Pyrazolo-pyrimidine carboxamides

In a recent report, Gregg and coworkers outline the use of conventional resin-bound isocyanates in scavenging amines for the synthesis of a large library of aryl pyrazolo-pyrimidine carboxamides (Scheme 8.4). Various primary as well as secondary amines were utilized in the amidation of activated nitro phenyl ester. Subsequent scavenging of amines with polystyrene isocyanate afforded the target... 

Pyrazolo[3,4-d]pyrimidines are of considerable chemical and pharmacological importance as purine analogues [75], Various compounds with related structures also possess antitumor and antileukemia activities [76]. Therefore, the investigation about new methods and synthesis of new derivatives of these compounds attracted considerable amount of interest. Reaction of 5-amino-l-phenyl-l/7-pyrazolo-4-carboxamide with aromatic aldehyde in the presence of HPAs, HjPWjjO q and Hj [NaP5W29MoO,jJ, gave derivatives of 6-aryl-l//-pyrazolo[3,4-r ]pyrimidin-4[5//]-ones. It was confirmed that HPA with Preyssler structure shows higher activity and yields due to the higher number of acidic protons (Scheme 3.29) [77]. 

Reaction of 5-amino-l-phenyl-177-pyrazole-l-carboxamide with aromatic aldehydes in the presence of heteropolyacid Hi4[NaP5W3oMoOio] gave derivatives of 6-aryl-l-pyrazolo[3,4-t/]pyrimidin-4-[5//]ones <2006MI1>. 

Reaction of 5-aminopyrazole-4-carboxamides with acid amides gives pyrazolo[3,4-d] pyrimidines (56JA784 58JOC191 61GEP1106331 ... 

USP482361). Compound 184 is converted into the pyrazolo[4,3- /]-pyrimidine derivative 185 by formamide. Amines convert 184 into carboxamide 186, which affords 187 upon treatment with formamide (78MI1). Reduction of 181 in the presence of formic acid gives the pyrazole derivative 183, which when treated with DMF affords the pyrazolo[4,3-d]pyrimidine derivative 182 (81USP4822361 83FES369). 

A halogen substituent at C-4 of the pyrazolo[3,4-c ]pyrimidine ring system is readily replaced by active methylene reagents (76S824, 76YZ1352). For example, treatment of the derivatives (207) with active methylene reagents in the presence of sodium hydride results in the formation of derivatives (208) in 70-80% yield (Equation (21)). The methylsulfonyl derivative (209) is converted into the carboxamide (211) when treated with cyanide ion intermediacy of the nitrile (210) seems most likely (Scheme 16) <82JMC1334>. 

Aldehydes, arylideneanilines, carboxylic acids and orthoesters have been used as one-oarbon units for binding the two amino functions of 4-amino-l-alkyl-3-propylpyrazole-5-oarboxamide to give l,6-dihydro-pyrazolo[4,3-<7]pyrimidin-7-ones <05MC619 05JHC751>. A modified efficient synthesis of variably substituted pyrazolo[4,3-<7]pyrimidm-7-ones has been described using a pyrazole-5-carboxylic acid, which was selectively brominated at position 4 and then converted into the carboxamide. Microwave irradiation gave better yields in the conversion of the carboxamides to pyrazolo[4,3-J]pyrimidinones <05JHC1085>. 

The formamide reaction has been successfully used to convert a 2-amino-pyridine-3-carboxamide to pyrido[2,3-d]pyrimidin-4-ones (see 3)220 3-aminopyrazole-4-carboxamide (see 15) to pyrazolo[3,4-rf ] pyrimidin-4-ones (see 16)118 4-aminopyrazole-3-carboxamide to pyrazolo[4,3-d]pyrimi-din-7-ones (see 17)221 many 4-amino-1,2,3-triazole-5-carboxamides (see 20) to 8-azapurin-6-ones (see 21)157,217-222—226 and 4-aminoimidazole-5-car-boxamides (see 18) to purin-6-ones (see 19).124-202-227 228 Secondary amines are suitable starting materials, as in the conversion of 4-amino-l,2,3-triazole-5-(jV-methyl)carboxamide and its 3-benzyl63 and... 

Thiourea has been used similarly to prepare, at 175°C (3 hr) up to 205°C (20 min), good yields of annelated 2-thioxopyrimidin-4-ones such as 8-methyl-2-thioxo-8-azapurin-6-one (156) from 4-amino-1,2,3-triazole-5-car-boxamides (see 20),254 as well as pyrazolo[4,3-d]- and pyrazolo[3,4-d]pyri-midinediones from the appropriate aminopyrazolecarboxamides (see 15) 24,221 and thieno[2,3-d]pyrimidine-2,4-diones (see 12) from 2-amino-thiophene-3-carboxamide.25 5... 

The l-aryl-3-trifluorometylpyrazole-5-carboxamide group is present in many of the orally available blood coagulation factor Xa inhibitors. Pinto and co-workers found in their medicinal chemistry program that a fluorinated pyrazole was an optimal five-membered heterocyclic core. Thus, two members of the 3-trifluoromethylpyrazole-5-carboxamide series were advanced to preclinical development (Fig. 2a) [81]. An additional structural modification, the incorporation of an aminobenzisoxazole moiety at N1 instead of the benzylamine group, led to the discovery of razaxaban (Fig. 2b), a potent, selective, and orally bioavailable inhibitor of factor Xa with in vivo efficacy in antithrombotic models [82], The amide hydrolysis observed in vivo could be modulated by introducing bicyclic core variants at the carboxamide portion, such as l/f-pyrazolo[4,3-rf pyrimidin-7(6//)-oneor 1,4,5,6-tetrahydropyrazolo-[3,4-c]pyridine-7-one [83]. 

SCHEME 2.108 Synthesis of 6-thioxo-4,5,6,7-tetrahydro-4//-pyrazolo[3,4-their reactions with CS2. 

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