Pyrazolo pyrimidine-3-carboxylates

N-( l-Acetyl-3-methyl-5-pyrazolyl)aminomethylenemalonate (1103) was cyclized to pyrazolo[l,5-a]pyrimidine-6-carboxylate (1102, R = 2-Me) in 82% yield by heating in boiling diphenyl ether for 10 min (74AP177). 

At the same time, the cyclization of N-( 1 -substituted 3-pyrazolyl)amino-methylenemalonates (1104) by refluxing in a 1 4.4 mixture of polyphos-phoric acid and phosphoryl chloride for 30 min gave 1-substituted pyrazolo[l,5-u]pyrimidine-6-carboxylates (1105) in good yields (83GEP-3309432). 

Pyrazolo[l,5-a]pyrimidine-6-carboxylates (1402) were prepared in 70% yields in the reaction of 3-aminopyrazoles and diethyl amino(trichloro-methyl)methylenemalonate in boiling ethanol in the presence of sodium ethoxide for 6 hr (78JPR533). 

Ready formation of pyrazolo[3,4-4 pyrimidines from reaction of 5-aminopyrazole -carboxylic acid derivatives is a well-established route to derivatives of this ring system. A recent application is the conversion of 286 into 288 by reaction with formamide and NIS 287 (Equation 40) <2002BML1687>. 

Ethyl 5-aminopyrazole -carboxylates are converted into pyrazolo[3,4- / pyrimidines via condensation with Ph3P/Bt2 subsequent reaction with an arylazocyanate and further reacting two carbodiimide with amines. Yields ranged from 13 to 65% dependant on the substituent <2006MI1584, 2007BMCL2203>. A similar approach was used for synthesis of triazolo[4,5- / pyrimidine-7(6)ones from ethyl 4-aminothiazolo-5-carboxylates <2007MIxx>. 

Generally pyrazolo[4,3-d]pyrimidines are prepared from pyrazole-5-carboxylic acid derivatives 180 via nitration to yield 181, which on esterification and reduction affords 184 (72CCC2786 78M11 79BCJ208 80MI35 ... 

Chebanov et al. [202] noted that condensation of the unsaturated acids 236 with 5-aminopyrazoles 220-222 never yielded isomers with opposite location of the aryl and carboxyl groups on the pyridine or pyrimidine rings, respectively. In the case of the multicomponent reaction of aminopyrazoles 220-222 with pyruvic acid 239 and aromatic aldehydes a different direction was observed. Refluxing of the starting materials in acetic acid led exclusively to pyrazolo[3,4-Z ]pyridine-4-carboxylic acids 249-251 instead of the anticipated carboxylic acids 243-248 (Scheme 3.69). The three-component procedures led only to the formation of heteroaromatized compounds even under a nitrogen atmosphere [202]. 

Pyrazophos ethyl 2-[(diethoxyphosphinothioyl)oxy]-5-methyl pyrazolo[1,5-aJ pyrimidine-6-carboxylate Hoe 2873 Afugan Curamil... 

The reaction of 5-aminopyrazole-4-carboxylates with amides affords pyrazolo[3,4-d]pyrimidines <79AP(312)703, 87MI 712-02). The synthesis of allopurinol (53) by reaction of ethyl ethoxymethyl-enecyanoacetate, hydrazine, and formamide probably proceeds via intermediacy of ethyl 5-amino-1 //-pyrazole-4-carboxylate which then condenses with formamide to yield intermediate (318) which readily cyclizes to allopurinol (53) <74NEP7507554>. 

Allopurinol, 1,5-dihydro-4//-pyrazolo[3,4-d]pyrimidin-4-one (53), was first synthesized by Robins <56JA784> and by Schmidt <58HCA1052) from 5-aminopyrazole-4-carboxylic acid derivatives. Several syntheses starting from a simple acyclic intermediate have been reported. Thus, reacting ethyl alkoxymethylene cyanoacetate with hydrazine and formamide at 14(M80°C gave allopurinol in high yield. An acid catalyst lowers the temperature required for cyclization of the intermediate 4-alkoxycarbonyl-3-aminopyrazole and raises the purity and the yield of allopurinol <69BRPI 284084). 

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 synthesis of pyrazolo[5,1 -6]purin-2-ones 261 started from ethyl 7-amino-pyrazolo[l,5-a]pyrimidine-6-carboxylates 262, following hydrazinolysis and reaction with HN02 gave the corresponding azide and the modified Curtius reaction closed the third pyrazole ring of 261. The final tricyclic 261 can be hydrolyzed to 6,7-diamino-pyrazolo[l, 5-a]purines (68CPB2195) (Scheme 77). 

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