In organic chemistry, atoms other than carbon and hydrogen are generally referred to as heteroatoms. The most common heteroatoms are nitrogen, oxygen and sulfur. Now I present to you an article called Pyrimidines. I. Synthesis of pyrimidinethiols, published in 1961, which mentions a compound: 6307-44-4, mainly applied to , Recommanded Product: 6307-44-4.
cf. CA 54, 6747a. The 9 previously unknown isomers of the 22 possible substituted pyrimidinethiols, containing H, HO, NH2, and SH as substituents were synthesized and methods for preparation of some of the previously reported compounds were improved. Various derivatives of RC:N.CR1:N.CR2:CH (I) were prepared for preliminary screening as antitumor agents. HOCH2CH2OH (200 ml.), 125 g. 4,5-Cl(MeS)C4H2N2, and 200 g. NaSH heated slowly to 100° with frothing and bubbling, the mixture carefully heated to 150° and kept 30 min., the solution poured into 1500 ml. H2O and the boiled, decolorized hot filtrate acidified with AcOH, the precipitate reprecipitated from hot dilute aqueous NH4OH with AcOH gave 85 g. I (R = H, R1 = R2 = SH), converted by concentrated HBr to I (R = R1 = H, R2 = SH). NaHS (42 g.) and 13 g. 4,6,2-Cl(HO)(MeS)C4HN2 in 120 ml. HOCH2CH2OH heated 30 min. at 150°, the cooled mixture poured into 500 ml. H2O and the boiled decolorized solution filtered, acidified with AcOH to pH 5 and the refiltered solution adjusted to pH 1.0 with dilute HCl, the product reprecipitated from solution in dilute NH4OH with HCl, and the product recrystallized from HCONMe2-H2O gave 9.0 g. I (R = OH, R1 = R2 = SH), m. 262-4° (method A). The appropriate chloropyrimidine (60 g.) in 500 ml. absolute alc. refluxed 3 hrs. with 150 g. NaHS, the chilled mixture filtered and the alc. washed precipitate boiled in 1 l. H2O, the decolorized solution filtered, the filtrate acidified and the precipitate recrystallized from the appropriate solvent gave RC:N.CR1: N.CR2:CR3 (II) (method B). In method C the procedure was the same but no precipitate was formed. The light yellow alc. solution was diluted with 1 l. boiling H2O and acidified and the precipitate recrystallized The appropriate chloropyrimidine (40 g.) and 40 g. (H2N)2CS in 500 ml. absolute alc refluxed 2 hrs. the mixture chilled and the precipitated ligroine-washed product purified by reprecipitation and recrystallization gave II (method D). The appropriate chloropyrimidine (35 g.) and 70 g. powd. NaHS in 400 ml. H2O was autoclaved 4 hrs. at 150°/8 atm., the solution boiled and the decolorized solution filtered, acidified with AcOH [for the preparation of I (R = NH2, R1 = SH, R2 = OH)] or dilute HCl [for the preparation of I (R = SH, R1 = R2 = OH)], and the products purified by recrystallization (method E). I (R = NH2, R1 = SH, R2 = OH) (50 g. finely powd. and dried at 100°) refluxed 2 hrs. with 150 g. P2S5 in 1.5 l. dry C5H5N, excess C5H5N evaporated in vacuo and the residue diluted cautiously with 750 ml. H2O, the mixture refluxed 2 hrs. on a steam bath with evolution of H2S, the chilled mixture filtered and adjusted to pH 2, the volume reduced to 33% in vacuo and the cooled concentrate filtered, the residue taken up in dilute NH4OH and the boiled decolorized solution filtered, acidified with dilute HCl and the precipitate recrystallized from HCONMe2-H2O gave 35 g. I (R = H2N, R1 = R2 = SH). Purified P2S5 (125 g.) and 52 g. I (R = R1 = H, R2 = OH) refluxed 1 hr. with stirring in l. C5H5N, the hot solution poured into 1 l. H2O and the solution heated on a steam bath 3 hrs., the filtered solution evaporated in vacuo to 200 ml., refrigerated and the H2O-washed product recrystallized from 500 ml. boiling H2O gave 42 g. I (R = R1 = H, R2 = SH). I(R = R2 = Cl, R1 = NH2) (33 g.) added to 1 l. 4:1 alc.-H2O containing 40 g. NaOH saturated with H2S, the mixture refluxed with stirring 2 hrs. with passage of H2S, treated with C and the filtered solution acidified with AcOH gave 42 g. I (R = SH, R1 = NH2, R2 = Cl), m. 302° (decomposition), λ 260 mμ (ε 9800, pH 1), λ 280 mμ (ε 12,500, pH 11), converted by autoclaving with NaHS to I (R = SH, R1 = R2 = OH). I (R = R2 = OH, R1 = SH)(60 g.)in 1 l. 2N NaOH stirred 3 hrs. with dropwise addition of 50 g. Me2SO4, the solution boiled with addition of C and the decolorized filtered solution acidified to pH 1.0 with HCl gave 50 g. I (R = R1 = OH, R1 = MeS) (III), m. above 360° (H2O). III (80 g.) refluxed 2 hrs. with 500 ml. POCl3, excess POCl3 removed in vacuo and the residue poured with stirring over crushed ice, the mixture stirred 20 min. at 0°, filtered and the precipitate washed in ice H2O until the pH of the washings was no longer below 5, the material dried 16 hrs. in vacuo and recrystallized from MeOH and H2O gave 64 g. I (R = R2 = Cl, R1 = MeS) (IV), m 43°. Treatment of IV with NaHS at 150° in HOCH2CH2OH gave I (R = R1 = R2 = SH). NaHS (75 g.) in 500 ml. MeOH at 50° stirred with portionwise addition of 50 g. IV, the mixture stirred 30 min. before dilution with 1 l. H2O, the solution boiled with C and the filtered solution acidified, the product reprecipitated from dilute NH4OH with AcOH, and recrystallized from HCONMe2-H2O gave 40 g. I (R = R2 = HS, R1 = MeS), m. above 360°. IV (50 g.) refluxed with stirring 4 hrs. in 500 ml. 2N NaOH, the solution decolorized and the filtered solution acidified with AcOH, the precipitate purified by reprecipitation and recrystallized from HCONMe2-H2O gave 40 g. I (R = Cl, R1 = MeS, R2 = OH), m. 208°. Absolute MeOH (150 ml.) at 0° treated with 30 g. finely powd. IV, the mixture stirred 45 min. with passage of dry Cl, filtered from 8 g. product, and the filtrate evaporated at 20° in a stream of dry air gave 12 g. product; the crops combined and recrystallized from EtOAc and C7H16 gave 17 g. I (R = R2 = Cl, R1 = MeSO2) (V), m. 119°. V (15 g.) warmed in 200 ml. N NaOH, the filtered solution chilled and the precipitate washed with cold H2O and alc., the dry salt (11.6 g.) in 150 ml. H2O carefully neutralized with HCl and the solution evaporated in vacuo, the residue taken up in boiling Me2CHOH and diluted with C7H16 gave 5 g. I (R = R2 = Cl, R1 = OH), m. 262° (Me2CHOHC7H16). The ultraviolet absorption spectra of the completed series of I showed the approx. maximum of the major peak of I in solutions at pH 1.0 were 280, 300-20, 320-40, and 360-70 mμ for 2-pyrimidinethiols, 4-pyrimidinethiols, 2,4-pyrimidinedithiols, and 4,6-pyrimidinedithiols, resp. Data for I and for a number of known thiopyrimidines, II, not previously published are recorded for comparison [R, R1, R2, R3, m.p. (solvents), and % yield given]: H, SH, H, H, 229-30° (alc.), 70; H, H, SH, H, 190-2° (H2O), 69; H, OH, SH, H, 298-300° (H2O-HCONMe2), 88; H, SH, OH, H, 310-12° (H2O), 73; H, NH2, SH, H, 231-3° (H2O-HCONMe2), 68; OH, H, SH, H, 247° (H2O), 79; H2N, H, SH, H, 306° (H2O-HCONMe2), 61; H, SH, SH, H, 300° (H2O), 70; HS, H, SH, H, 250-2° (H2O), 70; OH, SH, OH, H, above 360° (H2O-HCONMe2), 84; OH, OH, SH, H, 245° (H2O), 54; H2N, OH, SH, H, 355° (H2O-HCONMe2), 43; OH, H2N, SH, H, above 360° (H2O-HCONMe2), 82; H2N, H2N, SH, H, above 360° (reprecipitation), 50; H2N, SH, OH, H, above 360° (reprecipitation), 91; H2N, SH, H2N, H, above 360° (reprecipitation), 93; OH, SH, SH, H, 262-4° (H2O-HCONMe2), 79; H2N, SH, SH, H, above 360° (H2O-HCONMe2), 60; SH, OH, SH, H, 266-7° (H2O-HCONMe2), 46; SH, H2N, SH, H, 267° (H2O), 76; SH, SH, SH, H, above 360° (reprecipitation), 70; Cl, H2N, H, Cl, above 360° (reprecipitation), 63; Me, H2N, SH, H, 321° (reprecipitation), 84; Me, H2N, SH, Br, 207° (H2O-HCONMe2), 98; Me, SH, SH, H, above 360° (H2O-HCONMe2), 70; H, SH, SH, CO2H, 261-3° (H2O-HCONMe2), 63; SH, H, SH, Cl, 215-17° (reprecipitation), 70; SH, H, SH, Br, 213° (reprecipitation), 92; SH, H2N, SH, Ph, 266-8° (H2O-HCONMe2), 60; H, MeS, SH, H, 203° (H2O-HCONMe2), 96; Me, MeS, SH, H, 239° (H2O-HCONMe2), 78; SH, MeS, SH, H, above 360° (H2O-alc.), 80. For comparison of structure and biol. activities in pyrimidine thiols, a number of new related 4-pyrimidine thiols substituted in position 5 were synthesized. Thiopyrimidine (0.08 mole) stirred in 250 ml. N NaOH treated with a stoichiometric amount of the appropriate alkyl halide, the mixture stirred 3 hrs. and the H2O-washed precipitate recrystallized gave the corresponding alkylthiopyrimidine (method A). Similarly, the above reaction mixture on failure to give a precipitate was acidified with AcOH and the product recrystallized to yield the required alkyl thiopyrimidine (method B). The yields ranged from 80 to 95%. Phys. data for alkylthio- and aralkylthiopyrimidines are listed [R, R1, R2, R3 of formula II, method of synthesis, m.p. (solvent, if other than HCONMe2 + H2O) given]: MeS, H, OH, H, B, 230° (H2O); PhCH2S, H, OH, H, B, 238-9°; 2,4-Cl2C6H3CH2S, H, OH, H, B, 191.3°; MeS, H, H2 N, H, A, 168-70°; EtS, H, H2N, H, A, 147-9°; PhCH2S, H, H2N, H, A, 140°; 2,4-Cl2C6H3CH2S, H, H2N, H, A, 184-6°; p-O2NC6H4CH2S, H, H2N, H, A, 165-7°; MeS, H, MeS, H, A, 52-4° (C7H16); MeS, H, MeS, H2N, A, 79°; MeS, H, MeS, Cl, A, 118-20°; EtS, H, EtS, Cl, A, 58-9°; PhCH2S, H, PhCH2S, Cl, A, 86-8°; 2,4-Cl2C6H3CH2S, H 2,4-Cl2C6H3CH2S, Cl, A, 155°; MeS, H, MeS, Br, A, 155°; PrS, H, PrS, Br, A, 44-6°; PhCH2S, H, PhCH2S, Br, A, 95-7°; 2,4-Cl2C6H3CH2S, H, 2,4-Cl2C6H3CH2S, Br, A, 149°; p-O2NC6H4CH2S, H, p-O2NC6H4CH2S, Br, A, 168-70°; PhCH2S, OH, OH, H, B, 242°; H, OH, o-ClC6H4CH2S, H, A, 174-6°; H, OH, 2,4-Cl2C6H3CH2S, H, A, 193-4°; MeS, H2N, H, H, A, 150-3°; Et, H2N, H, H, A, 155°; PhCH2S, H2N, H, H, A, 178-80°; 2,4-Cl2C6H3CH2S, H2N, H, H, A, 155-7°; o-ClC6H4CH2S, H2N, Me, H, A, 143-5°; MeS, H2N, Cl, H, A, 106-8°; EtS, H2N, Cl, H, A, 109-10°; PrS, H2N, Cl, H, A, 105-6°; PrS, H2N, Me, Br, A, 95-7°; o-ClC6H4CH2S, H2N, Me, Br, A, 138-40°; p-O2NC6H4CH2S, H2N, Me, Br, A, 226-8°; EtS, H2N, EtS, H, A, 54°; PrS, H2N, PrS, H, A, 85-7°; PhCH2S, H2N, PhCH2S, H, A, 134-6°; 2,4-Cl2C6H3CH2S, H2N, 2,4-Cl2C6H3CH2S, H, A, 159-61°; MeS, H2N, MeS, Ph, A, 128-9° (C7H15); PhCH2S, H2N, PhCH2S, Ph, A, 207-9° (C7H15); o-ClC6H4CH2S, H2N, o-ClC6H4CH2S, Ph, A, 174-5° (EtOAc); 2,4-Cl2C6H3CH2S, H2N, 2,4-Cl2C6H3CH2S, Ph, A, 164-7° (PhMe); MeS, MeS, Me, H, A, 43-5° (C7H15); 2,4-Cl2C6H3CH2S, MeS, Me, H, A, 100-2°; H2N, MeS, MeS, H, A, 121-3°; MeS, MeS, MeS, H, A, 114-16°; H, MeS, MeS, CO2H, B, 201-3°; PhCH2S, PhCH2S, Me, H, A, 37-9° (C7H15); o-ClC6H4CH2S, o-ClC6H4CH2S, o-ClC6H4CH2S, H, A, 117-18° (H2O-alc.); 2,4-Cl2C6H3CH2S, 2,4-Cl2C6H3CH2S, H, H, A, 94-6° (C7H15); 2,4-Cl2C6H3CH2S, 2,4-Cl2C6H3CH2S, Me, H, A, 107-9° (C7H15); H2N, 2,4-Cl2C6H3CH2S, 2,4-Cl2C6H3CH2S, H, A, 125-7° (C7H15); 2,4-Cl2C6H3CH2S, 2,4-Cl2C6H3CH2S, 2,4-Cl2C6H3CH2S, H, A, 120-4°. Other II prepared were (R, R1, R2, R3, method of synthesis, and m.p. (solvent) given): MeS, OH, H2N, H, B, 294° (H2O); MeS, H2N, Me, H, A, 152°; EtS, H2N, Me, H, A, 122-4°; BuS, H2N, Me, H, A, 70-2°; PhCH2S, H2N, Me, H, A, 118-20°; 2,4-Cl2C6H3CH2S, H2N, Me, H, A, 157-60°; p-O2NC6H4CH2S, H2N, Me, H, A, 157-9°; MeS, H2N, OH, H, B, 274-6°; EtS, H2N, OH, H, B, 248°; PrS, H2N, OH, H, B, 228-32°; BuS, H2N, OH, H, B, 240-2°; C6H11S, H2N, OH, H, B, 185°; MeS, H2N, Me, Br, A, 140-2°; PhCH2S, H2N, Me, Br, A, 135-7°; MeS, H2N, MeS, H, A, 116-18°; OH, MeS, MeS, H, B, 197° (H2O). Ultraviolet maximum at pH 1 and 11 were given for the II prepared
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Reference:
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com