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CAS No. : | 126430-46-4 | MDL No. : | MFCD00143681 |
Formula : | C11H13BrO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JJUJDJNFXYNOKI-UHFFFAOYSA-N |
M.W : | 257.12 | Pubchem ID : | 3832489 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.36 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 59.79 |
TPSA : | 26.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.7 cm/s |
Log Po/w (iLOGP) : | 2.7 |
Log Po/w (XLOGP3) : | 3.05 |
Log Po/w (WLOGP) : | 2.75 |
Log Po/w (MLOGP) : | 2.99 |
Log Po/w (SILICOS-IT) : | 3.3 |
Consensus Log Po/w : | 2.96 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.28 |
Solubility : | 0.136 mg/ml ; 0.000529 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.27 |
Solubility : | 0.139 mg/ml ; 0.000539 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.56 |
Solubility : | 0.00707 mg/ml ; 0.0000275 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 1.94 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P305+P351+P338-P312-P337+P313 | UN#: | N/A |
Hazard Statements: | H302-H312-H319 | Packing Group: | N/A |
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 |
---|---|---|
83% | With potassium carbonate In dichloromethane for 2 h; | To a solution of 4-bromobutyryl chloride (Aldrich Chemical Company, Wisconsin), (10.27 g, 55.4 mmol) in 100 mL of dichloromethane was added benzyl alcohol (Aldrich Chemical Company, Wisconsin), (6.29 g, 58.1 mmol), followed by potassium carbonate (8.3 g, 60 mmol) in four portions. After 2 hours, water was added, and the layers were separated. The organic layer was washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent gave the title compound (11.87 g, 83percent yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.36 (m, 5H), 5.14 (s, 2H), 3.46 (t, J=6.4 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 2.20 (quin, J=6.6 Hz, 2H). |
82% | With dmap In dichloromethane at 20℃; for 2 h; | [00140] Benzyl alcohol (3.1 ml_, 30 mmol) was added to a solution of Compound 1 (3.47 ml_, 30 mmol) and 4-dimethylaminopyridine (732 mg, 6 mmol) in dichloromethane (100 ml_). The reaction was stirred for 2 hours at room temperature then quenched with 1 M HCI (100 ml_). The organic phase was washed once more with 1 M HCI (100 ml_), dried over MgS04, filtered, dried by rotary evaporation and was dried under vacuum to yield Compound 2 as a colorless oil (6.29 g, 24.5 mmol, 82percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: With S-phenyl benzenethiosulfinate; diisopropyl-carbodiimide In dichloromethane at 20℃; for 2 h; |
General procedure: General Procedure for Benzyl Protection of the Bromo-Acid (1c, 1d) [0103] Diisopropylcarbodiimide (DIC) (3.59 mmol, 1.3 eq) was added to a mixture of the bromo-acid (4-bromobutyric acid or 5-bromovaleric acid) (2.76 mmol, 1 eq) and DPTS (3.04 mmol, 1.1 eq) in dry DCM (30 mL) and was allowed to react for 2 hours at room temperature. Benzyl alcohol (4.14 mmol, 1.5 eq) was added and allowed to react overnight. The reaction was washed water and brine, and the DCM was removed by evaporation. Hexanes was added and the resulting white precipitate was removed by filtration. The hexanes was removed from the filtrate by evaporation resulting in an oil which was purified by silica gel chromatography (Hexanes/Ethyl Acetate 3.5/1). Benzyl 4-bromobutyrate (1c) [0104] 70percent yield [0105] 1H NMR (500 MHz, CDCl3) 2.22 (p 2H), 2.58 (t, 2H), 3.48 (t, 2H), 5.16 (s, 2H), 7.40 (m, 5H) [0106] 13C NMR (125 MHz, CDCl3): 28.0, 32.7, 33.0, 66.7, 128.5, 128.6, 128.9, 136.1, 172.6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.88 g | 60% Sodium hydride (1.05 g, 26.2 mmol) was suspended in THF (50 mL), to which di-tert-butyl malonate (5.86 mL, 26.2 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 20 minutes. Under ice cooling, sodium iodide (0.37 g, 2.49 mmol) was added, the compound (6.41 g, 24.9 mmol) obtained in Production Example 8 was then added dropwise and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with diethyl ether and washed with water, and the aqueous layer was then extracted with diethyl ether. The organic layers were combined, washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulphate. Following filtration, the solvent was removed by distillation under reduced pressure to obtain the titled compound (9.88 g, 25.2 mmol). 1H-NMR(600MHz,CDCl3)delta(ppm):1.42-1.49(m,18H),1.65-1.72(m,2H),1.80-1.87(m,2H),2.3 9(t,J=7.52 Hz,2H),3.13(t,J=7.52Hz,1H),5.11(s,2H),7.29-7.40(m,5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dichloromethane; acetonitrile; | Reference Example 11 4.7 g of 1,2,4-triazole and 9.5 g of potassium carbonate were added to a solution of 15 g of <strong>[126430-46-4]benzyl 4-bromobutyrate</strong> in 150 ml of acetonitrile. The mixture was refluxed by heating, for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added 30 ml of methylene chloride. The insolubles were collected by filtration and washed. The filtrate and the washings were combined and purified by silica gel column chromatography (eluant: methylene chloride/methanol=50/1) to obtain 11.6 g of benzyl 4-(1,2,4-triazol-1-yl)butyrate as a colorless oily substance. 1 H-NMR (200 MHz, CDCl3) delta ppm: 2.14-2.32 (2H, m), 2.32-2.44 (2H, m), 4.24 (2H, t, J=6.7 Hz), 5.13 (2H, s), 7.30-7.45 (5H, m), 7.94 (1H, s), 8.00 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In dichloromethane; for 2h; | To a solution of 4-bromobutyryl chloride (Aldrich Chemical Company, Wisconsin), (10.27 g, 55.4 mmol) in 100 mL of dichloromethane was added benzyl alcohol (Aldrich Chemical Company, Wisconsin), (6.29 g, 58.1 mmol), followed by potassium carbonate (8.3 g, 60 mmol) in four portions. After 2 hours, water was added, and the layers were separated. The organic layer was washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent gave the title compound (11.87 g, 83% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) delta 7.36 (m, 5H), 5.14 (s, 2H), 3.46 (t, J=6.4 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 2.20 (quin, J=6.6 Hz, 2H). |
82% | With dmap; In dichloromethane; at 20℃; for 2h; | [00140] Benzyl alcohol (3.1 ml_, 30 mmol) was added to a solution of Compound 1 (3.47 ml_, 30 mmol) and 4-dimethylaminopyridine (732 mg, 6 mmol) in dichloromethane (100 ml_). The reaction was stirred for 2 hours at room temperature then quenched with 1 M HCI (100 ml_). The organic phase was washed once more with 1 M HCI (100 ml_), dried over MgS04, filtered, dried by rotary evaporation and was dried under vacuum to yield Compound 2 as a colorless oil (6.29 g, 24.5 mmol, 82%). |
With triethylamine; In dichloromethane; at 20℃; for 2h; | To a solution of benzyl alcohol (1 mL) and triethylamine (2.69 mL) in dichloromethane (15 mL) was added 4-bromobutyryl chloride (1.68 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 8/1) to give benzyl 4-bromobutyrate (2.45 g). To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-beta-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.17 g) in acetone (3 mL) were added cesium carbonate (0.16 g), benzyl 4-bromobutyrate (0.1 g) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature for 2 days. The reactionmixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 10/1 - 3/1) to give 1-(3-benzyloxycarbonylpropyl)-3-(beta-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.14 g). This material was dissolved in tetrahydrofuran (5 mL) . To the solution was added 10% palladium-carbon powder (50 mg) , and the mixture was stirred at room temperature'under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 1/2 - dichloromethane/methanol = 15/1) to give the title compound (95 mg). 1H-NMR (CDCl3) delta ppm: 1.04 (9H, s), 1.13 (9H, s), 1.15 (9H, s), 1.17 (9H, s), 1.35 (9H, s), 2.15-2.3 (2H, m), 2.3-2.45 (2H, m), 2.8-3.4 (4H, m), 3.95-4.05 (1H, m), 4.05-4.15 (1H, m), 4.31 (1H, dd, J=12.2Hz, 1.7Hz), 4.35-4.55 (2H, m), 5.2-5.35 (1H, m), 5.35-5.45 (1H, m), 5.45-5.55 (1H, m), 6.03 (1H, d, J=8.1Hz), 6.7 (1H, d, J=4.9Hz), 6.9-7.0 (2H, m), 7.15-7.25 (2H, m), 8.27 (1H, d, J=4.9Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | General procedure: General Procedure for Benzyl Protection of the Bromo-Acid (1c, 1d) [0103] Diisopropylcarbodiimide (DIC) (3.59 mmol, 1.3 eq) was added to a mixture of the bromo-acid (4-bromobutyric acid or 5-bromovaleric acid) (2.76 mmol, 1 eq) and DPTS (3.04 mmol, 1.1 eq) in dry DCM (30 mL) and was allowed to react for 2 hours at room temperature. Benzyl alcohol (4.14 mmol, 1.5 eq) was added and allowed to react overnight. The reaction was washed water and brine, and the DCM was removed by evaporation. Hexanes was added and the resulting white precipitate was removed by filtration. The hexanes was removed from the filtrate by evaporation resulting in an oil which was purified by silica gel chromatography (Hexanes/Ethyl Acetate 3.5/1). Benzyl 4-bromobutyrate (1c) [0104] 70% yield [0105] 1H NMR (500 MHz, CDCl3) 2.22 (p 2H), 2.58 (t, 2H), 3.48 (t, 2H), 5.16 (s, 2H), 7.40 (m, 5H) [0106] 13C NMR (125 MHz, CDCl3): 28.0, 32.7, 33.0, 66.7, 128.5, 128.6, 128.9, 136.1, 172.6 | |
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 20℃; for 3h; | To a mixture of 4-bromobutyric acid (1 g), benzyl alcohol (0.65 g) and triphenyl phosphine (1.57 g) in tetrahydrofuran (12 mL) was added diethyl azodicarboxylate (40% toluene solution, 2.88 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 20/1) to give the title compound (0.69 g).1H-NMR (CDCl3) delta ppm: 2.15-2.25 (2H, m), 2.56 (2H, t, J=7.1Hz), 3.46 (2H, t, J=6.5Hz), 5.13 (2H, s), 7.25-7.4 (5H, m) | |
6.41 g | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2.5h; | Benzyl alcohol (2.84 mL, 27.3 mmol), 4-bromobutanoic acid (5.01 g, 30.0 mmol) and DMAP (0.33 g, 2.73 mmol) were dissolved in methylene chloride (50 mL), added with EDC (6.5 g, 34.1 mmol) under ice cooling and stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure and then dissolved in diethyl ether. The solution was washed sequentially with a saturated sodium hydrogen carbonate aqueous solution, water and a 10% citric acid aqueous solution and dried over anhydrous magnesium sulphate. Following filtration, the solvent was removed by distillation under reduced pressure to obtain the titled compound (6.41 g, 24.9 mmol). 1H-NMR(600MHz,CDCl3)delta(ppm):2.20(quin,J=6.83Hz,2H),2.56(t,J=7.15Hz,2H),3.46(t,J=6. 51Hz,2H),5.13(s,2H),7.28-7.42(m,5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 1.5h; | To a stirred suspension of Intermediate A (1.2g, 3.24mmol) in DMF (1OmI) was added 4- bromo-butyric acid benzyl ester (1g, 3.89 mmol), NaI (0.486g, 3.24mmol) and K2CO3 (0.89g, 6.48mmol). Stirring at RT was continued for 1.5h. The reaction mixture was diluted with EtOAc (100ml) and washed with water (2 x 50ml). The EtOAc layer was then dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (0.06%NH3 / 2.94% MeOH / 97% DCM) afforded the desired product as a yellow oil (917mg, 75%). m/z 376 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; sodium iodide; In DMF (N,N-dimethyl-formamide); at 20℃; | To a solution of 4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-beta-D-glucopyranosyloxy)-1H-pyrazole (0.2 g) in N,N-dimethylformamide (3 mL) were added <strong>[126430-46-4]benzyl 4-bromobutyrate</strong> (0.1 g), cesium carbonate (0.18 g) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 3/1 - 2/1) to give the title compound (0.16 g).1H-NMR (CDCl3) delta ppm: 1.04 (9H, s), 1.05-1.2 (33H, m), 2.05-2.15 (2H, m), 2.25 (3H, s), 2.56 (2H, t, J=7.3Hz), 2.7-2.85 (1H, m), 3.53 (2H, s), 3.8-3.9 (1H, m), 3.94 (2H, t, J=6.2Hz), 4.1 (1H, dd, J=12.5Hz, 4.1Hz), 4.16 (1H, dd, J=12.5Hz, 2.0Hz), 5.13 (2H, s), 5.15-5.25 (2H, m), 5.36 (1H, t, J=9.6Hz), 5.65 (1H, d, J=8.1Hz), 6.54 (1H, dd, J=8.5Hz, 2.7Hz), 6.64 (1H, d, J=2.7Hz), 6.81 (1H, d, J=8.5Hz), 7.25-7.4 (5H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
a) Preparation of 4-bromobutyric acid benzyl ester 4-bromobutyric acid (10.6 g, 60 mmole) was dissolved in thionyl chloride (20 mml), and the reaction was kept for 4 hr. The solution was evaporated and coevaporated with toluene several times. The residue was redissolved in dichloromethane (120 ml), and then benzyl alcohol (4.14 ml, 40 mmole) was added. The solution was cooled down to -50 C. and triethylamine (10 ml, 72 mmole) was added. The reaction mixture was slowly warmed to room temperature. After 3 hr, the reaction mixture was poured into sodium bicarbonate aqueous solution and the organic phase was washed with water and dried, giving the titled product, 6.8 g. | ||
Step 1 4-Bromo-butyric Acid Benzyl Ester To an ice cold solution of 5 g of 4-bromobutyric acid and 5.5 g of benzylchloroformate in 100 mL of dichloromethane was added 5 mL of triethylamine and then 700 mg of 4-dimethylaminopyridine. A vigorous exothermic reaction ensued with evolution of carbon dioxide. After stirring for 3 h, the mixture was diluted with 100 mL of dichloromethane and washed with 200 mL of saturated sodium bicarbonate, dried over magnesium sulfate, and concentrated to an oil. Azeotropic drying with toluene gave 8 g of 4-bromobutyric acid benzyl ester as a clear oil. | ||
Step 1 4-Bromo-butyric acid benzyl ester: To an ice cold solution of 5 g of 4-bromobutyric acid and 5.5 g of benzylchloroformate in 100 mL of dichloromethane was added 5 mL of triethylamine and then 700 mg of 4-dimethylaminopyridine. A vigorous exothermic reaction ensued with evolution of carbon dioxide. After stirring for 3 h, the mixture was diluted with 100 mL of dichloromethane and washed with 200 mL of saturated sodium bicarbonate, dried over magnesium sulfate, and concentrated to an oil. Azeotropic drying with toluene gave 8 g of 4-bromobutyric acid benzyl ester as a clear oil. |
2.55 g (37%) | (b) Benzyl alcohol (28 mL, 270 mmol) and triethylamine (3.8 mL, 27 mmol) were combined and stirred over an ice bath, under nitrogen (N2). 4-Bromobutyryl chloride (1) (3.1 mL, 27 mmol) was added in a dropwise fashion, then the reaction was stirred an additional 30 minutes. The completed reaction was poured into 250 mL H2 O and extracted with Et2 O (3*200 mL). The ether extracts were combined, dried over MgSO4, and solvent removed in vacuo. Resulting crude product was purified by column chromatography, eluding with EtOAc/Hex (10/90) to afford 2.55 g (37%) of the desired benzyl 4-bromobutyrate (2a). 1 H NMR (200 MHz, CDCl3) d 7.4 (s, 5H), 5.2 (s, 2H), 3.4 (t, 2H), 2.6 (t, 2H), 2.2 (p, 2H); mass spec (DCl, NH3) (M+NH4)+ 275. | |
(a) Benzyl 4-bromobutanoate 80% Sodium hydride dispersion in oil (0.18 g, 5.9 mmol) was added portionwise to a stirred solution of benzyl alcohol (0.64 g, 5.9 mmol) in anhydrous tetrahydrofuran (10 ml) under nitrogen. After a further 1 hour at room temperature, the reaction mixture was cooled to -70 C. and a solution of 4-bromobutanoyl chloride (1.0 g, 5.4 mmol) in anhydrous tetrahydrofuran (3 ml) added dropwise. After 0.5 hour, the cooling bath was removed and the reaction mixture quenched at room temperature with 5% aqueous ammonium chloride solution (20 ml) and then extracted with dichloromethane (3*20 ml). The combined extracts were washed with saturated brine, dried (Na2 SO4) and evaporated under reduced pressure, then the residue was purified by column chromatography on silica gel, eluding with dichloromethane, to give the required ester as a gum. Rf 0.60 (SS 16). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen; N-ethyl-N,N-diisopropylamine;palladium; In ethanol; acetonitrile; | Step 2 4-(3-Benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-butyric Acid A mixture of 0.9 g of <strong>[126430-46-4]4-bromobutyric acid benzyl ester</strong>, 0.5 g of 3-benzyl-8-aza-bicyclo[3.2.1]octane, 0.6 mL of N,N-diisopropylethylamine and 20 mL of acetonitrile was heated to 80 C. for 4 h. The mixture was cooled, concentrated under reduced pressure and partitioned between chloroform and saturated sodium carbonate. After drying over magnesium sulfate the extracts were concentrated to a thick oil, 1.4 g, which was a mixture of the benzyl ester of 4-(3-benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-butyric acid, <strong>[126430-46-4]benzyl 4-bromobutyrate</strong>, and butyrolactone. Hydrogenation over 0.5 g of palladium on carbon in 100 mL of ethanol under 1 atm of hydrogen overnight gave 0.9 g of 4-(3-benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-butyric acid after drying under vacuum at 100 C. overnight which was homogeneous by TLC (90:10:1 chloroform:methanol:ammonium hydroxide). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra(n-butyl)ammonium hydroxide; In 1,4-dioxane; N,N-dimethyl-formamide; | b) Preparation of 4-(N-Boc-L-valyloxy)butyric acid benzyl ester N-Boc-L-valine (1.3 g, 6 mmole) was dissolved in dioxane (5 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40%, 3.8 ml, 6 mmole), and the solution was evaporated and coevaporated with toluene several times. The residue was dissolved in DMF (15 ml) and <strong>[126430-46-4]4-bromobutyric acid benzyl ester</strong> (1.28 g, 5 mmole) was added to it. The reaction was kept for 18 hr, and then poured into sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic phase was dried and the product was isolated with silica gel column chromatography, 1.2 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen; N-ethyl-N,N-diisopropylamine;palladium; In ethanol; acetonitrile; | Step 2 4-(4-Benzyl-piperidin-1-yl)-butyric acid: A mixture of 0.9 g of <strong>[126430-46-4]4-bromobutyric acid benzyl ester</strong>, 0.5 g of 4-benzylpiperidine, 0.6 mL of N,N-diisopropylethylamine and 20 mL of acetonitrile was heated to 80 C. for 4 h. The mixture was cooled, concentrated under reduced pressure and partitioned between chloroform and saturated sodium carbonate. After drying over magnesium sulfate the extracts were concentrated to a thick oil, 1.4 g, which was a mixture of the benzyl ester of 4-(4-benzyl-piperidin-1-yl)-butyric acid, benzyl 4- bromobutyrate and butyrolactone. Hydrogenation over 0.5 g of palladium on carbon in 100 mL of ethanol under 1 atm of hydrogen overnight gave 0.9 g of 4-(4-benzyl-piperidin-1-yl)-butyric acid after drying under vacuum at 100 C. overnight which was homogeneous by TLC (90:10:1 chloroform:methanol:ammonium hydroxide). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In hexane; ethyl acetate; N,N-dimethyl-formamide; | Example 29 A mixture of methyl 1-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-hydroxyindole-3-acetate (0.474 g), benzyl 4-bromobutylate (0.34 g) and potassium carbonate (0.19 g) in N,N-dimethylformamide (5 ml) was stirred at 50 C. for 8 hours. After being cooled to room temperature, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give methyl 5-[3-(benzyloxycarbonyl)propoxy]-1-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-3-acetate (0.36 g). IR (Neat): 3100, 2950, 1725, 1615, 1575, 1480 cm-1 NMR (CDCl3, delta) 1.40 (9H, s), 2.08-2.21 (2H, m), 2.60 (2H, t, J=7.3 Hz), 3.70 (3H, s), 3.74 (2H, s), 4.05 (2H, t, J=6.0 Hz), 5.13 (2H, s), 5.32 (2H, s), 6.80 (1H, dd, J=2.3, 8.8 Hz), 6.96 (1H, s), 7.05 (1H, d, J=2.3 Hz), 7.05-7.11 (3H, m), 7.31-7.35 (7H, m), 7.45 (1H, d, J=8.5 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With potassium carbonate; In acetone; | REFERENCE EXAMPLE 33 A mixture of <strong>[126430-46-4]4-bromobutyric acid benzyl ester</strong> (23.7 g), imidazole (8.1 g), potassium carbonate (14.0 g) and acetone (400 ml) was stirred under refluxing conditions for 6 hours. After the reaction mixture was cooled to room temperature, the insoluble solid was filtered off, the filtrate was concentrated. The residual oily substance was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (20:1, v/v) to yield 4-(1-imidazolyl)butyric acid benzyl ester (7.3 g, 33%) as an oily substance. NMR (delta ppm in CDCl3): 2.11 (2H, m), 2.34 (2H, t, J=6.8 Hz), 3.99 (2H, t, J=6.8 Hz), 5.12 (2H, s), 6.87 (1H, S), 7.05 (1H, s), 7.30-7.40 (5H, m). |
33% | With potassium carbonate; In acetone; | REFERENCE EXAMPLE 8 A mixture of <strong>[126430-46-4]benzyl 4-bromobutyrate</strong> (23.7 g), imidazole (8.1 g), potassium carbonate (14.0 g) and acetone (400 ml) was stirred under reflux for 6 hours. After cooling the mixture to room temperature, the insoluble material was filtered off, and the filtrate was concentrated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/methanol (20/1, v/v) gave benzyl 4-(1-imidazolyl)butyrate (7.3 g, 33%) as an oil. NMR (delta ppm in CDCl3): 2.11 (2H,m), 2.34 (2H,t,J=6.8 Hz), 3.99 (2H,t,J=6.8 Hz), 5.12 (2H,s), 6.87 (1H,s), 7.05 (1H,s), 7.30-7.40 (5H,m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In dichloromethane; | REFERENCE EXAMPLE 26 A mixture of <strong>[126430-46-4]benzyl 4-bromobutanoate</strong> (58.6 diethylamine (58.3 g) and dichloromethane (1000 ml) was stirred under reflux for 14 hours. The reaction mixture was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate gave benzyl 4-(N,N-diethylamino)butanoate (33.8 g, 60%). NMR (delta ppm in CDCl3): 0.99 (6H,t,J=7.2 Hz), 1.78 (2H,quintet,J=7.2 Hz), 2.39 (2H,t,J=7.2 Hz), 2.49 (4H,q,J=7.2 Hz), 5.11 (2H,s), 7.30-7.41 (5H,m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h; | To a solution of hydrochlorothiazide (ONBIO, Inc., Ontario, Canada) (8.62 g, 29 mmol) in 30 mL of DMF was added cesium carbonate (4.68 g, 14.4 mmol) and the product of Example 53a (7.39 g, 28.7 mmol) and the mixture was stirred for 18 hours at room temperature. The solids were removed via filtration, and the solvent was removed under vacuum. The residue was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified via column chromatography on silica gel, 10 to 75% ethyl acetate in dichloromethane gradient. Evaporation of the solvent gave the title compound (8.71 g, 64% yield) as a white amorphous solid: 1H NMR (400 MHz, d6-DMSO) delta 8.02 (s, 2H), 7.52 (s, 2H), 7.36 (m, 5H), 7.06 (s, 1H), 5.09 (s, 2H), 4.90 (s, 2H), 2.94 (t, J=7.0 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H), 1.87 (quin, J=7.1 Hz, 2H); Mass spectrum (API-TIS) m/z 474 (MH+), 491 (MNH4+), 964 (2MNH4+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;sodium iodide; In acetone; at 20℃; for 48h; | To a solution of benzyl alcohol (1 mL) and triethylamine (2.69 mL) in dichloromethane (15 mL) was added 4-bromobutyryl chloride (1.68 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 8/1) to give <strong>[126430-46-4]benzyl 4-bromobutyrate</strong> (2.45 g). To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-beta-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.17 g) in acetone (3 mL) were added cesium carbonate (0.16 g), <strong>[126430-46-4]benzyl 4-bromobutyrate</strong> (0.1 g) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature for 2 days. The reactionmixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 10/1 - 3/1) to give 1-(3-benzyloxycarbonylpropyl)-3-(beta-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.14 g). This material was dissolved in tetrahydrofuran (5 mL) . To the solution was added 10% palladium-carbon powder (50 mg) , and the mixture was stirred at room temperature'under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 1/2 - dichloromethane/methanol = 15/1) to give the title compound (95 mg). 1H-NMR (CDCl3) delta ppm: 1.04 (9H, s), 1.13 (9H, s), 1.15 (9H, s), 1.17 (9H, s), 1.35 (9H, s), 2.15-2.3 (2H, m), 2.3-2.45 (2H, m), 2.8-3.4 (4H, m), 3.95-4.05 (1H, m), 4.05-4.15 (1H, m), 4.31 (1H, dd, J=12.2Hz, 1.7Hz), 4.35-4.55 (2H, m), 5.2-5.35 (1H, m), 5.35-5.45 (1H, m), 5.45-5.55 (1H, m), 6.03 (1H, d, J=8.1Hz), 6.7 (1H, d, J=4.9Hz), 6.9-7.0 (2H, m), 7.15-7.25 (2H, m), 8.27 (1H, d, J=4.9Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Example 19 4-[1-Cyclohexyl-5-(3,3-dimethyl-2-oxo-butyl)-2,4-dioxo-1, 2, 4, 5-tetrahydro-1, 3, 5- benzotriazepin-3-yl]-N- [3-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-butyramide Step a. [1-CYCLOHEXYL-5- (3, 3-DIMETHYL-2-OXO-BUTYL)-2, 4-DIOXO-1, 2, 4, 5-tetrahydro-1, 3, 5- BENZOTRIAZEPIN-3-YLJ-BUTYRIC ACID BENZYL ESTER. A DMF (10ML) solution of l-cyclohexyl-5- (3, 3-dimethyl-2-oxo-butyl)-2, 4-DIOXO-1, 2,4, 5-tetrahydro-1, 3,5-benzotriazepine (Example 13 Step b) (250mg, 0.70mmol) was stirred with NaH (40mg, 60% suspension in mineral oil, LMMOL) for 0. 5h at ambient temperature. Benzyl-4-bromobutyrate (J. Med. Chez. 1996,39, 5176) (300mg, 1. 17MMOL) was added and the mixture was stirred at 60C for 72h. After cooling, the reaction mixture was poured into ethyl acetate/water (1: 1, 25ML) and the organic layer was separated and washed with brine (2X20ML) then water (2X20ML) and dried (MGSO4). SOLVENT concentration afforded the crude product, which was purified by chromatography (gradient 20: 1- 5 : 1CH2Cl2/EtOAc) to afford an oil (210mg, 57%). 1H (CDC13) 7.34-7. 29 (5H, M), 7.27-7. 16 (3H, M), 6.96 (LH, m), 5.01 (2H, s), 4.68 (2H, M), 3.83 (1H, M), 3.51 (2H, m), 2.15-1. 75 (8H, m), 1.66-1. 18 (11H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 32h; | Example l(iotaiotaiota) Synthesis of compound 3Compound 2 (0 1 g, 0 270 mmol) was dissolved in dry DMF (5 mL) and potassium carbonate added (1 1 eq 0 297 mmol, 0 041 g) The alkyl bromide (1 1 eq 0 297 mmol, 81 7 mg) was added portion wise following the reaction by HPLC-mass spectrometry by taking approximately 0 1 mL volume from the reaction and diluting with 1 1 0 1% formic acid in water acetonit?le (10 mL) The reaction was stirred at room temperature for 16 hours A further 0 25 equivalents of the alkyl bromide was added and the <n="21"/>reaction stirred for a further 16 hours The reaction mixture was concentrated to dryness under vacuum This was used in the next step without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate; In acetonitrile; at 20 - 90℃; | Example 47; Preparation of 4-nitrosotetrahydro-2H-pyran-4-yl 4-({2-[4-(2-methylpropyl)phenyl]propanoyl}oxy)butanoate; Benzyl 4-({2-[4-(2-methylpropyl)phenyl]propanoyl}oxy)butanoate was synthesized from benzyl-4-bromo)butanoate, 2-[4-(2-methylpropyl)phenyl]propanoic acid and potassium carbonate.To a solution of benzyl-4-bromobutanoate (2.0 g, 7.8 mmol) in acetonitrile (20 ml) at ambient temperature was added potassium carbonate (1.13 g, 8.2 mmol) and 2-[4-(2-methylpropyl)phenyl]propanoic acid (1.6 g, 7.8 mmol). The reaction was heated to 90 C. for 18 hours and monitored by TLC (4:1 heptane:EtOAc) The mixture was allowed to cool to room temperature and concentrated in vacuo. The crude product was partitioned between water and EtOAc and the organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with heptane:EtOAc (4:1, v:v) and isolated as a clear, colorless oil (2.5 g, 84% yield). 1H NMR (250 MHz, CHLOROFORM-d) delta ppm 7.30-7.46 (5H, m), 7.02-7.23 (4H, m), 5.11 (2H, s), 3.99-4.21 (2H, m), 3.68 (1H, q, 7.2 Hz), 2.43 (2H, d, 7.2 Hz), 2.27-2.39 (2H, m), 1.73-2.04 (3H, m), 1.48 (3H, d, 7.2 Hz) 0.89 (6H, d, 6.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In acetonitrile; at 90℃; for 18h; | Benzyl-4-(acetoxy)butanoate was synthesized from 4-bromobenzylbutyrate and potassium acetate. To a solution of 4-bromobenzylbutyrate (1.0 g, 3.89 mmol) in acetonitrile (25 ml) was added potassium acetate (5.94 g, 7.78 mmol). The reaction was heated to 90 C. for 18 hours and monitored by TLC (4:1 heptane:EtOAc) The mixture was allowed to cool to room temperature and concentrated in vacuo. The crude product was extracted with water:EtOAc and the organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The title compound was isolated in sufficient purity without need for further purification. (0.8 g, 87% yield). 1H NMR (250 MHz, DMSO-d6) delta 7.29-7.41 (5H, m), 5.09 (2H, s), 4.01 (2H, t, 6.5 Hz), 2.44 (2H, t, 7.3 Hz), 1.97 (3H, s), 1.85 (2H, quin, 6.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In acetonitrile; at 20 - 90℃; | Example 46; Preparation of 4-[(4-nitrosotetrahydro-2H-pyran-4-yl)oxy]-4-oxobutyl 2-(acetyloxy)benzoate; Benzyl 4-[2-(acetyloxy)phenyl]carbonyloxy}butanoate was synthesized from benzyl-4-bromo)butanoate, 2-(acetyloxy)benzoic acid and potassium carbonate. To a solution of benzyl-4-bromobutanoate (0.5 g, 1.9 mmol) in acetonitrile (5 ml) at ambient temperature was added potassium carbonate (0.28 g, 2.0 mmol) and 2-(acetyloxy)benzoic acid (0.35 g, 1.9 mmol). The reaction was heated to 90 C. for 18 hours and monitored by TLC (4:1 heptane:EtOAc) The mixture was allowed to cool to room temperature and concentrated in vacuo. The crude product was partitioned between water and EtOAc and the organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with heptane:EtOAc (4:1, v:v) and isolated as a clear, colorless oil (0.556 g, 81% yield). 1H NMR (250 MHz, DMSO-d6) delta 7.29-7.41 (5H, m), 5.09 (2H, s), 4.01 (2H, t, 6.5 Hz), 2.44 (2H, t, 7.3 Hz), 1.97 (3H, s), 1.85 (2H, quin, 6.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | [00141] A suspension of 2-oxa-7-azaspiro[3.5]nonane hemioxalate (3.77 g, 17.38 mmol), potassium carbonate (4.8 g, 34.76 mmol), and triethylamine (4.85 ml_, 34.76 mmol) was stirred in dry dimethylformamide (20 ml_) for 10 minutes. A solution of Compound 2 (4.47 g, 17.38 mmol) in dry dimethylformamide (5 ml_) was added and the reaction stirred at 60 C for 1 hour. Solvent was azeotroped with toluene by rotary evaporator. Crude residue was dissolved in methanol and purified by ISCO flash chromatography to yield Compound 3 as a colorless oil (3.53g, 1 1 .7 mmol, 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium carbonate; In acetone; for 24h;Reflux; | To an acetone (3 mL)solution of 19 (77 mg, 0.067 mmol), <strong>[126430-46-4]benzyl 4-bromobutanoate</strong> (28 mg, 0.1mmol) and K2CO3 (30 mg, 0.2 mmol) were added. After refluxingfor 24 h, the reaction mixture was diluted with ethyl acetate and the organicphase was washed with water and brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue waspurified by flash column chromatography (ethyl acetate / n-hexanes = 1 : 1) to afford the benzyl butanoate 19' (35 mg, 64%). 1H-NMR (600 MHz, CD3OD) delta 8.21(s, 1H), 8.04 (bs, 1H), 7.33-7.23 (m, 5H), 7.11 (d, 2H, J =8.4 Hz), 6.88 (d, 1H, J = 7.8 Hz), 6.77 (d, 2H, J =8.4 Hz), 6.73 (d, 1H, J = 7.8 Hz), 6.23 (d, 1H, J =1.8 Hz), 5.10 (s, 2H), 4.42 (bs, 1H), 4.28 (dd, 1H, J = 10.8and 3.6 Hz), 3.94 (t, 2H, J = 6 Hz), 3.90 (s, 3H), 3.85 (s,3H), 3.79 (s, 3H), 3.71 (s, 3H), 3.22 (dd, 1H, J = 13.8 and3.6 Hz), 3.09 (bs, 1H), 3.03 (bs, 1H), 2.78-2.74 (m, 1H), 2.61(t, 1H, J =13.8 Hz), 2.55 (t, 2H, J = 7.2 Hz), 2.10 (m, 2H), 1.41 (s,9H); 13C-NMR (150 MHz, CD3OD) delta 191.3, 173.0,171.1, 169.3, 159.7, 159.2, 154.4, 146.7, 137.4, 135.9, 131.0, 130.3, 128.5,128.2, 128.2, 124.4, 120.3, 114.7, 110.0, 108.7, 96.0, 69.2, 66.6, 66.3, 61.6,61.3, 60.4, 56.1, 55.6, 53.4, 48.3, 48.3, 37.7, 32.2, 31.5, 30.8, 28.3, 24.6,22.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In acetone; for 24h;Reflux; | To an acetone (3 mL)solution of 7-hydroxy-5,6-dimethoxychroman-4-one (22) (77 mg, 0.34 mmol),<strong>[126430-46-4]benzyl 4-bromobutanoate</strong> (88 mg, 0.34 mmol) and K2CO3 (142mg, 1.0 mmol) were added. After refluxing for 24 h, the reaction mixture wasdiluted with ethyl acetate and the organic phase was washed with water andbrine, dried over anhydrousMgSO4 and concentrated under reducedpressure. The residue was purified by flash column chromatography (ethylacetate / n-hexanes = 1 : 2) toafford the butanoate (23) (110 mg, 80%). 1H-NMR (600 MHz, CDCl3) delta 7.30 (s, 5H), 6.18 (s, 1H), 5.09 (s, 2H), 4.39 (t, 2H, J = 6.0 Hz), 4.01 (t, 2H, J = 6.0 Hz), 3.87 (s, 3H), 3.73 (s, 3H), 2.67 (t, 2H, J = 6.0 Hz), 2.57 (t, 2H, J = 7.2 Hz), 2.17 (m, 2H); 13C-NMR (150 MHz, CDCl3) delta 189.1,172.6, 159.9, 158.5, 154.4, 137.4, 135.8, 128.5, 128.3, 128.2, 109.6, 96.8,67.5, 66.8, 66.4, 61.6, 61.2, 38.7, 30.5, 24.2; HRMS (EI): mass calcd for C22H24O7[M + H]+, 400.1522; found, 400.1529. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With N-ethyl-N,N-diisopropylamine; potassium iodide; In acetonitrile; at 80℃; for 5.5h; | Compound 11 was synthesized in accordance with the following scheme. Synthesis of compound 10 is disclosed in J. Le Notre et al.. Adv. Synth. Catal. 349, 432 (2007), and synthesis was carried out on the basis thereof. Compound 9 (102.8 mg, 0.347 mmol, 1 eq.) and compound 10 (756.9 mg, 2.94 mmol, 8.5 eq.) were dissolved in acetonitrile (4 mE), N,N-diisopropylethylamine (512 pL, 2.94 mmol, 8.5 eq.) and a small amount of potassium iodide were added, and the mixture was heated and refluxed for 5.5 hours at 80 C. Water was added and then extracted using dichloromethane, the organic phase was washed using water and a saturated sodium chloride solution and dried using anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by medium-pressure silica gel chromatography (eluent:n-hexane/ethyl acetate=86/14 to 65/35) to obtain the objective compound 11(91.7 mg, 56%). 1H NMR (400 MHz, CDCl3): delta 0.45 (s, 6H), 1.93(quin, 2H, J=7.2 Hz), 2.41 (t, 2H, J=7.2 Hz), 2.90 (s, 3H),2.94 (s, 6H), 3.34 (t, 2H, J=7.2 Hz), 3.95 (s, 2H), 5.10 (s,2H), 6.68 (dd, 1H, J=8.4, 2.8 Hz), 6.74 (dd, 1H, J=8.4, 2.8Hz), 6.95 (d, 1H, J=2.8 Hz), 6.99 (d, 1H, J=2.8 Hz), 7.15 (d,1H, J=8.4 Hz), 7.18 (d, 1H, J=8.4 Hz), 7.31-7.36 (m, 5H); 13C NMR (100 MHz, CDCl3): delta-2.7, 22.4, 31.8, 38.6, 39.2,41.2, 52.4, 66.4, 113.8, 114.2, 117.2, 117.3, 117.7, 128.3,128.4, 128.5, 128.65, 128.67, 134.8, 136.0, 136.1, 136.2,147.3, 148.8, 173.2; HRMS (ESI+): Calcd for [M+H]+,473.26188, Found, 473.26185 (-0.0 mmu). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 75℃; for 16h; | To a solution of di-tert-butyl 2,2'-[(2-[2-(tert-butoxy)-2-oxoethyl]amino}ethyl) azanediyl]diacetate (3.4 g, 8.45 mmol, Tetrahedron Lett., 2006, 47, 6277) in AcCN (140 mL) was added <strong>[126430-46-4]benzyl 4-bromobutanoate</strong> (2.35 g, 9.14 mmol), and K2CO3 (3.50 g, 25.3 mmol). The resulting mixture was stirred at 75 C for 16h. Upon completion, the reaction mixture was cooled down to rt. The inorganics were removed by filtration and the filtrate was concentrated. The resulting residue was purified by flash chromatography on silica gel (40 g), eluting with 0- 100% EtOAc in hexane, to give the title compound. 1H NMR (CDCl3) delta 7.39-7.28 (m, 5H), 5.10 (s, 2H), 3.44 (s, 4H), 3.26 (s, 2H), 2.82-2.72 (m, 4H), 2.65-2.61 (m, 2H), 2.42-2.37 (m, 2H), 1.81-1.73 (m, 2H), 1.48-1.40 (m, 27H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.88 g | The compound (3.84 g, 9.78 mmol) obtained in Example A-13-(1) was dissolved in THF (30 mL), to which 60% sodium hydride (0.43 g, 10.8 mmol) was added under water cooling, and the mixture was stirred at room temperature for 30 minutes. A solution of <strong>[126430-46-4]benzyl 4-bromobutanoate</strong> (3.02 g, 11.7 mmol) in THF (10 mL) was added and refluxed under heating for 18 hours. The reaction solution was cooled to room temperature and diluted with diethyl ether. The organic layer was washed sequentially with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulphate. Following filtration, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/cyclohexane) to obtain the titled compound (1.88 g, 3.31 mmol). 1H-NMR(600MHz,CDCl3)delta(ppm):1.43(s,18H),1.47-1.54(m,4H),1.78-1.85(m,4H),2.36(t,J=7 .34Hz,4H),5.10(s,4H),7.27-7.40(m,10H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In acetonitrile at 80℃; for 4h; | 3.1 Step 1 : Preparation of 4-(benzyloxy)-4-oxobutyl((benzyloxy)carbonyl)-L-valinate. Potassium carbonate (2.0 g, 14.3 mmol, 1.5 equiv) was added to a solution of carbobenzyloxy-L-valine 5 (2.52 g, 10.0 mmol, 1.05 equiv) and benzyl 4-bromobutanoate 6 (2.46 g, 9.5 mmol, 1.0 equiv) in acetonitrile (40 mL). The reaction was warmed to 80°C and stirred for four hours. The reaction was cooled to room temperature, filtered, and evaporated to dryness. The crude residue was dissolved in ethyl acetate and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered, concentrated, and dried under high vacuum to yield 4-(benzyloxy)-4-oxobutyl((benzyloxy)carbonyl)-L-valinate 4 in quantitative yield. 'H NMR was performed at 600 MHz with chloroform-c/ as solvent to characterize the titled compound, results are as follows: d = 7.39 - 7.25 (m, 10 H), 5.25 (d, J = 9.2 Hz, 1 H), 5.15 - 4.98 (m, 4 H), 4.27 (dd, /= 9.1, 4.7 Hz, 1 H), 4.22 - 4.03 (m, 2 H), 2.43 (t, /= 7.4 Hz, 2 H), 2.13 (td, /= 6.9, 4.7 Hz, 1H), 2.05 - 1.90 (m, 2H), 0.94 (d, / = 6.9 Hz, 3H), 0.86 (d, / = 6.9 Hz, 3H). |
Tags: 126430-46-4 synthesis path| 126430-46-4 SDS| 126430-46-4 COA| 126430-46-4 purity| 126430-46-4 application| 126430-46-4 NMR| 126430-46-4 COA| 126430-46-4 structure
[ 103-40-2 ]
4-(Benzyloxy)-4-oxobutanoic acid
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[ 25109-86-8 ]
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[ 103-40-2 ]
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P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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