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With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 105 - 110℃; Inert atmosphere
the 121g (leq) ELTA 1200ml and dimethylformamide (DMF) was stirred clear solution; sequentially added 323g (4eq) 2- chloroethyl methyl ether, 944g (8eq) of anhydrous potassium carbonate and 23.6gTetrabutylammonium bromide; purged with nitrogen three times,Under nitrogen, the reaction was heated to 105~110 ° C 13~14h; the filter cake was rinsed DCM until the filtrate was colorless; the combined filtrate was concentrated under reduced pressure to a fraction distilled off; the residue was added DCM, cooled to room temperature , washed with 3Ν K0H, the DCM phase was separated, washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to 45 ° C to give 210g oil ELTB, yield 96.4percent
70%
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 14 h;
To a solution of 3,4-dihydroxybenzaldehyde (10 g, 72.5 mmol) (Aldrich) in DMF (200 mL) was added 2-chloroethyl methyl ether (16.5 mL, 181.2 mmol) (Aldrich), potassium carbonate (50 g, 362.3 mmol) and a catalytic amount of potassium iodide (Aldrich). The reaction mixture was heated at 85° C. for 14 hours. The reaction mixture was cooled down, diluted with EtOAc and washed with brine. The organic phase was dried over anhydrous sodium sulfate, evaporated to afford 3,4-bis-(2-methoxy-ethoxy)-benzaldehyde as an oil and was used in the next step without further purification. (Yield 11 g, 70percent).
Reference：
[1] Patent: CN105566233, 2016, A, . Location in patent: Paragraph 0015; 0052
[2] Journal of Medicinal Chemistry, 1982, vol. 25, # 4, p. 435 - 440
[3] Patent: US2012/184548, 2012, A1, . Location in patent: Page/Page column 23; 24
2
[ 6482-24-2 ]
[ 139-85-5 ]
[ 80407-64-3 ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h;
a) 3,4-bis (2-methoxyethoxy) benzaldehyde:; To 3, 4-dihydroxy benzaldehyde of the formula Il (25g, 0.1811 mole), potassium carbonate (6Og, 0.4347 mole) in N, N-dimethyl formamide (120ml) was added 2-bromoethylmethyl ether (50.4g, 0.3625 mole). The mixture was stirred at 1000C for 2 hours, cooled to room temperature, filtered inorganics. The clear filtrate was concentrated under vacuum and the residue was dissolved in methylene chloride, washed with water and dried over calcium chloride. ^Evaporation yielded 3,4-bis (2-methoxyethoxy) benzaldehyde of formula III (45g, 98percent).NMR spectrum (CDCI3): δ 3.46 (s, 6H), 3.81 (m, 4H), 4.22 (m, 4H), 7.00(d, 1 H), 7.43(s, 1 H), 7.45(d, 1 H) and 9.83(s, 1 H).
98%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h;
a) 3,4-bis (2-methoxyethoxy) benzaldehyde:; To 3, 4-dihydroxy benzaldehyde of the formula Il (25g, 0.1811 mole), potassium carbonate (6Og, 0.4347 mole) in N, N-dmethyl formamide (120ml) was added 2-bromoethylmethyl ether (50.4g, 0.3625 mole). The mixture was stirred at 1000C for 2 hours, cooled to room temperature, filtered inorganics. The clear filtrate was concentrated under vacuum and the residue was dissolved in methylene chloride, washed with water and dried over calcium chloride. Evaporation yielded 3,4-bis (2- methoxyethoxy) benzaldehyde of formula III (45g, 98percent).NMR spectrum (CDCI3): δ 3.46 (s, 6H), 3.81 (m, 4H), 4.22 (m, 4H), 7.00(d, 1 H), 7.43(S1 1H)1 7.45(d, 1 H) and 9.83(s, 1 H).
With tetrabutylammomium bromide; potassium carbonate; In N,N-dimethyl-formamide; at 105 - 110℃;Inert atmosphere;
the 121g (leq) ELTA 1200ml and dimethylformamide (DMF) was stirred clear solution; sequentially added 323g (4eq) 2- chloroethyl methyl ether, 944g (8eq) of anhydrous potassium carbonate and 23.6gTetrabutylammonium bromide; purged with nitrogen three times,Under nitrogen, the reaction was heated to 105~110 C 13~14h; the filter cake was rinsed DCM until the filtrate was colorless; the combined filtrate was concentrated under reduced pressure to a fraction distilled off; the residue was added DCM, cooled to room temperature , washed with 3Nu K0H, the DCM phase was separated, washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to 45 C to give 210g oil ELTB, yield 96.4%
96.8%
With sodium iodide; In N,N-dimethyl-formamide;Reflux;
67.4 g of Intermediate 1 was charged into 337 ml of DMF, 115 g of <strong>[627-42-9]2-chloroethyl methyl ether</strong> and 3.5 g of sodium iodide were added, and the mixture was heated to reflux for 6-8 hours. The reaction solution was concentrated to dryness under reduced pressure. 337 ml of water was added, and the mixture was extracted 4 times with 270 ml of 4 EA.The combined organic layers were washed twice with 300 ml × 2 of saturated brine.After drying over anhydrous sodium sulfate, it was concentrated to dryness to give 120 g of Intermediate 2 (yield: 96.8%).
70%
With potassium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 85℃; for 14h;
To a solution of 3,4-dihydroxybenzaldehyde (10 g, 72.5 mmol) (Aldrich) in DMF (200 mL) was added <strong>[627-42-9]2-chloroethyl methyl ether</strong> (16.5 mL, 181.2 mmol) (Aldrich), potassium carbonate (50 g, 362.3 mmol) and a catalytic amount of potassium iodide (Aldrich). The reaction mixture was heated at 85 C. for 14 hours. The reaction mixture was cooled down, diluted with EtOAc and washed with brine. The organic phase was dried over anhydrous sodium sulfate, evaporated to afford 3,4-bis-(2-methoxy-ethoxy)-benzaldehyde as an oil and was used in the next step without further purification. (Yield 11 g, 70%).
With potassium carbonate In N,N-dimethyl-formamide at 100℃;
98%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2h;
a
a) 3,4-bis (2-methoxyethoxy) benzaldehyde:; To 3, 4-dihydroxy benzaldehyde of the formula Il (25g, 0.1811 mole), potassium carbonate (6Og, 0.4347 mole) in N, N-dimethyl formamide (120ml) was added 2-bromoethylmethyl ether (50.4g, 0.3625 mole). The mixture was stirred at 1000C for 2 hours, cooled to room temperature, filtered inorganics. The clear filtrate was concentrated under vacuum and the residue was dissolved in methylene chloride, washed with water and dried over calcium chloride. ^Evaporation yielded 3,4-bis (2-methoxyethoxy) benzaldehyde of formula III (45g, 98%).NMR spectrum (CDCI3): δ 3.46 (s, 6H), 3.81 (m, 4H), 4.22 (m, 4H), 7.00(d, 1 H), 7.43(s, 1 H), 7.45(d, 1 H) and 9.83(s, 1 H).
98%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2h;
a
a) 3,4-bis (2-methoxyethoxy) benzaldehyde:; To 3, 4-dihydroxy benzaldehyde of the formula Il (25g, 0.1811 mole), potassium carbonate (6Og, 0.4347 mole) in N, N-dmethyl formamide (120ml) was added 2-bromoethylmethyl ether (50.4g, 0.3625 mole). The mixture was stirred at 1000C for 2 hours, cooled to room temperature, filtered inorganics. The clear filtrate was concentrated under vacuum and the residue was dissolved in methylene chloride, washed with water and dried over calcium chloride. Evaporation yielded 3,4-bis (2- methoxyethoxy) benzaldehyde of formula III (45g, 98%).NMR spectrum (CDCI3): δ 3.46 (s, 6H), 3.81 (m, 4H), 4.22 (m, 4H), 7.00(d, 1 H), 7.43(S1 1H)1 7.45(d, 1 H) and 9.83(s, 1 H).
71%
Stage #1: 3,4-dihydroxybenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;
Stage #2: 2-Bromoethyl methyl ether In N,N-dimethyl-formamide at 100℃; for 5h; Inert atmosphere;
71%
Stage #1: 3,4-dihydroxybenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;
Stage #2: 2-Bromoethyl methyl ether In N,N-dimethyl-formamide at 100℃; for 5h; Inert atmosphere;
63%
Stage #1: 3,4-dihydroxybenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 23℃; for 1h; Inert atmosphere;
Stage #2: 2-Bromoethyl methyl ether In N,N-dimethyl-formamide at 100℃; for 5h; Inert atmosphere;
With HCl·DMPU; hydroxylamine hydrochloride In acetonitrile at 60℃;
94%
With trifluorormethanesulfonic acid; O-benzenesulfonyl-acetohydroxamic acid ethyl ester; acetic acid In dichloromethane at 23℃; for 48h; Inert atmosphere;
87.9%
With formic acid; hydroxylamine hydrochloride; sodium formate at 90 - 100℃; for 8h;
3 The third step: the synthesis of intermediate 3:
120 g of the intermediate 3 was placed in 240 ml of formic acid, 42.4 g of hydroxylamine hydrochloride and 67.5 g of sodium formate were added, and the mixture was heated to 90-100 ° C for 8 hours. Cool down to room temperature, add 960 ml of water, and extract 4 times with 360 ml × 4 EA.The combined organic layers were washed twice with 400 ml × 2 of saturated brine. After drying over anhydrous sodium sulfate, it was concentrated to dryness to give 104.3 g of Intermediate 3 (yield 87.9%).
Multi-step reaction with 2 steps
1: hydroxylamine hydrochloride; pyridine / methanol / Heating
2: acetic anhydride / 110 °C
With hydroxylamine hydrochloride; acetic anhydride
7 Example 7
Reaction of 3,4-dihydroxybenzaldehyde (i) with 2-chloroethyl methyl ether gives 3,4-bis(2-methoxyethoxy)benzaldehyde (ii),Then ii is treated with hydroxylamine hydrochloride and acetic anhydride to give 3,4-bis(2-methoxyethoxy)benzonitrile (iii).3,4-bis(2-methoxyethoxy)benzonitrile (iii) Nitration with concentrated nitric acid in acetic acid to give 2-nitro-3,4-bis(2-methoxyethoxy)benzonitrile(iv).2-Nitro-3,4-bis(2-methoxyethoxy)benzonitrile (iv) is oxidized with hydrogen peroxide to give 2-nitro-4,5-bis(2-methoxyethoxy)benzeneFormamide (v), then v-reduced with ammonium formate under Pd/C catalysis to give 2-amino-4,5-bis(2-methoxyethoxy)benzamide (vi). 2-amino-4,5-bis(2-methoxyethoxy)benzamide (vi) according to the actualThe description of Example 1 can be converted to 6,7-bis[(2-methoxy)-ethoxy]-quinazolinone (vii).6,7-bis [(2-methoxy)(Ethyl)-ethoxy]-quinazolinone (vii) is reacted with phosphorus oxychloride in triethylamine to give 4-chloro-6,7-bis(2-methoxyethoxy)Base) quinazoline (viii).4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (viii) with HCl as initiator in DMFReaction with 3-ethynylaniline can give erlotinib hydrochloride.
Multi-step reaction with 2 steps
1: hydroxylamine hydrochloride; sodium carbonate / dimethyl sulfoxide / 0.5 h / 20 °C
2: sodium carbonate; fluorosulfonyl fluoride / dimethyl sulfoxide / 12 h / 20 °C
With potassium carbonate; In acetone; at 25 - 30℃; for 6h;Reflux; Heating;
Example-12 Preparation of 3,4-bis-(2-methoxy-ethoxy)-benzaldehyde 80.0 g (0.57 mol) of 3,4-dihydroxy benzaldehyde and 800.0 ml of acetone were charged into 2.0 L4 necked round bottom flask, connect to a mechanical stirrer, thermo meter socket and condenser at 25-30 C. Reaction mass was stirred for 20 min.324.0 g (1.74 mol) of 1-iodo-2-methoxy-ethane and 240.0 g (1.70 mol) of potassium carbonate were charged. Reaction mass was heated to reflux. Reaction mass temperature was maintained at reflux for 6 hours. Reaction mass temperature was cooled to 25-30 C. and inorganic solid was filtered. Acetone was completely distilled under vacuum at below 60 C. Remaining mass was diluted with 400.0 ml of DM water. Compound was extracted with 400.0 ml of ethyl acetate and organic layer was dried with sodiumsulphate. Ethyl acetate was completely distilled under vacuum and finally applied high vacuum at below 60 C. 69.20 g of crude product (Oil) was obtained (yield: 47.0% by theory). Spectral Data:FT-IR:3448.5, 2932.7,2889.4, 2825.0, 1685.8, 1586.2, 1508.8, 1437.7, 1276.1, 11988.9, 1125.6, 1050.2, 810.4, 743.4, 653.6, 588.1.MS: 255.4[M+1]
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