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CAS No. : | 94790-37-1 | MDL No. : | MFCD00075445 |
Formula : | C11H16F6N5OP | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UQYZFNUUOSSNKT-UHFFFAOYSA-N |
M.W : | 379.24 | Pubchem ID : | 2733084 |
Synonyms : |
|
Num. heavy atoms : | 24 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.36 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 9.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 79.02 |
TPSA : | 67.85 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -4.88 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 5.26 |
Log Po/w (WLOGP) : | 6.88 |
Log Po/w (MLOGP) : | 3.11 |
Log Po/w (SILICOS-IT) : | -1.84 |
Consensus Log Po/w : | 2.68 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.58 |
Solubility : | 0.000987 mg/ml ; 0.0000026 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -6.43 |
Solubility : | 0.000139 mg/ml ; 0.000000368 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -2.04 |
Solubility : | 3.43 mg/ml ; 0.00906 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.51 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P273-P280-P301+P312+P330-P302+P352+P312-P305+P351+P338+P310 | UN#: | 3077 |
Hazard Statements: | H302+H312-H315-H318-H411 | Packing Group: | Ⅲ |
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 |
---|---|---|
In N-methyl-acetamide; | 2'-Deoxy-pseudoisocytidine CPG (3) To a solution of 17 mg of 5-trifluoromethyl-4'-(3-carboxypropionyl)-5'-dimethoxytrityl-2'-deoxyuridine, obtained above, in 0.6 mL of dimethylformamide (DMF) was added 8.3 mg of <strong>[94790-37-1]2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate</strong> (HBTU), 5.7 muL of diisopropylethyl amine (DIPEA) and 594 mg of CPG (37 muM/g). The mixture was shaken for 2 hours and then washed with DMF (4*20 mL) and THF (2*20 mL). The 5-trifluoromethyl-2'-deoxyuridine CPG product was dried under high vacuum for 4 hours. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The compounds disclosed hereinafter were prepared according to the following procedure: The carboxylic acid (0.06 mmol) was dissolved with N,N-diisopropylethylamine (DIEA) (0.106 mmol) and dichloromethane (DCM) (0.3 mL). To this mixture was added 1-hydroxybenzotriazole hydrate (HOBT) (0.06 mmol) in N,N-dimehtylformamide (DMF) (0.02 mL). To the reaction were added 3-amino-4, 6-dimethyl-2-(4-{2-[([(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}amino)pyridine (0.044 mmol) in DCM (0.3 mL) and DMF (0.08 mL), then O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) (0.13 mmol) in DMF (0.25 mL). The reaction solution was stirred for 6 hr at room temperature, then heated at 40 C. over night. After removal of the solvent, the residue was dissolved in MeOH (0.8 mL). The solution was loaded onto a Varian BondElute SCX cartridge (500 mg/3 mL) which was preconditioned with 2 mL of MeOH. The solid-phase matrix was washed with 5 mL of MeOH and then eluted with 2N ammonia/MeOH (3 mL). After the removal of solvent, the product was used for the next step reaction. [1954] The intermediate product of 1st step was dissolved with EtOH (2 mL), then to the reaction solution was added excess 2N aq.NaOH (1 mL). The reaction mixture was stirred at 40 C. to 70 C. over night. After the reaction finished, the solvent was removed. To the residue was added 2N aq.HCl (1 mL, adjusted with pH 7.0). The aqueous layer was extracted with DCM (1 mL×3). The organic layer was concentrated to afford the residue. The crude product was purified by preparative LC/MS (Shiseido capcellpack UG 80 C18 (20×50 mm) eluting with MeOH/0.1% HCOOH (v/v, 20/80 to 90/10) to give the title compound as a formate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 2-chloro-N-hydroxy-acetamidine (781 mg, 7.2 mmol), 5-chloro-thiophene-3- carboxylic acid (1.4 g), HBTU (3.55 g) and DIPEA (1.3 g) in DMF (20 ml) was stirred at ambient temperature for 1 h before heated at [120 C] for 4 h under argon. Removal of the solvent in vacuo followed by silica gel chromatography of the obtained residue using 0- 20% EtOAc in n-heptane yielded 38.5 mg of the faster eluting 3-chloromethyl-5- (5-chloro- [THIOPHEN-3-YL)- [1,] 2,4] oxadiazole as a syrup, followed by 65 mg of the slower eluting [1- [5-] [(5-CHLORO-THIOPHEN-3-YL)- [1,] 2,4] [OXADIAZOL-3-YLMETHOXY]-LH-BENZOTRIAZOLE] as a white solid. 3-CHLOROMETHYL-5- (5-CHLORO-THIOPHEN-3-YL)- [1,2,4]oxadiazole: 1H NMR (CDC13) d (ppm): 8. 01 (d, 1H), 7.50 (d, [1H),] 4.63 (s, 2H). 1-[5-(5-CHLORO-THIOPHEN-3-YL)- [1,2,4]oxadiazol-3-YLMETHOXY]-1H-BENZOTRIAZOLE : 1H NMR (CDC13) d (ppm): 7.97 (m, 2H), 7.52 (dt, 1H), 7.44 (m, 2H), 7.34 (m, 1H), 5.70 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 4h; | A mixture of 8 (1 gram), HBTU [(O-BENZOTRIAZOLE-N,] N, N', N'-tetramethyl- [URONIUM-HEXAFLUORO-PHOSPHATE)] (1.36 grams Cl (2 equiv)), DIPEA (N, N- [DIISOPROPYLETHYLAMINE) (1.6 ML (3 EQUIV) ) AND DMF (DIMETHYLFORMAMIDE) (30] ml) was stirred at room temperature for four hours to form the activated ester 9 (42% yield). 2 equivalents of sodium 2-chloropyrid-4-ylamide (generated from the reaction of 4-amino-2-chloropyridine with sodium hydride) in DMF was added. The reaction mixture was separated by preparative TLC, and identified [BY 1H] NMR and MS as intermediate 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); for 0.166667h; | 2 3-diamino-N-(4-methyl-cyclohexyl)-propionamide BOC20 (17.1 g) was added to a solution of D, L-2, 3-diaminopropionic acid (5.0 g) and triethylamine (24.8 ml) in DIOXANE/WATER 1 : 1 (76 ML). The solution was stirred overnight. EtOAc (100 ml) was added and the water phase was acidified with 1M HC1. The phases were separated and the organic phase was washed with brine, dried and concentrated to a give 8. 5 g of 2, 3-bis-tert-butoxycarbonylamino-propionic acid as a white solid. 6.0 g of the product was dissolved in DMF (180 ml) with HBTU (8.95 g) and diisopropylethylamine (10.2 ML). The resulting solution was stirred for 10 min before 4,4- DIMETHYL-CYCLOHEXYLAMINE hydrochloride (3.25 g) was added. The solution was stirred for 3. 5 h at room temperature and then diluted with 250 ml CH2C12. The mixture was washed with 1M HCl, water, NAHCO3 (SAT) and brine, dried and concentrated to give 7.63g of a crude product which was used without further purification. 7.0 g of the coupling product was added to 30 ml of an ice-cold 2. 5M HCL/MEOH solution. The mixture was then stirred at room temperature for 6 h before being neutralized with 1M NaOH. The aqueous solution was then extracted with CH2C12. The organic phase was dried and concentrated to give 2.66 G. 1H NMR (DMSO) 6 7.62 (bd, 1 H) 2.98 (M, 1 H) 2.64 (M, 1 H) 1.72 (M, 2 H) 1.63 (M, 2 H) 1.28 (M, 1 H) 1.15 (m, 2 H) 0.94 (M, 2 H) 0.84 (d, 3 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); for 0.0833333h; | Example 3 N-(4F4-DIMETHYLCYCLOHEXYL)-3-METHYL-5, 6,7, 8-TETRAHYDROQUINOXALINE-2-CARBOXAMIDE A solution of 3-methyl-5, 6,7, 8-TETRAHYDRO-QUINOXALINE-2-CARBOXYLIC acid (10.5 mg), HBTU (25 mg) and diisopropyl ethyl amine (28.5 1LL) in DMF (1 ml) was stirred for 5 min. 4,4- Dimethyl-cyclohexylamine hydrochloride (10 mg) was then added and the resulting solution was stirred 3h under a nitrogen atmosphere. The reaction mixture was diluted with 2ml water and extracted twice with EtOAc. The combined organic phases were washed with 1M HCl, NAHC03 (SAT), water and brine, dried and concentrated. Flashchromatography (SIOZ, HEPTANE/ETOAC 4: 1) afforded 4.1 mg of the title COMPOUND. LH NMR (CDC13) 6 7.85 (bd, 1 H) 3.79-3. 89 (M, I H) 2.91-2. 96 (M, 4 H) 2.90 (s, 3 H) 1.92 (M, 4 H) 1.84 (m, 2 H) 1.22-1. 50 (M, 8 H) 0.95 (s, 3 H) 0.93 (s, 3 H). MS (ES) M/Z 302 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
322.9 mg (96%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; quinoclamine; water; | Part A Preparation of methyl 2-(6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexanoylamino)-3-(4-hydroxyphenyl)propanoate 6-(4,6-Diphenyl(2-pyridyloxy))-2,2-dimethylhexanoic acid (0.200 g, 0.513 mmol) was dissolved in dimethylformamide (5 mL). Diisopropylethylamine (223 muL, 1.53 mmol) was added, and the reaction was stirred for 5 min. H-Tyr(Obzl)-Ome (0.198 g, 0.616 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.214 g, 0.564 mmol) were added, and the reaction was stirred under nitrogen for 60 h. The reaction was concentrated to an oil under high vacuum. The oil was dissolved in 50:50 ACN/H2O and lyophilized. The crude product was then purified by preparative HPLC Method 2 to give 322.9 mg (96%) of product. ESMS: Calcd. For C42H44N2O5, 656.33; Found, 657.5 [M+H]+1 HPLC Method 5.Rt=22.768 min Purity=100% |
322.9 mg (96%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; quinoclamine; water; | Part A Preparation of methyl 2-(6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexanoylamino)-3-(4-hydroxyphenyl)propanoate 6-(4,6-Diphenyl(2-pyridyloxy))-2,2-dimethylhexanoic acid (0.200 g, 0.513 mmol) was dissolved in dimethylformamide (5 mL). Diisopropylethylamine (223 muL, 1.53 mmol) was added, and the reaction was stirred for 5 min. H-Tyr(OBzl)-OMe (0.198 g, 0.616 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.214 g, 0.564 mmol) were added, and the reaction was stirred under nitrogen for 60 h. The reaction was concentrated to an oil under high vacuum. The oil was dissolved in 50:50 ACN/H2O and lyophilized. The crude product was then purified by preparative HPLC Method 2 to give 322.9 mg (96%) of product. ESMS: Calcd. for C42H44N2O5, 656.33; Found, 657.5 [M+H]+1 |
322.9 mg (96%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; quinoclamine; water; | Part A Preparation of methyl 2-(6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexanoylamino)-3-(4-hydroxyphenyl)propanoate 6-(4,6-Diphenyl(2-pyridyloxy))-2,2-dimethylhexanoic acid (0.200 g, 0.513 mmol) was dissolved in dimethylformamide (5 mL). Diisopropylethylamine (223 muL, 1.53 mmol) was added, and the reaction was stirred for 5 min. H-Tyr(OBzl)-OMe (0.198 g, 0.616 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.214 g, 0.564 mmol) were added, and the reaction was stirred under nitrogen for 60 h. The reaction was concentrated to an oil under high vacuum. The oil was dissolved in 50:50 ACN/H2O and lyophilized. The crude product was then purified by preparative HPLC Method 2 to give 322.9 mg (96%) of product. ESMS: Calcd. for C42H44N2O5, 656.33; Found, 657.5 [M+H]+1. HPLC Method 5.Rt=22.768 min Purity=100% |
322.9 mg (96%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; quinoclamine; water; | Part A: Preparation of methyl 2-(6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexanoylamino)-3-(4-hydroxyphenyl)propanoate 6-(4,6-Diphenyl(2-pyridyloxy))-2,2-dimethylhexanoic acid (0.200 g, 0.513 mmol) was dissolved in dimethylformamide (5 mL). Diisopropylethylamine (223 muL, 1.53 mmol) was added, and the reaction was stirred for 5 min. H-Tyr(OBzl)-OMe (0.198 g, 0.616 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.214 g, 0.564 mmol) were added, and the reaction was stirred under nitrogen for 60 h. The reaction was concentrated to an oil under high vacuum. The oil was dissolved in 50:50 ACN/H2O and lyophilized. The crude product was then purified by preparative HPLC Method 2 to give 322.9 mg (96%) of product. ESMS: Calcd. for C42H44N2O5, 656.33; Found, 657.5 [M+H]+1 HPLC Method 5.Rt=22.768 min Purity = 100% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.2 mg (63%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; | Part C Preparation of N-(1-(N-(5-((tert-butoxy)carbonylamino)-5-(N-(2,3,4,5,6-pentahydroxyhexyl)carbamoyl)pentyl)carbamoyl)-2-(4-benzyloxyphenyl)ethyl)-6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexanamide 6-Amino-2-((tert-butoxy)carbonylamino)-(N-(2,3,4,5,6-pentahydroxyhexyl)hexanamide (0.050 g, 0.122 mmol) was dissolved in dimethylformamide (3 mL). Diisopropylethylamine (63.8 muL, 0.366 mmol) was added, and the reaction was stirred for 5 min. 2-(6-(4,6-Diphenyl(2-pyridyloxy))-2,2-dimethylhexanoylamino)-3-(4-hydroxyphenyl)propanoic acid (0.0942 g, 0.146 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.050 g, 0.134 mmol) were added, and the reaction was stirred under nitrogen for 72 h. The reaction was concentrated to an oil under high vacuum. The oil was then purified by preparative HPLC Method 2 to give 79.2 mg (63%) of product. ESMS: Calcd. For C58H75N5O12, 1033.54; Found, 1034.5 [M+H]+1HPLC Method 5. Rt=19.290 min Purity=84% |
79.2 mg (63%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; | Part C Preparation of N-(1-(N-(5-((tert-butoxy)carbonylamino)-5-(N-(2,3,4,5,6-pentahydroxyhexyl)carbamoyl)pentyl)carbamoyl)-2-(4-benzyloxyphenyl)ethyl)-6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexanamide 6-Amino-2-((tert-butoxy)carbonylamino)-(N-(2,3,4,5,6-pentahydroxyhexyl)hexanamide (0.050 g, 0.122 mmol) was dissolved in dimethylformamide (3 mL). Diisopropylethylamine (63.8 muL, 0.366 mmol) was added, and the reaction was stirred for 5 min. 2-(6-(4,6-Diphenyl(2-pyridyloxy))-2,2-dimethylhexanoylamino)-3-(4-hydroxyphenyl)propanoic acid (0.0942 g, 0.146 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.050 g, 0.134 mmol) were added, and the reaction was stirred under nitrogen for 72 h. The reaction was concentrated to an oil under high vacuum. The oil was then purified by preparative HPLC Method 2 to give 79.2 mg (63%) of product. ESMS: Calcd. for C58H75N5O12, 1033.54; Found, 1034.5 [M+H]+1 |
79.2 mg (63%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; | Part C Preparation of N-(1-(N-(5-((tert-butoxy)carbonylamino)-5-(N-(2,3,4,5,6-pentahydroxyhexyl)carbamoyl)pentyl)carbamoyl)-2-(4-benzyloxyphenyl)ethyl)-6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexanamide 6-Amino-2-((tert-butoxy)carbonylamino)-(N-(2,3,4,5,6-pentahydroxyhexyl)hexanamide (0.050 g, 0.122 mmol) was dissolved in dimethylformamide (3 mL). Diisopropylethylamine (63.8 muL, 0.366 mmol) was added, and the reaction was stirred for 5 min. 2-(6-(4,6-Diphenyl(2-pyridyloxy))-2,2-dimethylhexanoylamino)-3-(4-hydroxyphenyl)propanoic acid (0.0942 g, 0.146 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.050 g, 0.134 mmol) were added, and the reaction was stirred under nitrogen for 72 h. The reaction was concentrated to an oil under high vacuum. The oil was then purified by preparative HPLC Method 2 to give 79.2 mg (63%) of product. ESMS: Calcd. for C58H75N5O12, 1033.54; Found, 1034.5 [M+H]+1. HPLC Method 5. Rt=19.290 min Purity=84% |
79.2 mg (63%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; | Part C: Preparation of N-(1-(N-(5-((tert-butoxy)carbonylamino)-5-(N-(2,3,4,5,6-pentahydroxyhexyl)carbamoyl)pentyl)carbamoyl)-2-(4-benzyloxyphenyl)ethyl)-6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexanamide 6-Amino-2-((tert-butoxy)carbonylamino)-(N-(2,3,4,5,6-pentahydroxyhexyl)hexanamide (0.050 g, 0.122 mmol) was dissolved in dimethylformamide (3 mL). Diisopropylethylamine (63.8 muL, 0.366 mmol) was added, and the reaction was stirred for 5 min. 2-(6-(4,6-Diphenyl(2-pyridyloxy))-2,2-dimethylhexanoylamino)-3-(4-hydroxyphenyl)propanoic acid (0.0942 g, 0.146 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.050 g, 0.134 mmol) were added, and the reaction was stirred under nitrogen for 72 h. The reaction was concentrated to an oil under high vacuum. The oil was then purified by preparative HPLC Method 2 to give 79.2 mg (63%) of product. ESMS: Calcd. for C58H75N5O12, 1033.54; Found, 1034.5 [M+H]+1 HPLC Method 5. Rt=19.290 min Purity = 84% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
171 mg (63%) | With N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; In N,N-dimethyl-formamide; | Part A Preparation of 2-((tert-butoxy)carbonylamino)-N-(6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexyl)-3-((fluoren-9-ylmethoxy)carbonylamino)propanamide To a solution of 6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexylamine (130 mg, 0.347 mmol) in DMF (6 mL) was added diisopropylethylamine (0.18 mL, 1.04 mmol) followed by 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (158 mg, 0.416 mmol). After stirring at room temperature for 15 min, Boc-DAP(Fmoc)-OH (178 mg, 0.416 mmol) was added. The mixture was stirred for 24 h, concentrated under high vacuum and purified by reverse-phase HPLC (water-acetonitrile gradient containing 0.1% TFA) to afford 171 mg (63%) of a white powdered solid. ESMS: Calculated for C48H54N4O6, 782.40 Found 783.5 [M+H]+1; Rt=23.382 min (87.9% pure, Vydac C18 column; gradient 20 to 100% acetonitrile/water+0.1% TFA over 30 min). |
171 mg (63%) | With N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; In N,N-dimethyl-formamide; | Part A: Preparation of 2-((tert-butoxy)carbonylamino)-N-(6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexyl)-3-((fluoren-9-ylmethoxy)carbonylamino)propanamide To a solution of 6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexylamine (130 mg, 0.347 mmol) in DMF (6 mL) wasadded diisopropylethylamine (0.18 mL, 1.04 mmol) followed by 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (158 mg, 0.416 mmol). After stirring at room temperature for 15 min, Boc-DAP(Fmoc)-OH (178 mg, 0.416 mmol) was added. The mixture was stirred for 24 h, concentrated under high vacuum and purified by reverse-phase HPLC (water-acetonitrile gradient containing 0.1% TFA) to afford 171 mg (63%) of a white powdered solid. ESMS: Calculated for C48H54N4O6, 782.40 Found 783.5 [M+H]+1; Rt= 23.382 min (87.9% pure, Vydac C18 column; gradient 20 to 100% acetonitrile/water + 0.1% TFA over 30 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.9 mg (42%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; quinoclamine; water; | Part A Preparation of N-(6-(4-benzo[d]1,3-dioxolan-5-yl-6-phenyl(2-pyridyloxy))-2,2-dimethylhexyl)-2-((tert-butoxy)carbonylamino)-3-(4-hydroxyphenyl)propanamide 1-Amino-2,2-dimethyl-6-[(4-(3,4-methylenedioxyphenyl)-6-phenyl-2-pyridinyl)oxy]-hexane (0.100 g, 0.239 mmol) was dissolved in dimethylformamide (5 mL). Diisopropylethylamine (104.1 muL, 0.598 mmol) was added, and the reaction was stirred for 5 min. Boc-Tyr-OH (0.081 g, 0.287 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.100 g, 0.263 mmol) were added, and the reaction was stirred under nitrogen for 24 h. The reaction was concentrated to an oil under high vacuum. The oil was dissolved in 50:50 ACN/H2O and lyophilized. The crude product was then purified by preparative HPLC Method 2 to give 67.9 mg (42%) of product. ESMS: Calcd. For C40H47N3O7, 681.34; Found, 680.3 [M-H]-1HPLC Method 5. Rt=19.238 min Purity=98% |
67.9 mg (42%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; quinoclamine; water; | Part A Preparation of N-(6-(4-benzo[d]1,3-dioxolan-5-yl-6-phenyl(2-pyridyloxy))-2,2-dimethylhexyl)-2-((tert-butoxy)carbonylamino)-3-(4-hydroxyphenyl)propanamide 1-Amino-2,2-dimethyl-6-[(4-(3,4-methylenedioxyphenyl)-6-phenyl-2-pyridinyl)oxy]-hexane (0.100 g, 0.239 mmol) was dissolved in dimethylformamide (5 mL). Diisopropylethylamine (104.1 muL, 0.598 mmol) was added, and the reaction was stirred for 5 min. Boc-Tyr-OH (0.081 g, 0.287 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.100 g, 0.263 mmol) were added, and the reaction was stirred under nitrogen for 24 h. The reaction was concentrated to an oil under high vacuum. The oil was dissolved in 50:50 ACN/H2O and lyophilized. The crude product was then purified by preparative HPLC Method 2 to give 67.9 mg (42%) of product. ESMS: Calcd. for C40H47N3O7, 681.34; Found, 680.3 [M-H]-1 |
67.9 mg (42%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; quinoclamine; water; | Part A Preparation of N-(6-(4-benzo[d]1,3-dioxolan-5-yl-6-phenyl(2-pyridyloxy))-2,2-dimethylhexyl)-2-((tert-butoxy)carbonylamino)-3-(4-hydroxyphenyl)propanamide 1-Amino-2,2-dimethyl-6-[(4-(3,4-methylenedioxyphenyl)-6-phenyl-2-pyridinyl)oxy]-hexane (0.100 g, 0.239 mmol) was dissolved in dimethylformamide (5 mL). Diisopropylethylamine (104.1 muL, 0.598 mmol) was added, and the reaction was stirred for 5 min. Boc-Tyr-OH (0.081 g, 0.287 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.100 g, 0.263 mmol) were added, and the reaction was stirred under nitrogen for 24 h. The reaction was concentrated to an oil under high vacuum. The oil was dissolved in 50:50 ACN/H2O and lyophilized. The crude product was then purified by preparative HPLC Method 2 to give 67.9 mg (42%) of product. ESMS: Calcd. for C40H47N3O7, 681.34; Found, 680.3 [M-H]-1 HPLC Method 5. Rt=19.238 min Purity=98% |
Yield | Reaction Conditions | Operation in experiment |
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With 4-methyl-morpholine; citric acid; In N,N-dimethyl-formamide; | Example 1 Synthesis of 3-nitro-N-(1H-benzoimidazol-2-yl)-benzamide (1). A 200 mL flask was charged with 2.25 g 3-nitrobenzoic acid (13.46 mmol, 1.0 equiv), 3.59 g 2-aminobenzimidazole (26.92 mmol, 2.0 equiv), 5.63 g O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 14.81 mmol, 1.10 equiv), and 1-hydroxybenzotriazole hydrate (HOBT, 14.13 mmol, 1.05 equiv). The flask was then charged with 40 mL DMF, stirring was initiated (magnetic stirrer) and 1.71 mL N-methylmorpholine (NMM, 15.48 mmol, 1.15 equiv) was added in one portion to the suspension. After 6 h, the suspension was diluted with 200 mL of a 10% citric acid solution. After stirring an additional 30 min, the suspension was filtered and the resulting solid was washed (2*H2O, then 2*sat. NaHCO3). The solid was then triturated with EtOAc (30 mL), filtered, and dried under reduced pressure to give 3.16 g of the product as a tan solid (11.2 mmol). 1H NMR (DMSO-d6, 400 MHz) delta12.60 (broad s, 2 H), 8.96 (t, J=2.1 Hz, 1 H), 8.55 (d, J=7.8 Hz, 1 H), 8.38 (m, 1 H), 7.78 (t, J=7.9 Hz, 1 H), 7.43 (dd, J=3.2, 5.9 Hz, 2 H), 7.18 (dd, J=3.2, 5.9 Hz, 2 H); MS: ESI(-) m/z 281.1 (M-H). |
Yield | Reaction Conditions | Operation in experiment |
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With 4-methyl-morpholine; citric acid; In methanol; N,N-dimethyl-formamide; | (d) 3-Nitro-N-(5-(2',2'-dimethylpropionyl)-1H-benzoimidazol-2-yl)benzamide A dry flask was charged with 2.56 g 3-nitrobenzoic acid (15.3 mmol, 1.0 equiv), 4.65 g 2-amino-5-(2',2'-dimethylpropionyl)benzimidazole (prepared above in step (c), 19.9 mmol, 1.3 equiv), 2.18 g 1-hydroxybenzotriazole hydrate (HOBT, 16.1 mmol, 1.05 equiv), and 6.39 g O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 16.8 mmol, 1.10 equiv). 45 mL DMF was then added followed by 1.94 mL N-methylmorpholine (NMM, 17.6 mmol, 1.15 equiv). The resulting slurry was allowed to stir for 20 h, and was then diluted with a 10% citric acid solution and extracted (3*EtOAc). The organics were washed (1*10% citric acid, 2*sat. NaHCO3, 1*brine), dried (Na2SO4), and concentrated under reduced pressure. The resulting solid was triturated from MeOH, filtered, washed (3*MeOH), and dried under reduced pressure to give the product as a tan solid (4.87 g, 12.7 mmol): 1H NMR (DMSO-d6, 400 MHz) delta12.60 (broad s, 2 H), 8.96 (t, J=1.9 Hz, 1 H), 8.55 (d, J=7.8 Hz, 1 H), 8.41 (dd, J=1.5, 8.2 Hz, 1 H), 7.81 (t, J=7.9 Hz, 1 H), 7.45 (d, J=8.6 Hz, 1 H), 7.16 (d, J=2.2 Hz, 1 H), 6.91 (dd, J=2.2, 8.5 Hz, 1 H), 1.30 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
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With 4-methyl-morpholine; In N,N-dimethyl-formamide; | (d) 3-Carboxymethyl-N-(1 -(2-morpholin-4-yl-ethyl)-1H-benzoimidazol-2-yl)-benzamide A portion of the product 1-(2-morpholin-4-yl-ethyl)-2-aminobenzimidazole obtained above (100 mg, 0.406 mmol, 1.0 equiv) was combined in a flask with 169 mg O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 0.447 mmol, 1.1 equiv), 73.2 mg 3-carboxymethylbenzoic acid (0.406 mmol, 1.0 equiv) and 58 mg 1-hydroxybenzotriazole hydrate (HOBT, 0.426 mmol, 1.05 equiv) followed by the addition of 2 mL DMF and 51 muL N-methylmorpholine (NMM, 0.467 mmol, 1.15 equiv). The solution was allowed to stir for 24 h followed by dilution with 30 mL sat. NaHCO3. The resulting solution was extracted (1*EtOAc), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 2-4% MeOH/CH2Cl2) gave the product as a tan solid (53 mg, 0.130 mmol). 1H NMR (DMSO-d6, 400 MHz) delta12.8 (s, 1 H), 8.82 (s, 1 H), 8.44 (m, 1 H), 8.08 (m, 1 H), 7.64 (m, 1 H), 7.55 (m, 2 H), 7.25 (m, 2 H), 4.39 (m, 2 H), 3.85 (s, 3 H), 3.48 (m, 4 H), 2.71 (m, 2 H), 2.50 (m, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
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With 4-methyl-morpholine; In N,N-dimethyl-formamide; | (d) cis-4-(5-fluoro-2-(3-trifluoromethyl-benzoylamino)-benzoimidazol-1-yl)-cyclohexanecarboxylic acid ethyl ester 305 mg cis-4-(2-amino-5-fluoro-benzoimidazol-1-yl)-cyclohexanecarboxylic acid ethyl ester (1.0 mmol, 1.0 equiv) was combined in a flask with 569 mg O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (FIBTU, 1.5 mmol, 1.5 equiv), 285 mg 3-trifluoromethylbenzoic acid (1.5 mmol, 1.5 equiv) and 203 mg 1-hydroxybenzotriazole hydrate (HOBT, 1.5 mmol, 1.5 equiv), followed by the addition of 12 mL DMF and 165 muL N-methylmorpholine (NMM, 1.5 mmol, 1.5 equiv). The solution was allowed to stir for 24 h and then diluted with sat. NaHCO3. The solution was extracted (2*EtOAc), washed (1*brine), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 20% EtOAc/hexane) gave 0.39 g of the product as a tan solid (0.82 mmol). |
Yield | Reaction Conditions | Operation in experiment |
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With 4-methyl-morpholine; In N,N-dimethyl-formamide; | (g) N-[1-(3-fluorophenyl)-5-piperidino-1-ylmethyl-1H-benzoimidazol-2-yl]-3-trifluoromethyl-benzamide 500 mg 1-(3-fluorophenyl)-5-piperidin-1-ylmethyl-1H-benzoimidazol-2-ylamine (1.54 mmol, 1.0 equiv) was combined in a flask with 877 mg O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 2.32 mmol, 1.5 equiv), 440 mg 3-trifluoromethylbenzoic acid (2.32 mmol, 1.5 equiv) and 312 mg 1-hydroxybenzotriazole hydrate (HOBT, 2.32 mmol, 1.5 equiv) followed by the addition of 12 mL DMF and 254 muL N-methylmorpholine (NMM, 2.32 mmol, 1.5 equiv). The solution was allowed to stir for 24 h and then diluted with sat. Na2HCO3. The solution was extracted (2*10% MeOH/CH2Cl2), washed (1*brine), dried (NaSO4) and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 5% MeOH/CH2Cl2) gave 0.2 g of the product as a tan solid (0.2 mmol). 1H NMR (DMSO-d6, 400 MHz) 13.0 (s, 1 H), 8.35 (s, 1 H), 8.30 (d, J=7.6 Hz, 1 H), 7.88 (d, J=7.6 Hz, 1 H), 7.72 (m, 3 H), 7.62 (m, 2 H), 7.47 (t, J=7.6 Hz, 1 H), 7.22 (broad s, 2 H), 3.55 (s, 2 H), 2.38 (broad s, 4 H), 1.5 (m, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
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190.5 mg (116%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; | Part A Preparation of tert-butyl 2-(6-(4-benzo[d]1,3-dioxolan-5-yl-6-phenyl(2-pyridyloxy))-2,2-dimethylhexanoyl-amino)-3-(4-(tert-butoxy)phenyl)propanoate 6-(4-Benzo[d]1,3-dioxolan-5-yl-6-phenyl(2-pyridyloxy))-2,2-dimethylhexanoic acid (0.100 g, 0.231 mmol) was dissolved in dimethylformamide (5 mL). Diisopropylethylamine (100.5 muL, 0.578 mmol) was added, and the reaction was stirred for 5 min. H-Tyr(OtBu)-OtBu.HCl (0.0838 g, 0.254 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.0964 g, 0.254 mmol) were added, and the reaction was stirred under nitrogen for 24 h. The reaction was concentrated to a residue under high vacuum to give 190.5 mg (116%) of product. The crude product was utilized in the next step. ESMS: Calcd. For C43H52N2O7, 708.38; Found 709.5 [M+H]+1 HPLC Method 5.Rt=23.043 min Purity=87% |
190.5 mg (116%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; | Part A Preparation of tert-butyl 2-(6-(4-benzo[d]1,3-dioxolan-5-yl-6-phenyl(2-pyridyloxy))-2,2-dimethylhexanoyl-amino)-3-(4-(tert-butoxy)phenyl)propanoate 6-(4-Benzo[d]1,3-dioxolan-5-yl-6-phenyl(2-pyridyloxy))2,2-dimethylhexanoic acid (0.100 g, 0.231 mmol) was dissolved in dimethylformamide (5 mL). Diisopropylethylamine (100.5 muL, 0.578 mmol) was added, and the reaction was stirred for 5 min. H-Tyr(OtBu)-OtBu.HCl (0.0838 g, 0.254 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.0964 g, 0.254 mmol) were added, and the reaction was stirred under nitrogen for 24 h. The reaction was concentrated to a residue under high vacuum to give 190.5 mg (116%) of product. The crude product was utilized in the next step. ESMS: Calcd. for C43H52N2O7, 708.38; Found 709.5 [M+H]+1 HPLC Method 5.Rt=23.043 min Purity =87% |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; In N-methyl-acetamide; dichloromethane; ethyl acetate; | 1.4. 1,1-Dimethylethyl (S)-[4-(6-aminopyrid-3-yl)-1-([4-ethylpiperid-3-yl)carbonyl]butyl]-carbamate 2.1 g (5.5 mmol) of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) are added portionwise with stirring, at 0 C. under nitrogen, to a mixture of 2.0 g of (S)-6-amino-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]pyridine-3-pentanoic acid (5.5 mmol), 1.14 g (7.5 mmol) of 4-ethylpiperidine hydrochloride, N,N-diisopropyl-ethylamine (DIEA) (25 ml; 14 mmol) in dichloromethane (30 ml) and 3 ml of anhydrous dimethylformamide (DMF). The mixture is allowed to warm to room temperature and stirring is continued for 18 hours. The reaction mixture is taken up in 250 ml of ethyl acetate and is washed with 50 ml of 0.1 N hydrochloric acid solution and with 50 ml of saturated sodium hydrogen carbonate solution and with 50 ml of saturated sodium chloride solution. The product obtained is then dried over sodium sulphate and then filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluding under pressure with ethyl acetate. 1.48 g of 1,1-dimethylethyl (S)-[4-(6-aminopyrid-3-yl)-1-([4-ethylpiperid-3-yl)carbonyl]butyl]carbamate are obtained in the form of a viscous oil. Yield (%)=74 |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In dichloromethane; water; N,N-dimethyl-formamide; | Example 2b 5,6-Dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic Acid (4-fluorophenyl)amide A mixture of 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid hydrobromide (58 mg), <strong>[94790-37-1]O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate</strong> (181 mg), triethylamine (0.07 mL), 4-fluoroaniline (30 mg), and N,N-dimethylformamide (4 mL) is heated at 400 for 18 hours. The mixture is cooled to room temperature, treated with water (15 mL), and extracted with ethyl acetate (3*50 mL). The combined organic layers are washed with water (2*15 mL) and brine (1*15 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by preparative thin layer chromatography on silica gel, eluding with 5% methanol in dichloromethane, to give 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid (4-fluorophenyl)amide, pale brown solid, 18 mg: LRMS calcd 296.30, found [M+H] 297.2. |
Yield | Reaction Conditions | Operation in experiment |
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190.5 mg (116%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; | Part A Preparation of tert-butyl 2-(6-(4-benzo[d]1,3-dioxolan-5-yl-6-phenyl(2-pyridyloxy))-2,2-dimethylhexanoylamino)-3-(4-(tert-butoxy)phenyl)propanoate 6-(4-Benzo[d]1,3-dioxolan-5-yl-6-phenyl(2-pyridyloxy))-2,2-dimethylhexanoic acid (0.100 g, 0.231 mmol) was dissolved in dimethylformamide (5 mL). Diisopropylethylamine (100.5 muL, 0.578 mmol) was added, and the reaction was stirred for 5 min. H-Tyr(OtBu)-OtBu-HCl (0.0838 g, 0.254 mmol) and 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.0964 g, 0.254 mmol) were added, and the reaction was stirred under nitrogen for 24 h. The reaction was concentrated to a residue under high vacuum to give 190.5 mg (116%) of product. The crude product was utilized in the next step. ESMS: Calcd. for C43H52N2O7, 708.38; Found 709.5 [M+H]+1 |
Yield | Reaction Conditions | Operation in experiment |
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With 4-methyl-morpholine; In N-methyl-acetamide; hexane; | (ii) N-(4-Methylphenyl)-2-[(1,1-dimethylethoxy)carbonyl]amino]-6-methylbenzamide Firstly N-methylmorpholine (6.15 mL, 5.64 g, 55.8 mmol) and then O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10.15 g, 26.8 mmol) are added to a stirred mixture of 2-[(1,1-dimethylethoxy)carbonyl]amino)-6-methylbenzoic acid (5.60 g, 22.3 mmol) and p-toluidine 4.78 g, 44.6 mmol) in dry dimethylformamide (110 mL) under an argon atmosphere, and stirred at 18 C. for 16 hours. The solvent is evaporated off under reduced pressure to give a residue which is treated with aqueous sodium hydrogen carbonate solution (200 mL of 10%) and extracted with dichloromethane (3*100 mL). The combined extracts are washed with aqueous citric acid solution (100 mL of 10%), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 20% ethyl acetate in hexane, and recrystallized from tert-butylmethyl ether-hexane to give the title compound as a colourless crystalline solid, m.p. 250 C. |
Yield | Reaction Conditions | Operation in experiment |
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77% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | EXAMPLE 83 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared from Example 38, 200.0 mg, 0.70 mmol), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (316.9 mg, 0.84 mmol), N,N-diisopropylethylamine (365 mL, 2.09 mmol), and 2-amino-1,3,4-thiadiazole (140.8 mg, 1.39 mmol) in dry N,N-dimethylformamide (2 mL) was stirred at 25 C. under nitrogen for 20 h. The reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1*50 mL), a 10% aqueous hydrochloric acid solution (1*100 mL), and a saturated aqueous sodium chloride solution (1*100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide (197.3 mg, 77%) as a white foam: mp 90-91 C.; EI-HRMS m/e calcd for C16H17Cl2N3OS (M+) 369.0469, found 369.0476. |
77% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | EXAMPLE 83 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 200.0 mg, 0.70 mmol), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (316.9 mg, 0.84 mmol), N,N-diisopropylethylamine (365 mL, 2.09 mmol), and 2-amino-1,3,4-thiadiazole (140.8 mg, 1.39 mmol) in dry N,N-dimethylformamide (2 mL) was stirred at 25 C. under nitrogen for 20 h. The reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (100 mL). The organic layer was washed sequentially with a saturated aqueous sodium bicarbonate solution (1*50 mL), a 10% aqueous hydrochloric acid solution (1*100 mL), and a saturated aqueous sodium chloride solution (1*100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide (197.3 mg, 77%) as a white foam: mp 90-91 C.; EI-HRMS m/e calcd for C16H17Cl2N3OS (M+) 369.0469, found 369.0476. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | EXAMPLE 58 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared in Example 38, 625.2 mg, 2.18 mmol), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (908.3 mg, 2.39 mmol), N,N-diisopropylethylamine (1.1 mL, 6.53 mmol), and 3-aminopyridazine (310.6 mg, 3.27 mmol) in dry N,N-dimethylformamide (11 mL) was stirred at 25 C. under nitrogen for 72 h. The reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (200 mL). The organic layer was washed with a 10% aqueous hydrochloric acid solution and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide (493.8 mg, 62%) as a white foam: mp 70-71 C.; EI-HRMS m/e calcd for C18H19Cl2N3O (M+) 363.0905, found 363.0908. |
62% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | EXAMPLE 58 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 625.2 mg, 2.18 mmol), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (908.3 mg, 2.39 mmol), N,N-diisopropylethylamine (1.1 mL, 6.53 mmol), and 3-aminopyridazine (310.6 mg, 3.27 mmol) in dry N,N-dimethylformamide (11 mL) was stirred at 25 C. under nitrogen for 72 h. The reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (200 mL). The organic layer was washed with a 10% aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide (493.8 mg, 62%) as a white foam: mp 70-71 C.; EI-HRMS m/e calcd for C18H19Cl2N3O (M+) 363.0905, found 363.0908. |
Yield | Reaction Conditions | Operation in experiment |
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70% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; Petroleum ether; | Example 83 Preparation of 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic Acid Methyl Ester Diisopropylethylamine (2.3 mL, 13.2 mmol) was added dropwise to a solution of 3-bromo-4-(methoxycarbonyl)benzoic acid (Example 76; 861 mg, 3.32 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.39 g, 3.65 mmol), 1H-indole-4-methanamine hydrochloride salt (Example 68; 528 mg, 3.98 mmol) and 1-hydroxybenzotriazole (493 mg, 3.65 mmol) in N,N-dimethylformamide (6.5 mL) at 0 C. The solution was allowed to warm to room temperature and then was stirred for 24 h. After the reaction mixture was concentrated under vacuum to remove most of the N,N-dimethylformamide, the residue was diluted with ethyl acetate (50 mL) and washed with 1N hydrochloric acid solution (10 mL), water (10 mL), saturated aqueous sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, evaporated and the residue was chromatographed (silica gel, 25-35% ethyl acetate in petroleum ether) to provide 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid methyl ester (900 mg, 70% yield) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
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73% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Example 78 Preparation of 2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic Acid Methyl Ester Diisopropylethylamine (8.4 mL, 48.2 mmol) was added dropwise to a cooled (~0 C.) solution of with 3-bromo-4-(methoxycarbonyl)benzoic acid (Example 76; 5.00 g, 19.3 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (7.31 g, 19.3 mmol), 3-hydroxybenzylamine hydrochloride salt (Example 69; 3.37 g, 21.2 mmol) and 1-hydroxybenzotriazole (2.6 g, 19.2 mmol) in N,N-dimethylformamide (50 mL). After the solution was allowed to stir at ~0 C. for 1 h, then at room temperature for 4 h, it was concentrated in vacuo (~1 mm) to remove most of the N,N-dimethylformamide. The residue was partitioned between ethyl acetate and 1N hydrochloric acid solution (200 mL each). The ethyl acetate layer was washed with 1N hydrochloric acid solution (2*100 mL) and the combined aqueous layers were extracted with ethyl acetate (50 mL). The combined ethyl acetate layers were washed with saturated sodium bicarbonate solution (2*100 mL) and brine, then dried (MgSO4), filtered and evaporated under reduced pressure. The solid residue was crystallized from hot ethyl acetate (~60 mL) and hexanes (15 mL) to give 2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid methyl ester (5.15 g, 73% yield) as colorless crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | A solution of 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid (202.5 mg, 0.67 mmol) in dry N,N-dimethylformamide (3.3 mL) was treated with N,N-diisopropylethylamine (350 muL, 2.00 mmol), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (303.8 mg, 0.80 mmol), and 2-aminothiazole (133.7 mg, 1.34 mmol). The reaction mixture was stirred at 25 C. under nitrogen for 15 h. The reaction mixture was then concentrated in vacuo to remove N,N-dimethylformamide. The residue was diluted with ethyl acetate (150 mL), and the organic phase was washed with a 10% aqueous hydrochloric acid solution (1*75 mL) and a saturated aqueous sodium chloride solution (1*75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-N-thiazol-2-yl-propionamide (87.5 mg, 34%) as a white solid: mp 244-246 C.; EI-HRMS m/e calcd for C21H27N3O2S (M+) 385.1824, found 385.1832. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; hydrogenchloride; dmap; sodium hydroxide; In 1-methyl-pyrrolidin-2-one; methanol; | EXAMPLE 88 Preparation of dl-[5-Cyclohexylmethyl-2-(3-methyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-yl)-trans-4,5-dihydro-oxazol-4-yl]-(4-methyl-piperazin-1-yl)-methanone To a solution of dl-5-cyclohexylmethyl-2-(3-methyl-4-{3-[tert-butoxycarbonyl-(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-yl)-trans-4,5-dihydro-oxazole-4-carboxylic acid ethyl ester (15.0 mg) in methanol (1 ml) was added 1.0 N aqueous sodium hydroxide (1.0 ml) and the mixture was stirred at room temperature for 20 hours. After addition of 1.0 N aqueous hydrochloric acid (1.0 ml) the solvent was removed under reduced pressure to give a white solid. The solid was then dissolved in 1-methyl-2-pyrrolidinone (1.5 ml) and N-methyl-piperazine (14 mul), <strong>[94790-37-1]2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate</strong> (HBTU: 44 mg), 4-dimethylaminopyridine (15 mg) and pyridine (75 mul) were added. The solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (Fuji Silysia, DU-3050) using 2:3 mixture of n-hexane and ethyl acetate as an eluent to give dl-[5-cyclohexylmethyl-2-(3-methyl-4-{3-[tert-butoxycarbonyl-(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-yl)-trans-4,5-dihydro-oxazol-4-yl]-(4-methyl-piperazin-1-yl)-methanone (2.4 mg). FAB-MS: m/z 688 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; hydrogenchloride; dmap; sodium hydroxide; In methanol; | To a solution of 4-{3-[tert-butoxycarbonyl-(pyridin-3-ylmethyl)-amino]-propoxy}-3-methyl-benzofuran-2-carboxylic acid ethyl ester (121 mg) in methanol (5 ml) was added 1.0 N aqueous sodium hydroxide (1.0 ml) and the mixture was stirred at room temperature for 15 hours. After addition of 1.0 N aqueous hydrochloric acid (1.0 ml) the solvent was removed under reduced pressure to give a white solid (174 mg) which contained a desired carboxylic acid and sodium chloride. Whole white solid, dl-2-amino-4-cyclohexyl-3-hydroxy-butyric acid ethyl ester (74 mg), <strong>[94790-37-1]2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate</strong> (HBTU: 196 mg), 4-dimethylaminopyridine (200 mg), pyridine (1 ml) and 1-methyl-2-pyrrolidinone (4 ml) were mixed and stirred at room temperature for 6.5 hours. The resulted solution was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate. After filtration and removal of ethyl acetate, the crude product (317 mg) was purified by silica gel column chromatography using 3:2 mixture of n-hexane and ethyl acetate as an eluent to give dl-2-[(4-{3-[tert-butoxycarbonyl-(pyridin-3-ylmethyl)-amino]-propoxy}-3-methyl-benzofuran-2-carbonyl)-amino]-4-cyclohexyl-3-hydroxy-butyric acid ethyl ester (119 mg). FAB-MS: m/z 652 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.52 g (57%) | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | A. A solution of [4-(1,1-dimethylethoxy)carbonylamino-piperidin-1-yl]acetic acid (0.5 g, 1.94 mmol), <strong>[94790-37-1]2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate</strong> (0.73 g, 1.94 mmol), and N,N-diisopropylethylamine (1.5 mL, 8.71 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 5 min. beta-(3-Pyridinylmethyl)-4-fluorophenethylamine dihydrochloride 25 (0.586 g, 1.94 mmol) was added, and the resultant solution was stirred at room temperature for 24 h. The solution was poured into a saturated solution of aqueous sodium bicarbonate (~100 mL) and the product was extracted into dichloromethane (~100 mL). The organic layer was washed with water (5*~100 mL) and dried over sodium sulfate. The solvent was evaporated in vacuo to give the piperidineacetamide 28 as an oil, 0.52 g (57%): 1H NMR(CDCl3) delta 0.98-1.25 (m, 2 H), 1.45 (s, 9 H), 1.71-1.79 (m, 2 H), 2.05-2.17 (m, 2 H), 2.41-2.50 (m, 2 H), 2.75-3.00 (m, 3 H), 3.04-3.17 (m, 1 H), 3.33-3.47 (m, 2 H), 3.72-3.83 (m, 1 H), 4.36 (br s, 1 H), 6.93-7.14 (m, 7 H), 7.25 (m, 1 H), 8.24 (s, 1 H), 8.39 (d, 1 H); MS m/e 471 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; In dichloromethane; | [2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester To a solution of 2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-ethanone (0.066 g, 0.17 mmol) in methylene chloride (2 mL) at ambient temperature was added N-methylmorpholine (0.025 mL, 0.23 mmol), 3-tert-butoxycarbonylamino-propionic acid (0.044 g, 0.23 mmol) and O-benzotriazole-1-yl-N,N,N', N'-tetramethyluronium hexafluorophosphate (0.076 g, 0.20 mmol). The resulting solution was stirred at ambient temperature for 60 hours, then concentrated. Radial chromatography (2 mm plate) gave the title compound (0.114 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With hydrogenchloride; In 1,4-dioxane; ethyl acetate; N,N-dimethyl-formamide; | A. (3-Benzo[d]Furan-2-Yl(1H-Indazol-5-Yl))-N-(2-Methoxyethyl)Carboxamide To a solution of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (218 mg, 0.60 mmol) in N,N-dimethylformamide was added O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (250 mg, 0.66 mmol). After stirring for 4 hours the solvent was removed and the material was extracted with ethyl acetate, and the extracts were washed with 1 N HCl, and saturated aqueous sodium carbonate. The organic layer was dried, filtered, and concentrated. The material was taken up in a solution of 4 N HCl in dioxane and stirred for four hours. The reaction was neutralized to pH 7 and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by semi-preprative HPLC. The product was taken up in ethyl acetate and washed with aqueous sodium bicarbonate (45 mg, 35% yield). 1H NMR (DMSO-d6) delta 13.8 (s, 1H), 8.8 (m, 1H), 8.0 (d, 1H), 7.6-7.8 (m, 4H), 7.4 (m, 2H), 3.5 (s, 4H), 3.3 (s, 3H), ES-MS (m/z) 336 [M+1]+. |
35% | With hydrogenchloride; In 1,4-dioxane; ethyl acetate; N,N-dimethyl-formamide; | A. (3-Benzo[d]furan-2-yl(1H-indazol-5-yl))-N-(2-methoxyethyl)carboxamide To a solution of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (218 mg, 0.60 mmol) in N,N-dimethylformamide was added O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (250 mg, 0.66 mmol). After stirring for 4 hours the solvent was removed and the material was extracted with ethyl acetate, and the extracts were washed with 1 N HCl, and saturated aqueous sodium carbonate. The organic layer was dried, filtered, and concentrated. The material was taken up in a solution of 4 N HCl in dioxane and stirred for four hours. The reaction was neutralized to pH 7 and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by semi-preprative HPLC. The product was taken up in ethyl acetate and washed with aqueous sodium bicarbonate (45 mg, 35% yield). 1H NMR (DMSO-d6) delta 13.8 (s, 1H), 8.8 (m, 1H), 8.0 (d, 1H), 7.6-7.8 (m, 4H), 7.4 (m, 2H), 3.5 (s, 4H), 3.3 (s, 3H), ES-MS (m/z) 336 [M+1]+. |
35% | With hydrogenchloride; In 1,4-dioxane; ethyl acetate; N,N-dimethyl-formamide; | A. (3-Benzo [d] furan-2-yl(1H-indazol-5-yl))-N-(2-methoxyethyl)carboxamide To a solution of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (218 mg, 0.60 mmol) in N,N-dimethylformamide was added O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (250 mg, 0.66 mmol). After stirring for 4 hours the solvent was removed and the material was extracted with ethyl acetate, and the extracts were washed with 1 N HCl, and saturated aqueous sodium carbonate. The organic layer was dried, filtered, and concentrated. The material was taken up in a solution of 4 N HCl in dioxane and stirred for four hours. The reaction was neutralized to pH 7 and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by semi-preprative HPLC. The product was taken up in ethyl acetate and washed with aqueous sodium bicarbonate (45 mg, 35% yield). 1H NMR (DMSO-d6) delta 13.8 (s, 1H), 8.8 (m, 1H), 8.0 (d, 1H), 7.6-7.8 (m, 4H), 7.4 (m, 2H), 3.5 (s, 4H), 3.3 (s, 3H), ES-MS (m/z) 336 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With methylamine; | A (3-Benzo[d]Furan-2-Yl(1H-Indazol-5-Yl))-N-Methylcarboxamide The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (300 mg, 0.82 mmol), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (341 mg, 0.9 mrnol) and methylamine (45 mL, 0.9 mmol); (15 mg, 6% yield). RT 7.164 20-100% ODS at 1 mL/min method, ES-MS (m/z) 292 [M+1]+. |
6% | With methylamine; | A (3-Benzo[d]furan-2-yl(1H-indazol-5-yl))-N-methylcarboxamide The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (300 mg, 0.82 mmol), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (341 mg, 0.9 mmol) and methylamine (45 mL, 0.9 mmol); (15 mg, 6% yield). RT 7.164-100% ODS at 1 mL/min method, ES-MS (m/z) 292 [M+1]+. |
6% | With methylamine; | A (3-Benzo[d]furan-2-yl(1H-indazol-5-yl))-N-methylcarboxamide The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (300 mg, 0.82 mmol), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (341 mg, 0.9 mmol) and methylamine (45 mL, 0.9 mmol); (15 mg, 6% yield). RT 7.164 20-100% ODS at 1 mL/min method, ES-MS (m/z) 292 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.49 g (85%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 48 Preparation of (S)-Azepane-1-carboxylic acid [1-(4-benzhydryl-piperazine-1-carbonyl)-3-methyl-butyl]-amide (S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.300 g, 1.17 mmol, Example 1, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.408 mL, 2.34 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.444 g, 1.17 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid benzhydrylpiperazine (0.295 g, 1.17 mmol) was then added. After stirring for, sequentially, 10 minutes at 0 C. and 40 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (50% EtOAc in hexanes) to provide 0.49 g (85%) of the pure titled compound as a white foam; mp 66-74 C. APCI-MS m/z 491.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In diethyl ether; N,N-dimethyl-formamide; | Step A. (S)-(1-Methoxycarbamoyl-3-methyl-butyl)-carbamic acid tert-butyl ester N-tert-Butoxycarbonyl-L-leucine monohydrate (2.5 g, 10 mmol, Bachem Inc., Torrance, Calif.) was dissolved in dry DMF (15 mL) under nitrogen atmosphere and cooled to 5 C. To this solution were added, in succession, N,N-diisopropylethylamine (5.3 mL, 30 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.8 g, 10 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; O,N-dimethylhydroxylamine hydrochloride (1.1 g, 11 mmol, Aldrich, Milwaukee, Wis.) was then added. After additional 30 minutes stirring at 0 C., the reaction mixture was mixed with 75 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution (50 mL), brine (50 mL), saturated aqueous NaHCO3 solution (50 mL), brine (2*50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording 2.3 g of desired product as a clear oil which was used in the subsequent reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.536 g (87%) | In diethyl ether; hexane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 43 Preparation of (S)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-2-methyl-butyl)-amide (S)-2-[(Azepane-1-carbonyl)-amino]-3-methyl-pentanoic acid (0.300 g, 1.17 mmol, Example 16, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N,-diisopropylethylamine (0.408 mL, 2.34 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.444 g, 1.17 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.337 g, 1.17 mmol) was then added. After stirring for, sequentially, 10 minutes at 0 C. and 30 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane, then 60% EtOAc in hexane) to provide 0.536 g (87%) of the pure titled compound as a white foam: mp 64-77 C. APCI-MS m/z 527.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.326 g (75%) | In diethyl ether; hexane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 41 Preparation of (S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentan-1-one (S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid (0.200 g, 0.873 mmol, Example 27, Step A) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N,-diisopropylethylamine (0.304 mL, 1.75 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.331 g, 0.873 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.252 g, 0.873 mmol) was then added. After stirring for, sequentially, 15 minutes at 0 C. and 40 minutes at ambient temperature, reaction mixture was mixed with 50 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (50% EtOAc in hexane) to provide 0.326 g (75%) of the pure titled compound as a white foam: mp 56-65 C. APCI-MS m/z 500.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.4% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | EXAMPLE 23 {2-[3-Cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (prepared as in Example 22A, 263.0 mg, 1.0 mmol) in N,N-dimethylformamide (10 mL) was treated with O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (379 mg, 1.0 mmol), (2-amino-thiazol-4-yl)-acetic acid ethyl ester (279 mg, 1.5 mmol) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol). The reaction mixture was stirred at 25 C. for 5 h. The reaction mixture was then poured into a 2N aqueous hydrochloric acid solution (25 mL) and extracted with ethyl acetate (3*25 mL). The combined organic layers were washed with water (1*75 mL), a saturated aqueous sodium bicarbonate solution (1*75 mL), and a saturated aqueous sodium chloride solution (3*75 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl }-acetic acid ethyl ester (70.0 mg, 39.4%) as a pale yellow oil: FAB-HRMS m/e calcd for C21H25N3O5S (M+H)+ 432.1593, found 432.1595. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.1 g (96%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; hexane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 31 Preparation of (S)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-amide (S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.56 g, 2.2 mmol) was dissolved in dry DMF (7 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.76 mL, 4.4 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.82 g, 2.2 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.63 g, 2.2 mmol, Acros Organics, Pittsburgh, Pa.) was then added. After sequentially 30 minutes stirring at 0 C. and 2 hours at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 1.1 g (96%) of the pure titled compound as a white foam: mp 78-86 C. APCI-MS m/z 527.0 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.43 g (68%) | With N-ethyl-N,N-diisopropylamine; In methanol; diethyl ether; chloroform; N,N-dimethyl-formamide; | EXAMPLE 39 Preparation of (S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-dimethylamino-4-methyl-pentan-1-one dihydrochloride (S)-2-Dimethylamino-4-methyl-pentanoic acid (0.200 g, 1.26 mmol, Example 20, Step A) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.438 mL, 2.51 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.476 g, 1.26 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.362 g, 1.26 mmol) was then added. After sequentially 15 minutes stirring at 0 C. and 20 minutes at ambient temperature, reaction mixture was mixed with 150 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (5% methanol in chloroform). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to provide 0.43 g (68%) of the pure titled compound as a white solid; mp 220-205 C. APCI-MS m/z 430.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.63 g (78%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; hexane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 46 Preparation of 1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-[methyl-(3-methyl-butyl)-amino]-pentan-1-one dihydrochloride 4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid (0.300 g, 1.39 mmol, Example 28, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.485 mL, 2.79 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.528 g, 1.39 mmol). The resulting reaction mixture was stirred at that temperature for 25 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.402 g, 1.39 mmol) was then added. After stirring for, sequentially, 20 minutes at 0 C. and 40 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (30% EtOAc in hexane). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl, subsequent concentration in vacuo and drying under vacuum provided 0.63 g (78%) of the pure titled compound as a white solid: mp 173-186 C. APCI-MS m/z 486.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.284 g (60%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; hexane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 42 Preparation of (S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-morpholin-4-yl-pentan-1-one 4-Methyl-2-morpholin-4-yl-pentanoic acid (0.200 g, 0.994 mmol, Example 23, Step A) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.346 mL, 1.99 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.379 g, 0.994 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.287 g, 0.994 mmol) was then added. After stirring for, sequentially, 10 minutes at 0 C. and 20 minutes at ambient temperature, reaction mixture was mixed with 50 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane) to provide 0.284 g (60%) of the pure titled compound as a white foam; mp 55-63 C. APCI-MS m/z 472.3.0 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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8.88 g (95%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 51 Preparation of (S)-(1-Benzyl-2-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester N-tert-Butoxycarbonyl-L-phenylalanine (4.60 g, 17.3 mmol, Bachem Inc., Torrance, Calif.) was dissolved in dry DMF (33 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (6.04 mL, 34.7 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.58 g, 17.4 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (5.00 g, 17.3 mmol) was then added. After stirring for, sequentially, 15 minutes at 0 C. and 30 minutes at ambient temperature, reaction mixture was mixed with 120 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*120 mL), brine (2*120 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (30% EtOAc in hexanes) to provide 8.88 g (95%) of the pure titled compound as a off-white foam: mp 54-74 C. APCI-MS m/z 536.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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0.58 g (86%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; hexane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 34 Preparation of (R)-Azepane-1-carboxylic acid {1-(4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-amide (R)-2-[{Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.33 g, 1.3 mmol, Example 2, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.45 mL, 2.6 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.49 g, 1.3 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.37 g, 1.3 mmol) was then added. After additional 90 minutes stirring at 0 C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*50 mL), brine (2*50 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 0.58 g (86%) of the pure titled compound as a white foam: mp 71-84 C. APCI-MS m/z 527.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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In methanol; diethyl ether; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 38 Preparation of (S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-cyclohexylamino-4-methyl-pentan-1-one A suspension of (S)-2-cyclohexylamino-4-methyl-pentanoic acid (0.556 g, 2.62 mmol) and 1-bis(4-fluorophenyl)methyl piperazine (0.378 g, 1.31 mmol) in dry DMF (7 mL) was treated with Triton B (2.40 mL, 5.28 mmol, 40 weight percent solution in methanol), a clear solution was obtained. The resulting reaction solution was cooled to 0 C. in an ice-water bath. To this solution was added solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.993 g, 2.62 mmol). After stirring at 0 C. for 30 minutes, the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 60 mL of diethyl ether and 60 mL of saturated aqueous NaHCO3 solution. White solid which forms was removed by filtration. The two layers of the filtrate were separated; the organic layer was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2*50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (30% EtOAc in hexanes) affording 0.48 g (76%) of the pure titled compound as a white foam: mp 45-54 C. APCI-MS m/z 484.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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0.42 g (76%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; hexane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 44 Preparation of (S)-4-Phenyl-piperazine-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-amide (S)-4-Methyl-2-[(4-phenyl-piperazine-1-carbonyl)-amino]pentanoic acid (0.300 g, 0.939 mmol, Example 17, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.327 mL, 1.88 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.356 g, 0.939 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.271 g, 0.939 mmol) was then added. After stirring for, sequentially, 10 minutes at 0 C. and 40 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane, then 60% EtOAc in hexane) to provide 0.42 g (76%) of the pure titled compound as a light yellow foam: mp 83-91 C. APCI-MS m/z 590.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.45 g (82%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; hexane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 33 Preparation of (S)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-2-methyl-propyl)-amide (S)-2-[(Azepane-1-carbonyl)-amino]-3-methyl-butyric acid (0.26 g, 1.1 mmol, Example 26, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.40 g, 1.1 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.31 g, 1.1 mmol) was then added. After additional 90 minutes stirring at 0 C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*50 mL), brine (2*50 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 0.45 g (82%) of the pure titled compound as a white foam; mp 72-82 C. APCI-MS m/z 513.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.53 g (78%) | With N-ethyl-N,N-diisopropylamine; In methanol; diethyl ether; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 47 Preparation of (S)-4-Methyl-piperazine-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-amide (S)-2-[(4-Methyl-piperazine-1-carbonyl)-amino]-4-methyl pentanoic acid (0.300 g, 1.23 mmol, Example 29, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.129 mL, 2.47 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.468 g, 1.23 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.356 g, 1.23 mmol) was then added. After stirring for, sequentially, 10 minutes at 0 C. and 20 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (20% MeOH in EtOAc) to provide 0.53 g (78%) of the pure titled compound as a white foam: mp 65-78 C. APCI-MS m/z 528.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.63 g (72%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; N,N-dimethyl-formamide; | EXAMPLE 5 Preparation of (S)-Azepane-1-carboxylic acid [1-(3,3-diphenyl-propylcarbamoyl)-3-methyl-butyl]-amide (S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.51 g, 2.0 mmol, Example 1, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.68 mL, 3.9 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.74 g, 2.0 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; 3,3-diphenylpropylamine (0.41 g, 1.9 mmol, Aldrich, Milwaukee, Wis.) was then added. After additional 30 minutes stirring at 0 C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo, a white solid was obtained. Recrystallization from EtOAc-hexanes afforded 0.63 g (72%) of the pure titled compound as a white solid; mp 144-145 C. APCI-MS m/z 450.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.39 g (59%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; hexane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 24 Preparation of (S)-4-Methyl-2-piperidin-1-yl-pentanoic acid (3,3-diphenyl-propyl)-amide monohydrochloride (S)-4-Methyl-2-piperidin-1-yl-pentanoic acid monohydrobromide (0.300 g, 1.51 mmol, Example 22, Step A) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.524 mL, 3.01 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.571 g, 1.51 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; 3,3-diphenylpropylamine (0.318 g, 1.50 mmol) was then added. After stirring for, sequentially, 10 minutes at 0 C. and 45 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.39 g (59%) of the pure titled compound as a white foam: mp 58-65 C. APCI-MS m/z 393.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.31 g (50%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; hexane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 25 Preparation of (S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid (3,3-diphenyl-propyl)-amide monohydrochloride (S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid (0.300 g, 1.32 mmol, Example 21, Step A) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.460 mL, 2.63 mmol) and solid O-benzotriazol-1-yl-N,N,N',N '-tetramethyluronium hexafluorophosphate (0.501 g, 1.32 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; 3,3-diphenylpropylamine (0.279 g, 1.32 mmol) was then added. After stirring for, sequentially, 15 minutes at 0 C. and 30 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.31 g (50%) of the pure titled compound as a white foam: mp 67-86 C.; APCI-MS m/z 421.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | (R)-N-{2-Chloro-4-[2-(iso-propylaminocarbonyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide N-Methylmorpholine (1.22 ml) and o-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.092 g) were added to a solution of (R)-N-[2-chloro-4-(2-carboxyphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 125) (0.10 g) and 2-propylamine (0.024 ml) in DCM (20 ml) at (0 C. The reaction mixture was stirred at this temperature for 30 minutes then allowed to warm to room temperature, stirred for a further 3 hours then evaporated to dryness. The residue was purified by chromatography on a silica gel Mega Bond Elut column eluding with 50% ethyl acetate/hexane then triturated with ether/hexane to give the title compound (0.05 g) as a solid. NMR (CDCl3): 1.3 (d, 6H), 1.6 (s, 3H), 4.2-4.32 (m, 1H), 5.8 (brd, 1H), 7.4 (d, 1H), 7.5-7.7 (m, 3H), 7.9 (dd, 1H), 8.05-8.13 (m, 2H), 8.6 (d, 1H), 9.3 (brs, 1H); MS (ESP-): 491. |
Yield | Reaction Conditions | Operation in experiment |
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0.21 g (37%) | With N-ethyl-N,N-diisopropylamine; In methanol; diethyl ether; hexane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 45 Preparation of (S)-Azepane-1-carboxylic acid {1-[4-(9H-fluoren-9-yl)-piperazine-1-carbonyl]-3-methyl-butyl}-amide (S)-2-[(Azepane-1-carbonyl)-amino]4-methyl-pentanoic acid (0.300 g, 1.17 mmol, Example 1, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.816 mL, 4.68 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.444 g, 1.17 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 9-piperazinofluorene dihydrochloride (0.293 g, 1.17 mmol, Maybridge Chemical Co. Ltd., Tintagel Cornwall, U.K.) was then added. After stirring for, sequentially, 20 minutes at 0 C. and 20 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (50% EtOAc in hexane containing 1% MeOH to provide 0.21 g (37%) of the pure titled compound as a white foam: mp 63-73 C. APCI-MS m/z 489.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.67 g (82%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; N,N-dimethyl-formamide; | EXAMPLE 3 Preparation of (S)-Azepane-1-carboxylic acid [1-(benzhydryl-carbamoyl)-3-methyl-butyl]-amide (S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.51 g, 2.0 mmol, Example 1, Step B) was dissolved in dry DMF (6 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (1.0 mL, 5.7 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.74 g, 2.0 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; aminodiphenylmethane hydrochloride (0.43 g, 2.0 mmol, Aldrich, Milwaukee, Wis.) was then added. After additional 30 minutes stirring at 0 C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo, a white solid was obtained. Recrystallization from EtOAc-hexanes afforded 0.67 g (82%) of the pure titled compound as a white solid: mp 180-181 C. APCI-MS m/z 422.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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With ammonium hydroxide; In dichloromethane; acetone; | Example 1 3-(4-Isopropyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic Acid ((R,S)-1,2-Dimethyl-propyl)-amide Dihydrochloride 2.3 g (5.0 mmol) of crude 3-(4-isopropyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid dihydrochloride (compound of Description 4) were dissolved in 200 ml of a 1:1 mixture of CH2Cl2/CH3CN; 2.5 g (6.5 mmol) of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate (HBTU) were added and the reaction mixture was cooled to 0 C. 1.15 ml (10 mmol) of 1,2-dimethylpropylamine, dissolved in 10 ml of dry CH2Cl2, were added dropwise and the reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated in vacuo to dryness and the residue was taken up with EtOAc and washed with H2O, 1 N NaOH and brine, dried over Na2SO4 and evaporated to dryness to yield a crude material which was purified by flash column chromatography on 230-400 mesh silica gel, utilising a mixture of CH2Cl2/MeOH 95:5 containing 0.5% NH4OH (28%). The residue was dissolved in acetone and acidified with HCl/Et2O; the precipitate so formed was recovered by suction filtration to yield 0.3 g of title compound as a yellow solid. C29H38N4O.2HCl; MW=531.57; IR: (KBr) 3413, 2965, 2670, 1649, 1546 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
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1.4 g (90%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; N,N-dimethyl-formamide; | EXAMPLE 6 Preparation of (S)-{1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester N-tert-butoxycarbonyl-L-leucine (0.84 g, 3.4 mmol, Bachem Inc., Torrance, Calif.) was dissolved in dry DMF (7 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (1.8 mL, 10 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.3 g, 3.4 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; benzenebutanamine, 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (1.0 g, 3.4 mmol) was then added. After additional 30 minutes stirring at 0 C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 2% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. Concentration in vacuo followed by drying under vacuum afforded 1.4 g (90%) of the pure titled compound was obtained as a white foam: mp 50-55 C. APCI-MS m/z 475.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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150 mg (60%) | In methanol; diethyl ether; ethyl acetate; N,N-dimethyl-formamide; | Step B A suspension of (S)-2-cyclohexylamino-4-methyl-pentanoic acid (108 mg, 0.51 mmol) and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (151 mg, 0.51 mmol) in dry DMF (4 mL) was treated with Triton B (0.92 mL, 2.0 mmol, 40 weight percent solution in methanol, Aldrich, Milwaukee, Wis.), then sonicated for a few seconds, a clear solution was obtained. The clear solution was concentrated in vacuo to remove most of the methanol, then cooled to 0 C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.19 g, 0.51 mmol) was then added. After stirring at 0 C. for 20 minutes the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*50 mL), brine (2*50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (60% EtOAc in hexanes). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 150 mg (60%) of the pure titled compound as a white foam; mp 75-85 C. APCI-MS m/z 457.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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368 mg (35%) | With 4-methyl-morpholine; In methanol; diethyl ether; N,N-dimethyl-formamide; | Step B A suspension of (S)-2-isopropylamino-4-methyl-pentanoic acid (433 mg, 2.50 mmol), N-methylmorpholine (0.275 mL, 2.50 mmol), and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (750 mg, 2.52 mmol) in dry DMF (12 mL) was treated with Triton B (2.27 mL, 4.99 mmol, 40 wt percent solution in methanol, Aldrich, Milwaukee, Wis.), a clear solution was obtained and cooled to 0 C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.940 g, 2.50 mmol) was then added. After stirring at 0 C. for 90 minutes the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 100 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (100 mL), brine (100 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (EtOAc:hexanes:MeOH 50:50:5). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 368 mg (35%) of the pure titled compound as a white foam: mp 100-103 C. Anal. C25H34N2OF2.1.0HCl: C, 66.28; H, 7.79; N, 6.18; F, 8.39; Cl, 7.83. Found: C, 66.22; H, 7.72; N, 5.80; F, 8.37; Cl, 7.51. |
Yield | Reaction Conditions | Operation in experiment |
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0.432 g (63%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; hexane; ethyl acetate; N,N-dimethyl-formamide; | Step B (S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid (0.300 g, 1.31 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.684 mL, 3.93 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.496 g, 1.31 mmol). The resulting reaction mixture was stirred at that temperature for 25 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.390 g, 1.31 mmol) was then added. After stirring for, sequentially, 15 minutes at 0 C. and 30 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (70% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.432 g (63%) of the pure titled compound as a white foam; mp 75-92 C. APCI-MS m/z 473.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.060 g (10%) | In diethyl ether; N-ethyl-N,N-diisopropylamine; N,N-dimethyl-formamide; | Step C (R)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic (0.300 g, 1.17 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession N,N-diisopropylethylamine (0.612 mL, 3.51 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.444 g, 1.17 mmol). The resulting reaction mixture was stirred at that temperature for 40 minutes, 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.306 g, 1.17 mmol) was then added. After stirring for, sequentially, 25 minutes at 0 C. and 50 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*60 mL), brine (2*60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a solid. Recrystallization from EtOAc afforded 0.060 g (10%) of the pure titled compound as a white solid: mp 161-163 C. APCI-MS m/z 500.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; | EXAMPLE 2 A mixture of 3-(3-allyl-2,5-dimethyl-1,4-benzoquinonyl)-3-methylbutyric acid (1.38 g), 4-[bis(2-chloroethyl)amino]-N-methylaniline dihydrochloride (1.6 g), 2-(1-benzotriazolyl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (1.99 g), triethylamine (1.52 g) and acetonitrile (30 ml) was stirred at ambient temperature for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 17:3 mixture of hexane and ethyl acetate as eluent. There was thus obtained 3-(3-allyl-2,5-dimethyl-1,4-benzoquinonyl)-N-{4-[bis(2-chloroethyl)amino]phenyl}-3-methyl-N-methylbutyramide (0.88 g); NMR Spectrum: (CDCl3) 1.3 (s, 6H), 2.0 (s, 3H), 2.1 (s, 3H), 2.73 (s, 2H), 3.1 (s, 3H), 3.2 (d, 2H), 3.62-3.82 (m, 8H), 5.04 (m, 2H), 5.8 (m, 1H), 6.65-7.1 (m, 4H); Mass Spectrum: (M+H+) 509, 507, 505. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.60 g (83%) | With N-ethyl-N,N-diisopropylamine; In diethyl ether; N,N-dimethyl-formamide; | Step F (S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic (0.37 g, 1.4 mmol) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.76 mL, 4.4 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.55 g, 1.5 mmol, Novabiochem, La Jolla, Calif.). The resulting reaction mixture was stirred at that temperature for 30 minutes; 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.43 g, 1.4 mmol) was then added. After additional 30 minutes stirring at 0 C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo, a white solid was obtained. Recrystallization from EtOAc afforded 0.60 g (83%) of the pure titled compound as a white solid; mp 163-164 C.; APCI-MS m/z 500.6 (MH+); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
300 mg (39%) | With 4-methyl-morpholine; In methanol; diethyl ether; N,N-dimethyl-formamide; | Step B A suspension of (S)-4-methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid (430 mg, 2.00 mmol), N-methylmorpholine (0.220 mL, 2.00 mmol), and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (597 mg, 2.00 mmol) in dry DMF (10 mL) was treated with Triton B (1.82 mL, 4.00 mmol, 40 weight percent solution in methanol, Aldrich, Milwaukee, Wis.), a clear solution was obtained and cooled to 0 C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.760 g, 2.00 mmol) was then added. After stirring at 0 C. for 30 minutes, was added, the cooling bath was then removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 50 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2*50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (EtOAc:hexanes:MeOH 50:50:5) to give 300 mg (39%) of the pure titled compound as a clear oil. APCI-MS m/z 459.4 (MH+). Anal. C27H35N2O2F2.0.4H2O: C, 69.77; H, 7.76; N, 6.03; H2O, 1.55. Found: C, 69.81; H. 7.76; N, 5.74; H2O, 1.61. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In diethyl ether; N,N-dimethyl-formamide; | Step A. (S)-{1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-methyl-carbamic acid tert-butyl ester N-tert-Butoxycarbonyl-N-methyl-L-leucine (0.42 g, 1.7 mmol, Bachem Inc., Torrance, Calif.) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.90 mL, 5.2 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.66 g, 1.7 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.51 g, 1.7 mmol) was then added. After additional 30 minutes stirring at 0 C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. Concentration in vacuo followed by drying under vacuum afforded the crude desired product which was used in the subsequent reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; | To a solution of 5-(benzo[d][1,3]dioxol-5-yl)isoxazole-3-carboxylic acid (0.231 g, 0.992 mmol) in N,N'-dimethylformamide (3 mL) was added N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (0.376 g, 0.992 mmol), diisopropylethylamine (0.256 g, 1.98 mmol) and <strong>[14593-04-5]3-amino-3-phenyl-propan-1-ol</strong> (0.150 g, 0.992 mmol). The reaction mixture was stirred at 25 C. for 0.5 h. The reaction mixture was directly purified by Prep-HPLC (Waters Xbridge 150*25 5 mum column; 37-67% acetonitrile in a 10 mM ammonium bicarbonate solution in water, 12 min gradient) to give (5-(benzo[d][1,3]dioxol-5-yl)isoxazol-3-yl)(2-phenylazetidin-1-yl)methanone (53 mg, 0.141 mmol, 14%) as a yellow solid. 1H NMR (400 MHz, Chloroform-d) delta 7.31-7.34 (m, 3H), 7.24-7.27 (m, 2.6vH), 7.16-7.24 (m, 2H), 6.82-6.84 (m, 1H), 6.71 (s 1H), 6.5 (s, 1H), 5.96 (d, J=1.2, 2H), 5.86-5.88 (m, 1H), 5.3-5.5 (m, 1H), 4.59-4.68 (m, 1H), 4.25-4.32 (m, 1H), 2.78-2.85 (m, 1H), 2.10-2.28 (m, 1H); LCMS (ESI m/z: 349.1 [M+H]+. |
Tags: 94790-37-1 synthesis path| 94790-37-1 SDS| 94790-37-1 COA| 94790-37-1 purity| 94790-37-1 application| 94790-37-1 NMR| 94790-37-1 COA| 94790-37-1 structure
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