* 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.
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 4, p. 871 - 887
[2] Agricultural and Biological Chemistry, 1980, vol. 44, # 2, p. 235 - 243
2
[ 254973-61-0 ]
[ 769-30-2 ]
[ 5768-39-8 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 21, p. 3133 - 3137
3
[ 5768-39-8 ]
[ 769-30-2 ]
Reference：
[1] Chemische Berichte, 1958, vol. 91, p. 36,38
4
[ 5768-39-8 ]
[ 66411-55-0 ]
Reference：
[1] Journal of the Chemical Society, 1926, p. 2932
[2] Journal of Medicinal Chemistry, 1990, vol. 33, # 5, p. 1406 - 1413
[3] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 6, p. 1609 - 1616
[4] Patent: US5332735, 1994, A,
[5] Synthetic Communications, 2010, vol. 40, # 19, p. 2897 - 2907
[6] Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 2, p. 635 - 644
[7] Patent: US2015/307443, 2015, A1, . Location in patent: Paragraph 0362
5
[ 33842-16-9 ]
[ 5768-39-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium hydroxide In methanol; water at 20℃; for 3 h;
A solution of methyl benzo[ ][1 ,3]dioxole-4-carboxylate (0.4 g, 2.22 mmol) in methanol (8.0 mL) was treated with 2.0 M aqueous KOH (2.2 mL) and the solution stirred at rt for 3 hours. The mixture was concentrated to ~3 mL volume, diluted with water (5 mL) and acidified to pH ~3 using 2.0 M HCI. The resulting precipitate was removed by filtration, washed with water then diethyl ether and dried in vacuo to give benzo[ ][1 ,3]dioxole-4-carboxylic acid as a beige solid (0.38 g, 97percent).1H NMR (400 MHz, DMSO-d6): δ = 7.28 (dd, J= 8.0, 1.2 Hz, 1H),6.97 (dd, J=8.0, 1.2 Hz, 1H),6.89 (t, J=8.0Hz, 1 H), 6.12 (s, 2H);13C NMR(100 Hz, DMSO-de) 165.5, 148.9, 148.5, 122.9, 121.6, 113.8, 112.5, 102.1.
61%
at 50℃; for 5 h;
Compound P-2 (500 mg, 2.8 mmol) was weighed and suspended in 5 mL of water. Add 2N NaOH aqueous solution 10mL, Heat to 50°C for about 5 hours, The reaction solution is clear. Pour the reaction solution into ice water, Adjust pH to acidic with 2N dilute HCl There is a solid precipitated, Filtering, Dry powder 280mg, Yield 61percent. Used for the next reaction without purification.
Reference：
[1] Patent: WO2016/131098, 2016, A1, . Location in patent: Page/Page column 167; 168; 169
[2] Steroids, 2010, vol. 75, # 12, p. 967 - 973
[3] Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 2, p. 635 - 644
[4] European Journal of Medicinal Chemistry, 2017, vol. 140, p. 604 - 614
[5] Journal of Medicinal Chemistry, 2004, vol. 47, # 4, p. 871 - 887
[6] Patent: CN104016960, 2018, B, . Location in patent: Paragraph 0084-0087; 0094-0096
[7] Patent: WO2004/4732, 2004, A1, . Location in patent: Page/Page column 66
[8] Patent: WO2004/5284, 2004, A1, . Location in patent: Page 68
6
[ 23158-06-7 ]
[ 5768-39-8 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With water; sodium hydroxide In methanol at 20℃; for 3.5 h; Stage #2: With hydrogenchloride In methanol; water
To a solution of the compound of the previous step (16 g) in methanol (170 ml) was added a solution of sodium hydroxide (9.9 g) in water (40 ml), and the mixture was stirred at room temperature for 3.5 hr. The reaction solution was acidified with concentrated hydrochloric acid, and the mixture was concentrated. The resulting precipitate was collected by filtration to give the title compound (13 g, 95percent). NMR(300MHz, CDCl3)δ:6.14(2H, s), 6.90(1H, t, J=7.8Hz), 7.03(1H, dd, J=7.5, 1.2Hz), 7.46(1H, dd, J=8.1, 1.2Hz).
With dihydrogen peroxide; potassium carbonate In methanol; water
2,3-(methylenedioxy)benzoic acid A solution of 2,3-(methylenedioxy)benzaldehyde (160mg, 1.06mmol), potassium carbonate (960 mg, 6.9 mmol) and 2.4mL of hydrogen peroxide (30-32 wt.percent solution in water) in 10 mL of methanol was stirred for 16 hours at room temperature. The mixture was washed with diethyl ether. The water layer was acidified with 1 N aq. HCl to pH>1, then extracted with ethyl acetate. The organic layer was dried over MgSO4, then concentrated to give the desired product (170mg, 96percent). EI-MS (m/z) 164.8 (M-).
Reference：
[1] Chemische Berichte, 1958, vol. 91, p. 36,38
21
[ 5768-39-8 ]
[ 75-65-0 ]
[ 97174-59-9 ]
[ 111081-10-8 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 2, p. 259 - 262
22
[ 5768-39-8 ]
[ 97174-59-9 ]
[ 111081-10-8 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 2, p. 259 - 262
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 2, p. 259 - 262
PREPARATION 13: 2,3-METHYLENEDIOXYBENZOYL CHLORIDE By carrying out the procedure as in Preparation 1--Stage B, but replacing 4,5-methylenedioxy-2-nitrobenzoic acid by 2,3-methylenedioxybenzoic acid, the title product is obtained.
With thionyl chloride; for 2h;Reflux;
Example 3 Synthesis of Benzo[1,3]dioxole-4-carboxylic acid (3-chloro-phenyl)-amide: Benzo[d][1,3]dioxole-4-carboxylic acid (112.5 mg, 0.68 mmol) was refluxed in thionyl chloride (4 mL) for 2 hours, and then concentrated. The residue was redissolved in dry methylene chloride (3 mL) and concentrated. This process was repeated three times. The resulting clear oil was then dissolved in dry methylene chloride (2 mL) and added dropwise to a stirred solution of 3-chloroaniline (130 mg, 1.02 mmol), triethylamine (0.48 mL, 3.4 mmol) in methylene chloride (6 mL) at 0 C. The mixture was then stirred at 25 C. for 2 hours. The mixture was then diluted with ethyl acetate and washed with HCl (2N) twice, saturated NaHCO3, and brine. The organic phase was concentrated, and the residue was purified on silica gel (24 g), eluted with a gradient of ethyl acetate and hexanes from 1:9 to 3:7 to give <strong>[5768-39-8]benzo[1,3]dioxole-4-carboxylic acid</strong> (3-chloro-phenyl)-amide as a white solid (80.0 mg, 43%). 1H NMR (300 MHz, CDCl3): delta 8.71 (broad s, 1H), 7.71 (t, J=2.0 Hz, 1H), 7.58 (dd, J=6.4, 3.2 Hz, 1H), 7.48 (ddd, J=8.2, 2.0, 0.9 Hz, 1H), 7.25-7.18 (m, 1H), 7.05 (ddd, J=7.9, 2.0, 1.2 Hz, 1H), 6.98-6.90 (m, 2H), 6.11 (s, 2H); Calculated for C14H10ClNO3, 275.03; MS (ESI) (m/z) observed 276.1 (M+1)+.
With dihydrogen peroxide; potassium carbonate; In methanol; water;
2,3-(methylenedioxy)benzoic acid A solution of <strong>[7797-83-3]2,3-(methylenedioxy)benzaldehyde</strong> (160mg, 1.06mmol), potassium carbonate (960 mg, 6.9 mmol) and 2.4mL of hydrogen peroxide (30-32 wt.% solution in water) in 10 mL of methanol was stirred for 16 hours at room temperature. The mixture was washed with diethyl ether. The water layer was acidified with 1 N aq. HCl to pH>1, then extracted with ethyl acetate. The organic layer was dried over MgSO4, then concentrated to give the desired product (170mg, 96%). EI-MS (m/z) 164.8 (M-).
With hydrogenchloride; potassium hydroxide; silver nitrate; In ethanol; water;
Preparation of 2,3-methylenedioxybenzoic acid To a solution of 0.85 g (5.66 mmol) of 2,3-methylenedioxybenzaldehyde (Aldrich) in EtOH at 0 C. was added a solution of 2.12 g (12.45 mmol) of AgNO3 in 7.5 mL of H2O. To this was then added a solution of 1.74 g (31.4 mmol) of KOH in 12 mL of H2O. After 2 h, the reaction mixture was filtered and the filter was washed with EtOH. The filtrate was concentrated and the pH was adjusted to pH=2 to 3 with 6N HCl. The title compound precipitated out and was isolated by filtration to give the title compound. 1H NMR (CDCl3) delta6.16 (s, 2H), 6.92 (t, 1H, J=8 Hz), 7.04 (d, 1H, J=8 Hz), 7.48 (d, 1H, J=8 Hz);
A mixture of the material so obtained, a 2N aqueous potassium hydroxide solution (15.5 ml) and methanol (40 ml) was stirred at ambient temperature for 2 hours. The solution was concentrated to about one quarter of the original volume and cooled in an ice bath. The mixture was acidified to pH 3.5 by the addition of a 2N aqueous hydrochloric acid solution. The resultant precipitate was collected by filtration and washed in turn with water and diethyl ether. There was thus obtained 2,3-methylenedioxybenzoic acid (1.87 g); NMR Spectrum: (DMSOd6) 6.1 (s, 1H), 6.9 (t, 1H), 7.15 (d,. 1H), 7.3 (d, 1H), 13.0 (br s, 1H).
With diphenylphosphoranyl azide; triethylamine; In 1,4-dioxane; for 10h;Heating / reflux;
To a refluxing solution of commercially available 2, 3-methylenedioxybenzoic acid G1 (485 mg; 2. 92 MMOL) in 1,4-dioxane (8.0 mL) and t-butanol (2.5 mL) was added TEA (430, UL ; 3.08 MMOL) and diphenylphosphoryl azide (DPPA, 630 P. L ; 2.92 MMOL) and refluxed for 10 h. The mixture was evaporated, diluted with chloroform, washed with 5 % citric acid (3x), water, saturated sodium bicarbonate and brine, dried (MGS04), filtered and evaporated to provide the crude product. Flash column purification on silica gel with hexane : EtOAc (75 : 25) provided the pure Boc-amino compound G2 (257 mg; 37%)
With diphenyl phosphoryl azide; triethylamine; In 1,4-dioxane; for 5h;Heating / reflux;
The material so obtained was suspended in anhydrous dioxane (30 ml) and anhydrous diphenylphosphoryl azide (2.45 ml), triethylamine (1.6 ml) and tert-butanol (9 ml) were added. The mixture was heated to reflux for 5 hours. The mixture was cooled to ambient temperature, concentrated by evaporation and diluted with ethyl acetate. The organic phase was washed in turn with a 5% aqueous citric acid solution, water, an aqueous sodium bicarbonate solution and brine and dried over magnesium sulphate. The solvent was evaporated and the residue was purified by column chromatography on silica using a 19: 1 mixture of petroleum ether (b. p. 40-60C) and ethyl acetate as eluent. There was thus obtained tert-butyl 2,3-methylenedioxyphenylcarbamate (1.98 g) as a solid; NMR Spectrum: (CDC13) 1.55 (s, 9H), 5.95 (s, 2H), 6.4 (br s, 1H), 6.55 (d, 1H), 6.8 (t, 1H), 7.45 (d, 1H).
With diphenyl phosphoryl azide; triethylamine; In 1,4-dioxane; for 5h;Heating / reflux;
The material so obtained was suspended in anhydrous dioxane (30 ml) and anhydrous diphenylphosphoryl azide (2.45 ml), triethylamine (1.6 ml) and tert-butanol (9 ml) were added. The mixture was heated to reflux for 5 hours. The mixture was cooled to ambient temperature, concentrated by evaporation and diluted with ethyl acetate. The organic phase was washed in turn with a 5% aqueous citric acid solution, water, an aqueous sodium bicarbonate solution and a saturated brine solution and dried over magnesium sulphate. The solvent was evaporated and the residue was purified by column chromatography on silica using a 19: 1 mixture of petroleum ether (b. p. [40-60C)] and ethyl acetate as eluent. There was thus obtained tert-butyl N- (2, 3-methylenedioxyphenyl) carbamate (1.98 g) as a solid; NMR Spectrum : (CDC13) 1.55 (s, 9H), 5.95 (s, 2H), 6.4 (br s, 1H), 6.55 (d, 1H), 6.8 (t, 1H), 7.45 (d, [ 1H).]
With potassium hydroxide; In methanol; water; at 20℃; for 3h;
A solution of methyl benzo[ ][1 ,3]dioxole-4-carboxylate (0.4 g, 2.22 mmol) in methanol (8.0 mL) was treated with 2.0 M aqueous KOH (2.2 mL) and the solution stirred at rt for 3 hours. The mixture was concentrated to ~3 mL volume, diluted with water (5 mL) and acidified to pH ~3 using 2.0 M HCI. The resulting precipitate was removed by filtration, washed with water then diethyl ether and dried in vacuo to give benzo[ ][1 ,3]dioxole-4-carboxylic acid as a beige solid (0.38 g, 97%).1H NMR (400 MHz, DMSO-d6): delta = 7.28 (dd, J= 8.0, 1.2 Hz, 1H),6.97 (dd, J=8.0, 1.2 Hz, 1H),6.89 (t, J=8.0Hz, 1 H), 6.12 (s, 2H);13C NMR(100 Hz, DMSO-de) 165.5, 148.9, 148.5, 122.9, 121.6, 113.8, 112.5, 102.1.
61%
With water; sodium hydroxide; at 50℃; for 5h;
Compound P-2 (500 mg, 2.8 mmol) was weighed and suspended in 5 mL of water. Add 2N NaOH aqueous solution 10mL, Heat to 50C for about 5 hours, The reaction solution is clear. Pour the reaction solution into ice water, Adjust pH to acidic with 2N dilute HCl There is a solid precipitated, Filtering, Dry powder 280mg, Yield 61%. Used for the next reaction without purification.
A mixture of the material so obtained, a 2N aqueous potassium hydroxide solution (15.5 ml) and methanol (40 ml) was stirred at ambient temperature for 2 hours. The solution was concentrated to about one quarter of the original volume and cooled in an ice bath. The mixture was acidified to pH 3.5 by the addition of a 2N aqueous hydrochloric acid solution. The resultant precipitate was collected by filtration and washed in turn with water and diethyl ether. There was thus obtained 2,3-methylenedioxybenzoic acid (1.87 g); NMR Spectrum: (DMSOd6) 6.1 (s, 1H), 6.9 (t, 1H), 7.15 (d, 1H), 7.3 (d, 1H), 13.0 (br s, 1H).
A mixture of the material so obtained, a 2N aqueous potassium hydroxide solution (15.5 ml) and methanol (40 ml) was stirred at ambient temperature for 2 hours. The solution was concentrated to about one quarter of the original volume and cooled in an ice bath. The mixture was acidified to pH3.5 by the addition of a 2N aqueous hydrochloric acid solution. The resultant precipitate was collected by filtration and washed in turn with water and diethyl ether. There was thus obtained 2, [3-METHYLENEDIOXYBENZOIC] acid (1.87 g); NMR Spectrum : [(DMSOD6)] 6.1 (s, [1H),] 6.9 (t, [1H),] 7.15 (d, [1H),] 7.3 (d, [1H),] 13.0 (br s, [1H).] The material so obtained was suspended
With n-butyllithium; sodium hydrogencarbonate; In hexane;
a) Preparation of 2,3-methylenedioxyphenylcarboxylic acid A solution of 1,3-benzodioxole (3.09 g, 32 mmol) in dry ether (50 mL) was treated dropwise at -10 C. with 2.5M n-butyllithium (15 mL, 35 mmol) in hexane. When the addition was complete, the mixture was stirred under reflux for one hour. After cooling to room temperature, it was added to crushed solid carbon dioxide, and after 24 hours, the residue was treated with 10% aq. NaHCO3 and ether. The alkali layer was separated, washed with ether, then acidified with cold concentrated HCl, and extracted with chloroform. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure (1.1 g, 20%). EI-MS m/z 167 (M+H)+
With n-butyllithium; sodium hydrogencarbonate; In hexane;
a)Preparation of 2,3-methylenedioxyphenylcarboxylic acid A solution of 1,3-benzodioxole (3.09 g, 32 mmol) in dry ether (50 mL) was treated dropwise at -10 C. with 2.5 M n-butyllithium (15 mL, 35 mmol) in hexane. When the addition was complete, the mixture was stirred under reflux for one hour. After cooling to room temperature, it was added to crushed solid carbon dioxide, and after 24 hours, the residue was treated with 10 % aq. NaHCO3 and ether. The alkali layer was separated, washed with ether, then acidified with cold concentrated HCl, and extracted with chloroform. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure (1.1 g, 20%). EI-MS m/z 167 (M+H)+
With n-butyllithium; sodium hydrogencarbonate; In hexane;
a) Preparation of 2,3-methylenedioxyphenylcarboxylic acid A solution of 1,3-benzodioxole (3.09 g, 32 mmol) in dry ether (50 mL) was treated dropwise at -10 C. with 2.5 M n-butyllithium (15 mL, 35 mmol) in hexane. When the addition was complete, the mixture was stirred under reflux for one hour. After cooling to room temperature, it was added to crushed solid carbon dioxide, and after 24 hours, the residue was treated with 10% aq. NaHCO3 and ether. The alkali layer was separated, washed with ether, then acidified with cold concentrated HCl, and extracted with chloroform. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure (1.1 g, 20%). EI-MS m/z 167 (M+H)+
(-)-6-Chloro-N-[(1,4-diazabicyclo[2.2.2]oct-2-yl)methyl]-1,3-benzodioxolane-4-carboxamide dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-chloro-succinimide; In methanol; dichloromethane; water; acetic acid;
A suspension of 5.0 g (30.1 mmol) of 1,3-benzodioxolane-4-carboxylic acid in 50 ml of acetic acid is prepared, it is heated to 70 C., 1.0 g of N-chlorosuccinimide is added over 15 min, heating is continued for 30 min, 1.0 g of N-chlorosuccinimide is again added and, after heating for a further 15 min, 2.0 g of N-chlorosuccinimide are added, i.e. a total of 4.0 g (30.1 mmol), and heating is maintained at 70 C. for 2 h. The mixture is allowed to cool, is poured onto 150 ml of water and the solid is collected by filtration, washed with water and dried under vacuum. 1.72 g of solid are obtained, which solid is purified by chromatography on a column of silica gel, elution being carried out with a 95/5/0.5 mixture of dichloromethane, methanol and acetic acid. After recrystallization from a mixture of ethanol and water, 1.13 g of compound are obtained. Melting point: 210 C.
EXAMPLE 11 Preparation of 2,3-methylenedioxy-N-[(4-benzyl-2-morpholinyl)methyl]benzamide The title compound is prepared in substantially the same manner as in Example 6(1), using <strong>[110859-47-7]2-aminomethyl-4-benzylmorpholine</strong> and 2,3-methylenedioxybenzoic acid, respectively, in place of 2-aminomethyl-4-(4-cyanobenzyl)morpholine and 4-amino-5-chloro-2-methoxybenzoic acid in Example 6(1). The free base thus obtained is treated in substantially the same manner as in Example 6(2) to give the fumarate 1/4 hydrate of the title compound, mp 144-146 C. (recrystallized from ethanol).
N-[3-(1-imidazolyl)propyl]-2,3-methylenedioxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride; triethylamine; In dichloromethane; 1,2-dichloro-ethane; N,N-dimethyl-formamide;
Example 11 Preparation of N-[3-(1-imidazolyl)propyl]-2,3-methylenedioxybenzamide (compound 11) Thionyl chloride (0.8 ml) and DMF (0.02 ml) were added to a solution of 2,3-methylenedioxybenzoic acid (1.22 g) in 1,2-dichloroethane (5 ml), and the mixture was heated under reflux in a nitrogen flow for an hour. The solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (10 ml) and added dropwise to triethylamine (1.02 ml) and N-(3-aminopropyl)imidazole (0.63 g) in methylene chloride (10 ml) while cooling with ice, stirred in a nitrogen flow for an hour, then poured into water. The organic layer was washed with aqueous saturated sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was separated by silica gel column chromatography eluding with chloroform/methanol (19:1 by volume) to obtain the objective N-[3-(1-imidazolyl)propyl]-2,3-methylenedioxybenzamide (compound 11)(1.3 g, 65 %) as an oil. NMR delta (CDCl3): 2.06 (2H, tt), 3.41 (2H, dt), 3.99 (2H, t), 6.03 (2H, s), 6.91 (3H, m), 7.00 (2H, s), 7.47 (2H, m)
4-(3chloro-phenylamino)-3-(2,3-methylenedioxy-benzoylamino)-1H-pyrazolo[3,4-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With NMM; In tetrahydrofuran; water; dimethyl sulfoxide;
EXAMPLE 6 Under a nitrogen atmosphere, 320 mul (2.9 mmol) of NMM and 210 1 (1.6 mmol) of isobutyl chloroformate are added at -20 C. to 250 mg (1.5 mmol) of 2,3-methylenedioxybenzoic acid [for preparation see: Chem. Ber. 104 (1971) 2347] in 3.2 ml of THF and then stirred for 45 min. 378 mg (1.45 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine (see Step 1.6) are then added and the reaction mixture is allowed to rise to RT and is stirred for 1 hour to complete the reaction. The reaction mixture is poured into 100 ml of water and stirred for 1 hour, and the crude product is filtered off and washed with water and ethanol. Dissolution in 3 ml of DMSO at =110 C., cooling, filtering and washing with ethanol yield 4-(3chloro-phenylamino)-3-(2,3-methylenedioxy-benzoylamino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC:tRet(grad20-100/20)=16.5; FAB-MS: (M+H)+=409.
To a solution of the compound of the previous step (13 g) in acetone (200 ml) were added triethylamine (12 ml) and ethyl chlorocarbonate (8.0 ml) under ice-cooling, and the mixture was stirred for 30 min. Then, sodium azide (5.5 g) was added to the solution under ice-cooling, and the mixture was stirred for 1 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. Toluene (160 ml) was added to the residue, and the mixture was heated under reflux for 1 hr. tert-Butanol (40 ml) was added, and the mixture was further heated under reflux for 3.5 hr. The reaction solution was concentrated, ethyl acetate was added, and the precipitate was removed by filtration. The solvent was evaporated under reduced pressure. The residue was dissolved in CHCl3 (50 ml), trifluoroacetic acid (30 ml) was added, and the mixture was stirred at room temperature for 8 hr. The reaction solution was poured into aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (13 g, 100%). NMR(300MHz, CDCl3)delta:3.57(2H, br), 5.92(2H, s), 6.30-6.36(2H, m), 6.67(1H, dd, J=7.8, 0.3Hz).
To a solution of the compound of the previous step (16 g) in methanol (170 ml) was added a solution of sodium hydroxide (9.9 g) in water (40 ml), and the mixture was stirred at room temperature for 3.5 hr. The reaction solution was acidified with concentrated hydrochloric acid, and the mixture was concentrated. The resulting precipitate was collected by filtration to give the title compound (13 g, 95%). NMR(300MHz, CDCl3)delta:6.14(2H, s), 6.90(1H, t, J=7.8Hz), 7.03(1H, dd, J=7.5, 1.2Hz), 7.46(1H, dd, J=8.1, 1.2Hz).
Method C; BenzoH ,31dioxole-4-carboxylic acidhydrazide (Intermediate compound); A mixture of 1 ,3-benzimidazole-4-carboxylic acid (3.0 g, 17,5 mmol), sulfuric acid (0.17 g, 1.75 mmol) and methanol (40 ml) was stirred at reflux for 15 h. The mixture of the intermediate benzo[1 ,3]dioxole-4-carboxylic acid methyl ester was allowed to reach room-temperature. Hydrazine monohydrate (8.5 g, 175 mmol) was added and the mixture was stirred at reflux for 15 h. The mixture was evaporated, water was added and the crystalline product was isolated by filtration. Yield 2.15 g (68%).
(S)-ethyl 2-(tert-butoxy)-2-(4,7-dimethyl-6-(trimethylsilyl)isoindolin-5-yl)acetate[ No CAS ]
(S)-ethyl 2-(2-(benzo[d][1,3]dioxole-4-carbonyl)-4,7-dimethyl-6-(trimethylsilyl)isoindolin-5-yl)-2-(tert-butoxy)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
288 mg
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; for 1.5h;
Step 3(S) -Ethyl 2-(2-(benzo[d][1, 3]dioxole-4-carbonyl)-4, 7-dimethyl-6-(trimethylsilyl)isoindolin-5-yl) -2- (tert-butoxy)acetate. A solution of crude (S)-ethyl 2-(tert-butoxy)-2-(4,7-dimethyl-6- (trimethylsilyl)isoindolin-5-yl)acetate (207 mg, 0.547 mmol, 100 % yield) was disolved in EtOAc (5 mL) and treated with benzo[d][1 ,3]dioxole-4-carboxylic acid (182 mg, 1 .094 mmol), followed by NEt3 (0.229 mL, 1 .642 mmol), and then T3P (0.977 mL, 1 .642 mmol). The reaction was stirred for 1 .5 h, poured over sat. NaHCO3, and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2504, and concentrated in vacuo to give (S)-ethyl 2-(2- (benzo[d] [1 ,3]dioxole-4-carbonyl)-4,7-dimethyl-6-(trimethylsilyl) isoindolin-5-yl)-2-(tert- butoxy)acetate (288 mg, 0.547 mmol, 100 % yield). LC/MS (m/z) ES+ = 526.3 (M+1).
(R)-1-((S,Z)-2-(2-(benzyloxy)-2-oxoethylidene)-4-oxoazetidin-3-yl)ethyl benzo[d][1,3]dioxole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 16h;Inert atmosphere;
General procedure: To a solution of alcohol A (1 equiv), in CH2Cl2 (10mL/mmol) under inert atmosphere, the desired acid (3a-j) (1.58 equiv) and DMAP (0.2 equiv) were added. The mixture was then cooled to 0C and DCC (1.58 equiv) was added; the system was allowed to reach room temperature in 15min and left under stirring overnight. After 16h (TLC monitoring) the reaction mixture was quenched with water at 0C and extracted with CH2Cl2 (3×15mL). The collected organic phases were dried on Na2SO4 and evaporated. The residue was treated with EtOAc (2×20mL) and filtered to separate dicyclohexylurea precipitate. The solution was then evaporated and purified by flash-chromatography to afford the desired beta-lactams functionalized with O-protected polyphenolic residues (1a, 1b, 1e, 4c, 4d, or 4f-j).
Compound P-1 (100 mg, 0.6 mmol) was weighed and suspended in 5 mL of dry CH2Cl2. A solution consisting of oxalyl chloride (76 mg, 0.6 mmol) and 2 mL of dry CH2Cl2 was added dropwise. After the addition, the mixture was stirred at room temperature for 1 h. After 1 hour, the solvent was distilled off under reduced pressure. Dissolved in 5 mL of dry CH2Cl2 In an ice bath was added dropwise from anhydrous ethanol (139 mg, 3 mmol), A solution consisting of triethylamine (183 mg, 1.8 mmol) and 5 mL of dry CH2Cl2 was added. Add about 30min, After the addition, the reaction is performed at room temperature for 1 hour. After the reaction, pour into ice water. Extraction with ethyl acetate (50 mL × 2) The organic phase was washed twice with water and dried over anhydrous Na2SO4 overnight. Filtering, Concentrated pale yellow solid, Separation with 300-400 mesh silica gel column chromatography, The eluent was n-hexane:ethyl acetate=3:1 (v/v) to obtain 78 mg of white crystals. Yield 67%.
benzo[1,3]dioxole-4-carboxylic acid 2,2,2-trifluoroethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
Compound P-1 (100 mg, 0.6 mmol) was weighed out Resuspended in 5 mL of dry CH2Cl2 Addition of oxalyl chloride (76mg, 0.6mmol) And 2mL dry CH2Cl2 solution, After the addition, the mixture was stirred at room temperature for 1 h. After 1 hour, the solvent was distilled off under reduced pressure. Dissolved in 5 mL of dry CH2Cl2 It was added dropwise to 2,2,2-trifluoroethanol (301 mg, 3 mmol) in an ice bath, A solution consisting of triethylamine (183 mg, 1.8 mmol) and 5 mL of dry CH2Cl2 was added. Add about 30min, After the addition, the reaction is performed at room temperature for 1 hour. After the reaction, pour into ice water. Extraction with ethyl acetate (50 mL × 2) The organic phase was washed twice with water and dried over anhydrous Na2SO4 overnight. Filtering, Concentrated pale yellow solid, Separation with 300-400 mesh silica gel column chromatography, The eluent was n-hexane:ethyl acetate=3:1 (v/v) to obtain 109 mg of white crystals. Yield 73%.
N-(5-bromopyridin-3-yl)benzo[d][1,3]dioxole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 50℃; for 2h;
A mixture of 5-bromopyridin-3-amine (300 mg, 1.73 mmol), benzo[d][l,3]dioxole- 4-carboxylic acid (431 mg, 2.60 mmol) and EDCI.HC1 (497 mg, 2.60 mmol) in pyridine (4 mL) was stirred at 50 C for 2 h. The reaction mixture turned into brown solution from yellow. The reaction mixture was concentrated and the residue was diluted with water (25 mL), and then extracted with EtOAc (25 mL x3). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na2S04 and concentrated. The crude product was triturated with pentane/EtOAC (10 mL, 1/1) to give N-(5-bromopyridin-3-yl)benzo[d][l,3]dioxole-4- carboxamide (385 mg, yield: 69%) as a yellow solid. (1662) NMR (400 MHz, CDCb) d 6.20 (2H, s), 6.99-7.07 (2H, m), 7.64 (1H, d , J= 7.5, 1.8 Hz), 8.44 (1H, d, J= 2.0 Hz), 8.57 (1H, d, J= 2.3 Hz), 8.60-8.63 (1H, m), 8.83 (1H, brs).
1-(2-(benzo[d][1,3]dioxole-4-carboxamido)ethyl)-N-((R)-2-(2,4-dimethylphenyl)-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide[ No CAS ]
2-methyl-3-phenyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine[ No CAS ]
benzo[d][1,3]dioxol-4-yl(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In ethyl acetate; at 20℃; for 1h;Inert atmosphere;
General procedure: To a solution of 2-methyl-3-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, Intermediate 1, (150 mg, 0.7 mmol) in dichloromethane (DCM) (5.0 mL) was added HATU (348 mg, 0.91 mmol), followed by DIPEA (0.6 mL, 3.5 mmol) and 1-naphthoic acid (222 mg, 1.3 mmol), and the mixture stirred at room temperature for 1 h. The reaction mixture was diluted with water and the aqueous layer extracted with DCM (*2). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase HPLC (Method A) to afford the title compound as a white solid (94 mg, 36% yield). MS (ESI): mass calcd. for C24H21N3O, 367.1; m/z found, 368.1 [M+H]+. 1H NMR (400 MHz, Methanol-d4) delta 8.12-7.93 (m, 2H), 7.89-7.74 (m, 1H), 7.67-7.35 (m, 9H), 5.20-4.92 (m, 2H), 4.46-4.22 (m, 1H), 4.13-3.98 (m, 0.3H), 3.76 (d, J=54.9 Hz, 3H), 3.52-3.41 (m, 1H), 2.93-2.75 (m, 0.7H), 2.57-2.30 (m, 1H).
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