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Chemical Structure| 186519-89-1
Chemical Structure| 186519-89-1
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Product Details of [ 186519-89-1 ]

CAS No. :186519-89-1 MDL No. :MFCD09909367
Formula : C12H8ClN3O2S Boiling Point : -
Linear Structure Formula :- InChI Key :HPWMGRLPNPQCQX-UHFFFAOYSA-N
M.W : 293.73 Pubchem ID :10946306
Synonyms :

Safety of [ 186519-89-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
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Application In Synthesis of [ 186519-89-1 ]

* 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 [ 186519-89-1 ]
  • Downstream synthetic route of [ 186519-89-1 ]

[ 186519-89-1 ] Synthesis Path-Upstream   1~8

  • 1
  • [ 186519-89-1 ]
  • [ 35808-68-5 ]
Reference: [1] Patent: WO2012/158795, 2012, A1,
[2] Patent: WO2012/158764, 2012, A1,
[3] Patent: WO2013/191965, 2013, A1,
[4] Patent: WO2014/22569, 2014, A1,
[5] Patent: US8673925, 2014, B1,
[6] Patent: WO2014/184069, 2014, A1,
[7] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 1103 - 1110
  • 2
  • [ 186519-89-1 ]
  • [ 100-51-6 ]
  • [ 16019-34-4 ]
Reference: [1] Tetrahedron Letters, 1998, vol. 39, # 32, p. 5685 - 5688
  • 3
  • [ 186519-89-1 ]
  • [ 876343-10-1 ]
YieldReaction ConditionsOperation in experiment
77%
Stage #1: With iodine; lithium diisopropyl amide In tetrahydrofuran
Stage #2: With sodium hydroxide In tetrahydrofuran; methanol at 20℃; for 2 h;
4-Chloro-7-(phenylsulfonyl)-7H-pyrrolo [2,3-d]pyrimidine (1) [20], (5.42g, 18.5mmol) was iodinated as previously described [20]. This gave a 9: 1 mixture of 2 and 3 (6.0g) which was mixed with THF (125mL) and 5M NaOH solution in MeOH (21mL). After 2h stirring at room temperature, a saturated aqueous NH4Cl-solution (125mL) was added and the mixture concentrated. The formed precipitate was collected by filtration and washed with water. Trituration from boiling acetonitrile (1g/10mL) gave 3.96g (14.2mmol, 77percent) of 4 as a white solid, mp 219°C (dec.) (lit. [20] 220°C); 1H NMR (400MHz, DMSO-d6) δ: 12.57 (s, 1H), 8.51 (s, 1H), 6.88 (s, 1H). The 1H NMR data is in agreement with that previously reported [20].
Reference: [1] European Journal of Medicinal Chemistry, 2016, vol. 124, p. 583 - 607
[2] European Journal of Pharmaceutical Sciences, 2014, vol. 59, # 1, p. 69 - 82
[3] Patent: WO2015/959, 2015, A1,
  • 4
  • [ 186519-89-1 ]
  • [ 876343-09-8 ]
YieldReaction ConditionsOperation in experiment
74%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 1 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; n-heptane; ethylbenzene for 1 h;
4-Chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-i ]pyrimidine (36) Compound 35 (10.0 g, 34.0 mmol) was mixed with dry THF (300 ml) under nitrogen atmosphere, and cooled to -78 °C. Lithium diisopropylamide (2M in THF/n-heptane/ethylbenzene, 26 mL, 51.1 mmol) was added drop wise over 30 minutes using a syringe pump. After 1 hour, iodine (11.2 g, 44.3 mmol) dissolved in dry THF (60 ml) was added drop wise over 30 minutes using a syringe pump. The reaction mixture was stirred for 1 hour before HC1 (1M, 180 ml) was added. The mixture was stirred until the temperature reached 22 °C, and concentrated. To this residue CH2C12 (250 ml) and water (200 ml) were added. The layers were separated and the aqueous phase was extracted with CH2C12 (2 x 90 ml). The combined organic phases were washed with brine (100 ml), dried over Na2S04, filtered and concentrated. The crude, yellow product was crystallised from acetonitrile (150 ml). This gave 10.5 g (25.1 mmol, 74 percent) of compound 53 as a pale yellow solid, mp 190 °C (dec); purity: 99percent (HPLC), tR= 25.9 min; 1H NMR (400 MHz, DMSO-d6) δ: 8.77 (s, 1H), 8.12 - 8.09 (m, 2H), 7.82 - 7.78 (m, 1H), 7.71 -7.67 (m, 2H), 7.34 (s, 1H); I3C NMR (100 MHz, DMSO-de) δ: 153.3, 152.1, 150.0, 137.2, 135.5, 130.0 (2C), 127.6 (2C), 120.6, 116.6, 84.6; IR (neat, cm 1): 1394, 1087, 724; HRMS (EI, m/z): 418.8988 (calcd. Ci2H702N3S35ClI, 418.8987, [M]+).
63%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran at -78℃; for 1 h;
After 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (5 g, 1.0 eq) obtainedin Step 1-1 was dissolved in tetrahydrofuran (150 ml), 1.5 M lithium diisopropylamide (17.02ml, 1.5 eq) was added dropwise at -78°C under nitrogen. After stirring the mixture at -78°C for 1 hour, iodine (5.62 g, 1.3 eq) was dissolved in tetrahydrofuran (30 ml) and added dropwise. After stirring the mixture at -78°C for 1 hour, IN hydrochloric acid (90 ml) was added. The temperature was raised to room temperature and the mixture was concentrated under reducedpressure. Water was added and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was slurried in acetonitrile (50 ml) and then filtered to obtain the title compound (4.48 g, yield: 63percent).
59%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: With iodine In tetrahydrofuran at 20℃; for 2 h;
To a solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 17 mmol) in THF (100 mL) was added LDA (10.2 mL, 20 mmol) at -78 °C. The mixture was stirred at -78 °C for 0.5 h followed by addition of I2(8.6 g, 34 mmol) and allowed to warmed to rt while stirring for another 2 h. It was then diluted with water (80 mL) and extracted with EtOAc (100 mL x 2). The organic layer was washed with water (60 mL), brine (60 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford a residue was purified by column chromatography (EtOAc/Petroleum ether = 1:1) to give the title compound (4.2 g, yield 59percent). ESI-MS (M+H)+: 419.9.1H NMR (400 MHz, DMSO-d6) : 8.78 (s, 1H), 8.12-8.10 (m, 2H), 7.80 (t, J = 7.6 Hz, 1H), 7.71-7.68 (m, 2H), 7.39 (s, 1H).
Reference: [1] ChemMedChem, 2014, vol. 9, # 11, p. 2516 - 2527
[2] Patent: WO2015/959, 2015, A1, . Location in patent: Page/Page column 62-63
[3] Patent: WO2018/88780, 2018, A1, . Location in patent: Page/Page column 13
[4] Patent: WO2015/89327, 2015, A1, . Location in patent: Paragraph 0264
[5] Patent: WO2006/17443, 2006, A2, . Location in patent: Page/Page column 56
[6] Patent: WO2010/7116, 2010, A2, . Location in patent: Page/Page column 77
[7] Patent: WO2010/7114, 2010, A2, . Location in patent: Page/Page column 111
[8] European Journal of Pharmaceutical Sciences, 2014, vol. 59, # 1, p. 69 - 82
  • 5
  • [ 186519-89-1 ]
  • [ 876343-09-8 ]
Reference: [1] European Journal of Medicinal Chemistry, 2016, vol. 124, p. 583 - 607
  • 6
  • [ 186519-89-1 ]
  • [ 74-88-4 ]
  • [ 252723-16-3 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at -78℃; for 0.05 h;
Stage #2: at 20℃; for 4 h;
Stage #3: With water; ammonium chloride In tetrahydrofuran
Step 2To the solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (3 g,12.6 mmol, 1.0 eq) and TMEDA (3,0 mL, 18,9 mmol, 1.5 eq) in THE (120 mL) at -78 °C was added n-BuLi (7.5 mL, 18.9 mmol, 1.5 eq). After 3 min, C3/4I (3.7 mL, 59.2 mmol, 4.7 eq) was added. After 3 h, the reaction mixture was warmed to RT over 1 h. The reaction was quenched by addition of sat NH4CI (10 roL). EtOAc (200 mL) and water (100 mL) was added. The organic layer was separated, dried and concentrated to afford 4-chloro-6-methyl- 7-(phenylsu]fonyl)-7H-pyrrolo[2,3-d]pyrimidine as a brown solid (6.7 g, 90 percent in yield).
90%
Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at -78 - 20℃; for 4 h;
Step 2To the solution of 4-chloro-7-(phenylsulfonyl)-7H.-pyrrolo[2,3-d]pyrimidme (3 g,12.6 mmol, 1 .0 eq) and TMEDA (3.0 mL, 18.9 mmol, 1.5 eq) in THF ( 120 mL), n-BuLi (7.5 mL, 18.9 mmol, 1.5 eq) was added at -78 °C. After 3 min, CH3I (3.7 mL, 59.2 mmol, 4.7 eq) was added. After 3 h, the reaction mixture was warmed to RT over 1 h. The reaction was quenched by addition of sat NH CI (10 mL) at -78 °C. EtOAc (200 mL) and water (100 mL) was added. The organic layer was separated, dried and concentrated to afford 4-ch3oro-6- met yl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine as a brown solid (6.7 g, 90 percent in yield).
90%
Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at -78℃; for 0.05 h;
Stage #2: at -78 - 20℃; for 1 h;
To the solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (3 g, 12.6 mmol, 1.0 eq) and TMEDA (3.0 mL, 18.9 mmol, 1.5 eq) in THE (120 mL), n-BuLi (7.5 mU 18.9 mmol, 1.5 eq) was added at —78 °C. After 3 mm, CH3I (3.7 mU 59.2 mmol, 4.7 eq) was added. After 3 h, the reaction mixture was warmed to RT over 1 h. The reaction was quenched by addition of sat NH4C1 (10 mL) at —78 °C. EtOAc (200 mL) and water (100 mL) was added. The organic layer was separated, dried and concentrated to afford 4-chlor0-6-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine as a brown solid (6.7 g, 90 percent in yield).
90%
Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at -78℃; for 0.05 h;
Stage #2: at 20℃; for 4 h;
Step 2. To the solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (3 g,12.6 mmol, 1.0 eq) and TMEDA (3.0 mL, 18.9 mmol, 1.5 eq) in THF (120 mL), n-BuLi (7.5 mL, 18.9 mmol, 1.5 eq) was added at -78 °C. After 3 min, CH3I (3.7 mL, 59.2 mmol, 4.7 eq)was added. After 3 h, the reaction mixture was warmed to RT over 1 h. The reaction was quenched by addition of sat NH4Cl (10 mL) at -78 °C. EtOAc (200 mL) and water (100 mL) was added. The organic layer was separated, dried and concentrated to afford 4-chloro-6- methyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine as a brown solid (6.7 g, 90 percent in yield).
90%
Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at -78℃; for 0.05 h;
Stage #2: at 20℃; for 4 h;
Step 2
To the solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (3 g, 12.6 mmol, 1.0 eq) and TMEDA (3.0 mL, 18.9 mmol, 1.5 eq) in THF (120 mL), n-BuLi (7.5 mL, 18.9 mmol, 1.5 eq) was added at -78° C. After 3 min, CH3I (3.7 mL, 59.2 mmol, 4.7 eq) was added.
After 3 h, the reaction mixture was warmed to RT over 1 h.
The reaction was quenched by addition of sat NH4Cl (10 mL) at -78° C. EtOAc (200 mL) and water (100 mL) was added.
The organic layer was separated, dried and concentrated to afford 4-chloro-6-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine as a brown solid (6.7 g, 90percent in yield).
80%
Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -78℃; Schlenk technique; Inert atmosphere
Stage #2: at 20℃; Schlenk technique; Inert atmosphere
In a Schlenk flask under argon atmosphere 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (8 g, 27 mmol) was dissolved in dry THF(200 mL) and cooled to −78 °C. TMEDA (5.2 g, 45 mmol) and n-BuLi(18.4 mL, 43 mmol, 2.5 M in hexane) were added dropwise at the sametime, then MeI (8.8 mL, 137 mmol) was added and the reaction mixturewas heated to rt and stirred overnight. The mixture was mixed with aqNH4Cl (300 mL), extracted with ethyl acetate three times, washed withwater and brine, dried over MgSO4 and filtered. Purification by flashcolumn chromatography (cyclohexane/ethyl acetate 4:1) afforded 5 as awhite solid in a yield of 80percent.
43%
Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -78℃; for 0.05 h;
Stage #2: at -78 - 20℃; for 4 h;
Synthesis of Compound 18.2. N,N,N,N-tetramethylethane-1,2-diamine (0.8 ml, 0.057 mol) and 1.6 M n-BuLi in hexane (3.62 ml, 0.057mol) added at the same time over 5 min to a solution of compound 18.1 (1 g, 34 mmol) in THF (30 ml) at -78° C. After 3 min, methyl iodide (1.1 ml, 0.017 mol) was added to the reaction. After 3 hr, the reaction was warmed to 20° C. over an 1 hr. Reaction mixture was cooled to -78° C. and NH4Cl sat. was added. The reaction was extracted (EtOAc 3.x.50 ml), dried (Na2SO4) and evaporated. The residue was purified by flash chromatography using hexane/DCM (SiO2, 95/5) as eluant to afford compound 18.2 (450 mg, 43percent ). 1H-NMR (200 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.16-8.12 (m, 2H), 7.76-7.60 (m, 3H), 6.74 (s, 1H). MS m/z 308 [M+1]+.

Reference: [1] Patent: WO2012/158795, 2012, A1, . Location in patent: Page/Page column 101-102
[2] Patent: WO2012/158764, 2012, A1, . Location in patent: Page/Page column 115
[3] Patent: WO2013/191965, 2013, A1, . Location in patent: Page/Page column 191
[4] Patent: WO2014/22569, 2014, A1, . Location in patent: Page/Page column 96
[5] Patent: US8673925, 2014, B1, . Location in patent: Page/Page column 241
[6] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 1103 - 1110
[7] Patent: US2009/5359, 2009, A1, . Location in patent: Page/Page column 26
[8] Patent: US6635762, 2003, B1, . Location in patent: Page/Page column 24
[9] Patent: WO2014/184069, 2014, A1, . Location in patent: Page/Page column 53; 54
  • 7
  • [ 186519-89-1 ]
  • [ 784150-41-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7431 - 7448
  • 8
  • [ 186519-89-1 ]
  • [ 1187594-09-7 ]
Reference: [1] Patent: CN107176955, 2017, A,
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