2-(hydroxymethyl)benzamide

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.92 g of phthalide are transformed according to C. Y. Belke, S. C. K. Su, J. A. Shafer (J. Am. Chem. Soc., 93, 4552 (1971)), into 2-hydroxymethylbenzamide (melting point 147°-149° C.) which by treatment with lithium-aluminium hydride according to R. M. Laird, R. E. Parker (J. Chem. Soc., 4784 (1965)), and then with gaseous hydrogen chloride dissolved in ethyl ether, gives 2-hydroxymethylbenzylamine hydrochloride which after crystallization from an ethanol/ethyl ether mixture shows melting point of 177°-179° C. (G. Pifferi, L. Fontanella, E. Decelli, R. Monguzzi, J. Heterocyclic Chem., 9, 1209 (1972), melting point 177°-178° C.). I.R. (KBr) 3260 cm-1 (OH), 2595 cm-1 (NH3+), 1020 cm-1 (C--O), 760 cm-1 (phenyl).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.92 g of phthalide are transformed according to C. Y. Belke, S. C. K. Su, J. A. Shafer (J. Am. Chem. Soc., 93, 4552 (1971)), into 2-hydroxymethylbenzamide (melting point 147°-149° C.) which by treatment with lithium-aluminium hydride according to R. M. Laird, R. E. Parker (J. Chem. Soc., 4784 (1965)), and then with gaseous hydrogen chloride dissolved in ethyl ether, gives 2-hydroxymethylbenzylamine hydrochloride which after crystallization from an ethanol/ethyl ether mixture shows melting point of 177°-179° C. (G. Pifferi, L. Fontanella, E. Decelli, R. Monguzzi, J. Heterocyclic Chem., 9, 1209 (1972), melting point 177°-178° C.). I.R. (KBr) 3260 cm-1 (OH), 2595 cm-1 (NH3+), 1020 cm-1 (C--O), 760 cm-1 (phenyl).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To explore the effectiveness of cyanide in the assistance of hydroxylamine mediated cleavage for solid phase library synthesis, hydroxymethylbenzamide (HMBA-AM) resin was chosen for the well-established compatibility between the ester linkage and Fmoc- and Boc-chemistry, and its stability towards Mitsunobu and reductive amination conditions. A solid phase library of DL-phenylalanine and several constrained analogs (AAa–c, Scheme 3) was prepared on the HMBA resin by the esterification of the Fmoc protected DL-aminoacids using standard DCC coupling conditions at room temperature overnight. The resin-bound Fmoc aminoacids BBa–c were deprotected with piperidine-DMF (1:4) and sulfonated with 4-methoxybenzenesulfonyl chloride to give Compounds IIIa–c. In this instance, the optimal reaction conditions for cleavage from the resin of the sulfonamide esters to yield the free hydroxamic acids (IVa–c, Table 2) were 5:5:2 THF:MeOH:50% aqueous NH2OH and 5 mg (0.08 mmol, 40 to 80 mol %) of KCN for 100 to 200 mg of loaded resin. at room temperature overnight to give Compounds IIIa–c

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To explore the effectiveness of cyanide in the assistance of hydroxylamine mediated cleavage for solid phase library synthesis, hydroxymethylbenzamide (HMBA-AM) resin was chosen for the well-established compatibility between the ester linkage and Fmoc- and Boc-chemistry, and its stability towards Mitsunobu and reductive amination conditions. A solid phase library of DL-phenylalanine and several constrained analogs (AAa–c, Scheme 3) was prepared on the HMBA resin by the esterification of the Fmoc protected DL-aminoacids using standard DCC coupling conditions at room temperature overnight. The resin-bound Fmoc aminoacids BBa–c were deprotected with piperidine-DMF (1:4) and sulfonated with 4-methoxybenzenesulfonyl chloride to give Compounds IIIa–c. In this instance, the optimal reaction conditions for cleavage from the resin of the sulfonamide esters to yield the free hydroxamic acids (IVa–c, Table 2) were 5:5:2 THF:MeOH:50% aqueous NH2OH and 5 mg (0.08 mmol, 40 to 80 mol %) of KCN for 100 to 200 mg of loaded resin. at room temperature overnight to give Compounds IIIa–c

反応条件: temp:17.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of triethylamine (TEA, 0.658 g, 0.91 ml, 6.50 mmol, 1.5 equiv.) in 1,2-dichloroethane (3 ml) was added dropwise under stirring and cooling with ice to a suspension of AlCl3 (0.635 g, 4.76 mmol, 1.1 equiv.) in 1,2-dichloroethane (7 ml). The temperature was maintained at 15-20° C. during the addition and the mixture was then allowed to warm up at room temperature. A solution of 1-dimethoxytrityl-6-amino-hexan-1-ol (16) (2.00 g, 4.76 mmol, 1.1 equiv., prepared as described by Woo and Fung (1996), International Pat. App. Pub. No. WO 96/05215) and 6-nitrophthalide (18) (0.766 g, 4.33 mmol, 1.0 equiv.) in 1,2-dichloroethane (3 ml) was added over a period of 20 min and the mixture was stirred at room temperature overnight. The completion of the reaction was confirmed by TLC analysis (EtOAc containing 1% TEA). The reaction mixture was then quenched with an ice-water mixture (30 ml) and stirred for an additional 30 min. The resulting suspension was filtered through a bed of Celite® and the filter cake was washed with 1,2-dichloroethane (10 ml). The organic phase of the combined filtrates was separated, washed with water (30 ml) and brine (20 ml), dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (35-75% EtOAc in hexanes, gradient elution) yielding 0.20 g (8%) of compound (20) as a pale yellow oil. Rf=0.2 (hexanes/EtOAc 1:1, v/v, containing 1% TEA). 1H NMR (300 MHz, CD3CN) δ 8.32-8.27 (m, 2H), 7.76-7.73 (m, 1H), 7.47-7.44 (m, 2H), 7.33-7.20 (m, 8H), 6.87 (d, J=9.1 Hz, 4H), 4.69 (d, J=5.9 Hz, 2H), 4.14 (t, J=5.9 Hz, 1H), 3.77 (s, 6H), 3.35 (q, J=6.5 Hz, 2H), 3.03 (t, J=6.4 Hz, 2H), 1.64-1.55 (m, 4H), 1.43-1.28 (m, 4H). 13C NMR (75 MHz, CD3CN) δ 167.4, 158.8, 147.7, 145.9, 136.9, 130.1, 128.2, 128.0, 126.9, 125.1, 122.9, 113.2, 85.8, 63.3, 62.3, 55.1, 39.8, 29.8, 29.1, 26.7, 26.0. to warm up at room temperature the mixture was stirred at room temperature overnight The reaction mixture was then quenched with an ice-water mixture (30 ml) stirred for an additional 30 min The resulting suspension was filtered through a bed of Celite® the filter cake was washed with 1,2-dichloroethane (10 ml) The organic phase of the combined filtrates was separated washed with water (30 ml) and brine (20 ml) dried over MgSO4 concentrated The crude product was purified by flash chromatography (35-75% EtOAc in hexanes, gradient elution)

反応条件: temp:17.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of triethylamine (TEA, 0.824 g, 1.13 ml, 8.14 mmol, 1.5 equiv.) in 1,2-dichloroethane (3 ml) was added dropwise under stirring and cooling with ice to a suspension of AlCl3 (0.796 g, 5.97 mmol, 1.1 equiv.) in 1,2-dichloroethane (7 ml). The temperature was maintained at 15-20° C. during the addition and the mixture was then allowed to warm up at room temperature. A solution of 1-dimethoxytrityl-6-amino-hexan-1-ol (16) (2.505 g, 5.97 mmol, 1.1 equiv., prepared as described by Woo and Fung (1996), International Pat. App. Pub. No. WO 96/05215, which is incorporated herein by reference in its entirety) and phthalide (17) (0.728 g, 5.43 mmol, 1.0 equiv.) in 1,2-dichloroethane (3 ml) was added over a period of 20 min and the mixture was stirred at room temperature overnight. The completion of the reaction was confirmed by TLC analysis (EtOAc containing 1% TEA). The reaction mixture was then quenched with an ice-water mixture (30 ml) and stirred for further 30 min. The resulting suspension was filtered through a bed of Celite® and the filter cake was washed with 1,2-dichloroethane (10 ml). The organic phase of the combined filtrates was separated, washed with water (30 ml) and brine (20 ml), dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (15-70% EtOAc in hexanes containing 1% of TEA, gradient elution) yielding 0.80 g (27%) of compound (19) as a pale yellow oil. Rf=0.68 (EtOAc containing 1% TEA). 1H NMR (400 MHz, CD3CN) δ 7.61-7.19 (m, 14H), 6.85 (d, J=8.9 Hz, 4H), 5.33 (s, 1H), 4.50 (s, 2H), 3.75 (s, 6H), 3.32 (q, J=6.6 Hz, 2H), 3.01 (t, J=6.6 Hz, 2H), 1.63-1.53 (m, 4H), 1.44-1.28 (m, 4H). to warm up at room temperature was added over a period of 20 min the mixture was stirred at room temperature overnight The reaction mixture was then quenched with an ice-water mixture (30 ml) stirred for further 30 min The resulting suspension was filtered through a bed of Celite® the filter cake was washed with 1,2-dichloroethane (10 ml) The organic phase of the combined filtrates was separated washed with water (30 ml) and brine (20 ml) dried over MgSO4 concentrated The crude product was purified by flash chromatography (15-70% EtOAc in hexanes containing 1% of TEA, gradient elution)

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 143 g (0.948 moles) of 2-carbamoyl-benzyl alcohol, 2.3 g (0.0226 moles) of sodium bromide, 6.7 g of Adogen 464 and 806 ml of isopropyl acetate were stirred together in a two liter flask and cooled in a water bath. 504 ml of a 14% w/v solution of sodium hypochlorite (1.0 mole) was added to the stirred mixture over 40 minutes and at 30° C. Vigorous agitation was maintained during the addition and for a further 2 hours. The two-phase reaction mixture was then warmed to 50° C. to dissolve all solids. The organic phase was separated and the medium distilled off. The formed solid was recrystallized from 3 volumes of toluene to form 99 g of the desired product as a pale brown solid; m.p. 112° C.; yield 70%. cooled in a water bath Vigorous agitation was maintained during the addition and for a further 2 hours The two-phase reaction mixture to dissolve all solids The organic phase was separated the medium distilled off The formed solid was recrystallized from 3 volumes of toluene

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.92 g of phthalide are transformed according to C. Y. Belke, S. C. K. Su, J. A. Shafer (J. Am. Chem. Soc., 93, 4552 (1971)), into 2-hydroxymethylbenzamide (melting point 147°-149° C.) which by treatment with lithium-aluminium hydride according to R. M. Laird, R. E. Parker (J. Chem. Soc., 4784 (1965)), and then with gaseous hydrogen chloride dissolved in ethyl ether, gives 2-hydroxymethylbenzylamine hydrochloride which after crystallization from an ethanol/ethyl ether mixture shows melting point of 177°-179° C. (G. Pifferi, L. Fontanella, E. Decelli, R. Monguzzi, J. Heterocyclic Chem., 9, 1209 (1972), melting point 177°-178° C.). I.R. (KBr) 3260 cm-1 (OH), 2595 cm-1 (NH3+), 1020 cm-1 (C--O), 760 cm-1 (phenyl).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To explore the effectiveness of cyanide in the assistance of hydroxylamine mediated cleavage for solid phase library synthesis, hydroxymethylbenzamide (HMBA-AM) resin was chosen for the well-established compatibility between the ester linkage and Fmoc- and Boc-chemistry, and its stability towards Mitsunobu and reductive amination conditions. A solid phase library of DL-phenylalanine and several constrained analogs (AAa–c, Scheme 3) was prepared on the HMBA resin by the esterification of the Fmoc protected DL-aminoacids using standard DCC coupling conditions at room temperature overnight. The resin-bound Fmoc aminoacids BBa–c were deprotected with piperidine-DMF (1:4) and sulfonated with 4-methoxybenzenesulfonyl chloride to give Compounds IIIa–c. In this instance, the optimal reaction conditions for cleavage from the resin of the sulfonamide esters to yield the free hydroxamic acids (IVa–c, Table 2) were 5:5:2 THF:MeOH:50% aqueous NH2OH and 5 mg (0.08 mmol, 40 to 80 mol %) of KCN for 100 to 200 mg of loaded resin. at room temperature overnight to give Compounds IIIa–c