2-氨基-1-苯丙烷-1-ol

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of cyanuric chloride (1.84 gr) in acetonitrile (20 ml), kept at a temperature of −20° C. under stirring, dropwise were subsequently added solutions of 3,4-methylenedioxy-aniline (1.37 gr) in acetonitrile (20 ml) and diisopropylethylamine (DIPEA) (1.29 gr) in acetonitrile (20 ml). After stirring at −20° C. for 1 hour, again dropwise were subsequently added solutions of DIPEA (1.29 gr) in acetonitrile (20 ml) and (1 S,2R)-(+)-norephedrine (1.51 gr) in acetonitrile (20 ml). The mixture was allowed to warm to room temperature and was stirred for another 2 hours. The resulting reaction mixture was concentrated in vacuo. After addition of ethylacetate (250 ml) the organic layer was subsequently washed with a solution of HCl in water (1M, 100 ml), a solution of NaOH in water (1 M, 100 ml) and brine (50 ml). The organic layer was dried over sodiumsulphate, filtered and concentrated in vacuo. The resulting product was purified by column chromatography using silicagel and a mixture of heptane: ethylacetate (3:1) as the eluent. The resulting pure product (formula (9), see above, example B-44, see table) was obtained as a white solid in 80% yield. kept at a temperature of −20° C. After stirring at −20° C. for 1 hour was stirred for another 2 hours The resulting reaction mixture was concentrated in vacuo After addition of ethylacetate (250 ml) the organic layer was subsequently washed with a solution of HCl in water (1M, 100 ml) The organic layer was dried over sodiumsulphate filtered concentrated in vacuo The resulting product was purified by column chromatography a mixture of heptane: ethylacetate (3:1) as the eluent

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In the practice of this invention, the 2-nitro-1-phenyl-1-propanol is dissolved in a lower alkyl alcohol, preferably isopropyl alcohol. The mixture is placed in a vessel suitable for high pressure reactions and equipped with agitation means, e.g. a rocking bomb or a stirred bomb. Acetic acid is added to the solution to produce the acetate salt of 2-amino-1-phenyl-1-propanol during the reduction reaction. The mixture is placed in a vessel suitable for high pressure reactions equipped with agitation means, e.g. a rocking bomb

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Commercially available reagents and solvents were obtained as follows: HPLC-grade solvents, Fisher; anhydrous solvents, Aldrich; diisopropyl azodicarboxylate (DIAD, 95%), Lancaster; 4-aminobenzyl alcohol, Alfa Aesar; Z-val-OSu, Advanced ChemTech; L-citrulline, Novabiochem; (1S, 2R)-(+)-norephedrine and other commercially available reagents, Aldrich. Cbz-val-cit-PAB-OH (1) (Dubowchik, G. M.; Firestone, R. A. Cathepsin B-Sensitive Dipeptide Prodrugs. 1. A Model Study of Structural Requirements for Efficient Release of Doxorubicin. Bioorg. Med. Chem. Letts. 1998, 8, 3341–3346; Dubowchik, G. M.; Mosure, K.; Knipe, J. O.; Firestone, R. A. Cathepsin B-Sensitive Dipeptide Prodrugs. 2. Models of Anticancer Drugs Paclitaxel (Taxol), Mitomycin C and Doxorubicin. Bioorg. Med. Chem. Letts. 1998, 8, 3347–3352) and combretastatin A-4 (VIIIb) (Pettit, G. R.; Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R. K.; Schmidt, J. M.; Hogan, F. Antineoplastic Agents. 291. Isolation and Synthesis of Combretastatin A-4, A-5, and A-6. J Med. Chem. 1995, 38, 1666–1672) were synthesized as previously described. 1H NMR spectra were recorded on a Varian Gemini 300 MHz spectrophotometer. Flash column chromatography was performed using 230–400 mesh ASTM silica gel from EM Science. Analtech silica gel GHLF plates were used for thin-layer chromatography. HPLC was performed using a Waters Alliance system with a photodiode array detector. Combustion analyses were determined by Quantitative Technologies, Inc., Whitehouse, N.J. Commercially available reagents and solvents were obtained

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In the practice of this invention, the 2-nitro-1-phenyl-1-propanol is dissolved in a lower alkyl alcohol, preferably isopropyl alcohol. The mixture is placed in a vessel suitable for high pressure reactions and equipped with agitation means, e.g. a rocking bomb or a stirred bomb. Acetic acid is added to the solution to produce the acetate salt of 2-amino-1-phenyl-1-propanol during the reduction reaction. The mixture is placed in a vessel suitable for high pressure reactions equipped with agitation means, e.g. a rocking bomb

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Commercially available reagents and solvents were obtained as follows: HPLC-grade solvents, Fisher; anhydrous solvents, Aldrich; diisopropyl azodicarboxylate (DIAD, 95%), Lancaster; 4-aminobenzyl alcohol, Alfa Aesar; Z-val-OSu, Advanced ChemTech; L-citrulline, Novabiochem; (1S, 2R)-(+)-norephedrine and other commercially available reagents, Aldrich. Cbz-val-cit-PAB-OH (1) (Dubowchik, G. M.; Firestone, R. A. Cathepsin B-Sensitive Dipeptide Prodrugs. 1. A Model Study of Structural Requirements for Efficient Release of Doxorubicin. Bioorg. Med. Chem. Letts. 1998, 8, 3341–3346; Dubowchik, G. M.; Mosure, K.; Knipe, J. O.; Firestone, R. A. Cathepsin B-Sensitive Dipeptide Prodrugs. 2. Models of Anticancer Drugs Paclitaxel (Taxol), Mitomycin C and Doxorubicin. Bioorg. Med. Chem. Letts. 1998, 8, 3347–3352) and combretastatin A-4 (VIIIb) (Pettit, G. R.; Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R. K.; Schmidt, J. M.; Hogan, F. Antineoplastic Agents. 291. Isolation and Synthesis of Combretastatin A-4, A-5, and A-6. J Med. Chem. 1995, 38, 1666–1672) were synthesized as previously described. 1H NMR spectra were recorded on a Varian Gemini 300 MHz spectrophotometer. Flash column chromatography was performed using 230–400 mesh ASTM silica gel from EM Science. Analtech silica gel GHLF plates were used for thin-layer chromatography. HPLC was performed using a Waters Alliance system with a photodiode array detector. Combustion analyses were determined by Quantitative Technologies, Inc., Whitehouse, N.J. Commercially available reagents and solvents were obtained

实验步骤: 11-01 12:11: 16：00 去甲麻黄碱（89mg，0.5mmol，1.0e.q）和TEA（0.4mL，1.42mmol，3.0eq）溶于THF(5mL)，冰浴下（0℃）滴入氯乙酰氯（0.45mL，0.57mmol，1.2e.q）, 0℃搅拌1h 17：00 tlc监控（D/M=5/1），有部分原料，补加0.2mL氯乙酰氯， 17：30 tlc监控，原料反应完毕，萃取，浓缩后得到粗品，送LC-MS确认为目标分子量。 11.1 11：30 粗品溶于THF（5mL）加入NaH（28.45mg，1.19mmol，2.5e.q），r.t.搅拌5h 17：00 TLC监控原料未能反应完全，继续r.t搅拌反应

实验步骤: 11-15 17:56: 16:00将第一步产物M-CCAD303613-1（36g，1.0eq）溶于甲醇（300mL），搅拌加入10%Pd/C （5g，0.15eq）,置换氢气3次。r.t搅拌，TLC监控 11/16 9:00点板（P/E=5/1），原料未反应完，补充氢气 11/17 确认原料点反应完全，产物点D/M=10/1爬起。硅藻土过滤Pd/C，旋干甲醇，得浅黄色油状，将2N的盐酸加入于粗品中，有白色析出，并变浑浊，加入水和EA，加入盐酸至PH为1，并通过TLC确认有机相无产物，水相用EA萃1-2次，水相再用2N的NaOH调PH至8-9，水相会析出白色，加入DCM 萃取2-3次，并通过TLC确认水相无产物，合并有机相，浓缩得9.2g油状物。

实验步骤: 11-14 13:38: 16:00将第一步产物M-CCAD303613-1（14.26g，1.0eq）溶于甲醇（140mL），搅拌加入10%Pd/C （2.2g，0.15eq）,置换氢气3次。r.t搅拌，TLC监控 11/15 9:00点板（P/E=5/1），原料未反应完，补充氢气 16:00确认原料点反应完全，产物点D/M=10/1爬起。硅藻土过滤Pd/C，旋干甲醇，得浅黄色油状，将2N的盐酸加入于粗品中，有白色析出，并变浑浊，加入水和EA，加入盐酸至PH为1，并通过TLC确认有机相无产物，水相用EA萃1-25次，水相再用2N的NaOH调PH至8-9，水相会析出白色，加入EA萃取2-3次，并通过TLC确认水相无产物，合并有机相，浓缩得3g油状物。

实验步骤: 11-03 17:57: 9：30 将M-CCAD303613-3（1g，1.0e.q）溶于超干THF(20mL）将其加入干燥后的100mL三口瓶中，再滴入TEA（1.38mL，1.5eq），降温至0℃一下，搅拌下在干冰-乙醇浴下（-5℃）慢滴入氯乙酰氯（0.64mL，1.2e.q）（注意无水）,控制温度小于 0℃，持续10min，并搅拌1h 11:00 反应液呈棕红，浑浊状，TLC监控（D/M=10/1）确认原料点反应完毕，(P/E=3/1)产物点磷钼酸染色，rf=0.3 后处理：EA，水萃取3次，无水硫酸钠干燥，浓缩；硅胶柱纯化：柱效约1/15，P/E=8/1出第一个点，4/1出第二个点，3/1出产物点（核磁确认结构），收集浓缩得1g，yield=67% 11.07 9：30将纯化后的产物（1g，1.0eq）溶于超干THF（20mL）于干燥后的50mL双口瓶（注意无水），分批加入NaH（439.16g，2.5eq，60%）,在氮气下分三批加入于反应瓶中，加毕后室温搅拌6h 16：00TLC（P/E=3/1）确认原料反应完毕，产物点板（p/e=1/2），rf=0.4,结束反应， 后处理：搅拌下加入饱和氯化铵淬灭，至无气泡生成，水和EA萃取3次，lcms有目标分子量：192 纯化：硅胶柱纯化，柱效：1/10，P/E=5/1冲出第一个点，4/1,2/1,1/1均无点冲出，1/2冲出最下点，1/4出产物点，浓缩后得200mg，yield=24%，核磁确认