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CAS No. : | 760-58-7 | MDL No. : | MFCD22377852 |
Formula : | C7H9NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JYFREZOLRUHBAQ-ZZXKWVIFSA-N |
M.W : | 139.15 | Pubchem ID : | 5956093 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.43 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 36.81 |
TPSA : | 61.09 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.23 cm/s |
Log Po/w (iLOGP) : | 1.26 |
Log Po/w (XLOGP3) : | 1.3 |
Log Po/w (WLOGP) : | 1.18 |
Log Po/w (MLOGP) : | 0.54 |
Log Po/w (SILICOS-IT) : | 0.46 |
Consensus Log Po/w : | 0.95 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.39 |
Solubility : | 5.67 mg/ml ; 0.0408 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.18 |
Solubility : | 0.913 mg/ml ; 0.00656 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.23 |
Solubility : | 82.9 mg/ml ; 0.596 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.33 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280 | UN#: | N/A |
Hazard Statements: | H302+H312+H332 | 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 |
---|---|---|
83% | With ammonium acetate In tolueneReflux | Step 1 - 2-Cyano-4-methyl-2-pentenoic acidA stirred suspension of cyanoacetic acid (42.5g, 0.5 mol), ammonium acetate(1 .56g, 0.02 mol, 4 molpercent) and isobutyraldehyde (55ml, 39.66g, 0.55 mol, 1 .1 eq) in toluene (130ml) was heated to reflux with Dean-Stark removal of water. When generation of water ceased, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a yellow solid (79.5g). Hexane (150ml) was added and the suspension was stirred at 400rpm for 1 hour. The solid was filtered, washed with hexane (2 x 50ml) and dried to provide the title compound as a yellow crystalline solid (58.5g, 83percent yield). |
11.2 g | Stage #1: for 30 h; Stage #2: With piperidine In methanol for 1 h; |
To a solution of 2-cyanoacetic acid (8.7g, 102 mmol) in methanol (200mL) was added 2-methylpropanal (18.6 mL, 204 mmol) and the solution was stirred with a slight exotherm noted. After 30 minutes, added piperidine (1 1.1 mL, 1 12 mmol) and continued stirring for 1 h before removing solvent in vacuo with gentle heating. The thick material was diluted with ether and washed with 125mL of 1.0M HC1 and then washed with brine. The organic phase was dried over sodium sulfate and concentrated to afford a colorless oil weighing 11.2 g of 2- cyano-4-methylpent-2-enoic acid which precipitated on standing. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyrrolidine; pyridine; at 20℃; | Into a 100-mL round-bottom flask, was placed 2-cyanoacetic acid (2 g, 23.51 mmol, 1.00 eq.), pyridine (10 mL), 2-methylpropanal (1.85 g, 25.66 mmol, 1.09 eq.), pyrrolidine (400 mg, 5.62 mmol, 0.24 eq.). The resulting solution was stirred for 1.5 h at rt. The reaction was then quenched by the addition of hydrogen chloride:H20 (12:20 mL). The resulting solution was extracted with ethyl acetate (2 x 20 mL). The organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.9 g (89%) of 2-cyano-4-methylpent-2-enoic acid as a light yellow solid. |
83% | With ammonium acetate; In toluene;Reflux; | Step 1 - 2-Cyano-4-methyl-2-pentenoic acidA stirred suspension of cyanoacetic acid (42.5g, 0.5 mol), ammonium acetate(1 .56g, 0.02 mol, 4 mol%) and isobutyraldehyde (55ml, 39.66g, 0.55 mol, 1 .1 eq) in toluene (130ml) was heated to reflux with Dean-Stark removal of water. When generation of water ceased, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a yellow solid (79.5g). Hexane (150ml) was added and the suspension was stirred at 400rpm for 1 hour. The solid was filtered, washed with hexane (2 x 50ml) and dried to provide the title compound as a yellow crystalline solid (58.5g, 83% yield). |
11.2 g | To a solution of 2-cyanoacetic acid (8.7g, 102 mmol) in methanol (200mL) was added 2-methylpropanal (18.6 mL, 204 mmol) and the solution was stirred with a slight exotherm noted. After 30 minutes, added piperidine (1 1.1 mL, 1 12 mmol) and continued stirring for 1 h before removing solvent in vacuo with gentle heating. The thick material was diluted with ether and washed with 125mL of 1.0M HC1 and then washed with brine. The organic phase was dried over sodium sulfate and concentrated to afford a colorless oil weighing 11.2 g of 2- cyano-4-methylpent-2-enoic acid which precipitated on standing. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Step 3 - 2-Cyano-4-methylpentanoic acid (by sodium borohydride reduciton) A suspension of 4-methyl-2-cyano-2-butenoic acid (10g, 71 .9mmol) in water (60ml_) was cooled to 0C with an ice bath, then NaHCO3 (7.25g, 1 .2 eq.) was added slowly to the mixture. The mixture is stirred for 15 mins to provide a clear solution, then NaBH4 (5.44g, 2 eq.) was added slowly at 0C and the reaction was stirred at room temperature for 5h. The mixture was cooled down to 0C and a solution of HCI 20% (44ml_, 4 eq.) was slowly added to the mixture (pH= 2-3). The product was extracted with EtOAc (3x 30ml_) and the combined organic phases were washed with water (3x 20 ml_), dried over MgSO , filtered and evaporated under reduced pressure to give material identical to that obtained by the hydrogenation route (10.2g, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 0℃;Inert atmosphere; | Step 4To a 25 mL round bottom flask, (R)-4-(4-phenoxyphenyl)-6-(piperidin-3-yl)-lH- pyrazolo[4,3-c]pyridin-3-amine (O.lg, 0.00025 mole) and <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (0.046g, O.00033mole) were taken in dry DCM (lmL) and the solution was cooled to 0C under argon atmosphere. To above, PyBrOP (0.133g, 0.000285mole) was added slowly followed by triethylamine (0.1 mL, 0.000778 mole) at 0 C. The completion of the reaction was monitored on TLC using MeOH: DCM (1 :9) as a mobile phase. After completion of the reaction the reaction, the crude material was directly loaded onto a column packed with 100- 200 mesh sized silica eluting with neat ethyl acetate to afford 38 mg of the title compound. MS (pos. ion) m/z: 507 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | 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 dichloromethane; at 20℃; for 4h;Inert atmosphere; | Step 5. To a mixture of (R)-3-(4-(2,3difluorophenoxy)-2-fluorophenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.23 mmol, 1.0 eq), <strong>[760-58-7]2-cyano-4-methyl-pent-2-enoic acid</strong> (38 mg, 0.27 mmol, 1.2 eq) and DIEA (88 mg, 0.68 mmol, 3.0 eq) in 10 ml DCM was added HATU (130 mg, 0.34 mmol, 1.5 eq). The reaction mixture was stirred for 4 h at RT under N2. The mixture was purified by Pre-HPLC to give the title compound (25 mg, 40% yield). LCMS: m/z (562.2) (M+H)+. |
40% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 4h;Inert atmosphere; | Step 5 To a mixture of (R)-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.23 mmol, 1.0 eq), <strong>[760-58-7]2-cyano-4-methyl-pent-2-enoic acid</strong> (38 mg, 0.27 mmol, 1.2 eq) and DIEA (88 mg, 0.68 mmol, 3.0 eq) in 10 ml DCM was added HATU (130 mg, 0.34 mmol, 1.5 eq). The reaction mixture was stirred for 4 h at RT under N2. The mixture was purified by Pre-HPLC to give the title compound (25 mg40% yield). LCMS: m/Z+ (562.2) (M+H)+1HNMR (400 MHz, CDCl3): delta 0.784?1.186 (m, 7H), 1.765?2.254 (m, 5H), 2.861?4.937 (m, 4H), 6.218 (m, 0.4H), 6.857?7.600 (m, 6H), 8.255 (s, 1H) and 9.888 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.2 g | With triethylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 0℃; for 0.25h;Inert atmosphere; | To a 25 mL one necked round bottom flask, benzyl (2-(4-chlorobenzamido)-l- (pyrrolidin-2-ylmethyl)-lH-benzo[d]imidazol-5-yl)methyl((S)-3,3-dimethylbutan-2-yl)carbamate TFA salt (0.55 g, 0.00091 mole), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (0.380 g, 0.00274 mole) were added in CH2C12 (3 mL), followed by addition of PyBrOP (0.466 g, 0.001 mole) and TEA (0.63 mL,0.0045 mole) at 0 C under nitrogen atmosphere and the reaction mixture was stirred for 15 min at same temperature. After the completion of the reaction, the reaction mixture was purified using column purification by eluting compound with 25% ethyl acetate in hexanes to yield 0.2g of benzyl (2-(4-chloro-benzamido)-l-((l-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2- yl)methyl)-lH-benzo[d]imidazol-5-yl)methyl((S)-3,3-dimethylbutan-2-yl)carbamate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.27 g | With triethylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 0℃; for 0.5h;Sealed tube; | To a 25 mL sealed tube under nitrogen atmosphere, benzyl (2-(4-(difluoromethyl)- benzamido)-l-(pyrrolidin-2-ylmethyl)-lH-benzo[d]imidazol-5-yl)methyl((S)-3,3-dimethylbutan- 2-yl)carbamate as TFA salt (0.5 g, 0.000683 mole), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (0.284 g, 0.002049 mole) and PyBrOP (0.350 g, 0.000751 mole) were taken in CH2C12 (5 mL) and cooled to 0 C. TEA (0.47 mL, 0.003415 mole) was added drop wise to a reaction mixture and to stir at 0 C for 30 min. After completion of the reaction, water was added to reaction mixture and product was extracted with EtOAc. The combined organic layer was dried over a2S04 and evaporated to get crude. The crude compound was purified by column purification using 60-120 mesh size neutral silica by eluting with 20% EtOAc in hexanes to yield 0.27g of benzyl (l-((l-(2- cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-2-(4-(difluoromethyl)benzamido)-lH- benzo[d]imidazol-5-yl)methyl((S)-3,3-dimethylbutan-2-yl)carbamate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 mg | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1.66667h; | To a solution of (R)-5-(difluoromethyl)-N-(5-(hydroxymethyl)-l-(pyrrolidin-2- ylmethyl)-lH-benzo[d]imidazol-2-yl)thiophene-2-carboxamide (27 mg, 0.07 mmol), 2-cyano-4- methyl-pent-2-enoic acid (13.87 mg, 0.10 mmol), HATU (25.24 mg, 0.07 mmol), DIPEA (0.01 mL, 0.07 mmol) in DMF (10 mL) was stirred at rt for 100 minutes. The reaction mixture was evaporated to afford an oil which was worked up with DCM and water. The organic layers were dried (MgS04) and concentrated and the oil was purified by chromatography to obtain 10 mg of (R)-N-( 1 -((1 -(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)- 1 H- benzo[d]-imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamideas white solid. MS (pos. ion) m/z: 528 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 4h; | To the solution of 5-(difluoromethyl)-N-(5-((2,6-dimethylmorpholino)methyl)-l-((R)- pyrrolidin-2-ylmethyl)-lH-benzo[d]imidazol-2-yl)thiophene-2-carboxamide (65 mg, 0.13 mmol), DIPEA (0.07 mL, 0.39 mmol), <strong>[760-58-7]2-cyano-4-methyl-pent-2-enoic acid</strong> (53.88 mg, 0.39 mmol) and DMF (4 mL) was stirred for 10 minutes and then added HATU (98.09 mg, 0.26 mmol). The reaction mixture was stirred at room temperature. After 4 h, the crude mixture was concentrated and purified by chromatography to obtain 55 mg (68%) of N-(l-(((R)-l-(2-cyano-4-methylpent- 2-enoyl)pyrrolidin-2-yl)methyl)-5-((2,6-dimethylmorpholino)methyl)-lH-benzo[d]imidazol-2- yl)-5-(difluoromethyl)thiophene-2-carboxamide as off white solid. MS (pos. ion) m/z: 625 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.4 mg | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | (R)-3-Methyl-N-( 1 -(pyrrolidin-2-ylmethyl)- 1 H-benzo[d]imidazol-2-yl)benzamide (prepared as in Example 50 but substituting 3-methylbenzoic acid for 5- (difluoromethyl)thiophene-2-carboxylic acid) was dissolved in N,N-dimethylformamide (10 mL). DIEA (231.9 mg, 1.79 mmol, 4.00 equiv), HATU (255.8 mg, 0.67 mmol, 1.50 equiv), and <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (93.6 mg, 0.67 mmol, 1.50 equiv) were added to the reaction mixtureand the resulting solution was stirred overnight at rt. The reaction was quenched with water and the resulting solution was extracted with dichloromethane, and the combined organic layers were concentrated under vacuum. The crude product (100 mg) was purified by Prep HPLC to afford 47.4 mg of (R)-N-(l-((l-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-lH- benzo[d]imidazol-2-yl)-3-methylbenzamide as a white solid. LC-MS (m/z): 456.3 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
173 mg | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | (R)-5-(Difluoromethyl)-N-(l-(pyrrolidin-3-yl)-lH-benzo[d]imidazol-2-yl)thiophene-2- carboxamide (prepared as in Example 50 but substituting (R)-tert-butyl 3-aminopyrrolidine-l- carboxylate for (R)-tert-butyl 2-(aminomethyl)pyrrolidine-l -carboxylate) was dissolved in 20 mL of DMF. TEA (335.1 mg, 3.31 mmol), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (153.6 mg, 1.10 mmol, and HATU (629.5 mg, 1.66 mmol) were added to the reaction mixture. The resulting solution was stirred overnight at rt and then concentrated under vacuum. The crude product was purified by Prep-HPLC to afford 173 mg of (R)-N-(l-(l-(2-cyano-4-methylpent-2- enoyl)pyrrolidin-3-yl)-lH-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide LC-MS m/z: 484.2 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.19 g | With triethylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 0℃; for 0.25h;Inert atmosphere; | To a 50 mL one necked round bottom flask were added benzyl (2-(4-chlorobenzamido)-l- (piperidin-3-yl)-lH-benzo[d]imidazol-5-yl)methyl-((S)-3,3-dimethylbutan-2-yl)carbamate TFA salt (0.5 g,0.7150 mmole), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (0.298 g, 2.1450 mmole) and CH2CI2 (10 mL); followed by addition of PyBrOP (0.366 g, 0.7860 mmole) and TEA (0.3 mL) at 0 C under nitrogen atmosphere and stirred for 15 min at the same temperature. After completion of the reaction, the reaction mixture was purified using column purification by eluting compound with 20% ethyl acetate in hexanes to yield 0.19 g of benzyl (2-(4- chlorobenzamido)-l-(l-(2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)-lH-benzo[d]imidazol-5 yl)methyl((S)-3,3-dimethylbutan-2-yl)carbamate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34 mg | With triethylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In dichloromethane; at 20℃; | The mixture of l-(azetidin-3-yl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-amine (80 mg, 0.210 mmol, <strong>[760-58-7]2-cyano-4-methyl-pent-2-enoic acid</strong> (44.4 mg, 0.320 mmol), PyAOP (121.9 mg, 0.230 mmol) and TEA (0.09 mL, 0.640 mmol) in DCM (3 mL), were stirred overnight at room temperature. The solvent was removed and the residue was purified on a silica gel plate using 6:94 MeOH:CH2Ci2 to get 2-[3-[4-amino-3-(2-fluoro- 4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]azetidine-l-carbonyl]-4-methyl-pent-2- enenitrile (34 mg) as white powder. LC-MS (ES, m/z): 498 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.8% | With triethylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In dichloromethane; at 20℃; for 1h; | To a solution of <strong>[760-58-7]2-cyano-4-methyl-pent-2-enoic acid</strong> (30.7 mg, 0.220 mmol), 1- (azetidin-2-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (57.5 mg, 0.150 mmol in DCM (2 mL) was added PyAOP (86.2 mg, 0.160 mmol) and TEA (0.06 mL, 0.440 mmol) and the resulting yellow solution stirred at rt for lh. LCMS showed that the reaction was complete and the crude mixture was directly loaded onto a silica gel cartridge for purification (3 to 5% MeOH: CH2C12). Removal of solvent from cleanest fractions afforded 30mg of the desired compound 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l -yl]methyl]azetidine-l-carbonyl]-4-methyl-pent-2- enenitrile (30mg,0.0586mmol, 39.8% yield) as judged by LCMS. (M+l = 512). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12 mg | With triethylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In dichloromethane; at 20℃; for 1h; | To a solution of <strong>[760-58-7]2-cyano-4-methyl-pent-2-enoic acid</strong> (48.12 mg, 0.350 mmol) ,1- (azetidin-3-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 0.230 mmol) in DCM (2 mL) was added PyAOP (134.9 mg, 0.250 mmol) and TEA (0.1 mL, 0.690 mmol) and the resulting yellow solution stirred at rt for lh. LCMS showed that the reaction was completed and the crude mixture was directly loaded onto a silica gel cartridge for purification (0.2 to 3% MeOH: CH2C12). Removal of solvent from cleanest fractions afforded afforded 2-[3-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]methyl]azetidine-l-carbonyl]-4-methyl-pent-2-enenitrile (12 mg LCMS. (M+l = 512). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.3 g | To a 25 ml single neck round bottomed flask under nitrogen atmosphere, 2-cyano-4- methylpent-2-enoic acid (0.23 g, 1 .65 mmol) was dissolved in DMF (3 ml) and cooled to 0 C. To this, HATU (0.79 g, 2.06 mmol) was added and stirred at 0 C for 30 minutes. After 30 min, solution of tert-butyl (S)-(6-(methylamino)-l -((4-methylbenzyl)amino)-l-oxohexan-2- yl)carbamate (0.5 g, 1.37 mmol) in DMF (2 ml) and DIPEA (0.71 ml, 4.13 mmol) were added dropwise at 0 C. The reaction mixture was further stirred at 0 C for 1.5 h and then diluted with cold water and extracted with ethyl acetate. The combined organic layer was washed with water, dried and concentrated. The crude material was purified using flash column purification in 10 % MeOH in CH2C12 to get 0.3 g of tert-butyl (S)-(6-(2-cyano-N,4-dimethylpent-2-enamido)-l -((4- methylbenzyl)amino)- 1 -oxohexan-2-yl)carbamate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
150 mg | To a 250 ml three neck round bottomed flask under nitrogen atmosphere, 2-cyano-4- methylpent-2-enoic acid (55 mg, 0.39 mmol) was dissolved in DMF (1 ml) and cooled to 0 C. To the reaction mixture, HATU (223 mg, 0.58 mmol) was added and stirred at 0 C for 30 minutes. After 30 minutes, (S)-tert-butyl (3-(3-aminophenyl)-l-((4-methylbenzyl)amino)-l- oxopropan-2-yl)carbamate (150 mg, 0.39 mmol) dissolved in DMF (1 ml) was added dropwise followed by addition of DIPEA (0.2 ml, 1.17 mmol). The reaction mixture was stirred at rt for 1 h, poured into cold water and filtered under vacuum to give 150 mg of (S)-tert-butyl (3-(3-(2- cyano-4-methylpent-2-enamido)phenyl)-l -((4-methylbenzyl)amino)-l -oxopropan-2- yl)carbamate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
170 mg | To a 35 ml vial, under nitrogen atmosphere, <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (0.126 g, 0.9 mmol) was dissolved in DMF (1.5 ml) and cooled to 0 C. To the reaction mixture, HATU (0.429 g, 1 .13 mmol) was added and stirred at 0 C for 30 minutes. After 30 minutes, (S)-tert- butyl (3-(3-(methylamino)phenyl)-l-((4-methylbenzyl)amino)-l-oxopropan-2-yl)carbamate (0.3 g, 0.75 mmol) dissolved in DMF (1.5 ml) was added dropwise followed by addition of DIPEA (0.52 ml, 3 mmol) and stirred at 0 C to rt for 16 h. The reaction mixture was diluted with water and extracted using ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under vacuum and then purified by chromatography to yield 170 mg of (S)-tert- butyl (3-(3-(2-cyano-N,4-dimethylpent-2-enamido)phenyl)-l-((4-methylbenzyl)amino)-l- oxopropan-2-yl)carbamate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37 mg | To a 25 ml three neck round bottomed flask, under nitrogen atmosphere, 2-cyano-4- methylpent-2-enoic acid (57 mg, 0.41 mmol) was dissolved in DMF (2 ml) and cooled to 0 C. To the reaction mixture, HATU (234 mg, 0.62 mmol) was added and stirred at 0 C for 30 minutes. After 30 minutes, N-((2S,3R)-3-hydroxy-l -(((S)-l -((4-methylbenzyl)amino)-l -oxo-3- (piperidin-4-yl)propan-2-yl)amino)- l -oxobutan-2-yl)-5-methylisoxazole-3-carboxamide (200 mg, 0.41 mmol) was added dropwise followed by addition of DIPEA (0.2 ml, 1 .23 mmol) and stirring at rt for 1 h. The reaction mixture was poured onto cold water and the obtained solid was filtered under vacuum, washed with water and dried before purification by prep HPLC purification to yield 37 mg of the title compound. LC-MS (ES, m/z): 607 [M+FTJ. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35 mg | To a 10 ml vial, under nitrogen atmosphere, <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (59 mg, 0.42 mmol) was dissolved in DMF (1 ml) and cooled to 0 C. To the reaction mixture, HATU (161 mg, 0.42 mmol) was added and stirred at 0 C for 30 minutes. After 30 minutes, N-((2S,3R)- 1 -(((S)- 1 -((2-fluoro-4-methylbenzyl)amino)-3-(2-(methylamino)ethoxy)- 1 -oxopropan- 2-yl)amino)-3-hydroxy-l -oxobutan-2-yl)-5-methylisoxazole-3-carboxamide hydrochloride (150 mg, 0.28 mmol) dissolved in DMF (1 ml) was added dropwise followed by addition of DIPEA (0.14 ml, 0.85 mmol). The reaction mixture was stirred at 0 C to rt for 2 h. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The combined organic layer was washed with brine, concentrated and purified using flash column purification to yield 35 mg of the title compound. LC-MS (ES, m/z): 615.3 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 g | To a 50 ml single neck round bottomed flask under nitrogen atmosphere, 2-cyano-4- methylpent-2-enoic acid (0.95 g, 6.9 mmol) was dissolved in DMF (20 ml) and cooled to 0 C. HATU (3.26 g, 8.54 mmol) was added to the reaction mixture and stirred at 0 C for 30 minutes. Then, (S)-tert-butyl (6-amino-l-((4-methylbenzyl)amino)-l-oxohexan-2-yl)carbamate (2 g, 5.72 mmol) was added drop-wise followed by addition of DIPEA (2.95 ml, 3 mmol). The reaction mixture was stirred at 0 C for 1 h. Water was added to the reaction mixture and extracted with ethyl acetate, the collected organics were washed with water, saturated NaHC03 solution and dil. HC1 solution and the solvent removed. The crude material was purified by flash column purification in 30 % ethyl acetate in hexanes to get 1 g of (S)-tert-butyl (6-(2-cyano-4- methylpent-2-enamido)-l -((4-methylbenzyl)amino)-l -oxohexan-2-yl)carbamate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | Into a 25-mL round-bottom flask, was placed a solution of 8-[2-(4-aminophenyl)ethyl]-6- (2,6-dichloro-3,5-dimethoxyphenyl)-2-[[4-(diethylamino)butyl]amino]-7H,8H-pyrido[2,3-d]- pyrimidin-7-one (300 mg, 0.49 mmol, 1.00 equiv) in N,N-dimethylformamide (7 mL). 2-Cyano- 4-methylpent-2-enoic acid (74.8 mg, 0.54 mmol, 1.10 equiv), HATU (278.9 mg, 0.73 mmol, 3.00 equiv), and TEA (148.4 mg, 1.47 mmol, 3.00 equiv) were added to the reaction mixture. The resulting solution was stirred overnight at room temperature, and then it was diluted with water. The resulting solution was extracted with DCM/MeOH(10: l) and the organic layers combined, and concentrated under vacuum. The crude product (300 mg) was purified by Prep- HPLC with the following conditions (2-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, SunFire Prep CI 8 OBD Column, 5um, 19* 150mm,; mobile phase, water with 0.1% HCOOH and MeCN (22.0% MeCN up to 36.0% in 10 min, up to 100.0% in 2 min, down to 22.0% in 1 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 37 mg (10%) of 2-cyano-N-(4-[2- [6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-[[4-(diethylamino)butyl]amino]-7-oxo-7H,8H- pyrido[2,3-d]pyrimidin-8-yl]ethyl]phenyl)-4-methylpent-2-enamide; formic acid as a gray solid. LC-MS m/z: 736 [M+l-HCOOH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 mg | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h; | DIPEA (500 mg, 3.87 rnmol) was added to a stirred solution of N-((S)-2-phenyl-l- ((3aS,4S,6S,7aR)-3a,5,5-trimethylhexaliydro-4,6~metlianobenzo[d] | 1,3,2 jdioxaborol-2 -yl)emyl)-3-((R)- pyrrolidin-2-ylmethoxy)propanamide (800 mg, 1.76 mmol), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (245 mg, 1.76 mmol) and BOP (858 mg, 1 .94 mmol) in DMF (5 mL) at rt. After stirring at rt for 2 h, the reaction was quenched with water (20 mL) and diluted with EtOAc (40 mL), then washed with brine (2 x 5 mL), dried over Na2SC>4 and concentrated in vacuo. The crude residue was purified by Prep-HPLC to afford 3-(((R)- (0492) 1- (2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)-N-((S)-2-phenyl-l-((3aS,4S,6S,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[d][l ,3,2]dioxaborol-2-yl)ethyl)propanamide as a white solid (200 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25 mg | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h; | Into a 25-mL round-bottom flask was placed a solution of (R)-piperidin-2-ylmethyl ((R)-2-pheny]-l-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][l,3^ (0509) yl)ethyl)carbarnate (105 mg, 0.24 mmol, 1.00 eq.) in dichloromethane (2 mL), followed by 2-cyano-4- methylpent-2-enoic acid (40 mg, 0.29 mmol, 1.20 eq.), HATU (136 mg, 0.36 mmol, 1.50 eq.), and DIEA (92.4 mg, 0.71 mmol, 3.00 eq.). The resulting solution was stirred for 1 h at rt. The reaction was then quenched by the addition of water (2 mL). The resulting solution was extracted with dichloromethane, and the organic layers combined and washed with brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The resulting material was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, XBridge Prep C18 OBD Column: mobile phase, Water (0.05%NH3H2O) and ACN (76% ACN up to 77% in 7 min); Detector, UV 254/220nm. his gave ((R)-l- (2-cyano-4-methylpent-2-enoyl)piperidin-2-yl)methy] ((R)-2-phenyl-l -((3aS,4S,6S,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[d|[l ,3,2]dioxaborol-2-yl)ethyl)carbamate (25 mg) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 3h; | Into a 50-mL round-bottom flask was placed N-[(lR)-2-phenyl-l-[(l S,2S,6R,8S)- 2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0A[2,6]]decan-4-yl]ethyl]-3-(pyrrolidin-2-yl)propanamide (0522) (280 mg, 0.66 mmol, 1.00 eq.), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> ( 184 mg, 1.32 mmol, 2.00 eq.), HATU (753 mg, 1.98 mmol, 3.00 eq.), DIEA (426 mg, 3.30 mmol, 5.00 eq.) and dichioromethane (15 mL). The resulting solution was stirred for 3 h at rt. The resulting solution was extracted with dichioromethane (3 x 50 mL). The organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (HPLC- SHIMADZU): Column, XB ridge Prep CI 8 OBD Column, 19* 150mm, 5um; mobile phase, Water (0.05%TFA ) and ACN (hold 65.0% ACN in 12 min); Detector, uv 254nm . This resulted in the separation of two diastereomers. The first eluting fractions afforded 3-(l-(2-cyano-4-methylpent-2-enoyl)pyrrolidin- 2-yl)-N (R)-2-phenyl ^(3aS,4S,6S,7aR)-3a,5,5-trime mexahydro-4,6- methanobenzo[d] [l,3,2]dioxaborol-2-yl)ethyl)propanamide (40 mg, 11%, stereochemistry not assigned) as a white solid after the lyophilization. Isolation of the second eluting compound afforded 3~(l~(2-cyano~4~ methylpent-2 -enoyl)pyrrolidin-2-yl)-N-((R)-2 -phenyl- 1 -((3aS,4S,6S,7aR)-3a,5,5-trimethy]hexahydro-4,6- methanobenzo[d] [ l,3,2]dioxaborol-2-yl)ethyl)propanamide (30 mg, 8%, stereochemistry not assigned) as a white solid after the lyophilization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 3h; | Into a 50-niL round-bottom, flask was placed N-[(lR)-2-phenyl-l-[(lS,2S,6R,8S)- 2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0A[2,6]]decan-4-yl]ethyl]-3-(piperidin-2-y])propanamide (160 mg, 0.36 mmol, 1.00 eq.), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (101 mg, 0.73 mmol, 2.00 eq.), HATU (416 mg, 1.09 mmol, 3.00 eq.), DIEA (236 mg, 1.83 mmol, 5.00 eq.), and dichloromethane (16 mL). The resulting solution was stirred for 3 h at rt. The resulting solution was extracted with dichloromethane (3 x 50 mL) and the organic layers combined. The resulting mixture was washed with saturated sodium chloride (1 x 50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, XBridge Prep C18 OBD Column, 19* 150mm Sum; mobile phase, Water (0.05%TFA) and ACN (hold 68.0% ACN in 13 min); Detector, uv 254nm. The first eluting fractions were lyophilized to afford 3-(l-(2-cyano-4- methy]pent-2-enoyl)piperidin-2-y])-N-((R)-2-phenyl-l-((3aS,4S,6S,7aR)-3a,5,5-trimethy (0539) methanobenzo[d][l,3,2]dioxaborol-2-yl)ethyl)propanamide (10 mg, 5%) as a yellow solid. The later eluting fractions were lyophilized to afford 3-(l-(2-c}7ano-4-methylpent-2-enoyl)piperidin-2-yl)-N-((R)-2-phenyl- l~((3aS,4S,6S,7aR)~3a,5,5 .rimethylhexahydro~4,6~methanobenzo[d][l,3,2]di (0540) yl)ethyl)propanamide (10 mg, 5%) as a yellow solid after the lyophilization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h; | Into a 25-mL round-bottom flask was placed (2R)-pyrrolidin-2-ylmethyl N-[(lR)-2- phenyl-1 -[( 1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratncyc3o[6.1 .1.0A[2,6]]decan-4- yl] ethyl] carbamate (30 mg, 0.07 mmol, 1.00 eq.) followed by Nu,Nu-dimethylformamide (2 mL), 2-cyano-4- methyipent-2-enoic acid (14.68 mg, 0.11 mmol, 1.50 eq.), DIEA (22.70 mg, 0.18 mmol, 2.50 eq.), and HATU (40 mg, 0.11 mmol, 1.50 eq.). The resulting solution was stirred for 3 h at rt. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, and the organic layers combined. The resulting mixture was washed with sodium chloride, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, XBridge Prep C 18 OBD Column, 19* 150mm Sum; mobile phase. Water (10MMOL/L f J ( (), · () i 'WI U K)) and ACN (74.0% ACN up to 75 ,0% in 7 min); Detector, UV 254/220nm. This resulted in [(2R)-I -[2-cyano-2-(2-methylpropylidene)acetyl]p rolidin-2-yl]methyl N-[( lR)-2-phenyl-l -[( 1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0A[2,6]]decan-4- yl] ethyl] carbamate (6 mg, 16%) as a white solid after lyophilization |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 mg | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | into a 50-mL round-bottom flask, was placed a solution of (2R)-pyrrolidin-2-ylmethyl N-[(lR)-2-(l-benzofuran-3-yl)-l-[(^ (0656) boratricyc]o[6.1.1 .0A[2,6]]decan-4-yl]ethy]]carbamate (120 mg, 0,26 mmol, 1.00 eq.) in dichloromethane (3 mL), DIEA (100 mg, 0.77 mmol, 3.00 eq.), HATU (147 mg, 0.39 mmol, 1.50 eq.), and 2-cyano-4- methylpent-2-enoic acid (43 mg, 0.31 mmol, 1.20 eq.). The resulting solution was stirred for 1 h at it. The reaction was then quenched by the addition of 2 mL of water. The resulting solution was diluted with 10 mL of DCM. The resulting mixture was washed with 1x5 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep- HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19* 150mm, 5um; mobile phase, Water (10MMOL/L H4HCO3+0.1%NH3.H20) and ACN (70% ACN up to 85% in 7 min); Detector, UV 254/220nm. This resulted in 60 mg (40%) of [(2R)-l -[2-cyano-2-(2- methylpropylidene)acetyl]pyrro]idin-2-y]]methyl N-[( 1 R)-2-( 1 -benzofuran-3 -yl)- 1 -[( 1 S,2S,6R,8S)-2,9,9- trimethyl-3,5siioxa-4-boratricyclo[6.1.1.0A[2,6]]decan-4-yl]ethyl]carbamate as a white solid after the iyophilization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | 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 dichloromethane; at 20℃; | Into a 25-mL round-bottom flask, was placed (2S)-2-[(2,5- dichlorophenyl)formamido]-N-[(lR)-2-phenyl-l-[(lS,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0A[2,6] ] decan-4-yl] ethyl] -3 -[(2R)-pyrrolidin-2-ylmethoxy]propanamide (110 mg, 0.17 mmol, 1.00 eq.), dichloromethane (10 mL), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (28.6 mg, 0.21 mmol, 1.20 eq.), DIEA (33.19 mg, 0.26 mmol, 1.50 eq.), HATU (78.22 mg, 0.21 mmol, 1.20 eq.). The resulting solution was stirred for 1-2 h at rt. The reaction was then quenched by the addition of water. The resulting solution was extracted with of dichloromethane, and the organic layers combined. The resulting mixture was washed with sodium chloride (1 x 20 mL). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1 :1). This resulted in 0.06 g (46%) of (2S)-3-[[(2R)-l-[2-cyano-2-(2-methylpropylidene)acetyl]pyrrolidin-2-yl]methoxy]-2-[(2,5- dichlorophenyl)formamido]-N-[(lR)-2-phenyl-l-[(lS,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.l.l.0A[2,6]]decan-4-yl]ethyl]propanamide as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.67% | To a solution of <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (300 mg, 2.15 mmol) in DCM (5 mL) were added (COCl)2 (273.64 mg, 2.16 mmol) and one drop of DML. After stirring at rt for 1 h, the reaction solution was concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (3 mL) and added dropwise into a well-stirred solution of (R)-3-(3-(methylamino)phenyl)-N-((R)-2- phenyl-l-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d] [l,3,2]dioxaborol-2- yl)ethyl)-2-((2,2,2-trifhroroethyl)amino)propanamide (800 mg, 1.44 mmol) and DIPEA (556.43 mg, 4.31 mmol) in DCM (20 mL) at 0 C. The reaction was stirred at rt for 1 h, then washed with water (10 mL) and aq. NaHCC (10 mL, 5%), the organic extracts was dried over Na2S04 and concentrated in vacuo. The crude material was purified by prep-HPLC to afford 2-cyano-N,4-dimethyl-N-(3-((R)-3-oxo-3-(((R)-2- phenyl-l-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d] [l,3,2]dioxaborol-2- yl)ethyl)amino)-2-((2,2,2-trifluoroethyl)amino)propyl)phenyl)pent-2-enamide as white solid (250 mg, 25.67 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | To a solution of <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (177 mg, 1.27 mmol) and DIPEA (410 mg, 3.18 mmol) in DMF (8 mL) at 0 C was added HATU (483 mg, 1.27 mmol). After stirring at 0 C for 1 h, N-((R)-2-phenyl-l-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[d] [l,3,2]dioxaborol-2-yl)ethyl)-4-(piperidin-4-yl)butanamide (480 mg, 1.06 mmol) was added. The resulting mixture was stirred at rt for 4 h before partitioned between HC1 (1 N) and EtOAc. The organic layer was washed with aq. NaHCCb, water and brine, dried over Na2S04 and filtrated. The filtration was concentrated to dryness to afford 4-(l-(2-cyano-4-methylpent-2-enoyl)piperidin-4-yl)-N-((R)-2- phenyl-l-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d] [l,3,2]dioxaborol-2- yl)ethyl)butanamide (500 mg, 82%) as an off-white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.6 g | With triethylamine; 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℃; | A solution of (S)-6-amino-2-((S)-2-isobutyramidopropanamido)-N-((R)-3-methyl-l- ((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxaborol-2- yl)butyl)hexanamide (1.7 g, crude), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (0.443 g, 3.18 mmol), HATU (1.33 g, 3.498 mmol) and TEA (0.642 g, 6.36 mmol) in DMF (8 mL) , was stirred at rt for 4 h. Water (50 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine (3 x 20 mL), dried over Na2S04, and concentrated in vacuo and purified by flash column (silica:200-300 mesh, eluted with DCM:MeOH (50: 1) to afford (S)-6-(2-cyano-4-methylpent- 2-enamido)-2-((S)-2-isobutyramidopropanamido)-N-((R)-3-methyl-l-((3aS,4S,6S,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxaborol-2-yl)butyl)hexanamide as a yellow solid (0.6 g, 18% for 5 steps). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
190 mg | 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 dichloromethane; at 25℃; for 4h; | Into a lOO-mL round-bottom flask, was placed l-[(lR)-2-phenyl-l-[(lS,2S,6R,8S)- 2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6. l. l.0A[2,6]]decan-4-yl]ethyl]-3-[(2R)-pyrrolidin-2- y I methyl ]urea (631 mg, 1.48 mmol, 1 eq.), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (412.7 mg, 2.97 mmol, 2 eq.), HATU (1.1 g, 2.89 mmol, 2 eq.), DIEA (574.6 mg, 4.45 mmol, 3 eq.) and dichloromethane (20 mL). The resulting solution was stirred for 4 h at 25 C. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC to give 190 mg (23%) of 3-[[(2R)-l-[2-cyano-2-(2- methylpropylidene)acetyl]pyrrolidin-2-yl]methyl]-l-[(lR)-2-phenyl-l-[(lS,2S,6R,8S)-2, 9, 9-trimethyl- 3,5-dioxa-4-boratricyclo[6.l.l.0A[2,6]]decan-4-yl]ethyl]urea as a yellow solid after lyophilization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | 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 dichloromethane; at 20℃; | Into a 25-mL round-bottom flask, was placed a solution of l-[(lR)-2-phenyl-l- [(lS,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0A[2,6]]decan-4-yl]ethyl]-3-[(2R)- piperidin-2-ylmethyl]urea (73 mg, 0.17 mmol, 1.00 eq.) in dichloromethane (4 mL), DIEA (64.4 mg, 0.50 mmol, 3.00 eq.), HATU (95 mg, 0.25 mmol, 1.50 eq.), and <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (28 mg, 0.20 mmol, 1.20 eq.). The resulting solution was stirred for overnight at rt. The reaction was then quenched by the addition of H2O (2 mL). The resulting mixture was washed with brine (1 x 10 mL). The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (73 mg) was purified by prep- HPLC with the following conditions (2-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge Prep C18 OBD Column, 19 mm X150 mm 5um; mobile phase, Water (10 mmol/L NH4HCO3+0.1%NH3.H2O) and ACN (69% ACN up to 70% in 7 min); Detector, UV 254/220nm. This resulted in 28 mg (30%) of 3- [[(2R)-1 -[2-cyano-2-(2-methylpropylidene)acetyl]piperidin-2-yl] methyl] - 1 - [( 1 R)-2 -phenyl- 1 - [(lS,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0A[2,6]]decan-4-yl]ethyl]urea as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | 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 dichloromethane; at 20℃; for 3h; | Into a 50-mL round-bottom flask, was placed l-[(lR)-2-phenyl-l-[(lS,2S,6R,8S)- 2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6. l. l.0A[2,6]]decan-4-yl]ethyl]-3-[(2S)-piperidin-2- yl methyl ]urea (320 mg, 0.73 mmol, 1.00 eq.), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (122 mg, 0.88 mmol, 1.20 eq.), HATU (415 mg, 1.09 mmol, 1.50 eq.), DIEA (282 mg, 2.18 mmol, 3.00 eq.), dichloromethane (10 mL). The resulting solution was stirred for 3 h at rt. The resulting solution was extracted with dichloromethane (3 x 50 mL) and the organic layers combined. The resulting mixture was washed with 1x50 mL of sodium chloride(sat.). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by prep-HPLC with the following conditions (HPLC- SHIMADZU): Column, XBridge Prep C18 OBD Column, 19 X 150 mm, 5 um; mobile phase, Water (10 mmol/L NH4HCO3+0. l%NH3.H2O) and ACN (70.0% ACN up to 72.0% in 7 min); Detector, UV 254/220nm. This resulted in 65 mg (16%) of 3-[[(2S)-l-[2-cyano-2-(2-methylpropylidene)acetyl]piperidin- 2-yl]methyl]-l-[(lR)-2-phenyl-l-[(lS,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.l. l.0A[2,6]]decan-4-yl]ethyl]urea as a light yellow solid after the lyophilization |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
210 mg | 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 dichloromethane; at 25℃; for 4h; | Into a 100-mL round-bottom flask, was placed l-[(lR)-2-phenyl-l- [(1S,2S,6R,8S)- 2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0A[2,6]]decan-4-yl]ethyl]-3-[(2S)-pyrrolidin-2- yl methyl ]urea (607 mg, 1.43 mmol, 1.00 eq.), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (397 mg, 2.85 mmol, 2.00 eq.), HATU (1.1 g, 2.89 mmol, 2.00 eq.), DIPEA (552.7 mg, 4.28 mmol, 3.00 eq.), and dichloromethane (20 mL). The resulting solution was stirred for 4 h at 25 C. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC with the following conditions (2- AnalyseHPLC-SHIMADZU(HPLC- 10)) : Column, XBridge Prep C18 OBD Column, 19 X 150 mm, 5 um; mobile phase, Water (10 mmol/L NH4HCO3+0.1%NH3.H2O) and ACN (65.0% ACN up to 69.0% in 7 min); Detector, UV 254/220nm. This resulted in 210 mg (27%) of 3-[[(2S)-l-[2-cyano-2-(2- methylpropylidene)acetyl]pyrrolidin-2-yl]methyl]-l-[(lR)-2-phenyl-l-[(lS,2S,6R,8S)-2, 9, 9-trimethyl- 3,5-dioxa-4-boratricyclo[6.1.1.0A[2,6]]decan-4-yl]ethyl]urea as a yellow solid after the lyophilization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.32 g | With triethylamine; 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℃;Inert atmosphere; | A solution of (S)-6-amino-2-((2S,3R)-3-hydroxy-2-isobutyramidobutanamido)-N- ((R)-3-methyl-l-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d] [l,3,2]dioxaborol-2- yl)butyl)hexanamide (1.6 g, 2.83 mmol), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (0.394 g, 2.83 mmol), HATU (1.18 g, 3.11 mmol) and TEA (0.571 g, 5.66 mmol) in DMF (10 mL) , was stirred at rt for 3 h under argon. Water (50 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with brine (2 x 20 mL), dried over Na2S04, and concentrated in vacuo. The residue was purified by flash column (silica:200-300 mesh, eluted with DCM:MeOH (20: 1)) to afford (S)-6-(2-cyano-4-methylpent-2-enamido)-2-((2S,3R)-3-hydroxy-2-isobutyramidobutanamido)-N-((R)-3- methyl-l-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxaborol-2- yl)butyl)hexanamide as a yellow solid (0.32 g, 17%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
380 mg | To a solution of (S)-2-acetamido-6-amino-N-((R)-2-phenyl-l-((3aS,4S,6S,7aR)- 3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxaborol-2-yl)ethyl)hexanamide (167 mg, 1.2 mmol) and DIPEA (390 mg, 3 mmol) in DMF (5 mL) at 0 C was added BOP (530 mg, 1.2 mmol). After stirring at 0 C for 1 h, <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (470 mg, 1. mmol) was added. The resulting mixture was stirred at rt for 3 h, before being partitioned between HC1 (1M) and EtOAc. The organic layer was washed with aq. NaHC03, water and brine, dried over Na2S04 and filtrated. The filtrate was concentrated to dryness to afford (S)-2-acetamido-6-(2-cyano-4-methylpent-2-enamido)-N-((R)-2 -phenyl- l-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxaborol-2- yl)ethyl)hexanamide as an off-white solid (380 mg, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
400 mg | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; at 0 - 20℃; | DIPEA (0.96 g, 7.41 mmol) was added to a stirred solution of (S)-6-amino-N-((R)-2- phenyl-l-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d] [l,3,2]dioxaborol-2- yl)ethyl)-2-((2,2,2-trifluoroethyl)amino)hexanamide hydrochloride (1.35 g, 2.47 mmol), 2-cyano-4- methylpent-2-enoic acid (275 mg, 1.98 mmol) and BOP (1.092 g, 2.47 mmol) in DMF (10 mL) at 0 C. The mixture was stirred at rt for 2 h., then washed with brine (25 mL), dried over Na2S04 and concentrated in vacuo. The crude residue was purified by flash column chromatography with MeOH: dichlorome thane to afford (S)-6-(2-cyano-4-methylpent-2-enamido)-N-((R)-2-phenyl-l-((3aS,4S,6S,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxaborol-2-yl)ethyl)-2-((2,2,2- trifluoroethyl)amino)hexanamide as a white solid (400 mg, 25%). |
Tags: 760-58-7 synthesis path| 760-58-7 SDS| 760-58-7 COA| 760-58-7 purity| 760-58-7 application| 760-58-7 NMR| 760-58-7 COA| 760-58-7 structure
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