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CAS No. : | 56844-12-3 | MDL No. : | MFCD09264088 |
Formula : | C6H2BrClN2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CMIXHHOZGMSYKN-UHFFFAOYSA-N |
M.W : | 249.52 | Pubchem ID : | 12225261 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 50.12 |
TPSA : | 54.02 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.83 cm/s |
Log Po/w (iLOGP) : | 2.1 |
Log Po/w (XLOGP3) : | 2.81 |
Log Po/w (WLOGP) : | 3.11 |
Log Po/w (MLOGP) : | 2.01 |
Log Po/w (SILICOS-IT) : | 4.0 |
Consensus Log Po/w : | 2.81 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.76 |
Solubility : | 0.0431 mg/ml ; 0.000173 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.6 |
Solubility : | 0.0625 mg/ml ; 0.00025 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.07 |
Solubility : | 0.0212 mg/ml ; 0.0000849 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.48 |
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 |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | at 120℃; for 3 h; | Compound 3 (32.7 g, 142 mmol) was mixed with POCl3 (100 mL) and heated at 120 °C for 3 h. Then the mixture was quenched into 5 M aq NaOH (1 L) and ice. The pH was adjusted to 7 using a saturated aq NaHCO3 solution. The formed precipitate was isolated by filtration and washed with water (3×200 mL). Drying gave 31.0 g (124 mmol, 88percent) of 4 as a brown solid, mp. 112–118 °C. A fraction of this material was further purified: the dry material was applied to the top of a packed silica gel plug and eluted with CH2Cl2, mp. 114–118 °C; Rf (CH2Cl2/MeOH, 98/2)=0.67; 1H NMR (400 MHz, DMSO-d6) δ: 8.95 (s, 1H), 7.89 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 168.9, 153.2, 152.5, 130.2, 122.9, 118.5; IR (neat, cm−1): 3082, 1508, 1411, 959, 832, 816, 760; HRMS (EI, 70 eV, m/z): 247.8813 (calcd C6H2Br79Cl35N2S, 247.8811, M+). The 1H NMR spectrum corresponds with Ref. 41. 13C NMR spectroscopic data and a reference melting point have not been identified. |
72.7% | for 6 h; Reflux | [0121] 6-Bromothieno[2,3-d]pyrimidin-4(3H)-one (7.02 g, 30.4 mmol, 1.0 equiv) was taken up in 100 mL POCI3 and refluxed for 6 h. Upon completion, the reaction was concentrated in vacuo and the residue was taken up in 10 mL acetonitrile and heated to reflux for 10 min. The acetonitrile solution was then poured in a flask and cooled. The ppt was then filtered and washed with hexane to give 6-bromo-4-chlorothieno[2,3-d]pyrimidine (5.51 g, 72.7 percent yield) as a tan solid. NMR (400 MHz, CHLOROFORM-d) δ ppm 8.80 (s, 1 H), 7.47 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: at 80℃; for 1.5 h; Stage #2: With sodium hydrogencarbonate In waterCooling with ice |
Step B: Preparation of 6-bromo-4-chlorothieno[2,3-d]pyrimidine: To 6-bromothieno[2,3-d]pyrimidin-4-ol (3.0 g, 19.7 mmol) was added phosphorus oxychloride (5 mL). After heating to 80 °C for 1.5 hours, the reaction mixture was poured into saturated NaHCO3 and ice. The solid was filtered, washed with water and dried to provide the product (4.06 g, 83percent) as brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With n-butyllithium; carbon tetrabromide In tetrahydrofuran; hexane at -78℃; for 2.41667 h; | Examples 308 and 309 Synthesis of 6-bromo-4-chlorothieno[2,3-d]pyrimidine and 6-bromo-2-butyl-4-chlorothieno[2,3-d]pyrimidine n-BuLi (1.6 M in hexane, 1.9 ml, 2.5 mmol) in THF (8 ml) was cooled to -78° C. 4-Chlorothieno[2,3-d]pyrimidine (0.34 g, 2.0 mmol) was dissolved in THF (2 ml) and slowly added to the reaction mixture over 5 minutes. After 20 min, CBr4 (0.73 g, 2.2 mmol) in THF (3 ml) was slowly added to the reaction mixture. The temperature was maintained at -78° C. for 20 minutes and then warmed to room temperature for 2 hours. The mixture was poured into water and extracted with chloroform, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (EtOAc/hexane 40:1) to yield two pure compounds a white solid (example 203: 0.13 g, 25percent and example 204: 0.16 g, 26percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.1% | With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere | [0123] To diisopropylamine (1.028 ml, 7.21 mmol, 1.8 equiv) in 10 mL THF at 0 °C was added n-butyl lithium (3.76 ml, 6.01 mmol, 1.5 equiv). After 1 h, the LDA solution was transferred to a solution of 6-bromo-4-chlorothieno[2,3-d]pyrimidine (1.0 g, 4.01 mmol, 1.0 equiv) in 35 mL THF at -78 °C under nitrogen. The solution stirred for 1 h at -78 °C after which a mixture of 1.25 mL water and 5 mL THF was added slowly. The mixture was then warmed to 0 °C, poured into 60 mL water, and extracted with dichloromethane. The combined organic extracts were then dried over Na2SC> , filtered, and concentrated in vacuo to give a yellow solid which was chromatographed with 20percent EtOAc/Hexanes gradient elution to give 5-bromo-4-chlorothieno[2,3-d]pyrimidine (671 mg, 67.1 percent yield) as a tan solid. NMR (400 MHz, chloroform- ) δ ppm 8.85 (s, 1 H), 7.64 (s, 1 H). |
56% | With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 1 h; Inert atmosphere | Step 4: To a stirred solution of 6-bromo-4-chlorothieno[2,3-c]pyrimidine (3 g, 12.048 mmol) in THF (120 mL) was added 2M LDA solution in THF/heptane/ethylbenzene (9 mL, 18.072 mmol) at -78 °C under nitrogen. The reaction mixture was stirred for 1 h at -78 °C, a mixture of 3.75 mL water and 15 mL THF was added slowly. The mixture was warmed to 0 °C, poured onto water (180 mL). The reaction mixture was extracted with dichloromethane (2 x 50 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo to give crude product. The crude product was purified by flash column chromatography with 80 g silica column and 10percent EtOAc in Hexanes as eluent to give 5-bromo-4-chlorothieno[2,3- cdpyrimidine as yellow solid (1.7 g, 56percent). LCMS (ES) m/z = 248.9, 250.9 [M+H]+. H NMR (400 MHz, CDCI3) δ ppm 7.66 (s, 1 H), 8.87 (s, 1 H). |
55% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -100 - 0℃; for 0.916667 h; Stage #2: With ammonium chloride In tetrahydrofuran; water |
Lithium diisopropylamine (LDA) was prepared by addition of 2.5 molar BuLi (3.0 mL, 7.6 mmol) in hexanes to a ca. -50° C. solution of diisopropylamine (1.1 mL, 790 mg, 7.8 mmol) in anhydrous THF (15 mL). The solution was warmed to 0° C. for 10 min and then added dropwise to a solution of 6-bromo-4-chlorothieno[2,3-d]pyrimidine (which was prepared as disclosed in WO 2003053446) (2.0 g, 8.0 mmol) in THF (30 mL) cooled to -100° C. The mixture was maintained at -90 to -100° C. for 45 minutes and then quenched with saturated aqueous NH4Cl. The mixture was diluted with ethyl acetate (30 mL) and the separated organic phase was washed with water, brine, dried (Na2SO4) and evaporated. The residue was recrystallized from aqueous ethanol and the isolated solid was dissolved in dichloromethane and passed through a silica gel plug eluting with dichloromethane to yield 900 mg of material. A further 200 mg of product was obtained from the evaporated, recrystallization filtrate by reverse phase High Pressure Liquid Chromatography (HPLC) on a 50 mm.x.250 mm YMC-AQ eluting with 70/30 acetonitrile/0.1 percent v/v water-conc. H2PO4. Total yield was 1.1 g (55 percent). In later runs the crude bromide was recrystallized from acetonitrile. |
46% | With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere | To a stirred solution of 6-bromo-4-chlorothieno[2,3-c]pyrimidine (1 g, 4.0 mmol, 1 equiv) in THF (40 mL) was added 2M LDA in THF solution (3 mL, 6.0 mmol, 1.5 equiv) drop wise at -78 °C under nitrogen. The reaction was stirred for 1 h at -78 °C after which a mixture of water (1.25 mL) and THF (5 mL) was added slowly. The mixture was then warmed to 0 °C, poured onto water (60 mL), and extracted with DCM (2 x 30 mL). The combined organic extracts were combined and dried over Na2S04, filtered and concentrated. Purification: Purified by flash column chromatography, 24g silica column with 10percent EtOAc in hexane as mobile phase to give 5-bromo-4-chlorothieno[2,3-c]pyrimidine as yellow solid. Yield (0.46 g, 46 percent). LC-MS (ES) m/z = 248.9 [M+H]+. H NMR (400 MHz, CDCI3) δ 7.66 (s, 1 H), 8.87 (s, 1 H). |
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