Method for preparing intermediate of Fluoxapiprolin

Abstract

The present invention relates to a method for preparing [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidinyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl]methanesulfonate.

Description

[0001] The present invention relates to a method for preparing [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidinyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl]methanesulfonate.

[0002] [3-Chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidinyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl]methanesulfonate is an intermediate for fluoxapiprolin, a fungicide for controlling Oomycetes known from WO 2012 / 025557.

[0003] WO 2015 / 181097 discloses a method for preparing [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidinyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl]methanesulfonate (compound of formula (I)), which is carried out by a chloroacetyl-substituted compound of formula (II), which is reacted with piperidine-4-thiocarboxamide (III) by a Hantzsch reaction in the presence of hydrochloric acid and ethanol to obtain a piperidinium salt of formula (IV). The piperidinium salt of formula (IV) is then converted into a compound of formula (I) by reaction with chloroacetyl chloride in the presence of tributylamine and tetrahydrofuran as a solvent (see Scheme 1).

[0004] Scenario 1:

[0005]

[0006] This known method has many disadvantages and is therefore not suitable for use on an industrial scale. First, the method involves the filtration of the piperidinium chloride intermediate of formula (IV) to allow solvent exchange from an alcohol solvent to an aprotic solvent, which requires filtering equipment and a large amount of solvents and causes the intermediate to be partially lost via the filtrate. Secondly, the tributylamine used in the second step must be removed from the organic phase by using hydrochloric acid to complete thorough protonation in the reaction quenching. Otherwise, the desired product (compound of formula (I)) will not be able to fully crystallize out. However, the recycling of tributylamine will then require the neutralization of the previously formed tributylammonium salt solution so as to free the tributylamine again. Therefore, this known method produces a large amount of waste. Third, the strong base tributylamine must be fed in parallel with chloroacetyl chloride to limit its adverse effect on chloroacetyl chloride, which complicates the production operation.

[0007] The coupling of acid chlorides with cyclic secondary amines in the presence of organic bases such as triethylamine, N,N-diisopropylamine or pyridine is also known from WO 2008 / 013622.

[0008] In light of the above prior art, an object of the present invention is to provide an improved process for preparing [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidinyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl]methanesulfonate. In particular, the process should be suitable for larger scale production and produce less waste.

[0009] The above object is achieved by a method for preparing a compound of formula (I)

[0010]

[0011] The method comprises the following steps:

[0012] (a) making a compound of formula (II)

[0013]

[0014] With the compound of formula (III)

[0015]

[0016] The reaction is carried out in the presence of hydrogen chloride and an alcohol solvent to obtain the hydrochloride of formula (IV)

[0017]

[0018] as well as

[0019] (b) reacting the hydrochloride of formula (IV) with chloroacetyl chloride in the presence of a pyridine base, an aprotic solvent and an aromatic solvent having a boiling point of at least 160° C. to obtain a compound of formula (I),

[0020] Wherein between steps (a) and (b), the alcohol solvent is removed by distillation.

[0021] The inventors were surprised to find that the filtration of the chlorinated piperidinium salt intermediate can be avoided by the method of the present invention, and the amount of the waste material produced can be significantly reduced. Pyridine base allows to distill and remove the alcohol solvent almost completely before adding the aprotic solvent used in the second step. In addition, the additional use of hydrochloric acid for protonation reaction can be greatly reduced or avoided completely. Therefore, the amount of the alkali required for neutralization pyridine base can be limited only to the amount of hydrogen chloride produced in the chemical reaction.

[0022] In step (a) of the process of the present invention, the compound of formula (II) is reacted with the compound of formula (III) in the presence of hydrogen chloride and an alcohol solvent to obtain the hydrochloride of formula (IV).

[0023] Suitable alcohol solvents are methanol, ethanol, n-propanol (propanol), isopropanol, n-butanol (butanol), isobutanol, sec-butanol and tert-butanol. Preferred alcohol solvents are isopropanol and ethanol. Ethanol is most preferred.

[0024] Preferably, the hydrogen chloride is used in the form of hydrochloric acid, more preferably hydrochloric acid having an HCl concentration of at least 20% by weight, more preferably at least 30% by weight, in particular at least 35% by weight.

[0025] The reaction of step (a) is carried out at a temperature of -20°C to +120°C, preferably at a temperature of 20°C to +100°C, more preferably at a temperature of 40°C to 80°C, under standard pressure.

[0026] Preferably, the compound of formula (III) is first converted into the corresponding hydrochloride salt in the presence of an alcohol solvent before adding the compound of formula (II).

[0027] The amount of hydrogen chloride used in step (a) is preferably in the range of 1 mol to 3 mol, more preferably 1 mol to 2 mol, most preferably 1 mol to 1.5 mol, per 1 mol of the compound of formula (II).

[0028] The amount of the compound of formula (III) used in step (a) is preferably in the range of 1 mol to 3 mol, more preferably 1 mol to 2 mol, most preferably 1 mol to 1.5 mol, per 1 mol of the compound of formula (II).

[0029] The reaction time is not critical and can be selected in the range of several minutes to several hours, depending on the batch size and the temperature. Suitable reaction times are, for example, 2 h to 10 h.

[0030] In step (b) of the process of the present invention, the hydrochloride of formula (IV) is reacted with chloroacetyl chloride in the presence of a pyridine base, an aprotic solvent and an aromatic solvent having a boiling point of at least 160° C. to obtain a compound of formula (I).

[0031] The amount of chloroacetyl chloride used in step (b) is preferably in the range of 1 mol to 5 mol, more preferably 1.5 mol to 4 mol, most preferably 1.5 mol to 2.5 mol, per 1 mol of the compound of formula (IV).

[0032] The reaction of step (b) is preferably carried out at a temperature of 0°C to +120°C, more preferably at a temperature of 20°C to 80°C, most preferably at a temperature of 30°C to 60°C under standard pressure.

[0033] The reaction time is not critical and can be selected in the range of several minutes to several hours, depending on the batch size and the temperature. Suitable reaction times are, for example, 1 h to 5 h.

[0034] Preferably, the pyridine base is an alkylpyridine base.

[0035] Suitable alkylpyridines that can be used in the process of the present invention include collidines, lutadines, picolines, methylethylpyridine, diethylpyridine, 2-isopropylpyridine, 2-propylpyridine, 2-methyl-3-propylpyridine, 2-ethyl-5-propylpyridine, 2-methyl-5-tert-butylpyridine, 2-ethyl-3-pentylpyridine, 2-decylpyridine and 2-butyl-5-octylpyridine.

[0036] Preferred pyridine bases are selected from the group consisting of picoline, lutidines, collidine, methylethylpyridine and diethylpyridine. Most preferred is 2-methyl-5-ethyl-pyridine.

[0037] The amount of the pyridine base used is preferably in the range of 1 mol to 20 mol, more preferably 2 mol to 10 mol, most preferably 3 mol to 6 mol, per 1 mol of the compound of formula (IV).

[0038] Preferably, the aprotic solvent used in step (b) comprises a polar aprotic solvent.

[0039] Suitable polar aprotic solvents are ethers such as diethyl ether, methyl tert-butyl ether, dibutyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyltetrahydrofuran, tetrahydrofuran and 1,4-dioxane; ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl tert-butyl ketone; esters such as methyl acetate, ethyl acetate and butyl acetate; nitriles such as acetonitrile, propionitrile and butyronitrile; amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone; dimethyl sulfoxide; tetramethylene sulfone; hexamethylphosphoramide and DMPU.

[0040] Acetonitrile is particularly preferred.

[0041] Suitable aromatic solvents having a boiling point of at least 160° C. that can be used in the process of the present invention include 1,3,5-trimethylbenzene (mesitylene), 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 1,2-dimethoxybenzene (veratrole), 1,3-dimethoxybenzene, 1,4-dimethoxybenzene and mixtures thereof. The aprotic solvent and the aromatic solvent having a boiling point of at least 160° C. are preferably used in a weight ratio of 10:1 to 1:5, more preferably 5:1 to 1:2, and most preferably 3:1 to 1:1.

[0042] Preferably, the aromatic solvent having a boiling point of at least 160° C. is mesitylene. The polar aprotic solvent and mesitylene are preferably used in a weight ratio of 10:1 to 1:5, more preferably 5:1 to 1:2, most preferably 3:1 to 1:1.

[0043] Preferably, the solvent is changed from an alcoholic solvent to an aprotic solvent between steps (a) and (b) without any filtering method, in particular by means of distillation. Preferably, at least 95% by weight, more preferably at least 97% by weight, in particular at least 99% by weight of the alcoholic solvent is removed by said distillation. If hydrochloric acid is used in step (a), which is preferred according to the invention, part of the water from the hydrochloric acid, preferably at least 90% by weight, more preferably at least 95% by weight, most preferably at least 98% of the water from the hydrochloric acid, is also removed by said distillation.

[0044] Preferably, at least part of the pyridine base and at least part of the aromatic solvent having a boiling point of at least 160° C., preferably mesitylene, are added before distilling the alcohol solvent.

[0045] Preferably, in step (b) the compound of formula (IV) is used without prior isolation, such as filtration.

[0046] In a preferred embodiment of the method of the present invention, the alcohol solvent used in step (a) is ethanol, the pyridine base is 2-methyl-5-ethylpyridine, the aprotic solvent used in step (b) is acetonitrile, and the aromatic solvent having a boiling point of at least 160° C. used in step (b) is mesitylene.

[0047] In this embodiment, acetonitrile and mesitylene are preferably used in a weight ratio of 10:1 to 1:5, more preferably 5:1 to 1:2, most preferably 3:1 to 1:1.

[0048] Preferably, at the end of the reaction in step (b), the reaction is stopped (quenched) by another solvent exchange. Preferably, most of the solvent is changed from the aprotic solvent back to the alcohol solvent, wherein the alcohol solvent used for quenching is preferably selected from ethanol, 1-butanol and 2-butanol, particularly preferably ethanol. The solvent exchange can be carried out by (i) distilling off most of the aprotic solvent, preferably acetonitrile, and (ii) adding an alcohol solvent, preferably selected from ethanol, 1-butanol and 2-butanol, more preferably ethanol.

[0049] Preferably, at the end of the reaction of step (b), acetonitrile is removed by distillation and recycled, and the ethanol distillate obtained during the solvent exchange between steps (a) and (b) is reused for quenching the reaction to obtain the compound of formula (I). The compound of formula (I) is then filtered out, washed with water and dried.

[0050] The present invention also relates to a method for preparing fluoxapiprolin, which comprises the method for preparing the compound of formula (I) of the present invention and further comprises step (c) of reacting the compound of formula (I) obtained in step (b) with 3,5-bis(difluoromethoxy)-1H-pyrazole.

[0051] The present invention is illustrated by the following examples:

[0052] Example 1

[0053] 32.8 g of piperidine-4-thiocarboxamide (226 mmol, 1.2 equivalents) was stirred with 221 g of ethanol at room temperature. 24.1 g of concentrated HCl (37% aqueous solution) was added at room temperature. After stirring for 10 min, 70 g of 3-chloro-2-[3-(chloroacetyl)-4,5-dihydro-1,2-oxazol-5-yl]phenyl methanesulfonate (188 mmol, 1.0 equivalents) was added. The mixture was heated to reflux and stirred for 5 h under these conditions.

[0054] 120 g of mesitylene and 91.1 g (772 mmol, 4.0 equivalents) of 2-methyl-5-ethylpyridine were added. Most of the ethanol was distilled off through a vigreux column under gradually decreasing vacuum. After 247 g of distillate was obtained, the distillation was stopped.

[0055] 250 g of acetonitrile were added and a further 82 g of distillate were distilled off at 450 mbar. The internal temperature was adjusted to 40° C. and 42 g (368 mmol, 1.96 eq.) of chloroacetyl chloride were added within 3 h.

[0056] 132 g of acetonitrile were distilled off at 250 mbar. 242 g of industrial ethanol were added and the temperature was lowered to 0° C. After stirring overnight, the suspension was filtered, washed with 400 g of water and dried to give 84 g of [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidinyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl]methanesulfonate (purity 94.0%, yield 81.0%).

[0057] Example 2

[0058] 32.8 g of piperidine-4-thiocarboxamide (226 mmol, 1.2 equivalents) was stirred with 221 g of ethanol at room temperature. 24.1 g of concentrated HCl (37% aqueous solution) was added at room temperature. After stirring for 10 min, 70 g of 3-chloro-2-[3-(chloroacetyl)-4,5-dihydro-1,2-oxazol-5-yl]phenyl methanesulfonate (188 mmol, 1.0 equivalents) was added. The mixture was heated to reflux and stirred for 5 h under these conditions.

[0059] 120 g of mesitylene and 91.1 g (772 mmol, 4.0 equivalents) of 2-methyl-5-ethylpyridine were added. Most of the ethanol was distilled off through a vigreux column under gradually decreasing vacuum. After 233 g of distillate was obtained, the distillation was stopped.

[0060] 250 g of acetonitrile were added and a further 82 g of distillate were distilled off at 450 mbar. The internal temperature was adjusted to 40° C. and 42 g (368 mmol, 1.96 eq.) of chloroacetyl chloride were added within 3 h.

[0061] 133 g of acetonitrile was distilled off at 250 mbar. 231 g of industrial ethanol was added and the temperature was reduced to 0 ° C. After stirring overnight, the suspension was filtered and washed with a combination of the second distillate (33 g) and 30 g of ethanol. The filter cake was washed with 60 g of water and dried to obtain 83.6 g of [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidinyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl]methanesulfonate (purity 94.8%, yield 81.3%).

[0062] Example 3

[0063] 32.8 g of piperidine-4-thiocarboxamide (226 mmol, 1.2 equivalents) was stirred with 221 g of ethanol at room temperature. 24.1 g of concentrated HCl (37% aqueous solution) was added at room temperature. After stirring for 10 min, 70 g of 3-chloro-2-[3-(chloroacetyl)-4,5-dihydro-1,2-oxazol-5-yl]phenyl methanesulfonate (188 mmol, 1.0 equivalents) was added. The mixture was heated to reflux and stirred for 5 h under these conditions.

[0064] 120 g of mesitylene and 91.1 g (772 mmol, 4.0 eq.) of 2-methyl-5-ethylpyridine (recycled from a previous batch) were added. Most of the ethanol was distilled off through a vigreux column under decreasing vacuum. After 247 g of distillate was obtained, the distillation was stopped.

[0065] 250 g of acetonitrile (recycled from a previous batch) were added and a further 81 g of distillate were distilled off at 450 mbar. The internal temperature was adjusted to 40° C. and 42 g (368 mmol, 1.96 eq.) of chloroacetyl chloride were added within 3 h.

[0066] Approximately 130 g of acetonitrile were distilled off at 250 mbar. 244 g of industrial ethanol were added and the temperature was lowered to 0 ° C. After stirring overnight, the suspension was filtered and washed with 150 g of 2-butanol. The filter cake was washed with 400 g of water and dried to obtain 86.8 g of [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidinyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl]methanesulfonate (purity 95.3%, yield 84.8%).

[0067] Example 4

[0068] 32.8 g of piperidine-4-thiocarboxamide (226 mmol, 1.2 equivalents) was stirred with 221 g of ethanol at room temperature. 24.1 g of concentrated HCl (37% aqueous solution) was added at room temperature. After stirring for 10 min, 70 g of 3-chloro-2-[3-(chloroacetyl)-4,5-dihydro-1,2-oxazol-5-yl]phenyl methanesulfonate (188 mmol, 1.0 equivalents) was added. The mixture was heated to reflux and stirred for 5 h under these conditions.

[0069] 120 g of mesitylene and 91.1 g (772 mmol, 4.0 equivalents) of 2-methyl-5-ethylpyridine were added. Most of the ethanol was distilled off through a vigreux column under gradually decreasing vacuum. After 241 g of distillate was obtained, the distillation was stopped.

[0070] 200 g of acetonitrile were added and a further 33 g of distillate were distilled off at 450 mbar. The internal temperature was adjusted to 40° C. and 42 g (368 mmol, 1.96 eq.) of chloroacetyl chloride were added within 3 h.

[0071] 135 g of acetonitrile were distilled off at 250 mbar. 241 g of industrial ethanol were added and the temperature was lowered to 0° C. After stirring overnight, 17.1 g of HCl (20% aqueous solution; 0.5 equivalent) was added and stirring was continued for 2 h. The suspension was filtered and washed with a combination of the second distillate (33 g) and 30 g of ethanol. The filter cake was washed with 60 g of water and dried to give 82.1 g of [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidinyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl]methanesulfonate (purity 95.2%, yield 80.2%).

[0072] Example 5

[0073] 32.8 g of piperidine-4-thiocarboxamide (226 mmol, 1.2 equivalents) was stirred with 221 g of ethanol at room temperature. 24.1 g of concentrated HCl (37% aqueous solution) was added at room temperature. After stirring for 10 min, 70 g of 3-chloro-2-[3-(chloroacetyl)-4,5-dihydro-1,2-oxazol-5-yl]phenyl methanesulfonate (188 mmol, 1.0 equivalents) was added. The mixture was heated to reflux and stirred for 5 h under these conditions.

[0074] 120 g of mesitylene and 91.1 g (772 mmol, 4.0 equivalents) of 2-methyl-5-ethylpyridine were added. Most of the ethanol was distilled off through a vigreux column under gradually decreasing vacuum. After 253 g of distillate was obtained, the distillation was stopped.

[0075] 255 g of acetonitrile were added and a further 89 g of distillate were distilled off at 450 mbar. The internal temperature was adjusted to 40° C. and 42 g (368 mmol, 1.96 eq.) of chloroacetyl chloride were added within 3 h.

[0076] 127g acetonitrile was distilled out at 250mbar. 253g industrial ethanol was added and the temperature was reduced to 0°C. After stirring overnight, 150g water was added and stirring was continued for 2h. The suspension was filtered and washed with a combination of acetonitrile / ethanol (30g) and 50g ethanol in a mass ratio of 78:22. The filter cake was washed with 60g water and dried to obtain 81.6g [3-chloro-2- [3- [2- [1- (2-chloroacetyl) -4-piperidinyl] thiazole-4-yl] -4,5-dihydroisoxazol-5-yl] phenyl] methanesulfonate (purity 93.8%, yield 78.5%).

[0077] Example 6

[0078] 32.8 g of piperidine-4-thiocarboxamide (226 mmol, 1.2 equivalents) was stirred with 221 g of ethanol at room temperature. 24.1 g of concentrated HCl (37% aqueous solution) was added at room temperature. After stirring for 10 min, 70 g of 3-chloro-2-[3-(chloroacetyl)-4,5-dihydro-1,2-oxazol-5-yl]phenyl methanesulfonate (188 mmol, 1.0 equivalents) was added. The mixture was heated to reflux and stirred for 5 h under these conditions.

[0079] 120 g of mesitylene and 91.1 g (772 mmol, 4.0 equivalents) of 2-methyl-5-ethylpyridine were added. Most of the ethanol was distilled off through a vigreux column under gradually decreasing vacuum. After 242 g of distillate was obtained, the distillation was stopped.

[0080] 250 g of acetonitrile were added and a further 83 g of distillate were distilled off at 450 mbar. The internal temperature was adjusted to 40° C. and 42 g (368 mmol, 1.96 eq.) of chloroacetyl chloride were added within 3 h.

[0081] 131g acetonitrile was distilled out at 250mbar. 121g industrial ethanol was added and the temperature was reduced to 0°C. After stirring overnight, 100g water was added and stirring was continued for 2h. The suspension was filtered and washed with a combination of acetonitrile / ethanol (30g) and 50g ethanol in a mass ratio of 78:22. The filter cake was washed with 60g water and dried to obtain 87.3g [3-chloro-2- [3- [2- [1- (2-chloroacetyl) -4-piperidinyl] thiazole-4-yl] -4,5-dihydroisoxazol-5-yl] phenyl] methanesulfonate (purity 95.7%, yield 85.7%).

[0082] Example 7

[0083] 234.3 g of piperidine-4-thiocarboxamide (1.61 mol, 1.2 equivalents) was stirred with 2250 g of ethanol at room temperature. 172.2 g of concentrated HCl (37% aqueous solution) was added at room temperature. After stirring for 10 min, 500 g of 3-chloro-2-[3-(chloroacetyl)-4,5-dihydro-1,2-oxazol-5-yl]phenyl methanesulfonate (1.34 mmol, 1.0 equivalents) was added. The mixture was heated to reflux and stirred for 5 h under these conditions.

[0084] 862.5 g of mesitylene and 651.5 g (5.37 mmol, 4.0 equivalents) of 2-methyl-5-ethylpyridine were added. Most of the ethanol was distilled off through a packed column under gradually decreasing vacuum. After 2438 g of distillate was obtained, the distillation was stopped.

[0085] 1429 g of acetonitrile were added and a further 223 g of distillate were distilled off at 450 mbar. The internal temperature was adjusted to 40° C. and 301 g (2.63 mmol, 1.96 eq.) of chloroacetyl chloride were added within 3 h.

[0086] 1168 g of acetonitrile were distilled off at 250 mbar. 1285 g of 2-butanol were added and the mixture was transferred at 5° C. to a second reactor containing 3200 g of water and 424 g of concentrated hydrochloric acid. The temperature of the entire mixture was adjusted to 5° C. After stirring overnight, the suspension was filtered, the filter cake was washed twice with 2-butanol and twice with water, and after drying, 607 g of [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidinyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl]methanesulfonate (purity 94.8%, yield 82.6%) were obtained.

[0087] Example 8

[0088] 34.6 g of piperidine-4-thiocarboxamide (232 mmol, 1.2 eq) was stirred with 315 g of ethanol at room temperature. 24.7 g of concentrated HCl (37% aqueous solution) was added at room temperature. After stirring for 10 min, 70 g of 3-chloro-2-[3-(chloroacetyl)-4,5-dihydro-1,2-oxazol-5-yl]phenyl methanesulfonate (193 mmol, 1.0 eq) was added. The mixture was heated to reflux and stirred for 5 h under these conditions.

[0089] 120 g of mesitylene and 93.5 g (772 mmol, 4.0 equivalents) of 2-methyl-5-ethylpyridine were added. Most of the ethanol was distilled off through a vigreux column under gradually decreasing vacuum. After 339 g of distillate was obtained, the distillation was stopped.

[0090] 250 g of acetonitrile were added and a further 88 g of distillate were distilled off at 450 mbar. The internal temperature was adjusted to 40° C. and 43.2 g (368 mmol, 1.96 eq.) of chloroacetyl chloride were added within 3 h.

[0091] 137.6 g of acetonitrile were distilled off at 250 mbar. 180 g of 1-butanol were added, and the mixture was transferred to a second reactor containing 450 g of water and 60.9 g of concentrated hydrochloric acid at 5° C., and the temperature of the entire mixture was adjusted to 5° C. After stirring overnight, the suspension was filtered, the filter cake was washed twice with water, and after drying, 92.2 g of [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidinyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl]methanesulfonate (purity 90.3%, yield 83.2%) was obtained.

Claims

1. Method for preparing the compound of formula (I) The following steps are included (a) making a compound of formula (II) With the compound of formula (III) The reaction is carried out in the presence of hydrogen chloride and an alcohol solvent to obtain the hydrochloride of formula (IV) as well as (b) reacting the hydrochloride of formula (IV) with chloroacetyl chloride in the presence of an alkylpyridine base, a polar aprotic solvent and an aromatic solvent having a boiling point of at least 160° C. to obtain a compound of formula (I), in, Between steps (a) and (b), the alcohol solvent is removed by distillation, In step (b), the compound of formula (IV) is used without prior isolation, at least part of the pyridine base and at least part of the aromatic solvent having a boiling point of at least 160° C. are added before distillation of the alcohol solvent; as well as The alcohol solvent used in step (a) is selected from methanol, ethanol, n-propanol (propanol), isopropanol, n-butanol (butanol), isobutanol, sec-butanol and tert-butanol.

2. The method according to claim 1, wherein the alkyl pyridine base is selected from the group consisting of picoline, lutidine, collidine, methylethylpyridine and diethylpyridine.

3. The method according to any one of claims 1 or 2, wherein the alkylpyridine base is 2-methyl-5-ethylpyridine.

4. The method according to any one of claims 1 or 2, wherein the alcohol solvent used in step (a) is selected from isopropanol and ethanol.

5. The method according to any one of claims 1 or 2, wherein the alcohol solvent used in step (a) is ethanol.

6. The process according to any one of claims 1 or 2, wherein the hydrogen chloride is used in the form of hydrochloric acid.

7. The method according to any one of claims 1 or 2, wherein the polar aprotic solvent used in step (b) is selected from the group consisting of ethers, ketones, esters, nitriles, amides, dimethyl sulfoxide, tetramethylene sulfone, hexamethylphosphoramide and DMPU.

8. The method according to any one of claims 1 or 2, wherein the polar aprotic solvent used in step (b) is acetonitrile.

9. The process according to any one of claims 1 or 2, wherein the aromatic solvent having a boiling point of at least 160°C is selected from 1,3,5-trimethylbenzene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 1,2-dimethoxybenzene, 1,3-dimethoxybenzene, 1,4-dimethoxybenzene and mixtures thereof.

10. The process according to any one of claims 1 or 2, wherein the aromatic solvent having a boiling point of at least 160°C is mesitylene.

11. The method according to any one of claims 1 or 2, wherein the alcohol solvent is ethanol, the alkylpyridine base is 2-methyl-5-ethylpyridine, and wherein the polar aprotic solvent in step (b) is acetonitrile, and step (b) is carried out in the presence of mesitylene.

12. The method of claim 11, wherein at the end of the reaction in step (b), the reaction is quenched by (i) distilling most of the acetonitrile and (ii) adding ethanol, 1-butanol or 2-butanol.

13. The process according to claim 11, wherein the ethanol used in step (a) is removed by distillation and reused in step (b) to quench the reaction to obtain the compound of formula (I), and wherein the acetonitrile used in step (b) is also recycled.

14. The process according to any one of claims 1 or 2, wherein the amount of hydrogen chloride used in step (a) is in the range of 1 mol to 3 mol per 1 mol of the compound of formula (II).

15. The process according to any one of claims 1 or 2, wherein the amount of hydrogen chloride used in step (a) is in the range of 1 mol to 2 mol per 1 mol of the compound of formula (II).

16. The process according to any one of claims 1 or 2, wherein the amount of hydrogen chloride used in step (a) is in the range of 1 mol to 1.5 mol per 1 mol of the compound of formula (II).

17. The method according to any one of claims 1 or 2, wherein the amount of chloroacetyl chloride used in step (b) is in the range of 1 mol to 5 mol per 1 mol of the compound of formula (IV).

18. The method according to any one of claims 1 or 2, wherein the amount of chloroacetyl chloride used in step (b) is in the range of 1.5 mol to 4 mol per 1 mol of the compound of formula (IV).

19. The method according to any one of claims 1 or 2, wherein the amount of chloroacetyl chloride used in step (b) is in the range of 1.5 mol to 2.5 mol per 1 mol of the compound of formula (IV).

20. The method according to any one of claims 1 or 2, wherein the amount of the alkylpyridine base used in step (b) ranges from 1 mol to 20 mol per 1 mol of the compound of formula (IV).

21. The method according to any one of claims 1 or 2, wherein the amount of the alkylpyridine base used in step (b) is in the range of 2 mol to 10 mol per 1 mol of the compound of formula (IV).

22. The process according to any one of claims 1 or 2, wherein the amount of the alkylpyridine base used in step (b) is in the range of 3 mol to 6 mol per 1 mol of the compound of formula (IV).

23. A method for preparing fluoxapiprolin, comprising the method according to any one of claims 1 to 22, further comprising the step (c) of reacting the compound of formula (I) obtained in step (b) with 3,5-bis(difluoromethyl)-1H-pyrazole.

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