* 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 water; sodium hydroxide In methanol at 25 - 30℃; for 1 h;
To a solution of methyl 2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)-3- phenyipropanoate (2.Og, 4.69mmol) in MeOH (20m1), NaOH (0.38g, 9.38mmol) in H20 (lOmI) was added at 25-30°C. The reaction mixture was stirred for lh at 25-30°C. After lh MeOH was evaporated & aqueous layer was acidified with citric acid solution, solid was obtained. Filter the solid & dried it to get the title compound as a white solid (1.89, 98percent yield); ESI-MS: 413.2 (M+H).
2.3 g
at 20℃; for 3 h;
(BOC)FF–OH (2): Compound 1(3.0 g, 7.0 mmol) was dissolved in methanol (30 ml) and 1(N) NaOH (10 ml) was added into the solution. The reaction mixture was stirred for 3 h at room temperature. Reaction mixture was concentrated to completely remove the methanol under reduced pressure. The residue was acidified with 1 N HCl (15 ml) and extracted in dichloromethane (3×25 ml). The combined organic layer was washed with water followed by brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to form compound 2 (2.3 g, 5.5 mmol). mp=82–84 °C, Rf [5percent methanol in dichloromethane]=0.3, =−00.02 [c 0.12, methanol]. 1H NMR (400 MHz, CD3OD, TMS, δ ppm): 1.23 (s, 9H); 2.5–2.6 (m, 1H); 2.70–2.95 (m, 2H); 3.0–3.2 (m, 1H); 4.15–4.18 (m, 1H); 4.53–4.57 (m, 1H); 7.09–7.15 (m, 10H); FTIR (KBr, cm−1): 1520 (amide II); 1660 (amide I); FABMS (M+1): 413; Anal. Calcd for C23H28N2O5, C, 66.97; H, 6.84; N, 6.79; found, C, 67.11; H, 6.66; N, 6.12.
Reference:
[1] Patent: WO2016/181408, 2016, A2, . Location in patent: Page/Page column 32
[2] Chemical Communications, 2016, vol. 52, # 28, p. 5045 - 5048
[3] Journal of the American Chemical Society, 2016, vol. 138, # 38, p. 12387 - 12394
[4] European Journal of Medicinal Chemistry, 1992, vol. 27, # 3, p. 179 - 186
[5] Angewandte Chemie - International Edition, 2017, vol. 56, # 43, p. 13288 - 13292[6] Angew. Chem., 2017, vol. 129, p. 13473 - 13477,5
[7] Chemistry - A European Journal, 2009, vol. 15, # 28, p. 6902 - 6909
[8] Soft Matter, 2012, vol. 8, # 20, p. 5621 - 5628
[9] Chemistry - An Asian Journal, 2013, vol. 8, # 1, p. 113 - 120
[10] Organic Letters, 2004, vol. 6, # 20, p. 3433 - 3436
[11] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 4, p. 1102 - 1106
[12] Polymer, 2012, vol. 53, # 8, p. 1694 - 1702
[13] Tetrahedron, 2013, vol. 69, # 8, p. 2004 - 2009
[14] Chemical Communications, 2014, vol. 50, # 42, p. 5551 - 5553
2
[ 24424-99-5 ]
[ 2577-40-4 ]
[ 13122-90-2 ]
Yield
Reaction Conditions
Operation in experiment
71%
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 3.5 h;
A solution of (Boc) 20 (800 mg, 3.5 mmol) in 1,4-dioxane (5 ML) was added to a cold (0 °C) solution OF DI-L-PHE-PHE (1 g, 3.20 mmol) in 1,4-dioxane (6 mL) and 1N NAOH (3.3 mL). The mixture was stirred at 0-5 C FOR 2 hours. Another portion of (BOC) 20 (100 mg) was added and the mixture was stirred for an additional 60 minutes at 0-5 °C then at room temperature for 30 minutes. The mixture was then evaporated to dryness. The solid was taken in a mixture of water/EtOAc and pH was adjusted to 2 with 2N HCI. The aqueous layer was extracted 3 times with EtOAc. The combined organic layers were dried with brine and the solvent was evaporated. Some solid was insoluble in a mixture of EtOAc/CHC13 : it was removed by filtration. The desired N Boc-L-Phe-L-Phe 1 was obtained as a white foamy solid (913.7 mg, 2.215 mmol, 71percent yield).
Reference:
[1] Patent: WO2004/113275, 2004, A2, . Location in patent: Page 158; 159
[2] Journal of the American Chemical Society, 2007, vol. 129, # 10, p. 2959 - 2966
[3] Angewandte Chemie - International Edition, 2008, vol. 47, # 9, p. 1758 - 1761
3
[ 63-91-2 ]
[ 3674-06-4 ]
[ 13122-90-2 ]
Reference:
[1] Chemistry - A European Journal, 2013, vol. 19, # 50, p. 16934 - 16937
[2] Research on Chemical Intermediates, 2017, vol. 43, # 10, p. 5305 - 5320
[3] Chemical Communications (Cambridge, United Kingdom), 2018, vol. 54, # 86, p. 12222 - 12225
4
[ 2577-90-4 ]
[ 13122-90-2 ]
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 4, p. 1102 - 1106
[2] Organic Letters, 2004, vol. 6, # 20, p. 3433 - 3436
[3] Soft Matter, 2012, vol. 8, # 20, p. 5621 - 5628
[4] Chemistry - An Asian Journal, 2013, vol. 8, # 1, p. 113 - 120
[5] Patent: WO2016/181408, 2016, A2,
[6] Angewandte Chemie - International Edition, 2017, vol. 56, # 43, p. 13288 - 13292[7] Angew. Chem., 2017, vol. 129, p. 13473 - 13477,5
5
[ 474316-97-7 ]
[ 13122-90-2 ]
Reference:
[1] Journal of Organic Chemistry, 2002, vol. 67, # 20, p. 6902 - 6910
Reference:
[1] Liebigs Annalen der Chemie, 1988, p. 331 - 336
[2] European Journal of Medicinal Chemistry, 1992, vol. 27, # 3, p. 179 - 186
[3] Soft Matter, 2012, vol. 8, # 20, p. 5621 - 5628
[4] Chemistry - An Asian Journal, 2013, vol. 8, # 1, p. 113 - 120
[5] Chemical Communications, 2014, vol. 50, # 42, p. 5551 - 5553
[6] Chemical Communications, 2016, vol. 52, # 28, p. 5045 - 5048
[7] Journal of the American Chemical Society, 2016, vol. 138, # 38, p. 12387 - 12394
[8] Patent: WO2016/181408, 2016, A2,
[9] Research on Chemical Intermediates, 2017, vol. 43, # 10, p. 5305 - 5320
[10] Angewandte Chemie - International Edition, 2017, vol. 56, # 43, p. 13288 - 13292[11] Angew. Chem., 2017, vol. 129, p. 13473 - 13477,5
8
[ 63-91-2 ]
[ 13122-90-2 ]
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 4, p. 1102 - 1106
[2] Soft Matter, 2012, vol. 8, # 20, p. 5621 - 5628
[3] Chemistry - An Asian Journal, 2013, vol. 8, # 1, p. 113 - 120
[4] Chemistry - An Asian Journal, 2013, vol. 8, # 1, p. 113 - 120
[5] Chemical Communications, 2016, vol. 52, # 28, p. 5045 - 5048
9
[ 63-91-2 ]
[ 113035-34-0 ]
[ 13122-90-2 ]
Reference:
[1] Liebigs Annalen der Chemie, 1988, p. 331 - 336
10
[ 7524-50-7 ]
[ 13122-90-2 ]
Reference:
[1] European Journal of Medicinal Chemistry, 1992, vol. 27, # 3, p. 179 - 186
[2] Chemical Communications, 2014, vol. 50, # 42, p. 5551 - 5553
[3] Journal of the American Chemical Society, 2016, vol. 138, # 38, p. 12387 - 12394
11
[ 16879-80-4 ]
[ 13122-90-2 ]
Reference:
[1] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 23, p. 8365 - 8373
12
[ 24424-99-5 ]
[ 13122-90-2 ]
Reference:
[1] Soft Matter, 2012, vol. 8, # 20, p. 5621 - 5628
[2] Chemistry - An Asian Journal, 2013, vol. 8, # 1, p. 113 - 120
[3] Chemical Communications, 2016, vol. 52, # 28, p. 5045 - 5048
With dicyclohexyl-carbodiimide; In 1,2-dimethoxyethane; at 0℃; for 2h;Inert atmosphere;
(BOC)FF-NHS (3): Compound 2 (0.5 g, 1.2 mmol) and N-Hydroxy succinimide (0.153 g, 1.3 mmol) were dissolved in 1,2-dimethoxy ethane (10 ml) and reaction mixture was cooled to 0 C under nitrogen atmosphere. A solution of DCC (0.274 g, 1.3 mmol) in 1,2-dimethoxy ethane (5 ml) was added into the reaction mixture dropwise and reaction mixture was stirred for 2 h at 0 C. After which the reaction mixture was kept in a freezer overnight. The reaction mixture was filtered and filtrate was concentrated under reduced pressure. Solid material was washed with diethyl ether and dried under high vaccum. Crude compound 3 (0.6 g, 1.1 mmol) was directly used for synthesis of compounds 4 and 6.
With dicyclohexyl-carbodiimide; In dichloromethane; at -5℃;
General procedure: A round-bottom flask was charged with amino acid (2.5 mmol), NaHCO3 (5 mmol, or 7.5 mmol in the case of using TFA salt of amino acid) and THF-H2O (1:1,20 mL). A solution of succinimide-activated amino acid (2.75 mmol) in THF (15 mL) was added dropwise to the mixture, and the reaction was stirred at rt for 1-2 days. THF was removed on a rotary evaporator, the reaction mixture was acidified with 0.5 M HCl to pH 2, and the product was extracted with ethyl acetate (3 x 30 mL). The organic layers were washed with water and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, the product was purified by column chromatography on silica gel.
{(S)-1-[(S)-1-((1S,2R,3S)-1-Cyclohexylmethyl-2,3-dihydroxy-5-methyl-hexylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester[ No CAS ]
(E)-(2R,5S)-5-((3R,4S)-4-Amino-2,2-difluoro-3-hydroxy-6-methyl-heptanoylamino)-2-benzyl-7-methyl-oct-3-enoic acid methyl ester; compound with trifluoro-acetic acid[ No CAS ]
2(R,S)-<<hydroxy<1(R)-<N-<(tert-butoxycarbonyl)-L-phenylalanyl-L-phenylalanyl>amino>-3-methylbutyl>phosphinyl>methyl>-3-methylbutanoyl-L-isoleucyl-L-histidine amide[ No CAS ]
With water; sodium hydroxide; In methanol; at 25 - 30℃; for 1h;
To a solution of methyl 2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)-3- phenyipropanoate (2.Og, 4.69mmol) in MeOH (20m1), NaOH (0.38g, 9.38mmol) in H20 (lOmI) was added at 25-30C. The reaction mixture was stirred for lh at 25-30C. After lh MeOH was evaporated & aqueous layer was acidified with citric acid solution, solid was obtained. Filter the solid & dried it to get the title compound as a white solid (1.89, 98% yield); ESI-MS: 413.2 (M+H).
2.3 g
With methanol; sodium hydroxide; at 20℃; for 3h;
(BOC)FF-OH (2): Compound 1(3.0 g, 7.0 mmol) was dissolved in methanol (30 ml) and 1(N) NaOH (10 ml) was added into the solution. The reaction mixture was stirred for 3 h at room temperature. Reaction mixture was concentrated to completely remove the methanol under reduced pressure. The residue was acidified with 1 N HCl (15 ml) and extracted in dichloromethane (3×25 ml). The combined organic layer was washed with water followed by brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to form compound 2 (2.3 g, 5.5 mmol). mp=82-84 C, Rf [5% methanol in dichloromethane]=0.3, =-00.02 [c 0.12, methanol]. 1H NMR (400 MHz, CD3OD, TMS, delta ppm): 1.23 (s, 9H); 2.5-2.6 (m, 1H); 2.70-2.95 (m, 2H); 3.0-3.2 (m, 1H); 4.15-4.18 (m, 1H); 4.53-4.57 (m, 1H); 7.09-7.15 (m, 10H); FTIR (KBr, cm-1): 1520 (amide II); 1660 (amide I); FABMS (M+1): 413; Anal. Calcd for C23H28N2O5, C, 66.97; H, 6.84; N, 6.79; found, C, 67.11; H, 6.66; N, 6.12.
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 3.5h;
A solution of (Boc) 20 (800 mg, 3.5 mmol) in 1,4-dioxane (5 ML) was added to a cold (0 C) solution OF DI-L-PHE-PHE (1 g, 3.20 mmol) in 1,4-dioxane (6 mL) and 1N NAOH (3.3 mL). The mixture was stirred at 0-5 C FOR 2 hours. Another portion of (BOC) 20 (100 mg) was added and the mixture was stirred for an additional 60 minutes at 0-5 C then at room temperature for 30 minutes. The mixture was then evaporated to dryness. The solid was taken in a mixture of water/EtOAc and pH was adjusted to 2 with 2N HCI. The aqueous layer was extracted 3 times with EtOAc. The combined organic layers were dried with brine and the solvent was evaporated. Some solid was insoluble in a mixture of EtOAc/CHC13 : it was removed by filtration. The desired N Boc-L-Phe-L-Phe 1 was obtained as a white foamy solid (913.7 mg, 2.215 mmol, 71% yield).
6-<i>tert</i>-butoxycarbonylamino-2-[2-(2-<i>tert</i>-butoxycarbonylamino-3-phenyl-propionylamino)-3-phenyl-propionylamino]-hexanoic acid methyl ester[ No CAS ]
Trimethyl-(10-{(S)-3-phenyl-2-[(S)-3-phenyl-2-((S)-3-phenyl-2-tridecanoylamino-propionylamino)-propionylamino]-propionyloxy}-decyl)-ammonium; bromide[ No CAS ]
(R)-4-{(3R,5R,8R,9S,10S,13R,14S,17R)-3-[(S)-2-((S)-2-tert-Butoxycarbonylamino-3-phenyl-propionylamino)-3-phenyl-propionylamino]-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl}-pentanoic acid[ No CAS ]
(R)-4-{(3R,5R,8R,9S,10S,12S,13R,14S,17R)-12-Acetoxy-3-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-phenyl-propionylamino)-3-phenyl-propionylamino]-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl}-pentanoic acid[ No CAS ]
(R)-4-{(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-7,12-Diacetoxy-3-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-phenyl-propionylamino)-3-phenyl-propionylamino]-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl}-pentanoic acid[ No CAS ]
(R)-4-{(3R,5R,8R,9S,10S,12S,13R,14S,17R)-12-Acetoxy-3-[(S)-2-((S)-2-amino-3-phenyl-propionylamino)-3-phenyl-propionylamino]-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl}-pentanoic acid pentafluorophenyl ester[ No CAS ]
(R)-4-{(3R,5R,8R,9S,10S,13R,14S,17R)-3-[(S)-2-((S)-2-tert-Butoxycarbonylamino-3-phenyl-propionylamino)-3-phenyl-propionylamino]-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl}-pentanoic acid pentafluorophenyl ester[ No CAS ]
(R)-4-{(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-7,12-Diacetoxy-3-[(S)-2-((S)-2-amino-3-phenyl-propionylamino)-3-phenyl-propionylamino]-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl}-pentanoic acid pentafluorophenyl ester[ No CAS ]
(R)-4-{(3R,5R,8R,9S,10S,12S,13R,14S,17R)-12-Acetoxy-3-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-phenyl-propionylamino)-3-phenyl-propionylamino]-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl}-pentanoic acid pentafluorophenyl ester[ No CAS ]
(R)-4-{(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-7,12-Diacetoxy-3-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-phenyl-propionylamino)-3-phenyl-propionylamino]-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl}-pentanoic acid pentafluorophenyl ester[ No CAS ]
(10-{(S)-1-[(S)-1-((S)-1,3-Bis-dodecyloxycarbonyl-propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-phenyl-ethylcarbamoyl}-decyl)-trimethyl-ammonium; bromide[ No CAS ]
((S)-1-{(S)-1-[(1S,2S)-1-Cyclohexylmethyl-2-hydroxy-4-(propane-2-sulfonyl)-butylcarbamoyl]-2-phenyl-ethylcarbamoyl}-2-phenyl-ethyl)-carbamic acid tert-butyl ester[ No CAS ]
L-(N-Boc)-Phe-L-Phe-homotaurine isobutyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
HOBT (340 mg, 2.215 mmol) was added to a cold (0-5 C) solution OF N-BOC-L- Phe-L-Phe 1 (913.7 mg, 2. 215 MMOL) and homotaurine isobutyl ester 2 (423 mg, 2,21 mmol) in dichloromethane (anhydrous, 30 mL). After 5 minutes, a solution of 1- CYCLOHEXYL-3-(2-MORPHOLIN, OETHYL) CARBODIIMIDE METHO-P-TOLUENESULFONATE (982 MG, 2.215 mmol) in dichloromethane (10 mL) was added dropwise. The solution was stirred overnight at room temperature. The mixture was diluted with dichloromethane (50 mL) and the organic layer was washed sequentially with 1N NAHS04, aqueous saturated NAHCO3, and brine, and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. Three compounds in the mixture were shown on TLC. Since the impurities were less soluble in methanol, repeated treatment with methanol followed by filtration removed most of the impurities. Column chromatography on silica gel (2% MeOH in CHC13) afforded the tripeptide 3 as amber glassy solid (156.1 mg, 12%).