* 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.
General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 °C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2*2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 .x. 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 .x. 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22.
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 264 - 273
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2794 - 2809
[3] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 51, p. 566
[4] Journal of Organic Chemistry, 1952, vol. 17, p. 149,153
[5] Patent: US2004/102450, 2004, A1, . Location in patent: Page/Page column 70
[6] Chemistry and Biodiversity, 2018, vol. 15, # 6,
2
[ 2305-36-4 ]
[ 25171-19-1 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 1759,1765
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 461 - 467
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5141 - 5156
[4] Patent: WO2017/69980, 2017, A1,
[5] Antimicrobial Agents and Chemotherapy, 2017, vol. 61, # 6,
[6] Patent: WO2018/33082, 2018, A1,
3
[ 27329-27-7 ]
[ 2305-36-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With palladium 10% on activated carbon; hydrogen In ethanol at 20℃;
Toasolutionof2-nitro-4-methylbenzoicacid(500mg,2.76mmol)inEtOH(5.50mL) was added 10percent palladium on charcoal (8percent w/w). The reaction mixture wassequentiallyevacuatedandpurgedwithhydrogenthreetimesthenstirredunderhydrogenat approximately atmospheric pressure and room temperature. The reaction wasmonitored by TLC and upon completion the catalyst was filtered off through a pad ofCeliteTM.Thesolventwasremovedinvacuotogive2-amino-4-methylbenzamide(416mg,2.75mmol,quant.)asawhiteamorphoussolid;mp181–183°C,lit.177–179°C.
Reference：
[1] Synthesis (Germany), 2017, vol. 49, # 1, p. 135 - 144
[2] Organic Letters, 2012, vol. 14, # 6, p. 1444 - 1447
[3] Journal of Organic Chemistry, 2016, vol. 81, # 19, p. 9046 - 9074
[4] American Chemical Journal, 1888, vol. 10, p. 474,483
[5] Chemische Berichte, 1888, vol. 21, p. 1998
[6] Patent: CN105503646, 2016, A, . Location in patent: Paragraph 0004; 0006; 0007
4
[ 53078-85-6 ]
[ 2305-36-4 ]
Yield
Reaction Conditions
Operation in experiment
59%
With tert.-butyl lithium In hydrogenchloride; diethyl ether; water; pentane
a. 2-Amino-4-methylbenzoic acid To a cold (-78° C.) stirred solution of 2-bromo-5-methylaniline (10.0 g, 53.7 mM) in anhydrous ethyl ether (500 mL) under a nitrogen atmosphere was added t-butyllithium (127 mL of 1.7M solution, 214.8 mM) in pentane over a 15 min period during which time the temperature of the reaction was not allowed to exceed -65° C. After stirring at -78° C. for an additional 1.5 hr, the reaction mixture was quenched with an excess of crushed Dry Ice (solid CO2). After the Dry Ice had evaporated, water was added to the reaction mixture and the organic layer was separated and discarded. The aqueous layer was acidified with iN hydrochloric acid and then extracted with two portions of ethyl acetate. The combined extracts were dried (MgSO4), filtered and concentrated to provide the title amino acid (4.8 g, 59percent) as a tan crystalline solid; MS(CI): 152 (M+H).
Reference：
[1] Patent: US5599814, 1997, A,
5
[ 81115-52-8 ]
[ 62-53-3 ]
[ 103-84-4 ]
[ 2305-36-4 ]
Yield
Reaction Conditions
Operation in experiment
0.12 g
at 20 - 110℃; for 10 h;
Aniline (0.18 g, 2 mmol) was added into a solution of 2-acetylamino-4-methylbenzoic acid (0.19 g, 1 mmol) in toluene(10 mL) at room temperature. The mixture was stirred and refluxed for 10 h at 110°C. The solvent was evaporated under reduced pressure. The mixture was separated by column chromatography to give 2-amino-4-methylbenzoic acid (3, 0.10 g)and N-acetylaniline (4, 0.12 g). 2-Amino-4-methylbenzoic acid (3)16: Mp: 188.2–189.6°C.1H NMR (400 MHz, CDCl3) δ 7.81(d, J = 8.0Hz), 6.51–6.48(m,2H), 2.28(s, 3H). Its 1H NMR data and melting point were consistent with those of standard sample.N-acetylaniline (4)17: Mp: 117.8–118.8°C. 1H NMR(400 MHz, CDCl3) δ 7.65 (br, 1H, NH), 7.50(d, 2H, J =8.0Hz), 7.30(t, 2H, J = 8.0Hz), 7.09(t, 1H, J = 7.4Hz), 2.15(s,3H). Its 1H NMR data and melting point were consistent with those of standard sample.
Reference：
[1] Phosphorus, Sulfur and Silicon and the Related Elements, 2017, vol. 192, # 9, p. 1040 - 1047
6
[ 33900-96-8 ]
[ 2305-36-4 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1953, vol. 23, p. 1028,1030; engl. Ausg. S. 1077, 1079
[2] Zhurnal Obshchei Khimii, 1953, vol. 23, p. 606,609; engl. Ausg. S. 629, 632
7
[ 1128-47-8 ]
[ 2305-36-4 ]
Reference：
[1] Chemische Berichte, 1925, vol. 58, p. 1467
8
[ 39549-79-6 ]
[ 2305-36-4 ]
Reference：
[1] Chemische Berichte, 1888, vol. 21, p. 1539[2] Journal fuer Praktische Chemie (Leipzig), 1889, vol. <2> 40, p. 15
9
[ 26830-96-6 ]
[ 2305-36-4 ]
Reference：
[1] Chemische Berichte, 1888, vol. 21, p. 1539[2] Journal fuer Praktische Chemie (Leipzig), 1889, vol. <2> 40, p. 15
10
[ 26830-95-5 ]
[ 2305-36-4 ]
Reference：
[1] American Chemical Journal, 1888, vol. 10, p. 474,483
Reference：
[1] Chemische Berichte, 1925, vol. 58, p. 1467
13
[ 2305-36-4 ]
[ 1829-21-6 ]
Reference：
[1] Chemische Berichte, 1893, vol. 26, p. 1733
[2] Journal of Organic Chemistry, 2017, vol. 82, # 4, p. 2263 - 2268
[3] Advanced Synthesis and Catalysis, 2018, vol. 360, # 19, p. 3709 - 3715
14
[ 2305-36-4 ]
[ 93012-36-3 ]
Reference：
[1] Helvetica Chimica Acta, 1946, vol. 29, p. 922,924
15
[ 2305-36-4 ]
[ 81335-87-7 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1929, p. 583
[2] Angewandte Chemie, International Edition, 2014, vol. 53, # 36, p. 9603 - 9607,5[3] Angewandte Chemie, 2014, vol. 126, # 36, p. 9757 - 9761,5
[4] Journal of Organic Chemistry, 2016, vol. 81, # 19, p. 9046 - 9074
[5] Organic Letters, 2017, vol. 19, # 19, p. 5236 - 5239
[6] Organic Letters, 2018, vol. 20, # 10, p. 2939 - 2943
[7] Organic Letters, 2018, vol. 20, # 10, p. 2880 - 2883
[8] Journal of the American Chemical Society, 2018, vol. 140, # 30, p. 9400 - 9403
[9] Organic Letters, 2018,
[10] Patent: WO2007/67612, 2007, A1, . Location in patent: Page/Page column 62
16
[ 67-56-1 ]
[ 2305-36-4 ]
[ 18595-17-0 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: at 0℃; for 16 h; Reflux Stage #2: With sodium hydrogencarbonate In water
Concentrated sulphuric acid (1 mL) was added to a solution of 2-amino-4-methyl-benzoic acid (1.0 g, 6.62 mmol) in dry methanol (10 mL) at 0° C., and then heated at reflux for 16 hr. The mixture was cooled to room temperature and concentrated in vacuo. The crude compound was diluted with water (25 mL) and basified with sodium bicarbonate (10 mL). The aqueous layer was extracted with ethyl acetate (2*50 mL) and the combined organic layers were washed with water (50 mL), brine (50 mL) and dried over sodium sulfate. The organic layer was concentrated under reduced pressure affording 2-amino-4-methyl-benzoic acid methyl ester (900 mg, 82percent) as yellow liquid.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 3, p. 963 - 968
[2] Tetrahedron, 2009, vol. 65, # 2, p. 563 - 578
[3] Patent: US2011/160231, 2011, A1, . Location in patent: Page/Page column 10
[4] Chemische Berichte, 1930, vol. 63, p. 1455,1462
[5] Advanced Synthesis and Catalysis, 2018, vol. 360, # 10, p. 1919 - 1925
17
[ 2305-36-4 ]
[ 18595-17-0 ]
Reference：
[1] Patent: US5599814, 1997, A,
18
[ 2305-36-4 ]
[ 18595-17-0 ]
Reference：
[1] Patent: US5658858, 1997, A,
19
[ 186581-53-3 ]
[ 2305-36-4 ]
[ 18595-17-0 ]
Reference：
[1] Journal of Organic Chemistry, 2010, vol. 75, # 20, p. 7033 - 7036
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 3 h; Inert atmosphere Stage #2: With ammonium hydroxide In water; N,N-dimethyl-formamide for 16 h;
Compound 22 (3.00 g, 19.8 mmol) in dry DMF (100 mL) under Ar was treated with EDC.HCl (4.17 g, 21.8 mmol) and HOBt (3.33 g, 21.8 mmol) for 3 h, after which aq. NH3 (35percent, 20 mL) was added and the mixture was stirred for 16 h. The evaporation residue, in EtOAc, was washed twice with water and with brine. Drying and evaporation gave 25 (2.04 g, 69percent) as an off-white solid: mp 151-153 °C (lit. [62] mp 148 °C); 1H NMR ((CD3)2SO) δ 2.22 (3 H, s, Me), 6.35 (1 H, dd, J = 8.0, 1.2, 5-H), 6.52 (1 H, d, J = 0.5 Hz, 3-H), 6.57 (2 H, s, NH2), 6.95 (1 H, brs, CONHH), 7.48 (1 H, d, J = 8.0 Hz, 6-H), 7.65 (1 H, brs, CONHH); 13C NMR ((CD3)2SO) (HSQC/HMBC) δ 21.03 (Me), 111.14 (1-C), 115.61 (5-C), 116.44 (3-C), 128.77 (6-C), 141.55 (2-C), 150.31 (4-C), 171.19 (C=O).
64%
With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1 h;
To a stirred solution of 2-amino-4-methyl-benzoic acid (300 mg, 1.99 mmol) in THF (6 mL),EDC.HCl (569 mg, 2.98 mmol), HOBt·NH3 (447 mg, 2.98 mmol) and DIPEA (1.06 mL, 5.96mmol) were added at RT and stirred for 1 h (TLC indicated complete consumption of startingmaterial). The reaction mixture was diluted with water (30 mL), extracted with EtOAc (3 x25 mL). The combined organic extracts were dried over Na2S04, concentrated under reducedpressure to give the crude compound which was purified by flash column chromatography(100-200 silica gel, 5 g, 50percent EtOAc-Hexane) to afford 2-amino-4-methyl-benzamide (190mg, 64percent) as a white solid 1H NMR [300 MHz, DMSO-d6]: J 7.62 (brs, 1H), 7.42 (d, J = 8.1 Hz, 1H), 6.93 (brs, 1H),6.54-6.46 (m, 3H), 6.30- 6.27 (m, 1H), 2.15 (s, 3H).
60%
With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; N,N-dimethyl-formamide at 20℃; for 24 h; Inert atmosphere
Accordingtoaliteratureprocedure,3toasolutionof2-amino-3-methylbenzoicacid(151mg,1.00mmol,1.0eq)indegassedDMF(2.00mL)wereaddedHOBt(162mg,1.20mmol,1.2eq.),EDCI.HCl(230mg,1.20mmol,1.2eq.),N,N-diisopropylethylamine(350μL,2.00mmol,2.0eq),and7MNH3/MeOH(429μL,1.50mmol,1.5eq.).Thesolutionwasstirredatroomtemperaturefor24hoursthenpouredoverwaterandtheaqueouslayerextractedwithEtOAc(320mL),thecombinedorganiclayerswashedwithbrine(25mL),driedwithNa2SO4andconcentratedinvacuo.TheresiduewaspurifiedbyFCC(gradient50percentEtOAc/hexanes to 80percent EtOAc/hexanes) to give 2-amino-3-methylbenzamide (90.0 mg,0.599mmol,60percent)asawhiteamorphoussolid;mp:144–146°C,lit.144–145°C.
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 316 - 327
[2] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 53; 54
[3] Synthesis (Germany), 2017, vol. 49, # 1, p. 135 - 144
With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; under 760.051 Torr;
Toasolutionof2-nitro-4-methylbenzoicacid(500mg,2.76mmol)inEtOH(5.50mL) was added 10% palladium on charcoal (8% w/w). The reaction mixture wassequentiallyevacuatedandpurgedwithhydrogenthreetimesthenstirredunderhydrogenat approximately atmospheric pressure and room temperature. The reaction wasmonitored by TLC and upon completion the catalyst was filtered off through a pad ofCeliteTM.Thesolventwasremovedinvacuotogive2-amino-4-methylbenzamide(416mg,2.75mmol,quant.)asawhiteamorphoussolid;mp181-183C,lit.177-179C.
With iron(III) chloride; hydrazine hydrate; sodium hydroxide; In water; at 70℃; for 1h;
15 g of 3-nitro-4-methylbenzoic acid and 9 g of sodium hydroxide were weighed into a 500 mL three-necked flask and 100 mLDistilled water, and then add 2g of ferric chloride and 5g of activated carbon, water bath heated to 70 , and then dropping 12g hydrazine hydrateReaction 1h, filtered to obtain light yellow powder;Into a 500 mL three-necked flask, 15 g of the above-prepared light was addedYellow powder and 1 g of pyridine and 100 mL of acetonitrile were added and the temperature was raised to 50 C while stirring.Dropping speed was controlled so that the dropping was completed in 1 hour, and the reaction was kept for 4 hours and cooled to room temperature.To the aboveStep in the three-neck flask by adding 1g mass concentration of 80% acetic acid solution, start the mixer,Stirring at 300r / min for 20min. After stirring, the mixture is poured into a refluxing device and heated to60 C, and 10 mL of a 40% aqueous solution of methylamine was dropwise added thereto to control the dropping speed,30min within the drop is completed, insulation reaction 1h;To the mixed solution after the completion of the above reaction, 50 mL of distilled water was addedWater, stirring 10min and then into the separatory funnel, put it aside 1h layered, separated from the organic phase, spare;The organic phase was transferred to a 500 mL three-necked flask, heated in a water bath to 40 C,20g of sulfonyl chloride and 10mL of acetonitrile were added under stirring. The dropping rate was controlled so as to be added dropwise within 1 hour, and the reaction was kept for 3 hours.To room temperature, filtered to filter residue, into the oven, at 105 drying in the 3-amino-6-chloro-N,Methylbenzamide.
General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2·2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 × 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22.
at 130 - 175℃; for 4h;
A. 7-Methyl-3H-quinazolin-4-one. A solution of 2-amino-4-methylbenzoic acid (31.6 g, 206 mmol) in formamide (60 ML) is heated to 130 C. for 1 hour, then at 175 C. for 3 hours.The solution is poured into 500 ML of ice water.The resulting solid is collected by filtration and further dried under reduced pressure.The title compound (26.2 g, 170 mmol) is obtained as a white solid. MS (EI): m/z 159 (M+).
at 120℃;
General procedure: The mixtures of anthranilic acid or respective 5-substituted-2-aminobenzoicacid (1) (1 mmol) and an excess of formamide (10 mmol) in around-bottom flask were heated at 120 C with stirring for 3-5 h. Thereaction was checked by TLC. After the starting materials completelydisappeared, the resulting mixtures were cooled to room temperatureand then poured into ice-cold water. The light or dark brown precipitateswere formed. The precipitates were filtered and washed threetimes with water (20 mL each) and dried to give quinazoline-4(3H)-onederivatives (2). These intermediates were used for the next step withoutfurther purification.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 2h;
To a mixture of lithium tetrahydroaluminum (30.1 g, 793.9 mmol) and dry tetrahydrofuran (800 mL) was added dropwise 2-amino-4-methylbenzoic acid (100.0 g, 661.6 mmol) and the dried A solution of tetrahydrofuran (500 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Water (15 mL) was added dropwise to quench, and a solution of sodium hydroxide (25 g) and 1 water (100 mL) was added. Filter, extract the filtrate with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The concentrate was crystallized from ethyl acetate / petroleum ether to obtain Inter-1 (79.0 g, yield 87%).
To a solution of 2-amino-4-methylbenzoic acid (1.0 g, 6.62 mmol) in THF (10 mL) is added drop wise BH3 THF (1.0 M, 16.6 mL, 16.6 mmol) and the mixture is stirred at RT for 3 days. Excess BH3 is quenched with 1 N HCI at 0 0C. The solvent is evaporated to obtain a white solid. The solid is washed with water, and then hexane to remove the water. The solid is then dried in an oven to obtain the title compound).
7-Methyl-10-oxo-10H-pyridazino[6,1-b]quinazoline-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine;
EXAMPLE 4 7-Methyl-10-oxo-10H-pyridazino(6,1-b)quinazoline-2-carboxylic acid. A reaction mixture containing 4-methylanthranilic acid (4.76 g, 31.6 mmol), <strong>[5096-73-1]6-chloropyridazine-3-carboxylic acid</strong> (5.0 g, 31.6 mmol) and 50 ml of glacial acetic is heated at reflux for 67 hrs. The reaction mixture is cooled and the precipitate which formes is collected, m.p. 239-247 C. (dec.). Recrystallization of the crude material from pyridine gives the analytical sample, m.p. 246-249 C. (dec.).
With ammonium hydroxide; ammonia; copper(II) sulfate; In water; toluene;
I. 3-Methyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one 25 g 2-bromo-4-methylbenzoic acid was treated with 150 mL of 28% aqueous ammonia, 50 g gaseous ammonia, 1 g CuSO4 at 140 C. for 12 hours in an autoclave, then concentrated in vacuo, dissolved in a minimal amount of water, pH adjusted to 6 with 4N HCl. The precipitate was filtered, washed with ice cold water, and dried at 60 C. The residue was extracted with THF and concentrated in vacuo, giving a light brown crystalline solid. Yield of combined material: 14 g 4-methylanthranilic acid. 6.4 g of this acid was suspended with stirring in 100 mL toluene. 11 mL 1-Aza-2-methoxy-1-cycloheptene (1) (Aldrich) were added and the mixture was refluxed under a Dean-Stark trap for 12 hours. Then the toluene was removed by distillation in vacuo, followed by removal of excess (1) in vacuo (11 mm Hg) at 140 C. The dark brown residue crystallized. It was purified by column chromatography (6:1 chloroformethyl acetate) followed by recrystallization from hexane-ethyl acetate to give 7.1 g of pure 3-methyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one as white, shiny crystals.
methyl 3,4-dichloro-2-(N-methyl-N-methylsulphonytamino)-benzoate[ No CAS ]
[ 18595-17-0 ]
Yield
Reaction Conditions
Operation in experiment
In methanol; dichloromethane;
REFERENCE EXAMPLE 23 A mixture of 2-amino-4-methylbenzoic acid (15.0 g) and concentrated suiphuric acid (20 ml) was heated under reflux with methanol for 18 hours. After removal of the solvent the residue was dissolved in dichloromethane, basified with sodium carbonate solution and the organic phase was washed with water, dried (anhydrous magnesium sulphate) and the solvent evaporated to give methyl 2-amino-4-methylbenzoate, m.p. 41-43 C. By proceeding in a similar manner the following compounds were prepared from the appropriately substituted starting materials: methyl 3,4-dichloro-2-(N-methyl-N-methylsulphonytamino)-benzoate, NMR 2.95(s,3H), 3.28(s,3H), 3.89(s,3H), 7.5(d,1H), 7.71(d,1H);
b. Methyl 2-amino-4-methylbenzoate A solution of 2-amino-4-methylbenzoic acid (5.20 g, 34.3 mM) in methanol (70 mL) was cooled in an ice bath and saturated with hydrogen chloride gas. The resulting solution was refluxed for 3 hr and the cooled and poured into an excess of saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium bicarbonate and then dried (MgSO4), filtered and concentrated to leave the title amino ester (5.66 g, 85.7%) as a brown oil; MS(CI): 166 (M+H).
With potassium carbonate In ethyl acetate at 20℃; for 0.25h;
105.105a
To a solution of 2-amino-4-methylbenzoic acid (1.00 g, 6.62 mmol) in ethyl acetate (15.0 mL) were added potassium carbonate (0.914 g, 6.62 mmol) and triphosgene (0.883 g, 2.98 mmol). Following stirring at ambient temperature for 15 min., the reaction mixture was treated with water, filtered, washed with water and hexanes, and dried in vacuo to afford the title compound as an off- white solid (1.16 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.7 (s, 1 H), 7.80 (d, J=8.1 Hz, 1 H), 7.08 (dd, J=8.0, 0.9 Hz, 1 H), 6.93 (s, 1 H), 2.38 (s, 3 H). MS(ES+) m/e 178 [M+H]+
In tetrahydrofuran at 0℃; for 5h; Inert atmosphere; Large scale;
11
Under electromagnetic stirring and ice-water bath cooling,Add 1j (2000mg, 13.23mmol) to a 150mL round bottom flask,Tetrahydrofuran (45 mL), wait for the reaction system to cool, and then slowly add triphosgene (1335 mg, 4.49 mmol).Under N2 protection, stir for 5h. After the reaction, the solvent was removed under reduced pressure, and an appropriate amount of petroleum ether was added and sonicated to fully suspend the precipitated solid in petroleum ether.After suction filtration and drying, 2170 mg of a gray solid of compound 2k was obtained (93% yield).
In tetrahydrofuran at 20℃;
In tetrahydrofuran at -5℃; for 5h;
Stage #1: 2-amino-4-methyl benzoic acid In 1,4-dioxane Reflux;
Stage #2: bis(trichloromethyl) carbonate In 1,4-dioxane Reflux;
Step 4:
General procedure: The mixture of 2-aminobenzoic acid (1 equivalent) and 1,4-dioxane were heatedat reflux. Then, a solution of triphosgene (BTC, 0.4 equivalent) in 1,4-dioxane wasadded dropwise to the above mixture over 30 min. After that, this solution was refluxovernight. Then the solvent was removed under reduced pressure, and PE/EA = 2:1was added to the obtained residue with vigorous stirring. The precipitate wascollected by filtration, washed with Petroleum ether, and dried to give the isotaicanhydride as a solid in theoretical yield.
In tetrahydrofuran at 20℃; for 6h;
4.1.1. Synthetic procedure for 2
General procedure: To a solution of different 2-aminobenzoic acid (5.0 mmol) in 20 mLanhydrous tetrahydrofuran (THF) was added triphosgene (BTC, 0.445 g,1.67 mmol) in batches. The reaction mixture was stirred at room temperaturefor 6 h and then poured into ice water. The resulting solid werefiltrated to obtain compounds 1, which were dissolved in 10 mL ofanhydrous N,N-dimethyl formamide (DMF), and then sodium hydride(NaH, 0.096 g, 4.0 mmol) was added in batches at 0. The reactionmixture was stirred at 0 for 30 min, and then methyl iodide (CH3I,0.469 g, 3.3 mmol) was added dropwise. The reaction was detected byTLC. After completion, the reaction mixture was poured into the icewater. The resulting solid were filtrated to obtain compounds 2.
Multi-step reaction with 4 steps
1: sulfuric acid / 67 h / Reflux
2: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere
3: acetic acid; bromine / 120 h / 20 °C
4: sodium hydroxide; water / 20 h / 90 °C
9.04 g
With hydrogen bromide In water; dimethyl sulfoxide at 10 - 35℃;
10.A A) 2-amino-5-bromo-4-methylbenzoic acid
To a mixture of 2-amino-4-methylbenzoic acid (6.14 g) and DMSO (60 mil) was added hydrobromic acid (48% v/v, 23 mL) at 0°C, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (150 mL) and the mixture was stirred for 30 min. The precipitate was collected by filtration, washed with water and dried to give the title compound (9.04 g) . (1428) MS, found: 230.0, 232.0.
Compound 22 (3.00 g, 19.8 mmol) in dry DMF (100 mL) under Ar was treated with EDC.HCl (4.17 g, 21.8 mmol) and HOBt (3.33 g, 21.8 mmol) for 3 h, after which aq. NH3 (35%, 20 mL) was added and the mixture was stirred for 16 h. The evaporation residue, in EtOAc, was washed twice with water and with brine. Drying and evaporation gave 25 (2.04 g, 69%) as an off-white solid: mp 151-153 C (lit. [62] mp 148 C); 1H NMR ((CD3)2SO) delta 2.22 (3 H, s, Me), 6.35 (1 H, dd, J = 8.0, 1.2, 5-H), 6.52 (1 H, d, J = 0.5 Hz, 3-H), 6.57 (2 H, s, NH2), 6.95 (1 H, brs, CONHH), 7.48 (1 H, d, J = 8.0 Hz, 6-H), 7.65 (1 H, brs, CONHH); 13C NMR ((CD3)2SO) (HSQC/HMBC) delta 21.03 (Me), 111.14 (1-C), 115.61 (5-C), 116.44 (3-C), 128.77 (6-C), 141.55 (2-C), 150.31 (4-C), 171.19 (C=O).
64%
With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h;
To a stirred solution of 2-amino-4-methyl-benzoic acid (300 mg, 1.99 mmol) in THF (6 mL),EDC.HCl (569 mg, 2.98 mmol), HOBt·NH3 (447 mg, 2.98 mmol) and DIPEA (1.06 mL, 5.96mmol) were added at RT and stirred for 1 h (TLC indicated complete consumption of startingmaterial). The reaction mixture was diluted with water (30 mL), extracted with EtOAc (3 x25 mL). The combined organic extracts were dried over Na2S04, concentrated under reducedpressure to give the crude compound which was purified by flash column chromatography(100-200 silica gel, 5 g, 50% EtOAc-Hexane) to afford 2-amino-4-methyl-benzamide (190mg, 64%) as a white solid 1H NMR [300 MHz, DMSO-d6]: J 7.62 (brs, 1H), 7.42 (d, J = 8.1 Hz, 1H), 6.93 (brs, 1H),6.54-6.46 (m, 3H), 6.30- 6.27 (m, 1H), 2.15 (s, 3H).
60%
With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;
Accordingtoaliteratureprocedure,3toasolutionof2-amino-3-methylbenzoicacid(151mg,1.00mmol,1.0eq)indegassedDMF(2.00mL)wereaddedHOBt(162mg,1.20mmol,1.2eq.),EDCI.HCl(230mg,1.20mmol,1.2eq.),N,N-diisopropylethylamine(350muL,2.00mmol,2.0eq),and7MNH3/MeOH(429muL,1.50mmol,1.5eq.).Thesolutionwasstirredatroomtemperaturefor24hoursthenpouredoverwaterandtheaqueouslayerextractedwithEtOAc(320mL),thecombinedorganiclayerswashedwithbrine(25mL),driedwithNa2SO4andconcentratedinvacuo.TheresiduewaspurifiedbyFCC(gradient50%EtOAc/hexanes to 80% EtOAc/hexanes) to give 2-amino-3-methylbenzamide (90.0 mg,0.599mmol,60%)asawhiteamorphoussolid;mp:144-146C,lit.144-145C.
1.2 Example 1
15 g of 3-nitro-4-methylbenzoic acid and 9 g of sodium hydroxide were weighed into a 500 mL three-necked flask and 100 mLDistilled water, and then add 2g of ferric chloride and 5g of activated carbon, water bath heated to 70 , and then dropping 12g hydrazine hydrateReaction 1h, filtered to obtain light yellow powder;Into a 500 mL three-necked flask, 15 g of the above-prepared light was addedYellow powder and 1 g of pyridine and 100 mL of acetonitrile were added and the temperature was raised to 50 ° C while stirring.Dropping speed was controlled so that the dropping was completed in 1 hour, and the reaction was kept for 4 hours and cooled to room temperature.To the aboveStep in the three-neck flask by adding 1g mass concentration of 80% acetic acid solution, start the mixer,Stirring at 300r / min for 20min. After stirring, the mixture is poured into a refluxing device and heated to60 ° C, and 10 mL of a 40% aqueous solution of methylamine was dropwise added thereto to control the dropping speed,30min within the drop is completed, insulation reaction 1h;To the mixed solution after the completion of the above reaction, 50 mL of distilled water was addedWater, stirring 10min and then into the separatory funnel, put it aside 1h layered, separated from the organic phase, spare;The organic phase was transferred to a 500 mL three-necked flask, heated in a water bath to 40 ° C,20g of sulfonyl chloride and 10mL of acetonitrile were added under stirring. The dropping rate was controlled so as to be added dropwise within 1 hour, and the reaction was kept for 3 hours.To room temperature, filtered to filter residue, into the oven, at 105 drying in the 3-amino-6-chloro-N,Methylbenzamide.
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