。 - i.式15の化合物:
ii.式17または17aの化合物:
iii.式19または19aの化合物:
iv.アミノアルコール20または20a:
またはそれらの混合物のテトラゾールを形成して化合物1または1a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む、請求項15に記載の方法。 - i.式15の化合物:
を得る工程と、
ii.ケトン16:
iii.ニトリル24または24a:
iv.アミノアルコール20または20a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールであり、かつ
R’はHまたはTMSである)
を含む、請求項15に記載の方法。 - i.式15の化合物:
ii.式23または23aの化合物:
iii.ニトリル24または24a:
またはそれらの混合物を得る工程と、
iv.アミノアルコール20または20a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールであり、かつ
R’はHまたはTMSである)
を含む、請求項15に記載の方法。 - i.式15の化合物:
ii.式23または23aの化合物:
iii.式19または19aの化合物:
iv.アミノアルコール20または20a:
またはそれらの混合物のテトラゾールを形成して化合物1または1a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールであり、かつ
R’はHまたはTMSである)
を含む、請求項15に記載の方法。 - i.式15の化合物:
ii.式23または23aの化合物:
iii.式19または19aの化合物:
iv.式9または9aの化合物:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールであり、かつ
R’はHまたはTMSである)
を含む、請求項15に記載の方法。 - i.式19または19aの化合物:
ii.アミノアルコール20または20a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む、請求項16に記載の方法。 - i.式19または19aの化合物:
ii.アミノアルコール9または9a:
(式中、Rは、ハロ、−O(C=O)−アルキル、−O(C=O)−置換アルキル、−O(C=O)−アリール、−O(C=O)−置換アリール、−O(C=O)−O−アルキル、−O(C=O)−O−置換アルキル、−O(C=O)−O−アリール、−O(C=O)−O−置換アリール、−O(SO2)−アルキル、−O(SO2)−置換アルキル、−O(SO2)−アリールまたは−O(SO2)−置換アリールである)
を含む、請求項16に記載の方法。
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CA2942976C (en) | 2022-05-10 |
CA2942976A1 (en) | 2015-09-24 |
WO2015143142A1 (en) | 2015-09-24 |
JP6518683B2 (ja) | 2019-05-22 |
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EP3119754A4 (en) | 2017-12-13 |
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AU2015231275B2 (en) | 2019-03-07 |
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