Pyrazole ester

PDE4 (Table 1, entry 10) A library of about 20,000 "scaffold" compounds with molecular weights of 125-350 Da were screened in a combination of biochemical assays and crystallography studies to identify the PDE4 inhibitor pyrazole ester derivative 38 [45]. A 4000-fold increase in potency was achieved after only two rounds of chemical synthesis to give 39. 

The pyrazole ester 333 is converted into 334 upon treatment with sodium ethoxide in ethanol at 80 °C (Equation 47) <2000JHC1247>. 

The 3H-pyrazole esters represented by the general formula 106, in which R and R are alkyl groups, have been reported89 to give, not... 

Huisgen, Gotthardt, and Grashey518 have shown that 4,5-diphenyl-isosydnone (99) reacts with EPP in p-cymene at 150° giving the corresponding pyrazole ester (103) in 53% yield. Ohtaand Kato have stated 519 that these mesoionic-l,3,4-oxadiazoles do not react with dialkyl acetylenedicarboxylates either thermally or photochemically. McCarthy,... 

In addition, the conversion of a compound collection of drug-like heterocycles as might be used in a medicinal chemistry program was investigated. An equimolar mixture of 20 pyrazole acids, synthesized by a split-and-mix approach, was treated with methyl resin 10 (Ri = CH3, 5 equiv.) for 6 h to yield the respective pyrazole esters. All 20 pyrazole acids in the starting reaction mixture and all their corresponding 20 pyrazole methyl esters in the product mixture could be identified by FT-ICR MS coupled to micro-HPLC with a relative mass error <2.2 ppm. 

A regioselective synthesis of arylpyrazole esters is shown in Figure 2. Cyclization of the ketoester enamines 6 with trifluoroethyUiydrazine gave almost exclusive formation of pyrazole esters of formula 9a. 

In addition to NBS, bromine may serve as the electrophile in the bromination reaction as well. As shown below, bromination of the pyrazole-ester with bromine as -5 °C in CH2CI2 produced the corresponding 4-bromopyrazole, with concurrent o-bromination of the / -methoxyphenyl group at the C5 position. 

Ethyldiazoacetate (EDAC) has become a commonly utilized 1,3-dipole in the Pechmann pyrazole synthesis. In efforts toward the rational design of growth inhibitors of Mycobacterium tuberculosis, Kozikowski and co-workers utilized this strategy for the synthesis of the pyrazole ester. Treatment of a mixture of alkyne and EDAC under microwave conditions resulted in the preparation of the pyrazole ester as a mixture of H and 2H tautomers. The pyrazole ester proved inactive in the anti-TB assay, thereby proving the importance of an isoxazole moiety for anti-TB activity, as previous work by these authors suggested. ... 

Table 2. Postemergence Herbicidal activity at 16 g/Ha of Isomeric Pyrazole Esters.

When 3 was treated with two equivalents of sodium cyanide in DMF and heated to 100°C for two hours the 5-cyano-pyrazole ester 9 was produced and converted to the corresponding carboxamide 11 (Figure 3). Compound 11 was active at 0.5 Ib/acre in the greenhouse, and this derivative was pursued as a preemergent cereal herbicide (, 2). ... 

The ability of stronger Lewis acids to reverse the regioselective alkylation observed with sulfuric acid was further demonstrated in the preparation of the 3-cyano-pyrazole esters 29a-g. The reaction of the appropriate olefin (two equivalents) with 26 and boron trifluoride... 

A large variety of newer poly(ether imide)s has been described. Included among these are perfluorinated polymers (96), poly(ester ether imide)s (97), poly(ether imide)s derived from A/,Ar-diamino-l,4,5,8-naphthalenetetracarboxyHcbisimide (98), and poly(arylene ether imide ketone)s (99). In addition, many other heterocyHc groups have been introduced into polyether systems, eg, poly(pyrazole ether)s (100) and poly(aryl ether phenylquinoxaLine)s (101) poly(aryl ether oxazole)s with trifluoromethyl groups (102) and polyethers with other heterolinkages, eg, poly(arylether azine)s (103). 

Methylpyrazole has been investigated as a possible treatment for alcoholism. The stmcture—activity relationship (SAR) associated with a series of pyrazoles has been examined ia a 1992 study (51). These compounds were designed as nonprostanoid prostacyclin mimetics to inhibit human platelet aggregation. In this study, 3,4,5-triphenylpyrazole was linked to a number of alkanoic acids, esters, and amides. From the many compounds synthesized, triphenyl-IJT-pyrazole-l-nonanoic acid (80) was found to be the most efficacious candidate (IC g = 0.4 //M). 

N-Unsubstituted pyrazoles and imidazoles add to unsaturated compounds in Michael reactions, for example acetylenecarboxylic esters and acrylonitrile readily form the expected addition products. Styrene oxide gives rise, for example, to 1-styrylimidazoles (76JCS(P1)545). Benzimidazole reacts with formaldehyde and secondary amines in the Mannich reaction to give 1-aminomethyl products. 

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

The methylhydrazone of acetophenone (112) underwent ready reaction with n-butyl-lithium giving the dianion (113) reaction with acid derivatives such acid chlorides or esters resulted in pyrazole (114) formation whereas with aldehydes, pyrazolines were obtained (76SC5). With dichloromethyleneiminium salts (115), 5-dimethylaminopyrazoles... 

The pyrazole analogues of anthranilic acids or anthranilonitriles are a convenient source of [5.6] fused systems (for a general review see (80T2359)). Thus 5-amino-4-cyanopyrazoles (in some examples an ester or a hydrazido group replaced the cyano group) have been transformed into pyrazolo[3,4-d]pyrimidines (552) and into pyrazolo[2,3-e]diazepinones (553), and 4-amino-5-methoxycarbonylpyrazoles have been converted into pyrazolo[4,3-d]pyrimidines (554). 

Pyrazolo[3,4-d]pyridazines (555) can be prepared readily from hydrazines and pyrazoles substituted in positions 4 and 5 with an acyl and an ester group, or with two ester groups. 4,5-Pyrazolinediones have been used as starting materials for the synthesis of the quinoxaline derivatives (548) (see above) and of pyrazolo[3,4-e][l,2,4]triazines (556)... 

Diethyl 0-(3-methyl-5-pyrazolyl) phosphate (722) and 0,0-diethyl 0-(3-methyl-5-pyrazolyl) phosphorothioate (723) were prepared in 1956 by Geigy and they act, as do all organophosphates in both insects and mammals, by irreversible inhibition of acetylcholinesterase in the cholinergic synapses. Interaction of acetylcholine with the postsyn-aptic receptor is therefore greatly potentiated. 0-Ethyl-5-n-propyl-0-(l-substituted pyrazol-4-yl)(thiono)thiolphosphoric acid esters have been patented as pesticides (82USP4315008). 

Dimetilan (dimethylcarbamic acid l-[(dimethylamino)carbonyl]-5-methyl-l//-pyrazol-3-yl ester 724) and isolan (dimethylcarbamic acid 3-methyl-l-isopropyl-l//-pyrazol-5-yl... 

Organophosphates and carbamates containing a pyrazole ring, useful as insecticides as discussed earlier (Section 4.04.4.1.2), are metabolized mainly through hydrolysis of the ester function (B-80MI40406). 

Methylvinyldiazirine (199) rearranges at room temperature in the course of some days. Formation of the linear isomer is followed by electrocyclic ring closure to give 3-methyl-pyrazole. The linear diazo compound could be trapped by its reaction with acids to form esters, while the starting diazirine (199) is inert towards acids (B-71MI50801). 

Pyrazole-3,4-dicarboxylic acid, 1-phenyl-dimethyl ester synthesis, 5, 150 Pyrazole-3,5-dione, 1-phenyl-alkylation, 5, 230 synthesis, 5, 290... 

Katritzky and co-workers studied the mechanism of this reaction in detail. His work involved a NMR study of 16 reactions of methyl-, phenyl-, 1,2-dimethyl-, and l-methyl-2-phenylhydrazine with /3-keto esters. In many cases starting materials, intermediates, and products were detected simultaneously. Most reactions proceed by nucleophilic addition of the less hindered hydrazine nitrogen atom to the keto carbon of the keto ester. For example, the pathway given in Scheme 3 for the reaction of methyl 3-oxobutanoate 9 with methyl- or phenyUiydrazine 2 (R = Me or Ph) was found to be dominant. The initially formed addition product 10 dehydrates to hydrazone 11, which then isomerizes to hydrazone 12. Intermediate 12 then cyclizes to pyrazol-3-one 13, which tautomerizes to the kinetically more stable pyrazol-3-otie 14 [87JCS(P2)969]. 

Many more 2,3-dihydro-3//-pyrazol-3-one derivatives 22 are reported in the literature. Most of these compounds have been synthesized by the -keto ester-hydrazine mefliod (Scheme 6) (Table II). 

More recently, Tietze and Steinmetz (96SL667) used the patented polystyrene-resin methodology for for the solid-phase synthesis of a large number of diverse )3-keto esters 40a-h. These were reacted with phenylhydrazine in THF at room temperature to give hydrazones 41a-h that were then cychzed into 2-phenyl 5-substituted pyrazol-3-ones 42a-h by heating in toluene at 1(X)°C (Scheme 12). 

One year later, Tietze and co-workers (97BMC1303) presented a general and straightforward method for the synthesis of diverse polymer-bound -keto esters starting from acid chlorides and Meldrum s acid. One such resin-bound y3-keto ester, 43, was treated with hydrazine hydrate in THF to afford resin-ffee N-2-unsubstituted pyrazolone 44 in 84% yield (Scheme 13). In the same paper, the synthesis of a large number of 4,5-disubstituted 2-phenyl-2,4-dihydro-37/-pyrazol-3-ones was reported. 

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