CA2082464A1 - Process for the production of mono- and bis-hydrazones of carbonothioic dihydrazide - Google Patents

Abstract

Mo-3690 PROCESS FOR THE PRODUCTION OF MONO- AND
BIS-HYDRAZONES OF CARBONOTHIOIC DIHYDRAZIDE
ABSTRACT OF THE DISCLOSURE
Mono- and bis-thiocarbohydrazones are made by reacting thiocarbohydrazide or a salt thereof with a carbonyl compound in the presence of water at a temperature of from about 55 to about 95°C. A key feature of this process is that no organic solvent is included in the reaction mixture.

Mo3450

Description

2082~6~
Mo-3690 PROCESS FOR THE PRODUCTION OF MONO- AND
BIS-HYDRAZONES OF CARBONOTHIOIC DIHYDRAZIDE
BACKGROUND OF_THE INVENTION
The present invention relates to a process for the production of hydrazones of carbonothioic dihydrazide.
The hydrazones of carbonothioic dihydrazide are known to be effective in inhibiting or preventing the growth of cellulolytic micro-organisms. One method for producing these fungicides is disclosed in US Patent 3,734,757. US 3,734,757 teaches that such hydrazones are produced by a condensation type of reaction between an aldehyde or ketone and thiocarbohydrazide in the presence of a few drops of glacial acetic acid and mixture of water and organic solvent. A large excess (i.e., a molar excess of greater than two) of aldehyde or ketone is taught to be necessary in this process if an intractable mixture of mono- and di-substituted derivatives is to be avoided. The impure mixture of reaction products obtained by this disclosed process is said to exhibit good fungicidal properties even though the condensation reaction product is not isolated.
US Patent 4,058,526 discloses that the condensation of thiocarbohydrazide with an a~ueous solution of 3,3-dimethyl-2-oxo-butyric acid to produce 3-mercapto-4-amino-6-tert-butyl-1,2,4-triazine-5-one or its 3-thione tautomer creates a waste disposal problem because the waste water from this process contains organic materials ti.e., organic solvents, water insoluble unreacted ketone, etc.) which can not be d;scharged into streams.
It would therefore be advantageous to develop a process for producing thiocarbohydrazones in which organic solvents need not be employed.

35158LMW~500 ~24~

SUMMARY OF THE INVENTION
It is an object of the present invention to provide an improved process for the production of thiocarbohydrazones in which no organic solvents are employed.
It is another object of the present invention to provide a process for the production of thiocarbohydrazone in the absence of an organic solvent without sacrificing product yield.
It is a further object of the present invention to provide a process for the production of thiocarbohydrazone in which the reaction temperature is significantly lower than that used in the prior art processes.
It is also an object of the present invention to provide a process for the production of substantially pure thiocarbohy-drazone fungicides from which organic materials such as solvents need not be removed.
These and other objects which will be apparent to those skilled in the art are accomplished by reacting thiocarbohy-drazide or a salt thereof and a carbonyl compound in the presence of water at a temperature of from about 55 to about 95C. No organic solvent is employed in the process. An acid may be added to the reaction mixture directly in a preferred embodiment of the invention. An aqueous solution of a mineral acid salt of the thiocarbohydrazide may also be employed as the starting material.
DETAILED DESCRIPTION OF THE INVENTION
lhe present invention relates to an improved process for the production of thiocarbohydrazones in which thiocarbo-hydrazide or a salt thereof is reacted with a carbonyl compound in the presence of water at a temperature of from about 55-95C. A key feature of this process is that no organic solvent is included in the reaction mixture.
The process of the present invention may be represented by the following equation:

Mo3690 3 2082~

H2NN-~-NNH2 + R-C-R'~ N-N-~-N-N=~

II III

in which R and R' each represent a hydrogen atom or an alkyl, alkenyl, aryl, aralkyl, aralkenyl or heterocyclic group. R and R' taken together may also represent a divalent group derived from a cyclic ketone such as a cyclopentanone or cyclohexanone in which R and R' together represent tetramethylene or pentamethylene, respectively. R preferably represents an aryl or aralkyl group and R' preferably represents hydrogen or an alkyl group having from 1 to 3 carbon atoms.
Thiocarbohydrazide which is represented by formula I is known and may be produced in accordance with any of the known techniques for its production. It has been found that use of thiocarbohydrazide which has been dissolved in hot water prior to addition of the carbonyl compound is particularly advantageous in that more pure monohydrazones are generally obtained as products.
The carbonyl compounds represented by formula II include any of the known aromatic or aliphatic aldehydes and ketones.
The nature of the aldehyde or ketone is not critical and a wide variety of such compounds may be used. For example, aliphatic aldehydes and ketones, both saturated and unsaturated, aromatic compounds such as aryl aldehydes, aralkyl aldehydes, diaryl ketones, alkyl and aryl ketones, heterocyclic aldehydes and ketones, and aldehydes and ketones containing more than one aldehydic or ketonic group. Specific examples of such carbonyl compounds include: formaldehyde t acetaldehyde, valeraldehyde, hexanal, heptanal, octanal, nonanal, decanal, undecanal, dodecanal, octadecenal, 9-undecenal, benzaldehyde, Mo3690 2~82~

m-nitrobenzaldehyde, 2,4-dichlorobenzaldehyde, anisaldehyde, o-chlorobenzaldehyde, p-chlorobenzaldehyde, o-dimethyl-aminobenzaldehyde, o-hydroxybenzaldehyde, cumaldehyde, phenylacetaldehyde, cinnamaldehyde, furfural, 2-thiophen-aldehyde, acetone, methyl ethyl ketone, cyclopentanone, 2-octanone, acetophenone and benzophenone. Preferred carbonyl compounds include: o-hydroxybenzaldehyde, p-chlorobenzaldehyde, anisaldehyde, o-chlorobenzaldehyde and phenylacetaldhyde.
The reaction mixture may also optionally include an acid, preferably a mineral acid. Although acid is not required in the process of the present invention, if an acid is employed, it may be used in catalytic quantities (i.e., approximately 1 gm/mole), in an equivalent amount or even in excess. In a preferred embodiment, mineral acid is added to the thio-carbohydrazide in water to form the corresponding mineral acid salt before the carbonyl compound is added to the reaction vessel.
In carrying out the process of the present invention, water may be used in any amount which will result in a mixture that can be stirred. It has been found that use of two liters of water for each mole of thiocarbohydrazide or thiocarbo-hydrazide salt generally results in a reaction mixture which is easily stirred. More water may, of course, be used but such excess is unnecessary and will increase the amount of water to be treated upon completion of the reaction. Use of less water is, of course, also possible particularly where powerful stirring apparatus are available. However, the use of powerful stirring equipment will increase the cost of production.
The thiocarbohydrazide and carbonyl compound are generally reacted in quantities such that one mole of thiocarbohydrazide is available for every two moles of carbonyl compound.
However, these materials may be employed in quantities such that the molar ratio of carbonyl compound to thiocarbohydrazide is from about 1.5:1.0 to about 0.9:1.0, preferably from about 1.0:1.0 to about 1.1:1Ø
Mo3690 ~2~

The process of the present invention may be carried out at temperatures of from about 55 to about 95C, preferably from about 60 to about 70C and most preferably at a temperature of about 65C. The reaction time is generally from about 1 to about 10 hours, preferably from about 3 to 5 hours and most preferably about 4 hours.
The product thiocarbohydrazone may be readily recovered from the reaction mixture by any of the known techniques.
Simple filtration of the reaction mixture is just one technique which is suitable.
Prior to isolation of the product thiocarbohydrazone from the reaction mixture, it may be advantageous (particularly if an equivalent amount or an excess of acid was included in the reaction mixture) to neutralize the reaction mixture.
Once the thiocarbohydrazone has been removed from the reaction mixture, the purity of the product may be improved by washing with an organic solvent such as methanol, ethanol, ispropanol, and acetone. Such washing is, however, optional.
The product of the process of the present invention may be used directly in the production of fungicide formulations.
In the process of the present invention, the desired thiocarbohydrazone is generally obtained in a yield of at least 90%, often in yields of from about 97 to about 99%.
Having thus described our invention7 the following examples are given as being illustrative thereof. All parts and percentages given in these examples are parts by weight and percentages by weight, unless otherwise indicated.
EXAMPLES
Example 1 20 ml of water were charged at room temperature to a round bottomed flask equipped with a mechanical stirrer, thermometer and condenser. 26.8 gm (0.25 moles) of thiocarbohydrazide were then added to the flask, followed by the addition of 62.3 gm ~0.5 moles) of salicylaldehyde. The contents of the flask were Mo3690 2 ~

then heated to 80C and maintained at a temperature of from 80 to 82C for two and one-half hours. 400 ml of water were added to the flask and the contents of the flask were heated to 95C
and mainta;ned at that temperature for approximately 15 minutes. A pale white solid was recovered by filtration. The solid was washed with water and oven dried. The solid bis-thiocarbohydrazone thus produced was recovered in a yield of 89.3% and had an active ingredient content of 95.2%.

Example 2 400 ml of water were charged to a round bottomed flask equipped with a mechanical stirrer, thermometer and condenser at ambient temperature. 21.3 ml (0.255 moles) of concentrated hydrochloric acid and 27.3 gms (0.255 moles) of thiocarbo-hydrazide were then added to this flask. The contents of the flask were heated to 60C with stirring to dissolve the thiocarbohydrazide. After the contents had dissolved, the temperature was raised to 80C and maintained at that temperature while 62.3 gms (0.5 moles) of salicylaldehyde were added. Upon completion of the aldehyde addition, the contents of the flask were heated at 82-88C for two hours. The hot contents of the flask were then filtered, rinsed with water and dried. 78.7 gms of bis-thiocarbohydrazone were recovered (98.3% yield). HPLC indicated a purity of 100%.

Example 3 500 gms of water were charged to a round bottomed flask equipped with a mechanical stirrer, thermometer and condenser at ambient temperature. 0.36 moles of hydrochloric acid and 26.8 gms (0.25 moles) of thiocarbohydrazide were added with stirring to the flask. The contents of the flask were then heated to 55C until a clear solution was obtained. 64.8 gms (Q.52 moles) of salicylaldehyde were then added over a period Mo3690 4 ~ '~

, of 15 minutes. The temperature of the contents of the flask were maintained at a temperature of from 55 to 60C during this addition. Upon completion of the aldehyde addition, the contents of the flask were maintained at 55C for 4.5 hours.
Sodium hydroxide was added to the contents of the flask until the pH of the mixture was 5.5. The resultant mixture was then passed through a filter and the solids recovered were rinsed with water and dried. 79.4 grams of the bis-thiocarbohydrazone were recovered (97.6% yield).

Example 4 400 ml of water were charged to a round bottomed flask equipped with a mechanical stirrer, thermometer and condenser at ambient temperature. 24.5 gms (0.25 moles) of concentrated hydrochloric acid and 26.8 gms (0.25 moles) of thiocarbohydrazide were then added to the flask with stirring.
The contents of the flask were heated with stirring to 60DC
until the mixture was clear. 63.5 gms (0.51 moles) of salicylaldehyde wer then added to the flask over a period of 15 minutes. The temperature of the contents of the flask were maintained at 60-65C during the addition of the aldehyde.
Upon completion of the addition of aldehyde, the contents of the flask were maintained at 60-65C for 7 hours. Upon completion of this heating, the pH of the reaction mixture was adjusted to a pH of 6. The solids present in the mixture were recovered by filtration and dried. 77.7 gms of the desired bis-thiocarbohydrazone were recovered (99.0% yield). HPLC
indicated a purity of A.l. of 100%.

Mo3690 2n~2~4 Example 5 The procedure of Example 3 was repeated using the same reactants in the same amounts with the exception that 12.7 gms (0.125 moles) of sulfuric acid were substituted for the hydrochloric acid used in Example 3. 78.0 grams of the desired bis-thiocarbohydrazone (96.3% yield) were recovered. The product thiocarbohydrazone had a melting point of 201C.

Example 6 The procedure of Example 3 was repeated using the same reactants in the same amounts with the exception that 14.2 gms (0.125 moles) of phosphoric acid were substituted for the hydrochloric acid. 78.0 gms of the desired bis-thio-carbohydrazone (98.9% yield) were recovered. The product thiocarbohydrazone had a melting point of 201C.
Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.

Mo3690

Claims (16)

1. A process for the production of thiocarbohydrazones in which no organic solvent is employed comprising reacting thiocarbohydrazide or a salt thereof and a carbonyl compound in the presence of water at a temperature of 55-95°C.

2. The process of Claim 1 in which the thiocarbohydrazide is in the form of an aqueous solution of a mineral acid salt of thiocarbohydrazide.

3. The process of Claim 2 in which the salt of thiocarbohydrazide is selected from the group consisting of thiocarbohydrazide salts of hydrochloric acid thiocarbohydrazide salts of sulfuric acid, thiocarbohydrazide salts of phosphoric acid and mixtures thereof.

4. The process of Claim 1 in which an acid is included in the reaction mixture.

5. The process of Claim 4 in which the acid is a mineral acid selected from the group consisting of sulfuric acid, phosphoric acid, hydrochloric acid and mixtures thereof.

6. The process of Claim 5 in which the carbonyl compound is represented by the formula in which R and R' each a represents a hydrogen atom or an alkyl, alkenyl, aryl, aralkyl, aralkenyl or heterocyclic group.

7. The process of Claim 6 in which the reaction is carried out at a temperature of from about 60 to about 70°C.

8. The process of Claim 1 in which the carbonyl compound is represented by the formula Mo3690 in which R and R' each represents a hydrogen atom or an alkyl, alkenyl, aryl, aralkyl, aralkenyl or heterocyclic group.

9. The process of Claim 8 in which R represents an aryl or aralkyl group and R' represents hydrogen or an alyl group having from 1 to 3 carbon atoms.

10. The process of Claim 8 in which the reaction is carried out at a temperature of from about 60 to about 70°C.

11. The process of Claim 1 in which the carbonyl compound is salicylaldehyde.

12. The process of Claim 1 in which a pH basic material is added to the reaction mixture containing the thiocarbohydrazone in an amount sufficient to neutralize any acid remaining in the reaction mixture prior to recovery of the thiocarbohydrazone.

13. The process of Claim 12 in which the thiocarbohy-drazone is recovered from the reaction mixture and washed with an organic solvent.

14. The process of Claim 13 in which the organic solvent wash is selected from the group consisting of methanol, ethanol, isopropanol, and acetone and mixtures thereof.

15. The process of Claim 1 in which the thiocarbohydrazide is dissolved in hot water and the carbonyl compound is an aldehyde.

16. The process of Claim 1 in which approximately two liters of water are used for each mole of thiocarbohydrazide included in the reaction mixture.

Mo3690