| 74% |
Stage #1: thieno[3,2-b]pyridin-7-ol With trichlorophosphate In 1,1-dichloroethane for 2h; Heating / reflux;
Stage #2: With water monomer; Sodium hydrogenocarbonate In dichloromethane |
14.H
Step H: Preparation of 7-chlorothienor3,2-blpyridine: A mixture of thieno[3,2-b]pyridin-7-ol (2.50 g, 16.5 mmol) and POCl3 (3.1 mL, 33 mmol) in dichloroethane (10 mL) was stirred for 2 hours at reflux. The mixture was concentrated and the dark residue was resuspended in dichloromethane (50 mL). The solution was carefully neutralized with saturated NaHCO3 solution. The mixture was extracted with dichloromethane, dried over MgSO4, and concentrated to give the title compound (2.09 g, 74%) as a brown solid. |
| 72% |
With trichlorophosphate at 105℃; for 4h; |
A; 1; 1.1
A stirred suspension of thieno[3,2-b]pyridin-7-ol (1, 5.0 g, 33.1 mmol) in POCls(15 mL) was heated to 105°C in an oil bath for 4 hrs. The resultant solution was cooled toroom temperature and the POCls was removed under reduced pressure. The residue wascooled in an ice/water bath and cold water was added. The water was made basic withconcentrated NlrLtOH solution and extracted with EtOAc. The organic extract was driedover anhydrous sodium sulfate and concentrated to produce an oil which was purified bycolumn chromatography (eluent EtOAc-hexane, 1:4) to afford the title compound as abrown solid (4.5 g, 72% yield). .H NMR (400 MHz, CDC13) 8 (ppm): 8.60 (d, J= 4.9 Hz,1H), 7.80 (d, J= 5.5 Hz, 1H), 7.60 (d, J= 5.5 Hz, 1H), 7.30 (d, J= 4.9 Hz, 1H). |
| 72% |
With trichlorophosphate at 105℃; for 4h; |
1.2
Step 2. 7-Chlorothieno[3,2-b]pyridine (2) A stirred suspension of thieno[3,2-b]pyridin-7-ol; (5.0 g, 33.1 mmol) in POCl3 (15 mL) was heated at 105° C. in an oil bath for 4 hrs. The resultant solution was cooled to room temperature and the POCl3 was removed under reduced pressure. The residue was cooled in an ice/water bath and cold water was added. The mixture was made basic with concentrated NH4OH solution and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate and concentrated to produce oil, which was purified by column chromatography (eluent EtOAc-hexane, 1:4) to afford the title compound as a brown solid (4.5 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.60 (d, J=4.9 Hz, 1H), 7.80 (d, J=5.5 Hz, 1H), 7.60 (d, J=5.5 Hz, 1H), 7.30 (d, J=4.9 Hz, 1H). |
| 71% |
Stage #1: thieno[3,2-b]pyridin-7-ol With trichlorophosphate In 1,2-dichloro-ethane for 2h; Heating / reflux;
Stage #2: With Sodium hydrogenocarbonate In dichloromethane; water monomer for 0.5h; |
1.A
Example 1; Preparation of N-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide; Step A: Preparation of 7-chlorothieno[3,2-b]pyridine; To a stirred solution of POCl3 (28.6 mL, 313 mmol) in 1,2-dichloroethane (200 mL) was added commercially available thieno[3,2-b]pyridin-7-ol (94.7 g, 626 mmol) as a powder in one portion. The reaction was stirred for 2 hours at reflux under N2. The mixture was concentrated, using toluene (3×100 mL) to azeotrope. The dark residue was resuspended in CH2Cl2 (1 L), and a saturated aqueous solution of NaHCO3 (500 mL) was carefully added. The mixture was stirred for 30 minutes until bubbling had ceased. The biphase was separated, and the aqueous was re-extracted with CH2Cl2 (500 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated, to obtain a brown oil, which crystallized upon standing (38.4 g, 71%). 7-Chlorothieno[3,2-b]pyridine has also been prepared using oxalyl chloride (WO 99/24440). 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J=5 Hz, 1H), 7.80 (d, J=6 Hz, 1H), 7.60 (d, J=6 Hz, 1H), 7.29 (d, J=5 Hz, 1H). |
| 71% |
With oxalyl dichloride |
1.A
Example 1; Preparation of N-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide; Step A: Preparation of 7-chlorothieno[3,2-b]pyridine; To a stirred solution of POCl3 (28.6 mL, 313 mmol) in 1,2-dichloroethane (200 mL) was added commercially available thieno[3,2-b]pyridin-7-ol (94.7 g, 626 mmol) as a powder in one portion. The reaction was stirred for 2 hours at reflux under N2. The mixture was concentrated, using toluene (3×100 mL) to azeotrope. The dark residue was resuspended in CH2Cl2 (1 L), and a saturated aqueous solution of NaHCO3 (500 mL) was carefully added. The mixture was stirred for 30 minutes until bubbling had ceased. The biphase was separated, and the aqueous was re-extracted with CH2Cl2 (500 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated, to obtain a brown oil, which crystallized upon standing (38.4 g, 71%). 7-Chlorothieno[3,2-b]pyridine has also been prepared using oxalyl chloride (WO 99/24440). 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J=5 Hz, 1H), 7.80 (d, J=6 Hz, 1H), 7.60 (d, J=6 Hz, 1H), 7.29 (d, J=5 Hz, 1H). |
| 66% |
With trichlorophosphate at 105℃; for 2h; |
44-B.i
[001237] (i) Production of 7-chlorothieno[3,2-b]pyridine[001238] A mixture of thieno[3,2-b]pyridin-7-ol (3.8 g, 25 mmol) and phosphorus oxychloride (18 g,120 mmol) was stirred at 1050C for 2 hr. The reaction mixture was added to ice water, and basified with8N aqueous sodium hydroxide solution. Ethyl acetate was added, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane= 10/90- »30/70), and the obtained solution was concentrated under reduced pressure to give the title compound (2.8 g, 66%) as a pale-yellow solid.[001239] 1H-NMR (DMSOd6, 300 MHz) δ 7.59 (IH, d, J = 5.1 Hz), 7.69 (IH, d, J = 5.5 Hz), 8.28(IH, d, J = 5.5 Hz), 8.67 (IH, d, J = 5.1 Hz). |
| 60.5% |
With oxalyl dichloride In chloroform at 0 - 20℃; Heating / reflux; |
135.4
A 2-L, 3-neck, rb flask equipped with a mechanical overhead stirrer, a 250-mL addition funnel, and a thermocouple w/N2-inlet adapter was charged with thieno[3,2-b]pyridin-7-ol (144 g, 952 mmol), chloroform (700 mL) and anhydrous N,N-dimethylformamide (100 ml, 1297 mmol). The heterogeneous mixture was cooled in an ice bath with stirring, then oxalyl dichloride (166 ml, 1905 mmol) was added dropwise via the addition funnel. Towards the end of the addition, the exotherm had diminished so the remaining reagent was added more quickly, which resulted in rapid off- gassing and the eruption of a portion of the contents out of the vessel. Upon complete addition, the mixture was allowed to stir out for 2 h, at which point LC-MS analysis indicated only about 10% conversion to the desired product (71556-13-A). The ice bath was removed, and the mixture was heated to reflux with a mantle. The heterogeneous mixture quickly turned homogeneous upon reaching temperature, and LC-MS indicated complete conversion after 1 h (at) reflux (71556-13 -B). After standing at ambient temp over the weekend, an orange solid had formed from the dark brown supernate. The mixture was cooled in an ice bath, then diluted with MTBE (800 mL), resulting in the exothermic precipitation of copious amounts of a dense, mustard-brown solid. The solid was isolated by vacuum filtration and washed with MTBE until the filtrate was colorless to yield the solid and a cloudy, bright orange filtrate. The solid product was then carefully partitioned between DCM (1 L) and sat'd aq. NaHCO3 (1 L). The phases were mixed and the light brown aqueous layer was back extracted with DCM (500 mL). The combined organic layers were washed with sat'd brine, then dried over anhydrous Na2SO4. MTBE (500 mL) was added, then concentrated by about 200 mL, then hexane (500 mL) was added to form a dark brown precipitate. The mixture was further concentrated by 100 mL, then cooled in an ice bath. The mixture was then filtered and washed with hexane/MTBE (200 mL). The filtrate was then concentrated to dryness to yield the title compound as a light brown oil that crystallized to a dark rust colored, oily solid (97.7 g, 60.5% yield). EPO |
| 50% |
Stage #1: thieno[3,2-b]pyridin-7-ol With thionyl chloride at 80℃; for 4h;
Stage #2: With Sodium hydrogenocarbonate In water monomer; ethyl acetate |
76
Thieno [3, 2, b] pyridin-7-ol (200 mg; 1.32 mmol) was added to thionyl chloride (1.57 g; 13.2 mmol), followed by a drop of DMF. The solution was stirred at 80°C for 4 hours. The cooled solution was diluted with ethyl acetate and neutralised to pH 7 with a saturated solution of sodium hydrogen carbonate (25 ml). The organic layer was washed with brine, dried and concentrated to yield the title compound (112 mg; 50%); Mass Spectrum: M+H 170. |
|
With trichlorophosphate Heating; |
|
|
With trichlorophosphate |
|
| 16 g |
With N,N-dimethyl-formamide; trichlorophosphate In dichloromethane at 50℃; for 5h; |
1.1 Step 1:
Synthesis of 7-chlorothieno[3,2-b]pyridine (Compound 1b)
DMF (7.24 g) and phosphorus oxychloride (30.36 g) were added to a solution of Compound 1a (15 g) in DCM (60 mL) at room temperature. The reaction proceeded at an elevated temperature of 50°C for 5 hours. The reaction liquid was poured slowly into warm water and was adjusted to pH > 8 with sodium hydroxide. The organic layer from DCM extraction was dried and concentrated. Purification by column chromatography (Eluent System B) gave Compound 1b (16 g). MS (ESI, m/z): 170.1 [M+H]+. |
| 16 g |
With N,N-dimethyl-formamide; trichlorophosphate In dichloromethane at 50℃; for 5h; |
1.1 Step 1:
Synthesis of 7-chlorothieno[3,2-b]pyridine (Compound 1b)
DMF (7.24 g) and phosphorus oxychloride (30.36 g) were added to a solution of Compound 1a (15 g) in DCM (60 mL) at room temperature. The reaction proceeded at an elevated temperature of 50°C for 5 hours. The reaction liquid was poured slowly into warm water and was adjusted to pH > 8 with sodium hydroxide. The organic layer from DCM extraction was dried and concentrated. Purification by column chromatography (Eluent System B) gave Compound 1b (16 g). MS (ESI, m/z): 170.1 [M+H]+. |
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