* 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.
In a typical reaction, 73 mL of acetic anhydride (780 mmol) and 63 mL pyridine (780 mmol) were combined in a round-bottomed flask and chilled on ice. After 5-10 min, 8.6 g (100 mmol) l-methionine methyl ester HCl were added and the reaction mixture was allowed to slowly return to room temperature overnight. The next morning, the reaction was quenched with cold water and extracted four times with 75 mL of methylene chloride. The extracts were then rinsed three times each with 1 M HCl, saturated sodium bicarbonate solution, and water. The extracts were then dried over MgSO4, filtered, and evaporated under reduced pressure, yielding a yellow oil which crystallized upon standing. The crude product was recrystallized in ethyl ether at -20 °C. Crystals (19.3 g, 94 mmol, 94percent) were isolated by vacuum filtration. Mp = 41.7-42.4 °C. 1H NMR ([2H]-chloroform, TMS = 0.0 ppm): δ 1.86-2.20 (m, 2H), δ 2.00 (s, 3H), δ 2.05 (s, 3H), δ 2.45-2.60 (m, 2H), δ 3.75 (s, 3H), δ 4.62-4.70 (m, 1H), δ 6.13-6.19 (bd, 1H).
Reference：
[1] Tetrahedron Asymmetry, 2011, vol. 22, # 3, p. 283 - 293
[2] Chemical and pharmaceutical bulletin, 1986, vol. 34, # 3, p. 986 - 998
2
[ 2491-18-1 ]
[ 501-53-1 ]
[ 56762-93-7 ]
Reference：
[1] Synthetic Communications, 1989, vol. 19, # 20, p. 3457 - 3468
[2] European Journal of Organic Chemistry, 2008, # 18, p. 3107 - 3112
[3] Organic Syntheses, 1992, vol. 70, p. 29 - 29
[4] Journal of Organic Chemistry, 1980, vol. 45, # 24, p. 4817 - 4820
[5] Tetrahedron Letters, 2010, vol. 51, # 24, p. 3226 - 3228
3
[ 13139-17-8 ]
[ 2491-18-1 ]
[ 56762-93-7 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 16, p. 3507 - 3518
4
[ 67-56-1 ]
[ 63-68-3 ]
[ 2491-18-1 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 0℃; for 16 h; Inert atmosphere; Reflux
Synthesis Example 1 \\ ,L-Methionine (0.5g, 1 equivalent) was suspended in methanol (30ml C = 0.1M) in a 100ml flask equipped with a magnetic stirrer and placed under nitrogen. Thionyl chloride (0.5ml, 2 equivalents) was added to the solution dropwise at 0°C then heated under reflux for 16 hours. The reaction mixture was then evaporated to yield a pale yellow solid. The solid was triturated with hot diethyl ether and the solution discarded to leave the title compound 2 as a white solid which was further dried under vacuum. (0.65561 g, 98percent yield).1H NMR (D20, 500MHz) δΗ: 4.24(1 H, m, 3) 3.79(3H, s, 1), 2.63(2H, t, 5), 2.25(1 H, m, 4), 2.16(1H, m, 4), 2.06(1H, s, 6)13C NMR( D20, 125MHz) 6C: 170.58 (2), 53.64(1), 51.70(3), 28.71(4), 28.41(5), 13.85(6).IR (neat, vmax, cnV1): 2880.8/2676,2 (CH3, CH2, CH), 2016.2, 1742.2 (C=0, ester), 1483.6, 1443.5, 1227 + 1194.7 + 1149.8 + 1079.5 (C-O).HRMS m/z (+ESI): C6Hi4N02S, mass found = 64.074 (Error = 0.07ppm)
98%
at 0℃; for 16 h; Inert atmosphere; Reflux
L-Methionine (0.5 g, 1 equivalent) was suspended in methanol (30 ml C=0.1M) in a 100 ml flask equipped with a magnetic stirrer and placed under nitrogen. Thionyl chloride (0.5 ml, 2 equivalents) was added to the solution dropwise at 0° C. then heated under reflux for 16 hours. The reaction mixture was then evaporated to yield a pale yellow solid. The solid was triturated with hot diethyl ether and the solution discarded to leave the title compound 2′ a white solid which was further dried under vacuum. (0.65561 g, 98percent yield). [0377] 1H NMR (D2O, 500 MHz) δH: 4.24 (1H, m, 3) 3.79 (3H, s, 1), 2.63 (2H, t, 5), 2.25 (1H, m, 4), 2.16 (1H, m, 4), 2.06 (1H, s, 6) [0378] 13C NMR (D2O, 125 MHz) δc: 170.58 (2), 53.64 (1), 51.70 (3), 28.71 (4), 28.41 (5), 13.85 (6). [0379] IR (neat, vmax, cm−1): 2880.8/2676.2 (CH3, CH2, CH), 2016.2, 1742.2 (C═O, ester), 1483.6, 1443.5, 1227+1194.7+1149.8+1079.5 (C—O). [0380] HRMS m/z (+ESI): C6H14NO2S, mass found=164.074 (Error=0.071 ppm)
89%
at 20℃; for 24 h; Inert atmosphere; Reflux
Using the general methyl esterification conditions, L-methionine (8, 2.00 g, 13.4 mmol) was treated with thionyl chloride (2.00 mL, 26.8 mmol) in methanol(20 mL) to afford the title compound as a white powder (1.95 g, 89percent); νmax (KBr pellet): 3080 (s), 1747(s), 2840 (w), 1236 (s); δH (300 MHz, CDCl3): 2.28 (3H, s), 2.28–2.33 (2H, m), 2.67–2.77 (2H, m), 3.87(3H, s), 4.16–4.30 (1H, m); δC (75.4 MHz, CD3OD): 15.4, 30.5, 31.1, 53.2, 54.2, 171.2; m/z (ES+): 164 (100percent, [M+H]+). Data in agreement with literature [62].
67%
at 20℃; Cooling with ice
General procedure: This compound has previously been described5 and can be purchased from Toronto Research. To a round bottom flask containing MeOH (50 mL) and cooled in an ice bath was added SOCl2(6.1 mL, 84 mmol) dropwise over 5 min. L-Leucine 1e (5.0 g, 38) was then added and the mixture was left to stir overnight at rt. The reaction mixture was concentrated on the rotovap using MeOH (2 x 50 mL) to chase away excess thionyl chloride. Diethyl ether (50 mL) was added to the resulting solids and followed by a combination of scratching and sonication to produce a white solid which was filtered, rinsing with diethyl ether (3 x 10 mL). Product was further purified by recrystallization by partially dissolving solids in hot EtOAc (50 mL) followed by cooling to rt and filtration. Yield: 3.9 g (56percent). [α]D24 +18.8° (c 0.50, MeOH). >98percent pure by NMR. 1H NMR ((CD3)2SO) δ 8.61 (br s, 3H), 3.95 (t, J = 7, 1H), 3.74 (s, 3H), 1.75 (m, 1H), 1.65 (m, 2H), 0.89 (d, J = 7, 6H).
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 1, p. 201 - 215
[2] Journal of the American Chemical Society, 2017, vol. 139, # 40, p. 14077 - 14089
[3] Patent: WO2012/131313, 2012, A1, . Location in patent: Page/Page column 49
[4] Patent: US2014/39200, 2014, A1, . Location in patent: Paragraph 0376-0380
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2006, vol. 45, # 8, p. 1942 - 1944
[6] Organic Preparations and Procedures International, 2001, vol. 33, # 4, p. 341 - 349
[7] Synthetic Communications, 2010, vol. 40, # 8, p. 1161 - 1179
[8] Molecules, 2014, vol. 19, # 12, p. 20751 - 20767
[9] Organic Syntheses, 1992, vol. 70, p. 29 - 29
[10] Tetrahedron Letters, 2017, vol. 58, # 34, p. 3347 - 3349
[11] Archiv der Pharmazie, 2011, vol. 344, # 8, p. 494 - 504
[12] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 20, p. 5000 - 5006
[13] Synthetic Communications, 2008, vol. 38, # 5, p. 684 - 696
[14] Biomedicine and Pharmacotherapy, 2017, vol. 88, p. 1163 - 1172
[15] Journal of Biological Chemistry, 1949, vol. 180, p. 63
[16] Tetrahedron, 1990, vol. 46, # 15, p. 5325 - 5332
[17] European Journal of Medicinal Chemistry, 1985, vol. 20, # 6, p. 509 - 512
[18] Synthetic Communications, 1995, vol. 25, # 4, p. 561 - 568
[19] Journal of Medicinal Chemistry, 2006, vol. 49, # 24, p. 7215 - 7226
[20] Tetrahedron, 2004, vol. 60, # 43 SPEC. ISS., p. 9649 - 9657
[21] Journal of the American Chemical Society, 2008, vol. 130, # 15, p. 5052 - 5053
[22] European Journal of Organic Chemistry, 2008, # 14, p. 2423 - 2429
[23] Journal of Chemical Research, 2011, vol. 35, # 1, p. 47 - 50
[24] Journal of Chemical Research, 2012, vol. 36, # 4, p. 206 - 209
[25] Letters in Organic Chemistry, 2011, vol. 8, # 3, p. 210 - 215
[26] Asian Journal of Chemistry, 2012, vol. 24, # 3, p. 1227 - 1236
[27] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 12, p. 3807 - 3815
[28] Asian Journal of Chemistry, 2012, vol. 24, # 3, p. 1237 - 1241
[29] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 12, p. 1185 - 1190
[30] Polyhedron, 2018, vol. 143, p. 70 - 82
[31] Patent: CN105145577, 2018, B, . Location in patent: Paragraph 0035; 0039
[32] Amino Acids, 2018, vol. 50, # 10, p. 1461 - 1470
5
[ 163926-92-9 ]
[ 2491-18-1 ]
Reference：
[1] Journal of the American Chemical Society, 1995, vol. 117, # 11, p. 3302 - 3303
With thionyl chloride at 0 - 45℃; for 10h; Inert atmosphere;
98%
With thionyl chloride at 0℃; for 16h; Inert atmosphere; Reflux;
1a
Synthesis Example 1 ,L-Methionine (0.5g, 1 equivalent) was suspended in methanol (30ml C = 0.1M) in a 100ml flask equipped with a magnetic stirrer and placed under nitrogen. Thionyl chloride (0.5ml, 2 equivalents) was added to the solution dropwise at 0°C then heated under reflux for 16 hours. The reaction mixture was then evaporated to yield a pale yellow solid. The solid was triturated with hot diethyl ether and the solution discarded to leave the title compound 2 as a white solid which was further dried under vacuum. (0.65561 g, 98% yield).1H NMR (D20, 500MHz) δΗ: 4.24(1 H, m, 3) 3.79(3H, s, 1), 2.63(2H, t, 5), 2.25(1 H, m, 4), 2.16(1H, m, 4), 2.06(1H, s, 6)13C NMR( D20, 125MHz) 6C: 170.58 (2), 53.64(1), 51.70(3), 28.71(4), 28.41(5), 13.85(6).IR (neat, vmax, cnV1): 2880.8/2676,2 (CH3, CH2, CH), 2016.2, 1742.2 (C=0, ester), 1483.6, 1443.5, 1227 + 1194.7 + 1149.8 + 1079.5 (C-O).HRMS m/z (+ESI): C6Hi4N02S, mass found = 64.074 (Error = 0.07ppm)
98%
With thionyl chloride at 0℃; for 16h; Inert atmosphere; Reflux;
1a Synthesis Example 1a-L-Methionine methyl ester hydrochloride (2)
L-Methionine (0.5 g, 1 equivalent) was suspended in methanol (30 ml C=0.1M) in a 100 ml flask equipped with a magnetic stirrer and placed under nitrogen. Thionyl chloride (0.5 ml, 2 equivalents) was added to the solution dropwise at 0° C. then heated under reflux for 16 hours. The reaction mixture was then evaporated to yield a pale yellow solid. The solid was triturated with hot diethyl ether and the solution discarded to leave the title compound 2′ a white solid which was further dried under vacuum. (0.65561 g, 98% yield). [0377] 1H NMR (D2O, 500 MHz) δH: 4.24 (1H, m, 3) 3.79 (3H, s, 1), 2.63 (2H, t, 5), 2.25 (1H, m, 4), 2.16 (1H, m, 4), 2.06 (1H, s, 6) [0378] 13C NMR (D2O, 125 MHz) δc: 170.58 (2), 53.64 (1), 51.70 (3), 28.71 (4), 28.41 (5), 13.85 (6). [0379] IR (neat, vmax, cm-1): 2880.8/2676.2 (CH3, CH2, CH), 2016.2, 1742.2 (C═O, ester), 1483.6, 1443.5, 1227+1194.7+1149.8+1079.5 (C-O). [0380] HRMS m/z (+ESI): C6H14NO2S, mass found=164.074 (Error=0.071 ppm)
96%
With thionyl chloride at 25 - 30℃; for 0.666667h; microwave irradiation;
95%
With thionyl chloride for 8h; Heating;
90%
With thionyl chloride
89%
With thionyl chloride at 20℃; for 24h; Inert atmosphere; Reflux;
L-Methionine methyl ester hydrochloride salt (13)
Using the general methyl esterification conditions, L-methionine (8, 2.00 g, 13.4 mmol) was treated with thionyl chloride (2.00 mL, 26.8 mmol) in methanol(20 mL) to afford the title compound as a white powder (1.95 g, 89%); νmax (KBr pellet): 3080 (s), 1747(s), 2840 (w), 1236 (s); δH (300 MHz, CDCl3): 2.28 (3H, s), 2.28-2.33 (2H, m), 2.67-2.77 (2H, m), 3.87(3H, s), 4.16-4.30 (1H, m); δC (75.4 MHz, CD3OD): 15.4, 30.5, 31.1, 53.2, 54.2, 171.2; m/z (ES+): 164 (100%, [M+H]+). Data in agreement with literature [62].
88%
With hydrogenchloride at 0℃; for 0.25h;
82%
With thionyl chloride for 16h; Reflux;
79%
With hydrogenchloride at 0℃;
67%
With thionyl chloride at 20℃; Cooling with ice;
Methyl L-leucinate hydrochloride (9e)
General procedure: This compound has previously been described5 and can be purchased from Toronto Research. To a round bottom flask containing MeOH (50 mL) and cooled in an ice bath was added SOCl2 (6.1 mL, 84 mmol) dropwise over 5 min. L-Leucine 1e (5.0 g, 38) was then added and the mixture was left to stir overnight at rt. The reaction mixture was concentrated on the rotovap using MeOH (2 x 50 mL) to chase away excess thionyl chloride. Diethyl ether (50 mL) was added to the resulting solids and followed by a combination of scratching and sonication to produce a white solid which was filtered, rinsing with diethyl ether (3 x 10 mL). Product was further purified by recrystallization by partially dissolving solids in hot EtOAc (50 mL) followed by cooling to rt and filtration. Yield: 3.9 g (56%). [α]D24 +18.8° (c 0.50, MeOH). >98% pure by NMR. 1H NMR ((CD3)2SO) δ 8.61 (br s, 3H), 3.95 (t, J = 7, 1H), 3.74 (s, 3H), 1.75 (m, 1H), 1.65 (m, 2H), 0.89 (d, J = 7, 6H).
65.35%
With thionyl chloride
65%
With thionyl chloride at 0℃; Reflux;
With hydrogenchloride
With thionyl chloride for 2h; Heating;
With thionyl chloride for 4h; Heating;
With acetyl chloride for 4h; Heating;
Stage #1: methanol With thionyl chloride at 0℃; for 0.5h;
Stage #2: L-methionine Heating;
With thionyl chloride
With thionyl chloride at 20℃;
With thionyl chloride
With thionyl chloride
With thionyl chloride
With acetyl chloride Reflux;
With thionyl chloride at 55℃; for 6h;
Stage #1: methanol With thionyl chloride at 0℃; for 1h;
Stage #2: L-methionine at 90℃; for 15h;
With thionyl chloride
Stage #1: methanol With thionyl chloride at -11℃; for 1h;
Stage #2: L-methionine at 20 - 65℃; for 7h;
1.1 Step 1. Preparation of L-methionine methyl ester hydrochloride:
0.12 mol of thionyl chloride was slowly dropped into 50 mL of anhydrous methanol at -11 °C.After stirring for 1 hour, 0.1 mol of L-methionine was added.After stirring at room temperature for 3 hours, stirring at 65°C for 4 hours, rotary evaporation,The reaction product was dissolved in a mixed solvent of ethyl acetate and petroleum ether (1:1 by volume), and crystals were obtained at 0°C.
With thionyl chloride at 20℃; Cooling with ice;
General procedure forthepreparation ofaminoacids methyl ester (2a-2g) (Brenner andHuber1953)
General procedure: Amino acid (1mmol) was added to methanol (2ml) and thenfask cooled in an ice bath for 1-2min. Thionyl chloride(2mmol) was injected slowly to the amino acid-methanolmixture. The mixture was stirred overnight at room temperature.After the completion of the reaction, the solventwas evaporated and washed with Et2Oto yield a white solidprecipitate (Yield 95%).
With thionyl chloride at 0℃; Reflux;
With thionyl chloride at 0 - 20℃;
Stage #1: L-methionine With chloro-trimethyl-silane at 20℃; for 0.333333h;
Stage #2: methanol at 20℃; for 24h;
With thionyl chloride at 0℃; Reflux; Inert atmosphere; Sealed tube;
With thionyl chloride at 0 - 65℃; for 8h; Inert atmosphere;
With 2,6-dimethylpyridine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate In water at 20℃; for 1h; Green chemistry;
93%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; for 4h; Inert atmosphere;
General Procedure for the Formation of Carboxylatesand Subsequent Coupling Reaction
General procedure: To a solution of Cbz-Ala-Phe-OMe (0.3 g, 0.81 mmol) in dioxane (2 mL) at r.t.were added LiOH (25 mg, 1 mmol) and H2O (0.35 mL, 19.44mmol, 24 molar equiv). Stirring at r.t. and monitoring byHPLC showed complete saponification and a clear,homogeneous solution generally after 3 h.Amino acid H-AA-OMe, HCl (0.9 mmol) and HATU (0.463g, 1.22 mmol) were added and the mixture was stirred at r.t.until completion, generally 4 h.The diastereomeric purity was measured at this stage, beforeisolation and purification.After concentration in vacuo, the residue was purified bysilica gel chromatography with a mixture of CH2Cl2-EtOAcas eluent to afford the pure tripeptide as a white solid.
81%
With pentafluorophenyl diphenyl-phosphinate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 1.5h; Ambient temperature;
72%
With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide for 16h;
72%
With N-ethylmorpholine;; benzotriazol-1-ol; dicyclohexyl-carbodiimide
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In acetonitrile for 0.25h; Ambient temperature; Yield given;
With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide
6.72 g
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere; Sealed tube;
In a typical reaction, 73 mL of acetic anhydride (780 mmol) and 63 mL pyridine (780 mmol) were combined in a round-bottomed flask and chilled on ice. After 5-10 min, 8.6 g (100 mmol) l-methionine methyl ester HCl were added and the reaction mixture was allowed to slowly return to room temperature overnight. The next morning, the reaction was quenched with cold water and extracted four times with 75 mL of methylene chloride. The extracts were then rinsed three times each with 1 M HCl, saturated sodium bicarbonate solution, and water. The extracts were then dried over MgSO4, filtered, and evaporated under reduced pressure, yielding a yellow oil which crystallized upon standing. The crude product was recrystallized in ethyl ether at -20 C. Crystals (19.3 g, 94 mmol, 94%) were isolated by vacuum filtration. Mp = 41.7-42.4 C. 1H NMR ([2H]-chloroform, TMS = 0.0 ppm): delta 1.86-2.20 (m, 2H), delta 2.00 (s, 3H), delta 2.05 (s, 3H), delta 2.45-2.60 (m, 2H), delta 3.75 (s, 3H), delta 4.62-4.70 (m, 1H), delta 6.13-6.19 (bd, 1H).
With potassium carbonate In methanol at 55℃; for 23h;
1
(S) Methyl 2-amino-4-methylsulfanylbutyrate hydrochloride (750 mg, 3.76 mmol) and 2,2,2-trifluoro-l-(4-fluoro-phenyl)-ethanone (721 mg, 3.76mmol) was dissolved in methanol (15 mL) and then potassium carbonate (1.04 g, 7.52 mmol) was added to the solution. The mixture was stirred at 55 0C for 23 hours and then concentrated to dryness on a rotovap. The residue was combined with toluene (20 mL) and the mixture was concentrated to dryness on a rotovap. The residue was combined with acetonitrile (10 mL) and the mixture was stirred at approximately - 300C. Zinc borohydride, prepared by adding a IM zinc chloride solution in ether (5.64 mL) to a mixture of sodium borohydride (427 mg, 11.28 mmol) stirring in ether (1OmL) and then stirring this mixture 19 hours, was added and the reaction stirred for approximately 7 hours at reduced temperature and then an additional 16 hours at room temperature. The reaction mixture was quenched with IN HCl, diluted with ethyl acetate, and washed with brine (2X50mL). The organic layer was dried and concentrated to provide 25'-[2,2,2-trifluoro-liS'-(4- fluorophenyl)ethylamino]-4-methylsulfanylbutyric acid (1.15 g) as solid.
With sodium hydrogencarbonate In dichloromethane at 0 - 20℃; for 24h;
85%
With sodium hydrogencarbonate In dichloromethane; water at 5 - 20℃; for 24h;
4.1.1. Methyl 2-(2-(2-acetamidophenyl)-2-oxoacetamido)acetate (2a)
General procedure: To a stirred solution of the N-acetylisatin (0.50 g, 2.6 mmol) in dichloromethane (10 mL) was added a mixture of glycine methyl ester hydrochloride (1.10 g, 8.9 mmol) and saturated sodium hydrogen carbonate solution (3 mL) in water (7 mL) at 5 °C. The reaction mixture was warmed to room temperature and stirred for 24 h. The organic layer was diluted with dichloromethane (20 mL) and extracted with aqueous hydrochloric acid (0.5 M, 15 mL) and water (20 mL). The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by gravity column chromatography over silica with dichloromethane to give the title compound 2a as an off-white solid (0.45 g, 62%).
With triethylamine; In acetonitrile; at 115℃; for 0.25h;Microwave irradiation; Sealed vessel; Inert atmosphere;
Example 22 (S)-N-[5-((S)-1,2-Dihydroxy-ethyl)-pyrazin-2-yl]-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyramide A mixture of (S)-2-amino-4-methylsulfanyl-butyric acid methyl ester hydrochloride (Aldrich, 199 mg, 1 mmol) and <strong>[346603-68-7]2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester</strong> (prepared as in Example 1, 297 mg, 1 mmol) in acetonitrile (5 mL) and triethylamine (280 muL, 2 mmol) was placed in a microwave reaction vessel and sealed. The reaction mixture was then placed in a microwave reactor and heated at 115 C. for 15 min. After this time, the reaction mixture was cooled and concentrated with silica gel (2 g) in vacuo. The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes) to afford (S)-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (137 mg, 40%) as a colorless viscous oil: HR-ES(+) m/e calcd for C15H16NO3SF3 [M+H]+ 348.0876, observed 348.0874; 1H NMR (400 MHz, CHLOROFORM-d) delta 8.07 (d, J=7.46 Hz, 1H), 7.83 (d, J=7.67 Hz, 1H), 7.64 (t, J=7.67 Hz, 1H), 5.25 (dd, J=4.69, 10.44 Hz, 1H), 4.79 (d, J=17.47 Hz, 1H), 4.53 (d, J=17.47 Hz, 1H), 3.77 (s, 3H), 2.38-2.62 (m, 3H), 2.16-2.31 (m, 1H), 2.13 (s, 3H).
General procedure: To a stirred suspension of theophyline-7-acetic acid (200 mg, 1 eq) and L-aminoacid methyl ester.HCl (1.05 eq) in CH2Cl2 (20 ml) was added N-ethyldiisopropylamine (1.1 eq). After 10 min the reaction became a clear solution and EDC (1.1 eq), and HOBt (1.1 eq) were added. The mixture was stirred overnight at r.t., then washed with water (2 x 20 ml) and sat. aq. NaHCO3 (20 ml). For hygroscopic compounds (2a-b, 2e, 2h), was done a back-extraction of the combined aqueous layers with CH2Cl2:MeOH = 10:1. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The product was purified by filtration through a pad of silica gel (EtOAc/MeOH = 4:1).
(2'S)-2,6-bis<(1-methoxycarbonyl-3-thiomethyl)propylaminocarbonyl>pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In dichloromethane at 20℃; for 24h; Inert atmosphere;
3.3. Peptide Coupling Method
General procedure: Amino acid methyl ester (as free amine or HCl salt, 0.2-1.8 g, 2 eq.) pyridine-2,6-dicarboxylic acid (5, 1 eq.) and N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 2 eq.) were dissolved in DCM or chloroform (20-40 mL) and triethylamine or DIPEA (2 eq. for free amine, 4 eq. for HCl salt) was added. The reaction mixture was stirred at room temperature for 22-48 h while monitored by TLC. Additional DCM or chloroform (10-20 mL) was added and the solution washed with equivalent volumes of water, 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and brine. The organic phase was dried over MgSO4 then concentrated in vacuo to give the crude product (generally a yellow oil) which was purified by column chromatography.
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-3-methylthio)propyl)amino) methyl)-2-furyl)-4-quinazolinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49.4%
Stage #1: (S)-methyl 2-amino-4-(methylthio)butanoate hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h;
Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 48h;
Stage #3: With water; sodium hydroxide In tetrahydrofuran for 2h;
28 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-3-methylthio)propyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS26)
Example 28 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-3-methylthio)propyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS26) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of methionine methyl ester hydrochloride (0.40 g, 2 mmol) and diisopropylethylamine (0.26 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74 g, 3.5 mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 2 h, and then adjusted to PH˜7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a brown solid (0.30 g, 49.4%), i.e. the compound of Number MS26. m.p.: 131-133° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.66 (s, 2H), 3.59 (t, 1H), 2.60 (t, 2H), 2.14 (s, 3H), 1.91 (m, 2H); ESI-MS m/z: 607[M+H]+.
General procedure: N-Hydroxybenzotriazole (0.48-0.54 g, 3.5-4.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.67-0.77 g, 3.5-4.0 mmol) were added to a cooled solution of <strong>[1405-86-3]glycyrrhizin</strong>ic acid (0.82 g, 1 mmol) in 15-20 mL of DMF. The reaction mixture was stirred for 1 h at 0-5C, then 5-6 h at 22-24C. Then hydrochloride of amino acid ester (3.5-4.0 mmol) and N-ethylmorpholine (0.6-0.8 mL, 5.0-7.0 mmol) were added and the reaction mixture was kept for 24 h at 22-24C. Next, the reaction mixture was diluted with cold water and acidified with citric acid to pH ~ 3-4. The precipitate was filtered off, washed with water, dried, and re-precipitated from aqueous ethanol.
methyl (2S)-4-(methylsulfanyl)-2-[2-(methylsulfanyl)benzoyl]amino}butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
General procedure: A solution of triethylamine (1.60mL, 11.50mmol) in CH2Cl2 (5mL) was added dropwise to a stirred suspension of the corresponding amino acid methyl ester hydrochloride (3.75mmol) in CH2Cl2 (10mL) at -5C under an argon atmosphere. The reaction mixture was stirred for 30min. Then, a solution of <strong>[1442-03-1]2-(methylsulfanyl)benzoyl chloride</strong> (0.70g, 3.75mmol) in CH2Cl2 (10mL) was added dropwise. The resulting mixture was stirred at 0-5C for 1h and poured into distilled water (75mL). The organic layer was separated, sequentially washed with a dilute aqueous solution of hydrochloric acid, saturated aqueous solution of NaHCO3, and water, and dried over anhydrous Na2SO4. The solvent was removed under vacuum. The resulting residue was purified by column chromatography on silica gel (eluent: CH2Cl2-MeOH (100:1) (3a,b), EtOAc-acetone (1:2) (3c)) to give ligands 3a-c as white crystalline solids. In the case of histidine derivative 3c, the product of double acylation (compound 4) was also isolated.
methyl (2S)-2-(1-imino-3-oxo-1,3-dihydro-2H-isoindol-2-yl)-4-(methylsulfanyl)butanoate[ No CAS ]
methyl (2S)-2-[[(2-cyanophenyl)carbonyl]amino]-4-(methylsulfanyl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 83%
2: 7%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃;
General procedure A for the synthesisof compounds 8a-8i and 9a-9h
General procedure: To a suspension of 0.735 g 2-cyanobenzoic acid (5,5 mmol) in 50 cm3 DCM 1.4 cm3 TEA (10 mmol), methylester L-a-amino acid hydrochloride (5 mmol), and 0.675 gHOBt (5 mmol) were added. The mixture was stirred at0 C and 0.970 g EDCI (5.05 mmol) was added. Then, themixture was stirred at room temperature overnight. Theprecipitate was filtered off and the filtrate was evaporatedunder reduced pressure. The residue was diluted with50 cm3 DCM, washed with solution of 0.1 N HCl(3 9 25 cm3), 15 cm3 brine, then dried over MgSO4 andconcentrated under reduced pressure. The residue waspurified by flash column chromatography (gradient elutionof ethyl acetate/petroleum ether 0:100-70:30) to afford thedesired products as separate fractions of 9a-9h, then 8a-8i.
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