4-Chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine

Synthesis of Compound 18.3. A mixture of potassium tert-butoxide (450 mg, 4 mmol) and compound 18.2 (250 mg, 0.8 mmol) in THF (7.5 ml) was stirred for 16 hr. Saturated NaHCO4-Chloro-6-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2, 3-d]pyrimidine(3, 35 g, 10, 9 mmol) was dissolved in THF, potassium tert-butoxide(6.12 g, 54, 6 mmol) was added and the mixture was stirred for 3 h at rt.NaHCO3 (100 mL) was added and the mixture was extracted with ethylacetate three times, washed with water and brine, dried over MgSO4 andfiltered. Purification by flash column chromatography(cyclohexane/ethyl acetate 4:1) afforded 6 as a white solid in a yield of70percent.Step 3To the solution of 4-cMoro-6-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2, 3-d]pyrimidine(10 g, 32.5. mmol, 1.0 eq) in THF (400 mL), t-BuOK (18.23 g, 163.0 mmol, 5 eq) was added and stirred at RT for 12 h. Sat, MaHC0Step 3To the solution of 4-chloro-6-methyl-7-(phenylsuIfonyl)-7H-pyrrolo[To the solution of 4-chloro-6-methyl-7-(phenylsulfonyl)-7H-pynolo[2, 3-d]pyrimidine (10 g, 32.5. mmol, 1.0 eq) in THF (400 mL), t-BuOK (18.23 g, 163.0 mmol, 5 eq) was added and stirred at RT for 12 h. Sat. NaHCO3 (50 mL) was added and extracted with EtOAc. The organic layers were separated, dried and concentrated to afford 4-chloro-6-methyl-7H-pyrrolo[2, 3-d]pyrimidine as a brown solid (2.7 g, 50 percent in yield).Step 3. To the solution of 4-chloro-6-methyl-7-(phenylsulfonyl)-7H-pyrrolo [2, 3-d]pyrimidine (10 g, 32.5. mmol, 1.0 eq) in THF (400 mL), t-BuOK (18.23 g, 163.0 mmol, 5 eq) was added and stirred at RT for 12 h. Sat. NaHCO3 (50 mL) was added and extracted with EtOAc. The organic layers were separated, dried and concentrated to afford 4-chloro-6-methyl-7H-pyrrolo[2, 3-d]pyrimidine as a brown solid (2.7 g, 50 percent in yield).Step 3 To a solution of 4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (500 mg, 3.27 mmol) in DMF (5 mL) caesium carbonate (2.13 g, 6.54 mmol) and benzensulfonyl chloride (417 μ, 3.27 mmol) were added. The mixture was stirred at room temperature for 1.5 hours, then diluted with ethylacetate and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The residue was chromatographed on a silica gel column eluted with dichloroethane/ethylacetate 7/3 affording 761 mg (79percent) of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2, 3-d]pyrimidine (cmpd (XVIII), step h). To a solution of 2M in THF lithium diisopropylamide (0.83 mL, 1.65 mmol) in dry THF (5 mL) cooled to -78°C, under argon atmosphere, the last intermediate (400 mg, 1.37 mmol) dissolved in 5 mL of dry THF, was added dropwise during 10 minutes. The mixture was maintained in these conditions for 1 hour and then methyl iodide was added (0.11 mL, 1.78 mmol). The mixture was stirred 2 hours and during this time further 0.21 mL of methyl iodide were added. After 4 hours the temperature was driven to -10°C and a saturated aqueous solution of ammonium chloride was added. The product was then extracted with ethylacetate, the organic layer dried over Na2S04 and evaporated affording 4-chloro-6-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2, 3-d]pyrimidine (cmpd (XX), step i). This intermediate (1.37 mmol) was dissolved in 10 mL of THF and 5 mL of methanol and 0.5 g of sodium hydrate were added. The mixture was stirred at room temperature for 1 hour, then the solvent removed in vacuo. The residue was taken up with ethylacetate and washed with a saturated aqueous solution of ammonium chloride and extracted again with ethylacetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated, .giving 223 mg of 4-chloro-6-methyl-7H-pyrrolo[2, 3-d]pyrimidine (cmpd (XXI), step j). This intermediate (1.37 mmol) was dissolved in chloroform (10 mL) and N-iodo succinimide (308 mg, 1.37 mmol) was added. The mixture was refluxed for 1.5 hours, cooled to room temperature, diluted with dichloromethane, washed with aqueous Na2S203 and ammonium chloride. The organic layer was dried over Na2S04 and evaporated. The residue was chromatographed on a silica gel column 1 , 2-dichloroethane/ethylacetate 6/4, giving 110 mg of 4-chloro- 5- iodo-6-methyl-7H-pyrrolo[2, 3-d]pyrimidine (cmpd (XXII), step d). The last intermediate (0.39 mmol) was dissolved in DMF (3 mL) and additioned with caesium carbonate (257 mg, 0.79 mmol) and iodoethane (47 μ, 0.59 mmol). The mixture was stirred at room temperature for 2 hours, thenpoured into water and extracted twice with ethylacetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was finally puriufied by chromatography on a silica gel column eluted with dichloromethane/ethylacetate giving 51 mg of 4-chloro-7-ethyl-5-iodo-6-methyl-7H-pyrrolo[2, 3-d]pyrimidine (cmpd (IV), step e). 1H NMR (401 MHz, DMSO-d6) δ ppm 1.24 - 1.32 (m, 3 H) 2.54 (s, 3 H) 4.36 (q, J=7.16 Hz, 2 H) 8.58 (s, 1 H)6.14. Example 14(S)-N-(3-bromophenyl)-N'-cyano-2-methyl-4-(6-methyl-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)piperazine-1-carboximidamide A. Preparation of 4-chloro-6-methyl-7H-pyrrolo[2, 3-d]pyrimidine. In a sealed tube, ethyl 2-amino-5-methyl-1H-pyrrole-3-carboxylate (150 mg, 0.9 mmol, prepared according to literature procedures, J. Heterocyclic Chem., 23:1555 (1985)) was dissolved in formamide (4.5 ml), formic acid (2.3 ml) and DMF (1.0 ml) and heated to 155° C. for 12 h. The reaction was concentrated, taken up with NaHCO

Molecular Weight:167.59
XLogP3:2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:167.0250249
Monoisotopic Mass:167.0250249
Topological Polar Surface Area:41.6
Heavy Atom Count:11
Complexity:153
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes