* 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.
Example 17. Example 2 was repeated except that the nitration reaction temperature was 70 °C. 1) Nitrification reaction: 200 g of raw material is dissolved in 3 L of glacial acetic acid to dissolve as material I, concentrated sulfuric acid is used as material II, and concentrated nitric acid is used as material III.Adjust the flow rate of the flow pump so that the flow rate of the material I is 20 ml/min, and the flow rate of the material II is 10 ml/min.The flow rate of the material III is 6 ml/min, the molar ratio of the raw material to the HNO3 is 1:1.5, and the mass ratio of the concentrated nitric acid to the concentrated sulfuric acid is 1:4.The reaction temperature is 60 ° C, the residence time of the reaction is 60 seconds, and the temperature of the cooling module is 20 ° C.Collecting the reaction liquid flowing out from the outlet of the cooling module for post-treatment, which means that glacial acetic acid is recovered by distillation under reduced pressure.The residue was added to 1.2 L of water and extracted twice with 1 L of ethyl acetate.The organic phase is washed with a saturated sodium hydrogencarbonate solvent until neutral, dried over anhydrous sodium sulfate, and then evaporated.The nitrated product was obtained in 215.21 g, the yield was 90.58percent, and the purity was 98.95percent.
90%
at 40℃; for 2 h;
c) 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile:; To 70percent nitric acid (84ml) maintained at 4O0C was added 3,4-bis(2- methoxyethoxy) benzonitrile (42g) of the formula V slowly over a period of 2 hours under stirring. After complete addition of the compound, stirring continued for further an hour, quenched the reaction mass in ice-water, filtered, washed the precipitate with water and dried the material at 500C to get yellow solid i.e. 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile of the formula Vl (44.5g, 90percent); m.p. 139-143°C.NMR (CDCI3): δ 3.45 (s, 6H), 3.82(m, 4HO, 4.30(m, 4H), 7.28(s, 1H) and 7.85(s, 1 H).
90%
at 40℃; for 3 h;
c) 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile:; To 70percent nitric acid (84ml) maintained at 4O0C was added 3,4-bis(2- methoxyethoxy) benzonitrile (42g) of the formula V slowly over a period of 2 hours under stirring. After complete addition of the compound, stirring continued for further an hour, quenched the reaction mass in ice-water, filtered, washed the precipitate with water and dried the material at 500C to get yellow solid i.e. 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile of the formula Vl (44.5g, 90percent); m.p. 139-143°C.NMR (CDCI3): δ 3.45 (s, 6H), 3.82(m, 4HO, 4.30(m, 4H), 7.28(s, 1H) and 7.85(s, 1 H).
47%
at 20 - 50℃; for 48 h;
Nitric acid (65 percent, 16.2 g, 254.5 mmol) was dropwise added directly into flask containing 3,4-bis(2-methoxyethoxy)benzonitrile (12.8 g, 50.9 mmol). The mixture was then heated with stirring to 50 °C until starting material was completely dissolved. After stirring for two days at RT the reaction mixture was dissolved with water (50 ml) and formed precipitate was filtered off and washed with water (100 ml). After crystallization from chloroform the title compound was obtained in form of white crystals (7.1 g, 47 percent). Spectral data were in agreement with literature.Chandregowda, Venkateshappa; Rao, Gudapati Ventakeswara; Reddy, Goukanapalli Chandrasekara Heterocycles, 2007 , vol. 71, 1 p. 39 - 48.
47%
at 20 - 50℃;
Nitric acid (65 percent, 16.2 g, 254.5 mmol) was dropwise added directly into flask containing 3,4- bis(2-methoxyethoxy)benzonitrile (12.8 g, 50.9 mmol). The mixture was then heated with stirring to 50 °C until starting material was completely dissolved. After stirring for two days at RT the reaction mixture was dissolved with water (50 ml) and formed precipitate was filtered off and washed with water (100 ml). After crystallization from chloroform the title compound was obtained in form of white crystals (7.1 g, 47 percent). Spectral data were in agreement with literature. Chandregowda, Venkateshappa; Rao, Gudapati Ventakeswara; Reddy, Goukanapalli Chandrasekara Heterocycles, 2007 , vol. 71 , 1 p. 39 - 48.
Reference：
[1] Patent: CN108358798, 2018, A, . Location in patent: Paragraph 0055; 0065; 0075; 0085; 0094-0099; 0102
[2] Patent: WO2007/138612, 2007, A2, . Location in patent: Page/Page column 10
[3] Patent: WO2007/138613, 2007, A2, . Location in patent: Page/Page column 11-12
[4] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 3, p. 909 - 914
[5] Heterocycles, 2007, vol. 71, # 1, p. 39 - 48
[6] Patent: EP2769723, 2014, A1, . Location in patent: Paragraph 0150-0151
[7] Patent: WO2014/128206, 2014, A1, . Location in patent: Page/Page column 48-49
[8] Patent: CN106957274, 2017, A, . Location in patent: Paragraph 0051-0054
[9] Patent: CN107445907, 2017, A, . Location in patent: Paragraph 0062; 0063; 0064; 0065
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 3, p. 909 - 914
9
[ 819813-71-3 ]
[ 236750-65-5 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 3, p. 909 - 914
10
[ 99-50-3 ]
[ 236750-65-5 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 3, p. 909 - 914
11
[ 121-33-5 ]
[ 236750-65-5 ]
Reference：
[1] Patent: CN106957274, 2017, A,
12
[ 4421-08-3 ]
[ 236750-65-5 ]
Reference：
[1] Patent: CN106957274, 2017, A,
13
[ 236750-65-5 ]
[ 950596-58-4 ]
Yield
Reaction Conditions
Operation in experiment
90.42%
With palladium 10% on activated carbon; hydrogen In methanol at 90℃; for 0.00833333 h;
Example 30. Example 1 was repeated, which differs from Example 1 in that the nitration product has a catalytic reaction residence time of 30 s. 2) catalytic hydrogenation reaction: 200 g of the nitrification product obtained in the previous step is dissolved in 5 L of anhydrous methanol,Subsequently, 10 g of a Pd/C catalyst having a Pd content of 10percent is added, and the mixture is stirred and mixed to form a material IV.H2 is used as material V, and the flow rate of the slurry pump is adjusted so that the flow rate of the material IV is 40.0 g/min, and the flow rate of the gas flow meter is adjusted to 700 ml/min.The molar ratio of nitro compound to H2 is 1:3.5, the reaction temperature is 90 ° C, the temperature of the cooling module is 25 ° C, and the residence time of the reaction is 25 s.The reaction pressure is 1.5 MPa, and the reaction liquid flowing out from the outlet of the cooling module is collected for post-treatment.The post-treatment means that the catalyst Pd/C is recovered by filtration, the organic solvent is recovered by distillation under reduced pressure, and the residue is added with 1.2 L of acetone to stir the solvent.Add 450 ml of concentrated hydrochloric acid, stir and crystallize for 1 h, filter, and put the filter cake into 2 L of water.Add 2mol/L NaOH solution to adjust the pH of the system to about 8.0, and add 2L of ethyl acetate to extract twice.Add 1 L of ethyl acetate each time and combine the organic phases.After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give an amine product of 160.83 g,yield: 8.077percent, purity 99.43percent.
Reference：
[1] Organic Process Research and Development, 2007, vol. 11, # 5, p. 813 - 816
[2] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 3, p. 909 - 914
[3] Patent: CN108358798, 2018, A, . Location in patent: Paragraph 0052; 0057; 0067; 0077; 0087; 0112-0119; 0123
[4] Patent: WO2007/138612, 2007, A2, . Location in patent: Page/Page column 10-11
[5] Patent: WO2007/138613, 2007, A2, . Location in patent: Page/Page column 10-11
[6] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 689 - 697
Stage #1: 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile With sodium dithionite In water; ethyl acetate at 20 - 55℃; for 1.16667h;
Stage #2: With hydrogenchloride In water; ethyl acetate at 60 - 65℃;
Step-a) Preparation of 4, 5-bis (2-methoxyethoxy)-2-aminobenzonitrile
Charged first lot of 4,5-bis-(2-methoxyethoxy)-2-nitrobenzo nitrile (100 gm) of the compound of formula (A), Purified water (1682 ml) and sodium dithionite (187 gm) at 20-30° C. in a reaction flask. Stirred the reaction mass for 5-10 min. Charged second lot (48 gm) of 4, 5-bis-(2-methoxyethoxy)-2-nitrobenzo nitrile of the compound of formula (A) at 20-30° C. Added purified water (18 ml) at 20-30° C. The reaction mixture was heated at 50-55° C. and maintained this temperature for 1.0 hr. Raised the temperature of reaction mass to 60-65° C. Added conc hydrochloric acid (208.4 ml) in 45-60 min at 60-65° C. Stirred the reaction mass for 30 min. at 60-65° C. The reaction mass was cooled down to 15-20° C. and used sodium hydroxide solution (215 ml) to adjust the pH of the reaction mass to 10-12. Raised the temperature of reaction mass to 25-30° C. (if not in range). Charged ethyl acetate (804 ml) and stirred for 30 min at 25-30° C. and separate the organic layer. The aqueous layer was extracted two times with ethyl acetate (350 ml). Combined all three ethyl acetate layers and charged purified water (252 ml) for washing. Stirred for 30 min at 30° C. and separate the organic layer. Washed the organic layer with brine solution (504 ml). Stirred the mass for 30 min at 30° C. Add activated Charcoal (10 g) and stirred for 30 min at 25-30° C. Filtered the mass through hyflo and washed by ethyl acaetate (196 ml). Distilled out ethyl acetate under vacuum below 55° C. Cooled the residue to 25-30° C. Charged hexane (400 ml) and stirred for 1 hr at 30° C. Filtered and washed by 47 ml ethyl acetate. Dried the material for 12 hrs at 50-55° C. (0074) Yield: Dry wt 85 gm (95%)
90%
Stage #1: 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile With sodium dithionite In water at 50℃; for 3h;
Stage #2: With hydrogenchloride In water at 65℃; for 0.5h;
90.42%
With 10% Pd/C; hydrogen In methanol at 90℃; for 0.00833333h;
30
Example 30. Example 1 was repeated, which differs from Example 1 in that the nitration product has a catalytic reaction residence time of 30 s. 2) catalytic hydrogenation reaction: 200 g of the nitrification product obtained in the previous step is dissolved in 5 L of anhydrous methanol,Subsequently, 10 g of a Pd/C catalyst having a Pd content of 10% is added, and the mixture is stirred and mixed to form a material IV.H2 is used as material V, and the flow rate of the slurry pump is adjusted so that the flow rate of the material IV is 40.0 g/min, and the flow rate of the gas flow meter is adjusted to 700 ml/min.The molar ratio of nitro compound to H2 is 1:3.5, the reaction temperature is 90 ° C, the temperature of the cooling module is 25 ° C, and the residence time of the reaction is 25 s.The reaction pressure is 1.5 MPa, and the reaction liquid flowing out from the outlet of the cooling module is collected for post-treatment.The post-treatment means that the catalyst Pd/C is recovered by filtration, the organic solvent is recovered by distillation under reduced pressure, and the residue is added with 1.2 L of acetone to stir the solvent.Add 450 ml of concentrated hydrochloric acid, stir and crystallize for 1 h, filter, and put the filter cake into 2 L of water.Add 2mol/L NaOH solution to adjust the pH of the system to about 8.0, and add 2L of ethyl acetate to extract twice.Add 1 L of ethyl acetate each time and combine the organic phases.After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give an amine product of 160.83 g,yield: 8.077%, purity 99.43%.
90.2%
With molybdenum(IV) oxide; hydrazine hydrate; pyrographite In ethanol at 20℃; for 7h; Green chemistry;
15 Preparation of 2-Amino-4,5-bis(2-methoxyethoxy)benzonitrile
Example 15 Preparation of 2-Amino-4,5-bis(2-methoxyethoxy)benzonitrile 2.96 g (10 mmol) of 2-nitro-4,5-bis (2-methoxyethoxy) benzonitrile, 38.4 mg (0.3 mmol) of MoO2, 0.12 g of activated carbon and 30 mL of ethyl alcohol were added into a 50 mL flask. Then 1.88 g (30 mmol) of hydrazine hydrate (80%) was added dropwise at room temperature and reacted at room temperature for 7 hours until TLC analysis showed the raw materials were reacted completely and then filtered, concentrated filtrate, extracted with 20 mL of ethyl acetate and 10 mL of water, the obtained organic phase was washed and concentrated to near dry, slurryed with petroleum ether, finally, get 2.4 g of light yellow solid, the molar yield was 90.2%, HPLC purity was 99%. 1HNMR data: 1HNMR (400 MHz, CDCl3) δ: 7.41 (s, 1H), 7.04 (s, 1H), 3.61-3.66 (m, 4H), 2.47-2.55 (m, 4H), 3.24 (s, 3H), 3.21 (s, 3H).
90.2%
With molybdenum(IV) oxide; pyrographite; hydrazine hydrate In ethanol at 20℃; for 7h;
15 Example 15: Synthesis of 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile
A 4 ml 5-neck flask was charged with 2.96 g (10 mmol) of 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile, 38.4 mg (0.3 mmol) of molybdenum dioxide, and 0.12 g of activated carbon. 30 ml of absolute ethanol was added dropwise to a solution of hydrazine hydrate (80%) at a temperature of 1.88 g (30 mmol). After the reaction was completed at room temperature for 7 h, TLC monitoring showed that the reaction was completed, filtered, and the filtrate was concentrated, then ethyl acetate (20 mL) and water (10 ml) were added and extracted. The organic phase was washed with water and concentrated to near dryness, slurried with petroleum ether to give 2.4g desired product as a pale yellow solid, yield 90.2%, HPLC purity 99%.
Stage #1: 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile With iron; acetic acid In water at 30℃; for 2.5h;
Stage #2: In water
d
(d) 2-amino-4, 5-bis (2-methoxyethoxy) benzonitrile:; To 4,5-bis (2-methoxyethoxy)-2-nitrobenzonitrile(10 g) was added acetic acid (75ml) and water(75ml), stirred the reaction mass for about 10 min, added Iron powder (7g) in portions over a period of 2hrs, Stirred the reaction mixture for about Vz hr at 300C adjusted PH of the reaction mass to 7. Extracted the material into ethylacetate, the organic layer was dried over sodium sulfate and concentrated to yield crystalline yellow solid. Which was further recrystallized from methanol (6g) mp 74-77 0C1HNMR (CDCI3): δ 3.43(s, 6H), 3.73(m, 4H), 4.08(m, 4H), 4.20(brs, 2H), 6.25(s, 1 H), 6.90(s, 1 H)
Stage #1: 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile With sodium dithionite In ethanol; water at 50℃; for 1.5h;
Stage #2: With hydrogenchloride In water at 70 - 80℃; for 2h;
4.1.1 General procedure for the synthesis of 3a-3i
General procedure: A mixture of 2 (0.01mol) in water (15mL) and ethanol (15mL) was stirred and heated up to 50°C. Na2S2O4 (0.03mol) was added within an hour. The resultant mixture was stirred for about 30min. Then concentrated HCl (8mL) was added slowly in 2hat 70-80°C. The mixture was cooled to 25°C and adjusted pH to 9-11 with 20% sodium hydroxide (100mL). The obtained mixture was extracted with ethyl acetate (3×60mL) and the combined organic extracts were washed with water (2×100mL) and brine (1×100mL), then dried over anhydrous Na2SO4. The organic solvent was evaporated to give compound 3 as green yellow solid (yield 66-89%).
With nitric acid In dichloromethane at 20℃; for 12h;
4 The fourth step: the synthesis of intermediate 4:
04.3 g of the intermediate 4 was poured into 208 ml of dichloromethane, and 41.3 g of fuming nitric acid was added dropwise at room temperature, and the reaction was carried out for 12 hours at room temperature.208 ml of water was added, filtered, washed with water and dried to give 115 g of Intermediate 4 (yield: 93.5%).
92.33%
With sulfuric acid; nitric acid; acetic acid at 70℃; for 0.0166667h;
17
Example 17. Example 2 was repeated except that the nitration reaction temperature was 70 °C. 1) Nitrification reaction: 200 g of raw material is dissolved in 3 L of glacial acetic acid to dissolve as material I, concentrated sulfuric acid is used as material II, and concentrated nitric acid is used as material III.Adjust the flow rate of the flow pump so that the flow rate of the material I is 20 ml/min, and the flow rate of the material II is 10 ml/min.The flow rate of the material III is 6 ml/min, the molar ratio of the raw material to the HNO3 is 1:1.5, and the mass ratio of the concentrated nitric acid to the concentrated sulfuric acid is 1:4.The reaction temperature is 60 ° C, the residence time of the reaction is 60 seconds, and the temperature of the cooling module is 20 ° C.Collecting the reaction liquid flowing out from the outlet of the cooling module for post-treatment, which means that glacial acetic acid is recovered by distillation under reduced pressure.The residue was added to 1.2 L of water and extracted twice with 1 L of ethyl acetate.The organic phase is washed with a saturated sodium hydrogencarbonate solvent until neutral, dried over anhydrous sodium sulfate, and then evaporated.The nitrated product was obtained in 215.21 g, the yield was 90.58%, and the purity was 98.95%.
90%
With nitric acid at 40℃; for 2h;
c
c) 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile:; To 70% nitric acid (84ml) maintained at 4O0C was added 3,4-bis(2- methoxyethoxy) benzonitrile (42g) of the formula V slowly over a period of 2 hours under stirring. After complete addition of the compound, stirring continued for further an hour, quenched the reaction mass in ice-water, filtered, washed the precipitate with water and dried the material at 500C to get yellow solid i.e. 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile of the formula Vl (44.5g, 90%); m.p. 139-143°C.NMR (CDCI3): δ 3.45 (s, 6H), 3.82(m, 4HO, 4.30(m, 4H), 7.28(s, 1H) and 7.85(s, 1 H).
90%
With nitric acid at 40℃; for 3h;
c
c) 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile:; To 70% nitric acid (84ml) maintained at 4O0C was added 3,4-bis(2- methoxyethoxy) benzonitrile (42g) of the formula V slowly over a period of 2 hours under stirring. After complete addition of the compound, stirring continued for further an hour, quenched the reaction mass in ice-water, filtered, washed the precipitate with water and dried the material at 500C to get yellow solid i.e. 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile of the formula Vl (44.5g, 90%); m.p. 139-143°C.NMR (CDCI3): δ 3.45 (s, 6H), 3.82(m, 4HO, 4.30(m, 4H), 7.28(s, 1H) and 7.85(s, 1 H).
90%
With nitric acid In acetic acid at 0℃; for 4h;
85%
With nitric acid In acetic acid at 45 - 50℃; for 8h;
47%
With nitric acid at 20 - 50℃; for 48h;
4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile
Nitric acid (65 %, 16.2 g, 254.5 mmol) was dropwise added directly into flask containing 3,4-bis(2-methoxyethoxy)benzonitrile (12.8 g, 50.9 mmol). The mixture was then heated with stirring to 50 °C until starting material was completely dissolved. After stirring for two days at RT the reaction mixture was dissolved with water (50 ml) and formed precipitate was filtered off and washed with water (100 ml). After crystallization from chloroform the title compound was obtained in form of white crystals (7.1 g, 47 %). Spectral data were in agreement with literature.Chandregowda, Venkateshappa; Rao, Gudapati Ventakeswara; Reddy, Goukanapalli Chandrasekara Heterocycles, 2007 , vol. 71, 1 p. 39 - 48.
47%
With nitric acid at 20 - 50℃;
4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile
Nitric acid (65 %, 16.2 g, 254.5 mmol) was dropwise added directly into flask containing 3,4- bis(2-methoxyethoxy)benzonitrile (12.8 g, 50.9 mmol). The mixture was then heated with stirring to 50 °C until starting material was completely dissolved. After stirring for two days at RT the reaction mixture was dissolved with water (50 ml) and formed precipitate was filtered off and washed with water (100 ml). After crystallization from chloroform the title compound was obtained in form of white crystals (7.1 g, 47 %). Spectral data were in agreement with literature. Chandregowda, Venkateshappa; Rao, Gudapati Ventakeswara; Reddy, Goukanapalli Chandrasekara Heterocycles, 2007 , vol. 71 , 1 p. 39 - 48.
Stage #1: 3,4-bis(2-methoxyethoxy)-benzonitrile With acetic acid at 20℃;
Stage #2: With nitric acid at 5 - 55℃;
1.4 (4) Fourth stage:Synthesis of 4,5-bis (2-methoxyethoxy) -2-nitrobenzene acetonitrile
3,4-bis (2-methoxyethoxy) benzeneacetonitrile from the vacuum dryer D0301 enters the reactor R0401,With stirring into the amount of glacial acetic acid, 3,4-bis (2-methoxyethoxy) benzene acetonitrile to be fully dissolved at room temperatureReactor R0401 access to the jacket cold saline, to maintain the reaction solution was 5 , and then slowly drop concentrated nitric acid,Until the concentration of concentrated nitric acid is added dropwise, the reaction kettle was heated to 55 ° C for reaction; 5-6 hours after the reaction,Sampling port 04001 sampling analysis qualified, the reaction liquid into the stirred tank by the material P0401 R0402,While stirring into the process water, a large amount of solid product was precipitated, the solid-liquid mixture was sent to the filter F0401 by the pump P0402, the filtrate into the acid wastewater recovery tank V0401, the filter cake was washed with process water, sampling port 04002 take water to detect the pH to meet the requirements You can stop the cake washing; cake from the exit into the vacuum dryer D0401,After drying, the product 4,5-bis (2-methoxyethoxy) -2-nitrophenylacetonitrile was obtained.
With nitric acid
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.
Stage #1: 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile With iron(III) chloride; hydrazine hydrate In methanol; water for 3h; Heating;
Stage #2: formic acid With hydrogenchloride In water at 90 - 130℃; Further stages.;
Multi-step reaction with 3 steps
1.1: sodium dithionite / water / 3 h / 50 °C
1.2: 0.5 h / 65 °C
2.1: acetic acid; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C
3.1: acetic acid / toluene / 5 h / 60 °C
Multi-step reaction with 2 steps
1.1: sodium dithionite / water / 3 h / 50 °C
1.2: 0.5 h / 65 °C
2.1: acetic acid; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal / toluene / 4 h / 105 °C
Multi-step reaction with 2 steps
1: sodium dithionite / water / 2.5 h / 50 °C
2: acetic acid / toluene / 3 h / 105 °C / Dean-Stark
With dihydrogen peroxide; potassium carbonate; sodium hydroxide In ethanol; water at 0 - 20℃;
4,5-bis(2-methoxyethoxy)-2-nitrobenzamide
4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile (6.6 g, 23.3 mmol) was dissolved in ethanol. Then K2CO3 (0.5 g, 3.5 mmol) and NaOH (35.0 ml, 1M solution in water) were added. The resulting mixture was cooled to 0° C and then hydrogen peroxide (46.0 ml, 30% solution in water) was added dropwise with vigorous stirring. The reaction mixture was aged at RT overnight then water (100 ml) was added. Extraction with ethyl acetate afforded crude product (6.1 g, 83 %) which was used in the next reaction without additional purification. Spectral data were in agreement with literature.
With dihydrogen peroxide; potassium carbonate; sodium hydroxide In ethanol; water at 0 - 20℃;
4,5-bis(2-methoxyethoxy)-2-nitrobenzamide
4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile (6.6 g, 23.3 mmol) was dissolved in ethanoL Then 2C03 (0.5 g, 3.5 mmol) and NaOH (35.0 ml, 1M solution in water) were added. The resulting mixture was cooled to 0° C and then hydrogen peroxide (46.0 ml, 30% solution in water) was added dropwise with vigorous stirring. The reaction mixture was aged at RT overnight then water (100 ml) was added. Extraction with ethyl acetate afforded crude product (6.1 g, 83 %) which was used in the next reaction without additional purification. Spectral data were in agreement with literature.
With dihydrogen peroxide
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: potassium carbonate; sodium hydroxide; dihydrogen peroxide / ethanol; water / 0 - 20 °C
2: palladium on activated charcoal; ammonium formate / ethanol / 2 h / Reflux
Multi-step reaction with 2 steps
1: sodium hydroxide; dihydrogen peroxide; potassium carbonate / ethanol; water / 0 - 20 °C
2: ammonium formate; palladium on activated charcoal / ethanol / 2 h / Reflux
With hydrazine hydrate In water at 20 - 30℃; for 3h;
1.1 1) Synthesis of compound II (2-amino-4,5-bis (2-methoxyethoxy) benzamide)
(A mixture of 214 g of compound I (4,5-bis (2-methoxyethoxy) -2-nitrobenzonitrile)Raney Ni 50g was suspended in about 2 L of water, mechanically stirred,500 mL of an aqueous solution containing 141 mL of hydrazine hydrate was added dropwise, and the mixture was added dropwise to room temperature (about 20 to 30 ° C) for 3 hours, and TLC was monitored until completion of the reaction. Add sodium hydroxide solution Ph value to 11-12 between,Add about 2L dichloromethane extraction 2 times, organic phase saturated salt water washing, anhydrous sodium sulfate drying, steaming,A crude product of 170 g of compound II was obtained in a yield of 83%.
Multi-step reaction with 2 steps
1: dihydrogen peroxide
2: palladium on activated charcoal; ammonium formate
Multi-step reaction with 3 steps
1.1: sodium dithionite / ethanol; water / 1.5 h / 50 °C
1.2: 2 h / 70 - 80 °C
2.1: acetic acid / 0.25 h / 35 - 40 °C
3.1: acetic acid / 0.25 h / 130 °C
Stage #1: 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile With palladium on activated charcoal; hydrogen In ethanol at 20℃; for 2.5h;
Stage #2: With hydrogenchloride In ethanol; water
1.5 (5) Fifth stage:Synthesis of 4,5-bis (2-methoxyethoxy) -2-aminophenylacetonitrile hydrochloride
4,5-bis (2-methoxyethoxy) -2-nitrophenylacetonitrile coming out of the vacuum drier D0401 was fed to the hydrogenation reduction reactor R0501, and then an appropriate amount of catalyst Pd / C was added thereto, while stirring Solvent anhydrous ethanol,Stirred at room temperature for 30min, vacuum hydrogenation reactor R0501 vacuum operation, and then into the hydrogen,Maintain the reactor pressure 50psi, stirred at room temperature for 2h, at the sampling port 05001 sampling test after passing,The reaction solution was sent to the filter F0501 by the material pump P0501 to remove the catalyst Pd / C,The filtrate into the salt reactor R0502, while stirring while dropping 12mol / L of concentrated hydrochloric acid,Sampling port 05002 sampling analysis, stop dropping concentrated hydrochloric acid, the reactor R0502 after the vacuum was heated,The solvent was evaporated under reduced pressure to remove the absolute ethanol, the solvent anhydrous ethanol into the anhydrous ethanol recovery tank V0501,The solid product is the product 4,5-bis (2-methoxyethoxy) -2-aminophenylacetonitrile hydrochloride.
Stage #1: 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile With iron(III) chloride; pyrographite; hydrazine hydrate In methanol for 4h; Reflux;
Stage #2: With water; potassium hydroxide for 12h; Reflux;
5 The fifth step: Synthesis of Intermediate 5:
115 g of the intermediate 4 was placed in 690 ml of methanol, and 11.5 g of activated carbon, 5.8 g of ferric chloride and 47.6 g of 80% hydrazine hydrate were added, and the mixture was heated to reflux for 4 hours.After hot filtration, the filtrate was concentrated to dryness under reduced pressure, and 690 ml of water and 230 g of potassium hydroxide were added, and the mixture was warmed to reflux for 12 hours.The temperature was lowered to room temperature, and hydrochloric acid was added dropwise to adjust the pH to 3-4, filtered and dried to give 102 g of Intermediate 5 (yield: 92.1%).
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