* 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.
Reference：
[1] Bulletin of the Chemical Society of Japan, 1981, vol. 54, # 4, p. 1263 - 1264
2
[ 1149-26-4 ]
[ 13139-28-1 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.25 h; Stage #2: With ammonium chloride In N,N-dimethyl-formamide at 23℃; for 16 h;
[0197] To a stuffed solution of compound I (10 g, 39.84 mmol, 1 eq) in DMF (100 mL) was added DIPEA (19.7 mL, 119.5 mmol, 3 eq) and HATU (18.17 g, 47.8 mmol, 1.2 eq) at 0°C and the resulting mixture was stuffed for 15 mm. To the mixture was added ammonium chloride (10.7 g, 199.2 mmol, 5 eq) and the resulting mixture was allowed to stir at 23°C for another 16 h. The mixture was poured into ice cold water (500 mL), the organic components were extracted with EtOAc (3 x 500 mL) and the combined organic layers were washed with aqueous ammonium chloride solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was recrystallized from ethanol to obtain the title compound (9.8 g, 98percent) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) ö 7.35 (m, 6H), 7.12 (d, 1H, J = 9 Hz), 7.01 (s, 1H), 5.03 (s, 2H), 3.80 (t, 1H, J = 8 Hz), 1.95 (m, 1H), 0.85 (m, 6H). LCMS: mlz = 251.2 [M+Hj , RT = 2.81 minutes, (Program P1, Column Y).
93%
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. 4.3.7 Cbz-l-Val-NH2 4d 117 mg (93percent); >99percent ee; coloress solid; mp: 172-175 °C; [α]D25 = +17.8 (c 0.99, DMSO); 1H NMR (400 MHz, DMSO-d6): δ 0.83 (d, J = 6.8 Hz, 3H, CH3), 0.86 (d, J = 6.8 Hz, 3H, CH3), 1.94 (ddd, J = 6.7, 6.8, 6.8 Hz, 1H, CH(CH3)2), 3.80 (dd, J = 6.7, 8.8 Hz, 1H, CHCO), 5.03 (s, 2H, OCH2C6H5), 7.03 (br, 1H, CONHA), 7.16 (d, J = 8.8 Hz, 1H, NHCH), 7.29-7.39 (m, 6H, CONHB, C6H5); 13C NMR (100 MHz, DMSO-d6): δ 18.0, 19.3, 30.1, 60.0, 65.3, 127.6, 127.7, 128.3, 137.1, 156.1, 173.2; IR (KBr, vmax/cm-1): 3381 (CONH), 3319 (CONH), 3203 (CONH), 1654 (CON); HRMS (ESI-TOF): Calcd for C13H18N2O3Na (M+Na)+: 273.1210, found: 273.1193; The enantiomeric ratio was determined by HPLC (Chiralcel AD: hexane/2-propanol = 90/10): Tr 11.5 min.
63.8%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -78℃; for 1 h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 20℃; for 2 h;
Step 1. To a solution of 27-1 (8 g, 31.8 mmol) and Et3N (6.43 g, 63.6 mmol) in dry THF (100 mL) at -78°C was added dropwise a solution of ethyl chloro formate (3.45 g, 31.8 mmol) in THF (10 mL). After the reaction was stirred at -78°C for 1 h, NH3.H20 (5 mL) was added. The reaction was warmed to r.t. over 2 h. White solid was collected by filtration and dried to give 27-2 (5.1 g, 63.8percent).
53.15%
With pyridine; di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate In 1,4-dioxane at 0 - 20℃;
To a solution of (S)-2-(benzyloxycarbonylamino)-3-methylbutanoic acid (10.0 g, 39.84 mmol) in 1,4-dioxane (50 mL) was added di-tert-butyl dicarbonate (11.95 g, 51.79mmol) in portions at 0°C. Then pyridine (2 mL, 25.76 mmol) was added drop-wise at 0°C, followed by ammonium bicarbonate (3.94 g, 50.43 mmol) in portions. The reaction was stirred at room temperature overnight. The mixture was poured into ice water and filtered. The filter cake was washed with water and dried under vacuum. The filter cake was then re-crystallized from dioxane/water (80 mL, 9: 1, v/v) to give (S)-benzyl (1-amino-3-methyl-1-oxobutan-2-yl)carbamate(5.3 g, 53.15percent yield) as a white solid. LC-MS (ESI) found: 251 [M+Hf’, ee>99percent, (CHIRALPAK AS-H, 15percent ethanol/ hexane)
Reference：
[1] Patent: WO2015/95128, 2015, A1, . Location in patent: Paragraph 0195; 0196; 0197
[2] Tetrahedron Asymmetry, 2017, vol. 28, # 12, p. 1690 - 1699
[3] Chemische Berichte, 1983, vol. 116, # 5, p. 2037 - 2040
[4] Tetrahedron Letters, 1995, vol. 36, # 39, p. 7115 - 7118
[5] Chemical Communications, 2017, vol. 53, # 75, p. 10362 - 10365
[6] Journal of Organic Chemistry, 2009, vol. 74, # 11, p. 4177 - 4187
[7] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 120
[8] Patent: WO2018/31877, 2018, A1, . Location in patent: Paragraph 00158
[9] Chemische Berichte, 1964, vol. 97, p. 1197 - 1206
[10] Journal of Organic Chemistry, 1999, vol. 64, # 2-5, p. 1657 - 1666
[11] Organic and Biomolecular Chemistry, 2006, vol. 4, # 1, p. 38 - 40
[12] Organic Letters, 2007, vol. 9, # 13, p. 2521 - 2524
[13] Chemistry - A European Journal, 2006, vol. 12, # 20, p. 5383 - 5397
[14] Journal of Organic Chemistry, 2009, vol. 74, # 15, p. 5260 - 5266
[15] Organic and Biomolecular Chemistry, 2012, vol. 10, # 48, p. 9660 - 9663
[16] Chemistry Letters, 2013, vol. 42, # 6, p. 580 - 582
3
[ 24210-19-3 ]
[ 13139-28-1 ]
Reference：
[1] Journal of the Chemical Society. Perkin transactions 1, 1976, # 3, p. 259 - 264
[2] Synthesis (Germany), 2015, vol. 47, # 23, p. 3758 - 3766
4
[ 2018-66-8 ]
[ 13139-28-1 ]
Reference：
[1] Journal of the American Chemical Society, 1994, vol. 116, # 15, p. 6545 - 6557
5
[ 3496-11-5 ]
[ 13139-28-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 17, p. 3289 - 3299
6
[ 119153-86-5 ]
[ 13139-28-1 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 3, p. 591 - 600
[2] Amino Acids, 2010, vol. 39, # 2, p. 533 - 538
[3] Organic and Biomolecular Chemistry, 2012, vol. 10, # 48, p. 9660 - 9663
[4] Chemistry Letters, 2013, vol. 42, # 6, p. 580 - 582
[0197] To a stuffed solution of compound I (10 g, 39.84 mmol, 1 eq) in DMF (100 mL) was added DIPEA (19.7 mL, 119.5 mmol, 3 eq) and HATU (18.17 g, 47.8 mmol, 1.2 eq) at 0C and the resulting mixture was stuffed for 15 mm. To the mixture was added ammonium chloride (10.7 g, 199.2 mmol, 5 eq) and the resulting mixture was allowed to stir at 23C for another 16 h. The mixture was poured into ice cold water (500 mL), the organic components were extracted with EtOAc (3 x 500 mL) and the combined organic layers were washed with aqueous ammonium chloride solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was recrystallized from ethanol to obtain the title compound (9.8 g, 98%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) oe 7.35 (m, 6H), 7.12 (d, 1H, J = 9 Hz), 7.01 (s, 1H), 5.03 (s, 2H), 3.80 (t, 1H, J = 8 Hz), 1.95 (m, 1H), 0.85 (m, 6H). LCMS: mlz = 251.2 [M+Hj , RT = 2.81 minutes, (Program P1, Column Y).
93%
General procedure: To a colorless solution of 150mg (0.50mmol) of Cbz-L-Phe-OH 3a in 10mL of THF were added 67muL (0.70mmol, 1.4equiv) of ClCO2Et and 209muL (1.5mmol, 3.0equiv) of Et3N at 0C. After stirring for 30min at 0C, 0.75 ml of a 1.0M aqueous solution of NH4Cl (0.75mmol, 1.5equiv) were added at 0C to the colorless suspension. The mixture was stirred for 30min at 0C 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 (86% yield) of Cbz-L-Phe-NH2 4a. 4.3.7 Cbz-l-Val-NH2 4d 117?mg (93%); >99% ee; coloress solid; mp: 172-175?C; [alpha]D25?=?+17.8 (c 0.99, DMSO); 1H NMR (400?MHz, DMSO-d6): delta 0.83 (d, J?=?6.8?Hz, 3H, CH3), 0.86 (d, J?=?6.8?Hz, 3H, CH3), 1.94 (ddd, J?=?6.7, 6.8, 6.8?Hz, 1H, CH(CH3)2), 3.80 (dd, J?=?6.7, 8.8?Hz, 1H, CHCO), 5.03 (s, 2H, OCH2C6H5), 7.03 (br, 1H, CONHA), 7.16 (d, J?=?8.8?Hz, 1H, NHCH), 7.29-7.39 (m, 6H, CONHB, C6H5); 13C NMR (100?MHz, DMSO-d6): delta 18.0, 19.3, 30.1, 60.0, 65.3, 127.6, 127.7, 128.3, 137.1, 156.1, 173.2; IR (KBr, vmax/cm-1): 3381 (CONH), 3319 (CONH), 3203 (CONH), 1654 (CON); HRMS (ESI-TOF): Calcd for C13H18N2O3Na (M+Na)+: 273.1210, found: 273.1193; The enantiomeric ratio was determined by HPLC (Chiralcel AD: hexane/2-propanol?=?90/10): Tr 11.5?min.
63.8%
Step 1. To a solution of 27-1 (8 g, 31.8 mmol) and Et3N (6.43 g, 63.6 mmol) in dry THF (100 mL) at -78C was added dropwise a solution of ethyl chloro formate (3.45 g, 31.8 mmol) in THF (10 mL). After the reaction was stirred at -78C for 1 h, NH3.H20 (5 mL) was added. The reaction was warmed to r.t. over 2 h. White solid was collected by filtration and dried to give 27-2 (5.1 g, 63.8%).
53.15%
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate; In 1,4-dioxane; at 0 - 20℃;
To a solution of (S)-2-(benzyloxycarbonylamino)-3-methylbutanoic acid (10.0 g, 39.84 mmol) in 1,4-dioxane (50 mL) was added di-tert-butyl dicarbonate (11.95 g, 51.79mmol) in portions at 0C. Then pyridine (2 mL, 25.76 mmol) was added drop-wise at 0C, followed by ammonium bicarbonate (3.94 g, 50.43 mmol) in portions. The reaction was stirred at room temperature overnight. The mixture was poured into ice water and filtered. The filter cake was washed with water and dried under vacuum. The filter cake was then re-crystallized from dioxane/water (80 mL, 9: 1, v/v) to give (S)-benzyl (1-amino-3-methyl-1-oxobutan-2-yl)carbamate(5.3 g, 53.15% yield) as a white solid. LC-MS (ESI) found: 251 [M+Hf?, ee>99%, (CHIRALPAK AS-H, 15% ethanol/ hexane)
General procedure: The appropriate N-protected amino/peptide acid (1.0 mmol) was dissolved in THF, to which NMM (1.5 mmol) and ECF (1.5 mmol) were added at -15 C, followed by the addition of NH4HCO3 (1.5 mmol) to obtain the corresponding amide. The reaction mixture was stirred until the completion of the reaction and the progress of the reaction was checked by TLC. After the removal of THF, the product was extracted into ethyl acetate (15 mL) and the organic layer was washed with dilute HCl solution (10 mL) or citric acid solution (10 mL) in the case of the Boc-protected compounds, then with Na2CO3 solution (15 mL x 2), water (15 mL) and brine (15 mL). The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The amide thus formed was then treated with P2S5 (0.5 mmol) to form the thioamide under ultrasonic conditions for 2-3 hrs. The resulting thioamide in dry THF was reacted with chloroacetaldehyde (1.0 mmol) under reflux conditions for 2 hrs. N-Protected thiazoles were obtained in good yield after simple acid-base work up and purified through column chromatography using EtOAc:hexane (3:7) as an eluent.
With ammonium hydroxide; In water; at 20℃; for 16h;Inert atmosphere;
General procedure: A 0.2 M solution of the corresponding methyl ester in aq NH4OH (28-30%) was stirred at r.t. for 16 h. The solvent was evaporated to affordthe amide, which was, in some cases, purified by silica gel chromatography. The known amides 3, 33 5a,34 5b, 6c 5h,35 11a,36 11b,37 11c,3611e,38 11h,4 11i,39 11j,39 13,40 14,41 20,42 and 2343 were synthesized following the general procedure described above. Compound 5e was synthesized following the literature.44
2-[2-(1-benzyloxycarbonylamino-2-methyl-propyl)-5-methyl-oxazole-4-carbonyl]-amino}-3-(1<i>H</i>-indol-3-yl)-3-oxo-propionic acid methyl ester[ No CAS ]
2-[2-(1-benzyloxycarbonylamino-2-methyl-propyl)-5-(3-bromo-benzyl)-oxazole-4-carbonyl]-amino}-3-(4-bromo-1<i>H</i>-indol-3-yl)-propionic acid methyl ester[ No CAS ]
(R)-2-((S)-2-{(S)-2-[(E)-2-((S)-2-Amino-3-methyl-butyrylamino)-but-2-enoyloxy]-3-phenyl-propionyloxy}-4-methyl-pentanoylamino)-4-methyl-pentanoic acid pentafluorophenyl ester; compound with trifluoro-acetic acid[ No CAS ]
A solution of 14001a (10.0 g, 40.0 mmol Indofine chemicals) in toluene (150 mL) was treated with BH3-DMS (-2 M, 40 mL) and heated at 90 C overnight. The reaction mixture was cooled to 0 C and diluted with 2 M aq. NaOH. The reaction mixture was heated at 90 C for 15 min. The aqueous layer was extracted with CH2CI2 and the combined organic layers were dried (MgS04) filtered concentrated in vacuo to yield 11 g of 14001b.
General procedure: To a solution of an N-Cbz-2-aminoalkanamide 1 (3.0 mmol) and aldehyde 2 (3.5 mmol) in dried acetonitrile (15 mL) was added aryldichlorophosphine 3 (4.0 mmol) under stirring and a nitrogen atmosphere. After the N-Cbz-2-aminoalkanamide 2 was dissolved completely, the resulting solution was stirred in refluxing acetonitrile at 80 C for 1 h. The reaction mixture was allowed to cool to room temperature under stirring. Hydroxyl ester 6 or ethanol (6.0 mmol) was added dropwise. After stirring for 15 min, triethylamine (1.67 mL, 1.22 g, 12 mmol) was added dropwise and the resulting reaction mixture was stirred for another 6 h. After removal of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate (50 mL×3), saturated brine (50 mL×2), and dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was separated on a silica gel column with a mixture of petroleum ether (30-60 C) and ethyl acetate as an eluent with gradient elution to give the desired product phosphinodepsipeptide 7. (Caution: The silica gel column was buffered by 0.5% triethylamine before the sample was loaded. The desired peptide 7 shows very weak fluorescent intensity under UV light. It is better to monitor collective fractions in the column separation after concentration). The aqueous solution was adjusted to pH 1 with 6 mol/L HCl and extracted with ethyl acetate (50 mL×3), the organic phase was dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was crystallized from a mixture of ethyl acetate and hexanes or methanol (ethanol) and diethyl ether to afford the corresponding phosphinic acid 5.
((S)-2-methyl-1-thiocarbamoylpropyl)carbamic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90.6%
With Lawessons reagent; In tetrahydrofuran; at 70℃; for 16h;
Step 2. A solution of 27-2 (3 g, 12 mmol) and Lawesson's Reagent (9.7 g, 24 mmol) in dry THF (60 mL) was stirred 70C for 16 h. Solvent was removed and residue was purified by column (EtOAc: henaxe= 1 :3) to give 27-3 (2.9 g, 90.6%). LCMS (ESI): m/z 267.1 [M+H+], 289.1 [M+Na+].
31%
With Lawessons reagent; In dichloromethane; at 23℃;Reflux;
[0199] To a stirred solution of compound 11(5.5 g, 22 mmol, 1 eq) in dry CH2C12 (100 mL) at 23C was added Lawesson?s reagent (5.5 g, 13.2 mmol, 0.7 eq) and the mixture was heated at reflux for 2-3 h. The mixture was cooled to room temperature and concentrated in vacuo to obtain a crude material which was purified by gravity column chromatography using silica gel (100-200 mesh), eluting with 1.5% MeOH/CH2C12 to obtain the title compound (1.8 g, 31%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) oe 9.63 (s, 1H), 9.21 (s, 1H), 7.32 (m, 5H), 7.13 (d, 1H, J= 9Hz), 5.03 (s, 2H), 4.03 (m, 1H), 2.06 (m, 1H), 0.95 (m, 6H). LCMS: m/z = 267.2 [M+Hj, RT = 3.10 minutes, (Program P1, Column Y).
With tetraphosphorus decasulfide; In tetrahydrofuran;Sonication;
General procedure: The appropriate N-protected amino/peptide acid (1.0 mmol) was dissolved in THF, to which NMM (1.5 mmol) and ECF (1.5 mmol) were added at -15 C, followed by the addition of NH4HCO3 (1.5 mmol) to obtain the corresponding amide. The reaction mixture was stirred until the completion of the reaction and the progress of the reaction was checked by TLC. After the removal of THF, the product was extracted into ethyl acetate (15 mL) and the organic layer was washed with dilute HCl solution (10 mL) or citric acid solution (10 mL) in the case of the Boc-protected compounds, then with Na2CO3 solution (15 mL x 2), water (15 mL) and brine (15 mL). The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The amide thus formed was then treated with P2S5 (0.5 mmol) to form the thioamide under ultrasonic conditions for 2-3 hrs. The resulting thioamide in dry THF was reacted with chloroacetaldehyde (1.0 mmol) under reflux conditions for 2 hrs. N-Protected thiazoles were obtained in good yield after simple acid-base work up and purified through column chromatography using EtOAc:hexane (3:7) as an eluent.
7-(4-((4-((S)-2-(2-((S)-1-(benzyloxycarbonylamino)-2-methylpropyl)thiazol-5-yl)propanamido)benzyloxy)carbonyl)piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid[ No CAS ]
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