Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-22
2002-09-17
Ramsuer, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06452019
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to an improved process for the preparation of 4,5-diamino-1-(2′-hydroxyethyl)pyrazole and acid addition salts thereof such as the addition salt from sulfuric acid. More specifically, this invention pertains to a process for the preparation of 4,5-diamino-1-(2′-hydroxyethyl)pyrazole and acid addition salts thereof by a novel combination of steps beginning with an alkyl(alkoxymethylene)-cyanoacetate and a substituted hydrazine.
The 1-substituted-4,5-diaminopyrazoles and their addition salts are known to be especially useful as developers in combination with various couplers and an oxidizing agent for coloring keratinous fibers, particularly human hair. See, for example, U.S. Pat. Nos. 5,931,973; 5,769,902; 5,718,731; and 5,663,366.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,663,366 discloses the preparation of 1-substituted-4,5-diamino-pyrazoles by means of a six-step process starting with pyrazole, which is difficult to handle because it is hygroscopic and an irritant. In the disclosed process, the pyrazole is first nitrated to give 4-nitropyrazole using a mixture of sulfuric and nitric acids and the 4-nitropyrazole is brominated to provide 3,5-dibromo-4-nitropyrazole. The 3,5-dibromo-4-nitropyrazole then is hydroxyethylated, using 1-bromo-2-hydroxyethane with sodium hydride in N,N-dimethylformamide as solvent, to provide 3,5-dibromo-1-(2′-hydroxy-ethyl)-4-nitropyrazole, which is then reacted with a large excess of benzylamine to provide 5-benzylamino-3-bromo-1-(2′-hydroxyethyl)-4-nitropyrazole which then is recrystallized from toluene/ligroine (1:1). Finally, the product is obtained by a complicated hydrogenation using 10 weight percent palladium-on-activated carbon (Pd/C). Under the reduction conditions, the 3-bromo group is removed, along with the benzyl group while the nitro group is reduced to amino. The product then is isolated as the sulfuric or hydrochloric acid salt. It is known that halogen atoms such as bromine and chlorine deactivate noble metal catalysts, thus posing problems in reusing the metal catalysts. This overall procedure requires the isolation of at least five products and also requires a recrystallization and the handling of very toxic reagents such as nitric acid and bromine.
German Patent DE 3432983 discloses the preparation of 4,5-diamino-1-substituted pyrazole hydrochlorides having the structure:
wherein R′ is benzyl; benzyl substituted with halogen or hydroxy; C
1
-C
8
-alkyl; C
1
-C
4
-alkyl substituted with hydroxy. The hydrochloride compounds are not isolated but are reacted to give 1,5-disubstituted-1H-pyrazolo-(3,4-b)-pyrazines. The procedure described in DE 3432983 for the preparation of 4,5-diamino-1-substituted-pyrazole hydrochlorides utilizes a plurality of reactions and isolation of intermediate compounds.
(1) Ethyl(ethoxymethylene)cyanoacetate is reacted with a substituted hydrazine hydrochloride to provide an ethyl ester of 5-amino-1-substituted-pyrazole-4-carboxylic acid in the presence of a sodium alkoxides in methanol. The methanol is removed by distillation and replaced by acetone to allow the removal of the sodium chloride salt. The acetone from the filtrate is then removed by distillation and replaced with ethanol to facilitate the isolation of the solid product, ethyl 5-diamino-1-substituted pyrazole-4-carboxylate, which is recrystallized from ethanol.
(2) The isolated ethyl 5-diamino-1-substituted pyrazole-4-carboxylate is dissolved in methanol and hydrolyzed to the carboxyl compound by heating in the presence of 10% aqueous sodium hydroxide solution. Methanol is removed by distillation and the residue dissolved in dilute hydrochloric acid to provide the solid 5-amino-4-carboxy-1-substituted-pyrazole which is isolated by filtration, dried and then recrystallized from methanol.
(3) The isolated 5-amino-4-carboxy-1-substituted-pyrazoles is heated at 160-170° C. to effect decarboxylation to produce a 5-amino-1-substituted-pyrazole which is distilled under reduced pressure.
(4) The 5-amino-1-substituted-pyrazole was dissolved in ethanol and the resulting solution was added drop-wise to a solution of hydrogen chloride in ethanol. To the resulting solution is added drop-wise isoamyl nitrite. to nitrosate the 5-amino-1-substituted-pyrazole, producing a 5-amino-4-nitroso-1-substituted-pyrazole hydrochloride that is isolated and recrystallized.
(5) Finally, the 5-amino-4-nitroso-1-substituted-pyrazole hydrochloride is dissolved in methanol and hydrogenated in the presence of palladium-carbon catalyst. The catalyst is removed by filtration and the 4,5-diamino-1-substituted pyrazole hydrochloride is isolated by removing of the methanol or reacted directly in the methanol without isolation to provide a 1,5-disubstituted-1H-pyrazolo-(3,4-b)-pyrazine.
The process disclosed in DE 3432983 utilizes a number of isolation, recrystallization and drying operations which increase significantly the cost of preparing 4,5-diamino-1-substituted pyrazole acid salts.
Example 4 of U.S. Pat. No. 2,989,537 describes the preparation of 5-amino-4-ethoxycarbonyl-1-(2′-hydroxyethyl)-pyrazole by reacting ethyl(ethoxymethylene)-cyanoacetate with 2-hydroxyethylhydrazine in ethanol and distilling the product under vacuum at high temperature. The isolated solid product then is hydrolyzed by heating with 2N aqueous sodium hydroxide solution followed by acidification with 6N hydrochloric acid to give 5-amino-4-carboxy-1-(2′-hydroxyethyl)-pyrazole. This hydrolysis procedure in water leaves some undissolved material that must be removed by filtration. The carboxy intermediate is, heated at 160-170° C. to complete the decarboxylation and the 5-amino-1-(2′-hydroxyethyl)-pyrazole is purified by distillation under vacuum at high temperature.
In summary, the prior art procedures involve multiple isolations of intermediate products by crystallizations, recrystallizations, high temperature vacuum distillations, and other procedures and, in some cases, involve the handling and disposal of some very toxic solvents such as chlorinated hydrocarbons.
BRIEF SUMMARY OF THE INVENTION
I have developed a process comprising a plurality of process steps which provide a convenient synthesis of 4,5-diamino-1-(2′-hydroxyethyl)pyrazole and acid addition salts thereof such as the addition salt from sulfuric acid. The present invention provides an improved process for the preparation 4,5-diamino-1-(2′-hydroxyethyl)-pyrazole and acid addition salts thereof by means of the steps comprising:
(i) heating a mixture comprising an alkyl(ethoxymethylene)cyanoacetate, 2-hydroxy-ethylhydrazine and an alkanol to form a product solution of 5-amino-4-alkoxy-carbonyl-1-(2′-hydroxyethyl)pyrazole (I) in an alkanol;
(ii) heating the mixture of the product solution of step (i) and aqueous alkali metal hydroxide to saponify the alkoxycarbonyl ester group of (I) and remove alkanol present from the mixture and then adding sufficient acid to produce an aqueous product mixture of 5-amino-4-carboxy-1-(2′-hydroxyethyl)pyrazole (II);
(iii) separating (II) from the product mixture of step (ii) to obtain (II) as a water-wet solid;
(iv) heating water-wet (II) from step (iii) to first vaporize and remove water present and then decarboxylate (II) to produce 5-amino-1-(2′-hydroxyethyl)pyrazole (III);
(v) contacting (III) with an inorganic acid in an alkanol and contacting the resulting solution of the acid salt of (III) with a nitrosating agent to convert the acid salt of (III) to the acid salt of 5-amino-1-(2′-hydroxyethyl)-4-nitrosopyrazole (IV);
(vi) separating the acid salt of (IV) from the product mixture of step (v) to obtain the acid salt of (IV) as an alkanol-wet solid;
(vii) dissolving the alkanol-wet acid salt of (IV) from step (vi) in an alkanol to produce an alkanol solution of the acid salt of (IV) and adding a base to the solution to produce an alkanol solution of 5-amino-1-(2′-hydroxyethyl)-4-nitrosopyrazole (IV);
(viii) contacting the alkanol solution of (IV) from step (vii) w
Blake Michael J.
Eastman Chemical Company
Graves, Jr. Bernard J.
Ramsuer Robert W.
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