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CAS No. : | 4244-84-2 | MDL No. : | MFCD00012909 |
Formula : | C5H12ClNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RJCGNNHKSNIUAT-UHFFFAOYSA-N |
M.W : | 153.61 | Pubchem ID : | 458475 |
Synonyms : |
CarnoSyn;Ethyl 3-aminopropanoate hydrochloride;Ethyl 3-aminopropionate hydrochloride
|
Chemical Name : | Ethyl 3-aminopropanoate 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 : | 37.11 |
TPSA : | 52.32 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) : | -7.04 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.28 |
Log Po/w (WLOGP) : | 0.7 |
Log Po/w (MLOGP) : | 0.39 |
Log Po/w (SILICOS-IT) : | -0.05 |
Consensus Log Po/w : | 0.26 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.7 |
Solubility : | 30.3 mg/ml ; 0.197 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.94 |
Solubility : | 17.6 mg/ml ; 0.115 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.76 |
Solubility : | 26.8 mg/ml ; 0.174 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.24 |
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 |
---|---|---|
87% | at -10℃; for 2 h; Reflux | Freshly distilled thionyl chloride (250 mL) was added drop-wise to stirring absolute EtOH (400 mL) at –10 ºC. After 20 min at –10 ºC, β-alanine (82.56 g, 0.93 mol) was slowly added to the thionyl chloride/EtOH solution. This mixture was refluxed for 2 h. Excess thionyl chloride was distilled off and the volume of the solution was reduced by half under vacuum. The white precipitate that crystallized from the reduced solution was filtered and washed with cold diethylether to give β-alanine ethyl ester hydrochloride as a white crystalline powder (124.34 g, 87percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 24h; | Synthesis of 3-[(1H-indole-2-carbonyl)-amino]-propionic acid ethyl ester, compound 4, was as follows. To a mixture of 2-indolecarboxylic acid (161 mg, 1.0 mmol), DMAP (200 mg, 6 mmol) and alanine ethyl ester hydrochloride (168 mg, 1.1 mmol) in 10 mL anhydrous CH2Cl2 was added EDCI (215 mg, 1.1 mmol) at 0o C. The mixture then was stirred at 0o C. for 4 hours and at room temperature for 20 hours. The mixture was washed with water (20 mL) and 10percent HCl (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to yield product 4 as a white solid (230 mg, 88.5percent). Mp 158-160o C. 1H NMR: [0128] MHz, CDCl3) d 1.28 (t, 3H, J=7.2 Hz), 2.69 (t, 2H, J=5.7 Hz), 3.78 (q, 2H, J=6.0 Hz), 4.18 (q, 2H, J=6.9, 7.2 Hz), 6.89 (s, 1H), 7.05 (s, 1H), 7.13-7.68 (m, 4H), 9.86 (s, 1H). 13C NMR: (74.47 MHz, CDCl3) d 14.1, 33.9, 34.9, 60.8, 102.2, 111.9, 120.4, 121.8, 124.3, 127.5, 130.5, 136.4, 161.7, 172.8. IR: (NaCl) 3377, 3352, 1716, 1624, 1552, 1325, 1207, 748 cm-1. HRMS m/e calcd for C14H16N2O3 (M) 260.1161, found 260.1159. |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 24h; | General procedure: To a solution of beta-alanine ethyl ester HCl (3.49 g, 22.72 mmol) and DMAP (4.26 g, 34.86 mmol) in anhydrous dichloromethane (20 mL) at 0 °C was added a solution of carboxylic acid 10 (2.58 g, 20.62 mmol) in anhydrous dichloromethane (15 mL) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (4.35 g, 22.69 mmol) dissolved in dichloromethane (10 mL). The solution was stirred at 0 C (4 h), then at room temperature (20 h). Concentration of the solvent under reduced pressure, addition of water, extraction with dichloromethane, drying (MgSO4), and concentration under reduced pressure afforded an oil which was purified on a silica gel column (3percent MeOH/dichloromethane) toafford the ester as a white solid (4.02 g, 87percent). The ester was hydrolysed using the same method as compound 7 to yield the product as an off-white solid (86percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; In ethyl acetate; at 20℃; for 63h;Inert atmosphere; | Compound 2 (30.00 g, 0.11 mol) was takenin a 500 mL round-bottom flask followed by the addition of beta-alanine ethyl ester hydrochloride (17.05 g, 0.11 mol) andEtOAc (100 mL), which had been dried over molecular sieves.TEA (35.5 mL, 0.25 mol) was dissolved in EtOAc (50 mL) anddried over sieves, and this mixture was added dropwise to thereaction mixture, while being stirred over a period of 15 hunder a nitrogen atmosphere. The reaction mixture was thenstirred for an additional 48 h during which a white precipitatewas formed. The precipitate was removed by filtration, and thefiltrate was washed with 1 M HCl (2 × 100 mL) and thendeionized (DI) water (1 × 100 mL). The organic layer wasthen dried over anhydrous magnesium sulfate and filtered, andthe solvent was removed by rotary evaporation to give 3 as ayellow solid (25.00 g, 89percent yield). Mp: 120?124 °C. TLC (1:1EtOAc/hexane): Rf = 0.42. 1H NMR (CDCl3): delta 7.47 (d, J =1.2 Hz, 1H), 6.99 (d, J = 1.6 Hz, 1H), 6.62 (s, 1H), 4.12 (q, J =7.2 Hz, 2H), 3.91 (s, 3H), 3.58 (q, J = 6 Hz, 2H), 2.54 (t, J =7.2 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H). 13C NMR: delta 171.63,160.34, 134.23, 128.32, 126.71, 107.86, 60.42, 37.78, 35.41,34.11, 14.51. IR: 3360.6, 3129.1, 1711.7, 1655.6, 1547.5,1423.7, 1355.0, 1310.1, 1197.2, 1136.4, 1111.5, 1086.4, 1020.9,986.5, 885.1, 848.4, 810.1, 821.0, 748.7, 700.1, 603.3, 595.5,583.0. HRMS (ESI): m/z for C11H15N3O5 [M + H]+ calcd270.1084, found 270.1084. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With diisopropylamine; In tetrahydrofuran; at 20℃; for 7h;Inert atmosphere; Reflux; | General procedure: 2-(Trichloroacetyl)-1H-pyrrole (6, 675 mg, 3.18 mmol) was dissolved in anhydrous THF (50 mL) under argon atmosphere followed by anhydrous DIPA (2.50 mL, 13.0 mmol) and beta-alanine ethyl ester hydrochloride (980 mg, 6.38 mmol). The reaction was refluxed (4 h) and then stirred at room temperature (3 h). The solvents were removed under vacuum followed by addition of 1 M HCl (50 mL). Solid residues were removed by filtration and the aqueous solution was extracted with ethyl acetate, dried (MgSO4) and concentrated under reduced pressure to afforded an oil which was puried on a silica gel column (EtOAc/Petrol 60-80, gradient from 10 to 100percent EtOAc) to afford the ester as a white solid (420.8 mg, 63percent). mp = 84-85 °C; IR 3364, 3335, 2965, 1714, 1622, 1528 cm-1; 1H NMR δ 1.18 (3H, t, J = 7.1 Hz), 2.54 (2H, t, J = 7.0 Hz), 3.46 (2H, dt, J = 7.0, 5.5 Hz), 4.07 (2H, q, J = 7.1 Hz), 6.07 (1H, m), 6.74 (1H, m), 6.84 (1H, m), 8.09 (1H, t, J = 5.5 Hz), 11.45 (1H, s); 13C NMR δ 14.4, 34.5, 35.2, 60.3, 108.9, 110.2, 121.6, 126.5, 161.1, 171.7; LRMS (ES+), m/z 211.1 [M + H]+, 233.1 [M + Na]+. The ester was dissolved in THF (10 mL). After complete dissolution, lithium hydroxide hydrate (252 mg, 6.00 mmol) was added to the stirred solution. The mixture was reuxed and monitored by TLC until complete. The resulting suspension was ltered, addition of water, neutralisation with concentrated hydrochloric acid, extraction with ethyl acetate, drying (MgSO4) and removal of the solvent afforded the desired acid as a white solid (357 mg, 98percent). mp = 155-157 C; IR 3435, 3363, 3312, 2824, 1678, 1624 cm-1; 1H NMR δ 2.49 (2H, t, J = 7.1 Hz), 3.40 (2H, dt, J = 7.1 5.5 Hz), 6.07 (1H, m), 6.73 (1H, m), 6.84 (1H, m), 8.05 (1H, t, J = 5.5 Hz), 11.43 (1H, s), 12.24 (1H, br s); 13C NMR δ 34.5, 35.2, 108.9, 110.2, 121.6, 126.5, 161.1, 173.3; LRMS (ES+) m/z 204.9 [M + Na]+, (ES-) m/z 181.0 [M-H]- |
With triethylamine; | EXAMPLE 4: The invention provides pharmaceutical compositions comprising dibromo- hymenialdesine (dBHD),1 and dBHD analogs, e.g., as described herein, and methods for making and using them. The invention also provides methods for making the compositions and pharmaceutical compositions of this invention, e.g., comprising protocols as illustrated inFigure 9, also illustrated as this scheme: <n="37"/>20002071040As shown in this scheme (above), after prep. HPLC purification, approximately 5 mg of 7 was obtained. Comparing condition 4 and ondition 5, we found condition 4 was better, i.e., gave a higher yield: 15 mg of compound 7 was the yield in total from the two reactions.The preparation following condition 6 and 7 was scaled up in parallel, and it was found that condition 6 was better; i.e., gave a higher yield: .8 g of 7 was obtained from the two batches. A second scaled up preparation of 7 gave a yield of 2.9 g, which was obtained from 5 g of 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In tetrahydrofuran; at 0 - 60℃; for 6h; | Example 47; Ethyl 3-(tert-butoxycarbonylamino)propanoate (30) (Scheme 6); To a stirred suspension of beta-alanine ethyl ester hydrochloride (29) (2 g, 0.01 mol) in 20 mL THF at ice-bath temperature was added triethylamine (2.8 mL, 0.02 mol) followed by a solution of di-tert-butylcarbonate (11) (2.62 g, 0.012 mol) in 10 mL THF at room temperature. The resulting mixture was heated at 60 C. for 6 h. The reaction mixture was filtered (to remove triethylamine hydrochloride salt) and the filtrate was concentrated on rotavapor. The residue was dissolved in ethyl acetate (50 mL), washed with water (25 mL×2), dried (Na2SO4) and evaporated to give the pure compound 30. Colorless oil (2.8 g, 99%). 1H NMR (400 MHz, CDCl3): delta 1.19 (t, J=7.2 Hz, 3H); 1.36 (s, 9H); 2.43 (t, J=6.4 Hz, 2H); 3.48 (t, J=6.4 Hz, 2H); 4.07 (q, J=7.2 Hz, 2H). MS (ESI): m/z=218.4 (M+H+). |
92% | Ethyl 3-((tert-butoxycarbonyl) amino) propanoate (31):To a solution of compound 30 (20 g, 0.13 mol) in CH2C12 (20 mL), cooled to 0C, Et3N (53 mL, 0.39 mol) was added dropwise and stirred for 30 min. Boc-anhydride (34 mL, 78.1 mmol) was added to the reaction mixture at 0C and the stirred at RT for 16 h. The reaction was quenched with saturated NH4C1 solution and the aqueous layer was extracted with CH2C12 (3 x 150 mL). The combined organic extracts were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford compound 31 (26 g, 92%) as a liquid.TLC: 30% EtOAc/Hexane (Rf: 0.7) 1H NMR (500MHz, CDC13): delta 5.01 (br s, 1H), 4.16 (q, J = 7.5 Hz, 2H), 3.39 (d, J = 6.0 Hz, 2H), 2.51 (t, J = 5.5 Hz, 2H), 1.43 (s, 9H), 1.26 (t, J = 7.5 Hz, 3H). | |
75% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 1.5h;Inert atmosphere; | /V,/V-diisopropylethylamine (2.2 eq, 44 mmol) was added dropwise to a solution of b-alanine ethyl ester hydrochloride (1 eq, 20 mmol) in CH2Cl2 (80 mL) at 0 C followed by the dropwise addition of di-/ /7-butyl dicarbonate (1.1 eq, 22 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash purification column chromatography (10:40:50, EtOAc:CH2Cl2:Hexanes) yielded ethyl 3-((/eri-butoxycarbonyl)amino)propanoate (S2, 3.25 g, 15.0 mmol, 75%) as a colorless oil. 3H NMR (500 MHz, Chloroform-d): d 5.01 (s, 1H), 4.15 (q, / = 7.2 Hz, 2H), 3.48 - 3.27 (m, 2H), 2.51 (t, J = 6.1 Hz, 2H), 1.43 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, Chloroform-d): d 172.64, 155.92, 79.48, 60.78, 36.26, 34.81, 28.54, 14.35 |
With triethylamine; In dichloromethane; at 20℃; for 20h; | 4). 59.9 cm3 or triethylamine and then 46.88 g of di-tert-butyl dicarbonate are successively added at a temperature in the region of 20 C., under an argon atmosphere, to 30 g (195 mmol) of beta-alanine ethyl ester hydrochloride in solution in 1000 cm3 of dichloromethane. After stirring for 20 hours at a temperature in the region of 20 C., the reaction mixture is successively washed with twice 500 cm3 of water, twice 500 cm3 of a 0.1N aqueous hydrochloric acid solution and twice 500 cm3 of a saturated aqueous sodium bicarbonate solution. The organic phase is dried and then concentrated to dryness under reduced pressure (2.7 kPa) to give 45.6 g of a colorless oil which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 by volume)]. 40.5 g of ethyl 3-tert-butyloxycarbonylaminopropionate are obtained in the form of a colorless oil. EI MS spectrum: m/z 258 [M+H]+(base peak). | |
With sodium carbonate; In diethyl ether; | A solution of compound BB-28-1 (10 g, 85.36 mmol) in diethylether (18.6 g, 85.36 mmol) was dissolved in ether (100 mL) and sodium carbonate The reaction was stirred at 25 & lt; 0 & gt; C overnight. After completion of the reaction the solid was removed by filtration, the filtrate was concentrated to give the title compound BB-28-2 (yellow solid, 14g,crude). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;platinum(IV) oxide; In ethanol; at 60℃; under 2327.23 Torr; for 4h; | Example 32 (5.28 g, 0.022 mole), beta-alanine ethylester hydrochloride (3.84 g, 0. 025 mole), and catalyst (PtO2, 1.0 g, Engelhard Corp.) are added to 75 mL of absolute ethanol. The reactor is pressured up to 45 psig with hydrogen while heating to 60° C. After four hours, the reactor is vented and the catalyst is removed by filtration. Sixty-five mL of ethanol was distilled yielding a precipitate in the remaining ethanol. After filtration, the precipitate is recrystallized from methanol. The title compound is obtained as a white solid with a melting point of 215-220C whose structure is consistent with HNMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With potassium carbonate;tetrabutylammomium bromide; In DMF (N,N-dimethyl-formamide); at 70 - 80℃; for 25h; | To a solution of (2-Chloromethyl-5-methoxy-phenyl)-acetic acid ethyl ester (248 mg; 1.02 mmol) in DMF (1 mL) was added beta-alanine ethyl ester hydrochloride (188 mg; 1.23 mmol), K2CO3 (423 mg; 3.06 mmol), and tetrabutylammonium bromide (small scoop). The reaction mixture was heated to 70° C. for 1 h and then the temperature was increased to 80° C. and stirring was continued for a further 24 h. The mixture was cooled, diluted with EtOAc and washed with 1N HCl (aq) (1.x.), water (1.x.) and brine (1.x.). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by FCC (silica gel; elution with 2:1 EtOAc:hexanes) giving 92 mg (33percent) of 15-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | To a solution of the 4-bromomethylphenylsulfonylchloride (10 g, 37 mmol) in CH2Cl2 (200 mL) at 0°C was added diisopropylethylamine (16 mL, 93 mmol) followed by ethyl-3-aminopropionate hydrochloride (5.1 g, 37 mmol)). The reaction was stirred for 10 minutes at 0°C and the solvent was evaporated at room temperature under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N HCl (3x), H2O, aqueous NaHCO3 (3x), brine (3x) and dried over MgSO4. The solvent was concentrated to give a syrup. Addition of ethyl ether induced crystallization of the product as a white solid (10 g, 30 mmol, 81percent).1H NMR (CDCl3): delta 1.24 (t, 3H), 2.55 (t, 2H), 3.22 (qt, 2H), 4.13 (qt, 2H), 4.50 (s, 2H), 5.28 (t, 1H), 7.53 (d, 2H), 7.85 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 66h; | Step B. 3- (3-Fluoro-4-hydroxy-benzoylamino)-propionic ethyl ester; Combine 3-Fluoro-4-hydroxy-benzoic acid (l.Og, 6.4mmol), PyBOP (4.0g, 7.69mmol), 3-amino-propionic acid ethyl ester hydrochloride (1.47g, 9.6mmol) and ethyl- diisopropyl-amine (4.55mL, 25.6mmol) in N, N-dimethyl-formamide (20mL). Stir for sixty-six hours at room temperature. Dilute reaction with ethyl acetate and water. Wash organic layer with saturated solution of ammonium chloride and water. Extract combined aqueous fraction with ethyl acetate. Wash combined organic fractions with saturated sodium chloride solution. Dry organic fraction with Na2S04, filter and concentrate under reduced pressure. Purify on silica gel chromatography (20-80percent Ethyl acetate/ hexanes gradient) to provide 1.24g of title compound (76percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; In toluene; at 10 - 20℃; for 3h; | andAlanine ethyl ester hydrochloride (14.8 g, 96.4 mmol, 1.1 eq. ) was dissolved in toluene (260 mL) and cooled to 10°C. NEt3 (5.1 g, 50.0 mmol, 1.0 eq. ) was first added and then a solution of 4-Phenyl-butyric acid chloride (16.0 g, 87.6 mmol, 1.0 eq. ) in toluene (50 mL). The solution was allowed to warm up and then stirred for 3 h at room temperature. The solution was concentrated under reduced pressure, ethyl acetate (150 mL) and water (200 mL) were added. The layers were separated, the organic layer was washed twice with an aqueous solution of 5percent HCI (150 mL), with a saturated aqueous solution of NaHCO3 (150 mL), with a saturated aqueous solution of NaCI (150 mL) and then dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography using ethyl acetate/hexane (1: 1) to yield 3- (4-Phenyl-butyrylamino)- propionic acid ethyl ester (20.5 g, 89 percent) as a colorless oil.-Rf (ethyl acetate/hexane) = 0.36 ;'H NMR (CDCI3, 300 MHz) = 1.20 (t, J = 7.2 Hz, 3H), 1.86-1. 98 (m, 2H), 2.11-2. 16 (m, 2H), 2.48 (t, J = 6.2 Hz, 2H), 2.57-2. 62 (m, 2H), 3.45 (q, J = 6.1 Hz, 2H), 4.09 (q, J = 7.2 Hz, 2H), 6.47 (br s, 1 H), 7.11-7. 28 (m, 5H). 3- (4-Phenyl-butyrylamino)-propionic acid ethyl ester (9. 1 g, 34.7 mmol, 1. 0 eq.) was dissolved in EtOH (75 mL) and NaOH (1. 88g, 46. 8 mmol, 1. 4 eq.), dissolved in water (25 mL), was added and the solution stirred for 16 h at room temperature. The solvent was evaporated and the residue was taken up in TBME (100 mL). An aqueous solution of 25 percent H2SO4 (10 mL) was added and the layers were separated. The aqueous layer was extracted twice with TBME (100 mL). The organic layers were combined, washed with a saturated aqueous solution of NaCI (100 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure to yield 3- (4-Phenyl-butyrylamino)-propionic acid (7.3 g, 90 percent) as a beige solid.'H NMR (CDCI3, 300 MHz) d= 1.77-1. 87 (m, 2H), 2.05-2. 11 (m, 2H), 2.41-2. 53 (m, 4H), 3.37 (q, J = 6.0 Hz, 2H), 6.52 (t, J = 5.9 Hz, 1H), 7.03-7. 18 (m, 5H). 3- (4-Phenyl-butyrylamino)-propionic acid (2. 0 g, 8.5 mmol, 1. 0 eq.) was dissolved in DMF (213 mL) and CH2C12 (100 mL). 4-Hydroxy-pyrrolidine-2-carboxylic acid ethyl ester hydrochloride (1. 7 g, 8.5 mmol, 1. 0 eq.) was added, cooled to 5°C and NEt3 (1. 7 g, 17.0 mmol, 2.0 eq. ) and HBTU (4.2 g, 11.1 mmol, 1.3 eq. ) were added. The solution stirred for 72 h at room temperature. The solvent was evaporated under reduced pressure and the residue was taken up in ethyl acetate (500 mL) and an aqueous solution of 5 percent HCI (250 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed with an aqueous solution of 5 percent (200 mL), twice with a saturated aqueous solution of NaHCO3 (200 mL), twice with a saturated aqueous solution of NaCI (200 mL) and then dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography using CH2CI2/MeOH (9: 1) to yield 4-Hydroxy-1- [3- (4-phenyl-butyrylamino)-propionyl]- pyrrolidine-2-carboxylic acid ethyl ester (2.2 g, 70 percent) as a slightly yellow oil.-Rf (CH2CI2/MeOH (9: 1) ) = 0.50 ; 'H NMR (CDCI3, 300 MHz) 8= 1.16-1. 22 (m, 3H), 1.79-2. 57 (m, 9H), 3.30-3. 78 (m, 5H), 4.01-4. 16 (m, 3H), 4.38-4. 49 (m, 2H), 6.37-6. 42 (m, 1H), 7.07- 7.22 (m, 5H) ;'3C NMR (CDC13, 75.5 MHz) 6= 14. 1, 27.1, 34.4, 34. 9, 35.2, 35. 9, 37. 7, 55. 3, 57. 8, 61. 2, 69. 8, 125.9, 128. 3, 128.4, 141. 5, 170.9, 172.4, 173.2 ; MS m/z = 377 (100) [M++H]. The compound has a calculated Log POW of 0.96. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With 4-methyl-morpholine; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; | The starting material was prepared as follows: A solution of beta-alanine ethyl ester hydrochloride salt (5) (3.07 g; 0.02 mmol), N-(tertbutoxycarbonyl)glycine (3.5 g; 0.02 mmol), DCCI (4.12 g; 0.02mmol) and 4-methylmorpholine (2.2 ml) in dichloromethane (60 ml) was stirred overnight under argon atmosphere at ambient temperature. After filtration the residue was purified by flash chromatography eluding with dichloromethane/ethanol (96/4) to give ethyl 3-[(2-tertbutoxycarbonylaminoacetyl)amino]propanoate (6). Yield: 62percent 1H NMR spectrum (CDCl3): 1.27 (t, 3H); 1.45 (s, 9H); 3.55 (m, 2H); 3.77 (d, 2H); 4.15 (q, 2H); 5.3 (br s, 2H); 6.56 (br s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; 1,1'-carbonyldiimidazole; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide; | REFERENCE EXAMPLE 32A Production of N-(6-Chloroimidazo[1,2-b]pyridazine-2-carbonyl) beta-Alanine Ethyl Ester 1.98 g of <strong>[14714-24-0]6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid</strong> was suspended in 25 ml of N,N-dimethylformamide; 1.78 g of N,N'-carbonyldiimidazole was added, followed by stirring at room temperature for 1 hour. To this mixture, 1.69 g of beta-alanine ethyl ester hydrochloride and 1.53 ml of triethylamine were added, followed by further stirring for 3 hours. Ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 2.57 g of the title compound. Melting point: 132-134 C.; Elemental analysis (for C12H13N4O3Cl): Calculated (.%): C, 48.58; H, 4.42; N, 18.88; Found (%): C, 48.43; H, 4.33; N, 18.68. |
Yield | Reaction Conditions | Operation in experiment |
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96% | N-Fmoc-beta-alanine (311 mg, 1.0 mmol) in anhydrous CH2Cl2 (20 mL) under N2 was cooled to 0° C. HOBt (168 mg, 1.1 mmol) and EDC (230 mg, 1.2 mmol) were added and the solution was stirred for 30 min at 0° C. beta-Alanine ethyl ester hydrochloride (169 mg, 1.1 mmol) in anhydrous CH2Cl2 (10 mL) and DIEA (180 muL, 1.1 mmol) were added. The reaction was warmed to 23° C. and stirred for 16 h. The reaction solution was diluted with CH2Cl2 (30 mL) and washed with aqueous HCl (5percent, 30 mL), followed by aqueous NaOH (0.1 M, 30 mL), and deionized H2O (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Flash column chromatography (hexanes/ethyl acetate, 1:2) afforded 5 (394 mg, 96percent) as a white solid, mp 158.5-159° C.; 1H NMR (300 MHz, CDCl3) delta 7.74 (d, J=7.5 Hz, 2H), 7.58 (d, J=7.5 Hz, 2H), 7.38 (m, J=7.5 Hz, 2H), 7.29 (m, J=7.5 Hz, 2H), 6.53 (br m, 1H), 5.77 (br m, 1H), 4.34 (d, J=7.1 Hz, 2H), 4.18 (t, J=7.1 Hz, 1H), 4.11 (q, J=7.1 Hz, 2H), 3.50 (m, 4H), 2.52 (t, J=6.0 Hz, 2H), 2.40 (t, J=5.7 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) delta 172.6, 171.6, 156.7, 144.0, 141.3, 127.8, 127.1, 125.2, 120.1, 66.8, 60.9, 47.3, 37.2, 36.0, 35.0, 34.1, 14.3; IR (film) nu max 3319, 3069, 2978, 2955, 2884, 1732, 1689, 1634, 1538, 1446, 1270, 1190 cm-1; CI 411.1922 m/z (MH+, C23H27N2O5 requires 411.1920). |
Yield | Reaction Conditions | Operation in experiment |
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With anhydrous phosphorus trichloride; In pyridine; | EXAMPLE 15 Ethyl 3-N-(1-Ethyl-1,4-Dihydro-7-Methyl-4-Oxo-1,8-Naphthyridine-3-Carbonyl)Aminopropionate 6.90 g (50 mmol) of phosphorus trichloride are added to a solution of ethyl 3-aminopropionate hydrochloride (15.3 g; 0.1 mol) in 400 ml of pyridine. After stirring for 2 hours at ambient temperature, 23.1 g (0.1 mol) of 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid are added and the mixture is heated at 105/115 C. for 16 hours. After cooling, the solvent is evaporated off under reduced pressure and the residue is then taken up with normal hydrochloric acid. The aqueous solution is extracted with chloroform and the chloroform extract is washed with dilute hydrochloric acid, then with dilute sodium hydroxide solution and finally with water. After evaporation of the solvent, the residue is taken up with ether and then with hot ethanol. After filtration and drying, the title derivative is obtained in the form of white crystals with a melting point of 178 C., which, in TLC on a silica plate in the system toluene 10/ethyl formate 10/formic acid 1, give a single spot of Rf=0.50. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; oxalyl dichloride; diethyl ether; dichloromethane; ethyl acetate; | (a) (+-)-3-[[2-[(Acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]propanoic acid, ethyl ester A solution of (+-)-2-[(acetylthio)methyl]-3-phenylpropanoic acid (0.95 g., 4.0 mmole) in ethyl ether (8 ml.) is treated, under a drying tube, with oxalyl chloride (0.37 ml., 4.2 mmole), followed cautiously with a catalytic amount of diemthylformamide (3 drops). The mixture is stirred for one hour at room temperature and then concentrated in vacuo. Tetrahydrofuran (5 ml.) is added to the residue and removed in vacuo to chase any remaining oxalyl chloride. The residue, a two-phase (yellow and green) liquid, is treated with methylene chloride (5 ml.), and the soluble portion is decanted into a dropping funnel. This solution is added dropwise, under nitrogen, to a cold (ice/methanol) mixture of beta-alanine, ethyl ester, hydrochloride (0.61 g., 4.0 mmole) and diisopropylethylamine (1.46 ml., 8.38 mmole) in methylene chloride (10 ml.), over 10 minutes. After stirring for 3 hours the resulting slurry is filtered and concentrated. The residue is treated with ethyl acetate (50 ml.) and again filtered and the filtrate is washed with 10% potassium bisulfate, water, saturated sodium bicarbonate, and 50% brine (30 ml. each), then dried over Na2 SO4 and concentrated in vacuo. The residue, a viscous yellow oil (1.20 g.), is purified on a column of 80 g. silica gel (230-400 mesh), eluding with 7:2 hexane/acetone. Fractions containing the desired product (TLC) are pooled and concentrated to give 1.04 g. of (+-)-3-[[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]propanoic acid, ethyl ester as a clear almost colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide; | Reference Example 32 Production of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)beta-alanine ethyl ester 1.98 g of <strong>[14714-24-0]6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid</strong> was suspended in 25 ml of N,N-dimethylformamide; 1.78 g of N,N'-dicarbonylimidazole was added, followed by stirring at room temperature for 1 hour. To this mixture, 1.69 g of beta-alanine ethyl ester hydrochloride and 1.53 ml of triethylamine were added, followed by further stirring for 3 hours. Ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 2.57 g of the title compound. Melting point: 132-134 C. Elemental analysis (for C12H13N4O3Cl): | |
With triethylamine; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide; | Reference Example A32 Production of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl) beta-alanine ethyl ester <strong>[14714-24-0]6-Chloroimidazo[1,2-b]pyridazine-2-carboxylic acid</strong> (1.98 g) was suspended in N,N-dimethylformamide (25 ml); N,N'-dicarbonylimidazole (1.78 g) was added thereto, followed by stirring at room temperature for 1 hour. To this mixture, beta-alanine ethyl ester hydrochloride (1.69 g) and triethylamine (1.53 ml) were added, followed by further stirring for 3 hours. Ice water was added to the reaction mixture; the crystals precipitated were collected by filtration, washed with water and dried to give the title compound (2.57 g). melting point: 132-134C elemental analysis for C12H13N4O3Cl Calculated (%): C,48.58; H,4.42; N,18.88 Found (%): C,48.43; H,4.33; N,18.68 |
Yield | Reaction Conditions | Operation in experiment |
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82% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 24h; | Example 21 Synthesis of 1,5-dioxo-1,2,3,4,5,10-hexahydro-azepino[3,4-b]indole-7-carboxylic acid pyridin-3-ylamide 5-Bromoindole-2-carboxylic acid (6.20 g, 25.8 mmol) and DMAP (5.60 g, 45.8 mmol) were suspended in anhydrous methylene chloride (400 mL) under an atmosphere of nitrogen and cooled to 0° C. EDCI (6.20 g, 32.3 mmol) and beta-alanine ethyl ester hydrochloride (4.77 g, 31.1 mmol) were added, and the reaction mixture stirred at 0° C. for 4 h, then at room temperature for 20 h. Water was added, and the organic layer separated and subsequently washed with 10percent HCl, then dried over Na2SO4, filtered, and concentrated to give 3-[(5-Bromo-1H-indole-2-carbonyl)-amino]-propionic acid ethyl ester (7.21 g, 82percent) as an analytically pure pale yellow powder. |
Yield | Reaction Conditions | Operation in experiment |
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89% | With triethylamine; In dichloromethane; at 0 - 25℃; for 17.0833h;Molecular sieve; | Example 12; 4R-(4-Benzyloxy-phenyl)-3R-(4-fluoro-phenyl)-1-[3-(4-fluoro-phenyl)-3-O-propyl]-azetidin- 2-one; Step A; 3-[(4-Benzyloxy-benzylidene)-amino]-propionic acid ethyl ester ; EPO <DP n="44"/>A solution of beta-alanine ethyl ester hydrochloride (20.7 g, 135 mmol), Et3N (20.5 g, 202 mmol) and 4 A molecular sieves (40 g) in CH2CI2 (300 mL) was stirred at 0 0C while 4- benzyloxybenzaldehyde (28.6 g, 135 mmol) was added as a solid over 5 min. The reaction mixture was then warmed to 25 0C and stirred at that temperature for 5 hrs. TLC analysis indicated that reaction was not yet; consequently, MgSO4 (10 g) was added and the reaction was stirred for an additional 12 hrs at 25 0C after which time reaction was complete as determined by TLC analysis. The reaction mixture was then filtered to remove solids, and the filtrate was concentrated to provide 3-[(4-benzyloxy-benzylidene)- amino]-propionic acid ethyl ester (37.3, 89percent) as a pale yellow solid of sufficient purity for use in the next step without additional purification; MS(APCI+): m/z 312.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | To a solution of 4-chloro-2-(2'-ethoxybiphenyl-4-yl)-6-fluoroquinoIine-3-carbonitrile (Example 233, 100 mg, 0.25 mmol) and beta alanine ethyl ester chloride (76.3 mg, 0.50 mmol) in DMF (5 ml_) was added triethylamine (0.21 ml_, 1.50 mmol). The reaction was stirred at rt for 30 min and then the reaction was diluted with water (50 ml_). The product was extracted with ethyl acetate (3 x 15 ml.) and then the combined organic extracts were washed with brine, dried with sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography using 25percent ethyl acetate/hexanes to afford 119 mg (99percent) of desired product. 1H EPO <DP n="110"/>NMR (300 MHz DMSO- d6) delta 8.23 (dd, 1 H), 7.92 (dd, 1 H), 7.87 (br s, 1 H), 7.82-7.62 (m, 5 H), 7.39-7.30 (m, 2 H), 7.13-7.08 (m, 1 H), 7.03 (ddd, 1 H), 4.12-4.00 (m, 6 H), 2.86 (t, 2 H), 1.30 (t, 3 H), 1.12 (t, 3 H); ES-MS m/z 484.2 [M+H]+, LCMS RT (min) 3.11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In dichloromethane; at 0 - 20℃; for 5h; | Example 28 Ethyl 3-(2-chloroacetamido)propanoate 31 (Scheme 10) To a stirred solution of ethyl 3-aminopropionate hydrochloride 25 (0.01 mole) and triethylamine (0.02 mole) in DCM (25 ml) at ice-bath temperature was added dropwise a solution of chloroacetyl chloride 30 (0.01 mol) in DCM (5 ml). The resulting mixture was stirred at ice-bath temperature for 1 hour and at room temperature for 4 hours. The reaction mixture was poured into ice-cold water (50 ml). The mixture was extracted with DCM (25 ml*2), washed with water (25 ml), dried over sodium sulfate (Na2SO4) and evaporated the solvent. The residue was filtered through a short silica gel column using 0-50percent ethyl acetate and hexane as eluent to give the pure chloroamide 31 as light yellow oil in 99percent yield (1.91 g). 1H NMR (400 MHz, CDCl3): delta 1.16 (3H, t, J=6.4 Hz); 2.45 (2H, t, J=6.8 Hz); 3.30 (2H, q, J=6.8 Hz); 4.01 (2H, s); 4.05 (2H, q, J=6.4 Hz); 8.27 (1H broad s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 1h; | 5.1.43 Ethyl 3-[(3-ethoxy-3-oxo-propyl)amino]-3-oxo-propanoate (33) To a solution of beta-alanine ethyl ester hydrochloride (9.29 g, 60.5 mmol) and N,N-diisopropylethylamine (21.6 mL, 124 mmol) in CH2Cl2 (100 mL) was added ethyl malonyl chloride (7.90 mL, 61.7 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. 1 N HCl aqueous solution (100 mL) was added to the reaction mixture and resultant mixture extracted 3 times with CH2Cl2 (50 mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was chromatographed (NH silica gel, EtOAc/CH2Cl2 = 0-20percent) to give the title compound (11.56 g, 50.0 mmol, 83percent) as a pale yellow oil. 1H NMR (CDCl3) delta: 1.29-1.33 (6H, m), 2.58 (2H, t, J = 6.3 Hz), 3.32 (2H, s), 3.60 (2H, q, J = 6.3 Hz), 4.18-4.25 (4H, m), 7.54 (1H, s). |
72% | EXAMPLE 6; Preparation of piperidine-2,4-dione; A solution of mu-alanine ethylester hydrochloride (13.8 g, 90mmol) in dichloromethane (90 mL) and TEA (13.8 mL, 99 mmol) was stirred at RT for one hour. More TEA (13.8 mL, 99 mmol) was added, the solution was cooled to 0° C. under stirring and ethylmalonylchloride (12.6 mL, 99 mmol) was added dropwise. After one hour at 0° C., the reaction mixture was stirred one hour at RT. A 15percent aqueous solution of K2CO3 (90 mL) was added and the layers were separated. The organic phase was washed with 10percent HCl (90 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was chromatographed on flash silica gel (450 g, eluant: ethyl acetate/n-hexane 2:1) to give N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester as a yellow oil (15 g, 64.9 mmol, 72percent yield). TLC: DCM/MeOH 20:1, iodine vapours. Sodium metal (610 mg, 26.6 mmol) was dissolved in dry MeOH (25 mL) at RT under stirring and inert atmosphere. After complete dissolution the mixture was stirred 10' longer, then N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester (6.15 g, 26.6 mmol) in dry toluene (150 mL) is added dropwise. After addition the reaction mixture was stirred at 90° C. for 6 hours, cooled to RT, water (30 mL) was added and the layers were separated. The organic phase was washed with water (2.x.10 mL), the joined aqueous phases were acidified with 37percent HCl and extracted thoroughly (.x.20 or more) with a mixture of DCM/MeOH (5:1). After drying over Na2SO4 and concentration, 3-methoxycarbonylpiperidin-2,4-dione as a pink solid was obtained (4 g, 23.4 mmol, 88percent yield). 3-Methoxycarbonylpiperidin-2,4-dione (4 g, 23.4 mmol) is dissolved in acetonitrile containing 1percent of water (250 mL) and refluxed 4 hours. The reaction mixture is concentrated to give piperidine-2,4-dione, as a yellow solid (2.4 g, 21.2 mmol, 90percent yield). 1H NMR (400 MHz, DMSO-D6) delta ppm 2.43-2.49 (m, 2 H) 3.24 (s, 2 H) 3.28-3.45 (m, 2 H) 8.07 (s, 1 H). | |
72% | A solution of beta-alanine ethylester hydrochloride (13.8 g, 90 mmol) in dichloromethane (90 ml.) and triethylamine (TEA, 13.8 ml_, 99 mmol) was stirred at room temperature for 1 hour. More TEA (13.8 ml_, 99 mmol) was added, the solution was cooled to 00C under stirring and ethylmalonylchloride (12.6 ml_, 99 mmol) was added dropwise. After 1 hour at 00C, the reaction mixture was stirred 1 hour at room temperature. A 15percent aqueous solution of K2CO3 (90 ml.) was added and the layers were separated. The organic phase was washed with 10percent HCI (90 ml_), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was chromatographed on flash silica gel (450 g, eluant: ethyl acetate/n-hexane 2:1 ) to give N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester as a yellow oil (15 g, 64.9 mmol, 72percent yield). Sodium metal (610 mg, 26.6 mmol) was dissolved in dry MeOH (25 ml.) at room temperature under stirring and inert atmosphere. After complete dissolution the mixture was stirred 10' longer, then N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester (6.15 g, 26.6 mmol) in dry toluene (150 ml.) was added dropwise. After addition, the reaction mixture was stirred at 900C for 6 hours, cooled to room temperature, water (30 ml.) was added and the layers were separated. The organic phase was washed with water (2x10 ml_), the combined aqueous phases were acidified with 37percent HCI and extracted thoroughly with a mixture of DCM/MeOH (5:1 ). After drying over Na2SO4 and concentration, 3-methoxycarbonylpiperidin-2,4-dione as a pink solid was obtained (4 g, 88percent yield). 3-Methoxycarbonylpiperidin-2,4-dione (4 g, 23.4 mmol) was dissolved in acetonitrile containing 1percent of water (250 ml.) and refluxed for 4 hours. The reaction mixture was concentrated to give the title compound, as a yellow solid (2.4 g, 90percent yield). 1 H NMR (400 MHz, DMSO-D6) delta ppm 2.43 - 2.49 (m, 2 H) 3.24 (s, 2 H) 3.28 - 3.45 (m,2 H) 8.07 (s, 1 H). |
39% | EXAMPLE 1; 5-methyl-2-((5-methyl-1H-imidazol-4-yl)methyl)-3,4-dihydro-2H-pyrido[4,3-b]indol-1(5H)-one hydrochloride; Step 1 N-(2-ethoxycarbonyl-ethyl)-malonamicacid ethyl ester:; Triethylamine (22.2 g, 0.22 mol, 2.2 equiv) was added to a solution of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (15.4 g, 100.26 mmol, 1.0 equiv) and dichloromethane (100 mL). The resulting mixture was stirred for about 1 hour, and then ethyl 3-chloro-3-oxopropanoate (16.6 g, 110.23 mmol, 1.1 equiv) was added dropwise at about 0° C. After stirring at ambient temperature for about 2 hours, the mixture was washed sequentially with a 19percent potassium carbonate solution (50 mL) and a 10percent hydrochloric acid solution (50 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromotagraphy (ethyl acetate/petroleum ether (1:3-1:1)) to give the title product as yellow liquid (9 g, yield=39percent). LC-MS: m/z=232 (MH)+. | |
To a solution of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (20 g, 0.13 mol) dissolved in dichloromethane (400 mL) at 0° C. was added triethylamine (37.2 mL, 0.272 mol) dropwise. The mixture was stirred for 1 hour at 0° C., and then ethyl malonyl chloride (16.8 mL, 0.13 mol) was added dropwise. The mixture was stirred for 1 hour, then poured into 75 mL of a saturated aqueous solution of ammonium chloride, and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2×50 mL), washed with water (50 mL), dried with Na2SO4, filtered, concentrated and purified by silica gel column chromatography eluted with petroleum ether/ethyl acetate (50:1) to give the titled compound. 1H NMR (400 MHz, CDCl3) delta ppm 7.50 (s, 1H), 4.14-4.22 (m, 4H), 3.54-3.59 (m, 2H), 3.29 (s, 2H), 2.55 (t, J=6.2 Hz, 2H), 1.25-1.30 (m, 6H) | ||
Example 1A ethyl 3-(3-ethoxy-3-oxopropylamino)-3-oxopropanoate To a solution of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (20 g, 0.13 mol) dissolved in dichloromethane (400 mL) at 0° C. was added triethylamine (37.2 mL, 0.272 mol) dropwise. The mixture was stirred for 1 hour at 0° C., and then ethyl malonyl chloride (16.8 mL, 0.13 mol) was added dropwise. The mixture was stirred for 1 hour, then poured into 75 mL of a saturated aqueous solution of ammonium chloride, and extracted with dichloromethane (3*50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2*50 mL), washed with water (50 mL), dried with Na2SO4, filtered, concentrated and purified by silica gel column chromatography eluted with petroleum ether/ethyl acetate (50:1) to give the titled compound. 1H NMR (400 MHz, CDCl3) delta ppm 7.50 (s, 1H), 4.14-4.22 (m, 4H), 3.54-3.59 (m, 2H), 3.29 (s, 2H), 2.55 (t, J=6.2 Hz, 2H), 1.25-1.30 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | 3-(4-Fluoro-benzylamino)-propionic acid ethyl ester A suspension of beta-alanine ethyl ester hydrochloride salt (2.0 g, 13.0 mmol), 4-fluorobenzaldehyde (1.61 g, 13.0 mmol), sodium acetate (2.13 g, 26.0 mmol), and 4 A molecular sieves (0.5 g/mmol) in methanol (50 mL) was treated with sodium cyanoborohydride (1.63 g, 26.0 mmol). The reaction was stirred at 25 C. for 4 h, diluted with a saturated aqueous sodium bicarbonate solution (150 mL), and extracted with ethyl acetate (3*50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by flash column chromatography (ISCO RediSep column, 20 to 70% ethyl acetate in hexanes) to give 3-(4-fluoro-benzylamino)-propionic acid ethyl ester (2.08 g, 71%) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta: 1.26 (t, 3H, J=7.0 Hz), 2.52 (t, 2H, J=6.5 Hz), 2.88 (t, 2H, J=6.2 Hz), 3.76 (s, 2H), 4.14 (q, 2H, J=6.8 Hz), 6.96-7.01 (m, 2H), 7.26-7.28 (m, 2H). LC-MS (ESI) calculated for C12H11FNO2: 225.3, found 226.2 [M+H+]. | |
47% | With sodium cyanoborohydride; acetic acid; In methanol; dichloromethane; at 20℃; for 16h; | To a solution of ethyl beta-alaninate hydrogen chloride (1/1) (200 mg, 1.30 mmol) and 4- fluorobenzaldehyde (170 muIota, 1.6 mmol) in dichloromethane (8.0 ml, 120 mmol) and methanol (2.0 ml, 49 mmol) was added sodium cyanoborohydride (164 mg, 2.60 mmol) and glacial acetic acid (89 muIota, 1.6 mmol). The mixture was stirred for 16 h at room temperature. Approximately 20 mL saturated aqueous sodium hydrogencarbonate solution were added and vigorously stirred for 10 min at room temperature. The phases were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried with a water repellant filter and concentrated. The residue was dissolved with ethyl acetate, adsorbed on isolute and purified over Biotage Isolera Four (Biotage SNAP Cartridge KP-Sil 25 g; 0-60% ethyl acetate in hexane) [108] to afford 138 mg (47% yield) of the title compound. LC-MS (Method H): Rt = 1.05 min; MS (ESIpos): m/z = 226 [M+H]+ 1H NMR (400 MHz, Chloroform-d) delta [ppm]: 1.25 (t, 3H), 1.73 (br s, 1H), 2.52 (t, 2H), 2.88 (t, 2H), 3.77 (s, 2H), 4.14 (q, 2H), 7.00 (t, 2H), 7.23-7.32 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | 3-fluoro-4-nitro-benzoic acid tert-butyl ester (Ig, 4.14mmol) and Beta-Alanine ethyl ester hydrochloride 1.037g, 6.75 mmol) were dissolved in DMF (10ml). To the solution DIEA 0.872 g, 6.75 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml), extracted with Ethyl acetate <n="191"/>3 x, dried over MgSCH, filtered and evaporated to dryness to afford 1.2g of solid was obtained (86percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20℃; for 16h; | To a solution of 3-Fluoro-4-nitrobenzonitrile (1.0 g, 6.0 mmol) in DMA (5 inL) were added Beta-Alanine ethyl ester HCl (1.4 g, 9.03 mmol) and DIPEA (1.6 mL, 9.03 mmol). The reaction mixture was stirred at room temperature for 16 h (the recation was completed; the reaction mixture turned to orange from yellow in color). The reaction mixture was then diluted with ethyl acetate and washed with water (x4). The organic phase was then dried over Na2SO4 and concentrated to afford 1.53 g (96%) of the desired product as yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In tetrahydrofuran; at 20℃; for 2h; | A mixture of 92 beta-alanine ethyl ester hydrochloride (911mg, 5.39mmol), 93 2-chloro-1,3-dinitrobenzene (1.00g, 4.94mmol), 94 triethylamine (2.07mL, 14.9mmol) and 95 THF (50mL) was stirred at room temperature for 2h. To the reaction mixture were added beta-alanine ethyl ester hydrochloride (455mg, 2.96mmol) and triethylamine (1.03mL, 7.39mmol) at room temperature and the resultant mixture was stirred at room temperature for 2h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0?20percent EtOAc/n-hexane gradient mixture to give 96 4 as an oil (1.39g, 4.92mmol, quant). 1H NMR (CDCl3, 300MHz) delta 1.26 (t, J=7.1Hz, 3H), 2.66 (t, J=5.8Hz, 2H), 3.23?3.31 (m, 2H), 4.17 (q, J=7.1Hz, 2H), 6.78 (t, J=8.2Hz, 1H), 8.17 (d, J=8.2Hz, 2H), 8.53 (brs, 1H). |
With triethylamine; In tetrahydrofuran; at 20℃; for 2h; | Reference Example 24 Ethyl N-(2,6-dinitrophenyl)-beta-alaninate A mixture of beta-alanine ethyl ester hydrochloride (911 mg, 5.39 mmol), 2-chloro-1,3-dinitrobenzene (1.00 g, 4.94 mmol), triethylamine (2.07 mL, 14.9 mmol) and tetrahydrofuran (50 mL) was stirred at room temperature for 2 hr. To the reaction mixture were added beta-alanine ethyl ester hydrochloride (455 mg, 2.96 mmol) and triethylamine (1.03 mL, 7.39 mmol) at room temperature and the resultant mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluding with a 0-20percent ethyl acetate/n-hexane gradient mixture to give the title compound as an oil (1.39 g, 4.92 mmol, 99.6percent). 1H NMR (CDCl3) delta 1.26 (t, J=7.1 Hz, 3H), 2.66 (t, J=5.8 Hz, 2H), 3.23-3.31 (m, 2H), 4.17 (q, J=7.1 Hz, 2H), 6.78 (t, J=8.2 Hz, 1H), 8.17 (d, J=8.2 Hz, 2H), 8.53 (brs, 1H). MS Calcd.: 283; MS Found: 284 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With thionyl chloride; at -10℃; for 2h;Reflux; | Freshly distilled thionyl chloride (250 mL) was added drop-wise to stirring absolute EtOH (400 mL) at ?10 ºC. After 20 min at ?10 ºC, beta-alanine (82.56 g, 0.93 mol) was slowly added to the thionyl chloride/EtOH solution. This mixture was refluxed for 2 h. Excess thionyl chloride was distilled off and the volume of the solution was reduced by half under vacuum. The white precipitate that crystallized from the reduced solution was filtered and washed with cold diethylether to give beta-alanine ethyl ester hydrochloride as a white crystalline powder (124.34 g, 87percent). |
With thionyl chloride; at -5 - 78℃; for 1.5h;Reflux; | General procedure: A mixture of alanine (3.56 g, 0.04 mol) in ethanol (30 mL), with thionyl chloride (3.6 mL) dropwise added at -5 °C, was refluxed in ethanol at 78 °C under stirring within 1.5 h. Subsequently, the solution was distilled in vacuum to afford Alanine ethyl ester hydrochloride 2a in >80percent yield. The physical constants of 2a-2l are identical with the corresponding data in reference [24]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | 4- [ (4-CYCLOHEXYLBENZYL)- (4-TRIFLUOROMETHOXYBENZYL) amino] benzoic acid (300 mg; 0.62 MMOL) was dissolved in a mixture of DCM (2.0 ml) and DMF (1.0 ML). Ethyl dimethylaminopropyl carbodiimid hydrochloride (144 mg; 0.75 MMOL) and 1-hydroxybenzotriazol (113 mg; 0.75 MMOL) were added. The mixture was stirred at ambient temperature for 2h, then (3-ALANINE ethyl ester hydrochloride (142 mg; 0.93 MMOL) and DIPEA 318 ul, 1.86 MMOL) were added. The mixture was left stirring at room temperature over night, then diluted with DCM (25 mi) and washed twice with water and once with brine. The organic solution was then dried with anhydrous sodium sulphate and taken to dryness by rotary evaporation, to give 310 mg (86percent) of clear oil. HPLC-MS (Method (B) ) : m/z: 583 (M+1), Rt: 6.13 min. APOS;H-NMR (CDCI3) : 8 1. 19 (t, 3H); 1.25-1. 45 (m, 5H); 1.60-1. 90 (m, 5H); 2.49 (m, 1H) ; 2.54 (t, 2H); 3.65 (q, 2H); 4.12 (q, 2H); 4.61 (s, 2H); 4.65 (s, 2H); 6.62 (t, 1H) ; 6.69 (d, 2H); 7.09 (d, 2H); 7.15 (d, 2H); 7.19 (d, 2H); 7.21 (d, 2H); 7.60 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a solution of methylthiophene carboxylic acid (20 g, 0.14 mol) in DMF (30 mL) was added at 0°C carbonyldimimidazole (23 g, 0.14 mol) in portions of 10 g. After stirring at 0°C for 1 hour, a solution of ethyl 3-aminopropionate hydrochloride (21 g, 0.14 mol) in DMF (30 mL) was added followed by triethylamine (20 mL, 0.14 mol). The mixture was stirred at ambient temperature for 16 hours, filtered by suction, and the filtrate was concentrated. The residue was dissolved in ethyl acetate (100 mL), washed with water (2 x 50 mL), 1N hydrochloric acid (2 x 50 mL), sodium bicarbonate solution (2 x 50 mL), brine (50 mL), dried (MgSO4), and concentrated. Addition of hexane to the residue induced the crystallization of ethyl 3-([(5-methyl-2-thienyl)carbonyl]amino}propionate (27 g, 80percent).1H NMR (CDCl3): delta 1.28 (t, 3H), 2.50 (s, 3H), 2.62 (t, 2H), 3.68 (q, 2H), 4.17 (q, 2H), 6.60 (brd s, 1H), 6.66 (d, 1H), 7.30 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With caesium carbonate; XPhos;palladium diacetate; In toluene; for 2h;Reflux; Inert atmosphere; | To degassed toluene (200 mL) was added palladium acetate (0.30 g, 1.3 mmol) and x-phos (1.3 g, 2.7 mmol) and the mixture degassed a further 5 minutes. To the reaction mixture was then added cesium carbonate (35.0 g, 107 mmol), beta alanine ethyl ester hydrochloride (6.2 g, 40.4 mmol) and <strong>[101184-73-0]2-(4-bromophenyl)-2-methylpropanenitrile</strong> (6.0 g, 26.8 mmol). The reaction mixture was heated at reflux for 2 hours, cooled and filtered through celite. Filtrate concentrated and the residue further purified on silica eluding with 25% ethyl acetate in heptane to give ethyl 3-(4-(2-cyanopropan-2-yl)phenylamino)propanoate (4.05 g, 58%) as a yellow solid. 1H NMR (300 MHz, CDCl3): delta ppm 1.26 (t, 3H), 1.66 (s, 6H), 2.60 (t, 2H), 3.44 (t, 2H), 4.15 (q, 2H), 4.18 (br s, 1H), 6.61 (d, 2H), 7.26 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With caesium carbonate; XPhos;palladium diacetate; In toluene; for 6h;Reflux; | To degassed toluene (200 mL) was added palladium acetate (0.21 g, 0.9 mmol) and x-phos (0.89 g, 1.9 mmol) and the mixture degassed a further 5 minutes. To the reaction mixture was then added cesium carbonate (24.3 g, 74.6 mmol), beta alanine ethyl ester hydrochloride (4.3 g, 28 mmol) and 1-bromo-4-trifluoromethoxybenzene (4.5 g, 18.7 mmol). The reaction mixture was heated at reflux for 6 hours, cooled and filtered through a pad of celite. Filtrate concentrated and the residue purified on silica gel eluding with a gradient from 10% to 15% ethyl acetate in heptane to give ethyl 2-(4-(trifluoromethoxy)phenylamino)acetate (3.35 g, 65%) as a yellow oil. 1H NMR (300 MHz, CDCl3): delta ppm 1.26 (t, 3H), 2.60 (t, 2H), 3.42 (t, 2H), 4.16 (q, 2H), 6.57 (dd, 2H), 7.03 (dd, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With caesium carbonate; N-ethyl-N,N-diisopropylamine; XPhos;palladium diacetate; In toluene; at 110℃; for 20h; | To degassed toluene (11.8 mL) was added beta alanine ethyl ester hydrochloride (0.354 g, 2.3 mmol), 4-tert-butylphenyl trifluoromethanesulfonate (0.5 g, 2 mmol), X-Phos (87 mg, 0.18 mmol), palladium acetate (42 mg, 0.186 mmol), diisopropylethyl amine (0.3 ml, 2 mmol), and cesium carbonate (1.73 g, 5.31 mmol). Reaction mixture was stirred at 110° C. for 20 hours. Reaction cooled to room temperature, diluted with water and extracted with ethyl acetate. Pooled organic layers washed with brine, dried over sodium sulfate and concentrated. Residue purified on silica eluding with 1percent methanol in dichloromethane to give ethyl 3-(4-tert-butylphenylamino)propanoate (0.17 g, 40percent) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.24 (s, 12H) 2.59 (t, J=6.44 Hz, 2H) 3.42 (t, J=6.44 Hz, 2H) 4.13 (q, J=7.06 Hz, 2H) 6.57 (d, J=8.72 Hz, 2H) 7.20 (d, J=8.72 Hz, 2 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 20h; | Intermediate 16-1: Ethyl 3-(2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)propanoate A mixture of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (88 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 muL, 0.57 mmol) in DMF (342 muL) were treated with a solution of 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 muL, 0.57 mmol) in DMF (2049 muL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL), and washed with water (5 mL). The organic layer was evaporated to afford ethyl 3-(2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)propanoate (387 mg, 151percent) which was used without further purification. 1H NMR (400.13 MHz, CDCl3) delta 1.18 (3H, t), 1.28 (3H, d), 2.48 (2H, t), 2.66 (3H, s), 2.81 (7H, s), 2.89-2.93 (10H, m), 3.48 (3H, t), 4.07 (2H, t), 5.23 (5H, s), 7.19 (4H, s), 7.20 (1H, s), 7.29-7.31 (1H, m), 7.35 (1H, d), 7.49-7.51 (2H, m), 7.58-7.61 (2H, m), 7.95 (2H, s). m/z (ES+), (M+H)+=495 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | A mixture of 2,6-dichloro-3-nitropyridine (137; 1 .92 g, 1 0 mmol), <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> ( 1 .7 g, 1 1 mmol), and diisopropylethylamine (3.9 g, 30 mmol) in dimethylformamide ( 10 mL) was stirred at room temperature overnight. The reaction progress was monitored by TLC. Saturated NaHCCb solution was added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic layers were washed with water and brine, then concentrated to give ethyl 3-((6-chloro-3-nitropyridi n-2-yl)amino)propanoate (138; 2.8g, 100percent) as a pale yel low oil. MS (ESI) calcd for C10H 12CIN3O4: 273.67. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; | Example 4-63-[6-Propyl-4-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)thieno[2,3-d]pyrimidine-2-carbonyl]amino}propionic acid ethyl ester The compound obtained from Example 4-2 (20.5 mg, 0.05 mmol), 3-aminopropionic acid ethyl ester; hydrochloric acid salt (8.4 mg, 0.055 mmol) were dissolved in N,N-dimethylformamide (2 mL) and then HATU (24.6 mg, 0.065 mmol) was added thereto. The resulting mixture was cooled to 0° C., triethylamine (20.1 mg, 0.2 mmol) was added dropwise thereto and stirred at room temperatue for 16 hours. The resulting mixture was distilled under reduced pressure and then purified by column chromatography with the 95:5 mixture of dichloromethane and methanol to give the title compound (22.9 mg, 90percent).1H NMR (500 MHz, CDCl3); delta 8.57 (1H, m), 7.09 (1H, s), 5.34 (2H, s), 4.42 (4H, s), 4.16 (2H, q), 3.75 (2H, m), 2.91 (2H, t), 2.65 (2H, m), 1.79 (2H, m), 1.26 (3H, t), 1.01 (3H, t) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3.5h; | Example 333-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propionic acid ethyl ester To a solution of 0.18 g (0.37 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) in 2 mL N,N-dimethylformamide were added 0.148 g (0.39 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.25 mL (1.49 mmol) N,N-diisopropylethylamine. To the light brown solution 0.060 g (0.39 mmol) beta-alanine ethylester hydrochloride (commercially available, CAS RN 4244-84-2) was added and the solution was stirred at room temperature for 3.5 hours. The solution was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane: ethyl acetate (100:0 to 0:100) to afford 0.185 g (85percent) of the title compound as a light brown foam. MS (ESI): m/z=583.15 [M+H]+. |
85% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3.5h; | To a solution of 0.18 g (0.37 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H- quinoxaline-l-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) in 2 mL N,N- dimethylformamide were added 0.148 g (0.39 mmol) 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafiuorophosphate (HATU, commercially available, CAS RN 148893-10- 1) and 0.25 mL (1.49 mmol) N,N-diisopropylethylamine. To the light brown solution 0.060 g (0.39 mmol) beta-alanine ethylester hydrochloride (commercially available, CAS RN 4244-84-2) was added and the solution was stirred at room temperature for 3.5 hours. The solution was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane : ethyl acetate (100 : 0 to 0 : 100) to afford 0.185 g (85percent) of the title compound as a light brown foam. MS (ESI): m/z = 583.15 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In ethanol; at 80℃; for 1.5h;Microwave irradiation; Inert atmosphere; | To a solution of tert-butyl (1-(4-(6-chloro-5-nitro-3-phenylpyridin-2- yl)phenyl)cyclobutyl)carbamate (1.03 g, 2.14 mmol) in EtOH (8 ml) was added triethylamine (1.49 ml, 10.72 mmol) and ethyl 3-aminopropanoate.HCI (1.65 g, 10.72 mmol) under nitrogen. The resulting mixture was stirred for 1.5 hours at 80°C under microwave irradiation. Water was added and the mixture was extracted with AcOEt (3 x 15ml). The combined organic phases were dried over Na2S04 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 30percent EtOAc in cyclohexane) to give the title compound (1.2 g, quantitative). 1H NMR (500 MHz,CDCI3): 8.50 (1 H, s), 8.38 (1H, s), 7.32 (2H, d), 7.23 -7.18 (5H, m), 7.09 -7.07 (2H, m), 5.00 (1H, br s), 4.12 (2H, q), 3.98 (2H, q), 2.71- 2.68 (2H, t), 2.52-2.20 (4H, m), 2.00-1.95 (1 H, m), 1.79 -1.65 (1 H, m), 1.40-1.10 (9H, br), 1.20 (3H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; at 20℃; for 18h; | To a mixture of 4 (110 g, 0.628 mol) in Et3N (96 mL, 0.690 mol) was added beta-alanine·HCl (106 g, 0.690 mol), and then the mixture was stirred at room temperature for 18 h. The resulting white slurry was dispersed between Et2O and H2O, and then the organic layer was washed with brine. The product was back-extracted with 3 N HCl 200 mL × 2). The aqueous phase was washed with Et2O and made basic with 12 N NaOH (100 mL) and extracted with Et2O (×2). The organic layer was dried and concentrated to provide 5 (101.0 g, 55%) as an oil. 1H NMR (CDCl3) delta: 1.17-1.29 (6H, m), 2.46 (2H, t, J = 6.7 Hz), 2.90 (2H, t, J = 6.4 Hz), 2.91 (1H, dd, J = 12.2, 6.2 Hz), 3.27 (1H, dd, J = 12.2, 8.8 Hz), 3.78 (1H, dd, J = 8.4, 6.2 Hz), 4.05-4.20 (4H, m), 7.20-7.40 (5H, m). The amino NH signal was not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; | Example 3; A mixture of 0.99 g (4.00 mmol) of <strong>[80745-07-9]4-methoxy-2,3,6-trimethyl-benzenesulphonyl chloride</strong>, 0.69 g (4.51 mmol) of R-alanine ethylester hydrochloride, 2.23 ml (15.98 mmol) of triethylamine and 20 ml dichloromethane is stirred overnight at ambient temperature. The reaction mixture is then washed with 0.5 M HCl, saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo.C15H23NO5S (329.41)[M+H]+=330TLC: silica gel, petroleum ether/ethyl acetate 2:1, Rf value=0.43 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; | To a solution of <strong>[10235-65-1]4,6-dichloro-2-(2-pyridinyl)pyrimidine</strong> (500 mg, 2.212 mmol) in 1 ,4-Dioxane (5 mL), was added DIPEA (1 .159 mL, 6.64 mmol) and ethyl beta-alaninate hydrochloride (374 mg, 2.433 mmol) and the reaction heated in a Biotage microwave at 80 C for 2 h. A further portion of ethyl b-alaninate hydrochloride (34.0 mg, 0.221 mmol) was added and the reaction mixture heated in a Biotage microwave at 80 C for 2 h in total. The reaction mixture was then partitioned between DCM and water. The aqueous layers were re-extracted, the organics were combined, passed through a hydrophobic frit and the solvent removed by vacuum to give a brown oil (688mg). The product was left under high vacuum overnight to give ethyl A/-[6-chloro-2-(2-pyridinyl)-4-pyrimidinyl]-p-alaninate as a brown solid (533mg, 79%).LCMS (Method A): rt = 0.69 min, MH+ = 307.06 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In methanol; dichloromethane; at 20℃; for 17h; | Step G:(+/-)-3-({5-[3-methyl-1-(4'-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid ethyl ester(+/-)-5-[3-Methyl-1-(4'-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid (636 mg, theoretical 596 mg, 1.39 mmol) was combined with N-(3-dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride (399 mg, 2.08 mmol), 1-hydroxybenzotriazole hydrate (319 mg, 2.08 mmol), and anhydrous dichloromethane (10 mL). Beta-alanine ethyl ester hydrochloride (256 mg, 1.67 mmol) was added followed by triethylamine (0.386 mL, 2.78 mmol).This was stirred at room temperature as a solution for 17 h before the reaction was partitioned between ethyl acetate and sat. NH4Cl.The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4.Purification by silica gel flash chromatography (ethyl acetate/heptanes followed by methanol/ethyl acetate) gave impure material.The residue was partitioned between ethyl acetate and sat. NaHCO3.The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4 and concentrated in vacuo to give (+/-)-3-({5-[3-methyl-1-(4'-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid ethyl ester (0.687 g, 94percent) as a clear oil. 1H NMR (400 MHz, CDCl3, 5): 8.17 (t, J=6.2 Hz, 1H) 8.09 (s, 2H) 7.62-7.73 (m, 4H) 7.56 (d, J=8.2 Hz, 2H) 7.40 (d, J=8.2 Hz, 2H) 4.53-4.58 (m, 1H) 4.44-4.52 (m, 1H) 4.11-4.19 (m, 2H) 3.72 (q, J=6.2 Hz, 2 H) 2.61 (t, J=6.0 Hz, 2H) 1.66-1.87 (m, 3H) 1.21-1.29 (m, 3H) 1.04 (d, J=6.0 Hz, 3H) 0.99 (d, J=5.9 Hz, 3H); MS (M+1): 529.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With 1,8-diazabicyclo[5.4.0]undec-7-ene;palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; molybdenum hexacarbonyl; In acetonitrile; at 170℃; for 0.0333333h;Microwave irradiation; | Step B:(+/-)-ethyl 3-(6-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)nicotinamido)propanoate5-Bromo-2-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)pyridine (81 mg, 0.180 mmol), <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (85 mg, 0.55 mmol), molybdenumhexacarbonyl (50 mg, 0.18 mmol), tri-tert-butylphosphonium tetrafluoroborate (8.4 mg, 0.028 mmol), palladium(II)acetate (2 mg, 9 mumol), and 1,8-diazabicycloundec-7-ene (150 muL, 1.1 mmol) were placed in a microwave vial and suspended in dry acetonitrile (2 mL).The vial was capped and heated by a Biotage Initiator microwave to 170° C. for 2 minutes.The resulting dark amber mixture was filtered through a 1" plug of silica gel, and eluted with ethyl acetate.The residue was concentrated and purification by column chromatography (0-100percent ethyl acetate in heptane) gave (+/-)-ethyl 3-(6-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)nicotinamido)propanoate (42 mg, 45percent) as a pale amber glass. 1H NMR (400 MHz, CDCl3, delta): 8.63 (dd, J=2.2, 0.9 Hz, 1H), 8.01-7.97 (m, 2H), 7.82 (s, 1H), 7.48-7.40 (m, 3H), 6.94-6.85 (m, 3H), 5.30 (dd, J=7.90, 4.8 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.74-3.68 (m, 2H), 2.65-2.60 (m, 2H), 2.05-1.87 (m, 2H), 1.63-1.39 (m, 2H), 1.28-1.23 (m, 3H), 0.96 (t, J=7.4 Hz, 3H). MS (M+1): 505.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 48h; | Step B:ethyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propanoate, Isomers 1 and 2To a mixture of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (418 mg, 2.72 mmol), 4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzoic acid (732 mg, 1.82 mmol), 1-hydroxybenzotriazole hydrate (292 mg, 1.91 mmol), and N,N-diisopropylethylamine (1.20 mL, 7.26 mmol) in tetrahydrofuran (18.2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (557 mg, 2.90 mmol).The mixture was stirred for 48 hours at ambient temperature.The reaction mixture was concentrated and the crude material was purified by column chromatography (0-100percent ethyl acetate in heptane) to afford racemic ethyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propanoate (684 mg, 85percent) as a solid.The racemate was further purified via chiral SFC to afford 300 mg of Isomer 1 and 300 mg of Isomer 2, which were used in conversion to the final enatiopure products. 1H NMR (400 MHz, CDCl3,delta): 7.94 (q, J=0.8 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 6.84 (t, J=5.8 Hz, 1H), 6.53 (d, J=8.8 Hz, 2H), 4.42-4.34 (m, 1H), 4.31 (d, J=4.7 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.71 (q, J=6.1 Hz, 2H), 2.63 (t, J=5.9 Hz, 2H), 1.88-1.71 (m, 2H), 1.53-1.31 (m, 2H), 1.27 (t, J=7.0 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.3% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | General procedure: trans-Cinnamic acid (1.49, 10.0 mmol) and HOBt (2.263 g, 15 mmol) were dissolved in DMF (50 mL). EDC.HCl (2.865 g, 15 mmol) was added, followed by beta-alanine ethyl ester hydrochloride (1.53 g, 10 mmol) and DIPEA (5.3 mL, 30 mmol) and the solution was stirred at RT for 16 h. The solvent was removed in vacuo and the residual oil was re-dissolved in EtOAc (100 mL), the organic phase was washed with 5percent w/v aqueous sodium hydrogen carbonate solution (2 ×100 mL) then 5percent w/v citric acid solution (2× 30 mL) and brine, before being dried on MgSO4. The solvent was evaporated in vacuo to afford the product (1.48 g, 59.8percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.7% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | General procedure: trans-Cinnamic acid (1.49, 10.0 mmol) and HOBt (2.263 g, 15 mmol) were dissolved in DMF (50 mL). EDC.HCl (2.865 g, 15 mmol) was added, followed by beta-alanine ethyl ester hydrochloride (1.53 g, 10 mmol) and DIPEA (5.3 mL, 30 mmol) and the solution was stirred at RT for 16 h. The solvent was removed in vacuo and the residual oil was re-dissolved in EtOAc (100 mL), the organic phase was washed with 5% w/v aqueous sodium hydrogen carbonate solution (2 ×100 mL) then 5% w/v citric acid solution (2× 30 mL) and brine, before being dried on MgSO4. The solvent was evaporated in vacuo to afford the product (1.48 g, 59.8% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | General procedure: trans-Cinnamic acid (1.49, 10.0 mmol) and HOBt (2.263 g, 15 mmol) were dissolved in DMF (50 mL). EDC.HCl (2.865 g, 15 mmol) was added, followed by beta-alanine ethyl ester hydrochloride (1.53 g, 10 mmol) and DIPEA (5.3 mL, 30 mmol) and the solution was stirred at RT for 16 h. The solvent was removed in vacuo and the residual oil was re-dissolved in EtOAc (100 mL), the organic phase was washed with 5percent w/v aqueous sodium hydrogen carbonate solution (2 ×100 mL) then 5percent w/v citric acid solution (2× 30 mL) and brine, before being dried on MgSO4. The solvent was evaporated in vacuo to afford the product (1.48 g, 59.8percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | General procedure: trans-Cinnamic acid (1.49, 10.0 mmol) and HOBt (2.263 g, 15 mmol) were dissolved in DMF (50 mL). EDC.HCl (2.865 g, 15 mmol) was added, followed by beta-alanine ethyl ester hydrochloride (1.53 g, 10 mmol) and DIPEA (5.3 mL, 30 mmol) and the solution was stirred at RT for 16 h. The solvent was removed in vacuo and the residual oil was re-dissolved in EtOAc (100 mL), the organic phase was washed with 5% w/v aqueous sodium hydrogen carbonate solution (2 ×100 mL) then 5% w/v citric acid solution (2× 30 mL) and brine, before being dried on MgSO4. The solvent was evaporated in vacuo to afford the product (1.48 g, 59.8% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 24h; | General procedure: To a solution of beta-alanine ethyl ester HCl (3.49 g, 22.72 mmol) and DMAP (4.26 g, 34.86 mmol) in anhydrous dichloromethane (20 mL) at 0 °C was added a solution of carboxylic acid 10 (2.58 g, 20.62 mmol) in anhydrous dichloromethane (15 mL) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (4.35 g, 22.69 mmol) dissolved in dichloromethane (10 mL). The solution was stirred at 0 C (4 h), then at room temperature (20 h). Concentration of the solvent under reduced pressure, addition of water, extraction with dichloromethane, drying (MgSO4), and concentration under reduced pressure afforded an oil which was purified on a silica gel column (3percent MeOH/dichloromethane) toafford the ester as a white solid (4.02 g, 87percent). mp = 136-137 °C; IR 3348, 2983, 2944, 1730, 1639, 1546 cm 1; 1H NMR delta 1.18 (3H, t, J = 7.1 Hz), 2.53 (2H, t, J = 7.1 Hz), 3.40 (2H, dt, J = 7.1, 5.5 Hz), 3.82 (3H, s), 4.06 (2H, q, J ¼ 7.1 Hz), 5.99 (1H, dd, J = 3.9, 2.6 Hz), 6.72 (1H, dd, J = 3.9, 1.7 Hz), 6.88 (1H, dd, J = 2.6, 1.7 Hz), 8.04 (1H, t, J = 5.5 Hz); 13C NMR (CDCl3) delta 14.6, 34.7, 34.9, 37.2, 61.2,107.6,112.0, 126.0, 128.4, 162.2, 173.3; LRMS (ES+) m/z 224.9 [M + H]+, 247.0 [M + Na]+. The ester was hydrolysed using the same method as compound 7 to yield the product as an off-white solid (86percent). mp = 136-137 °; IR 3398, 2976, 2546, 1721, 1714 cm-1 ; 1H NMR delta 2.47 (2H, t, J = 7.1 Hz), 3.37 (2H, dt, J = 7.1, 5.5 Hz), 3.82 (3H, s), 5.99 (1H, dd, J = 3.9, 2.6 Hz), 6.73 (1H, dd, J = 3.9, 1.7 Hz), 6.88 (1H, dd, J = 2.6, 1.7 Hz), 8.02 (1H, t, J = 5.5 Hz), 12.2 (1H, br s); 13C NMR 7.38 (2H, m), 7.56 (1H, d, J = 8.0 Hz), 8.33 (1H, d, J = 7.9 Hz), 8.79 (1H, t, J = 5.0), 11.12 (1H, s),11.80 (1H, s); 13C NMR delta 30.5, 37.8, 112.5, 112.7,120.9,124.5,124.7,125.1,130.0,136.6,154.0,164.6; LRMS (EI+) m/z = 229.1 [M]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In tetrahydrofuran; at 100℃; | Ethyl 3-(3-fluoro-2-nitrophenylamino)propionate (Step 1). A round bottomed flask was charged with <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (1 g, 6.51 mmol), l,3-difluoro-2- nitrobenzene (1.036 g, 6.51 mmol), potassium carbonate (2.70 g, 19.53 mmol), and a stirbar. THF (35 mL, 0.2 M) was added, and the mixture was stirred at 100 °C overnight. The mixture was concentrated with celite and purified by silica gel chromatography (eluting withhexanes/ethyl acetate) to yield ethyl 3-(3-fluoro-2-nitrophenylamino)propionate as a yellow amorphous solid (1.473g, 5.75 mmol, 88percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Example 187A. ethyl 3-(4-(3-(3,4-dichlorophenyl)propylcarbamoyl)-3-hydroxy-2- anoate[00235] To a solution of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (30.0 mg, 0.195 mmol) in methanol (3 mL) was added DIPEA (0.102 mL, 0.586 mmol) and paraformaldehyde (5.87 mg, 0.195 mmol). The reaction was heated to 60 °C for 5 min using microwave irradiation. The solution was cooled to rt and transferred to a second vessel charged with Intermediate 5 (70 mg, 0.195 mmol). The reaction mixture was heated to 100 °C for 15 min using microwave irradiation. After cooling to rt, the reaction was diluted with EtOAc (300 mL) containing 5percent citric acid (3 mL). The mixture was washed with a solution of saturated brine and water (1 : 1), dried over MgS04, filtered and evaporated to dryness in vacuo to provide crude Example 187A (84 mg, 90percent yield), which was carried onto the next step without further purification. HPLC/MS (Method C) RT = 2.90 min, [M+H]+ 430.0. | |
Example 187A. ethyl 3-(4-(3-(3,4-dichlorophenyl)propylcarbamoyl)-3-hydroxy-2- anoate [00207] To a solution of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (30.0 mg, 0.195 mmol) in methanol (3 mL) was added DIPEA (0.102 mL, 0.586 mmol) and paraformaldehyde (5.87 mg, 0.195 mmol). The reaction was heated to 60 °C for 5 min using microwave irradiation. The solution was cooled to rt and transferred to a second vessel charged with Intermediate 5 (70 mg, 0.195 mmol). The reaction mixture was heated to 100 °C for 15 min using microwave irradiation. After cooling to rt, the reaction was diluted with EtOAc (300 mL) containing 5percent citric acid (3 mL). The mixture was washed with a solution of saturated brine and water (1 : 1), dried over MgS04, filtered and evaporated to dryness in vacuo to provide crude Example 187A (84 mg, 90percent yield), which was carried onto the next step without further purification. HPLC/MS (Method C) RT = 2.90 min, [M+H]+ 430.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; dichloromethane; | Ethyl N-[6-chloro-2-(2-pyridinyl)-4-pyrimidinyl]-beta-alaninate Hunig's base (11.94 mL, 68.3 mmol) was added over 1 min to a stirred suspension of 4,6-dichloro-2-(pyridin-2-yl)pyrimidine (5.15 g, 22.78 mmol) and ethyl 3-aminopropanoate hydrochloride (3.85 g, 25.06 mmol) in 1,4-Dioxane (55 mL) at rt under N2. The resultant suspension was heated at 60 C for 6 h by which time a solution had formed and then allowed to stand at rt for 72 h. The solution was then reheated to 60 C for 3 h. Upon cooling, the solvent was evaporated under reduced pressure to give an orange oil. The oil was dissolved in CH2Cl2 (400 mL) and then washed with sat. aq. NaHCO3 (2 x 100 mL), brine (100 mL) and then passed through a hydrophobic frit. The solution was evaporated under reduced pressure to give an orange oil which was then dried under high vaccum at 40 C for 12 h to give the title compound as an orange solid (6.94 g, 99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | To a stirred solution of 7-(diethylamino)-2-oxo-2H-chromene-3-carboxylic acid (2.02 g, 7.73mmol) in dry DCM (160 mL) were added N-methylmorpholine(3.40 mL, 30.9 mmol) and TBTU (3.73 g, 11.6 mmol). After stirring for 30 min, ethyl3-aminopropanoate, chloride salt, (1.78 g, 11.6 mmol) was added tothe reaction mixture and stirring was continued at room temperature forapproximately 2.5 h under argon atmosphere. The reaction was followed on TLCchromatography plates using CH2Cl2/CH3OH (9/1) as the eluent. The reaction mixture was washedwith H2O (5 × 50 mL), and dried with anhydrous Na2SO4.The resulting crude product was purified by flash column chromatography usingCH2Cl2/MeOH (50/1). After evaporation of the solvent thedesired product was obtained as yellow crystals (1.63 g, 58percent): mp 129?133 °C. Rf(CH2Cl2:CH3OH, 20:1+ 3? CH3COOH) = 0.67. IR (KBr) 3811,3790, 3696, 3663, 3329, 3047, 2973, 2281, 1728, 1612, 1529, 1513, 1412, 1352,1267, 1230, 1190, 1135, 1075, 1017, 998, 794 cm-1. 1H-NMR (CDCl3, 300 MHz):delta 1.23-1.32 (m, 9H, 2 × -CH2CH3,-COO-CH2CH3), 2.66 (t, 2H, J = 6.52 Hz, -CONH-CH2CH2-COO-), 3.47(q, 4H, J = 7.11 Hz, 2 × -CH2CH3), 3.71-3.77(m, 2H, -CONH-CH2CH2-COO-), 4.20 (q, 2H, J= 7.14 Hz, -COO-CH2CH3), 6.51 (d, 1H, J =2.46 Hz, H8-Ar), 6.65 (dd, 1H, J1 = 2.48 Hz, J2= 8.95 Hz, H6-Ar), 7.43 (d, 1H, J = 8.93 Hz, H5-Ar),8.70 (s, 1H, H4-Ar), 9.08 (t, 1H, J = 5.89 Hz, -CONH-CH2CH2-COO-) ppm. 13C-NMR(CDCl3, 75 MHz): delta 12.77, 14.55, 29.99, 34.82, 35.59, 45.39, 60.96, 96.83, 108.61, 110.27, 110.46,131.40, 148.27, 152.87, 157.96, 162.82, 163.48, 172.15 ppm. HRMS (ESI): Calcd for C19H24N2O5 [M+H]+ 361.1763,found 361.1774. Anal. Calcd. for C19H24N2O5 ×0.33 THF: C 63.53; H 6.99; N 7.29. Found: C 63.88, H 6.92, N 7.57. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In acetonitrile; at 40℃; | Heat a solution of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (80.0 g, 0.52 mol), benzylbromide (186.7 g, 1.1 mol) and K2C03 (179.4 g, 1.3 mol) in acetonitrile (1 L) at 40 °C overnight. Concentrate the mixture to dryness, treat with water, extract with EtOAc (3x), wash the combined organics with brine, dry over Na2S04, concentrate to dryness and purify via silica gel chromatography (Pet Ether/EtOAc, 50: 1) to afford the title compound (150 g, 97 percent yield). 1H NMR (400 MHz, CDC13): delta 7.35-7.21 (m, 10 H), 4.09 (q, J= 7.2 Hz, 2 H), 3.58 (s, 4 H), 2.82 (t, J= 7.2 Hz, 2 H), 2.50 (t, J= 7.2 Hz, 2 H), 1.21 (t, J= 7.2 Hz, 3 H). |
97% | With potassium carbonate; In acetonitrile; at 40℃; | A solution of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (80.0 g, 0.52 mol), benzylbromide (186.7 g, 1.1 mol) and K2CO3 (179.4 g, 1.3 mol) in MeCN (1 L) was heated at 40° C. overnight. The mixture was concentrated to dryness, poured into water, extracted with EtOAc (3*) and the combined organics were washed with brine, dried over Na2SO4 and purified via silica gel chromatography to give ethyl 3-(dibenzylamino)propanoate (150 g, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | [00514] Step 1: A mixture of intermediate 243f (108 mg, 0.32 mmol, 1.0 eq), ethyl 3- aminopropanoate hydrochloride (100 mg, 0.65 mmol, 2.0 eq), HATU (246 mg, 0.65 mmol, 2.0 eq) and TEA (65 mg, 0.38 mmol. 2.0 eq) in DMF (3 mL) was stirred at rt for 1 h. The mixture was directly purified by reversed phase HPLC (MeCN/water~0.05percent ammonia) to give 271a (200 mg, 76percent) as a brown solid. ESI-MS (M+H)+: 618.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.5% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 16h; | Step 1: synthesis of ethyl 3- [(4-chloro-2-nitrophenyl)amino]propanoate A mixture of 4-chloro-1-fluoro-2-nitrobenzene (10.0 g, 57.0 mmol), ethyl 3-aminopropanoatehydrochloride (8.75 g, 57.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (36.0 g, 0.285 mol) in tetrahydrofuran (150 mL) was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water and then extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water (200 mL x 3), and then dried over Na2504, then filtered andconcentrated in vacuo. The residue was purified by flash chromatography (EtOAc:PE = 1:2) toafford ethyl 3- [(4-chloro-2-nitrophenyl)amino]propanoate (10. Og, yield: 64.5percent). |
64.5% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 16h; | Step 1: synthesis of ethyl 3-[(4-chloro-2-nitrophenyl)amino]propanoate A mixture of 4-chloro-1-fluoro-2-nitrobenzene (10.0 g, 57.0 mmol), <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (8.75 g, 57.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (36.0 g, 0.285 mol) in tetrahydrofuran (150 mL) was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water and then extracted with EtOAc (200 mL*3). The combined organic layers were washed with water (200 mL*3), and then dried over Na2SO4, then filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc:PE=1:2) to afford ethyl 3-[(4-chloro-2-nitrophenyl)amino]propanoate (10.0 g, yield: 64.5percent). |
64.5% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 16h; | A mixture of 4-chloro-1-fluoro-2-nitrobenzene (10.0 g, 57.0 mmol), <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (8.75 g, 57.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (36.0 g, 0.285 mol) in tetrahydrofuran (150 mL) was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water and then extracted with EtOAc (200 mL×3). The combined organic layers were washed with water (200 mL×3), and then dried over Na2SO4, then filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc:PE=1:2) to afford ethyl 3-[(4-chloro-2-nitrophenyl)amino]propanoate (10.0 g, yield: 64.5percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | General procedure: Ethyl 3-(pentacosa-10,12-diynoylamido)propanoate (EPCDP): 10,12-Pentacosadiynoic acid (0.38g, 1.0mmol) and 1-hydroxybenzotriazole hydrate (HOBt·H2O; 0.20g, 1.5mmol) were stirred to dissolve in CH2Cl2 (3mL). The solution was then added with a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC; 0.29g, 1.5mmol) in CH2Cl2 (5mL) and stirred for 1h. The mixture of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (0.18g, 1.2mmol) and triethylamine (0.56mL, 4.0mmol) in CH2Cl2 (5mL) was added dropwise into the mixture at 0°C. The resulting mixture was stirred at room temperature for 3h. The mixture was evaporated and the crude product was eluted through a silica gel column using hexane and ethyl acetate (1:1v/v) as the eluent. After the solvent removal, ethyl-3-pentacosa-10,12-diynamidopropanoate (EPCDP) was obtained as a white solid (0.41g, 87percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | General procedure: Ethyl 3-(pentacosa-10,12-diynoylamido)propanoate (EPCDP): 10,12-Pentacosadiynoic acid (0.38g, 1.0mmol) and 1-hydroxybenzotriazole hydrate (HOBt·H2O; 0.20g, 1.5mmol) were stirred to dissolve in CH2Cl2 (3mL). The solution was then added with a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC; 0.29g, 1.5mmol) in CH2Cl2 (5mL) and stirred for 1h. The mixture of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (0.18g, 1.2mmol) and triethylamine (0.56mL, 4.0mmol) in CH2Cl2 (5mL) was added dropwise into the mixture at 0°C. The resulting mixture was stirred at room temperature for 3h. The mixture was evaporated and the crude product was eluted through a silica gel column using hexane and ethyl acetate (1:1v/v) as the eluent. After the solvent removal, ethyl-3-pentacosa-10,12-diynamidopropanoate (EPCDP) was obtained as a white solid (0.41g, 87percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: Ethyl 3-(pentacosa-10,12-diynoylamido)propanoate (EPCDP): 10,12-Pentacosadiynoic acid (0.38g, 1.0mmol) and 1-hydroxybenzotriazole hydrate (HOBt·H2O; 0.20g, 1.5mmol) were stirred to dissolve in CH2Cl2 (3mL). The solution was then added with a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC; 0.29g, 1.5mmol) in CH2Cl2 (5mL) and stirred for 1h. The mixture of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (0.18g, 1.2mmol) and triethylamine (0.56mL, 4.0mmol) in CH2Cl2 (5mL) was added dropwise into the mixture at 0°C. The resulting mixture was stirred at room temperature for 3h. The mixture was evaporated and the crude product was eluted through a silica gel column using hexane and ethyl acetate (1:1v/v) as the eluent. After the solvent removal, ethyl-3-pentacosa-10,12-diynamidopropanoate (EPCDP) was obtained as a white solid (0.41g, 87percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | General procedure: Ethyl 3-(pentacosa-10,12-diynoylamido)propanoate (EPCDP): 10,12-Pentacosadiynoic acid (0.38g, 1.0mmol) and 1-hydroxybenzotriazole hydrate (HOBt·H2O; 0.20g, 1.5mmol) were stirred to dissolve in CH2Cl2 (3mL). The solution was then added with a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC; 0.29g, 1.5mmol) in CH2Cl2 (5mL) and stirred for 1h. The mixture of <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (0.18g, 1.2mmol) and triethylamine (0.56mL, 4.0mmol) in CH2Cl2 (5mL) was added dropwise into the mixture at 0°C. The resulting mixture was stirred at room temperature for 3h. The mixture was evaporated and the crude product was eluted through a silica gel column using hexane and ethyl acetate (1:1v/v) as the eluent. After the solvent removal, ethyl-3-pentacosa-10,12-diynamidopropanoate (EPCDP) was obtained as a white solid (0.41g, 87percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 90℃; for 24h; | 3-[ 4-(N-methoxy-N-methyl-amino )-6-prop-2-ynylamino-[ 1, 3, 5 ]triazin-2-ylamino ]- propionic acid ethyl ester (135): A mixture of of N-(4-chloro-6-prop-2-ynylamino-[l,3,5]triazin-2-yl)- 0,N-dimetnyl-hydroxylamine (2) (500 mg, 2.20 mmol), beta-alanine ethyl ester hydrochloride (676 mg, 4.40 mmol) and N,N-diisopropylethylamine (1.14 mL, 6.60 mmol) in 1,4-dioxane (10 mL) was heated at 90°C for 24 h. A saturated NaHC03 solution (30 mL) was added and the resulting suspension was extracted with CH2CI2 (3 x 30 mL). The combined organic extracts were washed with water (75 mL) and dried over solid anhydrous Na2S04. After filtration, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99: 1) to CH2Cl2/EtOH (95 :5) to yield 3-[4-(N- methoxy-N-methyl-amino)-6-prop-2-ynylamino-[l ,3,5]triazin-2-ylamino]-propionic acid ethyl ester (135) (580 mg, 86percent). 400 MHz 1H NMR (CDC13, ppm): delta 5.37 (IH, br s), 5.06 (IH, br s), 4.25-4.15 (2H, m), 4.15 (2H, q, J=7.1 Hz), 3.76 (3H, s), 3.72- 3.61 (2H, m), 3.28 (3H, s), 2.60 (2H, t, J=6.1 Hz), 2.20 (IH, t, J=2.4 Hz), 1.26 (3H, t, J=7.1 Hz). ESI-MS (m/z): 309 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20 - 80℃; for 4h; | Example 79: Ethyl 3-((4-bromothiazol-2-yl)methylamino)propanoate [00229] A mixture of <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (1.91 g, 10.0 mmol, 1.0 eq), ethyl 3-aminopropanoate HC1 (1.75 g, 15.0 mmol, 1.5 eq) in DCE (30 mL) was stirred at 80C for 2 h. The mixture was cooled down to rt, and NaBH(AcO)3 (5.3 g, 25.0 mmol, 2.5 eq) was added, the resultant mixture was stirred at rt for 2 h. The reaction mixture was diluted with EA (60 mL), followed by filtration, the filtrate was concerntrated in vacuo, and the residue was purified by column chromatography on silica gel (PE/EA = 5/1) to give the title compound as a yellow oil (1.1 g, 37% yield). LCMS mlz 293.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine; In ethanol; at 80℃; for 72h; | To a mixture of 30 (5.00 g, 29.0 mmol) in EtOH (50 mL) were added beta-alanine ethyl ester hydrochloride (11.1 g, 72.4 mmol) and triethylamine (20.2 mL, 145 mmol), and the mixture was stirred at 80 °C for 3 days. The mixture was concentrated in vacuo. The residue was diluted with 50percent EtOAc/n-hexane, and the resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo and purified by flash column chromatography (silica gel, 0-30percent EtOAc in n-hexane) to give 31 (6.03 g, 82percent) as a yellow oil. 1H NMR (DMSO-d6) delta 1.16 (t, 3H, J = 7.1 Hz), 2.36-2.38 (m, 4H) 2.59 (t, 2H, J = 6.9 Hz), 3.67 (q, 2H, J = 6.9 Hz), 4.05 (q, 2H, J = 7.1 Hz), 6.64 (d, 1H, J = 5.0 Hz), 8.16 (d, 1H, J = 5.0 Hz); MS (ESI) m/z 254 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In a centrifuge tube beta-alanine ethyl ester hydrochloride (11.27 g, 73 mmol) dissolved in 70 mL N,N-dimethylformamide(DMF) and a solution of triethylamine (5.93 g, 59 mmol) in 20 mL DMF was added. The tube was shaken immediately and allowed to stand for 1 h at room temperature.The precipitate was removed by centrifugation and the clear solution of beta-alanine ethyl ester (2) was mixed with N-tertbutoxycarbonyl-1,2-ethanediamine (3, 11.73 g, 73 mmol), dissolved in 60 mL DMF.The solution of the amines 2 and 3 was added rapidly under vigorous stirring to cellulose phenyl carbonate 1 (10 g, DS 1.92, 49 mmol carbonate) dissolved in 150 mL DMF. The reaction mixture was allowed to react for 24 h at 60 °C. After precipitation into 2.5 L of water, the product was isolated by filtration.The product was washed three times with 1 L of water and dried in vacuum at 40 °C. Yield: 90percent, DSbeta-alanine ester 0.88, DSBoc-EDA 0.95 (determined by elemental analysis from nitrogen content assuming a total DS of 1.83 according to a conversion of carbonate of 95percent [21]), FTIR (KBr): 1716 cm (nuC=O, carbamate and ester); 13C NMR (100 MHz, MeOD) delta172.0 (C=O, ester), 157.0 (C=O, carbamate), 103.0 (C-1), 101.4(C-1'), 83?74 (C-2, C-3, C-4, C-5), 78.8 (CMe3), 63.0 (C-6),60.4 (OCH2), 40.5 (CH2), 39.9 (CH2), 36.5 (CH2), 34.1 (CH2),27.5 (C(CH3)3), 13.2 (CH3) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; | Example 174 [0591] ethyl 3-aminopropanoate, HCl salt (300 mg, 1.95 mmol) in dichloromethane (25.0 mL) and triethylamine (0.817 mL, 5.86 mmol) was treated at 0 C. with <strong>[42926-52-3]2-ethoxybenzoyl chloride</strong> (361 mg, 1.95 mmol). The reaction mixture was stirred at 0 C. for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-100% of EtOAc in hexanes to give 478 mg (92%) of the title product as a colorless oil which was used directly in the next reaction without further purification. LC-MS Retention Time: t2 (Method 2)=3.346 min; m/z (M+H)+ 266.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.13 g | Reference Example F-1 Ethyl N-[4-(1H-benzotriazol-1-ylmethoxy)benzyl]-beta-alaninate To a mixture of 1H-benzotriazole-1-methanol (1.22 g), 4-hydroxybenzaldehyde (1.00 g), triphenylphosphine (2.26 g) and chloroform (27 mL), diisopropyl azodicarboxylate (1.9 mol/L, solution in toluene, 4.53 mL) was added under cooling with ice. After being brought to room temperature, the mixture was stirred for 2.5 hours. Following the addition of triphenylphosphine (1.13 g) and diisopropyl azodicarboxylate (1.9 mol/L, solution in toluene, 2.27 mL), the mixture was stirred for an additional 40 minutes. To the reaction mixture, methanol (165 muL) and acetic acid (750 muL) were added and the resulting mixture was stirred at the same temperature for 20 minutes. To the reaction mixture, beta-alanine ethyl hydrochloride (1.38 g), triethylamine (1.26 muL) and sodium triacetoxyborohydride (2.60 g) were added and the mixture was stirred at room temperature for 1.5 hours. After adding 1 mol/L hydrochloric acid, the mixture was washed with diethyl ether. To the aqueous layer, an aqueous solution of 2 mol/L sodium hydroxide was added to provide a basic pH. Following extraction with chloroform, the combined organic layers were washed with saturated brine and thereafter passed through a phase separator for concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 100:0-50:50) to give the titled compound as a colorless oil (1.13 g). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.24 (t, J=7.1 Hz, 3 H) 2.47 - 2.52 (m, 2 H) 2.81 - 2.87 (m, 2 H) 3.71 (s, 2 H) 4.12 (q, J=7.1 Hz, 2 H) 6.54 (s, 2 H) 6.99 - 7.06 (m, 2 H) 7.19 - 7.25 (m, 2 H) 7.40 (ddd, J=8.3, 7.0, 1.0 Hz, 1 H) 7.53 (ddd, J=8.3, 7.0, 1.0, Hz, 1 H) 7.70 (dt, J=8.3, 1.0 Hz, 1 H) 8.07 (dt, J=8.3, 1.0 Hz, 1 H). MS ESI/APCI Dual posi: 355[M+H]+, 377[M+Na]+. MS ESI/APCI Dual nega: 353[M-H]-, 389[M+Cl]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium hydroxide; In methanol; water; dimethyl sulfoxide; at 20℃; for 2h; | General procedure: 1,4-Naphthoquinone (1, 14 mmol) dissolved in DMSO (20 mL) and the appropriate ethyl ester amino acid hydrochloride (15 mmol) dissolved in water (10 mL) were mixed in an Erlenmeyer flask at room temperature. The resulting mixture was immediately added to a stirred 3N solution of KOH (5 mL) in MeOH. This mixture was left under stirring and the reaction completion was monitored by TLC. After vacuum filtration the mixture was acidified by means of HCl (10percent), and the precipitate formed was vacuum filtered and washed with cooled water. The residue was chromatographed on silica gel column with n-hexane-CH2Cl2 (100:0 to 50:50 v/v) as eluent to afford the target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In toluene; at 20℃; for 39h;Cooling with ice; | About 7.23 g of ethyl 3-aminopropionate hydrochloride, 15.71 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 23.00 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 39 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl 3-[bis(trimethylsilyl)amino]propionate (3-BTMSAEP) as a colorless oil (11.03 g, 90percent yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: delta 3.91 (quartet, 2H, OCH2 protons), 3.21 (multiplet, 2H, NCH2CH2 protons), 2.36 (multiplet, 2H, NCH2CH2 protons), 0.91 (triplet, 3H, CH3 protons), 0.07 (singlet, 18H, Si-CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.4% | With HOAT; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | At room temperature,The intermediate from step J (65 mg, 0.126 mmol), HOAt (25 mg, 0.184 mmol) was added separately to DMF,Beta] -alanine ethyl ester hydrochloride (34 mg, 0.184 mmol), DIEA (64 [mu] L, 0.37 mmol) and EDCI (36 mg, 0.184 mmol).The reaction was allowed to proceed overnight at room temperature and quenched by addition of water.And extracted with ethyl acetate.The organic phase was washed with saturated brine,Dried over anhydrous sodium sulfate,The crude product obtained after concentration was separated by column chromatography (petroleum ether: ethyl acetate = 3: 1) to give the title compound (70 mg, 90.4percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In chloroform; at 5 - 10℃; | Beta-alanine ethyl ester hydrochloride(Manufactured by Tokyo Chemical Industry Co., Ltd.)And 1.17 g of triethylamine were stirred in 80 mL of chloroform,And cooled to 5 ° C.To this end,(1-20-a)The total amount of the wet cake,Was added at an internal temperature of 10 ° C. The reaction solution was subjected to TLCLayer chromatography (silica gel, developing solvent, chloroform / methanol = 85/15, v/ V), and then triethylamine was added until the reaction was completed.After the reaction solution was washed with water, the solution was filtered through a column chromatography (filler: silica gel, developing solvent85/15, v / v) to obtain the intermediate (1-20-bThe yield was 5.0 g (yield: 85percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | To a round bottom flask was added 213.2 mg (0.49 mmol) of 6a, 97.3 mg (1.23 mmol) of pyridine, and 10 mL of CH2C12. 140.9 mg (1.23 mmol) of MsC1 was added to the solution at 0 °C. After 30 minutes, 188.9 mg (1.23 mmol) of betaalanine ethyl ester hydrochloride and 97.3 mg (1.23 mmol) of pyridine in 10 mL of CH2C12 was added to the solution and warmed to 25 °C. After 1 h, the solution was dried in vacuo and triturated with ethyl acetate several times to give 9 (240 mg, 91 percent isolated yield).Physical Property: White solid, m.p. = 304-305 C.TLC: Rf= 0.23 (silica gel, 50percent ethyl acetate/hexanes).?H NMR (500 MHz, (CD3)2C0) oe 8.92 (d, 3H, J = 2.2 Hz), 8.19-8.12 (bs, 1H), 8.09 (dd, 3H,= 8.2, 2.2 Hz), 7.90 (d, 3H, J = 8.2 Hz), 6.40 (s, 1H), 4.19 (q, 2H, J = 7.2 Hz), 4. 14-4.08 (m, 2H), 2.99 (t, 2H, J = 6.6 Hz), 1.25 (t, 3H, J = 7.2 Hz).?3c NMR (125 MHz, (CD3)2C0) oe 171.3, 166.6, 150.5, 146.1, 144.5, 125.5, 122.4, 120.4, 60.2, 60.0, 53.1, 35.9, 33.6, 13.6.JR (neat): 3301, 2924, 1722, 1668, 1521, 1342, 1261, 1203, 1031, 800 cmi. HRMS (ESJ) calculated for C26H20N4NaO9 + [M+Naj 555.1122, found 555.1127. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine; In dichloromethane; at 20℃; for 4h; | General procedure: A solution of triethylamine (23.6 mmol, 3.2 mL) in CH2Cl2(5.5 mL) was added dropwise, under stirring to a mixture ofthe correspondent alanine methyl ester hydrochlorideenantiomer (3.2 mmol, 0.45 g) and methyl 3-(chlorosulfonyl)thiophene-2-carboxylate (3.2 mmol, 0.77 g). The reaction was stirred at r.t. for 4 h. After removing the solventunder reduced pressure, 1 N HCl (50 mL) was addedand the product was extracted with ethyl acetate (3 × 15mL). The combined organic layers, washed with NaHCO30.3M (6 mL) and water (2 × 10 mL), were dried withanhydrous Na2SO4. After concentration under reducedpressure, the product was obtained as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20℃; | General procedure: Compound 11 (0.40 mL, 3.1 mmol) was added to a solution ofDIPEA (0.80 mL, 4.6 mmol) and compound 12a (0.23 mL, 3.1 mmol)in DMA (5 mL) at 0 C. The mixture was stirred at rt overnight. Thereaction mixture was poured into water and extracted with EtOAc.The organic layer was separated, washed with water and brine,dried over MgSO4, and concentrated in vacuo. The residue waspurified by silica gel column chromatography (hexane:EtOAc = 4:1 to 1:1) to give compound 13a (723 mg, 2.73 mmol, 89percent) as anorange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In ethyl acetate; at 20℃; for 63h;Inert atmosphere; | Nitropyrrole 2 (30.00 g, 0.11 mol) was takenin a 500 mL round-bottom one-neck flask followed by additionof beta-alanine tert-butyl ester hydrochloride (17.05, 0.11 mol)and EtOAc (100 mL) that had been dried over sieves. TEA(35.5 mL, 0.25 mol) was dissolved in EtOAc (50 mL) driedover sieves, and this mixture was added dropwise to thereaction mixture, while being stirred over a period of 15 hunder a nitrogen atmosphere. The reaction mixtur was thenstirred for an additional 48 h, during which a white precipitatewas formed. The precipitate was removed by filtration, and thefiltrate was washed with 1 M HCl (2 × 100 mL) and DI water(1 × 100 mL). The organic layer was then dried over MgSO4and filtered and the solution concentrated by rotaryevaporation to give 10 as a yellow solid (0.197 g, 90percent yield).Mp: 103?105 °C. TLC (EtOAc): Rf = 0.66. 1H NMR (DMSOd6):delta 7.53 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.83 (t,J = 5.6 Hz, 1H), 3.95 (s, 3H), 3.56 (t, J = 6.4 Hz, 2H), 2.50 (t, J= 6.4 Hz, 2H), 1.42 (s, 9H). 13C NMR: delta 171.29, 159.67,134.28, 126.14, 125.80, 106.39, 80.83, 37.27, 34.50, 34.33,27.50. IR: 3408.5, 3347.2, 3147.8, 3135.2, 3123.5, 3116.2,3000.8, 2978.1, 2945.8, 1722.5, 1647.9, 1547.8, 1523.7, 1497.2,1417.3, 1368.3, 1311.1, 1267.7, 1221.3, 1151.5, 1111.7, 986.4,901.5, 873.8, 856.5, 842.6, 832.9, 821.5, 750.6, 596.3, 557.1.HRMS (ESI): m/z for C13H19N3O5 [M + Na]+ calcd 320.1217,found 320.1216. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.7% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h; | 1-(1-(2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)butyl)-1H-imidazole-5-carboxylic acid 12f(3.0g, 7.27mmol),Ethyl 3-aminopropanoate hydrochloride (1.72 g, 14.54 mmol),2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.53 g, 14.54 mmol)And N,N-diisopropylethylamine (6.30 mL, 36.35 mmol) was dissolved in 60 mL of N,N-dimethylformamide,The reaction was performed at room temperature for 3 hours.The reaction solution was diluted with ethyl acetate (300 mL) and the organic phase was washed with saturated sodium chloride solution (200 mL x 3).Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to give 3-(1-(1-(2',4',6 Ethyl trimethyl-[1,1'-biphenyl]-4-yl)butyl)-1H-indazole-5-carboxamido)propanoate, 12 g (3.60 g, white solid), yield : 96.7percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | 1-(1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)butyl)-1H-imidazole-5-carboxylic acid 1 g (328 mg,0.748 mmol) <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (172 mg, 1.12 mmol),1-Hydroxybenzotriazole (202 mg, 1.496 mmol),1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (287 mg, 1.496 mmol)And N,N-diisopropylethylamine (0.554 mL, 3.74 mmol)It was dissolved in 15 mL of N,N-dimethylformamide and reacted at room temperature for 12 hours.Add 200 mL of ethyl acetate, wash with water (100 mL × 3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure.3-(1-(1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)butyl)-1H-indazole-5-carboxamido) C Ethyl acetate 1h(372 mg, yellow oil), yield: 92.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; In acetonitrile; at 20℃; for 8h; | To a solution of 8.9 g of 2,2,2-trichloro-1-(pyridin-2-yl)ethanone in 150 ml of anhydrous acetonitrile, 7.38 g of ethyl beta-alanine hydrochloride and 8 ml of three Ethylamine was stirred for 8 hours at room temperature until the conversion of the raw material was complete. The solvent was removed by rotary evaporation and 40 mL of 2N NaOH solution was added. The mixture was stirred at room temperature for 10 hours.The liquid was extracted with ethyl acetate, the organic phase was washed with water, 1N HCl solution and saturated brine, dried over anhydrous Na 2 SO 4 , and the solvent was removed by evaporation under reduced pressure to give compound 3-(pyridinecarboxamide)propionic acid (6.9 g, Yield 89percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃; for 1h; | To a solution of benzoic acid 5 (674mg, 1.85mmol), beta-alanine ethyl ester hydrochloride (567mg, 3.69mmol), HOBt (565mg, 3.69mmol) and EDCI (708mg, 3.69mmol) in anhydrous DMF (9ml) was added DIEA (0.90ml, 5.54mmol). The reaction was stirred at 50°C for 1h. After cooling, the reaction mixture was diluted with EtOAc (300ml), and the organic layer was washed with H2O, brine and dried over MgSO4. The solution was filtered and the solvent was removed under reduced pressure. The residue was purified by SiO2 flash column chromatography to afford the desired product 5 (774mg, 90percent yield) as colorless oil. 1H NMR (600MHz, CDCl3) delta (ppm): 8.44 (s, 2H), 7.71 (d, J=8.4Hz, 2H), 7.46 (d, J=8.4Hz, 2H), 6.82 (t, J=5.4Hz, 1H), 5.91 (q, J=5.4, 7.8Hz, 1H), 4.16 (q, J=7.2, 14.4Hz, 2H), 3.71 (q, J=6, 12Hz, 2H), 2.62 (t, J=6Hz, 2H), 2.11?2.05 (m, 1H), 1.90?1.84 (m, 1H), 1.46?1.41 (m, 1H), 1.37?1.32 (m, 3H), 1.27 (t, J=7.2Hz, 3H), 0.88 (t, J=6.6Hz, 3H); 13C NMR (150MHz, CDCl3) delta (ppm): 172.9, 166.9, 163.3, 159.6, 144.8, 133.8, 127.0, 126.7, 111.9, 79.3, 60.8, 36.6, 35.3, 33.9, 27.6, 22.4, 12.2, 13.9; HRMS (ESI-TOF) m/z [M+H]+ calculated for C21H27BrN3O4+ 464.1179, found 464.1172. |
[ 3196-73-4 ]
Methyl 3-aminopropanoate hydrochloride
Similarity: 0.92
[ 6937-16-2 ]
Ethyl 4-aminobutanoate hydrochloride
Similarity: 0.80
[ 24549-12-0 ]
Methyl 3-(methylamino)propanoate
Similarity: 0.79
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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 |
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