CA1141390A - Preparation of pyrazoles - Google Patents
Preparation of pyrazolesInfo
- Publication number
- CA1141390A CA1141390A CA000352000A CA352000A CA1141390A CA 1141390 A CA1141390 A CA 1141390A CA 000352000 A CA000352000 A CA 000352000A CA 352000 A CA352000 A CA 352000A CA 1141390 A CA1141390 A CA 1141390A
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- Prior art keywords
- reaction
- acid
- hydrazine
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- Prior art date
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-
- 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
- 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
- C07D231/16—Halogen atoms or nitro radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Abstract of the disclosure: Pyrazoles are prepared by reacting 1,3-dicarbonyl compounds with hydrazines and a less than equivalent amount of acid at a pH of from 0 to 6.9. The pyrazoles obtainable by the novel process are valuable starting materials for the prepar-ation of dyes, crop protection agents and drugs.
Description
~ 35~D 0.~. C050/03~4 Preparation of pyrazoles me present invention relates to a novel process for the preparation of pyrazoles by reacting 1,3-dicar-bonyl compounds with hydrazines and a less than equiva-lent amount of acid at a pX of from 0 to 6.9.
Rodd, Chemistry of Carbon Compounds, volume IVa (Elsevier, N.Y., 1957), pages 246 - 249, discloses numerous syntheses of pyrazoles, for example by reacting hydrazines with 1,3-dicarbonyl compounds, by dehydration of hydrazones of ~-keto-esters, by cyclization of hydra-zo~es of a-cyano-ketones, by reaction of aldehyde-phenylhydrazones with ~-keto-esters in the presence of zinc chloride, by condensation of a-halohydrazones with sodium-keto compounds or by reaction of diazo compounds with acetylene derivatives. The more important methods of synthesis entail the reaction of derivatives of 1,3-dicarbonyl compounds with hydra-zine or hydrazine derivatives in an acid aqueous solution or with salts of hydrazine orhydrazine derivatives, togive diluteaqueous solutionsofpyrazole salts, For example J. Amer. Chem. Soc., 71 (1949), 3,997, describes the stoichiometric reaction of 1,1,3,3-tetraethoxypropane with hydrazine dihydrochloride in a water/ethanol mixture.
The solution is then e~aporated to dryness, the residue is taken up in water and the pyrazole is liberated from its salt in the solution by means of sodium bicarbonate.
The mixture is filtered, the filter residue is thoroughly washed with ether and the ether filtrate is used to extract the aqueous filtrate.
3~HD
Rodd, Chemistry of Carbon Compounds, volume IVa (Elsevier, N.Y., 1957), pages 246 - 249, discloses numerous syntheses of pyrazoles, for example by reacting hydrazines with 1,3-dicarbonyl compounds, by dehydration of hydrazones of ~-keto-esters, by cyclization of hydra-zo~es of a-cyano-ketones, by reaction of aldehyde-phenylhydrazones with ~-keto-esters in the presence of zinc chloride, by condensation of a-halohydrazones with sodium-keto compounds or by reaction of diazo compounds with acetylene derivatives. The more important methods of synthesis entail the reaction of derivatives of 1,3-dicarbonyl compounds with hydra-zine or hydrazine derivatives in an acid aqueous solution or with salts of hydrazine orhydrazine derivatives, togive diluteaqueous solutionsofpyrazole salts, For example J. Amer. Chem. Soc., 71 (1949), 3,997, describes the stoichiometric reaction of 1,1,3,3-tetraethoxypropane with hydrazine dihydrochloride in a water/ethanol mixture.
The solution is then e~aporated to dryness, the residue is taken up in water and the pyrazole is liberated from its salt in the solution by means of sodium bicarbonate.
The mixture is filtered, the filter residue is thoroughly washed with ether and the ether filtrate is used to extract the aqueous filtrate.
3~HD
2 0. .0~50/0 Since these syntheses start from salts ~ hydra-zine (or of its derivatives) in solution, it is unavoid-able that stoichiometric amounts of waste salts should be produced after using, for example, inorganic bases.
When dumped on an industrial scale, these salts cause substantial effluent problems and problems of protecting the environment. For example, using the above method (J. Amer. Chem. Soc., loc. cit.) more than 2 kg of sodium chloride are formed per kg of pyrazole produced.
We have found that pyrazoles of the formula '' R~l R
~.
; where the individual radicals Rl, R2 and R3 may be identical or different and each is hydrogen or an aliphatic, araliphatic or aromatic radical, R2 may also be halogen, -CN or -o-R4, R3 may also be -0 , and R4 is an aliphatic, araliphatic or aromatic radical, are obtained in an advantageous manner by reaction of a 1,3-dicarbonyl compound with a hydrazine in ~he presence of water and of an acid, if a 1,3-dicarbonyl compound of the formula II
o R20 R -C-C_c_Rl where Rl and R2 have the above meanings, is reacted with i~41390
When dumped on an industrial scale, these salts cause substantial effluent problems and problems of protecting the environment. For example, using the above method (J. Amer. Chem. Soc., loc. cit.) more than 2 kg of sodium chloride are formed per kg of pyrazole produced.
We have found that pyrazoles of the formula '' R~l R
~.
; where the individual radicals Rl, R2 and R3 may be identical or different and each is hydrogen or an aliphatic, araliphatic or aromatic radical, R2 may also be halogen, -CN or -o-R4, R3 may also be -0 , and R4 is an aliphatic, araliphatic or aromatic radical, are obtained in an advantageous manner by reaction of a 1,3-dicarbonyl compound with a hydrazine in ~he presence of water and of an acid, if a 1,3-dicarbonyl compound of the formula II
o R20 R -C-C_c_Rl where Rl and R2 have the above meanings, is reacted with i~41390
- 3 - o.Z. 0050/033~94 a hydrazine of the formula where R3has theabove meanings. in the presence of less than 2 equivalents of acid per mole of hydrazine III at from -10 to +100C, the pH of the reaction mixture during the reaction being from 0 to 6.9.
Further, we have found that the process accord-ing to the i~vention may be carried out advantageously if the proportion of the pyrazole I present in the reac-tion mixture in the form of the pyrazole salt is reacted with additional hydrazine III to give the free pyrazole I
Compared to the prior art, the process according to the in~ention surprisingly gives pyrazoles by a simpler and more economical method, and in better yield and greater purity. Substantial amounts of acid, and hence expensive neutralization and effluent purifi-cation operations, are saved; The process causes less pollution of the environment. A11 these advantageous results are surprising in view of the prior art. In the light of the conventional processes, lower conver-sions and yields and the formation of heterogeneous mixtures of starting base and end product base, and of their salts, were to be expected.
The starting material II is reacted with the starting material III in stoichiometric amounts, or using an excess of one component relative to the other, preferably using from 0.1 to 1.5, especially from 0.9 to 1.1, moles of starting material III per mole of starting material II. Preferred starting materials II
3~KD
Further, we have found that the process accord-ing to the i~vention may be carried out advantageously if the proportion of the pyrazole I present in the reac-tion mixture in the form of the pyrazole salt is reacted with additional hydrazine III to give the free pyrazole I
Compared to the prior art, the process according to the in~ention surprisingly gives pyrazoles by a simpler and more economical method, and in better yield and greater purity. Substantial amounts of acid, and hence expensive neutralization and effluent purifi-cation operations, are saved; The process causes less pollution of the environment. A11 these advantageous results are surprising in view of the prior art. In the light of the conventional processes, lower conver-sions and yields and the formation of heterogeneous mixtures of starting base and end product base, and of their salts, were to be expected.
The starting material II is reacted with the starting material III in stoichiometric amounts, or using an excess of one component relative to the other, preferably using from 0.1 to 1.5, especially from 0.9 to 1.1, moles of starting material III per mole of starting material II. Preferred starting materials II
3~KD
- 4 - 0.~.. 005~033~94 and III and accordingly preferred end products I are those where the individual radicals Rl, R2 and R3 may be identical or different and each is hydrogen, alkyl of 1 to 18, preferably of 1 to 6, carbon atoms, araIkyl or alkylaryl of 7 to 12 carbon atoms, phenyl or naphthyl, R2 may also be bromine or chlorine, -CN or -o-R4 and R3 may also be -0 4, R being alkyl of 1 to 18, preferably : 1 to 6, carbon atoms, aralkyl or alkylaryl of 7 to 12 carbon atoms, phenyl or naphthyl. The said radicals may in addition be substituted by groups which are inert under the reaction conditions, for example alkyl of 1 to 3 carbon atoms or cyano.
Instead of 1,3-dicarbonyl compounds II, materials which form these compounds under the reaction conditions are as a rule employed. In the main, bis-acetals, mono-acetals, bis-acylals and mono-acylals are.used.
Ad~antageous compounds to employ are those of the formula 6 , R, R 5 IV
H H X
or R - C - C - C - R5 H
R2 R~
or R1-C = C - C - R5 VI
H H
11~1390 _ 5 _ o.~. 0050/03389 where the individual radicals R5 and R6 may be identical or different and each is -oR4 or -o-C-R4, the two radicals R5 may also together be oxo, R5 may also be halogen, advantageously chlorine, and Rl, R2 and R4 have the above general and preferred meanings.
Where 1,1,3,3-tetramethoxypropane and hydrazine are used, the reaction can be represented by the following equation:
CH30-C-CX2-C-OC~3 + H~ ~H2 > ~ + 4CH30H .
H H
- Examples of suitable starting materials II are 1,1,3,3-tetramethoxy-, -tetraethoxy-, -tetrapropoxy-, -tetraisopropoxy-, -tetrabutyoxy-,-tetraisobutoxy-, -tetra-sec.-butoxy- and -tetra-tert.-butoxy-propanes which are unsubstituted or are a-substituted by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, benzyl, phenyl, chloro, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.-butoxy, isobutoxy, tert.-butoxy, benzoxy or phenoxy, 3,3-dimethoxy-, 3,3-diethoxy-, 3,3-dipropoxy-, 3,3-diiso-propoxy-, ~,3-dibutoxy-, 3,3-diisobutoxy-, 3,3-di-tert.-butoxy and 3,3-di-sec.-but~xy-propionaldehydes which are unsubstituted or a-substituted as above, and 1,1-dimethoxy-, l,l-diethoxy-, l,1-dipropoxy-, 1,1-diiso-propoxy-, 1 t l-dibutoxy-, l,l-diisobutoxy-, l,l-di-sec.-~ 3~KD
_ ~ _ 0.~. 0050~033Q94 butoxy- andl,l-di-tert~ -butoxypropanals which are unsubstituted or -substituted as above~homologous ~-oxo-butanals, ~-oxo-pentanals, ~-oxo-hexanals, ~-oxo-heptanals and ~-oxo-octanals which are unsubstituted or substituted as abo~e in the a-position; pentane-2,4-diones, hexane-2,4-diones, heptane-2,4-diones, oetane-2,4-diones, heptane-3,5-diones and octane-3,5-diones which are unsubstituted, or substituted as above, in the -position relative to both carbonyl groups; correspon-ding l,l-acetalized ~,~-unsaturated butenals, pentenals and hexenals which are unsubstituted or substituted as above in the a-positiOn; l~l-acetalized propargyl-Pldehydes and homologous ,~-unsaturated butynals, pentynals and hexynals.
Preferred compounds to use are 1,1,3,3-tetra-methoxypropane, 1,1,3,3-tetraethoxypropane, 1,1,3,3-tetraisobutoxypropane, 1,1,3,3-tetraisopropoxypropane, 1,1,3,3-tetrabutoxypropane and 1,1,3,3-tetrapropoxy-propane.
Examples of suitable hydrazines III are hydra-zine, which is unsubstituted or substituted by methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, tert.-butyl, isobutyl, benzyl, phenyl, acetyl, benzoyl or phenylacetyl . Instead of the hydrazines III, com-pound~s which form these hydrazines under the reaction 11~1390 - , - 0.~. CO~0/~33R~
conditions may also be used, for example the hydrazine hydrates, salts of the hydrazines, such as the sulfates or disulfonates, eg. the di-benzenesulfonates; and hydrazones, eg. with formaldehyde or acetaldehyde, together with amines, eg. ethylamine.Where salts are used, the total amount of free acid and acid bonded to hydrazine is always less than 2 equivalents per mole of hydrazine.
me reaction is carried out at from -10 to +100C, preferably from O to 100C, especially from 30 to 70C, under atmospheric or superatmospheric pressure, contin-uously or batchwise. Organic solvents which are inert under the reaction conditions may or may not be added.
Examples of suitable solvents are aromatic hydrocarbons, eg. toluene, ethylbenzene, o-, m- or p-xylene, isopropyl-benzene and methylnaphthalene; halohydrocarbons, especi-ally chlorohydrocarbons, eg. tetrachloroethylene, 1,1,2,2- and 1,1,1,2-tetrachloroethane, amyl chloride, dichloropropane, methylene chloride, dichlorobutane, carbon tetrachloride, 1,1,1- and 1,1,2-trichloroethane, trichloroethylene, pentachloroethane, 1,2-dichloroethane, l,l-dichloroethane, n-propyl chloride, 1,2-cis-dichloro-ethylene, n-butyl chloride, 2-, 3- and iso-butyl chloride, chlorobenzene, o-, p- and m-dichlorobenzene, o-, m- and p-chlorotoluene and 1,2,4-trichlorobenzene; ethers, eg.
ethyl propyl ether, methyl tert.-butyl ether, n-butyl ethyl ether, di-n-butyl ether, diisobutyl ether, diiso-amyl ether, diisopropyl ether, cyclohexyl methyl ether, li ~l390 - 8 - o.Z. 00~0~0338 diethyl ether, ethylene glycol dimethyl ether, tetra-hydrofuran and dioxane; alkanols and cycloaIkanols, eg.
ethanol, methanol, n-butanol, isobutanol, tert.-butanol, glycol, n-propanol, isopropanol, amyl alcohol, cyclo-hexanol, 2-methyl-pentan-4-ol, ethylene glycol monoethyl ether, 2-ethylhexanol and methylglycol, those of 1 to 4 carbon atoms being preferred; aliphatic and cyclo-aliphatic hydrocarbons, eg. heptane, pinane, nonane, gasoline fractions boiling within the range from 70 to 190C, cyclohexane, methylcyclohexane, decalin, petroleum ether, hexane, naphtha, 2,2,4-trimethylpentane, 2,2,3-trimethylpentane, 2,3,3-trimethylpentane and octane;
and mixtures of the above. Advantageously, the amount of solvent used is from 400 to 10,000 percent by weight, preferably from 100 to 500 percent by weight, based on starting material II.
Water is used in every case, advantageously in an amount of from 1 to 70, more especially from 1 to 10, moles per mole of hydrazine III. The water is advan-tageously added to the starting mixture together withanother reactant, for example together with the acid and/or together with the starting material III.
The reaction is carried out in the presence of less than 2 equivalents of acid, and advantageously with from 0.05 to 1.9, especially from 0.25 to 1.25, equivalents of acid per mole of starting material III.
Inorganic or organic acids may be used. Instead of monobasic acids, equivalent amounts of polybasic acids may also be employed. Examples of suitable acids are 1~1390 _ 9 ~ ,. 005c/03~a4 the following: inorganic acids, eg. hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid;
sulfonic acids, eg. benzenesulfonic acid and p-toluene-sulfonic acid; boron-containing acids, eg. boric acid and fluoboric acid; aliphatic carboxylic acids, eg.
chloroacetic acid, dichloroacetic acid, trichloroacetic acid, ~xalic acid, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, glycolic acid and a- and ~-chloropropionic acid; and mixtures of the above.
The acids may be used in a concentrated form, as mixtures with one another and/or as mixtures with a solvent, especially water. The preferred acid is hydrochloric acid. The reaction is carried out at a pH of from 0 to 6.9, preferably from 0.5 to 4, especially from 0.9 to 2.5.
The reaction may be carried out as follows:
a mixture of hydrazine III, acid and water is brought to the reaction pH and additional starting materials III
and II are then added simultaneously, with or without water and/or organic solvent, at a rate such that the reaction pH is always maintained. Advantageously, the reactants are added at from -lO to +60C over a period of from 5 to 30 minutes. The total reaction time is advantageously from 0.1 to 12 hours. It has proved to be an important advantage of the novel process that the total amount of acid which need be added is very small relative to the hydrazine derivative.
The end prod~ct can be isolated from the ~141390 - 10 - o,~.. 00~0~033~a4 reaction mixture in a conventional manner, for example by neutralizing and extracting the mixture and distilling the extract. In batchwise operation, neutralization may for example be ef~ected by an inorganic base, in which case, according to the invention, the amount of salt formed as a by-product is only that which corres-ponds to the small amount of acid employed. However, particularly in continuous operation, the pyrazoles I
are liberated, according to the invention, by adding the corresponding hydraz~ne III to thé reaction mixture, the pH advantageously being brought to 6 - 10 before carrying out the extraction. As is illustrated, for the example of pyrazole, by the equation below, this results in the re-formation of re-usable hydrazine salt in the solution.
N ~ HCl + H ~ -NH2 x H20 _~ ~ +~ ~ -NH2 x XCl + H20 ~ H
It is advantageous that acid losses only occur to the extent of acid being lost from the aqueous phase during distillation and extraction processes. The liberation of the end product I by means o~ additional hydrazine is advantageously carried out at 0 - 40C. Using the above method, the resulting hydrazine salt solution can be re-used in reactions which can in principle be repeated as often as desired, and this is a substantial and surprising advantage of the novel process.
The pyrazoles I obtainable by the process of the 11 ~139H3 - 11 - o.Z. 0050/03389 invention are valuable starting materials for the prepar-ation of dyes, crop protection agents and drugs. With regard to their use, reference may be made to the publi-cations mentioned earlier.
In the Examples which follow, parts are by weight and bear the same relation to parts by volume as that of the kilogram to the liter.
EX~MPLE 1 ' 320 parts of water and 20 parts (0.4 mole) of hydrazine hydrate are introduced into a stirred apparatus and brought to pH 1, at 40C, by adding 59 parts of aqueous 36 percent strength by weight hydrochloric acid (O.5 mole). The followingareaddedsimultaneouslyin ~rti~s o~er2~hours,from threestock vessels,soastomaintain apH
of 2 -3: 380 parts(7.6 moles) of hydrazine hydrate, ~4 parts of aqueous 36 percent strength by weight hydro-chloric acid (3.54 moles) and 1,312 parts (8 moles) of 3~3-tetramethoxypropane. The mixture assumes a temperature of 43 - 55C, without cooling. The speed of rotation of the l,1,3,3-tetramethoxypropane is kept constant at 540 parts by volume per hour whilst that of the hydrazine is set to 153 parts per hour; the pH is regulated by the addition of the hydrochloric acid, After finally stirring for 7 hours, the mixture is brought to pH 8 by adding 320 parts (4 moles) of NaOH, and 1,553 parts of a methanol/water mixture and then - 12 - 0.~. 00~0/033~94 distilled off in 2~ hours at 20 mbar/50C. The residue is stirred with 2,000 parts by volume of methylene chlor-ide and filtered- The filter residue contains 250 parts of NaC~ whilst distillation of the filtrate gives 445 parts (82 % of theory) of pyrazole of boiling point 60 -70C/0.3 mbar.
a) 12.9 parts (0.258 mole) of hydrazine hydrate are introduced into a stirred apparatus equipped with a pH electrode, and are neutralized with 50.6 parts of aqueous hydrochloric acid (0.506 mole), whilst cooling.
At this stage hydrazine hydrochloride precipitates.
1,1,3,3-Tetramethoxypropane and additional hydrazine hydrate are then added simultaneously at 45 - 50C, at a rate such that a pH of 1 - 2 is maintained, which requires the addition of 82 parts (0.5 mole) of 1,1,3,3-tetramethoxypropane and 15.5 parts (0.31 mole) of hydra-zine hydrate over 20 minutes. After completion of the addition, the pH is 1. The mixture is then stirred for 2 hours at 22CC.
b) 120 parts by volume (= 3/4)of this solution are thenbrought to pH 6.8 - 7.2 with 20.6 parts by volume (0.426 mole) of hydrazine hydrate, and the mixture is then extracted with 2 x 200 parts by volume of CH2C12~
orming a binding system of hydrazine hydrate phase and extract. Distillation of the extract gives 23.2 parts of pyrazole (85 % of theory) of ooiling point 60 - 70C/0.1 mbar.
c, The last quarter, namely 40 parts by volume, of 3~3 - 13 - 0.~ tO~
the reaction solution obtained in Example 2a) are then taken - this solution being at pH 1 - and 61.5 parts (0.375 mole) of 1,1,3,3-tetramethoxypropane,and the aqueous hydrazine hydrate phase (pH 6.9 - 7.2) extracted in b), are added over 20 minutes, similarly to Example 2a. The pH again assumes a value of 1 - 2. After a further 2 hours, the mixture is worked up in the same m~nner as in Example 2b). Distillation gives 21.45 parts (0.36 mole) of pyrazole (corresponding to 84 %
yield), of boiling point 60 - 70C/0.1 mbar.
d) Procedure c) is repeated for 10 further reac-- tions. Even in the lOth case, the pH of the reaction mixture is again 1.6 - 1.7 and the same results as in Example 2c) are obtained.
Instead of 1,3-dicarbonyl compounds II, materials which form these compounds under the reaction conditions are as a rule employed. In the main, bis-acetals, mono-acetals, bis-acylals and mono-acylals are.used.
Ad~antageous compounds to employ are those of the formula 6 , R, R 5 IV
H H X
or R - C - C - C - R5 H
R2 R~
or R1-C = C - C - R5 VI
H H
11~1390 _ 5 _ o.~. 0050/03389 where the individual radicals R5 and R6 may be identical or different and each is -oR4 or -o-C-R4, the two radicals R5 may also together be oxo, R5 may also be halogen, advantageously chlorine, and Rl, R2 and R4 have the above general and preferred meanings.
Where 1,1,3,3-tetramethoxypropane and hydrazine are used, the reaction can be represented by the following equation:
CH30-C-CX2-C-OC~3 + H~ ~H2 > ~ + 4CH30H .
H H
- Examples of suitable starting materials II are 1,1,3,3-tetramethoxy-, -tetraethoxy-, -tetrapropoxy-, -tetraisopropoxy-, -tetrabutyoxy-,-tetraisobutoxy-, -tetra-sec.-butoxy- and -tetra-tert.-butoxy-propanes which are unsubstituted or are a-substituted by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, benzyl, phenyl, chloro, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.-butoxy, isobutoxy, tert.-butoxy, benzoxy or phenoxy, 3,3-dimethoxy-, 3,3-diethoxy-, 3,3-dipropoxy-, 3,3-diiso-propoxy-, ~,3-dibutoxy-, 3,3-diisobutoxy-, 3,3-di-tert.-butoxy and 3,3-di-sec.-but~xy-propionaldehydes which are unsubstituted or a-substituted as above, and 1,1-dimethoxy-, l,l-diethoxy-, l,1-dipropoxy-, 1,1-diiso-propoxy-, 1 t l-dibutoxy-, l,l-diisobutoxy-, l,l-di-sec.-~ 3~KD
_ ~ _ 0.~. 0050~033Q94 butoxy- andl,l-di-tert~ -butoxypropanals which are unsubstituted or -substituted as above~homologous ~-oxo-butanals, ~-oxo-pentanals, ~-oxo-hexanals, ~-oxo-heptanals and ~-oxo-octanals which are unsubstituted or substituted as abo~e in the a-position; pentane-2,4-diones, hexane-2,4-diones, heptane-2,4-diones, oetane-2,4-diones, heptane-3,5-diones and octane-3,5-diones which are unsubstituted, or substituted as above, in the -position relative to both carbonyl groups; correspon-ding l,l-acetalized ~,~-unsaturated butenals, pentenals and hexenals which are unsubstituted or substituted as above in the a-positiOn; l~l-acetalized propargyl-Pldehydes and homologous ,~-unsaturated butynals, pentynals and hexynals.
Preferred compounds to use are 1,1,3,3-tetra-methoxypropane, 1,1,3,3-tetraethoxypropane, 1,1,3,3-tetraisobutoxypropane, 1,1,3,3-tetraisopropoxypropane, 1,1,3,3-tetrabutoxypropane and 1,1,3,3-tetrapropoxy-propane.
Examples of suitable hydrazines III are hydra-zine, which is unsubstituted or substituted by methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, tert.-butyl, isobutyl, benzyl, phenyl, acetyl, benzoyl or phenylacetyl . Instead of the hydrazines III, com-pound~s which form these hydrazines under the reaction 11~1390 - , - 0.~. CO~0/~33R~
conditions may also be used, for example the hydrazine hydrates, salts of the hydrazines, such as the sulfates or disulfonates, eg. the di-benzenesulfonates; and hydrazones, eg. with formaldehyde or acetaldehyde, together with amines, eg. ethylamine.Where salts are used, the total amount of free acid and acid bonded to hydrazine is always less than 2 equivalents per mole of hydrazine.
me reaction is carried out at from -10 to +100C, preferably from O to 100C, especially from 30 to 70C, under atmospheric or superatmospheric pressure, contin-uously or batchwise. Organic solvents which are inert under the reaction conditions may or may not be added.
Examples of suitable solvents are aromatic hydrocarbons, eg. toluene, ethylbenzene, o-, m- or p-xylene, isopropyl-benzene and methylnaphthalene; halohydrocarbons, especi-ally chlorohydrocarbons, eg. tetrachloroethylene, 1,1,2,2- and 1,1,1,2-tetrachloroethane, amyl chloride, dichloropropane, methylene chloride, dichlorobutane, carbon tetrachloride, 1,1,1- and 1,1,2-trichloroethane, trichloroethylene, pentachloroethane, 1,2-dichloroethane, l,l-dichloroethane, n-propyl chloride, 1,2-cis-dichloro-ethylene, n-butyl chloride, 2-, 3- and iso-butyl chloride, chlorobenzene, o-, p- and m-dichlorobenzene, o-, m- and p-chlorotoluene and 1,2,4-trichlorobenzene; ethers, eg.
ethyl propyl ether, methyl tert.-butyl ether, n-butyl ethyl ether, di-n-butyl ether, diisobutyl ether, diiso-amyl ether, diisopropyl ether, cyclohexyl methyl ether, li ~l390 - 8 - o.Z. 00~0~0338 diethyl ether, ethylene glycol dimethyl ether, tetra-hydrofuran and dioxane; alkanols and cycloaIkanols, eg.
ethanol, methanol, n-butanol, isobutanol, tert.-butanol, glycol, n-propanol, isopropanol, amyl alcohol, cyclo-hexanol, 2-methyl-pentan-4-ol, ethylene glycol monoethyl ether, 2-ethylhexanol and methylglycol, those of 1 to 4 carbon atoms being preferred; aliphatic and cyclo-aliphatic hydrocarbons, eg. heptane, pinane, nonane, gasoline fractions boiling within the range from 70 to 190C, cyclohexane, methylcyclohexane, decalin, petroleum ether, hexane, naphtha, 2,2,4-trimethylpentane, 2,2,3-trimethylpentane, 2,3,3-trimethylpentane and octane;
and mixtures of the above. Advantageously, the amount of solvent used is from 400 to 10,000 percent by weight, preferably from 100 to 500 percent by weight, based on starting material II.
Water is used in every case, advantageously in an amount of from 1 to 70, more especially from 1 to 10, moles per mole of hydrazine III. The water is advan-tageously added to the starting mixture together withanother reactant, for example together with the acid and/or together with the starting material III.
The reaction is carried out in the presence of less than 2 equivalents of acid, and advantageously with from 0.05 to 1.9, especially from 0.25 to 1.25, equivalents of acid per mole of starting material III.
Inorganic or organic acids may be used. Instead of monobasic acids, equivalent amounts of polybasic acids may also be employed. Examples of suitable acids are 1~1390 _ 9 ~ ,. 005c/03~a4 the following: inorganic acids, eg. hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid;
sulfonic acids, eg. benzenesulfonic acid and p-toluene-sulfonic acid; boron-containing acids, eg. boric acid and fluoboric acid; aliphatic carboxylic acids, eg.
chloroacetic acid, dichloroacetic acid, trichloroacetic acid, ~xalic acid, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, glycolic acid and a- and ~-chloropropionic acid; and mixtures of the above.
The acids may be used in a concentrated form, as mixtures with one another and/or as mixtures with a solvent, especially water. The preferred acid is hydrochloric acid. The reaction is carried out at a pH of from 0 to 6.9, preferably from 0.5 to 4, especially from 0.9 to 2.5.
The reaction may be carried out as follows:
a mixture of hydrazine III, acid and water is brought to the reaction pH and additional starting materials III
and II are then added simultaneously, with or without water and/or organic solvent, at a rate such that the reaction pH is always maintained. Advantageously, the reactants are added at from -lO to +60C over a period of from 5 to 30 minutes. The total reaction time is advantageously from 0.1 to 12 hours. It has proved to be an important advantage of the novel process that the total amount of acid which need be added is very small relative to the hydrazine derivative.
The end prod~ct can be isolated from the ~141390 - 10 - o,~.. 00~0~033~a4 reaction mixture in a conventional manner, for example by neutralizing and extracting the mixture and distilling the extract. In batchwise operation, neutralization may for example be ef~ected by an inorganic base, in which case, according to the invention, the amount of salt formed as a by-product is only that which corres-ponds to the small amount of acid employed. However, particularly in continuous operation, the pyrazoles I
are liberated, according to the invention, by adding the corresponding hydraz~ne III to thé reaction mixture, the pH advantageously being brought to 6 - 10 before carrying out the extraction. As is illustrated, for the example of pyrazole, by the equation below, this results in the re-formation of re-usable hydrazine salt in the solution.
N ~ HCl + H ~ -NH2 x H20 _~ ~ +~ ~ -NH2 x XCl + H20 ~ H
It is advantageous that acid losses only occur to the extent of acid being lost from the aqueous phase during distillation and extraction processes. The liberation of the end product I by means o~ additional hydrazine is advantageously carried out at 0 - 40C. Using the above method, the resulting hydrazine salt solution can be re-used in reactions which can in principle be repeated as often as desired, and this is a substantial and surprising advantage of the novel process.
The pyrazoles I obtainable by the process of the 11 ~139H3 - 11 - o.Z. 0050/03389 invention are valuable starting materials for the prepar-ation of dyes, crop protection agents and drugs. With regard to their use, reference may be made to the publi-cations mentioned earlier.
In the Examples which follow, parts are by weight and bear the same relation to parts by volume as that of the kilogram to the liter.
EX~MPLE 1 ' 320 parts of water and 20 parts (0.4 mole) of hydrazine hydrate are introduced into a stirred apparatus and brought to pH 1, at 40C, by adding 59 parts of aqueous 36 percent strength by weight hydrochloric acid (O.5 mole). The followingareaddedsimultaneouslyin ~rti~s o~er2~hours,from threestock vessels,soastomaintain apH
of 2 -3: 380 parts(7.6 moles) of hydrazine hydrate, ~4 parts of aqueous 36 percent strength by weight hydro-chloric acid (3.54 moles) and 1,312 parts (8 moles) of 3~3-tetramethoxypropane. The mixture assumes a temperature of 43 - 55C, without cooling. The speed of rotation of the l,1,3,3-tetramethoxypropane is kept constant at 540 parts by volume per hour whilst that of the hydrazine is set to 153 parts per hour; the pH is regulated by the addition of the hydrochloric acid, After finally stirring for 7 hours, the mixture is brought to pH 8 by adding 320 parts (4 moles) of NaOH, and 1,553 parts of a methanol/water mixture and then - 12 - 0.~. 00~0/033~94 distilled off in 2~ hours at 20 mbar/50C. The residue is stirred with 2,000 parts by volume of methylene chlor-ide and filtered- The filter residue contains 250 parts of NaC~ whilst distillation of the filtrate gives 445 parts (82 % of theory) of pyrazole of boiling point 60 -70C/0.3 mbar.
a) 12.9 parts (0.258 mole) of hydrazine hydrate are introduced into a stirred apparatus equipped with a pH electrode, and are neutralized with 50.6 parts of aqueous hydrochloric acid (0.506 mole), whilst cooling.
At this stage hydrazine hydrochloride precipitates.
1,1,3,3-Tetramethoxypropane and additional hydrazine hydrate are then added simultaneously at 45 - 50C, at a rate such that a pH of 1 - 2 is maintained, which requires the addition of 82 parts (0.5 mole) of 1,1,3,3-tetramethoxypropane and 15.5 parts (0.31 mole) of hydra-zine hydrate over 20 minutes. After completion of the addition, the pH is 1. The mixture is then stirred for 2 hours at 22CC.
b) 120 parts by volume (= 3/4)of this solution are thenbrought to pH 6.8 - 7.2 with 20.6 parts by volume (0.426 mole) of hydrazine hydrate, and the mixture is then extracted with 2 x 200 parts by volume of CH2C12~
orming a binding system of hydrazine hydrate phase and extract. Distillation of the extract gives 23.2 parts of pyrazole (85 % of theory) of ooiling point 60 - 70C/0.1 mbar.
c, The last quarter, namely 40 parts by volume, of 3~3 - 13 - 0.~ tO~
the reaction solution obtained in Example 2a) are then taken - this solution being at pH 1 - and 61.5 parts (0.375 mole) of 1,1,3,3-tetramethoxypropane,and the aqueous hydrazine hydrate phase (pH 6.9 - 7.2) extracted in b), are added over 20 minutes, similarly to Example 2a. The pH again assumes a value of 1 - 2. After a further 2 hours, the mixture is worked up in the same m~nner as in Example 2b). Distillation gives 21.45 parts (0.36 mole) of pyrazole (corresponding to 84 %
yield), of boiling point 60 - 70C/0.1 mbar.
d) Procedure c) is repeated for 10 further reac-- tions. Even in the lOth case, the pH of the reaction mixture is again 1.6 - 1.7 and the same results as in Example 2c) are obtained.
Claims (9)
1. A process for the preparation of pyrazoles of the formula I
where the individual radicals R1, R2 and R3 may be identical or different and each is hydrogen or an aliphatic, araliphatic or aromatic radical, R2 may also be halogen, -CN or -O-R4, R3 may also be -?-R4, and R4 is an aliphatic, araliphatic or aromatic radical, by reaction of a 1,3-dicarbonyl compoundwitha hydrazine in the presence of water and of an acid, wherein a 1,3-dicarbonyl compound of the formula II
where R1 and R2 have the above meanings, is reacted with a hydrazine of the formula where R3 has the above meanings, in the presence of less than 2 equivalents of acid per mole of hydrazine III at from -10 to +100°C, the pH of the reaction mixture during the reaction being from 0 to 6.9.
where the individual radicals R1, R2 and R3 may be identical or different and each is hydrogen or an aliphatic, araliphatic or aromatic radical, R2 may also be halogen, -CN or -O-R4, R3 may also be -?-R4, and R4 is an aliphatic, araliphatic or aromatic radical, by reaction of a 1,3-dicarbonyl compoundwitha hydrazine in the presence of water and of an acid, wherein a 1,3-dicarbonyl compound of the formula II
where R1 and R2 have the above meanings, is reacted with a hydrazine of the formula where R3 has the above meanings, in the presence of less than 2 equivalents of acid per mole of hydrazine III at from -10 to +100°C, the pH of the reaction mixture during the reaction being from 0 to 6.9.
2. A process as claimed in claim 1, wherein the proportion of the pyrazole I which is present in the reaction mixture as the pyrazole salt is reacted with additional hydrazine III to give the free pyrazole I.
O.Z. 0050/033894
O.Z. 0050/033894
3. A process as claimed in claim 1, wherein the reaction is carried out with from 0.1 to 1.5 moles of starting material III per mole of starting material II.
4. A process as claimed in claim 1, wherein the reaction is carried out at from 0 to +100°C.
5. A process as claimed in claim 1, wherein the reaction is carried out at from 30 to 70°C.
6. A process as claimed in claim 1, wherein the reaction is carried out in the presence of an organic solvent which is inert under the reaction conditions.
7. A process as claimed in claim 1, wherein the reaction is carried out with from 1 to 70 moles of water per mole of hydrazine III.
8. A process as claimed in claim 1, wherein the reaction is carried out with from 0.05 to 1.9 equiva-lents of acid per mole of starting material III.
9. A process as claimed in claim 1, wherein the reaction is carried out at a pH of from 0.5 to 4.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2922591.0 | 1979-06-02 | ||
| DE19792922591 DE2922591A1 (en) | 1979-06-02 | 1979-06-02 | METHOD FOR PRODUCING PYRAZOLES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1141390A true CA1141390A (en) | 1983-02-15 |
Family
ID=6072387
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000352000A Expired CA1141390A (en) | 1979-06-02 | 1980-05-15 | Preparation of pyrazoles |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0020964A1 (en) |
| JP (1) | JPS5629574A (en) |
| CA (1) | CA1141390A (en) |
| CS (1) | CS216930B2 (en) |
| DD (1) | DD151164A5 (en) |
| DE (1) | DE2922591A1 (en) |
| IL (1) | IL60057A0 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5561130A (en) * | 1992-07-28 | 1996-10-01 | Merck Sharp & Dohme Limited | Azacyclic compounds |
| US5569769A (en) * | 1993-08-23 | 1996-10-29 | Basf Aktiengesellschaft | Preparation of pyrazole and its derivatives |
| US6451734B1 (en) | 1996-11-04 | 2002-09-17 | Basf Aktiengesellschaft | Substituted 3-benzylpyrazoles and their use as herbicides |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3122261A1 (en) * | 1981-06-04 | 1982-12-23 | Bayer Ag, 5090 Leverkusen | Process for the preparation of pyrazoles |
| US5232940A (en) * | 1985-12-20 | 1993-08-03 | Hatton Leslie R | Derivatives of N-phenylpyrazoles |
| US6372774B1 (en) | 1985-12-20 | 2002-04-16 | Rhone-Poulenc Agriculture Ltd. | Derivatives of N-phenylpyrazoles |
| US5547974A (en) * | 1985-12-20 | 1996-08-20 | Rhone-Poulenc Agriculture Ltd. | Derivatives of N-phenylpyrazoles |
| IT1226387B (en) * | 1988-07-08 | 1991-01-15 | Seuref Ag | PROCESS FOR THE PREPARATION OF 1,4-DIARYL-3-PYRAZOL-ACETIC ACIDS |
| JP2861103B2 (en) * | 1988-10-26 | 1999-02-24 | 日産化学工業株式会社 | Method for producing 4-methylpyrazoles |
| US5532416A (en) * | 1994-07-20 | 1996-07-02 | Monsanto Company | Benzoyl derivatives and synthesis thereof |
| US5869688A (en) * | 1994-07-20 | 1999-02-09 | Monsanto Company | Preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity |
| US5698708A (en) * | 1996-06-20 | 1997-12-16 | Monsanto Company | Preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity |
| AU720882B2 (en) * | 1996-06-20 | 2000-06-15 | Monsanto Company | Preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity |
| DE19831656A1 (en) * | 1998-07-15 | 2000-01-20 | Basf Ag | Process for the preparation of pyrazoles |
| DE10057194C2 (en) * | 2000-11-17 | 2002-10-24 | Degussa | Process for the preparation of pyrazoles |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB641015A (en) * | 1946-12-21 | 1950-08-02 | Gen Aniline & Film Corp | Production of pyrazoles |
| US3200128A (en) * | 1962-06-06 | 1965-08-10 | Searle & Co | 5-cyclo-unsaturate-3-trifluoromethyl-pyrazoles |
| FR2230637B1 (en) * | 1973-05-22 | 1977-07-29 | Ugine Kuhlmann |
-
1979
- 1979-06-02 DE DE19792922591 patent/DE2922591A1/en not_active Withdrawn
-
1980
- 1980-05-08 EP EP80102515A patent/EP0020964A1/en not_active Withdrawn
- 1980-05-12 IL IL60057A patent/IL60057A0/en unknown
- 1980-05-15 CA CA000352000A patent/CA1141390A/en not_active Expired
- 1980-05-29 DD DD80221447A patent/DD151164A5/en unknown
- 1980-05-30 JP JP7160180A patent/JPS5629574A/en active Pending
- 1980-06-02 CS CS803880A patent/CS216930B2/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5561130A (en) * | 1992-07-28 | 1996-10-01 | Merck Sharp & Dohme Limited | Azacyclic compounds |
| US5569769A (en) * | 1993-08-23 | 1996-10-29 | Basf Aktiengesellschaft | Preparation of pyrazole and its derivatives |
| US6451734B1 (en) | 1996-11-04 | 2002-09-17 | Basf Aktiengesellschaft | Substituted 3-benzylpyrazoles and their use as herbicides |
Also Published As
| Publication number | Publication date |
|---|---|
| CS216930B2 (en) | 1982-12-31 |
| DD151164A5 (en) | 1981-10-08 |
| DE2922591A1 (en) | 1980-12-04 |
| IL60057A0 (en) | 1980-07-31 |
| JPS5629574A (en) | 1981-03-24 |
| EP0020964A1 (en) | 1981-01-07 |
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