There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type | HazMat fee for 500 gram (Estimated) |
Excepted Quantity | USD 0.00 |
Limited Quantity | USD 15-60 |
Inaccessible (Haz class 6.1), Domestic | USD 80+ |
Inaccessible (Haz class 6.1), International | USD 150+ |
Accessible (Haz class 3, 4, 5 or 8), Domestic | USD 100+ |
Accessible (Haz class 3, 4, 5 or 8), International | USD 200+ |
Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 56602-33-6 | MDL No. : | MFCD00011948 |
Formula : | C12H22F6N6OP2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MGEVGECQZUIPSV-UHFFFAOYSA-N |
M.W : | 442.28 | Pubchem ID : | 151348 |
Synonyms : |
|
Num. heavy atoms : | 27 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 12.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 95.3 |
TPSA : | 76.84 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -5.19 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 5.37 |
Log Po/w (WLOGP) : | 7.13 |
Log Po/w (MLOGP) : | 2.64 |
Log Po/w (SILICOS-IT) : | -2.1 |
Consensus Log Po/w : | 2.61 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.88 |
Solubility : | 0.00058 mg/ml ; 0.00000131 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -6.74 |
Solubility : | 0.000081 mg/ml ; 0.000000183 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -1.89 |
Solubility : | 5.68 mg/ml ; 0.0129 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.32 |
Signal Word: | Danger | Class: | 4.1 |
Precautionary Statements: | P210-P240-P241-P261-P264-P271-P280-P302+P352-P304+P340+P312-P332+P313-P370+P378-P403+P233-P405-P501 | UN#: | 1325 |
Hazard Statements: | H228-H315-H335 | Packing Group: | Ⅱ |
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 |
---|---|---|
57% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 26h; | Example 4; Synthesis of O6-(Benzotriazol-l-yl)-2'-deoxyinosine (28); [00106] In a 50 mL round-bottomed flask equipped with a stirring bar were placed 2'-deoxyinosine 24 (0.504 g, 2.00 mmol) and BOP (1.770 g, 4.00 mmol). DMF (20 mL) and DIPEA (0.70 mL, 4.00 mmol) were added and the mixture was allowed to stir at room temperature for 26 h. The reaction mixture was evaporated with toluene several times. The crude product was dissolved in EtOAc and washed with water. The organic layer was separated, dried over Na2SO4 and concentrated. Chromatographic purification (SiO2, elution with 10% MeOH in CH2Cl2) <n="46"/>afforded 0.421 g (57% yield) of compound 28 as a pale brownish-white foam. Rf (10% MeOH in CH2Cl2) = 0.38. 1H NMR (500 MHz, CDCl3): delta 8.43 (s, IH, Ar-H), 8.24 (s, IH, Ar-H), 8.16-8.14 (m, IH, Ar-H), 7.57-7.54 (m, IH, Ar-H), 7.49-7.46 (m, IH, Ar- H), 6.46 (dd, IH, H-I ', J- 9.2, 5.5), 5.10 (dd, IH, OH, J= 11.3, 2.3, CD3OD exchangeable), 4.83 (br m, IH, H-3'), 4.25 (br s, IH, H-4'), 3.97 (dt, IH, H-5 J= 12.8, 2.0), 3.82 (app td, IH, H-5', Japp ~ 11.9, 1.8), 3.07 (ddd, IH, U-T, J= 13.4, 9.5, 4.9), 2.42 (dd, IH, H-2 J= 13.6, 5.7), 2.05 (d, IH, OH, CD3OD exchangeable). 13C NMR (126 MHz, DMSO-rf6):delta 159.1, 153.1, 151.1, 144.8, 143.2, 129.1, 128.8, 125.2, 120.5, 120.3, 108.7, 88.9, 86.9, 72.2, 62.7, 40.9. FAB HRMS calcd for C16Hi6N7O4 (M+ + H) 370.1264, found 370.1258. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 23h;Product distribution / selectivity; | Example 3; Synthesis of O6-(Benzotriazol-l-ylV2>.3'.5>-tris-O-rtgrt-butyldimethylsilvninosine (27); [00104] As described for the synthesis of 26, 27 was prepared by a reaction between 2',3',5'-tris-O- (tert-butyldimethylsilyl)inosine (23) (3.055 g, 5.00 mmol), BOP (4.425 g, 10.0 mmol) and DIPEA (1.31 mL> 7.5 mmol) in dry THF (50.0 mL). Chromatographic purification (SiO2, elution with 20% EtQAc m hechianes) afforded 2.898 g (80% yield) of compound 27 as a white, foamy solid. Rf (20% EtOAc in hexanes) = 0.32. 1H NMR (500 MHz, CDCl3): delta 8.63 (s, IH, Ar-H), 8.40 (s, IH, Ar-H), 8.15 (d, IH, Ar-H, J = 8.3), 7.56-7.45 (m, 3H, Ar-H), 6.16 (d, IH, H-I ', J= 4.4), 4.58 (t, IH, H-T, J= 4.4), <n="45"/>4.34 (t, IH, H-3 J= 4.2), 4.18 (app q, IH, H-4', Japp ~ 3.1), 4.06 (dd, IH, H-5', J= 1 1.7, 3.4), 3.82 (dd, IH, H-5', J=I 1.7, 2.4), 0.98, 0.94, 0.82 (3s, 27H, tert-Bu), 0.17, 0.16, 0.11, 0.10, 0.0, -0.17 (6s, 18H, SiCH3). 13C NMR (126 MHz, CDCl3): delta 159.0, 153.9, 151.4, 143.9, 143.5, 129.0, 128.7, 124.8, 120.6, 120.0, 108.6, 88.9, 85.5, 76.4, 71.6, 62.2, 26.1, 25.8, 25.6, 18.5, 18.0, 17.8, -4.4, -4.7, -4.73, -5.0, -5.3, -5.4. FAB HRMS calcd for C34H58N7O5Si3 (M+ + H) 728.3807, found 728.3818. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; | Step 1 Commercial 9-((2R,4S,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-hydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one (5.02 g, 9.05 mmol) was suspended in THF (250 mL). To the mixture were added diisopropylethylamine (4.74 mL, 27.2 mmol) and 1H-benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (4.83 g, 10.9 mmol), and the mixture was stirred at room temperature for 2 days. Additional 1H-benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (8.00 g, 18.1 mmol) was added to the mixture, and the mixture was stirred overnight. Saturated sodium bicarbonate solution was added to the reaction solution, and the solvent was evaporated under reduced pressure until the amount of solvent was roughly half. The mixture was extracted with ethyl acetate and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by hexane/ethyl acetate silica gel column chromatography to obtain (2R,3S,5R)-5-(6-(1H-benzo[d][1,2,3]triazol-1-yloxy)-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)tetrahydrofuran-3-ol (5.77 g, 95%). 1H-NMR (CDCl3, 400 MHz) delta: 8.34 (s, 1H), 8.28 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.20-7.56 (m, 12H), 6.79-6.85 (m, 4H), 6.52 (t, J=6.5 Hz, 1H), 4.70-4.73 (m, 1H), 4.16-4.19 (m, 1H), 3.78 (s, 6H), 3.39-3.48 (m, 2H), 2.84-2.91 (m, 1H), 2.58-2.64 (m, 1H). ESI-MS (m/z): 672 (M+1) |
85% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 40h; | Example 31; Synthesis of O6-(Benzotriazol-l-yl)-5'-O-(4<4'-dimethoxytritv?-2'-deoxyinosine; evaporated, diluted with EtOAc (200 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated. Chromatographic purification (SiO2, packed with 1% DIPEA in EtOAc and elution with EtOAc) afforded 0.718 g (85% yield) of the title compound as a white foam. Rf (EtOAc) = 0.31. 1H NMR (500 MHz, CDCl3): delta 8.31 (s, IH, Ar-H), 8.28 (s, IH, Ar-H), 8.13 (d, IH, Ar-H, J= 8.2), 7.55-7.45 (m, 3H, Ar-H),7.38 (d, 2H, Ar-H, J= 7.3), 7.29-7.19 (m, 7H, Ar-H), 6.80 (d, 4H, Ar-H, J= 8.9), 6.52 (t, IH, H-I ', J= 6.4), 4.73 (br m, IH, H-3'), 4.20 (q, IH, H-4 J= 4.2), 3.77 (s, 6H, OCH3), 3.45 (dd of ABquartet, IH, US', J= 10.4, 4.6), 3.40 (dd of ABquartet, IH, H-5 J= 10.4, 5.0), 2.87 (app quint, IH, H-2', Japp ~ 6.6), 2.62 (ddd, IH, H-2', J = 13.4, 6.2, 4.3),2.39 (d, IH, 3'-OH, J= 3.1). 13C NMR (126 MHz, CDCl3): delta 159.1, 158.6, 153.5, 151.4, 144.4, 143.5, 135.5, 135.4, 130.0, 128.9, 128.8, 128.0, 127.9, 127.1, 124.8, 120.6, 120.1,113.2, 108.7, 86.8, 86.3, 85.0, 72.6, 63.5, 55.2, 40.3. FAB HRMS calcd for C37H34N7O6 (M+ + H) 672.2571, found 672.2583.; As shown in the reaction scheme above, reaction of the known 5'-O-DMT-2'-deoxyinosine 32 with 2 mol equivalents each of BOP and ( WO-Pr)2NEt at room temperature over 40 hours led to the O6-(benzotriazol-l-yl)-5'-O-DMT-2'-deoxyinosine 33 in 85% isolated yield. Finally, conversion of 33 to the phosphoramidite 34 was accomplished by conventional methods (47% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 68h; | Example 5; Synthesis of O6-(Benzotriazol-l-vDinosine (29); [00107] In a reaction vial equipped with a stirring bar were placed inosine 25 (0.100 g, 0.373 mmol) and BOP (0.330 g, 0.746 mmol). DMF (3.7 mL) and DIPEA (97.3 muL, 0.559 mmol) were added, the reaction vial was flushed with N2 and the mixture allowed to stir at room temperature for 68 h. To the reaction mixture water was added and the mixture was extracted withCH2Cl2. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated. Since the crude product contained residual DMF, toluene was added and evaporated several times. Chromatographic purification (SiO2, elution with 5% MeOH in CH2Cl2) afforded 76 mg (53% yield) of 29 as a white powder. Rf (5% MeOH in CH2Cl2) = 0.09. 1H NMR (500 MHz, DMSO-cfe): delta 8.95 (s, IH, Ar-H), 8.53 (s, IH, Ar-H), 8.21 (d, IH, Ar-H, J- 8.8), 7.80 (d, IH, Ar-H, J= 8.3), 7.66 (t, IH, Ar-H, J= 7.6), 7.56 (t, IH, Ar-H, J= 7.6), 6.09 (d, IH, H-I', J= 5.4), 5.55 (d, IH, OH, J= 5.9, D2O exchangeable), 5.24 (d, IH, OH, J= 5.4, D2O exchangeable), 5.07 (t, IH, OH, J= 5.6, <n="47"/>D2O exchangeable), 4.62 (q, IH, H-2', J= 5.4), 4.21 (q, IH, H-3', J- 4.7), 4.01 (m, IH, H-4'), 3.71 (m, IH, H-5'), 3.60 (m, IH, H-5'). 13C NMR (126 MHz, DMSO-J6):delta 159.0, 154.8, 151.9, 146.1, 143.5, 130.1, 129.3, 126.1, 120.7, 119.8, 110.2, 88.9, 86.5, 74.7, 70.9, 61.8. FAB HRMS calcd for Ci6Hi6N7O5 (M+ + H) 386.1213, found 386.1191. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine; In dichloromethane; ethyl acetate; | Step 2. N-(2-Aminophenyl)-4-[(3,4-dimethoxyphenylamino)-methyl]-benzamide (424b) In a 150 ml flask, a mixture of acid (1.92 g, 6.69 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 3.26 g, 7.37 mmol), triethylamine (1.87 ml, 13.4 mmol), o-phenylenediamine (1.30 g, 12.02 mmol) in methylenechloride (67 ml) was stirred at rt for 2 h. After solvents removal, the crude residue was dissolved in EtOAc (100 ml) and then washed with NaHCO3 saturated solution and brine 50 ml. The combined organic layers were dried over Na2SO4 and the filtrate was concentrated to dryness. The crude material was submitted to a chromatographic purification (column silica, 55%-70% EtOAc in 1% Et3N of hexanes) and then the all interested fractions were concentrated to dryness. The residue was suspended in minimum quantities of ethyl acetate and then filtered to afford final productproduct (1.49 g, 59%). 1H NMR (300 MHz, DMSO-d6) delta (ppm): 9.65 (s, 1H), 7.98 (d, J=7.9 Hz, 2H), 7.54 (d, J=7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 1H), 7.02 (dd, J=7.9, 7.9 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 6.72 (d, J=8.79 Hz, 1H), 6.45 (dd, J=7.5, 7.5 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 6.01-6.08 (m, 2H), 4.94 (s, 2H, NH2), 4.36 (d, J=6.16 Hz, 2H), 3.72 (s, 3H), 3.65 (s, 3H). |
59% | With triethylamine; In dichloromethane; ethyl acetate; | Step 2. N-(2-Aminophenyl)-4-[(3,4-dimethoxyphenylamino)-methyl]-benzamide (424b) In a 150 ml flask, a mixture of acid (1.92 g, 6.69 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 3.26 g, 7.37 mmol), triethylamine (1.87 ml, 13.4 mmol), o-phenylenediamine (1.30 g, 12.02 mmol) in methylenechloride (67 ml) was stirred at rt for 2 h. After solvents removal, the crude residue was dissolved in EtOAc (100 ml) and then washed with NaHCO3 saturated solution and brine 50 ml. The combined organic layers were dried over Na2SO4 and the filtrate was concentrated to dryness. The crude material was submitted to a chromatographic purification (column silica, 55%-70% EtOAc in 1% Et3N of hexanes) and then the all interested fractions were concentrated to dryness. The residue was suspended in minimum quantities of ethyl acetate and then filtered to afford final productproduct (1.49 g, 59%). 1H NMR (300 MHz, DMSO-d6) delta (ppm): 9.65 (s, 1H), 7.98 (d, J=7.9 Hz, 2H), 7.54 (d, J=7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 1H), 7.02 (dd, J=7.9, 7.9 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 6.72 (d, J=8.79 Hz, 1H), 6.45 (dd, J=7.5, 7.5 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 6.01-6.08 (m, 2H), 4.94 (s, 2H, NH2), 4.36 (d, J=6.16 Hz, 2H), 3.72 (s, 3H), 3.65 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; trifluoroacetic acid; In hexane; dichloromethane; ethyl acetate; N,N-dimethyl-formamide; | (27c) 4-Chlorobenzoic acid (258 mg) was dissolved in DMF (8 mL) prior to the addition of Hunig's base (1.0 mL). After cooling to 0 C., BOP Reagent (729 mg) was added. This was stirred for 15 min before (1S,2R)-1-(N-(t-butoxycarbonyl))-1,2-cyclopentanediamine, (27b), (300 mg) was added as a DMF solution (2 mL). The resulting mixture warmed to rt and was stirred overnight. EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO3 solution, and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. The resulting material was dissolved in CH2Cl2 (10 mL) and cooled to 0 C. TFA (1.2 mL) was added and the reaction was stirred for 2 h. This solution was concentrated prior to the addition of DMF (8 mL). After cooling to 0 C., Hunig's base (1 mL) and <strong>[17794-48-8][[3-(trifluoromethyl)benzoyl]amino]acetic acid</strong> (386 mg) were added. BOP Reagent (655 mg) was added next, and the mixture was stirred overnight. EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO3 solution, and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. This was stirred in 1:1 EtOAc/hexane and then filtered to give the title benzamide N-[2-[[(1S,2R)-2-[(4-chlorobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide (310 mg) as a solid. MS found: (M+H)+=468.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.5% | With sodium hydrogencarbonate; In methanol; N,N-dimethyl-formamide; | 4-(5-Cyclohexylimino-4-methyl-4,5-dihydro-[1,3,4]thiadiazol-2-yl)-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide To a solution of I37.1 (0.5 mmol, 200 mg) in DMF (2.5 mL), ethyl-diisopropyl-amine (1.6 mmol, 190 muL), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.6 mmol, 265 mg), 1-hydroxy-7-azabenzotriazole (0.25 mmol, 34 mg) and <strong>[73579-08-5]1-methyl-4-(methylamino)piperidine</strong> (0.6 mmol, 87 muL) were added, and the reaction mixture was stirred at RT overnight. The solvent was distilled under reduced pressure, and the residue was poured into water before extraction with dichloromethane. The organic layer was washed with brine and then with a saturated solution of NaHCO3, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using a gradient of dichloromethane containing 0percent to 15percent methanol, to give the desired product. Yield: 93.5percent. 1H-NMR (400 MHz, DMSO) delta ppm: 1.23-1.45 (m, 5H), 1.55-1.65 (m, 1H), 1.68-1.85 (m, 6H), 1.85-2.00 (m, 2H), 2.23-2.44 (m, 5H), 2.55-2.65 (m, 1H), 2.83 (s, 3H), 3.00-3.10 (m, 2H), 3.55 (s, 3H), 3.85-4.03 (m, 1H), 7.48 (dd, 2H), 7.70 (dd, 2H). MS (m/z)/M+1=428. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In ethyl acetate; N,N-dimethyl-formamide; | (11a) Glycine benzyl ester p-toluenesulfonate salt (6.03 g) was dissolved in DMF prior to the addition of Hunig's base (12.4 mL) and 2-(tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic acid (6 g) (Takagishi et al., Synlett 1992, 360). After cooling to 0 C., BOP Reagent (8.69 g) was added. The resulting mixture was warmed to rt and was stirred 96 h. EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl (aq), NaHCO3 solution (aq), and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue gave 2-tert-butoxycarbonylamino-5-trifluoromethyl-benzoylamino)-acetic acid benzyl ester (5.78 g). MS found: (M+Na)+=475.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With 4-methyl-morpholine; In N,N-dimethyl-formamide; | C. 4-(1,1-Dimethylethyl)-N-[5-[[[3-[[4-(2-pyrimidinyl)piperazin-1-yl]carbonyl]-4-methylphenyl]thio]methyl]thiazol-2-yl]benzamide A mixture of the product of Example 32, part B (0.250 g, 0.567 mmol), 1-(2-pyrimidyl) piperazine (0.121 g, 0.737 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (0.476 g, 1.08 mmol), 4-methylmorpholine (0.31 mL, 2.82 mmol) in DMF (6 mL) was heated at 65 C. for 5 h. The mixture was then diluted with ethyl acetate, washed with water, 1N NaOH solution, water, and brine. The solution was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified using flash column chromatography (ethyl acetate) to provide the desired product (0.210 g, 63%) as a white solid: LC/MS RT=3.94 min; mass spectrum (M+H)+=587.42. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1-methyl-pyrrolidin-2-one; sodium methylate; triethylamine; In tetrahydrofuran; methanol; ethanol; dichloromethane; water; ethyl acetate; toluene; | (+-)-4-[N-{(3RS,4SR)-N,3-Dimethyl-4-piperidinyl}phenylamino]-N,N-diethylbenzamide (7a) (+-)-2,6-Di-tert-butyl-4-methoxyphenyl-4-[N-{(3RS,4SR)-N,3-dimethyl-4-piperidinyl}phenylamino]benzoate (6a) (6.5 g, 11.99 mmol) in toluene (150 mL) and N-methylpyrrolidinone (NMP, 40 mL) was added to freshly prepared sodium methoxide (120 mmol) and heated at reflux for 4 h. After evaporation of the toluene under reduced pressure, the residue was dissolved in a mixture of MeOH and H2O (12:1, 150 mL) and heated at reflux for 1 h. After evaporation of the alcohol, the residue was taken up in water (400 mL) and extracted with hexanes (2*100 mL). The aqueous layer was made acidic (pH=1) with 10% HCl, saturated with NaCl, and extracted with a mixture of CH2Cl2 and THF (3:1, 5 ' 200 mL). After drying over Na2SO4, the solvents were evaporated under reduced pressure. This was then treated with diethylamine (1.2 mL), benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate (BOP a.k.a. Castro's reagent) (5.0 g, 11.31 mmol)), and triethylamine (4.2 mL) in THF (100 mL) for 30 min. The reaction mixture was next diluted with ether (300 mL), washed with water (2*75 mL), saturated NaHCO3 (75 mL), and dried over Na2SO4 providing a black oil following evaporation of the solvents under reduced pressure. Chromatography on silica gel using hexanes/ethyl acetate/ethanol/triethylamine (60:40:2:2) afforded 7a (4.10 g, 90%) as a yellow liquid. This was converted to the hydrochloride salt using 1N HCl in ether. 1H NMR (CD3OD) delta 1.07-1.38 (m, 12H), 1.42D1.61 (m, 1H), 1.68-1.92 (m, 1H), 2.86 (s, 3H), 3.03D3.21 (m, 1H), 3.27D3.60 (m, 6H), 4.30D4.48 (m, 1H), 6.80 (d, 2H, J=8.3 Hz), 7.14 (d, 2H, J=7.7 Hz), 7.26 (t, 3H, J=7.5 Hz), 7.40 (t, 2H, J=7.4 Hz); 13C NMR (CD3OD) delta 12.2, 25.6, 30.4, 44.5, 55.7, 56.0, 60.2, 119.4, 127.4, 128.8, 130.7, 130.8, 146.1, 150.8, 173.8. Anal. (C24H34ClN3O.H2O): C, H, N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine; In dichloromethane; | (A) 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide: A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared in Example 38, 2.0 g, 6.96 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (4.62 g, 10.44 mmol), and 2-aminothiazole (1.05 g, 10.44 mmol) in methylene chloride (50 mL) at 25 C. was treated with triethylamine (2.9 mL, 20.88 mmol). The reaction mixture was stirred for 14 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3*10 mL). The combined organic layers were sequentially washed with water (1*10 mL), a 1N aqueous sodium hydroxide solution (1*10 mL), a 1N aqueous hydrochloric acid solution (1*10 mL), and a saturated aqueous sodium chloride solution (1*10 ML). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide (2.48 g, 96%) as a white solid: mp 143.5-145.5 C.; EI-HRMS m/e calcd for C17H18Cl2N2OS (M+) 368.0516, found 368.0516. |
96% | With triethylamine; In dichloromethane; | (A) 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 2.0 g, 6.96 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (4.62 g, 10.44 mmol), and 2-aminothiazole (1.05 g, 10.44 mmol) in methylene chloride (50 mL) at 25 C. was treated with triethylamine (2.9 mL, 20.88 mmol). The reaction mixture was stirred for 14 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3*10 mL). The combined organic layers were sequentially washed with water (1*10 mL), a 1N aqueous sodium hydroxide solution (1*10 mL), a 1N aqueous hydrochloric acid solution (1*10 mL), and a saturated aqueous sodium chloride solution (1*10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide (2.48 g, 96%) as a white solid: mp 143.5-145.5 C.; EI-HRMS m/e calcd for C17H18Cl2N2OS (M+) 368.0516, found 368.0516. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | EXAMPLE 57 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (102 mg, 0.23 mmol), 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared in Example 38, 60 mg, 0.21 mmol), N,N-diisopropylethylamine (73 muL, 0.42 mmol), and 2-aminooxazole (27 mg, 0.31 mmol) in dry N,N-dimethylformamide (1 mL) was stirred at 25 C. under nitrogen for 15 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with a 1N aqueous hydrochloric acid solution, washed with water, and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide (34.9 mg, 47%) as a white solid: mp 134-136 C.; EI-HRMS m/e calcd for C17H18Cl2N2O2(M+) 352.0745, found 352.0750. |
47% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | EXAMPLE 57 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (102 mg, 0.23 mmol), 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 60 mg, 0.21 mmol), N,N-diisopropylethylamine (73 muL, 0.42 mmol), and 2-aminooxazole (27 mg, 0.31 mmol) in dry N,N-dimethylformamide (1 mL) was stirred at 25 C. under nitrogen for 15 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide (34.9 mg, 47%) as a white solid: mp 134-136 C.; EI-HRMS m/e calcd for C17H18Cl2N2O2 (M+) 352.0745, found 352.0750. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-ethyl-N,N-diisopropylamine; methylamine; In tetrahydrofuran; N,N-dimethyl-formamide; | EXAMPLE 103 6-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide A solution of 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid (prepared in Example 46, 125 mg, 0.31 mmol), N,N-diisopropylethylamine (0.10 mL, 0.61 mmol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (142 mg, 0.32 mmol) in N,N-dimethylformamide (15 mL) at 25 C. was treated dropwise with a 2.0M solution of methylamine in tetrahydrofuran (0.16 mL, 0.32 mmol). The resulting reaction mixture was stirred at 25 C. for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide (83 mg, 64%) as white solid: mp 229.1-231.7 C.; FAB-HRMS m/e calcd for C21H23Cl2N3O2 (M+H)+ 420.1245, found 420.1247. |
64% | With N-ethyl-N,N-diisopropylamine; methylamine; In tetrahydrofuran; N,N-dimethyl-formamide; | EXAMPLE 103 6-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide A solution of 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid (prepared as in Example 46, 125 mg, 0.31 mmol), N,N-diisopropylethylamine (0.10 mL, 0.61 mmol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (142 mg, 0.32 mmol) in N,N-dimethylformamide (15 mL) at 25 C. was treated dropwise with a 2.0M solution of methylamine in tetrahydrofuran (0.16 mL, 0.32 mmol). The resulting reaction mixture was stirred at 25 C. for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide (83 mg, 64%) as white solid: mp 229.1-231.7 C.; FAB-HRMS m/e calcd for C21H23Cl2N3O2 (M+H)+420.1245, found 420.1247. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; | A solution of 2-(4-benzoylamino-phenyl)-3-cyclopentyl-propionic acid (20.2 mg, 0.06 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (39.8 mg, 0.09 mmol), and 2-aminothiazole (9.0 mg, 0.09 mmol) in methylene chloride (2 mL) at 25 C. was treated with N,N-diisopropylethylamine (0.25 mL, 0.18 mmol). The reaction mixture was stirred at 25 C. for 16 h. At this time, the mixture was poured into water (50 mL) and extracted with ethyl acetate (3*25 mL). The combined organic extracts were washed with a 1N aqueous hydrochloric acid solution (1*25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded {N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-benzamide (95%) as a white solid: mp 285-290 C.; EI-HRMS m/e calcd for C24H25N3O2S (M+) 419.1667, found 419.1667. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine; In dichloromethane; | A solution of 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-propionic acid (150 mg, 0.47 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.20 mL, 1.41 mmol) and 2-aminothiazole (75 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25 C. for 18 h. At this time, the reaction was diluted with water (10 mL). The organic phase was separated and washed with a 1N aqueous sodium hydroxide solution, and a saturated aqueous sodium chloride solution. The aqueous layers were each back-extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-N-thiazol-2-yl-propionamide (134 mg, 71%) as a pale yellow solid: mp 185-187 C.; EI-HRMS m/e calcd for C24H23N3OS (M+) 401.1561, found 401.1555. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; Petroleum ether; | Example 100 Preparation of 3,5-dimethyl-N-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]-4-hydroxybenzamide To a solution of 3,5-dimethyl-4-hydroxybenzoic acid (1.53 g, 9.2 mmol) in dichloromethane (30 mL) at 0 C. was added benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate (4.45 g, 10 mmol), 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzenemethanamine (Example 70; 3.28 g, 13.8 mmol), followed by diisopropylethylamine (4.9 mL, 27.6 mmol) slowly dropwise. After stirring 1 h, the reaction was warmed to 25 C. and stirred for 1 h. The solvent was removed under reduced pressure and the residual oil was diluted with ethyl acetate (100 mL) and washed with 1N hydrochloric acid solution (2*25 mL), saturated aqueous sodium bicarbonate solution (2*25 mL), water (25 mL) and brine (25 mL). The organic layer was dried (MgSO4), filtered, evaporated and flash chromatographed (silica gel, 20-30% ethyl acetate in petroleum ether) to give 3,5-dimethyl-N-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]-4-hydroxybenzamide (3.1 g, 87% yield) as an off-white foam. Also prepared by this route using the appropriate amine were the following: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; | A solution of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.62 g, 1.41 mmol) and 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid (0.29 g, 0.95 mmol) in methylene chloride (10 mL) was treated with N,N-diisopropylethylamine (500 muL, 2.87 mmol) and 2-aminothiazole (140 mg, 1.27 mmol). The mixture was stirred under nitrogen at 25 C. for 14 h. The reaction mixture was then washed with a 6N aqueous hydrochloric acid solution (1*15 mL) and washed with a saturated aqueous sodium chloride solution (1*25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (0.26 g, 71%) as a white solid: EI-HRMS m/e calcd for C18H21ClN2OS2 (M+) 380.0783, found 380.0792. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.2% | With triethylamine; In dichloromethane; | A solution of 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-propionic acid (171 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.86 mmol) in methylene chloride (5 mL) was stirred at 25 C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1*10 mL), a 1N aqueous sodium hydroxide solution (1*10 mL), and a half-saturated aqueous sodium chloride solution (1*10 mL). The aqueous layers were back extracted with methylene chloride (1*10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 ethyl acetate/methanol) afforded 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-l-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (151 mg, 71.2%) as a white foam: EI-HRMS m/e calcd for C24H29N3O2S (M+) 423.1980, found 423.1980. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; In dichloromethane; | This solid, triethylamine (14 mL, 0.1 mol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (22 g, 0.05 mol) were dissolved in CH2Cl2 (400 mL) and allowed to stir at RT overnight The mixture was concentrated and the residue was purified by flash column chromatography (silica gel, 0.2% methanol/CH2Cl2) to yield the title compound (9.5 g, 55%): MS(ES) m/e 352.2 [M+H]+; 1H NMR (400 MHz, CDCl3) delta7.12-7.16 (m, 3H), 6.97-7.00 (m, 3H), 6.91-6.94 (d, J=8.47 Hz, 1H), 6.79 (dd, J=2.75,8.47 Hz, 1H), 5.01 (d, J=17.26 Hz, 1H), 4.92 (d, J=11.48 Hz, 1H), 4.07 (dt, J=7.82 Hz, J=13.57 Hz, 1H), 3.92 (d, J=17.26 Hz, 1H), 3.85 (m, 1H), 3.79 (s, 3H), 3.52 (m, 1H), 3.25 (dd, J=17.61 Hz, J=11.76, 1H), 2.78 (m, 2H), 2.65 (dd, J=17.26 Hz, J=7.26 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; N,N-dimethyl-formamide; | A. (2R)-(t-Butyloxycarbonylamino)-4-morpholin-4-yl-4-oxobutyric Acid Benzyl Ester A solution of D-N-t-butyloxycarbonylaspartic acid benzyl ester (2.53 g, 7.82 mmol) in 30 mL of DMF is treated sequentially with benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (4.15 g, 9.38 mmol), 1-hydroxy-7-azabenzotriazole (1.28 g, 9.38 mmol), diisopropylethylamine (2.5 g, 19.6 mmol) and morpholine (0.82 g, 9.38 mmol). The mixture is stirred at RT for 16 h and is then partitioned between EtOAc and water. The organic solution is washed with water and brine, dried over anhydrous MgSO4 and concentrated. Chomatography on silica gel (eluant; 5% MeOH in dichloromethane) affords 2.91 g (95%) of (2R)-(t-butyloxycarbonylamino)-4-morpholin-4-yl-4-oxobutyric acid benzyl ester as a pale oil. | |
With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; N,N-dimethyl-formamide; | A. (2R)-(t-Butyloxycarbonylamino)-4-morpholin-4-yl-4-oxobutyric acid benzyl ester A solution of D-N-t-butyloxycarbonylaspartic acid benzyl ester (2.53 g, 7.82 mmol) in 30 mL of DMF is treated sequentially with benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (4.15 g, 9.38 mmol), 1-hydroxy-7-azabenzotriazole (1.28 g, 9.38 mmol), diisopropylethylamine (2.5 g, 19.6 mmol) and morpholine (0.82 g, 9.38 mmol). The mixture is stirred at RT for 16 h and is then partitioned between EtOAc and water. The organic solution is washed with water and brine, dried over anhydrous MgSO4 and concentrated. Chomatography on silica gel (eluant; 5% MeOH in dichloromethane) affords 2.91 g (95%) of (2R)-(t-butyloxycarbonylamino)-4-morpholin-4-yl-4-oxobutyric acid benzyl ester as a pale oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; water; | Example A3.2 Z-(S)-N-(2-{4-[3-(4-Chloro-phenyl)-allyloxy]-3-methoxy-phenyl}-ethyl)-2-ethanesulfonylamino-3-methyl-butyramide To a mixture of BOC-L-Valin (48 g), 4-(2-Amino-ethyl)-2-methoxy-phenol hydrochloride (45 g) and diethyl-isopropylamine (64.6 g) in dimethylformamide (900 ml) is added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (97.8 g) in one portion. The reaction mixture is stirred for 4 hours at room temperature. Water (1000 ml) is then added. The mixture is extracted with ethyl acetate (2*500 ml). The organic layers organic layers are washed with brine (2*400 ml), dried (MgSO4) and evaporated. The residue is purified by flash column chromatography on silica gel (ethyl acetate/hexane 1:2). (S)-{1-[2-(4-Hydroxy-3-methoxy-phenyl)-ethylcarbamoyl]-2-methyl-propyl}-carbamic acid tert.-butyl ester is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With triethylamine; In N,N-dimethyl-formamide; | Example 10 3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-quinolin-2-yl-propionamide A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 1, 100 mg, 0.34 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (166 mg, 0.38 mmol), triethylamine (0.096 mL, 0.68 mmol), and <strong>[580-22-3]2-aminoquinoline</strong> (75 mg, 0.52 mmol) in dry N,N-dimethylformamide (2 mL) was stirred at 25 C. for 14 h. The reaction mixture was then diluted with water and ethyl acetate, and the layers were separated. The organic layer was sequentially washed with a saturated aqueous sodium bicarbonate solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-quinolin-2-yl-propionamide (70 mg, 50%) as a white foam: mp 172-173 C.; EI-HRMS m/e calcd for C23H22Cl2N2O(M+) 412.1109, found 412.1108. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In dichloromethane; | Example 8 N-(1H-Benzoimidazol-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 1, 0.300 g, 1.04 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.707 g, 1.60 mmol), and 2-aminobenzimidazole (0.213 g, 1.6 mmol) in methylene chloride (10 mL) at 25 C. was treated with triethylamine (0.45 mL, 3.2 mmol). The reaction mixture was stirred at 25 C. for 16 h. The reaction mixture was then diluted with water (20 mL) and extracted with methylene chloride (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded N-(1H-benzoimidazol-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (0.396 g, 95%) as a white solid: mp 193.4-196.8 C.; EI-HRMS m/e calcd for C21H2,Cl2N3O (M+) 401.1062, found 401.1058. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; | Example 5 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(6-methanesulfonyl-benzothiazol-2-yl)-propionamide A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 1, 0.213 g, 0.74 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.434 g, 0.98 mmol), and 2-amino-6-methanesulfonylbenzothiazole (0.219 g, 0.96 mmol) in methylene chloride (15 mL) at 25 C. was treated with N,N-diisopropylethylamine (0.45 mL, 4.88 mmol). The reaction mixture was stirred at 25 C. for 14 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3*10 mL). The combined organic layers were sequentially washed with water (1*10 mL), a 1N aqueous sodium hydroxide solution (1*10 mL), a 1N aqueous hydrochloric acid solution (1*10 mL), and a saturated aqueous sodium chloride solution (1*10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(6-methanesulfonyl-benzothiazol-2-yl)-propionamide (0.296 g, 80%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; In N,N-dimethyl-formamide; | A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (50 mg, 0.17 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (83 mg, 0.19 mmol), triethylamine (0.048 mL, 0.34 mmol), and <strong>[2933-29-1]2-amino-4,5,6,7-tetrahydrobenzothiazole</strong> (40 mg, 0.26 mmol) in dry N,N-dimethylformamide (1 mL) was stirred at 25 C. for 14 h. The reaction mixture was then diluted with water and ethyl acetate, and the layers were separated. The organic layer was sequentially washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium chloride solution, and water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-propionamide (56 mg, 79%) as a white solid: mp 170-171 C.; EI-HRMS m/e calcd for C21H24Cl2N2OS (M+) 422.0986, found 422.0982. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With triethylamine; In dichloromethane; | A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (50 mg, 0.17 mmol), benzotriazol- 1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (119 mg, 0.27 mmol), triethylamine (70 AL, 0.51 mmol), and 2-aminobenzthiazole (41 mg, 0.27 mmol) in methylene chloride (5 mL) was stirred at 25 C. under nitrogen for 2.33 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was sequentially washed with a 1N aqueous hydrochloric acid solution (1*10 mL), water (1*10 mL), and a saturated aqueous sodium chloride solution (1*10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide (48 mg, 66%) as a white solid: mp 206-209 C.; EI-HRMS m/e calcd for C22H24N2O3S2(M+) 428.1228, found 428.1233. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.5% | With triethylamine; In N,N-dimethyl-formamide; | Example 33 N-Benzooxazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 32, 50 mg, 0.15 mmol), triethylamine (0.060 mL, 0.44 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (98 mg, 0.22 mmol), and 2-aminobenzoxazole (30 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 3 h. The reaction mixture was then diluted with water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated. The resulting organic layer was washed with a saturated aqueous sodium chloride solution (1*25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded N-benzooxazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide (13 mg, 19.5percent) as a yellow solid: mp 106-110° C.; EI-HRMS m/e calcd for C22H23N3O6S (M+) 457.1308, found 457.1323. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In dichloromethane; | A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.311 mmol), triethylamine (0.13 mL, 0.933 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (206 mg, 0.467 mmol), and 2-aminobenzothiazole (70 mg, 0.467 mmol) in methylene chloride (3 mL) was stirred at 25 C. for 3 h. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) to afford N-benzothiazol-2-yl-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (118 mg, 84%) as a white foam: mp 115-118 C. (foam to gel); EI-HRMS m/e calcd for C23H23N3O3S3 (M+) 453.1181, found 453.1173. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In dichloromethane; | Example 28 N-(1H-Benzoimidazol-2-yl)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 26, 100 mg, 0.311 mmol), triethylamine (0.13 mL, 0.933 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (206 mg, 0.467 mmol), and 2-aminobenzimidazole (62 mg, 0.467 mmol) in methylene chloride (3 mL) was stirred at 25 C. for 3 h. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40S, Silica, 1/3 h-hexanes/ethyl acetate) to afford N-(1H-benzoimidazol-2-yl)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (129 mg, 95%) as a yellow solid: mp 148-152 C.; EI-HRMS m/e calcd for C23H24N4O3S (M+) 436.1569, found 436.1573. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; In dichloromethane; | Example 27 N-Benzooxazol-2-yl-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 26, 100 mg, 0.311 mmol), triethylamine (0.13 mL, 0.933 mmol), benzotriazol- 1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (206 mg, 0.467 mmol), and 2-aminobenzoxazole (63 mg, 0.467 mmol) in methylene chloride (3 mL) was stirred at 25° C. for 3 h. The reaction mixture was then diluted with water (40 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (40 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded N-benzooxazol-2-yl-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (75 mg, 55percent) as a yellow foam: mp 108-112° C.; EI-HRMS m/e calcd for C23H23N3O4S (M+) 437.1409, found 437.1409. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.6% | With triethylamine; In dichloromethane; | (A) N-Benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 30, 182 mg, 0.50 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), and 2-aminobenzothiazole (113 mg, 0.75 mmol) in methylene chloride (10 mL) at 25 C. was treated with triethylamine (0.21 mL, 1.50 mmol). The reaction mixture was stirred at 25 C. for 48 h. The reaction mixture was then diluted with methylene chloride (25 mL) and washed with a 3N aqueous hydrochloric acid solution (1*25 mL), water (1*25 mL), and a saturated aqueous sodium chloride solution (3*25 mL). The organic layer was dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 70/30 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide (205 mg, 82.6%) as a white solid: mp 105-110 C.; EI-HRMS m/e calcd for C23H23F3N2O3S2 (M+) 496.1102, found 496.1102. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; In dichloromethane; | A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (300 mg, 1.01 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (717 mg, 1.62 mmol), triethylamine (420 muL, 3.03 mmol), and <strong>[32955-21-8]2-amino-thiazole-5-carboxylic acid ethyl ester</strong>: (279 mg, 1.62 mmol) in methylene chloride (10 mL) was stirred at 25 C. under nitrogen for 14 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was sequentially washed with a 1N aqueous hydrochloric acid solution (1*10 mL), water (1*10 mL), and a saturated aqueous sodium bicarbonate solution (1*10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 10/11 hexanes/ethyl ether) afforded 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl ester (448 mg, 98%) as a white solid: mp 100-103 C.; EI-HRMS m/e calcd for C21H26N2O5S2(M+) 450.1283, found 450.1285. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; water; | Example E9 2-(1,1-Dimethylethoxycarbonylamino)-N-{2-[3-methoxy-4-(4-chlorophenyl-prop-2-ynyloxy)-phenyl]-ethyl}-3-methylbutyramide To a mixture of BOC-L-valine (4.7 g), 4-(2-amino-ethyl)-2-methoxy-phenol hydrochloride (4,5 g) and ethyl-diisopropyl-amine (6,5 g) in dimethylformamide (90 ml) is added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (9.8 g) in one portion. The mixture is stirred at room temperature for 4 hours. Then water (400 ml) is added. The mixture is extracted with ethyl acetate (2*400 ml) and washed with brine (2*200 ml). The organic layers are collected, dried (MgSO4) and evaporated. 2-(1,1-dimethylethoxycarbonylamino)-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-3-methylbutyramide is obtained which is purified by flash column chromatography on silica gel (ethyl acetate/hexane 2:3); oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With triethylamine; In dichloromethane; | EXAMPLE 159 3-Cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide A mixture of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 14, 250 mg, 0.732 mmol), triethylamine (0.306 mL, 2.19 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (487 mg, 1.10 mmol), and <strong>[74-69-1]4-amino-2-methylpyrimidine</strong> (120 mg, 1.10 mmol) in methylene chloride (5 mL) was stirred at 25 C. for 24 h. The reaction mixture was then diluted with water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/3 hexanes/ethyl acetate) afforded impure 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide. Re-purification by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 then 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide (59 mg, 18%) as a white foam: mp 96-99 C. (foam to gel); EI-HRMS m/e calcd for C20H24N4O5S (M+) 432.1467, found 432.1470. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In water; N,N-dimethyl-formamide; | Example 3 Preparation of N-(3-hydroxypropyl)-2-anthraquinonecarboxamide (2) To a stirred suspension of <strong>[117-78-2]anthraquinone-2-carboxylic acid</strong> (Aldrich, 10.00 g, 39.64 mmol) in DMF (130 ml), was added (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (17.54 g, 39.66 mmol) and trethylamine (11.05 ml, 79.28 mmol). The resulting mixture (initially a clear green solution) was stirred at room temperature for 10 min. before dropwise addition of 3-amino-1-propanol (3.34 ml, 43.67 mmol). The reaction mixture (clear brown solution) was stirred at room temperature in the dark for 17 hours. The solution was poured in a thin stream into water (300 ml) containing some ice. The precipitated material was isolated by filtration and recrystallized from boiling 96percent ethanol (ca. 200 ml) and gave the title compound 2 as a bright yew solid (6.93 g, 57percent yield). 1H NMR (250 MHz, DMSO-d6) delta: 1.74 (2H, quintet, J=6.52 Hz, CH2), 3.25-3.44 (2H, m, CH2), 3.50 (2H, broad t, J=5.80 Hz, CH2), 4.53 (1H, broad s, OH), 7.76-8.00 (2H, m, Ar), 8.04-8.36 (4H, m, Ar), 8.56 (1H, d, J=1.55 Hz, Ar), 8.89 (1H, t, J=5.42 Hz, NH). 13C NMR (250 MHz, DMSO-d6) delta: 32.32, 36.96, 58.68, 125.50, 126.83, 126.85, 127.05, 132.79, 133.04, 133.08, 134.45, 134.66, 139.49, 164.62, 182.11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In dichloromethane; ethyl acetate; | (C) A solution of 2-(4methoxybenzenesulfonylamino)-2-methylpropionic acid (1.08 grams, 3.95 mmole) in methylene chloride (120 mL) was cooled in an ice bath. Triethylamine (2.2 mL, 15.8 mmole), (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (2.6 grams, 5.88 mmole) and O-benzylhydroxylamine hydrochloride (0.95 grams, 5.95 mmole) were subsequently added. The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed successively with aqueous 1 N hydrochloric acid solution, aqueous saturated sodium bicarbonate solution, water and brine. After drying over sodium sulfate, the solvent was evaporated to afford an oil from which the desired product, N-benzyloxy-2-(4-methoxybenzenesulfonylamino)-2-methyl-propionamide (1.41 grams, 95%), a white solid, was obtained by chromatography on silica gel eluding with 1:2 ethyl acetate/hexanes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; | (G) Diisopropylethylamine (4.3 mL, 24.6 mmole) and (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate (11.0 grams, 24.9 mmole) were added sequentially to a solution of 1-[(4'-fluorobiphenyl-4-sulfonyl)-(2-methoxycarbonylethyl)-amino]cyclopentane-1-carboxylic acid (10.1 grams, 22.4 mmole) in N,N-dimethylformamide (170 mL). The mixture was stirred for 4 hours. Additional diisopropylethylamine (7.8 mL, 44.6 mmole) and O-benzylhydroxylamine hydrochloride (4.64 grams, 29.1 mmole) were then added and the resulting mixture was stirred at 60 C. for 16 hours. After concentration under vacuum, the residue was taken up in water and acidified with 1 N aqueous hydrogen chloride solution. The mixture was extracted with ethyl acetate and the extract was washed sequentially with water, saturated aqueous sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate and concentrated to give a solid which upon trituration with 7:3:1 hexane/ethyl acetate/methylene chloride provided 3-[(1-benzyloxycarbamoylcyclopentyl)-(4'-fluorobiphenyl-4-sulfonyl)amino]propionic acid methyl ester as a white crystalline solid (10.65 grams, 86%). |
86% | With N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; | (G) Diisopropylethylamine (4.3 mL, 24.6 mmole) and (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate (11.0 grams, 24.9 mmole) were added sequentially to a solution of 1-[(4'-fluorobiphenyl-4-sulfonyl)-(2-methoxycarbonylethyl)-amino]cyclopentane-1-carboxylic acid (10.1 grams, 22.4 mmole) in N,N-dimethylformamide (170 mL). The mixture was stirred for 4 hours. Additional diisopropylethylamine (7.8 mL, 44.6 mmole) and O-benzylhydroxylamine hydrochloride (4.64 grams, 29.1 mmole) were then added and the resulting mixture was stirred at 60C for 16 hours. After concentration under vacuum, the residue was taken up in water and acidified with 1N aqueous hydrogen chloride solution. The mixture was extracted with ethyl acetate and the extract was washed sequentially with water, saturated aqueous sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate and concentrated to give a solid which upon trituration with 7:3:1 hexane/ ethyl acetate/ methylene chloride provided 3-[(1-benzyloxycarbamoylcyclopentyl)-(4'-fluorobiphenyl-4-sulfonyl)amino]propionic acid methyl ester as a white crystalline solid (10.65 grams, 86%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In dichloromethane; ethyl acetate; | 1) Synthesis of 1-(4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carbonyl)pyrrolidine In 3 ml of dichloromethane were dissolved 0.20 g of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid, 0.20 ml of triethylamine and 0.06 ml of pyrrolidine at room temperature, and 0.35 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate was added and the mixture was stirred for 4 hours. The mixture was extracted with water and diethyl ether, and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography eluding with n-hexane containing 33% ethyl acetate to give 0.21 g of 1-(4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carbonyl)pyrrolidine as a colorless solid (yield 92%). 1 H NMR (270 MHz, CDCl3) delta ppm: 0.27 (s, 9H), 1.37 (s, 9H), 1.42 (s, 9H), 1.59 (s, 3H), 1.73-1.88 (m, 4H), 3.22 (d, 1H, J=15.8 Hz), 3.45-3.78 (m, 4H), 4.06 (d, 1H, J=15.8 Hz), 6.67 (s, 1H). Mass: 431 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium carbonate; sodium carbonate; triethylamine;palladium; In methanol; water; ethyl acetate; N,N-dimethyl-formamide; | REFERENCE EXAMPLE 21 2-[[2-Amino-3-(1H-imidazol-4-yl)-1-oxopropyl]amino]-4,7-anhydro-1-cyclohexyl-1,2,5,6-tetradeoxy-L-arabino-Heptitol To a mixture of 0.289 g of Nalpha -(benzyloxycarbonyl)-L-histidine and 0.014 ml of triethylamine in 2 ml of N,N-dimethylformamide is added 0.44 g of benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (BOP). The mixture is stirred 1 minute and 0.200 g of 2-amino-4,7-anhydro-1-cyclohexyl-1,2,5,6-tetradeoxy-L-arabino-Heptitol added. The mixture is stirred overnight at room temperature and diluted with 5 ml of ethyl acetate. The mixture is washed three times with 1 ml of 2M sodium carbonate and with 1M citric acid-1M-sodium citrate buffer and brine. The organic layer is concentrated to give 0.35 g of a foam. Chromatography on silica gel with dichloromethane-methanol-ammonium hydroxide (9:1.2:0.2) gives 0.30 g of a glass. To the preceding glass (0.30 g) and 0.4 g of ammonium carbonate in 7 ml of methanol under nitrogen is added a slurry of 10% palladium on carbon in 1.5 ml of water. The mixture is stirred for 1.5 hour, filtered through diatomaceous earth and the filter pad washed with methanol. The filtrate is concentrated and the residue dissolved in 1 ml of methanol and 0.2 ml of concentrated ammonium hydroxide is extracted four times with 5 ml portions of chloroform. The extracts are combined, dried (Na2 SO4) and the solvent removed to give 0.19 g of solid; [alpha]D26 - 24+-1 (c, 1.003, CH3 OH). | |
With ammonium carbonate; sodium carbonate; triethylamine;palladium; In methanol; water; ethyl acetate; N,N-dimethyl-formamide; | REFERENCE EXAMPLE 23 2-[[2-Amino-3-(1H-imidazol-4-yl)-1-oxopropyl]-amino]-4,7-anhydro-1-cyclohexyl-1,2,5,6-tetradeoxy-L-arabino-Heptitol To a mixture of 0.289 g of Nalpha -(benzyloxycarbonyl)-L-histidine and 0.014 ml of triethylamine in 2 ml of N,N-dimethylformamide is added 0.44 g of benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (BOP). The mixture is stirred 1 minute and 0.200 g of 2-amino-4,7-anhydro-1-cyclohexyl-1,2,5,6-tetradeoxy-L-arabino-Heptitol added. The mixture is stirred overnight at room temperature and diluted with 5 ml of ethyl acetate. The mixture is washed three times with 1 ml of 2M sodium carbonate and with 1M citric acid-1M-sodium citrate buffer and brine. The organic layer is concentrated to give 0.35 g of a foam. Chromatography on silic gel with dichloromethane-methanol-ammonium hydroxide (9:1.2:0.2) gives 0.30 g of a glass. To the preceding glass (0.30 g) and 0.4 g of ammonium carbonate in 7 ml of methanol under nitrogen is added a slurry of 10% palladium on carbon in 1.5 ml of water. The mixture is stirred for 1.5 hour, filtered through diatomaceous earth and the filter pad washed with methanol. The filtrate is concentrated the residue in 1 ml of methanol and 0.2 ml of concentrated ammonium hydroxide is extracted four times with 5-ml portions of chloroform. The extracts are combined, dried (Na2 SO4) and the solvent removed to give 0.19 g of solid; [alpha]D26 -24+-1 (c, 1.003, CH3 OH). | |
With ammonium carbonate; sodium carbonate; triethylamine;palladium; In methanol; water; ethyl acetate; N,N-dimethyl-formamide; | REFERENCE EXAMPLE 19 2-[[2-Amino-3-(1H-imidazol-4-yl)1-oxopropyl]amino]-4,7-anhydro-1-cyclohexyl-1,2,5,6-tetradeoxy-L-arabino-Heptitol To a mixture of 0.289 g of Nalpha -(benzyloxycarbonyl)-L-histidine and 0.014 ml of triethylamine in 2 ml of N,N-dimethylformamide is added 0.44 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP). The mixture is stirred 1 minute and 0.200 g of 2-amino-4,7-anhydro-1-cyclohexyl-1,2,5,6-tetradeoxy-L-arabino-Heptitol added. The mixture is stirred overnight at room temperature and diluted with 5 ml of ethyl acetate. The mixture is washed three times with 1 ml of 2M sodium carbonate and with 1M citric acid-1M sodium citrate buffer and brine. The organic layer is concentrated to give 0.35 g of a foam. Chromatography on silica gel with dichloromethane-methanol-ammonium hydroxide (9:1.2:0.2) gives 0.30 g of a glass. To the preceding glass (0.30 g) and 0.4 g of ammonium carbonate in 7 ml of methanol under nitrogen is added a slurry of 10% palladium on carbon in 1.5 ml of water. The mixture is stirred for 1.5 hours, filtered through diatomaceous earth and the filter pad washed with methanol. The filtrate is concentrated. The residue in 1 ml of methanol and 0.2 ml of concentrated ammonium hydroxide is extracted four times with 5 ml portions of chloroform. The extracts are combined, dried (Na2 SO4) and the solvent removed to give 0.19 g of solid: [alpha]D26 -24+1(c, 1.003, CH3 OH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
480 mg (100%) | With triethylamine; In dichloromethane; ethyl acetate; | Step A: 2(R)-t-Butoxycarbonylamino-3-(t-butoxy)-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]propanamide To a solution of 200 mg (1.13 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) in 8 mL of dry methylene chloride was added 0.206 mL (1.48 mmol) of triethylamine, 553 mg (1.25 mmol) of <strong>[248921-66-6]BOC-D-serine t-butyl ether</strong> followed by 602 mg (1.36 mmol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate. The reaction mixture was stirred at room temperature for 2 hours then diluted with 100 mL of ethyl acetate, washed with 25 mL of 5% aqueous citric acid, 25 mL of saturated sodium bicarbonate and 25 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvents removed under vacuum. The residue was purified by flash chromatography on silica gel, eluding with ethyl acetate/hexane (55:45) to afford 480 mg (100%) of the product as a white foam. 1 H NMR (200 MHz,CDCl3): 1.20 (s,9H), 1.47 (s,9H), 1.92 (m,1H), 2.55-3.02 (m,3H), 3.38 (t,8 Hz,1H), 3.78 (m,1H), 4.15 (m,1H), 4.52 (m,1H), 5.45 (s,1H), 7.00 (m,1H), 7.10-7.35 (m,3H), 7.68 (d,4 Hz,1H), 8.05 (s,1H). FAB-MS: calculated for C22 H33 N3 O5 419; found 420 (M+H,20%), 426 (M+Li,40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71 mg (0.17 mmol, 100%) | With triethylamine; In dichloromethane; ethyl acetate; | Step A: 2(R)-t-Butoxycarbonylamino-3-phenyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-propanamide To a solution of 30 mg (0.17 mmol) 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1; Step B) in 2 mL methylene chloride at room temperature was added 50 mg (0.19 mmol, 1.1 eq) N-(t-butoxycarbonyl)-D-phenylalanine followed by 0.047 mL (34 mg, 0.34 mmol, 2 eq) of triethylamine and 113 mg (0.26 mmol, 1.5 eq) benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate. After 2 hours at room temperature, the mixture was added to 30 mL of ethyl acetate and washed with 5% citric acid (2*), saturated aqueous sodium bicarbonate and brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluding with ethyl acetate to afford 71 mg (0.17 mmol, 100%) of the product. 1 H NMR (200 MHz, CDCl3): 1.38 (s,9H), 1.9 (m,1H), 2.6-3.1 (m,5H), 4.44 (m,2H), 5.10 (br d,7 Hz,1H), 6.95 (d,8 Hz,1H), 7.1-7.3 (m,8H), 8.33 (br s,1H). FAB-MS: calc. for C24 H29 N3 O4 423; found 424 (M+H,65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76 mg (0.22 mmol, 77%) | With N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; | Step A: 3-t-Butoxycarbonylamino-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-propanamide To a solution of 50 mg (0.28 mmol) <strong>[86499-35-6]3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one</strong> (Example 1; Step A) in 2 mL methylene chloride at room temperature was added 56 mg (0.30 mmol, 1.05 eq) 3-(t-butoxycarbonylamino)propanoic acid followed by 0.1 mL diisopropylethylamine (74 mg, 0.57 mmol, 2 eq) and 190 mg (0.43 mmol, 1.5 eq) benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate. After 1 hour at room temperature, the mixture was added to 20 mL ethyl acetate and washed with 1M aqueous citric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed in vacuo. The residue was purified by medium pressure liquid chromatography on silica, eluding with ethyl acetate/hexane (2:1) to afford 76 mg (0.22 mmol, 77%) of product as a white solid. 1 H NMR (200 MHz, CDCl3): 1.40 (s,9H), 1.95 (m,1H), 2.40 (t,6 Hz,2H), 2.6-3.0 (m,3H), 3.36 (q,6 Hz, 2H), 4.52 (m,1H), 5.15 (br t,1H), 6.58 (br d,1H), 7.0-7.3 (m,4H), 7.6 (br s,1H). FAB-MS: calc. for C18 H25 N3 O4 347; found 348 (M+H,35%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; methanol; sodium bicarbonate; toluene; | EXAMPLE 2: N-(5-cyanopentyl)-3-oxo-4-aza-5alpha-androstane-17beta-carboxamide 1.59 g of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (Castros reagent), 0.6 ml of methylmorpholine and 2.3 ml of 6-aminocapronitrile are added to a suspension of 957 mg (3 mmol) of 3-oxo-4-aza-5alpha-androstane-17beta-carboxylic acid in 6.6 ml of dimethylformamide and the mixture is stirred for 2 hours at room temperature. The resulting solution is diluted with chloroform and washed in succession with sodium hydrogen carbonate solution, water and saturated sodium chloride solution. The organic phase is dried with sodium sulfate and concentrated to dryness under a water-jet vacuum. The residue is chromatographed over a column of silica gel using a mixture of toluene/methanol (97:3) as eluant, yielding N-(5-cyanopentyl)-3-oxo-4-aza-5alpha-androstane-17-carboxamide, m.p. 213-215,[alpha]D =+41.0 (c=0.488 in chloroform) after crystallisation from methylene chloride/diisopropyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | a) 3.78 ml of 4-ethylmorpholine, 4.42 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and a solution of 2.25 g of N-cyclohexylglycine ethyl ester (J. Heterocycl. Chem. 23, 1986, 929-933) in 8 ml of DMF are added to a solution of 2.89 g of N-Boc-L-aspartic acid beta-t-butyl ester in 50 ml of DMF. The reaction mixture is stirred at room temperature, then evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is dried, evaporated and the residue is chromatographed on silica gel with ethyl acetate/hexane 1:1. There are thus isolated 4.5 g of t-butyl-(S)-3-(1-t-butoxyformamido)-N-cyclohexyl-N-[(ethoxycarbonyl)methyl]succinamate, Fab-MS: 457 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In hexane; dichloromethane; ethyl acetate; | d [R-(R*,S*)]-2,3,4,5-Tetrahydro-3-[[2-[[(4-methoxyphenyl)methyl]thio]-2-methyl-1-oxo-3-phenylpropyl]amino]-2-oxo-1H-benzazepine-1-acetic acid, 1,1-dimethylethyl ester and [S-(R*,R*)]-2,3,4,5-tetrahydro-3-[[2-[[(4-methoxyphenyl)methyl]thio]-2-methyl-1-oxo-3-phenylpropyl]amino]-2-oxo-1H-benzazepine-1-acetic acid, 1,1,-dimethylethyl ester A solution of the product from part (c) (497 mg., 1.57 mmol., 1.09 eq.) was cooled to 0 C. (ice-salt bath), treated with a solution of <strong>[109010-60-8](S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H-benzazepine-1-acetic acid, 1,1-dimethylethyl ester</strong> [prepared according to the procedure of Watthey et al., J. Med. Chem. 28, p. 1511-1516 (1985)] (417 mg., 1.44 mmol.) in dry methylene chloride (2.9 ml.) followed by triethylamine (0.2 ml., 1.45 mmol.) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (642 mg., 1.45 mmol.). The reaction mixture was stirred at 0 C. for 1.0 hour then at room temperature for 2.5 hours after which it was evaporated to dryness. The syrup obtained was redissolved in ethyl acetate (50 ml.) and the resulting solution washed with 0.5N hydrochloric acid (2*8.3 ml.), water (8.3 ml.) and brine (8.3 ml.), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuo. The crude product was chromatographed on a silica gel column (Merck), eluding the column with ethyl acetate:hexane (1:4) to give 709 mg. of a mixture of isomeric products. Rechromatography of the isomer mixture on a silica gel column and elution with ethyl acetate:methylene chloride (1:99, 2:98) gave 340 mg. of the [R-(R*,S*)] title product; [alpha]D =-72 (c=0.66, methanol); TLC(ethyl acetate:hexane, 1:1) Rf =0.70 and 316 mg. of the [S-(R*,R*)title product; [alpha]D =-142 (c=0.5, methanol); TLC(ethyl acetate:hexane, 1:1) Rf =0.87. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethyl acetate; N,N-dimethyl-formamide; | (1) To a DMF solution (80 ml) containing 3-(2-aminopropyl)-7-methoxyindole (12.24 g) and <strong>[16273-37-3]3-chloromandelic acid</strong> (7.46 g) is added benzotriazole-N-oxytris(dimethylamino)phosphonium hexafluorophosphate (17.68 g), and then thereto is added dropwise triethylamine (9.8 ml). The mixture is stirred at room temperature for five hours, and to the reaction mixture is added ethyl acetate. The mixture is washed successively with water, 10% aqueous citric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture is evaporated to remove the solvent under reduced pressure, and the residue is purified by silica gel column chromatography (eluent; ethyl acetate/n-hexane=1:1?2:1) to give N-[3-(7-methoxyindol-3-yl)-2-propyl]-3-chloromandelamide (14.02 g) as an oily product. 1 H-NMR spectrum (CDCl3):1.12, 1.18(3H,d,J=7 Hz,CHCH3),2.82-2.95(2H,m,CH2 CH),3.97(3H,s,OCH3),4.33(1H,m,CHCH3),4.85(1H,s,CHOH), 6.65 (1H,m),6.86-7.37(7H,m),8.26(1H,d,J=13Hz,CONH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; | A. 3-[(Triphenylmethyl)thio]-N-methoxy-N-methylpropanamide. To a stirred solution of S-trityl-3-mercaptopropionic acid (4.5 g, 12.9 mmol, prepared according to Kwang et al., J. Med. Chem. , 13 , (1970) 414) in CH2Cl2 (40 mL) was added N,N-diisopropylethylamine (2.2 mL, 12.9 mmol) followed by benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (5.7 g, 12.9 mmol). After several minutes, N,O-dimethylhydroxylamine hydrochloride (1.31 g, 13.5 mmol) was added along with additional diisopropylethyl amine (2.2 mL, 12.9 mmol). The solution was stirred for 2 hours at room temperature. Additional CH2Cl2 was added (80 mL) and the solution was washed with 1N KHSO4 (3x), saturated NaHCO3 (3x) and brine (2x). The organic layer was dried (MgSO4) and concentrated. The residue was recrystallized twice using ethyl acetate/hexanes to yield Compound A (4.12 g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 4-methyl-morpholine; In dichloromethane; | E. (R*)-N-[[1-[N-[N-[(1,1-Dimethylethoxy)carbonyl]-S-(triphenylmethyl)-L-cysteinyl]-L-valyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]-L-methionine, 1,1-dimethylethyl ester. To a solution of Compound D (100 mg, 0.22 mmol) in dichloromethane (1 mL) at 0C under argon were added sequentially N-t-butyloxycarbonyl-S-trityl-L-cysteine (122 mg, 0.26 mmol), N-methylmorpholine (0.033 mL, 0.3 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (115 mg, 0.26 mmol). The reaction mixture was allowed to warm to room temperature over 2 hours, and then stirred overnight (16 hours). The reaction mixture was diluted with chloroform (5 mL) and washed sequentially with 1N HCl, saturated NaHCO3 and brine (5 mL each). Purification by flash silica gel column chromatography eluding with 30% ethyl acetate in hexanes afforded Compound E (160 mg, 81%). TLC Rf0.11 (70% ethyl acetate in hexanes, visualized by UV, ceric ammonium molybdate). MS: (FAB) (M+H)+= 895+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; | C.(R*)-2-[N-[N-[(1,1-Dimethylethoxy)carbonyl]-S-(triphenylmethyl)-L-cysteinyl]-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, phenylmethyl ester. To a solution of N-t-butyloxycarbonyl-S-trityl-L-cysteine (7.78 g, 16.8 mmol) in dimethylformamide (80 mL) at 0C under N2 was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (7.42 g, 16.8 mmol) and N,N-diisopropylethylamine (2.92 mL, 16.8 mmol). After stirring for 30 minutes, Compound B (6.96 g, 16.8 mmol, 1 eq) and N,N-diisopropylethylamine (2.92 mL, 16.9 mmol) were added. After stirring for 16 hours at 0, the reaction was diluted with ethyl acetate (500 mL) and washed sequentially with saturated sodium bicarbonate (100 mL) and 10% lithium chloride (4 x 100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified on silica gel (400 mL, eluding with 1:4 to 3:7 ethyl actetate/hexane) to give Compound C (10.46 g, 77%). mp: 85-87C TLC: Rf= 0.40 (2:1 hexane/ethyl acetate, visualized by ceric ammonium sulfate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; | D. (S)-1,2,3,4-Tetrahydro-2-[3-methyl-N-[(phenylmethoxy)carbonyl]-L-valyl]-3-isoquinolinecarboxylicacid, methyl ester To a solution of Compound C (5.31 g, 20 mmol) in dichloromethane (80 mL) at 0C under argon were sequentially added diisopropylethylamine (10.6 mL, 60 mmol), benzotriazol-1-yloxytris- (dimethylamino)phosphonium hexafluorophosphate (5.08 g, 20 mmol) and <strong>[78183-55-8](S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid, methyl ester, hydrochloride</strong> (5.68 g, 25 mmol). The reaction mixture was allowed to warm to 5C over 2 hours, and then stirred overnight (16 hours). The mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate and brine (50 mL each). The organic layer was dried (magnesium sulfate), filtered and concentrated to afford an oil. Purification by flash silica gel column chromatography eluding with 20% ethyl acetate in hexanes afforded Compound D (4.0 g, 45%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With ammonium chloride; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; In ammonium hydroxide; ethanol; water; N,N-dimethyl-formamide; acetonitrile; | Step 2. Preparation of ethyl beta-[[N-2-[[[4-(aminoiminomethyl)phenyl]amino]carbonyl]pyrrolidylcarbonyl]amino]-3-pyridinepropanoate A portion of the acid (0.37 g; 1.4 mmoles) and ethyl beta-[3-amino(3-pyridyl)]-propanoate dihydrochloride (0.46 g; 1.5 mmoles) were dissolved and stirred in N,N-dimethylformamide (50 ml). To this mixture, benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.66 g; 1.5 mmoles) and N,N-diisopropylethylamine (0.36 g; 3 mmoles) were added. The reaction was carried out for another hour and the mixture was then taken down to dryness. The residue was dissolved in ethanol (100 ml) and the solution was saturated with HCl gas for 2 hrs. The reaction mixture was evaporated to dryness under reduced pressure and the remaining residue was redissolved in ethanol (100 ml). The solution was treated with ammonium chloride (1 g) in ammonium hydroxide (10 ml) at room temperature for 4 hrs. Ethanol was removed on rotaevaporator and the residue was purified by HPLC using acetonitrile/water/trifluoroacetic acid. The desired fractions were collected and lyophilized to give 490 mg of white solid (72% yield). FAB-MS: MH+=453.2. Elemental analysis: C23H28N6O4.2CF3COOH.H2O |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Step B: t-Butyl 3-isopropyl-3-[(2R,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]carbazate To a stirred solution of the product of Step A (0.111 g; 0.386 mmol), the product of Example 2, Step B (0.13022 g; 0.386 mmol), benzotriazol- 1 -yloxytris (dimethylamino)phosphonium hexafluorophosphate (0.205 g; 0.46 mmol) and 1-hydroxybenzotriazole (0.052 g; 0.384 mmol) in 1 ml of anhydrous DMF was added, N,N-diisopropylethylamine (0.24 ml; 1.38 mmol). After stirring for 12 hours at room temperature the reaction was diluted to 30 ml with ethyl acetate and washed with water, 2% potassium bisulfate, 5% sodium bicarbonate and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography (silica gel, ethyl acetate) gave 0.152 g (65% yield) of the title product melting at 109-114 C.; Rf (C)=0.36; Rf (D)=0.37; NMR (CDCl3) 1.0 (m, 6H, val, isopropyl CH3); 1.42 (s, 9H, t-butyl CH3); 2.5-3.1 (m, 7H, asn CH2, butyl CH2 -1,-4, CH-3); 3.44 (m, 1 H, isopropyl CH); 4.21 (m, 1 H, butyl CH-2); 4.55 (s, 1 H, OH); 4.94 (m, 1H, asn CH-alpha); 5.4-6.2 (m, 3H, amide); 6.7-8.4 (m, 11H, aromatic); 9.25 (m, 1H, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine; In N,N-dimethyl-formamide; for 1h; | Intermediate X (1235 mg, 2.70 mmol), triethylamine (1.04 mL, 7.53 mmol), and Benzotriazol-l-yloxytris(dimethylamino)-phosphonium hexafluoro-phosphate (BOP, 1220 mg, 2.76 mmol) was combined along with DMF (20 mL). The mixture was allowed to stir until complete by HPLC (1 hour). The reaction mixture was diluted with 5 volumes of EtOAc and washed with pH 7 buffer, brine, and copious amounts of H2O. The organic layer was dried (Na2SO4) and concentrated to give an off-white powder (953 mg, 77% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 4h; | Example 1; Synthesis of 9-(2-Deoxy-3,5-bis-O-(tert-butyldimethylsilv?-beta-D-eryt/?A-o- pentofuranosv?purin-6-yloxy- (tris(dimethylamino')phosphonium') hexafluorophosphateand the mixture was allowed to stir at room temperature for 4 h and then evaporated. The crude material was taken up in CH2Cl2 and washed with water. The organic layer was separated, dried over Na2SO4 and concentrated. Purification by preparative thin layer <n="42"/>chromatography (SiO2, 5% MeOH in CH2Cl2) afforded -10 mg (6% yield) of the product as a clear gum. Rf (5% MeOH in CH2Cl2) = 0.26. 1H NMR (500 MHz, CDCl3): delta 8.68 (s, IH, Ar-H), 8.50 (s, IH, Ar-H), 6.54 (t, IH, H-I ', J= 6.4), 4.63 (m, IH, H-3'), 4.06 (q, IH, H-4', J= 3.3), 3.89 (dd, IH, H-5', J= 11.2, 3.7), 3.79 (dd, IH, H-5 J= 11.2, 2.9), 2.66 (app quint, IH, H-2', Japp ~ 6.4), 2.52 (ddd, IH, U-T, J= 13.2, 5.9, 3.9), 2.92 (d, 18H, NCH3, JH-P = 11.2), 0.92, 0.90 (2s, 18H, tert-Bu), 0.11, 0.09, 0.08 (3s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3):delta 154.4, 152.7, 151.5, 144.5, 123.0, 88.4, 85.2, 71.9, 62.7, 41.4, 37.3 (d, Jc-P= 4.5), 25.9, 25.7, 18.4, 18.0, -A.I, -4.8, -5.4, -5.5. 31P NMR (202 MHz, CDCl3):delta 35.44 (s, P[N(CH3)2]3), -143.31 (septet, PF6, JPjF = 712). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
c) N-{5 - [4-(dimethylamino)pyrido [3,2-d]pyrimidin-6-yl] -3-pyridinyl}benzenesulfonamide, N-{5-[4-(4-morpholinyl)pyrido[3,2-d]pyrimidin-6- yl] -3 -pyridinyl} benzenesulfonamide. To a mixture of 6-chloropyrido[3,2-d]pyrimidin-4(lH)-one (1.10 mmol, seeWO2006/ 135993) and benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.43 mmol) in acetonitrile (6.0 mL) was added 1,8- diazabicyclo[5.4.0]undec-7-ene (1.65 mmol). After 15 min at room temperature, morpholine (1.65 mmol) was added dropwise and the reaction mixture was stirred for 18 h at room temperature and 4 h at 60 0C. The reaction was poured into water (60 mL) and brine (10 mL) and the organics were extracted with (3 x 55 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (20- 50% ethyl acetate/hexanes) provided a 2:1 mixture of 6-chloro-iV,jV- dimethylpyrido[3,2-(i]pyrimidin-4-amine and 6-chloro-4-(4-morpholinyl)pyrido[3,2- (ijpyrimidine (118 mg). A mixture of the pyridopyrimidines (118 mg), N- [5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.678 mmol), and dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.017 mmol) in saturated aq sodium bicarbonate (0.5 mL) and 1,4-dioxane (2.5 mL) was irradiated in a microwave at 120 0C for 30 min. The reaction mixture was poured into water (70 mL) and brine (10 mL) and the organics were extracted with (3 x 60 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-10% methanol/ethyl acetate) provided the coupled products mixture. This product mixture was then separated by prep etaPLC (Chiralcel OJ-eta 21 x 250 mm column) using an eluent of 70:30:0.1 heptane:ethanol:isopropylamine to afford lambda/-{5-[4-(dimethylamino)pyrido[3,2- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 1h; | Example 1 4-(1H-Benzo[d][1,2,3]triazol-1-yloxy)quinazoline To a solution of 4-hydroxyquinazoline (730 mg, 5 mmol) and BOP (2.6 g, 6 mmol) in MeCN (40 mL) was added DBU (1.13 mL, 7.5 mmol) at room temperature. The resultant mixture was stirred for 1 hour at room temperature. The solvent was removed under vacuum, the crude mixture was purified by a flash chromatography on SiO2 column eluted with EtOAc/hexane (1:1) to give the desired product 1.08 g (84%). 1H NMR (DMSO-d6, 400 MHz): delta (ppm) 8.76 (s, 1H), 8.60 (d, J=4.0 Hz, 1H), 8.25-8.16 (m, 3H), 8.00 (t, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H). 13C NMR (DMSO-d6, 400 MHz): 165.7, 153.2, 151.9, 143.1, 136.1, 129.6, 128.8, 128.1, 125.7, 123.0, 120.3, 113.1, 110.0. HRMS (ES-MS) [(M+H)+]: for C14H9N5O 264.0879, found 264.0879. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Example 102 4-(1H-Benzo[d][1,2,3]triazol-1-yl)quinazoline To a solution of a hydroxyquinazoline (292 mg, 0.5 mmol), and BOP (1060 mg, 2.4 mmol) was added DBU (0.45 mL, 3.0 mmol) at room temperature under nitrogen. The resultant mixture was stirred for 5-10 min at room temperature, after which benzotriazole (714 mg, 6.0 mmol) was added. The reaction mixture was monitored by LCMS till complete consumption of starting material (30 hrs). The solvent was removed under vacuum, the crude reaction mixture was purified by a flash chromatography on SiO2 column eluted with hexanes/EtOAc to give the desired product (380 mg, 77%). 1H NMR (DMSO-d6, 400 MHz): delta (ppm) 9.38 (s, 1H), 8.92 (d, J=8.4 Hz, 1H), 8.46 (d, J=8.0 Hz, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.19-8.14 (m, 2H), 7.91 (t, J=6.8 Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H). 13C NMR (DMSO-d6,400 MHz): 155.0, 154.0, 153.0, 145.6, 135.4, 132.5, 130.2, 129.7, 128.8, 127.0, 126.3, 120.1, 117.2, 115.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Benzotriazole-1 -yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP, 9.52 g, 21.5 mmol) was added slowly to a stirring solution of 6- ethyl-2-(methylthio)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (Example 26) (3.6 g, 17.2 mmol), Et3N (3.0 mL, 21.5 mmol) in NMP (100 mL) at 0C. The stirring was continued for 30 minutes at 0C, and then 30 minutes at room temperature. HOBt (2.33 g, 17.2 mmol) and Et3N (2.4 mL, 17.2 mmol) was added. The mixture was heated to 40C for 12 h (LC-MS monitoring reaction). Water (300 mL) was added to the reaction mixture. The precipitate was collected by filtration and dried to give 4.4 g (78%) of 1 -(6-Ethyl-2-(methylthio)-7H- pyrrolo[2,3-d]pyrimidin-4-yloxy)-lH-benzo[d][l,2,3]triazole. MS (ESI) m/z 327 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20℃; for 16h; | Terf-butyl (3f?)-3-aminopiperidine-1-carboxylate (1.49 g, 7.46 mmol) was added to a stirred solution of 3-(4-hydroxypyrimidin-2-yl)pyrazolo[1 ,5-a]pyridine-5-carbonitrile (Preparation 3b, 0.70 g, 2.98 mmol), (benzotriazol-l-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (1.71 g, 3.88 mmol) and 1 ,8-diazabicyclo[5.4.0] undec-7-ene (0.67 mL g, 4.48 mmol) in Lambda/,Lambda/'-dimethylformamide (15 mL) and the resulting mixture was stirred at room temperature for 16 hours. Then the solvent was removed under reduced pressure and the residue was taken up in a mixture of dichloromethane and 4% aqueous sodium hydrogencarbonate solution. The organic layer was separated, dried (MgS04) and evaporated in vacuo. The crude product was purified by flash chromatography (99:1 dichloromethane/methanol) to give a residue that was repurified by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to give the title compound (0.83 g, 66%) and 3-(4-(1 H-benzo[d][1 ,2,3]triazol-1-yloxy) pyrimidin-2-yl)pyrazolo[1 ,5-a]pyridine-5-carbonithle (0.10 g) as the main reaction byproduct.LRMS (m/z): 420 (M+1 )+, 418 (M-1)H-NMR delta (300 MHz, CDCI3): 0.7-0.9 (m, 4H), 1. 5 (s, 9H), 1.6-1.7 (m, 2H), 1.7-1.9 (m, 2H), 2.0-2.1 (m, 1 H), 5.0 (bs, 1 H), 6.3 (d, 1 H), 7.0 (dd, 1 H), 8.3 (d, 1 H),8. 6 (d, 1 H), 8.8 (s, 1 H), 9.1 (t, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h; | Methanamine (4.4 ml, 8.83 mmol) was added to a stirring solution of DIEA (3 ml, 17.65 mmol), BOP (2.9 g, 6.62 mmol), and 2-(4- fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylic acid (1.4 g, 4.41 mmol) in DMF (44 ml) at 0C. It was allowed to warm to rt and stir for 1 hr. The mixture was concentrated and diluted with EtOAc and washed with 1M HC1, and sat NaCl. The organic phase was dried over Na2S04, filtered and concentrated to give a crude product which was triturated with MeOH to give the methyl amide, nitro phenol- hmpa adduct (1.7 g, 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine; In N,N-dimethyl-formamide; at 0℃; for 2h; | A mixture of BOP (5.16 g 11.7 mmol), <strong>[2840-28-0]3-amino-4-chlorobenzoic acid</strong> (2 g, 11.7 mmol) (Aldrich), triethylamine (2.95 g, 29.1 mmol) and dimethylformamide (20 mL) was stirred at 0 C. for 2 hours then diluted with water (60 mL). The mixture was stirred for 20 minutes, then the solid was collected by filtration washing with water (100 mL). The solid was air dried overnight to give 1H-benzo[d][1,2,3]triazol-1-yl 3-amino-4-chlorobenzoate as an off-white solid. (Yield 2.6 g, 77%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.8% | With triethylamine; In N,N-dimethyl-formamide; at 0℃; for 3h; | A mixture of BOP (2.33 g, 5.28 mmol), 5-amino-4-chloro-2-fluorobenzoic acid (1 g, 5.28 mmol), triethylamine (1.33 g, 13.2 mmol) and dimethylformamide (10 mL) was stirred at 0 C. for 3 hours then diluted with water (60 mL). The mixture was stirred for 20 minutes, then the solid was collected by filtration, washing with water (100 mL). The solid was air dried overnight to give 1H-benzo[d][1,2,3]triazol-1-yl 5-amino-4-chloro-2-fluorobenzoate as an off-white solid. (Yield 1.6 g, 98.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.1 g; 66% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20℃; for 16h; | Tert-butyl (3R)-3-aminopiperidine-1-carboxylate (1.49 g, 7.46 mmol) was added to a stirred solution of 3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile (preparation 3b, 0.70 g, 2.98 mmol), (benzotriazol-1-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (1.71 g, 3.88 mmol) and 1,8-diazabicyclo[5.4.0] undec-7-ene (0.67 mL g, 4.48 mmol) in N,N'-dimethylformamide (15 mL) and the resulting mixture was stirred at room temperature for 16 hours. Then the solvent was removed under reduced pressure and the residue was taken up in a mixture of dichloromethane and 4% aqueous sodium hydrogencarbonate solution. The organic layer was dried (MgS04) and evaporated in vacuo. The crude product was purified by flash chromatography (99:1 dichloromethane/methanol) to give a residue that was repurified by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to give the title compound (0.83 g, 66%) and 3-(4-(1H-benzo[d][1,2,3]triazol-1-yloxy)pyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile (0.10 g) as the main reaction byproduct.LRMS (m/z): 420 (M+1t, 418 (M-1)-.1H-NMR delta (300 MHz, CDCl3): 0.7-0.9 (m, 4H), 1.5 (s, 9H), 1.6-1.7 (m, 2H), 1.7-1.9 (m, 2H), 2.0-2.1 (m, 1H), 5.0 (bs, 1H), 6.3 (d, 1H), 7.0 (dd, 1H), 8.3 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.1 (t, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 2℃; for 24h;Inert atmosphere; | Step 2: Introduction of the O6-Benzotriazolyl Group. In a clean, dry round-bottomed flask equipped with a stifling bar were placed the 2-[(4-phenyl)-1,2,3-triazol-1H-yl]-2',3'-5'-tri-O-(tert-butyldimethylsilyl)inosine derivative 3 (160.0 mg, 0.212 mmol), BOP (187.7 mg, 0.424 mmol), and i-Pr2NEt (45 muL, 0.318 mmol) in dry THF (4.0 mL). The reaction mixture was flushed with nitrogen gas, and stirred at room temperature for 24 h, at which time TLC indicated complete reaction. The mixture was diluted with EtOAc and washed with water containing a small amount of NaCl, the aqueous layer was separated and reextracted with EtOAc. The combined organic layer was dried over Na2SO4 and evaporated to dryness. Chromatographic purification of the crude material on a silica gel column using 20% EtOAc in hexanes provided 101.4 mg (55% yield) of 31 as a white foam. Rf(SiO2/20% EtOAc in hexanes)=0.57. 1H NMR (CDCl3): delta 8.75 (s, 1H, Ar-H), 8.21 (d, 1H, Ar-H, J=8.4 Hz), 7.87 (s, 1H, Ar-H), 7.74 (d, 2H, Ar-H, J=7.3 Hz), 7.59-7.49 (m, 3H, Ar-H), 7.40 (t, 2H, Ar-H, J=7.4 Hz), 7.33 (t, 1H, Ar-H, J=7.4 Hz), 6.21 (d, 1H, H-1', J=3.7 Hz), 4.61 (t, 1H, H-2', J=3.9 Hz), 4.37 (t, 1H, H-3', J=4.6 Hz), 4.22 (app q, 1H, H-4', Japp?3.6 Hz), 4.14 (dd, 1H, H-5', J=3.6, 11.6 Hz), 3.85 (dd, 1H, H-5', J=2.5, 11.6 Hz), 0.98, 0.93, and 0.85 (3s, 27H, t-Bu), 0.19, 0.17, 0.12, 0.09, 0.06, and 0.02 (6s, 18H, SiCH3). 13C NMR (CDCl3): delta159.7, 155.1, 147.9, 147.8, 145.4, 143.6, 129.8, 129.4, 129.2, 129.0, 128.8, 126.1, 125.3, 120.9, 119.4, 118.5, 108.8, 89.7, 85.4, 76.6, 71.2, 62.1, 26.3, 26.0, 25.9, 18.8, 18.3, 18.1, -4.1, -4.6, -5.1, -5.2. FIRMS calculated for C42H63N10O5Si3 [M+H]+: 871.4285, found: 871.4298. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 24h; | General procedure: In a dry vial equipped with a stirring bar was placed BOP (0.486 mg, 1.1 mmol) in anhydrous THF (5 mL). The alcohol (1.36 mmol) was added, followed by the dropwise addition of DBU (1.36 mmol). The reaction mixture was stirred at room temperature for the duration indicated in Table 1. The mixture was diluted with EtOAc, washed with brine, and then with water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated under reduced pressure. Products were purified by chromatography on a silica gel column using a gradient of EtOAc in hexanes. The products from these reactions were identical to those produced from the reactions ofBt-OTs for which full characterization is provided. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 24h; | General procedure: In a dry vial equipped with a stirring bar was placed BOP (0.486 mg, 1.1 mmol) in anhydrous THF (5 mL). The alcohol (1.36 mmol) was added, followed by the dropwise addition of DBU (1.36 mmol). The reaction mixture was stirred at room temperature for the duration indicated in Table 1. The mixture was diluted with EtOAc, washed with brine, and then with water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated under reduced pressure. Products were purified by chromatography on a silica gel column using a gradient of EtOAc in hexanes. The products from these reactions were identical to those produced from the reactions ofBt-OTs for which full characterization is provided. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 48h; | General procedure: In a dry vial equipped with a stirring bar was placed BOP (0.486 mg, 1.1 mmol) in anhydrous THF (5 mL). The alcohol (1.36 mmol) was added, followed by the dropwise addition of DBU (1.36 mmol). The reaction mixture was stirred at room temperature for the duration indicated in Table 1. The mixture was diluted with EtOAc, washed with brine, and then with water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated under reduced pressure. Products were purified by chromatography on a silica gel column using a gradient of EtOAc in hexanes. The products from these reactions were identical to those produced from the reactions ofBt-OTs for which full characterization is provided. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 48h; | General procedure: In a dry vial equipped with a stirring bar was placed BOP (0.486 mg, 1.1 mmol) in anhydrous THF (5 mL). The alcohol (1.36 mmol) was added, followed by the dropwise addition of DBU (1.36 mmol). The reaction mixture was stirred at room temperature for the duration indicated in Table 1. The mixture was diluted with EtOAc, washed with brine, and then with water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated under reduced pressure. Products were purified by chromatography on a silica gel column using a gradient of EtOAc in hexanes. The products from these reactions were identical to those produced from the reactions ofBt-OTs for which full characterization is provided. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 72h; | General procedure: In a dry vial equipped with a stirring bar was placed BOP (0.486 mg, 1.1 mmol) in anhydrous THF (5 mL). The alcohol (1.36 mmol) was added, followed by the dropwise addition of DBU (1.36 mmol). The reaction mixture was stirred at room temperature for the duration indicated in Table 1. The mixture was diluted with EtOAc, washed with brine, and then with water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated under reduced pressure. Products were purified by chromatography on a silica gel column using a gradient of EtOAc in hexanes. The products from these reactions were identical to those produced from the reactions ofBt-OTs for which full characterization is provided. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 48h; | General procedure: In a dry vial equipped with a stirring bar was placed BOP (0.486 mg, 1.1 mmol) in anhydrous THF (5 mL). The alcohol (1.36 mmol) was added, followed by the dropwise addition of DBU (1.36 mmol). The reaction mixture was stirred at room temperature for the duration indicated in Table 1. The mixture was diluted with EtOAc, washed with brine, and then with water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated under reduced pressure. Products were purified by chromatography on a silica gel column using a gradient of EtOAc in hexanes. The products from these reactions were identical to those produced from the reactions ofBt-OTs for which full characterization is provided. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 48h; | General procedure: In a dry vial equipped with a stirring bar was placed BOP (0.486 mg, 1.1 mmol) in anhydrous THF (5 mL). The alcohol (1.36 mmol) was added, followed by the dropwise addition of DBU (1.36 mmol). The reaction mixture was stirred at room temperature for the duration indicated in Table 1. The mixture was diluted with EtOAc, washed with brine, and then with water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated under reduced pressure. Products were purified by chromatography on a silica gel column using a gradient of EtOAc in hexanes. The products from these reactions were identical to those produced from the reactions ofBt-OTs for which full characterization is provided. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 48h;Inert atmosphere; | General procedure: The corresponding 2-amino-6-aryl-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-diones (13{x}) (0.50mmol) [14] was suspended in 13mL of anhydrous acetonitrile. Then, BOP (0.75mmol) and DBU (1.25mmol) were added into the solution. The system was stirred at room temperature for 2 days under nitrogen atmosphere. After this period, 200mL of water were added and the resulting precipitate was filtered, washed with water and dried in vacuo over phosphorus pentoxide to afford the corresponding 14{x} that can be used without further purification. 4.1.2.1 4-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-2-amino-6-(4-fluorophenyl)-3,4,5,6-tetrahydropyrido[2,3-d]pyrimidine-7(8H)-one (14{2}) Starting from compound 13{2} to afford 14{2} in 74% yield, white solid. IR (KBr), numax (cm-1): 3425, 3337, 3223, 1637, 1575, 1510, 1356, 1237, 1160, 1088, 847, 738. 1H NMR (400 MHz, DMSO-d6): delta 10.95 (s, 1H), 8.13 (dt, J = 8.4, 0.9 Hz, 1H), 7.70-7.61 (m, 2H), 7.51 (ddd, J = 8.1, 6.4, 1.6 Hz), 7.39 (dd, J = 8.7, 5.6 Hz, 2H), 7.21 (t, J = 8.9 Hz, 1H), 6.59 (s, 2H, NH2), 4.11 (dd, J = 10.7, 6.9 Hz, 1H), 3.29-3.12 (m, 2H). 13C NMR (100.6 MHz, DMSO-d6): delta 172.4, 166.0, 161.8, 161.0, 143.2, 135.4, 130.8 (d, J = 7.9 Hz, C12), 129.5 (C17), 128.9, 125.6 (C18), 120.3 (C19), 115.6 (d, J = 21.1 Hz, C13), 110.0, 109.8 (C16), 86.0 (C5), 45.4 (C7), 24.5 (C6). |
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 48h;Inert atmosphere; | General procedure: The starting material of pyrido[2,3-d]pyrimidine (V) (0.50 mmol) (synthesized as described in M. Camarasa et al., Mol. Diver. 2013, 17, 525-536) was suspended in 13 mL of anhydrous ACN. Then, BOP (0.75 mmol) and DBU (1.25 mmol) were added into the solution. The system was stirred at room temperature for 2 days under nitrogen atmosphere. After this period, 200 mL of water was added and the resulting precipitate was filtered, washed with water and dried in vacuo over phosphorus pentoxide to afford the corresponding 4-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-6-aryl- 3,4,5,6-tetrahydropyrido[2,3-d]pyrimidine-7(8H)-one (VI) as a brownish solid. 1H N M R (400 MHz, DMSO-G(6): delta 10.95 (s, 1H), 8.13 (dt, J = 8.4, 0.9 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.51 (ddd, J = 8.1, 6.4, 1.6 Hz), 7.39 (dd, J = 8.7, 5.6 Hz, 2H), 7.21 (t, J = 8.9 Hz, 1H), 6.59 (s, 2H, N H2), 4.11 (dd, J = 10.7, 6.9 Hz, 1H), 3.29 - 3.12 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 48h;Inert atmosphere; | General procedure: The corresponding 2-amino-6-aryl-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-diones (13{x}) (0.50mmol) [14] was suspended in 13mL of anhydrous acetonitrile. Then, BOP (0.75mmol) and DBU (1.25mmol) were added into the solution. The system was stirred at room temperature for 2 days under nitrogen atmosphere. After this period, 200mL of water were added and the resulting precipitate was filtered, washed with water and dried in vacuo over phosphorus pentoxide to afford the corresponding 14{x} that can be used without further purification. 4.1.13 4-((1H-benzo[d] [1,2,3]triazol-1-yl)oxy)-6-(4-fluorophenyl)-2-(phenylamino)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (22{2,10}) Starting from compound 21{2,10} and using procedure described in 4.1.2. to afford 22{2,10} in 88% yield, white solid. 1H NMR (400 MHz, DMSO-d6): delta 11.19 (s, 1H, NH), 9.46 (s, 1H, NH), 8.23 (d, J = 8.5 Hz, 1H), 7.76 (dt, J = 8.4, 0.9 Hz, 1H), 7.69-7.64 (m, 1H), 7.56 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.43 (dd, J = 8.7, 5.5 Hz, 2H, C12-CHx2), 7.23 (t, J = 8.9 Hz, 2H, C13-CHx2), 6.95-6.90 (m, 2H), 6.85-6.79 (m, 2H), 6.75-6.77 (m, 1H, C18-CH), 4.19 (dd, J = 11.0, 7.0 Hz, 1H, C7-CH), 3.41-3.29 (m, 2H, C6-CH2). HRMS (70 eV, EI): m/z calculated for C25H18N7O2F: 467.1506, [M]+, found: 467.1508. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 48h;Inert atmosphere; | General procedure: The corresponding 2-amino-6-aryl-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-diones (13{x}) (0.50mmol) [14] was suspended in 13mL of anhydrous acetonitrile. Then, BOP (0.75mmol) and DBU (1.25mmol) were added into the solution. The system was stirred at room temperature for 2 days under nitrogen atmosphere. After this period, 200mL of water were added and the resulting precipitate was filtered, washed with water and dried in vacuo over phosphorus pentoxide to afford the corresponding 14{x} that can be used without further purification. 4.1.14 4-((1H-benzo[d] [1,2,3]triazol-1-yl)oxy)-6-(4-fluorophenyl)-2-phenoxy-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (22{2,14}) Starting from compound 21{2,14} and using procedure described in 4.1.2. to afford 22{2,14} in 72% yield, white solid. IR (KBr), numax (cm-1): 3061, 2977, 2863, 1714, 1635, 1581, 1512, 1412, 1364, 1219, 1099, 746. 1H NMR (400 MHz, DMSO-d6): delta 11.50 (s, 1H, NH), 8.07 (dt, J = 8.4, 0.9 Hz, 1H, C22), 7.70-7.60 (m, 2H, C19-CH, C20-CH), 7.53-7.49 (m, 1H, C21-CH), 7.41 (dd, J = 8.7, 5.5 Hz, 2H, C12-CHx2), 7.22 (t, J = 8.9 Hz, 2H, C13-CHx2), 7.11-7.00 (m, 3H, C18-CH, C17-CHx2), 6.84-6.78 (m, 2H, C16-CHx2), 4.20 (dd, J = 11.5, 7.1 Hz, 1H, C7-CH), 3.44-3.34 (m, 2H, C6-CH2). 13C NMR (100.6 MHz, DMSO-d6): delta 171.5, 165.9, 162.2, 162.1, 161.4 (d, J = 243.5 Hz, C14), 151.6, 142.5, 134.3 (d, J = 3.1 Hz, C11), 130.5 (d, J = 8.2 Hz, C12), 129.1 (C20), 129.1 (C17), 128.3, 125.1 (C21), 125.0 (C18), 120.8 (C16), 119.9 (C22), 115.2 (d, J = 21.3 Hz, C13), 109.2 (C19), 92.9 (C5), 44.3 (C7), 24.0 (C6). HRMS (70 eV, EI): m/z calculated for C25H17N6O3F: 468.1346, [M]+, found: 468.1337. Anal. Calcd. (%) for C25H17FN6O3: C, 64.10; H, 3.66; N, 17.94. Found: C, 64.06; H, 3.62; N, 18.04. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 48h;Inert atmosphere; | General procedure: The corresponding 2-amino-6-aryl-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-diones (13{x}) (0.50mmol) [14] was suspended in 13mL of anhydrous acetonitrile. Then, BOP (0.75mmol) and DBU (1.25mmol) were added into the solution. The system was stirred at room temperature for 2 days under nitrogen atmosphere. After this period, 200mL of water were added and the resulting precipitate was filtered, washed with water and dried in vacuo over phosphorus pentoxide to afford the corresponding 14{x} that can be used without further purification. 4.1.2.2 4-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-2-amino-6-(2,6-difluorophenyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (14{4}) Starting from compound 13{4} to afford 14{4} in 93% yield, white solid. IR (KBr), numax (cm-1): 3374, 3207, 2895, 1698, 1651, 1571, 1470, 1371, 1273, 1247, 1008, 785. 1H NMR (400 MHz, DMSO-d6): delta 11.03 (s, 1H, NH), 8.13 (dt, J = 8.4, 0.9 Hz, 1H, C15-CH), 7.80 (dt, J = 8.3, 0.9 Hz, 1H, C18-CH), 7.64 (ddd, J = 8.3, 6.9, 0.9 Hz, 1H, C16-CH), 7.51 (ddd, J = 8.4, 6.9, 1.0 Hz, 1H, C17-CH), 7.49-7.42 (m, 1H, C14-CH), 7.16 (t, J = 8.7 Hz, 2H, C13-CHx2), 6.63 (s, 2H, NH2), 4.51 (dd, J = 13.9, 7.5 Hz, 1H, C7-CH), 3.31-3.25 (m, 1H, C6-CH), 3.10-3.03 (m, 1H, C6-CH). 13C NMR (100.6 MHz, DMSO-d6): delta 170.0, 165.5, 161.4, 160.9 (d, J = 247.2 Hz, C12), 160.8 (d, J = 246.8 Hz, C12), 160.4, 142.7, 129.9 (t, J = 10.6 Hz, C14), 128.9 (C16), 128.5, 125.1 (C17), 119.8 (C15), 114.7 (t, J = 18.5 Hz, C11), 111.8 (dd, J = 22.3, 2.5 Hz, C13), 109.6 (C18), 85.1 (C5), 36.1 (C7), 22.4 (C6). Anal. Calcd. (%) for C19H13F2N7O2: C, 55.75; H, 3.20; N, 23.95. Found: C, 56.06; H, 3.22; N, 23.78. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
600 mg | 6-Amino-7-methoxy-4-hydroxyquinazoline (0.5 g, 2.62 mmol) was added to DMF (5 mL).Then add BOP (1.51g, 3.41mmol)And DBU (0.50ml, 3.33mmol),Heating to 40 to 50 C, after 2 hours of reaction,3-Alkynylphenylamine hydrochloride (0.16 g, 2.54 mmol) was added, and after 18 hours of reaction,20 ml of water was added to precipitate a solid.After filtration, the resulting filter cake was added to a buffer solution of NaHCO3/Na2CO3 to adjust the pH to 8-9.After filtration, the filter cake was dried under reduced pressure at 50 C for two hours to obtain 600 mg of the target product.The 1H NMR was tested to be consistent with the final product of Example 1. |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
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 |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :