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CAS No. : | 132705-51-2 | MDL No. : | MFCD00077412 |
Formula : | C12H24BrF6N3P2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CYKRMWNZYOIJCH-UHFFFAOYSA-N |
M.W : | 466.18 | Pubchem ID : | 2733179 |
Synonyms : |
|
Num. heavy atoms : | 24 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 9.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 104.36 |
TPSA : | 36.9 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -4.59 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 6.41 |
Log Po/w (WLOGP) : | 8.11 |
Log Po/w (MLOGP) : | 3.19 |
Log Po/w (SILICOS-IT) : | 1.19 |
Consensus Log Po/w : | 3.78 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -6.57 |
Solubility : | 0.000125 mg/ml ; 0.000000269 mol/l |
Class : | Poorly soluble |
Log S (Ali) : | -6.98 |
Solubility : | 0.0000491 mg/ml ; 0.000000105 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -2.16 |
Solubility : | 3.22 mg/ml ; 0.0069 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.99 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P280-P305+P351+P338+P310 | UN#: | 3077 |
Hazard Statements: | H318-H410 | 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 |
---|---|---|
95% | In dichloromethane; | [1-(4-Chloro-phenyl)-cyclobutyl]-(3-hydroxymethyl-azepan-1-yl)-methanone iPrEtN (1.78 mL, 10.2 mmol) and pyBrOP (2.39 g, 5.12 mmol) were added at room temperature to a stirring solution of azepan-3-yl-methanol (0.4392 g, 3.41 mmol) and 1-(4-Chlorophenyl)-cyclobutanecarboxylic acid (1.0778 g, 5.12 mmol) in CH2Cl2 under N2. When the reaction was complete, the reaction was subjected to aqueous work-up. Silica gel purification (4:1 to 2:3 Hexanes: Ethyl acetate) provided the desired product in 95% yield (1.0395 g). LRMS: 321.91. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28%; 34% | With ammonium chloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h; | To a stirred mixture of 2-(2-chloro-5-hydroxybenzyl)-3-(5-fluoro-1-methyl-2- oxo-1, 2-dihydro-l'H-spiro [indole-3, 4'-piperidin]-1'-yl) propanoic acid (step 4 of example 51,0. 12 g, 0. 27 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (62 mg, 0.40 mmol), ammonium chloride (29 mg, 0.54 mmol) and diisopropylethylamine (0.19 mL, 1.1 mmol) in N, N-dimethylformamide (2 mL) was added bromotripyrrolidinophosphonium hexafluorophosphate (0.21 g, 0.40 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h, and quenched by the addition of sodium bicarbonate aqueous solution. The aqueous layer was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water (30 mL x 2) and brine, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (40/1), followed by column chromatography on silica gel eluting with dichloromethane/methanol (30/1) to afford 34 mg (28%) of 2-(2-chloro- 5-hydroxybenzyl)-3-(5-fluoro-1-methyl-2-oxo-1,2-dihydro-1'H-spiro [indole-3,4'- piperidin]-l'-yl) propanamide as a colorless amorphous solid and 46 mg (34%) of 1'- [2-(2-chloro-5-hydroxybenzyl)-3-oxo-3-pyrrolidin-1-ylpropyl]-5-fluoro-1- methylspiro [indole-3, 4'-piperidin] -2 (lH)-one as a colorless amorphous solid. <P>2-(2-Chloro-5-hydroxybenzyl)-3-(5-fluoro-1-methyl-2-oxo-1, 2-dihydro-1'H- spiro [indole-3, 4'-piperidin]-l'-yl) propanamide: 1H-NMR (CDC13) No.7. 42 (1H, br. s), 7.18 (1H, J=8.6 Hz), 7.18-7. 12 (1H, m), 7.04- 6.94 (1H, m), 6.93 (1H, J=2.8 Hz), 6.76 (1H, J=8.7, 4.3 Hz), 6.69 (1H, J=8.6, 2.8 Hz), 5.69 (1H, br. s), 3.19 (3H, s), 3.18-3. 01 (2H, m), 2.99-2. 52 (7H, m), 2.05-1. 90 (2H, m), 1.83-1. 65 (2H, m); MS (ESI) 446 (M + H) +, 444 (M-H)-. 1'- [2- (2-Chloro-5-hydroxybenzyl)-3-oxo-3-pyrrolidin-1-ylpropyl]-5-fluoro-1- methylspiro [indole-3, 4'-piperidin]-2 (1H)-one : IH-NMR (CDC13) No.7. 19-7.12 (1H, m), 7.16 (1H, J=8.6 Hz), 7.05 (1H, J=2.8 Hz), 7.02-6. 92 (1H, m), 6.79-6. 68 (2H, m), 3.50-2. 95 (8H, m), 3.18 (3H, s), 2.90-2. 60 (5H, m), 2.05-1. 50 (8H, m); MS (ESI) 500 (M + H) +, 498 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; ethyl acetate; | Example XXVIII 2-(2-methoxybenzimidazol-6-ylcarbonylamino)-3-phenylpropanoic acid The amino acid (452 mmol) and 2g (86 mg, 452 mmol) are dissolved in dry NMP (5 ml). Diisopropylethylamine (233 mg, 1.808 mmol) is added followed by PyBroP (253 mg, 542 mmol) in a single portion. The reaction is stirred overnight and then diluted with EtOAc (50 ml). The organics are washed with water, saturated NaHCO3, 10% citric acid, and brine (10 ml each), and then dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by passing the crude product through a plug of silica, eluding with 50% EtOAc/hexane followed by 80% EtOAc/hexane to yield the intermediate ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.76 g (93%) | In tetrahydrofuran; dichloromethane; | Step C To a stirred solution of 3-methoxy-4-bromo-2-thiophenecarboxylic acid (6.5 g, 27.4 mmol) in 140 mL of CH2Cl2, obtained from step B, was added bromo-tripyrrolidinophosphonium hexafluorophosphate (PyBrop, 12.8 g, 27.5 mmol), a 2.0 M solution of dimethyl amine in THF (34.5 mL, 69.0 mmol), and diisopropylethyl amine (12.0 mL, 68.7 mmol). After 3 d, the mixture was diluted with 100 mL of CH2Cl2, and washed with a 1.0 M sodium hydroxide aqueous solution (30 mL*3) and brine (30 mL). The organic solution was dried with Na2SO4, filtered, and concentrated to a dark yellow oil. This crude oil product was purified by flash column chromatography, eluding with CH2Cl2-hexanes (1:1, v/v). Removal of solvents afforded a creamy yellow solid, further dried on high vacuum, yielding 6.76 g (93%) of N,N'-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide (MH+=265.0, M+2 =266.1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.76 g (93%) | In tetrahydrofuran; dichloromethane; | Step C To a stirred solution of 3-methoxy-4-bromo-2-thiophenecarboxylic acid (6.5 g, 27.4 mmol) in 140 mL of CH2Cl2, obtained from step B, was added bromo-tripyrrolidinophosphonium hexafluorophosphate (PyBrop, 12.8 g, 27.5 mmol), a 2.0 M solution of dimethyl amine in THF (34.5 mL, 69.0 mmol), and diisopropylethyl amine (12.0 mL, 68.7 mmol). After 3 d, the mixture was diluted with 100 mL of CH2Cl2, and washed with a 1.0 M sodium hydroxide aqueous solution (30 mL*3) and brine (30 mL). The organic solution was dried with Na2SO4, filtered, and concentrated to an oil. This crude oil product was purified by flash column chromatography, eluding with CH2Cl2-hexanes (1:1, v/v). Removal of solvents afforded a solid, further dried on high vacuum, yielding 6.76 g (93%) of N,N'-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide (MH+=265.0, M+2=266.1). |
6.76 g (93%) | In tetrahydrofuran; dichloromethane; | Step C To a stirred solution of 3-methoxy4-bromo-2-thiophenecarboxylic acid (6.5 g, 27.4 mmol) in 140 mL of CH2Cl2, obtained from step B, was added bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop, 12.8 g, 27.5 mmol), a 2.0 M solution of dimethyl amine in THF (34.5 mL, 69.0 mmol), and diisopropylethyl amine (12.0 mL, 68.7 mmol). After 3 d, the mixture was diluted with 100 mL of CH2Cl2, and washed with a 1.0 M sodium hydroxide aqueous solution (30 mL*3) and brine (30 mL). The organic solution was dried with Na2SO4, filtered, and concentrated to an oil. This crude oil product was purified by flash column chromatography, eluding with CH2Cl2-hexanes (1:1, v/v). Removal of solvents afforded a solid, further dried on high vacuum, yielding 6.76 g (93%) of N,N'-dimethyl-3-methoxy4-bromo-2-thiophenecarboxamide (MH+=265.0, M+2=266.1). |
6.76 g (93%) | In tetrahydrofuran; dichloromethane; | Step C To a stirred solution of 3-methoxy-4-bromo-2-thiophenecarboxylic acid (6.5 g, 27.4 mmol) in 140 mL of CH2Cl2, obtained from step B, was added bromo-tripyrrolidinophosphonium hexafluorophosphate (PyBrop, 12.8 g, 27.5 mmol), a 2.0 M solution of dimethyl amine in THF (34.5 mL, 69.0 mmol), and diisopropylethyl amine (12.0 mL, 68.7 mmol). After 3 d, the mixture was diluted with 100 mL of CH2Cl2, and washed with a 1.0 M sodium hydroxide aqueous solution (30 mL*3) and brine (30 mL). The organic solution was dried with Na2SO4, filtered, and concentrated to an oil. This crude oil product was purified by flash column chromatography, eluding with CH2Cl2-hexanes (1:1, v/v). Removal of solvents afforded a solid, further dried on high vacuum, yielding 6.76 g (93%) of N,N'-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide (MH+=265.0, M+2=266.1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In dichloromethane; | [1-(4-Chloro-phenyl)-cyclobutyl]-(3-hydroxymethyl-azepan-1-yl)-methanone tPrEtN (1.78 mL, 10.2 mmol) and pyBrOP (2.39 g, 5.12 mmol) were added at room temperature to a stirring solution of azepan-3-yl-methanol (0.4392 g, 3.41 mmol) and 1-(4-Chlorophenyl)-cyclobutanecarboxylic acid (1.0778 g, 5.12 mmol) in CH2Cl2 under N2. When the reaction was complete, the reaction was subjected to aqueous work-up. Silica gel purification (4:1 to 2:3 Hexanes: Ethyl acetate) provided the desired product in 95% yield (1.0395 g). LRMS: 321.91. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine; In 1,4-dioxane; N,N-dimethyl-formamide; | Step 3 Synthesis of ethyl 3-[4-cyano-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]acrylate: 3.0 g (8.33 mmol) of ethyl 3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]acrylate was dissolved in a mixture of 20 ml of 4 N solution of hydrogen chloride in dioxane and 10 ml of dioxane. The obtained solution was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was dissolved in 50 ml of DMF. 2.22 g (9.17 mmol) of 1-(4-pyridyl)-4-piperidinecarboxyic acid hydrochloride, 4.27 g (9.17 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate and 3.48 ml (25.0 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 3 days. The solvent was evaporated, and the obtained crude product was purified by the silica gel column chromatography to obtain the title compound. Yield: 2.3 g (5.13 mmol) (62%) H-NMR (DMSO-d6) delta 1.26 (3H, t), 1.50-1.68 (2H, m), 1.68-1.73 (2H, m), 2.62-2.68 (1H, m), 2.94-3.06 (2H, m), 3.40-3.53 (2H, m), 3.95-4.25 (6H, m),6.76 (1H, dd), 6.94 (2H, d), 7.44 (1H, dd), 7.62 (1H, br), 7.83 (1H, dd), 7.90 (1H, d), 9.01 (1H, t), 8.15 (2H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PyBrOP Coupling Procedure To a stirred solution of bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 70 mg, 0.15 mmol), N-carbobenzyloxy-2-methylalanine (35.5 mg, 0.15 mmol), and Hunig's base (78 muL, 0.45 mmol) in dry dimethylformamide (1 mL) was added Intermediate 51 (50 mg, 0.14 mmol) at room temperature under a nitrogen atmosphere. The resulting golution wag allowed to stir at room temperature for 16 hours, then heated to 70 C. for 5 hours. The reaction was allowed to cool to room temperature, then concentrated in vacuo. The residue was purified via radial chromatography (1 mm plate with 3% MeOH in CH2Cl2) to provide Example 23 as a white foam (20 mg, 24%). 1H NMR (400 MHz, CDCl3, mixture of rotomers) delta: 7.43-7.15 (m, 9H), 6.82-6.62 (m, 3H), 5.64 (br s, 0.5H), 5.51 (br s, 0.5H), 5.15-5.08 (m, 3H), 3.97-3.15 (m, 13H), 1.58 (br s, 6H), 1.13 (br d, 3H), 0.68 (br s, 3H). LRMS (Electrospray, positive): Da/e 604.9 (m+18). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzenesulfonamide; N-ethyl-N,N-diisopropylamine; In 1,2-Dichloropropane; | Step 4: Resin bound (R)-3-[4-({(4-tert-butylcyclohexyl)-[2-(4-trifluoromethoxyPhenyl)acetyl]-amino}methyl)benzoylamino]-2-hydroxypropionic acid The above resin bound (R)-3-{4-[(4-tert-butylcyclohexylamino)methyl]benzoylamino}-2-hydroxypropionic acid was added 1,2-dichloropropane (500 muL) and BSA (100 muL) and the mixture was vortexed at 25 C. for 1 hour followed by filtration. To the resin was added a solution of <strong>[4315-07-5]4-(trifluoromethoxy)phenylacetic acid</strong> (400 umol) in a mixture of N-methyl-2-pyrrolidinone, 1,2-dichloropropane and diisopropylethylamine (4.5:4.5:1, 1 mL) was added followed by a solution of bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (400 mumol) in 1,2-dichloropropane (500 muL). The mixture was allowed to react for 3 hours at 50 C. and the resin was allowed to cool to 25 C. while washed with N-methyl-2-pyrrolidinone (4*1 mL), and DCM (10*1 mL) afforded the resin bound title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; ethyl acetate; acetonitrile; | Step c [4-(3,4-Dichloro-phenoxy)-[1,4']bipiperidinyl-1'-yl]-(3-methanesulfonyl-phenyl)-methanone acetate The product of Step b (0.15 g) was dissolved in THF (4 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP; 0.235 g), 3-methylsulphonylbenzoic acid (0.091 g) and N,N-di-iso-propylethylamine (0.238 ml) were added. After 18 hours at room temperature ethyl acetate and aqueous NaHCO3 solution were added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na2SO4 and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (45% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)) gave the title compound (0.095 g). 1H NMR: delta(DMSO-D6) 1.44-1.94 (8H, m), 2.37-2.77 (5H, m), 3.07-3.55 (6H, m), 4.40 (1H, m), 4.50-4.53 (1H, m), 6.96-8.02 (7H, m). Melting point: 60-61 C. becomes a gum. Melting point of free base: 154 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55 mg (44%) | With N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; | F 4-(tert-butyldimethylsilyloxy)-N1-(6-indolylcarbonyl)-N2-[1-(4-pyridyl)piperidin-4-yl]methoxycarbonyl-1,2-benzenediamine A mixture of indole-6-carboxylic acid (71 mg, 0.44 mmol), bromotris(pyrrolidino)phosphonium hexafluorophosphate (204 mg, 0.44 mmol) and diisopropylethylamine (0.153 mL, 0.88 mmol) in dry methylene chloride (5 mL) was stirred 10 min. 4-(tert-Butyldimethylsilyloxy)-N2-[1-(4-pyridyl)piperidin-4-yl]methoxycarbonyl-1,2-benzenediamine (100 mg, 0.22 mmol) and N,N-dimethylformamide (2 mL) were added and the resulting mixture stirred 64 h at ambient temperature. Saturated aqueous sodium hydrogen carbonate solution (4 mL) was added, and the resultant mixture stirred for 30 min. The mixture was partitioned between ethyl acetate and water, the organic solution separated, dried (anhydrous magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride, 9:1 methylene chloride/methanol, 9:1:0.1 methylene chloride/methanol/ammonium hydroxide) to yield 55 mg (44%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium acetate; triethylamine; In dichloromethane; ethyl acetate; acetonitrile; | EXAMPLE 24 This Example illustrates the preparation of 4-[4-(3,4-dichloro-phenoxy)-[1,4']bipiperidinyl-1'-carbonyl]-2H-isoquinolin-1-one (Compound 572 of Table I). 4-(3,4-Dichloro-phenoxy)-[1,4']bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP; 0.425 g), 1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (0.126 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO3 solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO4 and concentrated. Purification by RPHPLC (with a gradient eluent system (45% MeCN/NH4OAc aq (0.1%) to 95% MeCN//NH4OAc aq (0.1%))) (any excess NH4OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO3 followed by drying of the organics with Magnesium sulfate and evaporation of solvent) gave the title compound (0.153 g). MS: APCI+(M+H) 500 1H NMR (299.944 MHz CDCl3) delta 1.37-1.66 (2H, m), 1.73-1.88 (3H, m), 1.93-2.05 (3H, m), 2.41-2.51 (2H, m), 2.52-2.63 (1H, m), 2.75-2.86 (2H, m), 2.86-3.09 (2H, m), 3.71-3.90 (1H, m), 4.23-4.32 (1H, m), 4.77-4.93 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.27-7.32 (3H, m), 7.54-7.67 (1H, m), 7.57 (1H, t), 7.74 (1H, t), 8.46 (1H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium acetate; triethylamine; In dichloromethane; ethyl acetate; acetonitrile; | Step c [4-(3,4-Dichloro-phenoxy)-[1,4']bipiperidinyl-1'-yl]-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-methanone 4-(3,4-Dichloro-phenoxy)-[1,4']bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP; 0.425 g), 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (0.126 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO3 solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO4 and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (45% MeCN/NH4OAc aq (0.1%) to 95% MeCN//NH4OAc aq (0.1%)) (any excess NH4OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO3 followed by drying of the organics with magnesium sulfate and evaporation of solvent) gave the title compound (0.104 g). MS: APCI+(M+H) 491 1H NMR (399.978 MHz, CDCl3) delta 1.61 (1H, qd), 1.75-2.02 (7H, m), 2.42-2.51 (2H, m), 2.59-2.67 (1H, m), 2.75-2.86 (3H, m), 3.12-3.21 (1H, m), 4.23-4.29 (1H, m), 4.76-4.85 (1H, m), 5.23-5.32 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.16 (1H, ddd), 7.30 (1H, d), 7.58 (1H, dd), 8.07 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; ethyl acetate; acetonitrile; | EXAMPLE 23 This Example illustrates the preparation of 3-[4-(3,4-dichloro-phenoxy)-[1,4']bipiperidinyl-1'-carbonyl]-1-ethyl-7-methyl-1H-[1,8]naphthyridin-4-one (Compound 534 of Table I). 4-(3,4-Dichloro-phenoxy)-[1,4']bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP; 0.425 g), 1-ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (0.155 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO3 solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO4 and concentrated. Purification by RPHPLC (with a gradient eluent system (45% MeCN/NH4OAc aq (0.1%) to 95% MeCN//NH4OAc aq (0.1%)) %)) (any excess NH4OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO3 followed by drying of the organics with Magnesium sulfate and evaporation of solvent) gave the title compound (0.184 g; m.pt. 189-190 C.) MS: APCI+(M+H) 543 1H NMR (299.946 MHz, DMSO-D6) delta 1.37 (3H, t), 1.47-1.69 (5H, m), 1.78-1.84 (1H, m), 1.89-1.97 (2H, m), 2.36-2.41 (2H, m), 2.49-2.56 (1H, m), 2.66 (3H, s), 2.70-2.79 (3H, m), 2.95-3.04 (1H, m), 3.52-3.59 (1H, m), 4.38-4.57 (4H, m), 6.95-6.99 (1H, m), 7.22-7.24 (1H, m), 7.35-7.40 (1H, m), 7.46-7.51 (1H, m), 8.37 (1H, s), 8.43-8.45 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 mg (71%) | With N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; | D N4-Acetyl-N2-(4-t-butylbenzoyl)-N1-(6-indolylcarbonyl)-1,2,4-benzenetriamine To a stirring solution of 2-(4-t-butylbenzoyl)amino-4-(acetylamino)aniline (40 mg, 0.12 mmol), 6-indolecarboxylic acid (40 mg, 0.24 mmol) and bromotris(pyrrolidino)phosphonium hexafluorophosphate (112 mg, 0.12 mmol) in dichloromethane (10 mL) and DMF (1 mL) was added N,N-diisopropylethylamine (42 mg, 0.36 mmol). After 3 days, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed once with 1 N HCl, once with satd aq sodium bicarbonate, dried with MgSO4, filtered and concentrated in vacuo. The residue was then chromatographed over silica gel, eluding with 10% methanol/dichloromethane and the product containing fractions were combined and concentrated to give 40 mg (71%) of the title compound. 1H-NMR FD-MS, m/e 469.2 (M+) Analysis for C28H28N4O3: Calc: C, 71.78; H, 6.02; N, 11.96. Found: C, 69.22; H, 6.26; N, 11.26. |
Yield | Reaction Conditions | Operation in experiment |
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With dmap; N-ethyl-N,N-diisopropylamine; benzyl alcohol; In water; N,N-dimethyl-formamide; | Example 40 Benzyl cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphth-2-ylmethyl) aminoacetate hydrochloride Lithium cis-N-methyl-N-[(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphth-2-yl)methyl]aminoacetate (prepared as described in Process 1, 249.8 mg), PyBrOP (374.2 mg), 4-dimethylaminopyridine (67.5 mg), diisopropylethylamine (0.151 cm3) and benzyl alcohol (0.079 cm3) were dissolved in dry N,N-dimethylformamide (10 cm3) and stirred overnight under nitrogen. The solvent was evaporated, and the residue taken up into water (25 cm3) and extracted into dichloromethane (3*25 cm3), which was dried (Na2SO4) and the solvent evaporated. The crude product was purified by column chromatography [silica, eluding with petroleum ether (b. p. 40-60 C.)-diethyl ether (1:1)] to afford the desired compound as its free base. This was taken up into dichloromethane and converted to the hydrochloride salt; positive ion ESI (M+H)+430.3. |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; In N,N-diethyl-N-isopropylamine; N,N-dimethyl-formamide; | Step B: Resin Bound 3-{4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]benzoylamino}propionic Acid To the above resin bound Fmoc beta-alanine was added 500 muL of a 20% solution of piperidine in DMF. Upon shaking 30 min, the resin was drained and washed with 1 mL DMF containing 1-hydroxybenzotriazole (50 mg/mL) and DMF (2*1 mL). Then 200 mumol 4-[(9H-fluoren-9-yl-methoxycarbonylamino)methyl]benzoic acid (74.2 mg) dissolved in a mixture of 430 muL DMF and 70 muL diethylisopropylamine was added followed by 200 mumol bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 93 mg) dissolved in 500 muL DMF. The mixture was shaken for 4 hours at 25 C. followed by filtration and washing of the resin with 3*1 mL DMF. | |
With benzotriazol-1-ol; In N,N-diethyl-N-isopropylamine; N,N-dimethyl-formamide; | Resin Bound 3-{4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]benzoylamino}-propionic Acid To the above resin bound Fmoc beta-alanine was added 500 muL of a 20% solution of piperidine in DMF. Upon shaking for 30 min, the resin was drained and washed with 1 mL DMF containing 1-hydroxybenzotriazole (50 mg/mL) and DMF (2*1 mL). Then 200 mumol <strong>[164470-64-8]4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]benzoic acid</strong> (74.2 mg) dissolved in a mixture of 430 muL DMF and 70 muL diethylisopropylamine was added followed by 200 mumol bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 93 mg) dissolved in 500 muL DMF. The mixture was shaken for 4 hours at 25 C. followed by filtration and washing of the resin with 3*1 mL DMF. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-ethyl-N,N-diisopropylamine; N,N-dimethyl-formamide; | Step B: Resin Bound 3-[cyclopropylmethyl-(4-formylbenzoyl)amino]propionic Acid To the above resin bound N-(cyclopropylmethyl) 3-aminopropionic acid (50 mg) was added 200 mumol 4-formylbenzoic acid (30 mg) dissolved in a mixture of 430 muL DMF and 70 muL diisopropylethylamine followed by 200 mumol bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 93 mg) dissolved in 500 muL DMF. The mixture was shaken at 25 C. for 4 hours followed by filtration and washing of the resin with 3*1 mL DMF and 1 mL trimethylorthoformate. |
Yield | Reaction Conditions | Operation in experiment |
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In N,N-dimethyl-formamide; | (a) [3aR-(3aalpha,4alpha,6alpha,6aalpha)]-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-N-(2-hydroxyethyl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide N,N-Diisopropylethylamine (0.52 ml) was added to a solution of ethanolamine (66 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.56 g) and the product of Example 1 step (g) (0.45 g) in DMF (15 ml). The reaction mixture was stirred at room temperature for 1 hour then concentrated. Chromatography (SiO2, ethyl acetate as eluant) gave the subtitle compound (0.18 g). MS (APCI) 494 (M+H+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; methylamine; In 1,4-dioxane; acetonitrile; | a (2S)-2-Amino-5-(methylamino)-5-oxo-pentanamide N,N-Diisopropylethylamine (2.0 ml) was added to a solution of (4S)-5-amino-4-[[(1,1-dimethylethoxy)carbonyl]amino]-5-oxo-pentanoic acid (0.49 g), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.20 g) and methylamine (0.16 g) in acetonitrile (20 ml). The reaction mixture was stirred at room temperature for 2 hours then concentrated. The residue was taken into 4M HCl in 1,4-dioxane (20 ml), stirred for 4 hours then concentrated. Purification (Preparative C18 125 A bulk packing material, water:methanol, gradient elution 0:100 to 100:0) gave the sub-title compound (0.48 g). NMR deltaH (d6-DMSO) 8.24 (2H, br s), 8.00-7.98 (1H, m), 7.95 (1H, be s), 7.58 (1H, br s), 3.74 (1H, br s), 2.56 (3H, d), 2.26-2.12 (2H, m), 2.10-1.92 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; In N-methyl-acetamide; hydrogenchloride; 2-Methylpentane; dichloromethane; | i 2-[[2-aminoacetyl]amino]-4-thiazoleacetic acid, ethyl ester A mixture of N-(tert-butoxycarbonyl)glycine (3.1 g), 2-amino-4-thiazoleacetic acid ethyl ester (3 g) and bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (7.54 g) in dimethylformamide (20 ml) was treated with N,N-diisopropylethylamine (6 ml). After 25 minutes N,N-dimethyl-4-aminopyridine (1.96 g) was added. After 24 hours the mixture was partitioned between ethyl acetate and brine. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, IN HCl and brine, dried (MgSO4) and evaporated. The residue was purified by chromatography eluding with 50% ethyl acetate in isohexane. The product (0.77 g) was dissolved in dichloromethane (25 ml) and trifluoroacetic acid (10 ml). After 2 hours the mixture was evaporated. The residue was partitioned between ethyl acetate and sodium bicarbonate solution. The aqueous phase was repeatedly extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated. Yield 0.41 g. MS: APCI(+ve): 244 M+1). |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; triethylamine; In N-methyl-acetamide; dichloromethane; | i 2-[[2-[[5-{2,8-Dimethyl-5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]thiazol-4-ylcarbonyl]amino]-4-thiazole acetic acid, ethyl ester The product from example 8(0.11 g) and 2-amino-4-thiazoleacetic acid ethyl ester (0.063 g) were dissolved in dry dimethylformamide (5 ml). Bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (0.11 g) and triethylamine (0.08 ml) were added and the mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with brine/HCl and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated. The residue was purified by chromatography eluding with 10% ethyl acetate in dichloromethane and used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; N-ethyl-N,N-diisopropylamine; In aqueous ammonium acetate; N,N-dimethyl-formamide; | i 2-[[5-{2,8-Dimethyl-5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-N-methylsulphonyl-4-oxazolecarboxamide The product of example 37(0.2 g), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (0.38 g), 4-dimethylaminopyridine (0.07 g), methanesulphonamide (0.095 g) and N,N-diisopropylethylamine (0.43 ml) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 16 h. The mixture was partitioned between aqueous tartaric acid and ethyl acetate. The organic solution was dried (MgSO4) and evaporated. Purification was by reverse phase silica gel chromatography (C18-sep-pak) eluding with 50% methanol in 0.1% aqueous ammonium acetate. Yield 0.032 g. MS: APCI(-ve): 547(M-1, 100%). 1H NMR: delta (DMSO) 12.71(s, 1H), 12.1-12.2(br s, 1H), 8.88(s, 1H), 7.46(d, 2H), 7.1-7.2(m, 4H), 7.08(s, 1H), 6.82(s, 2H), 5.76(s, 1H), 5.11(s, 2H), 3.35(s, 3H), 3.0-3.1(m, 4H), 2.27(s, 6H), 1.7-1.8(m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; aniline; In hexane; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate; | Example 11 2-{1-[Isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl}N-phenyl-acetamide According to Process F, a mixture of {1-[Isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl}-acetic acid (200 mg, 0.400 mmol), prepared as in Intermediate 29, aniline (0.033 mL, 0.356 mmol), and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (167 mg, 0.356 mmol) in anhydrous DCM (3 mL) is treated with diisopropylethylamine (0.170 mL, 0.978 mmol) and stirred at ambient temperature under nitrogen. After 1.5 hrs., the solvent is removed in vacuo and the residue is purified by chromatography on flash grade silica gel using 60% ethyl acetate in n-hexane. Fractions containing the product are combined, concentrated in vacuo and triturated with n-hexane. After removing the solvent in vacuo, the product is dried overnight at ambient temperature under high vacuum to provide the title compound (123 mg, 0.214 mmol) as a white solid. The product is lyophilized from acetonitrile/water. 1 H NMR (300 MHz, d6-DMSO) delta=0.86-0.96 (m, 6H); 3.14 (d, J=6.9 Hz, 2H); 3.77 (S, 3H); 4.03-6.12 (M, 2H); 4.23 (D, J=16.8 HZ, 1H); 4.59-6.73 (M, 1H); 6.97-7.08 (M, 3H); 7.15-7.32 (M, 6H); 7.36-7.66 (M, 9H); 10.15 (S, 1H). MS (FAB): [M+H]+ =575. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In dichloromethane; | A. (2S-cis)-2-[N-Methoxy-N-methyl amino]carbonyl-4-phenylmethoxy-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester [S-(R*,R*)]-4-Phenylmethoxy-1,2-pyrrolidinedicarboxylic acid, 1,1-dimethylethyl ester (2.0 g, 6.2 mmol), N,O-Dimethylhydroxylamine hydrochloride (670 mg, 6.9 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (3.2 g, 6.9 mmol) and 4-dimethylaminopyridine (300 mg, 2.5 mmol) were dissolved in methylene chloride (10 mL). N,N-Diisopropylethylamine (2.3 g, 3.0 mL, 17 mmol) was added dropwise over 15 minutes. The reaction mixture was stirred for 2 hours at room temperature, and then concentrated. Flash chromatography (silica gel, 5.0 X 15 cm, 40% ethyl acetate, 60% hexane) of the residue provided Compound A (1.9 g), as a clear oil. MS (M+Na)+ 387+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
620 mg (84%) | With 2-(Dimethylamino)pyridine; N-ethyl-N,N-diisopropylamine; In dichloromethane; | A. (2S-trans)-4-[[(9-Fluorenylmethoxy)-carbonyl]amino]-2-[(methoxymethylamino)carbonyl]-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester To a solution of (2S-trans)-4-[[(9-Fluorenylmethoxy)carbonyl]amino]-1,2-pyrrolidinedicarboxylic acid 1-(1,1-dimethylethyl) ester (0.70 g, 1.5 mmol) (prepared analogously to the method described in Rosen, T., et al., Synthesis 40 (1988)), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (700 mg, 1.5 mmol) and N,O-dimethylhydroxylamine hydrochloride dissolved in methylene chloride (20 mL) were added dimethylaminopyridine (20 mg, 0.16 mmol) and diisopropylethylamine (790 muL, 0.16 mmol). The solution was stirred for 6 hours and concentrated. The residue was chromatographed on a flash silica gel column (5 x 20 cm) eluding with 1:1/ethyl acetate/hexanes to afford 620 mg (84%) of compound A. MS: (M+H)+ 496+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap; In dichloromethane; | A. cis-N-Methoxy-3-[(triphenylmethyl)thio]cyclopentanecarboxamide Cis-3-[(Triphenylmethyl)thio]-cyclopentanecarboxylic acid (1.0 g, 2.58 mmol), N,O-dimethylhydroxamate·HCl (278 mg, 2.84 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.33 g, 2.84 mmol) and 4-dimethylaminopyridine (100 mg, 0.815 mmol) were dissolved in methylene chloride (20 mL). N,N-Diisopropylethylamine (701 mg, 1.0 mL, 5.42 mmol) were added dropwise and the reaction mixture was stirred for 2 hours at room temperature, concentrated and chromatographed (silica gel, 5.0 X 15 cm, 40% ethyl acetate, 60% hexane). Fractions containing the desired compound were collected and concentrated to yield compound A as a clear oil (1.0 g, 90 %), MS: (M+H)+ 432+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N-methyl-acetamide; | Step 1 Synthesis of methyl 2-acetamido-3-[4-cyano-2-[2-[[1-(pyridine-4-yl)piperidine-4-carbonyl]amino]ethoxy]phenyl]acrylate trifluoroacetate: 1.0 g (2.94 mmol) of methyl 2-acetamido-3-[4-cyano-2-(2-aminoethoxy)phenyl]acrylate hydrochloride, 0.79 g (3.24 mmol) of 1-(pyridine-4-yl)piperidine-4-carboxylic acid hydrochloride and 1.64 ml of triethylamine were stirred in dimethylformamide. 1.51 g (3.24 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate was added to the resultant mixture under cooling with ice, and they were stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was treated by the reversed phase high-performance liquid chromatography with silica gel, having octadodecyl group chemically bonded thereto, as the filler. After the elution with a mixed solvent of water and acetonitrile containing 0.1 % (v/v) of trifluoroacetic acid, the fraction of the intended product was freeze-dried to obtain the title compound. Yield: 360 mg (0.73 mmol) (25%). H-NMR (DMSO-d6) delta 1.50-1.70 (2H, m), 1.75-1.90 (2H, m), 1.95 (3H, s), 2.50 (1H, m), 3.15-3.30 (2H, m), 3.42 (2H, dt), 3.65 (3H, s), 4.10-4. 22 (4H, m), 7.15-7.21 (3H, m), 7.44 (1H, d), 7.58 (1H, s), 7.68 (1H, d), 8.09 (1H, t), 8.21 (2H, d), 9.65 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With 2-(Dimethylamino)pyridine; N-ethyl-N,N-diisopropylamine; In dichloromethane; | A. (R)-4-[(N-Methoxy-N-methylamino)carbonyl]-3-thiazolidinecarboxylic acid, 1,1-dimethylethyl ester (R)-3,4-Thiazolidinedicarboxylic acid, 3-(1,1-dimethylethyl) ester (1g, 4.97 mmol), bromotris-pyrrolidino-phosphonium hexafluorophosphate (5.1g, 10.93 mmol), and dimethylaminopyridine (200 mg, 1.6 mmol) were dissolved in methylene chloride (20 mL). N,O-Dimethylhydroxylamine hydrochloride (1.07 g, 10.93 mmol) and N,N-diisopropylethylamine (4.5 mL, 25.7 mmol) were added. The reaction mixture stirred for 1 hour at room temperature and was concentrated and chromatographed (silica gel, 7.1 X 20 cm, 40% ethyl acetate, 60% hexane). Fractions containing the desired compound were collected and concentrated to yield Compound A as a white solid (700 mg, 51%). (M+H)+ 277+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | PyBrOP Coupling Procedure: To a stirred solution of bromo-trispyrrolidino-phosphonium hexafluorophosphate (PyBrOP; 70 mg; 0.15 mmol), N-carbobenzyloxy-2-methylalanine (35.5 mg; 0.15 mmol), and Hunig's base (78 muL; 0.45 mmol) in dry dimethylformamide (1 mL) was added the free pyrrolidine (50 mg; 0.14 mmol) at room temperature under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 16 hours, then was heated to 70 C. for 5 hours. The reaction was allowed to cool to room temperature and was concentrated in vacuo. The residue was purified via radial chromatography (1 mm chromatotron plate with 3% methanol in dichloromethane) to provide the amide as a white foam (20 mg; 24%). 1H NMR (CDCl3, 400 MHz, mixture of rotomers): delta 7.43-7.15 (m, 9H), 6.82-6.62 (m, 3H), 5.64 (br s, 0.5H), 5.51 (br s, 0.5H), 5.15-5.08 (m, 3H), 3.97-3.15 (m, 13H), 1.58 (br s, 6H), 1.13 (br d, 3H), 0.68 (br s, 3H). LRMS (Electrospray, positive): Da/e 604.9 (m+18). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; In 2-Methylpentane; dichloromethane; N,N-dimethyl-formamide; | ix 2-[(2-Aminoacetyl)amino]-4-thiazoleacetic acid ethyl ester A mixture of N-(tert-butoxycarbonyl)glycine (3.1 g), 2-amino-4-thiazoleacetic acid ethyl ester (3 g) and bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (7.54 g) in N,N-dimethylformamide (20 ml) was treated with N,N-diisopropylethylamine (6 ml). After 25 minutes 4-(dimethylamino)pyridine (1.96 g) was added. After 24 hours the mixture was partitioned between ethyl acetate and brine. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, 1N HCl and brine, dried (MgSO4) and evaporated. The residue was purified by chromatography eluding with 50% ethyl acetate in isohexane. The product (0.77 g) was dissolved in dichloromethane (25 ml) and trifluoroacetic acid (10 ml). After 2 hours the mixture was evaporated. The residue was partitioned between ethyl acetate and sodium bicarbonate solution. The aqueous phase was repeatedly extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated. Yield 0.41 g. MS: APCI (+ve): 244 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; ethyl acetate; N,N-dimethyl-formamide; acetonitrile; | Example 9 2-[3-(2-Amino-phenylcarbamoylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide A stirring solution of 100 mg (0.20 mmol) of [1-(Isopropyl-phenyl-carbamoylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-acetic acid, prepared as in Intermediate 7, 32 mg (0.30 mmol, 1.5 equiv) of 1,2-phenylene diamine, 187 mg (0.40 mmol, 2.0 equiv) of bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP), and 80 mg (0.60 mmol, 3.0 equiv) of diisopropylethylamine in 2 mL of DMF is heated at 50 C. for 48 h. The DMF is removed in vacuo and the residue is dissolved in 20 mL of EtOAc and extracted with 20 mL 1N HCl. The organic layer is dried (MgSO4) and the solvent removed in vacuo. The resulting oil is purified by silica gel flash column chromatography using dichloromethane/MeOH 20/1 as eluent followed by further purification via reverse phase MPLC using a C-18 column and 60% acetonitrile/40% H2 O with 0.1% TFA as eluent followed by lyophilization to afford 30 mg of the title compound as a white amorphous solid: 1 H NMR (CDCl3, 300 MHz) delta9.38 (s, 0.7H), 9.17 (s, 0.3H), 7.53-7.04 (m, 17H), 6.81 (d, 1H, J=4.7), 4.97 (m, 1H), 4.57 (d, 0.5H, J=16.6), 4.27 (s, br, 2H), 3.87 (d, 0.5H, J=16.6), 3.36 (d, 1H, J=15.6), 3.13 (d, 1H, J=15.6), 2.60 (d, 0.5H, J=15.3), 2.42 (d, 0.5H, J=15.3), 1.61 (s, 1H), 1.22 (s, 2H), 1.09 (m, 6H); low resolution MS (FAB)m/e 590 (MH+), 482. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; dichloromethane; | Typically, Fmoc-Trp(Boc) (80 mg, 1.5*10-4 mole) dissolved in CH2Cl2 (3 ml) under nitrogen atmosphere was mixed with various combinations of coupling reagents (1.5*10-4 mole) and bases (1.5*10-4 mole). PLGA with lactic/glycolic acid 50/50 ratio (0.43 g, 5*10-5 mole) dissolved in 7 ml of CH2Cl2 was then added to the solution. The coupling reaction was carried out at room temperature for 4~6 hrs. The resulting solution was diluted with the addition of 20 ml CH2Cl2 and washed with brine. An organic layer was separated, concentrated, and dried under vacuum. The conjugated Fmoc-Trp(Boc)-PLGA was further purified by the following precipitation procedure. The product mixture dissolved in 2 ml CH2Cl2 was precipitated by the addition of 30 ml diethyl ether. This precipitation was repeated three times. The separation of unconjugated free Fmoc-Trp(Boc) from a mixture of Fmoc-Trp(Boc)-PLGA conjugate and unreacted PLGA was confirmed by gel permeation chromatography (GPC). The conjugate was lyophilized and stored at -20 C. until use. Coupling reagents, 2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (HBTU), N-hydroxybenzotriazole (HOBt), benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) were obtained from Novabiochem. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; N-ethyl-N,N-diisopropylamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate; | C) N-[2-[4-(Diethylaminomethyl)phenyl]-1-(N-ethyl-N-isopropylcarbamoyl)-ethyl]-3-(benzo[1,3]dioxol-5-yl)-3-(naphthalene-2-sulphonylamino)propionamide hydrochloride 0.46 g of bromotripyrrolidinophosphonium hexafluorophosphate and 0.33 ml of DIPEA are added to a mixture of 0.6 g of the compound obtained in the preceding step and 0.126 ml of N-ethylisopropylamine in 15 ml of DCM, and the mixture is stirred for 24 hours at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with water, with saturated NaHCO3 solution and with saturated NaCl solution, the organic phase is extracted with a pH 4 buffer solution, the aqueous phase is basified by adding saturated NaHCO3 solution and extracted with DCM, the organic phase is washed with saturated NaHCO3 solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluding with a DCM/MeOH mixture (95/5; v/v). The product obtained is dissolved in EtOAc, acidified to pH 1 by adding hydrochloric ether and diluted with ether, and the precipitate formed is filtered off by suction. 0.058 g of the expected product is obtained. NMR: delta (ppm): 0.6-1.4: unres.: 15H; 2.2-3.3: unres.: 10H; 3.7-4.9: unres.: 5H; 5.3-5.8: unres.: 2H; 6.3-8.5: unres.: 16H; 10.5: s: 1H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; water; acetic acid; ethyl acetate; acetonitrile; trifluoroacetic acid; | Step b N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-[(2-hydroxyethyl)-sulfonyl]benzamide acetate To a solution of the product of Step a (0.20 g), the product of Example 3, Step b (0.25 g) and diisopropylethyl amine (0.33 ml) in dichloromethane (5 ml) was added PyBrOP (0.37 g) and the mixture stirred for 24 hours. Purification by Biotage 40M eluding 20% MeCN/2% 880 ammonia/78% dichloromethane gave a colourless oil (0.49 g) which was dissolved in trifluoroacetic acid (9 ml) and water (1 ml) and stirred for 15 minutes. The solvents were evaporated under reduced pressure and purification by reverse phase HPLC (with a gradient eluent system 25% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAc(aq) (0.1%)) (any excess NH4OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO3 followed by drying of the organics with MgSO4 and evaporation of solvent) and formation of the acetate salt by dissolving in acetic acid and evaporation of the excess acid gave the title product (0.050 g). MS: ESI(+ve) 501 (M+H) 1H NM (400 MHz, CDCl3) delta 1.79-1.87 (2H, m), 1.95-2.04 (3H, m), 2.42 (2H, t), 2.65 (2H, t), 2.77 (2H, t), 3.43 (2H, t), 3.58 (2H, q), 3.80 (2H, t), 4.29-4.35 (1H, m), 6.76 (1H, dd), 6.92-6.97 (1H, m), 7.00 (1H, d), 7.31 (1H, d), 7.65 (1H, t), 8.05 (1H, d), 8.10 (1H, d), 8.30 (1H, t) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; In water; ethyl acetate; N,N-dimethyl-formamide; acetonitrile; | EXAMPLE 441 N-{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-methanesulfonylamino-benzamide A mixture of 6-amino-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-3-carbonitrile (21 mg, 0.05 mmol), 3-methanesulfonylamino-benzoic acid (16 mg, 0.075 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (36 mg, 0.075 mmol) and diisopropylethyl amine (35 L, 0.20 mmol) were stirred in 1 ml of DMF at room temperature for 10 h, followed by an additional 16 h of stirring at 60 C. The mixture was allowed to cool by to room temperature where upon it was treated with 50 ml of EtOAc. The mixture was washed with water, (3*10 ml), followed by brine (5 ml) and then dried over Na2SO4. The solvent was removed in vacuo, and the resulting residue was purified by silica gel chromatography using a 20-30% gradient of EtOAc in dichoromethane to give 22.0 mg of compound XX as a light yellow solid. Retention Time: 6.56 min. (Princeton chromatography HTS column, 5 micron, 4.6*50 mm, eluding with 5-100% of acetonitrile in water over 8 minutes containing 0.1% TFA, 1.2 mL/min, monitoring at 215 nm.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Fmoc-Val-Lys(Boc)-Val-Ile-Gly-Rink-amide resin was preparedby manual solid phase synthesis in 2 ml polypropylene reactorswith polyethylene frits (MultiSynTech) using a standard Fmoc protocolwith single couplings (4-fold excess of Fmoc amino acid,HOBt, and HBTU, respectively, and 8 equiv. DIPEA, 2 h couplingtime). After removal of the Fmoc group, followed by washing eighttimes with DMF, 2.5 equiv. of the crude Cbz-Phe-Glu(CMK)-OH inthe presence of 2.5 equiv. PyBroP and 5 equiv. DIPEA was coupledovernight to the resin. After washing with DMF and dichloromethane(DCM), the peptide was cleaved by a mixture of TFA/water(97.5:2.5, v/v) over 1 h at room temperature. The solvent was removedby evaporation, the remaining residue was purified by preparativeHPLC, and the product was finally obtained as lyophilizedTFA salt (white lyophilized solid with 95% purity based on detectionat 220 nm; HPLC: 46.75 min; MS: calc. 955.5, found 956.8(M+H)+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | A solution of sodium 2-( 1 -((ir, 4r)-4-(cyanomethyl)cyclohexyl)- 1, 6-dihydroimidazo[4, 5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate (Intermediate 4, 200 mg, 0.557 mmol), 4-(piperidin-4-yl)morpholine (94.8 mg, 0.557 mmol ), DIPEA (144 mg, 1.11 mmol), and DMF (5 mL) was stirred at 0 C for 1 h. Then PyBrOP (311 mg, 0.668 mmol) was added and stirred at room- temperature overnight. The mixture was quenched with 10 mL water and was purified by preparative acidic HPLC using a Boston Green ODS 150 mm x30 mm, Sjim column (eluent:water (0.05% HC1)-ACN from 0% to 30%, v/v) and then by preparative basic HPLC using a Kromasil 150 mm x 25 mm, lOjim column (eluent: water (0.05% ammonia hydroxide v/v)-ACN from 10% to 40%, v/v) to provide the title compound (25 mg, 9% yield) as a white solid. MS (ESI): mass calcd. for C27H35N702, 489.29; m/z found, 490.3 [M+H]t ?H NIVIR (400MHz, DMSO-d6): oe 11.85 (br s, 1H), 8.51 -8.47 (m, 1H), 7.48-7.44 (m, 1H), 6.72-6.68 (m, 1H),4.42-4.29 (m, 2H), 4.25 (d, J= 8.4 Hz, 2H), 4.16-4.07 (m, 1H), 3.59- 3.52 (m, 4H), 3.15 -3.05 (m, 1H), 2.69-2.63 (m, 1H), 2.58 (d, J= 6.0 Hz, 3H), 2.47 - 2.41 (m, 5H), 2.07 - 1.90 (m,6H), 1.85 - 1.74 (m, 2H), 1.42 - 1.27 (m, 3H), 1.27 - 1.13 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | A solution of sodium 2-( 1 -((ir, 4r)-4-(cyanomethyl)cyclohexyl)- 1, 6-dihydroimidazo[4, 5- d]pyrrolo[2,3 -b]pyridin-2-yl)acetate (Intermediate 4, 200 mg, 0.557 mmol), (1 S,3R,5R,75)-3 - aminoadamantan-1-ol hydrochloride (113 mg, 0.557 mmol ), DIPEA (144 mg, 1.11 mmol), and DMF (5 mL) was stirred at 0 C for 1 h. Then PyBrOP (311 mg, 0.668 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with10 mL water and purified by preparative basic HPLC using a Kromasil 150mm x 25 mm, lOjim column (eluent: water (0.05% ammonia hydroxide v/v)-ACN from 22% to 32%, v/v) to provide the title compound (30.1 mg, 11% yield) as a white solid. MS (ESI): mass calcd. for C28H34N602, 486.3; m/z found, 487.3 [M+H]t ?HNMR(400MHz, DMSO-d6): oe 11.84 (br s, 1H), 8.49 (s, 1H), 7.93 (br s, 1H), 7.47 - 7.44 (m, 1H), 6.72 - 6.68 (m, 1H), 4.51 (s, 1H), 4.49 -4.39 (m, 1H), 3.93 (br s, 2H), 2.61 (d, J= 5.6 Hz, 2H), 2.41 -2.28 (m, 2H), 2.12 (br s, 2H), 2.05- 1.92 (m, 5H), 1.89- 1.77 (m, 6H), 1.58- 1.34 (m, 8H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | A mixture of sodium 2-( 1 -((ir, 4r)-4-(cyanomethyl)cyclohexyl)- 1, 6-dihydroimidazo[4, 5- d]pyrrolo[2,3-b]pyridin-2-yl)acetate (Intermediate 4, 200 mg, 0.557 mmol), 2-(4- aminophenyl)acetonitrile hydrochloride (93.8 mg, 0.557 mmol), DIPEA (144 mg, 1.11 mmol), and DMF (5 mL) was stirred at 0 C for 1 h. PyBrOP (311 mg, 0.668 mmol) was added and stirred at room temperature overnight. The mixture was quenched with 10 mL water and waspurified by preparative HPLC using a Kromasil 150mm x25mm, lOjim column (eluent: water(0.05% ammonia hydroxide v/v)-ACN from 27% to 37%, v/v) and then by preparative TLC(CH2C12: MeOH = 10:1) to provide the title compound (12 mg, 4% yield) as a white solid. MS(ESI): mass calcd. for C26H25N70, 451.2; m/z found, 452.2 [M+H]. ?H NMR (400MHz,CD3OD): oe 8.55 (s, 1H), 7.62 (d, J 8.8 Hz, 2H), 7.49 (d, J= 3.6 Hz, 1H), 7.33 (d, J= 8.4 Hz,2H), 6.86 (d, J= 3.6 Hz, 1H), 4.68 -4.54 (m, 2H), 4.31 -4.25 (m, 1H), 3.86 (s, 2H), 2.67-2.49 (m, 4H), 2.20 - 2.05 (m, 5H), 1.55 - 1.41 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 0.0166667h; | General procedure: To a solution of diTBS-dT (1) in THF ([1]=0.3M) were added coupling reagent (PyAOP, PyBOP, PyBrOP, or HATU, 2 eq) and DBU (2 eq). The reaction was stirred at 20C for 1min. Then the solution was concentrated in vacuo. Flash column chromatography on silica gel afforded 1a-1d in pure form. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; | a) Preparation of tert-butyl 4-(6-fluoro-1,2-benzoisothiazol-3-yl)piperazine-1-carboxylate (Compound IN-3-1) To a mixture of 6-fluorobenzo[d]isothiazol-3(2H)-one (2.00 g), triethylamine (8.22 mL), and 1,4-dioxane (59 mL) was added <strong>[132705-51-2]bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V)</strong> (6.06 g). After stirring at room temperature for an hour, to the reaction mixture was added tert-butylpiperazine-1-carboxylate (6.61 g), and the reaction mixture was stirred at 80 C. for 48 hours. Then, water was added to the reaction mixture, and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the titled compound (0.260 g). 1H-NMR (400 MHz, CDCl3) delta: 1.50 (9H, s), 3.46 (4H, t, J=5.0 Hz), 3.65 (4H, t, J=5.0 Hz), 7.12 (1H, ddd, J=8.7, 8.7, 2.3 Hz), 7.47 (1H, dd, J=8.3, 2.3 Hz), 7.84 (1H, dd, J=8.9, 4.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.9% | The crude product was diluted with DMF (2 mL), and triethylamine (0.61 mL; 4.34 mmol; 10.00 eq.), (3-fluoropyridin-2-yl)methanamine (219.16 mg; 1.74 mmol; 4.00 eq.) and <strong>[132705-51-2]bromo[tri(1-pyrrolidinyl)]phosphonium hexafluorophosphate</strong> (810.01 mg; 1.74 mmol; 4.00 eq.) were added. After being stirred at room temperature for 15 h, the mixture was diluted with Sat. NaHCO3. Following this, the mixture was extracted with EtOAc, the organic layers were combined, dried over MgSO4, and concentrated to give a crude product, which was purified by silica gel column chromatography (hexanes/EtOAc=1:1) to give tert-butyl N-[2,2-difluoro-2-(4-[(3-fluoropyridin-2-yl)methyl]amino}-[1,3]oxazolo[4,5-c]pyridin-2-yl)ethyl]carbamate (66 mg, 35.9% yield). LCMS [M+1]+ m/z: 424.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Step 4 To a solution of (3-fluoropyridin-2-yl)methanamine bis HCl salt (0.73 g; 3.65 mmol; 1.50 eq.) and 2-(2-[(tert-butoxy)carbonyl]amino}ethyl)-[1,3]oxazolo[4,5-c]pyridin-5-ium-5-olate (0.68 g; 2.43 mmol; 1.00 eq.) in THF (10 mL) was added Hunig's base DIPEA (1.70 mL; 9.74 mmol; 4.00 eq.) and <strong>[132705-51-2]bromo[tri(1-pyrrolidinyl)]phosphonium hexafluorophosphate</strong> (1.70 g; 3.65 mmol; 1.50 eq.). The mixture was stirred for 6 h at room temperature, and was diluted with EtOAc, washed with Sat. NH4Cl and Sat. NaHCO3 and brine. The organic layer was separated, dried and concentrated to give crude product, which was purified by column chromatography (DCM/MeOH/NH3=90:9:1) to give tert-butyl N-[2-(4-[(3-fluoropyridin-2-yl)methyl]amino}-[1,3]oxazolo[4,5-c]pyridin-2-yl)ethyl]carbamate (1.5 g, >100%)). LCMS [M+1]+ m/z: 388.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium bicarbonate; N-ethyl-N,N-diisopropylamine; | Reference Example 80-1 (Phenylmethyl) 4-[(3S)-3-(hydroxymethyl)-1-piperidinyl]-4-oxobutanoate To a solution of 4-oxo-4-phenylmethoxybutanoic acid (100 mg) and [(3S)-3-piperidinyl]methanol hydrochloride (73 mg) in chloroform (4.8 mL), N,N-diisopropylethylamine (0.17 mL) and bromotripyrrolidinophosphonium hexafluorophosphate (223 mg) were added, and the mixture was stirred at room temperature for 17 hours. A saturated aqueous solution of sodium hydrogen carbonate (5 mL) was added to stop the reaction. The resultant mixture was extracted with ethyl acetate, and the organic layer was passed through a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10:1 to 1:1) to give the title compound (200 mg) as a colorless oil. MS ESI/APCI Multi posi: 306[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine In acetonitrile at 0 - 20℃; for 3.5h; Inert atmosphere; | Synthesis of 3-cyano-1,2,4-triazol-1-yl-tris(pyrrolidine-1-yl)phosphonium hexafluorophosphate (PyCTP) 3-Cyano-1,2,4-triazole (0.946 g, 10 mmol) was dried by repeated coevaporation with dry pyridine and dry toluene and dissolved in dry CH3CN (40 mL). After adding triethylamine (1.39 mL, 10 mmol), PyBroP (4.66 g, 10 mmol) was added to the mixture at 0 °C while stirring. The mixture was warmed to rt and stirred for 3.5 h. The mixture was washed with a saturated NaHCO3 aqueous solution (1×100 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in dry CH2Cl2 (15 mL) and Et2O (20 mL) was added to the solution. A precipitated solid was collected by filtration, washed with Et2O, and dried under reduced pressure to give the product as a colorless solid (3.55 g, 7.50 mmol, 75% yield). Characterization data of 3-cyano-1,2,4-triazol-1-yl-tris(pyrrolidine-1-yl)phosphonium hexafluoro-phosphate (PyCTP) 1H NMR (400 MHz, CD3CN): δ 8.87 (s, 1H), 3.41-3.33 (m, 12H), 2.05-1.99 (m, 12H); 13C{1H} NMR (100 MHz, CD3CN): δ 152.2 (d, JPC = 8.7 Hz), 144.2 (d, JPC = 18.3 Hz), 112.5, 49.7 (d, JPC = 4.8 Hz), 27.2 (d, JPC = 9.6 Hz); 31P{1H} NMR (161 MHz, CD3CN) : δ 19.5; HRMS [ESI-time-of flight (TOF)]: m/z calcd for C15H25N7P + [M-PF6]+ , 334.1904; found 334.1905. |
Tags: 132705-51-2 synthesis path| 132705-51-2 SDS| 132705-51-2 COA| 132705-51-2 purity| 132705-51-2 application| 132705-51-2 NMR| 132705-51-2 COA| 132705-51-2 structure
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H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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