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CAS No. : | 56844-12-3 |
Formula : | C6H2BrClN2S |
M.W : | 249.52 |
SMILES Code : | ClC1=C(C=C(Br)S2)C2=NC=N1 |
MDL No. : | MFCD09264088 |
InChI Key : | CMIXHHOZGMSYKN-UHFFFAOYSA-N |
Pubchem ID : | 12225261 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
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 ? Topological Polar Surface Area: Calculated from | 54.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 2.1 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 2.81 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 3.11 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 2.01 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 4.0 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 2.81 |
Log S (ESOL):? ESOL: Topological method implemented from | -3.76 |
Solubility | 0.0431 mg/ml ; 0.000173 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -3.6 |
Solubility | 0.0625 mg/ml ; 0.00025 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -4.07 |
Solubility | 0.0212 mg/ml ; 0.0000849 mol/l |
Class? Solubility class: Log S scale | Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg | High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg | Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) | No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from | -5.83 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from | 0.0 |
Ghose? Ghose filter: implemented from | None |
Veber? Veber (GSK) filter: implemented from | 0.0 |
Egan? Egan (Pharmacia) filter: implemented from | 0.0 |
Muegge? Muegge (Bayer) filter: implemented from | 0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.55 |
PAINS? Pan Assay Interference Structures: implemented from | 0.0 alert |
Brenk? Structural Alert: implemented from | 0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from | No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 2.48 |
* 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% | With trichlorophosphate; at 120℃; for 3.0h; | 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, 88%) 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) delta: 8.95 (s, 1H), 7.89 (s, 1H); 13C NMR (100 MHz, DMSO-d6) delta: 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% | With trichlorophosphate; for 6.0h;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 % yield) as a tan solid. NMR (400 MHz, CHLOROFORM-d) delta ppm 8.80 (s, 1 H), 7.47 (s, 1 H). |
With trichlorophosphate; for 6.0h;Heating / reflux; | 6-Bromo-3No.-thieno[2,3-J]pyrirnidin-4-one (11.64g, 0.05mol) was added portion-wise to phosphoryl chloride (220ml) and the resulting mixture was heated under reflux for 6 hours. The excess phosphoryl chloride was then removed in vacua. The resulting residue was dissolved in dichloromethane (250ml) and washed with water (2xlOOml), followed by saturated sodium hydrogen carbonate solution (100ml). The organic layer was then dried (MgSCU) and the solvent was removed in vacuo to give 6-bromo-4-chlorothieno[2,3-d]pyrirnidine (9.06g) as a yellow solid, which was used without further purification. |
With trichlorophosphate; at 120℃; for 2.5h; | 6-Bromo-4-Chlorothieno[2,3-d]pyrimidine (4). Compound 3 (50.00 g, 216 mmol) was mixed with POCl3 (110 mL, 1180 mmol) and heated at 120 C for 2.5 h. Then the mixture was quenched into 5 M aq NaOH (900 mL) and ice. The formed precipitate was isolated by filtration and washed with water (3 x 200 mL). Drying gave 50.57 g (203 mmol, 94%) of 4 as a brown solid, mp. 113 - 114 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 CH2C12, mp. 1 15 - 116 C; R/(CH2Cl2/MeOH, 98/2) = 0.67; 1H NMR (400 MHz, DMSO-d6) delta: 8.95 (s, 1H), 7.89 (s, 1H); 13C NMR (100 MHz, DMSC /6) delta: 168.9, 153.2, 152.5, 130.2, 122.9, 118.5; IR (neat, cm 1): 3082, 1508, 14011 , 959, 832, 816, 760; HRMS (EI, 70 eV, m z): 247.8813 (calcd C6H2Br79Cl35N2S, 247.881 1, M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; bromine; acetic acid; In N,N-dimethyl-formamide; | EXAMPLE 19 This Example illustrates the preparation of several 4-amino-6-bromo-thieno[ 2,3-d] pyrimidines according to the invention (Compound Nos. 235-6, 241-2). A mixture of 3,4-dihydrothieno[ 2,3-d] pyrimidine-4-one (21 g), bromine (30 ml) and acetic acid (300 ml) was stirred at room temperature for three hours, poured into water/ice (1 l) and the 6-bromo derivative filtered off and dried (18.2 g). A portion (17.0 g) was treated with thionyl chloride (230 ml) and N,N-dimethylformamide (3 ml) and refluxed for forty minutes. Excess acid chloride was removed in vacuo and the residue was partitioned between chloroform and water. The organic layer was washed, dried and evaporated to give 6-bromo-4-chlorothieno[ 2,3-d] pyrimidine (14.7 g). This was treated with a number of amines basically as described in Example 5. | |
With thionyl chloride; bromine; acetic acid; In N,N-dimethyl-formamide; | EXAMPLE 19 This Example illustrates the preparation of several 4-amino-6-bromo-thieno [2,3-d] pyrimidines according to the invention (Compound Nos. 235-6, 241-2). A mixture of 3,4-dihydrothieno[2,3-d]pyrimidine-4-one (21 g), bromine (30 ml) and acetic acid (300 ml) was stirred at room temperature for three hours, poured into water/ice (1 l) and the 6-bromo derivative filtered off and dried (18.2 g). A portion (17.0 g) was treated with thionyl chloride (230 ml) and N,N-dimethylformamide (3 ml) and refluxed for forty minutes. Excess acid chloride was removed in vacuo and the residue was partitioned between chloroform and water. The organic layer was washed, dried and evaporated to give 6-bromo-4-chlorothieno[2,3-d]pyrimidine (14.7 g). This was treated with a number of amines basically as described in Example 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.1% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; at -78℃; for 1h;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 <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (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 20% EtOAc/Hexanes gradient elution to give 5-bromo-4-chlorothieno[2,3-d]pyrimidine (671 mg, 67.1 % yield) as a tan solid. NMR (400 MHz, chloroform- ) delta ppm 8.85 (s, 1 H), 7.64 (s, 1 H). |
56% | With lithium diisopropyl amide; In tetrahydrofuran; n-heptane; ethylbenzene; at -78℃; for 1h;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 10% EtOAc in Hexanes as eluent to give 5-bromo-4-chlorothieno[2,3- cdpyrimidine as yellow solid (1.7 g, 56%). LCMS (ES) m/z = 248.9, 250.9 [M+H]+. H NMR (400 MHz, CDCI3) delta ppm 7.66 (s, 1 H), 8.87 (s, 1 H). |
55% | 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 <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (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×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 1h;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 10% EtOAc in hexane as mobile phase to give 5-bromo-4-chlorothieno[2,3-c]pyrimidine as yellow solid. Yield (0.46 g, 46 %). LC-MS (ES) m/z = 248.9 [M+H]+. H NMR (400 MHz, CDCI3) delta 7.66 (s, 1 H), 8.87 (s, 1 H). |
A stirred solution of <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (4.0g, 0.016mol) in anhydrous tetrahydrofuran (100ml) was cooled in a dry-ice/acetone bath and treated, under a nitrogen atmosphere, with lithium diisopropylamide (1.8M solution in tetrahydrofuran, 9.0ml, 0.016mol) over about 20 minutes. The resultant dark solution was stirred in the cold for 1 hour and then treated with a mixture of water (5ml) and tetrahydrofuran (20ml) over about 20 minutes. The mixture was then allowed to warm up to about 0C before being poured into water (250ml) and extracted with dichloromethane (SxlOOml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flashchromatography (silica) eluting with dichloromethane gave 5-bromo-4-chlorothieno[2,3-cQpyrimidine as a pale brown solid (3.8g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With triethylamine; In N,N-dimethyl-formamide; at 25℃; for 20h; | A mixture of <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (prepared as disclosed in WO 2003053446) (500 mg, 2.0 mmol), the amine hydrochloride (compound 117) (563 mg, 3.0 mmol) and triethylamine (505 mg, 5.0 mmol) in DMF (7 mL) was stirred at approximately 25 C. for 20 hours. After cooling, the mixture was diluted with water (20 mL) and extracted with ether (3*25 mL). The combined organics were washed with water, saturated brine, and dried (Na2SO4). Filtration and removal of solvent gave product as an off-white solid, 300 mg, 0.83 mmol, 41 percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | EXAMPLE 20 6-Bromo-N-(2,5-dimethoxyphenyl)thieno[3,2-d]pyrimidin-4-amine To a mixture of <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (96 mg, 0.38 mmol) and 2,5-dimethoxybenzenamine (65 mg, 0.42 mmol) in 2.5 mL of isopropanol was added 2 drops of concentrated HCl and the mixture was heated at 75 C. for 3 h. The reaction mixture was cooled to room temperature and diluted with 25 mL of ethyl acetate, and washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (40% ethyl acetate/hexane) to give the title compound (116 mg, 0.32 mmol, 84%). 1H NMR (CDCl3) 8.70 (s, 1H), 8.07 (d, 1H, J=3.0), 7.45 (s, 1H), 7.18 (s, 1H, broad), 6.87 (d, 1H, J=8.7), 6.67 (dd, 1H, J=9.0, 3.0), 3.88 (s, 3H), 3.83 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | 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, 83%) as brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; isopropyl alcohol; at 60℃; for 64h; | Step C: Preparation of N-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylpheal)-6-broLnothieno[2,3-d]pyrimidin-4-amine: To a solution of <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (0.569 g, 2.58 mmol) and 4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylbenzenamine (0.60 g, 2.51 mmol) in dichloroethane/isopropanol (11 mL) was added DIEA (0.44 mL, 2.51 mmol). After heating to 60 C for 64 hours, the reaction mixture was worked up with isopropanol/dichloromethane. The organic solution was dried and concentrated under reduced pressure. The residue was chromatographed (gradient 0% to 8% methanol/7N NH3/ethyl acetate). The crude product was purified further by reverse phase liquid chromatography. MS ESI (+) m/z 452, 454 (M+1, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) delta 9.69 (s, 1H), 8.63 (d, 1H, J = 7 Hz), 8.52 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.82 (d, 1H, J = 3 Hz), 7.78 (dd, 1H, J = 3 Hz, 9 Hz), 7.59 (s, 1H), 7.16 (d, 1H, J = 9 Hz), 6.96 (dd, 1H, J = 2 Hz, 7 Hz), 6.63 (s, 1H), 2.19 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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, 25% and example 204: 0.16 g, 26%).Example 3081H NMR (300 MHz, CDCl3, 25 C.): delta=8.82 (s, 1H, H-2), 7.49 (s, 1H, H-5) ppm.Example 3091H NMR (300 MHz, CDCl3, 25 C.): delta=7.4 (s, 1H, H-5), 2.99 (t, J=7.5 Hz, 2H, CH2CH2CH2CH3), 1.83 (quint, J=7.6 Hz, 2H, CH2CH2CH2CH3), 1.42 (sixtet, J=7.4 Hz, 2H, CH2CH2CH2CH3), 0.96 (t, J=7.4 Hz, 2H, CH2CH2CH2CH3) ppm. | ||
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, 25% and example 204: 0.16 g, 26%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 2h;Reflux; Inert atmosphere; | A solution of <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (0.12 g, 0.48 mmol), 4-fluorophenylboronic acid (67 mg, 0.48 mmol), K2CO3 (0.266 g, 1.92 mmol) and Pd(PPh3)4 in dioxane/H2O (3:1, 3 ml) was refluxed under N2 for 2 hours. After cooling to room temperature, 1N HCl was added slowly to neutralize the mixture to pH=7-8. The mixture was extracted with CH2Cl2, washed with water and brine and dried over Na2SO4. After removing the solvents under reduced pressure, the crude residue was purified by silica gel chromatography (hexane/EtOAc 30:1) to yield the title compound as a pale yellow solid (60 mg, 47%).1H NMR (300 MHz, CDCl3, 25 C.): delta=8.82 (s, 1H, CH-2), 7.70-7.74 (m, 2H, PhH), 7.52 (s, 1H, CH-5), 7.19 (t, J=8.4 Hz, 2H, PhH) ppm.HRMS: calcd for C12H7ClFN2S 265.00025, found 264.99949. |
47% | Example 310 Synthesis of 4-Chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine A solution of <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (0.12 g, 0.48 mmol), 4-fluorophenylboronic acid (67 mg, 0.48 mmol), K2CO3 (0.266 g, 1.92 mmol) and Pd(PPh3)4 in dioxane/H2O (3:1, 3 ml) was refluxed under N2 for 2 hours. After cooling to room temperature, 1N HCl was added slowly to neutralize the mixture to pH=7-8. The mixture was extracted with CH2Cl2, washed with water and brine and dried over Na2SO4. After removing the solvents under reduced pressure, the crude residue was purified by silica gel chromatography (hexane/EtOAc 30:1) to yield the title compound as a pale yellow solid (60 mg, 47%). 1H NMR (300 MHz, CDCl3, 25 C.): delta=8.82 (s, 1H, CH-2), 7.70-7.74 (m, 2H, PhH), 7.52 (s, 1H, CH-5), 7.19 (t, J=8.4 Hz, 2H, PhH) ppm. HRMS: calcd for C12H7ClFN2S 265.00025, found 264.99949. | |
47% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 2h;Inert atmosphere; Reflux; | Example 310 Synthesis of 4-Chloro-6(4-fluorophenyl)thieno[2,3-d]pyrimidine A solution of <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (0.12 g, 0.48 mmol), 4-fluorophenylboronic acid (67 mg, 0.48 mmol), K2CO3 (0.266 g, 1.92 mmol) and Pd(PPh3)4 in dioxane/H2O (3:1, 3 ml) was refluxed under N2 for 2 hours. After cooling to room temperature, 1N HCl was added slowly to neutralize the mixture to pH=7-8. The mixture was extracted with CH2Cl2, washed with water and brine and dried over Na2SO4. After removing the solvents under reduced pressure, the crude residue was purified by silica gel chromatography (hexane/EtOAc 30:1) to yield the title compound as a pale yellow solid (60 mg, 47%). 1H NMR (300 MHz, CDCl3, 25 C.): delta=8.82 (s, 1H, CH-2), 7.70-7.74 (m, 2H, PhH), 7.52 (s, 1H, CH-5), 7.19 (t, J=8.4 Hz, 2H, PhH) ppm. HRMS: calcd for C12H7ClFN2S 265.00025. found 264.99949. |
39% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; In 1,4-dioxane; at 110℃; for 26h;Inert atmosphere; | General procedure: Compound 1 (1.00 g, 4.02 mmol) was mixed with (4-fluorophenyl)boronic acid (4c) (844 mg, 6.03 mmol), fine powdered K2CO3 (1.68 g, 12.1 mmol), Pd2(dba)3 (186 mg, 0.20 mmol) and 1,4-dioxane (20 mL). The reaction was then stirred at 110 C for 26 h under N2 atmosphere. The solvent was removed and the product was dissolved in diethyl ether (150 mL) and washed with water (3 × 150 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was absorbed onto silica and purified by silica-gel column chromatography (n-pentane/acetone, 19/1), Rf = 0.28. Drying gave 415 mg (1.57 mmol, 39%) of 24c as a pale white solid, mp 142-143 C; HPLC purity: 91% (method B), tR = 23.5 min; 1H NMR (400 MHz, DMSO-d6) delta: 8.93 (s, 1H), 8.04-7.98 (m, 3H), 7.43-7.36 (m, 2H); 13C NMR (100 MHz, DMSO-d6) delta: 167.6, 163.0 (d, J = 248.6), 153.3, 152.8, 144.1, 130.8, 129.2 (d, J = 8.7, 2C), 128.5 (d, J = 3.1), 116.5 (d, J = 22.0, 2C), 115.1; 19F NMR (564 MHz, DMSO-d6) delta: -115.3 (s); IR (neat, cm-1): 3063, 1884, 1505, 1429, 1228, 1165, 813, 759, 670; HRMS (ESI, m/z): 264.9995 (calcd. C12H735ClFN2S, 264.9997, [M + H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With sodium carbonate; triphenylphosphine;palladium diacetate; In water; toluene; at 110℃;Inert atmosphere; | Example 106. Synthesis of 4-N-[6-cycIopropylthieno[2,3-d]pyrimidin-4-yl]-l-N,l- N-dimethylcyclohexane-l,4-diamine (1-184).Page 195 of 4072009184-0008 1-184[00498] Synthesis of 4-chloro-6-cyclopropylthieno[2,3-d]pyrimidine. A 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with commercially available <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (1.5 g, 6.01 mmol, 1.00 equiv), cyclopropylboronic acid (1.2 g, 13.97 mmol, 2.30 equiv), sodium carbonate (2.16 g, 20.38 mmol, 3.40 equiv), PPh3 (552 mg, 2.10 mmol, 0.35 equiv), Pd(OAc)2 (162 mg, 0.72 mmol, 0.12 equiv), water (7.5 mL) and methylbenzene (22.5 mL). The resulting solution was stirred overnight at 110 C in an oil bath. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 3 x 100 mL of dichloro methane and the organic layers combined. The resulting mixture was washed with 3 x 200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 15-1 :5). This resulted in 400 mg (32%) of 4-chloro-6-cyclopropylthieno[2,3-d]pyrimidine as a yellow solid.[00499] Synthesis of Compound 1-184. A 50-mL round-bottom flask was charged with 4- chloro-6-cyclopropylthieno[2,3-d]pyrimidine (400 mg, 1.90 mmol, 1.00 equiv), 1-N, 1-N- dimethylcyclohexane-l,4-diamine (324 mg, 2.28 mmol, 1.20 equiv) and potassium carbonate (393 mg, 2.84 mmol, 1.50 equiv) in N,N-dimethylformamide (10 mL). The resulting solution was stirred for 48 h at 45 C in an oil bath. The resulting solution was diluted with 150 mL of water. The resulting solution was extracted with 3 x 200 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3 x 300 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC (2No.- Waters 2767-2(HPLC-08)) under the following conditions: column: Xbridge Prep Phenyl, 5um, 19* 150mm; mobile phase: water (50 mM NH4HCO3) and CH3CN (10.0% CH3CN up to 33.0% in 2 min, up to 53.0% in 8 min, up to 100.0% in 1 min, down to 10.0% in 1 min); detector: UV 220 nm. This resulted in 43.3 mg (7%) of Compound 1-184 as a white solid. NMR: (400 MHz, CDC13) delta 8.41 (1H, s), 6.73 (1H, s), 4.77-4.75 (2H, d), 4.15- 4.05 (1H, m), 2.35 (6H, s), 2.31-2.27 (2H, d), 2.17-2.07 (1H, m), 2.01-1.96 (2H, d), 1.56-1.42Page 196 of 4072009184-0008 (2H, m). 1.34-1.21 (3H, m), 1.1 1-1.04 (2H, m), 0.78-0.85 (2H, m). MS: m/z 317 (M+H)+. |
Tags: 56844-12-3 synthesis path| 56844-12-3 SDS| 56844-12-3 COA| 56844-12-3 purity| 56844-12-3 application| 56844-12-3 NMR| 56844-12-3 COA| 56844-12-3 structure
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