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With hydrogenchloride; formic acid; water for 1h; Heating / reflux;
Synthesis of 2-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-5-ol (BA24dd); BA24 (3-(4-fluoro-3-methoxyphenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 30 mg, 0.10 mmol) was dissolved in a solution of formic acid (4.5 ml, 10 equivalents) and HCl (0.45 ml, 1 equivalent). The reaction was heated and stirred for one hour under an argon atmosphere. The reaction was then concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA24dd. ESI-MS (M+H)+ m/z calcd 309.1, found 309.1.
With hydrogenchloride In 1,4-dioxane; water at 75℃;
1
Compound 2-4 is synthesized as shown in Scheme 2. Compound 1-3 is reacted with isopropyl bromide in dimethylformamide with potassium carbonate at 800C, to provide the 1 -isopropyl pyrazolopyrimidine 2-1. This intermediate with the protected indolyl boronic acid species 2-2, using tetrakistriphenylphosphine palladium catalysis in DME-water solvent at 800C for 4-5 hours, to produce the Suzuki coupling product, compound 2-3. Removal of the protecting groups with acid in dioxane yields the product, 2-( 4-amino-lH-pyrazolo[3,4-d]pyrimidin-3-yl iodide (Cpd. 2-4).
With boron tribromide In dichloromethane at -10 - 25℃;
1
An alternative route to perform the Suzuki coupling is shown in Scheme 2-B. In this approach, methyl ether protection is used for the 5-hydroxy on the indolyl boronic acid. Palladium acetate and triphenylphosphine catalyze the coupling in the presence of sodium carbonate base to provide intermediate 2-6. Along with the desired product, some amount of partially de-protected product is also formed. The crude mixture is taken into the next step for complete Boc deprotection reaction with concentrated aqueous HCl in ethanol solution, and compound 2-7 is isolated as the HCl salt. The reaction is brought to approximately pH 8 with aqueous sodium carbonate to obtain the free base. Deprotection with borontribromide affords the final product, 2-( 4-amino-l-isopropyl- lH-pyrazolo[3,4-d]pyrimidin- 3-yl)-lH-indol-5-ol (Compound 2-4). This sequence can be generalized for other compounds of the invention. [
With boron tribromide In dichloromethane at -10 - 25℃;
3B Scheme 3-B. Synthesis of 2-(4-amino-1 -isopropyl- 1H-pyrazolo [3,4- d]pyrimidin-3-yl)- 1H-indol-7-ol (Compound 3-4).
The synthesis of 2-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-7-ol (Compound 3-4) is accomplished via the same reactions as in Schemes 1 and 2, using a 7-tert-butyldimethylsilyloxy (TBS) indolyl boronic acid instead of the 5-TBSO indolyl species illustrated. Alternatively, Compound 3-4 is synthesized via methoxy protected intermediates as shown in Scheme 3-B. 5-Methoxy indolyl boronic acid, compound 3-1 is coupled to pyrazolopyrimidine iodide (compound 2-1) using palladium acetate and triphenylphosphine in the presence of sodium carbonate base to provide intermediate 3-6. Along with the desired product, some partially deprotected product is also formed. The crude mixture is taken into the next step for complete Boc deprotection. Deprotection is accomplished with aqueous HCl in ethanol solution and compound 3-7 is isolated as the HCl salt. In the last step, the salt is brought to pH 8 in aqueous potassium carbonate to obtain the free base. This material is treated with boron tribromide to remove the methyl ether protection and yield the final product, Compound 3-4.
With hydrogenchloride In 1,4-dioxane; water at 75℃;
41 Scheme 1. Synthesis of 2-(4-amino- 1 H-pyrazolo [3,4-d]pyrimidin-3-yl) iodide (Compound 2-4).
Compound 2-4 is synthesized as shown in Scheme 2. Compound 1-3 is reacted with isopropyl bromide in dimethylformamide with potassium carbonate at 80° C., to provide the 1-isopropyl pyrazolopyrimidine intermediate, compound 2-1. This intermediate with the protected indolyl boronic acid species 2-2, using tetrakistriphenylphosphine palladium catalysis in DME-water solvent at 80° C. for 4-5 hours, to produce the Suzuki coupling product, compound 2-3. Removal of the protecting groups with acid in dioxane yields the product, 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl) iodide (Cpd. 2-4).