Pyrazolo pyridines, preparation

Table 27 Pyrazolo[3,4-b]pyridines prepared by oxidative cyclization (Equation 51) <1997SC2217>...

Substitution of two carbons in position 2,3 of the pentadienyl anion (see Section 6.1) creates a type 2,3 system. Such molecules are the dihydropyrazolo-pyridines (DHPP) 42.50 51 The 1,3 dipolar cycloaddition reaction, which is so effective as a method for synthesizing five-membered rings, can also be used to prepare spiroheterocyclic compounds of the 2,3 type. If a suitable bromo-substituted dibenzopentafulvene is reacted with pyridine the pyrazolo-pyridine 42 is formed in 30-90% yields (Scheme 18). 

When the 1-position is substituted, 3- and 5-aminopyrazoles react at the C-4 carbon atom, the reactivity of which is enhanced by the amino group. Thus pyrazolo[3,4-Z ]pyridines (545) are obtained either by the Skraup synthesis or from 1,3-diifunctional compounds. Here also aminopyrazolinones have been used instead of aminopyrazoles to prepare (545 R = OH). If 1,4-ketoesters (succinic acid derivatives) are used instead of /3-ketoesters, pyrazolo[3,4-Z ]azepinones (546) are obtained. 

Pyrazolopyridines isomeric to those described previously have been obtained by other methods. Thus, the derivative (558) was formed by Raney nickel reduction of the 4-nitrosopyrazole (557) (7UHC1035), and the pyrazolo[3,4-c]pyridine derivative (560) was prepared from the azide (559) (79CC627). 

The first microwave-assisted hetero-Diels-Alder cycloaddition reaction was described by Diaz-Ortiz and co-workers in 1998 between 2-azadiene 198 and the same electron-poor dienophiles as for the preparation of pyrazolo[3,4-b]pyridines 200 (Scheme 72) [127]. These dienes reacted with... 

MethyM-cthoxycarbonyl-5-bcnzoyl-hydrazino-l //-pyrazole 274, prepared by reacting benzoyl chloride and 3-methyM-cthoxycarbonyl-5-bcnzoyl-hydrazino-l //-pyrazole hydrochloride 273, in the presence of pyridine in acetonitrile, has been cyclized with phosphoryl chloride in benzene or toluene to give 7-ethoxycarbonyl-6-methyl-3-phenyl-l //-pyrazolo[5,l -/ 1,2,4 triazolc 55. This compound has been also synthesized through cyclization of... 

Deprotonation readily occurs at C-7, and the resulting anion can further react with various electrophiles. Thus, treatment with BuLi at — 78 °C followed by reaction with diiodoethane was used to prepare the 7-iodo derivatives depicted in Table 2, while the 7-chloro derivatives were prepared by lithiation with lithium diisopropylamide (LDA), followed by reaction with CCI4. The 7-formyl derivative of the parent pyrazolo[l,5- ]pyridine has been prepared in 82% yield by reaction of the BuLi-generated anion with ethyl formate <2001JME2691>. 

A cycloaddition process involving dipole 22, readily prepared from thiazolidine 21, was reported to produce adducts such as 23 in the presence of sufficiently reactive dipolarophiles <2000T10011>. These adducts furnished substituted pyrazolo[l,5- ]pyridines 24 in fair yields upon further heating and extrusion of sulfur. However, diphe-nylacetylene did not react with dipole 22 (Scheme 10). 

Pyrazolo[3,4-. ]pyridines have also been formed by reaction of the appropriate chloronitrile pyridine (Equation 50) <2002BML2925>. Pyrazolo[3,4-. ]pyridines can be prepared by oxidative cyclization with PIFA (Equation 51 Table 27) <1997SC2217>. 

A range of trifluoromethyl-containing pyrazolo[3,4- ]pyridines have been prepared, in good yield, from the reaction of 4,4,4-trifluoro-3-oxobutanoates with electron-rich amino pyrazoles (Equation 53 Table 29) <2003S1531>. 

Pyrazolo[3,4-r-]pyridines have been formed by cyclization of the chloronitrile 155 with hydrazine hydrate in good yield (Equation 56) <2003BML1581>. Townsend and co-workers have reported the preparation of 3-substituted... 

Using the same method as for the synthesis of the pyrazolo[4,3-dpyridine 181, Ponticelli and co-workers also prepared the corresponding pyrazolo[3,4-/ ]pyridine 182 (Equation 76) <2003S2518>. 

Tetrahydropyrazolo[3,4-f]pyridines have been prepared as cannabinoid modulators <2007W0112399>. The pyra-zolo[3,4-4pyridine, Apixaban (BMS-562247), has been found to be a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor xa <2007JMC5339>. Several pyrazolo[3,4-f]pyridines have been found to be potent inhibitors of human eosinophil phosphodiesterase <2007JMC344>. 

A series of pyrazolo[3,4-, pyridazinones 430 and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed ICso values in the range 0.14-1.4 pM. A good activity and selectivity profile versus PDE6 was found for compound 430 (6-benzyl-3-methyl-l-isopropyl-4-phenylpyrazolo[3,4-r/]pyridazin-7(6/7)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position 6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five- and six-membered heterocycles (pyrrole, isoxazole, pyridine, and dihydropyridine), as well as some open-chain models were prepared and evaluated. Besides the pyrazole, the best of the fused systems proved to be isoxazole and pyridine <2002MI227>. 

The reaction of 1,3-dicarbonyl compounds with 3-amino-5-pyrazolones has been used extensively in the preparation of pyrazolo[3,4-b]pyridines. A number of products are possible, depending on the reagent used and the direction of cyclization. As a consequence, many of the early reports proposed incorrect structures. 

The Skraup reaction and Friedlander synthesis have found application in the preparation of pyrazolo[3,4-fc]pyridines. Cyclization of l-benzyl-5-aminopyrazoles (51 R1 = CH2Ph R2 = H,Me)88,89 under usual Skraup conditions gave the 1-benzyl derivatives (73) in moderate yield. The 1 -H derivative (73, R1 = H, R2 = Ph), however, was isolated only in poor yield.89... 

A number of reduced pyrazolo[3,4-c]pyridines have been prepared by cyclization of 3-piperidones substituted in the 4-position. For example, reaction of 4-ethoxycarbonyl- or 4-cyano-3-piperidones (125 X = C02Et or CN) with hydrazine afforded the pyrazolones 126a (R1 = H)119 or amines 127,120 respectively. 

The Skraup reaction has been applied to the synthesis of pyrazolo[4,3-h]-pyridines (cf. Section II,A,8) but is limited, because of the vigorous conditions involved, to the preparation of alkyl- or phenyl-substituted derivatives. Thus under Skraup conditions 185 (R2 = H) furnished a moderate yield of 1-phenyl products (186, R1 = H,Me),4,89 which were assigned, using UV spectroscopy.4 Attempts to form the 2-substituted isomer from the 5-sub-stituted 4-aminopyrazole 185 (R1 = H R2 = Me) were unsuccessful.4... 

The chemistry used in the preparation of pyrazolo[ 1,5-a]pyridines is influenced by the presence of the bridgehead nitrogen. Syntheses involve the almost exclusive use of /V-aminopyridinium salts and often require the generation of ylides. 

Pyrazolo[4,3-c]pyridines gave 5-methiodides in excellent yield.144 154 A methiodide of pyrazolo[l,5-a]pyridine 199b (R1 = H) was also prepared but its structure was not assigned161 the parent compound 5 quaternized in the 1-position.209 The saturated amide, however, formed a 7a-quaternary salt (263) with benzyl chloride, which was converted to the 1-benzyl derivative via the internal salt 264.209... 

This high-pressure methodology was later used by several groups, e.g., for the preparation of 4-(dimethylamino)pyridine (DMAP) derivatives [91] and oligoanilines [92]. More intriguingly, the synthesis of enantiomerically pure C-6 substituted pyrazolo[3,4-d]pyrimidines 147 has been performed by SNAr reaction of 4-amino-6-chloro-l-phenylpyrazolo[3,4-d]pyrimidine (145) under high-pressure conditions at ambient temperature. Conventional synthetic conditions (reflux at 0.1 MPa) were unsuccessful. The S enantiomer displayed higher affinity and selectivity for the adenosine Al receptor than the R enantiomer (Scheme 40) [93]. 

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