| 94% |
With thionyl chloride; In N,N-dimethyl-formamide; for 24h;Reflux; |
3,4-Dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate (4 g, 17.1 mmol)Placed in 100mL conical flask,After adding 40 mL of thionyl chloride and 1 drop of DMF at room temperature,Heated to reflux for 24 hours;Most of the thionyl chloride was distilled off, ice water was added, filtered,After drying, 4-chloro-7-methoxyquinazolin-6-ol acetate (4.07 g) was obtained in a yield of 94% |
| 90.2% |
With thionyl chloride; In N,N-dimethyl-formamide; at 90℃; for 2h; |
Adding (7-methoxy-4-oxo-3,4-dihydroquinazoline)-6- obtained in Step 1 to a 50 mL round bottom flask Base-acetate (1 g), thionyl chloride (15 mL), N,N-dimethylformamide (75 muL) was reacted at 90 C for 2 h. The reaction was complete by TLC. After the reaction system was cooled to room temperature, the system was steamed under reduced pressure, and after spin-drying, 30 mL of ice water was added to a round bottom flask under ice-water bath, and stirred vigorously. The suspension was then transferred to a separatory funnel and extracted with 60 mL of chloroform and 30 mL of saturated aqueous sodium chloride. After the obtained chloroform solution is dried, sodium sulfate is removed by filtration, and the chloroform solution is evaporated under reduced pressure to give 4-chloro-7-methoxyquinazoline-6-yl acetate as a white solid. The yield was 90.2%. |
| 90% |
With thionyl chloride; N,N-dimethyl-formamide; at 85℃; for 5h; |
6-acetoxy-7-methoxy-4-oxo-3,4-dihydroquinazoline(3.0g, 12.87mmol) dissolved in thionyl chloride (45 mL, 64.36 mmo), DMF (5 mL) was added to help dissolve. The mixture was heated to reflux at 85 C for 5 hours. Cool to room temperature, remove the solvent and thionyl chloride under reduced pressure, and pour the residue into ice water (50 mL).Filtration, washing the solid with petroleum ether (50 mL) and drying under reduced pressure.Obtained a white solid (2.9 g, 90%).Go directly to the next step. |
| 86.1% |
With thionyl chloride; In N,N-dimethyl-formamide; for 2h;Reflux; |
6-carbethoxy-7-methoxy-4 (3H) -quinazolinone (5 g, 21.4 mmol) was added to the reactor,Thionyl chloride, 0.5 mL of N, N-dimethylformamide was added, and the mixture was heated to reflux for 2 hours. After completion of the reaction, thionyl chloride was removed by rotary evaporation, and saturated sodium hydrogencarbonate solution was added to the residue under ice-water bath and stirred until no gas evolved. The mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the solvent was removed by rotary evaporation to give 5.23 g of 4-chloro-6-ethoxycarbonyl-7-methoxy-4 (3H) -quinazoline as a pale yellow solid in a yield of 86.1%. |
| 85.4% |
With trichlorophosphate; In toluene; for 6h;Reflux; |
In a 100 ml reaction flask by adding 6-acetoxy-7- [...] -4-one (4g, 0.017mol), phosphorus oxychloride (24 ml), toluene (34 ml), slow heating, heating to reflux, the reaction 6h. After the reaction is ended, revolving off a solvent and phosphorus oxychloride, adding proper amount of crushed ice, intense stirring, chloroform extraction (3×25 ml), combined with the phase, using saturated NaHCO 3 washing (3×25 ml), the resulting the resulting solid with toluene is recrystallized to get white solid, yield 85.4%. |
| 84% |
With oxalyl dichloride; for 4h;Reflux; |
200 g (0.85 mol) of the compound of the formula I was added to a 2 L three-necked flask, 1.5 L of oxalyl chloride was added, and the mixture was heated to reflux for 4 hours, and the reaction was monitored by HPLC. The haloyl chloride was evaporated, and 0.5 L of dichloromethane was added to carry out the residual oxalyl chloride to give a crude VII. Further, 0.5 L of dichloromethane was added to dissolve the crude VII, washed once with a saturated aqueous solution of sodium hydrogencarbonate (400 mL) and brine (400 mL), and the organic phase was dried over anhydrous sodium sulfate. Methane, the remaining liquid is poured into about 2LThe crystals were stirred and stirred in n-hexane. Filtration, collection of solid, drying at 50 C to give a pale yellow compound of formula VII 180 g, a molar yield of 84%, purity 98%. |
| 77% |
With thionyl chloride; In N,N-dimethyl-formamide; for 3h;Reflux; |
A suspension of 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (1) (2.34 g) in SOCl2 (30 mL) and DMF (0.5 mL) was refluxed for 3 h. After that, the mixture was concentrated under reduced pressure to give 4-chloro-7-methoxyquinazolin-6-yl acetate (2). Yellow powder, yield: 77%. 1H NMR (300 MHz; d6-DMSO): 2.08 (s, 3H); 3.73 (s, 3H); 7.55 (s, 1H); 7.50 (s, 1H); 9.44 (s, 1H). MS (ESI+) m/z 253.6 (M + H)+. |
| 65% |
With trichlorophosphate; for 3h;Heating / reflux; |
A mixture of 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-yl acetate (0104) (2.0 g,8.5 mmol) and phosphoryl trichloride (20 ml) was stirred and heated to reflux for 3 hours. When a clear solution was obtained, the excessive phosphoryl trichloride was removed under reduced pressure. The residue was dissolved in dichloromethane (50ml) and the organic layer was washed with aqueous NaHCO3 solution (20ml><2) and brine (2OmIx 1) and dried over MgSO4, filtered and evaporated to give the title product 0105 as a yellow solid (IAg, 65%): LCMS: m/z 249[M+1]+; 1H NMR(CDCl3.) delta 2.40 (s, 3H), 4.03 (s, 3H), 7.44 (s, IH), 7.90 (s, IH), 8.95 (bs, IH). |
| 65% |
With trichlorophosphate; for 3h;Heating / reflux; |
A mixture of 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-yl acetate (0104) (2.0 g,8.5 mmol) and phosphoryl trichloride (20 ml) was stirred and heated to reflux for 3 hours. When a clear solution was obtained, the excessive phosphoryl trichloride was removed under reduced pressure. The residue was dissolved in dichloromethane (50ml) and the organic layer was washed with aqueous NaHCO3 solution (20ml><2) and brine (2OmIx 1) and dried over MgSO4, filtered and evaporated to give the title product 0105 as a yellow solid (IAg, 65%): LCMS: m/z 249[M+1]+; 1H NMR(CDCl3.) delta 2.40 (s, 3H), 4.03 (s, 3H), 7.44 (s, IH), 7.90 (s, IH), 8.95 (bs, IH). |
| 65% |
With trichlorophosphate; for 3h;Heating / reflux; |
Step 1h. 4-Chloro-7-methoxyquinazolin-6-yl acetate (Compound 110) A mixture of compound 109 (2.0 g, 8.5 mmol) and phosphoryl trichloride (20 mL) was stirred and heated to reflux for 3 hours. When a clear solution was obtained, the excessive phosphoryl trichloride was removed under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with aqueous NaHCO3 solution (20 mL*2) and brine (20 mL*1) and dried over MgSO4, filtered and evaporated to give the title product 110 as a yellow solid (1.4 g, 65%): LCMS: 253 [M+1]+. |
| 65% |
With trichlorophosphate; In dichloromethane; for 3h;Heating / reflux; |
Step 1d. 4-Chloro-7-methoxyquinazolin-6-yl acetate (Compound 0105) A mixture of 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-yl acetate (0104) (2.0 g, 8.5 mmol) and phosphoryl trichloride (20 ml) was stirred and heated to reflux for 3 hours. When a clear solution was obtained, the excessive phosphoryl trichloride was removed under reduced pressure. The residue was dissolved in dichloromethane (50 ml) and the organic layer was washed with aqueous NaHCO3 solution (20 ml*2) and brine (20 ml*1) and dried over MgSO4, filtered and evaporated to give the title product 0105 as a yellow solid (1.4 g, 65%): LCMS: m/z 249 [M+1]+; 1H NMR (CDC3.) delta 2.40 (s, 3H), 4.03 (s, 3H), 7.44 (s, 1H), 7.90 (s, 1H), 8.95 (bs, 1H). |
| 65% |
|
Step 1d. 4-Chloro-7-methoxyquinazolin-6-yl Acetate (Compound 0105); A mixture of 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-yl acetate (0104) (2.0 g, 8.5 mmol) and phosphoryl trichloride (20 ml) was stirred and heated to reflux for 3 hours. When a clear solution was obtained, the excessive phosphoryl trichloride was removed under reduced pressure. The residue was dissolved in dichloromethane (50 ml) and the organic layer was washed with aqueous NaHCO3 solution (20 ml×2) and brine (20 ml×1) and dried over MgSO4, filtered and evaporated to give the title product 0105 as a yellow solid (1.4 g, 65%): LCMS: m/z 249[M+1]+; 1H NMR (CDC3) delta 2.40 (s, 3H), 4.03 (s, 3H), 7.44 (s, 1H), 7.90 (s, 1H), 8.95 (bs, 1H). |
| 60% |
With thionyl chloride; N,N-dimethyl-formamide; at 100℃; for 3h;Inert atmosphere; |
The 1000 ml thionyl chloride (SOCl 2) placed in 2000 ml of the four protection of nitrogen in neck circle bottom flask, slowly dropping 10mLDMF catalytic (20 minutes drops end), adding 100g7-methoxy-4-oxo -3,4-dihydric quinazoline-6-yl ester, 100 C lower stirring 3 hours. Reaction fluid ice-bath cooling to room temperature, concentrated under reduced pressure to dry with 1000 ml of methylene chloride is dissolved, into 1000 ml ice water. Dichloromethane is used for extraction mixed solution 2 time, combined with the organic layer, washing with saturated sodium chloride aqueous solution 3 times. Separating the organic layer in the 250 ml triangular flask adding anhydrous sodium sulfate for drying 6 hours, vacuum filtration. Filtrate concentrated to dry, by ether washing, 65g (yield 60%) of compound 1, as a pale yellow powder. |
| 60% |
With thionyl chloride; N,N-dimethyl-formamide; at 100℃; for 3h;Inert atmosphere; |
The 1000mL thionyl chloride (of SOCl2) placed in the nitrogen 2000mL four-neck round bottom flask, was slowly added dropwise 10mLDMF catalytic (20 minutes after the dripping) was added 4-oxo-3,4-methoxy 100g7- dihydro-quinazolin-6-yl acetate, followed by stirring at 100 3 hours. The reaction solution was ice-cooled to room temperature, concentrated under reduced pressure was dissolved in 1000mL of methylene chloride to dryness, poured into ice-water 1000mL. Mixture was extracted twice with methylene chloride, the organic layers combined, washed with saturated aqueous sodium chloride solution three times. The separated organic layer was dried over anhydrous sodium sulfate was added 6 hours in a 250mL Erlenmeyer flask, filtered under reduced pressure. The filtrate was concentrated under reduced pressure to dryness, washed with diethyl ether to give 65g (60% yield) of Compound 1 as a pale yellow powder |
| 60% |
With thionyl chloride; N,N-dimethyl-formamide; at 100℃; for 3h;Inert atmosphere; |
The 1000mL thionyl chloride (of SOCl2) placed2000mL of nitrogen four-neck round bottom flask was slowly dropped 10mLDMF catalysis (20 minutes drops End), was added 100g7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yl acetate, followed by stirring at 100 3 hours. The reaction solution was cooled to ice bath temperature, concentrated under reduced pressure was dissolved in 1000mL of methylene chloride to dryness, poured into ice water 1000mL. Mixture was extracted twice with methylene chloride, the organic layers combined, washed with saturated aqueous sodium chloride solution three times. The separated organic layer was dried over anhydrous sodium sulfate was added 6 hours in a 250mL Erlenmeyer flask, filtered under reduced pressure. The filtrate was concentrated under reduced pressure to dryness, washed with diethyl ether to give 65g (60% yield) of Compound 1 as a pale yellow powder. |
| 60% |
With thionyl chloride; In N,N-dimethyl-formamide; at 100℃; for 3h;Inert atmosphere; |
The 1000mL thionyl chloride (of SOCl2) Was placed in a nitrogen 2000mL four-neck round bottom flask, was slowly added dropwise (2ml / min) 10mLDMF catalyzed 100g7- was added 4-oxo-3,4-dihydro-methoxy-quinazolin-6-yl acetate, 100 stirred for 3 hours.The reaction solution was ice-cooled to room temperature, concentrated under reduced pressure was dissolved in 1000mL of methylene chloride to dryness, poured into ice-water 1000mL.Mixture was extracted twice with methylene chloride, the organic layers combined, washed with saturated aqueous sodium chloride solution three times.The separated organic layer was dried over anhydrous sodium sulfate was added in a 250mL flask and dried for 6 hours and filtered under reduced pressure.The filtrate was concentrated under reduced pressure to dryness, washed with diethyl ether to give 65g (60% yield) of Compound 1 as a pale yellow powder. |
| 60% |
With thionyl chloride; In N,N-dimethyl-formamide; at 100℃; for 3h;Inert atmosphere; |
1000 mL of thionyl chloride (SOCl2) was placed in a 2000 mL nitrogen blanketed four-necked round bottom flask and 10 mL of DMF was slowly added dropwise over 20 minutes. 100 g7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate was stirred at 100 C for 3 hours. The reaction solution was ice-cooled to room temperature, concentrated under reduced pressure to dryness, dissolved in 1000 mL of methylene chloride, and poured into 1000 mL of ice water. The mixture was extracted twice with dichloromethane, and the combined organic layers were washed three times with a saturated aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous sodium sulfate for 6 hours in a 250 mL Erlenmeyer flask, and filtered under reduced pressure. The filtrate was concentrated to dryness under reduced pressure and washed with diethyl ether to give 65 g (60% yield) of Compound 1 as a pale yellow powder. |
| 48% |
With thionyl chloride; N,N-dimethyl-formamide; for 2h;Inert atmosphere; Reflux; |
Under argon, quinazolinone 9 (1.79?g, 7.64?mmol) was dissolved in thionyl chloride (14.5?mL) and DMF (73.0?muL) was added. The mixture was stirred 2?h?at reflux then toluene was added and removed under vacuum. The product was purified by flash column chromatography using hexane/EtOAc (85:15) to afford 10 as a cream solid (923?mg, 48%). Mp: 157-159?C; IR (ATR, ZnSe): nu (cm-1) 2986, 1755, 1619, 1559, 1432, 1350, 1203, 1145, 1015, 912, 809, 703; 1H NMR (500?MHz, CDCl3): delta (ppm) 8.95 (s, 1H), 7.90 (s, 1H), 7.43 (s, 1H), 4.02 (s, 3H), 2.40 (s, 3H). 13C NMR (126?MHz, CDCl3): delta (ppm) 168.7, 161.0, 157.4, 154.3, 151.7, 142.5, 119.0, 118.6, 108.3, 56.8, 20.7; HRMS-ESI calcd for C11H10ClN2O3 [M+H]+ 253.0375 found 253.0381. |
|
With thionyl chloride; N,N-dimethyl-formamide; at 85℃; for 1.5h;Product distribution / selectivity; |
Step 6. Product step 5 (8.54 mmol) was converted into 4-chloro-7-hydroxy-6-methoxyquinazoline or 4-chloro-6-hydroxy-7-methoxyquinazoline, respectively, (58-95%) by reacting them with thionyl chloride (12 mL) and DMF (0.3 mL) at 85 C for 1.5 h. Excess thionyl chloride was removed by distillation. Traces of thionyl chloride were removed by aceotropic distillation wit toluene (two times). Alternatively the products step 5 can be converted into the chlorides by reacting them with a mixture of POCl3 and PCl5. The acetyl groups were removed by hydrolysis with ammonium hydroxide (5 mL, 28-30 wt%) in dioxane / water (100 mL / 20 mL) at 0 C to r.t. |
|
With thionyl chloride; In DMF (N,N-dimethyl-formamide); at 90℃; for 4h; |
The 4-amino-7-methoxy-6-(3-piperidinopropoxy)quinazoline used as a starting material was prepared as follows :- A mixture of 6-acetoxy-7-methoxyquinazolin-4-one (International Patent Application WO 96/15118, Example 39 thereof; 15 g), thionyl chloride (215 ml) and DMF (4.3 ml) was stirred and heated to 90 C. for 4 hours. The mixture was cooled to ambient temperature and the thionyl chloride was evaporated. The material so obtained was dissolved in toluene and the solution was washed with a saturated aqueous sodium bicarbonate solution. The organic No. solution was dried over magnesium sulphate and evaporated. There was thus obtained 6-acetoxy-4-chloro-7-methoxyquinazoline (14.8 g) which was used without further purification. A mixture of a portion (5 g) of the material so obtained, diphenylmethyleneamine (3.75 g), caesium carbonate (25.67 g) and xylene (200 ml) was stirred at ambient temperature for 30-minutes. Racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.227 g) and palladium diacetate (0.221 g) were added and the mixture was stirred and heated to 135 C. for 16 hours. The mixture was cooled to ambient temperature and diethyl ether (600 ml) was No. added. The mixture was filtered and the filtrate was evaporated. There was thus obtained N-diphenylmethylene-6-acetoxy-7-methoxyquinazolin-4-amine (7.12 g); Mass Spectrum: M + H+ 398. A mixture of a portion (3.09 g) of the material so obtained, concentrated ammonium hydroxide solution (0.88 g/ml approximately 14M; 60 ml) and methanol (120 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated. Toluene (200 ml) was added and the mixture was evaporated again. The residue was triturated under diethyl ether (50 ml). There was thus obtained N-diphenylmethylene-6-hydroxy-7-methoxyquinazolin-4-amine (0.93 8 g); Mass Spectrum: No. M + H+ 356. A mixture of the material so obtained, 3-piperidinopropyl chloride (0.55 g), potassium carbonate (1.46 g) and DMF (50 ml) was stirred and heated to 65 C. for 16 hours. The resultant mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic solution was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated The residue was purified by column No. chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained N-dphenylmethylene-6-(3-piperidinopropoxy)-7-methoxyquinazolin-4-amine (0.277 g); NMR Spectrum: (DMSOd6) 1.3 (br s, 2H), 1.42 (br s, 4H), 1.88 (t, 2H), 2.28 (br s, 4H), 2.38 (t, 2H), 3.92 (s, 3H), 4.07 (t, 2H), 7.0 (s, 1H), 7.23 (s, 1H), 7.2-7.65 (br m, 10H), 8.62 (s, 1H); Mass Spectrum: M + H+ 481. A mixture of the material so obtained, 3N aqueous hydrochloric acid solution (2 ml) and THF (14 ml) was stirred at ambient temperature for 3 hours. The mixture was evaporated and the residue was treated with a 2N aqueous sodium hydroxide solution (10 ml). The resultant precipitate was isolated, washed with water (10 ml) and dried under vacuum. There was thus obtained 4-amino-7-methoxy-6-(3-piperidinopropoxy)quinazoline (0.202 g); NMR Spectrum: No. (DMSOd6) 1.36 (br s, 2H), 1.47(br s, 4H), 1.93 (t, 2H), 2.25-2.43 (br m, 6H), 3.88 (s, 3H), 4.05 (t, 2H), 7.04 (s, 1H), 7.35 (br s, 2H), 7.55 (s, 1H), 8.23 (s, 1H); Mass Spectrum: M + H+ 317. |
|
With thionyl chloride; |
Example 30 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(3-(4-morph olino)propoxy)-7-methoxy-quinazoline 6,7-dimethoxy-quinazolone was reacted with methanesulfonic acid and L-methionine under reflux for 2 h, and then the mixture was poured into ice water to deposit a solid, which is 6-hydroxy-7-methoxy-quinazolone intermediate. After the hydroxyl group therein was protected by acylation, the intermediate was treated with SOCl2 to obtain 4-chloro-6-acetoxy-7-methoxy-quinazoline. |
|
N,N-dimethyl-formamide; In thionyl chloride; |
Step 3 4-Chloro-7-methoxyquinazolin-6-yl acetate: A catalytic amount of N,N-dimethylformamide was added to a solution of 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (2.7 g, 11.53 mmol, 1.00 equiv) in thionyl chloride (35 mL). The resulting solution was stirred at about 83 C. for about 1 hour, and then was cooled to ambient temperature and thionyl chloride was removed by evaporation. The title product was isolated as a hydrochloride salt (5.0 g, (crude)). |
|
|
A mixture of 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (8.7 g, 0.037 mol), thionyl chloride (120 ml, 1.65mol) and DMF(I ml) was stirred and heated to 55 0C for 6 hours. The mixture was cooled to room temperature and thionyl chloride was evaporated. The solid was dissolved in chloroform and the solution was washed with sodium bicarbonate and brine, the chloroform was evaporated under reduced pressure to give 7.9 g of a gray product. MS (ESI) m/z: 253 (M+l). |
|
With thionyl chloride; In N,N-dimethyl-formamide; at 70℃; for 3h; |
A suspension of 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (2.00 g), DMF (0.20 mL) and thionyl chloride (30 mL) was stirred at 70 C for 3 h. The mixture was concentrated in vacuo, and the residue was used for the next step without further purification. |
|
With thionyl chloride; In N,N-dimethyl-formamide; at 70℃; for 3h; |
A suspension of 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (2.00 g), DMF (0.20 mL) and thionyl chloride (30 mL) was stirred at 70 C. for 3 h. The mixture was concentrated in vacuo, and the residue was used for the next step without further purification. |
|
With triethylamine; trichlorophosphate; In toluene; at 80℃; for 4h; |
Amixture of 1 (1.0 g, 4.27 mmol), triethylamine (1.2 mL, 8.66 mmol) and phosphorus oxychloride (1.2 mL, 13.11 mmol) in toluene (15 mL) was heated to 80 C for 4 h, which directly to the next step reaction without purification. |
|
With triethylamine; trichlorophosphate; In acetonitrile; at 80℃; |
10g of compound GG4 placed 40ml of acetonitrile, followed by adding 8.3 g of phosphorus oxychloride, 5.4 g of triethylamine, and the reaction was heated to 80 C, the reaction was complete after TLC monitoring |
|
With thionyl chloride; for 2.5h;Reflux; |
20 ml of thionyl chloride was added to the intermediate M-1 (2.34 g, 10 mmol)Reflux for 2.5 hours. Evaporated under reduced pressureThionyl chloride,Dichloromethane extraction,Dried over anhydrous sodium sulfate,The crude product obtained by spin-removing the solvent was intermediate M-2 (2.22 g, 88%). |
|
With thionyl chloride; N,N-dimethyl-formamide; at 85℃; for 1.5h;Product distribution / selectivity; |
Step 6. Product step 5 (8.54 mmol) was converted into 4-chloro-7-hydroxy-6-methoxyquinazoline or 4-chloro-6-hydroxy-7-methoxyquinazoline, respectively, (58-95%) by reacting them with thionyl chloride (12 mL) and DMF (0.3 mL) at 85 C. for 1.5 h. Excess thionyl chloride was removed by distillation. Traces of thionyl chloride were removed by aceotropic distillation wit toluene (two times). Alternatively the products step 5 can be converted into the chlorides by reacting them with a mixture of POCl3 and PCl5. The acetyl groups were removed by hydrolysis with ammonium hydroxide (5 mL, 28-30 wt %) in dioxane/water (100 mL/20 mL) at 0 C. to r.t. |
|
With phosphorus pentachloride; trichlorophosphate;Product distribution / selectivity; |
Step 6. Product step 5 (8.54 mmol) was converted into 4-chloro-7-hydroxy-6-methoxyquinazoline or 4-chloro-6-hydroxy-7-methoxyquinazoline, respectively, (58-95%) by reacting them with thionyl chloride (12 mL) and DMF (0.3 mL) at 85 C. for 1.5 h. Excess thionyl chloride was removed by distillation. Traces of thionyl chloride were removed by aceotropic distillation wit toluene (two times). Alternatively the products step 5 can be converted into the chlorides by reacting them with a mixture of POCl3 and PCl5. The acetyl groups were removed by hydrolysis with ammonium hydroxide (5 mL, 28-30 wt %) in dioxane/water (100 mL/20 mL) at 0 C. to r.t. |
| 25 g |
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In toluene; at 70 - 100℃; for 3.5h; |
23.4 g of 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate,39g DIEA, 280mL of toluene addedIn a 1000 mL reaction bottle,Warm up to 70 C, heat stirring for 0.5 h,Add 45g of phosphorus oxychloride,Then heat up to 90 ~ 100 C,Stirring at this temperature for 3 h,After the TLC reaction was completed, the mixture was cooled to room temperature, concentrated to dryness under reduced pressure, and finally 50 mL of ethanol was added and stirred at room temperature for 0.5 h.Filtering,Then drying at 40 to 50 C to obtain 25 g of compound 2; |
| 21.5 g |
With thionyl chloride; In N,N-dimethyl-formamide; at 80℃; for 6h; |
6-Hydroxy-7-methoxy-4-ketoquinazoline (20 g, 0.11 mol, ie compound B1), acetic anhydride (150 mL, 1.6 mol) and pyridine (20 mL, 0.25 mol) were sequentially added to a 500 mL circle In the bottom flask, after heating to 100 C for 1 h, add 4-dimethylaminopyridine (0.9 g, 0.0073piomicron 1), continue the reaction for 5 h, stop the reaction, evaporate acetic anhydride under reduced pressure, and add cold to the reaction solution. The saturated sodium carbonate solution (500 mL) was stirred, suction filtered, and the filter cake was transferred to a round bottom flask and stirred with a large amount of ice water, suction filtered, and the filter cake was washed with distilled water until RhoEta = 7, and dried to give a yellow-white solid ( Compound B2). This was sequentially added to a 500 mL three-neck round bottom flask with thionyl chloride (190 mL, 2.0 mol), and the mixture was heated to 80 C for reflux for 20 min, and N,N-dimethylformamide was slowly added from a constant pressure dropping funnel. (4.4 mL, 0.52 eq) was added dropwise to the reaction mixture. After reacting for 6 h, the reaction was stopped, cooled, and the thionyl chloride was recovered under reduced pressure. Toluene was added with stirring, and toluene was added under reduced pressure. Toluene (250 mL) was added to the reaction mixture and stirred for about 1 h, dichloromethane (120 mL*2) Extract and separate the organic layer,Wash with water (80 mL * 2), dry over anhydrous sodium sulfate, and dilute dichloromethane under reduced pressure.Obtained 21.5 g of an off-white solid, yield: 81.9%. |
|
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In toluene; at 75℃; for 3h; |
At 75 C, phosphorus oxychloride (5 mL) was added dropwise to a solution of compound 6 (5 g) and DIPEA (4.13 ml) in toluene (45 ml) over 20 min. After the addition was completed, the reaction mixture was stirred at the current temperature. 3hrs. After the reaction is completed, it is directly put into the next step |
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