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Chemical Structure| 7306-68-5
Chemical Structure| 7306-68-5
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Product Details of [ 7306-68-5 ]

CAS No. :7306-68-5 MDL No. :MFCD00022821
Formula : C10H11ClN4O Boiling Point : -
Linear Structure Formula :- InChI Key :QSTASPNCKDPSAH-UHFFFAOYSA-N
M.W : 238.67 Pubchem ID :97740
Synonyms :
6-Chloro-9-(tetrahydro-2-pyranyl)purine

Calculated chemistry of [ 7306-68-5 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.5
Num. rotatable bonds : 1
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 59.79
TPSA : 52.83 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.34
Log Po/w (XLOGP3) : 1.21
Log Po/w (WLOGP) : 1.85
Log Po/w (MLOGP) : 0.75
Log Po/w (SILICOS-IT) : 1.58
Consensus Log Po/w : 1.55

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.43
Solubility : 0.882 mg/ml ; 0.0037 mol/l
Class : Soluble
Log S (Ali) : -1.92
Solubility : 2.89 mg/ml ; 0.0121 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.86
Solubility : 0.328 mg/ml ; 0.00137 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.87

Safety of [ 7306-68-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 7306-68-5 ]

* 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.

  • Upstream synthesis route of [ 7306-68-5 ]
  • Downstream synthetic route of [ 7306-68-5 ]

[ 7306-68-5 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 7306-68-5 ]
  • [ 2004-03-7 ]
Reference: [1] Molecules, 2005, vol. 10, # 8, p. 1015 - 1020
[2] Molecules, 2005, vol. 10, # 8, p. 1015 - 1020
[3] Nucleosides, Nucleotides and Nucleic Acids, 2000, vol. 19, # 7, p. 1123 - 1134
  • 2
  • [ 7306-68-5 ]
  • [ 700-49-2 ]
Reference: [1] Patent: CN105130989, 2017, B,
  • 3
  • [ 110-87-2 ]
  • [ 87-42-3 ]
  • [ 7306-68-5 ]
YieldReaction ConditionsOperation 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
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[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
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[22] Patent: CN105837572, 2016, A, . Location in patent: Paragraph 0147
  • 4
  • [ 110-87-2 ]
  • [ 87-42-3 ]
  • [ 7306-68-5 ]
YieldReaction ConditionsOperation 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

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[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
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  • [ 7306-68-5 ]
YieldReaction ConditionsOperation 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
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  • [ 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
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  • [ 7306-68-5 ]
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