* 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.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane; acetonitrile for 1.5 h; Reflux
A solution of methyl 2-fluoro-5-methylbenzoate (6.72 g, 40 mmol)Was added to the reaction flask, CC14 (1 OOmL) was added, NBS (7.47 g, 42 mmol) was added, ΑIBN (1.29 g, 8 mmol)(100 mL) was added, washed with saturated NaCl (50 mL X3), dried over anhydrous magnesium sulfate, column chromatography (ΕΑ: Ρ = 1: 150), and the reaction mixture was heated to reflux. Afforded 6.4 g of white solid in 65percent yield.
55%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 6.5 h; Inert atmosphere; Reflux
A mixture of 1 f (4.67 g, 27.8 mmol), NBS (5.22 g, 29.2 mmol) and AIBN (2.73 g, 16.7 mmol) in CCI4 (280 mL) was refluxed under N2 for 6.5 h. The solvents were removed and the residue was suspended with ether. The solid was filtered off. The filtrate was concentrated and purified by silica gel chromatography to give desired product 1 g (3.8 g, 55percent yield)
13.5%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3 h; Inert atmosphere; Reflux
The 2-fluoro-5-methyl benzoic acid methyl ester (100 mg, 0 . 60mmol), NBS (112 mg, 0 . 63mmol), AIBN (60 mg, 0 . 36mmol) is added in the reaction bottle, by adding CCl4(5 ml), Ar atmosphere reflow 3h, raw material a small amount of residual, reducing pressure and evaporating solvent, adding anhydrous ethyl ether (10 ml), vacuum filtration, filtrate turns on lathe does, column chromatography, to obtain 20 mg of white solid, yield 13.5percent.
13.5%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3 h; Reflux; Inert atmosphere
Methyl 2-fluoro-5methylbenzoate (100 mg, 0.60 mmol), NBS (112 mg, 0.63 mmol), AIBN (60 mg, 0.36 mmol) were sequentially added to the reaction flask.Add CCl4 (5mL), reflux under Ar atmosphere for 3h, a small amount of raw materials remained,The solvent was evaporated under reduced pressure. EtOAc (EtOAc)The filtrate was spin-dried, column chromatography,20 mg of a white solid were obtained in a yield of 13.5percent.
Reference：
[1] Patent: CN107098886, 2017, A, . Location in patent: Paragraph 0137; 0138
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 17, p. 3189 - 3202
[3] Patent: WO2012/125521, 2012, A1, . Location in patent: Page/Page column 35; 36
[4] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 22, p. 3217 - 3220
[5] Patent: CN105461697, 2016, A, . Location in patent: Paragraph 0128; 0129; 0130
[6] Patent: CN108727343, 2018, A, . Location in patent: Paragraph 0245; 0247; 0248
[7] Patent: US2003/158256, 2003, A1,
[8] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
2
[ 2967-93-3 ]
[ 709-45-5 ]
Reference：
[1] Bioorganic and medicinal chemistry, 2002, vol. 10, # 9, p. 3013 - 3021
3
[ 321-12-0 ]
[ 74-88-4 ]
[ 2967-93-3 ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium carbonate In acetoneHeating / reflux
Example 143; Synthesis of (5)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-l-ylmethyl}-2-fluoro-benzoic acid; Step 1; Preparation of 2-Fluoro-5-methyl-benzoic acid methyl ester; Heat a mixture of 2-fluoro-5-methyl-benzoic acid (1.0 g, 6.48 mmol), iodomethane (1.38g, 9.73 mmol), and potassium carbonate (2.68 g, 19.44 mmol) in acetone (20 mL) atreflux overnight. Cool the reaction and filter through Celite.(R).. Concentrate the filtrateunder reduced pressure to provide the title compound as a colorless gum (0.895 g, 82percent).
SOCI2 (1 mL) was added dropwise to acid 1e (1 1 g) in MeOH (60 mL). The solution was refluxed for 20 h. MeOH was removed on rotovapor, and the residue was dissolved in ether. The organic layer was washed with water, saturated NaHC03, brine, dried over Na2S04, filtered and concentrated to afford clear oil 1f (10.6 g, 88percent yield)
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; acetonitrile; for 1.5h;Reflux;
A solution of methyl 2-fluoro-5-methylbenzoate (6.72 g, 40 mmol)Was added to the reaction flask, CC14 (1 OOmL) was added, NBS (7.47 g, 42 mmol) was added, AlphaIBN (1.29 g, 8 mmol)(100 mL) was added, washed with saturated NaCl (50 mL X3), dried over anhydrous magnesium sulfate, column chromatography (EpsilonAlpha: Rho = 1: 150), and the reaction mixture was heated to reflux. Afforded 6.4 g of white solid in 65% yield.
55%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 6.5h;Inert atmosphere; Reflux;
A mixture of 1 f (4.67 g, 27.8 mmol), NBS (5.22 g, 29.2 mmol) and AIBN (2.73 g, 16.7 mmol) in CCI4 (280 mL) was refluxed under N2 for 6.5 h. The solvents were removed and the residue was suspended with ether. The solid was filtered off. The filtrate was concentrated and purified by silica gel chromatography to give desired product 1 g (3.8 g, 55% yield)
13.5%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 3h;Inert atmosphere; Reflux;
The 2-fluoro-5-methyl benzoic acid methyl ester (100 mg, 0 . 60mmol), NBS (112 mg, 0 . 63mmol), AIBN (60 mg, 0 . 36mmol) is added in the reaction bottle, by adding CCl4(5 ml), Ar atmosphere reflow 3h, raw material a small amount of residual, reducing pressure and evaporating solvent, adding anhydrous ethyl ether (10 ml), vacuum filtration, filtrate turns on lathe does, column chromatography, to obtain 20 mg of white solid, yield 13.5%.
13.5%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 3h;Reflux; Inert atmosphere;
Methyl 2-fluoro-5methylbenzoate (100 mg, 0.60 mmol), NBS (112 mg, 0.63 mmol), AIBN (60 mg, 0.36 mmol) were sequentially added to the reaction flask.Add CCl4 (5mL), reflux under Ar atmosphere for 3h, a small amount of raw materials remained,The solvent was evaporated under reduced pressure. EtOAc (EtOAc)The filtrate was spin-dried, column chromatography,20 mg of a white solid were obtained in a yield of 13.5%.
With N-Bromosuccinimide; azobisisobutyronitrile; In tetrachloromethane; hexane; ethyl acetate;
To a solution of methyl 2-fluoro-5-methylbenzoate (17.16 g, 102.1 mmol) in CCl4(250 mL) is added NBS (18.2 g, 102.1 mmol) and AIBN (0.83 g, 5.1 mmol), and the resulting solution is refluxed for 3 hours. After cooling, the mixture is filtered through celite, evaporated, and chromatographed (silica, 5 to 15% EtOAc/hexane) to yield methyl 5-bromomethyl-2-fluorobenzoate, as a white solid.
With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; at 80℃; for 12h;
General procedure: A mixture of methyl 2-fluoro-3-methylbenzoate (1g, 6.0mmol), NBS (1.3g, 7.1mmol) and di-benzoyl peroxide (BPO) (144.0mg, 84.4mmol) in 1,2-dichloroethane (5mL) was heated to 80C, and stirred for 12h. After cooling to r.t., the precipitated solid was separated by filtration. The filtrate was evaporated in vacuo and the residue was dissolved in ethers (15mL) and washed with NaHCO3 (2N, 15mL). The organic layer dried over Na2SO4, filtered and concentrated to give a crude product (1.2g, 82%), which was used in the next step reaction without further purification.
(3aS,4R,8R,8aS)-5-(3-Amino-benzyl)-4,8-dibenzyl-2,2-dimethyl-7-(3-thiophen-2-yl-1H-indazol-5-ylmethyl)-hexahydro-1,3-dioxa-5,7-diaza-azulen-6-one[ No CAS ]
(3aS,4R,8R,8aS)-5-(3-Amino-benzyl)-4,8-dibenzyl-2,2-dimethyl-7-(3-thiophen-3-yl-1H-indazol-5-ylmethyl)-hexahydro-1,3-dioxa-5,7-diaza-azulen-6-one[ No CAS ]
(3aS,4R,8R,8aS)-5-(3-Amino-benzyl)-4,8-dibenzyl-2,2-dimethyl-7-[3-(1H-pyrazol-3-yl)-1H-indazol-5-ylmethyl]-hexahydro-1,3-dioxa-5,7-diaza-azulen-6-one[ No CAS ]
(3aS,4R,8R,8aS)-5-(3-Amino-benzyl)-4,8-dibenzyl-7-[3-(4-fluoro-phenyl)-1H-indazol-5-ylmethyl]-2,2-dimethyl-hexahydro-1,3-dioxa-5,7-diaza-azulen-6-one[ No CAS ]
(3aS,4R,8R,8aS)-5-(3-Amino-benzyl)-4,8-dibenzyl-7-[3-(4-methoxy-phenyl)-1H-indazol-5-ylmethyl]-2,2-dimethyl-hexahydro-1,3-dioxa-5,7-diaza-azulen-6-one[ No CAS ]
(3aS,4R,8R,8aS)-5-(3-Amino-benzyl)-4,8-dibenzyl-7-[3-(3-methoxy-phenyl)-1H-indazol-5-ylmethyl]-2,2-dimethyl-hexahydro-1,3-dioxa-5,7-diaza-azulen-6-one[ No CAS ]
(3aS,4R,8R,8aS)-5-(3-Amino-benzyl)-7-[3-(3-amino-phenyl)-1H-indazol-5-ylmethyl]-4,8-dibenzyl-2,2-dimethyl-hexahydro-1,3-dioxa-5,7-diaza-azulen-6-one[ No CAS ]
(3aS,4R,8R,8aS)-5-(3-Amino-benzyl)-4,8-dibenzyl-2,2-dimethyl-7-[3-(3-trifluoromethyl-phenyl)-1H-indazol-5-ylmethyl]-hexahydro-1,3-dioxa-5,7-diaza-azulen-6-one[ No CAS ]
(3aS,4R,8R,8aS)-5-(3-Amino-benzyl)-4,8-dibenzyl-2,2-dimethyl-7-[3-(4-trifluoromethyl-phenyl)-1H-indazol-5-ylmethyl]-hexahydro-1,3-dioxa-5,7-diaza-azulen-6-one[ No CAS ]
3-tert-Butoxycarbonyloxy-5-[(3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethyl-7-(3-nitro-benzyl)-6-oxo-hexahydro-1,3-dioxa-5,7-diaza-azulen-5-ylmethyl]-indazole-1-carboxylic acid tert-butyl ester[ No CAS ]
5-[(3aS,4R,8R,8aS)-7-(3-Amino-benzyl)-4,8-dibenzyl-2,2-dimethyl-6-oxo-hexahydro-1,3-dioxa-5,7-diaza-azulen-5-ylmethyl]-3-(3-amino-phenyl)-indazole-1-carboxylic acid tert-butyl ester[ No CAS ]
5-[(3aS,4R,8R,8aS)-4,8-Dibenzyl-2,2-dimethyl-7-(3-nitro-benzyl)-6-oxo-hexahydro-1,3-dioxa-5,7-diaza-azulen-5-ylmethyl]-3-(4-formyl-phenyl)-indazole-1-carboxylic acid tert-butyl ester[ No CAS ]
HOBt (842 mg, 6.23 mmol), and EDCI (1.19g, 6.23 mmol) were added to 2-fluoro-5- methyl-benzoic acid methyl ester (800 mg, 5.19 mmol) in acetonitrile (10.3 mL, 197 mmol) at room temperature. After two hours a mixture of hydrazine monohydrate (0.5 [ML,] 10.38 mmol) in acetonitrile (5.2 mL, 98.6 mmol) and cyclohexene (0.13 mL, 1.28 mmol) was added dropwise at [0C.] After 15 minutes, the solvent was removed using a rotoevaporator and the residue was diluted with ethyl acetate, quenched with water (few mL), washed with sodium carbonate (several times), dried over sodium sulfate, filtered and concentrated to afford 2-fluoro-5-methyl-benzoic acid hydrazide (663 mg, 76%, yellow [SOLID). LH NMR] (DMSO) 8 (ppm): 9.48 (bs, 1H), 7.31 (m, 2H), 7.14 (m, 1H), 4.53 (bs, 2H), 2.30 (s, 3H).
With potassium carbonate; In acetone;Heating / reflux;
Example 143; Synthesis of (5)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-l-ylmethyl}-2-fluoro-benzoic acid; Step 1; Preparation of 2-Fluoro-5-methyl-benzoic acid methyl ester; Heat a mixture of <strong>[321-12-0]2-fluoro-5-methyl-benzoic acid</strong> (1.0 g, 6.48 mmol), iodomethane (1.38g, 9.73 mmol), and potassium carbonate (2.68 g, 19.44 mmol) in acetone (20 mL) atreflux overnight. Cool the reaction and filter through Celite.(R).. Concentrate the filtrateunder reduced pressure to provide the title compound as a colorless gum (0.895 g, 82percent).
With thionyl chloride; In methanol; ethyl acetate;
To a solution of <strong>[321-12-0]2-fluoro-5-methylbenzoic acid</strong> (20.0 g, 0.13 mol) in MeOH (100 mL) is added thionyl chloride (1.9 mL, 26.0 mmol) dropwise, via syringe, and the solution is refluxed overnight. After cooling, the solvent is evaporated, and the residue is taken up in ethyl acetate (200 mL), extracted with sat'd aq. NaHCO3 (50 mL), brine (50 mL), water (50 mL), dried (MgSO4), and chromatographed (silica, 5percent EtOAc/hexane) to yield methyl 2-fluoro-5-methylbenzoate, as a clear oil.
(R)-tert-butyl 2-(4-(5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoyl)piperazine-1-carbonyl)-2-methylpyrrolidine-1-carboxylate[ No CAS ]
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