* 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 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 72 h; Inert atmosphere; Sealed tube
Step A: To a round-bottom flask was weighed Boc-L-valine (1.03 g, 4.74 mmol), N-hydroxysuccinimide (1.22 g, 10.6 mmol), and EDC (1.60 g, 8.35 mmol). The reagents were dissolved in dry DCM (30 mL), the flask sealed via rubber septum, purged with argon, and the reaction stirred at ambient temperature. After 3 days no Boc-valine remained by TLC (after staining with ninhydrin), so the reaction was washed with water and sat. aq. NaHCO3, the aqueous layer extracted with DCM, combined organic layers washed with brine, dried over Na2SO4, and filtered. The filtrate was then evaporated and dried in vacuo giving Boc-L-valine-succinate as a white solid (1.52 g, 100percent). 1H-NMR (300 MHz, CDCl3): ^ 4.98 (br d, 1H), 4.58 (dd, 1H), 2.82 (m, 4H), 2.27 (m, 1H), 1.44 (s, 9H), 1.03 (dd, 6H). Boc-L-valine-L-citrulline (3):
13.28 g
Stage #1: at 20℃; for 0.05 h; Stage #2: With dicyclohexyl-carbodiimide In tetrahydrofuran; dichloromethane at 0 - 20℃; for 18 h;
[000701 A solution of N-Hydroxysuccinimide (5.0 g, 43.44 mmol) and Boc-Val-OH (la, 9.462 g, 43.44 mmol ) in THF (83 mL) was stirred in room temperature for 3.0 minutes. Then DCC (9.856 g, 45.57 mmol) in CH2C12 (83 mL) was slowly added to the solution at 0°C and then warmed to room temperature. The reaction mixture was stirred for further 18 hours. The solution was cooled to 0°C and the precipitate was filtered and washed with EA (100 mL), dried over reduced pressure to give Boc-Val-OSu (ib, 13.28 g). ‘H NMR (500 MHz, DMSO-d6): ö: 5.02 (d, 1H), 4.60 (d, 1H), 2.85 (s, 4H), 2.31 (m, 1H), 1.48 (m, 9H), 1.05 (m, 6H). MS (M+1 ): 314.8.
Reference：
[1] Patent: WO2016/160615, 2016, A1, . Location in patent: Paragraph 0444; 0445
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2461 - 2480
[3] Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2852 - 2857
[4] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1984, p. 2305 - 2308
[5] Journal of Organic Chemistry, 1986, vol. 51, # 24, p. 4580 - 4585
[6] Journal of the American Chemical Society, 1992, vol. 114, # 17, p. 6653 - 6661
[7] Nucleosides and Nucleotides, 1998, vol. 17, # 9-11, p. 2135 - 2141
[8] Synlett, 2005, # 18, p. 2802 - 2804
[9] Chemistry - A European Journal, 2001, vol. 7, # 19, p. 4280 - 4295
[10] Patent: US2011/65796, 2011, A1, . Location in patent: Page/Page column 23-24
[11] Organic and Biomolecular Chemistry, 2011, vol. 9, # 11, p. 4182 - 4187
[12] Patent: WO2014/100762, 2014, A1, . Location in patent: Paragraph 240; 244
[13] Biochimica et Biophysica Acta - General Subjects, 2015, vol. 1850, # 9, p. 1849 - 1854
[14] Patent: WO2015/196167, 2015, A1, . Location in patent: Paragraph 0269; 0273
[15] Patent: WO2016/109802, 2016, A1, . Location in patent: Paragraph 00068; 00069; 00070
[16] Journal of Molecular Biology, 2018, vol. 430, # 6, p. 842 - 852
Reference：
[1] Journal of Organic Chemistry, 1987, vol. 52, # 12, p. 2364 - 2367
4
[ 13734-41-3 ]
[ 96935-01-2 ]
[ 3392-12-9 ]
Reference：
[1] Synthesis, 1991, # 9, p. 689 - 691
5
[ 13734-41-3 ]
[ 35150-08-4 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: With ammonium chloride In tetrahydrofuran; water at 0℃; for 0.5 h;
General procedure: To a colorless solution of 150mg (0.50mmol) of Cbz-L-Phe-OH 3a in 10mL of THF were added 67μL (0.70mmol, 1.4equiv) of ClCO2Et and 209μL (1.5mmol, 3.0equiv) of Et3N at 0°C. After stirring for 30min at 0°C, 0.75 ml of a 1.0M aqueous solution of NH4Cl (0.75mmol, 1.5equiv) were added at 0°C to the colorless suspension. The mixture was stirred for 30min at 0°C and 5mL of H2O was added to the resulted mixture. The colorless clear solution was extracted with 30mL of EtOAc and the aqueous layer was extracted with 20mL of EtOAc. The organic layers were combined, washed with 5mL of brine, and dried over anhydrous MgSO4. The crude product was chromatographed on silica gel with EtOAc to afford 129mg (86percent yield) of Cbz-L-Phe-NH2 4a. 4.3.11 Boc-l-Val-NH2 4f 106 mg (98percent); >99percent ee; coloress solid; mp: 149-152 °C; [α]30D = -2.4 (c 1.00, MeOH); 1H NMR (400 MHz, CDCl3): δ 0.94 (d, J = 6.8 Hz, 3H, CH3CH), 0.99 (d, J = 6.8 Hz, 3H, CH3CH), 1.45 (s, 9H, (CH3)3C), 2.16 (ddd, J = 6.7, 6.8, 6.8 Hz, 1H, CH(CH3)2), 3.96 (dd, J = 6.7, 7.8 Hz, 1H, CHCO), 5.03, 5.42, 5.89 (br, br, br, 1H, 1H, 1H, NH, NH2); 13C NMR (100 MHz, CDCl3): δ 17.8, 19.3, 28.3, 30.8, 59.5, 79.9, 156.0, 174.4; IR (KBr, vmax/cm-1): 3386 (CONH), 3345 (CONH), 3205 (CONH), 1680 (CON), 1641 (CON); HRMS (ESI-TOF): Calcd for C10H20N2O3Na (M+Na)+: 239.1366, found: 239.1340; The enantiomeric ratio was determined by HPLC (Chiralcel OD: hexane/2-propanol = 95/5): Tr 9.4 min.
Reference：
[1] Tetrahedron Asymmetry, 2017, vol. 28, # 12, p. 1690 - 1699
[2] Angewandte Chemie - International Edition, 2007, vol. 46, # 25, p. 4771 - 4774
[3] Angewandte Chemie, International Edition, 2009, vol. 48, # 23, p. 4198 - 4201
[4] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 7, p. 2647 - 2648
[5] Tetrahedron, 2009, vol. 65, # 46, p. 9536 - 9541
[6] Organic Letters, 2016, vol. 18, # 11, p. 2560 - 2563
[7] Organic Letters, 2017, vol. 19, # 13, p. 3454 - 3457
[8] Helvetica Chimica Acta, 1963, vol. 46, p. 870 - 889
[9] Journal of Organic Chemistry, 1996, vol. 61, # 23, p. 8207 - 8215
[10] European Journal of Medicinal Chemistry, 1998, vol. 33, # 6, p. 423 - 436
[11] Farmaco, 2000, vol. 55, # 11-12, p. 719 - 724
[12] Heterocycles, 2001, vol. 55, # 5, p. 835 - 840
[13] Tetrahedron Letters, 2007, vol. 48, # 8, p. 1465 - 1468
[14] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 3, p. 591 - 600
[15] Tetrahedron Letters, 1991, vol. 32, # 39, p. 5359 - 5362
[16] Journal of Organic Chemistry, 1973, vol. 38, p. 3565 - 3570
[17] Synthetic Communications, 2009, vol. 39, # 3, p. 395 - 406
[18] Journal of Organic Chemistry, 2009, vol. 74, # 15, p. 5260 - 5266
[19] Journal of Organic Chemistry, 2011, vol. 76, # 23, p. 9845 - 9851
[20] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 24, p. 7355 - 7358
[21] European Journal of Organic Chemistry, 2013, # 36, p. 8154 - 8161
[22] ChemBioChem, 2014, vol. 15, # 1, p. 157 - 169
[23] Journal of Organic Chemistry, 2014, vol. 79, # 9, p. 3895 - 3907
[24] Tetrahedron Letters, 2014, vol. 55, # 50, p. 6831 - 6835
[25] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 4, p. 401 - 406
[26] Amino Acids, 2018, vol. 50, # 11, p. 1595 - 1605
6
[ 13734-41-3 ]
[ 45233-75-8 ]
Reference：
[1] International Journal of Chemical Kinetics, 2006, vol. 38, # 6, p. 376 - 385
[2] Journal of Medicinal Chemistry, 1995, vol. 38, # 20, p. 4014 - 4018
[3] Helvetica Chimica Acta, 1994, vol. 77, # 4, p. 1124 - 1165
[4] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1992, # 7, p. 1187 - 1193
[5] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1986, p. 1655 - 1664
[6] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 11, p. 3055 - 3064
7
[ 13734-41-3 ]
[ 74-88-4 ]
[ 45170-31-8 ]
Yield
Reaction Conditions
Operation in experiment
99%
With sodium hydride In tetrahydrofuran at 20℃; for 24 h;
To a solution of N-BOC-valine 1 (217 mg, 1 mmol) and iodomethane(1.42 g, 10 mmol) in anhydrous tetrahydrofuran (THF,20 mL) was added neat sodium hydride (240 mg, 10 mmol). Thereaction mixture was stirred at room temperature for 24 h. The mixture was then quenched with water (30 mL). The reaction mixturewas extracted with ethyl acetate (EtOAc, 2 15 mL) and theaqueous solution was acidified to pH 3, after which it wasextracted with EtOAc (3 20 mL). The combined organic phasewas dried over anhydrous Na2SO4 and evaporated to afford the corresponding N-methylated product 2 (thick colorless oil), 99percentyield.
94%
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 25.5 h;
Example 14 Preparation of compound Boc-N-Me-Val-OH To a solution of Boc-L-Val-OH (2.0(3 g, 9.2 mmol) and methyl iodide (5.74 mL, 92 mmol) in anhydrous THF (40 mL) was added sodium hydride (3.68 g, 92 mmol) at 0 "C. The reaction mixture was stirred at 0 °C for 1.5 h, then warmed to r.t. and stirred for 24 h. The reaction was quenched by ice water (50 mL). After addition of water (100 mL), the reaction mixture was washed with ethyl acetate (50 mL x 3) and the aqueous solution was acidified to pH 3 then extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over Na2S04 and concentrated to afford Boc-N-Me-Val-OH (2.00 g, 94percent yield) as a white solid. 1H NMR (500 MHz, CDC13) δ 4.10 (d, / = 10.0 Hz, 1H), 2.87 (s, 3H), 2.37 - 2.13 (m, 1H), 1.44 (d, J = 26.7 Hz, 9H), 1.02 (d, J = 6.5 Hz, 3H), 0.90 (t, J = 8.6 Hz, 3H).
94%
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 25.5 h;
Example 37. Preparation of compound Boc-N-Me-Val-OH To a solution of Boc-L-Vai-OH (2.00 g, 9.2 mmoi) and methyl iodide (5.74 mL, 92 mmol) in anhydrous THE (40 mL) was added sodium hydride (3.68 g, 92 mmol) at 0 °C.The reaction mixture was stirred at 0 °C for 1.5 h, then warmed to r.t, and stirred for 24 h, The reaction was quenched by ice water (50 mL). After addition of water (100 mL), the reaction mixture was washed with ethyl acetate (50 mL x 3) and the aqueous soIuion was acidified to pH 3 then extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over Na2SO4 and concentrated to afford Boc-N-Me-Val-OH (2.00 g, 94percentyield) as a white solid. ‘H NMR (500 MHz, CDC13) 4.10 (d, J = 10.0 Hz, 1H), 2.87 (s,3H), 2.37 — 2.13 (m, 1H), 1.44 (d, J = 26.7 Hz, 9H), 1.02 (d, J = 6.5 Hz, 3H), 0.90 (t, J =8.6 Hz, 3H).
94%
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 25.5 h;
To a solution of Boc-L-Val-OH (2.00 g, 9.2 mmol) and methyl iodide (5.74 mL, 92 mmol) in anhydrous THF (40 mL) was added sodium hydride (3.68 g, 92 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 h, then warmed to r.t. and stirred for 24 h. The reaction was quenched by ice water (50 mL). After addition of water (100 mL), the reaction mixture was washed with ethyl acetate (3 × 50 mL) and the aqueous solution was acidified to pH 3 then extracted with ethyl acetate (3 × 50 mL). The combined organic phase was dried over Na2SO4 and concentrated to afford Boc-N-Me-Val-OH (2.00 g, 94percent yield) as a white solid.1H NMR (500 MHz, CDCl3) ^ 4.10 (d, J = 10.0 Hz, 1H), 2.87 (s, 3H), 2.37– 2.13 (m, 1H), 1.44 (d, J = 26.7 Hz, 9H), 1.02 (d, J = 6.5 Hz, 3H), 0.90 (t, J = 8.6 Hz, 3H).
91%
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 26 h; Inert atmosphere
General procedure: (S)-2-(Tert-butoxycarbonyl(methyl)amino)-3-hydroxypropanoic acid(6a) Gummy substance (This compound was prepared byadding neat sodium hydride (10 equiv.) in portion wiseover a period of 2.0 h to a cooled (0 °C) solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (1equiv.) and iodomethane (10 equiv.) in dry THF under astream of nitrogen. The reaction mixture was stirred at room temperature for 24 h under nitrogen atmosphere andthen diluted with ether (20 mL) and quenched with water(30 mL). The layers were separated and the aqueous layerwas extracted with ether (2 x9 15 mL), acidified to pH 3with a 20 percent aqueous solution of citric acid and extractedwith EtOAc (3 x 20 mL). The combined organic phasewas dried over Na2SO4 and evaporated to afford thecorresponding N-methylated product in 90 percent yield asGummy substance.)
89%
With sodium hydride In tetrahydrofuran at 0℃; for 19.5 h; Inert atmosphere
(2S)-2-[[(tert-butoxy)carbonyl] amino] -3 -methylbutanoic acid (63 g,289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before addingsodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form of a yellow oil.
89%
With sodium hydride In tetrahydrofuran at 0℃; for 19.5 h; Inert atmosphere
(2S)-2-[[(tert-butoxy)carbonyl] amino] -3 -methylbutanoic acid (63 g,289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before addingsodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form of a yellow oil.
89%
With sodium hydride In tetrahydrofuran at 0℃; for 19.5 h; Inert atmosphere
(2S)-2-[[(tert-butoxy)carbonyl] amino] -3 -methylbutanoic acid (63 g,289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before addingsodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form of a yellow oil.
89%
With sodium hydride In tetrahydrofuran at 0℃; for 19.5 h; Inert atmosphere
Compound 1ZA: (2S)—2—[ [(tert—butoxy)carbonyl] (methyl)amino]—3—methyl butanoic acid (2S)—2—[[Qert—butoxy)carbonyl]amino]—3—methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before adding sodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitationcontinued for 18 hours. The reaction was neutralised with 200 mL of water and thenconcentrated under reduced pressure. The residual aqueous phase was diluted with 4litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3times with 1.2 L of EtOAc. The organic phases were combined, dried over sodiumsulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form ofa yellow oil.
89%
With sodium hydride In tetrahydrofuran at 0℃; for 1.5 h; Inert atmosphere
Compound 1ZA: (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-methyl butanoic acid (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before adding sodium hydride (1 16 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3 and 4 with a IN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound IZA in the form of a yellow oil.
89%
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 19.5 h; Inert atmosphere
(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before adding sodium hydride (1 16 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3 and 4 with a IN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound IZA in the form of a yellow oil.
89%
With sodium hydride In tetrahydrofuran at 0℃; for 19.5 h; Inert atmosphere
Compound 1ZA: (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-methyl butanoic acid (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0° C. before adding sodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0° C., the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3 and 4 with a 1N solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89percent) of compound 1ZA in the form of a yellow oil.
89%
Stage #1: at 0℃; Inert atmosphere Stage #2: With sodium hydride In tetrahydrofuran at 0℃; for 19.5 h;
(2S)—2—[ [Qert—butoxy)carbonyl] amino]—3—methylbutanoic acid (63 g, 289.97 mmo 1,1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence ofiodomethane (181 mL). The solution was cooled to 0°C before adding sodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residualaqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3 and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form of a yellow oil.
1.29 g
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃;
Na2CO3 (1.26 g, 12.15 mmol) and Boc2O (1.94 g, 9.12 mmol) were added to a solution of L-valine 9 (0.712 g, 6.75 mmol) in H2O (10 mL) and THF (5 mL) at 0 °C. After the reaction mixture had been stirred at RT for 12 h, it was neutralized with HCl (10percent) until pH 2 was reached. The mixture was then extracted with EtOAc (3 × 25 mL), washed with brine and dried over anhyd. Na2SO4. Concentration gave the crude N-Boc-Valine 10 (1.3 g, 100percent). NaH (60percent in mineral oil, 1.22 g, 30.15 mmol) was added in portions to a solution of N-Boc-Valine (1.32 g, 6.72 mmol) and MeI (3.02 mL) in THF (25 mL) at 0 °C. After the reaction mixture had been stirred at RT for 36 h, it was poured into saturated aqueous NH4Cl solution (125 mL), extracted with EtOAc (3 × 150mL) and dried over anhyd. Na2SO4. Concentration gave N-methyl-N-Boc-Valine 11 (1.29 g, 92percent). K2CO3 (1.54 g 11.15 mmol), and allyl bromide (0.75 mL, 8.45 mmol) were added to a solution of N-methyl-N-Boc-Valine (1.25 g, 5.46 mmol) in DMSO (20 mL). After the mixture had been stirred at RT for 12 h, it was portioned between EtOAc (35 mL) and brine (35 mL). The organic phase was separated and aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phase was dried over anhyd. Na2SO4 and concentrated. Flash chromatography gave 12 (1.25 g, 80.9percent) as colorless oil. [α]D −85.1° (c 1.1 in CHCl3); IR (CDCl3): 2971, 2935, 1741, 1700, 1473, 1392, 1368, 1330, 1313, 1147, 993, 879, 773 cm−1; 1H NMR (300 MHz CDCl3): δ 5.97-5.84 (m, 1H), 5.34-5.20 (m, 2H), 4.62-4.60 (m, 2H), 4.47, 4.12 (due to the rotamers, both a d, J = 10.5 Hz, 1H), 2.85, 2.21 (due to the rotamers both as a s, 3H), 2.21-2.27 (m, 1H), 1.45 (s, 9H), 0.97 (d, J = 6.3 Hz, 3H), 0.89 (d, J = 6.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 172.3, 171.4, 157.4, 156.3, 133.6, 133.3, 119.5, 119.2, 81.2, 80.6, 66.4, 65.8, 64.6, 63.8, 32.8, 31.8, 28.6, 20.4, 19.8; HRMS (ESI+): m/z Calcd for C14H25NNaO4 (M+Na): 294.197. Found: 294.144.
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 11, p. 3832 - 3835
[2] Tetrahedron Asymmetry, 2014, vol. 25, # 22, p. 1450 - 1455
[3] Tetrahedron, 2006, vol. 62, # 2-3, p. 264 - 284
[4] Journal of Organic Chemistry, 2009, vol. 74, # 21, p. 8425 - 8427
[5] Organic and Biomolecular Chemistry, 2016, vol. 14, # 6, p. 2090 - 2111
[6] Patent: WO2015/151079, 2015, A2, . Location in patent: Page/Page column 67; 68
[7] Patent: WO2015/155753, 2015, A2, . Location in patent: Page/Page column 99
[8] Patent: WO2016/59622, 2016, A2, . Location in patent: Page/Page column 121
[9] Patent: WO2018/86139, 2018, A1, . Location in patent: Page/Page column 164
[10] Journal of Organic Chemistry, 1997, vol. 62, # 16, p. 5542 - 5549
[11] Medicinal Chemistry Research, 2016, vol. 25, # 6, p. 1148 - 1162
[12] Patent: WO2014/174060, 2014, A1, . Location in patent: Page/Page column 38
[13] Patent: WO2014/174064, 2014, A1, . Location in patent: Page/Page column 31
[14] Patent: WO2014/174062, 2014, A1, . Location in patent: Page/Page column 34; 35
[15] Patent: WO2015/162291, 2015, A1, . Location in patent: Page/Page column 115
[16] Patent: WO2015/162293, 2015, A1, . Location in patent: Page/Page column 135; 136
[17] Patent: WO2016/173682, 2016, A1, . Location in patent: Page/Page column 45
[18] Patent: US2017/112943, 2017, A1, . Location in patent: Paragraph 0293; 0294
[19] Patent: WO2017/72196, 2017, A1, . Location in patent: Page/Page column 117
[20] Journal of Organic Chemistry, 2007, vol. 72, # 4, p. 1315 - 1325
[21] Journal of Organic Chemistry, 2016, vol. 81, # 21, p. 10302 - 10320
[22] Beilstein Journal of Organic Chemistry, 2012, vol. 8, p. 2085 - 2090
[23] Canadian Journal of Chemistry, 1977, vol. 55, p. 906 - 910
[24] Tetrahedron, 1995, vol. 51, # 39, p. 10653 - 10662
[25] Tetrahedron Letters, 1998, vol. 39, # 40, p. 7373 - 7376
[26] Tetrahedron, 2000, vol. 56, # 41, p. 8119 - 8131
[27] Journal of Antibiotics, 2001, vol. 54, # 1, p. 22 - 28
[28] Organic Letters, 2004, vol. 6, # 13, p. 2253 - 2256
[29] Angewandte Chemie - International Edition, 2007, vol. 46, # 20, p. 3722 - 3724
[30] Chemistry - A European Journal, 2006, vol. 12, # 25, p. 6572 - 6584
[31] Synthesis, 2009, # 9, p. 1531 - 1544
[32] Tetrahedron, 2009, vol. 65, # 45, p. 9481 - 9486
[33] Organic and Biomolecular Chemistry, 2012, vol. 10, # 35, p. 7027 - 7030
[34] Journal of Natural Products, 2013, vol. 76, # 5, p. 974 - 978
[35] RSC Advances, 2015, vol. 5, # 80, p. 65402 - 65407
[36] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2016, vol. 55B, # 10, p. 1239 - 1242
Reference：
[1] Organic Process Research and Development, 2005, vol. 9, # 2, p. 185 - 187
14
[ 13734-41-3 ]
[ 3014-80-0 ]
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 9, p. 3895 - 3907
15
[ 13734-41-3 ]
[ 147-85-3 ]
[ 23361-28-6 ]
Yield
Reaction Conditions
Operation in experiment
31%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0 - 20℃; Stage #2: at 0 - 20℃;
EΞxample - 1: Preparation of 1-(2-Amino-3-methyl-butyryl)-pyrrolidine-2-carboxylic acid [3-oxo-1- (2,4,5-trifluoro-benryl)-3-(3-trmuoromethyl-6,6-dihydro-8H-['1.2,4]triazolo[4,3-a]pyra-.in-7- yl)-propyl]-amlde Hydrochloride STEP -1 : Preparation 1-(2-tert-Butoxycarbonylamino-3-methyl-butyryl)-pyrrolidiπfr-2-carboxylic acidTo a stirred solution of N-Boc L-Valine (Compound of formula 2) [8 gm, 0.037 mole] and tri ethyl amine (5.15 ml. 0.037 mole) in THF (120 ml), ethyl chloro formate (3 52 ml, 0.037 mole) was added dropwise at 0-5 0C. The reaction was stirred at 0 0C for 15 minutes and stirred at room temperature for 1 hour. Then keep the reaction at 0 C and add mixture of tri ethyl amine (10.3 ml, 0.074 mole) and THF (60 ml).Finally L-Proline (4.25 gm, 0-037 mole) was added to above mixture at 0 C. Reaction was stirred at 0 C for 30 minutes and stirred at room temperature for over night After being stirred, THF was concentrated under vacuum and residue was acidified with 1N HCI (till pH - 3). The product layer was extracted with ethyl acetate. The organic extracts were dried over Na2SO4 and concentrated to give (B). The resulted product was subjected to column chromatography using EtoAC / Hexane 5/5 as an elυentto give N-Boc Val-Pro (Compound of formula 3). (Yield = 3.Q gm, 31percent)
Reference：
[1] International Journal of Chemical Kinetics, 2006, vol. 38, # 6, p. 376 - 385
[2] Polish Journal of Chemistry, 1988, vol. 62, # 4-6, p. 457 - 464
[3] Recueil: Journal of the Royal Netherlands Chemical Society, 1980, vol. 99, # 4, p. 124 - 130
[4] Journal of Medicinal Chemistry, 1992, vol. 35, # 4, p. 641 - 662
[5] Journal of Photochemistry and Photobiology B: Biology, 2013, vol. 121, p. 75 - 85
[6] International Journal of Pharmacy and Pharmaceutical Sciences, 2017, vol. 9, # 9, p. 92 - 99
[7] Tetrahedron, 2018, vol. 74, # 12, p. 1184 - 1190
17
[ 13734-41-3 ]
[ 2462-34-2 ]
Reference：
[1] Chemistry - A European Journal, 2012, vol. 18, # 21, p. 6528 - 6541
[2] Journal of Organic Chemistry, 2015, vol. 80, # 9, p. 4235 - 4243
[3] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 1, p. 6 - 10
(S)-2-((S)-2-{(S)-2-[(S)-2-[(S)-2-Acetylamino-3-(1H-imidazol-4-yl)-propionylamino]-3-(1H-indol-3-yl)-propionylamino]-propionylamino}-3-methyl-butyrylamino)-propionic acid[ No CAS ]
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere;
General procedure: A mixture of L-valine p-TsOH salt 10a (100 mg, 0.30 mmol) and N-Boc valine (87.12 mg, 0.30 mmol) was taken in 2.5 mL of dry THF and cooled to 0 C under nitrogen atmosphere. After stirring, freshly distilled NMM (0.16 mL, 1.51 mmol) was added via syringe followed by HOBt (46.61 mg, 0.34mmol) and EDCI (65.18 mg, 0.34 mmol) in a single portion. The mixture was stirred overnight slowly warming to room temperature. After 12 hours, it was concentrated by a rotavapor and the residue was taken in EtOAc (20.0 mL), washed with saturated NaHCO3 solution followed by brine. The organic layer was dried over MgSO4, filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using hexane-EtOAc (8:2) to afford the title compound 11a
With 1-methyl-pyrrolidin-2-one; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 1.5h;
N-(tert-butoxycarbonyl)-L-valine(135.8mg, 0.62mmol), WSC * HCl(0.20g, 1.04mmol), 4-dimethylaminopyridine(10mg) and N-methyl-2-pyrrolidinone(1.5mL) were added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.20g, 0.52mmol) in tetrahydrofuran(3mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(277.2mg, 91.4percent) as a white solid.1H-NMR(CDCl3): delta 1.06(3H, d, J=6.9Hz),1.11(3H, d, J=6.9Hz), 1.37(9H, s), 2.24(1H, m), 4.16(1H, t, J=6.9Hz), 5.00(1H, d, J=6.9Hz), 7.22(1H, d, J=9.0Hz), 7.50(1H, dd, J=8.7, 2.7Hz), 7.66(1H, s),8.01(1H, d, J=2.4Hz), 8.26(2H, s), 8.96(1H, s).
Example A3.2 Z-(S)-N-(2-{4-[3-(4-Chloro-phenyl)-allyloxy]-3-methoxy-phenyl}-ethyl)-2-ethanesulfonylamino-3-methyl-butyramide To a mixture of BOC-L-Valin (48 g), 4-(2-Amino-ethyl)-2-methoxy-phenol hydrochloride (45 g) and diethyl-isopropylamine (64.6 g) in dimethylformamide (900 ml) is added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (97.8 g) in one portion. The reaction mixture is stirred for 4 hours at room temperature. Water (1000 ml) is then added. The mixture is extracted with ethyl acetate (2*500 ml). The organic layers organic layers are washed with brine (2*400 ml), dried (MgSO4) and evaporated. The residue is purified by flash column chromatography on silica gel (ethyl acetate/hexane 1:2). (S)-{1-[2-(4-Hydroxy-3-methoxy-phenyl)-ethylcarbamoyl]-2-methyl-propyl}-carbamic acid tert.-butyl ester is obtained.
(S)-{1-[2-(4-hydroxy-3-methoxy-phenyl)-ethylcarbamoyl]-2-methyl-propyl}-carbamic acid-tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide; water;
Example E9 2-(1,1-Dimethylethoxycarbonylamino)-N-{2-[3-methoxy-4-(4-chlorophenyl-prop-2-ynyloxy)-phenyl]-ethyl}-3-methylbutyramide To a mixture of BOC-L-valine (4.7 g), 4-(2-amino-ethyl)-2-methoxy-phenol hydrochloride (4,5 g) and ethyl-diisopropyl-amine (6,5 g) in dimethylformamide (90 ml) is added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (9.8 g) in one portion. The mixture is stirred at room temperature for 4 hours. Then water (400 ml) is added. The mixture is extracted with ethyl acetate (2*400 ml) and washed with brine (2*200 ml). The organic layers are collected, dried (MgSO4) and evaporated. 2-(1,1-dimethylethoxycarbonylamino)-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-3-methylbutyramide is obtained which is purified by flash column chromatography on silica gel (ethyl acetate/hexane 2:3); oil.
{(S)-2-Amino-1-[(S)-1-((S)-1-{(1S,2R)-1-benzyl-2-hydroxy-2-[3-(5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenylcarbamoyl]-ethylcarbamoyl}-3-methyl-butylcarbamoyl)-2-methyl-propylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester[ No CAS ]
{(S)-2-Amino-1-[(S)-1-((S)-1-{(1S,2R)-1-benzyl-2-hydroxy-2-[3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenylcarbamoyl]-ethylcarbamoyl}-3-methyl-butylcarbamoyl)-2-methyl-propylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester[ No CAS ]
On top of the scheme, an intermediate noted as 4-2 was first made by reacting tert- butoxycarbonyl-protected DL-valine with cyanuric chloride at room temperature in tetrahydrofuran as a solvent and in the presence of a triethylamine catalyst, and then adding <strong>[86386-73-4]fluconazole</strong> in the presence of sodium hydride in the same solvent (tetrahydrofuran), at a temperature between 00C and about 200C. Deprotection of the amino group of intermediate 4-2 was then carried out at room temperature by means of concentrated chlorhydric acid in dioxane and methanol as a solvent mixture, resulting into an intermediate noted as 4-3.
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 6h;
Example 11: (lalpha,5alpha,6beta)-3-{6-[(S)-l-(4-Butoxycarbonyl-piperazine-l-carbonyl)-2- methyl-propylcarbamoyll^-phenyl-pyrimidin^-ylJ-S-aza-bicyclop.l.Olhexane-- carboxylic acid:11.1. 4-((S)-2-tert-Butoxycarbonylamino-3-methyl-butyryl)-piperazine-l-carboxylic acid butyl ester:To a solution of Boc-(L)-Val-OH (400 mg) in DCM (12 mL) were added DIPEA (0.991 mL), DMAP (22 mg), HOBT hydrate (298 mg), EDCI hydrochloride (423 mg) and intermediate 1.4 (343 mg). The mixture was stirred at RT for 6 h. An aq. NaHCO3 solution was added to the mixture and the phases were separated. The org. phase was washed with brine, dried (MgStheta4) and evaporated off to afford 844 mg of the desired compound as beige oil. LC-MS: tR = 1.02 min; [M+H]+: 386.42.
(S)-2-(4'-(2-bromoacetyl)biphenyl-4-yl)-2-oxoethyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.8 g
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; acetonitrile; at 20℃; for 20.25h;
To a solution of 1,1?-(biphenyl-4,4?-diyl)bis(2-bromoethanone) (5 g, 12.6 mmol) and (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (2.74 g, 12.62 mmol) in MeCN (40 mL), THF (100 mL) and DMF (100 mL) was added DIPEA (2.315 mL, 13.26 mmol) dropwise in 15 min. The reaction mixture was stirred at rt for 20 h and diluted with EtOAc, washed with ice cold satd. citric acid (2×), water, brine, dried (MgSO4), and the residue was purified on a 160 g silica gel column (EtOAc/hex: 0 to 100%) to afford the product (2.8 g). LC-MS: retention time: 2.873 min (method YT-1); m/z 556.03 [M+Na]+; 1H NMR (400 MHz, DMSO-d6) delta ppm 8.07-8.19 (4H, m), 7.98 (4H, d, J=8.78 Hz), 7.26 (1H, d, J=8.53 Hz), 5.62-5.69 (1H, m), 5.51-5.57 (1H, m), 5.01 (2H, s), 4.01-4.10 (1H, m), 2.09-2.25 (1H, m), 1.41 (9H, s), 0.95-1.06 (6H, m).
2.8 g
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; acetonitrile; at 20℃; for 20h;
To a solution of 1,1?-(biphenyl-4,4?-diyl)bis(2-bromoethanone) (5 g, 12.6 mmol) and (S)-2-(tert-butoxycarbonylamino)-3 -methylbutanoic acid (2.74 g, 12.62mmol) in MeCN (40 mL), THF (100 mL) and DMF (100 mL) was added DIPEA (2.315 mL, 13.26 mmol) dropwise in 15 mm. The reaction mixture was stirred at rt for 20 h and diluted with EtOAc, washed with ice cold satd. citric acid (2 x), water, brine, dried (Mg504), and the residue was purified on a 160 g silica gel column (EtOAc/hex: 0 to 100%) to afford the product (2.8 g). LC-MS: retention time: 2.873mm (method YT-1); m/z 556.03 [M+Na] ?H NMR (400 MHz, DMSO-d6) ppm8.07 - 8.19 (4 H, m), 7.98 (4 H, d, J= 8.78 Hz), 7.26 (1 H, d, J= 8.53 Hz), 5.62 -5.69 (1 H, m), 5.51 - 5.57 (1 H, m), 5.01 (2 H, s), 4.01 -4.10 (1 H, m), 2.09 - 2.25 (1 H, m), 1.41 (9 H, s), 0.95 - 1.06(6 H, m).
(S)-2-(4'-(2-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)acetyl)biphenyl-4-yl)-2-oxoethyl 2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoate[ No CAS ]
2-((1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)hexadecanoic acid[ No CAS ]
Ac-KLIPNASLIENCTKAELK(Ac-KQAEDKVKASREAKKQVEKALEQLEDKVK)-SS-(2-amino-D,L-hexadecanoyl)-2-amino-D,L-hexadecanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12.5%
General procedure: LCP 1 was synthesised by coupling Dde-C16 onto pMBHA resin(0.45 mmol/g; 0.2 mmol scale) by using HBTU (4.0 equiv) andDIPEA (6.2 equiv) in DMF (2 1 h). Removal of the Dde-protectinggroup was performed by treatments with 2% hydrazine in DMF(2 30 min). The remaining LCP sequence was synthesised bymicrowave-assisted Boc-SPPS. Amino acid activation was achievedby dissolving Boc-amino acids (4.2 equiv) in 0.5 M HBTU(4.0 equiv) in DMF, followed by the addition of DIPEA (6.2 equiv).The amino acid coupling cycle consisted of Boc-deprotection withneat TFA at room temperature (2 1 min), 2 min DMF flow wash,followed by 10 min coupling with the pre-activated amino acid.The temperature was set at 70 C (35 W, 10 min) for all aminoacids, except for Cys and His, which were coupled at 50 C (35 W,10 min). N-terminal acetylation and final cleavage from resin wasperformed as reported previously.29 The lyophilised products werepurified by RP-HPLC. The collected fractions were analysed byESI-MS and RP-HPLC. Where appropriate, fractions were combinedand lyophilised to yield pure product.For the synthesis of LCP 2, Dde-C20 was coupled onto pMBHAresin (0.45 mmol/g; 0.2 mmol scale). The remaining proceduresfollowed that of the synthesis of LCP 1, as mentioned above.LCP 1 yield: 12.5%. Purity: 90%. Molecular weight: 6086.4. ESIMS:[M+4H]4+ m/z 1523.4 (calcd: 1522.6), [M+5H]5+ m/z 1218.4(calcd: 1218.3), [M+6H]6+ m/z 1015.7 (calcd: 1015.3), [M+7H]7+m/z 870.6 (calcd: 870.4), [M+9H]9+ m/z 677.5 (calcd: 677.3), [M+10H]10+ m/z 608.8 (calcd: 609.5). Rt = 25.0 min (0-100% solventB, 40 min, C4-column).
Ac-KLIPNASLIENCTKAELK(Ac-KQAEDKVKASREAKKQVEKALEQLEDKVK)-SS-(2-amino-D,L-eicosanoyl)-2-amino-D,L-eicosanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18.5%
General procedure: LCP 1 was synthesised by coupling Dde-C16 onto pMBHA resin(0.45 mmol/g; 0.2 mmol scale) by using HBTU (4.0 equiv) andDIPEA (6.2 equiv) in DMF (2 1 h). Removal of the Dde-protectinggroup was performed by treatments with 2% hydrazine in DMF(2 30 min). The remaining LCP sequence was synthesised bymicrowave-assisted Boc-SPPS. Amino acid activation was achievedby dissolving Boc-amino acids (4.2 equiv) in 0.5 M HBTU(4.0 equiv) in DMF, followed by the addition of DIPEA (6.2 equiv).The amino acid coupling cycle consisted of Boc-deprotection withneat TFA at room temperature (2 1 min), 2 min DMF flow wash,followed by 10 min coupling with the pre-activated amino acid.The temperature was set at 70 C (35 W, 10 min) for all aminoacids, except for Cys and His, which were coupled at 50 C (35 W,10 min). N-terminal acetylation and final cleavage from resin wasperformed as reported previously.29 The lyophilised products werepurified by RP-HPLC. The collected fractions were analysed byESI-MS and RP-HPLC. Where appropriate, fractions were combinedand lyophilised to yield pure product.For the synthesis of LCP 2, Dde-C20 was coupled onto pMBHAresin (0.45 mmol/g; 0.2 mmol scale). The remaining proceduresfollowed that of the synthesis of LCP 1, as mentioned above.LCP 1 yield: 12.5%. Purity: 90%. Molecular weight: 6086.4. ESIMS:[M+4H]4+ m/z 1523.4 (calcd: 1522.6), [M+5H]5+ m/z 1218.4(calcd: 1218.3), [M+6H]6+ m/z 1015.7 (calcd: 1015.3), [M+7H]7+m/z 870.6 (calcd: 870.4), [M+9H]9+ m/z 677.5 (calcd: 677.3), [M+10H]10+ m/z 608.8 (calcd: 609.5). Rt = 25.0 min (0-100% solventB, 40 min, C4-column).
(S)-(R)-1-methoxypropan-2-yl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Intermediate 279: (S)-(R)-1-methoxypropan-2-yl 2-((tert-butoxycarbonyl)amino)-3- methylbutanoate A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (1.0 g, 4.60 mmol), diisopropylethylamine (1.19 g, 1.608 mL, 9.21 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (846 mg, 5.52 mmol), EDC (1.06 g, 5.53 mmol), and <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> (1.037 g, 1.127 mL, 11.5 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (15 mL) and sat'd NaHCO3 (15 mL). The organic phase was washed with 1M hydrochloric acid (15 mL), water (15 mL) and brine (15 mL). The organic phase was dried and evporated under reduced pressure to give the title compound as a colourless oil (1.2 g, 90% yield). 1H NMR (CDCl3): delta 0.89 (m, 3 H), 0.96 (m, 3 H), 1.24 (d, J = 6.6 Hz, 3 H), 1.45 (s, 9H), 2.16 (m, 1H), 3.36 (s, 3H), 3.44 (m, 2H), 4.23 (m, 1H), 5.05 (m, 1H), 5.13 (m, 1H).
The titled peptide was synthesized on a model 430A peptide synthesizer (Applied Rio systems, Foster City, Calif., U.S.A.) which was modified to do accelerated Hoc-chemistry solid phase peptide synthesis (Schnolzer, M. et al., mt. J Peptide Protein Res., (1992), 40:180). 4-Methylbenzhydry- lamine (MHHA) resin (Peninsula, Helmont, Calif., U.S.A.), with a substitution of0.91 mmol/g was used. Hoc amino acids (Midwest Hio-Tech, Fishers, Ind., U.S.A.; Novabiochem., San Diego, Calif., U.S.A.) were used with the following side chain protection: Hoc-Ala-OH, Hoc-Arg(Tos)-OH, Hoc-His (DNP)-OH, Hoc-Val-OH, Hoc-Ecu-OH, Hoc-Gly-OH, HocGln-OH, Hoc-Eys(2C1Z)?--OH, Hoc-Ser(Hzl)-OH, Hoc-PheOH, Hoc-Glu(OcHex)-OH and Hoc-Pro-OH. Fmoc-Glu (OtHu)-OH (Novabiochem, San Diego, Calif., U.S.A.) was used for the residue at the 3rd position in the sequence. The synthesis was carried out on a 0.25 mmol scale. The Hoc groups were removed by two treatments with 100percent TFA each lasting one minute. Hoc amino acids (2.5 mmol) were preactivated with HH11J (2.0 mmol) and DIEA (1.0 mE) in 4 mE of DMF and were coupled without prior neutralization of the peptide-resin TFA salt. Coupling times were 5 minutes. At the end of the assembly of the first 25 residues on theAHI 430A® peptide synthesizer and before the coupling of Fmoc-Glu (OtHu)-OH, the protected peptide-resin was transferred into a reaction vessel on a shaker for manual synthesis. After removing the Hoc protecting group with two, one-minute treatments with 100percent TFA and a washing with DMF, the resin was mixed with Fmoc-Glu(OtHu)-OH (2.5 mmol) which was preactivated with HHTU (2.0 mmol), HOHt (2.0 mmol) and DIEA (1.0 mE) in 4 mE of DMF. The mixture was shaken for 2 hours. This coupling step was repeated. After washing with DMF, the resin was treated with a TFA solution containing 5percent water and 5percent TIS for 2 hours to remove the tHu protecting group in the side chain of the Glu residue. The resin was neutralized with 10percent DIEA in DMF and washed with DMF and DCM. The resin was then treated twice with hexylamine (2.0 mmol), DIC (2.0 mmol), HOHt (2.0 mmol) in 5 ml of DCM for two hours per treatment. The resin was washed with DMF and treated with 25percent piperidine in DMF for 30 minutes to remove the Fmoc protecting group. Afier washing with DMF and DCM, the resin was transferred into the reaction vessel on the AHI 430A peptide synthesizer for the assembly of the rest two residues. At the end of the assembly of the whole peptide chain, the resin was treated with a solution of 20percent mercaptoethanol/10percent DIEA in DMF for 2x30 mm to remove the DNP group on the His side chain. The N-terminal Hoc group was then removed by two treatments of 100percent TFA for 2 minutes. The peptide-resin was washed with DMF and DCM and dried under reduced pressure. The final cleavage was done by stirring the peptide-resin in 10 mE of HF containing 1 mE of anisole and dithiothreitol (50 mg) at 0° C. for 75 minutes. HF was removed by a flow of nitrogen. The residue was washed with ether (6x 10 mE) and extracted with 4N HOAc (6x10 mE). This crude product was purified on a reverse-phase preparative HPEC using a colunm (4x43 cm) of C18 DYNAMAX-100A°® (Varian, Walnut Creek, Calif., U.S.A.). The column was eluted with a linear gradient from 75percentAand25percent B to 55percentAand45percent B at flow rate of 10 mE/mm in an hour where A was 0.1percent TFA in water and B was 0.1percent TFA in acetonitrile. Fractions were collected and checked on an analytical HPEC. Those containing pure product were combined and lyophilized to dryness. 31.8 mg of a white solid was obtained. Purity was 89percent based on analytical HPEC analysis. Electro-spray ionization mass spectrometry (ESI MS) analysis gave the molecular weight at 3368.4 (in agreement with the calculated molecular weight of 3368.9).
General procedure: The relevant Boc-AA1-OH (1.1 equiv), TBTU (1.1 equiv) and DIEA (2.0 equiv) were dissolved in CH2Cl2 anhydrous at room temperature and the mixture stirred for 30 min prior to addition of bromothiazole 5 (1.0 equiv). The mixture was stirred and allowed to proceed at room temperature for further 23h, with periodic monitoring by TLC. The solvent was then reduced at 3mL and the residue was submitted to column chromatography on silica using DCM/Acetone 10:1 (v/v).
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 25℃; for 12h;Inert atmosphere;
A mixture of 14 (500 mg, 4 mmol) and LiAIH4(202 mg, 5 mmol) in THF (10 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 0 C for 12 h under N2atmosphere. The reaction mixture was quenched by saturated sodium potassium tartrate (0.8 mL) at 15 C, and then filtered. The mixture was diluted with H20 (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine (5 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give 15 (236 mg, 52%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.43 (d, J - 2.8 Hz, 1 H), 7.45-7.41 (m, 1 H), 7.31-7.27 (m, 1 H), 4.76 (s, 2H). A mixture of 15 (1 g, 8 mmol), DCC (3 g, 16 mmol), DMAP (96 mg, 786 umol) and A/-BOC-(S)-valine (2 g, 9 mmol) in DCM (5 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25 "C for 12 h under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si02, PE/EtOAc = 5:1) to give 16 (1 .3 g, 51 %) as a yellow liquid.1H N R (400 MHz, DMSO-de) 8.55 (s, 1 H), 7.71-7.83 (m, 1 H), 7.54-7.51 (m, 1 H), 7.25 (d, J = 8.0 Hz, 1 H), 5.22-5.13 (m, 2H), 3.91 (t, J = 7.2 Hz, 1 H), 2.06-2.02 (m, 1 H), 1.38 (s, 9H), 0.87 (d, J - 6.4 Hz, 6H).
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 0 - 15℃; for 14h;
To a mixture of A/-Boc-(S)-valine (300 mg, 1.38 mmol) and NaHC03(347mg, 4.14 mmol) in DMF(3 mL) was added 51 (341 mg, 1.52 mmol) at 0 C. The mixture was stirred at 15 C for 14 h. Then water (5 mL) was added, the mixture was extracted with MTBE (5 mL x 3). The combined organic phase was washed with brine (2 mL x 3), dried over Na2S04, filtered and concentrated in vacuum to give crude 52 (1 .4 g) as a brown oil.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;Inert atmosphere;
Irinotecan (13.0 g, 22.2 mmol) was dissolved in dichloromethane (500 mL) and N-tert-butyloxycarbonylvaline(9.63 g, 44.4 mmol), DMAP (5.42 g, 44.4 mmol). Under a nitrogen atmosphere, EDC (12.80 g, 66.7 mmol) in dichloromethane (280 mL) and the system was allowed to react overnight at room temperature. The reaction was complete by TLC and the reaction was washed with distilled water (500 mL) and saturated sodium chloride solution (500 mL) Drying over anhydrous sodium sulfate. Concentrated to dryness, the residue was purified by silica gel column, isopropyl ether precipitation, Drying under vacuum at room temperature to give a pale yellow solid 12.63g, yield 72.4percent
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃;Cooling with ice;
A solution of the amine (AU1) hydrochloride (1.08 g, 8.1 mmol), Boc-L- Valine (2.28 g, 10.5 mmol), and HBTU (3.98 g, 10.5 mmol) in CH3CN (40 mL) in an ice bath was treated with NEt3 (8.8 mL, 63 mmol). The solution was warmed to room temperature overnight then concentrated. The residue was suspended in aq. NaHC03 (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2S04) and concentrated. The residue was subjected to chromatography on a short plug of silica gel eluting with 50% EtOAc in hexanes. The product containing fractions were concentrated to a residue, which was then dissolved in CHCI3 (10 mL) and treated with TFA (10 mL). After 4 h, the solution was concentrated and the resulting residue was dissolved in EtOAc and washed with aq. NaHC03. The organic layer was dried (Na2S04) and concentrated to afford 1.28 g (80% over two steps) of the intermediate amide. The crude amide was dissolved in THF (75 mL) and treated with BH3*SMe2 (2.5 mL, 25 mmol). The resulting solution was heated at reflux overnight, then cooled in an ice bath to be quenched by addition of CH3OH. The resulting solution was concentrated twice from CH3OH then dissolved in CH2CI2 and washed with dilute aq. NaOH. The aqueous layer was back extracted with EtOAc. The combined organics were washed with aq. NaHC03 then brine, then dried (Na2S04). The concentrated residue was subjected to chromatography on silica gel eluting with a gradient up to 50% CMA80 to afford 0.63 g (53% from the amide) of the desired diamine AU2: lH NMR (300 MHz, CDCI3) delta 3.30 (br. s., 2H), 2.63 (ddd, = 3.30, 5.60, 10.13 Hz, 1H), 2.41 (dd, / = 3.30, 12.34 Hz, 1H), 2.17 (dd, / = 10.36, 12.24 Hz, 1H), 1.95-2.09 (m, 2H), 1.67- 1.83 (m, 4H), 1.50-1.67 (m, 1H), 1.23-1.37 (m, 4H), 0.87-0.97 (m, 6H); MS (ESI) mlz 183.3 (M + H)+.
(2S)-1-(((4-nitrophenoxy)carbonyl)oxy)ethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With silver(l) oxide; In neat (no solvent); at 90℃; for 0.25h;
A mixture of <strong>[101623-69-2]1-chloroethyl 4-nitrophenyl carbonate</strong> (0.5 g, 2.04 mmol), Boc-L-valine (0.89 g, 4.07 mmol) and silver oxide (0.47 g, 2.04 mmol) were mixed and heated in a pre-heated oil bath at 90 °C for 15 min. The reaction mixture was cooled to room temperature and triturated with EtOAc. The inorganic solids were separated by filtration, washed with EtOAc (3 xs). The filtrate was washed with water (4 xs), aqueous saturated NaHCCb, dried, filtered and concentrated in vacuum. The crude was purified by flash column chromatography [silica gel 24g, eluting with EtOAc in hexane 0-40percent] to give (2S)-l-(((4- nitrophenoxy)carbonyl)oxy)ethyl 2-((tert-butoxycarbonyl)amino)-3 -methylbutanoate (33a) (0.31 g, 35 percent yield). 1H MR (300 MHz, DMSO-i) delta 8.39 - 8.29 (m, 2H), 7.61 - 7.49 (m, 2H), 7.32 (dd, J= 11.9, 7.8 Hz, 1H), 6.79 (q, J= 5.3 Hz, 1H), 3.93 - 3.80 (m, 1H), 2.12 - 1.91 (m, 1H), 1.61 - 1.50 (m, 3H), 1.38 (d, J= 4.3 Hz, 9H), 0.96 - 0.83 (m, 6H); MS (ES+) 449.4 (M+Na)
4'-hydroxy-3,3',5,5'-tetraisopropylbiphenyl-4-yl 2-amino-3-methylbutyrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
With phosphorus pentoxide; In dichloromethane; at 20℃; for 8h;
3,3?,5,5?-tetraisopropyl-4,4?-dihydroxybiphenyl (1 g, 2.8 mmol), Boc-valine (0.73 g, 3.36 mmol), phosphorus pentoxide (1.987 g, 14 mmol), and 30 mL dichloromethane were added in a 50 mL round bottom flask, and stirred at room temperature for 8 h. After the reaction was complete, 10 mL of water was added thereto and stirred for 1 h. An appropriate amount of ammonia was added, extracted with methylene chloride, washed with water and then with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to give a white solid (0.16 g, 13percent). (0130) White solid, 4?-hydroxy-3,3?,5,5?-tetraisopropylbiphenyl-2-amino-3-methylbutyrate: 1H NMR (300 MHz, CDCl3) delta 7.57 (s, 2H), 7.51 (s, 2H), 5.35 (s, 1H), 5.12-5.10 (d, 2H),4.25-4.24 (d, 1H),3.05-3.02 (m, 4H), 2.68-2.66 (m, 1H), 1.21-1.18 (d, 24H), 0.92-0.90 (d, 6H).
(S)-tert-butyl (1-((2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
394.7 mg
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h;
l-(4-Amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl)-2-methylpropan- 2-ol (R848) (237.5 mg, 0.755 mmol) was dissolved into anhydrous N,N-dimethylformamide (5 ml). Boc-L-valine (263.4 mg, 1.2 mmol) and 4-(dimethylamino)pyridine (187.4 mg, 1.534 mmol) were added. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (236.1 mg, 1.232 mmol) was added. The resulting mixture was stirred at room temperature for 3 h. Water was added to quench the reaction. Brine was added. The mixture was extracted with ethyl acetate (2x50 ml). The combined organic solution was dried over anhydrous sodium sulfate, concentrated to dryness. The residue was purified with flash column chromatography on silica gel using 1-10% methanol/dichloromethane to afford product (394.7 mg) as white solid. 1H-NMR (500 MHz, CDCh) delta 8.99 (br., 1 H), 8.15-8.11 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 5.42 (m, 1H), 4.89 (br, 2 H), 4.77 (s, 2H), 3.63 (q, J = 7.0 Hz, 2H), 3.27 (m, 1H), 2.45 (br, 1H), 1.44 (s, 9H), 1.31 (br, 6H), 1.22 (t, J= 7.0 Hz, 3H), 1.14 (br, 3H), 0.93 (d, J= 6.0 Hz, 3H). LC-MS: 514 (MH+/z).
394.7 mg
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h;
1 -(4-Amino-2-(ethoxymethyl)-1 H-imidazo[4,5-c]quinolin-1 -yl)-2- methylpropan-2-ol (R848) (237.5 mg, 0.755 mmol) was dissolved into anhydrous N,Ndimethylformamide (5 ml). Boc-L-valine (263.4 mg, 1.2 mmol) and 4- (dimethylamino)pyridine (187.4 mg, 1.534 mmol) were added. N-(3- dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (236.1 mg, 1 .232 mmol) was added. The resulting mixture was stirred at room temperature for 3 h. Water was added to quench the reaction. Brine was added. The mixture was extracted with ethyl acetate (2x50 ml). The combined organic solution was dried over anhydrous sodium sulfate, concentrated to dryness. The residue was purified with flash column chromatography on silica gel using 1-10% methanol/dichloromethane to afford product (394.7 mg) as white solid.
394.7 mg
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h;
[00274] 1 -(4-Amino-2-(ethoxymethyl)-1 H-imidazo[4,5-c]quinolin-1 -yl)-2- methylpropan-2-ol (R848) (237.5 mg, 0.755 mmol) was dissolved into anhydrous N,N- dimethylformamide (5 ml). Boc-L-valine (263.4 mg, 1 .2 mmol) and 4- (dimethylamino)pyridine (187.4 mg, 1.534 mmol) were added. N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (236.1 mg, 1 .232 mmol) was added. The resulting mixture was stirred at room temperature for 3 h. Water was added to quench the reaction. Brine was added. The mixture was extracted with ethyl acetate (2x50 ml). The combined organic solution was dried over anhydrous sodium sulfate, concentrated to dryness. The residue was purified with flash column chromatography on silica gel using 1-10% methanol/dichloromethane to afford product (394.7 mg) as white solid. (0382) [00275] 1H-NMR (500 MHz, CDCI3) delta 8.99 (br., 1 H), 8.15-8.11 (m, 2H), 7.58 (t, J = 7.5 Hz, 1 H), 7.47 (t, J = 7.5 Hz, 1 H), 5.42 (m, 1 H), 4.89 (br, 2 H), 4.77 (s, 2H), 3.63 (q, J = 7.0 Hz, 2H), 3.27 (m, 1 H), 2.45 (br, 1 H), 1.44 (s, 9H), 1.31 (br, 6H), 1.22 (t, J = 7.0 Hz, 3H), 1.14 (br, 3H), 0.93 (d, J = 6.0 Hz, 3H). LC-MS: 514 (MHVz).
(3S,8S,9S,10R,13R,14S,17R)-17-((R)-6-hydroxy-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren3-yl (tert-butoxycarbonyl)-L-valinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 15h;
[0164] To a stirred solution of (tert-butoxycarbonyl)-L-valine (323 mg, 1.49 mmol) in DCM (10 mL) was added DMAP (273 mg, 2.23 mmol), DCC (461 mg, 2.23 mmol) followed by addition of a solution of 25-hydroxy cholesterol 1 (300 mg, 0.746 mmol) in DCM (5.0 mL). The resulting reaction mass was stirred at RT for 15h. After completion of reaction (TLC monitoring), the reaction mixture was filtered through Celite pad and washed with 70% EtOAc in hexane. The filtrate was washed with 5% citric acid (20 mL), saturated solution of NaHC03 (20 mL) and water (20 mL) sequentially. The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to get crude. The crude was purified over flash column (Silica l2g, Redisep), eluted with 25% EtOAc in hexane to give pure compound 1.27 (300 mg, Yield: 66%) as off white solid. 1H-NMR (400 MHz, CDCl3): d 5.37 (s, 1H), 5.01-5.03 (m, 1H), 4.65-4.68 (m, 1H), 4.16-4.18 (m, 1H), 2.30-2.32 (m, 2H), 2.10-2.20 (m, 1H), 1.94-1.99 (m, 2H), 1.85-1.88 (m, 4H), 1.52-1.60 (m, 2H), 1.33-1.45 (m, 15H), 1.17-1.20 (m, 10H), 1.09- 1.16 (m, 4H), 1.01-1.06 (m, 5H), 0.88-0.97 (m, 11H) and 0.67 (s, 3H). LCMS: 602.4 (M+H)+,99.48%.
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 50℃; for 20h;Inert atmosphere;
General procedure: Boc-Val-OH 19 (1.5 equiv) was dissolved in 3 mL DMF. To this was added HATU (2 equiv) and DIEA (5 equiv) to generate the activated ester prior to the addition of the appropriate N-alkyl methylamine hydrochloride 21a-d (1 equiv). The reaction mixture was stirred at 50 under nitrogen overnight. The reaction was diluted with water and extracted with EtOAc (5 × 50 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered through a bed of celite and concentrated in vacuo. The crude product was purified using flash silica gel column chromatography (50% EtOAc: 50% pet. ether), and the target compound obtained on vacuum concentration.
Dissolve 500 mg (1.4 mmol) of raw material icariin (ICT) in 15 ml of dichloromethane, add BOC-valine 270 mg (1.4 mmol),240 mg (1.5 mmol) of carbodiimide (EDCI), 25 mg (0.2 mmol) of 4-dimethylaminopyridine (DMAP), and stirred at room temperature for 1 h.After the reaction was completed, the solvent was distilled off under reduced pressure, and the ethyl acetate was dissolved and purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain 654 mg of a yellow solid product with a yield of 85%. The obtained yellow solid product was dissolved in 10 ml of dichloromethane, and 139 mg (1.39 mmol) of concentrated hydrochloric acid was added under stirring. After the dropwise addition, the mixture was stirred at room temperature for 20 min. The yellow solid product W-1 was 700 mg, and the total yield was 81%
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