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CAS No. : | 171567-86-5 | MDL No. : | MFCD21234526 |
Formula : | C7H13NO4 | Boiling Point : | No data available |
Linear Structure Formula : | - | InChI Key : | CEFVHPDFGLDQKU-RXMQYKEDSA-N |
M.W : | 175.18 | Pubchem ID : | 28377962 |
Synonyms : |
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Chemical Name : | (R)-2-((Methoxycarbonyl)amino)-3-methylbutanoic acid |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium carbonate; sodium hydroxide; at 20℃; for 3.25h;Cooling with ice; | General procedure: Preparative Example 1 Preparation of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid Sodium carbonate (1.83 g, 17.2 mmol) was added to 1 M sodium hydroxide solution (33 ml, 33 mmol) containing L-valine (3.9 g, 33.29 mmol) dissolved therein, which was cooled down by using ice water. Methyl chloroformate (2.8 ml, 36.1 mmol) was slowly added to the cooled reaction mixture. Once the loading was completed, the iced water was eliminated and the temperature of the mixture was raised to room temperature, followed by stifling for 3.25 hours. Then, the reaction product was washed with ether (17 ml) three times. The water later was cooled down with ice water and then acidized with HCl (conc. HCl) to pH 1?pH 2. The acidized water layer was extracted with dichloromethane (17 ml) three times, and the extracted organic was dried over MgSO4 and filtered. The filtered organic layer was concentrated under reduced pressure and as a result the target compound was obtained as a white solid (5 g, yield: 86%) without any additional purification procedure. 1H NMR (400 MHz, DMSO-d6, delta=2.5 ppm): 12.51 (br s, 1H), 7.32 (d, 1H), 3.84 (t, 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.88 (d, J=12, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.0% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | HATU (43.6 mg, 0.115 mmol) was added to a stirred solution of 2, 6-bis (2- ( (2S) -2 -pyrrolidirxyl) -lH-imidazol- 5-yl)benzo[l,2~d:4,5~d']bis[l,3] thiazole (27 mg, 0.029 mmol), (JR) -2- (methoxycarbonylamino) ~3-methylbutanoic acid (20.6 mg, 0.118 mmol) and DIEA (0.051 mL, 0.29 mmol) in dimethylformamide (2 mL) . The reaction was stirred overnight at room temperature. The reaction mixture was diluted with methanol (2 mL) and water (2 mL) , stirred for 15 min at room temperature and concentrated to dryness in vacuo. The residue was purified by preparative HPLC (acetonitrile/ water/ 0.1% TFA) to afford methyl ( (IR) -1- { { (2S) -2- {4- (6- (2- ( (2S) -1- ( (2R) -2- ( (methoxycarbonyl) amino) -3-methylbutanoyl) -2- pyrrolidinyl) -lH-imidazol-4-yl) [1, 3] thiazolo [5,4- f] [l,3]benzothiazol-2-yl) -IH- imidazol-2-yl) -1- pyrrolidinyl) carbonyl) -2-methylpropyl) carbamate bistrifluoroacetate (13.0 mg, 0.013 mmol, 44.0 % yield) as a pale yellow solid.LC-MS retention time 1.30 min; m/z 777.2 (MH+) . LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4 tnL/rain, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solventB, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% water / 0.1% TFA and solvent B was 90% acetonitrile / 10% water / 0.1% TPA. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD-O4) delta ppm 8.64 - 8.55(m, 2H) , 8.15 - 7.95 (m, 2H), 5.29 (dd, J=Q.1, 3.5 Hz, 2H), 4.27 (d, J 7.3 Hz, 2H), 4.16 - 4.04 (m, 2H) ,78 3.87 - 3.79 (m, 2H) , 3.68 (s, 6H) , 2.53 - 2.39 (m, 2H) , 2.31 - 2.01 (m, 8H) , 1.07 ~ 0.82 {m, 12H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | HATU (84 mg, 0.22 mmol) was added to a stirred solution of 5 '-(2,2'- bithiene-5,5'-diyl)bis(2-((2S)-2-pyrrolidinyl)-lH-imidazole) (40 mg, 0.092 mmol), <strong>[171567-86-5](R)-2-(methoxycarbonylamino)-3-methylbutanoic acid</strong> (40 mg, 0.23 mmol) and DIEA (0.16 mL, 0.92 mmol) in dimethylformamide (3 mL) at room temperature. The reaction was stirred for 16 h, diluted with methanol (2 mL) and water (2 mL) and stirred for 15 min. The reaction mixture was concentrated to dryness and purified by preparative HPLC (Waters Sunfire C18 column 30 X 150 mm 5u, eluted with a gradient of 20 to 90 % acetonitrile/water/0.1 % TFA). Fractions containing the desired product were concentrated and repurified by preparative HPLC (Waters Sunfire CI 8 column 30 X 150 mm 5u, eluted with a gradient of 30 to 100 % acetonitrile/water/10 mmol ammonium acetate) to yield the free base of the desired compound. A final preparative HPLC (Waters Sunfire C18 30 X 100 mm 5 u, eluted with a gradient of 10 to 85 % methanol/water/0.1 % TFA) purification was performed to yield a trifluoroacetate salt of methyl ((lR)-l-(((2S)-2-(4-(5'-(2-((2S)-l-((2R)-2- ((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-4-yl)- 2,2'-bithiophen-5-yl)-lH-imidazol-2-yl)-l-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate (21 mg, 0.021 mmol, 23 % yield) as an orange solid.[00134] LC-MS retention time 1.18 min; m/z 751.0 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nm. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/ 100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS Platform for LC in electrospray mode. XH NMR (500 MHz, MeOD-d4) delta ppm 7.71 (s, 2H), 7.46 (d, J=4.0 Hz, 2H), 7.35 (d, J=4.0 Hz, 2H), 5.30 - 5.26 (m, 2H), 4.24 (d, J=7.2 Hz, 2H), 4.14 - 4.07 (m, 2H), 3.86 - 3.77 (m, 2H), 3.65 (s, 6H), 2.56 - 2.46 (m, 2H), 2.24 - 2.14 (m, 6H), 2.11 - 1.99 (m, 2H), 1.02 (t, J=7.5 Hz, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | HATU (66 mg, 0.17 mmol) was added to a stirred solution of a TFA salt of 2,2'-bis(2-((2S)-2-pyrrolidinyl)-lH-imidazol-5-yl)-5,5'-bi-l,3-thiazole (40 mg, 0.045 mmol), <strong>[171567-86-5](R)-2-(methoxycarbonylamino)-3-methylbutanoic acid</strong> (31.3 mg, 0.179 mmol) and DIEA (0.078 mL, 0.45 mmol) in dimethylformamide (2 mL) at room temperature. The reaction was stirred for 3 h, diluted with methanol (2 mL) and water (2 mL) and stirred for 15 min. The reaction mixture was concentrated to dryness in vacuo and purified by preparative HPLC (Waters Sunfire CI 8 column 30 X 150 mm 5u, eluted with a gradient of 10 to 80 % acetonitrile/water/0.1 % TFA) to yield a trifluoroacetate salt of methyl ((lR)-l-(((2S)-2-(4-(2'-(2-((2S)-l-((2R)-2- ((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-4-yl)- 5,5'-bi-l,3-thiazol-2-yl)-lH-imidazol-2-yl)-l-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate (16 mg, 0.016 mmol, 36 % yield) as an orange solid. [00160] LC-MS retention time 2.24 min; m/z 753.2 (MH ). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX Luna C18 4.6x50mm S10 column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nm. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 90% methanol/10% water/0.1% TFA. MS data was determined using a MICROMASS Platform for LC in electrospray mode. XH NMR (500 MHz, MeOD-d4) delta ppm 8.1 1 (s, 2H), 7.96 (s, 2H), 5.30 - 5.29 (m, 2H), 4.25 (d, J=7.3 Hz, 2H), 4.12 - 4.01 (m, 2H), 3.84 - 3.76 (m, 2H), 3.68 (s, 6H), 2.52 - 2.43 (m, 2H), 2.26 - 2.20 (m, 6H), 2.09 - 1.99 (m, 2H), 1.05 - 0.95 (m, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | HATU (135 mg, 0.356 mmol) was added to a stirred solution of 5,5'-bis(2- ((2S)-2-pyrrolidinyl)-lH-imidazol-4-yl)-2,2'-bi-l,3-thiazole (40 mg, 0.091 mmol), <strong>[171567-86-5](R)-2-(methoxycarbonylamino)-3-methylbutanoic acid</strong> (80 mg, 0.456 mmol) and DIEA (0.16 mL, 0.91 mmol) in dimethylformamide (2 mL) at room temperature. The reaction was stirred for 16 h, diluted with methanol (2 mL) and water (2 mL), stirred for 15 min and concentrated to dryness in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire C18 column 30 X 150 mm 5u, eluted with a gradient of 10 to 70 % acetonitrile/water/0.1 % TFA) to yield a trifluoroacetate salt of methyl ((lR)-l-(((2S)-2-(4-(5'-(2-((2S)-l-((2R)-2-((methoxycarbonyl)amino)-3- methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-4-yl)-2,2'-bi-l,3-thiazol-5-yl)-lH- imidazol-2-yl)-l-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate (53 mg, 0.052 mmol, 46 % yield) as a yellow solid.[00188] LC-MS retention time 1.1 1 min; m/z 753.1 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nm. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/ 100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS Platform for LC in electrospray mode. XH NMR (500 MHz, MeOD-d4) delta ppm 8.27 (s, 2H), 7.87 (s, 2H), 5.32 - 5.35 (m, 2H), 4.24 (d, J=7.3 Hz, 2H), 4.12 - 4.04 (m, 2H), 3.86 - 3.86 (m, 2H), 3.65 (s, 6H), 2.57 - 2.43 (m, 2H), 2.25 - 2.02 (m, 8H), 1.07 - 0.95 (m, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Example 68Compound 95aTo a solution of <strong>[171567-86-5]N-methoxycarbonyl-D-valine</strong> (420 mg, 2.4 mmol) in DCM (10 mL) was added HOBt.H2O (367 mg, 2.4 mmol) in one portion and stirred at room temperature for 10 min. To the reaction mixture, EDC (460 mg, 2.4 mmol) was added and continually stirred for 30 min. A solution of compound 5a (458 mg, 1.0 mmol) in DCM (5 mL) was added and then stirred overnight at room temperature. After HOBt salt was removed by washing with water, the organic layer was dried over MgSO4, filtered and concentrated to give viscous yellow liquid. The liquid was purified by column chromatography over silica gel (methanol:DCM=1:20) to yield white solid 95a (425 mg, 55%). LC/MS (ESI): [M+2]+/2: 387, [M+1]+: 773, [M+23]+: 795 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; | Example I-XXPreparation of Compounds 324 and 325General Procedure I-GATo a solution of compound I-Ii (80 mg, 0.169 mmol) in anhydrous DCM (5 mL) were added compound I-XXa (59.2 mg, 0.338 mmol), HATU (128.4 mg, 0.338 mmol) and DIEA (54.4 mg, 0.42 mmol). The resulting mixture was stirred at r.t. overnight. After completion of the reaction, monitored by TLC, the mixture was poured into water (10 mL), extracted with CH2Cl2 (30 mL×3), the combined organic layers were dried over Na2SO4, concentrated in vacuo. The residue was purified by Prep-HPLC to afford compound 324 as a white solid (46 mg, yield 35%). MS (ESI) m/z (M+H)+ 789.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.06 g | Example N-28 To a mixture of (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine), 4 HCl (0.07 g, 0.116 mmol), <strong>[171567-86-5](R)-2-(methoxycarbonylamino)-3-methylbutanoic acid</strong> (0.041 g, 0.232 mmol) and HATU (0.097 g, 0.256 mmol) in DMF (1 mL) was added DIEA (0.081 mL, 0.465 mmol). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was purified by reverse phase HPLC to yield TFA salt of Example N-28 (0.06 g) as a white solid. LC/MS (Cond. N-1): [M+H]+ 771.71, Rt=3.29 min. 1H NMR (400 MHz, MeOD) ppm 7.79-8.02 (10H, m), 4.95 (2H, s), 4.06 (2H, d, J=7.53 Hz), 3.58-3.72 (6H, m), 2.03 (2H, dq, J=13.87, 6.84 Hz), 1.10-1.25 (18H, m), 0.89-1.08 (12H, m). | |
0.06 g | To a mixture of (lS,l'S)-l,l'-(4,4'-(biphenyl-4,4'-diyl)bis(lH-imidazole-4,2- diyl))bis(2,2-dimethylpropan-l -amine), 4 HC1 (0.07 g, 0.116 mmol), (R)-2- (methoxycarbonylamino)-3-methylbutanoic acid (0.041 g, 0.232 mmol) and HATU (0.097 g, 0.256 mmol) in DMF (1 mL) was added DIEA (0.081 mL, 0.465 mmol). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was purified by reverse phase HPLC to yield TFA salt of Example N-28 (0.06 g) as a white solid. LC/MS (Cond. N-l): [M+H]+771.71, Rt= 3.29 min. NMR (400 MHz, MeOD) ppm 7.79 - 8.02 (10 H, m), 4.95 (2 H, s), 4.06 (2 H, d, J=7.53 Hz), 3.58 - 3.72 (6 H, m), 2.03 (2 H, dq, J=13.87, 6.84 Hz), 1.10 - 1.25 (18 H, m), 0.89 - 1.08 (12 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.015 g | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | Example N-1 [0396] To a mixture of (1S,1?S)-1,1?-(5,5?-(biphenyl-4,4?-diyl)bis(oxazole-5,2-diyl))bis(2-methylpropan-1-amine) (0.03 g), <strong>[171567-86-5](R)-2-(methoxycarbonylamino)-3-methylbutanoic acid</strong> (0.024 g, 0.139 mmol) and HATU (0.058 g, 0.153 mmol) in DMF (1 mL) was added DIEA (0.049 mL, 0.279 mmol). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was purified by reverse phase HPLC to yield Example N-1 (0.015 g) as a white solid. LC/MS (Cond. N-1): [M+H]+ 745.49, Rt=4.183 min. 1H NMR (400 MHz, MeOD) ppm 7.74-7.87 (8H, m), 7.50 (2H, s), 4.92-5.01 (4H, m), 3.63 (6H, s), 2.30-2.44 (2H, m), 2.10 (2H, d, J=6.78 Hz), 1.04-1.12 (6H, m), 0.99 (16H, dd, J=9.41, 6.90 Hz), 0.96 (2H, s). |
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