Synthesis of 3-acylaminopyrazoles

Details Synthesis of 3-acylaminopyrazoles Synthesis of 3-acylaminopyrazoles

2002-10-29

2003-07-15

Ramsuer, Robert W. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S275400, C548S312400, C548S364100, C548S371700

Reexamination Certificate

active

06593477

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a process for synthesizing 3-acylaminopyrazole derivatives using hydrazine or a hydrazine salt.
BACKGROUND OF THE INVENTION
3-Acylaminopyrazole derivatives are known in the literature for numerous uses such as in pharmaceutical compositions as possible antitumor agents, enzyme inhibitors, and as useful for treatment of Alzheimer's disease, viral infections, auto-immune diseases and neurodegenerative diseases (see for example WO 01/12189), as bleach stabilizers (see for example DE 2622761), fungicides (see for example JP 62153283), dispersed dyes in photographic applications (see for example JP 07295131), as dye and ink precursors (see for example FR 2167809) and precursors for photographic coupler intermediates (see for example JP 09278758).
There are numerous methods for forming 3-acylaminopyrazoles. The simplest method consists of reacting the 3-aminopyrazole with the appropriate acylating reagent. The problem with this approach is that the acylating agent reacts at the ring nitrogens as well as at the desired exocyclic amino group to yield a mixture of products which leads to lower yields and hard to purify mixtures. This sequence is used in JP 09278758 to acylate 5-amino-3-tert-butyl-1H-pyrazole with pivaloyl chloride in 72.5% yield. Several ways around this problem are described in WO 01/12189 and include 1) oxidizing the amino group of the aminopyrazole to a nitro group, protecting the ring nitrogen with a t-BOC (tert butyloxycarbonate) group, hydrogenating the nitro group back to an amine, acylating with the desired reagent and deblocking the ring nitrogen; and 2) bis-acylating the aminopyrazole on both the desired exocylic nitrogen as well as the ring nitrogen and subsequent hydrolysis of the group on the ring nitrogen. These are long involved sequences which do not proceed in high yield and in the first case involves use of protecting groups which are later discarded wasting material and generating disposal problems and in the second case adding a group only to remove it again likewise wasting materials and causing disposal problems. It is known to react the aminopyrazole directly with an ester to give the desired acylaminopyrazole (J. Heterocyclic Chem. 26, 1713 (1989)) but this sequence involves elevated temperatures and the yield is only 72% crude and 56% purified.
It is a problem to be solved to develop a simple process that provides a high yield synthesis of 3-acylaminopyrazoles.
SUMMARY OF THE INVENTION
The invention provides a process for forming an N-acylamino pyrazole comprising contacting a N-acyl-3-oxo-imino ether compound either with a salt of hydrazine in the presence of a base or with hydrazine. This is a simple process that provides a high yield synthesis of 3-acylaminopyrazoles.
DETAILED DESCRIPTION OF THE INVENTION
The invention is summarized above.
The process of this invention provides pure acylaminopyrazole in high yield. The process, including the two preliminary reactions, is outlined below.
W is hydrazine or a salt of hydrazine provided that, when W is a salt, the reaction is carried out in the presence of a base.
An appropriate &bgr;-ketonitrile is subjected to the Pinner reaction to yield the imino ether which after neutralization is reacted with an acylating reagent and then reacted with hydrazine or a salt of hydrazine to give good yields of the 3-acylaminopyrazole. It should be noted that 1 and 2 can exist in tautomeric forms and furthermore that structures 4 and 5 can exist as mixtures of tautomeric forms as shown below.
In 4 the tautomeric forms can sometimes be isolated although both forms react to yield the pyrazole. In addition, there are other tautomeric forms that may be present for 4 and 5 involving tautomerization of the amide and location of the double bonds in the pyrazole ring. Accordingly, in the present invention, where only one tautomer is indicated for these compounds, the others are also within the scope of the present invention unless specifically noted otherwise.
The &bgr;-ketonitriles, 1 are common starting materials in the art and some are available commercially. They undergo the well known Pinner reaction (for review see Ann. Chim. (Paris) [14] 5, 23-27, pp.24-26) with an alcohol R″OH in the presence of an acid or base catalyst to yield an imino ether 2. Other methods of forming imino ethers are also known and may be used. The next step comprises reacting an acylating agent 3 with the neutralized solution of the imino ether 2 to yield the acylated imino ether 4. This simple process for acylating—acyclic &bgr;-keto-imino ethers is novel as the only other method reported in the literature is a low yield photolysis of isoxazoles (Tet Let. 28(47), 5797 (1987)) This product 4 can be isolated and without further purification submitted to the next reaction or without isolation and in the same reaction vessel be treated with hydrazine to yield the acyaminopyrazoles 5. If the reaction product 4 is isolated, no base needs to be used in the subsequent step but if both reactions are run in the same vessel without isolation extra hydrazine must be added or a strong base needs to be added along with the hydrazine. It is fortuitous that in this last reaction the pyrazole is formed exclusively; one might expect to also obtain triazole as well. It will be appreciated that compounds 4 and 5 can exist in tautomeric forms as described in the summary of the invention.
In the formulas 1, 2, 3, 4, 5, R can be an alkyl, aryl, heterocyclic or heteroatom-linked group. R′ can be an alkyl, aryl, or heterocyclic group linked to the rest of the compound by a fully substituted carbon atom in R′, and R″ can be an alkyl, aryl, or heterocyclic group. X is a conjugate base of strong acid e.g. Cl
−
, HSO
4
−
, H
2
PO
3
−
, CF
3
CO
2
Y is a optionally substituted alkyl or aryl group, H, Cl, Br, OR (R has same meaning as above), the nitrogen of a heterocyclic group such as hydantoin, benzotriazole, imidazole, succinimide, etc. and Z is a Cl, Br, imidazole, OCOR (where R has meaning above) or any such group that renders RCO an acylating group.
Preferably, R is an optionally substituted alkyl, aryl, or heterocyclic group containing no ionizable or nucleophilic substitutents such as OH, or NH
2
. Preferably, R′ is an optionally substituted alkyl, aryl, or heterocyclic group linked to the rest of the compound by a fully substituted carbon atom and containing no ionizable or nucleophilic substitutents such as OH or NH
2
; Desirably, X is a Cl
−
or HSO
4
−
radical; Y is a H, Cl, Br, OR (R has same meaning as above); and Z is a Cl, Br, imidazole, or OCOR (where R has meaning above).
More preferably, R is an optionally substituted alkyl, aryl, heterocyclic group containing no ionizable or nucleophilic substitutents such as OH or NH
2
; R′ is an optionally substituted tertiary alkyl, aryl, heterocyclic group linked to the rest of the compound by a fully substituted carbon atom, containing no ionizable or nucleophilic substitutents such as OH or NH
2
; R″ is an unsubstituted alky or aryl, group; X is a Cl; Y is a H; and Z is a Cl.
The base in the acylation reaction above can be any inorganic or organic base which doesn't cause decomposition of the starting material such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium acetate, potassium acetate, triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, 2,6-lutidene, N,N-dimethylaminopyridine. Preferably the base is sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium acetate, potassium acetate, pyridine, 2,6-lutidene, N,N-dimethylaniline, More preferably the base is sodium bicarbonate, sodium carbonate, 2,6-lutidene, N,N-dimethylaniline, or pyridine. The amount of base can vary from 2 equivalents to 4 equivalents but is preferably between 2 and 3 equivalents and more preferably 2.2-2.5 equivalents. The solvent for the acylation reaction can

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