2-aminopyrimidine compounds as potent HSP-90 inhibitors
http://www.google.com/patents/WO2008096218A1?cl=enCompound I of (C) Modulation:
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IC
Ethyl 2-amino-4-chloro-5, 7-dihydro - 6H Pyrrolo [3 and 4-D] pyrimidine-6 carboxylate
Step 1. Ethyl N (Ethoxycarbonyl) beta Alaninate (c)
Ethyl Acrylate (A) (50 mL, 460Mmol, 1.1 equiv), glycine ethyl Ester hydrochloride (b) (58.4 g, 418Mmol, 1 eq), and Triethylamine ( 58.3ML, 418Mmol, 1 eq) Containing Anhydrous EtOH (960 mL) of I WAS Stirred at Ambient temperature for about 72 hours. After the Reaction IS Complete, to Remove the Volatiles components in vacuo, and USED in Succession Intermediate crude to (c) as it IS.
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Step 2. Ethyl N (Ethoxycarbonyl)-N-(2-ethoxy-2-Oxoethyl) beta Alaninate (e)
crude intermediate (c) (418Mmol) CH 2 Cl 2 WAS Dissolved in (275 mL), Triethylamine (58.3ML, after Adding 418Mmol), WAS Added ethyl chloroformate (D) (39.8ML, 418Mmol). The Reaction Mixture Stirred at Ambient temperature for about 24 hours. After the Reaction WAS completed, we Have removed the Volatiles components in vacuo. The crude Product WAS then Distilled in vacuo (about 5 mmHg), WAS Dissolved in EtOAc, Which Saturated KHSO 4 in 3 times, Washed once with brine, Na 2 SO 4 and Dried. After Filtration and removal of the Volatiles components in vacuo, A clear oil of intermediate (e) as (74.8 g, 272Mmol), WAS Obtained in 65% yield in Two Steps.
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Step 3. Diethyl 4-oxo-pyrrolidine-1,3-dicarboxylate (f )
in Anhydrous EtOH (41.7ML) Solution of NaOEt Which HAD Been Cooled in an ice Bath (32.6ML) (21 wt% in EtOH), an intermediate in A Nitrogen atmosphere body and (e) (18.0 g, 65.2 mmol) it WAS Added. The ice Bath WAS removed, to Complete condensation in the Observation by TLC, the Mixture WAS Heated at 80 ° C. about 12 hours. The Mixture WAS Poured ONTO ice / Water and Extracted with EtOAc. The Solvent Na 2 SO 4 Dried over , filtered, and Evaporated to Give A crude intermediate (f) an off-white solid (14.05 g), Were USED in Succession without Purification.
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Step 4. Ethyl 2-amino-4-hydroxy-5, 7-dihydro 6H Pyrrolo [3 and 4-D] pyrimidine-6-carboxylate (h)
Intermediate (f) (14.05 g) and guanidine carbonate (g) (16.6 g, 91.9Mmol) I Suspension Refluxed in t butanol (147 mL) about 6 hours of. The Mixture WAS Cooled to Ambient temperature over about 2 hours. The Volatiles Were removed components in vacuo, Water WAS Added. KHSO 4 WAS Adjusted to about 6 to 7 pH USING. The Resulting Slurry WAS filtered to collect the Solids , after Which it WAS Washed with Water and Washed with EtOAc. The solid WAS Dried under VACUUM, intermediate (h) WAS Obtained in 87% yield as A Cream solid (11.9 g, 53.1 mmol). 1 H NMR (400 MHz, DMSO D6) delta ppm 11.01 (s, 1H), 6.97 (s, 0.5H, Possibility of tautomers), 6.70 (s, 2H), 4.25 (s, 4H), 4.13-4.03
(M, 2H), 1.22 (t , 3H) LCMS (M + H). + :. 225.2
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Step 5. Ethyl 2-amino-4-chloro-5, 7-dihydro - 6H Pyrrolo [3 and 4-D] pyrimidine-6 carboxylate I (C)
Intermediate (h) (11g, 49 mmol) and the Two Toluene Azeotroped. Anhydrous acetonitrile (250 mL) and POCl 3 (25 mL, 270 mmol) WAS Added and the Mixture WAS Refluxed for about 2.5 hours. Additional POCl 3 WAS Added (50 mL), the Mixture WAS FURTHER Refluxed for 2 hours.The Volatiles components Were Concentrated at 40 ° C. in vacuo to Give A red Solution. Was Added Anhydrous acetonitrile minimum amount WAS Transferred to the Solution IS Facilitated, and it then Poured it on ice in A Large beaker. FURTHER Rinsing the Flask with A Small amount of acetonitrile, Which WAS Added to the ice. The ice Mixture WAS Added Water (about 50 mL), it WAS to Facilitate Stirring. Until the ice Slurry Mixture IS Strongly Basic , Concentrated NH 4 WAS Added slowly with Stirring OH (25 mL), then, still Stirred Solution of 50% NaOH Aqueous Solution to A Slurry of ice (25 mL) WAS Also Added. Ice even it WAS Added. After Stirring for about 5 minutes as the ice Slurry WAS Added EtOAc. After Stirring for A FURTHER Few minutes in A beaker, and Water WAS Added to Facilitate the Melting of the ice. The Mixture WAS Poured into A Separatory Funnel and the Layers Were partitioned. The Aqueous Layer it WAS Extracted three times with EtOAc. KHSO Which IS Saturated and the combined EtOAc Extracts Four Two times with Aqueous Saturated NaHCO 3 2 times with an Aqueous Solution, Washed once with brine, Na 2 SO 4Dried over, filtered and Evaporated to A pale pink Powder WAS Obtained Which WAS Triturated with ethyl acetate, Compound I (C) pale pink solid (6.8 g, 28 mmol) as WAS Obtained in 57% yield. HPLC / LCMS Purity WAS Higher than 90%.
1 H NMR (400 MHz, DMSO-D6 ) delta ppm 7.20 (s, 2H), 4.48 (s, 2H), 4.45 (s,
2H), 4.17-4.08 (M, 2H), 1.24 (t, 3H)
LCMS (M + H). + :. 243.2 , 245.2
1H NMR
COSY
13C NMR PREDICT
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