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CAS No. : | 3014-80-0 | MDL No. : | MFCD00039085 |
Formula : | C5H13ClN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XFCNYSGKNAWXFL-WCCKRBBISA-N |
M.W : | 152.62 | Pubchem ID : | 13689583 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 38.73 |
TPSA : | 69.11 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.95 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.4 |
Log Po/w (WLOGP) : | 0.26 |
Log Po/w (MLOGP) : | -0.01 |
Log Po/w (SILICOS-IT) : | -0.78 |
Consensus Log Po/w : | -0.03 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.91 |
Solubility : | 18.9 mg/ml ; 0.124 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.42 |
Solubility : | 5.83 mg/ml ; 0.0382 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.07 |
Solubility : | 180.0 mg/ml ; 1.18 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.3 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
49% | With hydrogenchloride; sodium hydroxide; ammonia In hexane; dichloromethane | EXAMPLE 9 Preparation of (S)-2-amino-3-methylbutanamide hydrochloride Anhydrous ammonia was bubbled through 150 mL of methylene chloride cooled to 0° C. (ice-bath) until the solution was saturated. To this mixture cooled to 5° C. and under N2 was added dropwise trimethylaluminum (136.2 mL of a 2M solution in hexane, 272.4 mmol) available from Aldrich Chemical Co., (Milwaukee, Wis.). The resultant cloudly solution was allowed to warm to room temperature and stirred for 22 h. L-Valine (10.6 g, 90.79 mmol) was added portionwise and stirred for 18 h at room temperature. To this mixture, cooled to 0° C. (ice-water bath), was then added dropwise 190 mL of 6 N HCl until the pH was 2. The resultant mixture allowed to warm and stirred for 2 hours and then made basic (pH=11-12) with 50percent aqueous NaOH. To the basic solution was added 100 mL of methylene chloride and 100 mL of H2 O. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to dryness. The resultant residue was dissolved in 100 mL of methylene chloride and acidified with HCl gas. The solid that formed was filtered and dried under reduced pressure to give 6.8 g (49percent) of the title compound, mp 258°-260° C. IR (Nujol, cm-1), C=O (1686), N--H (3387, 3241). 1 H NMR and 13 C NMR (CDCl3) consistent with title product. Analysis calculated for C5 H13 ClN2 O: C, 39.35; H, 8.59; N, 18.35; Cl, 23.23; Found: C, 39.82; H, 8.52; N, 18.40; Cl, 23.13. MS: m/e 117 (M+ -Cl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In water; | <strong>[3014-80-0]L-valinamide hydrochloride</strong> (2.50 g, 16.4 mmol) was treated with a saturated solution OF K2C03 (75 mL). The mixture was extracted with EtOAc (3 x 75 mL). The organic extracts were combined, dried over NA2S04. The solid material was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The residual material was dried in vacuo. To a solution of L-valinamide (1.57 g, 13.5 mmol) in tetrahydrofuran (20 mL) was slowly added 1,3-propane sultone (1.61 g, 12.9 MMOL). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2 x 25 mL). The crude product was dissolved in water (60 mL) and treated with ion exchange resin Dowex Marathon C (strongly acidic, 15 g). The mixture was stirred for 15 minutes. The resin was removed by filtration. The filtrate was poured into EtOH (250 mL). The solid product, after the completion of the precipitation, was collected by filtration, and dried in vacuo, to afford compound EQ (1.6 g, 51percent). IH NMR (D2O, 500 MHz) No. PPM 3.63 (d, 1H), 3.05 (m, 2H), 2. 85 (m, 2H), 2.05 (m, 4H), 0.93 (d, 3H), 0. 88 (d, 3H). L3C NMR (D20, 125 MHZ) 5 PPM 170. 24., 65.92, 48.16, 46.31, 29.59, 21.31, 18.02, 17.07. [a] D= + 10. 5 ° (c= 0.0027 in water), ES-MS 237 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide; In DMF (N,N-dimethyl-formamide); dichloromethane; at 20℃; | Step I Fmoc-3-naphthalen-1-yl-D-alanine (2.01 g, 437.5 g/mol, 4.60 mmol, 1 eq) and DIPEA (783 lli, 129.12 g/mol, 0.755 g/cm3, 4.6 mmol, 1 eq) were dissolved in 20 ml of dry DCM. DCC (0.95 g, 206.33 g/mol, 4.58 mmol, 1 eq) and HOBt (0.70 g, 153.12 g/mol, 4.58 mmol, 1 eq) was added before the mixture was stirred at ambient temperature for 15 minutes. A solution of L- valine amide hydrochloride (0.70 g, 152.7 g/mol, 4.58 mmol, 1 eq) and DIPEA (783 pI, 129.12 g/mol, 0.755 g/cm3, 4.6 mmol, 1 eq) in dry DMF (20 ml) was added to the reaction mixture and the solution was stirred overnight at ambient temperature. Formed precipitation was filtered and washed with DCM. The compound was purified by slurrying the precipitation twice with MeOH (75 mi + 150 ml) after which the filtered precipitation was dried at ambient temperature yielding 1.84 g (75 percent) of the product, (2R)-2-(Fmoc-2-amino-3-naphthalen-1- ylpropionylamino)-3-methylbutyramide. MS-ESI+ (m/z): 536 [M+H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.8 g (49%) | With hydrogenchloride; sodium hydroxide; ammonia; In hexane; dichloromethane; | EXAMPLE 9 Preparation of (S)-2-amino-3-methylbutanamide hydrochloride Anhydrous ammonia was bubbled through 150 mL of methylene chloride cooled to 0° C. (ice-bath) until the solution was saturated. To this mixture cooled to 5° C. and under N2 was added dropwise trimethylaluminum (136.2 mL of a 2M solution in hexane, 272.4 mmol) available from Aldrich Chemical Co., (Milwaukee, Wis.). The resultant cloudly solution was allowed to warm to room temperature and stirred for 22 h. L-Valine (10.6 g, 90.79 mmol) was added portionwise and stirred for 18 h at room temperature. To this mixture, cooled to 0° C. (ice-water bath), was then added dropwise 190 mL of 6 N HCl until the pH was 2. The resultant mixture allowed to warm and stirred for 2 hours and then made basic (pH=11-12) with 50percent aqueous NaOH. To the basic solution was added 100 mL of methylene chloride and 100 mL of H2 O. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to dryness. The resultant residue was dissolved in 100 mL of methylene chloride and acidified with HCl gas. The solid that formed was filtered and dried under reduced pressure to give 6.8 g (49percent) of the title compound, mp 258°-260° C. IR (Nujol, cm-1), C=O (1686), N--H (3387, 3241). 1 H NMR and 13 C NMR (CDCl3) consistent with title product. Analysis calculated for C5 H13 ClN2 O: C, 39.35; H, 8.59; N, 18.35; Cl, 23.23; Found: C, 39.82; H, 8.52; N, 18.40; Cl, 23.13. MS: m/e 117 (M+ -Cl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | (2) 2-Amino-3-methylbutyramide hydrochloride To a solution of 1-carbamoyl-2-methylcarbamic acid t-butyl ester (2.81 g, 13.0 mmol) (obtained as described in Reference Example 47(1)) in 1,4-dioxane (28 ml) was added a solution of 4N hydrogen chloride in 1,4-dioxane (28 ml) in an ice bath, and then the mixture was stirred at room temperature overnight. After checking the completion of the reaction, ethyl acetate was added thereto, the reaction mixture was filtered and the obtained residue washed with ethyl acetate and dried to give (2S)-2-amino-3-methylbutyramide hydrochloride (1.94 g, yield 98percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 52 Synthesis of N'-[N-(Phenylacetyl)-L-alaninyl)-L-valinamide Following General Procedure T and using N-(phenylacetyl)-L-alanine (from Example B1 above) and <strong>[3014-80-0]L-valinamide hydrochloride</strong> (Bachem), the title compound was prepared as a solid (mp=>261° C.). NMR data was as follows: 1H-nmr (DMSO-d6): delta=8.31 (d, J=7.5 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.15-7.30 (m, 5H), 7.05 (s, 1H), 4.34 (quintet, J=7.2 Hz, 1H), 4.08 (dd, J=6.4, 15.3 Hz, 1H), 3.45 (s, 2H), 1.91 (m, 1H), 1.19 (d, J=7.0 Hz, 3H), 0.79 (d, J=6.7 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H). 13C-nmr (DMSO-d6): delta=172.8, 172.1, 170.0, 136.3, 129.0, 128.2, 126.3, 57.2, 48.2, 42.0, 30.5, 19.2, 17.9, 17.8. | ||
Example 52 Synthesis of N'-[N-(Phenylacetyl)-L-alaninyl]-L-valinamide Following General Procedure T and using N-(phenylacetyl)-L-alanine (from Example B1 above) and <strong>[3014-80-0]L-valinamide hydrochloride</strong> (Bachem), the title compound was prepared as a solid (mp=>261 ° C.). NMR data was as follows: 1H-nmr (DMSO-d6): delta=8.31 (d, J=7.5 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.15-7.30 (m, 5H), 7.05 (s, 1H), 4.34 (quintet, J=7.2 Hz, 1H), 4.08 (dd, J=6.4, 15.3 Hz, 1H), 3.45 (s, 2H), 1.91 (m, 1H), 1.19 (d, J=7.0 Hz, 3H), 0.79 (d, J=6.7 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H). 13C-nmr DMSO-d6): delta=172.8, 172.1, 170.0, 136.3, 129.0, 128.2, 126.3, 57.2, 48.2, 42.0, 30.5, 19.2, 17.9, 17.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In acetonitrile; at 80℃; for 24h; | 4-Chloro-2-chloromethylquinazoline (30 g, 97.5 mmoles) [prepared as described by: C. J. Shishoo, M. B. Devani, V. S. Bhadti, K. S. Jain and S. Anathan, J. Heterocyclic Chem., 27, 119-126 (1990), L-(+)-valinamide hydrochloride (21.5 g, 140.9 mmoles) and potassium carbonate (42.8 g, 309.7 mmoles) were added to anhydrous acetonitrile (500 mL) and the mixture was heated under reflux and under argon at 80° C. for 24 h. The mixture was evaporated to dryness and the residue was partitioned between dichloromethane and water. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (60.x.8.5 cm) using 2percent (10percent concentrated ammonium hydroxide in methanol)-dichloromethane as the eluant to give 2(S)-(-)-(2-aminomethylquinazolin-4-ylamino)-3-methylbutyramide (22.34 g, 78percent): FABMS: m/z 293.0 (MH+); HRFABMS: m/z 293.1166 (MH+). Calcd. for C14H18ClN4O: m/z 293.1169; 8H (CD3OD) 1.09 (6H, d, CH(CH3)2), 2.12 (3H, dq, CH(CH3)2), 4.57 (2H, s, CH2Cl), 4.77 (1H, d, CHCH(CH3)2), 4.87 (3H, s, NH and NH2), 7.49 (1H, ddd, H6), 7.68 (1H, ddd, H7), 7.75 (1H, dd, H5) and 8.18 ppm (1H, dd, H8); deltaC (CD3OD) CH3: 19.6, 19.6; CH2: obscured under MeOH; CH: 31.5, 61.7, 123.4, 127.7, 127.7, 134.4; C, 114.8, 150.4, 162.1, 163.1, 177.0; [alpha]D25° C.-10.6° (c=1.01, MeOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; | A solution of (S)-N-BOC-L-NAPHTHYLALANINE (630mg, 2MMOL), L-valineamide hydrochloride (306mg, 2mmol), 1-HYDROXYBENZOTRIAZOLE (306mg, 2MMOL) in dichloromethane was treated with EDC HC1 (768mg, 4MMOL) and diisopropylethylamine (1. 216ML, 7MMOL) and the mixture was stirred overnight. The dichloromethane was rotovaped, the residue was taken in ethylacetate. The ethylacetate solution was washed with IN HC1 (2 x lOmL), saturated sodiumbicarbonate solution (2 x lOmL) and finally with brine (2 x LOML). The ethylacetate solution was dried over anhydrous sodium sulphate and rotovaped. The residue on trituration with hexanes gave a whit solid. Yield: 625mg. (75percent). MS (M+NA) + : 436 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide; In 1,4-dioxane; water; at 20℃; for 2h;pH 8.0; | To 25.0 g of valinamide hydrochloride was added 325 ml of water, and the pH of the reaction solution became 8 by adding of a 8 weight percent aqueous sodium hydroxide solution. 35 ml of dioxane containing 31.94 g of 2,2,2-trifluoroethoxycarbonyl chloride and a 8 weight percent aqueous sodium hydroxide solution were added dropwise to the solution at the same time while maintaining the pH at 8 +/- 0.5 at room temperature. After the completion of dropwise addition, the solution was stirred for 2 hours and then the precipitate was filtered and vacuum dried. The obtained compound of a white solid was the title compound. Quantity: 37.80 g (Yield: 95percent) 1H NMR(DMSO-d6) delta0.89(3H,d,J=6.83Hz),0.86(3H,d,J=6.83Hz),1.98(1H,m),3.78(1H,dd ,J=6.83,8.78Hz),4.64(2H,m),7.05(1H,brs),7.37(1H,brs),7.61(1H,d ,J=8.78Hz). |
47% | With pyridine; In tetrahydrofuran; at 20℃; for 3h;Product distribution / selectivity; | To 30 ml of a THF solution containing 3.0 g of valinamide hydrochloride was added 5.25 ml of pyridine, and then 5 ml of THF containing 3.83 g of 2,2,2-trifluoroethoxycarbonyl chloride was added dropwise to the solution . The resulting mixture was stirred at room temperature for 3 hours, and then water and ethyl acetate were added to the mixture ,and carried out liquid separation. The organic layer was washed with 1N hydrochloric acid, a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and then dried over sodium sulfate. After removing sodium sulfate, IPE was added and the resulting mixture was stirred. The obtained white precipitate was the compound (I), while the yield was 47percent (quantity: 2.25 g). Even when the same reaction was carried out using triethylamine instead of pyridine, the yield was 30percent. From these reaction results, it was determined that, in Example 1 carried out with an aqueous solvent, the reaction yield was remarkably improved. |
30% | With triethylamine; In tetrahydrofuran; at 20℃; for 3h;Product distribution / selectivity; | To 30 ml of a THF solution containing 3.0 g of valinamide hydrochloride was added 5.25 ml of pyridine, and then 5 ml of THF containing 3.83 g of 2,2,2-trifluoroethoxycarbonyl chloride was added dropwise to the solution . The resulting mixture was stirred at room temperature for 3 hours, and then water and ethyl acetate were added to the mixture ,and carried out liquid separation. The organic layer was washed with 1N hydrochloric acid, a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and then dried over sodium sulfate. After removing sodium sulfate, IPE was added and the resulting mixture was stirred. The obtained white precipitate was the compound (I), while the yield was 47percent (quantity: 2.25 g). Even when the same reaction was carried out using triethylamine instead of pyridine, the yield was 30percent. From these reaction results, it was determined that, in Example 1 carried out with an aqueous solvent, the reaction yield was remarkably improved. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | To sodium borohydride (1.13g, 30 mmol) in glyme (30 ml) under nitrogen was added (S)-Valinamide hydrochloride (1.53g, 10 mmol) suspended in glyme (35 ml) with stirring.. The solution was cooled to 10°C and boron trifluoride etherate (4.9 ml, 40 mmol) in glyme (10 ml) was added dropwise over 20 min, then the mixture was heated at reflux for 16 h.. After cooling to ambient water (7.5 ml), followed by 3M NaOH (15 ml), was added and the resulting clear solution refluxed for 2h. Solvent was removed in vacuo to afford a white solid which was extracted with chloroform (3 x 10ml), the combined extract being evaporated to afford the diamine (0.34g).. This was dissolved in ethanol (15 ml) and treated with 2-hydroxy-3-tert-butyl-5-methyl benzaldehyde (1.28g, 6.6 mmol).. The solution was heated at reflux for 2h, cooled, concentrated in vacuo and the residue chromatographed on silica (Merck 9385, eluding with 0-6percent MeOH in chloroform) to afford the title compound, 0.73g (16percent yield). delta (CDCl3), 1.04 (6H, m), 1.39 (18H, 2s), 2.10 (1H, m), 2.24 (6H, s), 3.3 - 4.0 (3H, bm), 6.85 (2H, m), 7.09 (2H, m), 8.24 (2H, s), 13.60 (2H, bs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1524-[4-(2-{3-[(S)-1-Carbamoyl-2-(methyl)propyl]ureido}-ethyl)phenyl]methyl}-3-(beta-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole To a solution of 3-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-4-[4-(2-hydroxyethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole (2.13 g) and triethylamine (0.65 mL) in dichloromethane (20 mL) was addedmethanesulfonyl chloride (0.36 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-5-isopropyl-4-[4-(2-methanesulfonyloxyethyl)phenyl]methyl}-1H-pyrazole (2.4 g). This material was dissolved in N,N-dimethylformamide (20 mL). To the solution was added sodium azide (0.71 g), and the mixture was stirred at 80C° for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 1/1 - 1/2) to give 3-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-4-[4-(2-azidoethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole (1.55 g). The obtained 3-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-4-[4-(2-azidoethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole (1 g) was dissolved in tetrahydrofuran (5 mL). To the solution was added 10percent palladium-carbon powder (0.15 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-4-[4-(2-aminoethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole (0.96 g). The obtained 3-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-4-[4-(2-aminoethyl)-phenyl]methyl}-5-isopropyl-1H-pyrazole (0.48 g) was dissolved in dichloromethane (5 mL). To the solution were added triethylamine (0.13 mL) and 4-nitrophenyl chloroformate (0.18 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. A 1/6 amount of the reaction mixture was separated. To the part of the reaction mixture were added triethylamine (0.084 mL), <strong>[3014-80-0]L-valine amide hydrochloride</strong> (45 mg) and tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: ethyl acetate - ethyl acetate/methanol = 10/1) to give 3-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-4-[4-(2-{3-[(S)-1-carbamoyl-2-(methyl)propyl]ureido}ethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole (48 mg). This material was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28percent methanol solution, 0.013 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (0.2 mL). The resulting mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (29 mg).1HNMR (CD3OD) delta ppm: 0.9 (3H, d, J=7.0Hz), 0.95 (3H, d, J=6.5Hz), 1.1-1.2 (6H, m), 2.0-2.1 (1H, m), 2.71 (2H, t, J=7.1Hz), 2.85-3.0 (1H, m), 3.25-3.45 (6H, m), 3.6-3.75 (2H, m), 3.78 (1H, d, J=16.0Hz), 3.8-3.9 (1H, m), 4.04 (1H, d, J=5.9Hz), 5.04 (1H, d, J=7.4Hz), 7.05-7.15 (4H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 14h; | N-Methylmorpholine (0.87 ml, 7.9 mmol), 1-hydroxybenzotriazole (0.46 g, 3.41 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.65 g, 3.41 mmol) were added in this sequence to a solution of commercially available (R)-6-benzyloxycarbonylamino-2-tert-butoxycarbonylamino-hexanoic acid (1 g, 2.63 mmol) and commercially available (S)-2-amino-3-methylbutyramide hydrochloride (0.40 g, 2.63 mmol) in 12 ml of CH2Cl2 and 4 ml of DMF, and the mixture was stirred at RT for about 14 h. Flash chromatography (gradient heptane/AcOEt to CH2Cl2/MeOH) afforded 1 g of the product (79percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
540 mg | With sodium hydrogencarbonate; In acetonitrile; at 20℃; for 3h; | (1) To a suspension of <strong>[3014-80-0]L-valinamide hydrochloride</strong> (1.0 g) and sodium hydrogen carbonate (3.03 g) in acetonitrile (100 mL) was added p-nitrophenyl chloroformate (1.32 g), and the mixture was stirred at room temperature for 3 hr. Water was added thereto, the resulting mixture was stirred at room temperature overnight, and then acetonitrile was distilled off under reduced pressure. After extraction with ethyl acetate, the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform/methanol) to afford (5S)-5-(propan-2-yl)imidazolidine-2,4-dione (540 mg). (ESI pos.) m/z: 143 ([M+H]+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | Example 2 Synthesis of ethyl 5-[3-(1-amino-3-methyl-1-oxobutan-2-yl)carbamoyl)-1H-indazol-1-yl]pentanoate 3 (FIG. 2) EDC.HCl (2.4 g, 12.5 mmol), L-valinimide HCl (1.94 g, 12.7 mmol), HOBt hydrate (1.96 g, 12.6 mmol) and DIPEA (7.2 ml, 42 mmol) were added to a solution of 1-(5-ethoxy-5-oxopentyl)-1H-indazole-3-carboxylic acid 2 (2.43 g, 8.4 mmol) in DMF (40 ml) and the mixture was stirred at room temperature overnight under nitrogen. The solvent was removed in vacuo and the crude residue dissolved in water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed by brine (10 0 ml), dried over sodium sulphate, filtered and concentrated in vacuo. The crude product obtained was purified by column chromatography using 10% MeOH/chloroform to give ethyl 5-[3-((1-amino-3-methyl-1-oxobutan-2-yl)carbamoyl)-1H-indazol-1-yl]pentanoate 3 (2.43 g, 75%) as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;Inert atmosphere; | General procedure: To a stirring solution of 15, (S)-16 or (R)-16(0.10 g, 0.23 mmol), amino acid amide hydrochloride salt (0.24 mmol)and HBTU (0.091 g, 0.24 mmol) in dimethylformamide (5 mL) was added DIPEA(0.056 g, 0.44 mmol) and stirred under nitrogen until reaction was completed asmonitored by LCMS. Water was added and the precipitate was collected and thenwashed with water and methanol and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | B0cHN-Arg(Mtr) ketobenzothiazole-6-CONH-Val-amide. Under nitrogen atmosphere, at 0 °C anhydrous DMF (5 mL) was added into the round bottom flask containing BocHN-Arg(Mtr) ketobenzothiazole-COOH (0.060 g, 0.093 mmol) and HATU (0.042 g, 0.11 mmol). After stirring for 10 minutes, <strong>[3014-80-0]L-valine amide hydrochloride</strong> (0.0 17 g, 0.11 mmol), then N,N-diisopropylethylamine (0.062 g, 0.55 mmol) were added. The mixture was stirred overnight while being warmed to room temperature naturally. DMF was removed and to the resulting residue 20 mL water was added. The precipitate formed was filtered and dried. The product was purified by silica gel chromatography with CHC13/MeOH combination as eluent to give the title compound (0.049 g) in 70percent yield ?H NMR (400 MHz, METHANOL-d4) oe ppm 1.06 (d, J=1.57 Hz, 3 H) 1.08 (d, J=1.96 Hz, 3 H) 1.42 (s, 9 H) 1.56- 1.79 (m, 4 H) 2.04 (s, 3 H) 2.15 - 2.30 (m, 1 H) 2.55 (s, 3 H) 2.60 (s, 3 H) 3.20 - 3.28 (m, 2 H) 3.80 (s, 3 H) 4.45 (d, J=7.43 Hz, 1 H) 5.19 - 5.41 (m, 1 H) 6.57 (s, 1 H) 8.00 - 8.12 (m, 1 H) 8.13 - 8.29 (m, 1 H) 8.62 (s, 1 H). MS(ESI): found: [M + Hj, 746.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.128 g | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 180℃; for 5h;Microwave irradiation; | To a solution of 0.4 g of 6-chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-4-amine [0735] in acetonitrile was added <strong>[3014-80-0]L-valinamide hydrochloride</strong> [0740] (0.332 g, 2.175 mmol) and N,N-diisopropyl ethylamine. The reaction mixture was heated at 180° C. under microwave for 5 h. The reaction mixture was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 40percent ethyl acetate in pet ether to afford gave 0.128 g of (S)-2-((2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)-3-methylbutanamide [0741], Compound 200 as white solid. MS(M+1)+=448.2. 1H NMR (400 MHz, DMSO-d6) delta 9.53 (s, 1H), 8.48 (s, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.24 (d, J=7.7 Hz, 2H), 7.06 (bs, 1H), 6.05 (s, 1H), 5.98 (bs, 1H), 4.40 (bs, 1H), 2.54 (s, 3H), 2.18 (s, 3H), 2.15-2.05 (m, 1H), 0.94 (d, J=6.9 Hz, 6H). |
[ 75158-12-2 ]
(S)-2-Amino-3,3-dimethylbutanamide hydrochloride
Similarity: 0.97
[ 94787-97-0 ]
(S)-2-Aminohexanamide hydrochloride
Similarity: 0.86
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