Process for the preparation of (3,3,3-trifluoro-2-oxo-propoxy)phenyl derivatives

Abstract

The present invention relates to novel (3,3-dimethyl-2-oxo-butoxy)phenyl derivatives and (2- aryl-2-oxo-ethoxy]phenyl derivatives and to their application in a process for the preparation of (3,3,3-trifluoro-2-oxo-propoxy)phenyl derivatives and their further transformation into [(2- trifluoromethyl-1,3-dioxolan-2-yl)methoxy]phenyl derivatives and (2-ethoxy-3,3,3-trifluoro- prop-1-enoxy)phenyl derivatives suitable for use, e.g., as active ingredients, which have microbiocidal activity, in particular, fungicidal activity.

Description

[0001] Process for the preparation of (3,3,3-trifluoro-2-oxo-propoxy)phenyl derivatives

[0002] The present invention relates to novel (3,3-dimethyl-2-oxo-butoxy)phenyl derivatives and (2-aryl-2-oxo-ethoxy]phenyl derivatives and to their application in a process for the preparation of (3,3,3-trifluoro-2-oxo-propoxy)phenyl derivatives and their further transformation into [(2-trifluoromethyl-1 ,3-dioxolan-2-yl)methoxy]phenyl derivatives and (2- ethoxy-3,3,3-trifluoro-prop-1-enoxy)phenyl derivatives suitable for use, e.g., as active ingredients, which have microbiocidal activity, in particular, fungicidal activity.

[0003] The preparation of (3,3,3-trifluoro-2-oxo-propoxy)phenyl derivatives is described for instance in WO 2020 / 056090 and in WO 2021 / 183707. The process disclosed in these publications involves an introduction of a 3,3,3-trifluoro-2-oxo-propyl group via ring-opening of 2-(trifluoromethyl)oxirane. This process step is disadvantageous, because of high costs and several health and safety issues related to 2-(trifluoromethyl)oxirane. This epoxide reagent is toxic if inhaled and swallowed, also toxic in contact with skin as it causes skin and eye irritation. It is a highly flammable liquid and vapour as its boiling point is 25 - 32 °C, which produces peroxides during storage. Furthermore, the reaction of a phenol with 2-(trifluoromethyl)oxirane delivers only an intermediate (3,3,3-trifluoro-2-hydroxy-propoxy)phenyl derivative, which requires an additional oxidation step to yield the desired (3,3,3-trifluoro-2-oxo-propoxy)phenyl derivative.

[0004] Surprisingly, it has been now found that the preparation of (3,3,3-trifluoro-2-oxo- propoxy) phenyl derivatives can be performed much more advantageously by direct conversion of (3,3-dimethyl-2-oxo-butoxy)phenyl derivatives or (2-aryl-2-oxo-ethoxy]phenyl derivatives with a trifluoroacetate through a Claisen condensation - retro-Claisen C-C bond cleavage sequence. Trifluoroacetic acid esters are clearly more inexpensive and safer than 2- (trifluoromethyl)oxirane as used in WO 2020 / 056090 and WO 2021 / 183707.

[0005] According to the present disclosure, there is provided a compound of formula (I): wherein R1represents Ci-Cealkyl and R2represents C4-Cealkyl or aryl optionally substituted by halogen, cyano, Ci-Cealkyl and Ci-Cealkoxy.

[0006] According to the present disclosure, there is also provided a process for the preparation of a compound of formula (II), which may exist in form of the ketone of formula (II. a) or its corresponding hydrate of formula (II. b): wherein R1represents Ci-Cealkyl, the process comprising reacting a compound of formula (I): wherein R1represents Ci-Cealkyl and R2represents C4-Cealkyl or aryl optionally substituted by halogen, cyano, Ci-Cealkyl and Ci-Cealkoxy, with a compound of formula (III):

[0007] CF3CO2R3(III) wherein R3represents Ci-Cealkyl, and a base.

[0008] Preferably, the present invention relates to compound of formula (I): wherein R1represents Ci-C4alkyl and R2represents C^Cealkyl or phenyl optionally substituted by halogen, Ci-C4alkyl and Ci-C4alkoxy. Preferably, the present invention relates to a process for the preparation of a compound of formula (II), which may exist in form of the ketone of formula (I I. a) or its corresponding hydrate of formula (ll.b): wherein R1represents Ci-C4alkyl, the process comprising reacting a compound of formula (I): wherein R1represents Ci-C4alkyl and R2represents C4-Cealkyl or phenyl optionally substituted by halogen, Ci-C4alkyl and Ci-C4alkoxy, with a compound of formula (III):

[0009] CF3CO2R3(III) wherein R3represents Ci-C4alkyl, and a base.

[0010] More preferably, the present invention relates to compound of formula (I): wherein R1represents methyl or ethyl and R2represents t-butyl or phenyl. More preferably, the present invention relates to a process for the preparation of a compound of formula (II), which may exist in form of the ketone of formula (I I. a) or its corresponding hydrate of formula (ll.b): wherein R1represents methyl or ethyl, the process comprising reacting a compound of formula (I): wherein R1represents methyl or ethyl and R2represents t-butyl or phenyl, with a compound of formula (III):

[0011] CF3CO2R3(III) wherein R3represents methyl or ethyl, and a base.

[0012] According to one embodiment, the process of the invention is carried out in the presence of at least one solvent. Examples of suitable solvents include, for instance, ketones such as acetone and ethyl methyl ketone, nitriles such as acetonitrile, chlorinated hydrocarbons such as dichloromethane, chloroform and dichloroethane, aromatic hydrocarbons such as toluene and o-, m- and p-xylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, but also solvents such as N,N-dimethylformamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone. Mixtures of solvents can also be used in the process of the invention. The process of the invention is preferably carried out in the presence of methyl tert-butyl ether, dioxane, tetrahydrofuran or 2- methyltetrahydrofuran, more preferably in the presence of methyl tert-butyl ether or tetra hydrofuran. The compounds of formula (I) can be used in the agricultural sector and related fields of use, e.g., as intermediates in the preparation of active ingredients for controlling plant pests or on non-living materials for the control of spoilage microorganisms or organisms potentially harmful to man. The novel compounds are distinguished by a high-yielding and technically easy preparation and high handling safety for people preparing or working with this chemical.

[0013] As used herein, the term "halogen" or “halo” refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine.

[0014] As used herein, the terms "Ci-Cealkyl" and "Ci-C4alkyl" refer to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six or, respectively, four carbon atoms, and which is attached to the rest of the molecule by a single bond. Examples of Ci-Cealkyl and Ci-C4alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.

[0015] As used herein, the term "C4-C6alkyl" refers to a branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from four to six carbon atoms, and which is attached to the rest of the molecule by a single bond from a quarternary carbon atom. Examples of C4-Cealkyl include, but are not limited to, t-butyl and pivaloyl.

[0016] As used herein, the terms "Ci-Cealkoxy" and "Ci-C4alkoxy" refer to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six or, respectively, four carbon atoms, and which is attached to the rest of the molecule by an oxygen bridge. Examples of Ci-Cealkoxy and Ci-C4alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy and t- butoxy.

[0017] As used herein, the term "aryl” refers to a phenyl, naphthalenyl or anthracenyl radical.

[0018] Examples of suitable bases are sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, n-butyl lithium and tert-butyl lithium.

[0019] The process of the invention is advantageously carried out at a temperature of from 0°C to 180°C, preferably of from 0°C to 90°C, more preferably of from 20°C to 60°C. Very good results have been obtained when the process of the invention is carried out at a temperature of 55°C. Accordingly, the present reaction is carried out at a temperature in the range of from 0°C to 180°C, more preferably at a temperature in the range of from 20°C to 60°C.

[0020] The process of the invention is usually carried out at a pressure from 1 atm to 5 atm. Atmosphere (atm) herein refers to a unit of pressure, whrerein one atmosphere (1 atm) is defined as the average atmospheric pressure at sea level, or 101 ,325 pascals (Pa).

[0021] While any useful chemical reactor may be applied that allows for heating and a useful movement of the reaction components, preferably, the process of the invention is carried out in a microwave reactor.

[0022] The process of the invention advantageously further comprises one or more steps of isolating the compound (I) from the reaction mixture. Preferably, isolating the compound (I) comprises cooling and quenching of the reaction mixture with an aqueous acid, such as hydrochloric acid or sulfuric acid, followed by separation of an organic layer comprising the desired product from an aqueous layer, and optionally, washing, and drying of the isolated compound (I) fraction.

[0023] The process of the invention advantageously further comprises one or more purification steps, to obtain the isolated and purified compound (I) fraction. Accordingly, preferably, the process according to the invention further comprising formulating the isolated, or the isolated and purified compound (I) fraction into an agrochemical composition.

[0024] The compounds of formula (I), wherein R1and R2are as defined for formula (I), can be prepared by reaction of a compound of formula (IV), wherein R1is as defined for formula (I), with a compound of formula (V), wherein R2is as defined for formula (I) and R4is halogen, and a base. This is shown in Scheme 1 below.

[0025] Scheme 1 The compounds of formula (V), wherein R2is as defined for formula (I) and R4is halogen, can advantageously be prepared by reaction of a compound of formula (VI), wherein R2is as defined for formula (I), with a halogenation reagent, preferably with thionyl chloride, phosphorus oxychloride or oxalyl choride. This is shown in Scheme 2 below.

[0026] Scheme 2

[0027] The compounds of formula (VI), wherein R2is as defined for formula (I), can be prepared by reaction of 4-hydroxybenzylalcohol of formula (VII), with a compound of formula (VIII), wherein R2is as defined for formula (I) and R4is halogen, and a base. This is shown in Scheme 3 below.

[0028] Scheme 3

[0029] The compounds of formula (II), which can be obtained by the new process presented in this disclosure and wherein R1is as defined for formula (I), can be transformed by reaction with a compound of formula (IX), wherein R5is Ci-Cealkyl and R4is halogen, and a base into a compound of formula (X), wherein R1is as defined for formula (I) and R5is Ci-Cealkyl. This is shown in Scheme 4 below.

[0030] Scheme 4 The compounds of formula (II), which can be obtained by the new process presented in this disclosure and wherein R1is as defined for formula (I), can be transformed by reaction with ethylene glycol of formula (XI) and an acid into a compound of formula (XII), wherein R1is as defined for formula (I). This is shown in Scheme 5 below.

[0031] Scheme 5

[0032] EXAMPLES

[0033] Preparation examples

[0034] The Examples which follow serve to illustrate the invention. The compounds of formula (I) may be prepared according to the synthetic techniques described above.

[0035] Example 1 : This example illustrates the preparation of ethyl 1-[[4-[(Z)-2-ethoxy-3,3,3- trifluoro-prop-1-enoxy]phenyl]methyl]pyrazole-4-carboxylate

[0036] Step 1 : Preparation of 1-r4-(hydroxymethyl)phenoxy1-3,3-dimethyl-butan-2-one

[0037] In a 100 mL three necks flask under argon atmosphere, 4-(hydroxymethyl)phenol (1 g, 8.055 mmol) was dissolved in acetonitrile (24 mL). Then Potassium carbonate (2.25 g, 16.11 mmol) and 1-chloro-3,3-dimethyl-butan-2-one (CAS: 13547-70-1 , 1.33 mL, 9.66 mmol) were added and the resulting mixture was stirred at 50°C for 7 hrs and then one night at room temperature. The reaction mixture was then diluted with water and ethylacetate. The aqueous layer was acidified at pH 1 and extracted two times with ethylacetate. The combined organic layer was dried over MgSCU, filtered, and evaporated to get crude material. The crude was purified by chromatography over silica gel to obtain 1-[4- (hydroxymethyl)phenoxy]-3,3-dimethyl-butan-2-one (1.6 g, 7.2 mmol).

[0038] 1H NMR (400 MHz, DMSO) 5 ppm 4.41 (d, J=5.4 Hz, 2 H) 5.03 (t, J=5.6 Hz, 1 H) 5.08 (s, 2 H) 6.83 (d, J=8.4 Hz, 2 H) 7.15 - 7.28 (m, 2 H).

[0039] LC-MS rt: 0.79 min, 221 [M-H], Step 2: Preparation of 1-r4-(chloromethyl)phenoxy1-3,3-dimethyl-butan-2-one

[0040] A 100 ml three necks flask under argon atmosphere was charged at rt with 1-[4- (hydroxymethyl)phenoxy]-3,3-dimethyl-butan-2-one (1.5 g, 6.7 mmol) and dichloromethane (34 mL) . It was cooled down to 0-5°C with an ice bath and thionyl chloride (0.60 mL, 8.1 mmol) was added slowly with a syringe. The resulting mixture was stirred at 0-5°C for 30mi and then 1 hour at RT. The reaction mixture was transferred in a flask and was evaporated under reduced pressure at 45°C to afford 1-[4-(chloromethyl)phenoxy]-3,3-dimethyl-butan-2- one (1.646 g, 6.154 mmol) as a colorless oil.

[0041] 1H NMR (400 MHz, DMSO) 5 ppm 1.18 (s, 9 H) 4.72 (s, 2 H) 5.13 (s, 2 H) 6.83 - 6.91 (m, 2 H) 7.29 - 7.39 (m, 2 H).

[0042] LC-MS rt: 1.04 min, 241 [M+H],

[0043] Step 3: Preparation of ethyl 1-rf4-(3,3-dimethyl-2-oxo-butoxy)phenyl1methyllpyrazole-4- carboxylate

[0044] In a 100 mL flask under argon atmosphere, 1-[4-(chloromethyl)phenoxy]-3,3-dimethyl-butan- 2-one (1.6 g, 6.6 mmol) was dissolved in acetonitrile (20 mL, 380 mmol). Then potassium carbonate (1.9 g, 13 mmol) and ethyl 1 H-pyrazole-4-carboxylate (CAS 37622-90-5, 0.93 g, 6.6 mmol) were added and the resulting mixture was stirred at 50°C for 6 hrs. The reaction mixture was diluted with water and ethylacetate and the aqueous layer was extracted two times with ethylacetate. The combined organic layer was dried over MgSO4, filtered and evaporated. The crude obtained was purified by chromatography over silica gel to afford ethyl 1-[[4-(3,3-dimethyl-2-oxo-butoxy)phenyl]methyl]pyrazole-4-carboxylate (1.61 g, 4.67 mmol).1H NMR (400 MHz, DMSO) 5 ppm 1.16 (s, 9 H) 1.26 (t, J=7.1 Hz, 3 H) 4.20 (q, J=7.3 Hz, 2 H) 5.10 (s, 2 H) 5.27 (s, 2 H) 6.85 (d, J=8.7 Hz, 2 H) 7.23 (d, J=8.7 Hz, 2 H) 7.85 (s, 1 H) 8.40 (s, 1 H).

[0045] LC-MS rt: 1.00 min, 345 [M+H],

[0046] Step 4: Preparation of ethyl 1-H4-(3,3,3-trifluoro-2-oxo-propoxy)phenyl1methyllpyrazole-4- carboxylate

[0047] In a vial dry three neck flask, under argon atmosphere, ethyl 2,2,2-trifluoroacetate (0.38 mL, 3.19 mmol,) was solved in tetra hydrofuran (3.2 mL) and sodium hydride (60 mass%) in OIL (0.127 g, 3.19 mmol) was added by portion at 0-5°C. The suspension obtained was stirred 10’ at 0-5°C and ethyl 1-[[4-(3,3-dimethyl-2-oxo-butoxy)phenyl]methyl]pyrazole-4-carboxylate (0.55 g, 1.59 mmol,) previously dissolved in tetra hydrofuran (3.2 mL) was added dropwise. The resulting mixture was stirred 10' at 0-5°C, warm up to RT and stirred for 3 hours. The reaction mixture was then quenched by the addition of few drops of HCI 2 M to get pH 3-4, stirred 15 min at RT and then NaHCO3 sat sol was added to obtain a basic solution. The aqueous layer was extracted 2 times with ethylacetate. The combined organic layer was dried over MgSO4, filtered and evaporated under vacuum to get crude which was purified by chromatography over silica gel to afford ethyl 1-[[4-(3,3,3-trifluoro-2-oxo- propoxy)phenyl]methyl]pyrazole-4-carboxylate (0.37 g, 1.03 mmol).

[0048] 1H NMR (400 MHz, DMSO) 5 ppm 1.26 (t, J=7.1 Hz, 3 H) 4.03 (s, 2 H) 4.15 - 4.27 (m, 2 H) 5.29 (s, 2 H) 6.95 (d, J=8.7 Hz, 2 H) 7.21 - 7.32 (m, 4 H) 7.85 (s, 1 H) 8.41 (s, 1 H)

[0049] 1 H NMR (400 MHz, CDCI3) 5 ppm 1.35 (t, J=7.1 Hz, 3 H) 3.74 (s, 2 H) 4.21 (s, 2 H) 4.30 (q, J=7.0 Hz, 2 H) 5.28 (s, 2 H) 6.95 - 7.02 (m, 2 H) 7.26 (d, J=8.7 Hz, 2 H) 7.86 (s, 1 H) 7.95 (s, 1 H).

[0050] LC-MS: rt: 0.85 min, 375 [M+H], 355 [M-H],

[0051] 5: Preparation of ethyl 1-[[4-[(Z)-2-ethoxy-3,3,3-trifluoro-prop-1-

[0052] In a vial, 1-[[4-(3,3,3-trifluoro-2-oxo-propoxy)phenyl]methyl]pyrazole-4-carboxylate (0.1 g, 0.280 mmol) was dissolved in DMSO (0.84mL). Then cesium carbonate (0.192 g, 0.561 mmol) and bromoethane (0.043 mL, 0.561 mmol) were added and the resulting mixture was stirred at RT for 4 hrs. The reaction mixture was diluted with water and ethylacetate and the aqueous layer was extracted two times with ethylacetate. The combined organic layer was dried over MgSO4, filtered and evaporated under vacuum. The crude was purified by chromatography over silica gel to afford ethyl 1-[[4-[(Z)-2-ethoxy-3,3,3-trifluoro-prop-1- enoxy]phenyl]methyl]pyrazole-4-carboxylate (65 mg, 0.169 mmol).

[0053] 1H NMR (400 MHz, CDCI3) 5 ppm 1.32 - 1.39 (m, 6 H) 4.20 (q, J=6.9 Hz, 2 H) 4.27 - 4.35 (m, 2 H) 5.30 (s, 2 H) 6.77 - 6.81 (m, 1 H) 7.04 - 7.11 (m, 2 H) 7.30-7.28 (m, 2 H) 7.88 (s, 1 H) 7.96 (s, 1 H).

[0054] LC-MS: rt: 1.13 min, 385 [M+H],

Claims

CLAIMS1. A compound of formula (I):wherein R1represents Ci-Cealkyl, and R2represents C^Cealkyl or aryl optionally substituted by halogen, cyano, Ci-Cealkyl and Ci-Cealkoxy.

2. The compound according to claim 1, wherein R1represents methyl or ethyl.

3. The compound according to claim 1 or claim 2, wherein R2represents t-butyl or phenyl.

4. Ethyl 1-[[4-(3,3-dimethyl-2-oxo-butoxy)phenyl]methyl]pyrazole-4-carboxylate, Methyl 1- [[4-(3,3-dimethyl-2-oxo-butoxy)phenyl]methyl]pyrazole-4-carboxylate; Ethyl 1-{[p-(phen- acyloxy)phenyl]methyl}-1 H-pyrazole-4-carboxylate, or Methyl 1-{[p-(phenacyloxy)phenyl]- methyl}-1 H-pyrazole-4-carboxylate.

5. A process for the preparation of a compound of formula (II),in ketone form according to formula (II. a) or the corresponding hydrate form according to formula (ll.b), or mixtures thereof: l.b)comprising reacting a compound of formula (I):in the presence of a base, with a compound of formula (III):CF3CO2R3(III) , wherein R1represents Ci-Cealkyl, R2represents C^Cealkyl or aryl optionally substituted by halogen, cyano, Ci-Cealkyl and Ci-Cealkoxy, and R3represents Ci-Cealkyl: and optionally, isolating the obtained compound according to formula (II).

6. A process for the preparation of the compound according to formula (I), comprising reacting, in the presence of a base, a compound according to formula (IV):with a compound according to formula (V):wherein:R1represents Ci-Cealkyl,R2represents C^Cealkyl or aryl optionally substituted by halogen, cyano, Ci-Cealkyl andCi-Cealkoxy; andR4represents halogen, to obtain a compound according to formula (I):

7. The process according to claim 6, wherein R1represents methyl or ethyl, and / or wherein R2represents t-butyl or phenyl.

8. The process according to claims 6 or 7, further comprising reacting a compound according to formula (VI):with a halogenation reagent, preferably with thionyl chloride, phosphorus oxychloride or oxalyl choride, to obtain a compound according to formula (V):

9. The process according to claims 6 to 8, further comprising reacting a 4-hydroxy- benzylalcohol of formula (VII),with a compound of formula (VIII):wherein R2is as defined for formula (I) and R4is halogen, in the presence of a base, to obtain a compound of formula (VI):

10. The process according to any one of claims 6 to 9, further comprising reacting a compound according to formula (II) in the presence of a base, with a compound according to formula (IX):R5— R4(lX), into a compound of formula (X):wherein R5represents Ci-Cealkyl.11 . The process according to any one of claims 6 to 9, further comprising reacting a compound according to formula (II) in the presence of an acid with ethylene glycol (CH2OH)2 into a compound according to formula (XII):

12. The process according to any one of claims 1 to 11 , further comprising the step of providing a microbiocidal, in particular, fungicidal composition comprising a compound according to formula (II), (X) or (XII), and at least one additional additive, adjuvant, carrier, and optionally, one or more further biologically active ingredient(s).

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