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CAS No. : | 5619-04-5 | MDL No. : | MFCD00012593 |
Formula : | C4H10ClNO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 155.58 | Pubchem ID : | - |
Synonyms : |
H-DL-Ser-OMe.HCl
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 33.46 |
TPSA : | 72.55 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.7 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | -0.64 |
Log Po/w (WLOGP) : | -0.72 |
Log Po/w (MLOGP) : | -0.84 |
Log Po/w (SILICOS-IT) : | -1.04 |
Consensus Log Po/w : | -0.65 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.2 |
Solubility : | 97.4 mg/ml ; 0.626 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.41 |
Solubility : | 60.4 mg/ml ; 0.388 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.57 |
Solubility : | 583.0 mg/ml ; 3.75 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.79 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
94.2% | for 19 h; Cooling with ice; Reflux | In 100 ml of methanol is added in three-mouth bottle 30 ml, under the condition of the mechanical stirring ice-water bath, slow adds by drops two chlorine Asia sulphone 6.6 ml, after dripping, continue to stir 1h, the (II) 6.00g DL-serine (57mmol) inputs in three-mouth bottle, heating reflux reaction, reaction time 18h rear, reduced pressure distillation to remove the solvent, obtained after drying (III) 8.32g DL-serine methyl ester hydrochloride, yield 94.2percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methanol; ammonia |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.7% | With triethylamine; In ethyl acetate; at 20℃; for 2h;Cooling with ice; | After three 100mL flask DL- serine methyl ester hydrochloride was added 5.88g (38mmol), triethylamine 21.0 mL, 100mL of ethyl acetate, ice water bath, mechanical stirring, in 6.2 mL of acetyl chloride was slowly added dropwise, the addition was complete , continued at room temperature the reaction was stirred 2h. Then washed with saturated aqueous sodium bicarbonate, extracted with methylene chloride, dried over anhydrous sodium sulfate, and concentrated to give 6.53 g of a white solid, a yield of 84.7% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | With thionyl chloride; for 19h;Cooling with ice; Reflux; | In 100 ml of methanol is added in three-mouth bottle 30 ml, under the condition of the mechanical stirring ice-water bath, slow adds by drops two chlorine Asia sulphone 6.6 ml, after dripping, continue to stir 1h, the (II) 6.00g DL-serine (57mmol) inputs in three-mouth bottle, heating reflux reaction, reaction time 18h rear, reduced pressure distillation to remove the solvent, obtained after drying (III) 8.32g DL-serine methyl ester hydrochloride, yield 94.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; | A) Production of methyl 2-[(phenylcarbonyl)amino]prop-2-enoate To dichloromethane (400 mL) were added methyl serinate hydrochloride (45.0 g) and triethylamine (132 mL), and benzoyl chloride (77.0 mL) was added dropwise. After stirring at room temperature overnight, the reaction system was washed twice with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (300 mL), and 2,3,4,6,7,8,9,10-octahydroprimido[1,2-a]azepine(52.0 g) was added. The mixture was stirred at room temperature for 4 hr, and the reaction system was washed twice with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude product (67.0 g) of the title compound as a brown oil. 1H-NMR(CDCl3) delta 3.88(3H,s), 5.99(1H,s), 6.79(1H,s), 7.45-7.56(3H,m), 7.83(2H,d,J=7.2Hz),8.53(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 12.0833h; | Dry acetonitrile (100 mL) was added to a mixture of N-Boc-L-valine (2.17 g, 10 mmol) and serine methyl ester hydrochloride (1.86 g, 12 mmol) and stirred for 5 min. BOP (4.42 g, 10 mmol) and triethylamine (3.1 mL, 22 mmol) were added and the mixture was stirred at room temperature for 12 h. The mixture was then evaporated under reduced pressure and diluted with EtOAc and brine. The phases were separated and then aqueous phase was extracted with EtOAc. The combined organic phases were then washed successively with IN HCl, saturated NaHC03, and brine and then dried over Na2SO4, filtered and evaporated to give the amide as a <n="63"/>colorless oil, 3.18 g (100%); 1HNMR(CDCl3) delta 7.45 (dd, IH, J=I .4), 5.58 (d, IH, J=8.8), 4.45 (m, IH), 4.37 (m, IH), 3.79 (m, 2H), 3.54 (s, 3H), 1.88 (m, IH), 1.23 (s, 9H), 0.74 (d, 6H, J=6.6); 13C-NMR delta 172.3, 171.0, 162.9,. 156.0, 79.4, 62.3, 54.6, 52.3, 31.3, 28.2. 17.7, 17.4. |
100% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 12h; | e. Synthesis of Compound 205 (N-Boc Valine Amide) Dry acetonitrile (100 mL) was added to a mixture of N-Boc-L-valine (2.17 g, 10 mmol) and serine methyl ester hydrochloride (1.86 g, 12 mmol) and stirred for 5 min. BOP (4.42 g, 10 mmol) and triethylamine (3.1 mL, 22 mmol) were added and the mixture was stirred at room temperature for 12 h. The mixture was then evaporated under reduced pressure and diluted with EtOAc and brine. The phases were separated and then aqueous phase was extracted with EtOAc. The combined organic phases were then washed successively with 1N HCl, saturated NaHCO3, and brine and then dried over Na2SO4, filtered and evaporated to give the amide as a colorless oil, 3.18 g (100%); 1H NMR (CDCl3) ? 7.45 (dd, 1H, J=1.4), 5.58 (d, 1H, J=8.8), 4.45 (m, 1H), 4.37 (m, 1H), 3.79 (m, 2H), 3.54 (s, 3H), 1.88 (m, 1H), 1.23 (s, 9H), 0.74 (d, 6H, J=6.6); 13C-NMR ? 172.3, 171.0, 162.9, 156.0, 79.4, 62.3, 54.6, 52.3, 31.3, 28.2, 17.7, 17.4. |
100% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 12h; | Example 3. Preparation of Teroxazole Intermediate; A teroxazole intermediate that can be used to prepare compounds of the invention can be prepared as follows.; a. Synthesis of Compound 206 (N-Boc Valine Amide); Dr> acetonitrile (100 mL) was added to a mixture of N-Boc-L-valine (2.17 g, 10 mmol) and serine methyl ester hydrochloride (1.86 g, 12 mmol) and stirred for 5 min. BOP (4.42 g, 10 mmol) and triethylamine (3.1 mL, 22 mmol) were added and the mixture was stirred at room <n="34"/>temperature for 12 h. The mixture was then evaporated under reduced pressure and diluted with EtOAc and. brine. The phases were separated and then aqueous phase was extracted with EtOAc. The combined organic phases were then washed successively with IN HCl, saturated NaHCO3, and brine and then dried over Na2SO4, filtered and evaporated to give the amide as a colorless oil, 3.18 g (100%); 1H NMR (CDCl3) delta 7.45 (dd, IH, J=1.4), 5.58 (d, IH, J=8.8), 4.45 (m, IH), 4.37 (m, IH), 3.79 (m, 2H), 3.54 (s, 3H), 1.88 (m, IH), 1.23 (s, 9H), 0.74 (d, 6H, J=6.6); 13C-NMR delta 172.3, 171.0, 162.9, 156.0, 79.4, 62.3, 54.6, 52.3, 31.3, 28.2, 17.7, 17.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at 20℃; for 17h; | Example 28: Synthesis of (2S,5R)-2-( 5-(2-iminoimidazolidin-4-yl)-l ,3 ,4-oxadiazol-2-yl)-7 - oxo-l 6-dia abic clo 3.2.1 octan-6-yl hydrogen sulfate (Compound 767) ESI-MS (EI+, m/z): 374.2. 1H NMR (300 MHz, D20) delta 5.41 (dd, / = 10.1, 4.9 Hz, 1H), 4.76 (d, / = 6.3 Hz, 1H), 4.26 - 4.00 (m, 2H), 3.98 - 3.78 (m, 1H), 3.27 - 3.09 (m, 1H), 2.90 (d, / = 12.4 Hz, 1H), 2.34 - 2.01 (m, 3H), 2.01 - 1.70 (m, 1H). |
98% | With triethylamine; In dichloromethane; at 0 - 20℃; | 1.2. Synthesis of compounds of formula (II) ?#9658;Boc-Ser-OMe (1) To a suspension of serine methyl ester hydrochloride (4.4 g, 28 mmol, 1 equiv.) in dichloromethane (20mL) cooled at 0C, triethylamine (7.73 mL, 61.6 mmol, 2.2 equiv.) was added followed by Boc2O (6.86 g, 30.8 mmol, 1.1 equiv.) previously solubilized in dichloromethane (20 mL). The mixture was allowed to warm to room temperature and stirred overnight. Solvents were removed under vacuo, the oily crude product was taken up in ethyl acetate (25 mL), washed successively with KHSO4 1N (2x20 mL), NaHCO3 1N (20 mL), brine (20 mL), dried over MgSO4 and concentrated under vacuo to afford 6.0 g of desired product (98% yield, yellow oil) which was used without further purification. The obtained 1H NMR and 13C NMR spectra comply with the structure of the compound. IR (film): 3390, 2978, 1744, 1697, 1514, 1368, 1165 cm-1 |
96% | 3-hydroxy- l-methoxy-l-oxopropan-2-aminium chloride (5.0 g, 32.0 mmol, 1.0 equiv. ) and NaHCO3 (6.7 g, 80.0 mmol, 2.5 equiv. ) were added to a 500 mL RBF followed by dH20 (96 mL) and MeOH (96 mL). Next, Boc20 (10.5 g, 48.0 mmol, 1.5 equiv. ) was added to the reaction flask. The reaction was stirred for 8 h and the MeOH was evaporated on a rotary evaporator. The remaining aqueous layer was acidified with 0.5 M HCl (200 mL), transferred to a separatory funnel with EtOAc (100 mL) and extracted with EtOAc (3 x 100 mL). The organic layers were then washed with 20% NaHCO3 (1 x 100 mL) and sat. NaCl (1 x 100 mL). The organic layers were combined and dried over Na2S04, concentrated on a rotary evaporator, and dried under vacuum to give 6.80 g (96%) of 29 as a colorless oil. Rf= 0.61 (100% EtOAc); IR (film) 3389, 2976, 1743,1691, 1159, 1058 cm-1; 1H NMR (500 MHz, CDCl3) 8 5.61 (d, J= 7.5 Hz, 1H, carbamate-NH), 4.38 (br s, 1H, Boc-NH-CH), 3.96 (m, 1H, CH-CH), 3.88 (m, 1H, CH-CH), 3.78 (s, 3H, OCH3), 3.12 (br s, 1H, CH20H), 1.45 (s, 9H, t- butyl-CH3) ; 13C NMR (125 MHz, CDCl3) 8 171.6, 155.9, 80.4, 63.5, 55.8, 52.8, 28.4 ; LRMS (ESI-MS Only) : Mass calcd for CgHl7NNaO5 [M+Na] +, 242.22. Found 242. Spectroscopic data were consistent with the literature data for this compound. |
With triethylamine; In dichloromethane; at 0 - 20℃; | To a suspension of serine methyl ester hydrochloride (4.4 g, 28 mmol, 1 equiv.) in dichloromethane (2OmL) cooled at 00C, triethylamine (7.73 mL, 61.6 mmol, 2.2 equiv.) was added followed by BoC2O (6.86 g, 30.8 mmol, 1.1 equiv.) previously solubilised in dichloromethane (20 mL). The mixture was allowed to warm to room temperature and stirred overnight. Solvents were removed under vacuo, the oily crude product was taken up in ethyl acetate (25 mL), washed successively with KHSO4 IN (2x20 mL), NaHCO3 IN (20 mL), brine (20 mL), dried over MgSO4 and concentrated under vacuo to afford 6.0 g of desired product (98% yield, yellow oil) which was used without further purification.The obtained 1H NMR and 13C NMR spectra comply with the structure of the compound.IR (film) : 3390, 2978, 1744, 1697, 1514, 1368, 1165 cm"1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.6% | With triethylamine; In toluene; for 2h;Cooling with ice; | After three 100mL flask DL- serine methyl ester hydrochloride was added 5.88g (38mmol), triethylamine 15.8 mL, 100mL of toluene, mechanical stirring ice-water bath, was slowly added dropwise 11.5 mL of benzoyl chloride, the addition was complete, stirring was continued at room temperature the reaction 2h. Then washed with saturated aqueous sodium bicarbonate, extracted with methylene chloride, dried over anhydrous sodium sulfate, and concentrated to give 10.64 g of a white solid, a yield of 85.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine In dichloromethane at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; | (DL)-serine methyl ester hydrochloride (2.78g, 17.85mmol leq), BOP <n="36"/>(7.9g, 17.85mmol, leq) and 1 (6.Sg, 17.85mmol) were dissolved in dry CH3CN (10OmL). To this triethylamine (6.2mL, 44.6mmol, 2.5eq) was added and the reaction stirred at room temperature overnight. The solvent was then removed in vacuo and the residue was taken up in ethyl acetate. This was washed successively with brine, 2N HCl, 0.5N NaHCO3, water and brine. The organic layer was dried with sodium sulfate and concentrated to a clear oil weighing 8.6g, 100%. 1H NMR (CDCl3) delta 7.50 (m, IH), 7.31 (s, 5H), 6.12 (m, IH), 5.06 (m, 3H), 4.63 (m, IH), 4.30 (m, IH), 3.94 (m, 2H), 3.71 (s, 3H), 3.07 (m, 2H), 1.63 (m, 2H), 1.43 (m, HH). 13C NMR (CDCl3) delta 171.6, 170.3, 170.0, 155.7, 135.3, 127.6, 127.2, 127.1, 78.3, 66.1, 61.6, 53.8, 51.7, 51.7, 39.0, 31.4, 31.2,28.5, 27.5, 21.5. IR (thin film, NaCl) 3336, 3068, 3014, 2981, 2937, 2866, 1693, 1525, 1455, 1392, 1366, 1250, 1170, 1061, 912, 849, 755, 698, 666 cm'1 |
100% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; | b. Synthesis of Compound 2 (DL)-serine methyl ester hydrochloride (2.78 g, 17.85 mmol 1 eq), BOP (7.9 g, 17.85 mmol, 1 eq) and 1 (6.8 g, 17.85 mmol) were dissolved in dry CH3CN (100 mL). To this triethylamine (6.2 mL, 44.6 mmol, 2.5 eq) was added and the reaction stirred at room temperature overnight. The solvent was then removed in vacuo and the residue was taken up in ethyl acetate. This was washed successively with brine, 2N HCl, 0.5N NaHCO3, water and brine. The organic layer was dried with sodium sulfate and concentrated to a clear oil weighing 8.6 g, 100%. 1H NMR (CDCl3) ? 7.50 (m, 1H), 7.31 (s, 5H), 6.12 (m, 1H), 5.06 (m, 3H), 4.63 (m, 1H), 4.30 (m, 1H), 3.94 (m, 2H), 3.71 (s, 3H), 3.07 (m, 2H), 1.63 (m, 2H), 1.43 (m, 111H). 13C NMR (CDCl3) ? 171.6, 170.3, 170.0, 155.7, 135.3, 127.6, 127.2, 127.1, 78.3, 66.1, 61.6, 53.8, 51.7, 51.7, 39.0, 31.4, 31.2, 28.5, 27.5, 21.5. IR (thin film, NaCl) 3336, 3068, 3014, 2981, 2937, 2866, 1693, 1525, 1455, 1392, 1366, 1250, 1170, 1061, 912, 849, 755, 698, 666 cm-1 |
100% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; | b. Synthesis of Compound 302(DL)-serine methyl ester hydrochloride (2.78g, 17.85mmol leq), BOP (7.9g, 17.85mmol, leq) and 301 (6.8g, 17.85mmol) were dissolved in dry CH3CN (10OmL). To this triethylamine (6.2mL, 44.6mmol, 2.5eq) was added and the reaction stirred at room temperature overnight. The solvent was then removed in vacuo and the residue was taken up in ethyl acetate. This was washed successively with brine, 2N HCl, 0.5N NaHCO3, water and brine. The organic layer was dried with sodium sulfate and concentrated to a clear oil weighing 8.6g, 100%. H NMR <n="51"/>(CDCl3) delta 7.50 (m, IH), 7.31 (s, 5H), 6.12 (m, IH), 5.06 (m, 3H), 4.63 (m, IH), 4.30 (m, IH), 3.94 (m, 2H), 3.71 (s, 3H), 3.07 (m, 2H), 1.63 (m, 2H), 1.43 (m, 1IH).13C NMR (CDCl3) delta 171.6, 170.3, 170.0, 155.7, 135.3, 127.6, 127.2, 127.1, 78.3, 66.1, 61.6, 53.8, 51.7, 51.7, 39.0, 31.4, 31.2, 28.5, 27.5, 21.5. IR (thin film, NaCl) 3336, 3068, 3014, 2981, 2937, 2866, 1693, 1525, 1455, 1392, 1366, 1250, 1170, 1061, 912, 849, 755, 698, 666 cm"1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 12.0833h; | Dry acetonitrile (200 mL) was added to a mixture ofN-Boc-O-Benzyl serine (5.9 g, 20 mmol) and serine methyl ester hydrochloride (3.1 g, 20 mmol) and stirred for 5 min. BOP (8.84 g, 20 mmol) and triethylamine (6.2 mL, 44 mmol) were added and the mixture was stirred at room temperature for 12 h. The mixture was then evaporated under reduced pressure and diluted with EtOAc and brine. The phases were separated and then aqueous phase was extracted with EtOAc The combined organic phases were then washed successively with IN HCl, saturatedNaHCO3, and brine and then dried over Na2SO4, filtered and evaporated to give the amide as a colorless oil, 7.92 g (100 %); 1H NMR (CDCl3) delta 7.56 (d, IH, 1=7.6), <n="61"/>7.24 (m, 5H), 5.89 (d, IH, J=5.8), 4.59 (m, IH), 4.46 (s, 2H), 4.40 (m, IH), 3.98 (m, 4H), 3.62 (s, 3H), 1.38 (s, 9H); 13C-NMR delta 170.8, 155.9, 137.7, 128.4, 127.8, 80.3, 73.3, 70.2, 69.9, 62.5, 62.4, 60.4, 54.9, 54.6, 52.5, 28.3, 20.9, 14.2. |
100% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 12h; | a. Synthesis of Compound 201 (N-Boc Serine Amide) Dry acetonitrile (200 mL) was added to a mixture of N-Boc-O-Benzyl serine (5.9 g, 20 mmol) and serine methyl ester hydrochloride (3.1 g, 20 mmol) and stirred for 5 min. BOP (8.84 g, 20 mmol) and triethylamine (6.2 mL, 44 mmol) were added and the mixture was stirred at room temperature for 12 h. The mixture was then evaporated under reduced pressure and diluted with EtOAc and brine. The phases were separated and then aqueous phase was extracted with EtOAc. The combined organic phases were then washed successively with 1N HCl, saturated NaHCO3, and brine and then dried over Na2SO4, filtered and evaporated to give the amide as a colorless oil, 7.92 g (100%); 1H NMR (CDCl3) ? 7.56 (d, 1H, J=7.6), 7.24 (m, 5H), 5.89 (d, 1H, J=5.8), 4.59 (m, 1H), 4.46 (s, 2H), 4.40 (m, 1H), 3.98 (m, 4H), 3.62 (s, 3H), 1.38 (s, 9H); 13C-NMR ? 170.8, 155.9, 137.7, 128.4, 127.8, 80.3, 73.3, 70.2, 69.9, 62.5, 62.4, 60.4, 54.9, 54.6, 52.5, 28.3, 20.9, 14.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h;Nitrogen gasification; Stirring; | To a solution of example 44 (50 mg, 0.09 mmol) in DMF (5 ml) under N2 was added D,L-serine methyl ester hydrochloride (70 mg, 0.45 mmol, 5 eq.), then diisopropylethylamine (50 ul, 0.27 mmol, 3 eq). It was stirred at room temperature for 2 h, and then partitioned between ethyl acetate and 0.1N HCl. The organic layer was washed with H2O, brine, dried (MgSO4), filtered and concentrated. The crude material was purified by flash chromatography using 1-30% acetone in dichloromethane to give the title compound (33 mg, 58%). [00630] MS (ES) (m/z) 637.2 [M+1]. IR (KBr) 3676.62, 3361.32, 3017.09, 1748.50, 1669.24, 1600.15, 1507.87, 1464.59, 1452.69, 1412.75, 1286.17, 1267.41, 1131.66, 1148.36 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In tetrahydrofuran; water; at 0 - 20℃; for 3h; | To a solution of DL-serine methyl ester hydrochloride (30 g, 0.19 mol) in water(150 ml_) at 0C was added potassium carbonate (79 g, 0.57 mol) then 4-chlorobenzenesulfonyl chloride (44 g, 0.21 mol) in THF (150 mL) and the reactionwas allowed to warm to RT for 3 h. The mixture was then diluted with water andextracted with Et2O and EtOAc. The combined organic layers were washed with 5%citric acid solution, brine, then dried over sodium sulfate and concentrated to give48.5 g (88%) of sulfonamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide | 3.C C. C. Synthesis of n-benzyloxycarbonyl-β-alanylserine methyl ester N-Benzyloxycarbonyl-β-alanine N-hydroxysuccinimide ester (14.1 g, 44.0 mmoles; Bachem) was dissolved in 100 mL of dry N,N-dimethylformamide, and serine methyl ester hydrochloride (5.2 g, 43.6 mmoles) was added. The mixture was stirred at room temperature and N,N-diisopropylethylamine (10 mL, 57.4 mmoles) was added. The reaction was stirred overnight. The solvent was then removed on a rotary evaporator to give a clear colorless syrup. This material was partitioned between ethyl acetate (250 mL) and water (250 mL). The layers were separated, and the ethyl acetate layer was washed successively with half-saturated aqueous potassium bisulfate (200 mL, once), saturated aqueous sodium bicarbonate (200 mL, twice) and saturated aqueous sodium chloride (200 mL, once). The ethyl acetate solution was dried over anhydrous magnesium sulfate, filtered, and evaporated on a rotary evaporator to a clear colorless syrup. The syrup was dried well in vacuo to afford 10.4 g (74% yield) of an amorphous white solid. The purity of the product was confirmed by 1 H and 13 C NMR as well as by HPLC. 1 H NMR (300 MHz, DMSO-d6): δ 8.21 (doublet, 1H, NH[serine]), 7.33 (multiplet, 5H, ArH), 7.18 (triplet, 1H NH[β-alanine]), 5.00 (triplet, 1H, OH), 4.99 (singlet, 2H, Ar-CH2 O), 4.32 (multiplet, 11H, CH), 3.62 (multiplet, 2H, CH2 OH), 3.60 (singlet, 3H, CH3), 3.18 (quartet, 2H, NHCH2 CH2), 2.33 (triplet, 2H, NHCH2 CH2). 13 C NMR (75 MHz, DMSO-d6): δ 171.0, 170.5, 155.9, 137.2, 128.2, 127.6, 127.5, 65.1, 61.1, 54.5, 51.5, 36.9, 35.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; ozone; trifluorormethanesulfonic acid; In tetrahydrofuran; methanol; hexane; dichloromethane; cyclohexane; ethyl acetate; | Dissolve serine methyl ester hydrochloride (56 g, 0.36 mol) in tetrahydrofuran (300 mL) then cool to 0 C. and add 4-methylmorpholine (88 mL, 0.8 mol). Add, by dropwise addition, a solution of the N-phthaloyl-(S)-phenylalanine, acid chloride in tetrahydrofuran (200 mL). Allow to warm to room temperature and stir for 3 hours. Filter and concentrate the filtrate in vacuo. Dissolve the residue in ethyl acetate and separate the organic phase. Wash with water then saturated sodium chloride and dry (MgSO4). Evaporate the solvent in vacuo to give an oil. Purify by silica gel chromatography (gradient 50% ethyl acetate/hexane to ethyl acetate) to give the title compound (80.8 g, 67%) mp 129-132 C. Scheme D, step b: N-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-propenyl-L-serine, methyl ester Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add <strong>[51479-73-3]allyl trichloroacetimidate</strong> (26 g, 128 mmol) and trifluoromethanesulfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95-97 C. Scheme D, step c: [S-(R*, R*)]-N-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-3,4-dihydro-2H-1,4-oxazine-3-carboxylic acid, methyl ester Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-propenyl-L-serine, methyl ester (13 g, 29.8 mmol) in methylene chloride/methanol (10:1, 220 mL). Cool to -78 C. and sparge with a mixture of ozone/oxygen for approximately 10 minutes until a blue color persists. Sparge with nitrogen for 10 minutes at -78 C. to remove excess ozone. Treat with methylsulfide (60 mL, 0.82 mol) and allow to warm to room temperature. Stir at room temperature for 2.5 hours, evaporate the solvent in vacuo and dissolve the residue in ethyl acetate (200 mL). Wash with water, saturated sodium chloride, dry (Mg SO4) and evaporate the solvent in vacuo to give the intermediate N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester as a foam (13.6 g). | |
With 4-methyl-morpholine; ozone; trifluorormethanesulfonic acid; In tetrahydrofuran; methanol; hexane; dichloromethane; cyclohexane; ethyl acetate; | Dissolve serine methyl ester hydrochloride (56g, 0.36mol) in tetrahydrofuran (300mL) then cool to 0 C. and add 4-methylmorpholine (88mL, 0.8mol). Add, by dropwise addition, a solution of the N-phthaloyl-(S)-phenylalanine, acid chloride in tetrahydrofuran (200mL). Allow to warm to room temperature and stir for 3 hours. Filter and concentrate the filtrate in vacuo. Dissolve the residue in ethyl acetate and separate the organic phase. Wash with water then saturated sodium chloride and dry (MgSO4). Evaporate the solvent in vacuo to give an oil. Purify by silica gel chromatography (gradient 50% ethyl acetate/hexane to ethyl acetate) to give the title compound (80.8g, 67%) mp 129-132 C. Scheme F, step b: N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-propenyl-L-serine, methyl ester Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-L-serine, methyl ester (25g, 63mmol) in methylene chloride/cyclohexane (1:1, 600mL). Add <strong>[51479-73-3]allyl trichloroacetimidate</strong> (26g, 128mmol) and trifluoromethanesulfonic acid (5mL), 56.6mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95-97 C. Scheme F, step c: [S-(R*, R*)]-N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-3,4-dihydro-2H-1,4-oxazine-3-carboxylic acid, methyl ester Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-propenyl-L-serine, methyl ester (13g, 29.8mmol) in methylene chloride/methanol (10:1, 220mL). Cool to -78 C. and sparge with a mixture of ozone/oxygen for approximately 10 minutes until a blue color persists. Sparge with nitrogen for 10 minutes at -78 C. to remove excess ozone. Treat with methylsulfide (60mL, 0.82mol) and allow to warm to room temperature. Stir at room temperature for 2.5 hours, evaporate the solvent in vacuo and dissolve the residue in ethyl acetate (200mL). Wash with water, saturated sodium chloride, dry (MgSO4) and evaporate the solvent in vacuo to give the intermediate N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester as a foam (13.6g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; ozone; trifluorormethanesulfonic acid; In tetrahydrofuran; methanol; hexane; dichloromethane; cyclohexane; ethyl acetate; | Dissolve serine methyl ester hydrochloride (56 g, 0.36 mol) in tetrahydrofuran (300 mL) then cool to 0 C. and add 4-methylmorpholine (88 mL, 0.8 mol). Add, by dropwise addition, a solution of the N-phthaloyl-(S)-phenylalanine, acid chloride in tetrahydrofuran (200 mL). Allow to warm to room temperature and stir for 3 hours. Filter and concentrate the filtrate in vacuo. Dissolve the residue in ethyl acetate and separate the organic phase. Wash with water then saturated sodium chloride and dry (MgSO4). Evaporate the solvent in vacuo to give an oil. Purify by silica gel chromatography (gradient 50% ethyl acetate/hexane to ethyl acetate) to give the title compound (80.8 g, 67%) mp 129-132 C. Scheme D, step b: N-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-propenyl-L-serine, methyl ester Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add <strong>[51479-73-3]allyl trichloroacetimidate</strong> (26 g, 128 mmol) and trifluoromethanesulfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95-97 C. Scheme D, step c: [S-(R*, R*)]-N-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-3,4-dihydro-2H-1,4-oxazine-3-carboxylic acid, methyl ester Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-propenyl-L-serine, methyl ester (13 g, 29.8 mmol) in methylene chloride/methanol (10:1, 220 mL). Cool to -78 C. and sparge with a mixture of ozone/oxygen for approximately 10 minutes until a blue color persists. Sparge with nitrogen for 10 minutes at -78 C. to remove excess ozone. Treat with methyl sulfide (60 mL, 0.82 mol) and allow to warm to room temperature. Stir at room temperature for 2.5 hours, evaporate the solvent in vacuo and dissolve the residue in ethyl acetate (200 mL). Wash with water, saturated sodium chloride, dry (MgSO4) and evaporate the solvent in vacuo to give the intermediate N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester as a foam (13.6 g). | |
With 4-methyl-morpholine; ozone; trifluorormethanesulfonic acid; In tetrahydrofuran; methanol; hexane; dichloromethane; cyclohexane; ethyl acetate; | Dissolve serine methyl ester hydrochloride (56 g, 0.36 mol) in tetrahydrofuran (300 mL) then cool to 0 C. and add 4-methylmorpholine (88 mL, 0.8 mol). Add, by dropwise addition, a solution of the N-phthaloyl-(S)-phenylalanine, acid chloride in tetrahydrofuran (200 mL). Allow to warm to room temperature and stir for 3 hours. Filter and concentrate the filtrate in vacuo. Dissolve the residue in ethyl acetate and separate the organic phase. Wash with water then saturated sodium chloride and dry (MgSO4). Evaporate the solvent in vacuo to give an oil. Purify by silica gel chromatography (gradient 50% ethyl acetate/hexane to ethyl acetate) to give the title compound (80.8 g, 67%) mp 129-132 C. Scheme D, step b: N-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-propenyl-L-serine, methyl ester Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add <strong>[51479-73-3]allyl trichloroacetimidate</strong> (26 g, 128 mmol) and trifluoromethanesulfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95-97 C. Scheme D, step c: [S-(R*, R*)]-N-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-3,4-dihydro -2H-1,4-oxazine-3-carboxylic acid, methyl ester Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-propenyl-L-serine, methyl ester (13 g, 29.8 mmol) in methylene chloride/methanol (10:1, 220 mL). Cool to -78 C. and sparge with a mixture of ozone/oxygen for approximately 10 minutes until a blue color persists. Sparge with nitrogen for 10 minutes at -78 C. to remove excess ozone. Treat with methyl sulfide (60 mL, 0.82 mol) and allow to warm to room temperature. Stir at room temperature for 2.5 hours, evaporate the solvent in vacuo and dissolve the residue in ethyl acetate (200 mL). Wash with water, saturated sodium chloride, dry (MgSO4) and evaporate the solvent in vacuo to give the intermediate N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester as a foam (13.6 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h; | EXAMPLE 9; Preparation of 1,3-oxazole intermediate-2-(3-chlorophenyl)-1,3-oxazole-4-carboxylic acid; i) Methyl 2-[(3chlorobenzoyl)amino]-3-hydroxypropanoate; N-methylmorpholine (7.0 ml, 63.8 mmol) and EDCI (4.97 g, 31.9 mmol) were added to a mixture of 3-chlorobenzoic acid (5.0 g, 31.9 mmol), serine methyl ester hydrochloride (6.1 g, 31.9 mmol) and HOBt (4.31 g, 31.9 mmol) in DMF (100 ml) at 0 C. The mixture was allowed to warm to RT and stirred for 18 h. The mixture was diluted with ethyl acetate (300 ml) and then washed with water (3×250 ml) followed by brine. The organic extract was dried over Na2SO4 (anhydrous) and then concentrated in vacuo to give the title compound (7.2 g, 93%, pale yellow solid). 1H NMR (CDCl3) delta (ppm): 7.78 (s, 1 H), 7.66 (d, 1 H), 7.45, (dd, 1 H), 7.34 (t, 1 H), 7.25 (br, d, 1H), 4.82 (m, 1 H), 4.08 (m, 2 H), 3.79 (s, 3 H), 3.19 (br, t, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.5% | With potassium carbonate; In acetonitrile; at 20℃; for 24h; | Example 1.1: Methyl 2-(dibenzylamino)-3-hydroxypropanoate; Methyl serine hydrochloride (15 g, 0.096 mol) was stirred with potassium carbonate (66.6 g, 0.482 mol) and benzyl bromide (41.2 g, 0.24 mol) in acetonitrile (240 mL) at room temperature for 24 hours. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated with silica gel. The product was purified by column chromatography, eluting with 5-20 % ethyl acetate in hexanes, to give methyl 2- (dibenzylamino)-3-hydroxypropanoate (27 g, 93.5 %) as a pale-yellow sticky oil. 1H NMR (300 MHz, CDCl3): delta(ppm) 7.25-7.40 (m, 10H), 3.94 (d, 2H), 3.83 (s, 3H), 3.79 (m, 2H), 3.71 (d, 2H), 3.60 (t, IH) and 2.62 (t, IH). |
93.5% | With potassium carbonate; In acetonitrile; at 20℃; for 24h; | Methyl serine hydrochloride (15 g, 0.096 mol) was stirred with potassium carbonate (66.6 g, 0.482 mol) and benzyl bromide (41.2 g, 0.24 mol) in acetonitrile (240 mL) at room temperature for 24 hours. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated with silica gel. The product was purified by column chromatography, eluting with 5-20 % ethyl acetate in hexanes, to give methyl 2-(dibenzylamino)-3-hydroxypropanoate (27 g, 93.5 %) as a pale- yellow sticky oil. 1H NMR (300 MHz, CDCl3): delta(ppm) 7.25-7.40 (m, 10H), 3.94 (d, 2H), 3.83 (s, 3H), 3.79 (m, 2H), 3.71 (d, 2H), 3.60 (t, IH) and 2.62 (t, IH). |
56% | With potassium carbonate; In acetonitrile; at 20℃; for 12h; | To a mixture of methyl 2-amino-3-hydroxy-propanoate (15.0 g, 96.4 mmol, HCl salt) and benzyl bromide (36.3 g, 212 mmol, 25.2 mL) in acetonitrile (200 mL) was added potassium carbonate (66.6 g, 482 mmol). The mixture was stirred at rt for 12 h. On completion, the reaction mixture was filtered and washed with acetonitrile. The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography to give the title compound (16.1 g, 56% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 7.39-7.28 (m, 8H), 7.27-7.20 (m, 2H), 4.80 (dd, J=4.8, 6.0 Hz, 1H), 3.84-3.80 (m, 2H), 3.69 (s, 3H), 3.56 (d, J=14.4 Hz, 2H), 3.40-3.30 (m, 2H); LC-MS (ESI+) m/z 300.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | To a solution of I-A1-PD8 (1.0 g, 2.63 mmol) in DCM (3 mL) at RT was added CDI (0.46 g, 2.89 mmol) and stirred for 15 h. A suspension of serine methyl ester hydrochloride (0.61 g, 3.95 mmol) in DCM (4 mL) and TEA (1.1 mL, 7.90 mmol) was added and stirring continued for 15 h. After usual aqueous work-up and chromatographic purification, 0.706 g (51%) of I-A1-PD6 were obtained as a colorless oil. 1H NMR (CDCl3, 300 MHz): delta 1.25 (t, 3H, J=7.1 Hz), 1.35-1.51 (m, 10H), 2.28(s, 2H), 2.91-2.98 (m, 4H), 3.16 (d, 2H, J=9 Hz), 3.78 (s, 3H), 3.94-4.38 (m, 9H), 5.5 (bs, 1H), 6.0 (bs, 1H). MS: (ES)+: m/z 525 (M+H)+, 547 (M+Na)+. (ES)-: m/z 523 (M-H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; | A stirred solution of 4-[(1H-benzoimidazol-1-yl)methyl]benzoic acid (4 g, 15.87 mmol) in DMF at 0 C. is treated sequentially with EDC (3.6 g, 19 mmol), HOBt (2.5 g, 19 mmol), DIPEA (5.1 g, 39.5 mmol, 2.5 eq) and serine methyl ester hydrochloride (2.9 g, 19 mol), stirred at room temperature overnight and evaporated to dryness. The resultant residue is dissolved in EtOAc and water. The layers are separated and the organic layer is washed successively with 1M HCl, water, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure to give the title product in 64% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 8.23-8.26 (m, 2H); 7.9 (s, 2H); 7.87 (d, J=7.6 Hz, 2H); 7.70 (d, J=6 Hz, 1H); 7.33 (m, 3H); 7.20 (m, 2H); 5.54 (s, 2H); 4.90 (t, J=4 Hz, 1H); 4.60 (m, 1H); 3.84-3.90 (m, 2H); 3.70 (s, 3H). LCMS (ESI+) 354 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | A stirred solution of said benzoic acid (0.5 g, 1.87 mmol) in DMF at 0 C., was treated sequentially with EDC (0.47 g, 2.1 mmol, 1.2 eq), HOBt (0.29 g, 2.1 mmol, 1.2 eq), DIPEA (0.8 g, 4.2 mmol, 2.5 eq) and serine methyl ester hydrochloride (0.33 g, 2.1 mmol, 1.2 eq), stirred overnight at room temperature and evaporated under reduced pressure. The resultant residue was partitioned between EtOAc and water. The phases were separated. The organic phase was washed successively with 1M HCl, water, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. This residue was purified by column chromatography (silica, CHCl3:MeOH 4%) to afford the title product in 58% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 8.52 (d, J=8 Hz, 1H), 7.95 (s, 1H), 7.84 (d, J=8 Hz, 2H), 7.84 (d, J=8 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 2H), 7.14-7.23 (m, 2H), 5.05 (t, J=7.2 Hz, 1H), 4.53 (m, 1H), 4.37 (s, 2H), 3.77 (t, J=7.2 Hz, 1H), 3.70 (s, 3H), 3.64 (s, 3H). LCMS (ESI+) 367 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 8h; | b. Synthesis of compound 402; <n="60"/>A mixture of Z-dab(Boc)-OH (401, 6.3 g, 17.9 mmol), (DL)-serine methyl ester hydrochloride (2.8 g, 17.9 mmol) and BOP (8.7g, 19.7 mmol, 1.1 equiv.) was dissolved in DMF (50 mL) and stirred with diisopropyl ethylamine (6.8 mL, 39.4 mmol, 2.2 equiv.) at room temperature for 8h. Reaction mixture was concentrated on Kugelrohr, diluted with ethyl acetate (250 mL) and washed with 20% aqueous Citric acid (80 mL), saturated sodium bicarbonate solution (100 mL) and brine (100 mL). Organic layer was dried (Na2SO4), filtered and concentrated to get a foam like sticky compound weighing 8.0 g (99%); 1H NMR (CD3OD) delta 7.34 (m, 5H), 6.54 (m, IH), 5.10 (s, 2H), 4.51 (m, IH), 4.23 (m, IH), 3.88 (m, 2H), 3.72 (s, 3H), 3.17 (m, 2H), 1.98 (m, IH), 1.79 (m, IH), 1.43 (s, 9H); 13C NMR (CD3OD) delta 173.1, 170.7, 157.1, 136.7, 128.1, 127.6, 127.4, 78.8, 66.4, 61.3, 54.8, 52.8, 51.8, 36.6, 32.3, 27.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In a 200 mL round-bottomed flask was added sodium methoxide 30%wt. in MeOH (1.690 ml, 9.10 mmol) in MeOH (18 ml) to give a colorless solution. Cooled to -10C. 2,2-dichloroacetonitrile (7.30 ml, 91 mmol) was added dropwise over 15 minutes. Continued stirring at that temperature for 20 minutes. A suspension of methyl 2-amino-3- hydroxypropanoate hydrochloride (14.15 g, 91 mmol) in MeOH (15 ml) was added to the reaction mixture. Slowly warmed to 20C and stirred for 19.5 hours. CH2CI2 (51 ml) and water (29 ml) were added. Stirred vigorously for 5 minutes. Separated layers. The organic layer was concentrated to dryness on rotovap. The aqueous layer was extracted 2 times with CH2C (29 ml). The combined extracts were added to the concentrated 1st organic layer. The organic layer was dried over MgS04, filtered and concentrated to dryness to give methyl 2-(dichloromethyl)-4,5- dihydrooxazole-4-carboxylate (17.64 g, 83 mmol, 91% yield). 1H NMR (400 MHz, CDC ) delta ppm 6.29 (s, 1 H), 4.85 - 4.96 (m, 1 H), 4.76 (t, J = 8.6 Hz, 1 H), 4.61 - 4.72 (m, 1 H), 3.83 (s, 3H). | |
71% | With sodium methylate; In methanol; at -5 - 20℃; for 16h; | A solution of dichloroacetonitrile (215 g, 1.96 mol) in methanol (200 mL) was added drop-wise to a -5 C solution of sodium methoxide (15.4 g, 0.285 mol) in methanol (500 mL). A solution of ethyl serinate, hydrochloride salt (382 g, 2.45 mol) in methanol (300 mL) was then added to the -5 C reaction mixture, which was subsequently allowed to stir at room temperature for 16 hours. Dichloromethane (1 L) and water (800 mL) were added, and the aqueous layer was extracted with dichloromethane (1 L); the combined organic layers were concentrated in vacuo to provide the product as a yellow oil, which was used in the next step without additional purification. Yield: 300 g, 1 .4 mol, 71 %. 1H NMR (400 MHz, CDCI3) delta 6.29 (s, 1 H), 4.90 (dd, J=10.8, 8.3 Hz, 1 H), 4.74 (dd, J=8.8, 8.3 Hz, 1 H), 4.66 (dd, J=10.8, 8.9 Hz, 1 H), 3.82 (s, 3H). |
71% | With sodium methylate; In methanol; at -5 - 20℃; for 16h; | A solution of dichloroacetonitrile (215 g, 1 .96 mol) in methanol (200 mL) was added drop-wise to a -5 C solution of sodium methoxide (15.4 g, 0.285 mol) in methanol (500 mL). A solution of methyl 2-amino-3-hydroxypropanoate, hydrochloride salt (382 g, 2.45 mol) in methanol (300 mL) was then added to the -5 C reaction mixture, which was subsequently allowed to stir at room temperature for 16 hours. Dichloromethane (1 L) and water (800 mL) were added, and the aqueous layer was extracted with dichloromethane (1 L); the combined organic layers were concentrated in vacuo to provide the product as a yellow oil, which was used in the next step without further purification. Yield: 300 g, 1 .4 mol, 71 %.1H NMR (400 MHz, CDCI3) delta 6.29 (s, 1 H), 4.90 (dd, J=10.8, 8.3 Hz, 1 H), 4.74 (dd, J=8.8, 8.3 Hz, 1 H), 4.66 (dd, J=10.8, 8.9 Hz, 1 H), 3.82 (s, 3H). |
This compound was prepared according to the general procedure described by S. A. Hermitage, et al., 2001 Org. Proc. Res. Devel. 5:37-44. To methanol (10 mL) was added sodium methoxide (25% by weight in methanol) (1.15 mL, 5 mmol). The sodium methoxide solution was cooled in an acetone/ice bath to -15 0C (bath temperature) and dichloroacetonitrile (4 mL, 50 mmol) was added slowly, dropwise, over a 30min period with stirring under a nitrogen atmosphere. The temperature of the reaction mixture was maintained below -3 0C during the addition of dichloroacetonitrile. The reaction mixture was stirred with cooling for 20 min. To the cold reaction mixture was added DL-serine methyl ester hydrochloride (8.9 g, 57 mmol) via a powder addition funnel, followed by methanol (8 mL). The stirred reaction mixture was allowed to slowly warm to room temperature overnight. To the reaction mixture was added water (16 mL) and dichloromethane (30 mL). The mixture was transferred to a separatory funnel and the layers were separated. The aqueous phase was extracted with dichloromethane (16 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give 8.58 g (81% crude from dichloroacetonitrile) of methyl 2- (dichloromethyl)-4,5-dihydro-l,3-oxazole-4-carboxylate. 1H NMR (400 MHz, CDCl3): delta 6.28 (s, IH), 4.92-4.87 (m, IH), 4.77-4.72 (m, IH), 4.68-4.64 (m, IH), 3.82 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In tetrahydrofuran; at 80℃; for 12h;Inert atmosphere; | DL - serine methyl ester hydrochloride to (10.40g, 67mmol) tetrahydrofuran (250 ml) solution slowly adding triphosgene (20.00g, 67mmoL). Heating to 80 C stirring 12 hours. Cooling to room temperature, evaporating the solvent under reduced pressure, the crude product purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1), to obtain white solid (8.20g, 84.0%). |
84% | The serine methyl ester hydrochloride (800 mg, 5.16 mmol) was weighed into a two-necked flask, and 6 mL of anhydrous dichloromethane was added to the reaction solution under a nitrogen atmosphere.After the stirring is completely dissolved, the re-distilled triethylamine is added under stirring in an ice bath.After 15 minutes of reaction,Under a nitrogen atmosphere, 2 mL of a mixture solution of triphosgene (1.531 g, 5.16 mmol) in anhydrous dichloromethane was added dropwise, and the mixture was stirred at room temperature for 12 hours, and the reaction by TLC (basic potassium permanganate) was substantially complete. 20 mL of diethyl ether was added to the reaction system, and the mixture was frozen in a refrigerator for 30 minutes, and then filtered. The filtrate was placed in a refrigerator and frozen, filtered, and the filtrate was collected, concentrated, and purified by silica gel column chromatography ( petroleum ether: ethyl acetate = 1:2). Light yellow oil b-1 627 mg, yield 84%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 6-oxoheptanoic acid With triethylamine; isobutyl chloroformate In tetrahydrofuran at -30℃; for 1h; Inert atmosphere; Stage #2: methyl 2-amino-3-hydroxypropanoate hydrochloride In tetrahydrofuran at -30 - 20℃; for 2h; Inert atmosphere; | 3-Hydroxy-2-(6-oxo-heptanoylamino)-propionic acid methyl ester:; In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 6-oxo-heptanoic acid (2.00 g, 13.32 mmol) in THF (82 mL) at -30 0C was treated sequentially with Et3N (3.89 mL, 27.97 mmol) followed by isobutyl chloroformate (1.95 mL, 14.65 mmol). After stirring for 1 h at -30 0C, serine methylester hydrochloride (2.32 g, 14.65 mmol was added and the reaction mixture was allowed to warm gradually to rt and stirred for an additional 2 h at rt. The resulting suspension was filtered, the solid washed with THF and the filtrate was concentrated under reduced pressure. Purification of the residue by FC (97:3 EA-MeOH) gave the title compound as a colorless oil. TLC: rf (97:3 EA-MeOH) = 0.26. LC-MS-conditions 02: tR = 0.56 min [M+H]+ = 246.44. | |
Stage #1: 6-oxoheptanoic acid With triethylamine; isobutyl chloroformate In tetrahydrofuran at -30℃; for 1h; Inert atmosphere; Stage #2: methyl 2-amino-3-hydroxypropanoate hydrochloride In tetrahydrofuran at -30 - 20℃; for 2h; Inert atmosphere; | 3-Hydroxy-2-(6-oxo-heptanoylamino)-propionic acid methyl esterIn a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 6-oxo-heptanoic acid (2.00 g, 13.32 mmol) in THF (82 mL) at -30° C. was treated sequentially with Et3N (3.89 mL, 27.97 mmol) followed by isobutyl chloroformate (1.95 mL, 14.65 mmol). After stirring for 1 h at -30° C., serine methylester hydrochloride (2.32 g, 14.65 mmol was added and the reaction mixture was allowed to warm gradually to rt and stirred for an additional 2 h at rt. The resulting suspension was filtered, the solid washed with THF and the filtrate was concentrated under reduced pressure. Purification of the residue by FC (97:3 EA-MeOH) gave the title compound as a colorless oil. TLC:rf (97:3 EA-MeOH)=0.26. LC-MS-conditions 02: tR=0.56 min [M+H]+=246.44. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Methyl 3-hydroxy-2-(tritylamino)propanoate 10: To a solution of methyl 2- amino-3-hydroxypropanoate hydrochloride (39 g, 251 mmol) in CH2CI2 (460 ml) was added Et3N (52.1 g, 516 mmol) over 30 min at r.t. Then a solution of TrtCl (71.3 g, 256 mmol) in 390 mL CH2CI2 was added to the reaction mixture over 1.5 h at 25-30 C. The reaction mixture was stirred for overnight at r.t. Subsequently, 300 mL of water was added to the mixture and the mixture was stirred for 1 h. After separation, the aqueous layer was washed with CH2CI2. The organic layers were washed with brine, dried with Na2S04, and filtered. After concentrated in vacuo, compound 10 was obtained as white solid (90 g, quant.). 1H NMR (400 MHz, CDC13) delta 7.46-7.54 (m, 6H), 7.25-7.35 (m, 6H), 7.15-7.24 (m, 3H), 3.70-3.76 (m, 1H), 3.53-3.62 (m, 2H), 3.31 (s, 3H), 3.00 (d, 1H), 2.37 (t, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;Inert atmosphere; | A mixture of 3c (1.90 g, 4.11 mmol) and d,l-serine methyl ester hydrochloride (1.02 g, 6.58 mmol) in DMF (15 mL) was treated with TBTU (2.34 g, 6.17 mmol) and iPr2NEt (1.06 mL, 6.17 mmol) at 0C. The resulting reaction mixture was stirred for 18 h at room temperature. The mixture was poured in 80 mL of 10% aqueous LiCl and 70 mL AcOEt. The organic layer was separated and washed with 1N HCl, saturated aq. NaHCO3 and dried over Na2SO4. The crude was purified by column chromatography with 50% AcOEt in hexane to give 4c (1.72 g, 76% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | Step 6: Methyl-2-(R)-3-((tert-butoxycarbonyl)amino)-2,2-dimethylbutanamido)-3- hydroxypropanoate[00299] To a solution of (R)-3-((tert-butoxycarbonyl) amino)-2, 2- dimethylbutanoic acid (4.3 g, 18.59 mmoles) in DMF (230 mL) were added methyl 2- amino-3- hydroxypropanoate hydrochloride (5.78 g, 37.2 mmol), HATU (21.21 g, 55.8 mmol), and TEA (25.9 mL, 186 mmol). The mixture was stirred overnight at RT. The reaction was quenched with ice cold water (500 mL) and extracted with EtOAc (3x150 mL). The combined organic layer was dried over Na2S04 and the solvent was removed under vacuum. Crude product thus obtained was purified by ELSD combiflash (120 g silica column, 60% EtOAc: Pet-Ether) to afford a yellow oil (4.2 g, 68 %). ¾ NMR (400MHz, DMSO) delta ppm: 0.91-0.94 (m, 3H), 1.02-1.06 (m, 6H), 1.40 (s, 9H), 3.62 (s, 3H), 3.66-3.84 (m, 3H), 4.29-4.30 (m, 1H), 4.96-5.03 (m, 1H), 6.48-6.54 (m, 1H), 7.42 (dd, J=30, 6.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In dichloromethane; at 0 - 20℃; for 24h; | EXAMPLE 9; Methyl 2-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylateN, /V-diisopropylethylamine (1 1 ml_, 63.3 mmol) was added dropwise to a solution of methyl 4-fluorobenzimidate hydrochloride (10 g, 52.74 mmol) and DL-serine methyl ester HCI salt (9.9 g, 63.63 mmol) in dry CH2CI2 (200 ml.) at 0 C. The reaction mixture was stirred at room temperature for 24 h and then concentrated under reduced pressure. The reaction mixture was diluted with CH2CI2 and the organic layer was washed with H20 and brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to get methyl 2-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate (9.5 g, yield 81 %) as an orange liquid. 1H NMR (300 MHz, CDCI3) delta 8.02 - 7.97 (m, 2H), 7.13 - 7.07 (t, J = 8.7 Hz, 2H), 4.98 - 4.92 (m, 1 H), 4.73 - 4.57 (m, 2H), 3.83 (s, 3H). MS (ESI) m/z: Calculated for Cn H10FNO3: 223.06; found: 223.8 (M+H)+ |
81% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 24h; | N, N-Diisopropylethylamine (11 mL, 63.3 mmol) was added dropwise to a solution of methyl 4-fluorobenzimidate hydrochloride (10 g, 52.74 mmol) and DL-serine methyl ester HCl salt (9.9 g, 63.63 mmol) in dry CH2Cl2 (200 mL) at 0 C. The reaction mixture was stirred at room temperature for 24 h and then concentrated under reduced pressure. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to get methyl 2-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate (9.5 g, yield 81%) as an orange liquid. 1H NMR (300 MHz, CDCl3) delta 8.02 - 7.97 (m, 2H), 7.13 - 7.07 (t, J = 8.7 Hz, 2H), 4.98 - 4.92 (m, 1H), 4.73 - 4.57 (m, 2H), 3.83 (s, 3H). MS (ESI) m/z: Calculated for C11H10FNO3: 223.06; found: 223.8 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | To a solution of acid 8 (750 mg, 4.16 mmol) in DMF (20 mL) were added d,l-serine methyl ester hydrochloride (9, 710 mg, 4.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (880 mg, 4.59 mmol) and diisopropylethylamine (2.50 mL, 14.35 mmol). The resulting solution was stirred overnight at rt and the reaction mixture was concentrated to ?5 mL. To the crude mixture was added 0.1 M HCl (50 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with (0.1 M) HCl, water and brine, dried over MgSO4 and evaporated to give amide 10 (929 mg, 79%) as a white solid in sufficient purity for use in the next step: mp 132-133 C; 1H NMR (300 MHz, DMSOd6) delta 9.18 (s, 1H), 8.15 (d, J=7.5 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 6.58 (s, 1H), 6.50 (d, J=7.5 Hz, 1H), 5.02 (t, J=5.3 Hz, 1H), 4.34 (q, J=6.5 Hz, 1H), 3.68-3.58 (m, 2H), 3.62 (s, 3H), 2.67 (t, J=7.7 Hz, 2H), 2.38 (t, J=7.7 Hz, 2H), 2.16 (s, 3H); 13C NMR (75 MHz, DMSOd6) delta 172.2, 171.3, 154.9, 136.0, 129.4, 124.3, 119.6, 115.6, 61.3, 54.7, 51.8, 35.1, 25.3, 20.8; HRMS (ES-TOF) [M+H]+ calcd for C14H20NO5 282.1341, found 282.1332. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 12h;Inert atmosphere; | To a solution of d/124 l-serine-methoxyester hydrochloride (10.0g, 64.3mmol, 1.0eq.) in anhydrous 69 CH2Cl2 (300mL) at 0C, were added 62 Et3N (9.9mL, 70.7mmol, 1.1eq.), 34 Boc-d-alanine (12.2g, 64.3mmol, 1.0eq.), and 125 DCC (14.6g, 70.7mmol, 1.1eq.) sequentially. The reaction was allowed to warm to room temperature and stirred for 12h. All the solvent was evaporated in vacuo, the residue was triturated with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated in vacuo and title compound 126 41 was isolated via flash column chromatography on silica (EtOAc-CH2Cl2, 7:3) as a yellow resin (14.8g, 50.8mmol, 79% yield) which was directly used for the dehydrogenation step. Rf=0.23 (EtOAc-CH2Cl2, 7:3). 1H NMR (400MHz, CDCl3, mixture of epimers): delta 7.25-7.17 (m, 1H), 5.43-5.23 (m, 1H), 4.69-4.55 (m, 1H), 4.25-4.13 (m, 1H), 3.98-3.89 (m, 2H), 3.76 (s, 3H), 1.44-1.40 (m, 9H), 1.36 (d, J=6.8Hz, 3H). HRMS (ESI): calcd. for C12H22N2O6 [M+H]+ 313.1376 found 313.1373 |
41% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 48h; | Example 62.2-(6-Fluoro-l-methyl-lH-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-l-(4- cyanomethyl-oxazo 1-2 -yl)-ethyl] -amideStep 12-((R)-2-tert-Butoxycarbonylamino-propionylamino)-3 -hydroxy-propionic acid methyl ester A round-bottomed flask was charged with Boc-D-alanine (600 mg, 3.17 mmol) and DL-serine methyl ester hydrochloride (691 mg, 4.44 mmol). DMF (12 ml) was added followed by N,N- diisopropylethylamine (1.5 ml, 8.6 mmol) and HATU (1.33 g, 3.49 mmol). The yellow reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2x). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 422 mg (41%) of 2-((R)- 2-tert-butoxycarbonylamino-propionylamino)-3 -hydroxy-propionic acid methyl ester as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In dichloromethane; at 0 - 20℃; | To a suspension of serine methyl ester hydrochloride (S1, 4.667 g, 30.0 mmol) in CH2Cl2 (50 mL)was added Et3N (10.5 mL, 75.3 mmol). The resulting mixture was cooled to 0 C and TsCl (6.291 g,33.0 mmol) in CH2Cl2 (50 mL) was added dropwise to the above solution. The reaction was allowedto warm to room temperature and stirred overnight. After the reaction was quenched with a saturatedaqueous solution of NaHCO3 (30 mL), the organic portion was collected by extraction of CH2Cl2 (2 x30 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentratedunder reduced pressure. The residue was purified by column chromatography using EtOAc/hexane =1/1 as the eluent to give the N-tosyl-serine methyl ester (S2) as white solid (7.625 g, 93%). Spectroscopic data were consistent with those reported in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: ethyl benzimidate hydrochloride With sodium carbonate In dichloromethane; water Stage #2: methyl 2-amino-3-hydroxypropanoate hydrochloride In methanol; dichloromethane; water for 2h; Reflux; | 4.3 Methyl 2-phenyloxazoline-4-carboxylate 2 The protocol of Huang26 was modified as follows: The freebase of ethyl benzimidate 1 (37.25 g, 250 mmol), generated from the salt by basification with saturated aqueous Na2CO3 and extraction in CH2Cl2, was dissolved in 250 mL of MeOH. To this solution serine methyl ester hydrochloride (39 g, 250 mmol) was added and this was heated under reflux for 2 h. The mixture was cooled and diluted with acetone (250 mL). NH4Cl was filtered and washed with acetone. The solvents were evaporated, the residue was dissolved in CH2Cl2 (50 mL) and Et2O (200 mL)and filtered again. The organic layer was washed twice with water, with brine and dried on MgSO4. After filtration and removal of the solvents in vacuo, the title compound (43 g, 84%) was obtained as a pale pink oil. NMR data were in agreement with the literature;38 m/z (ESI) 206 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Step 1: Synthesis of Intermediate 1-22.1 To R5 (500 mg, 2.07 mmol) in DMF (5 mL) are added HATU (866.72 mg, 2.28 mmol) and DIPEA (1.43 mL, 8.29 mmol) and stirred at r.t. for 15 min. To the reaction mixture is added methyl 2- amino-3-hydroxy-propanoate hydrochloride (354.64 mg, 2.28 mmol) and stirred at r.t. for 4h. The reaction mixture is diluted with ACN and water and purified by reversed phase HPLC. Yield 79%, m/z 343 [M+H]+, rt 0.44 min, LC-MS Method X011 S03. | |
79% | To R5 (500 mg, 2.07 mmol) in DMF (5 mL) are added HATU (866.72 mg, 2.28 mmol) and DIPEA (1.43 mL, 8.29 mmol) and stirred at r.t. for 15 min. To the reaction mixture is added <strong>[5619-04-5]methyl 2-amino-3-hydroxy-propanoate hydrochloride</strong> (354.64 mg, 2.28 mmol) and stirred at r.t. for 4 h. The reaction mixture is diluted with ACN and water and purified by reversed phase HPLC. Yield 79%, m/z 343 [M+H]+, rt 0.44 min, LC-MS Method X011_S03. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With triethylamine; HATU; In dichloromethane; at 20℃; | A rbf was charged with DL-serine methyl ester hydrochloride (1.49 g, 9.57 mmol, Sigma- Aldrich Chemical Company, Inc.), HATU (4.37 g, 1 1.49 mmol, Sigma- Aldrich Chemical Company, Inc.) and DCM (22 mL). 2-Fluoropropionic acid (0.75 ml, 9.57 mmol, Alfa Aesar, A Johnson Matthey Company) and triethylamine (3.3 ml, 23.93 mmol, Sigma-Aldrich Chemical Company, Inc.) were added and the reaction mixture was allowed to stir at rt overnight. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, aqueous saturated NaHC03 solution, brine, and dried over MgS04. The solution was concentrated in vacuo and the crude product was purified by silica gel chromatography, eluting with a gradient of 1% to 10% MeOH in DCM, to provide methyl 2-(2-fluoropropanamido)-3-hydroxypropanoate (0.69 g, 3.60 mmol, 38 % yield). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.40 (t, .7=7.31 Hz, 5 H) 1.50 - 1.77 (m, 3 H) 3.23 (qd, J=7.31, 5.12 Hz, 3 H) 3.82 (s, 3 H) 3.88 - 4.15 (m, 2 H) 4.69 (dt, J=7.53, 3.69 Hz, 1 H) 4.87 - 5.21 (m, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | To a cooled (0 C) solution of sodium methoxide (25 wt % solution in methanol; 0.230 mL, 1.032 mmol) and MeOH (20 mL) was added dropwise difluoroacetonitrile (0.690 mL, 10.03 mmol) while maintaining an internal temperature of <1 C. After 20 min DL-serine methyl ester hydrochloride (1.55 g, 9.96 mmol) was added followed by MeOH (20 mL) and the reaction was allowed to warm to rt overnight. Subsequently, the reaction was heated to 55 C for 5 h. The reaction was cooled to rt and partitioned between DCM/water. The aqueous layer was extracted with DCM (3x) and the combined organic layers were washed with water and dried over MgS04. The filtrate was concentrated in vacuo to give 1.59 g (89%) of a light-brown oil. MS [M+H]+. Calculated for C6H7F2N03 : 179 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.8 g | With ammonia In methanol at 100℃; for 18h; | 3.1 2-amino-3-hydroxypropionamide A suspension of 2-amino-3-hydroxypropionic acid methyl ester hydrochloride (3 g, 19 mmol) in 10 % ammonia solution in MeOH (25 mL) was stirred in a seal-tube for 18 hours at 100 °C. The reaction was then concentrated to give 2-amino-3 -hydroxy -propionamide (1.8 g) as white solid. MS ESI calcd. For C3H9CIN2O2 [M + H]+ 141, found 141. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | General procedure: In a 100mL three necked flask, DMA (20 mL), 4-fluorobenzaldehyde 2a (1.24 g, 10 mmol), serine methyl ester hydrochloride (1.56 g, 10 mmol) and potassium carbonate (2.76 g, 20 mmol) were added. The resulting suspension stirred for 12 h at ambient temperature and then stirred for another 12 h with the addition of BrCCl3 (2.90 mL, 30 mmol) and DBU (4.60mL, 30 mmol) at 0C. The completion of the reaction was monitored by TLC. After completion of the reaction, the crude mixture was filtered and the filterate was evaporated under reduced pressure. Crude material was purified by silica gel chromatography using ethyl acetate/petroleum (1/3, V/V) as the eluent to give 5a (1.54 g, 70% yield) as a white solid. Mp 103 - 105 C; 1H NMR (400 MHz, CD3OD): delta 8.53 (s, 1H), 8.04 - 8.08 (m, 2H), 7.20 - 7.24 (m, 2H), 3.86 (s, 3H). MS (ESI) m/z: [M+H]+ 222.20, [M+Na]+ 244.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a 100mL three necked flask, DMA (20 mL), 4-fluorobenzaldehyde 2a (1.24 g, 10 mmol), serine methyl ester hydrochloride (1.56 g, 10 mmol) and potassium carbonate (2.76 g, 20 mmol) were added. The resulting suspension stirred for 12 h at ambient temperature and then stirred for another 12 h with the addition of BrCCl3 (2.90 mL, 30 mmol) and DBU (4.60mL, 30 mmol) at 0C. The completion of the reaction was monitored by TLC. After completion of the reaction, the crude mixture was filtered and the filterate was evaporated under reduced pressure. Crude material was purified by silica gel chromatography using ethyl acetate/petroleum (1/3, V/V) as the eluent to give 5a (1.54 g, 70% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-pyridinecarboxaldehyde; methyl 2-amino-3-hydroxypropanoate hydrochloride With potassium carbonate In N,N-dimethyl acetamide at 20℃; for 12h; Stage #2: With Bromotrichloromethane; 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl acetamide at 0 - 20℃; for 12h; | Step 1. Synthesis of methyl 2-(4-fluorophenyl)oxazole-4-carboxylate (5a) General procedure: In a 100mL three necked flask, DMA (20 mL), 4-fluorobenzaldehyde 2a (1.24 g, 10 mmol), serine methyl ester hydrochloride (1.56 g, 10 mmol) and potassium carbonate (2.76 g, 20 mmol) were added. The resulting suspension stirred for 12 h at ambient temperature and then stirred for another 12 h with the addition of BrCCl3 (2.90 mL, 30 mmol) and DBU (4.60mL, 30 mmol) at 0°C. The completion of the reaction was monitored by TLC. After completion of the reaction, the crude mixture was filtered and the filterate was evaporated under reduced pressure. Crude material was purified by silica gel chromatography using ethyl acetate/petroleum (1/3, V/V) as the eluent to give 5a (1.54 g, 70% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide; In acetonitrile; at 0 - 20℃; for 24h; | General procedure: 2-(4-Phenyl-1,2-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-1-ylsulfanyl)acetic acid (8) (0.340 g, 1.0 mmol), N,N'-dicyclohexylcarbodiimide (0.207 g, 1.0 mmol), and N-hydroxybenzotriazole (0.135 g, 1.0 mmol) were successively added to a cold solution (-5C) of the appropriate amino acid methyl ester hydrochloride (1.0 mmol) in acetonitrile (6 ml) containing triethylamine (0.14 ml, 1.0 mmol).The reaction mixture was stirred at 0C for 1 h, then at 5C for 1 h, then at room temperature for 8 h. The reaction mixture was set aside overnight. The precipitated N,N'-dicyclohexylurea was filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, filtered, and the filtrate was washed with 0.5 N HCl (30 ml), 3% NaHCO3 (30 ml), H2O (30 ml) and finally dried over Na2SO4 (10 g). After evaporation of the solvent, the remaining oily residue was triturated with petroleum ether (bp 40-60C) at 0C, and the formed solid was filtered off and crystallized from petroleum ether-ethylacetate, 1:3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine; In ethyl acetate; at 25℃; for 48h;Cooling; | General procedure: A solution of NaNO2 (0.340 g, 5.0 mmol) in cold water (3 ml) was added to a cold solution (-5C) of hydrazide 5 (0.300 g, 1.0 mmol) in a mixture of AcOH (6 ml), 1 N HCl (3 ml), and water (25ml). After stirring at -5 C for 15 min, a thick precipitate started to form. The reaction mixture was stirred for further 1 h and extracted by cold ethyl acetate (30 ml). The organic layer was washed with 3% NaHCO3 (30 ml), H2O (30 ml) and finally dried over Na2SO4 (10 g) to give an ethyl acetate solution of the azide 10. A solution of the appropriate amino acid ester hydrochloride (1.0 mmol) or morpholine (0.174 g, 2.0 mmol) in ethyl acetate (20 ml), containing, in the case of amino acid ester hydrochlorides, triethylamine (0.2 ml), was added to the azide 10 solution. The mixture was kept at -5C for 24 h, then at 25C for another 24 h. The reaction mixture was washed with 0.5 N HCl, water, 3% solution of NaHCO3 and finally dried over Na2SO4. The solution was evaporated to dryness and the residue was recrystallized from petroleum ether-ethyl acetate, 3:1, to give the desired N-coupled product 11a-f, 12, or 13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Triethylamine (7.25 ml, 52.1 mmol), p-anisaldehyde (6.15 ml, 50.6 mmol), and anhydrous magnesium sulfate (5.00 g) were added to a stirred solution of D,L-serine methyl ester hydrochloride (7.87 g, 50.4 mmol) in anhydrous DCM (50 ml). After 24 hours, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in anhydrous methanol (100 ml). The solution was cooled to 0 oC and was then treated portionwise with sodium borohydride (1.90 g, 50.2 mmol). After 4 hours, water (50 ml) and ethyl acetate (50 ml) were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 50 ml), and the combined organic extracts were washed with brine (50 ml), dried (MgSO4), filtered and concentrated in vacuo to give 3-hydroxy-2-(4-methoxy-benzylamino)-propionic acid methyl ester as a colourless oil (11.7 g, 97 %), Rf (ethyl acetate) 0.27; umax (film)/cm-1 3324 (br, OH and NH), 2951, 2838, 1735 (C=O), 1612, 1585, 1513, 1460, 1300, 1246, 1177, 1141, 1034, 822; deltaH (300 MHz, CDCl3) 7.24 (2H, d, J 8.6 Hz), 6.86 (2H, d, J 8.6 Hz), 3.80 (1H, d, J 12.9 Hz), 3.81-3.75 (1H, m), 3.79 (3H, s), 3.74 (3H, s), 3.68 (1H, d, J 12.9 Hz), 3.67-3.58 (1H, m), 3.43 (1H, dd, J 6.0, 4.5 Hz), 2.90-2.50 (2H, br); deltaC(75.5 MHz, CDCl3) 173.7, 159.3, 131.5, 130.0, 114.3, 62.8, 62.0, 55.7, 52.6, 51.8; m/z (EI) 238 (M-H)+, 208, 180, 136, 121, 109, 91 ,78; [Found: (M-H)+ 238.1076, C12H17NO4 requires (M-H)+ 238.1079]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium methylate; In methanol; at -5 - 20℃; for 16h; | A solution of dichloroacetonitrile (215 g, 1.96 mol) in methanol (200 mL) was added drop-wise to a -5 C solution of sodium methoxide (15.4 g, 0.285 mol) in methanol (500 mL). A solution of methyl 2-amino-3-hydroxypropanoate, hydrochloride salt (382 g, 2.45 mol) in methanol (300 mL) was then added to the -5 C reactionmixture, which was subsequently allowed to stir at room temperature for 16 hours. Dichloromethane (1 L) and water (800 mL) were added, and the aqueous layer was extracted with dichloromethane (1 L); the combined organic layers were concentrated in vacuo to provide the product as a yellow oil, which was used in the next step without further purification. Yield: 300 g, 1.4 mol, 71%. 1H NMR (400 MHz, CDCI3) oe 6.29 (5,1H), 4.90 (dd, J=10.8, 8.3 Hz, 1H), 4.74 (dd, J=8.8, 8.3 Hz, 1H), 4.66 (dd, J=10.8, 8.9 Hz, 1H), 3.82 (5, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Into a 500-mL, 3-necked round-bottom flask were placed methyl cyclopropanecarbimidate hydrochloride (13.6g, 100.00 mmol), 1.00 equiv.), <strong>[5619-04-5]methyl 2-amino-3-hydroxypropanoate hydrochloride</strong> (17.6 g, 112.82 mmol, 1.10 equiv.)and dichloromethane (150 mL). The resulting solution was stirred for 24 hours at room temperature, then added sodiumbicarbonate (16.8 g, 200.00 mmol), 2.00 equiv.). The resulting solution was stirred for 24 hours at room temperature.The solid was filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel columnand eluted with ethyl acetate/petroleum ether (1:2). This resulted in 8 g (47% yield) of methyl 2-cyclopropyl-4,5-dihydrooxazole-4-carboxylate as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; triethylamine; In dichloromethane; at 20 - 58℃; for 10h;Inert atmosphere; | To a solution of triethylamine (9.6 g, 98.2 mmol) and BzCl (9.3 g, 66.7 mmol) in CH2Cl2 kept under inert atmosphere was added D, L-serine methyl ester hydrochloride (4.5 g, 28.9 mmol).The mixture was stirred at room temperature for 7 hours,Then washed with saturated NaHCO3 solution (2 x 50 mL)Dried over anhydrous Na2SO4,Filter and evaporate.The white solid was dissolved in CH 2 Cl 2,Maintained at 58 C in an inert atmosphere,Then DBU (5.2 g, 33.9 mmol) was added.After stirring at the same temperature for 3 hours,The reaction was washed with water (50 mL) and saturated NaHCO3 solution (2 × 50 mL).The organic phase is dried over anhydrous Na2SO4,Filtered and evaporated,5.5 g of oily compound 1 are obtained,Yield (93%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | To a solution of 2-(bromomethyl)-4-chloro-1-nitrobenzene (0.97 g, 3.86 mmol, 1.0 eq.) in DMF (10 mL) was added DL-Serine methyl ester hydrochloride (0.6 g, 3.86 mmol, 1.0 eq.) and potassium carbonate (1.07 g, 7.71 mmol, 2.0 eq.). The resulting mixture was stirred at RT for 4 hours, concentrated in vacuo, diluted with EtOAc and washed with an aq. sol. of sat. NaHCO3. The organics were dried, concentrated in vacuo and the residue was purified by flash column chromatography eluting with 5% EtOAc in isohexane to give the title compound as a light yellow oil (0.77 g, 69 % yield). H NMR (400 MHz, CDCl3) delta 7.96 - 7.93 (m, 1H), 7.64 (d, J=2.3 Hz, 1H), 7.41 (dd, J=2.4, 8.7 Hz, 1H), 4.20 - 4.05 (m, 2H), 3.86 - 3.80 (m, 1H), 3.75 (s, 3H), 3.68 (dd, J=6.2, 11.3 Hz, 1H), 3.44 (dd, J=4.4, 6.3 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere; | General procedure: An appropriate alpha,beta-ynone 1a,b (0.88 mmol), K2CO3(483 mg, 3.50 mmol), extra dry DMF (6 ml), and protected amino acid 2a-e (1.31 mmol) were charged under inert gas flow into a pressure tube equipped with a magnetic stirrer.After stirring for 2 or 6-10 h (TLC observation) at 80C, the reaction mixture was concentrated under reduced pressure.The crude product was triturated with i-PrOH, filtered off, and recrystallized from i-PrOH or purified by column chromatography,eluent heptane-EtOAc, 4:1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate In N,N-dimethyl-formamide at 55℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | To a solution of methyl 2-amino-3-hydroxy-propanoate; hydrochloride (1.10 g, 7.06 mmol, CAS2104-89-4) in DMA (20 mL) was added NaHCO3 (1.19 g, 14.1 mmol). The mixture was stirred at rt for 2 hours. Then, to the mixture was added 2-chloropyridine-3-carbaldehyde (1 g, 7.06 mmol, CAS36404-88-3) in one portion. The mixture was stirred for 12 hours. Then, to the mixture was added bromo(trichloro)methane (4.20 g, 21.2 mmol) and DBU (3.23 g, 21.2 mmol) at 0 C. Then, the mixture was stirred at rt for an additional 12 hours. On completion, the mixture was quenched with water (20 mL) and extracted with EA (2×100 mL). The organic layer was washed with brine (30 mL) and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (1.2 g, 71% yield) as a white solid. LC-MS (ESI+) m/z 238.9 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In toluene Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl 2-amino-3-hydroxypropanoate hydrochloride; benzaldehyde With triethylamine In methanol at 0 - 25℃; for 6h; Stage #2: With sodium tetrahydroborate at 0 - 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.5% | Stage #1: biphenyl-4-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: methyl 2-amino-3-hydroxypropanoate hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 4h; | 5.3. The procedure for the synthesis of intermediate 10 To a solution of acid 8a (2.20 mmol, 0.43 g) in DMF (10 mL),HOBt (2.85 mmol, 0.39 g) and EDCI (2.85 mmol, 0.55 g) were addedand the mixture was stirred for 30 min at room temperature. Then,amino salt 9 (2.85 mmol, 0.44 g) and DIEA (5.70 mmol, 0.74 g) wereadded. The reaction was stirred and monitored with TLC. Themixture was poured into water and extracted with ethyl acetatethree times. The combined organic layers were dried over Na2SO4and evaporated under reduced pressure to afford intermediate 10,yield 76.5 %. |
76.5% | Stage #1: biphenyl-4-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: methyl 2-amino-3-hydroxypropanoate hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 4h; | 5.3. The procedure for the synthesis of intermediate 10 To a solution of acid 8a (2.20 mmol, 0.43 g) in DMF (10 mL),HOBt (2.85 mmol, 0.39 g) and EDCI (2.85 mmol, 0.55 g) were addedand the mixture was stirred for 30 min at room temperature. Then,amino salt 9 (2.85 mmol, 0.44 g) and DIEA (5.70 mmol, 0.74 g) wereadded. The reaction was stirred and monitored with TLC. Themixture was poured into water and extracted with ethyl acetatethree times. The combined organic layers were dried over Na2SO4and evaporated under reduced pressure to afford intermediate 10,yield 76.5 %. |
[ 66638-22-0 ]
(S)-3-Acetoxy-2-aminopropanoic acid hydrochloride
Similarity: 0.94
[ 3940-27-0 ]
DL-serine ethyl ester hydrochloride
Similarity: 0.94
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