WO2018094136A1 - T-butyl 2-carbamothioyl-2-(3-(5-(4-cyanophenoxy)pyridin-2-yl)-2-(2,4- difluorophenyl)-3,3-difluoro-2-hydroxypropyl)hydrazine-l- carboxylate and processes of preparation - Google Patents
T-butyl 2-carbamothioyl-2-(3-(5-(4-cyanophenoxy)pyridin-2-yl)-2-(2,4- difluorophenyl)-3,3-difluoro-2-hydroxypropyl)hydrazine-l- carboxylate and processes of preparation Download PDFInfo
- Publication number
- WO2018094136A1 WO2018094136A1 PCT/US2017/062147 US2017062147W WO2018094136A1 WO 2018094136 A1 WO2018094136 A1 WO 2018094136A1 US 2017062147 W US2017062147 W US 2017062147W WO 2018094136 A1 WO2018094136 A1 WO 2018094136A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- isothiocyanate
- compound
- hydrazine
- butyl
- difluorophenyl
- Prior art date
Links
- 0 CC*C(NC)=O Chemical compound CC*C(NC)=O 0.000 description 1
- JMZYBUGCQYDGST-UHFFFAOYSA-N N#Cc(cc1)ccc1Oc1ccc(C(C2(c(ccc(F)c3)c3F)OC2)(F)F)nc1 Chemical compound N#Cc(cc1)ccc1Oc1ccc(C(C2(c(ccc(F)c3)c3F)OC2)(F)F)nc1 JMZYBUGCQYDGST-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- 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
- C07D213/60—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 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
Definitions
- metalloenzyme inhibitor compounds and their use as fungicides.
- the disclosure of this application is expressly incorporated by reference herein.
- This patent application describes various routes to generate metalloenzyme inhibiting fungicides. It may be advantageous to provide more direct and efficient methods for the preparation of metalloenzyme inhibiting fungicides and related compounds, e.g., by the use of reagents and/or chemical intermediates which provide improved time and cost efficiency.
- the compound of Formula II may be prepared by contacting a compound of Formula III with i-butyl carbazate.
- R benzoyl or Me 3 Si.
- halogen refers to one or more halogen atoms, defined as F, CI, Br, and I.
- organometallic refers to an organic compound containing a metal, especially a compound in which a metal atom is bonded directly to a carbon atom.
- Room temperature is defined herein as about 20 °C to about 25 °C.
- references to the compounds of Formulas I- III are read as also including optical isomers and salts. Specifically, when compounds of Formulas I- III contain a chiral carbon, it is understood that such compounds include optical isomers and racemates thereof.
- Exemplary salts may include: hydrochloride salts, hydrobromide salts, hydroiodide salts, and the like.
- the benzoyl intermediate la was identified by LCMS (ESIMS m/z 696.1 [(M+H) + ]). After an additional 30 min, anhydrous hydrazine (1.47 mL, 46.9 mmol) was added. The mixture was stirred at 0 °C for 1 h then room temperature for 30 min. The reaction was diluted with ethyl acetate and washed with sat. ammonium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to a pale yellow oil. Methanol (25 mL) was added to the oil and after a few minutes of stirring a white precipitate had formed.
- Method B To a solution of i-butyl 2-(3-(5-(4-cyanophenoxy)pyridin-2-yl)-2-(2,4- difluorophenyl)-3,3-difluoro-2-hydroxypropyl)hydrazine-l-carboxylate (II, 1 g, 1.596 mmol) in ethyl acetate (9.4 mL) was added isothiocyanatotrimethylsilane (0.540 mL, 3.83 mmol) and the reaction was stirred at 80 °C for 18 h. NMR indicated incomplete conversion so additional isothiocyanatotrimethylsilane (0.540 mL, 3.83 mmol) was added and the reaction stirred at 80 °C for 6 h. NMR indication the reaction was still incomplete so more
- isothiocyanatotrimethylsilane (0.540 mL, 3.83 mmol) was added and the reaction stirred at 80 °C for 17 h. The reaction was allowed to cool to room temperature and 1 N HCl (10 mL) was added. The phases were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow foam. The yellow foam was dissolved in methylene chloride and purified by silica gel column chromatography eluting with 0-60% ethyl acetate/hexanes.
- Organic isothiocyanates for use in this process step may include acyl isothiocyanates such as, for example, benzoyl isothiocyanate (to make the compound of Formula la), and silyl isothiocyanates such as, for example, trimethylsilyl isothiocyanate (to make the compound of Formula lb).
- acyl isothiocyanates such as, for example, benzoyl isothiocyanate (to make the compound of Formula la)
- silyl isothiocyanates such as, for example, trimethylsilyl isothiocyanate (to make the compound of Formula lb).
- Cleaving reagents used to remove the R-group from the compound of Formula la to prepare the compound of Formula I may be selected from the group including hydrazine, ammonia, sodium methoxide, and methylamine.
- Cleaving reagents used to remove the R- group from the compound of Formula lb to prepare the compound of Formula I may be selected from: a) fluoride compounds such as, for example, a tetraalkylammonium fluoride and potassium fluoride, and b) an acid such as, for example, hydrochloric acid (HCl), hydrobromic acid (HBr), or sulfuric acid (H 2 S0 4 ).
- the contacting of the compound of Formula II with the organic isothiocyanate may be carried out between about -20 °C and about 100 °C, and the contacting with the cleaving reagent may be carried out between about -20 °C and about 100 °C.
- Solvents for use in this process step may include one or more than one of THF (tetrahydrofuran), EtOAc, 2-Me-THF, dioxane, MeCN (acetonitrile), and DME (1,2- dimethoxyethane) .
- i-Butyl 2-(3-(5-(4-cyanophenoxy)pyridin-2-yl)-2-(2,4-difluorophenyl)-3,3-difluoro-2- hydroxypropyl)hydrazine-l-carboxylate (II) may be prepared from 4-((6-((2-(2,4- difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)oxy)benzonitrile (III) as shown in Example 2.
- the contacting of the compound of Formula III with i-butyl carbazate may be carried out from about 25 °C to about 100 °C or from about 60 °C to about 90 °C.
- Solvents for use in this process step may include alcohols such as methanol, ethanol, and isopropanol, as well as aprotic solvents such as THF (tetrahydrofuran), acetonitrile, DMSO (dimethylsulfoxide), DMF (N,N-dimethylformamide), and mixtures of any of these solvents.
- alcohols such as methanol, ethanol, and isopropanol
- aprotic solvents such as THF (tetrahydrofuran), acetonitrile, DMSO (dimethylsulfoxide), DMF (N,N-dimethylformamide), and mixtures of any of these solvents.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/462,201 US20190276403A1 (en) | 2016-11-18 | 2017-11-17 | T-butyl 2-carbamothioyl-2-(3-(5-(4-cyanophenoxy)pyridin-2-yl)-2-(2,4-difluorophenyl)-3,3-difluoro-2-hydroxypropyl)hydrazine-1-carboxylate and processes of preparation |
EP17872175.9A EP3555047A4 (en) | 2016-11-18 | 2017-11-17 | T-butyl 2-carbamothioyl-2-(3-(5-(4-cyanophenoxy)pyridin-2-yl)-2-(2,4- difluorophenyl)-3,3-difluoro-2-hydroxypropyl)hydrazine-1-carboxylate and processes of preparation |
CN201780070404.XA CN109963837A (en) | 2016-11-18 | 2017-11-17 | 2- aminothio formoxyl -2- (the fluoro- 2- hydroxypropyl of 3- (5- (4- cyano-benzene oxygen) pyridine -2- base) -2- (2,4 difluorobenzene base) -3,3- two) hydrazine-l- t-butyl formate and preparation method |
BR112019009760A BR112019009760A2 (en) | 2016-11-18 | 2017-11-17 | t-Butyl 2-carbamothioyl-2- (3- (5- (4-cyanophenoxy) pyridin-2-yl) -2- (2,4-difluorophenyl) -3,3-difluoro-2-hydroxypropyl) hydrazine-1 - carboxylate and preparation processes |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662423858P | 2016-11-18 | 2016-11-18 | |
US62/423,858 | 2016-11-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2018094136A1 true WO2018094136A1 (en) | 2018-05-24 |
Family
ID=62145694
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2017/062147 WO2018094136A1 (en) | 2016-11-18 | 2017-11-17 | T-butyl 2-carbamothioyl-2-(3-(5-(4-cyanophenoxy)pyridin-2-yl)-2-(2,4- difluorophenyl)-3,3-difluoro-2-hydroxypropyl)hydrazine-l- carboxylate and processes of preparation |
Country Status (5)
Country | Link |
---|---|
US (1) | US20190276403A1 (en) |
EP (1) | EP3555047A4 (en) |
CN (1) | CN109963837A (en) |
BR (1) | BR112019009760A2 (en) |
WO (1) | WO2018094136A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020020813A1 (en) | 2018-07-25 | 2020-01-30 | Bayer Aktiengesellschaft | Fungicidal active compound combinations |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002092087A1 (en) * | 2001-05-11 | 2002-11-21 | Vertex Pharmaceuticals Incorporated | 2,5-disubstituted pyridine, pyrimidine, pyridazine and 1, 2, 4-triazine derivatives for use as p38 inhibitors |
WO2004018485A1 (en) * | 2002-08-26 | 2004-03-04 | Ranbaxy Laboratories Limited | Azole derivatives as antifungal agents |
WO2005066164A1 (en) * | 2003-12-22 | 2005-07-21 | Eli Lilly And Company | Opioid receptor antagonists |
WO2005092836A1 (en) * | 2004-03-15 | 2005-10-06 | Eli Lilly And Company | Opioid receptor antagonists |
WO2015143188A1 (en) * | 2014-03-19 | 2015-09-24 | Viamet Pharmaceuticals, Inc. | 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-substituted-pyridin-2-yl)-3-(1h-tetrazol-1-yl)propan-2-ols and proceses for their preparation |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11051514B2 (en) * | 2015-05-18 | 2021-07-06 | Mycovia Pharmaceuticals, Inc. | Antifungal compounds |
EP3541796A4 (en) * | 2016-11-18 | 2020-03-25 | Dow AgroSciences LLC | 4-((6-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(5-mercapto-1h |
EP3541799A4 (en) * | 2016-11-18 | 2020-04-01 | Dow Agrosciences Llc | 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(5-mercapto-1h-1,2,4-triazol-1-yl)propyl)pyridin-3-yl)oxy)benzonitrile and processes of preparation |
-
2017
- 2017-11-17 WO PCT/US2017/062147 patent/WO2018094136A1/en unknown
- 2017-11-17 US US16/462,201 patent/US20190276403A1/en not_active Abandoned
- 2017-11-17 BR BR112019009760A patent/BR112019009760A2/en not_active Application Discontinuation
- 2017-11-17 EP EP17872175.9A patent/EP3555047A4/en not_active Withdrawn
- 2017-11-17 CN CN201780070404.XA patent/CN109963837A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002092087A1 (en) * | 2001-05-11 | 2002-11-21 | Vertex Pharmaceuticals Incorporated | 2,5-disubstituted pyridine, pyrimidine, pyridazine and 1, 2, 4-triazine derivatives for use as p38 inhibitors |
WO2004018485A1 (en) * | 2002-08-26 | 2004-03-04 | Ranbaxy Laboratories Limited | Azole derivatives as antifungal agents |
WO2005066164A1 (en) * | 2003-12-22 | 2005-07-21 | Eli Lilly And Company | Opioid receptor antagonists |
WO2005092836A1 (en) * | 2004-03-15 | 2005-10-06 | Eli Lilly And Company | Opioid receptor antagonists |
WO2015143188A1 (en) * | 2014-03-19 | 2015-09-24 | Viamet Pharmaceuticals, Inc. | 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-substituted-pyridin-2-yl)-3-(1h-tetrazol-1-yl)propan-2-ols and proceses for their preparation |
Non-Patent Citations (2)
Title |
---|
SATTIGERI, J. A. ET AL.: "Synthesis of 2[(1R,2R)-2-(2,4-difluorophenyl)-2- hydroxy-1-methyl-3-(1H-1,2,4-triazol-yl)propyl]-4-[4-tetrafluoropropoxy) phenyl]-3-(2H,4H)-1,2,4-triazol-3-thione, a novel and potent azole antifungal agent", SYNTHETIC COMMUNICATIONS, vol. 40, no. 6, 2010, pages 833 - 838, XP055504413 * |
See also references of EP3555047A4 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020020813A1 (en) | 2018-07-25 | 2020-01-30 | Bayer Aktiengesellschaft | Fungicidal active compound combinations |
Also Published As
Publication number | Publication date |
---|---|
CN109963837A (en) | 2019-07-02 |
EP3555047A1 (en) | 2019-10-23 |
US20190276403A1 (en) | 2019-09-12 |
EP3555047A4 (en) | 2020-04-29 |
BR112019009760A2 (en) | 2019-08-13 |
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