CA1120043A - Preparation of substantially pure pyrazole compounds - Google Patents
Preparation of substantially pure pyrazole compoundsInfo
- Publication number
- CA1120043A CA1120043A CA000339923A CA339923A CA1120043A CA 1120043 A CA1120043 A CA 1120043A CA 000339923 A CA000339923 A CA 000339923A CA 339923 A CA339923 A CA 339923A CA 1120043 A CA1120043 A CA 1120043A
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- carbon atoms
- parts
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- acid
- product
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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
- C07D231/12—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
O.Z. 0050/033518 Abstract of the Disclosure: Pure substituted N-methyl-pyrazole-acetanilides are prepared from the crude pro-ducts, resulting from their synthesis, by dissolving in a concentrated aqueous mineral acid and precipitating with water.
Description
~z~
The present inYention relates to a process for the preparation of substantially pure pyrazole compounds of the general formula ~C~2 where O
` R is hydrogen, halogen, alkyl of up to S carbon atoms, alkoxy of up to 3 carbon atoms, perhaloalkyl of up to 3 carbon atoms or alkoxyalkyl of up to S carbon atoms, Rl is hygrogen, halogen, alkyl of up to 5 carbon àtoms, alkoxy of up to 3 carbon atoms, perhaloalkyl of up to 3 carbon atoms or alkoxyalkyl of up to 5 carbon atoms, R is hydrogen, halogen, alkyl of up to 5 carbon atoms, alkoxy of up to 3 carbon atoms, perhaloalkyl of up to 3 carbon atoms or alkoxyalkyl of up to 5 carbon atoms, or R together with R is an ortho-linked alkylene chain of up to 6 carbon atoms which is unsubstituted or substituted by alkyl of up to 4 carbon atoms, X is chlorine or bromine, and R3 and R4 are identical or different and each is hydrogen, alkyl, alkoxy, alkylthio, carbalkoxy or perfluoroalkyl, in each case of up to 4 carbon atoms, or halogen, phenyl, cyano or carboxyl,from the corresponding crude products, such . .
as are .
.. . . . .. . _ _ _ _ .
x qr
The present inYention relates to a process for the preparation of substantially pure pyrazole compounds of the general formula ~C~2 where O
` R is hydrogen, halogen, alkyl of up to S carbon atoms, alkoxy of up to 3 carbon atoms, perhaloalkyl of up to 3 carbon atoms or alkoxyalkyl of up to S carbon atoms, Rl is hygrogen, halogen, alkyl of up to 5 carbon àtoms, alkoxy of up to 3 carbon atoms, perhaloalkyl of up to 3 carbon atoms or alkoxyalkyl of up to 5 carbon atoms, R is hydrogen, halogen, alkyl of up to 5 carbon atoms, alkoxy of up to 3 carbon atoms, perhaloalkyl of up to 3 carbon atoms or alkoxyalkyl of up to 5 carbon atoms, or R together with R is an ortho-linked alkylene chain of up to 6 carbon atoms which is unsubstituted or substituted by alkyl of up to 4 carbon atoms, X is chlorine or bromine, and R3 and R4 are identical or different and each is hydrogen, alkyl, alkoxy, alkylthio, carbalkoxy or perfluoroalkyl, in each case of up to 4 carbon atoms, or halogen, phenyl, cyano or carboxyl,from the corresponding crude products, such . .
as are .
.. . . . .. . _ _ _ _ .
x qr
- 2 - o.Z. 0050/03351~
obtained. for example, from the industrial manufacture of the pyrazole compounds or suGh as are present in impure production batches of the pyrazole com?ounds, if the pro-duction process has not followed its proper course. or such as are obtained from a simplified process for the preparation of the pyrazole compounds without purifica-tion of the intermediate products, by treating the crude products with an aqueous solution of a strong acid and isolating the pure products from the aqueous solution.
The preparation of the above pyrazole compounds is disclosed in German Laid-Open Applicat70ns DOS
2,648.008 and DOS 2.704.281. According to the pro-cesses described there, the products are obtained as a ; solution or suspension in an organic solvent. eg. chloro-form, toluene. petroleum ether. ethyl acetate or gasoline, and must then be separated from this solvent. for example by evaporation of the solvent. or by filtration.
These methods are very easy to operate in a laboratory and also give very pure products.
If attempts are made to scale up these laborato~y processes. for example to pilot-plant or production operation' unexpected di~ficulties arise, of which some are mentioned below:
If the product is in the form of an organic solu-tion, the solvent must be evaporated off, if necessary under reduced pressure. Hereupon, the product prefer-entially crystallizes on the walls of the evaporation vessel used, for example a kettle. and cakes firmly onto these walls. It is known that it is extremely diffi-, 2~ ~ ~ 3 _ 3 _~ o.z. oOS0/03351~
cult to remove a solid product, in particular a caked-on product, from a reaction kettle having the conventional small inlet and outlet nozzles. In fact, the appara-tus must, for this purpose, be dismantled by expert staff, entailing considerable time and substantial labor.
The expert personnel, namely fitters, required for the purpose are furthermore normally not trained in the handl-ing of chemicals and in the observance of chemical safety regulations and could suffer injury through inhalation lo of. or contact with, adhering residual solvent. or pro-duct dust.
If it proves possible to obtain the product as a suspension in an organic solvent, the latter must be removed by flltration. Depending on the toxicity and explosive character of the solvent, the filtration mus~
be carried out with more or less troublesome safety measures. which again entail considerable expenditure of time, and substantial costs. Furthermore, in many cases a substantial amount of dissolved product is lost with 20 the filtrate. ~ -It is possiblej for example. ~o precipitate the product, dissolved in an organic solvent, by adding a second solvent which is miscible with the first but in which the product is sparingly soluble. However, the amount of produc~ precipitated, and its purity. dépends on the amount of the precipitant solvent.
The products can also be isolated in the conven-tional manner by precipitating them in the form of their salts from their solution in an anhydrous solvent, in .
~......................... . . . ..
0~3 - 4 - O.Z. 0050/033518 which the salts are insoluble, by adding excess anhydrous acid. for example by introducing gaseous hydrogen chlor- -ide. However, even then the organic solvent contain-ing the acid must be removed from the salt by filtration with due attention to all safe-ty regulations, and addi--tional difficulties are that the excess acid can adhere to the product and pollute the environment and exert a corrosive action. and that it is also present in the filtrate and presents difficulties on reprocessing or o destroying the solvent. Frequently. the addition of concentrated anhydrous acids, eg. hydrogen chloride.
sul~uric acid and nitric acid, to organic solvents also produces undesirable or even dangerous side-reactions.
Using the conventional precipitation of the products by means of an acid. there is the further disadvantage that not only the desired product itself, but all by-producls capable of conversion to salts are precipitated.
A further factor to be borne in mind is that the products precipitated as salts must be reconverted to the corres-ponding free bases in an additional process step.This is absolutely essential since the salts hydrolyze in a moist environment, for example on exposure to the atmosphere. and in doing so liberate pungent and corrosive acid.
A ~urther obstacle to scaling up the conventional and inherently very satisfactory laboratory process to pilot-plant or production operation is that ~or operation on a larger scale the available reagents and solvents are frequently not as pure as in the laboratory, and that the ~.~2~()43 personnel is not as well trained ln chemical matters as is laboratory personnel. As a result, the products obtained are in most cases con~aminated with by-products. The removal of these by-products is almost always very involved and only rarely succeeds completely. For example, some of the known products can be recrystallized from cyclohexane. However, in doing so the commonest impuritles, namely compounds of the general formula ;. ~,~ /H
R2~ --C-CH2X
Rl o - where R, Rl, R2 and X have the above meanings, can only be removed incompletely from the pyrazole compounds, since these impuri~ies are also sparingly soluble in cold cyclohexane.
Furthermore, substantial amounts of the pyrazole compounds are lost during recrystallization. Of course, on isolating the recrystallized subs~ances from organic solvents on a large scale, the problems described above a~ain arise.
It is an object of the present invention to provide a process by means of which it is possible to isolate the pyrazole compound in a simple manner and in high purity even from very large pilot-plant and production batchesl and by means of which even contaminated batches of the pyrazole compound can easily be purified.
The pyrazole compounds are aminals, cince they contain 2 nitrogen atoms bonded to one methylene group.
It has long been known to those skilled in the art that .
- 6 - o.Z~ 0050/033518 an aminal can be cleaved with an aqueous solution of a strong acid to give a carbonyl compound and two nitrogen compounds (P.A.S. Smith, Open-Chain Nitrogen Compounds, W.A. Benjamin, Inc., New York. Amsterdam 1965. Vol. I.
page 322).
It has been found, surprisingly. that though the pyrazole compounds possess aminal structures they are stable to strong aqueous acids and can even be dissolved undecomposed, in the form of their salts, in concentrated lo aqueous acids. Since. however. the pyrazole compounds are only very weak bases. they remain undissolved in dilute aqueous acids.
Accordingly, we have found that the above object is achieved, according to the in~ention, by a process wherein the crude products are treated with concentrated aqueous solutions of strong acids~ thereafter the aqueous solution is separated off and diluted with water, and the pure product which hereupon precipitates is separated from the aqueous fluid. For example. the solution of 20 the crude product in an organic solvent which is immis- -cible or only slightly miscible with water is intimately mixed with a concentrated aqueous solution of a strong acid and the aqueous phase is separated off and then diluted with water, whereupon the product precipitates in a pure form and can easily be filtered off from the aqueous suspension. and be dried.
However it is also possible, for example, intim-ately to mix crystalline crude product or contaminated crude product in a solid finely divided form with a con-, _ . . . ... , _ _ _ _ 7 ~ ~ o.z. oO~o/033518centrated aqueous acid, filter the mixture, dilute the filtrate with water and filter off the pure product which hereupon precipitates. Drying the moist pure products presents no technical problems or safety problems.
If the crude product is in the form of a solution in an organic solvent in which some of the impurities are only sparingly soluble, for example a solution in a straight-chain or cyclic paraffin hydrocarbon, eg.
hexane, heptane, octane, cyclohexane, petroleum ether.
naphtha, gasoline and the like. it is advisable to filter the mixture ~Jith the aqueous acid before ef~ecting the phase separation. in order to be able to achieve a sharp phase separation. Suitable solvents for the crude product are, in addition to those already mentioned, all solvents which are immiscible or only very slightly miscible with aqueous acids~ for example aromatic hydro-carbons, eg. benzene, toluene, xylene~ chlorobenzene, dichlorobenzene, chlorotoluene and higher alkylben~enes;
aliphatic chlorohydrocarbons, eg. methylene chloride, chloroform. dichloroethane and carbon tetrachloride, and ethers, eg. diethyl ether. diisopropyl ether and the like. It is also possible to use esters. amides.
nitriles and similar compounds as solvents. provided these are sufficiently stable to aqueous acids or provided the process is carried out sufficiently rapidly to prevent substantial hydrolysis of the solvent. Basic solvents.
which form salts with the acids used, must not be used.
Suitable acids are essentially all strong inorganic acids, such as, for example, hydrochloric acid, hydrobromic ' ~.~L2~
- 8 - O.Z. oOsO/O33518 acid. perchloric acld, sulfuric acid. nitric acid and phosphoric acidO The concentrated acid solutions employed should contain from lO to 70% by weight, especi-ally from 20 to 65% by weigh-t. of water; for example, hydrochloric acid o~ from 32 to 38% strength or sulfuric acid of from 40 to 80% strength may be used. Highly concentrated acids. for example 96% strength sulfuric acid or nitric acid of more than 50% strength, are rather unsuitable because they have an oxidizing action.
The amount of acid used must be selected so that all basic substances which are dissolved in the organic solvent or are present in the solid residue are converted to their salts. This requires at least an amount of acid equivalent to the theoretically calculated amount of the pyrazole compound. However, it is advisable to use from lO to l.00~/~ excess of acid. The use of a 2-fold to 5-fold molar excess has proved particularly advantageous. If in spite of using such an excess a proportion of the desired product nevertheless remains in the organic solvent or in the solid residue. the crude product can of course also be treated a second time, or several more times t with concentrated aqueous acid.
Of course. the pyrazole compounds can also be extracted continuously with acid from their solution or from a solid residue in which they are ~resent.
The temperature does not play a maJor role in the extraction, apart from the fact that if it is too high decomposition and poor phase separation may occur or an excessive amount of non-polar by-products may pass into . _ . , . , . . . . , _ , . . ~ ' ~ .
_ g _ o.z~ 0050/03351&
the aqueous phase, whilst if the -temperature is too 1GW~
the product, the solvent and the water may pre~ent diffi-culties through crystallizing out. Temperatures of from 0 to 50C, especially ambient temperature, have proved advantageous. The amount of water used for dilution should be such that the desired product precipi-tates substantially quantitatively. The amount of water can be from 2 to 100 times the-amount of acid. but for practical reasons it has proved most advantageous to o dilute the acid extract from 5-fold to 10-fold. The temperature during dilution îs relatively unimportant, but it is to be borne in mind that some of the substances to be precipitated have a low melting point and may therefore precipitate as oils. possibly including impuri-ties, i~ the temperature is too high, and also that on increasing the temperature the chemical resistance of the pyrazole compounds to aqueous acid may decrease. For this reason. the dilution is in general carried out at from 0C to 50C, most simply at ambient temperature.
The dilution may be carried out by adding the water to the acid. but in general it has proved better to run the acid into the water, with thorough stirring. Hereupon, only the desired pure pyrazole compound precipitates.
whilst all other dissolved substances remain in solution.
The pure product can then be filtered off, for example on a large suction filter, and be washed with water; the odor of the product thus obtained is so neutral that it is even possible to employ manual labor to shovel the product out of the filter and, if desired, , .., ,. . - ~
- 10 - O.Z. 0050/03351 charge it into a dryer.
If, however, the product is to be redissolved in an organic solvent for further conversion, it can of course be extracted with the desired solvent directly after precipitation from the dilute aqueous acid solu-tion. provided the solvent is immiscible with water.
From a chemical point of view. the basis of the process according to the invention i.s that in the first purification stage the weakly basic pyrazole compounds, o which are surprisingly stable to acid. dissolve in the concentrated acid together with other polar compounds. or compounds capable of salt formation. present in the reac-tion mixture, whilst the non-polar substances either remain in the organic solvent or, iP the latter is not used, can be filtered off as a solid residue. A
further chemical basis of the process is that the strongly acidic dissolved pyrazole acid addition salts redissociate into acid and pyrazole compound in a second purification stage merely on diluting the acid solution, whilst all other polar and salt-like compounds remain dissolved in the dilute acid produced on addition of water. It is `~
this two-fold purification which results in the high degree of purity of the end products.
The process according to the invention is excep-tionally suitable for isolating the pyrazole compounds from their crude reaction solutions and can also be handled very easily on a pilot-plant or production scale.
The process according to the invention can be employed easily even for purifying large quantities of contaminated ~L2~ 3 ~ O.Z. 0050/033518 pyrazole compounds. Using the novel process, even batches which have miscarried, ie. in which the reaction whereby the pyrazole compounds are prepared has not taken place properly. can be treated so as to isolate satis-~actorily the valuable pyrazole compounds. which may frequently only be present in small amounts in such batches.
Furthermore, the process can also be used to purify pyrazole compounds which have been prepared by a o simplified process. Xt is known that pyrazole com-pounds may be prepared by reacting a compound of the general formula ~ _ /c~2-x R2 1 \C-C~12X
where R, Rl, R2 and X have the above meanings, with a pyrazole of the general formula ~ ~4 H~
where R3 and R4 have the above meanings. in the presence or absence of a compound which binds hydrogen halide and in the presence of an inert solvent. ~Te have found that the manipulation of substantial amounts of N-halo-acetyl-N-halomethylanilines is extremely unpleasant and not without hazards. The substances are in general solid and cannot be pumped or conveyed through closed pipelines. Their vapors have a strong irritant action .2~3 - 12 - O.Z. 0550/03351~
on mucous membranes and contact with their dust can cause skin rashes. As an expert can readily see merely from their chemical formula. the compounds can eliminate the toxic gases formaldehyde and hydrogen chloride on contact with water, moist air. mucous membranes or moist skin.
. For these reasons, substantial amounts of such compounds can only be processed if expensive safety measures are taken.
Several methods ~or the preparation of these com-pounds are known. A simple method (U.S. Patent
obtained. for example, from the industrial manufacture of the pyrazole compounds or suGh as are present in impure production batches of the pyrazole com?ounds, if the pro-duction process has not followed its proper course. or such as are obtained from a simplified process for the preparation of the pyrazole compounds without purifica-tion of the intermediate products, by treating the crude products with an aqueous solution of a strong acid and isolating the pure products from the aqueous solution.
The preparation of the above pyrazole compounds is disclosed in German Laid-Open Applicat70ns DOS
2,648.008 and DOS 2.704.281. According to the pro-cesses described there, the products are obtained as a ; solution or suspension in an organic solvent. eg. chloro-form, toluene. petroleum ether. ethyl acetate or gasoline, and must then be separated from this solvent. for example by evaporation of the solvent. or by filtration.
These methods are very easy to operate in a laboratory and also give very pure products.
If attempts are made to scale up these laborato~y processes. for example to pilot-plant or production operation' unexpected di~ficulties arise, of which some are mentioned below:
If the product is in the form of an organic solu-tion, the solvent must be evaporated off, if necessary under reduced pressure. Hereupon, the product prefer-entially crystallizes on the walls of the evaporation vessel used, for example a kettle. and cakes firmly onto these walls. It is known that it is extremely diffi-, 2~ ~ ~ 3 _ 3 _~ o.z. oOS0/03351~
cult to remove a solid product, in particular a caked-on product, from a reaction kettle having the conventional small inlet and outlet nozzles. In fact, the appara-tus must, for this purpose, be dismantled by expert staff, entailing considerable time and substantial labor.
The expert personnel, namely fitters, required for the purpose are furthermore normally not trained in the handl-ing of chemicals and in the observance of chemical safety regulations and could suffer injury through inhalation lo of. or contact with, adhering residual solvent. or pro-duct dust.
If it proves possible to obtain the product as a suspension in an organic solvent, the latter must be removed by flltration. Depending on the toxicity and explosive character of the solvent, the filtration mus~
be carried out with more or less troublesome safety measures. which again entail considerable expenditure of time, and substantial costs. Furthermore, in many cases a substantial amount of dissolved product is lost with 20 the filtrate. ~ -It is possiblej for example. ~o precipitate the product, dissolved in an organic solvent, by adding a second solvent which is miscible with the first but in which the product is sparingly soluble. However, the amount of produc~ precipitated, and its purity. dépends on the amount of the precipitant solvent.
The products can also be isolated in the conven-tional manner by precipitating them in the form of their salts from their solution in an anhydrous solvent, in .
~......................... . . . ..
0~3 - 4 - O.Z. 0050/033518 which the salts are insoluble, by adding excess anhydrous acid. for example by introducing gaseous hydrogen chlor- -ide. However, even then the organic solvent contain-ing the acid must be removed from the salt by filtration with due attention to all safe-ty regulations, and addi--tional difficulties are that the excess acid can adhere to the product and pollute the environment and exert a corrosive action. and that it is also present in the filtrate and presents difficulties on reprocessing or o destroying the solvent. Frequently. the addition of concentrated anhydrous acids, eg. hydrogen chloride.
sul~uric acid and nitric acid, to organic solvents also produces undesirable or even dangerous side-reactions.
Using the conventional precipitation of the products by means of an acid. there is the further disadvantage that not only the desired product itself, but all by-producls capable of conversion to salts are precipitated.
A further factor to be borne in mind is that the products precipitated as salts must be reconverted to the corres-ponding free bases in an additional process step.This is absolutely essential since the salts hydrolyze in a moist environment, for example on exposure to the atmosphere. and in doing so liberate pungent and corrosive acid.
A ~urther obstacle to scaling up the conventional and inherently very satisfactory laboratory process to pilot-plant or production operation is that ~or operation on a larger scale the available reagents and solvents are frequently not as pure as in the laboratory, and that the ~.~2~()43 personnel is not as well trained ln chemical matters as is laboratory personnel. As a result, the products obtained are in most cases con~aminated with by-products. The removal of these by-products is almost always very involved and only rarely succeeds completely. For example, some of the known products can be recrystallized from cyclohexane. However, in doing so the commonest impuritles, namely compounds of the general formula ;. ~,~ /H
R2~ --C-CH2X
Rl o - where R, Rl, R2 and X have the above meanings, can only be removed incompletely from the pyrazole compounds, since these impuri~ies are also sparingly soluble in cold cyclohexane.
Furthermore, substantial amounts of the pyrazole compounds are lost during recrystallization. Of course, on isolating the recrystallized subs~ances from organic solvents on a large scale, the problems described above a~ain arise.
It is an object of the present invention to provide a process by means of which it is possible to isolate the pyrazole compound in a simple manner and in high purity even from very large pilot-plant and production batchesl and by means of which even contaminated batches of the pyrazole compound can easily be purified.
The pyrazole compounds are aminals, cince they contain 2 nitrogen atoms bonded to one methylene group.
It has long been known to those skilled in the art that .
- 6 - o.Z~ 0050/033518 an aminal can be cleaved with an aqueous solution of a strong acid to give a carbonyl compound and two nitrogen compounds (P.A.S. Smith, Open-Chain Nitrogen Compounds, W.A. Benjamin, Inc., New York. Amsterdam 1965. Vol. I.
page 322).
It has been found, surprisingly. that though the pyrazole compounds possess aminal structures they are stable to strong aqueous acids and can even be dissolved undecomposed, in the form of their salts, in concentrated lo aqueous acids. Since. however. the pyrazole compounds are only very weak bases. they remain undissolved in dilute aqueous acids.
Accordingly, we have found that the above object is achieved, according to the in~ention, by a process wherein the crude products are treated with concentrated aqueous solutions of strong acids~ thereafter the aqueous solution is separated off and diluted with water, and the pure product which hereupon precipitates is separated from the aqueous fluid. For example. the solution of 20 the crude product in an organic solvent which is immis- -cible or only slightly miscible with water is intimately mixed with a concentrated aqueous solution of a strong acid and the aqueous phase is separated off and then diluted with water, whereupon the product precipitates in a pure form and can easily be filtered off from the aqueous suspension. and be dried.
However it is also possible, for example, intim-ately to mix crystalline crude product or contaminated crude product in a solid finely divided form with a con-, _ . . . ... , _ _ _ _ 7 ~ ~ o.z. oO~o/033518centrated aqueous acid, filter the mixture, dilute the filtrate with water and filter off the pure product which hereupon precipitates. Drying the moist pure products presents no technical problems or safety problems.
If the crude product is in the form of a solution in an organic solvent in which some of the impurities are only sparingly soluble, for example a solution in a straight-chain or cyclic paraffin hydrocarbon, eg.
hexane, heptane, octane, cyclohexane, petroleum ether.
naphtha, gasoline and the like. it is advisable to filter the mixture ~Jith the aqueous acid before ef~ecting the phase separation. in order to be able to achieve a sharp phase separation. Suitable solvents for the crude product are, in addition to those already mentioned, all solvents which are immiscible or only very slightly miscible with aqueous acids~ for example aromatic hydro-carbons, eg. benzene, toluene, xylene~ chlorobenzene, dichlorobenzene, chlorotoluene and higher alkylben~enes;
aliphatic chlorohydrocarbons, eg. methylene chloride, chloroform. dichloroethane and carbon tetrachloride, and ethers, eg. diethyl ether. diisopropyl ether and the like. It is also possible to use esters. amides.
nitriles and similar compounds as solvents. provided these are sufficiently stable to aqueous acids or provided the process is carried out sufficiently rapidly to prevent substantial hydrolysis of the solvent. Basic solvents.
which form salts with the acids used, must not be used.
Suitable acids are essentially all strong inorganic acids, such as, for example, hydrochloric acid, hydrobromic ' ~.~L2~
- 8 - O.Z. oOsO/O33518 acid. perchloric acld, sulfuric acid. nitric acid and phosphoric acidO The concentrated acid solutions employed should contain from lO to 70% by weight, especi-ally from 20 to 65% by weigh-t. of water; for example, hydrochloric acid o~ from 32 to 38% strength or sulfuric acid of from 40 to 80% strength may be used. Highly concentrated acids. for example 96% strength sulfuric acid or nitric acid of more than 50% strength, are rather unsuitable because they have an oxidizing action.
The amount of acid used must be selected so that all basic substances which are dissolved in the organic solvent or are present in the solid residue are converted to their salts. This requires at least an amount of acid equivalent to the theoretically calculated amount of the pyrazole compound. However, it is advisable to use from lO to l.00~/~ excess of acid. The use of a 2-fold to 5-fold molar excess has proved particularly advantageous. If in spite of using such an excess a proportion of the desired product nevertheless remains in the organic solvent or in the solid residue. the crude product can of course also be treated a second time, or several more times t with concentrated aqueous acid.
Of course. the pyrazole compounds can also be extracted continuously with acid from their solution or from a solid residue in which they are ~resent.
The temperature does not play a maJor role in the extraction, apart from the fact that if it is too high decomposition and poor phase separation may occur or an excessive amount of non-polar by-products may pass into . _ . , . , . . . . , _ , . . ~ ' ~ .
_ g _ o.z~ 0050/03351&
the aqueous phase, whilst if the -temperature is too 1GW~
the product, the solvent and the water may pre~ent diffi-culties through crystallizing out. Temperatures of from 0 to 50C, especially ambient temperature, have proved advantageous. The amount of water used for dilution should be such that the desired product precipi-tates substantially quantitatively. The amount of water can be from 2 to 100 times the-amount of acid. but for practical reasons it has proved most advantageous to o dilute the acid extract from 5-fold to 10-fold. The temperature during dilution îs relatively unimportant, but it is to be borne in mind that some of the substances to be precipitated have a low melting point and may therefore precipitate as oils. possibly including impuri-ties, i~ the temperature is too high, and also that on increasing the temperature the chemical resistance of the pyrazole compounds to aqueous acid may decrease. For this reason. the dilution is in general carried out at from 0C to 50C, most simply at ambient temperature.
The dilution may be carried out by adding the water to the acid. but in general it has proved better to run the acid into the water, with thorough stirring. Hereupon, only the desired pure pyrazole compound precipitates.
whilst all other dissolved substances remain in solution.
The pure product can then be filtered off, for example on a large suction filter, and be washed with water; the odor of the product thus obtained is so neutral that it is even possible to employ manual labor to shovel the product out of the filter and, if desired, , .., ,. . - ~
- 10 - O.Z. 0050/03351 charge it into a dryer.
If, however, the product is to be redissolved in an organic solvent for further conversion, it can of course be extracted with the desired solvent directly after precipitation from the dilute aqueous acid solu-tion. provided the solvent is immiscible with water.
From a chemical point of view. the basis of the process according to the invention i.s that in the first purification stage the weakly basic pyrazole compounds, o which are surprisingly stable to acid. dissolve in the concentrated acid together with other polar compounds. or compounds capable of salt formation. present in the reac-tion mixture, whilst the non-polar substances either remain in the organic solvent or, iP the latter is not used, can be filtered off as a solid residue. A
further chemical basis of the process is that the strongly acidic dissolved pyrazole acid addition salts redissociate into acid and pyrazole compound in a second purification stage merely on diluting the acid solution, whilst all other polar and salt-like compounds remain dissolved in the dilute acid produced on addition of water. It is `~
this two-fold purification which results in the high degree of purity of the end products.
The process according to the invention is excep-tionally suitable for isolating the pyrazole compounds from their crude reaction solutions and can also be handled very easily on a pilot-plant or production scale.
The process according to the invention can be employed easily even for purifying large quantities of contaminated ~L2~ 3 ~ O.Z. 0050/033518 pyrazole compounds. Using the novel process, even batches which have miscarried, ie. in which the reaction whereby the pyrazole compounds are prepared has not taken place properly. can be treated so as to isolate satis-~actorily the valuable pyrazole compounds. which may frequently only be present in small amounts in such batches.
Furthermore, the process can also be used to purify pyrazole compounds which have been prepared by a o simplified process. Xt is known that pyrazole com-pounds may be prepared by reacting a compound of the general formula ~ _ /c~2-x R2 1 \C-C~12X
where R, Rl, R2 and X have the above meanings, with a pyrazole of the general formula ~ ~4 H~
where R3 and R4 have the above meanings. in the presence or absence of a compound which binds hydrogen halide and in the presence of an inert solvent. ~Te have found that the manipulation of substantial amounts of N-halo-acetyl-N-halomethylanilines is extremely unpleasant and not without hazards. The substances are in general solid and cannot be pumped or conveyed through closed pipelines. Their vapors have a strong irritant action .2~3 - 12 - O.Z. 0550/03351~
on mucous membranes and contact with their dust can cause skin rashes. As an expert can readily see merely from their chemical formula. the compounds can eliminate the toxic gases formaldehyde and hydrogen chloride on contact with water, moist air. mucous membranes or moist skin.
. For these reasons, substantial amounts of such compounds can only be processed if expensive safety measures are taken.
Several methods ~or the preparation of these com-pounds are known. A simple method (U.S. Patent
3,637,847) is to react an azomethine of the general formula Fl ~
where R, Rl and R2 have the above meanings. with a halo-acetyl halide of the general formula X-C~2-C x where X has the above meanings. The azomethines are synthesized by conventional methods from formaldehyde and anilines o~ the general formula R2~NH2 Rl .
where R, Rl and R2 have the above meanings, and are pur'-fied by distillation before being used. However, .. .. . .. .
, . . , .~ . .
~20~4~3 - 13 o.z. 0050/033518 German Published Application DAS 1.793,811 discloses that certain azomethines, which are of particular interest as intermediates for the preparation of pyrazole compounds, for example the azomethine where R and Rl are each methyl in the ortho-position to the nitrogen and R2 is hydrogen, are not stable and cannot be used for the synthesis of other compounds.
We have found, surprisingly. that a pyrazole com-pound may be obtained in high purity and good yield by reacting an aniline o~ the general formula R
Rl where R, Rl and R2 have the meanings given in Claim 1.
with paraformaldehyde in an inert organic solvent, dis-tilling off water and excess formaldehyde from the reac-tion mixture, reacting the reaction mixture with a halo-acetyl halide and then reacting it further with a pyra-zole of the gener~al formula ~/ N
where R3 and R4 have the meanings given in Claim 1, and ~ a compound which binds the hydrogen halide, and that this : process can be carried out without having to isolate and purify the intermediates described abovel if the pyrazole compound is isolated from its crude solution by the pro-.~ . . . .
- 14 - O.Z. 0050/033518 cess according to the invention. Even pyrazole com- -pounds which are based on azomethines which according to general ex,oerience and according to German Published Application DAS 1,793,811 are unstable can be prepared easily if the azomethines in question are not subjected to purification, distillation or other m~thods of iso-lation. but are converted further in the form of their crude solution.
In the said process, an aniline is reacted in the conventional manner with paraformaldehyde to give an azo-methine, water and formaldehyde are distilled off, the crude solution of the azomethine is mixed, in the s~me vessel or a different vessel. with a haloacetyl halide.
a pyrazole and a binder for the hydrogen halide are added to the mixture, the batch is treated according to the invention with a concentrated aqueous acid and the acid is separated off and diluted with water, whereupon the end product precipitates in a pure form and in good yield.
Of course, the reaction mixture can be washed with water before being treated with acid. In a particular embodiment of the process. an aqueous base is used as the binder for hydrogen halide. in the presence or absence of a phase transfer catalyst. in which case the reaction mixture is of course only treated with the concentrated acid after having separated off the aqueous phase.
The advantages of this process are that even unstable azomethines can be used and in particular that the intermediate referred to above, whîch presents prob-lems, need not be isolated. Since the entire reaction _ . _ , . " . , - ~
- 15 - o.Z. 0050/03351~
sequence can be carried out in one or two closed appara-tuses, without requiring intermediate isolation or work-ing-up operations. the operatives do not come into contact with the dangerous intermediates~ As is known to those skilled in the art, i~ in a multi-stage reaction the pro-ducts of the individual reaction steps are not isolated and purified, the impurities ultimately accumulate to an extent that isolation and purification of the end product become difficult. This, however, is not so in the lo present case, since the crude product can easily be puri-fied by the process according to the invention.
The process according to the invention for the purification of pyrazole compounds is of course also suit-able for the purification of crude solutions which have been obtained by other methods, for example as described in German Laid-Open Application DOS 2,704,281, and, in these cases also, very greatly reduces the labor involved.
The Examples which follow demonstrate the sim-plicity and reliability of the process according to the invention.
5,100 parts (by weight) of N-chloromethyl-2.6-dimethylchloroacetanilide and ll,OOO parts of toluene are mixed with 1,900 parts of 4-methylpyrazole and-the mix-ture is then stirred for 3 hours at 40-60C. 2,130 parts o~ triethylamine are added and the reaction mixture is stirred for 3 hours at 60C and overnight at room tem-perature (20C). It is then washed twice with lO,OOO
parts of water and is extracted once with 12,000 parts of . . _ . . . _ . .
i 16 -~, o.Z. 0050/03351 ~7% strength (by weight) hydrochloric acid. The extract is run into 60.000 parts o~ water, whilst stir-ring. and the precipitate is filtered off. After dry-ing, 4.750 parts of 95% pure N-(L~-methylpyrazol-l-yl-methyl)-2.6-dimethylchloroace-tanilide of melting point 98-100C are obtained.
540 parts of 4-me-thoxypyrazole are added to lg300 parts of N-chloromethyl-2-ethyl-6-methylchloroacet-, anilide and 3,000 parts of toluene. The mixture is kept at 60C for 4 hours, 500 parts of triethylamine are added, and the batch is stirred at 60C for 4 hours and overnight at room temperature. It is then diluted, with stirrinO,with 2,000 parts of water and the crys-tals which thereupon pre-cipitate are filtered off, washed with water and dried to give 750 parts o~ pure N-(4-methoxypyrazol-l-yl-methyl)-6-ethyl-2-methylchloroacetanilide of melting point 96-97C.
The organic phase of the filtrate is separated off and extracted once with 950 parts of 37 % strength hydro-chloric acid. m e crystals which precipitate on adding the extract dropwise to 6,000 parts of water are filteredoff and dried to give a further 660 parts of N-(4-methoxy-pyrazol-l-yl-methyl)-2-ethyl-6-methylchloroacetanil-'de, which is 98 ~o pure and has a melting point of 92-93C.
a) 14 parts of 94 % pure N-(pyrazol-l-yl-methyl)-2,6-dimethylchloroacetanilide of melting point 72-75C, the purity of which was determined by proton resonance spectroscopy9 are dissolved in 140 parts of toluene and - 17 - o.z. 0050/0335~8 the solution is extracted once by shaking with 40 parts o~
60 % strength sulfuric acid. m e sulfuric acid extract is run into 240 parts of water with thorough stirring and the crystals ~hich have precipitated are filtered off, washed with water and dried. 11 parts of 100 % pure N-(pyrazol-l-yl-methyl)-2,6-dimethylchloroacetanilide, of melting point 83C, are obtained.
b) 14 parts of 94 % pure N-(pyrazol-l-yl-methyl)-2,6~dimethylchloroacetanilide are dissolved in 140 parts of toluene and the solution is extracted with twice 40 parts of 50 % strength sulfuric acid. m e combined sulfuric acid extracts are hydrolyzed with water. The precipitate ~ormed is filtered off, washed with water and dried, giving 13 parts of a 100 % pure product, of melt-ing point 83C.
EXAMPL$ 4 a) 100 parts of a blackish brown smeary material which had resulted from a synthesis of N-(pyrazol-l-yl-methyl)-296-dimethylchloroacetanilide which did not proceed properly are stirred thoroughly with 180 parts of 37 % strength hydrochloric acid for half an hour.
After filtering, the filtrate is extracted with 50 parts of toluene and the hydrochloric acid solution is added dropwise to 1,000 parts by weight of water. After filtration and drying, 60 parts of 93 %
pure N-(pyrazol-l-yl-methyl)-2,6-dimethylchloroacetanilide of melting point 77C are obtained.
b) 100 parts of the smeary material referred to under a) are thoroughly stirred with 150 parts of toluene _ . . .
- 18 - O.Z0 0050/0335~
and the mixtureis ~iltered. The filtrate is extracted once by shaking with 180 parts of 37 % strength hydrochlo-ric acid. m e hydrochloric acid phase is added drop-wise to 900 parts of water and the product is filtered o~f and dried. 54 parts of 97 % pure N-(pyrazol-l-yl-methyl)-2,6-dimethylchloroacetanilide of melting point 78C are obtained.
c) 100 parts of the smeary product referred to under a) are dissolved in 180 parts of methylene chloride and o this solution is extracted first with 180 parts and then with 60 parts of 37 % strength hydrochloric acid. m e combined hydrochloric acid extracts are washed once with 50 parts of toluene to remove methylene chloride. m ey are then hydrolyzed as described under a) and b), and 56.5 parts of more than 99 % pure N-(pyrazol-l-yl-methyl)-2,6-dimethylchloroacetanilide, of melting point 83C, are obtained.
A crude solution of 133 parts of N-(2,6-dimethyl-phenyl)-methyleneimine in a toluene-cyclohexane mixture is added dropwise to a solution of 202 parts of bromo-acetyl bromide in 150 parts of naphtha. Since, instead of the desired crystalline N-bromomethyl-2,6-dimethyl-bromoacetanilide, only an oil which is difficult to isol-ate precipitates, 450 parts o~ toluene and 75 parts of pyrazole are added, the mixture is heated at 60C ~or 2 hoursand 110 parts of triethylamine are added dropwise, after which the mixture is hea~ed at 60C, washed with water, then with 5 % strength hydrochloric acid and then . .
, . . ~
:
~Q~
- 19 - o.Z. 0050/033518 again with water, and evaporated, 248 parts of a viscous oil being obtained. The latter is dissolved in 500 parts of toluene and the solution is extracted with 250 parts of 37 % strength hydrochloric acid. The extract is hydrolyzed by means of 1,500 parts of water, giving 190 parts of N-(pyrazol-1-yl-methyl)-2,6-dimethyl-bromoacetanilide of melting point 86C.
1,620 parts of water are removed from a mixture of 10,890 parts of 2,6-dimethylaniline and 4,050 parts of paraformaldehyde by refluxing with 50,000 parts of a toluene-cyclohexane mixture in the conventional manner.
After having been rapidly cooled to room temperature, the resulting solution of N-(2,6-dimethylphenyl)-methylene-imine, still containing impurities, ls reacted in the conventional manner with 10,800 parts of chloroacetyl chloride in 10,000 parts of toluene. 6,800 parts of pyrazole are then added, the mixture is stirred for 5 hours at 50C, after which 10,000 parts of triethyl-amine are added and the reaction mixture is stirred for 5 hours at 50C and overnight at room temperature. It is then washed with 30,000 parts of 5 % strength hydro-chloric acid and the organic phase is separated off and extracted with 30,000 parts of 37 % strength hydrochloric acid. The extract is stirred into 180~000 parts of ; water. The precipitate formed is filtered off, washed with water and dried 17,840 parts of-96 % pure N-(pyrazol-l-yl-methyl)-2,6~dimethylchloroacetanilide~ of melting point 78C, .,~ . ~
~ "
- - , ~2~3 - 20 - O.Z. 0050/03351 are obtained.
121 parts o~ a heavily contaminated batch of N-(pyrazol-l-yl-methyl)-2-ethyl-6-methylbromoacetanilide are dissolved in 300 parts of toluene, the solution is extracted with 200 parts of 37 % streng-th hydrochloric acid and the extract is hydrolyzed with water. 67 parts of the pure product, of melting point 71-73C, are obtained.
EX~PLE 8 900 parts of water are removed from 6,050 parts of 2,6-dimethylaniline and 2,400 parts of paraformaldehyde with the aid of a toluene-cyclohexane mixture, as descri~ed in Example 6, m e resulting solution is added to 6,000 parts o~ chloroacetyl chloride in 6,000 parts of toluene, after completion of the reaction 3,800 parts-of pyrazole are added, the mixture is kept at 50C for 4 hours, 5,500 parts of triethylamine are added and the batch is then heated ~or 6 hours at 50C. It is then washed with dilute (5 % strength) hydrochloric acid and ~iltered to remove a small amount of residue.
The toluene phase of the filtrate is extracted with twice 13,000 parts of 60 % strength sulfuric acid. The extract is stirred into 300,000 parts of water. The -precipitate formed is filtered off and dried, giving 8,800 parts of 98 % pure N-(pyrazol-l-yl-methyl)-2,6-dimethylchloroacetanilide, of melting point 81-83C.
18 parts of water are removed from 121 parts of .
~2~4~
- 21 - O.Z. 0050/033518 2,6-dimethylaniline and 45 parts of paraformaldehyde in 250 parts of a toluene-cyclohexane mixture, as described in Example 6. After having been rapidly cooled to room temperature, the resulting solution of N-(2,6-dimethyl-phenyl)-methyleneimine is reacted in the conventional manner with 113 parts of chloroacetyl chloride in 100 parts of toluene and the batch is then stirred for a further ~ hour at 80C. A mixture of 44 parts of NaOH, 75 parts of pyrazole and 6.8 parts of a mixture of 35 % by weight of dimethyldibenzylammonium chloride, 15 % of trimethylbenzylammonium chloride, 40 ~0 of water and 10 % of methanol in 200 par-ts of water is then added dropwise, after which the batch is stirred for 4 hours at room temperature. After having separated the organic phase from the water, the former is washed twice with 200parts of water and then extrac-ted once with 350 par-ts and thereafter with 175 parts of 55 % strength sul~uric acid. The combined sulfuric acid extracts are stirred into 3,000 parts of water and the precipitate formed is filtered off, washed with water and dried under reduced pressure at 50C.
210 parts of 98 % pure N-(p~razol-l-yl-methyl)-2,6-dimethylchloroacetanilide, of melting point 82C, are obtained.
where R, Rl and R2 have the above meanings. with a halo-acetyl halide of the general formula X-C~2-C x where X has the above meanings. The azomethines are synthesized by conventional methods from formaldehyde and anilines o~ the general formula R2~NH2 Rl .
where R, Rl and R2 have the above meanings, and are pur'-fied by distillation before being used. However, .. .. . .. .
, . . , .~ . .
~20~4~3 - 13 o.z. 0050/033518 German Published Application DAS 1.793,811 discloses that certain azomethines, which are of particular interest as intermediates for the preparation of pyrazole compounds, for example the azomethine where R and Rl are each methyl in the ortho-position to the nitrogen and R2 is hydrogen, are not stable and cannot be used for the synthesis of other compounds.
We have found, surprisingly. that a pyrazole com-pound may be obtained in high purity and good yield by reacting an aniline o~ the general formula R
Rl where R, Rl and R2 have the meanings given in Claim 1.
with paraformaldehyde in an inert organic solvent, dis-tilling off water and excess formaldehyde from the reac-tion mixture, reacting the reaction mixture with a halo-acetyl halide and then reacting it further with a pyra-zole of the gener~al formula ~/ N
where R3 and R4 have the meanings given in Claim 1, and ~ a compound which binds the hydrogen halide, and that this : process can be carried out without having to isolate and purify the intermediates described abovel if the pyrazole compound is isolated from its crude solution by the pro-.~ . . . .
- 14 - O.Z. 0050/033518 cess according to the invention. Even pyrazole com- -pounds which are based on azomethines which according to general ex,oerience and according to German Published Application DAS 1,793,811 are unstable can be prepared easily if the azomethines in question are not subjected to purification, distillation or other m~thods of iso-lation. but are converted further in the form of their crude solution.
In the said process, an aniline is reacted in the conventional manner with paraformaldehyde to give an azo-methine, water and formaldehyde are distilled off, the crude solution of the azomethine is mixed, in the s~me vessel or a different vessel. with a haloacetyl halide.
a pyrazole and a binder for the hydrogen halide are added to the mixture, the batch is treated according to the invention with a concentrated aqueous acid and the acid is separated off and diluted with water, whereupon the end product precipitates in a pure form and in good yield.
Of course, the reaction mixture can be washed with water before being treated with acid. In a particular embodiment of the process. an aqueous base is used as the binder for hydrogen halide. in the presence or absence of a phase transfer catalyst. in which case the reaction mixture is of course only treated with the concentrated acid after having separated off the aqueous phase.
The advantages of this process are that even unstable azomethines can be used and in particular that the intermediate referred to above, whîch presents prob-lems, need not be isolated. Since the entire reaction _ . _ , . " . , - ~
- 15 - o.Z. 0050/03351~
sequence can be carried out in one or two closed appara-tuses, without requiring intermediate isolation or work-ing-up operations. the operatives do not come into contact with the dangerous intermediates~ As is known to those skilled in the art, i~ in a multi-stage reaction the pro-ducts of the individual reaction steps are not isolated and purified, the impurities ultimately accumulate to an extent that isolation and purification of the end product become difficult. This, however, is not so in the lo present case, since the crude product can easily be puri-fied by the process according to the invention.
The process according to the invention for the purification of pyrazole compounds is of course also suit-able for the purification of crude solutions which have been obtained by other methods, for example as described in German Laid-Open Application DOS 2,704,281, and, in these cases also, very greatly reduces the labor involved.
The Examples which follow demonstrate the sim-plicity and reliability of the process according to the invention.
5,100 parts (by weight) of N-chloromethyl-2.6-dimethylchloroacetanilide and ll,OOO parts of toluene are mixed with 1,900 parts of 4-methylpyrazole and-the mix-ture is then stirred for 3 hours at 40-60C. 2,130 parts o~ triethylamine are added and the reaction mixture is stirred for 3 hours at 60C and overnight at room tem-perature (20C). It is then washed twice with lO,OOO
parts of water and is extracted once with 12,000 parts of . . _ . . . _ . .
i 16 -~, o.Z. 0050/03351 ~7% strength (by weight) hydrochloric acid. The extract is run into 60.000 parts o~ water, whilst stir-ring. and the precipitate is filtered off. After dry-ing, 4.750 parts of 95% pure N-(L~-methylpyrazol-l-yl-methyl)-2.6-dimethylchloroace-tanilide of melting point 98-100C are obtained.
540 parts of 4-me-thoxypyrazole are added to lg300 parts of N-chloromethyl-2-ethyl-6-methylchloroacet-, anilide and 3,000 parts of toluene. The mixture is kept at 60C for 4 hours, 500 parts of triethylamine are added, and the batch is stirred at 60C for 4 hours and overnight at room temperature. It is then diluted, with stirrinO,with 2,000 parts of water and the crys-tals which thereupon pre-cipitate are filtered off, washed with water and dried to give 750 parts o~ pure N-(4-methoxypyrazol-l-yl-methyl)-6-ethyl-2-methylchloroacetanilide of melting point 96-97C.
The organic phase of the filtrate is separated off and extracted once with 950 parts of 37 % strength hydro-chloric acid. m e crystals which precipitate on adding the extract dropwise to 6,000 parts of water are filteredoff and dried to give a further 660 parts of N-(4-methoxy-pyrazol-l-yl-methyl)-2-ethyl-6-methylchloroacetanil-'de, which is 98 ~o pure and has a melting point of 92-93C.
a) 14 parts of 94 % pure N-(pyrazol-l-yl-methyl)-2,6-dimethylchloroacetanilide of melting point 72-75C, the purity of which was determined by proton resonance spectroscopy9 are dissolved in 140 parts of toluene and - 17 - o.z. 0050/0335~8 the solution is extracted once by shaking with 40 parts o~
60 % strength sulfuric acid. m e sulfuric acid extract is run into 240 parts of water with thorough stirring and the crystals ~hich have precipitated are filtered off, washed with water and dried. 11 parts of 100 % pure N-(pyrazol-l-yl-methyl)-2,6-dimethylchloroacetanilide, of melting point 83C, are obtained.
b) 14 parts of 94 % pure N-(pyrazol-l-yl-methyl)-2,6~dimethylchloroacetanilide are dissolved in 140 parts of toluene and the solution is extracted with twice 40 parts of 50 % strength sulfuric acid. m e combined sulfuric acid extracts are hydrolyzed with water. The precipitate ~ormed is filtered off, washed with water and dried, giving 13 parts of a 100 % pure product, of melt-ing point 83C.
EXAMPL$ 4 a) 100 parts of a blackish brown smeary material which had resulted from a synthesis of N-(pyrazol-l-yl-methyl)-296-dimethylchloroacetanilide which did not proceed properly are stirred thoroughly with 180 parts of 37 % strength hydrochloric acid for half an hour.
After filtering, the filtrate is extracted with 50 parts of toluene and the hydrochloric acid solution is added dropwise to 1,000 parts by weight of water. After filtration and drying, 60 parts of 93 %
pure N-(pyrazol-l-yl-methyl)-2,6-dimethylchloroacetanilide of melting point 77C are obtained.
b) 100 parts of the smeary material referred to under a) are thoroughly stirred with 150 parts of toluene _ . . .
- 18 - O.Z0 0050/0335~
and the mixtureis ~iltered. The filtrate is extracted once by shaking with 180 parts of 37 % strength hydrochlo-ric acid. m e hydrochloric acid phase is added drop-wise to 900 parts of water and the product is filtered o~f and dried. 54 parts of 97 % pure N-(pyrazol-l-yl-methyl)-2,6-dimethylchloroacetanilide of melting point 78C are obtained.
c) 100 parts of the smeary product referred to under a) are dissolved in 180 parts of methylene chloride and o this solution is extracted first with 180 parts and then with 60 parts of 37 % strength hydrochloric acid. m e combined hydrochloric acid extracts are washed once with 50 parts of toluene to remove methylene chloride. m ey are then hydrolyzed as described under a) and b), and 56.5 parts of more than 99 % pure N-(pyrazol-l-yl-methyl)-2,6-dimethylchloroacetanilide, of melting point 83C, are obtained.
A crude solution of 133 parts of N-(2,6-dimethyl-phenyl)-methyleneimine in a toluene-cyclohexane mixture is added dropwise to a solution of 202 parts of bromo-acetyl bromide in 150 parts of naphtha. Since, instead of the desired crystalline N-bromomethyl-2,6-dimethyl-bromoacetanilide, only an oil which is difficult to isol-ate precipitates, 450 parts o~ toluene and 75 parts of pyrazole are added, the mixture is heated at 60C ~or 2 hoursand 110 parts of triethylamine are added dropwise, after which the mixture is hea~ed at 60C, washed with water, then with 5 % strength hydrochloric acid and then . .
, . . ~
:
~Q~
- 19 - o.Z. 0050/033518 again with water, and evaporated, 248 parts of a viscous oil being obtained. The latter is dissolved in 500 parts of toluene and the solution is extracted with 250 parts of 37 % strength hydrochloric acid. The extract is hydrolyzed by means of 1,500 parts of water, giving 190 parts of N-(pyrazol-1-yl-methyl)-2,6-dimethyl-bromoacetanilide of melting point 86C.
1,620 parts of water are removed from a mixture of 10,890 parts of 2,6-dimethylaniline and 4,050 parts of paraformaldehyde by refluxing with 50,000 parts of a toluene-cyclohexane mixture in the conventional manner.
After having been rapidly cooled to room temperature, the resulting solution of N-(2,6-dimethylphenyl)-methylene-imine, still containing impurities, ls reacted in the conventional manner with 10,800 parts of chloroacetyl chloride in 10,000 parts of toluene. 6,800 parts of pyrazole are then added, the mixture is stirred for 5 hours at 50C, after which 10,000 parts of triethyl-amine are added and the reaction mixture is stirred for 5 hours at 50C and overnight at room temperature. It is then washed with 30,000 parts of 5 % strength hydro-chloric acid and the organic phase is separated off and extracted with 30,000 parts of 37 % strength hydrochloric acid. The extract is stirred into 180~000 parts of ; water. The precipitate formed is filtered off, washed with water and dried 17,840 parts of-96 % pure N-(pyrazol-l-yl-methyl)-2,6~dimethylchloroacetanilide~ of melting point 78C, .,~ . ~
~ "
- - , ~2~3 - 20 - O.Z. 0050/03351 are obtained.
121 parts o~ a heavily contaminated batch of N-(pyrazol-l-yl-methyl)-2-ethyl-6-methylbromoacetanilide are dissolved in 300 parts of toluene, the solution is extracted with 200 parts of 37 % streng-th hydrochloric acid and the extract is hydrolyzed with water. 67 parts of the pure product, of melting point 71-73C, are obtained.
EX~PLE 8 900 parts of water are removed from 6,050 parts of 2,6-dimethylaniline and 2,400 parts of paraformaldehyde with the aid of a toluene-cyclohexane mixture, as descri~ed in Example 6, m e resulting solution is added to 6,000 parts o~ chloroacetyl chloride in 6,000 parts of toluene, after completion of the reaction 3,800 parts-of pyrazole are added, the mixture is kept at 50C for 4 hours, 5,500 parts of triethylamine are added and the batch is then heated ~or 6 hours at 50C. It is then washed with dilute (5 % strength) hydrochloric acid and ~iltered to remove a small amount of residue.
The toluene phase of the filtrate is extracted with twice 13,000 parts of 60 % strength sulfuric acid. The extract is stirred into 300,000 parts of water. The -precipitate formed is filtered off and dried, giving 8,800 parts of 98 % pure N-(pyrazol-l-yl-methyl)-2,6-dimethylchloroacetanilide, of melting point 81-83C.
18 parts of water are removed from 121 parts of .
~2~4~
- 21 - O.Z. 0050/033518 2,6-dimethylaniline and 45 parts of paraformaldehyde in 250 parts of a toluene-cyclohexane mixture, as described in Example 6. After having been rapidly cooled to room temperature, the resulting solution of N-(2,6-dimethyl-phenyl)-methyleneimine is reacted in the conventional manner with 113 parts of chloroacetyl chloride in 100 parts of toluene and the batch is then stirred for a further ~ hour at 80C. A mixture of 44 parts of NaOH, 75 parts of pyrazole and 6.8 parts of a mixture of 35 % by weight of dimethyldibenzylammonium chloride, 15 % of trimethylbenzylammonium chloride, 40 ~0 of water and 10 % of methanol in 200 par-ts of water is then added dropwise, after which the batch is stirred for 4 hours at room temperature. After having separated the organic phase from the water, the former is washed twice with 200parts of water and then extrac-ted once with 350 par-ts and thereafter with 175 parts of 55 % strength sul~uric acid. The combined sulfuric acid extracts are stirred into 3,000 parts of water and the precipitate formed is filtered off, washed with water and dried under reduced pressure at 50C.
210 parts of 98 % pure N-(p~razol-l-yl-methyl)-2,6-dimethylchloroacetanilide, of melting point 82C, are obtained.
Claims (5)
1, A process for the preparation of substantially pure pyrazole compounds of the general formula , where R is hydrogen, halogen, alkyl of up to 5 carbon atoms, alkoxy of up to 3 carbon atoms, perhaloalkyl of up to 3 carbon atoms or alkoxyalkyl of up to 5 carbon atoms, Rl is hydrogen, halogen, alkyl of up to 5 carbon atoms, alkoxy of up to 3 carbon atoms, perhaloalkyl of up to 3 carbon atoms or alkoxyalkyl of up to 5 carbon atoms, R2 is hydrogen, halogen, alkyl of up to 5 carbon atoms, alkoxy of up to 3 carbon atoms, perhaloalkyl of up to 3 carbon atoms or alkoxyalkyl of up to 5 carbon atoms.
or R2 together with R is an ortho-linked alkylene chain of up to 6 carbon atoms which is unsubstituted or sub-stituted by alkyl of up to 4 carbon atoms, X is chlorine or bromine, and R3 and R4 are identical or different and each is hydrogen, alkyl, alkoxy, alkylthio, carbalkoxy or per-fluoroalkyl, in each case of up to 4 carbon atoms, or halogen, phenyl, cyano or carboxyl, from the corresponding crude products, wherein the crude products are treated with concentrated aqueous solutions of strong acids, thereafter the aqueous solution is separated off and diluted with water, and the pure product which hereupon precipitates is separated from the aqueous fluid.
or R2 together with R is an ortho-linked alkylene chain of up to 6 carbon atoms which is unsubstituted or sub-stituted by alkyl of up to 4 carbon atoms, X is chlorine or bromine, and R3 and R4 are identical or different and each is hydrogen, alkyl, alkoxy, alkylthio, carbalkoxy or per-fluoroalkyl, in each case of up to 4 carbon atoms, or halogen, phenyl, cyano or carboxyl, from the corresponding crude products, wherein the crude products are treated with concentrated aqueous solutions of strong acids, thereafter the aqueous solution is separated off and diluted with water, and the pure product which hereupon precipitates is separated from the aqueous fluid.
2, A process as claimed in claim 1, wherein hydrochloric acid of from 32 to 38 % strength is used.
3. A process as claimed in claim 1, wherein sulfuric acid of from 40 to 80 % strength is used.
4. A process as claimed in claim 1, wherein the precipitated pure product is extracted from the aqueous fluid by means of an organic solvent which is suitable for the further processing of the product.
5. A process as claimed in claim 1, wherein a solu-tion of the crude product in a water-immiscible or only slightly water-miscible organic solvent is used as the starting material.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782849442 DE2849442A1 (en) | 1978-11-15 | 1978-11-15 | METHOD FOR PRODUCING MOST PURE PYRAZOLIC COMPOUNDS |
| DEP2849442.0 | 1978-11-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1120043A true CA1120043A (en) | 1982-03-16 |
Family
ID=6054668
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000339923A Expired CA1120043A (en) | 1978-11-15 | 1979-11-15 | Preparation of substantially pure pyrazole compounds |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0012216B1 (en) |
| JP (1) | JPS55129270A (en) |
| AR (1) | AR226546A1 (en) |
| AT (1) | ATE164T1 (en) |
| BR (1) | BR7907345A (en) |
| CA (1) | CA1120043A (en) |
| CS (1) | CS208793B2 (en) |
| DD (1) | DD146948A5 (en) |
| DE (2) | DE2849442A1 (en) |
| DK (1) | DK146534C (en) |
| HU (1) | HU178450B (en) |
| IL (1) | IL58625A (en) |
| PL (1) | PL119268B2 (en) |
| SU (1) | SU860699A1 (en) |
| UA (1) | UA7045A1 (en) |
| YU (1) | YU279479A (en) |
| ZA (1) | ZA796137B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250503A (en) * | 1989-07-29 | 1993-10-05 | Basf Aktiengesellschaft | Monoclinic metazachlor and composition |
| WO2013104478A1 (en) | 2012-01-13 | 2013-07-18 | Basf Se | Process for preparing acetanilides |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2610589A1 (en) * | 1987-02-09 | 1988-08-12 | Savard Franck | Directional wheel hub making it possible to give or adjust the caster independently of the caster angle, and appended systems making it possible to vary various parameters on a 2-wheeled vehicle |
| DE3925253A1 (en) * | 1989-07-29 | 1991-01-31 | Basf Ag | MONOCLINES METAZACHLOR AND METHOD FOR THE PRODUCTION THEREOF |
| DE4436293A1 (en) | 1994-10-11 | 1996-04-18 | Basf Ag | Stable mixture containing water and metazachlor |
| DE10210409A1 (en) * | 2002-03-09 | 2003-09-18 | Feinchemie Schwebda Gmbh | Purely triclinic metazachlor and process for its manufacture |
| DE10343277A1 (en) | 2003-09-18 | 2005-04-21 | Piesteritz Stickstoff | N- (1H-Azolyl-methyl) amides, process for their preparation and their use as nitrification inhibitors |
| HUE038015T2 (en) | 2006-03-30 | 2018-09-28 | Fmc Corp | Acetylene carbamide derivatives-polyurea polymers and microcapsules and formulations thereof for controlled release |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2704281A1 (en) * | 1977-02-02 | 1978-08-03 | Bayer Ag | Herbicidal N-heterocyclyl-methyl-halo-acetanilide derivs. - prepd. from a N-halomethyl-chloro:acetanilide and a heterocycle |
-
1978
- 1978-11-15 DE DE19782849442 patent/DE2849442A1/en not_active Withdrawn
-
1979
- 1979-11-02 IL IL58625A patent/IL58625A/en unknown
- 1979-11-06 DE DE7979104325T patent/DE2960705D1/en not_active Expired
- 1979-11-06 AT AT79104325T patent/ATE164T1/en not_active IP Right Cessation
- 1979-11-06 EP EP79104325A patent/EP0012216B1/en not_active Expired
- 1979-11-12 SU SU792841459A patent/SU860699A1/en active
- 1979-11-12 UA UA2841459A patent/UA7045A1/en unknown
- 1979-11-13 PL PL1979219574A patent/PL119268B2/en unknown
- 1979-11-13 BR BR7907345A patent/BR7907345A/en unknown
- 1979-11-13 JP JP14613379A patent/JPS55129270A/en active Granted
- 1979-11-14 ZA ZA00796137A patent/ZA796137B/en unknown
- 1979-11-14 HU HU79BA3885A patent/HU178450B/en unknown
- 1979-11-14 DD DD79216896A patent/DD146948A5/en unknown
- 1979-11-14 YU YU02794/79A patent/YU279479A/en unknown
- 1979-11-14 CS CS797794A patent/CS208793B2/en unknown
- 1979-11-14 DK DK481279A patent/DK146534C/en not_active IP Right Cessation
- 1979-11-15 CA CA000339923A patent/CA1120043A/en not_active Expired
-
1982
- 1982-01-01 AR AR22654682D patent/AR226546A1/en active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250503A (en) * | 1989-07-29 | 1993-10-05 | Basf Aktiengesellschaft | Monoclinic metazachlor and composition |
| US5300652A (en) * | 1989-07-29 | 1994-04-05 | Basf Aktiengesellschaft | Preparation of monoclinic metazachlor |
| WO2013104478A1 (en) | 2012-01-13 | 2013-07-18 | Basf Se | Process for preparing acetanilides |
| US9079862B2 (en) | 2012-01-13 | 2015-07-14 | Basf Se | Process for preparing acetanilides |
Also Published As
| Publication number | Publication date |
|---|---|
| CS208793B2 (en) | 1981-09-15 |
| DK146534B (en) | 1983-10-31 |
| EP0012216A1 (en) | 1980-06-25 |
| IL58625A (en) | 1982-08-31 |
| DE2960705D1 (en) | 1981-11-19 |
| UA7045A1 (en) | 1995-03-31 |
| YU279479A (en) | 1983-01-21 |
| SU860699A1 (en) | 1981-08-30 |
| PL119268B2 (en) | 1981-12-31 |
| PL219574A2 (en) | 1980-09-08 |
| DE2849442A1 (en) | 1980-05-29 |
| HU178450B (en) | 1982-05-28 |
| BR7907345A (en) | 1980-07-15 |
| DK146534C (en) | 1984-04-09 |
| ATE164T1 (en) | 1981-09-15 |
| ZA796137B (en) | 1980-11-26 |
| EP0012216B1 (en) | 1981-08-26 |
| AR226546A1 (en) | 1982-07-30 |
| JPS55129270A (en) | 1980-10-06 |
| DK481279A (en) | 1980-05-16 |
| JPH0316346B2 (en) | 1991-03-05 |
| IL58625A0 (en) | 1980-02-29 |
| DD146948A5 (en) | 1981-03-11 |
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