* 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.
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 6073,6076
2
[ 87-42-3 ]
[ 74-88-4 ]
[ 5440-17-5 ]
Yield
Reaction Conditions
Operation in experiment
42%
Stage #1: With methylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 50℃; for 5 h; Inert atmosphere
To a 1L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 6-chloro-9H-purine (15.4 g, 0.1 mol, 1 equiv) and tetrahydrofuran (155 mL) at 0 °C followed by the addition of MeMgCl (36.6 mL,1.0M THF solution, 1.1 equiv) dropwise with stirring. The mixture was stirred at 0 °C for 30 min. To this was added iodomethane (42.6 g, 3 equiv) dropwise with stirring. The resulting solution was stirred at 50 °C in an oil bath for 5 h, quenched by the addition of 50 mL of aqueous NH4C1 and extracted with dichloromethane (3x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and concentrated under vacuum. The crude product was re-crystallized from CH2CI2/ petroleum ether in the ratio of 1 : 10 to afford desired product as a greenish solid (7 g, 42percent).
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Reflux Stage #2: at 20℃; for 1 h;
To a solution of 6-chloro-9H-purine (3.00 g, 20.0 mmol) in anhydrous THF (100 mL)cooled to 0 oC, 60percent sodium hydride (1.2 g, 30.0 mmol) were added portionwise. After the reaction suspension was refluxed for 0.5 hour in the ice bath, MeI (2.82 g,20.0 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. The mixture was diluted in 100 mL H2O and extracted with EtOAc (30 mL x 3). The combined organic layer was dried with anhydrous MgCl2 and the solvent was evaporated in vacuum. The crude solid was purified through a silica gel column, eluting with 20 percent ether acetate/petroleum. White solid was obtained in a yield of 74.6percent (2.50 g). ESI-MS m/z: 169.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6): 3.72 (3H, s, CH3), 8.72 (1H, s, H-purine), 9.15 (1H, s, H-purine).
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 89, p. 581 - 596
[2] Synthesis, 2007, # 2, p. 219 - 224
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 18, p. 5134 - 5138[4] Angew. Chem., 2018, vol. 130, # 18, p. 5228 - 5232,5
[5] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 1, p. 139 - 149
[6] European Journal of Medicinal Chemistry, 2004, vol. 39, # 5, p. 433 - 447
[7] Patent: WO2014/75392, 2014, A1, . Location in patent: Page/Page column 123
[8] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 1126 - 1134
7
[ 87-42-3 ]
[ 74-88-4 ]
[ 5440-17-5 ]
[ 2346-74-9 ]
Reference：
[1] Tetrahedron, 2002, vol. 58, # 15, p. 2985 - 2996
[2] Journal of Organic Chemistry, 2018, vol. 83, # 12, p. 6334 - 6353
[3] Journal of Organic Chemistry, 2018, vol. 83, # 12, p. 6334 - 6353
[4] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 9, p. 3127 - 3133
[5] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7284 - 7288
[6] Organic Letters, 2016, vol. 18, # 1, p. 16 - 19
With sodium hydroxide In water at 100℃; for 0.166667 h; Microwave irradiation
General procedure: To a mixtureof uracil (0.056 g, 0.5 mmol) and NaOH (0.014 g, 0.6 mmol) in neat H2O (2mL), allyl bromide (0.052 mL, 0.6 mmol) was added. Then themixture was put intothe microwave reactor and irradiated at 0–400W(internal temperature: 100°C) for10 minutes. After completion of the reaction, the mixture was concentrated underreduced pressure and the residue was purified by column chromatography usingEtOAc-cyclohexane (9:1) as the eluent to afford 3a, yield 82percent.
44%
With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 2 h; Inert atmosphere
General procedure: 2.1 General procedure B: N9-alkylation 9H-Purine (1.0 eq.) and base (1.0-1.2 eq. specified below) was suspended in dry DMF (0.34 M) under nitrogen atmosphere. Alkyl or benzyl halide(1.0-1.6 eq.) was added at room temperature and the reaction mixture was stirred at this temperature (unless stated otherwise) until all starting material was consumed (monitored by TLC). The precipitate was filtered off and the solvent was removed under reduced pressure (often co-evaporated withtoluene). The crude product was purified by flash column chromatography.
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2016, vol. 35, # 2, p. 76 - 82
[2] European Journal of Medicinal Chemistry, 2004, vol. 39, # 5, p. 433 - 447
[3] Journal of Medicinal Chemistry, 1988, vol. 31, # 3, p. 606 - 612
[4] Tetrahedron Letters, 2014, vol. 55, # 18, p. 2929 - 2931
[5] Dalton Transactions, 2014, vol. 43, # 26, p. 9838 - 9842
[6] Proceedings of the National Academy of Sciences of the United States of America, 2017, vol. 114, # 16, p. E3178 - E3187
11
[ 100-44-7 ]
[ 87-42-3 ]
[ 1928-76-3 ]
Yield
Reaction Conditions
Operation in experiment
78%
With sodium hydroxide In water at 100℃; for 0.166667 h; Microwave irradiation
General procedure: To a mixtureof uracil (0.056 g, 0.5 mmol) and NaOH (0.014 g, 0.6 mmol) in neat H2O (2mL), allyl bromide (0.052 mL, 0.6 mmol) was added. Then themixture was put intothe microwave reactor and irradiated at 0–400W(internal temperature: 100°C) for10 minutes. After completion of the reaction, the mixture was concentrated underreduced pressure and the residue was purified by column chromatography usingEtOAc-cyclohexane (9:1) as the eluent to afford 3a, yield 82percent.
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2016, vol. 35, # 2, p. 76 - 82
[2] European Journal of Medicinal Chemistry, 2014, vol. 84, # C, p. 574 - 583
[3] Medicinal Chemistry Research, 2014, vol. 23, # 10, p. 4619 - 4626
12
[ 100-44-7 ]
[ 87-42-3 ]
[ 1928-76-3 ]
Yield
Reaction Conditions
Operation in experiment
56.4%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: for 24 h;
6-Chloropurine (2.00 g, 12.94 mmol) was added to a 25 mL single-necked flask.And add 8mL of DMF, stir at room temperature, the system is yellow liquid,Potassium carbonate (3.58 g, 25.88 mmol) was added to the system, and stirred at room temperature for half an hour, and benzyl chloride (3.28 g, 25.88 mmol) was slowly added dropwise to the system.After 24 hours, the reaction was almost complete, after the reaction was over,The reaction system was poured into a beaker and washed with a saturated ammonium chloride solution.It was then extracted with dichloromethane, washed repeatedly 3 times, and the organic layer was taken.It was dried over anhydrous magnesium sulfate for half an hour, filtered, and the magnesium sulfate solid was removed and evaporated.Remove DMF, get a yellow oily liquid, mix,Using (ethyl acetate: petroleum ether = 1:2) as eluent to give a white solid.mass 2.00g(theoretical quality 3.17g),The yield was 63.2percent.
Reference：
[1] Patent: CN108892668, 2018, A, . Location in patent: Paragraph 0030
13
[ 100-44-7 ]
[ 87-42-3 ]
[ 1928-76-3 ]
[ 1928-77-4 ]
Reference：
[1] Tetrahedron, 1994, vol. 50, # 32, p. 9743 - 9756
[2] Journal of Organic Chemistry, 1982, vol. 47, # 25, p. 4881 - 4884
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 3, p. 710 - 722
[4] Journal of Organic Chemistry, 1990, vol. 55, # 22, p. 5761 - 5766
14
[ 87-42-3 ]
[ 100-51-6 ]
[ 1928-76-3 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 13, p. 5012 - 5015
15
[ 87-42-3 ]
[ 108-88-3 ]
[ 1928-76-3 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 7, p. 3710 - 3718
Reference：
[1] Australian Journal of Chemistry, 1982, vol. 35, # 3, p. 525 - 534
[2] Australian Journal of Chemistry, 1982, vol. 35, # 3, p. 535 - 542
21
[ 87-42-3 ]
[ 2545-26-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7284 - 7288
22
[ 87-42-3 ]
[ 5404-86-4 ]
Reference：
[1] Chemistry - A European Journal, 2007, vol. 13, # 6, p. 1754 - 1762
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 16, p. 5551 - 5562
[3] Journal of Medicinal Chemistry, 1990, vol. 33, # 8, p. 2073 - 2080
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 886 - 898
23
[ 87-42-3 ]
[ 5404-86-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 19, p. 5974 - 5989
24
[ 1780-27-4 ]
[ 87-42-3 ]
Yield
Reaction Conditions
Operation in experiment
97.1%
at 15 - 25℃; for 12 h;
0 ° C, 80.5g formamidine hydrochloride (1mol) was dissolved in 200mL of ethanol, was slowly added dropwise with 100mL183.5g of 4,5,6-trichloropyrimidine (1mol) in ethanol, the dropwise addition was heated to 15 ~ 25 , the reaction was stirred for 12h.After the reaction was completed, the ethanol was evaporated to dryness, water was added and the mixture was extracted three times with ethyl acetate. The organic layer was dried to give 150 gOf 4-chloro-1H-pyrazolo [3,4-d] pyrimidine was obtained in a yield of 97.1percent
Reference：
[1] Patent: CN106883233, 2017, A, . Location in patent: Paragraph 0032; 0041; 0042
25
[ 68-94-0 ]
[ 87-42-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2004, vol. 2, # 5, p. 665 - 670
[2] Russian Journal of Organic Chemistry, 2002, vol. 38, # 7, p. 1053 - 1055
Example 147 1-[4-(6-(Methylamino)purin-9-yl)phenyl]-3-[3-(4-methylpiperazin-1-ylmethyl)-5-(trifluoromethyl)-phenyl]urea (Table 2, Compound 25) Step A Preparation of methyl-(9H-purin-6-yl)amine [Show Image] [Show Image] In 20 mL of a 40percent methylamine methanol solution and 20 mL of ethanol, 12.5 g (79 mmol) of 6-chloropurin was dissolved and the solution was sealed in a tube and stirred in the tube at 120°C for four hours. The reaction solution was concentrated, and then triturated with water and collected on a filter, washed with water, and then vacuum dried to obtain 10.78 g (90percent) of methyl-(9H-purin-6-yl)amine as a white solid. 1H-NMR (270 MHz, DMSO-d6) δ (ppm): 2.98(3H,br.s), 7.58(1H,br.s), 8.06(1H,s), 8.19(1H,br.s), 12.89(1H,br.s) ESI (LC-MS positive mode) m/z 150 (M+H)
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 5, p. 967 - 971
39
[ 68-12-2 ]
[ 87-42-3 ]
[ 938-55-6 ]
Yield
Reaction Conditions
Operation in experiment
82%
at 180℃; for 0.166667 h; Microwave irradiation
General procedure: A solution of 1 (1.10 g, 4.5 mmol), 2 (244 mg, 1 mmol), 3 (649 mg, 2.5 mmol), 4 (518 mg, 2 mmol), 5 (310 mg, 2 mmol), 6 (190 mg, 1 mmol) or 7 (340 mg, 2 mmol) in DMF (6 mL for 0.5 mmol of starting compound) was divided into several vials. Each vial contained starting compound (0.5 mmol) and DMF (6 mL). The solutions were heated under microwave irradiation. Reaction mixtures were collected and evaporated in vacuo. For 10, 11, 12, 13, and 16 the residue was applied on silica gel column and flash chromatographed. For 14 and 15 the residue was partitioned between water (60 mL) and EtOAc (50 mL). The water layer was extracted with EtOAc (3.x.40 mL), dried over anhydrous MgSO4, filtered, and evaporated.
Reference：
[1] Collection of Czechoslovak Chemical Communications, 2001, vol. 66, # 10, p. 1545 - 1592
[2] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 295 - 299
41
[ 506-59-2 ]
[ 87-42-3 ]
[ 938-55-6 ]
Reference：
[1] Chemical & Pharmaceutical Bulletin, 1980, vol. 28, # 6, p. 1920 - 1924
42
[ 1795-76-2 ]
[ 87-42-3 ]
[ 1637-39-4 ]
Yield
Reaction Conditions
Operation in experiment
96.8%
With triethylamine In ethanol for 5 h; Reflux
This embodiment is a method for synthesizing the hydroxyalkylene adenine (also known as zeatin), which is similar to the steps (1) to (5) of Example 1Except that Step : 154.5 g of 4-chloro-1H-pyrazolo [3,4-d] pyrimidine (1 mol) was dissolved in 200 mL of ethanol and 122 g of triethylamine (1.2 mol) Then slowly dropping 111g of 4-amino-2-methyl-2-butenol (1.1mol), dropping end heated to reflux, the reaction 5h.After the reaction was completed, the ethanol was evaporated to dryness, water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was spin-dried to give 212 gOf the gray powder of hydroxyadenine, the yield was 96.8percent.
Reference：
[1] Patent: CN106883233, 2017, A, . Location in patent: Paragraph 0047; 0048
[2] Tetrahedron, 1990, vol. 46, # 3, p. 913 - 920
43
[ 1795-76-2 ]
[ 87-42-3 ]
[ 1637-39-4 ]
Reference：
[1] Asian Journal of Chemistry, 2014, vol. 26, # 23, p. 8155 - 8157
44
[ 87-42-3 ]
[ 100-46-9 ]
[ 1214-39-7 ]
Yield
Reaction Conditions
Operation in experiment
96%
With triethylamine In ethanol for 5 h; Reflux
154.5 g of 4-chloro-1H-pyrazolo [3,4-d] pyrimidine (1 mol) was dissolved in 200 mL of ethanol,Of triethylamine (1.2mol), then 118g of benzylamine (1.1mol) was slowly added dropwise, the reaction mixture was heated to reflux for 5h.After the reaction was completed, the ethanol was evaporated to dryness, water was added, the mixture was extracted three times with ethyl acetate, and the organic layer was spin-dried to obtain 216 gOf white needles solid 6-benzylaminopurine with a yield of 96.0percent.
69%
With triethylamine In butan-1-ol at 110℃; for 3 h;
To a solution of 6-chloro-9H-purine (112 mg, 0.72 mmol) and TEA (161 pL, 1.15 mmol) in nBuOH (6 mL) at RT was gradually added benzyl amine (95.6 iL,0.86 mmol). The reaction mixture was stirred for 3 h at 110°C and subsequently cooled to0°C. The colorless precipitant was filtrated, washed with 10 mL ice-cold MeOH and dried in vacuo. The desired N-Benzyl-9H-purin-6-amine was obtained in 69percent yield (112 mg, 0.49 mmol) as colorless solid. R± 0.15 (DCM/EtOAc/MeOH 49:49:2). LCMS (ESI): calculated for [Ci2HiiN5+H]: 226, found 226 [M+H]t
61%
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 110℃; for 0.25 h; Microwave irradiation
6-chloro-9H-purine(0.11 g,0.712 mmol), benzylamine (0.155 mL, 1.42 mmol), N, N-diisopropylethylamine(0.248 mL, 1.42 mmol) and 1, 4 - dioxane (1 mL, 13 mmol) were placed in a 10 mLCEM microwave vial. The vial was capped and irradiated in a CEM microwave reactorfor 15 minutes at 110 °C.The reaction was concentrated, dissolved in DMF and the residue was purified bypreparative reverse phase HPLC to give N-benzyl-9H-purin-6-amine(1; 0.097 g,61percent) as an off white solid: 1H NMR (400 MHz, DMSO-d6)δ 12.92 (s, 1H), 8.13 (d, J = 26.2 Hz, 3H), 7.42 – 7.15 (m, 6H), 4.71(s, 2H); ESMSm/z 266.19 (M+1).
Reference：
[1] Patent: CN106883233, 2017, A, . Location in patent: Paragraph 0051; 0052
[2] Tetrahedron, 2007, vol. 63, # 24, p. 5323 - 5327
[3] Advanced Synthesis and Catalysis, 2015, vol. 357, # 1, p. 185 - 195
[4] Patent: WO2016/11394, 2016, A1, . Location in patent: Page/Page column 125; 126
[5] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 21, p. 4728 - 4732
[6] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 12, p. 3165 - 3168
[7] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
45
[ 110-87-2 ]
[ 87-42-3 ]
[ 7306-68-5 ]
Yield
Reaction Conditions
Operation in experiment
99.3%
With toluene-4-sulfonic acid In ethyl acetate at 90℃; for 1 h;
A suspension of 6-chloro-9H-purine (25.36 g, 164 mmol) and 4-methylbenzenesulfonic acid (0.565 g, 3.28 mmol) in EtOAc (250 mL) was treated with 3,4-dihydro-2H-pyran (44.9 mL, 492 mmol). The mixture was heated at 90 0C and the solid slowly dissolved over Ih. The flask was removed from the oil bath and the cloudy yellow solution was filtered and concentrated in vacuo. The pale yellow residue was dissolved in DCM and purified by flash chromatography (50percent EtOAc / hexane) (IL silica / 4 L solvent) to give 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (38.90 g, 99.3percent yield) as a colorless oil which slowly crystallized. MS (ESI, pos. ion) m/z: 239.1 [M+H]+
97%
With toluene-4-sulfonic acid In ethyl acetate at 90℃; for 0.1 h;
6-chloro-9H-purine (500 mg, 3.2 mmol), 4-methyl benzene sulfonic acid (12 mg, 0.07 mmol), and 3,4-dehydro-2H-pyran (0.9 mL, 9.7 mmol) were added into ethylacetate solvent and stirred. The reactant was stirred at 90°C for approximately 1 hour until the solid is dissolved completely. After concentrating the solvent, the residuals were refined by means of column chromatography, so that 749 mg of the target compound, 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (percentage yield: 97percent), was obtained.1H NMR(400MHz, CDCl3) δ 8.77 (s, 1H), 8.36(s, 1H), 5.80(dd, J = 10.4, 2.8 Hz, 1H), 4.21(m, 1H), 3.80(m, 1H), 2.21-1.67(m, 6H).
95%
With toluene-4-sulfonic acid In tetrahydrofuran for 15 h; Reflux
p-TSA (0.01 g) was added to a solution of 6-chloropurine(0.15 g, 1 mmol) in dry THF at reflux. After 3,4-dihydro-2H-pyran (0.098 g, 1.18 mmol) was added andthe mixture refluxed for 15 h. After cooling to ambienttemparature the reaction mixture was treated with 1 mL25percent NH4OH and sitirred for 5 min. The solution was evaporatedin vacuo and treated with 25 mL EtOAc, washedwith brine and water. The organic phase was dried overNa2SO4, the solvent was evaporated in vacuo, and recrystallizedfrom hexane petroleum ether to yield 2 (220 mg;95percent): mp 69–71 °C (67–69 °C30). 1H NMR (CDCl3) δ1.64–1.88 (m, 3H, H-pyran), 2.02–2.21 (m, 3H, H-pyran),3.80 (td, J1 = 2.8 Hz, J2 = 12 Hz, 1H, H-5’a in pyran), 4.20(d, 1H, H-5’b in pyran), 5.80 (dd, J1 = 10.8 Hz, J2 = 2.4Hz, 1H, H-1’ in pyran), 8.35 (s, 1H, H-8 in purine), 8.76(s, 1H, H-2 in purine). MS (ESI+) m/z: 239.70 (10percent)(M+H).
91%
Stage #1: at 60℃; for 0.5 h; Stage #2: With ammonia In water; ethyl acetate at 20℃;
Ethyl acetate (300 ml) was added to 6-chloropurine (25 g, 162 mmol) and tosylic acid monohydrate (460 mg, 2.43 mmol)and the resulting mixture was heated at 60° C. Dihydropyrane (16 ml, 178 mmol) was added and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was cooled to room temperature followed by the addition of 28percent aqueous ammonia solution (15 ml) and the organic layer was fractionated, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (35 g, 91percent) as a pale yellow solid.
89%
With toluene-4-sulfonic acid In ethyl acetate at 90℃; for 1 h;
General procedure: A suspension of 6-chloro-9H-purine (or 4-iodo-1H-pyrazole) (13mmol) and 4-methylbenzenesulfonic acid (0.12g, 0.65mmol) in EtOAc (25ml) was treated with 3,4-dihydro-2H-pyran (3.54ml, 39mmol). The mixture was heated at 90°C and the solid slowly dissolved over 1h. The flask was removed from the oil bath and the cloudy yellow solution was filtered and concentrated under vacuum. The pale yellow residue was purified by flash chromatography to give title compound.
83.2%
With toluene-4-sulfonic acid In ethyl acetate for 3 h; Reflux
A mixture of 6-chloro-9H-purine 17 (2.01 g, 13 mmol), 3,4-dihydro-2H-pyran (3.30 g, 39 mmol) and TsOH (516 mg, 0.3 mmol) dissolved in anhydrous ethyl acetate (30 mL) was refluxed for 3 h. Then cooled to the room temperature and washed with water and brine. The organic layer was dried (anhydrous Na2SO4) and concentrated to afford the compound 18 (2.62 g, 83.2 percent) as a yellow oil. ESI-MS m/z: 239.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6): δ 1.58–1.64 (2H, m, H-pyran), 1.69–1.78 (1H, m, H-pyran), 1.97–2.05 (2H, m, H-pyran), 2.32–2.37 (1H, m, H-pyran), 3.69–3.77 (1H, m, H-pyran), 4.03 (1H, d, J=5.4Hz, H-pyran), 5.80 (1H, dd, J=2.1Hz, J=10.9Hz, H-pyran), 8.81 (1H, s, H-purine), 8.91 (1H, s, H-purine).
82.1%
With toluene-4-sulfonic acid In ethyl acetate at 50℃; for 1 h;
6-Chloropurine (15.5 g) and p-toluenesulfonic acid (0.26 g) were dissolved in ethyl acetate (180 ml)Heated to 50 ° C, 2,3 dihydropyran (10.5ml) was slowly dropped to the reaction solution, the dropwise addition, stirring was continued for 1 hour at this temperature, slowly cooled to room temperature, stirred under saturated ammonium chloride solution (10ml ), Then washed twice with water, once with brine, dried and concentrated to give an oily crude which was recrystallized from n-hexane (150 ml)Chloro-9- (tetrahydro-2-pyranyl) -purine 19.6 g, yield 82.1percent.
80%
With toluene-4-sulfonic acid In ethyl acetate at 75℃; for 2.6 h;
Example 1B Compound 3 (4.60 kg) was treated with p-toluenesulfonic acid monohydrate and 3,4-dihydro-2H-pyran (DHP) in ethyl acetate at 75° C. for 2.6 hours. The reaction was monitored by HPLC. Upon completion of the reaction, Compound 4 was obtained as a yellow solid in 80percent yield with >99percent (AUC) purity by HPLC analysis.
72.2%
Stage #1: With toluene-4-sulfonic acid In water; ethyl acetate at 20 - 60℃; for 1.5 h; Stage #2: With ammonia In water; ethyl acetate at 20℃; for 0.0833333 h;
EXAMPLE 1 This example illustrates the preparation of 6-chloro-9-(2-tetrahydropyranyl)purine. A mixture of 6-chloropurine (60 g, 388 mmol) and tosic acid monohydrate (1 g) in ethylacetate (750 ml) was vigorously stirred at 50° C. 3,4-Dihydropyran (40 ml, 438 mmol) was added dropwise over a 30 min period, maintaining the reaction temperature between 55-60° C. (Robins et al., 1961). The solution was stirred for an additional hour during which time it was allowed to cool to room temperature. Concentrated aqueous ammonia (35 ml) was added and the solution stirred for 5 min. Homogenous dark-green solution was subsequently extracted with 2*200 ml water. The yellow ethylacetate extract was dried overnight over sodium sulphate and then cool at -20° C. Accrued yellow solid was dried again in vacuo over phosphorus pentoxide at 37° C. Yield: 66.9 g (72.2percent). MS (ES): [M+H]+=239 (100).
69%
With toluene-4-sulfonic acid In ethyl acetate for 2 h; Reflux
Step 1 : 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineTo a solution of 6-chloro-9H-purine (61.8 g, 0.4 mol) in EtOAc (300 mL) was added 3,4-dihydro-2H-pyran (101 g, 1.2 mol), followed by 4-methylbenzenesulfonic acid (1percent) and the resulting reaction mixture was heated to refluxing for 2 hrs. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was recrystallized with ether to afford the desired product (65.8 g, 69percent).1H NMR (CDCI3): ? 8.74 (1H, s), 8.33 (1H, s), 5.80-5.76 (1H, m), 4.20-4.16 (1H, m), 3.81-3.75 (1H, m), 2.09-2.00 (3H, m), 1.86-1.65 (4H, m).
11.3 g
With toluene-4-sulfonic acid In ethyl acetate for 2 h; Reflux
a, 6-Chloropurine (1, 7.7 g, 50 mmol)And p-toluenesulfonic acid (172 mg, 1 mmol) in EtOAc was stirred at room temperature,3,4-dihydro-2H-pyran (8.4 g, 100 mmol) was added dropwise,The reaction was heated to reflux for about 2 h;When the reaction solution is near the clear state,Hot filter to remove part of the raw materials 1,The filtrate was washed with water,Saturated salt water were washed,Collecting oil layer,Anhydrous Na2SO4 drying oil layer,Removal of the solvent gave 6-chloro-9- (tetrahydro-2H-2-pyran-2-yl) -9H-purine (Intermediate 2, 11.3 g);
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 20, p. 6189 - 6192
[2] Patent: WO2008/153947, 2008, A2, . Location in patent: Page/Page column 41; 61
[3] Patent: EP2647637, 2013, A2, . Location in patent: Paragraph 0060
[4] Acta Chimica Slovenica, 2017, vol. 64, # 3, p. 621 - 632
[5] Molecular Diversity, 2018, vol. 22, # 2, p. 343 - 358
[6] Patent: US2010/130492, 2010, A1, . Location in patent: Page/Page column 78
[7] Molecules, 2011, vol. 16, # 7, p. 5840 - 5860
[8] Archiv der Pharmazie, 2017, vol. 350, # 11,
[9] Tetrahedron Letters, 2001, vol. 42, # 46, p. 8161 - 8164
[10] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, # 11, p. 763 - 783
[11] Dyes and Pigments, 2014, vol. 105, p. 145 - 151
[12] European Journal of Medicinal Chemistry, 2014, vol. 73, p. 167 - 176
[13] European Journal of Medicinal Chemistry, 2014, vol. 89, p. 581 - 596
[14] Patent: CN106146503, 2016, A, . Location in patent: Paragraph 0014; 0015; 0016
[15] Patent: US2012/184568, 2012, A1, . Location in patent: Page/Page column 78
[16] Patent: US2008/9508, 2008, A1, . Location in patent: Page/Page column 8
[17] Patent: WO2013/71865, 2013, A1, . Location in patent: Page/Page column 25
[18] Organic and Biomolecular Chemistry, 2004, vol. 2, # 5, p. 665 - 670
[19] Patent: US2009/170879, 2009, A1, . Location in patent: Page/Page column 5-7
[20] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 23, p. 7244 - 7251
[21] Patent: US2012/122838, 2012, A1, . Location in patent: Page/Page column 79
[22] Patent: CN105837572, 2016, A, . Location in patent: Paragraph 0147
46
[ 110-87-2 ]
[ 87-42-3 ]
[ 7306-68-5 ]
Yield
Reaction Conditions
Operation in experiment
69%
With toluene-4-sulfonic acid In ethyl acetate for 2 h; Reflux
To a solution of 6-chloropurine (61.8 g, 0.4 mol) in ethyl acetate (300 mL) was added 3,4-dihydropyran (101 g, 1.2 mol) and the catalytic amount of p-toluenesulfonic acid (1percent). The reaction solution was heated under reflux for 2 hours. Water was added thereto, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting viscous material was recrystallized from diethyl ether to give the title compound (65.8 g, 69percent)
67%
With toluene-4-sulfonic acid In ethyl acetate for 2 h; Reflux
Synthesis of compound 7 (0183) R-3 =H, R-4 = H (0184) [0092] To a 1 L flask, 6-chloropurine (30 g, 194.1 mmole, 1 equiv.), 3, 4-dihydropyran (24.5 g, 291.1 mmol, 1.5 equiv.) and p-toluenesulfonic acid (PTSA) monohydrate (2.95 g, 15.5 mmol, 8percent equiv.) were added, followed by EtOAc (240 mL). The mixture was refluxed for 2 hrs. After the mixture cooled down, it was washed with NaHCCh (250 mL) to adjust pH = 7-8 and brine 150 mL x 3. The EtOAc layer was dried over Na2S04 and concentrated to dryness. The residue was purified by silica gel plug with hexane : EtOAc (2: 1, 1 : 1 and 1 :2 ) to afford 6-chloro-9-(tetrahydro-2H-pyran-2- yl)-9H-purine as an off-white solid (31.6 g , 67percent). (0185) R3 = D (0186) [0093] To a 100 mL round bottom flask under N2, at -40 °C under N2, n-BuLi (2.5 M, 23.5 mL, 58.7 mmol, 1.4 equiv.) was added drop wise to diisopropylamine (5.94 g, 58.7 mmol, 1.4 equiv) in THF (40 mL). The mixture temperature was raised to -10 °C. Then the mixture was cooled to -70 °C, 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (10 g, 41.9 mmol, 1 equiv.) in THF (20 mL) solution was added drop wise while maintaining the temperature below -68 °C. The mixture was stirred for 1 hr. and then 5 mL D20 was added. The mixture temperature rose to 10 °C. To the mixture, 2 N HC1 was added to adjust to pH = 8. The separated THF layer was concentrated. The aqueous phase was extracted with EtOAc (100 mL x 2). The EtOAc layer was combined with THF dryness and washed with brine (75 mL x 2), dried over Na2S04. The solvent was evaporated to give a red oil. Repeat the above H-D exchange procedure twice. The crude product was purified by silica gel plug with hexane:EtOAc (5: 1, 4: 1, 3: 1, 2.5: 1) to get compound 7 as yellow oil (5.6 g, 56percent).
67%
With toluene-4-sulfonic acid In ethyl acetate for 2 h; Reflux
To a 1 L flask, 6-chloropurine (30 g, 194.1 mmole, 1 equiv), 3, 4-dihydropyran (24.5 g, 291.1 mmol, 1.5 equiv) and PTSA monohydrate (2.95 g, 15.5 mmol, 8percent equiv) were added, followed by EtOAc (240 mL). The mixture was refluxed for 2 hours. After the mixture cooled down, it was washed with NaHCCh (250 mL) to adjust pH = 7-8 and brine 150 mL x 3. The EtOAc layer was dried over Na2SC>4 and concentrated to dryness. The residue was purified by silica gel plug with hexane : EtOAc (2: 1, 1 : 1 and 1 :2 ) to get 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine as an off-white solid (31.6 g, 67percent).
62%
With toluene-4-sulfonic acid In tetrahydrofuran at 84℃; for 22 h; Inert atmosphere
The compound was prepared from 6-chloropurine according to the literature (Taddei et al., Org. Biomol. Chem. 2004, 2, 665). A mixture of 6-chloropurine (20.0 g, 129 mmol), p-toluenesulfonic acid (0.23 g, 1.85 mmol), 3,4-dihydro-2H-pyran (14.5 ml, 159 mmol) in tetrahydrofuran (175 ml) was refluxed under argon at 84°C for 22 h. After cooling, concentrated ammonia (5 ml) was added, undissolved particles were filtered off and the filtrate evaporated to dryness. The yellowish oil was dissolved in ethyl acetate (250 ml) and extracted with brine (75 ml), water (2 x 75 ml) and then dried over sodium sulfate. The organic extracts were concentrated in vacuo into an yellow oil that was extracted with boiling cyclohexane (cca 250 ml). Light yellow cyclohexane extract was separated from the undissolved orange rest by decantation. The extraction procedure was repeated twice with 150 ml cyclohexane. The cyclohexane extracts were cooled in a fridge overnight to precipitate colourless crystals. Yield: 19.1 g, 62 percent. M.p.: 68°C. *H NMR (300 MHz, DMSO-<: δ 1.61 (2H, m, THP), 1.76 (1H, m, THP), 2.00 (2H, m, THP), 2.34 (1H, m, THP), 3.73 (1H, m, THP H40, 4.03 (1H, dm, / = 11 Hz, THP H3'), 5.80 (1H, dd, / = 2.3, 11 Hz, THP H2'), 8.81 (1H, s, H8), 8.92 (1H, s, H2). Examples 2 Syntheses of 6-alkylamino/aralkylamino-9-(tetrahydropyran-2-yl)-9H-purines
Reference：
[1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 5, p. 1938 - 1947
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 24, p. 4509 - 4515
[3] Patent: CN103102349, 2017, B, . Location in patent: Paragraph 0143-0145
[4] Patent: WO2017/87207, 2017, A1, . Location in patent: Paragraph 0092-0093
[5] Patent: WO2017/79003, 2017, A1, . Location in patent: Paragraph 0083
[6] Patent: WO2016/95880, 2016, A1, . Location in patent: Page/Page column 17; 18
[7] European Journal of Organic Chemistry, 2012, # 15, p. 2889 - 2893
[8] Patent: WO2016/183060, 2016, A1, . Location in patent: Page/Page column 55
47
[ 289-66-7 ]
[ 87-42-3 ]
[ 7306-68-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 30℃; for 2 h;
6-Chloropurine (19. 9 g, leq) was dissolved in dichloromethane (199 mL)A solution of 2-hydropyran (16. 3 g, L 5 eq)30 ° C for 2 hours,The reaction solution was added to water,Layered,The organic layer was washed with saturated sodium chloride solution,Dried over anhydrous sodium sulfate,Concentrated to dryness under reduced pressure. 27 g of solid,Scrape aside.Yield:90percent,purity:96percent (area normalization).
Reference：
[1] Patent: CN106279171, 2017, A, . Location in patent: Paragraph 0068; 0069
48
[ 142-68-7 ]
[ 87-42-3 ]
[ 7306-68-5 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 7, p. 3710 - 3718
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3418 - 3428
49
[ 110-87-2 ]
[ 1336-21-6 ]
[ 87-42-3 ]
[ 7306-68-5 ]
Reference：
[1] Patent: US4876257, 1989, A,
[2] Patent: US5164390, 1992, A,
50
[ 110-87-2 ]
[ 1336-21-6 ]
[ 87-42-3 ]
[ 7306-68-5 ]
Reference：
[1] Patent: US5252569, 1993, A,
51
[ 87-42-3 ]
[ 31383-66-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1980, vol. 23, # 5, p. 572 - 574
52
[ 87-42-3 ]
[ 13035-61-5 ]
[ 5987-73-5 ]
Yield
Reaction Conditions
Operation in experiment
69%
With trimethylsilyl trifluoromethanesulfonate In acetonitrile at 0 - 60℃; Molecular sieve; Inert atmosphere
10145] Compound LCDO6 was synthesized under standard glycosylation conditions. Briefly, 3-D-ribofuranose 1,2,3,5- tetraacetate (5.5 g, 17.3 mmol) and 6-chloropurine (2.7 g, 17.3 mmol) were dissolved in anhydrous MeCN (50 mL) containing molecular sieves (MS 4 A), followed by the addition ofTMSOTf (300 pL) at 0°C. under argon protection. The reaction mixture was heated at 60°C. overnight and quenched by addition of triethylamine to pH 7. The solvents were then removed and column chromatography (methanol :dichloromethane, 1:20) gave the product as a yellowish solid (4.9 g, 69percent). ‘H NMR (400 MHz, CDC13) ö 8.77 (s, 1H, H-8), 8.24 (s, 1H, H-2), 6.23 (d, 1H, J=5.4 Hz, H-i’), 5.94 (dd, 1H, J=5.4, 5.0 Hz, H-2’), 5.63 (dd, 1H, J=5.0, 4.5 Hz, H-3’), 4.35 (m, 3H, H-4’, H-5’), 2.26 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.01 (s, 3H, CH3).
Reference：
[1] Chinese Chemical Letters, 2011, vol. 22, # 12, p. 1439 - 1442
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3058 - 3065
[3] Patent: US2016/185805, 2016, A1, . Location in patent: Paragraph 0144; 0145
[4] Nucleosides, nucleotides and nucleic acids, 2002, vol. 21, # 1, p. 73 - 78
53
[ 87-42-3 ]
[ 13035-61-5 ]
[ 5987-73-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1478 - 1489
54
[ 87-42-3 ]
[ 13035-61-5 ]
[ 5987-73-5 ]
[ 515866-05-4 ]
Reference：
[1] Chemistry - A European Journal, 2011, vol. 17, # 23, p. 6369 - 6381
Reference：
[1] Crystal Growth and Design, 2012, vol. 12, # 6, p. 3025 - 3035
57
[ 2217-40-5 ]
[ 87-42-3 ]
[ 2922-28-3 ]
Reference：
[1] Patent: US5965563, 1999, A,
58
[ 87-42-3 ]
[ 14047-28-0 ]
Reference：
[1] Patent: CN104710424, 2017, B,
59
[ 87-42-3 ]
[ 1201438-56-3 ]
Reference：
[1] Patent: US2012/184568, 2012, A1,
60
[ 870281-86-0 ]
[ 87-42-3 ]
[ 870281-82-6 ]
Yield
Reaction Conditions
Operation in experiment
3.1 g
With triethylamine In <i>tert</i>-butyl alcohol at 30 - 85℃; for 24 h;
(S)-2-(1 -aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one prepared in example 26 (4.2 g) and t-Butanol (21 mL) were charged into a 100 mL round bottom flask. Triethylamine (3.91 mL) and 6-Chloropurine (2.5 g) were added at 30 00. The resultant reaction mixture was heated to85°C and stirred for 24 hours. The reaction mixture was evaporated completely under reduced pressure at 40°C. The resultant residue was diluted with water (100 mL) and stirred for 30 minutes. The precipitate was filtered and the solid was washed with water (30 mL) and n-Hexane (50 mL) and dried for 1 hour under vacuum. The crude was purified by chromatographyusing Si02 (1 00:200) (solvent MeOH: DCM: TEA:: 5: 94: 1). The eluted fractions were evaporated completely under vacuum. The isolated product was diluted in dichloromethane (100 mL) and the organic layer was washed with brine solution (2x25 mL). The organic layer dried over sodium sulphate (10 g) and evaporated under reduced pressure to yield 3.1 g of Idelalisib as pale yellow solid.Purity: 97.87percent by HPLC; chiral purity: 98.77percent by H PLC
With triethylamine; In butan-1-ol; at 90℃; for 4h;
General Procedure: 6-Benzylaminopurine derivatives were prepared according to the well known synthetic strategy which is depicted in Scheme 2, i.e. by the reaction of 6-chloropurine with the appropriate R-substituted benzylamine and triethylamine (Et3N) in the butanol solution, in a molar ratio of 3:4:5 [19]. The yields obtained were 70-80%. The single crystals of the discussed compounds were obtained by re-crystallization from N,N'-dimethylformamide.
With toluene-4-sulfonic acid; In ethyl acetate; for 2h;Reflux;
To a solution of 6-chloropurine (61.8 g, 0.4 mol) in ethyl acetate (300 mL) was added 3,4-dihydropyran (101 g, 1.2 mol) and the catalytic amount of p-toluenesulfonic acid (1%). The reaction solution was heated under reflux for 2 hours. Water was added thereto, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting viscous material was recrystallized from diethyl ether to give the title compound (65.8 g, 69%)
67%
With toluene-4-sulfonic acid; In ethyl acetate; for 2h;Reflux;
Synthesis of compound 7 (0183) R-3 =H, R-4 = H (0184) [0092] To a 1 L flask, 6-chloropurine (30 g, 194.1 mmole, 1 equiv.), 3, 4-dihydropyran (24.5 g, 291.1 mmol, 1.5 equiv.) and p-toluenesulfonic acid (PTSA) monohydrate (2.95 g, 15.5 mmol, 8% equiv.) were added, followed by EtOAc (240 mL). The mixture was refluxed for 2 hrs. After the mixture cooled down, it was washed with NaHCCh (250 mL) to adjust pH = 7-8 and brine 150 mL x 3. The EtOAc layer was dried over Na2S04 and concentrated to dryness. The residue was purified by silica gel plug with hexane : EtOAc (2: 1, 1 : 1 and 1 :2 ) to afford 6-chloro-9-(tetrahydro-2H-pyran-2- yl)-9H-purine as an off-white solid (31.6 g , 67%). (0185) R3 = D (0186) [0093] To a 100 mL round bottom flask under N2, at -40 C under N2, n-BuLi (2.5 M, 23.5 mL, 58.7 mmol, 1.4 equiv.) was added drop wise to diisopropylamine (5.94 g, 58.7 mmol, 1.4 equiv) in THF (40 mL). The mixture temperature was raised to -10 C. Then the mixture was cooled to -70 C, 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (10 g, 41.9 mmol, 1 equiv.) in THF (20 mL) solution was added drop wise while maintaining the temperature below -68 C. The mixture was stirred for 1 hr. and then 5 mL D20 was added. The mixture temperature rose to 10 C. To the mixture, 2 N HC1 was added to adjust to pH = 8. The separated THF layer was concentrated. The aqueous phase was extracted with EtOAc (100 mL x 2). The EtOAc layer was combined with THF dryness and washed with brine (75 mL x 2), dried over Na2S04. The solvent was evaporated to give a red oil. Repeat the above H-D exchange procedure twice. The crude product was purified by silica gel plug with hexane:EtOAc (5: 1, 4: 1, 3: 1, 2.5: 1) to get compound 7 as yellow oil (5.6 g, 56%).
67%
With toluene-4-sulfonic acid; In ethyl acetate; for 2h;Reflux;
To a 1 L flask, 6-chloropurine (30 g, 194.1 mmole, 1 equiv), 3, 4-dihydropyran (24.5 g, 291.1 mmol, 1.5 equiv) and PTSA monohydrate (2.95 g, 15.5 mmol, 8% equiv) were added, followed by EtOAc (240 mL). The mixture was refluxed for 2 hours. After the mixture cooled down, it was washed with NaHCCh (250 mL) to adjust pH = 7-8 and brine 150 mL x 3. The EtOAc layer was dried over Na2SC>4 and concentrated to dryness. The residue was purified by silica gel plug with hexane : EtOAc (2: 1, 1 : 1 and 1 :2 ) to get 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine as an off-white solid (31.6 g, 67%).
62%
With toluene-4-sulfonic acid; In tetrahydrofuran; at 84℃; for 22h;Inert atmosphere;
The compound was prepared from 6-chloropurine according to the literature (Taddei et al., Org. Biomol. Chem. 2004, 2, 665). A mixture of 6-chloropurine (20.0 g, 129 mmol), p-toluenesulfonic acid (0.23 g, 1.85 mmol), 3,4-dihydro-2H-pyran (14.5 ml, 159 mmol) in tetrahydrofuran (175 ml) was refluxed under argon at 84C for 22 h. After cooling, concentrated ammonia (5 ml) was added, undissolved particles were filtered off and the filtrate evaporated to dryness. The yellowish oil was dissolved in ethyl acetate (250 ml) and extracted with brine (75 ml), water (2 x 75 ml) and then dried over sodium sulfate. The organic extracts were concentrated in vacuo into an yellow oil that was extracted with boiling cyclohexane (cca 250 ml). Light yellow cyclohexane extract was separated from the undissolved orange rest by decantation. The extraction procedure was repeated twice with 150 ml cyclohexane. The cyclohexane extracts were cooled in a fridge overnight to precipitate colourless crystals. Yield: 19.1 g, 62 %. M.p.: 68C. *H NMR (300 MHz, DMSO-<: delta 1.61 (2H, m, THP), 1.76 (1H, m, THP), 2.00 (2H, m, THP), 2.34 (1H, m, THP), 3.73 (1H, m, THP H40, 4.03 (1H, dm, / = 11 Hz, THP H3'), 5.80 (1H, dd, / = 2.3, 11 Hz, THP H2'), 8.81 (1H, s, H8), 8.92 (1H, s, H2). Examples 2 Syntheses of 6-alkylamino/aralkylamino-9-(tetrahydropyran-2-yl)-9H-purines
With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 3h;
A suspension of 6-chloropurine (14, 40.0 g, 90.6 mmol),p-toluenesulfonic acid monohydrate (0.5 g, 2.63 mmol, 0.03 eq.), and 3,4-dihydro-2H-pyran (16, 35.4 mL, 136 mmol, 1.5 eq.) in DCM (400 mL) was stirred at room temperature for 3 h to give a slightly hazy solution. When HPLC analysis indicated the presence of< 0.1% purine 14, a 2.5% aq. Na2CO3 solution (200 mL) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 15 mm. The two layers were separated and the organic layer was treated with additional 2.5% aq. Na2CO3 (200 mL). The two layers were separated and the organic layer was dried over Na2SO4. The mixture was filtered and the resulting solid cake was rinsed with DCM (20 mL). The filtrate was concentrated to a minimal volume under reduced pressure at 35 C. n-Heptane (200 mL) was added to the concentrated filtrate and the mixture was stirred vigorously at room temperature until a solid suspension formed (up to 16 h). The precipitate was collected by filtration, rinsed with n-heptane (100 mL), and dried at 40 C under vacuum to afford crude 6-chloro-9- (tetrahydro-2H-pyran-2-yl)-9H-purine (17, 55.5 g, 89.8%) as a pale yellow solid, which was used without further purification. ?H NMR (300 IVIFIz, DMSO-d6) 8.90 (s, 1H), 8.79 (s, 1 H), 5.78 (d, J= 10.9 Hz, 1H), 3.99 (m, 1H), 3.70 (m, 1H), 2.31 (m, 1H), 1.99 (m, 2H), 1.74 (m, 1H), 1.58 (m, 2H); LCMS calc. for C,oH,2C1N40 (M+H): 239.04; Found: 239.1.
With toluene-4-sulfonic acid; In ethyl acetate; at 90℃; for 1h;
A suspension of 6-chloro-9H-purine (25.36 g, 164 mmol) and 4-methylbenzenesulfonic acid (0.565 g, 3.28 mmol) in EtOAc (250 mL) was treated with 3,4-dihydro-2H-pyran (44.9 mL, 492 mmol). The mixture was heated at 90 0C and the solid slowly dissolved over Ih. The flask was removed from the oil bath and the cloudy yellow solution was filtered and concentrated in vacuo. The pale yellow residue was dissolved in DCM and purified by flash chromatography (50% EtOAc / hexane) (IL silica / 4 L solvent) to give 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (38.90 g, 99.3% yield) as a colorless oil which slowly crystallized. MS (ESI, pos. ion) m/z: 239.1 [M+H]+
97%
With toluene-4-sulfonic acid; In ethyl acetate; at 90℃; for 0.1h;
6-chloro-9H-purine (500 mg, 3.2 mmol), 4-methyl benzene sulfonic acid (12 mg, 0.07 mmol), and 3,4-dehydro-2H-pyran (0.9 mL, 9.7 mmol) were added into ethylacetate solvent and stirred. The reactant was stirred at 90C for approximately 1 hour until the solid is dissolved completely. After concentrating the solvent, the residuals were refined by means of column chromatography, so that 749 mg of the target compound, 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (percentage yield: 97%), was obtained.1H NMR(400MHz, CDCl3) delta 8.77 (s, 1H), 8.36(s, 1H), 5.80(dd, J = 10.4, 2.8 Hz, 1H), 4.21(m, 1H), 3.80(m, 1H), 2.21-1.67(m, 6H).
95%
With toluene-4-sulfonic acid; In tetrahydrofuran; for 15h;Reflux;
p-TSA (0.01 g) was added to a solution of 6-chloropurine(0.15 g, 1 mmol) in dry THF at reflux. After 3,4-dihydro-2H-pyran (0.098 g, 1.18 mmol) was added andthe mixture refluxed for 15 h. After cooling to ambienttemparature the reaction mixture was treated with 1 mL25% NH4OH and sitirred for 5 min. The solution was evaporatedin vacuo and treated with 25 mL EtOAc, washedwith brine and water. The organic phase was dried overNa2SO4, the solvent was evaporated in vacuo, and recrystallizedfrom hexane petroleum ether to yield 2 (220 mg;95%): mp 69-71 C (67-69 C30). 1H NMR (CDCl3) delta1.64-1.88 (m, 3H, H-pyran), 2.02-2.21 (m, 3H, H-pyran),3.80 (td, J1 = 2.8 Hz, J2 = 12 Hz, 1H, H-5?a in pyran), 4.20(d, 1H, H-5?b in pyran), 5.80 (dd, J1 = 10.8 Hz, J2 = 2.4Hz, 1H, H-1? in pyran), 8.35 (s, 1H, H-8 in purine), 8.76(s, 1H, H-2 in purine). MS (ESI+) m/z: 239.70 (10%)(M+H).
92%
With toluene-4-sulfonic acid; In chloroform; at 0 - 20℃; for 5h;
DHP (4.79 g, 56.9 mmol, 5.2 mL, 1.1 eq) was added to a mixture of 6-chloro-9H- purine (8 g, 51.7 mmol, 1 eq) and TsOH.H2O (984 mg, 5.18 mmol, 0.1 eq) in CHCl3(80 mL) at 0C dropwise. The mixture was stirred at 20C for 5h. Water (100 mL) was added to the mixture and the mixture was extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was stirred in petroleum ether (100 mL) for 2 h, the precipitate was filtered and dried to give 6-chloro-9- tetrahydropyran-2-yl-purine (I-596) (11.3 g, 92% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) d 8.75 (s, 1 H) 8.34 (s, 1 H) 5.79 (dd, J=10.36, 2.43 Hz, 1 H) 4.13- 4.25 (m, 1 H) 3.73- 3.84 (m, 1 H) 2.00- 2.21 (m, 3 H) 1.65- 1.87 (m, 3 H).
91%
Ethyl acetate (300 ml) was added to 6-chloropurine (25 g, 162 mmol) and tosylic acid monohydrate (460 mg, 2.43 mmol)and the resulting mixture was heated at 60 C. Dihydropyrane (16 ml, 178 mmol) was added and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was cooled to room temperature followed by the addition of 28% aqueous ammonia solution (15 ml) and the organic layer was fractionated, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (35 g, 91%) as a pale yellow solid.
89%
With toluene-4-sulfonic acid; In ethyl acetate; at 90℃; for 1h;
General procedure: A suspension of 6-chloro-9H-purine (or 4-iodo-1H-pyrazole) (13mmol) and 4-methylbenzenesulfonic acid (0.12g, 0.65mmol) in EtOAc (25ml) was treated with 3,4-dihydro-2H-pyran (3.54ml, 39mmol). The mixture was heated at 90C and the solid slowly dissolved over 1h. The flask was removed from the oil bath and the cloudy yellow solution was filtered and concentrated under vacuum. The pale yellow residue was purified by flash chromatography to give title compound.
83.2%
With toluene-4-sulfonic acid; In ethyl acetate; for 3h;Reflux;
A mixture of 6-chloro-9H-purine 17 (2.01 g, 13 mmol), 3,4-dihydro-2H-pyran (3.30 g, 39 mmol) and TsOH (516 mg, 0.3 mmol) dissolved in anhydrous ethyl acetate (30 mL) was refluxed for 3 h. Then cooled to the room temperature and washed with water and brine. The organic layer was dried (anhydrous Na2SO4) and concentrated to afford the compound 18 (2.62 g, 83.2 %) as a yellow oil. ESI-MS m/z: 239.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6): delta 1.58-1.64 (2H, m, H-pyran), 1.69-1.78 (1H, m, H-pyran), 1.97-2.05 (2H, m, H-pyran), 2.32-2.37 (1H, m, H-pyran), 3.69-3.77 (1H, m, H-pyran), 4.03 (1H, d, J=5.4Hz, H-pyran), 5.80 (1H, dd, J=2.1Hz, J=10.9Hz, H-pyran), 8.81 (1H, s, H-purine), 8.91 (1H, s, H-purine).
82.1%
With toluene-4-sulfonic acid; In ethyl acetate; at 50℃; for 1h;
6-Chloropurine (15.5 g) and p-toluenesulfonic acid (0.26 g) were dissolved in ethyl acetate (180 ml)Heated to 50 C, 2,3 dihydropyran (10.5ml) was slowly dropped to the reaction solution, the dropwise addition, stirring was continued for 1 hour at this temperature, slowly cooled to room temperature, stirred under saturated ammonium chloride solution (10ml ), Then washed twice with water, once with brine, dried and concentrated to give an oily crude which was recrystallized from n-hexane (150 ml)Chloro-9- (tetrahydro-2-pyranyl) -purine 19.6 g, yield 82.1%.
80%
With toluene-4-sulfonic acid; In ethyl acetate; at 75℃; for 2.6h;
Example 1B Compound 3 (4.60 kg) was treated with p-toluenesulfonic acid monohydrate and 3,4-dihydro-2H-pyran (DHP) in ethyl acetate at 75 C. for 2.6 hours. The reaction was monitored by HPLC. Upon completion of the reaction, Compound 4 was obtained as a yellow solid in 80% yield with >99% (AUC) purity by HPLC analysis.
72.2%
EXAMPLE 1 This example illustrates the preparation of 6-chloro-9-(2-tetrahydropyranyl)purine. A mixture of 6-chloropurine (60 g, 388 mmol) and tosic acid monohydrate (1 g) in ethylacetate (750 ml) was vigorously stirred at 50 C. 3,4-Dihydropyran (40 ml, 438 mmol) was added dropwise over a 30 min period, maintaining the reaction temperature between 55-60 C. (Robins et al., 1961). The solution was stirred for an additional hour during which time it was allowed to cool to room temperature. Concentrated aqueous ammonia (35 ml) was added and the solution stirred for 5 min. Homogenous dark-green solution was subsequently extracted with 2*200 ml water. The yellow ethylacetate extract was dried overnight over sodium sulphate and then cool at -20 C. Accrued yellow solid was dried again in vacuo over phosphorus pentoxide at 37 C. Yield: 66.9 g (72.2%). MS (ES): [M+H]+=239 (100).
69%
With toluene-4-sulfonic acid; In ethyl acetate; for 2h;Reflux;
Step 1 : 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineTo a solution of 6-chloro-9H-purine (61.8 g, 0.4 mol) in EtOAc (300 mL) was added 3,4-dihydro-2H-pyran (101 g, 1.2 mol), followed by 4-methylbenzenesulfonic acid (1%) and the resulting reaction mixture was heated to refluxing for 2 hrs. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was recrystallized with ether to afford the desired product (65.8 g, 69%).1H NMR (CDCI3): ? 8.74 (1H, s), 8.33 (1H, s), 5.80-5.76 (1H, m), 4.20-4.16 (1H, m), 3.81-3.75 (1H, m), 2.09-2.00 (3H, m), 1.86-1.65 (4H, m).
With toluene-4-sulfonic acid;
The starting material for the compounds of the formula I is 6-chloro-9-(tetrahydropyran-2-yl)purine, synthesised from 6-chloropurine and 3,4-dihydopyran using p-toluenesulfonic acid according to the literature (Robins et al., J. Am. Chem. Soc. 83, 2574 (1961)).; Example 16-(4-hvdroxybenzylamino)-9-(tetrahydropyran-2-yl)purine. A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) 4-hydroxybenzylamine, and 5 mL of triethylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate solvent was evaporated and the residuum subsequently washed with 30 ml of diethylether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 80%, white solid. TLC (EtOAc:hexane (1:1) (v:v): single spot; HPLC: purity>98%. 1H-NMR (400 MHZ, DMSO): 1.57tt(2H, Ja=11.0 Hz, Jb=3.3 Hz); 1.72qq(1H, Ja=12 Hz, Jb=3.3 Hz); 1.95tt(2H, Ja=11 Hz, Jb=2.1 Hz); 2.27qq (1H, Ja=12.0 Hz, Jb=3.3 Hz); 3.67m(1H); 4.0dd(1H, Ja=11.0 Hz, Jb=2.1 Hz); 4.6s(2H); 5.63dd(1H, Ja=11.0 Hz, Jb=2.1 Hz); 6.67d(2H, J=8.4Hz); 7.15d(2H, J=8.4 Hz); 8.02bs (1H); 8.21s(1H); 8.33s(1H); 9.21s(1H). MS (ES): [M+H]+=326 (100).; Example 26-(3-hydroxybenzylamino)-9-(tetrahydropyran-2-yl)purine. A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) 3-hydroxybenzylamine, and 5 mL of triethylamine was refluxed in n-butanol for 3 hours. After removal of the n-butanol by vacuum evaporation water was added to remove the n-butanol residues. The resulting material was treated with water and partitioned into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of diethylether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 90%, white solid. TLC (EtOAc:hexane (1:1) (v:v): single spot; HPLC: purity>99%. 1H-NMR (400 MHZ, DMSO): 1.57m(2H); 1.70m(1H); 1.95m(2H); 2.27qq (1H, Ja=11.7 Hz, Jb=4.0 Hz); 3.66m(1H); 4.0d(1H); 4.63bs(2H); 5.67dd(1H, Ja=11.3 Hz, Jb=1.8 Hz); 6.58dd(1H, Ja=8.2 Hz, Jb=1.5 Hz); 6.73(d, 1H, J=7.7 Hz); 7.07t(1H, J=7.7 Hz); 8.21 s (1H); 8.33bs(1H); 8.36bs(1H); 9.26s(1H). MS (ES): [M+H]+=326 (100).; Example 36-(2-hydroxybenzylamino)-9-(tetrahydropyran-2-yl)purine. A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) 2-hydroxybenzylamine, and 5 mL of triethylamine was refluxed in n-propanol for 3 hrs. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate solvent was evaporated and the residuum subsequently washed with 30 ml of diethylether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 90%, white solid. TLC (EtOAc:hexane (1:1) (v:v): single spot; HPLC: purity>98%. 1H-NMR (400 MHZ, DMSO): 1.58m(2H); 1.70m(1H); 1.95m(2H); 2.26qq (1H, Ja=11.8 Hz, Jb=4.0 Hz); 3.67m(1H); 4.0d(1H, J=11.3 Hz); 4.64bs(2H); 5.63dd(1H, Ja=11.3 Hz, Jb=1.8 Hz); 6.73t(1H, J=7.5 Hz); 6.82(d, 1H, J=7.9 Hz); 7.06t(1H, J=7.5 Hz); 7.14d(1H, J=7.5 Hz); 8.21 s (1H); 8.35bs(1H); 8.37bs(1H); 9.82bs(1H). MS (ES): [M+H]+=326 (100).; Example 46-(2,3-dihydroxybenzylamino)-9-(tetrahydropyran-2-yl)purine. A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (2100 mg) 2,3dihydroxybenzylamine hydrochloride, and 7 mL of triethylamine was refluxed in n-propanol for 3 hrs. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate solvent was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 60%, white solid. TLC (CHCl3:methanol) (4:1) (v:v): single spot; HPLC: purity>98%. 1H-NMR (300 MHz, DMSO): 1.57m(2H); 1.71m(1H); 1.95m(2H); 2.27qq(1H, Ja =12 Hz, Jb=4.0 Hz); 3.67m(1H); 4.00d(1H, J=11.7 Hz); 4.58bs(2H); 5.63dd(1H, Ja=11.2 Hz, Jb=1.9 Hz); 6.55tt(1H, Ja=7.7 Hz, Jb=1.5 Hz); 6.63dd(1H, Ja=7.7 Hz, Jb=1.8 Hz); 6.66dd(1H, Ja=7.7 Hz, Jb=1.8 Hz); 8.24s(1H); 8.27bs(1H); 8.37s(1H), 8.96bs(1H), 9.53bs(1H). MS (ES): [M+H]+=342 (100).; Example 56-(E)-(4-hydroxy-3-methylbut-2-en-1-ylamino)-9-(tetrahydropyran-2-yl)purine. A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1754 mg) (E)-(4-hydroxy-3-methylbut-2-en-1-ylamine hemioxalate and 3 mL of triethylamine was refluxed in n-butanol for 3 hrs. After removal of the n-butanol by vacuum evaporation, the resulting material was treated with water and extracted i...
With toluene-4-sulfonic acid; In ethyl acetate; for 2h;Reflux;
(i) General Methods for the Synthesis of Cl-Wd and TsO-Wd Heterocycles: General conditions for the preparation of 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purines: To a solution of 6-chloro-9H-purine (A-1) (1.29 mol, 1 eq) and anhydrous TsOH (0.02 mol, 0.015 eq) in ethyl acetate (1000 mL), 3,4-dihydro-2H-pyran (1.94 mol, 1.5 eq) is added and the resulting mixture is stirred at reflux for 2 h. The reaction mixture is allowed to cool to RT, aqueous Na2CO3 solution (3%, 500 mL) is added and the resulting mixture is stirred for 10 min. The organic layer is separated, washed with water (2*500 mL) and brine (500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate is concentrated in vacuo. The product is dissolved in ethyl acetate (50 mL), and then n-heptane (500 mL) is added. The resulting mixture is stirred at RT for 1 h. The precipitate is collected by filtration, rinsed with heptane (100 mL) and dried in vacuo to afford the product, 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (A-2).
11.3 g
With toluene-4-sulfonic acid; In ethyl acetate; for 2h;Reflux;
a, 6-Chloropurine (1, 7.7 g, 50 mmol)And p-toluenesulfonic acid (172 mg, 1 mmol) in EtOAc was stirred at room temperature,3,4-dihydro-2H-pyran (8.4 g, 100 mmol) was added dropwise,The reaction was heated to reflux for about 2 h;When the reaction solution is near the clear state,Hot filter to remove part of the raw materials 1,The filtrate was washed with water,Saturated salt water were washed,Collecting oil layer,Anhydrous Na2SO4 drying oil layer,Removal of the solvent gave 6-chloro-9- (tetrahydro-2H-2-pyran-2-yl) -9H-purine (Intermediate 2, 11.3 g);
With methanesulfonic acid; In ethyl acetate; at 90℃; for 1h;
Step 5: Preparation of 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine 6-chloro-9H-purine (500 mg, 3.2 mmol), 4-methanesulfonic acid (12 mg, 0.07 mmol) and 3,4-dihydro-2H-pyran (0.9 mL, 9.7 mmol) were added to an ethyl acetate solvent, followed by stirring. The reaction mixture was stirred at 90C for about 1 hour until the solid was completely dissolved. After the solvent was removed by concentration, the residue was purified by column chromatography to afford the title compound. 1H NMR (400MHz, CDCl3): delta 8.77 (s, 1H), 8.36 (s,1H), 5.80 (dd, J = 10.4, 2.8 Hz, 1H), 4.21 (m, 1H), 3.80 (m, 1H), 2.21-1.67 (m, 6H)
To a solution of 6-chloro-9H-purine (3.00 g, 20.0 mmol) in anhydrous THF (100 mL)cooled to 0 oC, 60% sodium hydride (1.2 g, 30.0 mmol) were added portionwise. After the reaction suspension was refluxed for 0.5 hour in the ice bath, MeI (2.82 g,20.0 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. The mixture was diluted in 100 mL H2O and extracted with EtOAc (30 mL x 3). The combined organic layer was dried with anhydrous MgCl2 and the solvent was evaporated in vacuum. The crude solid was purified through a silica gel column, eluting with 20 % ether acetate/petroleum. White solid was obtained in a yield of 74.6% (2.50 g). ESI-MS m/z: 169.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6): 3.72 (3H, s, CH3), 8.72 (1H, s, H-purine), 9.15 (1H, s, H-purine).
48%
With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 15 - 30℃; for 24h;Inert atmosphere;
To the compound 6-chloro-7H-purinele 59a (154.0 mg, 1.0 mmol) at room temperature,Sodium hydrogen (mineral oil dispersion 60%,120.0 mg, 5.0 mmol) was mixed with N,N-dimethylacetamide (10 mL), and methyl iodide (426.0 mg,3.0 mmol), reacted at room temperature for 24 hours. The reaction was quenched by the addition of 5 mL of water and extracted with dichloromethane (30 mL×3).The machine phase was washed with saturated brine (30 mL). Dry the organic phase with anhydrous sodium sulfate, remove the desiccant by filtration, and pass the residuePurification by flash column chromatography gave the title compound 6-chloro-9-methyl-9H-purine (b) (80.0mg, 0.48mmol, white solid)Yield: 48%.
4.76%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;
[0501] Procedure: To a stirred solution of 6-chloro-9H-purine (1 g, 6.469 mmol) in DMF (10 mL) was added Cs2CO3 (2.31g, 7.107 mmol) followed by methyl iodide (0.80 mL, 12.93 mmol). Reaction mixture was stirred for 3 h at room temperature. Progress of the reaction was monitored by TLC. Reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 x 50mL). The combined organic layer was washed with brine (10mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The crude residue was purified by combiflash using methanol in dichloromethane to afford 6-chloro-9-methyl-9H-purineas off-white solid, (0.1 g, 4.76 %).1HNMR (400 MHz, DMSO-d6): delta 8.76 (s, 1H),8.62 (s, 1H), 3.84 (s, 3H).LC-MS (ES) m/z = 169.1 [M+H]+.
With potassium carbonate; In dimethyl sulfoxide; at 15 - 25℃;Inert atmosphere;
A mixture of 6-chloro-9H-purine (15.0 g, 97.4 mrnol), DM50 (200 mE) and K2C03 (20.2 g, 146 mmol) was treated dropwise with CH3I (20.7 g, 146 mmol) and stirred at RT overnight. Water (500 mL) was added and the resulting mixture was extracted with DCM (2 x500 mL). The combined organic extracts were washed with brine, dried with Na2SO4, Filtered and concentrated. The crude material was purified by column chromatography (1:1 petroleum ether/ethyl acetate) to give 6-chloro-9-methyl-9H-purine. MS (El) Calc?d for C6H5C1N4 [MH-H], 169; found, 169. A mixture of N-isopropylcyclohcxanamine (1.9 g, 13 mmol) in THF (30 niL) wascooled to -78 C, then n-BuLi (5.3 mL, 2.5 M, 13 mmol) was added dropwise and stirred at -78 C for 10 mm. Next, a solution of 6-chloro-9-methyl-9H-purine (1.5 g, 8.9 mmol) in THF(10 mL) was added dropwise and stirred for 15 mm at -78 C. To this mixture, a solution of 12(3.4 g, 13 mmol) in THF (10 mL) was added dropwise and the resulting mixture stirred for 1 h at-78 DC. The reaction was quenched by the addition of aqueous NH4C1 (20 mL). AqueousNa2SO3 (10 mL) was added and the precipitate was filtered. The filtrate was dried with Na2SO4,filtered and concentrated to give 6-chloro-8-iodo-9-methyl-9H-purine. MS (El) Calc?d for C6H5C1IN4 [M+Hfb, 295; found, 295. A solution of (S)-l-(3-hydroxypyrrolidin-l-yl)propan-1-onc (60 mg, 0.4 nrniol) in THF (3 mL) was treated with a 60% suspension of NaH in mineral oil (24 mg, 1 mmol). Theresulting mixture was stirred for 30 minutes at 0 C and 6-ehloro-8-iodo-9-methyl-9H-purine (100 mg, 0.34 mmol) was added. The reaction was stirred at room temperature for 15 h. The reaction mixture then was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The combined organic extracts was dried over Na2504, filtered and concentrated. The residue was purified by chromatography on Si02 (DCM/MeOH: 20/1) to afford 3-3 1. MS (El) Cale?dfor C13H171N502 [M+H], 402; found, 402.
With sodium hydride; In N,N-dimethyl-formamide; at 20℃;
General procedure: To a solution of 9H-purines (1.5 mmol) and sodium hydride(0.12 g, 60%) in anhydrous DMF (3 mL) was added iodomethane (0.42 g, 3 mmol). The resulting mixture was stirred at room temperatureuntil the starting material disappeared on TLC. Then thereaction solution was poured into water (20 mL), and extractedthree times with EtOAc (15 mL x 3). The combined organic layerwas dried over anhydrous Na2SO4 and concentrated under reducedpressure to yield crude 9-methyl-9H-purine, which was used innext step without further purification
154.5 g of 4-chloro-1H-pyrazolo [3,4-d] pyrimidine (1 mol) was dissolved in 200 mL of ethanol,Of triethylamine (1.2mol), then 118g of benzylamine (1.1mol) was slowly added dropwise, the reaction mixture was heated to reflux for 5h.After the reaction was completed, the ethanol was evaporated to dryness, water was added, the mixture was extracted three times with ethyl acetate, and the organic layer was spin-dried to obtain 216 gOf white needles solid 6-benzylaminopurine with a yield of 96.0%.
69%
With triethylamine; In butan-1-ol; at 110℃; for 3h;
To a solution of 6-chloro-9H-purine (112 mg, 0.72 mmol) and TEA (161 pL, 1.15 mmol) in nBuOH (6 mL) at RT was gradually added benzyl amine (95.6 iL,0.86 mmol). The reaction mixture was stirred for 3 h at 110C and subsequently cooled to0C. The colorless precipitant was filtrated, washed with 10 mL ice-cold MeOH and dried in vacuo. The desired N-Benzyl-9H-purin-6-amine was obtained in 69% yield (112 mg, 0.49 mmol) as colorless solid. R± 0.15 (DCM/EtOAc/MeOH 49:49:2). LCMS (ESI): calculated for [Ci2HiiN5+H]: 226, found 226 [M+H]t
61%
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 110℃; for 0.25h;Microwave irradiation;
6-chloro-9H-purine(0.11 g,0.712 mmol), benzylamine (0.155 mL, 1.42 mmol), N, N-diisopropylethylamine(0.248 mL, 1.42 mmol) and 1, 4 - dioxane (1 mL, 13 mmol) were placed in a 10 mLCEM microwave vial. The vial was capped and irradiated in a CEM microwave reactorfor 15 minutes at 110 C.The reaction was concentrated, dissolved in DMF and the residue was purified bypreparative reverse phase HPLC to give N-benzyl-9H-purin-6-amine(1; 0.097 g,61%) as an off white solid: 1H NMR (400 MHz, DMSO-d6)delta 12.92 (s, 1H), 8.13 (d, J = 26.2 Hz, 3H), 7.42 - 7.15 (m, 6H), 4.71(s, 2H); ESMSm/z 266.19 (M+1).
General procedure: A solution of 1 (1.10 g, 4.5 mmol), 2 (244 mg, 1 mmol), 3 (649 mg, 2.5 mmol), 4 (518 mg, 2 mmol), 5 (310 mg, 2 mmol), 6 (190 mg, 1 mmol) or 7 (340 mg, 2 mmol) in DMF (6 mL for 0.5 mmol of starting compound) was divided into several vials. Each vial contained starting compound (0.5 mmol) and DMF (6 mL). The solutions were heated under microwave irradiation. Reaction mixtures were collected and evaporated in vacuo. For 10, 11, 12, 13, and 16 the residue was applied on silica gel column and flash chromatographed. For 14 and 15 the residue was partitioned between water (60 mL) and EtOAc (50 mL). The water layer was extracted with EtOAc (3×40 mL), dried over anhydrous MgSO4, filtered, and evaporated.
With triethylamine; In butan-1-ol; at 90℃; for 4h;
Example 2 6-(3-chlorobenzylamino)purine 4 mmol of 6-chloropurine were dissolved in 20 mL of butanol and then 5 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90° C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity>97percent. Yield 94percent. Table 2 compound prepared by the method of example 2
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 105℃; for 24h;
6-chloropurine was combined with S-(-)-2-(diphenylmethyl)-pyrrolidine in n-butanol with two equivalents of diisopropylethylamine (N(iPr)2Et). The reaction was heated to 105 C. and allowed to react for 24 h. Solvent was removed from the reaction mixture in vacuo and the crude product purified by silica gel chromatography.
To a flask was added 6-chloro-9H-purine (1a, 0.77 g, 5.0 mmol), sodium methylate (1.35 g, 25.0 mmol) and anhydrous methanol (5 mL). The mixture was then refluxed under an argon atmosphere for 12 hours. The solvent was removed under reduced pressure. Water (8 mL) and methylbenzene (8 mL) were added to the residue and stirred for 0.5 hour. The solvent was poured into a separating funnel and aqueous phase was separated to acidified to neutral with 0.5 M HCl (aqueous). The solid was separated out as declining of pH and isolated by filtration to give yellow powder. Silica gel column chromatography (hexanes/ ethyl acetate, 2: 1, v: v) afforded the product as white powder: yield 0.32 g (43%); mp192-195 C ; 1H NMR (500 MHz, CD3OD) delta 8.55 (s, 1H), 8.34 (s, 1H), 4.23 (s, 3H); 13C NMR (101 MHz, CD3OD) delta 159.6, 151.7, 142.3, 117.1, 53.4; HRMS (ESI) m/z calcd. for C6H6N4O ([M - H]-): 149.0463, found 149.0464.
Example 1: Synthesis of methyl (9H-purin-6-yl)-amine A solution of 6-chloropurine (0.1 g, 0.6472 mmol) in methylamine (1.5 mL) was stirred at 100 C in an oil bath for 20 hours. The solvent of the resulting reaction mixture was evaporated off and a yellow semi-solid residue was obtained, which upon trituration with ethyl alcohol gave the title organic compound. Yield: 90 mg
6-Cyclohexylmethoxypurine (NU2017) Sodium (0.4 g, 17.4 mmol) was added to stirred cyclohexylmethanol (10 ml) under nitrogen. The reaction was stirred at 100 C. until no sodium remained. 6-Chloropurine (500 mg, 3.24 mmol) was added, and the reaction was stirred under nitrogen at 100 C. for 5 days. After cooling to room temperature, the mixture was neutralised with glacal acetic acid and the solvent was removed in vacuo. Water (20 ml) was added and the product was extracted into dichloromethane (3*30 ml). The combined organic extracts were dried over MgSO4, and the volume of the solvent was doubled. After filtering hot and removal of the solvent, recrystallisation from ethyl acetate gave the title compound as a white crystalline solid (600 mg, 70%), m.p. 210-211 C.; (Found: C, 62.30; H, 6.93; N, 24.36. Calc. for C12H16N4O: C, 62.05; H, 6.94; N, 24.12%); numax (cm-1) 3108, 3050,2930, 2849, 2801 (NH, C-H); deltaH (200 MHz, d6-DMSO) 8.479 (1H, s, C(2)H or C(8)H), 8.388 (1H, s, C(2)H or C(8)H), 4.348 (2H, d, J=6.2 Hz, OCH2), 1.854-1.692 (6H, m, cyclohexyl), 1.357-0.984 (5H, m, cyclohexyl); deltaC (50 MHz, d6-DMSO) 159.40, 155, 151.57, 142.88, 118, 71.41 (OCH2), 37.08, 29.40, 26.24, 25.47 (cyclohexyl); m/z 233 (MH+, 76%), 202 (33), 149 ([M-C6H11]+, 32%), 137 (100), 120 ([MH-C7H13O]+, 44%), 108 (30), 93 (27), 81 (65), 67 (62), 55 (88), 41 (89).
32%
With sodium;Inert atmosphere; Reflux;
General procedure: To a solution of Na (1.36 equiv) in the appropriate alcohol (20 equiv) was added the appropriately substituted purine under an argon atmosphere. The reaction mixture was stirred at reflux for 2-6 h and then allowed to stir at room temperature overnight under argon. Deionized water (10-20 mL) was added and the reaction mixture was neutralized by addition of acetic acid. The neutralized solution was then extracted with diethyl ether. The ethereal layers were pooled, dried over Na2SO4, concentrated, and dried in vacuum over P2O5 at 25 C. In most cases, the crude material was purified by column chromatography (CC) over silica gel G.
EXAMPLE 10 N6 -(1-tetralyl) adenine hydrochloride salt A solution of 6-chloropurine (1.546 g, 10 mM) and 1-aminotetralin(1.472 g, 10 mM) in isopropanol (60 ml) is heated to reflux for about 20 h. The resulting salt suspension is then cooled to room temperature, filtered and the residue washed with ice-cooled isopropanol to give almost pure title compound in 80percent yield. MS m/z 301 NMR delta ppm (DMSO-d3): 1.70 (m, 4H), 2.6-2.9 (m, 4H), 7.0-7.3 (m, 3H), 8.46, 8.62 (two s, 2H), 10.9 (bs, 1H).
A mixture of 6-chloropurine (3.09 g, 20 mmol), 4-benzoyl-benzyl chloride (6.05 g, 22 mmol)and K2 CO3 (3.04 g, 22 mmol) in DMF (50 ml) was stirred overnight at rt, diluted with water (400 ml), and extracted with EtOAc (3*100 ml) (Scheme 9)52. The combined organic layers were washed with water and brine, dried over MgSO4, concentrated in vacuo, and subjected to flash-chromatography on silica gel eluding with CH2 Cl2 -acetone (80:20). The fractions containing the higher Rf, the major component, were combined and concentrated in vacuo to give 2.86 g (41%) of 9-(4-benzoylbenzyl)-6-chloro-9H-purine.
In methanol; ethanol; at 120℃; for 4h;Sealed tube;
Example 147 1-[4-(6-(Methylamino)purin-9-yl)phenyl]-3-[3-(4-methylpiperazin-1-ylmethyl)-5-(trifluoromethyl)-phenyl]urea (Table 2, Compound 25) Step A Preparation of methyl-(9H-purin-6-yl)amine [Show Image] [Show Image] In 20 mL of a 40% methylamine methanol solution and 20 mL of ethanol, 12.5 g (79 mmol) of 6-chloropurin was dissolved and the solution was sealed in a tube and stirred in the tube at 120C for four hours. The reaction solution was concentrated, and then triturated with water and collected on a filter, washed with water, and then vacuum dried to obtain 10.78 g (90%) of methyl-(9H-purin-6-yl)amine as a white solid. 1H-NMR (270 MHz, DMSO-d6) delta (ppm): 2.98(3H,br.s), 7.58(1H,br.s), 8.06(1H,s), 8.19(1H,br.s), 12.89(1H,br.s) ESI (LC-MS positive mode) m/z 150 (M+H)
EXAMPLE 2 N-(1H-Pyrrol-1-yl)-9H-purin-6-amine A solution of 6-chloropurine (5 g, 32 mmole) and 1H <strong>[765-39-9]pyrrol-1-amine</strong> (3 g, 36 mmole) in 75 ml isopropanol stirred one hour at reflux then was cooled, diluted with ether and filtered to give 8 g of a solid, d.250 C. Four grams were dissolved in methanol, basified with triethylamine and the precipitate collected and dried to give 3 g of a solid, m.p.>260 C. This solid was recrystallized from methanol to give 2.6 g (71%) of N-(1H-pyrrol-1-yl)-9H-purin-6-amine d.310 C. Analysis: Calculated for C9 H8 N6: 53.99% C; 4.03% H; 41.99% N. Found: 53.67% C; 3.92% H; 41.64% N.
UV absorption spectrum lambdamax0.1N HCl: 267 nm. The infrared absorption spectrum completely coincided with the spectrum of the specimen of N6 -methyladenine prepared from 6-chloropurine and methylamine by a known method.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 16h;
To a solution of 4-aminophenethyl alcohol (3.0 g, 21.8 mmol) in tetrahydrofuran (100 mL) at room temperature was added di-t°rt-butyldicarbonate (5.2 g, 23.6 mmol) and triethylamine (4.7 mL, 32.8 mmol). The reaction was stirred for 16 h at room temperature. The solution was diluted with water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were dried over sodium sulfate and filtered. The protected amine was obtained as a white solid (4.3 g, 83%). This compound (1.7 g, 7.4 mmol) and triphenylphosphine (1.9 g, 7.4 mmol) were added to a suspension of 6-chloropurine (761 mg, 4.9 mmol) in dry tetrahydrofuran (13 mL) at room temperature. The resulting mixture was evaporated to dryness. Dry tetrahydrofuran (13 mL) was added and the suspension was cooled to O0C followed by dropwise addition of diethylazo- dicarboxylate (891 muL, 5.7 mmol). After 16 h reaction at room temperature, the solution was concentrated under reduced pressure. The crude residue was purified on a EPO <DP n="26"/>Biotage 25M column (silica, hexane/AcOEt 95:5 to 65:35) to yield N-9 alkylated purine as a white solid (1.8 g, quantitative).
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 105℃; for 24h;Heating / reflux;
1. 6-(2-diphenylmethylcyclopentylamino)purine (Compound 73) 6-chloropurine was combined with S-(-)-2-(diphenylmethyl)-pyrrolidine in n-butanol with two equivalents of diisopropylethylamine (N(IPr)2Et). The reaction was heated to 105C and allowed to react for 24 h. Solvent was removed from the reaction mixture in vacuo and the crude product purified by silica gel chromatography.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran;Heating / reflux;
EXAMPLE 3: Synthesis of 9-(l-Adamantylmethyl)-6-chloro-9H-purine (3) and related compounds of the invention.To a mixture of adamantan-1-yl-methanol (4.45 mmol), triphenylphosphine (1.52 g, 5.79 mmol) and 6-chloropurine (757 mg, 4.90 mmol) in THF (35 ml) was added dropwise to a solution of the diisopropyl azadicarboxylate (1.19 ml, 5.79 mmol) in THF (15 ml). The resulting mixture was stirred overnight (TLC control) and then heated to reflux for 2 hours. The reaction mixture was evaporated and the residue was chromatographed on silica gel column (200 g) in toluene - ethylacetate (6:1 - >? 4:1) and crystallized from water-methanol. 9-(l-Adamantylmethyl)-6-chloro-9H-purine (3) was obtained, m.p. = 145.4 - 146.7 C. For Ci6H19ClN4 (337.3) calculated: 63.46% C, 6.32% H, 11.71% Cl, 18.50% N; found: 63.32% C, 6.28% H, 11.89% Cl, 18.24% N. 1H NMR (DMSOd6): 1.47 m, 6 H (H-2 H-8' and H-9'); 1.51 bd, 3 H and 1.60 bd, 3 H, Jgem = 12.1 (H-4 H-6' and H-IO'); 1.90 bs, 3 H (H-3 H-5' and H-7'); 3.99 s, 2 H (CH2N); 8.61 s, 1 H (H-8); 8.76 s, 1 H (H-2). 13C NMR (DMSO-de): 27.69, 3 C (C-3 C-5' and CT); 34.54 (C-I '); 36.25, 3 C (C-4', C-6' and C-10'); 39.85, 3 C (C-2', C-8' and C-9'); 55.05 (CH2N); 130.57 (C-5); 148.61 (C-8'); 149.24 (C-6'); 151.72 (C-2'); 152.99 (C-4').
With triethylamine; In 1,2-dimethoxyethane; at 60.0℃;Reflux;
To a flask containing 6-chloropurine (1.55 g, 10.03 mmol) and trityl chloride (3.35 g, 12.03 mmol) in DME (10 mL) at 60 degrees Celsius was added triethylamine (1.82 mL, 13.04 mmol) over 5 min. The reaction was brought to a gentle reflux for 1.5 hours and then cooled. The reaction contents were partitioned between EtOAc and water. The aqueous was extracted an additional time and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated. The residue was chromatographed on silica gel using Hexanes-EtOAc to afford the product as a tan solid (3.15 g, 79% yield).1H NMR (400 MHz, CDCl3) delta ppm 7.13-7.34 (m, 15H) 8.11 (s, 1H) 8.44 (s, 1H)
With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 10h;
The 6-Chloropurine (168 mg, 1.09 mmol) and 6b (200 mg, 0.75 mmol) was treated with sodium hydride (21mg, 0.87 mmol) in DMF (2 mL) at room temperature for 10h. The resulting solution was poured into saturated NH4Cl solution, and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and then dried over Na2SO4, evaporated under reduce pressure. The residue was purified by a silica gel column chromatography (benzene:acetone=5:1) to give 7b as pale yellow powder (135 mg, 47 % yield).
6-Chloropurine (2.00 g, 12.94 mmol) was added to a 25 mL single-necked flask.And add 8mL of DMF, stir at room temperature, the system is yellow liquid,Potassium carbonate (3.58 g, 25.88 mmol) was added to the system, and stirred at room temperature for half an hour, and then iodomethane (5.51 g, 38.82 mmol) was slowly added dropwise to the system.After 24 hours, the reaction was almost complete, after the reaction was over,The reaction system was poured into a beaker and washed with a saturated ammonium chloride solution.It was then extracted with dichloromethane, washed repeatedly 3 times, and the organic layer was taken.It was dried over anhydrous magnesium sulfate for half an hour and filtered to remove magnesium sulfate solid.Rotary steaming to remove DMF to give a yellow oily liquid.Mix the sample and use (ethyl acetate: petroleum ether = 1:2) as the eluent.Obtained a white solid,Mass 1.23g (theoretical mass 2.18g),The yield was 56.4%.
General procedure: To a solution of Na (1.36 equiv) in the appropriate alcohol (20 equiv) was added the appropriately substituted purine under an argon atmosphere. The reaction mixture was stirred at reflux for 2-6 h and then allowed to stir at room temperature overnight under argon. Deionized water (10-20 mL) was added and the reaction mixture was neutralized by addition of acetic acid. The neutralized solution was then extracted with diethyl ether. The ethereal layers were pooled, dried over Na2SO4, concentrated, and dried in vacuum over P2O5 at 25 C. In most cases, the crude material was purified by column chromatography (CC) over silica gel G.
With triethylamine; In butan-1-ol; at 100℃; for 24h;Inert atmosphere;
General procedure: A solution of Et3N (0.24mL, 1.70mmol), 417 (100mg, 0.34mmol) and 6-chloropurine (55mg, 0.34mmol) in nBuOH (3.4mL) was stirred at 100C for 24h. The reaction mixture was cooled, concentrated and triturated with MeOH (2.5mL). The resulting solid was collected and dried to give tert-butyl 9-(9H-purin-6-yl)-1,9-diazaspiro[5.5]undecane-1-carboxylate as a yellow solid (107mg, 0.29mmol, 84%). A mixture of 4M HCl in dioxane (0.35mL, 2.80mmol) and tert-butyl 9-(9H-purin-6-yl)-1,9-diazaspiro[5.5]undecane-1-carboxylate (107mg, 0.28mmol) in MeOH (2mL) was stirred at rt for 48h. The mixture was concentrated and purified by ion exchange chromatography on acidic resin, eluting with 2M NH3 in MeOH to give 12 as an off-white solid (66mg, 0.24mmol, 84%).
With triethylamine; In butan-1-ol; at 100℃; for 24h;Inert atmosphere;
General procedure: A solution of Et3N (0.24mL, 1.70mmol), 417 (100mg, 0.34mmol) and 6-chloropurine (55mg, 0.34mmol) in nBuOH (3.4mL) was stirred at 100C for 24h. The reaction mixture was cooled, concentrated and triturated with MeOH (2.5mL). The resulting solid was collected and dried to give tert-butyl 9-(9H-purin-6-yl)-1,9-diazaspiro[5.5]undecane-1-carboxylate as a yellow solid (107mg, 0.29mmol, 84%). A mixture of 4M HCl in dioxane (0.35mL, 2.80mmol) and tert-butyl 9-(9H-purin-6-yl)-1,9-diazaspiro[5.5]undecane-1-carboxylate (107mg, 0.28mmol) in MeOH (2mL) was stirred at rt for 48h. The mixture was concentrated and purified by ion exchange chromatography on acidic resin, eluting with 2M NH3 in MeOH to give 12 as an off-white solid (66mg, 0.24mmol, 84%).
With copper diacetate; triethylamine; In N,N-dimethyl-formamide; at 50℃; for 24h;Molecular sieve;
General procedure: Method A, according to reported procedures 9bMethod B: Amixture of 6-chloropurine (1),boronic acid (2) (2 or 3 equiv. as specified Table 1), anhydrouscopper(II) acetate (1 equiv.),anhydrous triethylamine (2 or 3 equiv.) in dry DMF (15 mL/mmol) in the presence of 4Amolecular sieves (0.75 g/mmol of 1)was stirred vigorously at r.t. or 50C in a flask connected to a condenser opento air. When the reaction was judged complete, methanol was added and theresulting mixture was filteredthrough a pad of celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by flashchromatography on silica gel eluting with EtOAc/cyclohexane or CH2Cl2/CH3OH.
With copper diacetate; triethylamine; In N,N-dimethyl-formamide; at 50℃; for 14h;Molecular sieve;
General procedure: Method A, according to reported procedures 9bMethod B: Amixture of 6-chloropurine (1),boronic acid (2) (2 or 3 equiv. as specified Table 1), anhydrouscopper(II) acetate (1 equiv.),anhydrous triethylamine (2 or 3 equiv.) in dry DMF (15 mL/mmol) in the presence of 4Amolecular sieves (0.75 g/mmol of 1)was stirred vigorously at r.t. or 50C in a flask connected to a condenser opento air. When the reaction was judged complete, methanol was added and theresulting mixture was filteredthrough a pad of celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by flashchromatography on silica gel eluting with EtOAc/cyclohexane or CH2Cl2/CH3OH.
With copper diacetate; triethylamine; In N,N-dimethyl-formamide; at 50℃; for 5h;Molecular sieve;
General procedure: Method A, according to reported procedures 9bMethod B: Amixture of 6-chloropurine (1),boronic acid (2) (2 or 3 equiv. as specified Table 1), anhydrouscopper(II) acetate (1 equiv.),anhydrous triethylamine (2 or 3 equiv.) in dry DMF (15 mL/mmol) in the presence of 4Amolecular sieves (0.75 g/mmol of 1)was stirred vigorously at r.t. or 50°C in a flask connected to a condenser opento air. When the reaction was judged complete, methanol was added and theresulting mixture was filteredthrough a pad of celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by flashchromatography on silica gel eluting with EtOAc/cyclohexane or CH2Cl2/CH3OH.
With hydrogenchloride; In 1,4-dioxane; ethanol; at 110℃; for 10h;
General procedure: A mixture comprising 60.0 mg (307 mumol) 4-chloro-6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared according to intermediate exampLe 1a), 51 mg <strong>[56354-98-4]6-amino-1,3-benzothiazol-2(3H)-one</strong> (CAS-No: 56354-98-4), 1.75 mL ethanol and 16.9 muL hydrochloric acid (4M in dioxane) was reacted at 110C for 10 hours. The residue was digested in a mixture of diethyl ether and ethanol and dried to give 85.3 mg (85%) of the title compound.
In a round bottom flask, 45 mg of 6-chloropurine (CAS: 87-42-3, 154.5 g/mol, 0.292 mmol) and 40 mg of K2CO3 (potassium carbonate, CAS: 584-08-7, 138.2 g/mol, 0.292 mmol) were suspended in 5 mL of dry DMF. This mixture was stirred for 1 h at 70 C. Separately, 60 mg of mesylate 9b (253.0 g/mol; 0.24 mmol) and 29 mg of TBAI (tetrabutylammonium iodide, CAS: 311-28-4, 396.4 g/mol, 0.072 mmol), were dissolved in 3 mL of dry DMF in a round bottom flask. This mixture was added to the initial mixture, and the reaction was stirred for 12 h at 70 C. Excess water was added to the reaction mixture, which was later extracted with AcOEt (3 times). The organic extract was washed with water (5 times). The organic extract was washed with water (5 times), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. Flash chromatography afforded 2 mg of cyclic carbamate 10c (Hexanes/AcOEt 95:5, 9% yield) and 18 mg of product 10b (Hexanes/AcOEt 7:3, 25%). Rf = 0.09 (Hexanes/AcOEt, 1:1); IR (neat): numax = 3329 (N-H), 2976 (C-H), 1695 (C=O), 1654, 1595, 1170 (C-O) cm-1; 1H NMR (200 MHz; CHCl3): delta = 8.77 (s, 1H, CH2NCHN), 8.26 (1H, br s, NCHNCCl), 5.00 (br s, 1H, NH), 4.37 (t, J = 6.7 Hz, 2H, H-3), 3.13 (q, J = 6.0 Hz, 2H, H-1), 2.10 (quintet, J = 6.4 Hz, 2H, H-2), 1.45 (s, 9H, C(CH3)3) ppm; 13C NMR (50 MHz; CHCl3): delta = 156.3 (NCOO), 152.1 (CCl), 152.0 (NCHNCCl), 151.3 (CH2NCN), 145.8 (CH2NCHN), 131.8 (NCCCl), 79.9 (C(CH3)3), 42.0 (C-3), 37.4 (C-1), 30.7 (C-2), 28.5 (C(CH3)3) ppm; HRMS (ESI): m/z (M+Na) calcd for C13H18N5O2ClNa, 334.1041; found, 334.1046, Delta = 1.4 ppm.
(2S,4S)-4-((7H-purin-6-yl)amino)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39.7%
With triethylamine; In butan-1-ol; for 5h;Reflux;
6-Chloropurine was added to a solution of compound 6 (2.4 g, 10.0 mmol) and Et3N (2.02 g, 20.0 mmol) in butyl alcohol (50 mL). After refluxing for 5 h, the solvent was evaporated to yield the crude product which was purified by column chromatography eluting with PE/EA (3:1 v/v) to give compound 9 as white solid (1.1 g, yield: 39.7%).
To a 1L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 6-chloro-9H-purine (15.4 g, 0.1 mol, 1 equiv) and tetrahydrofuran (155 mL) at 0 C followed by the addition of MeMgCl (36.6 mL,1.0M THF solution, 1.1 equiv) dropwise with stirring. The mixture was stirred at 0 C for 30 min. To this was added iodomethane (42.6 g, 3 equiv) dropwise with stirring. The resulting solution was stirred at 50 C in an oil bath for 5 h, quenched by the addition of 50 mL of aqueous NH4C1 and extracted with dichloromethane (3x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and concentrated under vacuum. The crude product was re-crystallized from CH2CI2/ petroleum ether in the ratio of 1 : 10 to afford desired product as a greenish solid (7 g, 42%).
3-methyl-4-(purin-6-yl)-3,4-dihydro-2H-[1,4]benzoxazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
General procedure: Concentrated H2SO4(1.16 mmol in the case of amine 2a or 0.65 mmol in thecase of amines 2b,c,e,f) was added to a mixture of amine2a-,e,f (1.55 mmol) and 2 (20 ml). The mixture wasstirred at 60-70 until complete dissolution of amine.6-Chloropurine (1a) (200 mg, 1.29 mmol) was then added,and the obtained mixture was refluxed for 6 h, cooled, andtreated with aqueous ammonia to 8-9 with stirring. Theprecipitate that formed was filtered off and washed withcold water (3×3 ml). Compound 3a did not need furtherpurification, compounds 3b,c,e,f were purified by silica gelflash chromatography (eluent 95:5 CHCl3-MeOH).
General procedure: Concentrated H2SO4(1.16 mmol in the case of amine 2a or 0.65 mmol in thecase of amines 2b,c,e,f) was added to a mixture of amine2a-,e,f (1.55 mmol) and 2 (20 ml). The mixture wasstirred at 60-70 until complete dissolution of amine.6-Chloropurine (1a) (200 mg, 1.29 mmol) was then added,and the obtained mixture was refluxed for 6 h, cooled, andtreated with aqueous ammonia to 8-9 with stirring. Theprecipitate that formed was filtered off and washed withcold water (3×3 ml). Compound 3a did not need furtherpurification, compounds 3b,c,e,f were purified by silica gelflash chromatography (eluent 95:5 CHCl3-MeOH).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h;
General procedure: 6-Chloro-9H-purine (2 g, 12.9 mmol), K2CO3 (2.2 g,14.2 mmol), and the appropriate alkyl bromide or benzyl chloride derivative (14.2 mmol) were combined in DMF (25 mL) in a 100-mL round-bottomed flask, and the resulting mixture was stirred for 24 h at room temperature. After the reaction was completed (TLC), the mixture was poured into water (50 mL), and then extracted with CH2Cl2. The combined organic extracts were washed with water, dried (MgSO4), and concentrated to dryness in vacuo. The residue was purified by chromatography on silica gel, eluting with CH2Cl2, to give compounds 1a-1q as white solids.
With triethylamine; In tert-butyl alcohol; at 30 - 85℃; for 24h;
(S)-2-(1 -aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one prepared in example 26 (4.2 g) and t-Butanol (21 mL) were charged into a 100 mL round bottom flask. Triethylamine (3.91 mL) and 6-Chloropurine (2.5 g) were added at 30 00. The resultant reaction mixture was heated to85C and stirred for 24 hours. The reaction mixture was evaporated completely under reduced pressure at 40C. The resultant residue was diluted with water (100 mL) and stirred for 30 minutes. The precipitate was filtered and the solid was washed with water (30 mL) and n-Hexane (50 mL) and dried for 1 hour under vacuum. The crude was purified by chromatographyusing Si02 (1 00:200) (solvent MeOH: DCM: TEA:: 5: 94: 1). The eluted fractions were evaporated completely under vacuum. The isolated product was diluted in dichloromethane (100 mL) and the organic layer was washed with brine solution (2x25 mL). The organic layer dried over sodium sulphate (10 g) and evaporated under reduced pressure to yield 3.1 g of Idelalisib as pale yellow solid.Purity: 97.87% by HPLC; chiral purity: 98.77% by H PLC
With tetrabutyl-ammonium chloride; potassium carbonate; potassium iodide; In tetrahydrofuran; at 60℃; for 10h;
5. preparation of (S)-5-fluoro-3-phenyl-2-[1-(9H-purin-6-ylamino)propyl]-3H-quinazolin-4-oneIn a 50 ml reaction flask, will <strong>[870281-86-0](S)-2-(1-aminopropyl)-5-fluoro-3-phenyl-3H-quinazolin-4-one</strong> (5.0g, 16mmol) dissolved in anhydrous tetrahydrofuran (30 ml), stirring to dissolve, adding 6-chloropurine (2.8g, 18mmol) and tetrabutylammonium chloride (0.88g, 3 . 2mmol), potassium iodide (0.5g), potassium carbonate (2.5g, 18mmol) 60 C reaction 10 hours, concentrated under reduced pressure, in dichloromethane (50 ml) and water (50 ml) extraction, dichloromethane is used for water (50 ml) washing, combined with the organic layer with water (50 ml), saturated salt water (50 ml) washing, and drying with anhydrous sodium sulfate, concentrated the pressure, the obtained crude product, the resulting crude product is recrystallized in isopropanol to obtain compound (S)-5-fluoro-3-phenyl-2-[1-(9H-purin-6-ylamino)propyl]-3H-quinazolin-4-one (4.8g), total yield 74.4%, purity: 97%.
tert-butyl ((1s,3s)-3-(6-chloro-9H-purin-9-yl)cyclobutyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.25 g
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; for 4h;
To a solution of <strong>[389890-42-0]tert-butyl ((1r,3r)-3-hydroxycyclobutyl)carbamate</strong> (0.47 g, 2.51 mmol) and 6-chloropurine (0.58 g, 3.76 mmol) in tetrahydrofuran (15 mL) was added triphenylphospine (2 g, 7.6 mmol) was added at 0 oC. The reaction mixture was stirred at rt overnight. The mixture was concentrated and purified by flash column chromatography to give the compound 3 (0.25 g) as a yellow solid. 1H NMR (300 MHz, CDCl3) delta 8.81 (s, 1H), 8.69 (s, 1H), 5.11 (q, J = 6.0 Hz 1H), 3.85 (q, J = 6.0 Hz 1H), 3.32-3.29 (m, 2H), 3.09-3.06 (m, 2H), 1.49 (s, 9H).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 45℃; for 4h;
The compound u prepared in the above step 1 was treated with 4M HCl in dioxane to obtain the hydrochloride compound v from which the protecting group Boc was removed. Then, an amide compound w was prepared using PyBOP, which is a coupling agent (At this time, various reactions were conducted using EDC, HOBt, HATU, HOBt, HOAt, and T3P, The yield of amide preparation reaction using PyBOP was the best). The compound of the present invention was used to prepare the CDK inhibitory compound of the present invention by introducing various amines into the compound w (in the figure, x ' To finally produce a CDK inhibitory compound as a y 'compound) E.g, To the prepared compound w, acetic anhydride, TEA, and DCM to prepare a compound x, 3-picolylamine was reacted in ethanol at 90 DEG C for 3 hours to obtain a final CDK inhibitory compound N-((1s,3s)-3-(6-(pyridin-3-ylmethylamino)-9H-purin-9-yl)cyclobutyl)acetamide. In this manner, CDK inhibitory compounds having various amines introduced therein were prepared as in the following examples.
0 C, 80.5g formamidine hydrochloride (1mol) was dissolved in 200mL of ethanol, was slowly added dropwise with 100mL183.5g of <strong>[1780-27-4]4,5,6-trichloropyrimidine</strong> (1mol) in ethanol, the dropwise addition was heated to 15 ~ 25 , the reaction was stirred for 12h.After the reaction was completed, the ethanol was evaporated to dryness, water was added and the mixture was extracted three times with ethyl acetate. The organic layer was dried to give 150 gOf 4-chloro-1H-pyrazolo [3,4-d] pyrimidine was obtained in a yield of 97.1%
N-((4-((9H-purin-6-yl)amino)phenyl)sulfonyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.3%
With triethylamine; In butan-1-ol; at 110℃;
General procedure: Triethylamine (50 mL) was added to a stirred mixture of 6-chloro-9H-purine (1) (1.54 g, 0.01 mol) and different substitutedaromatic amines or pyrrolidine (0.012 mol) in butanol (5.0 mL) andthen refluxed at 110 C for 6 h. Then, vacuum filtration was appliedto remove the solvent and the compounds werewashed twice withbutanol. The yield of the pure compounds was 65.8e85.2%.
5-((9H-purin-6-yl)amino)isoindolin-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With (1S)-10-camphorsulfonic acid; In isopropyl alcohol; at 10℃; for 4h;Sealed tube;
Synthesis of 5-((9H-purin-6-yl)amino)isoindolin-1-one (Cpd. No. 1F) A mixture of 6-chloro-9H-purine (1, 0.15 g, 0.97 mmol), <strong>[222036-66-0]5-aminoisoindoline-1-one</strong> (2, 0.14 g, 0.97 mmol) and (1S)-(+)-camphor-10-sulfonic acid (0.27 g, 1.16 mmol) in isopropanol (10 mL) was heated in a sealed tube at 100° C. for 4 h. After completion of the reaction, the mixture was concentrated. The obtained solid was filtered and re-crystallized from ethanol and isopropanol to afford 5-((9H-purin-6-yl)amino)isoindolin-1-one (Cpd. No. 1F) as off-white solid. Yield: 0.15 g, 58percent; MS (ESI) m/z 267 [M+1]+; 1H NMR (400 MHz, DMSO-d6) delta 11.01 (s, 1H), 8.66 (s, 2H), 8.44 (s, 1H), 8.31 (d, J=1.9 Hz, 1H), 7.99 (dd, J=8.3, 1.8 Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 4.40 (s, 2H).
With methylmagnesium chloride; In tetrahydrofuran; at 70℃; for 12h;
[0498] Procedure: To a stirred solution of 6-chloro-7H-purine (1 g, 6.469 mmol) in Dry THF (20 mL) was added MeMgCl (0.53 g, 7.086 mmol) followed by methyl iodide (1.3 g, 9.158 mmol). Reaction mixture was stirred for 12 h at 70 C. Progress of the reaction was monitored by TLC. Reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 x 50mL). The combined organic layer was washed with brine (10mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The crude residue was purified by combiflash using methanol in dichloromethane to afford 6-chloro-7-methyl-7H-purine as white solid, (0.4 g, 36.46 %).1HNMR (400 MHz, DMSO-d6): delta 8.75 (s, 1H),8.71-(s, 1H), 3.96 (s, 3H). LC-MS (ES) m/z = 169.1 [M+H]+.
With triethylamine; In tert-butyl alcohol; at 30 - 85℃; for 24h;
To the mixture of 8.5 g of compound (3) and 42 ml t-butanol 7.8 ml of triethylamine and 5 g of 6-chloropurine were added at 30 C. The resultant reaction mixture was heated to 85 C. and stirred for 24 hours. The reaction mixture was evaporated completely under reduced pressure at 40 C. The resultant residue was diluted with 200 ml water and stirred for 30 minutes. The precipitate was filtered and the solid was washed with 60 ml water and 100 ml n-hexane and dried for 1 hour under vacuum to obtain 7 g of idelalisib. The overall yield based on starting 2-fluoro-6-nitro-N-phenylbenzamide is 19% of the theoretical yield. The purity of isolated solid was 61% (HPLC IN).
benzyl 4-[(9H-purin-6-ylamino)methyl]-1-piperidinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium hydroxide; triethanolamine; In N,N-dimethyl-formamide;
Step 2 Benzyl 4-[(9H-purin-6-ylamino)methyl]-1-piperidinecarboxylate In DMF (5 mL), benzyl 4-(aminomethyl)-1-piperidinecarboxylate (1.20 g, 4.83 mmol) and 6-chloropurine (448 mg, 2.49 mmol) were combined and treated with TEA in a single portion and aged under N2 at 100 C. for 18 h. The resulting reaction was diluted with sat. NaHCO3 and extracted with ethyl acetate (3*). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a brown oil which was purified by silica gel chromatography (20 g, 32-60 mum silica, 99:1:0.1 to 90:10:1 CH2Cl2:CH3OH:NH4OH) to give benzyl 4-[(9H-purin-6-ylamino)methyl]-1-piperidinecarboxylate as a brown oil. 1H NMR (400 MHz, CDCl3): delta8.42 (s, 1H, purine-H), 7.97 (s, 1H, purine-H), 7.36-7.29 (m, 5H, Ar-H), 6.21 (brs, 1H), 5.13 (s, 2H, CH2-Ar), 4.22 (brs, 2H, CHH), 3.43 (brs, 2H, CH2-N), 2.80 (brs, 2H, CHH), 1.95-1.79 (m, 3H, CHH, CH), 1.34-1.21 (m, 2H, CHH).
6-Chloropurine (5g, 32.35mmol) was dissolved in DMF (80mL) and finely pulverized anhydrous K2CO3 (8.96g, 64.83mmol) was added. The heterogeneous mixture was mixed at room temperature for 3h while CH3I (3×3.5mL, 168.66mmol) was slowly added. The reaction was monitored by TLC (CHCl3:MeOH 9:1). After this time, the reaction mixture was filtered and a small amount of DMF was added. Subsequently, the mixture was concentrated in vacuo, crude product was dissolved in EtOAc, and a small portion of distilled H2O was added. The EtOAc portion was separated, dried over anhydrous Na2SO4 and concentrated in vacuo. After 12h, the product was dissolved in 2-PrOH at 50C and purified with pulverized coal. The final product was concentrated in vacuo and a mixture of two isoforms was obtained. Yield: 3.86g (71%), HPLC: 89.30% (6Cl9MP) and 10.70% (6Cl7MP). 1H NMR (300MHz, DMSO-d6) delta (ppm): 3.86 (s, N9-CH3), 4.07 (s, N7-CH3), 8.65 (s, pur H86Cl9MP), 8.74 (s, pur H86Cl7MP), 8.77 (s, pur H2).
With triethylamine; In N,N-dimethyl-formamide; at 50℃; for 2h;
6-Chloropurine (0.2g; 1.29mmol) was dissolved in DMF (5mL). Et3N (0.44mL, 3.15mmol) and <strong>[40064-34-4]4-piperidone monohydrate hydrochloride</strong> (276mg, 1.77mmol) were added. The solution was heated at 50C for 2h. After cooling, the reaction mixture was refrigerated for 2 d. The resulting solid substance was filtered off and washed with distilled H2O. Glassy crystals were dissolved and yellow powder remained (portion I of the product, m=45mg). The filtrate was evaporated, the residuum was adsorbed on silica gel (1g) and purified by column chromatography (mobile phase CHCl3:MeOH:NH4OH 95:5:0.5, flow rate 10mL/min). Combined fractions with the product were partly evaporated to a total volume 15-20mL and refrigerated for 4 d. The emerging crystals were filtered off and air-dried (portion II of the product, m=72mg). The filtrate was evaporated to dryness (portion III of the product, m=0.1g). White powder. Yield: 216mg (77%). M.p.: 280-285C. HPLC Rt=8.8min (broad peak, Rt=6.7-9.9min) (40% MeOH+60% buffer); UV (60% MeOH+40% buffer) lambdamin 234nm, lambdamax 277nm. HPLC purity 98% (portion II). MS ESI+ (CV 13) m/z (rel. %): 218 [M+H]+ (47), 250 [M+CH3OH+H]+ (100); ESI- (CV 20) m/z (rel. %): 216 [M]- (100), 248 [M+CH3OH]- (32). 1H NMR (500MHz, DMSO-d6) delta (ppm): 2.53 (bs, 4H, piper H3, H5), 4.45 (bs, 4H, piper H2, H6), 8.20 (s, 1H, pur H8?), 8.30 (s, 1H, pur H2?), 13.15 (bs, 1H, pur NH). 13C NMR (125MHz, DMSO-d6) delta (ppm): 40.7 (piper C3, C5), 43.7 (piper C2, C6), 119.1 (pur C5?), 138.6 (pur C8?), 151.5 (pur C4?), 151.9 (pur C2?), 152.9 (pur C6?), 207.5 (piper C4).
(2S)-5-amino-5-oxo-2-[(9H-purin-6-ylamino)-acetyl]amino}pentanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium carbonate; In water; for 3.0h;pH 9.0;Reflux;
General procedure: To a suspensionof 0.108 g (0.700 mmol) of 6-chloropurine or 0.119 g (0.700 mmol) of 2-amino-6-chloropurine in 3.0 mL of water we added 0.227 g (1.40 mmol) ofglycyl-(S)-serine, glycyl-(RS)-serine, or 0.284 g (1.40 mmol) of <strong>[13115-71-4]glycyl-(S)-glutamine</strong>. The mixture was adjusted to pH 9 by adding sodium carbonate, refluxedfor 3 h, cooled to 0C, acidified to pH 3 with concentrated aqueous HCl, and kept for 12 h at 0C. The precipitate was filtered off and washed with cold water(3 × 0.2 mL).
Step 1: Preparation of 6-chloro-7-methyl-7H-purine To a 1 L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 6-chloro-9H-purine (15.4 g, 0.1 mol, 1 equiv) and tetrahydrofuran (155 mL) at 0 C. followed by the addition of MeMgCl (36.6 mL, 1.0M THF solution, 1.1 equiv) dropwise with stirring. The mixture was stirred at 0 C. for 30 min. To this was added iodomethane (42.6 g, 3 equiv) dropwise with stirring. The resulting solution was stirred at 50 C. in an oil bath for 5 h, quenched by the addition of 50 mL of aqueous NH4Cl and extracted with dichloromethane (3*50 mL). The combined organic layers were washed with brine (2*50 mL) and concentrated under vacuum. The crude product was re-crystallized from CH2Cl2/petroleum ether in the ratio of 1:10 to afford desired product as a greenish solid (7 g, 42%).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 7h;
commercially available compound, 6-chloro-9Hpurine 3.9 g, 2-iodoethyl methyl ether 7.6 g, .K2CO3And DMF (N, N-dimethylformamide) was added to a 250 mL flask and stirred at room temperature for 7 h. After TLC detection, the mixture was extracted with water and ethyl acetate, and the organic phase was evaporated under reduced pressure. Ether (boiling range 60-90 C) in a volume ratio of 1:3) was purified to afford compound 6-chloro-9-(2-methoxyethyl)-9H purine
With formic acid; In ethanol; at 78 - 80℃; for 1h;
dd to a 50 mL three-necked flask6-chloropurine 5.00g (32.35mmol)And thiourea 2.95g (38.82mmol),Thiolation using absolute ethanol as solvent,Use formic acid as a catalyst to raise the temperature to 78 80 and reflux for 1 h. The reaction is complete.Add the system to a saturated aqueous sodium hydroxide solution,And gradually add glacial acetic acid,White floes appear,Add an appropriate amount of distilled water,After stirring for 1 to 2 hours, a pale yellow powdery substance was obtained after filtering.Dried to obtain 4.1g of light yellow powder,The yield was 83.28%
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