Process for the preparation of symmetrical diacylhydrazines

Details Process for the preparation of symmetrical diacylhydrazines Process for the preparation of symmetrical diacylhydrazines

2001-03-09

2002-09-03

Killos, Paul J. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S149000, C564S311000

Reexamination Certificate

active

06444848

ABSTRACT:

The present invention relates to a process for the preparation of symmetrical diacylhydrazines.
More specifically, the present invention relates to a process for the preparation of symmetrical diacylhydrazines comprising the reaction of an ester with hydrazine, in its pure or hydrated state, to give a monoacylhydrazine which is subsequently reacted with a &bgr;-ketoester obtaining the desired symmetrical diacylhydrazine.
A further object of the present invention relates to the symmetrical diacylhydrazines obtained with the above process.
Various processes for the preparation of symmetrical diacylhydrazines are known in the art.
For example, the preparation of symmetrical diacylhydrazines can be easily effected by the reaction of hydrazine with acyl chlorides having general formula (Ia):
R—CO—Cl  (Ia)
wherein R represents a linear or branched C
1
-C
18
alkyl group, or an aryl group, operating according to the following reaction scheme (Scheme 1):
Scheme 1
2R—CO—Cl+1NH
2
NH
2
→1R—CO—NH—NH—CO—R+2H—Cl;
or by the reaction of the above hydrazine with anhydrides of carboxylic acids having general formula (Ib):
R—CO—O—CO—R  (Ib)
wherein R has the same meanings described above, according to the following reaction scheme (Scheme 2):
Scheme 2
2R—CO—O—CO—R+1NH
2
NH
2
→1R—CO—NH—NH—CO—R+2R—COOH;
as described, for example, in Houben Weyl (1967) Band 10/2, pages 127-135; and in Patai (1970): “The Chemistry of Amides”, Chapter 10, pages 533-535.
It is also known that, from the reaction of the acyl chlorides having general formula (Ia) described above, or anhydrides of carboxylic acids having general formula (Ib) described above, with hydrazine, operating with a molar ratio acyl chloride having general formula (Ia):hydrazine or anhydride of a carboxylic acid having general formula (Ib):hydrazine 1:1, according to the following reaction schemes (Scheme 3 and Scheme 4):
Scheme 3
1R—CO—Cl+1NH
2
NH
2
→1R—CO—NH—NH
2
+1H—Cl;
Scheme 4
1R—CO—O—CO—R+1NH
2
NH
2
→1R—CO—NH—NH
2
+1R—COOH;
monoacylhydrazines having general formula (IC) are obtained:
R—CO—NH—NH
2
  (Ic)
wherein R has the same meanings described above.
It is also possible to prepare mixed diacylhydrazines by reacting the monoacylhydrazines having general formula (Ic) described above, with an acyl chloride having general formula (Id):
R′—CO—Cl  (Id)
wherein R′ has the same meanings as R described above, on the condition that R and R′ are different from each other, according to the following reaction scheme (Scheme 5):
Scheme 5
1R—CO—NH—NH
2
+1R′—CO—Cl→1R—CO—NH—NH—CO—R′+1H—Cl.
It is also known that the reaction of the hydrazine with esters of carboxylic acids having general formula (Ie):
R—CO—OR″  (Ie)
wherein R has the same meanings described above and R″ represents a linear or branched C
1
-C
18
alkyl group, generally leads to the formation of monoacylhydrazines having general formula (Ic) described above, according to the following reaction scheme (Scheme 6)
Scheme 6
1R—CO—OR″+1NH
2
NH
2
→1R—CO—NH—NH
2
+1R″—OH;
as described, for example, in Houben Weyl (1952) Band 8, page 676-679; and in Patai (1970): “The Chemistry of Amides”, Chapter 10, pages 527-532. This reaction generally takes place using hydrated hydrazine (64% hydrazine; 36% water), in the presence of a polar solvent such as, for example, methanol, ethanol, dimethylformamide, water, etc. This hydrated hydrazine is a commonly used commercial product.
When the operation is carried out according to Scheme 6, the subsequent insertion of a second acyl group is generally very difficult and, when this insertion is possible, it is necessary to operate at high temperatures, for long reaction times and with the addition of acid catalysts.
In addition, in most cases, operating according to Scheme 6, the monoacylhydrazine which is formed by filtration or distillation of the reaction solvent and alcohol produced during the reaction, must be isolated. The formation of the symmetrical diacylhydrazine subsequently takes place by the elimination of a hydrazine mole from two moles of monoacylhydrazine having general formula (Ic) operating according to the following reaction scheme (Scheme 7):
Scheme 7
2R—CO—NH—NH
2
→R—CO—NH—NH—CO—R+NH
2
—NH
2
as described, for example, in Houben Weyl (1967) Band 10/2, pages 127-128.
Operating according to Scheme 7 above, in order to favour the progression of the reaction, the anhydrous hydrazine which is released, must be removed by distillation. As the distillation temperature of the anhydrous hydrazine is 113.5° C., it is necessary to use reaction temperatures of at least 150° C. and a high-boiling reaction solvent in order to be able to remove all the hydrazine released by the reaction, by means of distillation.
The elimination of the last percentages of hydrazine is very slow and consequently, owing to the high operating temperatures and long reaction times, numerous secondary products are formed which cause low yields and purities of the crystallized product obtained which rarely exceed 98%.
The undesired secondary products formed when operating according to Scheme 7 are tetrazine derivatives having the following general formulae (If) and (Ig)
wherein R has the same meanings defined above.
Or, in order to obtain diacylhydrazines, the monoacyl-hydrazine having general formula (Ic) can be reacted with a mole of acyl chloride having general formula (Ia), or with a mole of an anhydride of a carboxylic acid having general formula (Ib), operating according to the following reaction schemes (Scheme 8 and Scheme 9):
Scheme 8
1R—CO—NH—NH
2
+1R—CO—Cl→1R—CO—NH—NH—CO—R+1H—Cl;
Scheme 9
1R—CO—NH—NH
2
+1R—CO—O—CO—R→1R—CO—NH—NH—CO—R+1R—COOH.
The Applicant has now found a process for the preparation of symmetrical diacylhydrazines comprising the reaction of an ester with hydrazine, in its pure or hydrated state, to give a monoacylhydrazine which is subsequently reacted with a &bgr;-ketoester obtaining the desired symmetrical diacylhydrazine, capable of overcoming the disadvantages of the known art.
The present invention therefore relates to a process for the preparation of symmetrical diacylhydrazines having general formula (I):
R
1
—CO—NH—NH—CO—R
1
  (I)
wherein:
R
1
represents a linear or branched C
1
-C
18
alkyl group; a linear or branched C
2
-C
8
alkoxyalkyl group; a C
2
-C
8
cyanoalkyl group; a C
5
-C
8
cycloalkyl group, said cycloalkyl group optionally containing a heteroatom selected from oxygen, nitrogen and sulfur; a C
6
-C
18
aryl group; a C
7
-C
20
arylalkyl or alkylaryl group, said arylalkyl or alkylaryl groups optionally substituted with one or more hydroxyl groups, or with one or more linear or branched C
1
-C
8
alkoxyl groups; comprising:
(A) reacting an ester of a carboxylic acid having general formula (II):
R
1
—CO—OR
2
  (II)
wherein R
1
has the same meanings defined above and R
2
represents a linear or branched C
1
-C
18
alkyl group, with hydrazine, in its pure or hydrated state, obtaining a monoacylhydrazine having general formula (III):
R
1
—CO—NH—NH
2
  (III);
(B) reacting the monoacylhydrazine having general formula (III) obtained in step (A), with a &bgr;-ketoester having general formula (IV):
R
3
—CO—CH
2
—COOR
4
  (IV)
wherein R
3
represents a linear or branched C
1
-C
18
alkyl group, or a C
6
-C
18
aryl group and R
4
represents a linear or branched C
1
-C
18
alkyl group, obtaining the desired symmetrical diacylhydrazine having general formula (I).
Examples of C
1
-C
18
alkyl groups are: methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, isobutyl, t-amyl, isoamyl, 2-ethylhexyl, n-octyl, 1,1,3,3-tetramethylbutyl, n-dodecyl, 1,1,7,7-tetramethyloctyl, n-octadecyl, etc.
Examples of C
2
-C
8
alkoxyalkyl groups are: methoxyethyl, ethoxylethyl, ethoxypropyl, etc.
Examples of C
2
-C
8
cyanoalkyl groups are: cyanomethyl, cyanoethyl, cyanopropyl, etc.
Examples

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