Robins, Roland K. published an article in 1956, the title of the article was Potential purine antagonists. I. Synthesis of some 4,6-substituted pyrazolo[3,4-d]pyrimidines.Safety of 4-Chloro-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine And the article contains the following content:
EtOCH2CH(CN)2 (150 g.) added in 3-5-g. portions to 100 g. 85% N2H4.H2O with slight cooling, the mixture heated 1 hr. on the steam bath, diluted with 100 cc. H2O, and refrigerated overnight, the mushy solution filtered, and the solid washed with cold H2O yielded 97 g. 3-amino-4-cyanopyrazole (I), m. 174-5° (from H2O). I (0.5 g.) refluxed 8 hrs. with 100 cc. AcCl and evaporated to dryness on the steam bath, and the residue dissolved in 25 cc. boiling H2O, neutralized with NH4OH, and cooled gave 0.4 g. Ac derivative of I, m. 221-2° (from H2O). Finely powd. I (50 g.) added with stirring below 40° to 170 cc. concentrated H2SO4 (cooled to 20°) during 0.5 hr., and the solution stirred 1 hr. at room temperature, poured with stirring into 500 cc. H2O and 250 cc. ice, refrigerated overnight, and filtered yielded 67.0 g. 3-amino-4-pyrazolecarboxamide-0.5H2SO4 (II) (II.0.5H2SO4), m. 222-5° (from H2O). II.0.5H2SO4 (3 g.) in 50 cc. H2O adjusted with NH4OH to pH 9 and allowed to stand 3 days deposited 1.1 g. II, m. 187-9° (from H2O). II.0.5H2SO4 (75 g.) and 200 cc. HCONH2 heated 45 min. at 180-90°, cooled, diluted with 1 l. cold H2O, and filtered yielded 48.0 g. 4-hydroxypyrazolo[3,4-d]pyrimidine (III). II.0.5H2SO4 (100 g.) and 200 g. urea heated 20 min. at 160° and then 20 min. at 190° and dissolved in hot dilute aqueous NaOH, the boiling basic solution carefully acidified with AcOH and filtered after 10 min. yielded 74 g. 90-5% pure 4,6-di-OH analog (IIIa) of III. I (35 g.) and 70 g. CS(NH2)2 heated 0.5 hr. at 180° and 10 min. at 200°, cooled, and dissolved in hot dilute aqueous NaOH, the hot solution treated with C, and the boiling filtrate carefully acidified with glacial AcOH yielded 26.0 g. 4-amino-6-mercaptopyrazolo[3,4-d]pyrimidine (IV), light tan material. II.0.5H2SO4 (50 g.) with 100 g. CS(NH2)2 gave similarly 24.0 g. 4-OH analog (V) of IV. Dry III (10 g.) added to 300 cc. POCl3, the mixture refluxed 1.5 hrs. with 30 cc. PhNMe2, the excess POCl3 removed in vacuo, the sirupy residue poured with stirring into 100 cc. H2O and 400 g. crushed ice and extracted with Et2O, and the extract worked up gave 9.8 g. 4-chloropyrazolo[3,4-d]pyrimidine (VI), decomposed at 130-5° (from C6H6). III (10 g.) finely powd. and mixture with 50 g. P2S5, the mixture added in small portions with stirring to 300 cc. Tetralin at 165° during 0.5 hr., the mixture heated 4 hrs. with stirring at 190-5°, cooled, and filtered, the filter residue washed with petr. ether, dried, added carefully to 1 l. H2O at 80°, boiled 10 min., and treated with enough KOH to effect solution, the solution stirred with C and filtered, and the hot filtrate acidified with AcOH gave 10.1 g. 4-mercaptopyrazolo[3,4-d]pyrimidine (VII), white crystals, m. above 360° (from 30% EtOH). VI (2 g.) and 2 g. CS(NH2)2 refluxed 2 hrs. with 100 cc. absolute EtOH cooled and filtered gave 1.6 g. crude VII. VI (3 g.) in 150 cc. concentrated NH4OH concentrated on the steam bath to 50 cc., diluted with 200 cc. concentrated NH4OH, concentrated on the steam bath to 150 cc., boiled with C, filtered, and cooled gave 0.85 g. 4-aminopyrazolo[3,4-d]pyrimidine (VIII), colorless needles. I (30 g.) boiled 0.5 hr. with 60 cc. HCONH2, cooled, diluted with 100 cc. cold H2O, and filtered, the residue suspended in 400 cc. hot H2O, treated with 50 cc. concentrated HCl, boiled 15 min. with C, and the hot filtrate adjusted to pH 8 with concentrated NH4OH and cooled to room temperature gave 21.0 g. VIII, colorless solid. VI (5.0 g.) and alc. NH3 heated 12 hrs. at 100° in a bomb and filtered, and the crude residue dissolved in dilute HCl and reprecipitated with NH4OH gave 3.9 g. VIII. IIIa (10 g.) and 30 cc. PhNMe2 refluxed 1 hr. with 250 cc. POCl3, the mixture worked up in the usual manner, and the product isolated with Et2O gave 2.4 g. compound C12H10ClN4(sic), light yellow needles, m. 225-7° (from xylene). V (14 g.) and 10 g. NaOH in 300 cc. H2O shaken 10 min. at 5° with 12 g. MeI, charcoaled, filtered, and acidified with AcOH yielded 12.0 g. 4-hydroxy-6-methylmercaptopyrazolo[3,4-d]pyrimidine (IX). I (10 g.) heated 20 min. with 20 g. urea at 180-200°, the cooled solid dissolved in 2N NaOH, the solution boiled gently 10 min. with C, and the boiling filtrate acidified with glacial AcOH gave 4-amino-6-hydroxypyrazolo[3,4-d]-pyrimidine which was purified by reprecipitation IX (22.0 g.), 400 cc. POCl3, and 30 cc. PhNMe2 refluxed 0.5 hr. gave 16 g. 4-Cl analog of IX, m. 178-9° (decomposition) (from heptane). VII (5 g.) in 65 cc. 0.8N NaOH shaken 15 min. at 20° with 5.0 g. MeI, treated with C, filtered, and acidified with AcOH, the crude precipitate suspended in 100 cc. H2O and adjusted with NH4OH to pH 9 and filtered, and the residue washed and recrystallized from H2O yielded 4.1 g. 4-MeS analog of VII, m. 193°. IIIa (15 g.) and 80 g. P2S5 refluxed 4 hrs. with 900 cc. dry pyridine and evaporated in vacuo on the steam bath, the residue diluted with 600 cc. ice H2O, allowed to stand 0.5 hr. at room temperature, heated 2 hrs. on the steam bath, the solution refrigerated overnight, and the crude precipitate reprecipitated with AcOH from boiling aqueous alkali gave 12.6 g. 4-mercapto-6-hydroxypyrazolo[3,4-d]pyrimidine, light green needles. V (15 g.) and 65 g. P2S5 in 900 cc. dry pyridine gave similarly 12.0 g. 4,6-dimercaptopyrazolo[3,4-d]pyrimidine, light green solid. Finely powd. VI (4.5 g.) in 150 cc. H2O and 4 cc. concentrated NH4OH hydrogenated about 6 hrs. at 20 lb. pressure over 1.0 g. 10% Pd-C and filtered, the residue extracted with 100 cc. boiling H2O, the combined filtrates evaporated to dryness on the steam bath, the residue extracted 18 hrs. with 200 cc. PhMe in a Soxhlet apparatus, the extract evaporated, and the residue sublimed at 180-200° and 15 mm. yielded 2.65 g. pyrazolo[3,4-d]pyrimidine (X), colorless needles, m. 213-14°. VI (3.0 g.) heated 1 hr. on the steam bath with 0.6 g. Na dissolved in 30 cc. absolute EtOH, diluted with 20 cc. H2O, and neutralized with AcOH gave 1.3 g. 4-EtO derivative of X, m. 168-9°. 4-Cl analog (XI) of X (7.0 g.) in 150 cc. EtOH and 10 cc. concentrated NH4OH hydrogenated 24 hrs. over 2.7 g. Pd-C at 20 lb. pressure, filtered, and evaporated to dryness on the steam bath yielded 1.7 g. 6-methylmercaptopyrazolo[3,4-d]pyrimidine, white crystals, m. 210-12° (from 80% EtOH). XI (4.0 g.) heated 4 hrs. on the steam bath with 1.0 g. Na in 75 cc. absolute MeOH, neutralized with glacial AcOH, and cooled gave 3.1 g. 4-MeO analog of IX, m. 193-4° (from aqueous MeOH). VI (5-10 g.) added to 50-100 cc. of a 25-40% aqueous solution of a primary or secondary amine, heated 4 hrs. on the steam bath, refrigerated overnight, and filtered, and the residue washed with a little ice water and recrystallized gave the corresponding N-substituted-4-aminopyrazolo[3,4-d]pyrimidines (XII) (method A); VI (5-10 g.) added to about 0.15 mole primary or secondary amine in 150 cc. absolute EtOH, heated 4 hrs. on the steam bath, cooled overnight and filtered, and the crude product recrystallized gave the corresponding XII (method B) (N-substituents, m.p., % yield, and method given): H, Me, 227-8° (from H2O), 83, A; Me, Me, 233-4° (from C6H6-EtOH), 61, A; Et, Et, 186-7° (from aqueous EtOH), 85, A; H, iso-Pr, 253-4° (from H2O), 70, A; H, Ph, 263-4° (from EtOH), 55, B; H, PhCH2, 215-17° (from aqueous EtOH), 78, B; H, Et, 259-60° (from aqueous EtOH), 77, A; H, 1-furylmethyl, 223-5° (from EtOH), 82, B; Me, Ph, 234-6° (from EtOH), 63, B; H, Bu, 205-6° (from aqueous EtOH), 75, B; H, o-MeC6H4, 260-1° (from EtOH), 85, B. XI gave similarly the 6-MeS derivatives of XII (N-substituents, m.p., % yield, and method given): H, H, above 300° (from H2O), 58, A; Me, Me, 263-5° (aqueous EtOH), 45, A; H, NH2, above 300° (from H2O), 30, A; H, (CH2)2NEt2, 130-2° (from EtOH), 35, B. The solubilities of a number of 4,6-disubstituted-pyrazolo[3,4-d]pyrimidines (XIII) are tabulated (4 and 6-substituents, and solubility in H2O at 100° in parts of H2O necessary to dissolve 1 part XIII given): OH, H, 190; OH, OH, 800; NH2, H, 1000; MeNH, H, 10; Me2N, H, 10; SH, H, 500; H, MeS, 350; MeS, H, 300; H, H, 200 (at 30°). The ultraviolet absorption maximum of the various XIII described at pH 1 and 11 are listed. The experimental process involved the reaction of 4-Chloro-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine(cas: 85426-79-5).Safety of 4-Chloro-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine
4-Chloro-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine(cas:85426-79-5) belongs to pyrazoles-derivatives. The use of pyrazole derivatives is based on their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, sedative, muscle relaxant, neuroleptic, anticonvulsant, monoamine oxidase inhibitory, antidiabetic and antibacterial activities.Safety of 4-Chloro-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine
Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics