| US 7,498,434 B2 | ||
| Two-phase method for the synthesis of selected pyrazolopyrimidines | ||
| Gary Lee Cantrell, Troy, Ill. (US); Frank William Moser, Arnold, Mo. (US); and Robert Edward Halvachs, Belleville, Ill. (US) | ||
| Assigned to Mallinckrodt Inc, Hazelwood, Mo. (US) | ||
| Appl. No. 10/585,006 PCT Filed Dec. 02, 2004, PCT No. PCT/US2004/040241 § 371(c)(1), (2), (4) Date Jun. 28, 2006, PCT Pub. No. WO2005/070931, PCT Pub. Date Aug. 04, 2005. |
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| Claims priority of provisional application 60/536302, filed on Jan. 14, 2004. | ||
| Prior Publication US 2007/0155995 A1, Jul. 05, 2007 | ||
| Int. Cl. C07D 487/04 (2006.01); A61K 31/519 (2006.01) | ||
| U.S. Cl. 544—282 [514/259.3] | 35 Claims |
1. A method of making a substituted pyrazolopyrimidine, or pharmaceutically acceptable salt thereof, wherein the substituted
pyrazolopyrimidine is a compound of Formula I,
 R1 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, formyl, carboxyl, cyano, hydroxymethyl, N-hydroxyformimidoyl
and R4CO— wherein R4 is selected from the group consisting of hydrogen; alkyl(C1-C6); alkoxy(C1-C6); unsubstituted phenyl; phenyl mono- or disubstituted by halogen, alkyl(C1-C3) or alkoxy(C1-C3); phenyl, phenyl substituted by trifluoromethyl, alkylthio(C1-C3), alkylamino(C1-C3), dialkylamino(C1-C3), methylenedioxy, alkylsulfonyl(C1-C3) or alkanoylamino(C1-C3); naphthalenyl; thiazolyl; biphenyl; thienyl; furanyl; pyridinyl; substituted thiazolyl; substituted biphenyl; substituted
thienyl; and substituted pyridinyl, wherein the substituents are selected from one or two of the groups consisting of halogen,
alkyl(C1-C3) and alkoxy(C1-C3);
R2 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, cyano, cyanomethyl, carbamoyl or alkyl (C1-C3); and
R3 is selected from the group consisting of phenyl; o-trifluoromethylphenyl; m-trifluoromethylphenyl; m-methoxyphenyl; pyridyl;
pyridyl N-oxide; thienyl; furanyl; and substituted phenyl, wherein one or more of the positions is substituted by a group
represented by Formula II
 R5 is selected from the group consisting of hydrogen, alkyl(C1-C6), alkenyl(C2-C6), alkynyl, cycloalkyl(C3-C6)methyl, —CH2OCH3, —CH2CH2OCH3, —CH2CH2OH, —CH2CHOHCH2OH, and —[CH2CH2O]n=10-120; and
R6is selected from the group consisting of alkyl(C1-C6), cycloalkyl(C3-C6), —O-alkyl(C1-C6), —NH-alkyl(C1-C3), —N-dialkyl(C1-C3), —(CH2)nO-alkyl(C1-C3), —(CH2)nNH-alkyl(C1-C3) and —(CH2)nN-dialkyl(C1-C3), where n is an integer 1 to 3 inclusive;
the method comprising reacting an aminopyrazole compound or a salt thereof with a substituted 1-oxo-2-propenyl-compound or
a salt thereof under acidic conditions in a reaction medium including a two-phase mixture of an aqueous solution and a water-immiscible
organic liquid.
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