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CAS No. : | 52605-49-9 | MDL No. : | MFCD00012506 |
Formula : | C5H12ClNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NIDZUMSLERGAON-UHFFFAOYSA-N |
M.W : | 153.61 | Pubchem ID : | 171173 |
Synonyms : |
Sacrosine ethyl ester hydrochloride;N-[(Ethoxycarbonyl)methyl]-N-methylamine hydrochloride;Sarcosine ethyl ester hydrochloride
|
Chemical Name : | Ethyl 2-(methylamino)acetate hydrochloride |
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 37.2 |
TPSA : | 38.33 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.61 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.89 |
Log Po/w (WLOGP) : | 0.57 |
Log Po/w (MLOGP) : | 0.39 |
Log Po/w (SILICOS-IT) : | 0.02 |
Consensus Log Po/w : | 0.37 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.09 |
Solubility : | 12.5 mg/ml ; 0.0815 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.28 |
Solubility : | 8.07 mg/ml ; 0.0525 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.15 |
Solubility : | 10.8 mg/ml ; 0.0705 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.3 |
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 |
---|---|---|
97% | With thionyl chloride In ethanol at -10 - 55℃; | Thionyle chloride (65 mL, 900 mmol) was added dropwise under stirring to a solution of sarcosine (1) (20.0 g, 224 mmol) in EtOH (250 mL) cooled in an ice-water bath, while maintaining temperature around -10 °C. Then the reaction mixture was gently heated at 55 °C overnight until the mixture became clear. Solvent and traces of thionyl chloride were removed by evaporation under reduced pressure and the solid residue was washed with Et2O (3 * 50 mL). The remaining solid was well dried under vacuum to afford compound 2 (33.5 g, 218 mmol) as a white powder, which was used in the next step without further purification. Yield 97percent; mp 126 °C (Lit [52]. mp 125-127 C); IR (ATR) n cm1 2970-2440, 1742, 1229; 1HNMR (CDCl3, 400 MHz) δ 9.64 (br.s, 2H, NH2), 4.24 (q, 2H,3J 7.1 Hz, CH2CH3), 3.84 (t, 2H, 3J 5.7 Hz, NH2CH2), 2.80 (t, 3H,3J 5.2 Hz, NH2CH3), 1.26 (t, 3H, 3J 7.1 Hz, CH2CH3); 13C NMR(CDCl3, 101 MHz) δ 166.18 (CO2), 62.62 (CH2CH3), 48.94 (NH2CH2),33.34 (NH2CH3), 14.03 (CH2CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride; at 0 - 78℃; | To a solution of sarcosine (17) (1.0 g, 11.2 mmol)in EtOH (26 mL) SOCl2 (2.44 mL, 33.6 mmol) was added drop-wise at 0 C. The reaction mixture was heatedto reflux, kept overnight and the solvent was then removed under reduced pressure to give sarcosine ethyl ester(18, 1.72 g, 11.2 mmol, quant.) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.) ethanol, reflux, 11 h, 2.) pyridine, reflux, irradiation, 8 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 0.833333h;Cooling with ice; | A mixture of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (3.0 g, 19 mmoi) and N. N-diisopropyiethyiamine (5.8 g, 45 rnmol, 8.1 ml) in methylene chloride (90 ml) ws stirred in an ice bath treated with a solution of chioroacetyl chloride (2.0 g, 17 mmoi, 1.4 nil) in methylene chloride (10 nil) over 20 minutes. The mixture was stirred 30 minutes then washed with IN HC1 (50 ml), The aqueous layer was extracted with methylene chloride (50 ml) and the combined organic extracts were dried tMgSO) and evaporated to leave a reddish brown oil (1.3 g, 100%). HNMR (300 MHz, CDCi3): = 4.22 (q, J = 7.0 Hz, 2H, 3:1 conformational mix), 4.15 (s, 2H), 4.14 and 4.03 (s, 2H, 3:1 conformational mix), 3.19 and 3.03 (s, 31-1. 3:1 conformational mix), 1.29 (t, J = 7.0 Hz. SF1). |
With potassium carbonate; In water; at 20℃; for 0.5h; | Compound (2) was prepared by acylation of Compound (1) under Schotten-l3aumann conditions. More specifically, an aqueous solution of potassium carbonate and chloroacetyl chloride (3) was added to a vigorously stirred suspension of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (1) in a dialkyl ether (e.g., MTBE). The reaction proceeded quantitatively at ambient temperature within about 30 minutes. The crude reaction mixture can be optionally diluted with the dialkyl ether solvent (MTBE), and underwent phase separation. After the aqueous phase was removed, the title compound (2), which was present in the organic layer (i.e. MTBE), could be used directly for the coupling step (Step 2). | |
With potassium carbonate; In tert-butyl methyl ether; water; at 0 - 15℃; for 0.5h;Large scale; | In accordance with general reaction Scheme 1 , <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (1) (103.4 kg; 0.673 kmol) and MTBE (671 L) were charged to a reactor, followed by an aqueous solution of potassium carbonate (190.3 kg; 1 .38 kmol in 539 L water), while maintaining a temperature of below 10 C. The mixture was cooled to approximately 0-5 C, and chloroacetyl chloride (3) (91 .9 kg; 0.81 kmol) was added at such a rate to maintain the temperature below 15 C. The reaction mixture was warmed to approximately 20-25 C, and the lower aqueous layer was removed and the organic layer, which contained the side chain reactant (2), was washed with monobasic potassium phosphate solution (30.8 kg; pH 3.0-4.0). To the solution of (2) was added MTBE (550 L) and then concentrated by atmospheric pressure distillation to about half of the original volume, using a jacket temperature of 75 C. The moisture content of the solution was determined by Karl Fisher titration. Additional MTBE is added and the distillation is repeated until the moisture content of the solution is 1.3 equiv. with respect to the amount of TOFA to be used. If not, the amount of TOFA used in the coupling reaction is adjusted so that the molar ratio of (2):TOFA >1.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine In chloroform for 18h; Heating; | |
With triethylamine In chloroform | 12 3-(2-Chloro-6-methylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one EXAMPLE 12 3-(2-Chloro-6-methylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one The title compound was prepared by the procedure described in Example 1 using 9.2 g of 2-chloro-6-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12 g of triethyl amine, and 200 mL of chloroform. Crystallization from ethanol afforded the title compound (7.1 g) as an orange solid (7.1 g), m.p. 142°-145° C. Anal. Calcd. for. C11 H11 N2 O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.96; H, 4.26; N, 10.97. Mass spectrum (El, M.+) m/z 254. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine In chloroform for 18h; Heating; | |
With triethylamine In chloroform | 15 3-(2,6-Dichlorophenyl)-1-methyl-2-thioxo-imidazolidin-4-one EXAMPLE 15 3-(2,6-Dichlorophenyl)-1-methyl-2-thioxo-imidazolidin-4-one The title compound was prepared by the procedure described in Example 1 using 14.28 g of 2,6-dichlorophenyl-isothiocyanate, 10.75 g of sarcosine ethyl ester hydrochloride, 14.5 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl ether afforded the title compound (16.9 g) as a light peach solid, m.p. 207°-209° C. Anal. Calcd. for C10 H8 C12 N2 O S: C, 43.65; H, 2.93; N, 10.18. Found: C, 43.57; H, 2.61; N, 10.14. Mass spectrum (El, M.+) m/z 274. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In ethanol; acetonitrile; at 60℃; for 30h; | A mixture of 2-chloro-3,5-diphenyl-3H-thieno[2,3-d]pyrimidin-4-one (100 mg, 1 eq.), <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (227mg, 5eq.), triethylamine (250ixL, 6eq.)5 acetonitrile (1.5mL) and ethanol (0.5mL) was heated at 60C in a closed flask.After 24h, <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (227mg, 5eq.), triethylamine (250uL, 6eq.), acetonitrile (0.5mL) and ethanol (0.25mL) were added, and the reaction mixture was heated at 60C for an additional 6h. The reaction mixture was diluted with brine and extracted with CH2CI2. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with hexane and ethyl acetate, to afford [methyl-(4-oxo-3,5-diphenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)-amino]acetic acid ethyl ester (116 mg, 94 %) as an oil.[Methyl-(4-oxo-3,5-diphenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)-amino] acetic acid ethyl ester; *H NMR (CDCI3, 500MHz) 5 (ppm): 7.51 (m, 2H), 7.47 (m, 2H), 7.31-7.38 (m, 5H), 7.28 (m, 1H), 6.80 (s, 1H), 4.18 (q, 2H, J=7.2Hz), 3.93 (s, 2H), 2.58 (s, 3H), 1.29 (t, 3H,J=7.2Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | To a solution of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (19)(100 g, 0.65 mol) in 500 mL of a mixed solution of acetoneand water (volume ratio: ketone/water = 1/1) was addedpotassium carbonate (224.5 g, 1.62 mol) under ice-bath conditions, and the mixture was stirred for 1 h at room temperature.Di-tert-butyl dicarbonate (128 g, 0.58 mol) wasadded, and the reaction was complete after 12 h at roomtemperature. The reaction solution was evaporated underreduced pressure to remove most of the solvent. The organicphase was separated, and the aqueous phase was extractedwith dichloromethane 3 times. The combined organic layer was washed with water and brine, dried over anhydrousNa2SO4, filtered, and then evaporated under reduced pressureto give 21 as a colorless oil, yield: 117 g (92%).1H NMR (500 MHz, CDCl3): ae as a 1:1 mixture of rotamers:4.19-4.10 (m, 2H), 3.92 (s, 2H, rotamer), 3.84 (s, 2H,rotamer), 2.89 (s, 3H, rotamer), 2.87 (s, 3H, rotamer), 1.43(s, 9H, rotamer), 1.38 (s, 9H, rotamer), 1.27-1.19 (m, 3H);13C NMR (126 MHz, CDCl3): ae (ppm) as a 1:1 mixture ofrotamers: 169.8, 156.0, 155.4, 80.0, 60.9, 51.0, 50.2, 35.5,28.2, 14.2; MS (EI): m/z 217 [M]+. HRMS (EI): m/z [M]+calcd for C10H19O4N: 217.1309, found: 217.1304. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Triethylamine (0.78 kg, 7.75 mol) was added in 15-30 minutes with stirring to a thin suspension of sarcosine ethylene hydrochloride (1.00 kg, 6.51 mol) in dichloromethane (6.00 L). After stirring at room temperature for 1.5-2.0 hours, the mixture was filtered to remove the resulting triethylamine hydrochloride salt. The salt cake was washed with dichloromethane (2.00 L). The filtrate was cooled to 0-5 C; A solution of 3,5-dichlorophenyl isocyanate (1.47 kg, 7.81 mol) in dichloromethane was prepared at 20-25 C. The solution was added to the above cooled filtrate slowly in 30-60 minutes. The temperature was maintained below 10 C. during the addition. After the addition, the mixture was stirred at 20-25 C. for 12-14 hours. The completeness of the reaction was followed by HPLC. Upon reaction completion, TBME (16.00 L) was added in one portion. The resulting suspension was stirred at 20-25 C. for 2-3 hours and was then filtered. The filter cake was washed with TBME (4.50 L) and dried at maximum 40 C. to a constant weight. A suspension of the above filter cake in water (17.0 L, 10 L/kg input) was prepared and stirred at 20-25 C. for at least 16 hours. The suspension was filtered and the filter cake was washed with water (3*1.36 L) and dried at maximum 40 C. to a constant weight to a constant weight. 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (1.52 kg, 90%) was obtained as a white crystalline solid. mp=202-204 C. 1H NMR (DMSO-d6): 7.66 (1H, m), 7.51 (2H, m), 4.10 (2H, s), 3.35 (3H, s). 13C NMR (DMSO-d6): 8 Carbons (169.30, 155.00, 134.98, 134.15, 127.59, 125.30, 51.75, 29.79). Anal. Calcd for C10H8Cl2N2O2: C, 46.35; H, 3.1 1; N, 10.81; Cl, 27.36. Found: C, 46.43; H, 2.9; N, 10.73; Cl, 27.33. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine; In toluene; at 20℃; | STEP 2 Ethyl N-METHYL-N-L6-METHYL-2-NITROPYRIDIN-3-YRL QLYCINATE To a solution of 6-METHYL-2-NITROPYRIDIN-3-YL TRIFLUOROMETHANESULFONATE (7.00 g, 24.47 mmol, 1 eq) in toluene (40 mL) at room temperature under N2 WAS added sarcosine ester hydrochloride (9.4 g, 61.2 mmol, 2.5 eq) and followed by triethylamine (8.51 mL, 61.2 MMOL, 2.5 eq). The mixture was refluxed overnight under N2. The reaction was cooled to room temperature and quenched with water. The mixture was extracted three times with ethyl acetate and all organic extracts were combined, washed with brine, dried over NA2SO4. After filtration and concentration at reduced pressure, the crude mixture was purified by flash chromatography on silica gel (20% EA/Hex) to afford the desired product (4.3 g, 69% yield) as brown oil. H NMR (CDCI3) 8 1.02 (t, 3H), 2.50 (s, 3H), 2.95 (s, 3H), 3.88 (s, 2H), 4.20 (q, 2H), 7.27 (d, 1 H), 7.49 (d, 2H). |
69% | With triethylamine; In toluene;Heating / reflux; | To a solution of 6-methyl-2-nitropyridin-3-yl trifluoromethanesulfonate (7 g, 24.47 mmol, 1 eq) in toluene (40 mL) at room temperature under N2 was added sarcosine ester hydrochloride (9.4 g, 61.2 mmol, 2.5 eq) and followed by triethylamine (8.51 mL, 61.2 mmol, 2.5 eq). The mixture was refluxed overnight under N2.The reaction was cooled to room temperature and quenched with water. The mixture was extracted three times with ethyl acetate and all organic extracts were combined, washed with brine, dried over Na2SO4. After filtration and concentration at reduced pressure, the crude mixture was purified by flash chromatography on silica gel (20% EA/Hex) to afford the desired product (4.3 g, 69% yield) as brown oil. H NMR (400 MHz, CDCl3) delta 1.026 (t, 3H), 2.50 (s, 3H), 2.95 (s, 3H), 3.88 (s, 2H), 4.20 (q, 2H), 7.27 (d, 1H), 7.49(d, 2H). |
69% | With triethylamine;Heating / reflux; | Step 8. Synthesis of ethyl N-METHYL-N- (6-METHYL-2-NITROPYRIDIN- 3-YL) glycinate. To a solution of the product of step 7 (7 g, 24. 47 MMOL) in toluene (40 mL) at room temperature under N2 was added sarcosine ester hydrochloride (9.4 g, 61.2 MMOL) and followed by triethylamine (8.51 mL, 61.2 MMOL). The mixture was REFLUXED overnight under N2. The reaction was cooled to room temperature and quenched with water. The mixture was extracted three times with ethyl acetate and all organic extracts were combined, washed with brine, dried over NA2SO4. After filtration and concentration at reduced pressure, the crude mixture was purified by flash chromatography on silica gel (20% EA/Hex) to afford the desired product (4.3 G, 69%) as brown oil. H NMR (400 MHz, CDCI3) 6 1.026 (t, 3H), 2.50 (s, 3H), 2.95 (s, 3H), 3.88 (s, 2H), 4.20 (q, 2H), 7.27 (d, 1 H), 7.49 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With pyridine; In chloroform; at 20℃; for 15h; | To a solution of 1.00g (6.51 mmol) of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> in 10 mL of chloroform was added 2.0 mL of pyridine followed by 1.25g (6.51 mmol) of 4-hydroxybenzenesulfonyl chloride. The reaction was stirred at room temperature for 15h and then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 5% HCl solution and water, dried over MgSO4, filtered and concentrated in vacuo to provide 1.47g (83%) of the sulfonamide-phenol as a white solid. Electrospray Mass Spec 273.8 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 4-methyl-morpholine In ethanol for 96h; Heating / reflux; | 3.1 EXAMPLE 3; [0243] Preparation of 6-{Methyl[2-(trans-4-phenylcyclohexylamino)ethyl]amino}-3H-benzoxazol-2-one Step 1: To a solution of sarcosine ethyl ester hydrochloride (7.5 g, 49 mmol) in EtOH (150 mL) was added N-methylmorpholine (10.6 mL, 96 mmol) and 5-fluoro-2-nitrophenol 10 (6.4 g, 41 mmol). The mixture was heated under reflux for 4 days. The reaction mixture was cooled and partitioned between EtOAc and 1N HCl. The organic solution was washed with saturated NaCl and dried (MgSO4). Concentration under reduced pressure gave 11 (8.3 g, 81%): 1H NMR (500 MHz, CDCl3): δ7.95 (d, J=9 Hz, 1H), 6.25 (dd, J=9, 2 Hz, 1H), 6.20 (d, J=2 Hz, 1H), 4.24 (q, J=7 Hz, 2H), 4.14 (s, 2H), 3.20 (s, 3H), 1.26 (t, J=7Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h; | A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (1.98 g, 5.71 mmol) and <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (0.90 g, 5.86 mmol) in DMF (60 mL) was treated with triethylamine (2.6 mL, 18.5 mmol). After stirring at room temperature under N2 for 2 h, the cloudy mixture was diluted with H20 (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with H20 (3 x 50 mL) and brine (50 mL), dried OVER NA2SO4, filtered, and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2CL2/MEOH, 98: 2) gave the title compound (1.37 g, 79%) as a white solid : IH NMR (300 MHZ, CDCL3) 6 8. 03 (d, J= 2.3 Hz, 1H), 7.32 (d, J= 2.3 Hz, 1H), 5.76 (s, 2H), 4.20 (q, J= 7.1 Hz, 2H), 3.47 (s, 2H), 3.24 (s, 2H), 2.28 (s, 3H), 1.29 (t, J= 7.1 Hz, 3H); MS (ESI) mle 302 (M + H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.1% | With 2,6-di-tert-butyl-4-methyl-phenol; triethylamine; In methanol; at 90℃;Heating / reflux; | A mixture of N-{4-[3-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-propyl]-phenylj-acrylamide (2.80 g, 6.9 mmol), <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (5.30 g, 34.5 mmol), triethylamine (3.48 g, 34.5 mmol), and 2,6-di-terf-butyl-p-cresol (100 mg) in 60 mL of methanol was refluxed at 90 C overnight. After cooling, methanol was evaporated in vacuo. Ethyl acetate (400 mL) was added to the residue, washed with brine (3 x 50 mL), dried over sodium sulphate, and concentrated. Chromatography on silica gel column using dichloromethane:methanol (95:5) as eluent gave the desired product (3.18 g, 88.1%) as a yellowish oil, which was used immediately for the subsequent reaction. MS m/z 524 [C28H37N5O3S+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; | Example 71 5- {1-Ethyl-1- [4- (2-hydroxy-3, 3-dimethyl-cyclohexyloxy) -3-methyl-phenyl]- propyl}-benzofuran-2-carboxylic acid (175 mg, . 376 mmol) in dichloromethane (5 mL) is reacted with EDC (108 mg, . 564 mmol), HOBT (55 mg, . 395 mmol), triethylamine (0.2 ml, 1.5 mmol) and <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (75 mg, . 490 mmol) separately. The reactions are stirred overnight at RT. The reactions are diluted to 25 mL with dichloromethane and washed with 1N HCL, sat bicarb, and brine (1 x 10 mL) each followed by purification on silica with 30% ethyl acetate in hexanes to yield (100 mg, 66%) of each intermediate. MS (ES) m/e : 534.3 (M-1) The intermediates are hydrolyzed with 2N NaOH in an analogous fashion to Example 30 part E to yield (80 mg, 82%) of each isomer. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium hydrogencarbonate; In ethanol; at 60℃; | Reference Example 4 Synthesis of 5-hydroxy-1-methyl-1,6-dihydro-2H-pyridine-3-one To an ethanol solution (30 mL) of <strong>[52605-49-9]N-methylglycine ethyl ester hydrochloride</strong> (3.06 g, 20 mmol) were added sodium hydrogen carbonate (3.36 g, 40 mmol) and bromoacetone (1.68 mL, 20 mmol) and stirred over night at 60C. The reaction liquid was filtered, followed by concentration under reduced pressure and adding to residue thus obtained a 10% HCl solution (250 mL) and ethyl acetate (250 mL) for fractionation. To thus obtained water layer was added sodium hydrogen carbonate till pH>7, followed by extraction with ethyl acetate , drying with magnesium sulfate anhydride and concentration under reduced pressure to obtain an objective compound, ethyl N-methyl-N-(2-oxopropyl)-glycinate (2.58 g, 74%). Thus obtained compound was dissolved in tert-butanol (40 mL), followed by adding potassium tert-butoxide (1.67 g, 14.9 mmol) and stirring at room temperature for 30 minutes. The reacting liquid was concentrated under reduced pressure and residue thus obtained was purified with silica gel column chromatography (chloroform/methanol/30% ammonia water=6/2.5/0.5) to obtain an objective compound (1.83 g, 96%). MS(ESI) m/z 128 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; | N-[3-(tert-butyloxycarbonylamino)-propyl]-sarcosine ethyl ester A solution of 17.90 g 3-(tert-butyloxycarbonylamino)propyl bromide in 50 ml of acetonitrile is added dropwise to a mixture of 11.55 g of sarcosine ethylester hydrochloride and 28.8 ml of Huenig base in 200 ml of acetonitrile within 30 minutes while cooling with an ice bath. The reaction mixture is allowed to come up to ambient temperature overnight in the ice bath. Then the solvent is distilled off using the rotary evaporator, the residue is taken up in tert-butyl-methylether and washed with ice water. The organic phase is dried over magnesium sulphate and concentrated by evaporation. The crude product is chromatographed on a silica gel column with methylene chloride/methanol/concentrated aqueous ammonia solution (100:2:0.1). Yield: 20.62 g (30% of theory), Rf value: 0.50 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution=20:1:0.1) Mass spectrum (ESI*): m/z=275 [M+H]* |
In tert-butyl methyl ether; acetonitrile; | EXAMPLE X N-[3-(tert-butyloxycarbonylamino)propyl]sarcosine ethyl ester A solution of 17.90 g of 3-(tert-butyloxycarbonylamino)propyl bromide in 50 ml acetonitrile is added dropwise, within 30 minutes, to a mixture of 11.55 g of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> and 28.8 ml of Huinig's base in 200 ml acetonitrile while cooling with an ice bath. The reaction mixture is allowed to come back up to ambient temperature overnight in the ice bath. Then the solvent is distilled off using a rotary evaporator, the residue is taken up in tert-butyl methyl ether, and washed with ice-cold water. The organic phase is dried over magnesium sulfate and concentrated by evaporation. The crude product is chromatographed on a silica gel column with methylene chloride/methanol/concentrated aqueous ammonia solution (100:2:0.1). Yield: 20.62 g (30% of theory); Rf value: 0.50 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution=20:1:0.1); mass spectrum (ESI+): m/z=275 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | 13.94 ml of Huenig base are pipetted into a suspension of 9.37 g of sarcosine ethylester hydrochloride in 25 ml of tetrahydrofuran while cooling with an ice bath. Then a solution of 2.00 g of 4-[(3-bromophenyl)amino]-6-[(4-bromo-1-oxo-2-buten-1-yl)amino]-quinazoline in 10 ml of dimethylformamide is added dropwise within 15 minutes. The reaction mixture is allowed to come up to ambient temperature overnight in an ice bath. For working up, 25 ml of saturated sodium hydrogen carbonate solution and 50 ml of ethyl acetate are added. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The dark-brown oily residue is stirred with 50 ml of water, the precipitate formed is suction filtered and washed with water. The crude product is purified by chromatography on a silica gel column with methylene chloride/methanol (50:1 to 20:1). Yield: 1.00 g (46% of theory), Melting point: 182-183 C. Mass spectrum (ESI*): m/z=496, 498 [M-H]* |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.3% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h; | 1) [N-[N'-(2-Benzyloxycarbonyl)amino-2-methylpropionyl]-N-methylamino]acetic acid ethyl ester Sarcosine ethyl ester hydrochloride (7.77 g), 1-hydroxybenzotriazole (6.83 g), triethylamine (7.08 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.70 g) were added at room temperature to N-(2-benzyloxycarbonyl)amino-2-methylpropionic acid (10.0 g) in N,N-dimethylformamide (200 mL), followed by stirring for 20 hours. 1N HCl and ethyl acetate were added thereto for partitioning the reaction mixture. The organic layer was sequentially washed with saturated brine, saturated aqueous sodium hydrogencarbonate, and saturated brine, and then dried over magnesium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give [N-(N'-(2-benzyloxycarbonyl)amino-2-methylpropionyl)-N-methylamino]acetic acid ethyl ester as an oily product (13.1 g, 92.3%). 1H-NMR (300MHz, CDCl3) delta:1.26 (3H, t, J=7.16Hz), 1.65(6H, s), 3.16(3H, br s), 4.08(1H, br s), 4.18 (2H, q, J=7.16Hz), 5.09(2H,s), 5.55(1H, br s), 7.30-7.38(5H, m). MS (FAB) m/z: 337 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dmap; Diethylcyanamide; In dichloromethane; at 20℃; for 16h; | Example 5; Preparation of [(6-{ l-[4-(3,3-Dimethyl-2-oxobutoxy)-3-methylphenyl]-l- ethylpropyl } naphthalene-2-carbonyl)methylamino] acetic acid; A. [(6-{ l-[4-(3,3-Dimethyl-2-oxobutoxy)-3-methylphenyl]-l- ethylpropyl}naphthalene-2-carbonyl)methylamino] acetic acid ethyl ester; Dissolve 6-{ l-[4-(3 ,3 -dimethyl-2-oxobutoxy)-3 -methylphenyl]- 1- ethylpropyl}naphthalene-2-carboxylic acid (0.10 g, 0.222 mmol), sarcosine ethyl ester HCl (0.069 g, 0.45 mmol), DMAP (0.108 g, 0.89 mmol) and EEDC (0.086 g, 0.45 mmol) in CH2CL2 (2 mL). Stir the mixture at RT for 16 h. Dilute the reaction mixture with CH2CL2 and water. Acidify to pH 1 using IN HCl. Separate and disgard the the aqueous layer. Wash the organic layer with brine, dry over Na2SO4, and filter. Concentrate the filtrate and purify by silica gel radial chromatography (25:75 EtOAc:hex to 50:50 EtoAc:hex) to give the title compound as a white solid (0.093 g, 78%). MS (ES) m/e 546 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | 7V-Methyl glycine ethyl ester hydrochloride (255 mg, 1.66 mmol) was added to a suspension of 5-(4-z'e7Y-butylphenyl)-3-formyl-l-(4-isopiOpox)'phenyl)indole-2- carboxylic acid ethyl ester (400 mg, 0.83 mmol; see step (c) above) in MeOH (20 mL) and the pH was adjusted to 6 by the addition of a few drops of glacial acetic EPO <DP n="154"/>acid. After 1 h at rt, NaCNBH3 (75 mg, 1.18 mmol) was added and the mixture was stirred at rt for 24 h, poured into H2O and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4). concentrated and purified by chromatography to give the sub-title compound. Yield 400 mg (87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | A mixture of 5-(4-rerr-butylphenyl)-l-(4-cyclopent3'loxyphenyl)indole-2-carb- aldehyde (200 mg, 0.46 mmol; see Example 29, step (d)), JV-methyl glycine ethyl ester hydrochloride (138 mg, 0.90 mmol), sodium acetate (52 mg, 0.72 mmol) and methanol (11 mL) was stirred for 1 h at rt. NaCNBH3 (93 mg, 1.48 mmol) was added and the mixture was stirred at rt for a 24 h, poured into water and extracted with EtOAc. The combined extracts were washed with water and brine, dried (Na2SC^), concentrated and purified by chromatography to give the sub-title compound (120 mg, 49 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In dichloromethane; | 2.B)e) 10.6ml of 4-ethylmorpholine, 4.6g of N-(dimethyl- aminopropyl)-N'-ethylcarbodiimide hydrochloride, 244 mg of 4-dimethylaminopyridine and 3.1 g of sarcosine ethyl ester hydrochloride added in succession to a solution of 5.78 g of N-Boc-L-aspartic acid-beta-t-butyl ester in 100 ml of methylene chloride. After stirring the reaction mixture is poured into ice-cold 5% potassium hydrogen sulfate-10% potassium sulfate solution and extracted with ethyl acetate. The organic phase is washed with water, then dried, evaporated and the residue is chromatographed on silica gel with hexane-ethyl acetate (3:1). There are obtained 6.8 g of t-butyl (S)-3-t-butoxycarbonylamino-N-ethoxycarbonylmethyl-N-methylsuccinamate, MS (ion spray): 389.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In chloroform | 3 3-(5-Chloro-2-methoxyphenyl)-1-methyl-2-thioxo-imidazolidin-4-one EXAMPLE 3 3-(5-Chloro-2-methoxyphenyl)-1-methyl-2-thioxo-imidazolidin-4-one A mixture of sarcosine ethyl ester hydrochloride (7.68 g), 5-chloro-2-methoxyphenyl-isothiocyanate (10.0 g), triethyl amine (10.0 g) and chloroform (150 mL) was heated at reflux for 4.5 hours. The mixture was cooled to ambient temperature. The precipitated solid was collected, washed with chloroform and air dried to give the title compound (11.8 g) as an off-white solid, m.p. 245°-247° C. Anal. Calcd. for C11 H11 Cl N2 O2 S: C, 48.80; H, 4.10; N, 10.35. Found: C, 48.42; H, 3.96; N, 10.33. Mass spectrum (EI, M.+) m/z 270. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine; In N,N-dimethyl-formamide; at 150℃; for 0.25h;Microwave irradiation; | a) Ethyl Lambda/-methyl-Lambda/-[4-nitro-4'-(trifluoromethyl)-3-biphenylyl]glycinate 3-Fluoro-4-nitro-4'-(trifluoromethyl)biphenyl (example 13a, 0.500 g, 1.75 mmol) and <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (0.300 g, 1.95 mmol) in DMF (3.0 ml_) were treated with triethylamine (0.48 mL, 3.44 mmol) and heated to 15O0C in the microwave for 15 min. The reaction was diluted with ethyl acetate and washed with 1 N HCI and then water, dried over MgSOphi filtered and concentrated under reduced pressure. Column chromotography (4:1 hexane/ethyl acetate) provided the title compound (0.440 g, 65%) as a solid. 1H NMR (400MHz, D6-DMSO) delta 7.90 (m, 5H),7.33 (d, J = 1.6 Hz, 1 H), 7.26 (dd, J = 1.7, 6.8 Hz, 1 H), 4.19 (s, 2H), 4.13 (q, 2H)1 2.90 (s, 3H), 1.18 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With thionyl chloride; In ethanol; at -10 - 55℃; | Thionyle chloride (65?mL, 900?mmol) was added dropwise under stirring to a solution of sarcosine (1) (20.0?g, 224?mmol) in EtOH (250?mL) cooled in an ice-water bath, while maintaining temperature around -10?C. Then the reaction mixture was gently heated at 55?C overnight until the mixture became clear. Solvent and traces of thionyl chloride were removed by evaporation under reduced pressure and the solid residue was washed with Et2O (3?*?50?mL). The remaining solid was well dried under vacuum to afford compound 2 (33.5?g, 218?mmol) as a white powder, which was used in the next step without further purification. Yield 97%; mp 126?C (Lit [52]. mp 125-127 C); IR (ATR) n cm1 2970-2440, 1742, 1229; 1HNMR (CDCl3, 400 MHz) delta 9.64 (br.s, 2H, NH2), 4.24 (q, 2H,3J 7.1 Hz, CH2CH3), 3.84 (t, 2H, 3J 5.7 Hz, NH2CH2), 2.80 (t, 3H,3J 5.2 Hz, NH2CH3), 1.26 (t, 3H, 3J 7.1 Hz, CH2CH3); 13C NMR(CDCl3, 101 MHz) delta 166.18 (CO2), 62.62 (CH2CH3), 48.94 (NH2CH2),33.34 (NH2CH3), 14.03 (CH2CH3). |
With nitrogen; In phosphorus pentaoxide; ethanol; | (a) N-Methylglycine, ethyl ester, hydrochloride A suspension of N-methylglycine (10.0 g., 0.11 mole) in 120 ml. of ethanol is saturated with dry hydrochloric acid gas at 0 (ice-bath), allowed to warm to room temperature, and stirred for 16 hours. Nitrogen is passed through the clear solution to discharge excess hydrochloric acid. The solution is evaporated to dryness and the residue is repeatedly triturated with dry ethyl ether. The resulting white solid is filtered off, washed with ethyl ether, and dried in vacuo over phosphorus pentoxide to give 16.7 g. of N-methylglycine, ethyl ester, hydrochloride as a white solid; m.p. 119.5-121 (literature m.p. 122-123). | |
With nitrogen; In phosphorus pentaoxide; ethanol; | (a) N-Methylglycine, ethyl ester, hydrochloride A suspension of N-methylglycine (10.0 g., 0.11 mole) in 120 ml. of ethanol is saturated with dry hydrochloric acid gas at 0 (ice-bath), allowed to warm to room temperature, and stirred for 16 hours. Nitrogen is passed through the clear solution to discharge excess hydrochloric acid. The solution is evaporated to dryness and the residue is repeatedly triturated with dry ethyl ether. The resulting white solid is filtered off, washed with ethyl ether, and dried in vacuo over phosphorus pentoxide to give 16.7 g. of N-methylglycine, ethyl ester, hydrochloride as a white solid; m.p. 119.5-121 (literature m.p. 122-123). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium formate; acetic anhydride; In formic acid; diethyl ether; water; | e Preparation of ethyl 2-amino-1-methyl-1H-imidazole-5-carboxylate: Sarcosine ethyl ester hydrochloride (76 g) was added to a solution of sodium formate (37 g) dissolved in formic acid (163 ml) and the mixture was stirred at ambient temperature for 4 hours and filtered. Acetic anhydride (222 ml) was added dropwise to the filtrate (exotherm to 60 C.) and the mixture was allowed to stand at ambient temperature for 10 hours. The solvent was evaporated and the residue was triturated with acetone and the NaCl was filtered. The solvent was evaporated and the residue was distilled under high vacuum to give ethyl N-formyl sarcosine ester 50.6 g, bp 80-82 C. at 0.05 0.05 mmHg. Potassium-t-butoxide (52.3 g) was suspended in diethylether (500 ml) and cooled to 0 C. A solution of N-formyl sarcosine ether ester (67.66 g) and methyl formate (27.9 g) in diethylether (200 ml) was added dropwise over 30 minutes and the mixture was stirred at 0 C. for 1 hour. The solid product was filtered (76.6 g) and used immediately for the next stage. The ethyl-2-(N-formyl-N-methyl)-3-oxopropionate prepared as described above was dissolved in water and concentrated HCl (138 ml) was added. The mixture was heated on a steam bath for 30 minutes, cooled and the pH was adjusted to 5 by addition of concentrated NaOH. Cyanamide (19.3 g) was added and the mixture was heated at 100 C. for 1 hour. The mixture was allowed to cool and was basified with concentrated aqueous ammonium hydroxide, the solid was filtered, washed with water and dried under reduced pressure and was crystallized from EtOAc (300 ml) to give ethyl 2-amino-1-methyl-1H-imidazole-5-carboxylate yield 14.6 g. Methyl 2-amino-1-methyl-1H-imidazol-5-carboxylate and the corresponding ethyl ester may be prepared using the method described in J. Med. Chem 1972, 15, 1086. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.57 g (65%) | With triethylamine; In dichloromethane; | EXAMPLE 125A Ethyl 2-(((4(4-pyridinyloxy)phenyl)sulfonyl)methylamino)acetate A cloudy solution of sarcosine ethyl ester hydrochloride (3.1 g, 20 mmol) in dichloromethane (150 mL) was treated with triethylamine (6.13 mL, 44 mmol), cooled with an ice bath, then treated with <strong>[192329-81-0]4-(4'-pyridyloxy)benzene sulfonyl chloride</strong> (6.74 g, 22 mmol) (WO 98/50348, p.30) and stirred for 2.5 hours after which time the mixture was partitioned between water and dichloromethane. The organic layer was washed with sat. aq. NaHCO3, brine, dried and concentrated. The residue was suspended in dichloromethane, filtered, and the solid was washed with dichloromethane. The filtrate and washings were concentrated to give 4.57 g (65%) of the desired product. Rf 0.35 (5% MeOH: dichloromethane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; potassium carbonate; In dichloromethane; acetonitrile; | Step 1 N-[(3-Oxo-3-phenyl)propyl]sarcosine ethyl ester: A mixture of 3.37 g (20 mmol) 3-chloropropiophenone (Aldrich), (3.07 g, (20 mmol) sarcosine ethyl ester hydrochloride, 3.32 g (20 mmol) potassium iodide and 2.5 g potassium carbonate in 140 ml acetonitrile was heated under reflux with stirring for 2 hours (see Reaction 13, FIG. 2). The reaction mixture was filtered and the solvent evaporated. The residue was dissolved in dichloromethane, washed with water and dried over sodium sulphate. Evaporation of the solvent gave N-[(3-oxo-3-phenyl)propyl]sarcosine ethyl ester as a yellow oil which was used in step 2 without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In acetonitrile; at 80℃; for 18h; | Example B2; a) Preparation of compound 131; A mixture of intermediate 7 (prepared according to A2.d) (0.24 mmol), <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (0.24 mmol) and K2CO3 (0.24 mmol) in CH3CN (5 ml) was stirred at 80C for 18 hours. The mixture was cooled and poured into water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated. The residue was crystallized from diisopropyl ether. The precipitate was filtered off and dried. Yield: final compound 137 (100 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Step 5: To a solution of compound 3d (2.00 g, 7.57 mmol, 1 eq) in DMSO (25 mL), was added triethylamine (2.64 mL, 18.9 mmol, 2.5 eq) and <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (1.51 g, 9.84 mmol, 1.3 eq). The reaction mixture was stirred at ambient temperature for 72 h and the reaction was quenched by the addition of 0.1 N HCI and the mixture was acidified to pH 3. The product was extracted with EtOAc (3 X 40 mL) and the combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography using a gradient of EtOAc in hexanes ( from 10% to 100%) to provide compound 3e (1.40 g, 3.87 mmol, 51 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine; In dimethyl sulfoxide; at 80℃; for 2h; | Step 4:To a solution of 4c (524 mg, 2.64 mmol, 1 eq.) in DMSO (13 ml_) were added <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (609 mg, 3.96 mmol, 1.5 eq.) and Et3N (921 mul_,2.5 eq). The reaction mixture was stirred at 8O0C for 1 h, more sarcosine (203 mg, 1.32 mmol, 0.5 eq) was added, and the reaction mixture was stirred for an additional hour at 80C. The solution was diluted with EtOAc (100 ml_), and washed with EPO <DP n="51"/>aqueous saturated NaHCO3 (30 mL) and brine. The organic phase was dried overMgSO4 and concentrated. The crude material was purified by flash chromatography using 50% EtOAc in hexanes to afford 578 mg (74% yield) of the desired aniline 4d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate; In acetone; at 20℃; for 22h;Heating / reflux; | N-(2-carboethoxy)sarcosine ethyl ester (19). To a mixture of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (32.2 g, 0.21 mole), potassium carbonate (325 mesh; 86.9 g, 0.63 mole), and acetone (800 mL) was added a solution of compound 18 (60.7 g, ca. 0.21 mole, 85:15 18/17) in acetone (100 mL) at room temperature under N2. The mixture was stirred at reflux for 2 hr and then left at room temperature for 20 hr. The solid was removed by filtration (Celite) and the residue was washed with acetone. The filtrates were combined and evaporated to afford an oil. The oil was dissolved in 250 mL of 3 N HCl and washed with ether. The aqueous layer was basified with aqueous NaHCO3, and extracted with ether (3 x 250 mL). Evaporation of the ether solution yielded an oil that was vacuum distilled to afford 45.33 g (77%) of compound 19 |
77% | With potassium carbonate; In acetone; at 20℃; for 22h;Heating / reflux; | To a mixture of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (32.2 g, 0.21 mole), potassium carbonate (325 mesh; 86.9 g, 0.63 mole), and acetone (800 mL) was added a solution of compound 18 (60.7 g, ca. 0.21 mole, 85:15 18/17) in acetone (100 mL) at room temperature under N2. The mixture was stirred at reflux for 2 hr and then left at room temperature for 20 hr. The solid was removed by filtration (Celite) and the residue was washed with acetone. The filtrates were combined and evaporated to afford an oil. The oil was dissolved in 250 mL of 3 N HCl and washed with ether. The aqueous layer was basified with aqueous NaHCO3, and extracted with ether (3*250 mL). Evaporation of the ether solution yielded an oil that was vacuum distilled to afford 45.33 g (77%) of compound 19: bp 140-142 C./0.5 mm Hg; bp 182-183 C./10 mm Hg; 1H-NMR (CDCl3) delta 1.24 (t, 3H, J=7.1 Hz, CH3), 1.36 (t, 3H, J=7.1 Hz, CH3), 2.35 (s, 3H, NCH3), 3.27 (s, 2H, CH2Ar), 4.00 (s, 2H, NCH2), 4.14 (q, 2H, J=7.1 Hz, CH2CH3), 4.32 (q, 2H, J=7.1 Hz, CH2CH3), 7.28 (t, 1H, J=7.4 Hz, ArH), 7.42 (t, 1H, J=7.6 Hz, ArH), 7.52 (d, 1H, J=7.8 Hz, ArH), 7.74 (d, 1H, J=7.7 Hz, ArH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In butan-1-ol; for 4.5h;Heating / reflux; | Methyl 2-chloro-3-nitrobenzoate (2.0 g) obtained in the First Step was dissolved in n-butanol (20 ml), sodium carbonate (2.46 g) and sarcosine ethyl ester hydrochloride (2.14 g) were added, and the mixture was refluxed for 4.5 hours with stirring. The cooled reaction mixture was poured into a mixture of 1 M hydrochloric acid (50 ml)/ethyl acetate (50 ml) under ice-cooling with stirring. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain red oily substance containing the title compound which was supplied to the subsequent step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.9% | In tetrahydrofuran; ethanol; N,N-dimethyl acetamide; N,N-dimethyl-formamide; | (1) To a solution of <strong>[118-45-6]4-chlorophthalic anhydride</strong> (9.13 g, 50 mmol) in tetrahydrofuran (50 ml) was added 28% sodium methoxide-methanol solution (11.6 ml, 60 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, and, after making the mixture acidic with 1N hydrochloric acid, extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 ml) and oxalyl chloride (5.2 ml, 60 mmol) and N,N-dimethylformamide (3 drops) were added thereto. The mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (100 ml). To the obtained solution was added ethyl sarcosinate hydrochloride (9.22 g, 60 mmol). The obtained mixture was stirred at room temperature for 2 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml) and 20% sodium ethoxide ethanol solution (27.2 g, 80 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (100 ml) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the component eluted earlier was concentrated to give ethyl 7-chloro-4-hydroxy-2-methyl-1-oxo-1,2-dihydro3-isoquinolinecarboxylate (2.24 g, 20.9%) as crystals. Melting point 109-110 C. Elemental analysis for C13H12NO4Cl Calculated: C, 55.43; H, 4.29; N, 4.97. Found: C, 55.54; H, 4.22; N, 5.12. 1H-NMR(CDCl3) delta: 1.46 (3H, t, J=7 Hz), 3.68 (3H, s), 4.50 (2H, q, J=7.0 Hz), 7.70 (1H, dd, J=2.0, 8.6 Hz), 8.09 (1H, d, J=8.6 Hz), 8.43 (1H, d, J=2.0 Hz), 11.25 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.4% | Example 5 N-[(S)-N-benzyloxycarbonylphenylglycyl]sarcosine ethyl ester (Z-Phg-Sar-OEt) (S)-N-benzyloxycarbonylphenylglycine (5.00 g, 0.0175 mol) was dissolved in dichloromethane (20 ml), and triethylamine (2.44 ml, 0.0175 mol) was added at -10C or lower. To a solution of ethyl chloroformate (1.67 ml, 0.0175 mol) in dichloromethane (15 ml) was added the above-described solution at -10C or lower, and the mixture was stirred at the same temperature for 10 minutes to obtain a suspension. Separately, <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (2.82 g, 0.0184 mol) was suspended in dichloromethane (20 ml), triethylamine (2.56 ml, 0.0184 mol) was added at -10C or lower, the deposit was filtrated and washed with dichloromethane (10 ml), and the filtrate was added to the above-described suspension at -10C or lower, and the mixture was stirred for 15 minutes, and further, stirred at 0C for 30 minutes. This reaction mixture was poured into ice water (80 ml), and dichloromethane was once distilled off under reduced pressure. Ethyl acetate (40 ml) was added, insoluble substances were removed by filtration, the filtrate was partitioned, and an organic layer was washed sequentially with 10% hydrochloric acid (15 ml) and saturated sodium bicarbonate water (15 ml), dried over anhydrous magnesium sulfate, then, filtrated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate = 2:1) to obtain 3.87 g(yield 57.4%) of an oil of the title compound. 1H-NMR(ppm, CDCl3): delta 1.24 (t, 3H, J=7.0 Hz, CH3), 2.93 (s, 3H, NMe), 3.98 and 4.27 (2d, 2H, J= 17.2 Hz, CH2), 4.19 (q, 2H, J= 7.0 Hz, CH2), 5.04 and 5.01 (2d, 2H, J=12.0 Hz, CH2), 5.66 (d, 1H, J=7.6 Hz, CH), 6.25 (d, 1H, J=7.2 Hz, NH), 7.20-7.45 (m, 10H, aromatic). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With triethylamine; In acetonitrile; at 20 - 80℃; for 20h; | To a stirred solution of <strong>[372118-01-9]4,6-dichloro-pyridazine-3-carboxylic acid methyl ester</strong>(2.9 g, 14 mmol) and sarcosine ethyl ester hydrochloride (2.15 g, 14 mmol) in acetonitrile (75 ml) was added triethylamine (4.9 mL, 35 mmol). The resultant reaction mixture was stirred at room temperature for 2 hours before adding further triethylamine (4.9 mL, 35 mmol) and heating the reaction mixture at 80C for 18 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resultant residue treated with water and extracted with ethyl acetate (x 3), the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give a solid. The solid was triturated in hot methanol to give the title compound as a yellow solid (1.6 g, 45%). LCMS (method B): Rx = 2.64 min, M+H+ = 256. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | A mixture of compounds JV-methylglycine ethyl ester hydrochloride (7.00 mmol) and Et3N (1.033 ml) in acetonitrile (5 ml) was stirred for 20 minutes at room temperature. Compound 2-isocyanatopropane (6.65 mmol) was added dropwise to the reaction mixture and stirring was continued for 5 hours at room temperature. Then the reaction mixture was diluted with DCM (20 ml) and washed with H2O (10 ml). The organic layer was separated, dried over Na2SO4 and concentrated in vacuum. The residue was purified by Flash-chromatography (eluent: ethyl acetate). Yield: 0.908 g of intermediate 15 (64 %; yellowish oil). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution [(30] mL) of bis (trichloromethyl) carbonate (0.50 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.40 mL) in tetrahydrofuran under ice- cooling. After stirring under ice-cooling for 30 min., <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (0.77 g) was added. A solution [(1] [ML)] of triethylamine [(0.] 70 mL) in tetrahydrofuran was dropwise added and the mixture was stirred at room temperature for 1 hr. The precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (33 mL). [(R)-2- [ [ [3-METHYL-4- (2,] 2, [2-TRIFLUOROETHOXY)-2-] pyridyl] methyl] sulfinyl]-lH-benzimidazole sodium (1.37 g) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at [60C] overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane=1 : [1,] then ethyl acetate) to give the title compound (0.40 g) as a yellow amorphous solid. [H-NMR] [(CDCL3)] : 1.33 (3H, t, J=7. [LHZ),] 2.24 (3H, s), 3.10 (3H, [BS),] 3.70-4. 30 (2H, br), 4.28 (2H, q, J=7. lHz), 4.38 (2H, q, J=7.8Hz), 4.82-5. 10 (2H, br), 6.63 [(LH,] d, J=5. [5HZ),] 7.34-7. 52 (2H, m), 7.70- 7.90 (2H, m), 8.32 [(LH,] d, J=5.5Hz). | ||
To a solution of bis(trichloromethyl) carbonate (0.50 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.40 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 30 minutes under ice-cooling, and <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (0.77 g) was added thereto. A solution of triethylamine (0.70 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 1 hr. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (33 mL). To the solution were added (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole sodium salt (1.37 g) and 4-dimethylaminopyridine (catalytic amount), and stirred at 60C overnight. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate : hexane = 1 : 1, then ethyl acetate) to give title compound as yellow amorphous solid (0.40 g).1H-NMR(CDCl3) : 1.33 (3H,t,J=7.1Hz), 2.24(3H,s), 3.10(3H,bs), 3. 70-4.30 (2H, br), 4.28 (2H, q, J=7.1Hz), 4.38 (2H, q, J=7.8Hz), 4.82-5.10 (2H, br), 6.63 (1H, d, J=5.5Hz), 7.34-7.52 (2H,m), 7.70-7.90(2H,m), 8.32(1H,d,J=5.5Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine; In ethanol; for 48h;Reflux; | 5.11 Ethyl 6-ethyl-3-hydroxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo-[3,2-c]pyridine-2-carboxylate (7a) A mixture of 6a (7.00 g, 19.3 mmol), <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (5.94 g, 38.7 mmol), Et3N (29.7 mL, 193 mmol), and EtOH (100 mL) was stirred at reflux for 2 days. After cooling, the mixture was diluted with water and acidified with 5 M HCl aq. The resulting solid was collected and washed with water and hexane/AcOEt to give the title compound (5.70 g, 74%) as a white solid. 1H NMR (DMSO-d6) delta 1.18 (3H, t, J = 7.4 Hz), 1.31 (3H, t, J = 7.1 Hz), 2.56 (2H, q, J = 7.4 Hz), 3.80 (3H, s), 4.30 (2H, q, J = 7.1 Hz), 5.55 (2H, s), 6.43 (1H, s), 7.60 (2H, t, J = 7.6 Hz), 7.68-7.79 (1H, m), 8.00-8.21 (2H, m), 8.90 (1H, s). |
67% | With triethylamine; In ethanol; at 80 - 100℃; for 25h; | A mixture of the compound of Reference Example 4 (950 mg, 2.73 mmol), ethyl sarcosinate hydrochloride (839 mg, 5.46 mmol), triethylamine (2.27 mL, 16.4 mmol) and ethanol (10 mL) was stirred at 80C for 10 hr, triethylamine (2.27 mL, 16.4 mmol) was further added thereto, and the mixture was stirred at 100C for 15 hr. After cooling, water was added to the reaction mixture, and the mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent; ethyl acetate:methanol=10:1) to give the title compound (698 mg, 67%) as a brown solid. 1H-NMR (300MHz, DMSO-d6) delta:1.18 (3 H, t, J=7.4 Hz), 1.31 (3 H, t, J=7.1 Hz), 2.56 (2 H, q, J=7.6 Hz), 3.80 (3 H, s), 4.30 (2 H, q, J=7.2 Hz), 5.55 (2 H, s), 6.43 (1 H, s), 7.60 (2 H, t, J=7.6 Hz), 7.68-7.79 (1 H, m), 8.00-8.21 (2 H, m), 8.90 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution (30 mL) of bis(trichloromethyl)carbonate (0.50 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.40 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 30 min., <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (0.77 g) was added. A solution (1 mL) of triethylamine (0.70 mL) in tetrahydrofuran was dropwise added and the mixture was stirred at room temperature for 1 hr. The precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (33 mL). (R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole sodium salt (1.37 g) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:1, then ethyl acetate) to give the title compound (0.40 g) as a yellow amorphous solid.1H-NMR(CDCl3) : 1.33 (3H,t,J=7.1Hz), 2.24 (3H,s), 3.10 (3H,bs), 3.70-4.30(2H,br), 4.28 (2H,q,J=7.1Hz), 4.38 (2H,q,J=7.8Hz), 4.82-5.10(2H,br), 6.63 (1H,d,J=5.5Hz), 7.34-7.52(2H,m), 7.70-7.90(2H,m), 8.32 (1H,d,J=5.5Hz). | ||
Synthetic Example 31 Ethyl [methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]acetate (0654) (0655) To a solution (30 mL) of bis(trichloromethyl)carbonate (0.50 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.40 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 30 min., <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (0.77 g) was added. A solution (1 mL) of triethylamine (0.70 mL) in tetrahydrofuran was dropwise added and the mixture was stirred at room temperature for 1 hr. The precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (33 mL). (R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole sodium (1.37 g) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60 C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:1, then ethyl acetate) to give the title compound (0.40 g) as a yellow amorphous solid. (0656) 1H-NMR(CDCl3): 1.33 (3H, t, J=7.1 Hz), 2.24 (3H, s), 3.10 (3H, bs), 3.70-4.30 (2H, br), 4.28 (2H, q, J=7.1 Hz), 4.38 (2H, q, J=7.8 Hz), 4.82-5.10 (2H, br), 6.63 (1H, d, J=5.5 Hz), 7.34-7.52 (2H, m), 7.70-7.90 (2H, m), 8.32 (1H, d, J=5.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 49% 2: 35% | Stage #1: cinchomeronic anhydride; sarcosine ethyl ester hydrochloride With triethylamine In chloroform at 20℃; Stage #2: diazomethane In methanol at 20℃; Cooling with ice; Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In ethanol; at 20℃; | Ethyl N-methylglycinate hydrochloride salt (2) (30.0?g, 195?mmol) was suspended in a mixture of EtOH (200?mL) and ethyl formate (126?mL). Potassium carbonate (40.6?g, 294?mmol) was added under vigorous stirring and the suspension was stirred at rt overnight. The reaction mixture was then filtered and the precipitate was washed with EtOH (150?mL). The filtrate was concentrated and dissolved in a minimum amount of water (10?mL), followed by extraction with EtOAc (4?*?200?mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford compound 3 (24.3?g, 167?mmol) as a pale yellow liquid. Yield 85%; 1H NMR (CDCl3, 500?MHz) delta (two rotamers) 7.93 and 7.86 (s, 1H, CHO), 4.04 and 4.02 (q, 2H, 3J?=?7.2?Hz, CH2CH3), 3.91 and 3.85 (s, 2H, NCH2), 2.87 and 2.74 (s, 3H, NCH3), 1.12 and 1.10 (t, 3H, 3J?=?7.1?Hz, CH2CH3); 13C NMR (CDCl3, 75?MHz) delta (two rotamers) 168.76, 168.31 (CO2), 163.09, 162.85 (CHO), 61.62, 61.29 (OCH2CH3), 50.93, 45.72 (NCH2), 35.10, 30.76 (NCH3), 14.09 (OCH2CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In acetonitrile Reflux; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 0 - 20℃;Inert atmosphere; | To a solution of the residue in dichloromethane (22 mL) at 0 C under Ar were added successively HCl-Sar-OEt (519 mg, 3.38 mmol), PyBroP (1.36 g, 3.38 mmol) and dropwise diisopropylethylamine (1.5 mL, 9.0 mmol). The reaction mixture was warmed to room temperature and stirred for 20 h. The solution was partitioned between aqueous saturated NH4Cl (30 mL) and dichloromethane (20 mL). The aqueous layer was extracted with dichloromethane (2 × 20 mL) and the combined organic layers were dried over Na2SO4. Removal of the solvent and subsequent purification by column chromatography (petroleum ether/ethyl acetate 1:2) gave a colourless oil (342 mg, 43% yield). 1H NMR (400 MHz, CDCl3) 8.24 (br, 1H), 6.02-5.75 (m, 1H), 5.05 (br, 2H), 4.24-4.10 (m, 5H), 3.20-3.03 (m, 3H), 1.44 (s, 9H), 1.36 (d, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) 171.7, 168.8, 167.9, 155.4, 134.9, 104.2, 80.1, 61.2, 50.6, 48.8, 38.3, 28.2, 18.1, 14.0. MS (ESI, m/z) found 380.2 ([M+Na]+). [alpha]25D = + 20.5 (c 0.042, CHCl3). |
1.4 g | With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; for 14h;Inert atmosphere; | Ester 42 (1.20g, 4.41mmol, 1.0eq.) was dissolved in 132 THF-H2O-MeOH (4:2:1, 14.0mL) and cooled to 5C. 0.5n 99 LiOH (9.7mL) was added dropwise, the cooling bath was removed and stirring was continued for additional 60min at ambient temperature (monitored by TLC). The reaction mixture was diluted with CH2Cl2 and 1n KHSO4 (160mol%) was added. Brine was added to the aqueous layer which was then extracted three additional times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude carboxylic acid was dried for 2h under high vacuum, then dissolved in anhydrous 69 CH2Cl2 (43mL) and cooled to 0C. 133 Sarcosine methyl ester hydrochloride (1.02g, 6.61mmol, 1.5eq.) and PyBroP (3.08g, 6.61mmol, 1.5eq) were added followed by the dropwise addition of 134 DIPEA (1.71g, 2.1mL, 13.2mmol, 3.0eq.). The cooling bath was removed and stirring was continued for 14h at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was taken up in EtOAc. The organic layer was extracted with sat. aq. NH4Cl -1n HCl-brine (1:1:1, v/v). The layers were separated and the organic layer was dried over MgSO4. The solvent was removed under reduced pressure and the residue was subjected to flash column chromatography (cyclohexane-EtOAc, 1:7) to obtain title compound 135 43 as pale yellow solid (1.40g, 3.91mmol, 89% yield). Rf=0.36 (pure EtOAc). 1H NMR (400MHz, DMSO-d6, 296K, mixture of rotamers) delta 9.67 (s, 1H), 7.10-6.95 (m, 0.8H), 6.63 (br s, 0.2H), 5.41 (s, 0.6H), 5.25 (s, 0.4H), 4.66 (s, 0.6H), 4.50 (s, 0.4H), 4.18-3.99 (m, 5H), 2.99 (s, 1.8H), 2.87 (s, 1.2H), 1.37 (s, 9H), 1.23-1.15 (m, 6H). 13C NMR (101MHz, DMSO-d6, 296K, mixture of rotamers) delta 171.7, 168.9, 166.9, 155.1, 137.1, 101.3, 78.1, 60.5, 49.8, 48.5, 37.5, 28.2, 17.8, 14.1. 1H NMR (400MHz, DMSO-d6, 360K) delta 9.31 (s, 1H), 6.58 (br s, 1H), 5.44 (s, 1H), 4.68 (s, 1H), 4.16 (q, J=7.1Hz, 2H), 4.12 (s, 2H), 4.07 (q, J=6.9Hz, 1H), 2.99 (s, 3H), 1.41 (s, 9H), 1.25-1.21 (m, 6H). 13C NMR (101MHz, DMSO-d6, 360K) delta 171.2, 168.4, 166.6, 154.5, 136.6, 100.9, 78.0, 60.1, 49.9, 45.5, 27.8, 25.3, 17.4, 13.5. HRMS (ESI): calcd. for C16H27N3O6 [M+H]+ 380.1798 found 380.1798. [alpha]25D [alpha]D25 = +7.4 (c 0.71, MeOH). [alpha]20D [alpha]D20 = +16.8 (c 1.0, Me2CO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Example 7; [3-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-benzoyl]-methyl-amino}-acetic acid A solution of 3-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-benzoic acid (20 g, 54 mmol), DIEA (38 mL, 216 mmol), EDCI (15.47 g, 81 mmol) and HOAT (11 g, 81 mmol) in methylene chloride (800 mL) was stirred at room temperature for 1 h, followed by addition of <strong>[52605-49-9]N-methyl glycine ethyl ester hydrochloride</strong> (12.44 g, 81 mmol). The resulting mixture was stirred at room temperature for 24 h, then treated with EtOAc (1.5 L) and water (1.5 L). The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The oily residue was purified by column (0-35% EtOAc in hexane) to give [3-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-benzoyl]-methyl-amino}-acetic acid ethyl ester, 17 g (67%). LC-MS (ES) calculated for C26H25F2NO5, 469; found m/z 470 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 3h; | Example 13; [3-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-4-fluoro-benzoyl]-methyl-amino}-acetic acid To a mixture of 3-(4',5'-difluoro-2'-methoxybiphenyl-4-yloxymethyl)-4-fluorobenzoic acid (0.3 g, 0.77 mmol) and <strong>[52605-49-9]N-methyl-glycine ethyl ester hydrochloride</strong> (0.7 g, 4.5 mmol) in methylene chloride (40 mL) was added HOAT (0.2 g, 1.46 mmol), EDCI (0.3 g, 1.56 mmol) and triethylamine (1.4 mL, 10 mmol). The mixture was stirred at room temperature for 3 hrs and extracted with methylene chloride and dilute hydrochloric acid. The organic layer was dried and concentrated. The residue was purified through flash column chromatography (80 g silica gel, 5% to 60% ethyl acetate in hexanes over 25 minutes) to give amorphous material as [3-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-4-fluoro-benzoyl]-methyl-amino}-acetic acid ethyl ester (0.29 g, 77%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 12h; | {[3-(4-Bromo-2-fluoro-phenoxymethyl)-benzoyl]-methyl-amino}-acetic acid ethyl ester A solution of 3-(4-bromo-2-fluoro-phenoxymethyl)-benzoic acid (5.21 g, 16.02 mmol), <strong>[52605-49-9]N-methyl glycine ethyl ester hydrochloride</strong> (4.9 g, 32.05 mmol), DIEA (14 mL, 80.01 mmol), EDCI (6.1 g, 32.05 mmol) and HOAT (4.4 g, 32.05 mmol) in methylene chloride (300 mL) was stirred at room temperature for 12 h. The mixture was evaporated and the residue was purified by column (0-50% EtOAc in hexane) to give {[3-(4-bromo-2-fluoro-phenoxymethyl)-benzoyl]-methyl-amino}-acetic acid ethyl ester, 4.5 g (66%). LC-MS (ES) calculated for C19H19BrFNO4, 423; found m/z 424 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Preparation 79 [(S)-2-tert-Butoxycarbonylamino-3-(2-nitro-benzenesulfonylamino)-propionyl]-methyl-amino}-acetic acid ethyl ester (B) Free basing procedure of Sarcosine ethyl ester: Sarcosine ethyl ester hydrochloride (39.3 g, 256.8 mmol) was dissolved in water (300 mL), washed with Et2O (2*100 mL), pH adjusted to ~pH 8, extracted with CHCl3 (3*100 mL) and dried over Na2SO4 and finally filtered. To a solution of compound A (10.0 g, 25.7 mmol) in DMF (100 mL) was added HOBt (5.2 g, 38.5 mmol) and the reaction mixture was cooled to -10 C. To this reaction mixture, EDC-HCl (5.4 g, 28.2 mmol) was added in portions over 10 min and stirred at -10 C. for 20 min. To the reaction mixture, Sarcosine ethyl ester (256.8 mmol) in CHCl3 (300 mL) was added drop wise over 30 min. The reaction mixture was stirred at this temperature for 30 min followed by stirring at ambient temperature overnight. Solvents were then removed in vacuo, and the residue was dissolved in EtOAc (500 mL), washed with water (3*300 mL), saturated aqueous NaHCO3 (2*300 mL) and brine (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford compound B (11.5 g, 91%) as a cream solid. LC-MS [M+H] 489.5 (C19H28N4O9S+H, calc: 489.3). Purity >95% (UV/254 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 2: Preparation of ethyl-N-[2-[2-(4-chlorophenoxy) phenyl] acetyl]-n-methylglycinate. To a solution of <strong>[25563-04-6]2-(4-chlorophenoxy)-benzeneacetic acid</strong> (250 g) in toluene (700 mL) is slowly added a solution of SOCI2 (105 mL) in a mixture of toluene (1 14 mL) and DMF (20 mL) at 40-50C over 1 -2 hours. The solvent is evaporated under vacuum at 40-50C to afford a residue and any residual solvent is removed by adding and evaporating toluene (2x500 mL). The residue is dissolved in toluene (400 mL) and a solution of sarcosine ethyl ester hydrochloride and triethylamine (475 mL) in a mixture of DMF (1250 mL) and toluene (250 mL) is added at 0-5C. The reaction mixture is maintained at 25- 30C for 2-3 hours and water (2500 mL) is added. Organic and aqueous layers are separated and the aqueous layer is washed with toluene (250 mL). The combined organic layer is washed with saturated brine solution (1000 mL). After drying over anhydrous sodium sulfate, the solvent is removed under vacuum to afford the title compound as a residue, which is used for the next reaction step without further purification. Yield: 265.0 g. Purity by HPLC: 80.47%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | A mixture of the compound of Reference Example 77 (3.70 g, 11.4 mmol), ethyl sarcosinate hydrochloride (3.51 g, 22.9 mmol), diisopropylethylamine (9.93 mL, 57.0 mmol) and ethanol (37 mL) was stirred with heating under reflux for 3 hr. After cooling, to the reaction mixture was added 20% ethanol solution (15 mL) of sodium ethoxide, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added water (50 mL), and the mixture was acidified with 2N hydrochloric acid. The precipitate was collected by filtration, and washed successively with water and diisopropyl ether to give the title compound (3.92 g, 96%) as a yellow powder. 1H NMR (300 MHz, DMSO-d6) delta:1.02 (3 H, t, J = 7.4 Hz), 1.32 (3 H, t, J = 7.1 Hz), 2.18 (2 H, q, J = 7.4 Hz), 3.81 (3 H, s), 4.31 (2 H, q, J = 7.1 Hz), 6.49 (1 H, s), 7.28-7.40 (4 H, m), 8.87 (1 H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | A solution of the compound of Reference Example 68 (1.0 g, 4.62 mmol), ethyl sarcosinate hydrochloride (0.85 g, 5.54 mmol) and triethylamine (1.03 g, 10.16 mmol) in THF (20 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted twice with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.34 g, 98%) as a dark red oil. 1H NMR (300 MHz, DMSO-d6) delta:1.20-1.25 (6 H, m), 2.14 (3 H, s), 2.97 (3 H, s), 4.07-4.19 (4 H, m), 4.27 (2 H, s), 6.17 (1 H, d, J = 0.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Reference Example 7 Production of ethyl 5-bromo-6-ethyl-3-hydroxy-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate A mixture of the compound of Reference Example 6 (22.8 g, 78.0 mmol), ethyl sarcosinate hydrochloride (18.0 g, 117 mmol), triethylamine (54 mL, 387 mmol) and ethanol (200 mL) was stirred with heating under reflux for 22 hr. Then, ethyl sarcosinate hydrochloride (6.00 g, 39.1 mmol) and triethylamine (22 mL, 158 mmol) were added thereto, and the mixture was stirred with heating under reflux for 17 hr. To the reaction mixture was added water (250 mL), and the mixture was extracted with ethyl acetate (300 mL*3). The extract was washed successively with water (100 mL) and brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was removed by filtration, and the filtration was concentrated under reduced pressure. To the residue were added ethanol (200 mL) and a 20% ethanol solution (32.0 g, 94.0 mmol) of sodium ethoxide, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and to the residue was added water (250 mL), and the mixture was acidified with 5N hydrochloric acid (20 mL). The precipitate was collected by filtration, and washed with water to give the title compound (18.8 g, 73%) as a pale-orange solid. 1H NMR (300 MHz, DMSO-d6) delta:1.27 (3 H, t, J = 7.6 Hz), 1.33 (3 H, t, J = 7.1 Hz), 2.96 (2 H, q, J = 7.6 Hz), 3.88 (3 H, s), 4.33 (2 H, q, J = 7.1 Hz), 8.36 (1 H, s), 9.76 (1 H, br s). | |
73% | 5.13 Ethyl 5-bromo-6-ethyl-3-hydroxy-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (4b) A mixture of 6b (22.8 g, 78.0 mmol), ethyl sarcosinate hydrochloride (18.0 g, 117 mmol), Et3N (54 mL, 387 mmol) and EtOH (200 mL) was heated under reflux for 22 h. Then, ethyl sarcosinate hydrochloride (6.00 g, 39.1 mmol) and Et3N (22 mL, 158 mmol) were added, and the mixture was heated under reflux for 17 h. To the reaction mixture was added water (250 mL), and the mixture was extracted three times with AcOEt (300 mL). The extract was washed successively with water (100 mL) and brine (100 mL), and dried over MgSO4 and concentrated in vacuo. To the residue were added EtOH (200 mL) and a 20% solution of NaOEt in EtOH (32.0 g, 94.0 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, diluted with water (250 mL), and the mixture was acidified with 5 M HCl aq (20 mL). The precipitate was collected by filtration, and washed with water to give the title compound (18.8 g, 73%) as a pale orange solid. 1H NMR (DMSO-d6) delta 1.27 (3H, t, J = 7.6 Hz), 1.33 (3H, t, J = 7.1 Hz), 2.96 (2H, q, J = 7.6 Hz), 3.88 (3H, s), 4.33 (2H, q, J = 7.1 Hz), 8.36 (1H, s), 9.76 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Reference Example 211 Production of ethyl 3-ethyl-7-hydroxy-5-methyl-2-phenyl-5H-pyrrolo[2,3-b]pyrazine-6-carboxylate A mixture of the compound of Reference Example 210 (106 mg, 0.365 mmol), ethyl sarcosinate hydrochloride (101 mg, 0.660 mmol), triethylamine (1 mL) and ethanol (2 mL) was stirred for 14 hr with heating under reflux. Then, ethyl sarcosinate hydrochloride (100 mg, 0.651 mmol) and triethylamine (1 mL) were added thereto, and the mixture was stirred with heating under reflux for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mLx3). The organic layers were combined and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (1 mL), an ethanol solution (20%, 372 mg, 1.09 mmol) of sodium ethoxide was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate (10 mLx3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=19:1?1:2) to give the title compound (102 mg, 86%) as a pale-yellow powder. 1H NMR (300 MHz, DMSO-d6) delta:1.20 (3 H, t, J=7.5 Hz), 1.35 (3 H, t, J=7.1 Hz), 2.87 (2 H, q, J=7.5 Hz), 3.95 (3 H, s), 4.36 (2 H, q, J=7.1 Hz), 7.38 - 7.64 (5 H, m), 9.94 (1 H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Reference Example 238 Production of ethyl 2-bromo-3-ethyl-7-hydroxy-5-methyl-5H-pyrrolo[2,3-b]pyrazine-6-carboxylate A mixture of the compound of Reference Example 237 (1.53 g, 3.76 mmol), ethyl sarcosinate hydrochloride (607 mg, 3.95 mmol), triethylamine (2.6 mL, 18.7 mmol) and ethanol (20 mL) was stirred at room temperature for 2 hr. ethyl sarcosinate hydrochloride (51.4 mg, 0.335 mmol) was added thereto, and the mixture was further stirred for 1 hr. To the reaction mixture was added water (30 mL), and the mixture was extracted with ethyl acetate (30 mL*3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (20 mL), potassium tert-butoxide (840 mg, 7.49 mmol) was added thereto, and the mixture was stirred at 0C for 1 hr. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate (30 mL*3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitate was collected by filtration, and dried to give the title compound (978 mg, 79%) as a yellow powder. 1H NMR (300 MHz, DMSO-d6) delta:1.26 - 1.39 (6 H, m), 3.01 (2 H, q, J=7.5 Hz), 3.91 (3 H, s), 4.35 (2 H, q, J=7.0 Hz), 10.14 (1 H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Reference Example 3 Production of ethyl 4-chloro-5-hydroxy-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate A mixture of the compound of Reference Example 2 (3.53 g, 15 mmol), ethyl sarcosinate hydrochloride (2.53 g, 16.5 mmol), triethylamine (4.60 mL, 33 mmol) and THF (30 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, water was added thereto, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. To a solution of the residue in ethanol (100 mL) was added 20% ethanol solution (5.10 g, 15 mmol) of sodium ethoxide, which is diluted with ethanol (15 mL), and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid (18 mL) was added to the reaction mixture, and the mixture was diluted with water. The precipitated solid was collected by filtration, washed successively with water and diethyl ether to give the title compound (3.62 g, 89%) as a pale-brown powder. 1H NMR (300 MHz, CDCl3) delta:1.46 (3 H, t, J = 7.2 Hz), 2.74 (3 H, s), 3.94 (3 H, s), 4.49 (2 H, q, J = 7.1 Hz), 9.08 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In tetrahydrofuran; at 10 - 35℃; for 19.5h; | Reference Example 32 Production of ethyl 4-chloro-6-[(2-ethoxy-2-oxoethyl)(methyl)amino]-2-ethylpyrimidine-5-carboxylate A solution of the compound of Reference Example 31 (425 mg, 1.7 mmol), ethyl sarcosinate hydrochloride (262 mg, 1.7 mmol) and triethylamine (0.57 mL, 4.1 mmol) in THF (13 mL) was stirred at room temperature for 19.5 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted twice with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (560 mg, 99%) as a colorless oil. 1H NMR (300 MHz, CDCl3) delta:1.17 - 1.32 (6 H, m), 1.41 (3 H, t, J = 7.2 Hz), 2.72 (2 H, q, J = 7.6 Hz), 3.11 (3 H, s), 4.21 (2 H, q, J = 7.1 Hz), 4.28 (2 H, s), 4.40 (2 H, q, J = 7.2 Hz). |
99% | With triethylamine; In tetrahydrofuran; at 20℃; for 19.5h; | 5.4 Ethyl 4-chloro-6-[(2-ethoxy-2-oxoethyl)(methyl)amino]-2-ethylpyrimidine-5-carboxylate (5a) A solution of 6a (425 mg, 1.7 mmol), ethyl sarcosinate hydrochloride (262 mg, 1.7 mmol) and Et3N (0.57 mL, 4.1 mmol) in THF (13 mL) was stirred at room temperature for 19.5 h. The reaction mixture was diluted with saturated NaHCO3 aq, and extracted twice with AcOEt. The extracts were combined, washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (560 mg, 99%) as colorless oil. 1H NMR (CDCl3) delta 1.17-1.32 (6H, m), 1.41 (3H, t, J = 7.2 Hz), 2.72 (2H, q, J = 7.6 Hz), 3.11 (3H, s), 4.21 (2H, q, J = 7.1 Hz), 4.28 (2H, s), 4.40 (2H, q, J = 7.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 10 - 35℃; | Reference Example 72 Production of ethyl 4-chloro-5-hydroxy-7-methyl-2-(methylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate A mixture of the compound of Reference Example 70 (1.07 g, 4.0 mmol), ethyl sarcosinate hydrochloride (614 mg, 4.0 mmol), triethylamine (1.12 mL, 8.0 mmol) and THF (10 mL) was stirred at room temperature overnight. Water was added thereto, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. To a solution of the residue in THF (30 mL) was added potassium tert-butoxide (581 mg, 4.4 mmol), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (8 mL) and water were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=50:50?0:100). The precipitated solid was collected by filtration, and washed with diethyl ether to give the title compound (661 mg, 55%) as a pale-yellow powder. 1H NMR (300 MHz, CDCl3) delta:1.46 (3 H, t, J = 7.2 Hz), 2.62 (3 H, s), 3.91 (3 H, s), 4.48 (2 H, q, J = 7.1 Hz), 9.11 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iodine; sodium hydrogencarbonate In acetonitrile Reflux; Overall yield = 52.6 %; | 1.20 Ethyl 8-nitro-2-methyl-2H-benzo[f]isoindole-4,9-dione-1-carboxylate (4u) and ethyl 5-nitro-2-methyl-2H-benzo[f]isoindole-4,9-dione-1-carboxylate (4u'). General procedure: Typically, a mixture of 1,4-naphthoquinone (1a, 1.0 mmol, 0.158 g, 1.0 equiv), sarcosine ethyl ester hydrochloride (2a, 3.0 mmol, 0.4605 g, 3.0 equiv), paraformaldehyde (3a, 1.1 mmol, 0.0330 g, 1.1 equiv), Iodine (1.0 mmol, 0.2540 g, 1.0 equiv), sodium bicarbonate (3.0 mmol, 0.2520 g, 3.0 equiv) in acetonitrile (10.0 mL), was stirred at refluxing temperature under air condition until the staring material was consumed, as determined by GC-MS and TLC. The reaction mixture was poured into 8 mL saturated aqueous sodium thiosulfate and was extracted (3*10 mL) with CH2Cl2. The combined extracts were dried over MgSO4. The solvent was removed under vacuum, and the resulting crude product was purified by chromatography on silica gel eluted with CH2Cl2 to afford the desired product 4a as yellow solid (0.2643 g, yield 93.4%, mp 149-150 °C). Yield 93.4%, mp 152-153 °C; 1H NMR (500 MHz, CDCl3): δ (ppm) 8.26-8.24 (m, 1H), 8.23-8.21 (m, 1H), 7.74-7.69 (m, 2H), 7.48 (s, 1H), 4.52 (q, J=8.0 Hz, 2H), 3.95 (s, 3H), 1.50 (t, J=7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz): δ (ppm) 180.1, 178.7, 160.9, 135.9, 134.3, 133.4, 133.1, 128.0, 127.4, 126.6, 125.8, 123.6, 122.6, 62.1, 37.5, 14.2; GC-MS m/z 283.9 [M+H]+, 283.0, 239.2, 211.2, 183.0, 170.1, 113.2, 50.0; Anal. Calcd for C16H13NO4: C, 67.84; H, 4.63; N, 4.94. Found: C, 67.71; H, 4.73; N, 4.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine; In 1,2-dichloro-ethane; at 50℃; for 5h; | Di-tert-butyl [(trifluoromethyl)sulfonyl]carbonimidoyl} biscarbamate (di-Boc- triflylguanidine) (738 mg, 1.88 mmol) was charged to a flame dried flask and taken up in anhydrous 1,2-dichloroethane (7.4 mL). Then triethylamine (579 mu, 4.15 mmol) and ethyl N- methylglycinate hydrochloride (312 mg, 2.03 mmol) were added. The mixture was stirred at 50 C for 5 hours and cooled to room temperature. The reaction was diluted with methylene chloride and washed with 2 M aqueous sodium bisulfate, aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The organic was concentrated, and the crude product was purified on a silica gel column eluting with 50% ethyl acetate in hexanes to give the title compound in a 71% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: formic acid; sarcosine ethyl ester hydrochloride With sodium formate at 20℃; for 4h; Stage #2: With acetic anhydride at 20℃; for 4h; | 19 Compound 1077(8.54 mmol) was added to a solution of sodium formate (7.05 mmol) dissolved in formic acid (2.15 mL) and the mixture was stirred at RT for 4 h and filtered. Acetic anhydride (2.92 mL) was added to the filtrate and the mixture was stirred at RT for 4 h. The solvent was evaporated and the residue was distilled under high vacuum to give ethyl N-formyl sarcosine ester. Potassium-t-butoxide (6.14 mmol) was suspended in diethylether and cooled to 00 C. A solution of N-formyl sarcosine ether ester (6.2 mmol) and methyl formate (4.32 mmol) in diethylether (5 mL) was added over 30 minutes and the mixture was stirred for 1 hour. The solid product was filtered and was dissolved in water and concentrated HC1 (1.8 mL) was added. The mixture was heated on a steam bath for 30 minutes, cooled and the pH was adjusted to 5. Cyanamide (5.95 mmol) was added and the mixture was heated at 1000 C. for 1 hour. The mixture was allowed to cool; the solid was filtered to give compound 1078. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In acetone; at 20℃; for 35h;Inert atmosphere; Reflux; | To a suspension of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (7.16 g, 47 mmol) and K2CO3 (19.3 g, 0.14 mol) in acetone (200 mL) was added a solution of ethyl 5-bromo-2- (bromomethyl)benzoate (7.16 g, 47 mmol) in acetone (30 mL) under 2 atmosphere. The reaction was heated at reflux for 3 h, then cooled to rt and continued to stir for 32 h. The mixture was filtered through a pad of Celite, which was washed with acetone (100 mL). The filtrate was concentrated in vacuo and the resulted residue was dissolved in 3 M HC1 (100 mL). The solution was washed with Et20 (50 mL x 2), treated with saturated aqueous NaHCC until no gas bubbled, and then extracted with Et20 (100 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous a2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) =10/1) to give the title compound as colorless oil (13.3 g, 79%). MS (ESI, pos. ion) m/z: 358.1 [M + H]+; *H NMR (400 MHz, CDC13) delta (ppm): 7.85 (d, J = 2.12 Hz, 1H), 7.53 (dd, J= 8.20 Hz, 2.12 Hz, 1H), 7.42 (d, J= 8.28 Hz, 1H), 4.28-4.37 (q, J= 7.16 Hz, 2H), 4.07-4.18 (q, J= 7.12 Hz, 2H), 3.94 (s, 2H), 3.25 (s, 2H), 2.32 (s, 3H), 1.30-1.40 (t, J= 7.12 Hz, 3H), 1.17-1.29 (t, J= 7.12 Hz, 3H). |
79% | With potassium acetate; In acetone; at 20℃; for 35h;Reflux; | Under nitrogen protection,A mixture of sarcosine hydrochloride (7.16 g, 47 mmol) andPotassium carbonate (19.3 g, 0.14 mol)Suspended in acetone (200 mL)To this was added ethyl 5-bromo-2- (bromomethyl) benzoate (7.16 g, 47 mmol)Of acetone (30 mL).The reaction solution was refluxed for 3 hours,After cooling to room temperature, stirring was continued for 32 hours.The mixture was filtered through celite and the filter cake was washed with acetone (100 mL).The filtrate was collected and concentrated under reduced pressure. The resulting residue was dissolved in 3M hydrochloric acid (100 mL). The solution was treated with BEther (50 mL x2) and treated with saturated solution of sodium bicarbonate until no bubbles were produced, extracted with ethyl acetate (100 mL x 3)take. The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was passed through a silica gel columnChromatography (petroleum ether / ethyl acetate (v / v) = 10/1)The title compound was obtained as a colorless oil (13.3 g, 79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | for 5h;Alkaline conditions; | To a solution of 33a (3.0 g, 13 mmol) and pyridine (1.0 mL) in 100 mL of dichloromethane was added a solution of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (2.1 g, 13.5 mmol) in 10 mL of dichloromethane dropwise at 0 C. The resulting mixture was stirred at r.t. for 5 h before poured into ice-water. The mixture was extracted with DCM (3 Chi 100 mL). The combined organic phases were washed with 0.5 N aq. HCl and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column to afford 2.1 g of ethyl 2-(1-methyl-3-(o-tolyl)ureido)acetate 34a (94 %). ESI-MS m/z: 282 (M + H)+. |
94% | With pyridine; In dichloromethane; at 0 - 20℃; for 5h; | General procedure: To a solution of 33a (3.0 g, 13 mmol) and pyridine (1.0 mL) in100 mL of dichloromethane was added a solution of sarcosine ethylester hydrochloride (2.1 g, 13.5 mmol) in 10 mL of dichloromethanedropwise at 0 C. The resulting mixture was stirred at r.t. for5 h before poured into ice-water. The mixture was extracted withDCM (3 100 mL). The combined organic phases were washed with0.5 N aq. HCl and brine, dried over anhydrous Na2SO4 and filtered. Thefiltrate was concentrated to give the crude product, which was purifiedby column to afford 2.1 g of ethyl 2-(1-methyl-3-(o-tolyl)ureido)acetate 34a (94 %). ESI-MS m/z: 282 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.5% | for 5h;Alkaline conditions; | General procedure: To a solution of 33a (3.0 g, 13 mmol) and pyridine (1.0 mL) in 100 mL of dichloromethane was added a solution of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (2.1 g, 13.5 mmol) in 10 mL of dichloromethane dropwise at 0 C. The resulting mixture was stirred at r.t. for 5 h before poured into ice-water. The mixture was extracted with DCM (3 Chi 100 mL). The combined organic phases were washed with 0.5 N aq. HCl and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column to afford Ethyl 2-(1-methyl-3-(2-(trifluoromethyl)phenyl)ureido)acetate (34b). Yield 93.5%. ESI-MS m/z: 305 (M + H)+. |
93.5% | With pyridine; In dichloromethane; at 0 - 20℃; for 5h; | General procedure: To a solution of 33a (3.0 g, 13 mmol) and pyridine (1.0 mL) in100 mL of dichloromethane was added a solution of sarcosine ethylester hydrochloride (2.1 g, 13.5 mmol) in 10 mL of dichloromethane dropwise at 0 C. The resulting mixture was stirred at r.t. for 5 h before poured into ice-water. The mixture was extracted with DCM (3 100 mL). The combined organic phases were washed with 0.5 N aq. HCl and brine, dried over anhydrous Na2SO4 and filtered. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | for 5h;Alkaline conditions; | General procedure: To a solution of 33a (3.0 g, 13 mmol) and pyridine (1.0 mL) in 100 mL of dichloromethane was added a solution of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (2.1 g, 13.5 mmol) in 10 mL of dichloromethane dropwise at 0 C. The resulting mixture was stirred at r.t. for 5 h before poured into ice-water. The mixture was extracted with DCM (3 Chi 100 mL). The combined organic phases were washed with 0.5 N aq. HCl and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column to afford Ethyl 2-(3-(2-methoxyphenyl)-1-methylureido)acetate (34c) Yield 92.5%. ESI-MS m/z: 267 (M + H)+. |
92.5% | With pyridine; In dichloromethane; at 0 - 20℃; for 5h; | General procedure: To a solution of 33a (3.0 g, 13 mmol) and pyridine (1.0 mL) in100 mL of dichloromethane was added a solution of sarcosine ethylester hydrochloride (2.1 g, 13.5 mmol) in 10 mL of dichloromethane dropwise at 0 C. The resulting mixture was stirred at r.t. for 5 h before poured into ice-water. The mixture was extracted with DCM (3 100 mL). The combined organic phases were washed with 0.5 N aq. HCl and brine, dried over anhydrous Na2SO4 and filtered. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.6% | for 5h;Alkaline conditions; | General procedure: To a solution of 33a (3.0 g, 13 mmol) and pyridine (1.0 mL) in 100 mL of dichloromethane was added a solution of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (2.1 g, 13.5 mmol) in 10 mL of dichloromethane dropwise at 0 C. The resulting mixture was stirred at r.t. for 5 h before poured into ice-water. The mixture was extracted with DCM (3 Chi 100 mL). The combined organic phases were washed with 0.5 N aq. HCl and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column to afford Ethyl 2-(3-(2-fluorophenyl)-1-methylureido)acetate (34d) Yield 94.6%. ESI-MS m/z: 255 (M + H)+. |
94.6% | With pyridine; In dichloromethane; at 0 - 20℃; for 5h; | General procedure: To a solution of 33a (3.0 g, 13 mmol) and pyridine (1.0 mL) in100 mL of dichloromethane was added a solution of sarcosine ethylester hydrochloride (2.1 g, 13.5 mmol) in 10 mL of dichloromethane dropwise at 0 C. The resulting mixture was stirred at r.t. for 5 h before poured into ice-water. The mixture was extracted with DCM (3 100 mL). The combined organic phases were washed with 0.5 N aq. HCl and brine, dried over anhydrous Na2SO4 and filtered. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.2% | for 5h;Alkaline conditions; | General procedure: To a solution of 33a (3.0 g, 13 mmol) and pyridine (1.0 mL) in 100 mL of dichloromethane was added a solution of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (2.1 g, 13.5 mmol) in 10 mL of dichloromethane dropwise at 0 C. The resulting mixture was stirred at r.t. for 5 h before poured into ice-water. The mixture was extracted with DCM (3 Chi 100 mL). The combined organic phases were washed with 0.5 N aq. HCl and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column to afford Ethyl 2-(3-(4-chlorophenyl)-1-methylureido)acetate (34e) Yield 91.2%. ESI-MS m/z: 271 (M + H)+. |
91.2% | With pyridine; In dichloromethane; at 0 - 20℃; for 5h; | General procedure: To a solution of 33a (3.0 g, 13 mmol) and pyridine (1.0 mL) in100 mL of dichloromethane was added a solution of sarcosine ethylester hydrochloride (2.1 g, 13.5 mmol) in 10 mL of dichloromethane dropwise at 0 C. The resulting mixture was stirred at r.t. for 5 h before poured into ice-water. The mixture was extracted with DCM (3 100 mL). The combined organic phases were washed with 0.5 N aq. HCl and brine, dried over anhydrous Na2SO4 and filtered. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.8% | for 5h;Alkaline conditions; | General procedure: To a solution of 33a (3.0 g, 13 mmol) and pyridine (1.0 mL) in 100 mL of dichloromethane was added a solution of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (2.1 g, 13.5 mmol) in 10 mL of dichloromethane dropwise at 0 C. The resulting mixture was stirred at r.t. for 5 h before poured into ice-water. The mixture was extracted with DCM (3 Chi 100 mL). The combined organic phases were washed with 0.5 N aq. HCl and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column to afford Ethyl 2-(3-(3-chloro-4-fluorophenyl)-1-methylureido)acetate (34f) Yield 92.8%. ESI-MS m/z: 281 (M + H)+. |
92.8% | With pyridine; In dichloromethane; at 0 - 20℃; for 5h; | General procedure: To a solution of 33a (3.0 g, 13 mmol) and pyridine (1.0 mL) in100 mL of dichloromethane was added a solution of sarcosine ethylester hydrochloride (2.1 g, 13.5 mmol) in 10 mL of dichloromethane dropwise at 0 C. The resulting mixture was stirred at r.t. for 5 h before poured into ice-water. The mixture was extracted with DCM (3 100 mL). The combined organic phases were washed with 0.5 N aq. HCl and brine, dried over anhydrous Na2SO4 and filtered. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; In tetrahydrofuran; at 90℃; for 24h; | General procedure: General procedure B A solution of amino nucleophile (3 equiv.), triethylamine (10 equiv.), and Intermediate 1 (1 equiv.) was stirred in dioxane and water (2:1 ratio) at 90 C until complete consumption of starting material was observed by LC/MS. The solution was diluted withiN hydrochloric acid and dichloromethane. The layers were then separated and thelayer was extracted with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification yielded theproduct The title compound was prepared following general procedure B, except ethyl N-methylaminoacetate (as the HC1 salt, 1 equiv.) was the amine reactant, 2 equivalents of triethylamine was used, and contents were heated to 90 C for 24 h as a solution in THF. The reaction was cooled and diluted with ethyl acetate and water. The layers were separated, and the the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified via silica gel chromatography utilizing a 0-100% ethyl acetate/hexanes gradient to deliver the desired compound, Compound 1-167 (77 mg, 79% yield) as a white solid. 1H NMR (500 MHz, CDC13) oe ppm 8.46 (d, 1 H) 8.22 (d, 1 H) 7.28 (d, 1 H) 7.15 - 7.25 (m, 1 H)6.95 - 7.06 (m, 2 H) 6.81 - 6.89 (m, 1 H) 6.58 (d, 1 H) 5.95 - 6.00 (m, 2 H) 4.35 (s, 2 H) 4.23 (q, 2 H) 3.43 (d, 3 H) 1.25 (t, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate; In tetrahydrofuran; at 20℃; for 16h; | Example 8 Preparation of derivative No. 87: ethyl 2-(2-(5-(4-methoxybenzoyl)-2-phenylthiophen-3-yl)-N-methylacetamido) acetate 0.091 g (0.593 mmol) of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> were solubilized in 3 ml of tetrahydrofurane. To this solution, were added with magnetic stirring, 0.149 g (1.079 mmol) of potassium carbonate and 0.2 g (0.593 mmol) of 2-(5-(4-methoxybenzoyl)-2-phenylthiophen-3-yl)acetic acid. The mixture was stirred at r.t. for 16 h before being poured into 20 ml of water. The aqueous phase was extracted with 2*20 ml of dichloromethane. The combined organic phases were dried on Na2SO4 which was then removed by filtration and the obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/ethyl acetate gradient, 100% to 75% of dichloromethane, v/v). 0.133 g (yield=54%) of ethyl 2-(2-(5-(4-methoxybenzoyl)-2-phenylthiophen-3-yl)-N-methylacetamido)acetate were obtained as a pale brown oil. LC-MS: m/z=452 (MH+), UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) delta 7.88 (d, J=8.8 Hz, 2H), 7.66-7.39 (m, 6H), 7.12 (d, J=8.8 Hz, 2H), 4.15 (d, J=40.5 Hz, 4H), 3.87 (s, 3H), 3.74 (d, J=35.2 Hz, 2H), 2.92 (d, J=51.8 Hz, 3H), 1.15 (dd, J=13.1, 6.0 Hz, 3H). |
54% | With potassium carbonate; In tetrahydrofuran; at 20℃; for 16h; | 0.091 g (0.593 mmol) of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> were solubilized in 3 ml of tetrahydrofurane. To this solution, were added with magnetic stirring, 0.149 g (1.079 mmol) of potassium carbonate and 0.2 g (0.593 mmol) of 2-(5-(4-methoxybenzoyl)-2-phenylthiophen-3-yl)acetic acid. The mixture was stirred at r.t. for 16 h before being poured into 20 ml of water. The aqueous phase was extracted with 2*20 ml of dichloromethane. The combined organic phases were dried on Na2SO4 which was then removed by filtration and the obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/ethyl acetate gradient, 100% to 75% of dichloromethane, v/v). 0.133 g (yield=54%) of ethyl 2-(2-(5-(4-methoxybenzoyl)-2-phenylthiophen-3-yl)-N-methylacetamido)acetate were obtained as a pale brown oil. LC-MS: m/z=452 (MH+), UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) delta 7.88 (d, J=8.8 Hz, 2H), 7.66-7.39 (m, 6H), 7.12 (d, J=8.8 Hz, 2H), 4.15 (d, J=40.5 Hz, 4H), 3.87 (s, 3H), 3.74 (d, J=35.2 Hz, 2H), 2.92 (d, J=51.8 Hz, 3H), 1.15 (dd, J=13.1, 6.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: 5.13 Ethyl 5-bromo-6-ethyl-3-hydroxy-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (4b) A mixture of 6b (22.8 g, 78.0 mmol), ethyl sarcosinate hydrochloride (18.0 g, 117 mmol), Et3N (54 mL, 387 mmol) and EtOH (200 mL) was heated under reflux for 22 h. Then, ethyl sarcosinate hydrochloride (6.00 g, 39.1 mmol) and Et3N (22 mL, 158 mmol) were added, and the mixture was heated under reflux for 17 h. To the reaction mixture was added water (250 mL), and the mixture was extracted three times with AcOEt (300 mL). The extract was washed successively with water (100 mL) and brine (100 mL), and dried over MgSO4 and concentrated in vacuo. To the residue were added EtOH (200 mL) and a 20% solution of NaOEt in EtOH (32.0 g, 94.0 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, diluted with water (250 mL), and the mixture was acidified with 5 M HCl aq (20 mL). The precipitate was collected by filtration, and washed with water to give the title compound (18.8 g, 73%) as a pale orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In dichloromethane; at 20℃; for 16h; | To a solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl chloride (0.30 g, 0.83 mmol) in dichloromethane (4 mL) was added to a mixture of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong>(0.19 g, 1.24 mmol) and triethylamine (0.4 mL, 2.90 mmol) in dichioromethane (4.3 mL). After stirring at ambient temperature for 16 hours, the reaction mixture was concentrated in vacuo. Theresidue was partitioned between ethyl acetate (40 mL) and 1.ON hydrochloric acid solution (15 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (15 mL x 2) and brine (15 mL x 2); dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 20% ethyl acetate in hexanes) provided the title compound as a colorless foam (0.34 g, 92%): ?H NMR (300 MHz, CDC13) 56.95 (d, J 7.8 Hz,0.7H), 6.87 (d, J= 7.9 Hz, 0.3H), 6.53-6.48 (m, 1H), 4.27-4.16 (m, 3.3H), 3.95 (s, 0.7H), 3.51 (m,2H), 3.12 (s, 1H), 3.00 (m, 2H), 2.07-2.03 (m, 4H), 1.80-1.69 (m, 12H), 1.33-1.23 (m, 3H),0.93-0.85 (m, 2H), 0.66-0.55 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydrogencarbonate; In ethanol; at 80℃; for 24h; | 1002161 To a solution of <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (3.1 g, 20 mmol) in ethanol (30 mL) was added NaHCO3 (3.4 g, 40 mmol) and chloroacetone (1.6 mL, 20 mmol). The reaction mixture was stirred for 24 hours at reflux, then cooled to RT. The precipitate was filtered off, and the filtrate was diluted with EtOAc (125 mL), concentrated HC1 (8 mL) and water (30 mL) were added. The mixture was stirred for 15 mm, and the phases were separated. The aqueous phase was added NaHCO3 until pH = 10, the extracted with EtOAc (120 mL). The organic layer was washed with water, brine, dried over Na2SO4, concentrated, and purified on silica gel flash chromatography (DCM : MeOH = 10: 1), giving the Dl (3.2 g, 94% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | In a round-bottomed flask, thionicotinic acid is introduced into acetonitrile, followed by carbonyldiimidazole (CDI). The mixture is refluxed for 1 hour. The mixture is returned to ambient temperature and ethyl sarcosinate hydrochloride is added and then the heating is recommenced at 6000 for 3 hours and then overnight at ambient temperature.After the overnight period, the reaction medium is evaporated. The residue is purified on silica, 20/80 ethyl acetate/heptane.The fractions are evaporated and then the product is taken up in dichloromethane and precipitated from isopropyl ether.A light-yellow-coloured powder is obtained: Yield: 22%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.7% | With potassium carbonate; In ethylene glycol; at 110℃;Green chemistry; | 500mL ethylene glycol was added to the reaction flask, stirring was started, and then added at room temperature compound of formula II 100.0 grams (0.26mol) 59.8 g (0.39 mol) of the compound represented by Formula III,And 215.0 g (1.56 mol) of potassium carbonate. Heated to 110 C reaction TLC point disappeared raw material (developing solvent: ethyl acetate / petroleum ether = 1/1), the solvent was evaporated under reduced pressure, the residue was added 280mL isopropanol and 400mL of water mixed solvent, 5 ~ 10 C crystallization was stirred for 3 hours. The filter cake was washed with a mixed solvent of 100 mL of isopropanol and 150 mL of water and dried to give 93.8 g (compound of formula I) as an off-white solid powder with a yield of 92.7% DHPLC purity of 99.7% and chiral purity > 99% . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; mercury dichloride; In N,N-dimethyl-formamide; at 20℃; for 24h; | To a mixture of tert-butyl (((bis(benzyloxy)phosphoryl)amino)(methylthio)methylene)carbamate (388 mg, 0.86mmol), <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (131 mg, 0.86mmol), HgCl2 (700 mg, 2.58 mmol) in dry DMF (2 ml) wasadded triethylamine (120 l, 0.86 mmol).The resulting mixture was stirred for about 24 hours atroom temperature. Upon completion of the reaction, controlledwith HPLC-MS, diethyl ether (2 ml) was added andthe white precipitate was removed by filtration. The precipitatewas then washed twice with diethyl ether, the insolublesolid was discarded and the ethereal filtrate was evaporatedin vacuum. The product was purified by preparative HPLCto afford the title compound (244 mg, 55%). The qualitative analysis of the product was finally confirmedby ESI-MS.1H NMR (200 MHz, DMSO-d6): 1.28(t,3H),1.38 (s, 9H),3.05 (s, 3H),4.06 (q,2H),4.22 (s,2H),5.06 (s,4H),7.40-7.46(m,10H)13C NMR (50 MHz, DMSO-d6): 14.3,27.6,37.6,51.1,61.1,70.5,81.4,126.8,127.3,127.8,134.8,154.3, 160.4,170.2.ESI-MS m/z = 520.2 [M+H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.5% | General procedure: To a solution of 4-(5-(substituted phenyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (0.53mmol)in 10mL DCM was added methyl glycinate hydrochloride (0.80mmol), acetic acid (2.12mmol), and N,N-diisopropylethylamine (0.80mmol), and 10mL MeOH. After the reaction was stirred for 3h, sodium cyanoborohydride (0.53mmol) was added. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated. The residue was purified by silica gel flash column chromatography (DCM:MeOH=20:1) to afford compound 15-1a?15-3n (except for 15-1l). | |
57.5% | 3-Chloro-4-(5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (200 mg, 0.53 mmol) was dissolved in 35 mL dichloromethane.To this was added <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (123 mg, 0.80 mmol),Glacial acetic acid (0.12 ml, 2.12 mmol), N,N-diisopropylethylamine (0.14 ml, 0.80 mmol), 5 ml of methanol, and reacted at room temperature for 3 h, then sodium cyanoborohydride (33 mg, 0.53 mmol), argon The reaction was carried out for 5 h under protection. A saturated sodium hydrogencarbonate solution was added, and the mixture was extracted with dichloromethane (3×30 mL). Concentration, column chromatography, eluent: dichloromethane: methanol = 20:1, 141 mg of white solid, yield 57.5% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.9% | General procedure: To a solution of 4-(5-(substituted phenyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (0.53mmol)in 10mL DCM was added methyl glycinate hydrochloride (0.80mmol), acetic acid (2.12mmol), and N,N-diisopropylethylamine (0.80mmol), and 10mL MeOH. After the reaction was stirred for 3h, sodium cyanoborohydride (0.53mmol) was added. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated. The residue was purified by silica gel flash column chromatography (DCM:MeOH=20:1) to afford compound 15-1a?15-3n (except for 15-1l). | |
58.9% | Dissolving 3-fluoro-4-(5-(4-isopropoxy-3-cyanophenyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (200 mg, 0.57 mmol) In 35 ml of dichloromethane,To this was added <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (131 mg, 0.85 mmol),Glacial acetic acid (0.13ml, 2.28mmol),N,N-diisopropylethylamine (0.14 ml, 0.85 mmol), 5 ml of methanol,After reacting for 3 h at room temperature, sodium cyanoborohydride (36 mg, 0.57 mmol) was added, and the mixture was reacted under argon for 5 h. A saturated sodium hydrogencarbonate solution was added, and the mixture was extracted with dichloromethane (3×30 mL). Concentrated and separated by column chromatography. The eluent was dichloromethane: methanol = 20:1.A white solid 152 mg was obtained in a yield of 58.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.8% | General procedure: To a solution of 4-(5-(substituted phenyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (0.53mmol)in 10mL DCM was added methyl glycinate hydrochloride (0.80mmol), acetic acid (2.12mmol), and N,N-diisopropylethylamine (0.80mmol), and 10mL MeOH. After the reaction was stirred for 3h, sodium cyanoborohydride (0.53mmol) was added. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated. The residue was purified by silica gel flash column chromatography (DCM:MeOH=20:1) to afford compound 15-1a?15-3n (except for 15-1l). | |
68.8% | 4-(5-(4-Isopropoxy-3-cyanophenyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (200 mg, 0.60 mmol) was dissolved in dichloromethane (35 mL) in,To the mixture, <strong>[52605-49-9]sarcosine ethyl ester hydrochloride</strong> (126 mg, 0.90 mmol), glacial acetic acid (0.14 ml, 2.40 mmol), N,N-diisopropylethylamine (0.15 ml, 0.90 mmol), After reacting for 3 h at room temperature, sodium cyanoborohydride (38 mg, 0.60 mmol) was added, and the mixture was reacted under argon for 5 h. A saturated sodium hydrogencarbonate solution was added, and the mixture was extracted with dichloromethane (3×30 mL). Concentrated and separated by column chromatography. The eluent was dichloromethane: methanol = 20:1.A white solid 179 mg was obtained in a yield of 68.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.6% | Dissolving 3-fluoro-4-(5-(4-isopropoxy-3-cyanophenyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (200 mg, 0.57 mmol) In 35 ml of dichloromethane,To this was added piperidine acetate methyl ester hydrochloride (134 mg, 0.85 mmol),Glacial acetic acid (0.13ml, 2.28mmol),N,N-diisopropylethylamine (0.14 ml, 0.85 mmol), 5 ml of methanol,After reacting at room temperature for 3 h, sodium cyanoborohydride (36 mg, 0.57 mmol) was added.The reaction was carried out under argon for 5 h.A saturated sodium hydrogencarbonate solution was added, and the mixture was extracted with dichloromethane (3×30 mL). Concentration and column chromatography were carried out. The eluent was dichloromethane:methanol = 20:1 to yield white solid (150 mg, yield: 53.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 6h; | General procedure: 2.25 g of sarcosine were added to a cold solution of 5 mL ofacetyl chloride and 22.5 mL of alcohol. The mixture was then heated under reflux for 3 h, leading to the formation of sarcosinechlorohydrate. In the second step, sodium carbonate (K2CO3)(10 mmol) was added to the mixture with ethoxymethylenemalononitrile(10 mmol) and dimethylformamide(DMF) (30 mL). The reaction was heated for 6 h at 60 C. The mixture was then poured into 100 ml of water; the compound in the resulting precipitate was then filtered and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 6h; | General procedure: 2.25 g of sarcosine were added to a cold solution of 5 mL ofacetyl chloride and 22.5 mL of alcohol. The mixture was then heated under reflux for 3 h, leading to the formation of sarcosinechlorohydrate. In the second step, sodium carbonate (K2CO3)(10 mmol) was added to the mixture with ethoxymethylenemalononitrile(10 mmol) and dimethylformamide(DMF) (30 mL). The reaction was heated for 6 h at 60 C. The mixture was then poured into 100 ml of water; the compound in the resulting precipitate was then filtered and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In ethanol at 20℃; for 15h; | 1.8.1 Step 1 To a suspension of 2,4-dichloro-5,6-dimethylthieno[2,3-d]pyrimidine (150.00 mg; 0.64 mmol; 1.00 eq.) in EtOH (2 mL) was added ethyl methylglycinate HCl salt (170.70 mg; 1.13 mmol; 1.75 eq.), followed by triethylamine (0.31 mL; 2.25 mmol; 3.50 eq.). The mixture was stirred at room temperature for 15 h and concentrated to give a crude residue. The crude residue was diluted with water. The resulting precipitates were collected by filtration and dried under vacuum to give ethyl N-(2-chloro-5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)-N-methylglycinate (181.8 mg, 90%). |
90% | In ethanol at 20℃; for 15h; | 1.76.1 Step 1 To a suspension of 2,4-dichloro-5,6-dimethylthieno[2,3-d]pyrimidine (150.00 mg; 0.64 mmol; 1.00 eq.) in EtOH (2 mL) was added ethyl methylglycinate HCl salt (170.70 mg; 1.13 mmol; 1.75 eq.), followed by triethylamine (0.31 mL; 2.25 mmol; 3.50 eq.). The mixture was stirred at room temperature for 15 h and concentrated to give a crude residue. The crude residue was diluted with water. The resulting precipitates were collected by filtration and dried under vacuum to give ethyl N-(2-chloro-5,6- dimethylthieno[2,3-d]pyrimidin-4-yl)-N-methylglycinate (181.8 mg, 90%). |
90% | In ethanol at 20℃; for 15h; | 1.76.1 Step 1 To a suspension of 2,4-dichloro-5,6-dimethylthieno[2,3-d]pyrimidine (150.00 mg; 0.64 mmol; 1.00 eq.) in EtOH (2 mL) was added ethyl methylglycinate HCl salt (170.70 mg; 1.13 mmol; 1.75 eq.), followed by triethylamine (0.31 mL; 2.25 mmol; 3.50 eq.). The mixture was stirred at room temperature for 15 h and concentrated to give a crude residue. The crude residue was diluted with water. The resulting precipitates were collected by filtration and dried under vacuum to give ethyl N-(2-chloro-5,6- dimethylthieno[2,3-d]pyrimidin-4-yl)-N-methylglycinate (181.8 mg, 90%). |
[ 6290-05-7 ]
Diethyl 2,2'-azanediyldiacetate
Similarity: 0.93
[ 13515-93-0 ]
Methyl N-methylglycinate hydrochloride
Similarity: 0.93
[ 39987-25-2 ]
Dimethyl 2,2'-azanediyldiacetate hydrochloride
Similarity: 0.89
[ 136088-69-2 ]
tert-Butyl 2-(methylamino)acetate hydrochloride
Similarity: 0.84
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H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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