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CAS No. : | 128625-52-5 | MDL No. : | MFCD00077411 |
Formula : | C18H28F6N6OP2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VIAFLMPQBHAMLI-UHFFFAOYSA-N |
M.W : | 520.39 | Pubchem ID : | 2724699 |
Synonyms : |
|
Num. heavy atoms : | 33 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 12.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 129.54 |
TPSA : | 76.84 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -4.64 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 6.81 |
Log Po/w (WLOGP) : | 7.59 |
Log Po/w (MLOGP) : | 4.06 |
Log Po/w (SILICOS-IT) : | -0.1 |
Consensus Log Po/w : | 3.67 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -7.23 |
Solubility : | 0.0000307 mg/ml ; 0.0000000591 mol/l |
Class : | Poorly soluble |
Log S (Ali) : | -8.23 |
Solubility : | 0.00000305 mg/ml ; 0.0000000059 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -2.85 |
Solubility : | 0.742 mg/ml ; 0.00143 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.61 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P261-P264-P270-P272-P273-P280-P301+P312+P330-P302+P352-P305+P351+P338+P310-P333+P313-P391-P501 | UN#: | 3077 |
Hazard Statements: | H302-H315-H317-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 |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; | Production Example 12 Synthesis of Resin with Hydrophilic Spacer: Synthesis of TOYO-Pearl Resin (TSKgel AF-Amino) with Hexaethylene Glycol Derivative To TOYO-Pearl resin (TSKgel AF-amino; 0.01 mmol amine is present in 100 mul), {2-[2-(2-{2-[2-(9H-fluoren-9-yl-methoxycarbonylamino)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}acetic acid (Compound 8 obtained in Production Example 11; 21 mg, 0.04 mmol) in solution in a mixed solvent of methylene chloride (0.4 ml) and N-methyl-2-pyrrolidone (NMP; 0.1 ml) was added; benzotriazol-1-yl-oxy-tris-pyrolidino-phosphonium hexafluorophosphate (PyBOP; 26 mg, 0.05 mmol) and N,N-diisopropylethylamine (17 mul, 0.10 mmol) were further added, and this was followed by shaking at room temperature for 4 hours. After completion of the reaction, the resin was thoroughly washed with methylene chloride and DMF, after which the percent condensation yield was measured by the ninhydrin test (about 81%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.5% | With hydrogenchloride; N-ethyl-N,N-diisopropylamine; benzyl alcohol; In water; ethyl acetate; N,N-dimethyl-formamide; acetonitrile; | Synthesis of 5R-({5S-[(9H-fluoren-9-ylmethoxycarbonylamino)-methyl]-2,2-dimethyl-[1,3]dioxolan-4R-ylmethyl}-carbamoyl)-2,2-dimethyl-[1,3]dioxolan-4S-carboxylic acid benzyl ester (Compound 11) 2,2-Dimethyl-[1,3]dioxolan-4R,5R-dicarboxylic acid (740 mg, 3.89 mmol) was dissolved in 50 ml of acetonitrile, 1,1'-carbonyldiimidazole (CDI; 1.26 g, 7.78 mmol) was added, and this was followed by stirring at room temperature for 30 minutes. To the reaction system, benzyl alcohol (BnOH; 420 mg, 3.89 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU; 887 mg, 5.84 mmol) were added; this was followed by stirring at room temperature for 17 hours. After completion of the reaction, water was added to the reaction solution, and the solution was rendered weakly acidic by further adding 1N hydrochloric acid. The reaction solution was extracted with ethyl acetate, and the organic phase extracted was washed with saturated brine, after which it was dried with anhydrous magnesium sulfate. The organic phase obtained was concentrated under reduced pressure to yield the desired monobenzyl ester compound. The monobenzyl ester compound obtained, without purification, was dissolved in 100 ml of DMF, and the Compound 10 obtained in Production Example 19 (1.2 g, 3.14 mmol) was dissolved in 10 ml of DMF and added to the reaction system. Benzotriazol-1-yl-oxy-tris-pyrolidino-phosphonium hexafluorophosphate (PyBOP; 3.37 g, 6.48 mmol) and diisopropylethylamine (i-Pr2NEt; 1.25 g, 9.74 mmol) were added, and this was followed by stirring at room temperature for 17 hours. To the reaction solution, 100 ml of water was added; extraction with 100 ml of ethyl acetate was conducted three times. The organic phase extracted was washed with saturated brine, and the organic phase obtained was dried with anhydrous magnesium sulfate, after which it was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield the desired Compound 11 (0.49 g) at a percent yield of 23.5%. MS (m/z): 645 (MH+), 1H-NMR(CDCl3) delta: 1.33-1.39 (m, 6H), 1.43 (s, 3H), 1.50 (m, 3H), 3.42 (b, 2H), 3.53 (b, 2H), 3.75 (m, 1H), 4.21 (m, 1H), 4.37-4.48 (m, 2H), 4.76-4.82 (m, 2H), 5.25 (s, 2H), 5.29 (m, 1H), 6.93 (m, 1H), 7.28-7.41 (m, 9H), 7.59 (d, 2H, J=7.5 Hz), 7.75 (d, 2H, J=7.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.96 g (65%) | In pyridine; dichloromethane; water; | N,N-Diisopropylethylamine (1.95 mL, 11.48 mmol) was added to a solution of methyl 2-aminomethyl-5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heptadecafluorododecanoate (3.15 g, 5.74 mmol), 4-(4-dimethylaminophenylazo)benzoic acid 52 (1.55 g, 5.74 mmol), and pyBOP (3.13 g, 6.02 mmol) in pyridine (25 mL) and dichloromethane (45 mL). After 16 h at rt, water was added and the mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo, then the resultant residue was purified by silica gel chromatography (4:1 hexanes/ethyl acetate) to afford 2.96 g (65%) of Methyl 2-[[4-(4-dimethylaminophenylazo)benzoylamino]methyl]-5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heptadecafluorododecanoate, Rf 0.75 (1:1 hexanes/ethyl acetate). UV (methanol) lambdamax 430 nm; 1H NMR (500 MHz, CDCl3): delta 7.91 (2 H, d, J=9.0 Hz), 7.88 (2 H, d, J=8.5 Hz), 7.85 (2 H, d, J=8.5 Hz), 6.77 (2 H, d, J=9.0 Hz), 7.68 (1 H, br t, J=6.0 Hz), 3.79-3.64 (1 H, m), 3.77 (3 H, s), 3.68-3.62 (1 H, m), 3.12 (6 H, s), 2.87-2.82 (1 H, m), 2.32-2.18 (2 H, m), 2.09-2.00 (1 H, m), 1.94-1.87 (1 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | 463 mg of 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-5-carboxylic acid and 144 mg of methylamine hydrochloride were dissolved in 10 mL of N,N-dimethylformamide. To the mixture, 706 mg of (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate and 0.47 mL of N,N-diisopropylethylamine were added and stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with a mixture of ethyl acetate : toluene=5 : 1. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform: methanol=20 : 1], to give 401 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-5-((methylamino)carbonyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale brown foam. 1H-NMR (CDCl3) delta: 1.46 (9H, s), 1.76-1.93 (2H, m), 2.11-2.24 (2H, m), 2.72-2.94 (2H, m), 3.03 (3H, d, J=4.8 Hz), 3.27-3.42 (3H, m), 3.56-3.72 (2H, m), 3.87 (3H, s), 4.24 (4H, s), 4.26-4.33 (2H, m), 4.51-4.66 (2H, m), 6.41 (1H, d, J=9.7 Hz), 6.64-6.73 (2H, m), 6.74-6.81 (1H, m), 6.85-6.96 (2H, m), 8.04 (1H, d, J=9.7 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (S)-2-Amino-N-((S)-1-benzyl-2-ethylcarbamoyl-2-hydroxy-ethyl)-3-methyl-butyramide; In DMF (N,N-dimethyl-formamide); at 20℃; for 0.25h; | A suspension of the intermediate 59a) (269.5 mg) in 7 ml of DMF was reacted with 176.7 microl of diisopropylethylamine and 322.1 mg of PyBOP for 15 min. The aminoterminally deprotected dipeptide intermediate 39a) was added and the reaction mixture was stirred over night at room temperature. The solvent was evaporated in high vacuum and the remaining solid was taken up in 50 ml of ethyl acetate. After extraction with 30 ml of 0.1 n HCl, the org. phase was dried over MgSO4, filtered and evaporated. The remaining crude product was purified by silica gel chromatography with CH2Cl2/MeOH/AcOH 12:1:0.1. Rf = 0.13 (CH2Cl2/MeOH/AcOH 12:1:0.1), mp: 286 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 80 (R .-1-{ [(FURAN-2-VLMETHYL)-CARBAMOVL]-METHVL}-3-(2-HVDROXV-2 « 2-DIPHENVL-ACETOXY)-1-AZONIA- bicyclo [2.2. 2] octane trifluoroacetate To a solution of (R)-l-carboxymethyl-3- (2-hydroxy-2, 2-diphenyl-acetoxy)-l-azonia-bicyclo- [2.2. 2] octane trifluoroacetate [Example 62] (0.04 g, 0.078 mmol) in DCM (0. 5 ml) is added DIPEA (0. 056 ml) and C-furan-2-yl-methylamine (0. 056 ml, 0.634 mmol) followed by PYBOP (0. 055 g, 0.106 mmol) in DMF (1 ml). The reaction mixture is left to stir at room temperature over 48 hours. Initial purification is carried out using Solid Phase Extraction with a pH 8 pre- conditioned column (pH adjusted using Isolute CBA). Further purification is carried out using mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid to afford the titled compound. Alterbatively, to a solution of (R)-1-CARBOXYMETHYL-3- (2-HYDROXY-2, 2-DIPHENYL-ACETOXY)-1- AZONIA-BICYCLO- [2. 2.2] octane trifluoroacetate [Example 62] (0.04 g, 0.078 mmol) in DCM (O. 5 ml) is added DIPEA (0. 056 ml) and C-furan-2-yl-methylamine (0.021 ml, 0.234 mmol) followed by PyBroP (0. 055 g, 0.118 mmol) in DMF (1 ml). The reaction mixture is left to stir at room temperature over 48 hours. Initial purification is carried out using Solid Phase Extraction with a pH 8 pre-conditioned column (pH adjusted using Isolute CBA). Further purification is carried out using mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid to afford the titled compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); for 0.333333h; | The coupling of doxorubicin on the peptides via the intermediary of the succinic link was performed in 3 steps. To doxorubicin hydrochloride (1 eq.) dissolved in dimethylformamide (DMF) in the presence of diisopropylethylamine (DIEA, 2 eq.) was added succinic anhydride (1.1 eq., dissolved in DMF). After incubation of 20 minutes at ambient temperature, the thereby formed doxorubicin hemisuccinate was then activated by addition of PyBOP benzotriazol-1-yl-oxopyrrolidinephosphonium hexafluorophosphate (1.1 eq.) in DMF and DIEA (2 eq.). This second reaction mixture was incubated for 20 minutes. The peptide (1.2 eq. in DMF) was then added to the reaction mixture and coupled spontaneously on the doxorubicin hemisuccinate activated during a supplementary incubation of 20 minutes. The coupling product was then purified on preparative HPLC (high pressure liquid chromatography) then lyophilized. Each of the steps as well as the final product were checked with analytic HPLC and mass spectrometry. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.333333h; | Succinic anhydride (1, leq, dissolved in DMF) is added to doxorubicin chlorydrate (1 eq), solubilised in dimethylformamide (DMF) in the presence of Disopropylethylamine (DIEA, 2 eq).After 20 minutes incubation at room temperature, the doxorubicin hemisuccinate thus formed is then activated by the addition of PyBOP (Benzotriazol-1-yl-oxopyrrolidinephosphonium hexafluorophosphate 1.1 eq in DMF) and DIEA (2 eq). This second reactional mix is incubated for 20 minutes.The peptide (1.2 eq in DMF) is then added to the reactional mix and spontaneously combines with doxorubicin hemisuccinate activated during an additional 20 minutes incubation.The coupling product is then purified on HPLC (high pressure liquid chromatography) in preparation, and is then freeze dried.Each of the steps, and the final product, are checked by analytic HPLC and mass spectrometry. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; dichloromethane; at 20℃; for 18h; | Step 2: Synthesis of 5-bromo-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N,N-dimethyl-nicotinamide; 630 mg (1.90 mmol) of 5-bromo-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-nicotinic acid was suspended in 50 ml of dichloromethane. 6 ml of 2 M dimethylamine in THF and 850 mg (1.63 mmol) of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate were added and the resulting mixture was stirred for 18 h at ambient temperature. The resulting mixture was diluted with dichloromethane and washed with water. The aqueous phase was extracted with dichloromethane and the organic phases were combined, dried over sodium sulfate and evaporated to afford crude 5-bromo-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N,N-dimethyl-nicotinamide as a pale brown oil containing tris(pyrrolidinyl)phosphoramidate as a contaminant. MS: m/z 357 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With ammonia; In water; ethyl acetate; N,N-dimethyl-formamide; | (b) 1-Carbamoyl 1-ethoxy-2-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)phenyl]ethane Ammonia was bubbled through a mixture of compound (a) (2.9 g; 7.1 mmole) and benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (3.7 g; 7.1 n mmole) in DMF (30 ml) for 3 hours at room temperature. Water and ethyl acetate were added. The phases were separated, the organic phase was washed with water, dried with magnesium sulfate and the solvent was evaporated in vacuo. The crude product was crystallized in diethyl ether to give 2.5 g (yield 86%) of the desired product as a white powder. 1H-NMR (300 MHz; CDCl3): 1.13 (t, 3H, J=6.8 Hz), 2.80-2.90 (m, 1H), 3.05-3.14 (m, 6H), 3.36-3.56 (m, 2H), 3.84-3.91 (m, 1H), 4.14 (t, 2H, J=6.5 Hz), 5.38 (s br, I NH), 6.42 (s br, 1 NH), 6.80 (dm, 2H, J=8.8 Hz, unresolved), 7.15 (dm, 2H, J=8.8 Hz, unresolved), 7.19-7.27 (m, 2H), 7.34 (dm, 2H, J=8.1 Hz, unresolved). 3C-NMR (75 MHz; CDCl3): 15.2, 35.2, 37.3, 38.0, 66.6, 68.1, 81.4, 114.2, 122.0, 129.7, 130.58, 130.64, 138.0, 147.8, 157.3, 175.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With ammonia; In dichloromethane; water; N,N-dimethyl-formamide; | (a) 1-Carbamoyl-2-[4-(2-{4-tert-butyloxycarbonylaminophenyl}ethoxy)phenyl]-1-ethoxyethane 3-{4-[2-(4-tert-Butoxycarbonylamino phenyl}ethoxy]phenyl]-2-ethoxypropanoic acid (1.18 g, 2.75 mmole) and benzotriazol-1-yl-oxytri-pyrrolidinophosphoniumhexafluorophosphate (1.43 g, 2.75 mmole) were dissolved in dry DMF (20 ml). Ammonia gas was bubbled through the mixture for 5 minutes. After stirring at room temperature for 16 hours it was checked using HPLC that all the starting material was consumed. Water was added and extracted three times with ethyl acetate dried with magnesium sulfate and evaporated. The residue was redissolved in dichloromethane and chromatography on silica using a gradient system of dichloromethane:methanol (0-5%) gave 1.04 g (85% yield) of the desired product. 1H-NMR (500 MHz; CDCl3): 1.16 (t, 3H), 1.55 (s, 9H), 2.85-2.92 (m,1H), 3.06 (t, 2H), 3.08-3.14 (m, 1H), 3.41-3.48 (m, 1H), 3.50-3.58 (m, 1H), 3.92 (q, 1H), 4.14 (t, 2H), 5.91 (-NH2), 6.62 (-NH2), 6.72 (-NH,), 6.84 (d, 2H), 7.18 (d, 2H), 7.34 (d, 2H) 13C-NMR (125 MHz; CDCl3): 15.5, 28.6, 35.4, 38.4, 66.9, 69.0, 81.7, 114.5, 119.1, 129.8, 130.9, 133.2, 137.1, 157.8, 175.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; ethyl acetate; | A. (2S)-1-[(2'R)-3'-(Acetylaminomethylthio)-2'-(tert-butyloxycarbonylamino)-3'-methylbutanoyl]pyrrolidine-2-carbonitrile S-(Acetylaminomethyl)-N-(tert-butyloxycarbonyl)penicillamine (720 mg, 2.25 mmol) was dissolved in CH2Cl2 (30 mL). To this solution at 0 C. were added (2S)-pyrrolidine-2-carbonitrile hydrochloride (270 mg, 2.04 mmol) and PyBOP (1.3 g, 2.49 mmol), and the pH adjusted to pH9 with triethylamine. After 18 h at 0 C. to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (150 mL). The solution was washed with 0.3M KHSO4 (2*30 mL), sat. NaHCO3 (2*30 mL), water (2*30 mL) and brine (1*30 mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 75% ethyl acetate, 25% pet. ether) to give a colourless oil identified as (2S)-1-[(2'R)-3'-(acetylaminomethylthio)-2'-(tert-butyloxycarbonylamino)-3'-methylbutanoyl]pyrrolidine-2-carbonitrile (742 mg, 1.86 mmol, 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; ethyl acetate; | A. (2S)-1-[S-(Acetylaminomethyl)-N-(tert-butyloxycarbonyl)-L-cysteinyl]pyrrolidine-2-carbonitrile S-(Acetylaminomethyl)-N-(tert-butyloxycarbonyl)-L-cysteine (660 mg, 2.26 mmol) was dissolved in CH2Cl2 (30 mL). To this solution at 0 C. were added (2S)-pyrrolidine-2-carbonitrile hydrochloride (250 mg, 1.89 mmol) and PyBOP (1.3 g, 2.49 mmol), and the pH adjusted to pH9 with triethylamine. After 18 h at 0 C. to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (150 mL). The solution was washed with 0.3M KHSO4 (2*30 mL), sat. NaHCO3 (2*30 mL), water (2*30 mL) and brine (1*30 mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 75% ethyl acetate, 25% pet. ether) to give a colourless oil identified as (2S)-1-[S-(acetylaminomethyl)-N-(tert-butyloxycarbonyl)-L-cysteinyl]-pyrrolidine-2-carbonitrile (650 mg, 1.76 mmol, 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.19 g (54%) | In N,N-dimethyl-formamide; | Example 3 N-(1-carbamoyl-2-phenylsulfanylethyl)-2-pyridin-4-yl-1H-indole-5-carboxamide 0.20 g (0.84 mmol) of 2-pyridin4-yl-1H-indole-5-carboxylic acid was admixed with 0.21 g (1.07 mmol) of 2-amino-3-phenylsulfanylpropionic acid in 40 ml of DMF and, at 0 C., 0.66 g (1.27 mmol) of benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate and 0.37 ml (2.12 mmol) of N-ethyl-N,N-diisopropylamine were added, and the solution was stirred at 20 C. for 2 h. The solution was concentrated under reduced pressure and purified by medium pressure column chromatography (CH2Cl2/CH3OH: 9:1). This gave 0.19 g (54%) of N-(1-carbamoyl-2-phenyisulfanylethyl)-2-pyridin-4yl-1H-indole-5-carboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
171 mg (50%) | With N-ethyl-N,N-diisopropylamine; In dichloromethane; water; ethyl acetate; trifluoroacetic acid; | (b) (2S)-1-(Glycylisoleucyl)pyrrolidine-2-carbonitrile To a solution of Boc-glycine (0.21 g, 1.2 mmol) and PyBOP (0.62 g, 1.2 mmol) in dichloromethane (3 ml) was added DIPEA (522 mul, 3 mmol). To that solution was added the product of Example 5a (0.28 g, 0.9 mmol) followed by another portion of DIPEA (157 mul, 0.9 mmol). The reaction mixture was stirred overnight. The solvent was removed by rotary evaporation and the residue was taken up in ethyl acetate. The resulting solution was washed with 0.3M sodium bisulfate (2*), saturated sodium bicarbonate (2*), water and saturated sodium chloride. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed by rotary evaporation. The residue was dissolved in a mixture of TFA (95%) and water (5%) and the mixture was stirred overnight. Most of TFA and water was removed under reduced pressure. The residue was subjected to purification by reverse-phase HPLC to give the trifluoroacetate salt of the final product as a white powder; yield 171 mg (50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine; In (3R,4S)-3-benzyloxycarbonylamino-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester; dichloromethane; | Part I Preparation of (3R,4S)-3-benzyloxycarbonylamino-4-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester In a dry flask (3R,4S)-3-benzyloxycarbonylamino-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester (1.13 g, 3.00 mmol) was dissolved in dichloromethane (100 mL) and then triethylamine (1.67 mL, 12.0 mmol) and benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (1.56 g, 3.00 mmol) were added. The reaction was stirred 18 hours. The reaction mixture was diluted with water (25 mL) and extracted three times with ethyl acetate (25 mL). The combined organic extracts were dried with magnesium sulfate, filtered and concentrated in vacuo. The mixture was purified by flash chromatography with 50% ethyl acetate/hexanes to give a white solid (153 mg, 56%). 1H NMR (300 MHz, CDCl3), delta: 7.31 (m, 5H), 7.08 (m, 2H), 6.98 (m, 2H), 5.12 (m, 2H), 5.08 (m, 2H), 4.41 (m, 1H), 3.94 (m, 4H), 3.60 (m, 1H), 3.43 (m, 2H), 2.98 (m, 2H), 2.59 (m, 2H), 2.39 (m, 2H), 1.66 (m, 4H), 1.56 (s, 9H). MS (ESI), m+/z: (M+H)+=554.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine; In sodium hydroxide; dichloromethane; | Part B. Preparation of (3R,4S)-3-[(S)-3-(4-fluorobenzyl)-piperidine-1-carbonyl]-4-[(R)-1-phenyl-ethylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester. (S)-3-(4-flourobenzyl)-piperdine, mandelic acid salt (100 mg, 290 mumol) was dissolved in 1.0 M sodium hydroxide (4mL) and extracted with ethyl acetate (4*5mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The free base was used without further purification. A cloudy solution of (3R,4S)-4-[(R)-1-phenyl-ethylamino]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (80 mg, 240 mumol) in methylene chloride (5mL) was treated with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (151 mg, 290 mumol) and triethylamine (77 muL, 550 mumol) and stirred for 5 minutes. A solution of the (S)-3-(4-flourobenzyl)-piperdine prepared above in methylene chloride (5 mL) was added and the mixture was stirred at room temperature. After 18 h, the mixture was washed with water and saturated NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (50% ethyl acetate/hexanes) to provide the product as a gum (100 mg, 82%). 1H NMR (300 mHz, CD3OD) delta 7.32-6.95 (7H), 4.42-4.30 (1H), 3.90-2.48 (14H), 1.80-1.62 (3H), 1.40 (bs, 9H), 1.29 (d, 3H); mass spec. (ES+) m/z 510.4. |
Yield | Reaction Conditions | Operation in experiment |
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... preferable examples of the inert solvent include methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, pyridine or a mixture thereof, and the like. The aforesaid reaction is preferably carried out in the presence of condensing agents, for example N, N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate, bromotris-(dimethylamino)phosphonium hexafluorophosphate, |
Yield | Reaction Conditions | Operation in experiment |
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26% | With triethylamine; In methanol; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; N,N-dimethyl-formamide; | 1. N-(2-Hydroxyethyl)-2-(3-nitrophenyl)acetamide To a solution of 3-nitrophenylacetic acid (3.21 g, 17.7 mmol), ethanolamine (2.8 g, 46 mmol), and triethylamine (3.0 mL, 22 mmol) in anhydrous DMF (110 mL) was added a solution of <strong>[128625-52-5]benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate</strong> (PyBOP, 9.37 g, 18.0 mmol) in anhydrous DMF (80 mL). After stirring 16 hours at ambient temperature (under nitrogen), the reaction mixture was concentrated in vacuo, dissolved in DCM and filtered. The filtrate was washed with 10% aqueous citric acid, saturated aqueous NaHCO3, pH 7 buffer, and brine, dried over Na2SO4 and filtered. The evaporated filtrate was then purified by flash chromatography (10% methanol in DCM) giving the title compound (1.02 g, 26%) as a light yellow solid. 1H NMR (300 MHz, CDCl3/CD3OD) delta 8.18 (m, 1H), 8.11 (ddd, 1H, J=8.1 Hz, 2.4 Hz, 1.1 Hz), 7.72 (m, 1H), 7.60 (t, 1H, J=7.8 Hz), 3.62 (s, 2H), 3.44 (t, 2H, J=5.9 Hz), 3.16 (t, 2H, J=5.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; | Step A. To a solution of 3-chloro-2-nitrobenzoic acid (1 mmol) and aminomethylenediethyl phosphonate (1.1 mmol) in dichloromethane (5 mL)was added diisopropylethylamine (5 mmol) followed by pyBOP (1.5 mmol). The reaction was stirred at room temperature for 3 h and concentrated. The mixture was purified by chromatography to yield N-(diethylphosphonomethyl)-2-nitro-3-chlorobenzamide as a solid. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 14 2-(Methylthio)benzyl 3-(2,2-difluoro-2-(2-pyridyl-N-oxide)ethylamino)-6-chloropyrazin-2-one-1-acetamide The title compound was prepared according to the general pyBOP coupling procedure and was isolated as a colorless solid: 1H NMR (CD3OD, 300 MHz): delta8.37 (m, 1H), 7.71-7.69 (m, 1H), 7.56-7.54 (br m, 2H), 7.30-7.28 (br m, 3H), 7.15 (m, 1H), 6.70 (s, 1H), 4.86 (s, 2H), 4.57 (t, J=15 Hz, 2H), 4.46 (s, 2H), 2.48 (s, 3H). HRMS (FAB) M+H: 496.1034. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; | EXAMPLE 10 3-Cyclopentyloxy-4-methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridyl)benzamide To a solution of N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3 -pyridylmethyl)-3 -aminobenzoic acid (20 mg, 0.05 mmol) and pyBOP (40 mg. 0.08 mmol) in CH2Cl2 (2 mL) at room temperature was added diisopropylethylamine (20 L, 0. 1 mmol). After stirring for 15 min, 4-aminopyridine (15 mg, 0.15 mmol) was added and the mixture was allowed to stir 16 h. The mixture was diluted with EtOAc (25 mL) and washed with water (2*15 mL) and brine (15 mL), dried (MgSO4), and concentrated in vacuo. The crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the product was eluted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 min to give 22 mg of product. 1H NMR (CDCl3) delta8.70-8.40 (m, 3H), 8.24 (s, 1H), 7.72 (d, 1H, 9.0 Hz), 7.68-7.55 (m, 2H), 7.30-7.20 (m, 1H), 6.88 (d, 2H, J=8.5), 6.80-6.65 (m, 3H), 4.98 (s, 2H), 4.66 (p, 1H, J=4.1 Hz), 3.86 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In hexane; ethyl acetate; N,N-dimethyl-formamide; | Example 5 N-(1S-Cyanomethylcarbamoyl-3-methylbutyl)-4-(2-methylthiazol-4-yl)benzamide A mixture comprised of 2-amino-N-cyanomethyl-4-methylpentanamide p-toluenesulfonic acid salt (0.75 g, 2.3 mmol), 4-(2-methylthiazol-4-yl)benzoic acid (0.5 g, 2.3 mmol), PyBOP (1.2 g, 2.3 mmol) and triethylamine (1 mL, 5 mmol) in 10 mL of DMF was stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate solution (20 mL). The organic layer was separated, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. Product was purified from the residue by flash chromatography on a silica gel using 66% ethyl acetate in hexane to provide N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-(2-methylthiazol-4-4l)benzamide (0.5 g, 1.4 mmol). 1H NMR (DMSO-d6, ppm): delta 0.81 (m, 6H), delta 1.55 (m, 3H), delta 2.81 (s, 3H), delta 4.01 (m, 2H), delta 4.17 (m, 1H), delta 8.01 (m, 5H), delta 8.41 (d, I H), delta 9.01 (m, 1H); ES-Ms: 371.1 (M+H+). Proceeding as in Example 5 provided the following compounds of Formula I: N-(1-cyanomethylcarbamoyl-3-methylbutyl-1H-benzoimidazole-carboxamide (Compound 34); 1H NMR (DMSO-d6, ppm): delta 0.86 (d, 6H), delta 1.42 (m, 3H), delta 4.21 (s, 2 H), delta 4.81 (m, 1H), delta 7.6 (d, 1H), delta 8.01 (d, 1H), delta 8.23 (s, 1H), delta 8.81 (s, 1H), delta 9.2 (s, 1H); ES-Ms: 314.1 (M+H+); N-(1-cyanomethylcarbamoyl-3-methylbutyl)pyrazine-2-carboxamide (Compound 35); 1H NMR (DMSO-d6, ppm): delta 0.91 (d, 61H), delta 1.41 (m, 3 H), delta 4.21 (s, 2 H), delta 4.61 (m, 1H), delta 8.81 (m, 4 H), delta 9.2 (s, 1H); ES-Ms: 276.1 (M+H+); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran-dichloromethane; | Step g Preparation of 2-(2-Chloro-4-iodo-phenylamino)-4-dimethylsulfamoyl-benzoic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide A solution comprised of 2-(2-chloro-4-iodo-phenylamino)-4-dimethylsulfamoyl-benzoic acid, O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (1.25 molar equivalents), <strong>[128625-52-5]benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate</strong> (1.25 molar equivalents), and diisopropylethylamine (3 molar equivalents) in 1:1 v/v tetrahydrofuran-dichloromethane is stirred for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is purified by flash chromatography; elution with dichloromethane affords the desired product. The product may be recrystallized with an appropriate solvent like methanol if further purification is necessary. | |
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran-dichloromethane; | Step g: Preparation of 2-(2-chloro-4-iodo-phenylamino)-4-dimethylsulfamoylbenzoic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide A solution comprised of 2-(2-chloro-4-iodo-phenylamino)-4-dimethylsulfamoyl-benzoic acid, O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (1.25 molar equivalents), <strong>[128625-52-5]benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate</strong> (1.25 molar equivalents), and diisopropylethylamine (3 molar equivalents) in 1:1 v/v tetrahydrofuran-dichloromethane is stirred for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is purified by flash chromatography; elution with dichloromethane affords the desired product. The product may be recrystallized with an appropriate solvent like methanol if further purification is necessary. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran-dichloromethane; | Step a Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide A solution comprised of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid, O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (1.25 equiv.), <strong>[128625-52-5]benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate</strong> (1.25 equiv.), and diisopropylethylamine (3 equiv.) in 1:1 v/v tetrahydrofuran-dichloromethane is stirred for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is purified by flash chromatography; elution with dichloromethane affords the desired product. The product may be recrystallized with an appropriate solvent like methanol if further purification is necessary. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | To a cold (0 C.) solution of 1-(tert-butoxycarbonyl)-3-piperidine carboxylic acid (7.000 g, 30.531 mmol) in dichloromethane (200 mL) including triethylamine (4.681 mL, 33.584 mmol) were added <strong>[128625-52-5]benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate</strong> (15.885 g, 30.531 mmol), N,O-dimethylhydroxyamine (3.276 g, 33.584 mmol) and triethylamine (4.255 mL, 30.531 mmol) successively. The mixture was allowed to warm to room temperature, and the stirring was continued for 12 hrs. The reaction mixture was diluted with dichloromethane and washed with an aqueous 1N HCl solution, saturated aqueous NaHCO3 solution, and brine, successively. The organic phase was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=10/1-9/1) to give 3-[methoxy(methyl)amino]carbonyl}-1-piperidine-carboxylic acid tert-butyl ester as a white solid. (8.050 g, yield; 96%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | To a cold (0 C.) solution of 3-[(tert-butoxycarbonyl)amino]-cyclohexanecarboxylic acid (5.00 g, 20.6 mmol) in CH2Cl2 (50 mL) including triethylamine (3.1 mL, 22.2 mmol) were added benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexa-fluorophosphate (10.7 g, 20.6 mmol), N,O-dimethylhydroxyamine hydrochloride (2.21 g, 20.6 mmol) and Et3N (3.2 mL, 23.0 mmol) successively. The resulting mixture was allowed to warm to room temperature, and the stirring was continued for 18 hrs. The reaction mixture was diluted with CH2Cl2 and washed with 1N HCl, saturated aqueous NaHCO3 solution, and brine, successively. The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1:1) to give tert-butyl 3-([methoxy(methyl)amino]carbonyl}cyclohexylcarbamate as a colorless oil (5.39 g, yield; 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; | Benzyl 1S-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate A solution of 2-benzyloxycarbonylamino-4-phenylbutyric acid (5.05 g, 16.1 mmol) in dichloromethane (70 mL) was cooled to 0 C. and treated with diisopropylethylamine (2.82 mL, 16.2 mmol) added dropwise and then PyBOP (8.53 g, 16.4 mmol) added in one portion. The mixture was stirred for 5 minutes and then treated with N,O-dimethylhydroxylamine hydrochloride (1.73 g, 17.71 mmol) added in one portion. The mixture was neutralized with diisopropylethylamine (4.6 mL, 26.44 mmol) added dropwise, stirred for 2 hours at room temperature and then diluted with dichloromethane (70 mL). The dilution was washed sequentially with 1N aqueous hydrochloric acid (3*40 mL), saturated sodium bicarbonate (3*40 mL) and brine (40 mL) and then concentrated. The product was purified from the residue by column chromatography eluding with 2:3 ethyl acetate/hexane to provide benzyl 1S-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate (5.48 g, 15.4 mmol) as an oil. MS(PCI) m/z=357 (M+1). Proceeding as in Reference 1 provided tert-butyl 1S-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate; 1H NMR (CDCl3): delta 1.35 (s, 9H), delta 1.64-1.72 (m, 2H), delta 2.40-2.54 (m, 1H), delta 2.60-2.77 (m, 1H), delta 3.00 (s, 3H) 3.52 (s, 3H), delta 4.23 (m, 1H), delta 7.10-7.37 (m, 5H). | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; | Benzyl 1S-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate A solution of 2-benzyloxycarbonylamino-4-phenylbutyric acid (5.05 g, 16.1 mmol) in methylene chloride (70 mL) was cooled to 0 C. and treated with diisopropylethylamine (2.82 mL, 16.2 mmol) added dropwise and then PyBOP (8.53 g, 16.4 mmol) added in one portion. The mixture was stirred for 5 minutes and then treated with N,O-dimethylhydroxylamine hydrochloride (1.73 g, 17.71 mmol) was added in one portion. The mixture was neutralized with diisopropylethylamine (4.6 mL, 26.44 mmol) added dropwise, stirred for 2 hours at room temperature and then diluted with methylene chloride (70 mL). The dilution was washed with 1N aqueous hydrochloric acid (3*40 mL), saturated sodium bicarbonate (3*40 mL) and brine (40 mL) and then concentrated. The product was purified from the residue by column chromatography eluding with 2:3 ethyl acetatelhexane to provide benzyl 1S-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate (5.48 g, 15.4 mmol) as an oil. MS(PCI) m/z=357 (M+1). Proceeding as in Reference 13 provided tert-butyl 1S-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate; 1H NMR (CDCl3): delta 1.35 (s, 9H), delta 1.64-1.72 (m, 2H), delta 2.40-2.54 (m, 1H), delta 2.60-2.77 (m, 1H), delta 3.00 (s, 3H) 3.52 (s, 3H), delta 4.23 (m, 1H), delta 7.10-7.37 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; aniline; In N,N-dimethyl-formamide; | Example 26 Benzyl 3-methyl-1-[2-hydroxy-1-phenethyl-2-(4-phenylcarbamoyloxazol-2-yl)ethylcarbamoyl]butylcarbamate (Compound 255) A solution comprised of 2-[2-(2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxy-4-phenylbutyl]oxazole-4-carboxylic acid (0.05 g, 0.096 mmol), provided as in Example 7, in DMF (5 mL) was stirred while PyBOP (0.05 g, 0.096 mmol) and aniline (9 mg, 0.096 mmol) were added. The mixture was stirred for an additional 2 minutes and diisopropylethylamine (12.4 mg, 0.096 mmol) was added. The mixture was stirred for 2 hours at room temperature, poured into cold water 0 C. at and extracted with ethyl acetate (4*30 mL). The extracts were combined, dried (MgSO4) and then concentrated. The product was purified from the residue by flash chromatography eluding with 1:2 hexanes/ethyl acetate to provide benzyl 3-methyl-1-[2-hydroxy-1-phenethyl-2-(4-phenylcarbamoyloxazol-2-yl)ethylcarbamoyl]butylcarbamate (30 mg, 0.05 mmol) as a white solid. MS (ESI)) m/z=599 (M+1); 1H NMR (CDCl3): delta 0.8-1.05 (d, J=4 Hz, 6H), 1.35 (m, 1H), delta 1.55 (m, 1H), delta 2.00-2.15 (m, 2H), delta 2.62 (m, 2H), delta 2.80 (m, 2H), delta 3.65 (m, 2H), delta 4.11 (m, 1H1), delta 4.30 (m, 1H), delta 4.45 (m, 1H), delta 4.95 (s, 1H) 5.17 (s, 2H), delta 5.2 (d, J=4 Hz, 1H), delta 6.70 (d, J=5 Hz 1H), delta 7.1-7.45 (m, 15H) 7.7(d, J=4 Hz, 1H), delta 8.19 (s, 1H), delta 8.99 (s, 1H), (C34H38N4O6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Example 2 2S-Acetylamino-N-(2-oxazol-2-yl-2-hydroxy-1S-phenethylethyl)-3-cyclohexylpropionamide (Compound 2) A mixture comprised of 2-acetylamino-3-cyclohexylpropionic acid (0.45 g, 0.211 mmol), PyBOP (0.11 g, 0.21 mmol) and diisopropylethylamine (0.037 g, 0.211 mmol) in DMF (10 mL) was stirred for 15 minutes at room temperature and a solution comprised of 2S-amino-1-oxazol-2-yl-4-phenylbutan-1-ol trifluoroacetic acid salt, provided as in Reference 9, in DMF and neutralized with diisopropylethylamine was added. Additional diisopropylethylamine (0.037 g, 0.211 mmol) was added and the mixture was stirred for 2 hours at room temperature and then poured into 100 mL of ice cold water. The aqueous phase was extracted with ethyl acetate (3*25 mL) and the combined organic layers were washed sequentially with 1 N hydrochloric acid (2*25 mL), water (2*25 mL) and brine (2*25 mL), dried (MgSO4) and concentrated. Product was purified from the residue by flash chromatography eluding with 1:3 hexanes/ethyl acetate to provide 2S-acetylamino-N-(2-oxazol-2-yl-2-hydroxy-1S-phenethylethyl)-3-cyclohexylpropionamide (0.036 g, 0.084 mmol) as an oil. MS (ESI) m/z=428 (M+1); 1H-NMR (300 MHz, CD3OD): delta 0.80 (m, 2H), delta 1.12 (m, 4H), delta 1.40(m, 2H), delta 1.65 (m, 6H), delta 1.80 (m, 1H), delta 2.00 (m, 4H), delta 2.70 (m, 1H), delta 2.80 (m, 1H), delta 4.44 (m, 1H), delta 4.51 (m, 1H), delta 7.11-7.47 (m, 6H), delta 7.99 (s, 1H), (C24H33N3O4). |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; | (1) Preparation of 2-tert-butoxycarbonylamino-6-[2-(5-ethyl-4-methyl-1,3-thiazol-2-yl)ethyl]-4-morpholinopyridine 6-tert-butoxycarbonylamino-4-morpholinopyridine-2-ylpropionic acid (17.57 g) obtained by alkali hydrolysis of the compound obtained in Example 22-(3) and 2-amino-3-pentanone hydrochloride (8.25 g) were dissolved in methylene chloride (200 ml), and a solution of benzotriazol-1-yloxy-tris-pyrrolidinophosphoniumhexafluorophosphate (31.2 g) in methylene chloride (50 ml) and diisopropylethylamine (35 ml) were added thereto, followed by stirring at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 19 (S)-3-(1H-Imidazol-4-yl)-2-(3-naphthalen-1-yl-2-naphthalen-1-ylmethyl-propionylamino)-propionic acid, 2-thiophen-2-yl-ethyl ester Following the procedure of Example 7, but using benzotriazol-1-yloxy-tripyrrolidino phosphonium hexafluorophosphate (PyBOP) as the coupling agent and using 2-thiophen-2-yl-ethyl alcohol, there was obtained 60 mg of the product as a white solid, mp 203-206 C. The structure was confirmed by NMR and mass spectroscopy; (m+H)+ =588. |
Yield | Reaction Conditions | Operation in experiment |
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Step B 2-Benzyloxycarbonylamino-2-methyl- N-[7-nitro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]propanamide Prepared from N-carbobenzyloxy-2-methylalanine and 3(R)-amino-7-nitro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step A) substituting benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate for benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate according to the procedure described in Example 1, Step I. 1 H NMR (400 MHz, CDCl3): delta 1.48 (s, 3H), 1.49 (s, 3H), 2.00 (m, 1H), 2.73 (m, 2H), 2.92 (m, 1H), 4.45 (m, 1H), 5.07 (s, 2H), 5.30 (s, 1H), 7.05 (d, 8 Hz, 1H), 7.30 (m, 6H), 8.06 (dd; 8, 6 Hz; 1H), 8.13 (d, 2.5 Hz, 1H), 8.35 (s, 1H). FAB-MS: calculated for C22 H24 N4 O6 424; found 425 (M+H, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step A 2-Benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]propanamide Prepared from N-carbobenzyloxy-2-methylalanine and 3(R)-amino-2,3,4,5-tetrahydro-1H-benzazepin-2-one (Example 1, Step E) substituting benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate for benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate according to the procedure described in Example 1, Step I. 1 H NMR (200 MHz, CDCl3): delta 1.47 (s, 3H), 1.52 (s, 3H), 1.82 (m, 1H), 2.50-3.00 (m, 3H), 4.45 (m, 1H), 5.05 (s, 2H), 5.37 (s, 1H), 6.80-7.40 (m, 10H), 8.65 (s, 1H). FAB-MS: calculated for C22 H25 N3 O4 395; found 396 (M+H,100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step K 2-t-Butoxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]propanamide Prepared from N-t-butoxycarbonyl-2-methylalanine and 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step E) substituting benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate for benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate according to the procedure described in Example 1, Step I. 1 H NMR (200 MHz, CDCl3): delta 1.47 (s, 3H), 1.52 (s, 3H), 1.82 (m, 1H), 2.50-3.00 (m, 3H), 4.45 (m, 1H), 5.05 (s, 2H), 5.37 (s, 1H), 6.80-7.40 (m, 10H) and 8.65 (s, 1H). FAB-MS: calculated for C22 H25 N3 O4 395; found 396 (M+H, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step D 3-Benzyloxycarbonylamino-3-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide Prepared from 3-benzyloxycarbonylamino-3-methylbutanoic acid (Step C) and 3(R)-amino-2,3,4,5-tetrahydro-1H-benzazepin-2-one (Example 1, Step E) substituting benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate for benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate according to the procedure described in Example 1, Step I. 1 H NMR (200 MHz, CDCl3): delta 1.37 (s, 6H), 1.82 (m, 1H), 2.45-2.75 (m, 4H), 2.86 (m, 1H), 4.49 (m, 1H), 5.05 (dd; 10, 6 Hz; 2H), 5.55 (s, 1H), 6.73 (s, 1H), 6.96 (d, 4 Hz, 1H), 7.10-7.40 (m, 8H) and 8.68 (s, 1H). FAB-MS: calculated for C23 H27 N3 O4 409; found 410 (M+H, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With i-Pr2NEt; In methanol; dichloromethane; polyethylene; | Part B (3S)-3-[N-((2,3-Dihydro-2,2-Dimethyl-7-Benzofuranyloxy)Acetyl)Leucinyl]Amino-4-Oxobutanoic Acid An aliquot of the Part A resin (0.120 g, ca 0.032 mmol) was placed in a 6 mL Supelco fitration tube equipped with a 20 mum polyethylene frit, treated with piperidine-dimethylformamide (1.0 mL, 1:4 v/v) and mixed on an orbital shaker for 1 hr. The supernatant was removed by suction and the resin washed with dimethylformamide (4*1.0 mL) and CH2Cl2 (3*1.0 mL). The resin was treated with 0.5M iPr2NEt in N-methylpyrolidinone (0.40 mL, 0.20 mmol), (2,3-dihydro-2,2-dimethyl-7-benzofuranyloxy)acetic acid (0.026 g, 0.12 mmol) and 0.25M pyBOP in N-methylpyrolidinone (0.40 mL, 0.10 mmol). The mixture was mixed on an orbital shaker under an nitrogen atmosphere for 16 hrs. The supernatant was removed by suction and the resin washed succesively with dimethylformamide (3*1.0 mL) and CH2Cl2 (3*1.0 mL), methanol (2*1.0 mL) and Et2O (2*1.0 mL). The resin was treated with 1.0 mL of CH2Cl2 and allowed to re-swell for 15 min. The solvent was removed by suction and the resin treated with trifluoroacetic acid-CH2Cl2-anisole (1.0 mL, 4:3:1 v/v/v). After mixing on an orbital shaker under nitrogen for 6 hrs, the supernatant was removed by suction and the resin washed with CH2Cl2 (4*1.0 mL). The resin was treated with 37% aqueous formaldehyde-acetic acid-tetrahydrofuran-trifluoroacetic acid (1.0 mL, 1:1:5:0.025 v/v/v/v) and mixed on an orbital shaker under nitrogen for 4 hrs. The supernatant was collected by suction, the resin washed with tetrahydrofuran (3*0.5 mL). The combined filtrates were blown down under nitrogen. The residue was taken up in methanol (0.5 mL), filtered and applied directly to a 3 mL Supelco LC-18 reverse phase extraction tube which had been pre-conditioned with water, and eluted successively with 3 mL each of 10% MeOH-water, 30% MeOH-water, 60% MeOH-water and 90% MeOH-water. The product-containing fractions (TLC) were combined and evaporated to dryness to give the title compound (0.0084 g, 60%) as a colorless glass. TLC(AcOH-MeOH-CH2Cl2; 1:1:20) Rf=0.29. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | 1st Step (-)-(2S,3S)-2-tert.-butoxycarbonylamino-3-methyl-pentanoic acid-(1R,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phenyl ester (-14) The base was released with dichloromethane/aqueous sodium hydrogen carbonate solution from enantiomer (-7), which was prepared according to Example 10, and the dichloromethane was removed by distillation after drying the solution. 2.1 g (9.8 mmole) of the base obtained were dissolved in 140 ml of dry dichloromethane and mixed in succession at room temperature with 2.19 g (9.5 mmole) (-)-(2S,3S)-2-tert.-butoxycarbonyl-amino-3-methyl-pentanoic acid monohydrate, 2.63 ml (19 mmole) triethylamine and 4.94 g (9.5 mmole) benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium hexafluorophosphate. After stirring for 2 hours at room temperature, the solvent was distilled off and the residue (10.1 g) was introduced on to a 7*40 cm column packed with silica gel. Elution with 1/1 ethyl acetate/methanol gave 2.66 g of base (-14). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 2h; | The title compound from Step C above (256 mg), commercially available 4-aminomethyl-benzoic acid methyl ester hydrochloride (160 mg), PyBOP (800 mg) and NEt3 (202 muL) were dissolved in THF/DMF (2:1, 15 mL). The mixture was stirred at room temperature for 2 h, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/acetone) to afford the title compound (196 mg, 44%). [MH]+ = 570. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Example 2(a) 7-chloro-2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridine To a mixture of lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (6.59 g, 30 mmole) in DMF (100 ml) were added diisopropylethylamine, (6 ml, 4.45 g, 34.4 mmole), benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (16.16 g, 31 mmole) and S-(+)-2-(methoxymethyl)pyrrolidine (3.73 g, 32.4 mmole). The resultant reaction mixture was stirred at ambient temperature for 16 hours. The crude reaction mixture was poured into water (600 ml) and extracted with EtOAc (3*200 ml). The combined organic extracts were washed with water (4*200 ml), dried over Na2SO4 and concentrated, in vacuo, to give 8.8 g of an amber oil, which was purified by silica gel chromatography. Elution with Et2O:EtOAc (67:33) and evaporation of the appropriate fractions gave 6.89 g (74%) of an orange syrup. 1H NMR (DMSO-d6): delta8.62 (1H, d, J=5.0 Hz), 7.88 (1H, s), 7.35 (1H, d, J=5.0 Hz), 4.54-4.47 (1H, m), 3.93-3.75 (2H, m), 3.71-3.55 (2H, m), 3.37 (3H, s), 2.15-1.92 (4H, m). Anal. Calcd. for C14H15N2O2SCl: C, 54.10; H, 4.87; N, 9.01; S, 10.32; Cl, 11.41. Found: C, 53.96; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; | Ex. 1c (1R)-1-({(2S)-2-[(Benzyloxy)carbonyl]amino}-6-[(tert-butoxy-carbonyl)amino]hexanoyl}amino)-2-phenylethyl{3-[(2S)-2-([(1S)-1-(methoxycarbonyl)-3-methylbutyl]amino}carbonyl)tetrahydro-1H-pyrrol-1-yl]-2-methyl-3-oxopropyl}phosphinic acid 4.0 eq. of ethyldiisopropylamine, 1.50 eq. of PyBop and, after from 2 to 5 min, 1.45 eq. of Z-(NHBoc)-Lys-OH are added, one after the other, at 0 C. and under argon, to a solution of 1.0 eq. of the compound from Ex. 1b. After 15-30 min, the ice cooling is removed and the mixture is stirred overnight at room temperature. It is diluted with dichloromethane and consecutively washed with saturated sodium hydrocarbonate solution, 1N hydrochloric acid solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Crude yield: 207 mg of a viscous oil, LC-MS: rt (%), m/z (%)=4.456 (11.2%), 858 (100, M+H); 4.549 (32.7), 858 (100, M+H). The crude product is purified by means of preparative RP-HPLC. Yield: 40 mg (32.8% of theory). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydrogen sulphate; lithium hydroxide monohydrate; N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; methanol; dichloromethane; water; | EXAMPLE 56 (+-)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidinyl-1'-yl-1-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5ylmethyl)-2-oxo-ethyl]-amide To a solution of 3-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (20 mg, 1.0 equiv) in methanol (0.6 mL) was added lithium hydroxide monohydrate (4 mg, 2.2 equiv) in water (0.1 mL) and stirred for 4 h at room temperature. The solution was cooled to 0 C., treated with aqueous 1M potassium hydrogen sulfate (75 mul, 1.8 equiv), and concentrated to give the crude acid which was immediately used without purification. The crude acid was dissolved in dimethylformamide (0.3 mL) and sequentially treated with methylene chloride (0.15 mL), 4-piperidyl-piperidine (13 mg, 2 equiv), diisopropylethylamine (14 muL, 2 equiv), and PyBOP (22 mg, 1.1 equiv). The solution was stirred 1.5 h and concentrated. The product was purified by column chromatography to give a product which was tainted with HOBT. The HOBT was removed by passing the product through a plug of basic alumina, eluding with 10% methanol in methylene chloride. Concentration gave 18.3 mg (72%, 2 steps). 1H-NMR (CDCl3, 500 MHz) delta 1.25-1.32 (m, 6H), 1.40 (m, 4H), 1.54 (m, 5H), 1.65 (m, 4H), 1.83 (m, 2H), 2.30-2.56 (m, 8H), 2.81 (m, 4H), 3.04 (dt, J=57.1, 12.2, 1H), 3.43-3.60 (m, 2H), 4.00-4.17 (m, 2H), 4.18-4.26 (m, 3H), 4.49 (m, 1H), 4.62 (m, 1H), 5.03 (m, 1H), 5.80 (dd, J=16.8, 9.9, 1H), 6.69 (d, J=7.9, 1H), 6.90 (dd, J=7.3, 7.3, 1H), 6.99 (dd, J=7.6, 7.3, 1H), 7.13 (dd, J=7.6, 7.6, 1H), 7.19 (s, 1H), 7.66 (bd, J=12.8, 1H). Mass spec.: 646.43 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
599 mg (87%) | With triethylamine; N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; | (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4']bipiperidinyl-1'-yl-2-oxo-1-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}-amide To a solution of (R)-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid (554 mg, 0.88 mmol) and N,N-diisopropylethylamine (0.62 mL, 3.54 mmol) in methylene chloride (20 mL) was added a solution of 4-piperidinopiperidine (164 mg, 0.97 mmol) and PyBOP (460 mg, 0.88 mmol) in methylene chloride (15 mL). The reaction mixture was stirred for 16 h at room temperature. It was then concentrated to approximately 2 mL and subjected to flash column chromatography using methylene chloride/methanol/triethylamine (94:5:1) as eluent to give 599 mg (87%) of the title compound as a white solid. 1H-NMR (CD3CN, 300 MHz) delta 8.37 (s, 0.5H), 8.36 (s, 0.5H), 8.02-7.96 (m, 1H), 7.74 (s, 0.5H), 7.71 (s, 0.5H), 7.55-7.46 (m, 1H), 7.21-7.12 (m, 2H), 6.97-6.92 (m, 1H), 6.79 (d, J=8.1 Hz, 1H), 5.71 (t, J=8.1 Hz, 1H), 5.00 (dd, J=15.0, 8.1 Hz, 1H), 4.63-4.51 (m, 1H), 4.39-4.29 (m, 1H), 4.29 (s, 2H), 4.10-3.96 (m, 3H), 3.46-3.40 (m, 2H), 2.92-2.70 (m, 8H), 2.58-2.37 (m, 5H), 1.74-1.40 (m, 13H), 0.80-0.74 (m, 2H), -0.04 (s, 9H). Mass spec.: 778 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine; N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; methanol; dichloromethane; | EXAMPLE 11 (+-)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-1-(1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide To a solution of the 3-(1H-indazol-5-yl)-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid (95 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.82 mmol) in dimethylformamide (5 mL) was added a solution of 1,4-dioxa-8-azaspiro[4,5]decane (32 mg, 0.23 mmol) and PyBOP (107 mg, 0.21 mmol) in methylene chloride (5 mL). The reaction mixture was stirred for 16 h at room temperature. All solvent was removed using high vacuum. The residue was subjected to flash column chromatography using methylene chloride/methanol/triethylamine (93:5:2) to give the title compound as a white solid (67 mg, 56% yield). 1H-NMR (CDCl3, 500 MHz) delta 10.52 (s, 1H), 7.97 (s, 1H), 7.54 (s, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.20 (d, J=10.7 Hz, 1H), 7.16 (t, J=7.2 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.01 (s, 1H), 6.94 (t, J=8.6 Hz, 1 H, 6.67 (d, J=7.6 Hz, 1H), 5.64 (d, J=7.9 Hz, 1H), 5.16 (dd, J=15.0, 6.7 Hz, 1H), 4.56-4.49 (m, 1H), 4.25 (s, 2H), 4.11 (br t, J=15.6 Hz, 2H), 3.92-3.84 (m, 4H), 3.73-3.69 (m, 1H), 3.60-3.56 (m, 1H), 3.48-3.43 (m, 1H), 3.22-3.17 (m, 1H), 3.11 (d, J=6.7 Hz, 2H), 2.90-2.85 (m, 2H), 2.68-2.60 (m, 4H), 1.67-1.61 (m, 2H), 1.54-1.49 (m, 2H). Mass spec.: 588 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; | Step A: To a solution comprised of 2-(4-iodo-2-methyl-phenylamino)-3,4,5-trifluoro-benzoic acid (3.60 g, 8.84 mmol), O-(2-vinyloxyethyl)hydroxylamine (1.09 g, 10.5 mol) and diisopropylethylamine (2.80 mL, 16.0 mmol) in dichloromethane (50 mL) was added benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium-hexafluorophosphate (5.26 g, 10.1 mmol). The resultant solution was stirred 90 min at ambient temperature. The reaction mixture was diluted with ether (100 mL) and washed with water (3*50 mL) and saturated brine (50 mL). The organics were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography to afford 2-(4-iodo-2-methyl-phenylamino)-3,4,5-trifluoro-N-(2-vinyloxyethoxy)benzamide (3.17 g, 73%) as a pale-yellow foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; dichloromethane; | EXAMPLE 16 (+-)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidinyl-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide A stirred solution of (+-)-3-(7-methyl-1H-indazol-5-yl)-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid (65.7 mg, 0.138 mmol) in 2:1 dimethylformamide/methylene chloride (1.5 mL) at 0 C. was treated with 4-(1-piperidyl)-piperidne (46.5 mg, 2 equiv), diisopropylethylamine (0.048 mL, 2 equiv) and PyBOP (75.5 mg, 1.05 equiv). The ice bath was allowed to melt and the mixture was stirred at room temperature overnight. The solvents were removed under high vacuum and the residue was purified by flash chromatography on silica gel, eluding with 18:1 methylene chloride/methanol containing 1% triethylamine, to give the product as a pale-yellow solid (80.4 mg, 93%). 1H-NMR (CD3OD, 500 MHz) delta -0.28 (1H, m), 0.75 (1H, m), 1.2-2.0 (12H, m), 2.08 (2H, m), 2.4-2.5 (3H, m), 2.59 (3H, s), 2.68 (2H, m), 2.90 (4H, m), 3.08 (4H, m), 3.9-5.1 (4H, several m), 6.81 (1H, d), 6.96 (1H, t), 7.16 (3H, m), 7.49 (1H, s), 8.03 (1H, s). Mass spec.: 627.29 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | (b) l-(6-(lH-benzo[d][l,2,3]triazol-l-yloxy)-5-butyryl-3-cyanopyridin-2-yl)-N-(l- phenylcyclopropylsulfonyljpiperidine^-carboxamideA mixture of l-(5-butyryl-3-cyano-6-oxo-l,6-dihydropyridin-2-yl)piperidine-4-carboxylic acid (146 mg, 0.46 mmol), PyBop (563 mg, 1.08 mmol), DIPEA (0.4 mL, 297 mg, 2.30 mmol) in DCM (8 mL) was stirred at r.t for 20min and 1-phenylcyclopropane-l- sulfonamide (91 mg, 0.46 mmol) was added. The reaction mixture was stirred at r.t over night. NaHCOs(aq) was added and the mixture was extracted with DCM (x3). The combined organics was run through a phase separator and evaporated. The crude product was purified by preparative HPLC (Kromasil Cs lOmum, 50x250mm , using an incresaing gradient of 30% to 80 % MeCN with a second acidic eluent H2O/MeCN/FA 95/5/0.2) during 30 minutes) to give l-(6-(lH-benzo[d][l,2,3]triazol-l-yloxy)-5-butyryl-3- cyanopyridin-2-yl)-N-(l-phenylcyclopropylsulfonyl)piperidine-4-carboxamide as a white solid. Yield: 230 mg (81%). MS m/z: 614 (M+l), 612 (M-I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | Example 6; O-[3beta-O-(2',2'-Dimethylsuccinyl)-lup-20(29)-en-28-oyl]-1-hydroxybenzotriazole (11); A mixture of betulinic acid (200 mg, 0.44 mmol), PyBop (343 mg, 0.66 mmol), HOBT (88 mg, 0.66 mmol), DIEA (0.26 mL, 1.76 mmol), and NH4Cl (5 mg, 0.88 mmol) in DMF (4 mL) was stirred for 1 hour at room temperature. The mixture was then diluted with EtOAc (50 mL), washed with diluted HCl (1N) and brine, then dried over Na2SO4. The organic solution layer was then concentrated under vacuum and purifeid on a Silicon gel chromatography to yield the HOBT derivative of betulinic acid. Then, a mixture of above intermediate HOBT derivative of betulinic acid, 2,2-dimethylsuccinic anhydride (5 10 eq.), and DMAP (1 eq.) in pyridine (anhydrous, 4 mL) was refluxed overnight. The reaction mixture was concentrated under vacuum, then, dissolved in MeOH. The MeOH solution was purified with reverse phase HPLC to yield O-[3beta-O-(2',2'-Dimethylsuccinyl)-lup-20(29)-en-28-oyl]-1-hydroxybenzotriazole (11) (Yield 64%). Mp 151-154 C. Negative FABMS m/z 700 (M-H)-; HR-FABMS calcd for C42H58N3O6 700.4326, found 700.4326. 1H NMR (300 MHz, Pyridine-d5) delta 8.20 (1H, d, J=8.5 Hz, Ar-H), 7.67 (s, 1H, Ar-H), 7.64 (1H, dd, J=8.5 Hz, J=15.0 Hz, Ar-H), 7.42 (1H, dt, J=1.2 Hz, J=6.6 Hz, Ar-H), 4.88, 4.75 (each 1H, each s, CH2), 4.71 (1H, d, J=4.7 Hz, H-3), 3.13 (1H, dd, J=4.7 Hz, J=11.0 Hz, H-19), 2.91 (2H, d, J=6.0 Hz, -CH2-COOH), 2.65 (1H, d, J=2.8 Hz, CH), 2.38-2.47 (1H, m, CH), 2.31 (1H, t, J=12.0 Hz, H-13), 2.06-2.20 (1H, m, CH), 1.72 (3H, s, CH3-30), 1.53 (6H, s, -C(CH3)2-CH2-COOH), 0.71, 0.92, 0.95, 0.96, 1.02, (each 3H, s, 5×CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; for 2.5h; | A mixture of this material (10 g, 68.0 mmol) and PyBOP (38.9 g, 74.8 mmol) in acetonitrile (250 mL) was treated with DBU (12.2 mL, 81.6 mmol) and stirred for 2.5 h. The reaction mixture was filtered, and the precipitate was washed with diethyl ether (3 x 50 mL) and dried under vacuum. The title compound (13.51 g, 75%) was obtained as a cream-coloured solid. deltaEta (DMSO-de) 9.28 (dd, J 4.2, 1.6 Hz, 1H), 8.82 (s, 1H), 8.59 (dd, J 8.6, 1.5 Hz, 1H), 8.24-8.18 (m, 2H), 7.88-7.85 (m, 1H), 7.69-7.64 (m, 1H), 7.60-7.54 (m, 1H). LCMS (ES+) 265 (M+H)+, RT 1.23 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.4 g | In N,N-dimethyl-formamide; at 20℃; for 16h; | A mixture of 2-fluoro-3-nitro- pyridine (12 g), Et3N (30 mL), and racemic alanine (11.87 g) was refluxed in methanol (200 mL) overnight. The mixture was cooled to ambient temperature and the filtrate was concentrated in vacuo. The residue was partitioned between DCM and water. The organic layer was dried over Na2C03, filtered, and concentrated in vacuo to afford 2-(3-nitro- pyridin-2-ylamino)-propionic acid (7.8 g). This material was dissolved in AcOH (50 mL) and iron (8.2 g) was added. The mixture was refluxed for 1.5h. After cooling to ambient temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was washed with water and dried to afford 3-methyl-3,4-dihydro-lH-pyrido[2,3- b]pyrazin-2-one (1.4 g). This material was mixed with 5% aq NaOH (92 mL) and water (18 mL) before 30% aq hydrogen peroxide (9.2 mL) was added. The mixture was stirred at 60 C for l Oh. After cooling to ambient temperature the pH was adjusted to neutral to precipitate 3-methyl-lH-pyrido[2,3-b]pyrazin-2-one (1.2 g). This material was dissolved in DMF (10 mL) and treated with PyBroP (4.6 g) and DIPEA (1.6 mL) at ambient temperature of 16h. The precipitated white solid was filtered off, washed with ethanol and dried to afford 2-(benzotriazol-l -yloxy)-3-methyl-pyrido[2,3-b]pyrazine (0.4 g). This material (0.4 g) and hydrazine hydrate (0.5 mL) were refluxed in ethanol (5mL) for 10 min. After cooling to ambient temperature, the precipitated white solid was filtered off, washed with ethanol and dried to afford give Ila (0.2 g) sufficiently pure for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.7 g | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | (3-Methyl-pyrido[2,3-b]pyrazin-2-yl)-hydrazine (He). A mixture of 3,4-diamino pyridine (10 g) and ethyl pyruvate (53 g) in chloroform (100 mL) was stirred at ambient temperature overnight. The precipitated solid was filtered off, washed with DCM, and dried to afford 2-methyl-4H-pyrido[3,4-b]pyrazin-3-one (14 g) as a yellowish solid. 2 g of this material was suspended in DMF (10 mL) and treated with PyBroP (6 g) and DIPEA (3.3 mL,) at ambient temperature overnight. The precipitated solid was filtered off, washed with ethanol, and dried to afford 3-(benzotriazol-l -yloxy)-2-methyl-pyrido[3,4- b]pyrazine (1.7 g) as a white solid. This material was suspended in ethanol (50 mL), hydrazine hydrate was added, and resulting mixture was heated at 85 C for 15 min. The solid was filtered off, washed with ethanol, and dried to afford lie (0.95g) as a yellow solid sufficiently pure for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.7 g | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a suspension of 3-nitro-pyridin- 4-ylamine (15 g) in DCM (250 mL) was added triethyl amine (30 mL), Boc20 (23.5 g) and DMAP (1.31 g). The mixture was stirred at ambient temperature for 2 days. The solid was filtered off, and the filtrate was concentrated in vacuo. The residue was washed with MTBE. The yellow crystal was collected to afford (3-nitro-pyridin-4-yl)-carbamic acid ieri-butyl ester (17 g). This material and ethyl pyruvate (100 mL) were dissolved in ethanol (150 mL) and treated with hydrogen gas (50 psi) in the presence of 10% palladium on charcoal (3 g) at 50 C for two days. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica (eluent: pentane/EtOAc 10: 1 ? 2: 1) to afford 2-(4-iert-butoxycarbonylamino-pyridin-3- ylamino)-propionic acid ethyl ester (5 g) as a yellow solid. A larger sample of this compound prepared in a similar manner (9 g) was stirred in 4M HC1 in 1 ,4-dioxane (40 mL) at ambient temperature for 5h. The precipitated solid was filtered off, washed with MTBE, and dried. The filtrate was concentrated to dryness, washed with MTBE, and dried to afford a second crop of the product. Total yield of 3-methyl-3,4-dihydro-lH- pyrido[3,4-b]pyrazin-2-one hydrochloride (5 g) as a white solid. 2.2 g of this material was suspended in water (20 mL) and treated with 30% aq hydrogen peroxide (1.2 mL) and NaOH (to adjust pH to 7-8). The mixture was stirred at 75 C for 2 days. More 30% aq hydrogen peroxide (0.15 mL) was added, and stirring was continued for 2 additional days. The volatiles were removed in vacuo. The residue was washed with EtOAc to afford 3- methyl-lH-pyrido[3,4-b]pyrazin-2-one (0.8 g) as a yellowish solid. 0.7 g of this material and PyBroP (2.1 1 g) were suspended in DMF (3 mL). DIPEA (1.16 mL) was added and the mixture was stirred at ambient temperature overnight. The precipitated solid was filtered off, washed with ethanol, and dried to afford 2-(benzotriazol-l -yloxy)-3-methyl- pyrido[3,4-b]pyrazine (0.7 g) as a white solid. 430 mg of this material was suspended in ethanol (13 mL) and treated with hydrazine hydrate (0.5 mL) at 85 C for 20 min. The solid was filtered off, washed with ethanol, and dried to afford lid (180 mg) as a yellowish solid sufficiently pure for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.5 g | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; | To a solution of 4- chloro-pyridin-2-ylamine (5 g) in 96% aq H2SO4 (20 mL) at 0 C was added a mixture solution of 70% aq HN03 (2.5 mL) and 96% aq H2S04 (10 mL) drop-wise. After the addition was completed, the mixture was stirred at room temperature for 2h. The solution was poured onto ice/water and 6M aq. NaOH was added drop-wise to adjust pH to 9. Then the solid was filtered off, washed with water, and dried before it was purified by chromatography on alumina (eluent: pentane:EtOAc 2:1) to afford 4-chloro-3-nitro-pyridin-2-ylamine (1.2 g). 200 mg of this material was dissolved methanol (3mL) and NaOMe (125 mg) was added before the mixture was stirred at 60 C for 16h. 37%> aq HC1 was added drop-wise to adjust pH to 6. The mixture was cooled to 0 C, and the precipitated solid was filtered off, washed with water, and dried to afford 4-methoxy-3-nitro-pyridin-2-ylamine (180 mg). This material was dissolved in methanol (20 mL) and treated with hydrogen gas (1 bar) in the presence of 10%> palladium on charcoal at room temperature for 2h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 4-methoxy-pyridine-2,3-diamine (50 mg). This procedure was repeated to produce more material. In the next step, 4-methoxy-pyridine-2,3-diamine (6.8 g) was dissolved in ethanol (200 mL). To this solution was slowly added methyl pyruvate (4.9 mL) at room temperature, and the mixture was stirred at ambient temperature for 3h before the volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: pentane:EtOAc 5: 1 to 0: 1) to give afford 8-methoxy-2-methyl-4H-pyrido[2,3- b]pyrazin-3-one (6.1 g). To a suspension of 3 g of this material in DMF (12 mL) was added PyBroP (7.65 g) followed by DBU (3.58 g). The mixture was stirred overnight before the precipitated solid was filtered off, washed with ethanol, and dried to afford 3-(benzotriazol-l- yloxy)-8-methoxy-2-methyl-pyrido[2,3-b]pyrazine (3.5 g). 1.5 g of this material was dissolved in a mixture of ethanol (lOmL) and DCM (60mL). Hydrazine monohydrate (3.6g) was added, and the mixture was stirred overnight at ambient temperature before the volatiles were removed in vacuo. The residual solid was triturated from ethanol, filtered off, washed with ethanol, and dried to afford (8-methoxy-2-methyl-pyrido[2,3-b]pyrazin-3-yl)- hydrazine He (0.9 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.9% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; dichloromethane; at 20℃; for 0.333333h; | Step 3: Production of tert-butyl 4-{4-[(1H-benzo[d][1,2,3]triazo-1-yl)oxy]thieno[3,2-d]pyrimidin-7-yl}piperidine-1-carboxylate tert-Butyl 4-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (10.8 mg, 0.032 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (18.4 mg, 0.035 mmol) were dissolved in tetrahydrofuran (1 mL), and then a solution of 1,8-diazabicyclo[5,4,0]-7-undecene (5.7 muL, 0.038 mmol) in dichloromethane (0.5 mL) was added, followed by stirring at room temperature for 20 minutes. The reaction liquid was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=10:1) to give tert-butyl 4-{4-[(1H-benzo[d][1,2,3]triazo-1-yl)oxy]thieno[3,2-d]pyrimidin-7-yl}piperidine-1-carboxylate (12.3 mg, 84.9%) as a colorless oily substance. 1H-NMR (CDCl3) delta: 1.49 (9H, s), 1.65-1.76 (2H, m), 2.12 (2H, d, J=12.6 Hz), 2.86-3.02 (2H, m), 3.38 (1H, tt, J=3.4, 12.2 Hz), 4.29 (2H, brs), 7.46-7.52 (2H, m), 7.54-7.59 (1H, m), 7.72 (1H, s), 8.13-8.18 (1H, m), 8.66 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 0.666667h;Inert atmosphere; | 4-{4-[(1H-benzo[d][1,2,3]triazol-1-yl)oxy]furo[3,2-d]pyrimidin-7-yl}piperidine-1-carboxylate Under an argon atmosphere, tert-butyl 4-(4-hydroxyfuro[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (1.06 g, 3.22 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (1.81 g, 3.49 mmol) were dissolved in anhydrous tetrahydrofuran (17 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (656 mg, 4.31 mmol) was added to the solution, and then the resultant solution was stirred at room temperature for 40 minutes. Water was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give tert-butyl 4-{4-[(1H-benzo[d][1,2,3]triazol-1-yl)oxy]furo[3,2-d]pyrimidin-7-yl}piperidine-1-carboxylate (1.19 g, 83%) as a white amorphous. 1H-NMR (CDCl3) delta: 1.48 (9H, s), 1.72 (2H, ddd, J=4.0, 12.6, 25.0 Hz), 2.12-2.18 (2H, m), 2.84-2.98 (2H, m), 3.08 (1H, dddd, J=3.4, 3.6, 11.6, 11.8 Hz), 4.16-4.34 (2H, m), 7.45-7.52 (2H, m), 7.55-7.59 (1H, m), 7.80 (1H, d, J=1.0 Hz), 8.15 (1H, d, J=8.3 Hz), 8.53 (1H, s). |
Tags: 128625-52-5 synthesis path| 128625-52-5 SDS| 128625-52-5 COA| 128625-52-5 purity| 128625-52-5 application| 128625-52-5 NMR| 128625-52-5 COA| 128625-52-5 structure
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