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CAS No. : | 16234-14-3 | MDL No. : | MFCD08448158 |
Formula : | C6H2Cl2N2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AQECFYPZMBRCIA-UHFFFAOYSA-N |
M.W : | 205.06 | Pubchem ID : | 12712832 |
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 : | 47.44 |
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) : | -5.26 cm/s |
Log Po/w (iLOGP) : | 2.26 |
Log Po/w (XLOGP3) : | 3.23 |
Log Po/w (WLOGP) : | 3.0 |
Log Po/w (MLOGP) : | 1.85 |
Log Po/w (SILICOS-IT) : | 3.97 |
Consensus Log Po/w : | 2.86 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.75 |
Solubility : | 0.0363 mg/ml ; 0.000177 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.04 |
Solubility : | 0.0188 mg/ml ; 0.0000918 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -3.83 |
Solubility : | 0.03 mg/ml ; 0.000146 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.42 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P264-P270-P280-P301+P310+P330-P305+P351+P338-P337+P313-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301-H319 | Packing Group: | Ⅲ |
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 |
---|---|---|
80% | With ammonia In methanol at 20℃; Sealed tube | In a glass tube 2,4-dichlorothieno[3,2-d]pyrimidine (800 mg, 3.90 mmol) was suspended in MeOH (10 mL) and cooled to −60 to −70°C upon which ammonia was bubbled in the suspension. The glass tube was sealed and the suspension stirred at room temperature overnight to obtain a clear solution. The solvent was evaporated and the resulting crude compound was purified using column chromatography eluting first with 9:1 hexanes/EtOAc, followed by 8:2 hexanes/EtOAc to obtain 6 as an off-white solid (575 mg, 3.10 mmol, 80 percent). Rf 0.2 in 3:1 hexanes/EtOAc. Mp 272.3–274.2 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.73 (d, 1H, J=5.0Hz), 8.38 (br s, 2H, NH2), 8.60 (d, 1H, J=5.5Hz). 13C NMR (100 MHz, DMSO-d6): δ 114.2, 124.7, 136.6, 157.7, 160.6, 162.4. FAB-MS m/z for C6H4ClN3S calculated [M+H]+ 185.9887, found 185.9895 (35Cl), 187.9861 (37Cl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 20℃; for 1 h; | Reference Example 2: 2-Chloro-4-morpholin-4-yl-thienof3,2-dlpyrimidine(65) (65)A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine (64), (8.68g, 42.34mmol), morpholine (8.1 ImL, 2.2eq.) and MeOH (15OmL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield the title compound as a white solid (11.04 g, 100percent). EPO <DP n="32"/>1H NMR (400 MHz, J6-DMSO) 3.74 (4H, t, J=4.9Hz), 3.90 (4H, t, J=4.9Hz), 7.40 (IH, d, J=5.6Hz), 8.30 (IH, d, J=5.6Hz). |
100% | at 20℃; for 1 h; | A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine (VIII), (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield the title compound as a white solid (11.04 g, 100percent). 1H NMR (400 MHz, d6-DMSO) 3.74 (4H, t, J=4.9 Hz), 3.90 (4H, t, J=4.9 Hz), 7.40 (1H, d, J=5.6 Hz), 8.30 (1H, d, J=5.6 Hz). |
100% | at 20℃; for 1 h; | A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and methanol (150 mL) was stirred at room temperature for 1 hour. The reaction mixture was then filtered, washed with water and methanol, to yield the title compound as a white solid (11.04 g, 100percent). 1H NMR (400 MHz, d6-DMSO) 3.74 (4H, t, J=4.9 Hz), 3.90 (4H, t, J=4.9 Hz), 7.40 (1H, d, J=5.6 Hz), 8.30 (1H, d, J=5.6 Hz). |
100% | at 20℃; for 1 h; | A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine 3, (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (15OmL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield 2-chloro-4- moφholin-4-yl-thieno[3,2-d]pyrimidine 4 as a white solid (11.04 g, 100percent). 1H NMR (400 MHz, J6-DMSO) 3.74 (4H, t, J=4.9Hz), 3.90 (4H, t, J=4.9Hz), 7.40 (IH, d, J=5.6Hz), 8.30 (IH, d, J=5.6Hz). |
100% | at 20℃; for 1 h; | A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine 3, (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield 2-chloro-4- morpholin-4-yl-thieno[3,2-d]pyrimidine 4 as a white solid (11.04 g, 100percent). 1H NMR (400 MHz, J6-DMSO) 3.74 (4H, t, J=4.9Hz), 3.90 (4H, t, J=4.9Hz), 7.40 (IH, d, J=5.6Hz), 8.30 (IH, d, J=5.6Hz). |
100% | at 20℃; for 1 h; | A mixture of 2,4-dichloro-thieno[3,2-cφyrimidine (8.68 g, 42.34mmol), morpholine (8.11 mL, 2.2 equivalents) and methanol (150 mL) was stirred at room temperature for 1 hour. The reaction mixture was then filtered, washed with water to yield the title compound as a white solid (11.04 g, 100percent).<5H (400 MHz, d-6 DMSO) 8.30 (IH, d, J 5.6), 7.40 (IH, d, J 5.6), 3.90 (4H, t, J 4.9), 3.74(4H. U 4.9). |
100% | at 20℃; for 1 h; | Step If: 4-(2-Chlorothieno[3,2-d]pyrimidin-4-yl)morpholine (Compound 0111)A mixture of compound 0110 (8.68 g, 42.34 mmol) and morpholine (8.11 mL, 93.15 mmol) in methanol (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water (50 mL x 3) and methanol (50 mL x 1) to give the title compound 0111 (11.04 g, 100percent) as a white solid: LCMS: 256 [M+l]+; 1H NMR (400 MHz, DMSO-<3/4): δ 3.76 (t, J= 4.8 Hz, 4H), 3.91 (t, J= 4.8 Hz, 4H), 7.41(d, J= 5.6 Hz , 1H), 8.31 (d, J= 5.6 Hz , 1H). |
100% | at 20℃; for 1 h; | Step 1f: 4-(2-Chlorothieno[3,2-d]pyrimidin-4-yl)morpholine (Compound 0111)[0176]A mixture of compound 0110 (8.68 g, 42.34 mmol) and morpholine (8.11 mL, 93.15 mmol) in methanol (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water (50 mL×3) and methanol (50 mL×1) to give the title compound 0111 (11.04 g, 100percent) as a white solid: LCMS: 256 [M+1]+; 1H NMR (400 MHz, DMSO-d6): δ 3.76 (t, J=4.8 Hz, 4H), 3.91 (t, J=4.8 Hz, 4H), 7.41 (d, J=5.6 Hz, 1H), 8.31 (d, J=5.6 Hz, 1H). |
100% | at 20℃; for 1 h; | A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine 3, (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 as a white solid (11.04 g, 100percent). 1H NMR (400 MHz, d6-DMSO) 3.74 (4H, t, J=4.9 Hz), 3.90 (4H, t, J=4.9 Hz), 7.40 (1H, d, J=5.6 Hz), 8.30 (1H, d, J=5.6 Hz). |
100% | at 20℃; for 1 h; | In methanol (150 mL), compound 0110 (8.68g, 42.34mmol) and morpholine (8.11mL, 93.15mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water (50mL x 3) and methanol (50mL x 1), to give the title compound 0111 (11.04g, 100percent) as a white solid: |
100% | With n-butyllithium In methanol at -78℃; for 1 h; | A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine 3, (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 as a white solid (11.04 g, 100percent). |
100% | at 20℃; for 1 h; | Reference Example 5: 2-Chloro-4-morphoIin-4-yl-thieno f3,2-d] pyrimidine; <n="64"/>A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine (8.68 g, 42.34mmol), morpholine (8.11 mL, 2.2 equivalents) and methanol (150 mL) was stirred at room temperature for 1 hour. The reaction mixture was then filtered, washed with water to yield the title compound as a white solid (11.04 g, 100percent).<5H (400 MHz5 d-6 DMSO) 8.30 (IH, d, J 5.6), 7.40 (IH, d, J 5.6), 3.90 (4H, t, J 4.9), 3.74 (4H, t, J 4.9). |
100% | at 20℃; for 1 h; | Example 2; 2-Chloro-4-moφholin-4-yl-tbieno[3,2-d]pyrimidine 4 <n="137"/>[00268] A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidme 3, (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (15OmL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield 2-chloro-4- morpholin-4-yl-thieno[3,2-d]pyrimidine 4 as a white solid (11.04 g, 100percent). 1H NMR (400 MHz, J6-DMSO) 3.74 (4H, t, J=4.9Hz), 3.90 (4H, t, J=4.9Hz), 7.40 (IH, d, J=5.6Hz), 8.30 (lH, d, J=5.6Hz). |
99% | at 20℃; for 1 h; | A mixture of compound 13 (7.42, 1 equiv.) and morpholine (7.11 mL, 2.2 equiv) in methanol (150 mL) was stirred at rt for 1 h. The resulting precipitate was filtered, and then washed with water (3 x 50 ml) and remaining solid was dried in vacuo to furnish compound 14 (9.09 g, 99percent) as white solid. NMR (400 MHz, DMSO-<, ppm): δ 8.31 (d, / = 5.6 Hz, 1H), 7.41 (d, / = 5.6 Hz, 1H), 3.91 (t, / = 4.8 Hz, 4H), 3.76 (t, / = 4.8 Hz, 4H); ESI-MS: m/z 256.72 [M+H]+. |
91% | at 20℃; | Step m: 2-Chloro-4-morpholinothieno[3,2-d]pyrimidine (Compound 104) To a mixture of compound 103 (34.2 g, 167 mmol, 1.0 eq) and methanol (500 mL) was added morpholine (31.2 mL, 367 mmol, 2.2 eq) slowly. The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with methanol and dried in vacuo to give the desired product compound 104 as a light-yellow solid (39 g, 91percent). M.p.: 250-255° C. LCMS (m/z): 256.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6): δ 3.76 (t, J=5.2 Hz, 4H), 3.92 (t, J=5.2 Hz, 4H), 7.42 (d, J=5.2 Hz, 1H), 8.32 (d, J=5.2 Hz, 1H). |
91% | at 20℃; | To a mixture of compound 103 (34.2 g, 167 mmol, 1.0 eq) and methanol (500 mL) was added morpholine (31.2 mL, 367 mmol, 2.2 eq) slowly. The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with methanol and dried in vacuo to give the desired product compound 104 as a light- yellow solid (39 g, 91percent). M.p.: 250-255°C. LCMS (m/z): 256.0 [M+1f ‘H NMR (400 MHz, DMSO-d6): ö 3.76 (t, J= 5.2 Hz, 4H), 3.92 (t, J= 5.2 Hz, 4H), 7.42 (d, J 5.2 Hz,1H), 8.32 (d, J 5.2 Hz, 1H). |
72.3% | With triethylamine In ethanol for 10 h; Reflux | General procedure: A suspension of 300 mg of 2,6-dichloro-9H-purine (1), 2,4-dichlorothieno[3,2-d]pyrimidine (6) or 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (9) in 10mL of EtOH was added morpholine or 4-aminotetrahydropyran (1.2 equiv) and 300 mL of triethylamine. The mixtrue was refluxed for 10 h. After the disappearance of compounds 1, 6 or 9 detected by TLC, the solution was evaporated in vacuum to yield a syrup. Then, it was neutralized by concentrated ammonium hydroxide. After filtering off, the residue was washed with cold water and cold acetone successively to remove the triethylammonium hydrochloride. |
15.6 g | at 20℃; for 1 h; | To a stirred solution of compound 3 (16.9g, 83.2mmol) in dry methanol (300mL) and morphine (15.9g, 183.1mmol) was added. After the addition, the reaction mixture was stirred at room temperature for 1h. Separated gray solid was filtered and washed with water and methanol. The gray solid was dried and filtered. The crude product was found to be pure and taken to the next step without purification, yield a solid 4 (15.6g). Yield 73.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | for 2 h; Heating / reflux | To a suspension of the uracil (5g, 29mmol) in POCI3 (4OmL) was added diisopropylethylamine (13mL, 74mmol) and the reaction heated at reflux for 2h. The excess POCb and diisopropylethylamine were then removed by distillation under reduced pressure and the brown solid obtained dissolved in chloroform and partitioned against water. The aqueous phase was made basic by the addition of 5M NaOH, and extracted twice further with chloroform. The combined organic fractions were washed with water and brine, dried (Na2SO4) filtered and concentrated to afford the product as a pale brown solid (6.05g, quantitative yield). 1H NMR (CDCl3, 300 MHz): 8.16 (d, J=5.4Hz, IH), 7.56 (d, J=5.7Hz, IH); LRMS (ESI): m/z calcd for [M+H]+ 204.94, 206.94 found 205.1, 207.0. |
92% | at 105℃; for 16 h; | A mixtureof thieno [3,2-d] pyrimidine-2,4 (1H, 3H)-dione (Method 62,380 mg, 2.3 mmol), phosphorus oxychloride(10 ml) and diethylaniline(1 ml) was heated at105 C for 16 hrs. Solvent was then removed and ice was added to the mixture. The solid was filtered and gave pink colour solid product (432.4 mg, 92percent). 1H NMR (400 MHz):8 7.98 (d, J = 5.6 Hz, 1 H), 8. 94 (d,J = 5. 6 Hz, 1 H). |
87.3% | for 2 h; Reflux | Thieno[3,2-d]pyrimidine-2,4(lH,3H)-dione (2, 5 g, 29 mmol) was taken up in POCl3 (41 mL) to form a mixture. N,N-diisopropylethylamine (DIEA) (13 mL, 74 mmol) was added to the mixture and the mixture was heated to reflux for 2 h, after which product (3) was detected in the mixture by LCMS. The POCl3 and DIEA were then removed from the mixture under vacuum. Water was added to the resultant residue, and the obtained aqueous layer was extracted with dichloromethane (DCM). The aqueous layer was made basic by the addition of 5N NaOH and extracted with DCM. The combined DCM extracts were then dried over and concentrated to obtain a brown solid of 2,4- dichlorothieno[3,2-d]pyrimidine (3, 6.07g, 87.30percent).'HNMR (CDCIj): 8.15 (d, 1H), 7.66 (d, 1H). |
84% | With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 0 - 85℃; for 48 h; | Thieno [3,2-d] pyrimidine-2,4 (1 H, 3H) -dione(IX-1) (5.0 g, 29.7 mmol)And 3 mL of N, N-dimethylaniline were dissolved in acetonitrileWas dissolved in 25 mL,It was cooled to 0 ° C.,16 mL of phosphorus oxychloride was slowly added dropwise.The resulting purple slurry was heated to 80-85 ° C.,And the mixture was stirred for 24 hours.Further, phosphorus oxychloride (10 mL) was added and the mixture was heated for 24 hours.The obtained purple transparent solution was poured into ice water,The phosphorus oxychloride was completely decomposed.The slurry was filtered, the solid was dried at 45 ° C.,It was then dissolved in 100 mL of ethyl acetate,Washed with saturated sodium bicarbonate water, and 5 g of activated carbon was added and stirred.It was then filtered through celite and concentrated to afford the dichloro compound(IIa-1) 5.11 g (yield: 84percent). |
83% | With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 20 - 85℃; for 24 h; Cooling | Step l: 2,4-Dichlorothieno[3,2-d]pyrimidine (Compound 103) Phosphorous oxychloride (152 mL, 1.67 mol, 7.0 eq) was added slowly to cold solution of compound 102 (40 g, 238 mmol, 1.0 eq) and N,N-dimethylaniline (22.5 mL, 179 mmol, 0.75 eq) in acetonitrile (250 mL) while maintaining the temperature below 20° C. The mixture was then heated to 85° C. and stirred for 24 h. The reaction mixture was cooled to 15° C., and then poured slowly onto a mixture of ice and cold water (360 mL). The resulting slurry was filtered, rinsed with cold water (200 mL). The cake was dried in vacuum oven at 40° C. for 24 h to afford compound 103 (40.5 g, 83percent) as an off-white solid. M.p.: 245-250° C. LCMS (m/z): 205.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6): δ 7.75 (d, J=5.2 Hz, 1H), 8.71 (d, J=5.2 Hz, 1H). |
83% | With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline; acetonitrile at 15 - 85℃; for 24 h; | Phosphorous oxychloride (152 mL, 1.67 mol, 7.0 eq) was added slowly to cold solution of compound 102 (40 g, 238 mmol, 1.0 eq) and N,N-dimethylaniline (22.5 mL,179 mmol, 0.75 eq) in acetonitrile (250 mL) while maintaining the temperature below20°C. The mixture was then heated to 85°C and stirred for 24 h. The reaction mixture was cooled to 15°C, and then poured slowly onto a mixture of ice and cold water (360 mL). The resulting slurry was filtered, rinsed with cold water (200 mL). The cake was dried in vacuum oven at 40°C for 24 h to afford compound 103 (40.5 g, 83percent) as an off- whitesolid. M.p. :245-250°C. LCMS (m/z): 205.0 [M+1f. ‘H NMR (400 MHz, DMSO-d6): ö7.75 (d, J 5.2 Hz, 1H), 8.71 (d, J 5.2 Hz, 1H). |
82% | at 105 - 110℃; for 16 h; Inert atmosphere | In a dry flask, thieno[3,2-d]pyrimidin-2,4(1H,3H)-dione 4 (4.00 g, 23.78 mmol) was refluxed in freshly distilled POCl3 (50 mL) under nitrogen overnight (16 h) at which point the POCl3 was evaporated and the residue extracted with CH2Cl2 (50 mL). The organic layer was washed with saturated NaHCO3 solution (50 mL), brine (50 mL), dried over MgSO4 and concentrated. The residue was crystallized from EtOAc to obtain 1 as a pale green-yellow solid (4.00 g, 19.50 mmol, 82 percent). Mp: 135–137 °C. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H, J=5.0Hz), 8.12 (d, 1H, J=5.5Hz). 13C NMR (100 MHz, CDCl3): δ 124.6, 129.4, 139.3, 155.8, 156.3, 163.5. FAB-MS m/z for C6H2Cl2N2S calculated [M+H]+ 204.9388, found 204.9400 (2x35Cl), 206.9366 (35Cl 37Cl). |
82% | for 16 h; Inert atmosphere; Reflux | In a dry flask, thieno[3,2-d]pyrimidin-2,4(1H,3H)-dione 4 (4.00 g, 23.78 mmol) was refluxed in freshly distilled POCl3 (50 mL) under nitrogen overnight (16 h) at which point the POCl3 was evaporated and the residue extracted with CH2Cl2 (50 mL). The organic layer was washed with saturated NaHCO3 solution (50 mL), brine (50 mL), dried over MgSO4 and concentrated. The residue was crystallized from EtOAc to obtain 1 as a pale green-yellow solid (4.00 g, 19.50 mmol, 82percent). Mp: 135-137° C. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H, J=5.0 Hz), 8.12 (d, 1H, J=5.5 Hz). 13C NMR (100 MHz, CDCl3): δ 124.6, 129.4, 139.3, 155.8, 156.32, 163.5. FAB-MS m/z for C6H2Cl2N2S calculated [M+H]+ 204.9388. found 204.9400 (2× 35Cl), 206.9366 (35Cl37Cl). |
81.7% | at 0℃; for 8 h; Reflux | 50 g (0.30 mol) of intermediate Ila were placed in 87 mL (0.60 mol) of triethylamine,Ice bath down to 0 ° C,Keep 0 ° C slowly dropping300 mL (3.29 mol) of phosphorus oxychloride,2h plus completed, heated to reflux reaction 6h.After the reaction, the reaction solution was concentrated to 150 mL, and the residue was poured into 1000 g of ice water with stirring. A large amount of white solid was precipitated and filtered. The filter cake was washed with water at a temperature of 45 ° C for 24 h, 50.3 g of white flocculent crystals, Yield 81.7percent; purity 99.7percent |
79.6% | With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 50 - 85℃; Large scale | A mixture of compound 102 (16.7 kg, 99.41 mol, 1.0 equiv) and N, N-dimethylaniline (9.4 kg, 77.57Mole, 0.78 equiv.) Was added to anhydrous acetonitrile (138 kg). The mixture is cooled to 0 to 10 degrees Celsius, the phosphorus oxychloride(111.2 kg, 725.4 moles, 7.3 equiv) was added slowly to the mixture at 50 ° C. The mixture was heated to 80 to 85 degrees Celsius and stirred for 16 to 20 hours at this temperature Celsius, and the mixture was stirred at 80 to 85 degrees Celsius for 3 to 4 hours. The mixture was cooled to 20 to 30 degrees Celsius and then ice water (441 kg) was slowly added below 40 degrees Celsius. The mixture was cooled to 0 to 10 degrees Celsius and stirred at this temperature for 1 hour. Centrifuge, filter cake with ice water rinse (36 kg). The wet product was dried under vacuum at 55-60 ° C to give 2,4-dichlorothiophene [3,2-d] pyrimidine (18.2 kg, yield: 79.6percent) as a white product. |
75% | for 6 h; Heating / reflux | A mixture of lH-thieno[3,2-d]pyrimidine-2,4-dione (9.49g, 56.49mmol) and phosphorous oxychloride (15OmL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2- d]pyrimidine (64) as a white solid (8.68 g, 75percent) 1H NMR (400 MHz, CDCl3) 7.56 (IH, d, J=5.5Hz), 8.13 (IH, d, J=5.5Hz). |
75% | for 6 h; Heating / reflux | A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione (9.49 g, 56.49 mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine (VIII) as a white solid (8.68 g, 75percent) 1H NMR (400 MHz, CDCl3) 7.56 (1H, d, J=5.5 Hz), 8.13 (1H, d, J=5.5 Hz). |
75% | for 6 h; Heating / reflux | A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione (9.49 g, 56.49 mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 hours. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine as a white solid (8.68 g, 75percent). 1H NMR (400 MHz, CDCl3) 7.56 (1H, d, J=5.5 Hz). 8.13 (1H, d, J=5.5 Hz). |
75% | for 6 h; Heating / reflux | A mixture of methyl 3-amino-2-thiophenecarboxylate 1 (13.48 g, 85.85 mmol) and urea (29.75 g, 5 eq.) was heated at 190 °C for 2 hours. The hot reaction mixture was poured onto sodium hydroxide solution and any insoluble material was removed by filtration. The mixture was then acidified (HCl, 2N) to yield lH-thieno [3,2-d]pyrimidine-2,4-dione 2 as a white precipitate, which was collected by filtration and air dried (9.49g, 66percent). 1H NMR 400 MHz, J6-DMSO) 6.90 (IH, d, J=5.2Hz), 8.10 (IH5 d, J=5.2Hz), 11.60-11.10 (2H, br s). [00242] A mixture of lH-thieno[3,2-d]pyrimidine-2,4-dione 2 (9.49g, 56.49mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine 3 as a white solid (8.68 g, 75percent). 1H NMR (400 MHz, CDCl3) 7.56 (IH, d, J=5.5Hz), 8.13 (IH, d, J=5.5Hz). |
75% | Stage #1: for 6 h; Heating / reflux |
A mixture of lH-thieno[3,2-d]pyrimidine-2,4-dione 2 (9.49g, 56.49mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine 3 as a white solid (8.68 g, 75percent). 1H NMR (400 MHz, CDCl3) 7.56 (IH, d, J=5.5Hz), 8.13 (IH, d, J=5.5Hz). |
75% | With trichlorophosphate In acetonitrile for 24 h; Heating / reflux | To a suspension of lH-thieno[3,2-d]pyrimidine-2,4-dione (10.0 g, 59.52 mmol) in acetonitrile (50 mL) was added phosphorous oxychloride (300 mmol, 5 equivalents, 28 mL) and the mixture heated at reflux for 24 hours in a flask fitted with a mechanical stirrer. The reaction mixture was then cooled and poured cautiously onto ice-water (250 mL) maintaining the temperature below 20 0C. The mixture was filtered to yield 2,4-dichloro-thieno[3,2- d]pyrimidine as an off-white solid (9.15 g, 75percent). SH. (400 MHz, CDCl3) 8.13 (IH, d, J 5.5), 7.56 (IH, d, J 5.5). |
75% | for 6 h; Reflux | A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione 2 (9.49 g, 56.49 mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine 3 as a white solid (8.68 g, 75percent). H NMR (400 MHz, CDCl3) 7.56 (1H, d, J=5.5 Hz), 8.13 (1H, d, J=5.5 Hz). |
75% | for 6 h; Reflux | A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione 2 (9.49 g, 56.49 mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine 3 as a white solid (8.68 g, 75percent). |
75% | With trichlorophosphate In acetonitrile for 24 h; Heating / reflux | Reference Example 4: 2,4-Dichloro-tfaienor3,2-d1pyrimidme; To a suspension of lH-thieno[3,2-d]pyrimidine-2,4-dione (10.0 g, 59.52 mmol) in acetonitrile (50 mL) was added phosphorous oxychloride (300 mmol, 5 equivalents, 28 mL) and the mixture heated at reflux for 24 hours in a flask fitted with a mechanical stirrer. The reaction mixture was then cooled and poured cautiously onto ice-water (250 mL) maintaining the temperature below 20 °C. The mixture was filtered to yield 254-dichloro-thieno[3,2-d]pyrimidine as an off-white solid (9.15 g, 75percent). <5H (400 MHz, CDCl3) 8.13 (IH, d, J 5.5), 7.56 (IH, d, J 5.5). |
75% | for 6 h; Heating / reflux | A mixture of lH-thieno[3,2-d]pyrimidine-2,4-dione 2 (9.49g, 56.49mmol) and phosphorous oxychloride (15OmL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine 3 as a white solid (8.68 g, 75percent). 1H NMR (400 MHz, CDCl3) 7.56 (IH, d, J=5.5Hz), 8.13 (IH, d, J=5.5Hz). |
75% | for 6 h; Heating / reflux | A mixture of methyl 3-amino-2-tbiophenecarboxylate (20) (13.48 g, 85.85 mmol) and urea (21) (29.75 g, 5 equivalents) was heated at 1900C for 2 hours. The hot reaction mixture was then poured onto sodium hydroxide solution and any insoluble material removed by filtration. The mixture was then acidified (HCl, 2N) to yield IH- <n="38"/>thieno [3,2-d]pyrimidine-2,4-dione (22) as a white precipitate which was collected by filtration and air dried (9.49g, 66percent).A mixture of lH-thieno[3,2-d]pyrimidine-2,4-dione (22) (9.49 g, 56.49 mmol) and phosphorous oxy chloride (150 rnL) was heated at reflux for 6 hours. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine, (Ilia), as a white solid (8.68 g, 75percent). |
74% | for 10 h; Reflux | Step le: 2,4-Dichlorothieno[3,2-d]pyrimidine (Compound 0110)A mixture of compound 0109 (9.49 g, 56.49 mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 10 h. The solvent was then removed and the residue was poured onto ice/water with vigorous stirring to give title compound 0110 (8.62 g, 74percent) as a white solid: LCMS: 205 [M+l]+; 1H NMR (400 MHz, CDC13): δ 7.48 (d, J= 5.6 Hz, 1H), 8.05 (d, J= 5.6 Hz , 1H). |
74% | for 5 h; Reflux | Compound 1 (1 g, 5.9 mmol) was dissolved in phosphorus oxychloride (15 mL) and stirred under reflux for 5 h. Two-thirds of the solvent was removed under a vacuum. The mixture was poured into ice-water (50 mL). The precipitate that separated was collected by filtration, washed with water, and dried to give compound 2 as a white solid. Yield: 74percent, mp: 140–143 °C. 1H NMR (CDCl3, 300 MHz) δ: 7.55 (d, 1H, J = 6.00 Hz, S–CC–H), 8.13 (d, 1H, J = 6.00 Hz, S–C–H). MS-EI m/z 205 (M + 1). |
74% | for 10 h; Reflux | Step 1e: 2,4-Dichlorothieno[3,2-d]pyrimidine (Compound 0110)[0175]A mixture of compound 0109 (9.49 g, 56.49 mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 10 h. The solvent was then removed and the residue was poured onto ice/water with vigorous stirring to give title compound 0110 (8.62 g, 74percent) as a white solid: LCMS: 205 [M+1]+; 1H NMR (400 MHz, CDCl3): δ 7.48 (d, J=5.6 Hz, 1H), 8.05 (d, J=5.6 Hz, 1H). |
74% | at 110℃; for 5 h; | Compound 1 (1 g, 5.9 mmol) was dissolved in phosphorus oxychloride (15 mL) and stirred under reflux for 5 h. Two-thirds of the solvent was removed under vacuum. The mixture was poured into ice-water (50 mL). The precipitate that separated was collected by filtration, washed with water, and dried to give compound 2 as a white solid. Yield: 74percent, mp: 140–143 °C. 1H-NMR (CDCl3) δ: 7.55 (d,1H, J = 6.00 Hz, S-C=C-H), 8.13 (d, 1H, J = 6.00 Hz, S-C-H). MS-EI m/z 205 (M + 1). |
74% | for 10 h; Reflux | Compound 0109 (9.49g, 56.49mmol) was heated 10 h under reflux a mixture of and phosphorus oxychloride (150 mL). The solvent was then removed, stirring vigorously injected residue onto ice / water with to afford the title compound 0110 a (8.62g, 74percent) as a white solid: |
73.3% | at 200℃; for 3 h; | Preparation of 2,4-dichlorothienor3,2-< )pyrimidineThe compound (3.2 g, 19.4 mmol) obtained in Step 1 was dissolved in phosphorous oxy chloride (12 mL) and refluxed with stirring for 3 hours at 200 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and added dropwise to 4 °C distilled water with stirring vigorously. The resulting solid was filtered under a reduced pressure with washing using distilled water, and the resulting solid was dried under a reduced pressure to obtain the title compound (yield: 2.9 g, 73.3 percent).1H-NMR (300MHz, DMSO-d6) δ 8.74 (d, 1H), 7.78 (d, 1H). |
70% | for 10 h; Reflux | A mixture of compound 12 (8.68 g, 56.49 m mol) and POCl3 (150 mL) was heated at reflux for 10 h. After completion of the reaction, reaction mixture was concentrated to half of the initial volume. Then, it was poured onto child ice with vigorous stirring to get compound 13 (7.42 g, 70percent) as white solid. NMR (400 MHz, CDC13, ppm): δ 8.05 (d, / = 5.6 Hz, 1H), 7.48 (d, / = 5.6 Hz, 1H); ESI-MS: m/z 205.05 [M+H]+. |
67% | for 16 h; Reflux | General procedure: A total of 0.8 mL N,N-dimethylaniline was added to 3.0 g of thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione 6a in 20 mL POCl3. The mixture was then heated under reflux for 16 h. Excess POCl3 was removed in vacuo, and the resulting residue was treated with ice water to yield a precipitate. The solid was collected by filtration, washed with water and dried over a funnel to afford solid 7a (1.3 g, yield 35.5percent). 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 6.4 Hz, 1H), 7.43 (d, J = 6.4 Hz, 1H). |
41% | at 106℃; for 3 h; Inert atmosphere | Under a nitrogen streamThieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione (8.41 g, 50.0 mmol)Chloride (170 ml) was added thereto, and the mixture was stirred at 106 ° C for 3 hours. After completion of the reaction, ethyl acetate was added to the organic layerAnd the water was removed using MgSO4. After removal of the organic layer solvent, the residue was purified by column chromatography2,4-dichlorothieno [3,2-d] pyrimidine (4.2 g, 20.5 mmol, yield 41percent) was obtained. |
36% | at 135℃; for 5 h; | (1) 1 g of raw material B2With POCl3And PCl5The reaction was refluxed at 135 ° C for 5 h to give the intermediate C20.43 g, yield 36percent; the specific reaction equation is as follows: |
28% | at 116℃; for 5 h; | A mixture of thieno[3,2-d]pyrimidine-2,4(lH,3H)-dione (1.02 g, 6.07 mmol) and phosphonyl chloride (15 mL, 161 mmol) was heated at 116 0C for 5 h. Upon completion of the reaction, the reaction mixture was poured into ice and extract with ethyl acetate 3 times. The combined organic layers were, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography, eluting with Hexanes/Elhyl Acetate (9: 1) afforded the product as a white solid (343 mg, 28percent): [002391 1H NMR (DMSO, 300 MHz) δ 7.73 (d, J = 5.4 Hz, IH), 8.69 (d, J = 5.7 Hz, IH). |
16.9 g | for 6 h; Reflux | Compound 2 (23.8g, 140.7mmol) was dissolved in POC13 (200mL), the mixture was heated under reflux for 6h. After removal of most POC13 under pressure, the remaining reaction solution was slowly poured into ice/water while vigorously stirred yielding a gray precipitate. This was collected by filtration and air-dried to yield a gray solid 3 (16.9g). Yield 58.3percent. |
Yield | Reaction Conditions | Operation in experiment |
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61% | With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline at 125℃; for 22 h; | A solution of thienoyleneurea (6.0 g) and N,N-dimethylaniline (2.9 mL) in phosphorus oxychloride (35 mL) was heated at 125° C. (oil bath) for 22 h under argon. The solution cooled to 50° C. and was poured into cold water (0° C., 8.0 mL) while vigorously stirring. The precipitate was filtered, washed with water, and dissolved in EtOAc. The organic solution was filtered, washed with water, and the organic phase was dried over MgSO4, filtered and concentrated to afford a yellow precipitate (4.5 g, 61percent yield). |
Yield | Reaction Conditions | Operation in experiment |
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100% | at 100℃; | Preparation of 2,4-Dichloro-thieno[3,2-d]pyrimidineStep 1A 85 mg portion of thieno[3,2-d]pyrimidine-2,4-diol (0.5 mmol) is suspended in 1.25 mL POCl3. The mixture is heated at 100° C. overnight. POCl3 is removed under reduced pressure. The mixture is dissolved in dichloromethane and quenched with ice. The product is collected by extraction with dichloromethane (2.x.). The combined organic layers are dried over MgSO4 and concentrated to give the title compound in quantitative yield that was used in the next step without further purification. |
93% | for 14 h; Heating / reflux | 2,4-dichlorothieno[3,2-d]pyrimidine (III): 7.97 g (47.0 mmol) of thieno[3,2-d]pyrimidine-2,4-diol (II) is placed in 50 mL (54.5 mmol) of phosphorus oxychloride, then refluxed for 14 hours, with stirring. The mixture is then concentrated by evaporation, the residue is combined with ice water. The precipitate formed is suction filtered and dried. 9.00 g of product III (93percent) is obtained as a powder. |
80% | With 1-methyl-pyrrolidin-2-one; trichlorophosphate In tolueneReflux; Inert atmosphere | (see Scheme 1). To a suspension of theno[3,2-d]pyrimidine-2,4-diol (2) (8.0 g, 47.61 mmol) in toluene were added NMP (1.0 mL, catalytic) and POCl3 (35 mL) at room temperature. Following refluxing of the mixture tasted for 16 h. Upon completion of the reaction, excess of POCl3 was distilled off. The residue was poured into ice cold water and filtered off to give the compound 3 as off white solid, yield 80percent, mp 136–140 °C. 1H NMR spectrum, δ, ppm: 7.72 d (J = 5.5 Hz, 1H, ArH), 8.70 t (J = 4.4 Hz, 1H, ArH). ESI–MS: m/z: 204.9 [M + H]+. |
80% | With 1-methyl-pyrrolidin-2-one; trichlorophosphate In toluene for 16 h; Reflux | To a suspention of thieno[3,2-d]pyrimidine-2,4-diol (2) (8.0 g, 47.61 mmol) in toluene was added N-methyl-2-pyrrolidone(NMP) (1.0 mL, catalytic), followed by the addition and POCl3 (35 mL) at room temperature and heated to reflux for 16 h. After completion of reaction, excess POCl3 was removed by distillation, crude residue was poured into ice cold water and filtered the formed precipitate compound 3 as off white solid. Yield: 7.7g, 80 percent; m.p. 136-140 °C; 1H NMR (300 MHz, DMSO-d6): 8.70 (t, J = 4.4 Hz, 1H, ArH), 7.72 (d, J = 5.5 Hz,1H, ArH), ESI-MS: m/z, 204.9 (M+H)+. |
79% | With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 80 - 85℃; for 72 h; | 2,4-Dichlorothieno[3,2-i ]pyrimidine (15).; To a solution of 14 (500 mg, 2.97 mmol) and N,N-dimethylaniline (0.29 mL, 2.23 mmol) in MeCN (2.5 mL) cooled to 0 °C was slowly added POCI3 (1.4 mL, 14.9 mmol). The purple slurry was heated to 80-85 °C and stirred for 48 h. A second portion of POCI3 (1.0 mL) was added after 24 h. The resulting clear purple solution was poured into ice and water and stirred for 5 min. The slurry was filtered, and the solid was dried at 45 °C. The solid was dissolved in EtOAc, washed with sat. aq. NaHCC"3, and stirred with activated charcoal. The solution was filtered through Celite.(R). and concentrated to provide 15 (482 mg, 79percent) as a yellow solid: Mp 138.8-139.3 °C (H20); IR (ATR, neat) 3066, 3088, 1545, 1508, 1307, 1204, 798 cm"1; 1H NMR (DMSO-d6, 300 MHz) δ 8.70 (d, 1 H, J= 5.4 Hz), 7.74 (d, 1 H, J= 5.4 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 163.6, 154.8, 154.7, 142.4, 129.3, 124.1; HRMS (EI) m/z calcd for C6H2N2SCl2 203.9316, found 203.9312. |
74.4% | for 14 h; Heating / reflux | To a suspension of thieno[3,2-d]-pyrimidine-2,4-diol 1b (38.2 g, 227 mmol) in POCI3 (300 mL) was added dimethylaniline (8 mL). The mixture was refluxed for 14 h to give a homogenous solution. Excess of POCI3 was evaporated under vacuum. Chloroform EPO <DP n="61"/>(500 mL) was added to the oily residue and concentrated again. This process was repeated once. More chloroform (50 mL) was added and the suspension was slowly poured into ice-water (1.5 L) with vigorously stirring. After warming up to room temperature, the phases were separated. The precipitate in the aqueous phase was collected and dried to give a crude solid. The solid was dissolved in chloroform (500 mL) and insoluble impurities were removed by filtration. The filtrate was concentrated to give the title compound 1c as a yellow solid (34.7 g, 74.4percent). Rf: 0.32 (9:1 hexanes/ethyl acetate); Mp: 130-132 0C; APCI MS: m/z 206; H-NMR (300 MHz, DMSO-cfe): δ 8.12 (d, J = 5.46 Hz, 1 H), 7.55 (d, J = 5.46 Hz, 1H). |
60% | at 180℃; for 4 h; | A mixture of Example 1 (20 g, 119 mmol) in phenylphosphonic dichloride (120 ml, 850 mmol) was stirred and heated to 180 0C for 4 h. The resulting dark solution was cooled to 80 0C and transferred slowly by pipette onto stirred ice / water (800ml). After an hour of vigorous stirring, the yellow-orange precipitate was filtered off, washed and dried at 40 0C /. vac. The solid was dissolved in DCM (ca. 20 volumes). The solution was passed through a pad of silica and washed through with ethyl acetate : iso-hexane (1 :1 ). The filtrate was reduced /. vac. to yield 2,4-dichloro-thieno[3,2-d]pyrimidine (14.56 g, 60percent yield) as a yellow crystalline product. LC-MS: m/z = 205 [M+H+]; RT = 4.36 (LC-MS method 2) 1H-NMR: δH (400 MHz, d6-DMSO) 7.74 (1 H, d, J 5.52 Hz), 8.70 (1 H, d, J 5.52 Hz) |
51.2% | With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline for 3 h; | 2,4-Dihydroxythieno[3,2-d]pyrimidine (M1) (3.38 g, 0.020 mol) was added to the reaction flask.Phosphorus oxychloride (11.6 ml, 0.127 mol) was added.N,N-dimethylaniline (7.44 ml, 0.058 mol) was added dropwise with stirring at room temperature for 3 hours under reflux.Stop heating,Pour into 100ml of ice water.Precipitating a brownish black solid,Filtering,dry,Column chromatography (petroleum ether - ethyl acetate = 3: 1) to give a pale yellow solid 2.10g,The yield was 51.2percent. |
Yield | Reaction Conditions | Operation in experiment |
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100% | With hydrogen; sodium hydrogencarbonate In ethanol; ethyl acetate for 5 h; | 2,4-dichlorothieno[3,2-d]pyrimidine (3, 1.19 g, 5.8 mmol) was taken up in ethanol (25 mL) and ethyl acetate (25 mL) to form a mixture. NaHC03 (l . lg, 13.1 mmol), followed by 10percent Pd-C (0.206 g) were added to the mixture, and the mixture was stirred under hydrogen balloon for 5 h, after which product (4) was detected in the mixture by liquid chromatograpy-mass spectrometry (LCMS). The reaction mixture was then filtered through celite and concentrated to obtain an off white solid of 2-chlorothieno [3,2-d]pyrimidine (4, 0.990 g, quantitative). 'HNMR (CDC13): 9.17 (s, 1 H), 8.16-8.12 (d, 1 H), 7.55-7.51 (d, 1 H). |
96% | With hydrogen; sodium hydrogencarbonate In ethanol; ethyl acetate at 20℃; for 35 h; | To a solution of the dichloride (1 1.9g, 58mmol) in EtOAc (25OmL) and EtOH (25OmL) was added 10percent Pd/C (1.5g) and NaHCO3 (1 Ig, 130mmol). The reaction was evacuated to a hydrogen atmosphere and stirred at room temperature 16h. Further 10percentPd/C (560mg) and NaHCO3 (5.6g, 66mmol) were added and hydrogenation continued a further 19h. The solids were removed by filtration through celite, concentration of the filtrate then afforded the product as an off-white solid (9.5 Ig, 96percent). 1H NMR (CDCl3, 300 MHz): 9.14 (s, IH), 8.1 1 (d, J=5.7Hz, IH), 7.52 (d, J=5.4Hz, IH). |
90% | With hydrogen; sodium hydrogencarbonate In ethanol at 20℃; for 35 h; | 2-Chlorothieno[3,2-]pyrimidine (16).; To a solution of 15 (44.0 mg, 0.022 mmol) and NaHC03 (27.0 mg, 0.32 mmol) in EtOH (2.0 mL) was added 10percent Pd/C (8.90 mg, 20percent by wt). The suspension was stirred at room temperature under an atmosphere of H2 for 23 h. A second portion of 10percent> Pd/C (8.90 mg, 20percent> by wt) was added after 12 h. The reaction mixture was filtered through Celite.(R). with EtOAc washings. The filtrate was washed with H20/brine (4:1), dried (MgS04), and concentrated under reduced pressure to provide 16 (33.0 mg, 90percent) as white solid: Mp 164.9-165.5 °C (EtOAc); IR (ATR, neat) 3105, 3051, 2924, 1543, 1515, 1456, 1420, 1334, 1349, 1301, 1159, 794 cm"1; 1H NMR (DMSC fe 300 MHz) δ 9.50 (s, 1 H), 8.64 (d, 1 H, J= 5.4 Hz), 7.64 (d, 1 H, J= 5.4 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 162.7, 156.3, 155.3, 142.2, 130.1, 122.9; MS (EI) m/z 170 (M+, 100), 135 (72);HRMS (EI) m/z calcd for C6H3N2SC1 169.9705, found 169.9700. |
80% | With palladium 10% on activated carbon; hydrogen; N-ethyl-N,N-diisopropylamine In ethyl acetate for 5 h; | To a solution of 2,4-dichloro-thieno[3,2-d]pyrimidine 1 (300 mg, 1.46 mmol) in EtOAc, DIPEA (0.52 mL, 2.92 mmol) was added, followed by 10 percent Pd/C (300 mg) and the suspension shaken in a Parr hydrogenator at 45 psi of H2 pressure for 5 h. The reaction mixture was filtered over celite, the filtrate evaporated and the crude material loaded onto silica. The crude reaction mixture was purified using column chromatography eluting with 9:1 hexanes/EtOAc to obtain 5 as an off-white solid (200 mg, 1.17 mmol, 80 percent). Rf 0.1 in 9:1 hexanes/EtOAc. Mp 166.3–169.6 °C. 1H NMR (400 MHz, CDCl3): δ 7.47 (d, 1H, J=5.5Hz), 8.00 (d, 1H, J=5.0Hz), 9.11 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 123.8, 129.8, 139.1, 153.6, 157.5, 163.1. FAB-MS m/z for C6H3ClN2S calculated [M+H]+ 170.9778, found 170.9784 (35Cl), 170.9766 (37Cl). |
62.23% | With acetic acid; zinc In methanol at 70℃; for 3 h; | CompoundII-25 (20.51g, 0.1mol, 1.0eq.), Acetic acid (34.3mL, 0.6mol, 6.0eq.) Andmethanol(150mL) placed in a reaction flask was added portionwise at 25 to zinc dust (26.16g, 0.4mol, 4.0eq.), The addition was completed temperaturewas raised to 70 For 3hours, TLC the reaction was complete. Cooling, filtration and the filter cakewas washed twice with methanol, and the filtrate sand column chromatography toobtain compoundI-25 was 11.12g,63.23percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | With caesium carbonate In N,N-dimethylsulfoneamide at 20℃; for 1 h; | Preparation of 2-chloro-4-(3-nitrophenoxy)thieno[3,2- c/jpyrimidineThe compound (2.9 g, 14.2 mmol) obtained in Step 2 was dissolved in NN-dimethylsulfoneamide (70 mL), and 3-nitrophenol (1.9 g, 14.2 mmol) and cesium carbonate (9.2 g, 28.4 mmol) were added thereto, followed by stirring room temperature for 1 hour. After the reaction was complete, distilled water was added to the reaction mixture, and the resulting solid was filtered under a reduced pressure with washing with distilled water. The resulting solid was dried under a reduced pressure to obtain the title compound (yield: 4.0 g, 91.8 percent).1H-NMR (300MHz, CDC13) δ 8.25-8.17 (m, 2H), 8.08 (s, 1H), 7.69- 7.66 (m, 2H), 7.57 (d, 1H). |
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