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Structure of 56908-88-4 * Storage: {[proInfo.prStorage]}
* 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 4-methylmorpholine N-oxide In tetrahydrofuran for 12 h; Reflux
A solution of compound C (3.29 g, 10 mmol) and 4-methyl-n-oxo morpholine (3.51 g, 30 mmol) were dissolved in 60 mL of tetrahydrofuran and the reaction mixture was heated under reflux for 12 hours. The organic compound was dried over magnesium sulfate and dried over silica gel column chromatography using dichloromethane / petroleum ether (v / v = 2: 3) as eluent. After drying and steaming, the mixture was dried to give the intermediate D (2.42 g, yield 92percent) as a white solid.
Reference：
[1] Patent: CN106946777, 2017, A, . Location in patent: Paragraph 0063-0065
2
[ 145691-59-4 ]
[ 56908-88-4 ]
Yield
Reaction Conditions
Operation in experiment
2.5 g
With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 1 h;
General procedure: 3,5-Di-t-butylbenzoic acid (5.00 g, 0.021 mol) was dissolved in anhydrous THF (250 mL) under argon atmosphere and the solution cooled to 0 °C. Lithium aluminum hydride (1.62 g, 0.043 mol) was added in small portions and the solution stirred at room temperature overnight. The reaction was quenched with water, Et2O (100 mL) was added and the mixture acidified with concentrated HCl solution until the solid residue was dissolved. The medium was extracted with Et2O and the organic phase dried over MgSO4, filtered and concentrated to yield 4.31g of 5a. 1H NMR δ (CDCl3) 1.34 (s, 18H, di-t-butyl), 4.70 (s, 2H, PhCH2OH), 7.23 (d, 2H, J = 1.8 Hz, 2-CH and 6-CH), 7.38 (t, 1H, J = 1.8 Hz, 4-CH). Crude alcohol 5a (4.25 g) was dissolved in anhydrous CH2Cl2 (500 mL) and cooled at 0 °C. Triphenylphosphine (10.23 g, 0.039 mol) and carbon tetrabromide (12.93 g, 0.039 mol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography on silica gel with hexanes to yield 4.62 g (86percent) of bromide 5b.
Reference：
[1] Chemistry - A European Journal, 2012, vol. 18, # 24, p. 7473 - 7485
[2] European Journal of Organic Chemistry, 2007, # 16, p. 2700 - 2712
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1215 - 1227
[4] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4227 - 4237
3
[ 1611-92-3 ]
[ 56908-88-4 ]
Yield
Reaction Conditions
Operation in experiment
74%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 24 h; Reflux
1,3-dibromo-5-toluene (4.96 g, 20 mmol) was dissolved in 150 ml of tetrachloromethane and then benzoyl peroxide (0.36 g, 1.5 mmol) and N-bromosuccinimide (3.74 g, 21 mmol) was added thereto, and the reaction mixture was heated under reflux for 24 hours. The reaction solution was then poured into water and extracted with methylene chloride. The organic compound was dried over magnesium sulfate and treated with dichloromethane / petroleum ether (v / v = 2: 3) was chromatographed on silica gel as a eluent, dried and steamed to give intermediate C (4.87 g, 74percent yield) as a white solid.
48.3%
With N-Bromosuccinimide; dibenzoyl peroxide In hexane; benzene
Referential Example 22 Production of 3,5-Dibromobenzyl Bromide 3,5-Dibromotoluene (27.0 g; 108.0 mmol), N-bromosuccinimide (19.2 g; 108.0 mmol), and benzoyl peroxide (0.32 g) were added to benzene (200 ml), and the mixture was refluxed for 2.5 hours. The mixture was brought to room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in n-hexane (200 ml), and the mixture was left to stand overnight at room temperature. Crystals that precipitated were filtered off, and the filtrate was concentrated under reduced pressure, to thereby yield 17.2 g of the target compound (yield: 48.3percent). 1H-NMR (CDCl3, ppm); 4.36 (2H, s), 7.47 (2H, d, J=1.62 Hz), 7.60 (1H, t, J=1.62 Hz).
44%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane; hexane
3,5-dibromobenzyl bromide 3,5-dibromotoluene (78.92 g, 0.316 mole) was dissolved in 1.27 L of carbon tetrachloride; to this solution was added N-bromosuccinimide (61.65 g, 0.346 mole) at room temperature. A portion of dibenzoyl peroxide (0.6 g, 0.008 equivalents) was added and the solution heated to reflux temperature for 2.5 hours. The reaction mixture was cooled to room temperature, filtered and the solvent removed in vacuo to yield a solid. The solid was dissolved in 200 mL of warm hexane, filtered and cooled to room temperature. Crystallizations ensued; the crystals were filtered off and washed with cold hexane and air dried to give 45.15 g (44percent) of 3,5-dibromobenzyl bromide. 1 H-NMR(CDCl3); δ 7.6 (1H), 7.47 (2H), 4.36 (2H).
Reference：
[1] Patent: CN106946777, 2017, A, . Location in patent: Paragraph 0060-0062
[2] Patent: US6586633, 2003, B1,
[3] Recueil des Travaux Chimiques des Pays-Bas, 1926, vol. 45, p. 303
[4] Journal of Organic Chemistry, 1992, vol. 57, # 10, p. 2967 - 2970
[5] American Chemical Journal, 1908, vol. 40, p. 348
[6] Recueil des Travaux Chimiques des Pays-Bas, 1926, vol. 45, p. 303
[7] Journal of Organic Chemistry, 1992, vol. 57, # 10, p. 2967 - 2970
[8] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 19, p. 2903 - 2909
[9] Patent: US5254683, 1993, A,
[10] Patent: US2006/287287, 2006, A1, . Location in patent: Page/Page column 19
[11] Chemical Biology and Drug Design, 2017, vol. 90, # 6, p. 1271 - 1281
4
[ 56990-02-4 ]
[ 56908-88-4 ]
Reference：
[1] Supramolecular Chemistry, 2011, vol. 23, # 6, p. 480 - 485
[2] Chemistry - A European Journal, 2012, vol. 18, # 24, p. 7473 - 7485
5
[ 1611-92-3 ]
[ 56908-88-4 ]
[ 256386-08-0 ]
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 17, p. 5664 - 5670
[2] Tetrahedron Asymmetry, 2010, vol. 21, # 23, p. 2768 - 2774
6
[ 56908-88-4 ]
[ 145691-59-4 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1926, vol. 45, p. 303
7
[ 56908-88-4 ]
[ 143-33-9 ]
[ 188347-48-0 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 7, p. 2173 - 2185
8
[ 56908-88-4 ]
[ 188347-48-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1215 - 1227
9
[ 56908-88-4 ]
[ 188347-49-1 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 7, p. 2173 - 2185
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 24h;Reflux;
1,3-dibromo-5-toluene (4.96 g, 20 mmol) was dissolved in 150 ml of tetrachloromethane and then benzoyl peroxide (0.36 g, 1.5 mmol) and N-bromosuccinimide (3.74 g, 21 mmol) was added thereto, and the reaction mixture was heated under reflux for 24 hours. The reaction solution was then poured into water and extracted with methylene chloride. The organic compound was dried over magnesium sulfate and treated with dichloromethane / petroleum ether (v / v = 2: 3) was chromatographed on silica gel as a eluent, dried and steamed to give intermediate C (4.87 g, 74% yield) as a white solid.
48.3%
With N-Bromosuccinimide; dibenzoyl peroxide; In hexane; benzene;
Referential Example 22 Production of 3,5-Dibromobenzyl Bromide 3,5-Dibromotoluene (27.0 g; 108.0 mmol), N-bromosuccinimide (19.2 g; 108.0 mmol), and benzoyl peroxide (0.32 g) were added to benzene (200 ml), and the mixture was refluxed for 2.5 hours. The mixture was brought to room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in n-hexane (200 ml), and the mixture was left to stand overnight at room temperature. Crystals that precipitated were filtered off, and the filtrate was concentrated under reduced pressure, to thereby yield 17.2 g of the target compound (yield: 48.3%). 1H-NMR (CDCl3, ppm); 4.36 (2H, s), 7.47 (2H, d, J=1.62 Hz), 7.60 (1H, t, J=1.62 Hz).
45.15 g (44%)
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; hexane;
3,5-dibromobenzyl bromide 3,5-dibromotoluene (78.92 g, 0.316 mole) was dissolved in 1.27 L of carbon tetrachloride; to this solution was added N-bromosuccinimide (61.65 g, 0.346 mole) at room temperature. A portion of dibenzoyl peroxide (0.6 g, 0.008 equivalents) was added and the solution heated to reflux temperature for 2.5 hours. The reaction mixture was cooled to room temperature, filtered and the solvent removed in vacuo to yield a solid. The solid was dissolved in 200 mL of warm hexane, filtered and cooled to room temperature. Crystallizations ensued; the crystals were filtered off and washed with cold hexane and air dried to give 45.15 g (44%) of 3,5-dibromobenzyl bromide. 1 H-NMR(CDCl3); delta 7.6 (1H), 7.47 (2H), 4.36 (2H).
With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 3h;
A mixture of 3,5-dibromo-toluene (4.25 g, 17 mmol), NBS (3 g, 177 mmol), and AIBN (150 mg) in carbon tetrachloride (50 mL) was heated at 80 C. for 3 hours. The resulting mixture was run through a silicon gel column with dichloromethane as the eluant. The fraction was collected and solvent was removed by rotovap, crude 1,3-dibromo-5-(bromomethyl)benzene was obtained as a white residue
Intermediate 13. [4-(3,5-Dibromo-benzyloxy)-2-methyl-phenoxy]-acetic acid methyl ester.; [00107] 4-Hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 4 (0.36 g, 1.8 mmol) is dissolved in dry acetonitrile (3 mL). Cesium carbonate (1.31 g, 4 mmol) is added, followed by <strong>[56908-88-4]3,5-dibromobenzyl bromide</strong> 12 (0.78 g, 2.37 mmol). The mixture is stirred under nitrogen for 18 hours. The resulting red suspension is filtered, the solids are washed with more acetonitrile, and the resulting clear red solution is concentrated to oil. Silica gel chromatography (10% to 25% ethyl acetate in hexanes) yielded 13 as an oil that slowly solidifies to an off-white crystalline mass. IH-NMR (400MHz, CDC13) No. = 7.58 (d, J = 2 Hz, 1H), 7.47 (d, J = 2 Hz, 2H), 6.77 (s, 1H), 6.64 (m, 2H), 4.91 (s, 2H), 4.58 (s, 2H), 3.77 (s, 3H), 2.26 (s, 3H). MS calculated for C17H17Br2O4 (M+H+) 442.95, found 442.9.
Intermediate 35; Methyl 3-[4-(1 ,1 -dimethylethyl)phenyl]-1 -[3-[2- (methyloxy)ethyl]oxy}-5-(4-morpholinyl)phenyl]methyl}-1 /-/-indole-2- carboxylate <n="91"/>To a solution of 253 g (0.79 mol) of ethyl 3-(4-te/t-butylphenyl)-1H- indole-2-carboxylate in 1.5L of NMP was added 112 g (0.998 mol) of KOtBu over several minutes. The mixture was stirred at 32-350C over 1 hr, then 271.36 g of <strong>[56908-88-4]3,5-dibromobenzyl bromide</strong> was added over 25 min keeping the temperature below 5O0C. Stirred for 2.5 hr, then added 10 g of additional KOtBu followed by 15 g of additional tribromide. Stirred for 30 min at ambient temperature to give a crude solution of Intermediate 35a (Ethyl 1 -[(3,5- dibromophenyl)methyl]-3-[4-(1 ,1 -dimethylethyl)phenyl]-1 H-indole-2- carboxylate).
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 1h;
General procedure: 3,5-Di-t-butylbenzoic acid (5.00 g, 0.021 mol) was dissolved in anhydrous THF (250 mL) under argon atmosphere and the solution cooled to 0 C. Lithium aluminum hydride (1.62 g, 0.043 mol) was added in small portions and the solution stirred at room temperature overnight. The reaction was quenched with water, Et2O (100 mL) was added and the mixture acidified with concentrated HCl solution until the solid residue was dissolved. The medium was extracted with Et2O and the organic phase dried over MgSO4, filtered and concentrated to yield 4.31g of 5a. 1H NMR delta (CDCl3) 1.34 (s, 18H, di-t-butyl), 4.70 (s, 2H, PhCH2OH), 7.23 (d, 2H, J = 1.8 Hz, 2-CH and 6-CH), 7.38 (t, 1H, J = 1.8 Hz, 4-CH). Crude alcohol 5a (4.25 g) was dissolved in anhydrous CH2Cl2 (500 mL) and cooled at 0 C. Triphenylphosphine (10.23 g, 0.039 mol) and carbon tetrabromide (12.93 g, 0.039 mol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography on silica gel with hexanes to yield 4.62 g (86%) of bromide 5b.
on carrying out the operation according to the procedure of Example 2 starting with 6.6 g of <strong>[56908-88-4]3,5-dibromobenzyl bromide</strong> and 1.5 g of sodium methylthiolate, 5.8 g of (3,5-dibromobenzyl)methylsulfide are obtained in the form of an oil.
With triethylamine; In hydrogenchloride; methanol; N,N-dimethyl-formamide; methylamine;
Referential Example 23 Production of N-(3,5-Dibromobenzyl)methylamine Triethylamine (5.28 g; 52.2 mmol) was dissolved in 40% methylamine in methanol (100 ml). While the mixture was stirred at room temperature, <strong>[56908-88-4]3,5-dibromobenzyl bromide</strong> (17.2 g; 52.2 mmol) in N,N-dimethylformamide (20 ml) was added dropwise. The mixture was stirred overnight at room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in 2N hydrochloric acid (150 ml), and the mixture was extracted with diethyl ether (150 ml), to thereby exclude impurities. The aqueous layer was alkalinized with aqueous sodium hydroxide solution, and extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 11.3 g of the target compound as orange oily matter (yield: 77.7%). 1H-NMR (CDCl3, ppm); 2.43 (3H, s), 3.70 (2H, s), 7.42 (2H, s), 7.55 (1H, s).
methyl 5-(2-(-5-Hydroxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methylthioacetamido)benzene-1,3-dicarboxylate[ No CAS ]
[ 56908-88-4 ]
Methyl 5-(2-(5-(3,5-Dibromo)benzyloxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methylthioacetamido)benzene-1,3-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With potassium carbonate; In dichloromethane; ethyl acetate; acetonitrile;
Step 1 Methyl 5-(2-(5-(3,5-Dibromo)benzyloxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methylthioacetamido)benzene-1,3-dicarboxylate A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar and reflux condenser was charged with methyl 5-(2-(-5-Hydroxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methylthioacetamido)benzene-1,3-dicarboxylate (0.19 g, 0.27 mmol), prepared in step 4 of Example 4, 200 mesh K2CO3 (2.4 equiv.) and <strong>[56908-88-4]3,5-dibromobenzyl bromide</strong> (1.2 equiv.) in 7.5 mL of anhydrous acetonitrile. The reaction mixture was heated at 70 C. for 2 h. The reaction mixture was partitioned between AcOEt (30 mL) and H2O (20 mL). The aqueous layer was extracted with AcOEt(3*30 mL). The combined AcOEt extracts were washed with brine (50 mL), dried over Na2SO4 and filtered. The solvents were removed in vacuo. Purification of the residue by column chromatography on silica gel using 15% EtOAc in dichloromethane afforded 0.20 g of the product (77%).
tert-butyl trans-4-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step B:; tert-Butyl trans-4-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine-1-carboxylate To 3 g of the compound obtained in the Step above (9.42 mmol) in 30 ml of anhydrous dimethylformamide there are added 452 mg of sodium hydride as a 60% suspension in oil (11.3 mmol, 1.2 equivalents). After stirring for 30 minutes at ambient temperature there are added 3.1 g of <strong>[56908-88-4]3,5-dibromobenzyl bromide</strong> (9.42 mmol). A slight exothermic reaction is observed. The reaction mixture is then stirred overnight at ambient temperature, and subsequently the dimethylformamide is evaporated off. The residue obtained is taken up in dichloromethane. After washing with water, drying, filtration and evaporation, there are obtained 6 g of a residue which is purified by flash chromatography on 500 g of silica (eluant: dichloromethane/ethyl acetate 90/10) to yield tert-butyl trans-4-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine-1-carboxylate in the form of a meringue.
tert-butyl 4-{trans-2-[(3,5-dibromobenzyl)oxy-]-1,2,3,4-tetrahydronaphth-1-yl}piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step D:; tert-Butyl 4-{trans-2-[(3,5-dibromobenzyl)oxy-]-1,2,3,4-tetrahydronaphth-1-yl}piperazine-1-carboxylate At ambient temperature, to 0.44 g (11 mmol) of sodium hydride as a suspension in 20 ml of tetrahydrofuran there are added, over a few minutes, 3.3 g (10 mmol) of the compound obtained in the Step above, dissolved in 20 ml of tetrahydrofuran. The mixture is heated at 50 C. for 2 hours and there are then added, all at once, 3.3 g (10 mmol) of <strong>[56908-88-4]3,5-dibromobenzyl bromide</strong>, and then 3.7 g (10 mmol) of tetra-n-butylammonium iodide, and heating is carried out overnight at 70 C. The mixture is then poured into 100 ml of water and extraction with two quantities, each of 100 ml, of ethyl ether is carried out. The combined organic phases are washed and dried. After evaporation and flash chromatography on 300 g of silica (eluant: dichloromethane 100%, and then dichloromethane/ethyl acetate 90/10), the expected compound is collected.
tert-butyl trans-4-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}-1,4-diazepane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step B:; tert-Butyl trans-4-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}-1,4-diazepane-1-carboxylate At ambient temperature, to 0.76 g (19 mmol) of sodium hydride as a suspension in 20 ml of tetrahydrofuran there are added, over a few minutes, 6.0 g (17.3 mmol) of the compound obtained in the Step above, dissolved in 50 ml of tetrahydrofuran. The mixture is heated at 50 C. for 2 hours and there are then added, all at once, 5.7 g (17.3 mmol) of <strong>[56908-88-4]3,5-dibromobenzyl bromide</strong>, and then 6.4 g (17.3 mmol) of tetra-n-butylammonium iodide, and heating is carried out overnight at 70 C. The mixture is then poured into 200 ml of water and extracted with ethyl ether. The combined organic phases are washed and dried. After evaporation and flash chromatography on 500 g of silica (eluant: dichloromethane 100%, then dichloromethane/ethyl acetate 95/5 and then dichloromethane/ethanol 95/5), the expected compound is collected.
tert-butyl cis-4-(2-hydroxy-1,2,3,4-tetrahydro-1-naphthyl)-1-piperidinecarboxylate[ No CAS ]
[ 56908-88-4 ]
tert-butyl cis-4-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydro-1-naphthyl}-1-piperidinecarboxylate[ No CAS ]
tert-butyl trans-4-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydro-1-naphthyl}-1-piperidinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step G: tert-Butyl 4-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydro-1-naphthyl}-1-piperidinecarboxylate 241 mg of sodium hydride 60% in oil are introduced into a solution of 1.9 g of the compound obtained in the Step above in 20 ml of anhydrous tetrahydrofuran, cooled to 0 C. Stirring is carried out for 15 minutes and there are then added, still at that temperature, 20 mg of tetrabutylammonium iodide and finally 1.9 g of <strong>[56908-88-4]3,5-dibromobenzyl bromide</strong>. The mixture is allowed to return to ambient temperature and is stirred for 24 hours. The mixture is evaporated to dryness, taken up in water and dichloromethane and, after conventional treatment and chromatography on silica (eluant: dichloromethane), the expected product is isolated in the form of a white meringue (80% trans, 20% cis).
(2R,4S)-4-[5-(2-benzyloxycarbonylvinyl)pyrimidin-2-yl]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester[ No CAS ]
[ 56908-88-4 ]
(2R,4S)-4-[5-(2-benzyloxycarbonylvinyl)pyrimidin-2-yl]-(3,5-dibromobenzyl)}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(2R, 4S)-4- [5- (2-BenzyloxBTcarbonylviny1) pyrimidin-2-yl] amino-2- ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quino line-1-carboxylic acid ethyl ester (3.41 g) is dissolved in N, N-dimethylforrnamide (30 ml), and thereto is added sodium hydride (62.7%, 360 mg) under ice-cooling. The mixture is stirred under ice-cooling for 30 minutes, and thereto is added 3,5- dibromobenzyl bromide (3 g). The mixture is stirred at room temperature for one hour. To the reaction solution is added a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by chromatography (silica gel ; hexane: ethyl acetate = 9:1No.7 : 3) to give (2R, 4S)-4- { [5- (2-benzyloxycarbonyl- vinyl) pyrimidin-2-yl]-(3 5-dibromobenzyl)} amino-2-ethyl-6-trifluoromethyl- 3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (1.84 g). MS (m/z) : 801/803/805 [M+H] +
(2R,4S)-2-ethyl-4-[5-(2-methylsulfanylethoxy)pyrimidin-2-yl]amino-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester[ No CAS ]
[ 56908-88-4 ]
(2R,4S)-4-{(3,5-dibromobenzyl)-[5-(2-methylsulfanylethoxy)pyrimidin-2-yl]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(2R, 4S)-2-Ethyl-4- [5-(2-methylsulfanylethoxy) pyrimidin-2-yl] amino- 6-trifluoromethyl-3, 4-dihydro-2H-quinoline-l-carboylic acid ethyl ester (160 mg) is dissolved in N, N-dimethylformamide (1.5 ml), and thereto is added sodium hydride (62.7 %, 15 rag) under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and thereto is added 3,5- dibromobenzyl bromide (141 mg), and the mixture is stirred at room temperature for 19 hours. To the mixture is added a 0.5N hydrochloric acid and diethyl ether under ice-cooling, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1---+7 : 3) to give (2R, 4S)-4- { (3, 5-dibromobenzyl)- [5- (2-methylsulfanyl- ethoxy) pyrimidin-2-yl] amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H- quinoline-1-carboxylic acid ethyl ester (110 mg). MS (m/z): 733 [M+H] +
(2R*,4S*)-2-ethyl-4-[5-(morpholin-4-yl)pyrimidin-2-yl]amino-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester[ No CAS ]
[ 56908-88-4 ]
(2R*,4S*)-4-{(3,5-dibromobenzyl)-[5-(morpholin-4-yl)pyrimidin-2-yl]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(2R*, 4S*) -2-Ethyl-4- [5-(morpholin-4-yl) pyrimidin-2-yl] amino-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (2.57 g) is dissolved in N, N-dimethylformamide (20 ml), and thereto is added sodium hydride (62. 7 %, 257 mg) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added 3, 5-dibromobenzyl bromide (2.64 g) under ice-cooling, and the mixture is stirred at room temperature overnight. To the reaction solution are added water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane: ethyl acetate = 6 zu : 1) to give (2R*, 4S*)-4- { (3, 5-dibromobenzyl) - [5- (morpholin-4-yl) pyrimidin-2-yl] amino- 2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (2.41 g). MS (m/z): 788/780 [M+H] +
Step C; 4-(tert-Butyloxycarbonyl)-1-[(1RS)-1-(3,5-dibromobenzyloxymethyl)indan-1-yl]piperazine; To 30 ml of dimethylformamide and 5.4 mmol of sodium hydride 95% there is added, over 10 minutes, a solution of 3.6 mmol of the compound obtained in the step above in 50 ml of dimethylformamide. Heating at 50-60 C. is carried out for ½ hour and the temperature is then allowed to return to ambient temperature. 0.36 mmol of tetrabutylammonium iodide is then added and then, over 10 minutes, a solution of 5.4 mmol of <strong>[56908-88-4]3,5-dibromobenzyl bromide</strong> in 30 ml of dimethylformamide. Stirring is continued for 20 hours at ambient temperature. The solvent is evaporated off, and the residue is then redissolved in ethyl acetate. Washing with water and with sodium chloride solution is carried out. The organic phase is dried and evaporated. The product is purified by chromatography on silica gel (eluant: CH2Cl2/AcOEt 90/10) to yield the expected product. IR v CO 1688 cm-1
With samarium; mercury dichloride; In tetrahydrofuran; at 0 - 20℃; for 4h;Inert atmosphere;
General procedure: In a dry flask, 40 mesh samarium powder (108 mg, 0.72 mmol), TBS-E1 refPreviewPlaceHolder[44] (200 mg, 0.48 mmol) and 4-trifluoromethylbenzyl bromide (172 mg, 0.72 mmol) were weighed under a nitrogen atmosphere. The flask was purged with argon, anhydrous degassed THF (1.5 mL) was added and the solution cooled to 0 C. HgCl2 (29 mg, 0.107 mmol) was dissolved in anhydrous degassed THF (0.2 mL) and added to the cool mixture. The mixture was stirred under argon at 0 C for 2 h, at room temperature for 2 h, then filtered on celite and evaporated to give the crude TBS-18, which was submitted to the deprotection procedure (TBS hydrolysis with TBAF) as reported above to yield 18 (14%, two steps). The same procedure was used for the synthesis of 3-TBS-19 (57%), 3-TBS-20, 3-TBS-21 (49%) and TBS-22 (58%) which after hydrolysis of the TBS group afforded 20 (11%, two steps), 19, 21 and 22 (91-94%).
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