* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With potassium carbonate In dimethyl sulfoxide at 48℃; for 0.5 h; Stage #2: at 22 - 48℃; for 12.5 h;
Weigh respectively 2-amino-6-chloropurine 10mmol, anhydrous potassium carbonate 12mmol, the amount of 25mL DMSO was added to a 50mL round bottom flask, the oil bath was heated to 48 ° C, stirring reaction 30min;11 mmol of 2-chloromethyl-3,5-dimethylpyridine hydrochloride was weighed and added to the above reaction solution in 3 portions at intervals of 30 minutes.After reacting at 48 °C for 10 h, the temperature was set to 22 °C and stirred for 2 h. After the reaction was completed, the reaction solution was filtered and the filtrate was retained.The volume ratio of water: isopropyl alcohol = 1:1 mixed solution was added to the filtrate, until the solution became turbid to stop dropping, and the solution was placed in a refrigerator to stand still overnight. The filter residue was parent molecule BIIB021. 6-Chloro-9-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-9H-purin-2-amine (BIIB021):Light yellow solid; Yield: 77percent;
Reference：
[1] Patent: CN107857763, 2018, A, . Location in patent: Paragraph 0014-0016
2
[ 10310-21-1 ]
[ 848695-25-0 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: With potassium carbonate In dimethyl sulfoxide at 48℃; for 0.5 h; Stage #2: at 22 - 48℃; for 13.5 h;
Weigh the 2-amino-6-chloropurine 10mmol, anhydrous potassium carbonate 12mmol, measure 25mL DMSO into a 50mL round bottom flask, and raise the temperature in the oil bath to 48°C.The reaction was stirred for 30 min; 11 mmol of 2-chloromethyl-3,5-dimethylpyridine hydrochloride was weighed and added to the above reaction solution in 3 portions at intervals of 30 min. After reaction at 48 °C for 10 h, the temperature was set to 22 ° C and stirred for 2 h.After the reaction is completed, the reaction solution is suction-filtered, and the filtrate is retained; a mixed solution with a volume ratio of water:isopropanol = 1:1 is added to the filtrate, until the solution becomes turbid, and the solution is added dropwise. The solution is left in the refrigerator at rest overnight, and the filter is filtered. That is, the parent molecule BIIB021
Reference：
[1] Patent: CN107915736, 2018, A, . Location in patent: Paragraph 0025; 0026
3
[ 86604-75-3 ]
[ 10310-21-1 ]
[ 848695-25-0 ]
Reference：
[1] Organic Process Research and Development, 2015, vol. 19, # 3, p. 437 - 443
N-[6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-yl]-acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; at 20℃; for 0.0833333h;
Example 94: N- [6-CHLORO-9- (4-METHOXY-3, 5-DIMETHYL-PYRIDIN-2-YLMETHYL)-9H- PURIN-2-YL]-ACETAMIDE A suspension of 6-CHLORO-9- (4-METHOXY-3, 5-dimethyl-pyridin-2-ylmethyl) -9H- purin-2-ylamine (80 mg, 0.25 mmol) in acetic acid anhydride (2.2 g) was treated with one drop of concentrated H2S04 and stirred at r. t. for 5 min. Work-up (EtOAc), drying (MGS04) and evaporation gave the title compound as a white solid. HPLC Rt: 4.093 MIN. 1H-NMR (CDC13) : 5 8. 20 (s, 1H), 8.10 (s, 1H), 5.46 (s, 2H), 3.78 (s, 3H), 2.54 (s, 3H), 2.38 (s, 3H), 2.27 (s, 3H).
6-chloro-9-(4-methoxy-3,5-dimethyl-1-methoxy-pyridinium-2-methyl)-9H-purin-2-ylamine methylsulfate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane; for 3h;Heating / reflux;
Example 96: 6-CHLORO-9- (4-METHOXY-3, 5-DIMETHYL-L-METHOXY-PYRIDINIUM-2- methyl)-9H-purin-2-ylamine methyl sulfate salt A suspension of 6-CHLORO-9- (4-METHOXY-3, 5-DIMETHYL-1-OXY-PYRIDIN-2-YLMETHYL)- 9H-purin-2-ylamine (0.2 g, 0.56 mmol) in DCM (10 ml) was heated to reflux. Dimethyl sulfate (1.12 mmol) was added dropwise (Tarbit WO 99/10326) and heating was continued for 3h. Filtration and washing (hot acetone) gave the title compound as a beige solid. HPLC Rt: 3.379 MIN. 1H-NMR (d6-DMSO): 8 9.68 (s, 1H), 9.40 (s, 1H), 5. 85 (s, 2H), 4.42 (s, 3H), 4.15 (s, 3H), 4.12 (s, 3H), 2.70 (s, 3H), 2.47 (s, 3H).
N-[6-chloro-9-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-9H-2-purinyl]-(2-nitrophenyl)carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With pyridine; In ethanol; at -20 - 20℃;
Weigh 1.5mmol of compound A, dissolved in 2mL dry THF, add SOCl210 drops, 1 drop of pyridine,After refluxing at 70 C for 3 h, the solvent and excess SOCl2 were evaporated and sealed.Weigh 1mmol<strong>[848695-25-0]BIIB021</strong> dissolved in 15mL dry pyridine solution, ultrasonic heating until it is all dissolved;The pre-prepared acid chloride was added dropwise to the pyridine solution in an ethanol bath at -20C. The addition time was not less than 5 minutes.Stir vigorously 1h, 8-12h reaction at room temperature;Add the appropriate amount of chloroform to dilute the reaction solution and wash with saturated brine three times. Dry the organic layer with anhydrous magnesium sulfate or anhydrous sodium sulfate, filter by suction, and spin dry the filtrate. Separate the product by column chromatography with petroleum ether: acetic acid as the eluent. Ethyl = 2:1.The invention specifically prepares 15 compounds from B to B15, and its structure and characterization are as follows:N-[6-chloro-9-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-9H-2-purinyl]-(2-nitrophenyl)Formamide (B1): Flax powder; Yield: 57%.
Weigh respectively 2-amino-6-chloropurine 10mmol, anhydrous potassium carbonate 12mmol, the amount of 25mL DMSO was added to a 50mL round bottom flask, the oil bath was heated to 48 C, stirring reaction 30min;11 mmol of 2-chloromethyl-3,5-dimethylpyridine hydrochloride was weighed and added to the above reaction solution in 3 portions at intervals of 30 minutes.After reacting at 48 C for 10 h, the temperature was set to 22 C and stirred for 2 h. After the reaction was completed, the reaction solution was filtered and the filtrate was retained.The volume ratio of water: isopropyl alcohol = 1:1 mixed solution was added to the filtrate, until the solution became turbid to stop dropping, and the solution was placed in a refrigerator to stand still overnight. The filter residue was parent molecule BIIB021. 6-Chloro-9-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-9H-purin-2-amine (BIIB021):Light yellow solid; Yield: 77%;
2-chloromethyl-3,5-dimethylpyridine hydrochloride[ No CAS ]
[ 10310-21-1 ]
[ 848695-25-0 ]
Yield
Reaction Conditions
Operation in experiment
77%
Weigh the 2-amino-6-chloropurine 10mmol, anhydrous potassium carbonate 12mmol, measure 25mL DMSO into a 50mL round bottom flask, and raise the temperature in the oil bath to 48C.The reaction was stirred for 30 min; 11 mmol of 2-chloromethyl-3,5-dimethylpyridine hydrochloride was weighed and added to the above reaction solution in 3 portions at intervals of 30 min. After reaction at 48 C for 10 h, the temperature was set to 22 C and stirred for 2 h.After the reaction is completed, the reaction solution is suction-filtered, and the filtrate is retained; a mixed solution with a volume ratio of water:isopropanol = 1:1 is added to the filtrate, until the solution becomes turbid, and the solution is added dropwise. The solution is left in the refrigerator at rest overnight, and the filter is filtered. That is, the parent molecule BIIB021
9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-N6-(4-methoxyphenyl)-9H-purine-2,6-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 12h;Inert atmosphere;
Under an argon atmosphere 6-chloro-9 - ((4-methoxy-3,5-dimethyl-2-yl) methyl) -9H- purin-2-amine (150 mg, 0.47 mmol)Was dissolved in N, N-dimethylformamide (1.0 mL)After dissolving in the solvent, p-anisidine (72 mL, 0.59 mmol)And potassium carbonate (195 mg, 1.41 mmol)Was added to the reaction.Then, the mixture was stirred at 110 DEG C for 12 hours,The completion of the reaction was confirmed by TLC (dichloromethane: methanol = 10: 1).The reaction solution was cooled to room temperature and then concentrated under reduced pressure,The concentrate was separated and purified by column chromatography (dichloromethane: methanol = 40: 1, 25: 1) to obtain the desired compound (21 mg, 11% yield).
9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-6-phenoxy-9H-purin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
Under an argon atmosphere, phenol (0.04 mL, 0.47 mmol)Was dissolved in dimethylformamide (2.4 mL)And potassium tertiary butoxide (60 mg, 0.54 mmol) was added thereto.And the mixture was stirred at room temperature for 15 minutes.6-chloro-9 - ((4-methoxy-3,5-dimethylpyridin-2- yl) methyl)9H-purin-2-amine (150 mg, 0.47 mmol) was added to the reaction mixture,The mixture was stirred at 110 C for 12 hours,The completion of the reaction was confirmed by TLC (dichloromethane: methanol = 10: 1).The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent.The concentrate was separated and purified by column chromatography (dichloromethane: methanol = 40: 1) to obtain the desired compound (144 mg, 81% yield).
3-({2-amino-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9H-purin-6-yl}amino)propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
Amino-1-propanol (0.04 mL, 0.47 mmol) under an argon atmosphere,Was treated with sodium hydride (23 mg, 0.94 mmol) and dimethylformamide (1.0 mL) It was added to the mixture at 0 was stirred at room temperature for 30 minutes.6-chloro-9 - was added to the ((4-methoxy-3,5-dimethyl-2-yl) methyl) -9H- purin-2-amine (150 mg, 0.47 mmol), the reaction,The mixture was stirred at 110 C for 13 hours,The completion of the reaction was confirmed by TLC (dichloromethane: methanol = 10: 1).The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent.The concentrate was separated and purified by column chromatography (dichloromethane: methanol = 20: 1, 10: 1) to obtain the desired compound (102 mg, 61% yield).
6-(4-aminophenoxy)-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9H-purin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
General procedure: amino-1-propanol (0.04 mL, 0.47 mmol) under an argon atmosphere,Was treated with sodium hydride (23 mg, 0.94 mmol) and dimethylformamide (1.0 mL) It was added to the mixture at 0 was stirred at room temperature for 30 minutes.6-chloro-9 - was added to the ((4-methoxy-3,5-dimethyl-2-yl) methyl) -9H- purin-2-amine (150 mg, 0.47 mmol), the reaction,The mixture was stirred at 110 C for 13 hours,The completion of the reaction was confirmed by TLC (dichloromethane: methanol = 10: 1).The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent.The concentrate was separated and purified by column chromatography (dichloromethane: methanol = 20: 1, 10: 1) to obtain the desired compound (102 mg, 61% yield).In the same manner as in Example 18, 6-chloro-9 - ((4-methoxy-3,5-dimethyl-2-yl) methyl) -9H- purin-2-amine (150 mg, 0.47 mmol),4-Aminophenol (51 mg, 0.47 mmol),From the sodium hydride (23 mg, 0.94 mmol), the desired compound(117 mg, 63% yield).
4-[2-({2-amino-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9H-purin-6-yl}amino)ethyl]phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 110℃; for 12h;Inert atmosphere;
General procedure: Under an argon atmosphere 6-chloro-9 - ((4-methoxy-3,5-dimethyl-2-yl) methyl) -9H- purin-2-amine (150 mg, 0.47 mmol)Was dissolved in N, N-dimethylformamide (1.0 mL)After dissolving in the solvent, p-anisidine (72 mL, 0.59 mmol)And potassium carbonate (195 mg, 1.41 mmol)Was added to the reaction.Then, the mixture was stirred at 110 DEG C for 12 hours,The completion of the reaction was confirmed by TLC (dichloromethane: methanol = 10: 1).The reaction solution was cooled to room temperature and then concentrated under reduced pressure,The concentrate was separated and purified by column chromatography (dichloromethane: methanol = 40: 1, 25: 1) to obtain the desired compound (21 mg, 11% yield). Example 4 by the same manner, 6-chloro-9 - ((4-methoxy-3,5-dimethyl-2-yl) methyl) -9H- purin-2-amine (150 mg, 0.47 mmol),4- (2-aminoethyl) phenol (81 mg, 0.59 mmol),From potassium carbonate (195 mg, 1.41 mmol), the desired compound (110 mg, 56% yield).
3-({2-amino-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9H-purin-6-yl}amino)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With sodium hydride; In N,N-dimethyl-formamide; at 110℃; for 12h;Inert atmosphere;
General procedure: Under an argon atmosphere 6-chloro-9 - ((4-methoxy-3,5-dimethyl-2-yl) methyl) -9H- purin-2-amine (150 mg, 0.47 mmol)Was dissolved in N, N-dimethylformamide (1.0 mL)After dissolving in the solvent, p-anisidine (72 mL, 0.59 mmol)And potassium carbonate (195 mg, 1.41 mmol)Was added to the reaction.Then, the mixture was stirred at 110 DEG C for 12 hours,The completion of the reaction was confirmed by TLC (dichloromethane: methanol = 10: 1).The reaction solution was cooled to room temperature and then concentrated under reduced pressure,The concentrate was separated and purified by column chromatography (dichloromethane: methanol = 40: 1, 25: 1) to obtain the desired compound (21 mg, 11% yield). Example 4 by the same manner, 6-chloro-9 - ((4-methoxy-3,5-dimethyl-2-yl) methyl) -9H- purin-2-amine (150 mg, 0.47 mmol),2-Aminophenol (64 mg, 0.59 mmol),Potassium carbonate (195 mg, 1.41 mmol)(143 mg, 78% yield).
25 muetaiotaomicronIota of NH2-Fx-r-Fx-r-Fx-r on resin was reacted with Fmoc-S-trityl-L- penicillamine (4 eq, ChemPep Inc.), HBTU (4 eq), and DIPEA (8 eq) in 1 mL N,N- dimethyl formamide (DMF) for 2 hours at room temperature. The peptide was washed (2 x (0154) DMF/MeOH/DCM), cleaved from resin using trifluoroacetic acid:triisopropylsilane:water (95:2.5:2.5) and precipitated in ether at -20C for 1 hour. The precipitate was purified by RP- HPLC, dried under vacuum and dissolved in 0.5 mL acetonitrile:water (5:1 ). 2-mercpatoethanol (20 eq, Sigma-Aldrich) was added to the reaction mixture followed by iodine (10 eq) and the reaction was stirred for 30 minutes. The peptide was purified by HPLC and lyophilized. <strong>[848695-25-0]BIIB021</strong> ((6-chloro-9-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-9H-purin-2-amin 2 eq, Selleck Chemicals, Houston TX) was dissolved in 0.2 mL DCM along with 4- (Dimethylamino)pyridine (4 eq). The solution was chilled to -10C, and Triphosgene (0.71 eq, Sigma-Aldrich) was added and stirred for 10 minutes. The peptide was dissolved in 0.2 mL DMF and added to the solution, followed by stirring overnight at room temperature. The compound was purified via HPLC and lyophilized. The peptide was identified by ESI mass spectrometry, expected m/z = 1537.80, found m/z = 1537.82. The peptide was quantified using the <strong>[848695-25-0]BIIB021</strong> absorbance at 310 nm with an extinction coefficient of 8295 M"1cm"1 in PBS following overnight cleavage by 50 mM TCEP as the characteristic <strong>[848695-25-0]BIIB021</strong> absorbance was found to shift while attached to the peptide.
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