* 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.
Stage #1: With aminosulfonic acid In water; acetone at 0 - 5℃; for 0.333333 h; Stage #2: With sodium chlorite In water; acetone at 22 - 26℃; for 18 h;
A solution of 2,3-dihydrobenzo[b][l,4]dioxine-5-carbaldehyde (0.500 g, 3.04 mmol) in acetone (10 mL) was stirred at 0-5°C and aqueous solution of sulphamic acid (0.455 g, 4.5 mmol) was added. The reaction mass was stirred for 20 min. Then aqueous solution of sodium chlorite (0.421 g, 4.5 mmol) was added and the reaction was further continued at RT for 18 h. After completion of reaction, reaction mixture was concentrated under reduced pressure and reaction mass was quenched with water. Solid obtained was filtered off and vacuum dried to afford 0.332 g of desired product. 1H NMR (DMSO-de): δ 4.27 (s, 4H), 6.84 (t, J = 7.2 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 7.20 (d, J= 7.5 Hz, 1H), 12.5 (bs, 1H); MS [M+H]+: 181.12.
Reference：
[1] Journal of Organic Chemistry, 1948, vol. 13, p. 489,493
[2] Patent: US5919814, 1999, A,
3
[ 2411-83-8 ]
[ 4442-53-9 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 2, p. 635 - 644
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 11, p. 2947 - 2954
[3] Patent: CN106905335, 2017, A,
4
[ 303-38-8 ]
[ 4442-53-9 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 2, p. 635 - 644
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 11, p. 2947 - 2954
[3] Patent: CN106905335, 2017, A,
5
[ 24677-78-9 ]
[ 4442-53-9 ]
Reference：
[1] Patent: WO2013/153535, 2013, A1,
6
[ 493-09-4 ]
[ 124-38-9 ]
[ 4442-53-9 ]
[ 4442-54-0 ]
Reference：
[1] Chemical Communications, 2014, vol. 50, # 92, p. 14360 - 14363
7
[ 493-09-4 ]
[ 124-38-9 ]
[ 4442-53-9 ]
[ 4442-54-0 ]
Reference：
[1] Chemical Communications, 2014, vol. 50, # 92, p. 14360 - 14363
8
[ 4442-53-9 ]
[ 214894-89-0 ]
Reference：
[1] Patent: WO2017/155909, 2017, A1,
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1797 - 1809
9
[ 4442-53-9 ]
[ 274910-19-9 ]
Yield
Reaction Conditions
Operation in experiment
99%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 18 h;
To a solution of 2,3-dihydrobenzo[£][l,4]dioxine-5-carboxylic acid (5.00 g, 28.0 mmol) in THF (150 mL) at 0 °C was added lithium aluminium hydride (2.13 g, 56.0 mmol) in small portions. The reaction mixture was stirred at 0 °C for 10 min and stirred for a further 18 h at r.t. Water (150 mL) was added to the reaction mixture which was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure to obtain 20 as yellow oil (3.22 g, 99percent). 1H NMR (CDC13) δ 6.87-6.79 (m, 3H), 4.66 (s, 2H), 4.32-4.30 (m, 2H), 4.28-4.25 (m, 2H), 2.19 (bs, 1H). Found: [M+H-18]=149.5
99%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 18 h;
4.1.1.1. 6-Bromo-3-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-2-methoxyquinoline (VI: Y = 2,3-O(CH2)2O–). To a solution of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (5.00 g, 28.0 mmol)in THF (150 mL) at 0 C was added lithium aluminium hydride(2.13 g, 56.0 mmol) in small portions. The reaction mixture wasstirred at 0 C for 10 min and stirred for a further 18 h at 20 C.Water (150 mL) was added to the reaction mixture which wasextracted with EtOAc (2 100 mL). The combined organic layerswere washed with brine (100 mL), dried over Na2SO4, filteredand concentrated under reduced pressure to obtain (2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methanol as a yellow oil (3.22 g,99percent). 1H NMR (CDCl3, 400 MHz) d 6.87–6.79 (m, 3H), 4.66 (s, 2H),4.32–4.30 (m, 2H), 4.28–4.25 (m, 2H), 2.19 (bs, 1H). Found: [M+H-18] = 149.5.
Reference：
[1] Patent: WO2017/155909, 2017, A1, . Location in patent: Paragraph 0075
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1797 - 1809
10
[ 4442-53-9 ]
[ 64-17-5 ]
[ 261767-10-6 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 11, p. 1110 - 1118
[2] Patent: CN103664910, 2017, B, . Location in patent: Paragraph 011
PREPARATION 14: 2,3-ETHYLENEDIOXYBENZOYL CHLORIDE By carrying out the procedure as in Preparation 2--Stage B, but replacing 4,5-methylenedioxy-2-nitrobenzoic acid by 2,3-ethylenedioxybenzoic acid, the title product is obtained.
With thionyl chloride; at 70 - 80℃; for 4h;
General procedure: The starting two acids (<strong>[4442-53-9]2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid</strong> and 2,3-dihydrobenzo[b][1,4]dioxine-2-carboxylic acid) shoud be activated by firstly SOCl2: acid (100 mg) and (6-10 mL) was mixed and stirred at reflux 80 ? for 4 hours. The reaction mixture was cooled and evaporated to give reactive acyl chloride obtained as an oil, which would be dissolved in ethyl acetate (5-6 mL) in the next step.
With thionyl chloride; In N,N-dimethyl-formamide; for 4h;
General procedure: Method B: SOCl2 (10mL) was added to a stirred solution of compound 3 (20mmol) in anhydrous DMF (50mL). The reaction solution was allowed to stir at room temperature for approximately 4h. Then, active compound 4 (15mmol) and metronidazole (15mmol) were dissolved in CH2Cl2 followed by drop wise addition triethylamine and compound 5 was obtained with yield of 85percent. Compound 5 (10mmol), different substituted benzaldehydes (12mmol) and NaOH (15mmol) were dissolved in DMSO (30mL) at room temperature. The appropriate amount of water was then added in the residue and filtered. The resulting solid was collected and washed with cold water, dried and crystallized from anhydrous ethanol to get the desired compounds. All of the synthetic compounds gave satisfactory analytical and spectroscopic data, which were in full accordance with their depicted structures.
With thionyl chloride; at 85℃; for 1h;
Intermediate 35: 2-diazo-1-(2,3-dihvdro-1 ,4-benzodioxin-5-yl)ethanone; A solution of 1 g of 2,3-dihydro-1 ,4-benzodioxin-5-carboxylic acid (5.55 mmole, Aldrich) in 30.7 mL of SOCI2 was stirred at 850C for 1 h in a dry flask under nitrogen atmosphere. The excess of SOCI2 was removed under reduced pressure, the resulting crude oil was <n="76"/>dissolved in 20.3 ml. of MeCN and to this solution, a solution of TMSCHN2 2M in hexane (11.1 mmole, Aldrich) was added dropwise at O0C. The reaction mixture was warmed to RT and stirred for 2 h. A 1 M solution of citric acid was added and then extracted with AcOEt. The organic layer was washed with a saturated solution of NaHCC>3, dried over Na2SO4 and concentrated under reduced pressure. The crude oil was purified by flash chromatography (from CH to CH/AcOEt 80/20) to give the title compound as a yellow oil (489 mg, 42percent). 1H-NMR (500 MHz, CDCI3): delta 4.29-4.34 (2H, m), 4.35-4.40 (2H, m), 6.25 (1 H, s), 6.92 (1 H, t), 7.02 (1 H, dd), 7.46 (1 H, s); m/z (ES): 205 [M+H]+.
4-{2-[(2,3-Dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic acid methylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 40℃;
Example 8 Synthesis of 4-{2-[(2,3-Dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic acid methylamide (Table 2, Compound 110) 4-(2-Amino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (1 eq) and <strong>[4442-53-9]2,3-dihydro-1,4-benzodioxane-5-carboxylic acid</strong> (1 eq) were dissolved in DMF. To this solution were added DIPEA (3 eq) and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (1 eq). The mixture was stirred at 40° C. overnight, then diluted with ethyl acetate and washed once each with 1N HCl, saturated aqueous sodium bicarbonate, and brine, and finally dried with anhydrous sodium sulfate, filtered, and concentrated. This was purified by preparatory reverse phase HPLC. MH+=447.0.
5-{7-[4-(2-hydroxy-ethyl)-piperazine-1-sulfonyl]-2,3-dihydro-benzo[1,4]dioxin-5-yl}-1-methyl-3-propyl-1,6-dihydro-pyrazolo[4,3-<i>d</i>]pyrimidin-7-one[ No CAS ]
The mixture was combined with that arising from a second reaction performed at the same scale and under the same conditions. The solvents were removed in vacuo, the residue was dissolved in water (7000 ml), and the solution was washed with ethyl acetate (2*500 ml) and ether (2*500 ml). Charcoal (50 g) was added, and the mixture was stirred at ambient temperature for 30 minutes, then filtered. The filtrate was acidified by the addition of an excess of concentrated hydrochloric acid, and the resulting solid was collected by filtration, washed with water, and dried in vacuo at 95° C. to give 1,4-benzodioxan-5-carboxylic acid as an off-white solid (306.3 g), m.p. 165-173° C.
14
[ 4442-53-9 ]
2,3-dihydro-1,4-benzodioxin-5-amine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; PPA; hydroxylamine hydrochloride; In ethyl acetate;
1,4-Benzodioxan-5-carboxylic acid (120 g) was added in portions at 40° C. to a stirred mixture of hydroxylamine hydrochloride (52 g) and polyphosphoric acid (380 g), then the mixture was heated to an internal temperature of 120° C. The source of heat was removed, and the mixture was stirred vigorously until frothing subsided, then it was stirred at 165° C. for 90 minutes, cooled to 80° C., added to an excess of ice-water, and basified by the addition of 5M aqueous sodium hydroxide solution. The product was extracted into ethyl acetate (6*500 ml), the extracts were dried (MgSO4), and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (800 ml), and the cloudy solution was filtered then saturated with hydrogen chloride. The resulting solid was collected by filtration, washed with ethyl acetate, and dried in vacuo at ambient temperature to give 1,4-benzodioxan-5-amine monohydrochloride as a buff solid (65.9 g).
With nitric acid; acetic anhydride; In acetic acid;
7-nitro-1,4-benzodioxane-5-carboxylic acid 160 ml of acetic acid, 160 ml of acetic anhydride and 100 g of 1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was heated and a solution of 40 ml of nitric acid in 40 ml of acetic acid was added. The mixture was agitated at 40°-45° C. and then cooled. The crystals were dried off, washed and dried. 34 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 246° C.; yield: 27percent).
7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid 670 g of chlorosulfonic acid were introduced into a balloon flask provided with a condenser and a thermometer. 173 g of 1,4-benzodioxane-5-carboxylic acid were added in portions with the temperature being maintained at 5°-10° C. The mixture was heated at 55° C. and then cooled and poured into ice. The precipitate was dried off, washed and dried again. 250 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 210°-215° C.; yield: 93.5percent).
75%
With chlorosulfonic acid; at 70℃; for 3h;Inert atmosphere;
Synthesis of 7-(chlorosulfonyl)-2,3-dihydrobenzo[b] [l,4]dioxine-5-carboxylic acid (XIII):To a stirred solution of 2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylic acid XII (0.5 g, 2.77 mmol) was added chlorosulphonic acid (1.2 ml, 16.6 mmol) at 0°C under nitrogen atmosphere and the resulting mixture was heated at 70°C for 3 h. After completion of reaction, the reaction mixture was cooled, quenched with ice and extracted with DCM. The organic layer was dried over Na2S04 and evaporated under reduced pressure to afford product XIII in 75percent yield.
A 20-mL round bottom flask was charged with 2,3-dihydrobenzo[b][l,4]dioxine- 5-carboxy-lic acid (1.8 g, 1.0 mmol), bromine (3.16 g, 2.0 mmol), and acetic acid (2 mL). The reaction mixture was stirred at 120°C for 2 h and then cooled to 15°C. It was filtered and the solid was washed with acetic acid to afford the title compound as a white solid (3.0 g, 60percent). LCMS: ESI (3 minute run), m/z = 337 [M+l]+; Retention time: 1.21 minute.
With bromine; In acetic acid;
6,7-dibromo-1,4 -benzodioxane-5-carboxylic acid 1,440 ml of acetic acid and 360 g of 1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with an agitator, an introduction funnel and a condenser. The mixture was heated to 55° C. and then a solution of 700 g of bromine in 360 ml of acetic acid was added in portions. The mixture was heated to 120° C. and then cooled to 15° C. The precipitate was dried off, washed with acetic acid and dried. 332 g of 6,7-dibromo-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 212° C.). The structure was confirmed by nuclear magnetic resonance analysis.
2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid(pyridin-4-ylmethyl)amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
In tetrahydrofuran;
A. N,N'-Carbonyidiimidazole (1.62 g, 10 mmol) was added to a stirred solution of <strong>[4442-53-9]2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid</strong>(1.64 g, 10 mmol) in tetrahydrofuran (25 mL) and the resulting solution was heated at 60° C. for 15 minutes. The solution was cooled to room temperature and -4-(aminomethyl)pyridine (1.08 g, 10 mmol) was added. The reaction mixture was heated at 60° C. for 2 hours, cooled, poured into water, and extracted 3 times with ethyl acetate. The combined ethyl acetate extract was dried (Na2SO4) and evaporated in vacuo to a crystalline residue which was triturated with water, filtered, and dried in vacuo to give <strong>[4442-53-9]2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid</strong> (pyridin-4-ylmethyl)amide as a white solid (1.95 g, 72percent); m.p. 120-121° C.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
EXAMPLE 59; 2-r(7,3-Dihydro-benzori,41dioxine-5-carbonyl)-aminol-indan-2-carboxylic acid ethyl ester (59):To a solution of 2,3-dihydro-benzo[l,4]dioxine-5-carboxylic acid (351mg, 1.95mmol), 2- amino-indan-2-carboxylic acid ethyl ester (400mg, 1.95mmol), HATU (1.1 Ig, 2.93mmol) in anhydrous DMF (8mL) is added DIPEA (484muL, 2.93mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (7OmL) and washed with water (I x 1OmL) and brine (2 x 1OmL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (59) as white solid (650mg, 91 percent).1H NMR (CDCl3, 300MHz): delta 1.24(t, 3H), 3.39(d, 2H), 3.74(d, 2H), 4.21- 4.33(m, 6H), 6.90(t,IH), 6.98(dd, IH), 7.17-7.24(m, 4H), 7.69(dd, IH), 8.25(s, IH)LC/MS (ES+) m/z = 368.15
A.5.1 Synthesis of (IS^S.SRJ^-facylamino-methylJ-S-aza-bicycloIS.S.O]- octane-3-carboxylic acid tert. -butyl ester derivatives (general procedure)To a solution of the respective carboxylic acid R3-COOH (1 eq) in DMF (0.2 mmol/ 0.5 mL) are added successively DIPEA (5 eq) and TBTU (1 eq). The reaction mixture <n="47"/>is stirred for 15 min. at RT and then is added a solution of (1S,2S,5R)-1- aminomethyl-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid te/t.-butyl ester derivative (1 eq) in DMF (0.5 ml_). The stirring at RT is continued for 16 h, the reaction mixture is poured into water and diluted with EA. The org. phase is washed with sat. NaHCOs solution and water. After drying over anh. MgSO4 and removal of solvents in vacuo the desired compounds are obtained which are used without further purification.(1S,2S,5R)-2-[(3,4-Dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-methyl}-3- aza-bicyclo[3.3.0]octane-3-carboxylic acid tert. -butyl esterprepared by reaction of (I S^S.SR^I-aminomethyl-S-aza-bicyclobeta.S.OJ-octane-S- carboxylic acid te/t-butyl ester with commercially available 2,3-dihydro- benzo[1 ,4]dioxine-5-carboxylic acid.LC-MS: tR = 1.00 min; [M+H]+ = 403.
Example 45 Preparation of intermediate N- [l- (benzyl)-4-piperidinyl] methyl]-1, 4- benzodioxane-5-carboxamide A suspension of 1, 4-benzodioxan-5-carboxylic acid (1.80 g, 10.0 mmol) and 1,1'- carbonyldiimidazole (1.78 g, 11.0 mmol) in CH3CN (100 ml) was stirred at room temperature for 2 h. 1-Benzyl-4-aminomethylpiperidine (from example 37) (2.04 g, 10.0 mmol) in CH3CN (10 ml) was added to the mixture and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, added EtOAc (200 ml) and washed with H2O (3 x 50 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo to a solid material. The residue was separated with flash chromatography (Si02, EtOAc: MeOH, 1: 1) to leave the product as a white solid (2.31 g, 63.1 percent). 1H-NMR (200 MHz, CDCl3) : b 7.74 (dd, 1 H), 7.67 (t, 1 H), 7.34-7. 15 (m, 5 H), 7.03-6. 89 (m, 2 H), 4.43-4. 39 (m, 2 H), 4.33-4. 29 (m, 2 H), 3.52 (s, 2 H), 3.37 (t, 2 H), 2.93 (d, 2 H), 2.06-1. 93 (m, 2 H), 1.77-1. 50 (m, 3 H), 1.47-1. 28 (m, 2 H)
2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester[ No CAS ]
[ 4442-53-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
With sodium hydroxide; for 2h;Reflux;
A mixture of 2,3-dihydrobenzo [b] [1,4] dioxin-5-carboxylate (2.36 g, 12.39 mmol)And sodium hydroxide solution (15 mL, 10percent) was refluxed for two hours.After cooling to room temperature,The reaction mixture was neutralized with hydrochloric acid (1 mol L-1)There is solid precipitation,To give the compound 2,3-dihydrobenzo [b] [1,4] dioxin-5-carboxylic acid,As a white solid.Yield: 95percent.
With methanol; sodium hydroxide; In tetrahydrofuran; water; at 75℃; for 2h;
General procedure: Protocatechuic acid (1mmol) in methanol (30mL) was treated with concentrated sulfuric acid (0.5mL) under 90°C overnight. The solvent was removed leaving oil which was dissovled in ethyl acetate (20mL) and extracted with water (40mL). After drying the organic layer with anhydrous Na2SO4 and evaporating the solvent under reduced pressure a solid appeared. The solid was recyrstallized from ethanol to obtain the compound 1. In the three-necked flask under a nitrogen atmosphere, compound 1 (1mmol) was dissolved in dry acetone (10mL), and then added anhydrous potassium carbonate (2mmol). After that, the acetone solution containing dibromomethane (1mmol) was added dropwise then refluxed for 24h. The reaction solution was evaporated reduced pressure distillation. The appropriate amount of water was added in the residue and extracted with ethyl acetate (3×40mL). Combined organic layer and dried with anhydrous magnesium sulfate. The solvent was removed by reduced pressure steam to give compound 2. Compound 2 was then saponified (NaOH (aq)/MeOH/THF=1:1:1) at 75°C for two hours. Filtered and recrystallization led to 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid (compound 3).
Example 70aethyl-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylatePrepared as in Example 24a from 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and <strong>[4442-53-9]2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid</strong> as a brown solid. MS 480 (MH+).
(S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate[ No CAS ]
(S)-ethyl 4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)propoxy)-2-methylquinoline-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 81a (S)-ethyl 4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-propoxy)-2-methylquinoline-3-carboxylate Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 26b) and <strong>[4442-53-9]2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid</strong> as brown solid. MS 466 (MH+).
Example 81a (S)-ethyl 4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-propoxy)-2-methylquinoline-3-carboxylate Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and <strong>[4442-53-9]2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid</strong> as brown solid. MS 466 (MH+).
(S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate[ No CAS ]
(S)-ethyl 4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 106a (S)-ethyl 4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and <strong>[4442-53-9]2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid</strong> as brown solid (36%). MS 494 (MH+).
Example 106a (S)-ethyl 4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxy late Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and <strong>[4442-53-9]2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid</strong> as brown solid (36%). MS 494 (MH+).
(S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate[ No CAS ]
(S)-ethyl 4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)butoxy)-2-methylquinoline-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 99a(S)-ethyl 4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-butoxy)-2-methylquinoline-3-carboxylatePrepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and <strong>[4442-53-9]2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid</strong> as brown solid (40percent). MS 480 (MH+).
Intermediate 60:[0212] Triethylamine in acetone was added dropwise to the solution of 2,3- dihydrobenzo[b][l,4]dioxine-5-carboxylic acid (360 mg, 2 mmol) in water and acetone at 0°C. To the mixture was added ethyl carbonochloridate in acetone slowly. The mixture was stirred for 4 h then a solution of NaN3 (196 mg, 3.02 mmol) in water was added dropwise. The reaction mixture was stirred for 1 h then it was poured into ice water and extracted with Et20. The combined organic extracts were washed with brine, dried with MgS04, and concentrated in vacuo. The residue was dissolved in anhydrous toluene and the mixture was heated on a steam bath until nitrogen evolution had ceased. The toluene was then removed in vacuo and 20percent aq HCI (4 mL) was added and the solution was heated to reflux and stirred overnight. The reaction was concentrated under reduced pressure. The residue was dissolved in water, made strongly alkaline by the addition of 40percent aq NaOH, then extracted with Et20. The combined organic extracts were washed with brine, dried by MgS04, and purified by flash chromatography on silica gel column (PE:EtOAc=5:l) to give 2,3-dihydrobenzo[b][l,4]dioxin-5-amine (intermediate 60) (270 mg, 70percent). HPLC: 99percent, RT 1.214 min. MS (ESI) m/z 152.1 [M + H]+.
With diphenyl phosphoryl azide; triethylamine; In tetrahydrofuran; water; at 20 - 70℃; for 5h;
At room temperature, diphenyl phosphoryl azide (8.02g, 29mmol) and triethyl amine (4.2g, 42mmol) were added to a solution of <strong>[4442-53-9]2,3-dihydro-1,4-benzodioxane-5-carboxylic acid</strong> (5.0g, 28mmol) in anhydrous THF (110mL). The mixture was stirred for 2hrs, followed by adding water (30mL), heating to 70 °C and further reacting for 3hrs, then cooling to room temperature, being extracted with EA (100mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (PE:EA = 5:1) to give compound 11-f (1.58g, yield 37percent). LC-MS (ESI): m/z = 152 [M+H]+.
(5)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquino-line-3-carboxylate[ No CAS ]
(S)-ethyl 4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)butoxy)-2-methylquinoline-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 99a (S)-ethyl 4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-butoxy)-2-methylquinoline-3-carboxylate Prepared as in Example 24a from (5)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquino-line-3-carboxylate (Example 97b) and <strong>[4442-53-9]2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid</strong> as brown solid (40%). MS 480 (MH+).
Example 70a ethyl 4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate Prepared as in Example 24a from 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate (Example 24b) and <strong>[4442-53-9]2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid</strong> as a brown solid. MS 480 (MH+).
A solution of 2,3-dihydrobenzo[b][l,4]dioxine-5-carbaldehyde (0.500 g, 3.04 mmol) in acetone (10 mL) was stirred at 0-5°C and aqueous solution of sulphamic acid (0.455 g, 4.5 mmol) was added. The reaction mass was stirred for 20 min. Then aqueous solution of sodium chlorite (0.421 g, 4.5 mmol) was added and the reaction was further continued at RT for 18 h. After completion of reaction, reaction mixture was concentrated under reduced pressure and reaction mass was quenched with water. Solid obtained was filtered off and vacuum dried to afford 0.332 g of desired product. 1H NMR (DMSO-de): delta 4.27 (s, 4H), 6.84 (t, J = 7.2 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 7.20 (d, J= 7.5 Hz, 1H), 12.5 (bs, 1H); MS [M+H]+: 181.12.
2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.188 g
Solution of 2,3-dihydrobenzo[b][l,4]dioxine-5-carboxylic acid (0.300 g, 1.6 mmol) in DMF (3 mL) and potassium carbonate (0.442 g, 3.2 mmol) was heated at 60-70°C for 1 h. Then methyl iodide (0.454 g, 3.2 mmol) was added slowly and reaction was continued stirring at 80-90°C for 16 h. After completion of reaction, reaction mixture was concentrated under reduced pressure and quenched with water. Solid obtained was filtered off and vacuum dried to afford 0.188 g of desired product. 1H NMR (DMSO- e): delta 3.77 (s, 3H), 4.27 (m, 4H), 6.87 (t, J = 7.8 Hz, 1H), 7.052 (d, J = 7.5 Hz, 1H), 7.22 (d, J= 7.5 Hz, 1H); MS [M+H]+: 195.17.
With nitric acid; acetic anhydride; acetic acid; at 40 - 45℃; for 2h;
A solution of 2,3-dihydrobenzo [b] [1,4] dioxin-5-carboxylic acid (1 g, 5.56 mmol)Soluble in 4mL glacial acetic acid and 4mL acetic anhydride,After heating to 40 ° C,To this was added 0.6 mL of nitric acid and 0.6 mL of glacial acetic acid,Maintain the temperature 40 -45 heating two hours after the end of the reaction,Cool to room temperature.Add water to filter,The filtrate is placed in a refrigerator to cool the crystalline solid to precipitate,Get yellow crystal. Yield: 69percent.
With nitric acid; acetic anhydride; acetic acid; at 40 - 45℃; for 2h;
A solution of 2,3-dihydrobenzo[b][1,4]dioxine-5-carbonylic acid (1 g, 5.56 mmol) in 4 ml of acetic acid and 4 ml of acetic anhydride was heated to 40°C, and a solution 0.6 ml nitric acid in 0.6 ml acetic acid was added. The mixture was stirred at 40-45°C for 2h and then cooled to 5°C. The precipitate was filtered with suction filter, washed with 10 ml water, collected and dried to afford 700 mg of the title compound as white solid, which was used in the next stepwithout further purification. LCMS (ESI) calc?d for C9H7N06, [M+H]: 226, found: 226.
With potassium carbonate; In N,N-dimethyl-formamide;
General procedure: Method A: Reaction of metronidazole (12mmol) with different substituted benzaldehyde (16mmol) in 6mL DMSO by adding rapidly a stirred solution of sodium methoxide (12.8mmol) in methanol at room temperature resulted in the formation of target compounds 1a?1r. To a stirred solution of compounds 1a?1r (7mmol) in CH2Cl2 (15mL), 4-methylbenzoyl chloride (7mmol) and triethylamine (10mL) at room temperature were added and stirred for 5h. The precipitate was purified by column chromatography using EtOAc/hexane (1:6) as eluent to give pure compounds 2a?2r. Equimolar portions of the synthesized compounds 2a?2r (5mmol), compound 3 (5mmol) and K2CO3 (5mmol) were dissolved in approximately 15mL of DMF. The reaction solution was allowed to stir overnight at room temperature. The precipitate was purified by column chromatography using EtOAc/hexane (1:9) as eluent to give the pure compounds 3a?3r.
With potassium carbonate; In N,N-dimethyl-formamide;
General procedure: Method A: Reaction of metronidazole (12mmol) with different substituted benzaldehyde (16mmol) in 6mL DMSO by adding rapidly a stirred solution of sodium methoxide (12.8mmol) in methanol at room temperature resulted in the formation of target compounds 1a?1r. To a stirred solution of compounds 1a?1r (7mmol) in CH2Cl2 (15mL), 4-methylbenzoyl chloride (7mmol) and triethylamine (10mL) at room temperature were added and stirred for 5h. The precipitate was purified by column chromatography using EtOAc/hexane (1:6) as eluent to give pure compounds 2a?2r. Equimolar portions of the synthesized compounds 2a?2r (5mmol), compound 3 (5mmol) and K2CO3 (5mmol) were dissolved in approximately 15mL of DMF. The reaction solution was allowed to stir overnight at room temperature. The precipitate was purified by column chromatography using EtOAc/hexane (1:9) as eluent to give the pure compounds 3a?3r.
With potassium carbonate; In N,N-dimethyl-formamide;
General procedure: Method A: Reaction of metronidazole (12mmol) with different substituted benzaldehyde (16mmol) in 6mL DMSO by adding rapidly a stirred solution of sodium methoxide (12.8mmol) in methanol at room temperature resulted in the formation of target compounds 1a?1r. To a stirred solution of compounds 1a?1r (7mmol) in CH2Cl2 (15mL), 4-methylbenzoyl chloride (7mmol) and triethylamine (10mL) at room temperature were added and stirred for 5h. The precipitate was purified by column chromatography using EtOAc/hexane (1:6) as eluent to give pure compounds 2a?2r. Equimolar portions of the synthesized compounds 2a?2r (5mmol), compound 3 (5mmol) and K2CO3 (5mmol) were dissolved in approximately 15mL of DMF. The reaction solution was allowed to stir overnight at room temperature. The precipitate was purified by column chromatography using EtOAc/hexane (1:9) as eluent to give the pure compounds 3a?3r.
With potassium carbonate; In N,N-dimethyl-formamide;
General procedure: Method A: Reaction of metronidazole (12mmol) with different substituted benzaldehyde (16mmol) in 6mL DMSO by adding rapidly a stirred solution of sodium methoxide (12.8mmol) in methanol at room temperature resulted in the formation of target compounds 1a?1r. To a stirred solution of compounds 1a?1r (7mmol) in CH2Cl2 (15mL), 4-methylbenzoyl chloride (7mmol) and triethylamine (10mL) at room temperature were added and stirred for 5h. The precipitate was purified by column chromatography using EtOAc/hexane (1:6) as eluent to give pure compounds 2a?2r. Equimolar portions of the synthesized compounds 2a?2r (5mmol), compound 3 (5mmol) and K2CO3 (5mmol) were dissolved in approximately 15mL of DMF. The reaction solution was allowed to stir overnight at room temperature. The precipitate was purified by column chromatography using EtOAc/hexane (1:9) as eluent to give the pure compounds 3a?3r.
With potassium carbonate; In N,N-dimethyl-formamide;
General procedure: Method A: Reaction of metronidazole (12mmol) with different substituted benzaldehyde (16mmol) in 6mL DMSO by adding rapidly a stirred solution of sodium methoxide (12.8mmol) in methanol at room temperature resulted in the formation of target compounds 1a?1r. To a stirred solution of compounds 1a?1r (7mmol) in CH2Cl2 (15mL), 4-methylbenzoyl chloride (7mmol) and triethylamine (10mL) at room temperature were added and stirred for 5h. The precipitate was purified by column chromatography using EtOAc/hexane (1:6) as eluent to give pure compounds 2a?2r. Equimolar portions of the synthesized compounds 2a?2r (5mmol), compound 3 (5mmol) and K2CO3 (5mmol) were dissolved in approximately 15mL of DMF. The reaction solution was allowed to stir overnight at room temperature. The precipitate was purified by column chromatography using EtOAc/hexane (1:9) as eluent to give the pure compounds 3a?3r.
With potassium carbonate; In N,N-dimethyl-formamide;
General procedure: Method A: Reaction of metronidazole (12mmol) with different substituted benzaldehyde (16mmol) in 6mL DMSO by adding rapidly a stirred solution of sodium methoxide (12.8mmol) in methanol at room temperature resulted in the formation of target compounds 1a?1r. To a stirred solution of compounds 1a?1r (7mmol) in CH2Cl2 (15mL), 4-methylbenzoyl chloride (7mmol) and triethylamine (10mL) at room temperature were added and stirred for 5h. The precipitate was purified by column chromatography using EtOAc/hexane (1:6) as eluent to give pure compounds 2a?2r. Equimolar portions of the synthesized compounds 2a?2r (5mmol), compound 3 (5mmol) and K2CO3 (5mmol) were dissolved in approximately 15mL of DMF. The reaction solution was allowed to stir overnight at room temperature. The precipitate was purified by column chromatography using EtOAc/hexane (1:9) as eluent to give the pure compounds 3a?3r.
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