* 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.
With sodium tetrahydroborate; sodium hydrogencarbonate In ethanol; water at 15℃; Heating / reflux
To a mixture of (L)-leucine methyl ester HCl salt (254 g, 1.4 mol), NaHCO3, (118 g, 1.4 mol, 1.0 equiv.) and water (1.8 L) in EtOH (1.8 L) at 5° C. was added NaBH4, (159 g, 4.2 mol, 3.0 equiv.) in portions at such a rate that the reaction temp. did not exceed 15° C. (approximately 70 min). After the addition of NaBH4 was complete, the ice bath was removed and the reaction was heated to the reflux temp. overnight. The resulting mixture was cooled to room temp. with the aid of an ice bath. The resulting slurry was filtered and the solids were washed with EtOH (750 mL). The combined filtrates were concentrated to approximately 950 mL under reduced pressure. The residue was diluted with EtOAc (2.5 L) and extracted with a 1N NaOH solution (2.x.1 L). The aqueous layer was back-extracted with EtOAc (2.x.750 mL). The combined organics were dried (MgSO4) and concentrated under reduced pressure to yield (1S)-1-(hydroxymethyl)-3-methylbutylamine as a pale yellow oil (112 g, 65percent): 1H NMR (CDCl3) δ0.88-0.93 (m, 6H), 1.17 (t, J=7.7 Hz, 2H), 1.68-1.80 (m, 2H), 1.82 (br s, 2H), 2.86-2.91 (m, 1H), 3.22 (dd, J=10.7, 8.1 Hz 1H), 3.56, (dd, J=10.3, 3.6 Hz, 1H)
Stage #1: With sodium carbonate In water Stage #2: With CuZn0.3Mg0.1AlO(x); hydrogen In ethanol at 80℃; for 10 h; Autoclave
General procedure: The activity of catalyst for hydrogenation of R-phenylglycinemethyl ester was tested in a 0.5 L stainless steelautoclave under stirring at a speed of 500rpm. After 1g catalyst (20–40 mesh) was put in the reactor, the reactorwas swept with H2 five times to flush out air. Thenthe catalyst was reduced at 1MPa H2and 250 °C for 4h. After the autoclave was cooled in H2atmosphere to roomtemperature, 1.5g R-phenylglycine methyl esters (R-p-m)diluted in 150 mL ethanol was added (R-p-m/Cat = 1.5,wt.). The typical reaction conditions were at 5 MPa of H2 and 80 °C for 10 h. After the reaction was ended, theautoclave was cooled in H2atmosphere to room temperature.Then solid catalyst was separated by centrifugation.The product was purified by column chromatography on silica gel with ethyl acetate/methanol (3/2, v/v) as the eluent.Thus we obtained the light yellow powder product byrotary evaporation. Reactants and products were analyzedby High Performance Liquid Chromatograph (HPLC, Agilent1260 Infinity) equipped with an ultraviolet detector anda column (Eclipse XDB-C18, 150 × 4.6mm, 5mm particlesize), then the conversion of R-phenylglycine methyl ester(X), yield (Y) and chemoselectivity to R-phenylglycinol (S)were calculated [18, 19], in which the yield is the LC yield.And the ee value of products was determined by HPLCequipped with an ultraviolet detector (wavelength 258nm)and a chiral column (CHIRALPAK AY-H, 250 × 4.6mm,5m particle size) [19].
Reference：
[1] European Journal of Medicinal Chemistry, 1985, vol. 20, # 6, p. 509 - 512
[2] Chemistry - An Asian Journal, 2011, vol. 6, # 6, p. 1321 - 1324
8
[ 24424-99-5 ]
[ 7517-19-3 ]
[ 63096-02-6 ]
Yield
Reaction Conditions
Operation in experiment
96%
Stage #1: With potassium carbonate In water for 1 h; Stage #2: With guanidine hydrochloride In ethanol at 35 - 40℃; for 0.366667 h;
General procedure: Amino acid ester hydrochlorides and K2CO3 were suspended in water and stirred for one hour. The free amino acid esters were extracted with CH2Cl2 and dried with MgSO4. Evaporation of CH2Cl2 under reduced pressure gives free amino acid ester which should be immediately used for N-Boc protection. The free amino acid esters (1 mmol) in 1mL ethanol was added to a solution of di-tert-butyl dicarbonate (1.2 mmol) and guanidine hydrochloride (15 molpercent) in ethanol (1 mL) at 35-40 °C and stirred for appropriate time. The work up was similar to same procedure for amines.
60%
Stage #1: With potassium carbonate In water at 20℃; for 0.166667 h; Stage #2: With guanidine hydrochloride In ethanol at 35 - 40℃; for 1 h;
According to F. Jahani, M. Tajbakhsh, H. Golchoubian, S. Khaksar, Guanidine hydrochloride as an organocatalyst for N-Boc protection of amino Gross, Tetrahedron Letters 52 (2011) 1260–1264. l‑Leucine methylester hydrochloride (1 g, 5.5 mmol) wasdissolved in water (10 mL) with K2CO3 (0.83 g, 6.05 mmol) and stirred at RT for 10 minutes. Reaction mixture was washed with dichloromethane (3 x 10 mL) and collected organic phase was dried over Na2SO4. The solvent was removed by distillation and L-Leucine methylester with liberated amino group was isolated as clear oil. L-Leucine methylester was dissolved in absolute ethanol (10 mL) and heated to 35-40 °C. Solution of di-tert-butyl dicarbonate (1.44 g, 6.6 mmol) and guanidine hydrochloride (0.078 g, 0.83 mmol) was added and reaction mixture was stirred for 60 minutes. Ethanol was then removed by distillation and reaction mixture was suspended in ethyl acetate (20 mL). Undissolved catalyst was removed by filtration and residual solution was washed with citric acid 5percent in water (3 x 15 mL), hydrochloric acid 10percent in water (4 x 15 mL), dried over Na2SO4 and the volume reduced to colourless oil. The crude product was purified via column chromatography (silica gel 70 g, n‑hexane/ethyl acetate (6:1)). The product was obtained in yield 60 percent. (S)-Methyl 2-((tert-butoxycarbonyl)amino)-4-methylpentanoate 8a. Colourless oil; yield 60 percent. 1H NMR (400 MHz, CDCl3‑d1): δ 5.02-4.93 (1H, m, NH), 4.40-4.30 (1H, m, NH‑CH), 3.76 (3H, s, O‑CH3), 1.80-1.50 (3H, m, NH‑CH‑CH2‑CH-(CH3)2, 1.47 (9H, s, C(CH3)3), 1.03‑0.94 (6H, m, CH-(CH3)2). 13C NMR (100.79 MHz, CDCl3‑d1): δ 174.2, 156.2, 146.8, 86.1, 78.7, 52.4, 52.3, 28.8, 27.5, 24.2, 22.2, 20.9. CNH Analysis: Calc. for C12H23NO4 (245.32): C, 58.75; H, 9.45; N, 5.71. Found: C, 58.69±0.01; H 9.41±0.01; N, 5.67±0.01. HRMS: m/z calc. for C12H23NO4: 268.15193 [M+Na]+; found: 268.15196 [M+Na]+.
Reference：
[1] Tetrahedron Letters, 2011, vol. 52, # 12, p. 1260 - 1264
[2] Chemistry - A European Journal, 2013, vol. 19, # 12, p. 3817 - 3821
[3] Journal of Organic Chemistry, 1995, vol. 60, # 24, p. 8074 - 8080
[4] Chemical Biology and Drug Design, 2012, vol. 79, # 2, p. 216 - 222
[5] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 142 - 158
[6] Journal of Organic Chemistry, 2014, vol. 79, # 17, p. 8422 - 8427
9
[ 7517-19-3 ]
[ 63096-02-6 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 17, p. 6599 - 6601
[2] Organic and Biomolecular Chemistry, 2003, vol. 1, # 9, p. 1480 - 1485
10
[ 58632-95-4 ]
[ 7517-19-3 ]
[ 63096-02-6 ]
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 23, p. 8468 - 8474
11
[ 67-56-1 ]
[ 61-90-5 ]
[ 7517-19-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: for 1 h; Cooling with ice Stage #2: at 20 - 66℃; for 6.5 h;
Under ice bath, 100 ml round-bottom flask was added with 60 ml of methanol, and then slowly added with 4 ml of SOCl2 through constant pressure dropping funnel (with a drying tube on the top), and NaOH solution was used to absorb exhaust. After stirring for 1 h, 8 mmol of L-leucine was added and stirred at room temperature for 30 min, and then refluxed at 66° C. for 6 h. The reaction was tracked by TLC until the raw material disappears, with a solution of 2percent ninhydrin in ethanol as chromogenic reagent. The solvent was evaporated out to obtain L-leucine methyl ester hydrochloride. Yield: 100percent.
96%
Stage #1: at -13 - -10℃; for 2 h; Stage #2: at 50℃; for 3 h;
Take 115mL methanol, added to 250mL three-necked flask, Cool to -13 ° C in a low temperature stirred reaction bath (Reaction should ensure that the environment is anhydrous, In the three-necked flask branch pipe connected to the drying tube; The reaction generates HCl and SO2 gases, To use lye absorption device), Then 9.5 mL (0.131 mol) of freshly distilled SOCl2 was slowly added dropwise, When dropping the reaction temperature is controlled below -10° C , To be added dropwise after completion, continue to react at -10° C 2h, rise to room temperature, 15.4 g (0.118 mol) of leucine was added, and the temperature was raised to 50 ° C. for 3 hours, followed by TLC (With methanol and methylene chloride 1: 1 mixture as a developer, To prevent tailing, drop a drop of diethylamine per ml) Until the end of the reaction (about 3h) Stop the reaction. After the solvent was distilled off by rotary evaporation, A large amount of white solid appears. The product was purified by recrystallization from methanol to give pure leucine methyl ester hydrochloride in 96percent yield.
95%
at -5 - 20℃;
General procedure: A suspension of L-amino acid (50mmol) in methanol (50mL) was stirred under ice cold conditions. Thionyl chloride (5mL) was slowly dropped to the solution at−5°C. Then, the mixture was allowed to slowly warm to room temperature while being stirred. The reaction was monitored by TLC (N-butanol: water: acetic acid=4:1:1). When the reaction was completed, the solvent was evaporated under reduced pressure to afford the crude product, which was recrystallized from methanol/ether to give a white solid.
86%
With thionyl chloride In methanol at -15 - 20℃;
To a suspension of (L)-leucine, (315 g, 2.4 mol) in MeOH (3.2 L) at -15° C. was added SOCl2 (315 mL, 4.32 mol, 1.8 equiv.) dropwise at such a rate that the temp. of the reaction did not exceed 5° C. After the addition was complete, the reaction mixture was allowed to warm to room temp. and was stirred overnight. The resulting mixture was concentrated under reduced pressure and Et2O (3 L) was slowly added to the residue to produce a precipitate. The mixture was cooled with an ice bath, then treated with additional MeOH (3 L) relatively rapidly. After 1 h at 0° C., the crystals were collected and dried to give (L)-leucine methyl ester HCl salt as a white crystalline solid (394 g, 86percent): mp 147-149° C.; 1H-NMR (CD3OD) δ0.78-0.98 (m, 6 h), 1.58-1.72 (m, 3H), 3.76 (g, 3H), 3.92 (t, J=7.3 Hz, 1H)
72.2%
at -17 - 20℃; for 18 h;
To a suspension of l-leusine 26 (1.12 g, 8.54 mmol) in MeOH (9 mL)at -17 °C was slowly added thionylchloride (2.2 mL, 30.3 mmol) with stirring. Then, the mixture was brought tor.t. and stirred for further 18 h. The solution was concentrated in vacuo to give a white solid. The solid was re-crystalized to yield methylester hydrochloride salt 27 (1.12 g, 6.17 mmol72.2 percent).
56%
at 20℃; Cooling with ice
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] Patent: US2014/206741, 2014, A1, . Location in patent: Paragraph 0121
[2] Journal of Organic Chemistry, 2003, vol. 68, # 12, p. 5006 - 5008
[3] Synthetic Communications, 2010, vol. 40, # 8, p. 1161 - 1179
[4] Bulletin des Societes Chimiques Belges, 1991, vol. 100, # 1, p. 63 - 77
[5] Chemical Biology and Drug Design, 2012, vol. 79, # 2, p. 216 - 222
[6] Journal of the American Chemical Society, 2017, vol. 139, # 40, p. 14077 - 14089
[7] Organic Preparations and Procedures International, 2001, vol. 33, # 4, p. 341 - 349
[8] Organic Preparations and Procedures International, 2002, vol. 34, # 1, p. 87 - 94
[9] Chemistry - A European Journal, 2013, vol. 19, # 49, p. 16615 - 16624
[10] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2006, vol. 45, # 8, p. 1942 - 1944
[11] Synthetic Communications, 2008, vol. 38, # 5, p. 684 - 696
[12] Patent: CN105061236, 2016, B, . Location in patent: Paragraph 0034; 0039-0041
[13] Journal of Organic Chemistry, 1989, vol. 54, # 4, p. 937 - 947
[14] European Journal of Medicinal Chemistry, 2016, vol. 112, p. 196 - 208
[15] Journal of the Chemical Society, Perkin Transactions 2, 2001, # 9, p. 1863 - 1868
[16] Patent: US6353006, 2002, B1, . Location in patent: Page column 30
[17] Journal of Organometallic Chemistry, 1986, vol. 317, p. 93 - 104
[18] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2007, vol. 46, # 7, p. 1137 - 1142
[19] Synthetic Communications, 2008, vol. 38, # 23, p. 4107 - 4115
[20] Journal of Organic Chemistry, 2012, vol. 77, # 1, p. 317 - 331
[21] Biomedicine and Pharmacotherapy, 2017, vol. 88, p. 1163 - 1172
[22] Journal of Chemical Research, 2009, # 11, p. 665 - 667
[23] Tetrahedron Letters, 2014, vol. 55, # 32, p. 4445 - 4447
[24] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 20, p. 5000 - 5006
[25] New Journal of Chemistry, 2017, vol. 41, # 23, p. 14723 - 14729
[26] Tetrahedron, 1990, vol. 46, # 15, p. 5325 - 5332
[27] Tetrahedron Letters, 1980, vol. 21, p. 2077 - 2080
[28] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 6, p. 1629 - 1632
[29] Heterocycles, 1991, vol. 32, # 10, p. 1879 - 1895
[30] European Journal of Medicinal Chemistry, 1985, vol. 20, # 6, p. 509 - 512
[31] Phytochemistry (Elsevier), 1988, vol. 27, # 1, p. 77 - 84
[32] Journal of Physical Chemistry, 1994, vol. 98, # 27, p. 6862 - 6864
[33] Journal of Organometallic Chemistry, 1987, vol. 326, p. 289 - 298
[34] Journal of Organic Chemistry, 1997, vol. 62, # 20, p. 6862 - 6869
[35] Synthetic Communications, 1999, vol. 29, # 17, p. 3039 - 3049
[36] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1999, vol. 38, # 4, p. 505 - 507
[37] Tetrahedron Asymmetry, 2002, vol. 13, # 18, p. 2053 - 2059
[38] Canadian Journal of Chemistry, 2005, vol. 83, # 8, p. 1164 - 1170
[39] Journal of Medicinal Chemistry, 2006, vol. 49, # 24, p. 7215 - 7226
[40] Tetrahedron, 2007, vol. 63, # 31, p. 7334 - 7348
[41] Journal of Organic Chemistry, 2007, vol. 72, # 24, p. 9283 - 9290
[42] Chemical Communications, 2006, # 29, p. 3081 - 3083
[43] Acta Poloniae Pharmaceutica - Drug Research, 2007, vol. 64, # 6, p. 509 - 516
[44] Tetrahedron Asymmetry, 2009, vol. 20, # 5, p. 616 - 620
[45] Chemistry - A European Journal, 2008, vol. 14, # 35, p. 10888 - 10891
[46] European Journal of Organic Chemistry, 2008, # 14, p. 2423 - 2429
[47] Synlett, 2009, # 8, p. 1227 - 1232
[48] European Journal of Medicinal Chemistry, 2009, vol. 44, # 7, p. 2796 - 2806
[49] Zeitschrift fur Anorganische und Allgemeine Chemie, 2010, vol. 636, # 1, p. 236 - 241
[50] Journal of Chemical Research, 2011, vol. 35, # 1, p. 47 - 50
[51] Synthetic Communications, 2011, vol. 41, # 23, p. 3485 - 3490
[52] Letters in Organic Chemistry, 2011, vol. 8, # 5, p. 358 - 360
[53] Chemistry - An Asian Journal, 2011, vol. 6, # 1, p. 189 - 197
[54] Archiv der Pharmazie, 2011, vol. 344, # 8, p. 494 - 504
[55] Letters in Organic Chemistry, 2011, vol. 8, # 3, p. 210 - 215
[56] Asian Journal of Chemistry, 2012, vol. 24, # 3, p. 1227 - 1236
[57] Journal of Enzyme Inhibition and Medicinal Chemistry, 2012, vol. 27, # 2, p. 302 - 310
[58] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 12, p. 3807 - 3815
[59] Journal of Chemical Research, 2012, vol. 36, # 4, p. 206 - 209
[60] Biomacromolecules, 2012, vol. 13, # 8, p. 2446 - 2455
[61] Medicinal Chemistry Research, 2012, vol. 21, # 11, p. 3361 - 3368
[62] Organic and Biomolecular Chemistry, 2013, vol. 11, # 7, p. 1143 - 1148
[63] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 7, p. 1621 - 1627
[64] European Journal of Medicinal Chemistry, 2016, vol. 108, p. 21 - 27
[65] Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, vol. 28, # 4, p. 717 - 726
[66] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 5, p. 1067 - 1070
[67] RSC Advances, 2013, vol. 3, # 40, p. 18332 - 18338
[68] RSC Advances, 2014, vol. 4, # 24, p. 12275 - 12286
[69] Applied Organometallic Chemistry, 2014, vol. 28, # 7, p. 545 - 551
[70] Organic and Biomolecular Chemistry, 2014, vol. 12, # 41, p. 8318 - 8324
[71] Journal of Medicinal Chemistry, 2015, vol. 58, # 7, p. 3144 - 3155
[72] Oriental Journal of Chemistry, 2015, vol. 31, # 1, p. 417 - 421
[73] Medicinal Chemistry Research, 2015, vol. 24, # 7, p. 2825 - 2837
[74] Journal of Polymer Science, Part A: Polymer Chemistry, 2016, vol. 54, # 8, p. 1065 - 1077
[75] Tetrahedron, 2016, vol. 72, # 51, p. 8486 - 8492
[76] Patent: CN103864642, 2016, B, . Location in patent: Paragraph 0019-0021
[77] Organic Syntheses, 1988, vol. 66, p. 151 - 151
12
[ 61-90-5 ]
[ 7517-19-3 ]
Yield
Reaction Conditions
Operation in experiment
98%
With thionyl chloride In methanol
(1) Similarly to Example 20 and starting from 6.56 g (50.0 mmol) of D,L-leucine, 50 ml of methanol and 13.0 ml (180 mmol) of thionyl chloride, 8.93 g (yield: 98percent) of D,L-leucine methyl ester hydrochloride was obtained as a white powder. 1H-NMR (300 MHz, D2O); δ: 4.17 (1H, t, J=6.8 Hz), 3.87 (3H, s), 1.90 (1H, m), 1.78 (2H, m), 00 (3H, d, J=6.0 Hz), 0.99 (3H, d, J=6.0 Hz).
Stage #1: With ammonia In methanol at 50℃; for 48 h; Sealed tube Stage #2: With hydrogenchloride In 1,4-dioxaneSonication
This is a modification of a previously published procedure.11 This compound is commercially available from Alfa Aesar. To a glass pressure tube containing compound 9e (1.0 g, 5.5 mmol) in MeOH (10 mL) was added 7N NH3 in MeOH (7.9 mL,55 mmol). Reaction was sealed and heated to 50 °C for 2d. Compound was then concentrated in vacuo. Crude product was converted to an HCl salt by suspensionin 1,4-dioxane (10 mL), followed by addition of 4N HCl in 1,4-dioxane (1.7 mL, 6.8 mmol). Mixture was sonicated to help mix. Solvents and excess HCl were removed by rotovap, using 1,4-dioxane (10 mL) to chase away excess HCl. Product was purified by recrystallization from hot isopropyl alcohol, allowing crystals to form slowly at rt. Placed recrystallized solid under high vacuum to remove residual solvent. Yield: 0.55 g (60percent). mp 216-218 °C, [α]D24 +12.0° (c 0.50, MeOH), HPLC Purity (200 nm): >99percent with <0.5percent parent Leu evident. 1H NMR ((CD3)2SO) δ 8.29 (br s, 3H), 7.96 (s, 1H), 7.48 (s, 1H), 3.66 (m, 1H), 1.67 (m, 1H), 1.56 (m, 2H), 0.92 (d, J = 3, 3H), 0.90 (d, J = 3, 3H).
General procedure: To pyrazine-2-carboxylic acid (1mmol) in absolute THF (30mL) at 0C was added DCC (1mmol) and HOBt (1.2mmol), and the mixture was reacted for 40min. Then methyl l-phenylalaninate hydrochloride (1mmol) and 4-Methylmorpholine (NMM) were added and the react was performed until TLC showed the starting materials disappeared (12h). After the reaction finished, the resulting solid was filtered and the solvent was removed under vacuum. The white solid was dissolved in 50mL ethyl acetate and washed with 5% NaHCO3, 10% citric acid, 5% NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and evaporated to provide methyl ester 6a as colorless oil 0.28g (98% yield); mp: 152-155C. 1H NMR (CDCl3, 400MHz) 3.26 (m, 2H), 3.75 (s, 3H), 5.09 (m, 1H), 7.15-7.32 (m, 5H), 8.23 (d, 1H), 8.52 (d, 1H), 8.74 (d, 1H), 9.37 (s, 1H).
With triethylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 4h;
General procedure: To a solution of l-amino acid methyl ester hydrochloride in dichloromethane, triethylamine (1 equiv) and N-Boc-l-amino acid were added at -15 C, and DCC was added as a dichloromethane solution at 0 C. The reaction mixture was stirred at 0 C for 1 h. Then the solution was stirred at room temperature for 3 h. The dicyclohexylurea was removed by filtration from the reaction mixture. The solution was washed with 5% NaHCO3, 1 M HCl, and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated. The product was purified by silica gel column chromatography.
Stage #1: methyl (L)-leucinate hydrochloride With potassium carbonate In water for 1h;
Stage #2: di-<i>tert</i>-butyl dicarbonate With guanidine hydrochloride In ethanol at 35 - 40℃; for 0.366667h;
2.5. General procedure for N-tert-butoxycarbonylation of aminoacid esters (Table 2, entries 13-15):
General procedure: Amino acid ester hydrochlorides and K2CO3 were suspended in water and stirred for one hour. The free amino acid esters were extracted with CH2Cl2 and dried with MgSO4. Evaporation of CH2Cl2 under reduced pressure gives free amino acid ester which should be immediately used for N-Boc protection. The free amino acid esters (1 mmol) in 1mL ethanol was added to a solution of di-tert-butyl dicarbonate (1.2 mmol) and guanidine hydrochloride (15 mol%) in ethanol (1 mL) at 35-40 °C and stirred for appropriate time. The work up was similar to same procedure for amines.
95%
With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 12h;
93%
With sodium hydrogencarbonate In 1,4-dioxane for 18h; Ambient temperature;
75%
With triethylamine In tetrahydrofuran at 20℃; for 24h;
60%
Stage #1: methyl (L)-leucinate hydrochloride With potassium carbonate In water at 20℃; for 0.166667h;
Stage #2: di-<i>tert</i>-butyl dicarbonate With guanidine hydrochloride In ethanol at 35 - 40℃; for 1h;
1.2.1.2 General procedures for protecting amino group
According to F. Jahani, M. Tajbakhsh, H. Golchoubian, S. Khaksar, Guanidine hydrochloride as an organocatalyst for N-Boc protection of amino Gross, Tetrahedron Letters 52 (2011) 1260-1264. l-Leucine methylester hydrochloride (1 g, 5.5 mmol) wasdissolved in water (10 mL) with K2CO3 (0.83 g, 6.05 mmol) and stirred at RT for 10 minutes. Reaction mixture was washed with dichloromethane (3 x 10 mL) and collected organic phase was dried over Na2SO4. The solvent was removed by distillation and L-Leucine methylester with liberated amino group was isolated as clear oil. L-Leucine methylester was dissolved in absolute ethanol (10 mL) and heated to 35-40 °C. Solution of di-tert-butyl dicarbonate (1.44 g, 6.6 mmol) and guanidine hydrochloride (0.078 g, 0.83 mmol) was added and reaction mixture was stirred for 60 minutes. Ethanol was then removed by distillation and reaction mixture was suspended in ethyl acetate (20 mL). Undissolved catalyst was removed by filtration and residual solution was washed with citric acid 5% in water (3 x 15 mL), hydrochloric acid 10% in water (4 x 15 mL), dried over Na2SO4 and the volume reduced to colourless oil. The crude product was purified via column chromatography (silica gel 70 g, n-hexane/ethyl acetate (6:1)). The product was obtained in yield 60 %. (S)-Methyl 2-((tert-butoxycarbonyl)amino)-4-methylpentanoate 8a. Colourless oil; yield 60 %. 1H NMR (400 MHz, CDCl3-d1): δ 5.02-4.93 (1H, m, NH), 4.40-4.30 (1H, m, NH-CH), 3.76 (3H, s, O-CH3), 1.80-1.50 (3H, m, NH-CH-CH2-CH-(CH3)2, 1.47 (9H, s, C(CH3)3), 1.03-0.94 (6H, m, CH-(CH3)2). 13C NMR (100.79 MHz, CDCl3-d1): δ 174.2, 156.2, 146.8, 86.1, 78.7, 52.4, 52.3, 28.8, 27.5, 24.2, 22.2, 20.9. CNH Analysis: Calc. for C12H23NO4 (245.32): C, 58.75; H, 9.45; N, 5.71. Found: C, 58.69±0.01; H 9.41±0.01; N, 5.67±0.01. HRMS: m/z calc. for C12H23NO4: 268.15193 [M+Na]+; found: 268.15196 [M+Na]+.
With triethylamine In dichloromethane at 20℃; for 3h;
With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 20h;
(S)-5-amino-4-isobutyl-2,7-dimethyloctan-4-ol ((S)-L*)
The procedure was according to theprevious report29. A solution of Boc2O (8.73 g, 40 mmol, 1.0 equiv) in 1,4-dioxane (40 mL) wasadded to a solution of Methyl L-leucinate hydrochloride (7.99 g, 44 mmol, 1.1 equiv) and NaHCO3(10.08 g, 120 mmol, 3.0 equiv) in water (160 mL) at rt. The mixture was stirred at rt for 20 hr andthen extracted with DCM. The combined organic layers were dried over Na2SO4, filtered andconcentrated under reduced pressure. Silica gel chromatography (hexanes/EtOAc = 10:1) affordedmethyl (tert-butoxycarbonyl)-L-leucinate as colorless oil.Under N2 atmosphere, methyl (tert-butoxycarbonyl)-L-leucinate (1.96 g, 8.0 mol) was dissolved inEt2O (20 mL). The solution was cooled to 0 °C, and isobutyl magnesium bromide solution (20 mL,2.0 M in Et2O, 40 mmol, 5.0 equiv) was added dropwise over 15 min. The resulting mixture waswarmed to rt and stirred for 24 hr at 30 oC. Completion of the reaction was monitored by TLC. Thesolution was cooled to 0 °C again and carefully quenched with a saturated aqueous solution ofNH4Cl. The mixture was extracted with Et2O and washed with brine, dried over Na2SO4, filtered,and concentrated under reduced pressure to give the crude product. The crude material waspurified by flash column chromatography (petroleum ether/EtOAc = 50:1) to provide tert-butyl (S)-(5-hydroxy-5-isobutyl-2,7-dimethyloctan-4-yl)carbamate as a yellow oil in 32% yield (0.84 g).CF3COOH (1.5 mL, about 8.0 equiv) was added to a solution of tert-butyl (S)-(5-hydroxy-5-isobutyl-2,7-dimethyloctan-4-yl)carbamate (0.84 g, 2.6 mmol, 1.0 equiv) in DCM (10 mL), and the mixturewas stirred at rt. Completion of the reaction was monitored by TLC. The solution was cooled to0 °C, and saturated aqueous NaHCO3 was added carefully. The mixture was extracted with Et2Oand washed with saturated aqueous K2CO3, brine, dried over Na2SO4, filtered, and concentratedunder reduced pressure to give the crude product. The purity of product was detected by NMR.The crude amino alcohol could be used directly if the purity was enough, or the product could bepurified by flash column chromatography (MeOH/DCM = 10:1) to provide (S)-5-amino-4-isobutyl-2,7-dimethyloctan-4-ol as a yellow liquid in 88% yield (0.52 g).1H NMR (500 MHz, CDCl3) δ 3.39 (br, 1H), 2.74 (dd, J = 11.1, 2.1 Hz, 1H), 1.90 - 1.81 (m, 1H),1.81 - 1.66 (m, 2H), 1.53 (dd, J = 14.7, 7.6 Hz, 1H), 1.30 (dd, J = 14.7, 4.6 Hz, 1H), 1.24 - 1.17 (m,2H), 1.15 - 1.10 (m, 2H), 1.01 - 0.88 (m, 18H); 13C NMR (126 MHz, CDCl3) δ 75.8, 55.1, 44.6, 44.0, 42.0, 25.6, 25.5, 25.3, 25.1, 24.6, 24.5, 23.8,23.8, 21.2;HRMS (ESI) calcd. for C14H31NNaO [M+Na]+ m/z 252.2298, found 252.2294;IR (neat, cm-1) 3402, 2952, 2868, 1467, 1366, 1167, 803;[α]D23 = -13.7 (c = 0.35, EtOAc).
This is a modification of a previously published procedure.11 This compound is commercially available from Alfa Aesar. To a glass pressure tube containing compound 9e (1.0 g, 5.5 mmol) in MeOH (10 mL) was added 7N NH3 in MeOH (7.9 mL,55 mmol). Reaction was sealed and heated to 50 C for 2d. Compound was then concentrated in vacuo. Crude product was converted to an HCl salt by suspensionin 1,4-dioxane (10 mL), followed by addition of 4N HCl in 1,4-dioxane (1.7 mL, 6.8 mmol). Mixture was sonicated to help mix. Solvents and excess HCl were removed by rotovap, using 1,4-dioxane (10 mL) to chase away excess HCl. Product was purified by recrystallization from hot isopropyl alcohol, allowing crystals to form slowly at rt. Placed recrystallized solid under high vacuum to remove residual solvent. Yield: 0.55 g (60%). mp 216-218 C, [alpha]D24 +12.0 (c 0.50, MeOH), HPLC Purity (200 nm): >99% with <0.5% parent Leu evident. 1H NMR ((CD3)2SO) delta 8.29 (br s, 3H), 7.96 (s, 1H), 7.48 (s, 1H), 3.66 (m, 1H), 1.67 (m, 1H), 1.56 (m, 2H), 0.92 (d, J = 3, 3H), 0.90 (d, J = 3, 3H).
Methyl 2-(2-((tert-butoxycarbonyl)amino)pent-4-ynamido)-4-methylpentanoate 1 To a solution of Boc-L-propargylglycine (26.65 g; 125 mmol) in dry DMF (170 mL) was added EDCI (29.23 g; 152.5 mmol) and HOBt (23.5 g; 122.5 mmol), and the reaction mixture was stirred at room temperature for 40 min (solution A). In a separate RB flask, (L) Leu-OMe hydrochloride (22.72 g; 125 mmol) in dry DMF (82 mL) kept at 0 C was treated with diisopropyl ethyl amine (DIEA) (64.62 g; 500 mmol) and the solution was stirred for 25 min (solution B). Solution B was added to solution A and the reaction mixture was stirred overnight at room temperature. The solvent was removed on the rotary evaporator and the residue was taken up in dichloromethane (DCM) (600 mL) and washed sequentially with saturated sodium bicarbonate (2 x 200 mL), 5% HCl (2 x 200 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, leaving a crude product which was purified using flash chromatography (silica gel; hexane/ethyl acetate 75:25) to give 1 as a white solid (38.12 g ; 89% yield); NMR (CDC13) delta 8.2 (s, 1H), 7.0 (s, 1H), 4.3 (m, 1H), 4.1 (m, 1H), 3.6 (s, 3H), 2.8 (s, 1H), 2.4 (m, 2H), 2.3 (m, 1H), 1.6 (m, 2H), 1.5 (m, 1H), 1.38 (s, 9H), 0.87 (d, 6H).
89%
General procedure: To a solution of N-protected amino acid derivative (1.0 eq) in dry DMF was added EDCI (1.22 eq), HOBt (eq) and the reaction mixture was stirred at room temperature for 40 min (Solution A). In the meantime, O-protected amino acid/amine (1.0 eq) in dry DMF kept at 0 C was added DIEA (4 eq) and stirred for 25 min (Solution B). After that Solution B was transferred to Solution A and stirred overnight at room temperature. The solvent was removed on the rotary evaporator and residue was taken up with ethyl acetate, washed sequentially with saturated sodium bicarbonate, 5% HCl and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed on the rotary evaporator. See individual experiments for details.
(S)-2-[4-Bromo-6-((S)-1-methoxycarbonyl-3-methyl-butylcarbamoyl)-pyridine-2-carbonyl]-amino}-4-methyl-pentanoic acid methyl ester[ No CAS ]
2-[4-bromo-6-(2-<i>tert</i>-butoxy-1-<i>tert</i>-butoxycarbonyl-ethylcarbamoyl)-pyridine-2-carbonyl]-amino}-4-methyl-pentanoic acid methyl ester[ No CAS ]
2-[4-bromo-6-(2-<i>tert</i>-butoxy-1-<i>tert</i>-butoxycarbonyl-ethylcarbamoyl)-pyridine-2-carbonyl]-amino}-3-<i>tert</i>-butoxy-propionic acid <i>tert</i>-butyl ester[ No CAS ]
With triethylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 4h;
General procedure: To a solution of l-amino acid methyl ester hydrochloride in dichloromethane, triethylamine (1 equiv) and N-Boc-l-amino acid were added at -15 C, and DCC was added as a dichloromethane solution at 0 C. The reaction mixture was stirred at 0 C for 1 h. Then the solution was stirred at room temperature for 3 h. The dicyclohexylurea was removed by filtration from the reaction mixture. The solution was washed with 5% NaHCO3, 1 M HCl, and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated. The product was purified by silica gel column chromatography.
(S)-2-(2,6-dibromopyridin-4-ylamino)-4-methylpentanoic acid methyl ester[ No CAS ]
(S)-2-(6-bromo-4-nitropyridin-2-ylamino)-4-methylpentanoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%; 10%
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol;Heating / reflux;
To a solution of 2, 6-dibromo-4-nitro pyridine (1.24 g, 4.3 mmol) (Chem. Ber, 122,589) in 2- propanol (40 mL) was added (S)-leucine methyl ester hydrochloride (2.4 g, 13.1 mmol) and DIISOPROPYLETHYLAMINE (3.39 g, 26.3 mmol). The reaction was refluxed overnight, cooled and the solvent removed in vacuo. The residual oil was chromatographed (15% hexane in diethyl ether) to give the title compound as a white solid (0.64 g, 38%) and also (S)-2- (6-bromo-4- nitro-pyridin-2-ylamino) -4-methyl-pentanoic acid methyl ester as a side product (0.18 g, 10%).
N-(8-quinolinoyl)-L-leucine methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
f) N-(8-quinolinoyl)-L-leucine Methyl Ester Following the procedure of Example 1(h), except substituting L-leucine methyl ester hydrochloride for N-[2-(cis-2,6-dimethyl-4-morpholino)thiazol-4-ylcarbonyl]hydrazide and 8-quinoline carboxylic acid for N-(4-pyridylmethoxycarbonyl)-L-leucine, the title compound was prepared as a white solid (0.637 g, 41percent). MS (ESI): 301.2 (M+H)+.
N-[(R)-(2-Oxo-thiazolidine-4-yl)carbonyl]-L-leucine methylester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; chloroform;
Preparation of N-[(R)-(2-oxo-thiazolidine-4-yl)carbonyl]-L-leucine (Compound 2f). To a solution of (R)-(-)-2-oxo-thiazolidine-4-carboxylic acid (1.49 g, 10.2 mmols), L-Leucine methylester hydrochloride (1.85 g, 10.2 mmols) and N-methylmorpholinee (1.12 ml, 10.2 mmols) in anhydrous THF (15 ml), cooled at 0 C., was added, under stirring, a solution of DCDI (2.10 g, 10.2 mmols) and HBT (13 mg, 1 mmols) in anhydrous THF (8 ml). After standing one night at room temperature, the N,N'-dicyclohexylures and the hydrochloride of N-methylmorpholines were separated by filtration and the filtered substance was concentrated at reduced pressure. The product was purified by dilution of the raw reside with CHCl3 (50 ml) and extraction with saturated NaHCO3 solution (20 ml*2) and saturated NaCl solution (30 ml). Drying of the organic phase reunited on Na2SO4 and the removal of the solvent at reduced pressure provided the N-[(R)-(2-Oxo-thiazolidine-4-yl)carbonyl]-L-leucine methylester which was crystallized with EtOAc: 1.94 g (69%); m.p. 125-6 C.; [a]D22=-79 (1, methanol); IR (CHCl3): 3412, 2956, 1734, 1678, 1515, 1434, 1338, 1158 cm-1; 1H-NMR (CHCl3): d 0.90 and 0.95 [two s, 6, CH2CH(CH3)2], 1.42-74 [m, 3, CH2CH(CH3)2], 3.37-3.85 [m, 2, CH2S and 3.63 (s, 3, OCH3)], 4.18-4.69 (two m, 2, aCH and ring CH), 7.16 (d, 1, NH, J=8 Hz). Calculated for C11H17N2O4S: C, 48.34; H, 6.27; N, 10.25. Found C, 48.29; H, 6.80; N, 10.22%.
4-acetyl-1-piperazinecarboxylic acid, (S)1-carboxy-2-phenylethyl ester[ No CAS ]
[ 623-72-3 ]
[ 7517-19-3 ]
[ 530-62-1 ]
4-acetyl-1-piperazinecarboxylic acid, [S-(R*,R*)]-2-[[1-(methoxycarbonyl)-3-methylbutyl]amino]-2-oxo-1-(phenylmethyl)ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium hydrogencarbonate; In tetrahydrofuran; ethyl acetate-dichloromethane; dichloromethane;
REFERENCE EXAMPLE 77 [S-(R*,R*)[-2-[(1-Carboxy-3-methylbutyl)amino]-1-oxo-1-(phenylmethyl)ethyl 4-acetyl-1-piperazinecarboxylate To a solution of 5.6 g 4-acetyl-1-piperazinecarboxylic acid, (S)1-carboxy-2-phenylethyl ester in 125 ml of tetrahydrofuran under argon is added 2.84 g of N,N-carbonyldiimidazole. The mixture is stirred at room temperature for 2.5 hours and 3.98 g of L-leucine methyl ester hydrochloride added. The mixture is stirred ovenight, filtered to removed solid and the filtrate concentrated to dryness. The residue is dissolved in 100 ml of dichloromethane and the solution washed with 50 ml of 10% hydrochloric acid, 50 ml of 10% sodium bicarbonate and dried (MgSO4) The solvent is removed to give 7.7 g of a white foam. Chromatography over silica gel with ethyl acetate-dichloromethane (1:1) as solvent and then with ethyl acetatemethanol (9:1) gives 7.6 g of 4-acetyl-1-piperazinecarboxylic acid, [S-(R*,R*)]-2-[[1-(methoxycarbonyl)-3-methylbutyl]amino]-2-oxo-1-(phenylmethyl)ethyl ester as a clear foam; [alpha]D26 -41+-1 (c, 1.262, CH3 OH).
3 EXAMPLE 3
EXAMPLE 3 A solution of 12 g (48 mM) N-carbobenzoxy-L-proline in 30 ml chloroform was mixed with a solution of 7.3 g (40 mM) L-leucine methyl ester hydrochloride in 50 ml chloroform neutralized with 4 g (40 mM) triethylamine. 3.3 g (48 mM) n-Propyl isonitrile was added to the mixture which was then held at 40°-50°C for 45 hours. The reaction mixture was eveporated in a vacuum, and the residue was taken up in 300 ml ethyl acetate. Undissolved triethylamine hydrochloride was filtered off, and the filtrate was washed sequentially with dilute hydrochloric acid, sodium bicarbonate solution, and water, and dried over desiccated sodium sulfate as in Example 1. Upon evaporation of the solvent and crystallization of the residue from ethyl acetate and petroleum ether, 9.1 g N-carbobenzoxy-L-prolyl-L-leucine methyl ester was obtained (61 percent yield, based on the L-leucine methyl ester hydrochloride). When recrystallized from ethyl acetate and petroleum ether, the compound melted at 73.5°-75.5°C and had a specific rotation of [α]D25 = - 68° (C = 1.5, in ethanol). Calculated for C20 H28 O5 N2: 63.81% C; 7.50% H; 7.44% N. Found: 63.70% C; 7.35% H; 7.49% N.
With 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h;
To a stirred solution of 27 (504 mg,3.47 mmol) in dry CH2Cl2 (5 mL) was added Boc-NMe-l-Leu-OH(958 mg, 3.91 mmol) and HCTU (2.17 g, 5.25 mmol). After the solution was cooledto 0 C, DIPEA (2.40 mL,14.1 mmol) was dropwise added. The solution was warmed to room temperature and allowed to stir for 2h. The reaction was quenched with 5% KHSO4 aq.and extracted with EtOAc (5 mL x2). The extract was washed with saturated aqueous NaHCO3 (5 mL), with water (5 mL), and with brine (5 mL x2),dried with Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatographyon silica-gel with hexane-EtOAc (2 : 1) to obtain 28 (1.06 g, 2.85 mmol, 82.0 %) as a colorless oil.1H-NMR (400MHz, CDCl3): dH 6.49 (br s, 1H), 4.47-4.41(m, 1H), 3.73 (s, 3H), 2.75 (s, 3H),1.68-1.49 (m, 6H), 1.49 (s, 9H), 0.95 (d, J = 6.9 Hz, 6H), 0.91 (d, J= 6.9 Hz, 6H) ppm.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;
General procedure: To a stirred solution of 2-hydroxyhexadecanoic acid (1.0 mmol) and hydrochloride amino component (1.0 mmol) in CH2Cl2 (10 mL), Et3N (0.3 mL, 2.2 mmol) and subsequently 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (WSCI) (0.21 g, 1.1 mmol) and 1-hydroxybenzotriazole (HOBt) (0.14 g, 1.0 mmol) were added at 0 C. The reaction mixture was stirred for 1 h at 0 C and overnight at room temperature. The solvent was evaporated under reduced pressure and EtOAc (20 mL) was added. The organic layer was washed consecutively with brine, 1 N HCl, brine, 5% NaHCO3, and brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography using CH2Cl2/MeOH 99:1 as eluent.
Stage #1: methyl (L)-leucinate hydrochloride With triethylamine In tetrahydrofuran at 20℃;
Stage #2: N-Cbz-L-proline p-tolylthiol ester With N,O-bis-(trimethylsilyl)-acetamide In ethanol at 40℃; for 48h;
With triethylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 4h;
General procedure: To a solution of l-amino acid methyl ester hydrochloride in dichloromethane, triethylamine (1 equiv) and N-Boc-l-amino acid were added at -15 C, and DCC was added as a dichloromethane solution at 0 C. The reaction mixture was stirred at 0 C for 1 h. Then the solution was stirred at room temperature for 3 h. The dicyclohexylurea was removed by filtration from the reaction mixture. The solution was washed with 5% NaHCO3, 1 M HCl, and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated. The product was purified by silica gel column chromatography.
With triethylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 4h;
General procedure: To a solution of l-amino acid methyl ester hydrochloride in dichloromethane, triethylamine (1 equiv) and N-Boc-l-amino acid were added at -15 C, and DCC was added as a dichloromethane solution at 0 C. The reaction mixture was stirred at 0 C for 1 h. Then the solution was stirred at room temperature for 3 h. The dicyclohexylurea was removed by filtration from the reaction mixture. The solution was washed with 5% NaHCO3, 1 M HCl, and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated. The product was purified by silica gel column chromatography.
With triethylamine; In acetonitrile; at 115℃; for 0.25h;Microwave irradiation; Sealed vessel; Inert atmosphere;
Example 23 (S)-4-Methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid pyrazin-2-ylamide A mixture of (S)-2-amino-4-methyl-pentanoic acid methyl ester hydrochloride (Aldrich, 273 mg, 1 5 mmol) and <strong>[346603-68-7]2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester</strong> (prepared as in Example 1, 445 mg, 1 5 mmol) in acetonitrile (5 mL) and triethylamine (420 muL, 3.0 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, 20% ethyl acetate/hexanes) to afford (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid methyl ester (275 mg, 56%) as a colorless viscous oil.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 50h;
General procedure: Mycophenolic acid 1 (0.156 mmol), methyl ester amino acid hydrochloride 9 (0.178 mmol) and DMAP (0.178 mmol) was dissolved in dry DMF (3 mL). A reaction mixture was cooled to 0 C in an ice bath and with stirring was added EDCI (0.17053 mmol). The solution was stirred at 0 C for 2 h and after that time left at room temperature for 48 h. Progress of the reaction controlled by TLC plates. After completion of the reaction solution was poured into water (15 mL), extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated. The crude products were purified by chromatography (SiO2). Structures of synthesized derivatives 10 were established by spectroscopic methods (1H NMR, 13C NMR, MS, HPLC-MS, optical rotation and melting point). Ester hydrolysis: the methyl ester 10 was dissolved in MeOH (30 mL/g), and a solution of LiOH*H2O (3 mol equiv - 2-fold more for 10d and 10e) in an equal volume of water was added. When hydrolysis was complete (48 h), the solution was added to water and washed with ether. The aqueous phase was acidified with 2 N HCl and extracted with EtOAC. The extract was dried with MgSO4 and evaporated, and the residue was recrystallized [17].
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).
With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In 1-methyl-pyrrolidin-2-one; at 0℃; for 5h;
General procedure: To a stirred solution of <strong>[142-45-0]acetylenedicarboxylic acid</strong> (1, 0.57 g, 5 mmol) in NMP (10 mL) at 0 C a solution of the amine (12 mmol, 2.4 equiv) in NMP (5 mL) [for ammonium salts additionally NMM (2 mL) was used] was added dropwise. After 10 min DMTMM 5(4.0 g, 14 mmol, 2.8 equiv) was added and the mixture was stirred for 5 h. Workup A: The mixture was partitioned between EtOAc and H2O(100 mL each), and the organic layer was washed successively with brine (100 mL), sat. NaHCO3 (100 mL), 1 M HCl (100 mL), and brine (2 × 100 mL) [for compounds 7b,q,s-v,y brine was used instead of H2O, and the organic phase was washed with brine (4 × 100mL) only]. The solution was dried (MgSO4), the solvent was evaporated, and the residue was dissolved in a small amount of refluxingTHF. The major portion of 6-dimethoxy-1,3,5-triazin-2(1H)-one(8) was crystallized at -20 C, and the liquid phase containing the product was separated and evaporated. The remaining residue wasfurther purified by column chromatography and/or recrystallization as appropriate. Workup B: The mixture was poured into 1 M HCl (150 mL; for compounds 7h,x H2O was used instead) with stirring at 0 C, and stirring was continued for 15 min. The resulting solid was collected by filtration, washed with H2O, and dried under vacuum. The residue was dissolved in a small amount of refluxing THF and further purified as described above, except for compounds 7f,g,o, which were simply washed with CHCl3 (3 × 10 mL).
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h;
General procedure: To a solution of 11 (120 mg, 0.40 mmol) in DMF (4 mL) were added L-leucine methyl ester hydrochloride (87 mg, 0.48 mmol), HATU (182 mg, 0.48 mmol) and DIPEA (209 muL, 1.20 mmol) and the resultant mixture stirred at room temperature for 16 h. The solution was partitioned between EtOAc (50 mL) and H2O (50 mL). The organic phase was separated, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the solvent evaporated under reduced pressure. The residue was purified by preparative HPLC to yield intermediate (S)-methyl 4-methyl-2-(2-(5-(quinolin-3-yl)-1H-indol-1-yl)acetamido)pentanoate as a yellow solid (157 mg, 92%)
Compound 13 was preactivated with HATU (0.47 g, 1.23 mmol, 1 equiv.) and N,N-disopropylethylamine (0.64 mL, 3.68 mmol, 3 equiv.) in DMF (12 mL) for 15 min at room temperature under argon before a solution of L-Leucine methyl ester hydrochloride (0.25 g, 1.35 mmol, 1.1 equiv.) in DMF (5 mL) was added. The resulting mixture was stirred for 12 h then diluted with ethyl acetate (100 mL) and washed 10% aqueous citric acid, saturated aqueous NaHCO3 and brine. The organic layer was dried with anhydrous MgSO4, filtered and concentrated under reduced pressure. Crude product was purified by chromatography (SiO2, ethyl acetate/petroleum ether, 30/70, v/v) to give compound 14 (0.52 g) as a white solid in 86% yield.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
General procedure: To a cooled solution of Boc-L-leucine (1.0 equiv.), the amine/alpha-aminoester HCl (1.2-1.5 equiv.), and PyBop 1.2 equiv. (or EDCI*HCl1.2 equiv. and HOBt 1.2 equiv.) in anhydrous DMF was added diisopropylethylamine (3.3-4.0 equiv.) gradually. The reaction mixture was stirred at room temperature for 5 h to overnight, diluted with ethyl acetate (50 mL for every 5 mL DMF), then extracted with 1 M HCl (3), saturated sodium bicarbonate (3), and brine (2). The organic layer was then dried with anhydrous sodium sulfate and the solvent was evaporated under vacuum to give the products which were purified by flash chromatography whenever needed.
methyl (2S)-2-[(7E)-7-imino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-methylpentanoate[ No CAS ]
methyl (2S)-2-[(2-cyanopyridin-3-yl)carbonyl]amino}-4-methyl-pentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%; 9%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;
General procedure: To a solution of <strong>[73112-09-1]2-cyanonicotinic acid</strong> (4; 740 mg, 5 mmol) in CH2Cl2(30 mL) were added Et3N (1.39 mL, 10 mmol), the corresponding methyl ester of an amino acid hydrochloride (5 mmol) and HOBt (0.675 g, 5 mmol). The mixture was stirred at 0 and EDCI (0.967 g,5.05 mmol) was added. Then, the mixture was stirred at r.t. overnight.The mixture was diluted with CH2Cl2 (50 mL); then, the solution was washed with 0.1 M HCl (3 × 15 mL) and brine (20 mL), dried over MgSO4 and concentrated in vacuo.
To a cooled (0C) solution of C107-1 (10 g, 35.8 mmol) in DMF (40 mL), was added EDCI (8.5 g, 44.3 mmol), HOBt (7 g, 51.1 mmol), DIEA (14.3 mL, 85.2 mmol). The mixture was stirred at 0 C for 30 min, then C 107-2 was added (6.2 g, 34.1 mmol). The resulting solution was stirred at room temperature for 1 hour under nitrogen. The reaction mixture was poured into water and extracted with EtOAc twice. The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residual oil was purified by flash chromatography on silica gel to give C107-3 (13.5 g, yield 97.8%). MS (ESI) m/z: 351 [M+H-55]+.
General procedure: To a cold and stirred dry dichloromethane solution (25 mL, -20 C) of nalidixic acid (1 mmol),ethyl chloroformate (1 mmol) and triethylamine (1 mmol) were successively added. After 10 min,a cold methylene chloride solution (10 mL, -20 C) of an amino acid methyl ester, namely L-Valinemethyl ester, L-Leucine methyl ester, or L-Phenylalanine methyl ester (1 mmol) was added, with continuous stirring for 3 h and at RT overnight. The solution was then washed with water, 1 N HCl,1 N NaHCO3, and finally with water (250 mL). The solution was dried on anhydrous CaCl2 andevaporated. The oily residue was solidified by trituration with dry ether, filtered off, dried undervacuum, and recrystallized to afford the esters 2a-c, respectively, as previously described [37].
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.
(S)-methyl 2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-4-methylpentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃;
General procedure: To a stirred solutionof <strong>[50264-69-2]Lonidamine</strong> (200mg, 0.62mmol) and HOBt anhydrous(84 mg, 0.61 mmol) in DMF (5 mL), EDC·HCl(119 mg, 0.61 mmol) and NMM (0.61 mmol, 0.07 mL)were added at 0 C, followed by an ice-cold suspensionof amino acid derivative as hydrochloride or TFA salt andNMM (0.61mmol, 0.07mL) in DMF (5mL). After 10minat 0C, the reaction was stirred at r.t overnight. Later, thereaction mixture was evaporated to dryness and the residuewas taken up in EtOAc. The organic phase was washed with5% citric acid, NaHCO3s.s. and NaCl s.s., dried on Na2SO4anhydrous and evaporated to obtain the desired crude whiteproduct.
3-oxo-17β-(O-methyl-L-leucin-N-yl)carbonyl-28-norlup-20(29)-ene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.9%
In a 100 mL round bottom flask,Compound 2 (454 mg, 1.0 mmol) was dissolved in CH2Cl2 (5 mL)EDC (306 mg, 1.6 mmol) and DMAP (73 mg, 0.6 mmol) were added at 0 C.After stirring the reaction for 30 min,Further L-leucine methyl ester hydrochloride (543 mg, 3 mmol) and Et3N (303 mg, 3 mmol) were added.Stir at room temperature overnight, wash with water after TLC monitoring reaction.The organic phase is dried over Na2SO4.The syrupy compound 3 (343 mg, 0.59 mmol, 58.9%) was obtained by column chromatography.
58.9%
In a 100 mL round bottom flask, Compound 2 (454 mg, 1.0 mmol) was dissolved in CH2Cl2 (5 mL), EDC (306 mg, 1.6 mmol) and DMAP (73 mg, 0.6 mmol) was added at 0 C and stirred. After 30 minutes,Further L-leucine methyl ester hydrochloride (543 mg, 3 mmol) and Et3N (303 mg, 3 mmol) were added.After stirring overnight at room temperature, the mixture was washed with water and dried over Na 2SO 4 and evaporated to afford syrup compound 3 (343 mg, 0.59 mmol, 58.9%).
Synthesis of Compound 3: in a 100 mL round bottom flask,Compound 2 (454 mg, 1.0 mmol) was dissolved in CH2Cl2 (5 mL)EDC (306 mg, 1.6 mmol) and DMAP (73 mg, 0.6 mmol) were added at 0 C.After stirring the reaction for 30 min, L-leucine methyl ester hydrochloride was further added.(543 mg, 3 mmol) and Et3N (303 mg, 3 mmol).After TLC monitoring, the reaction was washed with water and the organic phase was dried over Na 2 SO 4 .Column chromatography to obtain syrup compound 3(343 mg, 0.59 mmol, 58.9%).
methyl N-(isoquinolin-4-ylmethyl)leucinate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
General procedure: Leucine methyl ester hydrochloride (4a) (1.eq) and anhydrousMeOH (excess) were placed in a round bottom flask equipped withCaCl2 tube, then triethylamine was added (1.1 eq.) and the reactionwas stirred for 15 min. After this time suitable aldehyde (5a-d) (1.1eq.) and sodium cyanoborohydride (1 eq.) were added respectively.The reactionwas stirred at RT for 3 days. After this time solvent wasevaporated. To the residual slurry water was added (50 ml) and themixture was extracted with ethyl acetate (3 20 ml). Organic layers were collected, washed with water and brine, dried overanhydrous MgSO4 and evaporated. Crude products were purified byflash chromatography (SiO2, petroleum ether/ethyl acetate 10:1).After column chromatography compounds were transformed intotheir hydrochlorides. The corresponding amine was put into around bottom flask with excess of 4M HCl in 1,4-dioxane andstirred for 5 min at RT. After this time solvent was evaporated andfinal product was precipitated from petroleum ether.
(2S)-methyl-2-(((2-methoxy-5-(3,4,5-trimethoxyphenethyl)phenoxy)(phenoxy)phosphoryl)amino)-4-methylpentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
Stage #1: methyl (L)-leucinate hydrochloride With triethylamine In dichloromethane at -70℃; for 0.5h; Green chemistry;
Stage #2: O-phenyl phosphorodichloridate In dichloromethane at -70℃; for 0.5h; Green chemistry;
Stage #3: erianin With triethylamine In dichloromethane at 0℃; for 4h; Green chemistry;
General procedure for synthesis of targetcompounds 5a-g, 6a-g
General procedure: Triethylamine (20 mmol) was dropwise added to a stirringsolution of amino acid ester hydrochloride (10 mmol) in CH2Cl2 (250 mL) at -70 °C. After 30 min, phenyldichlorophosphate (10 mmol) was dropwise added into thereaction mixture. The reaction mixture was under stirringfor 30 min at -70 °C before being warmed up to 0 °C in 3 h.Then a solution of CA-4 or erianin (10 mmol) and triethylamine(10 mmol) in CH2Cl2 was dropwise added, and thesolution was continually stirred for another 4 h at 0 °C.After the completion of reaction, the white solid (triethylaminehydrochloride) was filtered off and washed withdichloromethane (1 × 25 mL). The solvent of the filtrate wasevaporated to obtain the residue. Subsequentially the residuewas triturated with methyl tertbutyl ether (TBME,100 mL), and the triethylamine hydrochloride salt wasremoved by filtration. The filter cake was washed withTBME (50 mL), and the combined filtrate was concentratedunder reduced pressure to give a crude liquid. Then thecrude liquid was purified by flash column chromatographyusing petroleum ether/ethyl acetate (3:1) as eluent to givethe mixture of diastereomers 5a-g, 6a-g in 40-88% yields.
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