Pyrazolo pyrimidine preparation

Pyrazolo-pyrimidine anilines, (IV), and thiazolecarboxamide derivatives, (V), prepared by Das (4,5), respectively, mediated the production of inflammatory cytokines including TNF, IL-1, IL-6, and COX-II and were used in treating inflammatory bowel disorder. 

Anand, N.K. etal. Preparation and structure activity of pyrazolo-pyrimidine derivatives as antitumor agents and kinase modulators. PCX application W02005117909 (2005). 

Pyrazoles can be prepared by ring opening reactions of fused systems already containing the pyrazole nucleus. Thus several [5.5], [5.6] and [5.7] fused heterocycles have been opened to substituted pyrazoles, usually in basic medium. In general, the method has little preparative interest since another pyrazole derivative has usually been used to build the ring-fused system. However, due to the unexpected structures obtained, two publications are worthy of notice. 6//-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine (638) was readily obtained from the corresponding pyrazolopyrimidine by the action of diazomethane at room temperature (Scheme 59) (81H(15)265). When (638) was treated with potassium hydroxide, the pyrazole (640) was formed, probably via the diazepine (639). 

Novel thieno[2,3 3,4]pyrazolo[l,5-a]pyrimidines and triazines 58 can be prepared by reacting the thienopyrazoles 57 with 1,3-biselectrophiles <95MI02 96CA(124)176031>. 

A test library with three novel p38a inhibitory activity has been prepared, among them pyrazolo[3,4-c/]pyrimidine and pyrazolo[3,4-h]pyrazine with potent in vivo activity <06BMCL262>. A convenient route for the synthesis of pyrazolo[3,4-<7]pyrimidine involving Friedlander condensation of 5-aminopyrazole-4-carbaldehyde with formamide or benzamide has been reported <06JHC1169>. A facile synthesis of pyrazolo[3,4-<7]pyrimidines and pyrimido[4,5-<7]pyrimidin-4-one derivatives has been published <06SC2963>. 

Pyrazolo[5, l 3,4][l,2,4]triazino[5,6-d]pyrimidine 720 was prepared (89JHC853) by reaction of 716 with formamide. Treatment of 716 with aromatic amines gave 717, whose cyclization with triethyl ortho-... 

The 3-aminopyrazole 85.17 also reacted with 6 to yield the corresponding pyrazolo[a] pyrimidines 111 (19 examples) exclusively as sole regioisomers in excellent yields. Similarly the condensed variants 112 and 113 were prepared in high yields <90T577>. 

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). 

Several pyrazolo[3,4-rf pyrimidine derivatives were prepared via reaction of 289 with reagents that can furnish an N-C fragment, for example, urea, thiourea, and formamide <2002BML1687>. 

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 ... 

The first pyrazolo[l,5-c]pyrimidine derivative (191) was prepared by condensing thiosemicarbazide with heptane-2,4,6-trione in the presence of perhydroacetic acid (72CB388). This reaction was adopted for the preparation of derivatives of 191 (X = O, NH), and later used to synthesize other pyrazolo[ 1,5-c] pyrimidines (71GEP2131790). 

The pyrazolo[1,5-c]pyrimidine derivative 195 is prepared by reaction of 194 with ethoxycarbonyl isothiocyanate in a 1 2 ratio. It is not clear why excess ethoxycarbonyl isothiocyanate is required (83S478). 

Chloro, 3-bromo, 3-iodo, and 3-nitro derivatives of 5,7-dimethyl-pyrazolo[l,5-a]pyrimidine derivatives were prepared by chlorination, bromination, iodination, and nitration of 3-unsubstituted 5,7-dimethyl-pyrazolo[l,5-a]pyrimidines. Reaction with bromine and potassium thiocyanate gave a 3-thiocyanato derivative, which was converted into the mercapto derivative upon saponification. Nitrosation gives the 3-nitroso derivative and acylation with trifluoroacetic anhydride affords the trifluoroacetyl derivative (74JMC645 77JMC386). 

Similar to haloazoles and haloazines, 7-halo-substituted pyrazolo[l,5-a]-pyrimidine underwent nucleophilic substitution with a variety of nucleophilic reagents to yield substituted pyrazolo[l,5-a]pyrimidines (74GEP2343702 76JAP761789 83AP697). Thus, 7-chloropyrazolo[l,5-a]pyrimidines 228, generally prepared from the 7-oxo derivatives 227 and phosphorus oxychloride, are converted into the 7-thioxo derivative 229 by the action of thio-... 

Higashino et al. have exploited the reaction between active methylene compounds and pyrazolo[3,4-d]pyrimidines (89) (as free base,101 N-oxide,102,103 or salts92,101) to prepare a large number of 6,7-substituted derivatives (54 R2 = R3 = H). A mechanism was suggested.92... 

One final interesting preparation of pyrimido[5,4-ring transformation of pyrazolo[4,3-d]pyrimidines. Reaction of the A-oxides (272) with sodium ethoxide in.refluxing ethanol leads to the isolation of l,3-dimethyl-6-substituted pyrimido[5,4-[Pg.365]

Pyrazolo[l,5-a]pyrimidines and imidazo[l,2-fc]pyrazoles have been prepared from phosphine derivatives of 5-amino-3-phenylpyrazole in aza-Wittig reactions with selected a -chloroketones. 24°... 

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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