QueryQuery Results Date1. Query 19 reactions in2014-11-18 01h:54m:50s (EST)ReaxysSearch as: Product, As drawn, No salts, No mixtures色氨酸甲酯盐酸盐的制备在冰浴下,增加了100毫升圆底烧瓶与60毫升的甲醇,然后慢慢加4毫升SOCl2 恒压滴液漏斗(干燥管顶部),和氢氧化钠溶液吸收废气。

搅拌1小时后,8mmol的色氨酸(3 d)补充道,在室温下搅拌30分钟,然后回流在66°c 6 h。

反应是由薄层色谱跟踪,直到原料消失,2%茚三酮在乙醇溶液为显色剂。

溶剂蒸发了获得色氨酸甲酯盐酸盐。

收益率:100%。

+→Rx-ID: 3829969 View in Reaxys 1/19 Yield Conditions & References100 % thionyl chloride, Time= 4h, Heating; Tetrahedron; 57; nb. 51; (2001); p. 10181 - 10189View in Reaxys100 %(2) Preparation of L-Tryptophan Methyl Ester Hydrochloride Under ice bath, 100 ml round-bottom flask was addedwith 60 ml of methanol, and then slowly added with 4 ml of SOClthrough constant pressure dropping funnel (with adrying tube on the top), and NaOH solution was used to absorb exhaust. After stirring for 1 h, 8 mmol of L-tryptophan (3d) was added and stirred at room temperature for 30 min, and then refluxed at 66° C. for 6 h. Thereaction was tracked by TLC until the raw material disappears, with a solution of 2percent ninhydrin in ethanol aschromogenic reagent. The solvent was evaporated out to obtain L-tryptophan methyl ester hydrochloride. Yield:100percent.thionyl chloride methanol, ethanol, Time= 1h, Cooling with ice, Time= 6.5h, T= 20 - 66 °C; ; US2014/206741; (2014); (A1) English View in Reaxys98 % thionyl chloride, Time= 8h, Heating; Organic Preparations and Procedures International; 33; nb. 4; (2001); p. 341 - 349View in Reaxys98 % thionyl chloride, T= 0 - 60 °C; ACS Medicinal Chemistry Letters; 4; nb. 2; (2013); p. 235 - 238View in Reaxys97 % thionyl chloride, Time= 24h, T= -15 - 20 °C , Saturated gas, Inert atmosphere; Chemical Communications; 50; nb. 23; (2014); p. 3052 - 3054View in Reaxys96 % thionyl chloride, Time= 0.666667h, T= 25 - 30 °C , microwave irradiation; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; 45; nb. 8; (2006); p. 1942 - 1944Viewin Reaxys95 % acetyl chloride; Journal of Medicinal Chemistry; 57; nb. 8; (2014); p. 3324 - 3341View in Reaxys93 % thionyl chloride, T= 5 °C , RefluxTime= 4h, Reflux; Chirality; 25; nb. 10; (2013); p. 656 - 662View in Reaxys92 % thionyl chloride, Time= 6.5h, T= -10 - 25 °C; Journal of Chemical Information and Modeling; 53; nb. 1; (2013); p. 176 - 187View in Reaxys73 % thionyl chloride, Time= 7h, T= 60 - 70 °C; Bioorganic and Medicinal Chemistry; 15; nb. 14; (2007); p. 4903 - 4909View in Reaxys67 % thionyl chloride, Time= 9h, T= 20 °C; Dalton Transactions; 40; nb. 18; (2011); p. 5018 - 5025View in Reaxys63 % hydrogenchloride, T= 0 °C; Archiv der Pharmazie; 344; nb. 8; (2011); p. 494 - 504View in Reaxysthionyl chloride, Ambient temperature; Heterocycles; 32; nb. 10; (1991); p. 1879 - 1895View in Reaxysthionyl chloride, Time= 15h, Heating; European Journal of Medicinal Chemistry; 21; nb. 4; (1986); p. 333 - 338View in Reaxysthionyl chloride, Time= 18h, Heating, Yield given; Canadian Journal of Chemistry; 66; (1988); p. 779 - 782View in Reaxysacetyl chloride, Time= 4h, Heating; Synthetic Communications; 25; nb. 4; (1995); p. 561 - 568View in Reaxysthionyl chloride, 1.) -15 deg, 1 h, 2.) overnight, Yield given. Multistep reaction; Tetrahedron: Asymmetry; 6; nb. 8; (1995); p. 1947 - 1956View in Reaxysthionyl chloride, Time= 18h, Heating; Journal of Physical Organic Chemistry; 9; nb. 9; (1996); p. 639 - 644View in Reaxysthionyl chloride; Bioorganic and Medicinal Chemistry; 7; nb. 6; (1999); p. 1223 - 1236View in Reaxysthionyl chloride, T= -30 - -10 °C; Tetrahedron; 57; nb. 20; (2001); p. 4437 - 4442View in Reaxys3.84 g thionyl chloride, Time= 48h, T= 20 °C; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; 45; nb. 12; (2006); p. 2710 - 2715Viewin Reaxysthionyl chloride, Time= 6h; Tetrahedron; 63; nb. 31; (2007); p. 7334 - 7348View in Reaxysthionyl chloride, T= -42 °C; Bioorganic and Medicinal Chemistry Letters; 18; nb. 21; (2008); p. 5750 - 5752View in Reaxysthionyl chloride, T= 20 °C , Cooling; Chemistry - A European Journal; 14; nb. 35; (2008); p. 10888 - 10891View in Reaxysthionyl chloride, Time= 7h, T= 60 - 70 °C; European Journal of Medicinal Chemistry; 44; nb. 10; (2009); p. 3922 - 3929View in Reaxysthionyl chloride, Time= 2.5h, T= 0 °C , Reflux, Inert atmosphere; Tetrahedron; 66; nb. 45; (2010); p. 8722 - 8728View in Reaxysthionyl chloride; European Journal of Organic Chemistry; nb. 14; (2008); p. 2423 - 2429View in Reaxys; Zeitschrift furAnorganische und Allgemeine Chemie; 636; nb. 1; (2010); p. 236 - 241View in Reaxysthionyl chloride; Journal of Chemical Research; 35; nb. 1; (2011); p. 47 - 50View in Reaxys; Journal of Chemical Research; 36;nb. 4; (2012); p. 206 - 209View in Reaxysthionyl chloride, T= 0 - 25 °C; Chemistry - An Asian Journal; 6; nb. 1; (2011); p. 189 - 197View in Reaxysthionyl chloride; Letters in Organic Chemistry; 8; nb. 3; (2011); p. 210 - 215View in Reaxysthionyl chloride, T= 60 - 70 °C; Journal of Enzyme Inhibition and Medicinal Chemistry; 26; nb. 5; (2011); p. 688 - 695View in Reaxysthionyl chloride, Reflux; Journal of Peptide Science; 18; nb. 8; (2012); p. 535 - 540View in ReaxysExample 7 Synthesis of Amide 7: N-(D)-tryptophanamide of AmB In another preferred embodiment the inventionprovides the AmB analogue denominated amide 7: N-(D)-tryptophanamide of AmB, represented by formula VII;using D-tryptophan as the starting amine. Fort this derivative the same structural aspects of the synthesis of amide6 were taken into account and it was observed in its synthesis the possible effect on the antibiotic activity that hasthe change in the stereochemistry of this derivative regarding amide 6. For L-tryptophan and D-tryptophan, beforethe amide synthesis, it was necessary to perform the sterification reaction of the carboxylic acid to protect it in formof hydrochloride of the methyl ester of tryptophan. This synthesis was performed by reacting 1 equivalent of theamino acid L-tryptophan or D-tryptophan (L-Trp or D-Trp) with excess MeOH and 2 equivalents of Me3SiCl toprocure the white precipitate of the hydrochloride of the methyl ester of L-tryptophan or D-tryptophan. Scheme 6shows the reaction mechanism proposed for this synthesis. The first step in the reaction consists of thenucleophilic addition of the tryptophan carboxyl function (E) on the Si of MeSiCl (F) inducing the displacement ofthe Cl ion. The silicon esters (intermediates G and H) are in an equilibrium in which it is proposed that thedeprotonated form is more susceptible to the nucleophilic addition of MeOH. This will form the hydrochloride of themethyl ester tryptophan with trymethylsilanol as a byproduct of the reaction. The hydrochloride of the tryptophanmethyl ester is used for the synthesis of the amides of AmB incorporating only an excess of EtN as basic reagentin the method of Jarzebski. This liberates the form of the methyl ester of the tryptophan to act as amine in thereaction. It is reported that by incorporating the tryptophan structure in AmB polyene molecules they fluoresceunder UV light. The tryptophan methyl ester was used for the synthesis of AmB amides as a means to procureamides that fluoresce under UV light. This is a desirable characteristic for experiments of electrophysiology in unitchannel as because of this, the channels would present this type of fluorescence. Characterization of Amide N-(D)-tryptophanamide of AmB. The IR spectrum of the product is almost identical to that of amide 6, showing onlyslight differences in the intensity of the signals. The derivative had a value of R=0.62 for which it is qualitativelyconsidered that this product is non-polar regarding AmB. These two results help confirm that amide 7 has the samestructure of amide 6, and its epimer. During the process of purification of amide 7 two products were isolated:amide 7a and amide 7b. The IR spectra of both amides have a similar difference to that of amide 2a and amide 2bin the absorption band of the polyhydroxylated chain. Here the difference in the intensity of the bands is not toolarge. Because of this it is believed that this is the same structure, and it is supposed that the solvation with ether(of the purification) occurred in the polyhydroxylated chain for the amide 7b. Moreover, it is likely that the antibioticbehavior is diminished because the actual concentration of the derivative could be less than that contemplated inthe preparation of the amide solution. It is noteworthy that the rest of the spectra of both products are the same.Here, being the epimer (D) of the N-(L)-tryptophanamide, the same values of the derivative 6 are contemplated.Therefore, this synthesis is to determine whether the difference the epimers (L)-(D) stereochemistry will affect theantibiotic activity.chloro-trimethyl-silane; ; US2014/256663; (2014); (A1) English View in Reaxys+→Rx-ID: 3830149 View in Reaxys 2/19 Yield Conditions & References100 % thionyl chloride, Time= 4h, Heating; Tetrahedron; 57; nb. 51; (2001); p. 10181 - 10189View in Reaxys98 % Synthesis of methyl esters of L- and D-tryptophanes chlorohydrates; :1a,b 2a,b a : D b : L[0344] Thionylchloride(0.064 mol) was slowly added to a cooled (OC) suspension of tryptophane (0.049 mol) in methanol (150 mL). Thereaction mixture was warmed up to 4OC and stirred at this temperature for six hours. All solvents were removedand the solid residue was triturated with ether. The solid was filtered off to give the required product.[0345] D-tryptophane (2a): yield 98 percent, M.p. 232-233°C. NMRH (δ, ppm,DMSO-dψ, 300 MHz): 3.39 (2H, m, CH); 3.63(3H, s, CHO); 4.20 (1 H t, CH, J = 5.5 Hz); 7.07 (2H, dt, Ar, J = 21 Hz, 6 Hz); 7.26 (1 H, d, H, JH = 3 Hz); 7.39 (1 H,d, Ar, JH = 7.8 Hz); 7.53 (1 H, d, Ar, J = 7.8 Hz). NMRC (δ, ppm, DMSO-d6, 125.76 MHz): 26.01 (s), 52.61 (d),106.26(s), 111.45(s), 117.84(s), 118.50(s), 121.05(s), 124.80(s), 126.79(s), 136.13(s), 169.57(s). / 218(M).thionyl chloride, Time= 6h, T= 0 - 40 °C; ; WO2008/103470; (2008); (A2) English View in Reaxys97 % thionyl chloride, Time= 4h, T= 40 °C; RSC Advances; 4; nb. 3; (2014); p. 1204 - 1211View in Reaxys92.4 %thionyl chloride methanol, Time= 1 - 2h, Heating / reflux; ; WO2004/11463; (2004); (A1) English View in Reaxys92 % thionyl chloride, Time= 6.5h, T= -10 - 25 °C; Journal of Chemical Information and Modeling; 53; nb. 1; (2013); p. 176 - 187View in Reaxys86 % thionyl chloride, Time= 24h, Reflux; Organic and Biomolecular Chemistry; 11; nb. 19; (2013); p. 3255 - 3260View in Reaxys86 % Thionyl chloride (9.87 mmol, 0.72 mL) was added dropwise to a solution of D-tryptophan (1.000 g, 4.89 mmol) inmethanol (33 mL). The reaction was heated to reflux with vigorous stirring for 24 h. After cooling, the reactionmixture was concentrated under reduced pressure and residual methanol traces removed by azeotropic distillationwith dichloromethane (10 mL) under reduced pressure to give the title compound as a white solid (1.070 g,86percent). [0401] H NMR (500 MHz, DO) δ=7.52 (1H, d, J=7.9, 9-H), 7.46 (1H, d, J=8.1, 12-H), 7.26-7.10 (3H, m,4, 5, 9-H), 4.37 (1H, t, J=6.0, 2-H), 3.73 (3H, s, β-H), 3.44-3.31 (2H, m, 4-H). [0402] C NMR (126 MHz, DO)δ=170.4 (2-C), 136.3 (7-C), 126.4 (8-C), 125.4 (6-C), 122.3 (11-CH), 119.6 (10-CH), 118.1 (9-CH), 112.1 (12-CH),106.0 (5-C), 53.6 (13-CH), 53.3 (2-CH), 25.7 (4-CH). [0403] IR (diamond, v, cm) 3261 (NH st), 2870 (N-H st), 2023(Ar comb), 1748 (C═O st), 1229, 1211 (CO—O st as), 1181 (C—O st as). [0404] Acc. Mass (FAB): CHNOFound:219.1120 m/z Calculated: 219.1128 m/z.thionyl chloride, Time= 24h, Reflux; ; US2014/39200; (2014); (A1) English View in Reaxys80 % D-tryptophan (100 g) was suspended in methanol (500 mL) and the suspension added to a solution of thionylchloride (82.14 g) in methanol (500 mL) at 25-30° C under nitrogen atmosphere. The resultant solution was stirredat reflux for 3 to 4 hours and the reaction mixture was concentrated to a residual volume of 150 mL. To theconcentrated mixture dichloromethane (700 mL) was added and the resultant solution was cooled to 0- 5° C withcontinuous stirring for 0.5 hours. The solid so obtained was filtered, washed with dichloromethane (200 mL) anddried in air at 40-45° C to afford D-tryptophan methyl ester hydrochloride.Yield: 10O g (80percent)thionyl chloride, Time= 3 - 4h, T= 25 - 30 °C , Heating / reflux; ; WO2009/4557; (2009); (A2) English View in Reaxysthionyl chloride, Time= 18h, Heating, Yield given; Canadian Journal of Chemistry; 66; (1988); p. 779 - 782View in Reaxysthionyl chloride, Time= 0.5h, T= 0 °C Heating; Journal of Medicinal Chemistry; 49; nb. 24; (2006); p. 7215 - 7226View in Reaxyshydrogenchloride, Time= 3.5h, Heating, Esterification; Journal of Organic Chemistry; 65; nb. 10; (2000); p. 3173 - 3191View in ReaxysThionyl chloride (SOCl; 2.4 ml) is added to a suspension of D-tryptophan (3g; 14.7 mmoles) in 20 ml methanol,stirring under nitrogen atmosphere in ice bath. The solution is then refluxed (~68°C) for 1.5 hour. Methanol isevaporated and 20 ml of tert-butyl- methyl ether (MTBE) are added. The solution is stirred in ice bath for 1 hour,then it is filtered and the product is washed with cold MTBE. The obtained white solid is dried under vacuum at60C.thionyl chloride, Time= 1.5h, T= 0 - 68 °C; ; WO2009/37556; (2009); (A1) English; WO 2009/037556 A1View in Reaxysacetyl chloride, Reflux; Journal of Medicinal Chemistry; 56; nb. 7; (2013); p. 2936 - 2947View in Reaxys→Rx-ID: 25199344 View in Reaxys 3/19 Yield Conditions & References92.54 % General procedure: To a solution of DL-tryptophane (8.16 g, 0.040 mol) in methanol (80 mL) was added dropwiseSOCl (14.28 g, 0.120 mol), and the mixture was stirred at rt for 30 min. The solution was concentrated and filtered,then the residue was washed with acetone and dried under infrared light (IR) to give the compound 3a as a whitesolid (8.07 g, 92.54 percent). Mp = 220°C, lit. Mp = 221–222°C.thionyl chloride methanol, T= 20 °C; Bioorganic and Medicinal Chemistry; 21; nb. 21; (2013); p. 6466 - 6476View in ReaxysSynthesis of DL-tryptophan amide 50 g of DL-tryptophan available from Nakarai Chemicals, Kyoto, Japan, wassuspended in 500 ml of methanol and 40 ml of thionyl chloride was dropwise added thereto while vigorouslystirring. The reaction was exothermic and the reaction mixture was allowed to be refluxed for 10 hours whilestirring. Then, the solvent was distilled off and the resultant residue was washed with diethylether. Thus, DL-tryptophan methylester hydrochloride was obtained in the form of white crystals.thionyl chloride methanol; ; US4497957; (1985); (A1) English View in Reaxys+→Rx-ID: 33704021 View in Reaxys 4/19 Yield Conditions & References100 % EXAMPLE 2: SYNTHESIS OF TRYPTOPHAN METHYL ESTER APPENDEDNAPHTHALENETETRACARBOXYLICDIIMIDE (NDI 2)Synthesis of L-Tryptophan methyl ester hydrochloride:Anhydrous methanol (50 mL) is taken in a 100 mL 2-necked round bottom flask fitted with a reflux condenser andan additional dropping funnel and cooled to ice temperature. Acetylchloride (3 mL) is added drop wise through thedropping funnel. After 15 min, L-tryptophan (3 g) is added and the reaction mixture is refluxed at 70 °C for 6 h. Thereaction mixture is vacuo dried to obtain L-tryptophan methyl ester hydrochloride in quantitative yield and used forfurther reaction without purification.1 ,4,5, 8-Naphthalenetetracarboxy lie dianhydride (200 mg, 0.746 mmol) and L-tryptophan methyl ester hydrochloride (380 mg 1.491 mmol) are suspended in 20 mL of DMF in a 100 mL roundbottom flask. To this suspension is added 0.5 mL of triethylamine under inert atmosphere. The reaction mixture isrefluxed at 65 °C for 21 h. Solvent is evaporated under vacuo and the residue is purified by columnchromatography (15 percent methanol in chloroform) to obtain NDI 2 in good yield. Yield 86percent. H NMR: (400MHz, CDCI-CFCOOH) 8 3.64- 3.70, (dd, 2H, CH, J = 8 Hz, 8 Hz); 3.78-3.84, (dd, 2H, CH, J = 8 Hz, 8 Hz); 3.90 (s,6H, CH); 6.12-6.16 (dd, 2H, aCH, J = 8 Hz, 4 Hz); 6.86-7.02 (m, 6H, ArH); 7.13-7.15 (d, 2H, ArH, J = 8 Hz); 7.46-7.48 (d, 2H, ArH, J = 8 Hz); 8.57 (s, 4H, ArH). C NMR: (400 MHz, CDCI-CFCOOH) 8 24.5, 53.9, 55.1 , 1 10.2, 110.4, 1 18.6, 1 19.8, 122.4, 123.2, 126.1 , 126.6, 127.2, 131.8, 136.1 , 163.0, 172.5. MS (EI): m/z = 668.19 [M]+ forCH2N4O. Elemental analysis: Found: C, 68.23; H, 4.25; N, 8.35; Calcd: C, 68.26; H, 4.22; N, 8.38 for C38H8N0acetyl chloride, Time= 6h, T= 70 °C , Cooling; ; WO2012/98439; (2012); (A1) English View in Reaxys+→Rx-ID: 34011985 View in Reaxys 5/19 Yield Conditions & References86 % Synthesis Example 2a - (2f?)-3-(1H-indol-3-vl)-1-methoxy-1-oxopropan-2-aminium chlorideThionyl chloride (9.87mmol, 0.72 mL) was added dropwise to a solution of D- tryptophan (1.000 g, 4.89 mmol) in methanol (33 mL). Thereaction was heated to reflux with vigorous stirring for 24 h. After cooling, the reaction mixture was concentratedunder reduced pressure and residual methanol traces removed by azeotropic distillation with dichloromethane (10mL) under reduced pressure to give the title compound as a white solid (1.070 g, 86percent).H MR (500 MHz, D0)δ = 7.52 (1 H, d, 7=7.9, 9-H), 7.46 (1 H, d, 7=8.1 , 12-H), 7.26 - 7.10 (3H, m, 4, 5, 9-H), 4.37 (1H, t, J=6.0, 2-H),3.73 (3H, s, 3-H), 3.44 - 3.31 (2H, m, 4-H).1C NMR (126 MHz, D0) δ = 170.4 (2-C), 136.3 (7-C), 126.4 (8-C), 25.4(6-C),122.3 (11-CH), 119.6 (10-CH), 118.1 (9-CH), 112.1 (12-CH), 106.0 (5-C), 53.6 (13- CH), 53.3 (2-CH), 25.7(4-CH).IR (diamond, v cm) 3261 (NH st), 2870 (Nf-H st), 2023 (Ar comb), 1748 (C=0 St), 1229, 1211 (CO-0 st as),1181 (C-0 st as).Acc. Mass (FAB): CiH0 Found: 219.1120 m/z Calculated: 219.1128 m/zthionyl chloride methanol, Time= 24h, Reflux; ; WO2012/131313; (2012); (A1) English View in Reaxys+→Rx-ID: 3829903 View in Reaxys 6/19 Yield Conditions & References100 % hydrogenchloride, 3 A molecular sieve, Time= 2.5h, Heating; Synthetic Communications; 22; nb. 7; (1992); p. 979 - 985View in Reaxys92 % thionyl chloride, Time= 24h, T= -15 - 20 °C , Saturated gas, Inert atmosphere; Chemical Communications; 50; nb. 23; (2014); p. 3052 - 3054View in Reaxys91 % chloro-trimethyl-silane, Time= 12h, T= 20 °C; Molecules; 13; nb. 5; (2008); p. 1111 - 1119View in Reaxysthionyl chloride, Yield given; Bulletin des Societes Chimiques Belges; 103; nb. 4; (1994); p. 169 - 176View in Reaxysthionyl chloride, Time= 10h, T= 20 °C; Journal of Organic Chemistry; 73; nb. 14; (2008); p. 5609 - 5612View in Reaxysthionyl chloride, Reflux; Angewandte Chemie - International Edition; 52; nb. 49; (2013); p. 12942 - 12945; Angew. Chem.; 125; nb. 49;(2013); p. 13180 - 13183,4View in Reaxys→Rx-ID: 2992583 View in Reaxys 7/19 Yield Conditions & References96 % hydrogenchloride diethyl ether, T= 0 °C; Synthesis; nb. 7; (1988); p. 514 - 517View in Reaxys→Rx-ID: 33188001 View in Reaxys 8/19 Yield Conditions & References93% Preparation Example 25L-tryptophan Methyl Ester HydrochlorideUsing L-tryptophan as a raw material, the synthetic approach and work-up were analogous to that described in Preparation example 1. 3.02 g of white crystalwas obtained with a yield of 93p ercent, [α]D=+16.5° (c=1, CHOH), m.p.: 206-208° C.; ; US2012/135921; (2012); (A1) English View in Reaxys+→Rx-ID: 3829998 View in Reaxys 9/19 Yield Conditions & Referencesthionyl chloride water, Time= 0.666667h, T= 60 °C; Journal of the American Chemical Society; 112; nb. 7; (1990); p. 2566 - 2574View in Reaxys+→Rx-ID: 28197635 View in Reaxys 10/19 Yield Conditions & References73 % thionyl chloride, Time= 7h, T= 60 - 70 °C; European Journal of Medicinal Chemistry; 44; nb. 1; (2009); p. 131 - 142View in Reaxys+→Rx-ID: 1589804 View in Reaxys 11/19 Yield Conditions & References94.8 % thionyl chloride, 1) -10 deg C, 2 h; 2) RT, 2 d; Chemical and Pharmaceutical Bulletin; 32; nb. 4; (1984); p. 1313 - 1325View in Reaxys+Raney nickel →Rx-ID: 20378038 View in Reaxys 12/19 Yield Conditions & ReferencesReaction Steps: 21: 70 percent / EtAlCl / CHCl; hexane / 1 h / 0 °C2: 96 percent / 1N HCl / diethyl ether / 0 °Chydrogenchloride, ethylaluminum dichloride diethyl ether, hexane, dichloromethane; Synthesis; nb. 7; (1988); p. 514 - 517View in Reaxys+→Rx-ID: 31934484 View in Reaxys 13/19 Yield Conditions & Referenceswater-d2, T= 24.84 °C , pH= 7.1, aq. phosphate buffer; Organic and Biomolecular Chemistry; 9; nb. 21; (2011); p. 7457 - 7460View in Reaxys+→Rx-ID: 37905803 View in Reaxys 14/19 Yield Conditions & Referencesthionyl chloride, Time= 40h, T= 20 °C; Journal of the American Chemical Society; 136; nb. 16; (2014); p. 5900 - 5903View in Reaxys+→Rx-ID: 27237752 View in Reaxys 15/19 Yield Conditions & Referencesnot given; Journal of Organometallic Chemistry; 496; (1995); p. C1 - C4 ; (from Gmelin)View in Reaxys→Rx-ID: 37905797 View in Reaxys 16/19 Yield Conditions & ReferencesReaction Steps: 21: sodium; ammonia; Iron (III) nitrate nonahydrate / |Reflux2: thionyl chloride / 40 h / 20 °C Iron(III) nitrate nonahydrate, thionyl chloride, ammonia, sodium; Journal of the American Chemical Society; 136; nb. 16; (2014); p. 5900 - 5903View in Reaxys→Rx-ID: 38511770 View in Reaxys 17/19 Yield Conditions & ReferencesGeneral procedure: Example 7 Synthesis of Amide 7: N-(D)-tryptophanamide of AmB In another preferredembodiment the invention provides the AmB analogue denominated amide 7: N-(D)-tryptophanamide of AmB,represented by formula VII; using D-tryptophan as the starting amine. Fort this derivative the same structuralaspects of the synthesis of amide 6 were taken into account and it was observed in its synthesis the possible effecton the antibiotic activity that has the change in the stereochemistry of this derivative regarding amide 6. For L-tryptophan and D-tryptophan, before the amide synthesis, it was necessary to perform the sterification reaction ofthe carboxylic acid to protect it in form of hydrochloride of the methyl ester of tryptophan. This synthesis wasperformed by reacting 1 equivalent of the amino acid L-tryptophan or D-tryptophan (L-Trp or D-Trp) with excessMeOH and 2 equivalents of Me3SiCl to procure the white precipitate of the hydrochloride of the methyl ester of L-tryptophan or D-tryptophan. Scheme 6 shows the reaction mechanism proposed for this synthesis. The first stepin the reaction consists of the nucleophilic addition of the tryptophan carboxyl function (E) on the Si of MeSiCl (F)inducing the displacement of the Cl ion. The silicon esters (intermediates G and H) are in an equilibrium in which itis proposed that the deprotonated form is more susceptible to the nucleophilic addition of MeOH. This will form thehydrochloride of the methyl ester tryptophan with trymethylsilanol as a byproduct of the reaction. The hydrochlorideof the tryptophan methyl ester is used for the synthesis of the amides of AmB incorporating only an excess of EtNas basic reagent in the method of Jarzebski. This liberates the form of the methyl ester of the tryptophan to act asamine in the reaction. It is reported that by incorporating the tryptophan structure in AmB polyene molecules theyfluoresce under UV light. The tryptophan methyl ester was used for the synthesis of AmB amides as a means toprocure amides that fluoresce under UV light. This is a desirable characteristic for experiments of electrophysiologyin unit channel as because of this, the channels would present this type of fluorescence. Characterization of AmideN-(D)-tryptophanamide of AmB. The IR spectrum of the product is almost identical to that of amide 6, showing onlyslight differences in the intensity of the signals. The derivative had a value of R=0.62 for which it is qualitativelyconsidered that this product is non-polar regarding AmB. These two results help confirm that amide 7 has the samestructure of amide 6, and its epimer. During the process of purification of amide 7 two products were isolated:amide 7a and amide 7b. The IR spectra of both amides have a similar difference to that of amide 2a and amide 2bin the absorption band of the polyhydroxylated chain. Here the difference in the intensity of the bands is not toolarge. Because of this it is believed that this is the same structure, and it is supposed that the solvation with ether(of the purification) occurred in the polyhydroxylated chain for the amide 7b. Moreover, it is likely that the antibioticbehavior is diminished because the actual concentration of the derivative could be less than that contemplated inthe preparation of the amide solution. It is noteworthy that the rest of the spectra of both products are the same.Here, being the epimer (D) of the N-(L)-tryptophanamide, the same values of the derivative 6 are contemplated.Therefore, this synthesis is to determine whether the difference the epimers (L)-(D) stereochemistry will affect theantibiotic activity.chloro-trimethyl-silane; ; US2014/256663; (2014); (A1) English View in Reaxys→+Copyright © 2014 Reed Elsevier Properties SA. All rights reserved.Authorized use only. Reaxys® and the Reaxys® trademark are owned andprotected by Reed Elsevier Properties SA and used under license. 11/112014-11-18 01:57:42 Rx-ID: 25148199 View in Reaxys 18/19YieldConditions & References The tryptophan methylester hydrochloride thus obtained was suspended in 1 liter of ethyl acetate and 100 ml oftriethylamine was added thereto. The mixture was allowed to react for 1 hour while vigorously stirring. Theinsoluble matter (i.e. triethylamine hydrochloride) was filtered off and the filtrate was washed with a small amount of water. Thereafter, the solvent was distilled off to obtain 40 g of oily tryptophan methylester.; ; US4497957; (1985); (A1) English View in Reaxys →Rx-ID: 27883578 View in Reaxys 19/19YieldConditions & References 98 %; ; WO2008/103470; (2008); (A2) English View in Reaxys。