HK1230611A1 - 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-substituted-pyridin-2-yl)-3-(1h-tetrazol-1-yl)propan-2-ols and processes for their preparation - Google Patents

Description

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5-substituted-pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ols and methods for their preparation

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional patent application No. 61/955661, filed 3/19/2014, which is expressly incorporated herein by reference.

Technical Field

Provided herein are 2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5-substituted-pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ols and methods for their preparation.

Background

U.S. patent applications 13/527387, 13/527426 and 13/528283 describe, inter alia, certain metalloenzyme inhibitor compounds and their use as fungicides. The disclosure of each of which is expressly incorporated herein by reference. Each of these patents describes various ways to produce fungicides that inhibit metalloenzymes. It may be advantageous, for example, to provide a more direct and efficient process for preparing metalloenzyme-inhibiting bactericides and related compounds by using reagents and/or chemical intermediates that provide improved time and cost efficiency.

Disclosure of Invention

Provided herein are 2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5-substituted-pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ols and methods for their preparation. In one embodiment, provided herein is a process for preparing a compound of formula IV:

wherein R is₂Is selected from-CO₂Et, -C (O) Me, -C (O) Ph or-SO₂(4-MePh)，

The method comprises reacting III with R₂-CN.

In another embodiment, III may be prepared by contacting II with sodium azide and a solvent.

In another embodiment, II may be prepared by contacting I with trimethyl sulfoxide iodide and a base.

In another embodiment, VI may be prepared by reacting formula IV, wherein R₂is-CO₂The compound of Et is contacted with sodium hydroxide and the mixture of IV and sodium hydroxide is contacted with hydrochloric acid.

In another embodiment, VI may be prepared by reacting formula IV, wherein R₂Is one of-C (O) Me and-C (O) Ph with a base and a solvent.

In another embodiment, VI may be prepared by reacting formula IV, wherein R₂is-SO₂(4-MePh) with Zn and an acid.

The term "cyano" refers to a-C.ident.N substituent.

The term "hydroxy" refers to an-OH substituent.

The term "amino" refers to the group-NH₂And (4) a substituent.

The term "alkylamino" refers to the-N (H) -R substituent.

The term "dialkylamino" refers to-NR₂And (4) a substituent.

The term "halogen" or "halo" refers to one or more halogen atoms, defined as F, Cl, Br, and I.

The term "nitro" means-NO₂And (4) a substituent.

The term "lewis acid" refers to any substance that is an electron pair acceptor.

The term "organometallic" refers to metal-containing organic compounds, especially compounds in which the metal atom is directly bonded to a carbon atom.

Throughout this disclosure, the compounds of formulas V, IV, III, and II are read to also include optical isomers and salts. In particular, when the compounds of formulae V, IV, III and II contain branched alkyl groups, it is understood that such compounds include optical isomers and racemates thereof. Exemplary salts may include: hydrochloride, hydrobromide, hydroiodide and the like. In addition, the compounds of formulas V, IV, III, and II may include tautomeric forms.

Some of the compounds disclosed herein may exist as one or more isomers. One skilled in the art will appreciate that one isomer may be more active than the other. For clarity, the structures disclosed in this disclosure are drawn in only one geometric form, but are intended to represent all geometric and tautomeric forms of the molecule.

The above-described embodiments are intended to be exemplary only, and those skilled in the art will know or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the following claims.

Detailed Description

As shown in examples 1-7, the 2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5-substituted pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol provided herein can be prepared from 4- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-oxoethyl) pyridin-3-yl) oxy) benzonitrile.

Example 1: preparation of 4- ((6- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridin-3-yl) oxy) benzonitrile

In N₂To a magnetically stirred solution of trimethyl sulfoxide iodide (2.67g, 12.11 mmol) in anhydrous THF/DMSO (1:1, 39mL each) was added sodium hydride (0.485g, 12.11 mmol) under an atmosphere. The reaction mixture was stirred at room temperature (rt) for 1 hour, then cooled to 0 ℃. 4- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-oxoethyl) pyridin-3-yl) oxy) benzonitrile (4.00g, 9.32 mmol) in THF (39mL) was added slowly to keep the temperature below 5 deg.C (internal temperature probe). Will reactThe reaction was stopped by holding at 0 ℃ for 30 min (TLC indicated complete conversion to product) and adding saturated sodium bicarbonate. Brine was added and Et₂The combined organic phases were diluted with hexane and washed with brine (2 ×) and water (1 ×), dried (MgSO 4)₄) And concentrated to give the title compound as an amber oil (3.980g, 96%):¹H NMR(300MHz,CDCl₃)8.46(d,J＝2.7Hz,1H),7.73-7.62(m,2H),7.52(dd,J＝8.6,0.6Hz,1H),7.48-7.35(m,2H),7.13-7.02(m,2H),6.92-6.80(m,1H),6.75(ddd,J＝10.0,8.9,2.5Hz,1H),3.46(d,J＝5.1Hz,1H),3.03-2.96(m,1H)；ESIMS m/z 401([M+H]⁺)。

example 2: preparation of 4- ((6- (3-azido-2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxypropyl) pyridin-3-yl) oxy) benzonitrile

The method A comprises the following steps: a solution of 4- ((6- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridin-3-yl) oxy) benzonitrile (3.5g, 8.74 mmol) and sodium azide (1.705g, 26.2 mmol) in DMF (43.7mL) was heated at 50 ℃ for 17 hours. The reaction product was poured into NaHCO₃In a saturated aqueous solution of (5), the mixture is treated with Et₂O (3 ×) extraction the combined organic phases were washed with brine and dried (MgSO)₄) And concentrated to give the title compound as a brown oil (3.353g, 69%):¹H NMR(300MHz,CDCl₃)8.43(m,1H),7.67(m,3H),7.57(d,J＝8.7Hz,1H),7.43(dd,J＝8.7,2.7Hz,1H),7.09(m,2H),6.82(m,2H),6.20(s,1H),4.11(m,1H),3.94(dd,J＝12.9,2.3Hz,1H)；ESIMS m/z 444([M+H]⁺)。

the method B comprises the following steps: a solution of 4- ((6- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridin-3-yl) oxy) benzonitrile (0.480g, 1.199 mmol), sodium azide (0.234g, 3.60 mmol), and ammonium chloride (0.192g, 3.60 mmol) in MeOH (6.00mL) was heated at 50 ℃ for 17 hours. The reaction product was poured into NaHCO₃In a saturated aqueous solution of (5), the mixture is treated with Et₂O (3 ×) extraction the combined organic phases were dried (MgSO)₄) And concentrated to give the title compound as a yellow oil (410mg, 62%).

Example 3: preparation of ethyl 1- (3- (5- (4-cyanophenoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -3, 3-difluoro-2-hydroxypropyl) -1H-tetrazole-5-carboxylate

A mixture of 4- ((6- (3-azido-2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxypropyl) pyridin-3-yl) oxy) benzonitrile (0.500g, 0.902 mmol) and ethyl cyanoformate (0.134mL, 1.353 mmol) was heated uniformly in a screw cap vial at 120 ℃ for 16 hours. LCMS indicated complete conversion to the desired product. Of coarse products¹H NMR analysis indicated 80% conversion to product. The reaction mixture was diluted with DCM and purified by silica gel chromatography (0-100% EtOAc/hexanes) to give the title compound as a yellow oil (266mg, 54%):¹H NMR(300MHz,CDCl₃)8.23(d, J ═ 2.7Hz,1H),7.71(m,3H),7.44(m,2H),7.15(m,2H),6.80(m,3H),5.69(d, J ═ 14.2Hz,1H),5.57(d, J ═ 14.4Hz,1H),4.51(q, J ═ 7.1Hz,2H),1.43(t, J ═ 7.2Hz, 3H); IR (film) 2228,1740cm^-1；ESIMS m/z 444([M+H]⁺)。

Example 4: preparation of 4- ((6- (3- (5-acetyl-1H-tetrazol-1-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxypropyl) pyridin-3-yl) oxy) benzonitrile

Reacting 4- ((6- (3-azido-2- (2, 4-difluorophenyl) -1,1-Difluoro-2-hydroxypropyl) pyridin-3-yl) oxy) benzonitrile (0.500g, 0.902 mmol) and acetocyanide (0.096mL, 1.353 mmol) were heated uniformly in a screw cap vial at 120 ℃ for 16 hours. Of coarse products¹H NMR indicated 44% conversion to product. The reaction mixture was diluted with DCM and chromatographed (silica gel, 0-100% EtOAc/hexanes) to give the title compound as a yellow oil (104mg, 23%):¹H NMR(300MHz,CDCl₃)8.35(d, J ═ 2.7Hz,1H),7.70(m,3H),7.48(dd, J ═ 8.7,2.7Hz,1H),7.36(td, J ═ 8.9,6.5Hz,1H),7.14(m,2H),6.84(m,1H),6.73(m,1H),6.54(s,1H),5.63(d, J ═ 14.0Hz,1H),5.56(d, J ═ 14.9Hz,1H),2.81(s, 3H); IR (film) 2229,1714cm^-1；ESIMS m/z513([M+H]⁺)。

Example 5: preparation of 4- ((6- (3- (5-benzoyl-1H-tetrazol-1-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxypropyl) pyridin-3-yl) oxy) benzonitrile

A mixture of 4- ((6- (3-azido-2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxypropyl) pyridin-3-yl) oxy) benzonitrile (0.200g, 0.361 mmol) and benzoyl cyanide (0.064mL, 0.541 mmol) was heated uniformly in a screw cap vial at 120 ℃ for 16 hours. Of coarse products¹H NMR indicated 47% conversion to product. The reaction mixture was diluted with DCM and purified by silica gel chromatography (0-50% EtOAc/hexanes) to give the title compound as a yellow oil (73mg, 32%):¹H NMR(400MHz,CDCl₃)8.27(d, J ═ 2.7Hz,1H),8.20(dt, J ═ 8.5,1.5Hz,2H),7.72(m,3H),7.66(app d, J ═ 8.6Hz,1H),7.56(m,2H),7.46(dd, J ═ 8.6,2.7Hz,1H),7.31(td, J ═ 8.9,6.5Hz,1H),7.13(m,2H),6.81(ddd, J ═ 12.0,8.5,2.6Hz,1H),6.71(m,2H),5.71(d, J ═ 14.2Hz,1H),5.60(dd, J ═ 14.3,1.0, 1H); IR (film) 2229,1670cm^-1；ESIMS m/z 575([M+H]⁺)。

Example 6: preparation of 4- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (5-tosyl-1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) benzonitrile

A mixture of 4- ((6- (3-azido-2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxypropyl) pyridin-3-yl) oxy) benzonitrile (1.700g, 3.07 mmol) and 4-toluenesulfonylcyanide (0.834g,4.60 mmol) was heated uniformly in a vial at 100 ℃ for 16 hours. The reaction was cooled to room temperature, diluted with DCM and purified by silica gel chromatography (0-50% EtOAc/hexanes) to give the title compound as a light yellow foam (1.109g, 57%):¹H NMR(300MHz,CDCl₃)8.37(d, J ═ 2.7Hz,1H),7.98(d, J ═ 8.4Hz,2H),7.73(d, J ═ 8.6Hz,1H),7.68(m,2H),7.51(m,2H),7.42(d, J ═ 8.5Hz,2H),7.13(m,2H),6.83(m,2H),6.67(s,1H),5.70(d, J ═ 13.7Hz,1H),5.58(d, J ═ 14.2Hz,1H),2.48(s, 3H); IR (film) 3107,2229,1158cm^-1；ESIMS m/z 626([M+H]⁺)。

Example 7: preparation of 4- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) benzonitrile

The method A comprises the following steps: by saponification/decarboxylation of ethyl ester and extraction. To a solution of ethyl 1- (3- (5- (4-cyanophenoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -3, 3-difluoro-2-hydroxypropyl) -1H-tetrazole-5-carboxylate (0.097g, 0.179 mmol) in EtOH (0.203mL) and water (2.032mL) at room temperature was added 2N sodium hydroxide (0.447mL, 0.894 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction was then acidified with 1N HCl, resulting in the formation of an off-white precipitate. Using EtOAc extraction of the mixture and drying of the combined organic phases (MgSO)₄) And concentrated to give the title compound as a light yellow oil (83mg, 99%):¹H NMR(300MHz,CDCl₃)8.74(s,1H),8.26(d,J＝2.7Hz,1H),7.71(m,2H),7.62(d,J＝8.7Hz,1H),7.43(m,2H),7.19(s,1H),7.12(m,2H),6.76(m,2H),5.44(d,J＝14.4Hz,1H),5.23(dd,J＝14.4,1.5Hz,1H)；ESIMS m/z 469([M-H]^-)。

the method B comprises the following steps: by saponification/decarboxylation of ethyl ester and filtration. To a solution of ethyl 1- (3- (5- (4-cyanophenoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -3, 3-difluoro-2-hydroxypropyl) -1H-tetrazole-5-carboxylate (0.142g, 0.262 mmol) in EtOH (0.238mL) and water (2.380mL) at room temperature was added 2N sodium hydroxide (0.654mL, 1.309 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction was acidified with 1N HCl, resulting in the formation of an off-white precipitate, which was isolated by filtration and washed with water. The solid was dried under vacuum for 2 hours to give the title compound as a white crystalline solid (106mg, 86%).

The method C comprises the following steps: by using deacylation of piperidine. To a solution of 4- ((6- (3- (5-acetyl-1H-tetrazol-1-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxypropyl) pyridin-3-yl) oxy) benzonitrile (0.045g, 0.088 mmol) in EtOH (0.220mL) at room temperature was added piperidine (8.69 μ l, 0.088 mmol). The reaction was stirred at room temperature overnight. After 18 hours the product had started to form, but some starting material was still present. The reaction was heated at 40 ℃ for 24 hours. LCMS indicated complete consumption of starting material. 1N HCl was added and the mixture was extracted with DCM. The combined organic phases were dried (MgSO)₄) And concentrated to give the title compound as a pale yellow oil (37mg, 67%).

The method D comprises the following steps: by deacylation with sodium hydroxide. To a solution of 4- ((6- (3- (5-acetyl-1H-tetrazol-1-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxypropyl) pyridin-3-yl) oxy) benzonitrile (0.045g, 0.088 mmol) in EtOH (0.439mL) at room temperature was added a 10% aqueous sodium hydroxide solution (0.070mL, 0.176 mmol). The reaction was stirred at room temperature for 1 hour, after which timeTLC analysis indicated complete consumption of starting material. 1N HCl was added to form an off-white precipitate. The mixture was extracted with DCM and the combined organic phases were dried (MgSO)₄) And concentrated to give the title compound as a pale yellow oil (33mg, 76%).

The method E comprises the following steps: by debenzoylation with sodium hydroxide. To a solution of 4- ((6- (3- (5-benzoyl-1H-tetrazol-1-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxypropyl) pyridin-3-yl) oxy) benzonitrile (0.058g, 0.091 mmol) in EtOH (0.454mL) at room temperature was added 10% sodium hydroxide (0.073mL, 0.182 mmol). The reaction was stirred at room temperature for 30 minutes, after which TLC analysis indicated complete consumption of the starting material. 1N HCl was added to form an off-white precipitate. The mixture was extracted with DCM and the combined organic phases were dried (MgSO)₄) And concentrated to give the title compound as a pale yellow oil (39mg, 91%).

Method F: by de-sulphonation. To a solution of 4- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (5-tosyl-1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) benzonitrile (0.100g, 0.160 mmol) in acetic acid (3.20mL) was added zinc powder (0.105g, 1.601 mmol). The reaction was heated at 60 ℃ for 5 hours, after which LCMS indicated 53% conversion of the reaction to product. Additional Zn was added and the reaction was heated at 90 ℃ for 3 hours. The reaction was filtered through a plug of celite, washing with acetic acid. The mixture was concentrated to 1mL and water was added. With NaHCO₃The saturated aqueous solution neutralized the mixture exactly and the mixture was extracted with DCM. The combined organic phases were dried (MgSO)₄) And concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/hexanes) to give the title compound as a colorless oil (33mg, 44%).

Biological examples

Example A: evaluation of fungicidal Activity: leaf blight of wheat (Mycosphaerellagraminicola), anamorph: Septoria tritici (Septoria tritici), Bayer code SEPTTR:

the technical grade material shown in table 1 below was dissolved in acetone and then mixed with nine volumes of water containing 110ppm riton X-100. The bactericide solution was applied to wheat seedlings using an automatic spray booth outflow. All sprayed plants were allowed to air dry before further treatment. All fungicides were evaluated for activity against all target diseases using the methods described previously.

Wheat plants (variety Yuma) were grown from seeds in a greenhouse in a 50% mineral soil/50% soilless Metro mixture until the first leaf was fully emerged, 7-10 seedlings per pot. These plants are inoculated with an aqueous spore suspension of septoria tritici either before or after the fungicide treatment. After inoculation, plants were kept at 100% relative humidity (at 20 ℃ for one day in a dark dew chamber and then two to three days in a bright dew chamber) to allow spores to germinate and infect leaves. The plants were then transferred to a greenhouse set at 20 ℃ to allow disease to develop. When disease symptoms were fully expressed on the first leaf of untreated plants, infection levels were assessed on a scale of 0 to 100% disease severity. The ratio of disease severity of treated plants relative to untreated plants was used to calculate the percentage of disease control. The results are shown in table 1 below.

Example B: evaluation of fungicidal Activity: brown rust of wheat (Puccinia triticina; synonym: Puccinia recondita f.sp.tritici; Bayer code PUCCRT):

wheat plants (variety Yuma) were grown from seeds in a greenhouse in a 50% mineral soil/50% soilless Metro mixture until the first leaf was fully emerged, 7-10 seedlings per pot. These plants are inoculated with an aqueous spore suspension of puccinia triticina either before or after the fungicide treatment. After inoculation, plants were stored overnight at 100% relative humidity in a dark dew room at 22 ℃ to allow spores to germinate and infect leaves. The plants were then transferred to a greenhouse set at 24 ℃ to allow disease to develop. The fungicide formulation, application and disease assessment were performed according to the procedure described in example a. The results are shown in table 1 below.

In each case of table 1, the classification scale for septoria and puccinia is as follows:

table 1: biological data for the Compound of formula (IV)

^*SEPTTR-wheat leaf blight (septoria tritici)

^*PUCCRT-wheat leaf rust (wheat leaf rust)

^*1 DP-1 day protectant

^*3 DC-3 day treatment

^*1 DC-1 day treatment

Claims (16)

1. A process for preparing a compound of formula IV, comprising the steps of:

reacting a compound of formula III with R₂-CN is contacted with the catalyst,

wherein R is₂Is selected from-CO₂Et, -C (O) Me, -C (O) Ph and-SO₂(4-MePh)。

2. The method of claim 1, wherein the reacting a compound of formula III with R₂The step of-CN contacting is carried out at 90 ℃ to 130 ℃.

3. The method of claim 1, further comprising the step of contacting the compound of formula II with sodium azide and a solvent.

4. The method of claim 3, wherein the solvent is selected from the group consisting of dimethylformamide and methanol.

5. The process of claim 3, wherein the step of contacting the compound of formula II with sodium azide and a solvent is performed at 40 ℃ to 60 ℃.

6. The process of claim 3, further comprising the step of contacting the compound of formula I with trimethyl sulfoxide iodide and a base.

7. The process of claim 6, wherein the base is sodium hydride.

8. The method of claim 1, wherein R₂is-CO₂Et, the method further comprising the steps of:

contacting a compound of formula IV with sodium hydroxide to form a mixture;

contacting the mixture with hydrochloric acid.

9. The method of claim 1, wherein R₂Is one of-C (O) Me and-C (O) Ph, the process further comprising the steps of:

contacting a compound of formula IV with a base and a solvent.

10. The method of claim 9, wherein the solvent is ethanol.

11. The method of claim 9, wherein the base is one of sodium hydroxide and piperidine.

12. The process of claim 9, wherein the step of contacting the compound of formula IV with a base and a solvent is performed at 60 ℃ to 90 ℃.

13. The method of claim 1, wherein R₂is-SO₂(4-MePh), the method further comprising the steps of:

contacting a compound of formula IV with Zn and an acid.

14. The method of claim 13, wherein the acid is acetic acid.

15. A compound of the formula V,

wherein

R₁is-N₃Or

R₂is-CO₂Et, -C (O) Me, -C (O) Ph or-SO₂(4-MePh)。

16. A method of using a compound of formula IV of claim 1 for protecting a plant from attack by a phytopathogenic microorganism or for treating a plant infected with a phytopathogenic microorganism comprising applying a compound of formula IV, or a composition comprising the compound, to one of soil, a plant, a part of a plant, an area adjacent to a plant, a leaf, a root and a seed.