WO2016113741A1 - Process for preparing 1-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-1h-pyrazole - Google Patents

Process for preparing 1-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-1h-pyrazole Download PDF

Info

Publication number
WO2016113741A1
WO2016113741A1 PCT/IL2016/050047 IL2016050047W WO2016113741A1 WO 2016113741 A1 WO2016113741 A1 WO 2016113741A1 IL 2016050047 W IL2016050047 W IL 2016050047W WO 2016113741 A1 WO2016113741 A1 WO 2016113741A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
salt
iii
chlorophenyl
Prior art date
Application number
PCT/IL2016/050047
Other languages
French (fr)
Inventor
Gal SUEZ
Michael Grabarnick
Alexander FRENKLAH
Original Assignee
Adama Makhteshim Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Adama Makhteshim Ltd. filed Critical Adama Makhteshim Ltd.
Publication of WO2016113741A1 publication Critical patent/WO2016113741A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms

Definitions

  • the present subject matter relates to a process for preparing l-(4-chlorophenyl)-
  • the compound l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole of the formula (I) is an important intermediate for preparing inter alia the fungicidal agents such as pyraclostrobin, as described in WO 96/01256.
  • WO 96/01256 describes the preparation of 2-(3-pyrazolyloxy- methylene)nitrobenzene derivatives starting from o-nitrobenzyl bromides in general.
  • U.S. Patent No. 6,133,451 describes a process for preparing 2-(3-pyrazolyloxymethylene)nitrobenzene derivatives by bromination of o-nitrotoluene to give o-nitrobenzyl bromide in the presence of a nonpolar, aprotic solvent and then reacting the o-nitrobenzyl bromide with a 3-hydroxypyrazole in the presence of a base.
  • the present subject matter provides a process for preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole of formula (I)
  • the salt of the compound of formula (III) may be an organic salt or an inorganic salt of the compound of formula (III).
  • the inorganic salt comprises at least one of sodium salt, potassium salt, calcium salt, and magnesium salt.
  • the dehydrogenation step may be carried out with an oxidizing agent, such as for example molecular oxygen or air in the presence of a base.
  • the molar ratio of the compound of formula (IV) to the compound of formula (III) may be 1: 1 to 100: 1. In a further embodiment, the molar ratio of the compound of formula (IV) to the compound of formula (III) may be 1: 1 to 2: 1.
  • the polar aprotic solvent comprises at least one of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.
  • the present subject matter provides a process for preparing the compound of formula (II) by reacting 4-chlorophenylhydrazine hydrochloride of formula (V)
  • the solvent used in the dehydrogenation step may be the same solvent used in the preparation of the compound of formula (II).
  • the compound of formula (II) is not isolated prior to the dehydrogenation step.
  • the base used in the preparation of the compound of formula (II) may be the same base used in the dehydrogenation step.
  • the present subject matter provides a process for preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole of formula (I)
  • X is one of bromide, chloride, iodide, tosylate, mesylate, triflate.
  • the salt of l-(4-chlorophenyl)-3-hydroxy-lH- pyrazole of formula (III) is an organic salt or an inorganic salt of l-(4-chlorophenyl)-3- hydroxy-lH-pyrazole of formula (III).
  • the inorganic salt comprises at least one of sodium salt, potassium salt, calcium salt, and magnesium salt.
  • the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1: 1 to 100: 1.
  • the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1: 1 to 2: 1.
  • the polar aprotic solvent comprises at least one of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.
  • the compound of formula (III) and/or salt thereof is prepared by dehydrogenating l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II)
  • the dehydrogenation step is carried out with an oxidizing agent in the presence of a base.
  • the oxidizing agent comprises at least one of molecular oxygen and air.
  • the compound of formula (II) is prepared by reacting 4-chlorophenylhydrazine h drochloride of formula (V)
  • the solvent used in the dehydrogenation step is the same solvent used in the preparation of the compound of formula (II), and wherein the compound of formula (II) is not isolated prior to the dehydrogenation step.
  • the base used in the dehydrogenation step is the same base used in the preparation of the compound of formula (II).
  • the present subject matter provides a process for preparing l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or a salt thereof
  • the compound of formula (III) may be in the form of an organic salt or inorganic salt.
  • the inorganic salt comprises at least one of sodium salt, potassium salt, calcium salt, and magnesium salt.
  • the dehydrogenation step may be carried out with an oxidizing agent, such as for example molecular oxygen or air in the presence of a base.
  • the polar aprotic solvent comprises at least one of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.
  • the process further includes the step of reacting the resulting solution of formula (III) and/or salt thereof with the compound of formula (IV)
  • the compound of formula (II) may be prepared by reacting 4-chlorophenylhydrazine hydrochloride of formula (V)
  • the solvent used in the preparation of the compound of formula (II) may be the same solvent used in the dehydrogenation step.
  • the base used in the preparation of the compound of formula (II) may be the same base used in the dehydrogenation step.
  • the present subject matter provides a process for preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole of formula (I)
  • reaction is carried out in the solvent used in the dehydrogenation step, and wherein the compound of formula (III) and/or salt thereof is not isolated prior to its reaction with the compound of formula (IV) and wherein the compound of formula (II) is not isolated prior to the dehydrogenation step.
  • the herein described processes may be used in the production of pyraclostrobin.
  • the present subject matter relates to the use of the compound of formula (I) as prepared according to processes disclosed herein in the preparation of pyraclostrobin.
  • solvent system includes a mixture of at least two solvents.
  • the present subject matter provides a process for preparing l-(4-chlorophenyl)- 3-[(2-nitrophenyl)methoxy]-lH-pyrazole formula (I)
  • X is one of bromide, chloride, iodide, tosylate, mesylate, triflate
  • reaction is carried out in the same solvent used in the dehydrogenation step.
  • the process described herein is a one-pot process in which the resulting product of the dehydrogenation is directly used in the next step of producing 1- (4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole formula (I), without isolating l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole from the solvent and other components found in the mixture.
  • the present subject matter provides a process for preparing l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or salt thereof
  • the present subject matter provides a process for preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole of formula (I) wherein the process comprises: dehydrogenation of l-(4-chlorophenyl)-pyrazolidin-3- one of formula (II) to give l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or a salt thereof in the presence of a polar aprotic solvent and subsequent reaction of the resulting solution of formula (III) and/or salt thereof with the compound of formula (IV); wherein the reaction is carried out in the solvent used in the dehydrogenation step and wherein (III) and/or salt thereof is not isolated prior to its reaction with the compound of formula (IV).
  • the present process is advantageous in that it avoids the need for using expensive phase transfer catalysts.
  • the process is highly efficient, providing a short reaction time.
  • Another advantage of the present processes is that it provides a solvent which can be used in the dehydrogenation of the compound of formula (II) to obtain the compound of formula (III) and/or salt thereof as well as be used to dissolve both the compound of formula (III) and/or salt thereof and the compound of formula (IV) in the preparation of the compound of formula (I).
  • the step of reacting l-(4-chlorophenyl)-3 -hydroxy- lH-pyrazole of formula (III) and/or salt thereof with the compound of formula (IV) to form l-(4- chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole of formula (I) is conducted at temperatures lower when compared to those described in the prior art.
  • the present one-pot process reduces the cost of production, simplifies work-up, and minimizes any effluent disposal problems. Further, the present process achieves high yields compared to the methods known in the prior art.
  • the salt of l-(4-chlorophenyl)-3- hydroxy-lH-pyrazole is an organic or inorganic salt of l-(4-chlorophenyl)-3-hydroxy- lH-pyrazole.
  • inorganic salts may include but are not limited to sodium salt, potassium salt, calcium salt, and magnesium salt.
  • organic salts may include but are not limited to secondary amine salts, tertiary amine salts, quaternary amine salts, and aromatic carbocations such as pyridinium.
  • the compound of formula (III) may be in the form of a salt due to the results of the dehydrogenation of the compound of formula (II).
  • the compound of formula (III) may be converted into the form of a salt prior to or during its reaction with the compound of formula (IV).
  • the polar aprotic solvent may include but is not limited to acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, N- methyl pyrrolidinone and any combination thereof.
  • the polar aprotic solvent is dimethyl sulfoxide.
  • the polar aprotic solvent may include two or three or more polar aprotic solvents.
  • the dehydrogenation may be conducted in the presence of a solvent system which may which comprises at least one polar aprotic solvent and may further include other suitable polar or non-polar solvents.
  • suitable solvents may include but are not limited to (i) aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether; (ii) aromatic hydrocarbons such as toluene, o-xylene, m-xylene and p-xylene; (iii) halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene; and (iv) alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, and tert-butanol.
  • the molar ratio between the polar aprotic solvent and the other solvents in the solvent is from about 1: 1 to about 6: 1. In another embodiment, the molar ratio is from about 1: 1 to about 5: 1. In yet another embodiment, the molar ratio is from about 1: 1 to about 4: 1. In a further embodiment, the molar ratio is from about 1: 1 to about 3: 1. In yet a further embodiment, the molar ratio is from about 1.5: 1 to about 3: 1.
  • the dehydrogenation step may be carried out with an oxidizing agent in the presence of a base.
  • oxidizing agents may include but are not limited to air and molecular oxygen. In a specific embodiment the oxidizing agent is molecular oxygen.
  • bases may include but are not limited to alkali metal and alkaline earth metal alkoxides such as for example, sodium methoxide, sodium ethoxide, sodium butoxide, sodium isopropoxide, potassium ethoxide, potassium tert-butoxide and dimethoxy-magnesium and combinations thereof. In a specific embodiment the base is sodium methoxide.
  • the dehydrogenation may be carried out in the presence of metal salts.
  • the metal salts may include but are not limited to salts of iron in the oxidation state II or III (e.g. iron(II) chloride, iron(III) chloride, iron(II) sulfate and iron(III) sulfate), salts of copper in the oxidation state I or II (e.g. copper(I) chloride, copper(II) chloride, copper(I) sulfate and copper(II) sulfate) and also corresponding salts of main group or transition metals.
  • iron salts may include but are not limited to salts of iron in the oxidation state II or III (e.g. iron(II) chloride, iron(III) chloride, iron(II) sulfate and iron(III) sulfate), salts of copper in the oxidation state I or II (e.g. copper(I) chloride, copper(II) chloride, copper(I
  • the metal salts may be present in catalytic amounts. According to some embodiments, the molar ratio between the compound of formula (II) and the metal salts may be from about 1:0.001 to about 1:0.1. In another embodiment, the molar ratio between the compound of formula (II) and the metal salts may be from about 1:0.005 to about 1:0.05. In yet another embodiment, the molar ratio between the compound of formula (II) and the metal salts may be from about 1:0.01 to about 1:0.05. In a specific embodiment, the molar ratio between the compound of formula (II) and the metal salts is about 1:0.125.
  • the dehydrogenation step is conducted at a temperature from about 10°C to about 50°C, more preferably from about 10°C to about 35°C. In a specific example, the dehydrogenation step is conducted at a temperature of 15°C.
  • the base e.g. sodium methoxide
  • the sodium methoxide is added in portions to the reaction mixture of is 1- (4-chlorophenyl)-pyrazolidin-3-one of formula (II) over a period of about 30-40 minutes.
  • the molar ratio between the compound of formula (IV) and the compound of formula (III) and/or salt thereof is from about 1: 1 to about 100: 1. In another embodiment, the molar ratio between the compound of formula (IV) and the compound of formula (III) and/or salt thereof is from about 1: 1 to about 50: 1. In yet another embodiment, the molar ratio between the compound of formula (IV) and the compound of formula (III) and/or salt thereof is from about 1: 1 to about 10: 1. In a further embodiment, the molar ratio between the compound of formula (IV) and the compound of formula (III) and/or salt thereof is from about 1 : 1 to about 2: 1. In a specific embodiment, the molar ratio between the compound of formula (IV) and the compound of formula (III) and/or salt thereof is about 1.7: 1.
  • the step of reacting the compound of formula (III) and/or salt thereof with the compound of formula (IV) to form the compound of formula (I) is conducted at a temperature from about 25 C to about 50 C, more preferably from about 25 ° C to about 30 ° C.
  • the present subject matter provides a process for preparing of l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II)
  • the solvent used in the preparation of l-(4-chlorophenyl)-pyrazolidin-3-one may be the same solvent used in the abovementioned dehydrogenation step.
  • the solvent may be a polar aprotic solvent may include but is not limited to acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and any combination thereof.
  • the same solvent may be used from the first step of preparing l-(4-chlorophenyl)-pyrazolidin-3-one to the second step of preparing l-(4- chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or salt thereof through to the third step of preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole without isolation of any of the intermediate products.
  • the weight ratio between 4- chlorophenylhydrazine hydrochloride of formula (V) and the solvent is from about 1 : 1 to about 1: 100. In another embodiment, the weight ratio between 4- chlorophenylhydrazine hydrochloride of formula (V) and the solvent is from about 1 : 1 to about 1:50. In yet another embodiment, the weight ratio between 4- chlorophenylhydrazine hydrochloride of formula (V) and the solvent is from about 1 : 1 to about 1: 10.
  • the base used in the dehydrogenation step may be the same base used in the preparation of l-(4-chlorophenyl)-pyrazolidin-3-one .
  • the bases may include but are not limited to alkali metal and alkaline earth metal alkoxides such as for example, sodium methoxide, sodium ethoxide, sodium butoxide, sodium isopropoxide, potassium ethoxide, potassium tert-butoxide and dimethoxy-magnesium and combinations thereof.
  • alkyl acrylate used in the preparation of l-(4-chlorophenyl)- pyrazolidin-3-one may include but are not limited to methyl acrylate, ethyl acrylate, butyl acrylate, t-butyl acrylate, and any combination thereof.
  • additional amounts of the base and/or the alkyl acrylate may be slowly added to the mixture until full conversion is achieved.
  • the base and the alkyl acrylate may be added in alternate portions. For example, a portion of base may first be added to the mixture, after stirring a portion of the alkyl acrylate may be added to the mixture, after additional stirring an additional portion of base may be added etc. This may be continued until all of the necessary base and alkyl acrylate are added to the mixture.
  • the compound of formula (I) is an important intermediate and may be used in the preparation of pyraclostrobin, as described in US 6,255,489, incorporated herein by reference in its entirety.
  • reaction conditions in step (b) include but are not limited to oxidation, reduction, etherification, and esterification to obtain pyraclostrobin.
  • the progress of the reaction can be monitored using any suitable method, which can include, for example, chromatographic methods such as, e.g., high performance liquid chromatography (HPLC), thin layer chromatography (TLC), and the like.
  • chromatographic methods such as, e.g., high performance liquid chromatography (HPLC), thin layer chromatography (TLC), and the like.
  • the compound of formula (I) can be isolated from the reaction mixture by any conventional techniques well-known in the art. Such isolation techniques can be selected, without limitation, from the group consisting of concentration, extraction, precipitation, cooling, filtration, crystallization, centrifugation, and a combination thereof, followed by drying.
  • the compound of formula (I) can be optionally purified by any conventional techniques well-known in the art.
  • purification techniques can be selected, without limitation, from the group consisting of precipitation, crystallization, slurrying, washing in a suitable solvent, filtration through a packed-bed column, dissolution in an appropriate solvent, re-precipitation by addition of a second solvent in which the compound is insoluble, and a combination thereof.
  • l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II) was produced by adding 4.8 grams of methyl acrylate (55.9 mol) to the suspension and the suspension was then stirred for a few minutes. 3.02 grams (55.9 mol) of sodium methoxide was slowly added to the suspension at a rate of 0.1 mol every three minutes. This step was done in a N 2 atmosphere at 25°C.
  • the crude product was recrystallized using MCB.
  • the product was dried in a vacuum oven at 25 mbar at 70°C.
  • l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II) was produced by adding 4.8 grams of methyl acrylate (55.9 mol) to the suspension and the suspension was then stirred for a few minutes. 3.02 grams (55.9 mol) of sodium methoxide was slowly added to the suspension at a rate of 0.1 mol every three minutes. This step was done in a N 2 atmosphere at 25°C.
  • the crude product was recrystallized using MCB.
  • the product was dried in a vacuum oven at 25 mbar at 70°C.

Abstract

A process for preparing 1-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-1H- pyrazole of formula (I) comprising: dehydrogenation of 1-(4-chlorophenyl)-pyrazolidin- 3-one of formula (II) to give 1-(4-chlorophenyl)-3-hydroxy-1H-pyrazole of formula (III) and/or a salt thereof in the presence of a solvent comprising at least one polar aprotic solvent and subsequent reaction of the resulting solution of formula (III) and/or salt thereof with the compound of formula (IV) wherein the reaction is carried out in the solvent used in the dehydrogenation step and wherein the compound of formula (III) and/or salt thereof is not isolated prior to its reaction with the compound of formula (IV).

Description

PROCESS FOR PREPARING l-(4-CHLOROPHENYL)-3-[(2- NITROPHENYL)METHOXY]- 1H-PYRAZOLE
TECHNICAL FIELD
The present subject matter relates to a process for preparing l-(4-chlorophenyl)-
3-[(2-nitrophenyl)methoxy]-lH-pyrazole.
BACKGROUND
The compound l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole of the formula (I) is an important intermediate for preparing inter alia the fungicidal agents such as pyraclostrobin, as described in WO 96/01256.
WO 96/01256 describes the preparation of 2-(3-pyrazolyloxy- methylene)nitrobenzene derivatives starting from o-nitrobenzyl bromides in general.
U.S. Patent No. 6,133,451 describes a process for preparing 2-(3-pyrazolyloxymethylene)nitrobenzene derivatives by bromination of o-nitrotoluene to give o-nitrobenzyl bromide in the presence of a nonpolar, aprotic solvent and then reacting the o-nitrobenzyl bromide with a 3-hydroxypyrazole in the presence of a base.
The o-nitrobenzyl bromide does not undergo any intermediate isolation prior to its reaction with 3-hydroxypyrazole.
It would be highly desirable to have an improved process for the production of compound of formula (I) which is suitable for industrial use, highly efficient, low-cost, environmentally friendly, and provides a high yield in a short reaction time, thereby overcoming the deficiencies of the prior art. The present subject matter provides such a process.
It is therefore a purpose of the present subject matter to provide a one-pot process for the preparation of l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH- pyrazole.
It is yet another purpose of the present subject matter to provide a process that overcomes the disadvantages of the known art. SUMMARY
According to one aspect, the present subject matter provides a process for preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole of formula (I)
Figure imgf000003_0001
(I)
by the dehydrogenation of l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II)
OH
Figure imgf000003_0002
(II)
to give l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or a salt thereof
Figure imgf000003_0003
(HI)
in the presence of a polar aprotic solvent and the subsequent reaction of the resulting solution of formula (III) and/or salt thereof with the compound of formula (IV)
Figure imgf000003_0004
(IV)
wherein X is one of bromide, chloride, iodide, tosylate, mesylate, triflate; wherein the reaction is carried out in the reaction mixture resulting from the dehydrogenation step; and the compound of formula (III) and/or salt thereof is not isolated prior to its reaction with the compound of formula (IV). According to an embodiment, the salt of the compound of formula (III) may be an organic salt or an inorganic salt of the compound of formula (III). The inorganic salt comprises at least one of sodium salt, potassium salt, calcium salt, and magnesium salt. The dehydrogenation step may be carried out with an oxidizing agent, such as for example molecular oxygen or air in the presence of a base. According to an embodiment, the molar ratio of the compound of formula (IV) to the compound of formula (III) may be 1: 1 to 100: 1. In a further embodiment, the molar ratio of the compound of formula (IV) to the compound of formula (III) may be 1: 1 to 2: 1. The polar aprotic solvent comprises at least one of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.
According to another aspect, the present subject matter provides a process for preparing the compound of formula (II) by reacting 4-chlorophenylhydrazine hydrochloride of formula (V)
Figure imgf000004_0001
(V)
with a base in the presence of a solvent, and further reacting with an alkyl acrylate.
According to an embodiment, the solvent used in the dehydrogenation step may be the same solvent used in the preparation of the compound of formula (II). In this embodiment, the compound of formula (II) is not isolated prior to the dehydrogenation step. Further, the base used in the preparation of the compound of formula (II) may be the same base used in the dehydrogenation step.
According to a further aspect, the present subject matter provides a process for preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole of formula (I)
Figure imgf000004_0002
(I)
comprising: reacting l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or thereof
Figure imgf000005_0001
(Ill)
with the compound of formula (IV)
Figure imgf000005_0002
(IV)
in the presence of a polar aprotic solvent; wherein X is one of bromide, chloride, iodide, tosylate, mesylate, triflate.
According to an embodiment, the salt of l-(4-chlorophenyl)-3-hydroxy-lH- pyrazole of formula (III) is an organic salt or an inorganic salt of l-(4-chlorophenyl)-3- hydroxy-lH-pyrazole of formula (III). The inorganic salt comprises at least one of sodium salt, potassium salt, calcium salt, and magnesium salt. According to an embodiment, the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1: 1 to 100: 1. In a further embodiment, the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1: 1 to 2: 1. The polar aprotic solvent comprises at least one of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.
According to an embodiment, the compound of formula (III) and/or salt thereof is prepared by dehydrogenating l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II)
H
Figure imgf000005_0003
(II) in the presence of a polar aprotic solvent. The solvent used in the dehydrogenation step may be the same solvent used in the preparation of the compound of formula (I), and the compound of formula (III) and/or salt thereof is not isolated prior to its reaction with the compound of formula (IV). The dehydrogenation step is carried out with an oxidizing agent in the presence of a base. The oxidizing agent comprises at least one of molecular oxygen and air.
According to an embodiment, the compound of formula (II) is prepared by reacting 4-chlorophenylhydrazine h drochloride of formula (V)
Figure imgf000006_0001
(V)
with a base in the presence of a solvent, and further reacting with an alkyl acrylate. The solvent used in the dehydrogenation step is the same solvent used in the preparation of the compound of formula (II), and wherein the compound of formula (II) is not isolated prior to the dehydrogenation step. The base used in the dehydrogenation step is the same base used in the preparation of the compound of formula (II).
According to a further aspect, the present subject matter provides a process for preparing l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or a salt thereof
Figure imgf000006_0002
(III)
comprising:
dehydrogenation of l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II)
Figure imgf000006_0003
(Π)
in the presence of a polar aprotic solvent.
According to an embodiment, the compound of formula (III) may be in the form of an organic salt or inorganic salt. The inorganic salt comprises at least one of sodium salt, potassium salt, calcium salt, and magnesium salt. The dehydrogenation step may be carried out with an oxidizing agent, such as for example molecular oxygen or air in the presence of a base. The polar aprotic solvent comprises at least one of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.
According to an embodiment, the process further includes the step of reacting the resulting solution of formula (III) and/or salt thereof with the compound of formula (IV)
Figure imgf000007_0001
(IV)
to give a compound of formula (I)
Figure imgf000007_0002
(I)
wherein X is one of bromide, chloride, iodide, tosylate, mesylate, triflate; wherein the reaction is carried out in the solvent used in the dehydrogenation step and the compound of formula (III) and/or salt thereof is not isolated prior to its reaction with the compound of formula (IV). The compound of formula (II) may be prepared by reacting 4-chlorophenylhydrazine hydrochloride of formula (V)
Figure imgf000007_0003
(V)
with a base in the presence of a solvent and further reacting with an alkyl acrylate. The solvent used in the preparation of the compound of formula (II) may be the same solvent used in the dehydrogenation step. The base used in the preparation of the compound of formula (II) may be the same base used in the dehydrogenation step.
According to an aspect, the present subject matter provides a process for preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole of formula (I)
Figure imgf000008_0001
(I)
(i) by reacting 4-chlorophenylhydrazine hydrochloride of formula (V)
Figure imgf000008_0002
(V)
with a base in the presence of a solvent, and further reacting with an alkyl acrylate; (ii) dehydrogenating the formed l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II)
Figure imgf000008_0003
(II)
to give l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or a salt thereof
Figure imgf000008_0004
(HI)
in the presence of a polar aprotic solvent and
(iii) subsequent reacting the resulting solution of formula (III) and/or salt thereof with the compound of formula (IV)
Figure imgf000009_0001
wherein X is one of bromide, chloride, iodide, tosylate, mesylate, triflate;
wherein the reaction is carried out in the solvent used in the dehydrogenation step, and wherein the compound of formula (III) and/or salt thereof is not isolated prior to its reaction with the compound of formula (IV) and wherein the compound of formula (II) is not isolated prior to the dehydrogenation step.
In an embodiment, the herein described processes may be used in the production of pyraclostrobin.
In another embodiment, the present subject matter relates to the use of the compound of formula (I) as prepared according to processes disclosed herein in the preparation of pyraclostrobin.
DETAILED DESCRIPTION
Definitions
Prior to setting forth the present subject matter in detail, it may be helpful to provide definitions of certain terms to be used herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this subject matter pertains.
The term "solvent system" as used herein includes a mixture of at least two solvents.
The term "a" or "an" as used herein includes the singular and the plural, unless specifically stated otherwise. Therefore, the terms "a," "an," or "at least one" can be used interchangeably in this application.
Throughout the application, descriptions of various embodiments use the term
"comprising"; however, it will be understood by one of skill in the art, that in some specific instances, an embodiment can alternatively be described using the language "consisting essentially of or "consisting of."
For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages, or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. In this regard, used of the term "about" herein specifically includes +10% from the indicated values in the range. In addition, the endpoints of all ranges directed to the same component or property herein are inclusive of the endpoints, are independently combinable, and include all intermediate points and ranges.
Process for Preparing l-(4-chlorophenyl)-3-r(2-nitrophenyl)methoxyl-lH-pyrazole
The present subject matter provides a process for preparing l-(4-chlorophenyl)- 3-[(2-nitrophenyl)methoxy]-lH-pyrazole formula (I)
Figure imgf000010_0001
(I)
wherein the process comprises the dehydrogenation of l-(4-chlorophenyl)-pyrazolidin- 3 -one of formula (II)
Figure imgf000010_0002
(II)
to give l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or a salt thereof H
Figure imgf000011_0001
(III)
in the presence of a polar aprotic solvent and the subsequent reaction of the resulting solution of formula (III) and/or salt thereof with the compound of formula (IV)
Figure imgf000011_0002
(IV)
wherein X is one of bromide, chloride, iodide, tosylate, mesylate, triflate;
wherein the reaction is carried out in the same solvent used in the dehydrogenation step. The process described herein is a one-pot process in which the resulting product of the dehydrogenation is directly used in the next step of producing 1- (4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole formula (I), without isolating l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole from the solvent and other components found in the mixture.
In another embodiment the present subject matter provides a process for preparing l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or salt thereof
Figure imgf000011_0003
(III)
wherein the process comprises: dehydrogenation of l-(4-chlorophenyl)-pyrazolidin-3- one of formula (II)
Figure imgf000012_0001
(Π)
in the presence of a polar aprotic solvent.
In another embodiment, the present subject matter provides a process for preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole of formula (I) wherein the process comprises: dehydrogenation of l-(4-chlorophenyl)-pyrazolidin-3- one of formula (II) to give l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or a salt thereof in the presence of a polar aprotic solvent and subsequent reaction of the resulting solution of formula (III) and/or salt thereof with the compound of formula (IV); wherein the reaction is carried out in the solvent used in the dehydrogenation step and wherein (III) and/or salt thereof is not isolated prior to its reaction with the compound of formula (IV).
The present process is advantageous in that it avoids the need for using expensive phase transfer catalysts. In addition, the process is highly efficient, providing a short reaction time.
Another advantage of the present processes is that it provides a solvent which can be used in the dehydrogenation of the compound of formula (II) to obtain the compound of formula (III) and/or salt thereof as well as be used to dissolve both the compound of formula (III) and/or salt thereof and the compound of formula (IV) in the preparation of the compound of formula (I).
Further, the step of reacting l-(4-chlorophenyl)-3 -hydroxy- lH-pyrazole of formula (III) and/or salt thereof with the compound of formula (IV) to form l-(4- chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole of formula (I) is conducted at temperatures lower when compared to those described in the prior art.
The present one-pot process reduces the cost of production, simplifies work-up, and minimizes any effluent disposal problems. Further, the present process achieves high yields compared to the methods known in the prior art.
In an embodiment of the present processes, the salt of l-(4-chlorophenyl)-3- hydroxy-lH-pyrazole is an organic or inorganic salt of l-(4-chlorophenyl)-3-hydroxy- lH-pyrazole. Examples of inorganic salts may include but are not limited to sodium salt, potassium salt, calcium salt, and magnesium salt. Examples of organic salts may include but are not limited to secondary amine salts, tertiary amine salts, quaternary amine salts, and aromatic carbocations such as pyridinium.
According to an embodiment, the compound of formula (III) may be in the form of a salt due to the results of the dehydrogenation of the compound of formula (II). In another embodiment, the compound of formula (III) may be converted into the form of a salt prior to or during its reaction with the compound of formula (IV).
In one embodiment, the polar aprotic solvent may include but is not limited to acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, N- methyl pyrrolidinone and any combination thereof.
In a specific embodiment the polar aprotic solvent is dimethyl sulfoxide.
In some embodiment, the polar aprotic solvent may include two or three or more polar aprotic solvents.
According to some embodiments, the dehydrogenation may be conducted in the presence of a solvent system which may which comprises at least one polar aprotic solvent and may further include other suitable polar or non-polar solvents. Examples of suitable solvents may include but are not limited to (i) aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether; (ii) aromatic hydrocarbons such as toluene, o-xylene, m-xylene and p-xylene; (iii) halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene; and (iv) alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, and tert-butanol.
In an embodiment of the present processes, the molar ratio between the polar aprotic solvent and the other solvents in the solvent is from about 1: 1 to about 6: 1. In another embodiment, the molar ratio is from about 1: 1 to about 5: 1. In yet another embodiment, the molar ratio is from about 1: 1 to about 4: 1. In a further embodiment, the molar ratio is from about 1: 1 to about 3: 1. In yet a further embodiment, the molar ratio is from about 1.5: 1 to about 3: 1.
In a further, optional, embodiment of the present processes, the dehydrogenation step may be carried out with an oxidizing agent in the presence of a base.
Examples of oxidizing agents may include but are not limited to air and molecular oxygen. In a specific embodiment the oxidizing agent is molecular oxygen. Examples of bases may include but are not limited to alkali metal and alkaline earth metal alkoxides such as for example, sodium methoxide, sodium ethoxide, sodium butoxide, sodium isopropoxide, potassium ethoxide, potassium tert-butoxide and dimethoxy-magnesium and combinations thereof. In a specific embodiment the base is sodium methoxide.
In some embodiment, the dehydrogenation may be carried out in the presence of metal salts. The metal salts may include but are not limited to salts of iron in the oxidation state II or III (e.g. iron(II) chloride, iron(III) chloride, iron(II) sulfate and iron(III) sulfate), salts of copper in the oxidation state I or II (e.g. copper(I) chloride, copper(II) chloride, copper(I) sulfate and copper(II) sulfate) and also corresponding salts of main group or transition metals.
The metal salts may be present in catalytic amounts. According to some embodiments, the molar ratio between the compound of formula (II) and the metal salts may be from about 1:0.001 to about 1:0.1. In another embodiment, the molar ratio between the compound of formula (II) and the metal salts may be from about 1:0.005 to about 1:0.05. In yet another embodiment, the molar ratio between the compound of formula (II) and the metal salts may be from about 1:0.01 to about 1:0.05. In a specific embodiment, the molar ratio between the compound of formula (II) and the metal salts is about 1:0.125.
In one embodiment, the dehydrogenation step is conducted at a temperature from about 10°C to about 50°C, more preferably from about 10°C to about 35°C. In a specific example, the dehydrogenation step is conducted at a temperature of 15°C.
In another embodiment, during the dehydrogenation step, the base (e.g. sodium methoxide) may be added gradually to the reaction mixture over time. In a specific embodiment, the sodium methoxide is added in portions to the reaction mixture of is 1- (4-chlorophenyl)-pyrazolidin-3-one of formula (II) over a period of about 30-40 minutes.
In an embodiment of the present processes, the molar ratio between the compound of formula (IV) and the compound of formula (III) and/or salt thereof is from about 1: 1 to about 100: 1. In another embodiment, the molar ratio between the compound of formula (IV) and the compound of formula (III) and/or salt thereof is from about 1: 1 to about 50: 1. In yet another embodiment, the molar ratio between the compound of formula (IV) and the compound of formula (III) and/or salt thereof is from about 1: 1 to about 10: 1. In a further embodiment, the molar ratio between the compound of formula (IV) and the compound of formula (III) and/or salt thereof is from about 1 : 1 to about 2: 1. In a specific embodiment, the molar ratio between the compound of formula (IV) and the compound of formula (III) and/or salt thereof is about 1.7: 1.
In one embodiment, the step of reacting the compound of formula (III) and/or salt thereof with the compound of formula (IV) to form the compound of formula (I) is conducted at a temperature from about 25 C to about 50 C, more preferably from about 25°C to about 30°C.
Preparation of l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole
In another embodiment the present subject matter provides a process for preparing of l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II)
Figure imgf000015_0001
(II)
by reacting 4-chlorophenylhydrazine hydrochloride of formula (V)
Figure imgf000015_0002
(V)
with a base in the presence of a solvent and further reacting with an alkyl acrylate. The solvent used in the preparation of l-(4-chlorophenyl)-pyrazolidin-3-one may be the same solvent used in the abovementioned dehydrogenation step. The solvent may be a polar aprotic solvent may include but is not limited to acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and any combination thereof.
According to an embodiment, the same solvent may be used from the first step of preparing l-(4-chlorophenyl)-pyrazolidin-3-one to the second step of preparing l-(4- chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or salt thereof through to the third step of preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole without isolation of any of the intermediate products.
In an embodiment of the present processes, the weight ratio between 4- chlorophenylhydrazine hydrochloride of formula (V) and the solvent is from about 1 : 1 to about 1: 100. In another embodiment, the weight ratio between 4- chlorophenylhydrazine hydrochloride of formula (V) and the solvent is from about 1 : 1 to about 1:50. In yet another embodiment, the weight ratio between 4- chlorophenylhydrazine hydrochloride of formula (V) and the solvent is from about 1 : 1 to about 1: 10.
Further, the base used in the dehydrogenation step may be the same base used in the preparation of l-(4-chlorophenyl)-pyrazolidin-3-one . The bases may include but are not limited to alkali metal and alkaline earth metal alkoxides such as for example, sodium methoxide, sodium ethoxide, sodium butoxide, sodium isopropoxide, potassium ethoxide, potassium tert-butoxide and dimethoxy-magnesium and combinations thereof.
Further, the alkyl acrylate used in the preparation of l-(4-chlorophenyl)- pyrazolidin-3-one may include but are not limited to methyl acrylate, ethyl acrylate, butyl acrylate, t-butyl acrylate, and any combination thereof.
In order to ensure full conversion of 4-chlorophenylhydrazine hydrochloride of formula (V) to l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II) additional amounts of the base and/or the alkyl acrylate may be slowly added to the mixture until full conversion is achieved. According to an embodiment, the base and the alkyl acrylate may be added in alternate portions. For example, a portion of base may first be added to the mixture, after stirring a portion of the alkyl acrylate may be added to the mixture, after additional stirring an additional portion of base may be added etc. This may be continued until all of the necessary base and alkyl acrylate are added to the mixture.
The compound of formula (I) is an important intermediate and may be used in the preparation of pyraclostrobin, as described in US 6,255,489, incorporated herein by reference in its entirety.
In a further aspect of the subject matter there is provided a process for preparation of pyraclostrobin comprising:
a) preparing compound of formula (I) as described herein;
b) providing reaction conditions for preparation of pyraclostrobin. According to an embodiment the reaction conditions in step (b) include but are not limited to oxidation, reduction, etherification, and esterification to obtain pyraclostrobin.
The progress of the reaction can be monitored using any suitable method, which can include, for example, chromatographic methods such as, e.g., high performance liquid chromatography (HPLC), thin layer chromatography (TLC), and the like.
In yet another embodiment, the compound of formula (I) can be isolated from the reaction mixture by any conventional techniques well-known in the art. Such isolation techniques can be selected, without limitation, from the group consisting of concentration, extraction, precipitation, cooling, filtration, crystallization, centrifugation, and a combination thereof, followed by drying.
In yet another embodiment, the compound of formula (I) can be optionally purified by any conventional techniques well-known in the art. Such purification techniques can be selected, without limitation, from the group consisting of precipitation, crystallization, slurrying, washing in a suitable solvent, filtration through a packed-bed column, dissolution in an appropriate solvent, re-precipitation by addition of a second solvent in which the compound is insoluble, and a combination thereof.
The following examples illustrate the practice of the present subject matter in some of its embodiments, but should not be construed as limiting the scope of the present subject matter. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only without limiting the scope and spirit of the present subject matter. EXAMPLE 1
Preparation of l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole
An exemplary experimental procedure is described as follows: 100 grams of dimethyl sulfoxide, 10 grams (55.9 mol) of 4-chlorophenylhydrazine hydrochloride of formula (V) was added to a 250 ml three-neck flask in a N2 atmosphere and at room temperature. Over a period of 30 minutes, 3.02 grams (55.9 mol) of sodium methoxide was added to the solution. The mixture was then mixed for 10 minutes, until the 4- chlorophenylhydrazine hydrochloride was neutralized to produce 4- chlorophenylhydrazine. At this point the solution became darker in color and turned into a suspension.
l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II) was produced by adding 4.8 grams of methyl acrylate (55.9 mol) to the suspension and the suspension was then stirred for a few minutes. 3.02 grams (55.9 mol) of sodium methoxide was slowly added to the suspension at a rate of 0.1 mol every three minutes. This step was done in a N2 atmosphere at 25°C.
3.02 grams (55.9 mol) of sodium methoxide was slowly added to the l-(4- chlorophenyl)-pyrazolidin-3-one in a N2 atmosphere at 25-30°C. Oxygen was moderately bubbled through the solution for 2 hours using deep-pipe. The oxidation reaction was maintained at 40°C. The flask was kept in an ice-bath in order to prevent exotherm. Once the conversion of l-(4-chlorophenyl)-pyrazolidin-3-one to l-(4- chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) was complete, the oxygen bubbling was stopped.
Yield of l-(4-chlorophenyl)-3 -hydroxy- IH-pyrazole: 75%.
Preparation of l-(4-chlorophenyl)-3-r(2-nitrophenyl)methoxyl-lH-pyrazole
Using the same flask as used in the preparation of l-(4-chlorophenyl)-3- hydroxy-lH-pyrazole, a dropping funnel filled with 2-nitrobenzyl bromide of formula (IV) was connected. The ratio of 2-nitrobenzyl bromide to the l-(4-chlorophenyl)-3- hydroxy- IH-pyrazole present in the flask 1.7: 1 While being kept at a temperature of 25°C, the solution of 2-nitrobenzyl bromide was dropped into the flask at a rate of 0.5 ml/minute. After all of the 2-nitrobenzyl bromide was added to the flask, the reaction was mixed for 1 hour, until all of the l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole was consumed. A small amount of NaOH 15% was then added to the solution and the solution was then stirred for 30 minutes at 30°C. A small amount of H20 was added to the mixture in order to precipitate the crude product.
The crude product was recrystallized using MCB. The product was dried in a vacuum oven at 25 mbar at 70°C.
Yield of l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole: 70% with a purity of 99.1%. EXAMPLE 2
Preparation of l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole
An exemplary experimental procedure is described as follows: 100 grams of dimethyl sulfoxide, 10 grams (55.9 mol) of 4-chlorophenylhydrazine hydrochloride of formula (V) was added to a 250 ml three-neck flask in a N2 atmosphere and at room temperature. Over a period of 30 minutes, 3.02 grams (55.9 mol) of sodium methoxide was added to the solution. The mixture was then mixed for 10 minutes, until the 4- chlorophenylhydrazine hydrochloride was neutralized to produce 4- chlorophenylhydrazine. At this point the solution became darker in color and turned into a suspension.
l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II) was produced by adding 4.8 grams of methyl acrylate (55.9 mol) to the suspension and the suspension was then stirred for a few minutes. 3.02 grams (55.9 mol) of sodium methoxide was slowly added to the suspension at a rate of 0.1 mol every three minutes. This step was done in a N2 atmosphere at 25°C.
CuCl22H20 (2.5 mol % relative to compound (II)) was added to the l-(4- chlorophenyl)-pyrazolidin-3-one at 25-30°C. Air was moderately bubbled through the solution for 5 hours using deep-pipe. The oxidation reaction was maintained at 60°C. The flask was kept in an ice-bath in order to prevent exotherm. Once the conversion of l-(4-chlorophenyl)-pyrazolidin-3-one to l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) was complete, the oxygen bubbling was stopped.
Yield of l-(4-chlorophenyl)-3 -hydroxy- lH-pyrazole: 83%.
Preparation of l-(4-chlorophenyl)-3-r(2-nitrophenyl)methoxyl-lH-pyrazole
Using the same flask as used in the preparation of l-(4-chlorophenyl)-3- hydroxy-lH-pyrazole, a dropping funnel filled with 2-nitrobenzyl bromide of formula (IV) was connected. The ratio of 2-nitrobenzyl bromide to the l-(4-chlorophenyl)-3- hydroxy-lH-pyrazole present in the flask 1.7: 1. Sodium methoxide (1 mol equiv. versus compound (III) was added. While being kept at a temperature of 25°C, the solution of 2- nitrobenzyl bromide was dropped into the flask at a rate of 0.5 ml/minute. After all of the 2-nitrobenzyl bromide was added to the flask, the reaction was mixed for 1 hour, until all of the l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole was consumed. A small amount of NaOH 15% was then added to the solution and the solution was then stirred for 30 minutes at 25°C. A small amount of H20 was added to the mixture in order to precipitate the crude product.
The crude product was recrystallized using MCB. The product was dried in a vacuum oven at 25 mbar at 70°C.
Yield of l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH-pyrazole: 70% with a purity of 99.1%.
As demonstrated in the above example, a high yield of l-(4-chlorophenyl)-3-[(2- nitrophenyl)methoxy]-lH-pyrazole may be produced using the one-pot process described hereinabove. The results show higher efficiency of the reaction.
While the present subject matter has been shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that many alternatives, modifications and variations may be made thereto without departing from the spirit and scope thereof. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.
All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

WHAT IS CLAIMED IS:
1. A process for preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH- pyrazole of formula (I)
Figure imgf000021_0001
(I)
comprising: dehydrogenating l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II) H
Figure imgf000021_0002
(II)
to give l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or a salt thereof
Figure imgf000021_0003
(in)
in the presence of a polar aprotic solvent and subsequent reacting the resulting solution of formula (III) and/or salt thereof with the compound of formula (IV)
Figure imgf000021_0004
(IV) wherein X is one of bromide, chloride, iodide, tosylate, mesylate, triflate; wherein the reaction is carried out in the solvent used in the dehydrogenation step, and wherein the compound of formula (III) and/or salt thereof is not isolated prior to its reaction with the compound of formula (IV).
2. The process of claim 1, wherein the salt of l-(4-chlorophenyl)-3-hydroxy-lH- pyrazole of formula (III) is an organic salt or inorganic salt of l-(4-chlorophenyl)-3- hydroxy-lH-pyrazole of formula (III).
3. The process of claim 2, wherein the inorganic salt comprises at least one of sodium salt, potassium salt, calcium salt, and magnesium salt.
4. The process of any one of claims 1-3, wherein the dehydrogenation step is carried out with an oxidizing agent in the presence of a base.
5. The process of claim 4, wherein the oxidizing agent comprises at least one of molecular oxygen and air.
6. The process of any one of claims 1-5, wherein the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1: 1 to 100: 1.
7. The process of any one of claims 1-5, wherein the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1: 1 to 2: 1.
8. The process of any one of claims 1-7, wherein the polar aprotic solvent comprises at least one of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.
9. The process of any one of claims 1-8, wherein the compound of formula (II) is prepared by reacting 4-chlorophenylhydrazine hydrochloride of formula (V)
Figure imgf000022_0001
(V)
with a base in the presence of a solvent, and further reacting with an alkyl acrylate.
10. The process of claim 9, wherein the solvent used in the dehydrogenation step is the same solvent used in the preparation of the compound of formula (II), and wherein the compound of formula (II) is not isolated prior to the dehydrogenation step.
11. The process of claim 9 or 10, wherein the base used in the dehydrogenation step is the same base used in the preparation of the compound of formula (II).
12. A process for preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH- pyrazole of formula (I)
Figure imgf000023_0001
(I)
comprising: reacting l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or a salt thereof
Figure imgf000023_0002
(III) with the compound of formula (IV)
Figure imgf000023_0003
(IV) in the presence of a polar aprotic solvent; wherein X is one of bromide, chloride, iodide, tosylate, mesylate, triflate.
13. The process of claim 12, wherein the salt of l-(4-chlorophenyl)-3-hydroxy-lH- pyrazole of formula (III) is an organic salt or an inorganic salt of l-(4-chlorophenyl)-3- hydroxy-lH-pyrazole of formula (III).
14. The process of claim 13, wherein the inorganic salt comprises at least one of sodium salt, potassium salt, calcium salt, and magnesium salt.
15. The process of any one of claims 12-14, wherein the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1: 1 to 100: 1.
16. The process of any one of claims 12-14, wherein the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1: 1 to 2: 1.
17. The process of any one of claims 12-16, wherein the polar aprotic solvent comprises at least one of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.
18. The process of any one of claims 12-17, wherein the compound of formula (III) and/or salt thereof is prepared by dehydrogenating l-(4-chlorophenyl)-pyrazolidin-3- one of formula (II)
Figure imgf000024_0001
(II)
in the presence of a polar aprotic solvent.
19. The process of claim 18, wherein the solvent used in the dehydrogenation step is the same solvent used in the preparation of the compound of formula (I), and the compound of formula (III) and/or salt thereof is not isolated prior to its reaction with the compound of formula (IV).
20. The process of claim 18 or 19, wherein the dehydrogenation step is carried out with an oxidizing agent in the presence of a base.
21. The process of claim 20, wherein the oxidizing agent comprises at least one of molecular oxygen and air.
22. The process of any one of claims 18-21, wherein the compound of formula (II) is prepared by reacting 4-chlorophenylhydrazine hydrochloride of formula (V)
Figure imgf000025_0001
(V)
with a base in the presence of a solvent, and further reacting with an alkyl acrylate.
23. The process of claim 22, wherein the solvent used in the dehydrogenation step is the same solvent used in the preparation of the compound of formula (II), and wherein the compound of formula (II) is not isolated prior to the dehydrogenation step.
24. The process of claim 22 or 23, wherein the base used in the dehydrogenation step is the same base used in the preparation of the compound of formula (II).
25. A process for preparing l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) and/or a salt thereof
H
Figure imgf000025_0002
(III) comprising: dehydrogenating l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II)
H
Figure imgf000025_0003
(II)
in the presence of a polar aprotic solvent.
26. The process of claim 25, wherein the compound of formula (III) is in the form of an organic salt or an inorganic salt.
27. The process of claim 26, wherein the salt is an inorganic salt comprising at least one of sodium salt, potassium salt, calcium salt, and magnesium salt.
28. The process of any one of claims 25-27, wherein the dehydrogenation step is carried out with an oxidizing agent in the presence of a base.
29. The process of claim 28, wherein the oxidizing agent comprises at least one of molecular oxygen and air.
30. The process of any one of claims 25-29, wherein the polar aprotic solvent comprises at least one of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.
31. The process of any one of claims 25-30, further comprising the step of reacting the resulting solution of formula (III) and/or salt thereof with the compound of formula (IV)
Figure imgf000026_0001
(IV) to give a compound of formula (I)
Figure imgf000026_0002
wherein X is one of bromide, chloride, iodide, tosylate, mesylate, triflate; wherein the reaction is carried out in the solvent used in the dehydrogenation step and wherein the compound of formula (III) and/or salt thereof is not isolated prior to its reaction with the compound of formula (IV).
32. The process of any one of claims 25-31, wherein the compound of formula (II) is prepared by reacting 4-chlorophenylhydrazine hydrochloride of formula (V)
Figure imgf000027_0001
(V)
with a base in the presence of a solvent, and further reacting with an alkyl acrylate.
33. The process of claim 32, wherein the solvent used in the dehydrogenation step is the same solvent used in the preparation of the compound of formula (II), and wherein the compound of formula (II) is not isolated prior to the dehydrogenation step.
34. The process of claim 32 or 33, wherein the base used in the preparation of the compound of formula (II) is the same base used in the dehydrogenation step.
35. A process for preparing l-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-lH- pyrazole of formula (I)
Figure imgf000027_0002
(I)
comprising: reacting 4-chlorophenylhydrazine hydrochloride of formula (V)
Figure imgf000027_0003
(V)
with a base in the presence of a solvent, and further reacting with an alkyl acrylate; dehydrogenating the formed l-(4-chlorophenyl)-pyrazolidin-3-one of formula (II)
Figure imgf000028_0001
(Π)
to give l-(4-chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III) or a salt thereof
Figure imgf000028_0002
(Ill) in the presence of a polar aprotic solvent and subsequent reacting the resulting solution of formula (III) and/or salt thereof with the compound of formula (IV)
Figure imgf000028_0003
(IV) wherein X is one of bromide, chloride, iodide, tosylate, mesylate, triflate; wherein the reaction is carried out in the solvent used in the dehydrogenation step, and wherein the compound of formula (III) and/or salt thereof is not isolated prior to its reaction with the compound of formula (IV); and wherein the compound of formula (II) is not isolated prior to the dehydrogenation step.
36. The process of claim 35, wherein the base used in the dehydrogenation step is the same base used in the preparation of the compound of formula (II).
37. The process of claim 35 or 36, wherein the salt of l-(4-chlorophenyl)-3- hydroxy-lH-pyrazole of formula (III) is an organic or inorganic salt of l-(4- chlorophenyl)-3-hydroxy-lH-pyrazole of formula (III).
38. The process of claim 37, wherein the inorganic salt comprises at least one of sodium salt, potassium salt, calcium salt, and magnesium salt.
39. The process of any one of claims 35-38, wherein the dehydrogenation step is carried out with an oxidizing agent in the presence of a base.
40. The process of claim 39, wherein the oxidizing agent comprises at least one of molecular oxygen and air.
41. The process of any one of claims 35-40, wherein the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1: 1 to 100: 1.
42. The process of any one of claims 35-40, wherein the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1: 1 to 2: 1.
43. The process of any one of claims 35-42, wherein the polar aprotic solvent comprises at least one of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.
44. Use of the compound of formula (I) as prepared according to any of the above claims for producing pyraclostrobin.
45. A process for preparation of pyraclostrobin comprising a) preparing compound of formula (I) according to any of claims 1-43 b) producing reaction conditions for the preparation of pyraclostrobin.
PCT/IL2016/050047 2015-01-14 2016-01-14 Process for preparing 1-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-1h-pyrazole WO2016113741A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562103181P 2015-01-14 2015-01-14
US62/103,181 2015-01-14

Publications (1)

Publication Number Publication Date
WO2016113741A1 true WO2016113741A1 (en) 2016-07-21

Family

ID=55346154

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2016/050047 WO2016113741A1 (en) 2015-01-14 2016-01-14 Process for preparing 1-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-1h-pyrazole

Country Status (1)

Country Link
WO (1) WO2016113741A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106928145A (en) * 2017-04-17 2017-07-07 安徽广信农化股份有限公司 A kind of synthesis system of pyraclostrobin Intermediate nitro benzene
CN106946785A (en) * 2017-04-17 2017-07-14 安徽广信农化股份有限公司 A kind of synthesis technique of pyraclostrobin intermediate pyrazole alcohol
CN107778246A (en) * 2017-12-05 2018-03-09 利民化工股份有限公司 A kind of process for purification of bactericide pyraclostrobin intermediate pyrazole alcohol
WO2018091338A1 (en) * 2016-11-17 2018-05-24 Basf Se Process for the purification of 1-(4-chlorophenyl)pyrazol-3-ol
CN110105287A (en) * 2019-05-23 2019-08-09 江苏禾本生化有限公司 A kind of synthesis technology of pyraclostrobin
CN111018785A (en) * 2019-12-26 2020-04-17 武汉科技大学 Synthesis method and application of 1- (4-chlorphenyl) -3-pyrazole alcohol
CN111454208A (en) * 2020-05-29 2020-07-28 安徽国星生物化学有限公司 Production method of 2- [ (N-p-chlorophenyl) -3-pyrazolyloxymethyl ] nitrobenzene
CN113620879A (en) * 2021-06-16 2021-11-09 浙江禾本科技股份有限公司 Synthesis of 2[ (N-4-chlorphenyl) -1H-pyrazol-3-yloxymethyl ] nitrobenzene
CN115417818A (en) * 2022-09-02 2022-12-02 江苏七洲绿色科技研究院有限公司 Synthesis method of 1- (4-chlorphenyl) pyrazolidin-3-ketone

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001256A1 (en) 1994-07-06 1996-01-18 Basf Aktiengesellschaft Use of 2-[(dihydro)pyrazolyl-3'-oxymethylene]-anilides as pest-control agents and fungicides
US6133451A (en) 1997-07-30 2000-10-17 Basf Aktiengesellschaft Method for producing 2-(3-pyrazolyl-oxymethylene) nitrobenzenes
US6255489B1 (en) 1997-09-05 2001-07-03 Basf Aktiengesellschaft Method for producing (hetero)aromatic hydroxylamines
WO2013162072A1 (en) * 2012-04-27 2013-10-31 Sumitomo Chemical Company, Limited Tetrazolinone compounds and its use as pesticides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001256A1 (en) 1994-07-06 1996-01-18 Basf Aktiengesellschaft Use of 2-[(dihydro)pyrazolyl-3'-oxymethylene]-anilides as pest-control agents and fungicides
US6133451A (en) 1997-07-30 2000-10-17 Basf Aktiengesellschaft Method for producing 2-(3-pyrazolyl-oxymethylene) nitrobenzenes
US6255489B1 (en) 1997-09-05 2001-07-03 Basf Aktiengesellschaft Method for producing (hetero)aromatic hydroxylamines
WO2013162072A1 (en) * 2012-04-27 2013-10-31 Sumitomo Chemical Company, Limited Tetrazolinone compounds and its use as pesticides

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10538493B2 (en) 2016-11-17 2020-01-21 Basf Se Process for the purification of 1-(4-chlorophenyl)pyrazol-3-ol
CN109890794A (en) * 2016-11-17 2019-06-14 巴斯夫欧洲公司 The method for purifying 1- (4- chlorphenyl) pyrazoles -3- alcohol
CN109890794B (en) * 2016-11-17 2023-04-11 巴斯夫欧洲公司 Process for purifying 1- (4-chlorophenyl) pyrazol-3-ol
WO2018091338A1 (en) * 2016-11-17 2018-05-24 Basf Se Process for the purification of 1-(4-chlorophenyl)pyrazol-3-ol
CN106928145A (en) * 2017-04-17 2017-07-07 安徽广信农化股份有限公司 A kind of synthesis system of pyraclostrobin Intermediate nitro benzene
CN106946785A (en) * 2017-04-17 2017-07-14 安徽广信农化股份有限公司 A kind of synthesis technique of pyraclostrobin intermediate pyrazole alcohol
CN107778246A (en) * 2017-12-05 2018-03-09 利民化工股份有限公司 A kind of process for purification of bactericide pyraclostrobin intermediate pyrazole alcohol
CN110105287A (en) * 2019-05-23 2019-08-09 江苏禾本生化有限公司 A kind of synthesis technology of pyraclostrobin
CN110105287B (en) * 2019-05-23 2022-04-26 江苏禾本生化有限公司 Synthesis process of pyraclostrobin
CN111018785A (en) * 2019-12-26 2020-04-17 武汉科技大学 Synthesis method and application of 1- (4-chlorphenyl) -3-pyrazole alcohol
CN111454208A (en) * 2020-05-29 2020-07-28 安徽国星生物化学有限公司 Production method of 2- [ (N-p-chlorophenyl) -3-pyrazolyloxymethyl ] nitrobenzene
CN113620879A (en) * 2021-06-16 2021-11-09 浙江禾本科技股份有限公司 Synthesis of 2[ (N-4-chlorphenyl) -1H-pyrazol-3-yloxymethyl ] nitrobenzene
CN113620879B (en) * 2021-06-16 2023-05-05 浙江禾本科技股份有限公司 Synthesis of 2[ (N-4-chlorophenyl) -1H-pyrazol-3-yloxymethyl ] nitrobenzene
CN115417818A (en) * 2022-09-02 2022-12-02 江苏七洲绿色科技研究院有限公司 Synthesis method of 1- (4-chlorphenyl) pyrazolidin-3-ketone

Similar Documents

Publication Publication Date Title
WO2016113741A1 (en) Process for preparing 1-(4-chlorophenyl)-3-[(2-nitrophenyl)methoxy]-1h-pyrazole
IL175024A (en) 2-dihaloacyl-3-amino-acrylic acid esters, a process for their preparation, their use for producing 3-dihalomethyl-1h-pyrazole-4-carboxylic acid esters and 3-dichloromethylpyrazole-4-carboxylic acid esters
JP2018008985A (en) Process for preparation of (5-fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-1yl)-acetic acid esters
CN108947884A (en) A kind of Preparation Method And Their Intermediate of imrecoxib
CN110117256B (en) Synthesis method of bixafen
KR101583851B1 (en) Method for producing 3-methyl-2-thiophenecarboxylic acid
EP3303274B1 (en) Process for the synthesis of 9,9-bis(hydroxymethyl)fluorene
CN107987021A (en) A kind of preparation method of 3- difluoromethyls -1- methyl isophthalic acids H- pyrazoles -4- carboxylic acids
CN109734656B (en) Preparation method of nitrendipine
WO2014064712A2 (en) An improved process for the preparation of fulvestrant
CN112661668A (en) N-substituted amide compound and preparation method thereof
CN112679477B (en) Preparation method of celecoxib and intermediate thereof
KR20160027536A (en) Process for preparing an intermediate useful for the synthesis of silodosin
CN114349686B (en) 1, 4-dihydropyridine chiral hybrid hydrogenation reagent, preparation method and application thereof
CN104478799B (en) The preparation method of 1,4-diallyl isoquinolin
WO2016193212A1 (en) Process for the synthesis of 9,9-bis(methoxymethyl)fluorene
CN110734364A (en) Synthesis method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone
EP2835371B1 (en) Industrial method for manufacturing high-purity methiozoline
AU2012324824B2 (en) Processes for the preparation of 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and of its precursors
CN108503583B (en) Alkylation method of nitrogen-hydrogen-containing compound and application thereof
WO2007132990A1 (en) Process for the preparation of chiral glycidylphthalimide in highly optical purity
NZ586521A (en) Process for the preparation of 5-(2-ethyl-dihydro-1h-inden-2-yl)-1h-imidazole and salts thereof
JP2009527511A (en) Process for the preparation of 3,4-disubstituted phenylacetic acids and novel intermediates
RU2702121C1 (en) Method of producing 2-amino-nicotinic acid benzyl ester derivative
WO2023131947A1 (en) Process for the preparation of aryloxyphenoxypropionic acid derivatives in a non polar solvent with a tertiary amine catalyst

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16703860

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16703860

Country of ref document: EP

Kind code of ref document: A1