4-CHLORO-7-TOSYL-7H-PYRROLO[2,3-D]PYRIMIDINE

Preparation of Thiazolyl-Pyrrolo[2, 3-]Pyrimidines of the Invention; [0221] 4-Chloro-7-(toluene-4-sulfonyl)-7H-pyrroIo[2, 3-*/]pyrimidine; To a solution of (10 g, 65.1 mmol] of 4-Chloro-7H-pyrrolo[2, 3-d]pyrimidine in 25OmL of dry THF was cautiously added portionwise over 5 minutes time [2.86 g, 71.6 mmol] EXAMPLE 13-((3Λ, 4Λ)-4-Methyl-3-(methyl(7H-pyrrolo[2, 3-rf]pyrimidin-4- yl)amino)piperidin-l-yl)-3-oxopropanenitrile mono citrate salt (CP-690550 citrate salt)Step 1[00151] 4-Chloro-7-tosyl-7H-pyrrolor2, 3-6πpynmidine: At about O 4-chloro-7-tosyl-7H-pyrrolo[2, 3-d]pyrimidine; A slurry of 1 (307 mg, 2.00 mmol), Tosyl-chloride (418 mg, 2.20 mmol) and freshly ground KDissolve 4-chloro-pyrrolo[2, 3-d]pyrimidine or intermediate 2 (10 mmol) in acetone (35 mL), add p-toluenesulfonyl chloride (1 mmol) in an ice bath, and then add 2.0 mol/L NaOH solution (12·5 mmol, 6.2 mL) was stirred overnight at room temperature. After the reaction was completed, a large amount of white solids precipitated, which was filtered. The filter cake was washed with 20 mL of acetone/water (1:1) and dried to obtain Intermediate 3. 4-Chloro-7-p-toluenesulfonyl 7H-pyrrolo[2, 3-d]pyrimidine (3a) White solid, 95percent yieldPreparation of 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2, 3-d]pyrimidine:; To a clean, dry, nitrogen-purged reactor were charged acetone (87.5 ml), p-toluenesulfonyl chloride (17.1 g, 0.09 mol) and 4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (25.0 g, 0.16 mol). The reactor was cooled to between -5.0 to 5.0P-toluenesulfonyl chloride (67.5 g, 348 mmol, 1.10 eq.) and 4-chloro-7-Hpyrrolo[2, 3-d]pyrimidine (50 g, 320 mmol, 1.0 eq.) was dissolved in acetone (500 ml), sodium hydroxide solution (2 Min water, 200 ml, 1.20 eq.) was slowly added thereto at 0°C, and the reaction was stirred at 20°C for 6 hours to precipitate the solid. Filtration and washing with acetone and water gave the white target compound (90 g, yield = 90percent).A mixture of 4-c oro-7B~pyrfolo[2.s3-dJpyrimidme (10.0 g, 65 mraol), TsCl (13.7 g, 72 iirniol) and NaOH (40 ml, , 2N) in acetone (100 mL) was stirred at room temperature overnight. The resulting solid w s collected by filtration and washed with acetone and then with water to give the title compound as a white solid (16 g„ 80percent). H NM (400 MHz, CDCh) 5 8.7' (s, I B), 8.09 id J 8 0 Hz, 20), 7.77 (d, J 4.0 Hz, 1.H), 7.33 (4 J .0 1 . 2Π ). 6, 70 (d, -4.0 1 / , 2H). 2.40 (s, 3H), The mixture of 4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (3.0g, 20mM), NEt[0152] To a stirred solution of TsCI (1.35 g, 7.0 mmol) and 4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (1.0 g, 6.4 mmol) in acetone (10 mL) was added 2.0 M aqueous NaOH (8 mL, 16 mmol) at 0°C. The mixture was stirred at ambient temperature for 6 hours yielding a suspension. The solid product was collected by filtration and washed with acetone/water to afford the title compound as a white solid (0.9 g, 45percent). MS (ESl) calcd for C13H10C1N3025: 307.0; found:308.1[M+H]. 1H NMR (400 MHz, CDCI3) 6 8.77 (s, 1H), 8.09 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 4.0Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 4.0 Hz, 1H), 2.41 (s, 3H).Autoclave, 3.5L of acetone, p-toluenesulfonyl chloride and 1.36kg 1kg compound 7, followed by stirring under cooling to 0 ~ -5 , maintained at below 5 2.5M sodium hydroxide solution was added dropwise 3.5L, warmed to completion of the dropwise 20-30 deg.] C for 1 h, TLC monitoring completion of the reaction was filtered, washed with 50percent acetone, slurried, filtered, drained, and dried in vacuo 50 ° to give compound 6 about 2kg.A mixture of 66 g (0.43 mol) 4-chloro-7H-pyrrolo[2, 3-d]pyrimidine, 607 g dichloromethane, 3.0 g tetrabutylammonium chloride, 90 g tosyl chloride, 85 g potassium carbonate and 381 g water is stirred efficiently at room temperature until reaction is complete. The phases are separated and the organic phase is washed with 340 g water. The organic phase is treated with 6.0 g of activated charcoal, completed with 318 g water and the organic solvent removed by distillation. The mixture is supplemented by 318 g heptane and the product is centrifuged, washed with heptane and water and vacuum dried at a temperature of not more than 8o°C, yielding 124 g (yield: 0.40 mol, 94percent conversion rate) of 4-chloro-7-tosyl-7H-pyrrolo[2, 3-d]pyrimidine having a purity of 99.9 area-percent measured by HPLC.

Molecular Weight:307.76
XLogP3:3.2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:307.0182254
Monoisotopic Mass:307.0182254
Topological Polar Surface Area:73.2
Heavy Atom Count:20
Complexity:445
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes