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CAS No. : | 98946-18-0 | MDL No. : | MFCD00077410 |
Formula : | C6H10Cl3NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CQXDYHPBXDZWBA-UHFFFAOYSA-N |
M.W : | 218.51 | Pubchem ID : | 2734700 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.83 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 50.1 |
TPSA : | 33.08 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.47 cm/s |
Log Po/w (iLOGP) : | 2.49 |
Log Po/w (XLOGP3) : | 3.04 |
Log Po/w (WLOGP) : | 3.15 |
Log Po/w (MLOGP) : | 2.28 |
Log Po/w (SILICOS-IT) : | 2.41 |
Consensus Log Po/w : | 2.67 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.91 |
Solubility : | 0.268 mg/ml ; 0.00122 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.4 |
Solubility : | 0.0869 mg/ml ; 0.000398 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.83 |
Solubility : | 0.325 mg/ml ; 0.00149 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.86 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P337+P313-P305+P351+P338-P362+P364-P303+P361+P353-P332+P313-P403+P235 | UN#: | 1993 |
Hazard Statements: | H225-H315-H319 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | at 0 - 20℃; for 2 h; Heating / reflux | f-Butyl trichloroacetimidate (TBTA): Potassium /-butoxide (1M in f-butanol), 69 ml_ (0.069 mole), was dissolved in diethyl ether, 69 mL. This solution was added dropwise, over 30 minutes, to a cold, 0 °C, solution of trichloroacetonitrile, 100 g (0.69 mole), in diethyl ether, 69 mL. The mixture was allowed to warm to room temperature over one hour, and was then stirred for an additional hour with heating at reflux. The mixture was cooled to room temperature and evaporated under reduced pressure to yield an oil. The oil was dissolved in hexanes, 140 mL, and filtered to remove potassium salts. The filtrate was evaporated under reduced pressure and the residue was vacuum distilled. The fraction distilling at 2.4 mm Hg and 40 °C was collected. The yield was 105 g, 69percent based on trichloroacetonitrile. 1H nmr (300MHz CDCI3) δ (ppm): 1.58, (s, 9H), 8.21 (br, s, 1H). 13C (75.45 MHz, CDCI3) δ (ppm): 27.23, 83.86, 92.78, 160.33. (Armstrong et al.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With boron trifluoride diethyl etherate; In tetrahydrofuran; at 20℃; | To a solution of 6-hydroxy-1,3-benzoxathiol-2-one (9.2 g, 54.7 mmol) dissolved in 100 mL of tetrahydrofuran was added at room temperature a solution of t-butyl trichloroacetaimidate (23.9 g, 109.4 mmol) in tetrahydrofuran (50 mL) and boron trifluoride etherate (0.5 g, 3.5 mmol) and the mixture was stirred at room temperature overnight. Solid sodium bicarbonate (9.24 g, 110 mmol) was then added to the solution with stirring and the solution was filtered through a silica gel column and was washed with cold tetrahydrofuran. The filtrate was evaporated in vacuo to give a yellow oil which was purified by column chromatography eluting with methylene chloride to give 6-tert-butoxy-1,3- benzoxathiol-2-one (10.4 g, 85%). |
85% | With boron trifluoride diethyl etherate; In tetrahydrofuran; at 20℃; | [0590] To a solution of 6-hydroxy-1,3-benzoxathiol-2-one (9.2 g, 54.7 mmol) dissolved in 100 mL of tetrahydrofuran was added at room temperature a solution of t-butyl trichloroacetaimidate (23.9 g, 109.4 mmol) in tetrahydrofuran (50 mL) and boron trifluoride etherate (0.5 g, 3.5 mmol) and the mixture was stirred at room temperature overnight. Solid sodium bicarbonate (9.24 g, 110 mmol) was then added to the solution with stirring and the solution was filtered through a silica gel column and was washed with cold tetrahydrofuran. The filtrate was evaporated in vacuo to give a yellow oil which was purified by column chromatography eluting with methylene chloride to give 6-tert-butoxy-1,3- benzoxathiol-2-one (10.4 g, 85%). 1H-NMR (CDCl3, 400 MHz): delta 7.27 (d, J = 3.8 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.92 (dd, J1 = 8.6 Hz, J2 = 2.2 Hz, 1H), 1.39 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | (a) Preparation of tert-Butyl 6-bromohexanoate: 1.95 g (10 mmol) of 6-bromohexanoic acid dissolved in 10 ml of dichloromethane were introduced under a stream of nitrogen into a round-bottomed flask. A solution of 4.37 g (20 mmol) of tert-butyl 2,2,2-trichloroacetimidate in 20 ml of cyclohexane was added dropwise, followed immediately by 200 mul of trifluoroborane etherate. The mixture was stirred at room temperature for 5 minutes, 5 g of sodium bicarbonate were added, and the mixture was stirred for 1 minute. The suspension obtained was placed on a silica column which had been wetted beforehand with cyclohexane and the latter was eluted with a 8:2 cyclohexane/ethyl acetate mixture. After evaporation of the solvents, 1.63 g (65%) of a colorless oil was obtained. 1H NMR (CDCl3): 1.45 (s, 9H), 1.44 to 1.70 (m, 4H), 1.87 (m, 2H), 2.23 (t, J=7.5 Hz, 2H), 3.41 (t, J=6.75 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In cyclohexane; ethyl acetate for 18h; Inert atmosphere; | |
90% | In cyclohexane; ethyl acetate at 20℃; for 24h; | |
84% | In cyclohexane; ethyl acetate at 20℃; for 24h; |
82% | In cyclohexane; ethyl acetate at 60℃; for 24.5h; Inert atmosphere; | 4.8 (S)-N-(Fluoren-9-ylmethoxycarbonyl)-l-serine tert-butyl ester (14a) To a solution of Fmoc-L-Ser(OH)-OH (1.5g, 4.58mmol) in dry EtOAc (34.0mL) was added another solution of tert-butyl 2,2,2-trichloroacetimidate (1.475mL, 6.412mmol) in cyclohexane (4.5mL). The reaction mixture was stirred at the 60°C for 24.5h. The reaction mixture was then concentrated to give a crude product, which was first purified by recrystallization with DCM and hexane. The collected solid was purified again by flash chromatography with the eluent EtOAc/hexanes=4/6 to give the product 14a (1.438g, 82%) as a white solid. IR (neat) 3408 (O-H), 1729 (C=O), 1264 (C-O), 1157, 1081, 833, 729, 703cm-1; 1H NMR (300MHz, CDCl3) δ 7.77 (d, J=7.5Hz, 2H, Fmoc), 7.61 (d, J=7.2Hz, 2H, Fmoc), 7.40 (t, J=7.5Hz, 2H, Fmoc), 7.32 (t, J=7.2Hz, 2H), 5.72 (br d, J=5.7Hz, 1H, NH), 4.42 (d, J=6.9Hz, 2H, CO2CH2), 4.33 (br s, 1H, α-H), 4.23 (t, J=6.9Hz, 1H), 3.93 (br d, J=1.2Hz, 2H, β-H), 1.90 (br s, 1H, OH), 1.49 (s, 9H, t-Bu); 13C NMR (75MHz, CDCl3) δ 169.4 (C), 156.3 (C), 143.8 (C), 143.7 (C), 141.3 (C), 141.3 (C), 127.7 (CH×2), 127.1 (CH×2), 127.0 (CH×2), 125.0 (CH×2), 120.0 (CH), 83.0 (C), 67.1 (CH2), 63.7 (CH2), 56.6 (CH), 47.1 (CH3×3). |
68% | In cyclohexane; ethyl acetate at 20℃; for 24h; | 2.A EXAMPLE 22-Amino-3-tert-butoxy-3-oxopropyl 4- (nitrooxy) butanoate(corresponding to compound 405) Step A: tert-butyl 2- ((( 9H-fluoren-9-yl) methoxy) carbonylamino) -3-hydroxypropanoate To a solution of commercial N-Fmoc-L-serine (1.5 g, 4.58 mmol) in EtOAc (40 ml), a solution of t-butyl 2,2,2- trichloroacetimidate (4.00 g, 18.32 mmol) in cyclohexane (18 ml) was added dropwise. After stirring at room temperature for 24 hrs, the solution was evaporated and the residue was purified by flash chromatography (n-Hexane/EtOAc 70:3), yielding the title compound (1.20 g, 68%). |
58% | In cyclohexane; ethyl acetate at 22℃; for 16h; Inert atmosphere; | |
In cyclohexane; ethyl acetate | ||
In dichloromethane; cyclohexane | Synthesis of Fmoc-Sec(Bzh)-OtBu (5a) Starting from Fmoc-Ser-OH, 5a was synthesized in 3 steps following the similar procedure reported for the synthesis of Fmoc-Sec(MPM)-OMe.[S1] In brief, Fmoc-Ser-OH was treated with tert-butyl-2,2,2-trichloroacetimidate in a mixture solvent of DCM and cyclohexane (5:2) to yield the tert-butyl ester, which was then iodized with iodine, triphenylphosphine, and imidazole in DCM. The obtained crude product was reacted with di(benzhydryl) diselenide and sodium borohydride in a mixture solvent of MeOH and DMF (1:4). The crude product was purified by silica gel column chromatography (EtOAchexane 1:4) to afford 5a as pale yellow crystals in 50% total yield. Product 5a was used for subsequent reactions after recrystallization from DCMhexane. | |
4.32 g | In dichloromethane; ethyl acetate at 0 - 20℃; for 96h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 18h; | Reference example 1 tert-Butyl 4-fluoro-2-trifluoromethylbenzoate To a solution of <strong>[141179-72-8]4-fluoro-2-trifluoromethylbenzoic acid</strong> (5.00 g) in tetrahydrofuran (72.0 mL) were successively added tert-butyl 2,2,2-trichloroacetoimidate (8.18mL) and boron trifluoride diethyl ether complex (0.304 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 1 mol/L aqueous solution of sodium hydroxide and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L aqueous solution of sodium hydroxide, water, brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. To this residue were added diisopropyl ether-hexane and the insoluble was removed by filtration. This filtrate was concentrated under reduced pressure. The obtained crude product was purified by column chromatography on silica gel (eluent:ethyl acetate-hexane) to give tert-butyl 4-fluoro-2-trifluoromethylbenzoate (3.13 g). 1H-NMR(CDCl3) delta ppm: 1.58 (9H, s), 7.20-7.30 (1H, m), 7.35-7.45 (1H, m), 7.75-7.85 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With boron trifluoride dimethyl etherate; In tetrahydrofuran; cyclohexane; at 25℃; for 16h; | [000198] A solution of <strong>[36070-80-1]5-chloro-pyrazine-2-carboxylic acid</strong> (10.00 g, 63.07 mmol) in tetrahydrofuran (126 mL) was treated with a solution of TERT-BUTYL 2,2, 2- trichloroacetimidate (23 ML, 126.14 mmol) in cyclohexane (126 mL). The reaction was stirred at 25C for 5 min and then was treated with boron trifluoride dimethyl etherate (3.2 mL, 25.23 mmol). The resulting reaction mixture was stirred at 25C for 16 h and then was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (200 mL) and water (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 65M, Silica, 10% ethyl acetate/hexanes) afforded <strong>[36070-80-1]5-chloro-pyrazine-2-carboxylic acid</strong> TERT-BUTYL ester (12.73 g, 94%) as a colorless oil: EI-HRMS m/e calcd for C9HNCLN202 (M) 214.0502, found 214.0510. |
92% | With boron trifluoride diethyl etherate; In tetrahydrofuran; cyclohexane; at 25℃; for 16h; | A solution of <strong>[36070-80-1]5-chloropyrazine-2-carboxylic acid</strong> (200.0 g, 1.26 mol) in THF (2.5 L) was treated with a solution of tert-butyl 2,2,2-trichloroacetimidate (460 mL, 2.57 mol) in cyclohexane (2.5 L). The reaction was stirred at 25 C for 5 min and then treated with boron trifluoride dimethyl etherate (144.0 mL, 126 mmol). The resulting reaction mixture was stirred at 25 C for 16 h and then diluted with EtOAc (5.0 L), washed with a saturated aqueous sodium bicarbonate solution (4.0 L) followed by water (5.0 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (Silica 60-120 mesh, 10% EtOAc in hexanes) to give tert-butyl 5-chloropyrazine-2-carboxylate (250 g, 92%) as a colorless oil. MS (ESI, positive ion) m/z: 215.2 (M+1 )+. 1H NMR (400 MHz, CDCl3) delta 9.01 (d, J = 1.3 Hz, 1 H), 8.70 (d, J = 1.3 Hz, 1 H), 1.66 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With boron trifluoride diethyl etherate; In tetrahydrofuran; at 20℃; for 18h; | [1247] A solution of Example A (18 g, 62 mmol). in THF (250 mL, 0.25 M) was treated with trichloroacetimidate (28 mL, 155 mmol) and BF3.Et2O (18 mL, 1 mL/g) at ambient temperature. After 18 h the reaction mixture was quenched with solid NaHCO3 followed by water and stirred vigorously. Then the solvent was removed, and partitioned with ethyl acetate (250 mL). The organic layer was separated and washed with brine (3×80 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure to obtain the crude product. The title compound (19.2 g, 96%) was obtained by flash chromatography on silica gel eluting with 20% acetone:hexane. MS (ESI) m/e 320 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With boron trifluoride diethyl etherate; In tetrahydrofuran; at 20℃; for 16h; | Intermediate 1 TERT-BUTVL (4-BROMOPHENVL) ACETATE- Boron trifluoride etherate (0.46 mL) was added in one portion to a stirred solution of bromophenylacetic acid (5.00 g, 23.2 MMOL) and T-BUTYLTRICHLOROACETIMIDATE (10 g, 8.3 mL, 46 MMOL) in THF (50 mL) at room temperature under nitrogen. The resulting solution was stirred for 16 h then quenched with saturated sodium hydrogen carbonate solution (50 mL). The resulting suspension was extracted with ethyl acetate (3X50 mL) then the organic extracts combined, dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (20% diethyl ether: cyclohexane) to give the title compound as a colourless oil (4.93 g, 78%). LC/MS : 3.63 min; z/e 288 and 290, CALCD (M+18) 288 and 290.'H NMR (400 MHz: CDCI3) : 7.40 (2H), 7.15 (2H), 3.45 (2H), 1.40 (9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With boron trifluoride diethyl etherate; In diethyl ether; at 20℃;Inert atmosphere; | 4-Fluoro-3-nitrobenzoic acid (5.O g, 27.0 mmol) was dissolved in diethyl ether (70 mL) followed by addition of tert-butyl 2,2,2-trichloroacetimidate (6.05 ml, 32.4 mmol). BF3 OEt2 (0.137 mL, 1.08 mmol) was added dropwise via syringe, and the contents were stirred at room temperature overnight. Solid NaHCO3 (1.5 g) was added, and the mixture was stirred for an additional 30 min. The reaction mixture was diluted with ether, and the contents then concentrated in vacuo to dryness. The crude residue was purified by silica gel chromatography (eluent: 5-10% EtOAc in hexanes) to afford the product as an oil which solidifies on hi-vacuum drying (3.78 g, 58%). LC-MS (ES) m/z = 185.5 (M - t-butyl)+ 1H NMR (400 MHz, DMSO-d6) delta 8.51 (dd, J=I.3, 2.0 Hz, IH), 8.28 (ddd, J=8.6, 4.29, 2.3 Hz, IH), 7.73 (dd, J=I L l, 8.8 Hz, IH), 1.59 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In dichloromethane; at 20℃; for 72h; | To a suspension of <strong>[103213-32-7]Fmoc-Cys(Trt)-OH</strong> (11.7 g, 20.0 mmol, 1.0 equiv) in anhydrous CH CI (160 mL) was added ferf-butyl 2,2,2-trichloroacetimidate (8.74 g, 40.0 mmol, (0428) 2.0 equiv) and the mixture was stirred at ambient temperature for 3 d. The mixture was filtered through a pad of Celite and the solids were washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (Si02, PE/EtOAc 5:1) to give 81 (11.6 g, 18.1 mmol, (0429) 90%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage 1; - terf-Butyl lambda/-(ferf-butoxycarbonyl)-4-nitro-L-phenylalaninate To a solution of lambda/-(te/t-butoxycarbonyl)-4-nitro-L-phenylalanine (500mg, 1.61mmol) in 66% DCM / cyclohexane (3OmL) at O0C was added boron trifluoride diethyl etherate (10muL) followed immediately by dropwise addition over 10 minutes of te/t-butyl trichloroacetimidate (704mg, 3.22mmol) in cyclohexane (1 OmL). The mixture was allowed to warm to RT and stirred for 30 minutes before quenching with NaHCO3 powder (80mg). The crude mixture was filtered through Celiteand the filtrate concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (20% EtOAc / heptane) to give the product as a yellow solid (320mg, 54% yield). ESMS: m/z 389 [M+Naf. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With boron trifluoride diethyl etherate; In tetrahydrofuran; dichloromethane; at 20℃; for 16h; | [0122] Tert-butyl 2,2,2-trichloroacetimidate (17.20 ml, 96 mmol, 2 eq) was added to a stirred suspension of <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (10 g, 48.1 mmol, 1 eq) in dichloromethane (DCM) (100 mL) and tetrahydrofuran (THF) (50 mL), followed by dropwise addition of BF3?OEt2 (0.938 ml, 7.40 mmol, 10 mol%). The mixture was stirred at room temperature for 16 h, concentrated, quenched slowly with a saturated bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated bicarbonate and brine, then dried, and the crude product was purified in a Biotage (Charlotte, NC) flash system eluting with 5-30% ethyl acetate in hexanes over 12 column volumes. The product fraction was concentrated to provide tert-butyl <strong>[5198-88-9]2-bromothiazole-4-carboxylate</strong> 1 as a white solid (10.4 g, 82%). |
82% | With boron trifluoride diethyl etherate; In tetrahydrofuran; dichloromethane; at 20℃; for 16h; | [0127] tert-butyl 2,2,2-trichloroacetimidate (17.20 ml, 96 mmol, 2 eq) was added to a stirred suspension of <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (10 g, 48.1 mmol, 1 eq) in dichloromethane (DCM) (100 mL) and tetrahydrofuran (THF) (50 mL), followed by dropwise addition of BF3- OEt2 (0.938 ml, 7.40 mmol, 10 mol ). The mixture was stirred at room temperature for 16 h, concentrated, quenched slowly with a saturated bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated bicarbonate and brine, then dried, and the crude product was purified in a Biotage (Charlotte, NC) flash system eluting with 5-30% ethyl acetate in hexanes over 12 column volumes. The product fraction was concentrated to provide tert-butyl <strong>[5198-88-9]2-bromothiazole-4-carboxylate</strong> 1 as a white solid (10.4 g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With boron trifluoride diethyl etherate; In toluene; at 20.0℃; for 24.0h; | 3-Chloro-5-iodobenzoic acid (D52, 4.72 g, 16.71 mmol) in dichloromethane (16.71 ml.) was added to a stirring solution of 1 ,1-dimethylethyl 2,2,2-trichloroethanimidoate (7.30 g, 33.4 mmol) in toluene (33.4 ml.) at room temperature under argon. Boron trifluoride etherate (0.334 ml_, 2.64 mmol) was then added to the mixture and left to stir for 18 hours. 1 ,1-Dimethylethyl 2,2,2-trichloroethanimidoate (7.30 g, 33.4 mmol) was added and the solution allowed to stir for another 6 hours. Solid sodium bicarbonate was added to the reaction mixture which was then filtered through silica <n="64"/>and eluted with dichloromethane. The crude material (10.6 g) was then purified by flash chromatography (eluting with dichloromethane) to afford the title compound as a white solid.1H NMR delta (DMSOd6): 1.54 (9H, s), 7.85 (1 H, dd), 8.1 1-8.13 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With boron trifluoride diethyl etherate; In tetrahydrofuran; at 20℃;Cooling with ice; | A boron trifluoride-diethyl ether complex (91.7 IL) was added dropwise to a suspension of 2-methylpyrazine-5-carboxylic acid (1 g) and tert-butyl 2,2,2-trichloroacetimidate (4.75 g) in tetrahydrofuran (20 mL) under ice-cooling. The reaction solution was heated to room temperature and stirred for two hours. A saturated sodium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble matter was separated by filtration. The filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (1.4 g).1H-NMR (CDCl3) delta (ppm): 1.65 (s, 9H), 2.65 (s, 3H), 8.57 (d, J=1.2 Hz, 1H), 9.10 (d, J=1.6 Hz, 1H). | |
With boron trifluoride diethyl etherate; In tetrahydrofuran; at 20℃;Ice-cooling; | (1) Synthesis of t-butyl S-methylpyrazine^-carboxylateA boron trifluoride-diethyl ether complex (91.7 muL) was added drop wise to a suspension of 2-methylpyrazine-5-carboxylic acid (1 g) and tert-butyl 2,2,2- trichloroacetimidate (4.75 g) in THF (20 rnL) under ice-cooling. The reaction solution was warmed to RT, followed by stirring for 2 h. A saturated NaCl solution and EtOAc were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous MgSO4, and the insoluble matter was separated by filtration. The filtrate was concentrated and purified by silica gel columnchromatography to obtain the title compound (1.4 g). l H-NMR (CDCl3 ) delta (ppm): 1.65 (s, 9H), 2.65 (s, 3H), 8.57 (d, J = 1.2 Hz, IH), 9.10 (d, J = 1.6 Hz, IH). | |
With boron trifluoride diethyl etherate; In tetrahydrofuran; at 20℃;Ice-cooling; | (1) Synthesis of t-butyl 5-methylpyrazine-2-carboxylateA boron trifluoride-diethyl ether complex (91.7 muL) was added dropwise to a suspension of 2-methylpyrazine-5-carboxylic acid (1 g) and tert-butyl 2,2,2- trichloroacetimidate (4.75 g) in THF (20 mL) under ice-cooling. The reaction solution was warmed to RT, followed by stirring for 2 h. A saturated NaCl solution and EtOAc were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous MgSO4, and the insoluble matter was separated by filtration. The filtrate was concentrated and purified by silica gel columnchromatography to obtain the title compound (1.4 g). l H-NMR (CDCI3 ) delta (ppm): 1.65 (s, 9H), 2.65 (s, 3H), 8.57 (d, J = 1.2 Hz, IH), 9.10 (d, J = 1.6 Hz, IH). |
With boron trifluoride diethyl etherate; In tetrahydrofuran; at 20℃;Cooling with ice; | A boron trifluoride-diethyl ether complex (91.7 muL) was added dropwise to a suspension of 2-methylpyrazine-5-carboxylic acid (1 g) and tert-butyl 2,2,2-trichloroacetimidate (4.75 g) in THF (20 mL) under ice-cooling. The reaction solution was warmed to RT, followed by stirring for 2 h. A saturated NaCl solution and EtOAc were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous MgSO4, and the insoluble matter was separated by filtration. The filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (1.4 g). 1H-NMR (CDCl3) delta (ppm): 1.65 (s, 9H), 2.65 (s, 3H), 8.57 (d, J=1.2 Hz, 1H), 9.10 (d, J=1.6 Hz, 1H). | |
With boron trifluoride diethyl etherate; In tetrahydrofuran; at 20℃;Cooling with ice; | A boron trifluoride-diethyl ether complex (91.7 muL) was added dropwise to a suspension of 2-methylpyrazine-5-carboxylic acid (1 g) and tert-butyl 2,2,2-trichloroacetimidate (4.75 g) in THF (20 mL) under ice-cooling. The reaction solution was warmed to RT, followed by stirring for 2 h. A saturated NaCl solution and EtOAc were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous MgSO4, and the insoluble matter was separated by filtration. The filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (1.4 g). 1H-NMR (CDCl3) delta (ppm): 1.65 (s, 9H), 2.65 (s, 3H), 8.57 (d, J=1.2 Hz, 1H), 9.10 (d, J=1.6 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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70% | Intermediate 32; f-butyl 2-methylalaninateStage 1To a solution of Lambda/-[(benzyloxy)carbonyl]-2-methylalanine (1 g, 4.21 mmol) in DCM (10 ml anhydrous), cyclohexane (10 ml) at 00C under nitrogen was added boron trifluoride diethyl etherate (7mul, catalytic). terf-Butyl 2,2,2-trichloroacetimidate (1.51 ml, 8.43 mmol) in cyclohexane (10 ml) was then added slowly over 30 minutes before allowing to warm to RT. Reaction was allowed to stir at RT for 16 hours. To the crude reaction mixture was added 190 mg of NaHCO3 and the reaction filtered. The mother liquors were concentrated in vacuo. The crude extract was purified by column chromatography (10% EtOAc in heptane) to yield the desired product (0.863 g, 70%).1H NMR (300 MHz1 CDCI3) delta: 7.39-7.31 (5H, m), 5.46 (1 H, br s), 5.10 (2H, s), 1.54 (6H, s), 1.45 (9H, s). | |
70% | boron trifluoride diethyl etherate; In dichloromethane; cyclohexane; at 0 - 20℃;Inert atmosphere; | To a solution of N-[(benzyloxy)carbonyl]-2-methylalanine (1 g, 4.21 mmol) in DCM (10 mL anhydrous) and cyclohexane (10 mL) at 0 C. under nitrogen was added boron trifluoride diethyl etherate (7.7 ul, catalytic). tert-Butyl 2,2,2-trichloroacetimidate (1.51 mL, 8.43 mmol) in cyclohexane (10 mL) was then added slowly over 30 minutes before allowing to warm to RT. Reaction was allowed to stir at RT for 16 hours. To the crude reaction mixture was added 190 mg of NaHCO3 and the reaction filtered. The mother liquors were concentrated in vacuo. The crude extract was purified by column chromatography (10% EtOAc in heptane) to yield the desired product (0.863 g, 70% yield). 1H NMR (300 MHz, CDCl3) delta: 7.39-7.31 (5H, m), 5.46 (1H, br s), 5.10 (2H, s), 1.54 (6H, s), 1.45 (9H, s). |
70% | boron trifluoride diethyl etherate; In dichloromethane; cyclohexane; at 0 - 20℃;Inert atmosphere; | To a solution of lambda/-[(benzyloxy)carbonyl]-2-methylalanine (1 g, 4.21 mmol) in DCM (10 ml anhydrous), cyclohexane (10 ml) at 0 0C under nitrogen was added boron trifluoride diethyl etherate (7.7 mul, catalytic). ferf-Butyl 2,2,2-trichloroacetimidate (1.51 ml, 8.43 mmol) in cyclohexane (10 ml) was then added slowly over 30 minutes before allowing to warm to RT. Reaction was allowed to stir at RT for 16 hours. To the crude reaction mixture was added 190 mg of NaHCO3 and the reaction filtered. The mother liquors were concentrated in vacuo. The crude extract was purified by column chromatography (10% EtOAc in heptane) to yield the desired product (0.863 g, 70 % yield). 1H NMR (300 MHz, CDCI3) delta: 7.39-7.31 (5H, m), 5.46 (1H, br s), 5.10 (2H, s), 1.54 (6H, s), 1.45 (9H, s). |
70% | boron trifluoride diethyl etherate; In dichloromethane; cyclohexane; at 0 - 20℃;Inert atmosphere; | Stage 1 - terf-Butyl lambda/-[(benzyloxy)carbonyl]-2-methylalaninate <n="29"/>To a solution of lambda/-[(benzyloxy)carbonyl]-2-methylalanine (1 g, 4.21 mmol) in DCM (10 ml anhydrous), cyclohexane (10 ml) at 00C under nitrogen was added boron trifluoride diethyl etherate (7mul, catalytic). terf-Butyl 2,2,2-trichloroacetimidate (1.51 ml, 8.43 mmol) in cyclohexane (10 ml) was then added slowly over 30 minutes before allowing to warm to RT. Reaction was allowed to stir at RT for 16 hours. To the crude reaction mixture was added 190 mg of NaHCO3 and the reaction filtered. The mother liquors were concentrated in vacuo. The crude extract was purified by column chromatography (10% EtOAc in heptane) to yield the desired product (0.863 g, 70%). 1H NMR (300 MHz, CDCI3) delta: 7.39-7.31 (5H, m), 5.46 (1 H, br s), 5.10 (2H, s), 1.54 (6H, s), 1.45 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
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Step 1-2 The compound (234 g) obtained in step 1-1 and tetrahydrofuran (1200 ml) were mixed, and boron trifluoride-diethyl ether complex (8 ml) was added. Then, tert-butyl 2,2,2-trichloroacetimidate (361 ml) was added dropwise under ice-cooling. To this reaction mixture were added saturated aqueous sodium hydrogen carbonate solution (1200 ml) and water (1200 ml), and the aqueous layer was extracted with ethyl acetate (1200 ml). The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Hexane (1800 ml) was added to the obtained residue. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the compound described in the above-mentioned scheme (326 g) as a crude product.1H-NMR (CDCl3) delta: 1.63 (9H, s), 7.31 (1H, d, J=5.2 Hz), 8.31 (1H, d, J=5.2 Hz). | ||
With boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere; | To a solution of compound 63B (1 .0 g, 5.2 mmol, 1 .0 eq) in dry THF (6.0 mL) was added tert-butyl 2,2,2-trichloroacetimidate (1 .6 ml, 8.9 mmol, 1.7 eq) and BF3-Et20 (0.034 ml, 0.26 mmol, 0.05 eq) at 0 C. The reaction solution was stirred at room temperature for 2 hours under nitrogen atmosphere before it was quenched with saturated aqueous NaHCC>3. The mixture was extracted with EA and the organic layer was dried over Na2SC>4 After concentration under reduced pressure, compound 63C (1 .44 g, 99%) was obtained as light yellow oil, which was used for next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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76% | Step 1iert-Butyl Methyl Adtpate. 11 BA solution of 6-methoxy-6-oxohexanoic acid (11 A) (9.25 mL, 62.4 mmoi) and ferf-butyl 2,2,2-trichioroacetimidate (27.3 g, 125 mmol) in DCM (100 mL) was cooled to 0 C. BF3*Et20 (1.58 mL, 12.5 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for 2 h. The reaction was quenched with 10% aqueous K2C03. The organic layer was separated, dried (Na2S04), filtered, and concentrated. The residue was triturated in heptane, filtered, and the filtrate was concentrated to yield 11 B ( 0.3 g, yield = 76%): 1H NMR (300 MHz, CDCI3) 6 3.67 (s, 3H), 2.40-2.10 (m, 4H), 1 .80-1.50 (m, 4H), 1.43 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
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92% | In dichloromethane; at 20℃; for 16h; | At rt, a solution of tert-butyl 2,2,2-trichloroacetimidate (27.7 mL, 155 mmol) in CH2CI2 (50 mL) was added dropwise to a soln of <strong>[16694-18-1]4-bromothiophene-2-carboxylic acid</strong> (94; 16.0 g, 77.3 mmol) in CH2CI2 (150 mL). The mixture was stirred for 16 h. A precipitate was formed, which was removed by filtration. The filtrate was concentrated. FC (hexane/EtOAc 99:1 to 97:3) yielded 95 (18.7 g, 92%). |
92% | In dichloromethane; at 20℃; for 16h; | At rt, a solution of tert-butyl 2,2,2-trichloroacetimi- date (27.7 mE, 155 mmol) in CH2C12 (50 mE) was added dropwise to a soln of <strong>[16694-18-1]4-bromothiophene-2-carboxylic acid</strong> (94; 16.0 g, 77.3 mmol) in CH2C12 (150 mE). The mixture was stirred for 16 h. A precipitate was formed, which was removed by filtration. The filtrate was concentrated. FC (hexane/EtOAc 99:1 to 97:3) yielded 95 (18.7 g, 92%). |
Yield | Reaction Conditions | Operation in experiment |
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50% | With boron trifluoride diethyl etherate; In hexane; dichloromethane; at 20℃; for 96h;Inert atmosphere; | 1 g of cyclopent-3-en-1-ylmethanol (10.2 mmol, prepared as described in ref 26) was dissolved in 15 mL of hexane and 15 mL of CH2Cl2 under Ar atmosphere. The solution was cooled to 0 C over an ice bath and 2,56 g of t-butyl-2,2,2-trichloroacetimidate (11,3 mmol) and 720 mul of BF3·Et2O (4.4 mmol) were slowly added. The mixture was stirred at room temperature for 4 days. The reaction mixture was neutralized with solid NaHCO3 and filtered through Celite. The crude mixture was concentrated under reduced pressure and the product purified by column chromatography (2-10 EtOAc-petroleum ether) to give 785 mg of 4-(tbutoxymethyl)cyclopent-1-ene (50%). |
Yield | Reaction Conditions | Operation in experiment |
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88% | With copper(II) bis(trifluoromethanesulfonate); In nitromethane; at 20℃; for 2h;Inert atmosphere; | General procedure: To a dry round-bottom flask, equipped with a stirrer bar, under argon was added freshly distilled MeNO2 (2.5 mL), tert-butyl 2,2,2-trichloroacetimidate (0.45 mL, 2.5 mmol), amine (1.0 mmol), and CuOTf (18 mg, 0.05 mmol). The reaction was stirred at r.t. for 2 h, or until the reaction was observed to have gone to completion by TLC or 1H NMR spectroscopy of small aliquots of the reaction mixture. The reaction mixture was then diluted with EtOAc (25 mL) and washed with aq sat. NaHCO3 solution (20 mL). The aqueous phase was extracted with an additional portion of EtOAc (20 mL). The combined organic extracts were dried with Na2SO4 and filtered through a plug of alumina before being reduced in vacuo. The crude product was purified by flash column chromatography (typically 20:1, hexane-EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
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83% | With copper(l) iodide; silver perchlorate; In nitromethane; at 20℃; for 2h;Inert atmosphere; | General procedure: To a dry round-bottom flask, equipped with a stirrer bar, under argon was added freshly distilled MeNO2 (2.5 mL), tert-butyl 2,2,2-trichloroacetimidate (0.45 mL, 2.5 mmol), amine (1.0 mmol), and CuOTf (18 mg, 0.05 mmol). The reaction was stirred at r.t. for 2 h, or until the reaction was observed to have gone to completion by TLC or 1H NMR spectroscopy of small aliquots of the reaction mixture. The reaction mixture was then diluted with EtOAc (25 mL) and washed with aq sat. NaHCO3 solution (20 mL). The aqueous phase was extracted with an additional portion of EtOAc (20 mL). The combined organic extracts were dried with Na2SO4 and filtered through a plug of alumina before being reduced in vacuo. The crude product was purified by flash column chromatography (typically 20:1, hexane-EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
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95% | In dichloromethane; at 20℃; for 12h; | To a solution of <strong>[90259-31-7]2-bromo-6-methylbenzoic acid</strong> (10.00 g, 46.50 mmol) in DCM (150 niL) was added tert-butyl 2,2,2-trichloroacetimidate (16.66 niL, 93.00 mmol) at room temperature. The contents were stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using CombiFlash (40 g REDISEP column) using 5% ethyl acetate in hexane as an eluent to yield tert-butyl <strong>[90259-31-7]2-bromo-6-methylbenzoate</strong> (12 g, 95%). 1H NMR (400 MHz, DMSO-d6) delta ppm: 1.56 (s, 9 H), 2.29 (s, 3 H), 7.24-7.30 (m, 2 H), 7.47-7.49 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
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With boron trifluoride diethyl etherate; In tetrahydrofuran; | BF3*OEt2 (0.2 mL) is added to a mixture of <strong>[39891-13-9]2-chloropyridine-5-acetic acid</strong> (1.72 g, 10 mmol) and tert-butyl 2,2,2-trichloroacetimidate (3.58 mL, 20 mmol) in THF (20 mL), and the mixture is stirred overnight. The mixture is quenched with aq. sat. NaHC03 and extracted with EtOAc. The comb. org. layers are washed with brine, dried over MgS04, and concentrated under reduced pressure. Purification of the crude by FC (EtOAc / heptane 5:95? 40:60) yields the title product. LC-MS: tR = 0.85 min, MH+ = 228.29 (conditions 3). |
Yield | Reaction Conditions | Operation in experiment |
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88% | With boron trifluoride diethyl etherate; In tetrahydrofuran; dichloromethane; cyclohexane; at 20℃;Cooling with ice; | Step 1: Preparation of Compound a66 (0762) (0763) To a solution of Compound a64 (2.0 g, 9.3 mmol) in dichloromethane (10 mL), cyclohexane (18.5 ml) and THF (1 ml) was added a solution of Compound a65 (4.07 g, 18.6 mmol) in cyclohexane (6 ml) under ice-cooling. To the reaction solution was dropped boron trifluoride-diethyl ether complex (0.26 g, 1.86 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction solution was added sodium hydrogen carbonate (2 g), and the mixture was stirred at room temperature for 30 minutes. The insoluble material was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to yield Compound a66 (2.2 g, yield: 88%) as colorless oil. (0764) LC-MS: m/z=271. [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
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77.1% | With boron trifluoride diethyl etherate; In cyclohexene; at 20℃; for 16h; | 4-Bromo-2,6-difluorobenzoic acid (i .5 g, 6.33 mmol) was suspended in dichloromethane (iO mL). A solution of tert-butyl2,2,2-trichloroacetamidate (i.38 g, 6.33 mmol)in cyclohexane (30 mL) and BF3.Et20 (47.5 iL, 0.38 mmol) were added subsequently to the suspension. After stirring at room temperature for i 6 h, the reaction was cooled on an ice bath and solid NaHCO3 (0.5 g) was added in one portion. This mixture was stirred for iO mm and filtered over a silica plug. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (heptane/ethyl acetate = 7/3 v/v%) to provide the title compound as acolourless oil (i .43 g, 77.1 %). |
77.1% | With boron trifluoride diethyl etherate; In dichloromethane; cyclohexane; at 20℃; for 16h; | 4-Bromo-2,6-difluorobenzoic acid (1.5 g, 6.33 mmol) was suspended in dichloromethane (10 mL). A solution of tert-butyl 2,2,2-trichloroacetamidate (1 .38 g, 6.33 mmol) in cyclohexane (30 mL) and BF3.Et.2O (47.5 μ, 0.38 mmol) were added subsequently to the suspension. After stirring at room temperature for 16 h, the reaction was cooled on an ice bath and solid NaHCCh (0.5 g) was added in one portion. This mixture was stirred for 10 min and filtered over a silica plug. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (heptane/ethyl acetate = 7/3 v/v%) to provide the title compound as a colourless oil (1 .43 g, 77.1 %). |
Yield | Reaction Conditions | Operation in experiment |
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92% | With boron trifluoride diethyl etherate; In dichloromethane; cyclohexane; at 20℃; for 2.5h; | [00837] BF3.OEt2 (245 mu, 10%) was added to a solution of te/ -butyl 2,2,2-trichloroacet-imidate (13.0 g, 59.5 mmol) and <strong>[626-41-5]3,5-dibromophenol</strong> (5.0 g, 19.9 mmol) in DCM/cyclohexane (1 :1 ; 66 mL). The mixture was stirred at rt for 2 h. Cyclohexane (66 mL) was added and the flask was left in the fridge for 0.5 h. The solid was then filtered off. The organic solution was washed with sat. NaHC03 (3 chi 130 mL), dried over MgS04, filtered and the solvent was removed under reduced pressure. The crude was purified by chromatography (EtOAc/cyclohexane 0?5%) to give 1 ,3-dibromo-5-(fe/?-butoxy)benzene as a colourless oil (5.65 g, 92%). 'BuLi (7.3 mL, 1 1 .7 mmol) was added dropwise to a solution of 1 ,3- dibromo-5-(fe/?-butoxy)benzene (1 .64 g, 5.32 mmol) in THF (35.5 mL) at -78 C, and the mixture was stirred at -78 C for a further 0.5 h. (MeS)? (719 mu, 7.99 mmol) was added and the reaction was warmed to rt over 1 h. EtOAc was subsequently added. The organic solution was washed with 1 :1 hbO/brine, dried over MgSCv, filtered and the solvent was removed under reduced pressure. The crude was purified by chromatography (EtOAc/cyclohexane 0?10%) to afford (3-bromo-5-(fe/f- butoxy)phenyl)(methyl)sulfane as a colourless oil (1 .38 g, 94%). H NMR (500 MHz, CDCI3) delta 7.08 (t, J = 1 .6 Hz, 1 H), 6.93 (t, J = 1 .9 Hz, 1 H), 6.80 (t, J = 1 .8 Hz, 1 H), 2.46 (s, 3H), 1 .36 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
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84% | In diethyl ether; dichloromethane; for 108.0h; | To a stirred solution of commercially-available (R)-l-((benzyloxy)carbonyl)pyrrolidine-3-carboxylic acid (500 mg, 2 mmol) in 1 : 1 ether: DCM (4 mL) was added tert-butyl-2,2,2-trichloroacetimidate (0.716 mL, 4 mmol) and the resulting reaction for 36 h. Additional tert-butyl-2,2,2-trichloroacetimidate (0.4 mL, 2.2 mmol) was added and the mixture was stirred for 3 days. The resulting suspension was filtered and washed several times with 1 : 1 ether:DCM. The combined filtrate and washes were concentrated under reduced pressure, taken up in DCM with a drop of methanol, mixed with a small amount of silica and concentrated. The resulting silica mixture was dry-loaded onto a flash column and eluted with 14:5: 1 hexane: DCM: EtOAc solvent mix to provide 1-benzyl 3-(tert-butyl) (R)-pyrrolidine-l,3-dicarboxylate (516 mg, 84% yield). 1H NMR (300 MHz, Chloroform-d) delta 7.43 - 7.29 (m, 5H), 5.15 (s, 2H), 3.84 - 3.21 (m, 4H), 3.17 - 2.78 (m, 1H), 2.20 - 2.02 (m, 2H), 1.45 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
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31% | With pyridinium p-toluenesulfonate; In dichloromethane; at 10℃; | Step 1: Preparation 6-tert-butoxytetralin-1-one To a stirred solution of 6-hydroxytetralin-1-one (50 g, 308.29 mmol, 1 eq) in anhydrous dichloromethane (2000 mL) at 0 C. was added tert-butyl 2,2,2-trichloroethanimidate (67.36 g, 308.29 mmol, 55 mL, 1 eq) and pyridinium para-toluenesulfonate (7.75 g, 30.83 mmol, 0.1 eq). The reaction mixture was stirred at 10 C. for 3 hours. Additional portion of tert-butyl 2,2,2-trichloroethanimidate (67.36 g, 308.29 mmol, 55 mL, 1 eq) and pyridinium para-toluenesulfonate (7.75 g, 30.83 mmol, 0.1 eq) was added and the reaction mixture was stirred at 10 C. for 15 hours. This process was repeated three times. Thin layer chromatography (petroleum ether:ethyl acetate=3:1, Rf=0.8) showed that most of reactant still remained, the reaction mixture was stirred at 10 C. for 72 hours. The reaction mixture was quenched by addition of a solution of sodium hydrogen carbonate (1500 mL) at 15 C., and then extracted with dichloromethane (300 mL*3). The combined organic layers were washed with brine (300 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=100:1 to 50:1) to get 6-tert-butoxytetralin-1-one (21 g, 96.20 mmol, 31% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.8 Hz, 1H), 6.91 (dd, J=2.4, 8.8 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 2.93-3.90 (t, J=6.0 Hz, 2H), 2.63-2.60 (m, t, J=6.0 Hz, 2H), 2.13 (m, 2H), 1.43 (s, 9H) |
31% | To a stirred solution of 6-hydroxytetralin-1-one (50 g, 308.29 mmol, 1 eq) in anhydrous dichloromethane (2000 mL) at 0 C. was added tert-butyl 2,2,2-trichloroethanimidate (67.36 g, 308.29 mmol, 55 mL, 1 eq) and pyridinium para-toluenesulfonate (7.75 g, 30.83 mmol, 0.1 eq). The reaction mixture was stirred at 10 C. for 3 hours. Additional portion of tert-butyl 2,2,2-trichloroethanimidate (67.36 g, 308.29 mmol, 55 mL, 1 eq) and pyridinium para-toluenesulfonate (7.75 g, 30.83 mmol, 0.1 eq) was added and the reaction mixture was stirred at 10 C. for 15 hours. This process was repeated three times. Thin layer chromatography (petroleum ether:ethyl acetate=3:1, Rf=0.8) showed the most of reactant was still remained, the reaction mixture was stirred at 10 C. for 72 hours. The reaction mixture was quenched by addition a solution of sodium hydrogen carbonate (1500 mL) at 15 C., and then extracted with dichloromethane (300 mL*3). The combined organic layers were washed with brine (300 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=100:1 to 50:1) to get 6-tert-butoxytetralin-1-one (21 g, 96.20 mmol, 31% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.8 Hz, 1H), 6.91 (dd, J=2.4, 8.8 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 2.93-3.90 (t, J=6.0 Hz, 2H), 2.63-2.60 (m, t, J=6.0 Hz, 2H), 2.13 (m, 2H), 1.43 (s, 9H) | |
31% | To a stirred solution of 6-hydroxytetralin-l-one (50 g, 308.29 mmol, 1 eq) in anhydrous dichloromethane (2000 mL) at 0 C. was added tert-butyl 2,2,2-trichloroethanimidate (67.36 g, 308.29 mmol, 55 mL, 1 eq) and pyridinium para-toluenesulfonate (7.75 g, 30.83 mmol, 0.1 eq). The reaction mixture was stirred at 10 C. for 3 hours. Additional portion of tert-butyl 2,2,2-trichloroethanimidate (67.36 g, 308.29 mmol, 55 mL, 1 eq) and pyridinium para-toluenesulfonate (7.75 g, 30.83 mmol, 0.1 eq) was added and the reaction mixture was stirred at 10 C. for 15 hours. This process was repeated three times. Thin layer chromatography (petroleum ether: ethyl acetate=3:1, Rf=0.8) showed that most of reactant still remained, the reaction mixture was stirred at 10 C. for 72 hours. The reaction mixture was quenched by addition of a solution of sodium hydrogen carbonate (1500 mL) at 15 C., and then extracted with dichloromethane (300 mL×3). The combined organic layers were washed with brine (300 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=100:1 to 50:1) to get 6-tert-butoxytetralin-l-one (21 g, 96.20 mmol, 31% yield) as a yellow oil. 1H NMR (400 Mhz, CDCl3) δ 7.97 (d, J=8.8 Hz, 1H), 6.91 (dd, J=2.4, 8.8 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 2.93-3.90 (t, J=6.0 Hz, 2H), 2.63-2.60 (m, t, J=6.0 Hz, 2H), 2.13 (m, 2H), 1.43 (s, 9H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With boron trifluoride diethyl etherate; In tetrahydrofuran; for 1.0h;Inert atmosphere; | To a solution of <strong>[182247-45-6](S)-3-benzyl-4-methoxy-4-oxobutanoic acid</strong> (0.5g, 2.25mmol) and tert-butyl-2,2,2-trichloroacetimidate (0.8mL, 4.51mmol) in anhydrous THF (4mL) under Ar at 0C was added BF3.OEt2 (42muL, 0.34mmol) dropwise. The reaction mixture was stirred for 1h at 0C. Since conversion was incomplete (LCMS), additional tert-butyl-2,2,2-trichloroacetimidate (0.8mL, 4.51mmol) was added and mixture stirred for a further hour at 0C. Saturated NaHCO3 (5mL) was carrefully added and mixture extracted with EtOAc (2*10mL). The combined organic layer was dried over MgSO4, filtered and concentrated to dryness. The residue was then purified by flash chromatography on silica gel (5% EtOAc in cyclohexane) providing 4-(tert-butyl)-1-methyl-(S)-2-benzylsuccinate (0.54g, 87%). LCMS (Method B) m/z 223 (M+1 - tBu). HPLC purity>95% (254nm). 1H NMR (CDCl3) delta: 7.41 - 7.01 (m, 5H), 3.66 (s, 3H), 3.20 - 2.90 (m, 2H), 2.73 (m, 1H), 2.60 (dd, J=16.5, 9.1Hz, 1H), 2.33 (dd, J=16.5, 4.7Hz, 1H), 1.41 (s, 9H). To a solution of 4-(tert-butyl)-1-methyl-(S)-2-benzylsuccinate (0.54g, 1.93mmol) in THF/water (1/1, 8mL) was added LiOH (185mg, 7.73mmol) and the reaction mixture stirred at rt for 14h whereupon HCl (3M) was added to adjust pH to 1. Thereafter, the mixture was extracted with DCM (3*10mL) and the combined extracts dried (MgSO4), filtered and concentrated to dryness. The crude residue was purified by flash chromatography (40% EtOAc in cyclohexane) providing (S)-2-benzyl-4-(tert-butoxy)-4-oxobutanoic acid (18) (0.43g, 85%). LCMS (Method B) m/z 209 (M+1 - tBu). HPLC purity>98% (254nm). 1H NMR (CDCl3) delta: 10.49 (bs, 1H), 7.38 - 7.24 (m, 5H), 3.20 - 3.13 (m, 2H), 2.83 (dd, J=15.4, 10.4Hz, 1H), 2.62 (dd, J=16.6, 8.6Hz, 1H), 2.41 (dd, J=16.6, 4.6Hz, 1H), 1.48 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With boron trifluoride diethyl etherate; In hexane; dichloromethane; at 20℃; for 18h; | A mixture of <strong>[91182-60-4]5-(4-bromophenyl)-3-methylisoxazole-4-carboxylic acid</strong> (5.0 g, 17.7 mmol), tert- butyl 2,2,2-trichloroacetimidate (4.76 mL, 26.6 mmol), and BF3.OEt2 (0.23 mL, 1.77 mmol) in DCM (10 mL)/hexanes (10 mL) was stirred at RT for 18 h, after which 5 g NaHCCft was added. The reaction mixture was stirred at RT for 3 h, then was filtered through Celite, which was washed with EtOAc the washes were no longer UV- active. The combined filtrates were concentrated in vacuo. The crude product was chromatographed (220 g Si02 continuous gradient from 0% to 20% EtOAc/Hexanes over 35 min) to give the title compound (5.50 g, 92 % yield) as a white solid. LCMS, [M+H]+ = 338.0. 'H NMR (500 MHz, CDCl3) d 7.79 - 7.75 (m, 2H), 7.64 - 7.60 (m, 2H), 2.48 (s, 3H), 1.53 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In dichloromethane; at 20℃; for 12h; | Compound 1 (81.00 g, 344.01 mmol) was dissolved in dichloromethane (1.1 L).Then tert-butyl trichloroacetimidate (300.68 g, 1.38 mol) was added dropwise at room temperature,Reaction at 20 C for 12 hours,TLC (petroleum ether / ethyl acetate volume ratio = 5/1) showed that the reaction was complete.The reaction system was quenched by adding 1.5L of water,Then extracted with dichloromethane (3 * 0.5L), the organic phase was washed with brine,Then dried and concentrated to obtain the crude product,It was then separated and purified by column chromatography (volume ether / ethyl acetate volume ratio = 50 / to 5/1) to obtain compound 2 (85 g). The yield was 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With boron trifluoride diethyl etherate; In dichloromethane; cyclohexane; at 20℃; for 24h; | A solution of commercial Boc-L-lys(Cbz)OH (D) (1 g, 2.63 mmol)in CH2Cl2 (5.26 mL) and tert-butyl trichloroacetimidate (0.94 mL,5.26 mmol) in cyclohexane (5.26 mL) was added with boron trifluoridediethyl etherate (52.6 mL, 2.63 mmol). The mixture wasstirred for 24 h at room temperature. The solvent was evaporatedunder reduced pressure and replaced by CHCl3. The solution,washed with Brine, dried (Na2SO4) and evaporated under reducedpressure, gave a crude residue that, purified chromatographicallyon silica gel column (CH2Cl2 as eluent) afforded the oily product (S)-tert-butyl 6-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (E) (882 mg, 2.03 mmol) used withoutfurther purification. Yield 77%; 1H NMR (500 MHz, CDCl3)d 7.36e7.33 (m, 5H), 5.09 (s, 2H), 5.06 (bs, 1H), 4.82 (bs, 1H), 4.15(dd, J 11.6, 6.4 Hz, 1H), 3.21e3.17 (dd, J 12.7, 6.4 Hz, 2H), 1.77 (m,1H), 1.53e1.39 (m, 23H); 13C NMR (100 MHz, CDCl3) d 171.68,163.63, 156.22, 155.19, 136.07, 128.01, 127.57, 81.48, 79.31, 66.11,53.34, 40.14, 31.87, 28.82, 27.81, 27.47, 21.87; MS (ESI), m/z: 437(M1); Anal. Calcd. for C23H36N2O6: C, 63.28%; H, 8.31%; N, 6.42%;found: C, 63.30%; H, 8.29%; N, 6.39%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With boron trifluoride diethyl ether complex In tetrahydrofuran at 0 - 25℃; Inert atmosphere; | Step 1 - Tert-butyl 5-bromo-1H-indole-2-carboxylate To a stirred solution of 5-bromo-1H- indole-2 carboxylic acid (20.00 g, 83.31 mmol, CAS 7254-19-5) in THF (250.00 mL) was added tert- butyl 2,2,2-trichloroethanimidate (45.51 g, 208.29 mmol) in portions at 25 C under nitrogen atmosphere. To the above mixture was added BF3.Et2O (2.36 g, 16.66 mmol) dropwise over 10 min at 0 C. The resulting mixture was stirred for overnight at rt. On completion, the reaction was quenched with saturated aq. Na2CO3 (200 mL) and diluted with water (100 mL). The mixture was then extracted with EtOAc (3 × 100 mL), the combined organic layers were washed with water (3 × 100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (20 / 1), to afford the title compound (22.8 g, 92% yield) as a light yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.8, 1.9 Hz, 1H), 7.03 (dd, J = 2.2, 0.9 Hz, 1H), 1.57 (s, 9H); LC/MS (ESI, m/z): [(M - 1)]- = 293.9, 295.9. |
92% | With boron trifluoride diethyl ether complex In tetrahydrofuran at 0 - 25℃; Inert atmosphere; | Step 1 -tert-butyl 5-bromo-1H-indole-2-carboxylate To a stirred solution of 5-bromo-1H-indole-2 carboxylic acid (20.00 g, 83.31 mmol, CAS 7254-19-5) in THF (250.00 mL) was added tert-butyl 2,2,2-trichloroethanimidate (45.51 g, 208.29 mmol) in portions at 25 C under nitrogen atmosphere. To the above mixture was added BF3·Et2O (2.36 g, 16.66 mmol) dropwise over 10 min at 0 C. The resulting mixture was stirred for overnight at rt. On completion, the reaction was quenched with saturated aq. Na2CO3 (200 mL) and diluted with water (100 mL). The mixture was then extracted with EtOAc (3 × 100 mL), the combined organic layers were washed with water (3 × 100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (20 / 1), to afford the title compound (22.8 g, 92% yield) as a light yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.8, 1.9 Hz, 1H), 7.03 (dd, J = 2.2, 0.9 Hz, 1H), 1.57 (s, 9H); LC/MS (ESI, m/z): [(M - 1)]- = 293.9, 295.9. |
Tags: 98946-18-0 synthesis path| 98946-18-0 SDS| 98946-18-0 COA| 98946-18-0 purity| 98946-18-0 application| 98946-18-0 NMR| 98946-18-0 COA| 98946-18-0 structure
[ 2533-69-9 ]
Methyl 2,2,2-trichloroacetimidate
Similarity: 0.79
[ 2533-69-9 ]
Methyl 2,2,2-trichloroacetimidate
Similarity: 0.79
[ 81927-55-1 ]
Benzyl 2,2,2-trichloroacetimidate
Similarity: 0.61
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