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. : | 486-73-7 | MDL No. : | MFCD00006901 |
Formula : | C10H7NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XAAKCCMYRKZRAK-UHFFFAOYSA-N |
M.W : | 173.17 | Pubchem ID : | 68092 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 48.7 |
TPSA : | 50.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.86 cm/s |
Log Po/w (iLOGP) : | 1.21 |
Log Po/w (XLOGP3) : | 2.11 |
Log Po/w (WLOGP) : | 1.93 |
Log Po/w (MLOGP) : | -0.03 |
Log Po/w (SILICOS-IT) : | 1.82 |
Consensus Log Po/w : | 1.41 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.85 |
Log S (ESOL) : | -2.75 |
Solubility : | 0.311 mg/ml ; 0.00179 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.79 |
Solubility : | 0.278 mg/ml ; 0.0016 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.07 |
Solubility : | 0.147 mg/ml ; 0.000851 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.21 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 0 - 65℃; for 24 h; | To a solution of isoquinoline-1-carboxylic acid (10 g, 57.74 mmol) in MeOH (150 mL) was added concentrated sulfuric acid (15 mL) at 0° C. The mixture was warmed to 65° C. and stirred at 65° C. for 24 hours. After cooling to RT, the reaction mixture was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was separated and dried over Na2SO4, and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (11.2 g, 100percent). ESI-MS m/z [M+H]+ 188. |
49% | for 16 h; Inert atmosphere; Reflux | To a suspension of 1-isoquinoline carboxylic acid (3.00 g, 17.3 mmol) in MeOH (30 mL) was added SOCl2 (6.18 g, 3.79 mL, 52.0 mmol) via pipet. The resulting pale yellow solution was refluxed under a stream of nitrogen for 16 h. The solvent was then removed under vacuum affording pale yellow solids. The residue was dissolved into H2O (20 mL), neutralized with excess Na2CO3, and extracted with CH2Cl2 (4 * 20 mL). The organic extracts were combined, dried over Na2SO4, filtered, and the solvent removed by vacuum leaving behind a yellow oil. The oil was distilled under reduced pressure affording methyl 1-quinolinecarboxylate as a colorless oil (1.59 g, 49percent, bp = 144-145 °C, 700 mTorr).;1H NMR (CDCl3): 8.84 ppm (1H, d, J = 8.8 Hz); 8.63 ppm (1H, d, 5.6 Hz); 7.883 ppm (1H, d, J = 8.0 Hz); 7.83 ppm (1H, d, J = 5.6 Hz); 7.71 ppm (2H, m); 4.10 ppm (3H, s). 13C NMR (CDCl3): 166.35, 148.24, 141.65, 137.01, 130.65, 128.89, 127.20, 126.97, 126.46, 124.40, 53.06 ppm. IR (liquid film): 3055, 2951, 2849, 1720 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With platinum(IV) oxide; hydrogen; In acetic acid; under 5250.53 Torr; for 18h; | A 300 mL steel bomb was charged with isoquinoline-1-carboxylic acid (3 g, 17.32 mmol), acetic acid (100 mL) and platinum(IV) oxide (0.2 g, 0.88 mmol). The resulting mixture was hydrogenated at 7 Bar pressure for 18 hours with mechanical stirring. It was diluted with MeOH (80 mL), filtered through celite and rinsed with MeOH and acetic acid. The filtrate was concentrated to dryness go give a light grey solid. Trituration with MeOH gave 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (2.63 g, 86%) as a light grey solid that was used without any further purification. |
63% | In acetic acid; | PREPARATION 1 D-1,2,3,4-Tetrahydroisoquinolin-1-oyl-L-Prolyl-L-Arginine aldehyde Sulfate To a solution of isoquinoline-1-carboxylic acid (12.5, 0.072 mole) in 185 ml of glacial acetic acid was added 2 g of platinum oxide and the suspension was hydrogenated at room temperature under 60 psi hydrogen pressure in a Parr hydrogenation apparatus for 24 h. The reaction mixture was filtered though a filter pad (Celite) to remove the catalyst and the filtrate was evaporated to dryness in vacuo. The solid residue was triturated with water, filtered and dried to yield 8 g (63% yield) of DL-1,2,3,4-tetrahydroisoquinolin-1-carboxylic acid. FD-Mass spectrum 178 (MH+); 1 H NMR (DMSO-d6): delta 2.80-3.00 (m, 3H), 3.15 (m, 1H), 3.30-3.40 (m, 2H), 7.05-7.25 (m, 4H), 7.70 (m, 1H). |
63% | In acetic acid; | 1) DL-1,2,3,4-tetrahydroisoquinolin-1-carboxylic acid A solution of isoquinoline-1-carboxylic acid (12.5 g, 0.072 mole) in 185 ml of glacial acetic acid was hydrogenated at room temperature for 24 hours over 2 g of platinum oxide catalyst under 60 psi hydrogen pressure in a Parr hydrogenation apparatus. The reaction mixture was filteed through a filter pad (celite) and the filtrate evaporated to dryness in vacuo. The solid residue of product was triturated with water, filtered and dried to give 8 g (63% yield) of pure 1. FD-MS 178 (MH+) 1 H-NMR(DMSO) delta 2.80-3.00 (m, 3H), 3.10-3.20 (m, 1H), 3.30-3.40 (m, 2H), 7.05-7.25 (m, 4H), 7.65-7.75 (m, 1H). |
63% | In acetic acid; | 1) DL-1,2,3,4-tetrahydroisoquinolin-1-carboxylic acid. A solution of isoquinoline-1-carboxylic acid (12.5 g, 0.072 mole) in 185 ml of glacial acetic acid was hydrogenated at room temperature for 24 hours over 2 g of platinum oxide catalyst under 60 psi hydrogen pressure in a Parr hydrogenation apparatus. The reaction mixture was filteed through a filter pad (celite) and the filtrate evaporated to dryness in vacuo. The solid residue of product was triturated with water, filtered and dried to give 8 g (63% yield) of pure 1. FD-MS 178 (MH+) 1 H-NMR(DMSO) delta 2.80-3.00 (m, 3H), 3.10-3.20 (m, 1H), 3.30-3.40 (m, 2H), 7.05-7.25 (m, 4H), 7.65-7.75 (m, 1H). |
63% | In acetic acid; | EXAMPLE 24 D-1,2,3,4-Tetrahydroisoquinolin-1-carbonyl-L-Prolyl-L-Arginine Aldehyde Sulfate To a solution of isoquinoline-1-carboxylic acid (12.5, 0.072 mole) in 185 ml of glacial acetic acid was added 2 g of platinum oxide and the suspension was hydrogenated at room temperature under 60 psi hydrogen pressure in a Parr hydrogenation apparatus for 24 h. The reaction mixture was filtered though a filter pad (Celite) to remove the catalyst and the filtrate was evaporated to dryness in vacuo. The solid residue was triturated with water, filtered and dried to yield 8 g (63% yield) of DL-1,2,3,4-tetrahydroisoquinolin-1-carboxylic acid. FD-Mass spectrum 178 (MH+); 1 H NMR (DMSO-d6): delta 2.80-3.00 (m, 3H), 3.15 (m, 1H), 3.30-3.40 (m, 2H), 7.05-7.25 (m, 4H), 7.70 (m, 1H). |
PtO2; In acetic acid; | A. 1,2,3,4-Tetrahydro-<strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> A solution of <strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> (1.67 g) in glacial acetic acid (25 mL) was hydrogenated at 60 p.s.i. over PtO2 (270 mg). When the reaction was complete, the mixture was filtered through Celite, washing the solid pad with MeOH, and the filtrate was concentrated to dryness. The resultant white solid was triturated with cold water and filtered to provide the title compound (775 mg). | |
PtO2; In acetic acid; | A. 1,2,3,4-Tetrahydro-<strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> A solution of <strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> (1.67 g) in glacial acetic acid (25 ml,) was hydrogenated at 60 p.s.i. over PtO2 (270 mg). When the reaction was complete, the mixture was filtered through diatomaceous earth (Celite), washing the solid pad with MeOH, and the filtrate was concentrated to dryness. The resultant white solid was triturated with cold water and filtered to provide the title compound (775 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The compounds 1-12 were synthesized usingthe mixed anhydrides method of peptide synthesis(8). Suitable acid (10 mmol) was dissolved in DMF(15 mL) and THF (15 mL) was added. Next, Nmethylmorpholine(10 mmol, 1.1 mL) was addedand the mixture was stirred under nitrogen andchilled to -15OC. Isobutyl chloroformate (10 mmol,1.3 mL) was added dropwise to keep the temperaturebelow -15O. Then, benzylamine (10 mmol) inTHF was added in small portions and the reactionmixture was stirred at -15OC for 30 min and at roomtemperature for 1 h. The solution was concentratedin vacuo and the residue was dissolved in EtOAc (20mL). This solution was washed with 20 mL portionsof 1 M HCl, saturated NaHCO3 solution and saturatedNaCl solution, then dried with anhydrousMgSO4, filtered and concentrated in vacuo. Theobtained compounds were purified by crystallization.All stages of synthesis were controlled by TLC.The purity of the final compound was determined byHPLC and identity by 1H NMR. The compoundsobtained and tested are showed in Figure 1. | ||
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; at 20℃; for 16h; | General procedure: To a stirring solution of corresponding picolinic or nicotinic acids (1.0 eq.), EDCI (1.5 eq.) and HOBt (1.0 eq.)in CH2Cl2 at room temperature was added Et3N (2 eq.) dropwise, followed by the amine. The resultedmixture was stirred for 16 h and afterwards diluted by excess amount of CH2Cl2. The organic solution waswashed by water and dried over Na2SO4. A yellow residue was obtained after concentration and purified byflash column on silica gel to afford compound S2. To a solution of S2 (1.0 eq.) in THF at 78 was addedn-BuLi (1.1 eq.) or LDA (1.1 eq.) dropwise. The resulted mixture was stirred at this temperature for 15 min.A solution of corresponding acryloyl chloride (1.3 eq. while using n-BuLi and 2.5 eq. while using LDA) wasadded dropwise at 78. The reaction was warmed to room temperature gradually and stirred for another5 h . Afterwards, the reaction mixture was diluted with EtOAc and the organic solution was washed bywater and dried over Na2SO4. A brown residue was obtained after concentration and purified by flashcolumn on silica gel to afford the compound 4. Analytical data of 4q and 4r are consistent with the previousreports |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sulfuric acid; at 0 - 65℃; for 24h; | To a solution of isoquinoline-1-carboxylic acid (10 g, 57.74 mmol) in MeOH (150 mL) was added concentrated sulfuric acid (15 mL) at 0 C. The mixture was warmed to 65 C. and stirred at 65 C. for 24 hours. After cooling to RT, the reaction mixture was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was separated and dried over Na2SO4, and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (11.2 g, 100%). ESI-MS m/z [M+H]+ 188. |
49% | With thionyl chloride; for 16h;Inert atmosphere; Reflux; | To a suspension of 1-isoquinoline carboxylic acid (3.00 g, 17.3 mmol) in MeOH (30 mL) was added SOCl2 (6.18 g, 3.79 mL, 52.0 mmol) via pipet. The resulting pale yellow solution was refluxed under a stream of nitrogen for 16 h. The solvent was then removed under vacuum affording pale yellow solids. The residue was dissolved into H2O (20 mL), neutralized with excess Na2CO3, and extracted with CH2Cl2 (4 * 20 mL). The organic extracts were combined, dried over Na2SO4, filtered, and the solvent removed by vacuum leaving behind a yellow oil. The oil was distilled under reduced pressure affording methyl 1-quinolinecarboxylate as a colorless oil (1.59 g, 49%, bp = 144-145 C, 700 mTorr).;1H NMR (CDCl3): 8.84 ppm (1H, d, J = 8.8 Hz); 8.63 ppm (1H, d, 5.6 Hz); 7.883 ppm (1H, d, J = 8.0 Hz); 7.83 ppm (1H, d, J = 5.6 Hz); 7.71 ppm (2H, m); 4.10 ppm (3H, s). 13C NMR (CDCl3): 166.35, 148.24, 141.65, 137.01, 130.65, 128.89, 127.20, 126.97, 126.46, 124.40, 53.06 ppm. IR (liquid film): 3055, 2951, 2849, 1720 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 18h; | 6-Amino-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid methyl ester, 8, 1.69 grams (7.1 mmol) and 1-isoquinolinic acid (2.46 g, 14.2 mmol) are dissolved in 75 ml of dichloromethane. To this solution is added dimethylaminopyridine (0.87 g, 7.1 mmol) and dicyclohexylcarbodiimide (2.93 g,14.2 mmol). The reaction is stirred overnight, during which time a precipitate forms which is removed by filtration and washed with dichloromethane. The filtrate is concentrated and the residue is taken up in ether. (Any additional precipitates which form are also removed by filtration.) The residue is purified over silica (50% ethyl acetate:hexane), to afford 1.62 g (58% yield) of the desired product as a oil. 1H NMR (CDCl3): delta9.55 (m, 1H), 9.18 (d, J=7.3 Hz, 1H), 8.50 (d, J=5.5 Hz, 1H), 7.88-7.65 (m, 4H), 5.99-5.81 (m, 2H), 5.38 (m, 1H), 4.59 (dd, J=8.7,3.2 Hz, 1H), 4.26 (m, 1H), 3.76 (s, 3H), 3.03-2.86 (m, 2H), 2.60-2.50 (m, 2H), 2.23-1.98 (m, 4H). 13C NMR (CDCl3): delta172.7, 170.9, 165.7, 148.1, 140.8, 137.6, 130.6, 129.6, 128.7, 127.7, 127.2, 127.1, 126.4, 124.5, 60.5, 59.1, 52.3, 51.3, 35.1, 33.4, 27.5. ESI MS 394.14 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 91 percent / H2SO4 / 17 h / Heating 2: 85 percent / NaBH4; LiCl / tetrahydrofuran; ethanol / 17 h / 20 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / methanol / 16 h / 60 °C 2: sodium tetrahydroborate / methanol / 5 h / 20 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 5 h / 65 °C 2: sodium tetrahydroborate; ethanol; lithium chloride / tetrahydrofuran / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; | To the solution of [1-ISOQUINOLONECARBOXYLIC] acid (1.73 g, 10 mmol, Aldrich) in anhydrous N, [N-DIMETHYLFORMAMIDE] (30 mL) were added N, N- diisopropylethylaime (5.29 g, 40 mmol, Aldrich), [0-(7-AZABENZOTRIAZOL-1-YL)-] 1,1, 3,3-tetramethyluronium hexafluorophosphate (7.6 g, 20 mmol, PerSeptive Biosystems GmbH), [N,] O-dimethylhydroxylamine hydrochloride (1. [8] g, 20 mmol, Aldrich) subsequently at room temperature. The reaction solution was allowed to stir for overnight at room temperature. The N, N-Dimethylformamide was removed via vacuo and the resulting residue was diluted in ethyl acetate (50 mL). After being was washed by saturate aqueous sodium bicarbonate (50 [ML)] and brine (50 mL), the organic portion was dried over anhydrous magnesium sulfate and concentrated. The title compound was purified by column chromatography (silica gel, ethyl acetate) in form as yellow syrup in 94% yield (2.04 g, 9.4 mmol). [CL2HL2N202] MS (ESI, pos. ion) m/z: 217.1 [(M+1)] ; MS (ESI, neg. ion) m/z: 215.0 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); dichloromethane; at 20℃; for 18h; | To a solution of Benzyl 2-[(3S)-3-amino-4-oxo-2,3,4,5-tetrahydro-5H-1,5-benzoxazepin-5-yl]-ethanoate hydrochloride 1 (1.277 g, 3.52 mmol) and isoquinoline-1-carboxylic acid (670 mg, 3.87 mmol) in 10 ml each of dimethylformamide (DMF) and dichloromethane (CH2Cl2) was added N-hydroxybenzotriazole, (523 mg, 3.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (880 mg, 4.58 mmol) and triethylamine (Et3N) (1.2 ml, 8.8 mmol). The reaction was stirred at room temp. for 18 hrs. then diluted with ethyl acetate and washed with 10% NaHSO4, sat. NaHCO3, H2O, and sat. NaCl. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to afford a gum that was purified by flash column chromatography eluting with 7/3 (CH2Cl2/EtOAc) to afford 1.56 g (79%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); dichloromethane; at 20℃; for 12h; | (3-amino-2-oxo-2,3, 4, [7-TETRAHYDROAZEPIN-1-YL)] acetic acid methyl ester, 3, (0.365 g, 1.68 [MMOL)] is dissolved in 1: 1 [CH2CI2/DMF] and 1- isoquinoline-carboxylic acid (1.4 g, 8.1 [MMOL),] 1-hydroxybenzotriazole (0.35 g, 2.6 [MMOL),] and [1- (3-DIMETHYL-AMINOPROPYL)-3-ETHYL-CARBODIIMIDE HYDROCHLORIDE] (0.5 g, 2.6 [MMOL)] are added. The resulting solution is stirred at room temperature for 12 hours, diluted with EtOAc, washed with saturated NaHCO3 then brine, and dried [(MGS04).] The solvent is removed in vacuo and the resulting residue is purified over silica gel (EtOAc/hexane) to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); dichloromethane; at 20℃; for 1h; | The crude (3-amino-6-methyl-2-oxo- 2,3, 4, 7-tetrahydroazepin-1-yl}-acetic acid ethyl ester, 10, obtained in the previous step is dissolved in 6 mL of 1: 1 DMF: [CH2CI2AND] treated with <strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> (0.24 g, 1.2 [MMOL),] 1-hydroxybenzotriazole [(0.] 23 g, 1.5 [MMOL),] and [1- (3-DIMETHYL-AMINOPROPYL)-3-] ethyl-carbodiimide hydrochloride (0.32 g, 1.5 [MMOL).] The solution is stirred for 1 hour at room temperature, diluted with EtOAc, washed with saturated [NAHCO3,] saturated NaCI, and dried [(NA2SO4).] The solvent is removed in vacuo and the crude isolate is purified by HPLC to afford 70 mg (30% yield) of the desired [PRODUCT. 1H] NMR [(CDCL3) No. ] 9.51-9. 48 (d, J=8.1 Hz, 1H), 9.22-9. 20 (d, J=6.9 Hz, [1H),] 8.51-8. 49 (d, J=5.4 Hz, [1H),] 7.84-7. 77 (m, 2H), 7.72- 7.63 (m, 2H), 5.57 (bs, 1H), 5.48-5. 40 (m, [1H),] 4.775-4. 715 (d, [J=18] Hz, 1H), 4.24-4. 19 (q, d, [J=15.] 3,7. 5 Hz, [3H),] 3.27-3. 21 (d, [J=18] Hz, [1H),] 2.86-2. 81 (d, [J=16.] 5 Hz, 1H), 2.45-2. 36 (d, d, J=15,12. 6 Hz, 1H), 1.79 (s, 3H), 1.30-1. 25 (t, J=7.5 Hz, 3H) [; 13C (CDCI3)] 172.8, 169.2, 165.6, 148.2, 140.8, 137.5, 131.8, 130.5, 128.7, 127.7, 127.0, 124.5, 123.4, 61.6, 52.3, 50.8, 49.6, 32.6, 25.0, 14.3 ; MS 382 [(M+H) +.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 3h; | The crude residue obtained from the procedure herein above is combined with <strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> (2.6 g, 15.0 mmol), HOBt (2.68 g, 19.8 [MMOL),] and EDCI (3.8 g, 19.8 [MMOL)] in DMF (20 mL). The solution is stirred for 3 hours at room temperature then diluted with EtOAc, washed with saturated [NAHCO3,] saturated NaCI, and dried (Na2SO4). The solvent is removed in vacuo and the residue obtained purified by HPLC to afford 1.7 g (40% yield) of the desired product NMR [(CDCI3)] 8 9.49-9. 46 (d, J=7.8 Hz, [1H),] 9.20-9. 18 (d, J=6.9 Hz, 1H), 8.52-8. 50 (d, J=5.5 Hz, [1H),] 7.86-7. 78 (m, 2H), 7.72-7. 63 (m, 2H), 5.79 (bs, [1H),] 5.55-5. 47 (m, [1H),] 4.76-4. 69 (d, d, [J=17.] 3,2. 3 Hz, [1H),] 4.45-4. 40 (d, [J=17.] 4 Hz, 1H), 4.25-4. 19 (d, [J=17.] 4 Hz, [1H),] 4.15-3. 98 (m, 3H), 3.73 (s, 3H), 3.65-3. 59 (d, [J=17.] 4 Hz, [1H),] 2.97-2. 90 (d, d, [J=18.] 2,3. 9 Hz, 1H), 2.48-2. 29 (m, 3H) [;'3C (CDCI3) S] 172.7, 170.5, 165.9, 148.2, 141.0, 137.7, 136.3, 130.7, 128.9, [127¢7,] 127.2, 126.4, 124.7, 67.5, 60.8, 52.8, 50.3, 49.3, [48.] 1,32. 5,21. 4,14. 5; MS 384 (M+H) [+.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); dichloromethane; at 20℃; for 12h; | 6- [AMINO-5-OXO-1,] 3,4, 5,6, 7,7, 10, [10A-OCTAHYDRO-2-OXA- [4A]-AZABENZOCYCLOOCTENE-4-CARBOXYLIC] acid methyl ester, 29, (0.62 g, 1.68 [MMOL)] is dissolved in 1: 1 [CH2CI2/DMF] and 1- [ISOQUINOLINECARBOXYLIC] acid (1.4 g, 8.1 [MMOL),] 1-hydroxybenzotriazole (0.35 g, 2.6 [MMOL),] and 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (0.5 g, 2.6 [MMOL)] are added. The resulting solution is stirred at room temperature for 12 hours, diluted with EtOAc, washed with saturated [NAHCO3] then brine, and dried [(MGS04).] The solvent is removed in vacuo and the resulting residue is purified over silica gel (EtOAc/hexane) to afford 370 mg (54%) of the desired product NMR [(CDC13)] [8] 9.48 (d, J = 7.8 Hz, [1 H),] 9.40 (d, [J = 6. 9 HZ, 1H),] 8.45 (d, J = 54 Hz, 1H), 7.74 (m, 2H), 7.64 (m, 2H), 5.68 (br s, 2H), 5.37 (m, 1 H), 4.85 (d, [J =] 4.5 Hz, 1 H), 4.43 (m, 2H), 3.78-3. 58 (m, 3H), 3.71 (s, 3H), 3.12 (m, [1 H),] 2.84 (m, [1 H),] 2.60 (m, 1 H), 2.30 (d, J = 16.5 Hz, [1 H)] ; MS 410 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
t-butyl-9-(isoquinolin-1-oylamino)-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6-H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate To a solution of the amine I' (79 g, 0.265 mol) and isoquinolin-1-carboxylic acid (56 g, 0.32 mol) in dichloromethane:DMF (400 mL:400 mL) was added hydroxybenzotriazole (54 g, 0.4 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (74 g, 0.39 mol) and the resulting mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with 0.5N sodium bisulfate, water, sodium bicarbonate, brine, dried over sodium sulfate and concentrated in vacuo to afford 122 g of compound J' as an orange solid-foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; at 0 - 20℃; | To a stirred suspension of 1-isoquinoline carboxylic acid (10 g, 57.7 mmol) in dry dichloromethane (120 ml) at 0 C was added 2-methyl-propan-2-ol (12.1 ml, 128 mmol), 4-dimethylaminopyridine (3.53 g, 28.9 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (12.2 g, 63.5 mmol). The mixture was allowed to attain roomtemperature and stirred overnight. Water (100 ml) was added, the mixture filtered and the layers separated. The aqueous layer was extracted with dichloromethane (30 ml), the organic fractions combined, dried (MgSO4) and evaporated to give an oil. Purification by SPE (silica) eluting with cyclohexane, then cyclohexane/ethyl acetate (3:1 v/v) gave the title compound. MS calcd for (C14H15NO2+H)+:230. MS found (electrospray) (M+H)+ 230. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h; | To a solution OF 4- [ (4-BROMOPHENYL) (ethoxyimino) methyl]-1- (4-methyl-4-piperidinyl) piperidine (50 mg, 0.12 MMOL,), <strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> (25 mg, 0. 14 MMOL), and Et3N (44 mg, 0.43 MMOL) in DMF (3mL, anhydrous) was added HATU (60mg, 0. 16MMOL) at room temperature. After 16 h the reaction mixture was poured into ice water. The solid was collected by filtration and re- dissolved in CH2CI2. The organic phase was dried over NA2SO4, and concentrated in vacuo. The residue was purified by preparative TLC (CH2CI2-MEOH, 9: 1) to afford the title compound as a white solid. MS: 564 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-carbonyldiimidazole; In dichloromethane; at 20℃; | Portions of 1, 1'-carbonyldiimidazole (2.06g, 12.7mmol) are added to a stirred mixture of isoquinoline-l-carboxylic acid (2. 00g, 11. 6mmol) in dichloromethane (25ml). N, O- dimethylhydroxylamine hydrochloride (1.24g, 12. 7mmol) is added and the mixture is stirred at ambient temperature overnight. The reaction mixture is diluted with dichloromethane and then washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. The organic solution is dried with sodium sulfate, filtered, and concentrated to give 2. 5g of N-methyl N-methoxy isoquinoline-1- carboxamide, which is used in the next step without further purification: mass spectrum (ion spray): m/z = 217.0 (M+1). | |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; | Isoquinoline carboxylic acid a (5.0 g, 28.9 mmol), N.O-dimethy-hydroxylamine hydrochloride (3.1 g, 31.8 mmol) EDC (6.1 g, 32 mmol), DIPEA (5.7 mL, 32 mmol) and MeCN (50 mL) were mixed together and stirred at rt overnight. The MeCN was removed under reduced pressure and the residue partitioned between water (200 mL) and EtOAc (200 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were b as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | 4-[4-Bromo-2-[(isoquinoline-1-carbonyl)-amino]-5-(2-trifluoromethyl-phenoxymethyl)-phenyl]-piperazine-1-carboxylic Acid tert-butyl Ester (32B): 4-[2-Amino-4-bromo-5-(2-trifluoromethyl-phenoxymethyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 0.57 mmol) was dissolved in DMF with 1-carboxyisoquinoline (0.17 g, 1 mmol) and HBTU (0.38 g, 1 mmol). To this solution DIEA (0.4 mL, 2.3 mmol) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate and the organic layer washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated to a brown solid. The product was purified by silica chromatography (16% ethyl acetate/hexanes) to give 4-[4-bromo-2-[(isoquinoline-1-carbonyl)-amino]-5-(2-trifluoromethyl-phenoxymethyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid, 0.32 g, 0.47 mmol, 82% yield. 1H NMR (500 MHz, CDCl3) 9.66 ppm (1H, d) 8.88 ppm (1H, s), 8.50 ppm (1H, s), 7.81 ppm (2H, m), 7.65 ppm (2H m), 7.53 ppm (1H, d), 7.41 ppm (1H, m), 7.40 ppm (1H, s), 7.01 ppm (1H, d), 6.93 ppm, (1H, t), 5.12 ppm (2H, s), 3.65 ppm (4H, br s), 2.82 ppm (4H, br s), 1.41 ppm (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In hexane; ethyl acetate; N,N-dimethyl-formamide; | Method H: (S)-1-(Isoquinoline-1-carbonyl)-2-piperidinecarboxylic Acid Methyl Ester A stirred solution of (S)-1-Piperidine-carboxylic acid methyl ester hydrochloride (1.00 g, 5.57 mmol), in DMF (20 ml) at room temperature was treated with DIPEA (2.12 ml, 12.25 mmol). The resulting mixture was allowed to stir for 30 min before being treated with <strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> (964 mg, 5.57 mmol) and TBTU (1.79 g, 5.57 mmol). The mixture stirred at room temperature for 4 hr, diluted with ethyl acetate, washed with saturated aq.NaHCO3, saturated aq. NaCl, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (67% ethyl acetate in hexane) to afford the sub-title compound as a colourless gum (1.05 g, 63%): 1H NMR (400 MHz, CDCl3) delta 1.00-2.51 (6H, m), 3.05-3.38 (2H, m), 3.60-3.95 (3H, m), 4.35-4.95 (1H, m), 5.70-5.80 (1H, m), 7.55-7.95 (3H, m), 8.13-8.29 (1H, m), 8.48-8.61 (1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.6 g (50%) | In methanol; | (a) A mixture of 1-isoquinolinecarboxylic acid (25 g.0.14 mol), 25 g of AMBERLYST-15 (H+), and 300 ml of methanol was refluxed for 3 days. The reaction mixture was cooled, filtered, and the filtrate was concentrated in vacuo to afford 13.6 g (50%) of 1-isoquinolinecarboxylic acid methyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With dmap; benzotriazol-1-ol; In N,N-dimethyl-formamide; | (Step 1) Synthesis of methyl (3-chloro-4-((1-isoquinolinylcarbonyl)amino)phenyl)acetate In DMF (15 ml) were dissolved <strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> (1.00 g, 5.77 mmol), methyl 4-amino-3-chlorophenylacetate (1.23 g, 6.16 mmol), HOBt (0.16 g, 1.15 mmol), and DMAP (0.14 g, 1.15 mmol). To the resulting solution was added EDC HCl (1.33 g, 6.93 mmol), followed by stirring at room temperature for 14 hours. The reaction mixture was poured into water (40 ml). The crystals precipitated were collected by filtration under reduced pressure, washed with water and ether, dried under reduced pressure to give methyl (3-chloro-4-((1-isoquinolinylcarbonyl)amino)phenyl)acetate (1.14 g, 56%) as a brown solid. 1H-NMR (CDCl3) delta: 3.62 (s, 2H), 3.72 (s, 3H), 7.29 (m, 1H), 7.40 (d, J=1.9Hz, 1H), 7.71-7.78 (m, 2H), 7.88-7.91 (m, 2H), 8.58 (d, J=5.4Hz, 1H), 8.65 (d, J=8.3Hz, 1H), 9.71 (m, 1H), 11.02 (m, 1H). MS (ESI) m/z 355 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With dmap; benzotriazol-1-ol; In hexane; water; ethyl acetate; N,N-dimethyl-formamide; | (Step 1) Synthesis of ethyl (3-bromo-4-((1-isoquinolinylcarbonyl)amino)phenyl)acetate In DMF (15 ml) were dissolved <strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> (1.00 g, 5.77 mmol), ethyl 4-amino-3-bromophenylacetate (1.49 g, 5.77 mmol), HOBt (0.39 g, 2.89 mmol), and DMAP (0.14 g, 1.15 mmol). To the resulting solution was added EDC HCl (1.33 g, 6.93 mmol). After stirring at 60ØC for 5 hours, the reaction mixture was cooled to room temperature. Water was added, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane:ethyl acetate (4:1, v/v) eluate fractions, ethyl (3-bromo-4-((1-isoquinolinylcarbonyl)amino)phenyl)acetate (1.64 g, 69%) was obtained as a yellow solid. 1H-NMR (CDCl3) delta: 1.28 (t, J=7.1Hz, 3H), 3.60 (s, 2H), 4.17 (q, J=7.1Hz, 2H), 7.32 (dd, J=8.5,2.0Hz, 1H), 7.57 (d, J=2.0Hz, 1H), 7.71-7.78 (m, 2H), 7.88-7.91 (m, 2H), 8.59 (d, J=5.6Hz, 1H), 8.63 (d, J=8.5Hz/ 1H), 9.71 (m, 1H), 11.01 (broad s, 1H). MS (ESI) m/z 413 (M++1), 415 (M++3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With N-ethyl-N,N-diisopropylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In acetonitrile; | Following the general procedure of acid-amine coupling as shown in Example 2023, Compound 8 (25 mg, 0.033 mmol) was treated with isoquinoline-1-carboxylic acid (7.8 mg, 0.045 mmol), DIEA (0.0163 mL, 0.094 mmol) and the coupling reagent PyAOP (29.3 mg, 0.056 mmol) in acetonitrile (3 mL). After purification by Prep.HPLC column, an off-white solid as TFA salt was obtained as final 1:1 diastereomers (Compound 24) (17.8 mg, 59% yield). (Compound 24, 48110-186A): LC-MS (retention time: 1.547 minutes.), MS m/z 693(MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; | Example 19 Isoquinoline-1-carboxylic acid {trans-4-[(1S,4R)-2-(1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl)-ethyl]-cyclohexyl}-amide A solution o{trans-4-[2-(1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl)-ethyl]-cyclohexylamine (40 mg, 0.15 mmol) in CHCl3 (5 mL) was mixed with isoquinoline-1-carboxylic acid (28 mg, 0.16 mmol), EDC (28 mg, 0.15 mmol), HOBT (2 mg, 0.015 mmol) and DIEA (0.129 mL, 0.742 mmol). The resultant mixture was stirred at room temperature overnight, filtered and concentrated. Purification via a reverse phase HPLC then afforded the title compound (6 mg, 10%): LCMS (ES) m/z426 (M+H)+; 1H-NMR(CDCl3) delta 1.1 (m, 2H), 1.3 (m, 4H), 1.4 (m, 2H), 1.8 (m, 2H), 2.12 (m, 2H), 2.28 (m, 4H), 2.42 (m, 1H), 3.94 (m, 1H), 4.30 (s, 2H), 7.19 (m, 2H), 7.25 (m, 1H), 7.70 (m, 2H), 7.78 (d, 1H), 7.86 (d, 1H), 7.99 (d, 1H), 8.4(d, 1H), 9.6 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dicyclohexyl-carbodiimide;dmap; In dichloromethane; at 20℃; for 18h; | Ircinol A (0.075 mol) was dissolved in dry methylene chloride (0.075 mol). To this solution, carboxylic acids (0.075 mol) and dimethyl aminopyridine (catalytic amount) were added and stirred for about 5 minutes followed by the addition of N,N'-dicyclohexylcarbodiimide (0.075 mol). The reaction was allowed to stir at room temperature and progress was monitored on silica gel on a PTLC aluminum card. All the reactions were stopped after 18 hours and the reaction mixture was filtered and evaporated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | [328] Preparation 17; [329] 2-Diazo-l-(l-isoquinolinyl)-l-ethanone; [330] To <strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> (1.73g, lO.Ommol) and NMM (1.50 D , 1.4eq) was added anhydrous tetrahydrofuran (10 D ) under nitrogen atmosphere. While maintaining the mixture at 00C, isobutylchloroformate (1.36 D , 1.05eq) was added thereto and the mixture was stirred for about 2 hours. While maintaining the reaction mixture at 00C, diazomethane-ether solution (synthesized from 2.0eq of l-methyl-3-nitro-l-nitroso-guanidine, 20 D ) was added thereto to give diazoketone derivative (1 hour), which was then extracted with ethyl acetate, washed with water, EPO <DP n="27"/>saturated aqueous sodium bicarbonate solution, and aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4 ), and concentrated under reduced pressure. The residue was purified by column chromatography (10-15% EA/Hex) to give the title diazo derivative (1.50g, 76%, yellow powder).[331] * H-NMR (500MHz, CDCl ) delta 9.29(d, IH), 8.5 l(d, IH), 7.88-7.83(m, 2H),7.76-7.69 (m, 2H), 6.7 l(s, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; water; at 20℃; for 12h; | 1-Hydroxybenzotriazole hydrate (1.47 equiv of acid), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.47 equiv of acid), N,N-diisopropylethylamine (3.45 equiv of acid), and corresponding acid were added to a solution of compound 10 (1.0 equiv of acid) in dichloromethane (0.1 M). The reaction mixture was stirred at room temperature for 12 h and then washed with water. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The concentrate was purified with silica gel column chromatography to afford compound 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With 2-(1H-9-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Example 1.4: (S)-N-methyl-N-(4-M -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- isoquinoline-1 -carboxamideTo a solution of isoquinoline-1-carboxylic acid (43.3 mg, 0.25 mmol) in DMF (0.45 ml) were added solutions of 1-methyl-1 H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)- amide (65 mg, 0.23 mmol, in 0.2 ml DMF), HATU (130 mg, 0.34 mmol, in 0.25 ml DMF), and DIPEA (59.7 muIota, 0.34 mmol) and the reaction was stirred at rt over night. MeOH (1 ml) was added and the mixture was filtered. The filter cake was washed with MeOH (1 ml) and the combined solutions were purified by a preparative HPLC system using Waters ZQ MS detection under the following conditions: Waters SunfireTM C-18 column [150 x 30 mm, 5mu?iota particle size ]; the gradient was composed of eluent A (water containing 0.79 g/L ammonium carbonate) and eluent B (acetonitrile): 0 - 1.5 min (isocratic elution with 80 % A : 20 % B) at 50 ml/min; 1.5 - 10.0 min (linear gradient from 80 % A : 20 % B to 40 % A : 60 % B) at 50 ml/min; 10.0 - 10.1 min (linear gradient from 40 % A : 60 % B to 0 % A : 100 % B) at 50 ml/min; 10.1 - 14.0 min (isocratic elution with 0 % A : 100 % B) at 50 ml/min; The product was collected by MS detection. The solvent was removed by freeze drying to give the title compound as a colorless powder (54 mg, 53%). [1 H-NMR (DMSO, 600 MHz, rotamers) 8.46/8.34 (d, 1 H), 8.02/7.93 (t, 1 H), 7.97 (dd, 1 H), 7.84/7.77 (d, 1 H), 7.74 (dd, 1 H), 7.49-7.34 (m, 5H), 7.05/7.00 (t, 1 H), 6.88 (d, 1 H), 6.77-6.54 (m, 2H), 6.01/5.99 (dd, 1 H), 5.26 (br s, 1 H), 3.85/3.67 (s, 3H), 3.51-3.12 (m, 2H), 3.08-2.84 (m, 2H), 3.12/2.55 (s, 3H), 1.96-1.85/1.57- 1.50 (m, 2H); LCMS Rtc = 1.681/1.935 min (rotamers); [M+H]+ = 441.2; LCMS RtH =1.27/1.31 min (rotamers); [M+H]+ = 461.6]; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; at 20℃; | Example 1.84: (S)-N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2- l)-N-methylisoquinoline-1-carboxamide2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide (60 mg, 0.155 mmol), isoquinoline-1-carboxylic acid (29.5 mg, 0.17 mmol), and DIPEA (0.135 ml, 0.775 mmol) were dissolved in DCM (1 ml. T3P (50% in EtOAc, 0.055 ml, 0.385 mmol) was added and the reaction was stirred over night at rt. The solvents were evaporated under reduced pressure and the residue was purified by preparative HPLC (Waters HPLC 2767, sunfire 19x150mm 5muetaiota, eluent water and acetonitrile with TFA, grade from 5% to 90% acetonitrile over 15 min). The crude product was dissolved in DCM, filtered through a Varian PL-HC03 MP column (0.18 mmol), and the solvent was evaporated to obtain the product as colorless solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 8.45-8.30 (m, 1 H), 7.96 (d, 1 H), 7.84/7.77 (d, 1 H), 7.74 (dd, 1 H), 7.47-7.31 (m, 5H), 7.06/7.00 (t, 1 H), 7.65 (d)/6.53 (br s) (1 H), 6.69/6.41 (s, 1 H), 5.36 (br s, 1 H), 4.44-4.21 (m, 3H), 3.53-3.24 (m, 2H), 3.11/2.54 (s, 3H), 3.07-2.84 (m, 2H), 2.16/2.15 (s, 3H), 1.97-1.88/1.61-1.55 (m, 2H), 1.28/1.16 (t, 3H); LCMS Rtj = 1.02/1.07 min (rotamers); [M+H]+ = 470.2]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | A mixture of 2-amino-4-(5'-(4"-methylpiperazin-l "-yl)benzimidazol-2'-yl)aniline(7) (86 mg, 0.27 mmol), <strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> (83 mg, 0.48 mmol, 1.8 eq), polyphosphoric acid (3 g) and phosphorous pentoxide (0.6 g) was heated under nitrogen in a 180 C oil-bath for 10 h. After cooling ice- water (30 ml) was added and the resultant heavy suspension basified (pH 8) with concentrated ammonia solution (6-8 ml). The suspension was then extracted with n-butanol (2 x 30 ml), the extract washed with water (2 x 45 ml) and evaporated to give a brown glassy solid. The material was subjected to column chromatography with alumina (basic, act. I, 22 x 200 mm) eluting with 15:1 ethyl acetate/methanol to give l-(5 5"-(4,, ,-memylpiperazm- ''-yl)rjenzimidazol-2''- yl)benzimida/ol-2'-yl)isoquinoline as a dull yellow solid (70 mg), which was further purified by recrystallization from methanol (51 mg, 42%), mp 214-217 C.'H nmr (500 MHz, dt-MeOH + 4 drops d-TFA) 3.01, s, 3H, 4"'-MeN; 3.19, t (J =11.9 Hz), 2H, NCH2; 3.33, m (obs), NCH2; 3.68, d (J = 12.0 Hz), 2H, NCH2; 3.94, d (J = 13.0 Hz), 2H, NCH2; 7.25, d (J = 2.0 Hz), 1H, H4"; 7.36, dd (J = 2.0, 9.0 Hz), 1H, H6"; 7.67, d (J = 9.0 Hz), 1H, H7"; 7.85, m, 2H, H6, H7; 7.97-8.06, m, 4H, H4, H5, H6 H7'; 8.50, d (J = 1.0 Hz), 1H, H4'; 8.70, d ( J = 5.0 Hz), 1H, H3; 9.53, dd (J = 1.0, 8.5 Hz), 1H, H8. 13C nmr (125 MHz, Aj-MeOH + 5 drops HOAc) delta 43.5, 4"'-MeN; 49.1, C2"76"'; 54.5, C3"75"'; 102.1, C4"; 115.6, 1 16.1, 116.8, .117.0, C4 C6", C7 C7"; 122.8, C4 or C6'; 123.3, C5'; 123.7, C6' or C4; 127.6, C8a 128.1, 128.7, 129.5, 131.6, C5, C6, C7, C8;133.4, C7a"; 138.29, 138.34, 140.5, 141.5, C3a C3a", C4a, C7a'; 142.7, C3; 147.6,148.5, CI, C5"; 152.6, 154.3, C2', C2". MS (ESI +ve) m/z 919 (M2H+, 7%), 460 (MH+, 100). HRMS (ESI +ve) m/z 460.22445, C28H26N7 requires 460.22442 (Delta = 0.1 ppm). Cytotoxicity and radioprotection resultsC50 = 26.9PF = 36.9DMFm = 1.85DMF10 = 1.70 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; diisopropyl-carbodiimide; In dichloromethane; at 20℃; | General procedure: One milli mole of the carboxylic acid was dissolved in DCM. To this, 1.1 equiv of HOBt and the desired primary amine were added. Following this, 1 equiv of DIC was added to the mixture and the reaction was mixed overnight. Upon completion of the reaction, the diisopropylurea was filtered away and the DCM layer was washed with saturated bicarbonate solution (1×) and 2 M HCl (1×). The organic layer was dried over anhydrous sodium sulfate and the solvent was then removed under reduced pressure. Typical yields for all amide bond formations were 80%. A small portion of the resulting compounds were carried through and used for HPLC purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.6% | With pyridine; triphenyl phosphite; at 110℃; for 4h;Inert atmosphere; Schlenk technique; | General procedure: The ligands were synthesized according to published methods withminor modifications [26-28]. To a solution of either 8-aminoquinolineor picolinamide (5.00×10-3 mol) in 10 mL dry pyridine was added asolution of the corresponding picolinic acid or 1-isoquinolinecarboxylicacid or 3-isoquinolinecarboxylic acid (5.00×10-3 mol) in 10 mL. Themixture was stirred, heated to 110 C and triphenylphosphite(5.00×10-3 mol) was added drop-wise. The resulting brown solutionwas refluxed for 4 h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 10h; | General procedure: To a solution of compound 2 (1.0 eq) in CH2Cl2 was added the corresponding carboxylic acid (1.5 eq), DMAP (1.0 eq) and EDC (1.5 eq), then the mixture was stirred at room temperature for 10 h. The mixture was diluted with CH2Cl2, washed with saturated aq. NaHCO3 and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give the crude product. Purification by column chromatography (PE/EtOAc = 1:1) afforded the amide 3 as a white solid (yield 75-85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With polyphosphoric acid; at 180℃; for 6h;Inert atmosphere; | A mixture of isoquinoline-1-carboxylic acid (20.00mmol, 3.46g) and 1,2-phenylenediamine (20.00mmol, 2.16g) in polyphosphoric acid (PPA, 20mL) was heated at 180C under nitrogen for 6h. The reaction mixture was then cooled down to 80C and added deionized water (500mL) with stirring. The mixture was filtered and the residue was washed with water (100mL). The crude product was purified by silica gel column chromatography using an ethyl acetate-dichloromethane mixture (2:1, v/v) as eluent to afford Hbisq in 75% yield (3.68g, 15.00mmol). 1H NMR (500MHz, d6-DMSO, delta [ppm]): 9.99 (d, J=7.0Hz, 1H), 8.72 (d, J=5.5Hz, 1H), 8.10-8.11 (m, 1H), 8.03 (d, J=5.5Hz, 1H), 7.85-7.90 (m, 2H), 7.74-7.75 (m, 2H), 7.31-7.33 (m, 2H). IR (cm-1): v=3515 (w), 3061 (s), 1807 (m), 1624 (m), 1570 (s), 1502 (w), 1475 (w), 1448 (w), 1412 (w), 1387 (w), 1323 (w), 1228 (m), 1144 (s), 1106 (w), 1070 (w), 1012 (m), 918 (w), 748 (s), 550 (w), 474 (w), 445 (w). Tm (melting point): 194C. Anal. calcd for C16H11N3: C, 78.35; H, 4.52; N, 17.13. Found: C, 78.42; H, 4.49; N, 17.24. ESI-MS: m/z 246.14 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Coupling general procedure 4Ar2-COOH (1.Seq), HBTU (1.4 eq), HOBT (1.Seq) dissolved in DMF (20m1/mmol)were stirred at 25C for 0.Shours, then intermediates 12-17 (leq.) and DIPEA (3eq.) dissolved in DMF(lOml/mmol) were added. After 18 hours solvents were evaporated; residue poured in an aqueous saturated solution of NaHCO3 and extracted with dichloromethane. The crude was purified by silica gel column chromatography (DCM /AcOEt=9/1 to AcOEt 1 00%)According to generalprocedure 1, 2, 3 or 4 the following compounds 1-49 were prepared: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.0% | General procedure: At 0C, to a solution of 1.0 mmol of isoquinoline- 1 -carboxylic acid in anhydrous THF(20mL),0.135g(1.0mmol) of HOBt and 1.0 mmol of (2S,3R)- 2-Amino-3-hydroxy-N-octylbutanamide, (2S,3R)-2-Amino-3-hydroxy-N- dodecylbutanamide, (2S,3R)-2-Amino-3-hydroxy-N-tetradecylbutanamide, or (2S,3R)-2-Amino-3-hydroxy-N-octadecylbutanamide were added. After 5 min, 0.220g (1.1 mmol) of EDOHC1 was added, and the pH of the solution was adjusted to 8-9 with 4-methylmorpholine. The mixture was stirred at 0 C for 2 h and at room temperature overnight. On evaporation the residue was dissolved in 80 mL of ethyl acetate. The solution was washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, and saturated sodium chloride, and the organic phase was separated and dried over anhydrous magnesium sulfate for 2 h. After filtration and evaporation under reduced pressure crude product was obtained and recrystallized using ethyl acetate to obtain compounds NZJUlf, NZJU2f, NZJU3f, and NZJU4f. N-((2S,3R)-3-hydroxy- 1-oxo- 1 -(octylamino)butan-2-yl)- isoquinoline- 1 -carboxamide (NZJUlf) was obtained in a yield of 0.258 g (67.0%) as colorless powder. XH NMR (300 MHz, CDC13) delta 9.51 (d, J= 8.1 Hz, 1H), 9.08 (d, J= 8.0 Hz, 1H), 8.52 (d, J= 5.5 Hz, 1H), 7.92 - 7.79 (m, 2H), 7.79 - 7.61 (m, 2H), 6.89 (s, 1H), 4.66 - 4.46 (m, 2H), 3.32 - 3.1 1 (m, 2H), 1.56 - 1.42 (m, 2H), 1.34 - 1.04 (m, 13H), 0.82 (t, J= 6.7 Hz, 3H); 13C NMR (75 MHz, CDC13) delta 171.4, 167.5 , 147.2, 140.6, 137.5, 130.6, 128.8, 127.3, 127.0, 124.8 , 66.6, 56.9, 39.6, 31.7, 29.4, 29.2, 26.9, 22.6, 18.6, 14.1; ESI/MS (m/e) 386.20 [M+H]+; Anal. Calcd. For C22H31N3O3: C, 68.54; H, 8.1 1; N, 10.90%. Found: C, 68.47; H, 8.24; N, 10.86%. N-((2S,3R)-3-hydroxy- 1-oxo- 1 -(dodecylamino)butan-2-yl)- isoquinoline- 1 -carboxamide (NZJU2f) was obtained in a yield of 0.310 g (70.3%) as colorless powder. XH NMR (300 MHz, CDC13) delta 9.51 (d, J= 7.6 Hz, 1H), 9.08 (d, J= 7.8 Hz, 1H), 8.52 (d, J= 5.2 Hz, 1H), 7.95 - 7.80 (m, 2H), 7.80 - 7.62 (m, 2H), 6.89 (s, 1H), 4.67 - 4.45 (m, 2H), 3.35 - 3.09 (m, 2H), 1.57 - 1.41 (m, 2H), 1.37 - 0.98 (m, 21H), 0.87 (t, J= 6.4 Hz, 3H); 13C NMR (75 MHz, CDC13) delta 171.4, 167.3 , 147.3, 140.6, 137.4, 130.5, 128.8, 127.3, 127.0, 124.7, 66.6, 56.9, 39.6, 31.9, 29.6, 29.5, 29.4, 29.3, 26.9, 22.7, 18.6, 14.1; ESI/MS (m/e) 442 [M+H]+; Anal. Calcd. For C26H39N303: C, 70.71; H, 8.90; N, 9.52%. Found: C, 70.68; H, 8.86; N, 9.49%. N-((2S,3R)-3-hydroxy- 1-oxo- 1 -(tetradecylamino)butan-2-yl)- isoquinoline-1 -carboxamide (NZJU3f) was obtained in a yield of 0.317 g (67.6%) as colorless powder. XH NMR (300 MHz, CDC13) delta 9.51 (d, J= 8.3 Hz, 1H), 9.07 (d, J= 8.1 Hz, 1H), 8.52 (d, J= 5.5 Hz, 1H), 7.94 - 7.79 (m, 2H), 7.78 - 7.60 (m, 2H), 6.89 (s, 1H), 4.68 - 4.46 (m, 2H), 3.35 - 3.1 1 (m, 2H), 1.58 - 1.39 (m, 2H), 1.39 - 1.00 (m, 25H), 0.88 (t, J= 6.4 Hz, 3H); 13C NMR (75 MHz, CDC13) delta 171.2, 167.2 , 147.4, 140.6, 137.4, 130.5, 128.7, 127.3, 127.0, 124.7 , 66.7, 57.2, 39.6, 31.9, 29.7, 29.6, 29.4, 29.3, 28.3, 26.9, 22.7, 18.6, 14.1; ESI/MS (m/e) 470 [M+H]+; Anal. Calcd. For C28H43 3O3: C, 71.61 ; H, 9.23; N, 8.95%. Found: C, 71.58; H, 9.19; N, 8.98%. N-((2S,3R)-3-hydroxy- 1-oxo- 1 -(octadecylamino)butan-2-yl)- isoquinoline- 1 -carboxamide (NZJU4f) was obtained in a yield of 0.409 g (77.3%) as colorless powder. XH NMR (300 MHz, CDC13) delta 9.46 (d, J= 8.3 Hz, 1H), 9.08 (d, J= 7.4 Hz, 1H), 8.52 (d, J= 5.2 Hz, 1H), 7.94 - 7.83 (m, 2H), 7.81 - 7.62 (m, 2H), 6.95 (s, 1H), 4.68 - 4.47 (m, 2H), 3.37 - 3.15 (m, 2H), 1.54 - 1.40 (m, 2H), 1.38 - 1.00 (m, 33H), 0.88 (t, J= 6.2 Hz, 3H); 13C NMR (75 MHz, CDC13) delta 171.5, 167.4 , 147.4, 140.5, 137.4, 130.6, 128.8, 127.3, 127.0, 124.7, 66.7, 57.0, 39.6, 31.9, 29.7, 29.6, 29.4, 29.3, 26.9, 22.7, 18.6, 14.1; ESI/MS (m/e) 526 [M+H]+; Anal. Calcd. For C32H51N3O3: C, 73.10; H, 9.78; N, 7.99%. Found: C, 73.07; H, 9.86; N, 8.02%. | |
67.0% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 0 - 20℃;pH 8 - 9; | General procedure: To a solution of carboxylic acid (1.0 mmol) in anhydrous THF (20 mL) were added (2S,3R)-2-amino-3-hydroxy-N-alkylbutanamide 4a-d (1.0 mmol) and HOBt (1.0 mmol, 0.135 g) at 0 C. After the reaction mixture was stirred for 5 min, EDC·HCl (0.220 g, 1.1 mmol) was added. The pH value of the solution was adjusted to 8-9 with 4-methylmorpholine. The reaction mixture was stirred at 0 C for 2 h and overnight at room temperature. After evaporation of the mixture in vacuo, the residue was dissolved in ethyl acetate (50 mL). The solution was washed successively with saturated NaHCO3, 5% KHSO4, and saturated NaCl. The organic phase was separated and dried over anhydrous MgSO4. After filtration and evaporation in vacuo, residue was purified by recrystallization in petroleum ester/ethyl acetate to give the desired ceramide analogues 5xa-xj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 2h; | General procedure: To the solution of 4/11 (1 mmol), quinoline acids (1.1 mmol) and DMAP (12 mg, 0.1 mmol) in CH2Cl2 (15mL) was added DCC (0.4 g, 2 mmol) and the solution was stirred for 2 h at room temperature. Then, DCU was filtered off and the solution was concentrated under vacuum to get the crude compounds 5a-5g/12a-12g respectively, which were used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 2h; | General procedure: To the solution of 4/11 (1 mmol), quinoline acids (1.1 mmol) and DMAP (12 mg, 0.1 mmol) in CH2Cl2 (15mL) was added DCC (0.4 g, 2 mmol) and the solution was stirred for 2 h at room temperature. Then, DCU was filtered off and the solution was concentrated under vacuum to get the crude compounds 5a-5g/12a-12g respectively, which were used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With thionyl chloride; | To a stirred solution of isoquinoline-1-carboxylic acid (1.732 g, 10 mmol) in 3 mL ethanol was added thionyl chloride (6 mL) dropwise over 15 minutes. Then, the mixture was heated under reflux for 8 h. Ethanol was distilled out and the saturated NaHCO3 solution was added to adjust pH to 7. Extracted with ethyl acetate, and the organic layer was dried over anhydrous Na2SO4, evaporation of the ethyl acetate gave the ester (I) in 92% yield (1.85g) as a light yellow oily compound I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; isobutyl chloroformate; In tetrahydrofuran; N,N-dimethyl-formamide; at -15 - 20℃; for 1.5h;Inert atmosphere; | General procedure: Compounds 1-13 were synthesized using the mixed anhydrides method of peptide synthesis (10). Suitable acid (10 mmol) was dissolved in DMF (15 mL) and THF (15 mL) was added. Next, N-methylmorpholine (10 mmol, 1.1 mL) was added and the mixture was stirred under nitrogen and chilled to -15C. Isobutyl chloroformate (10 mmol, 1.3 mL) was added dropwise to keep the temperature below -15C. Then, benzylamine or halogenated benzylamine (10 mmol) in THF was added in small portions and the reaction mixture was stirred at -15C for 30 min, at room temperature for 1 h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc (20 mL). This solution was washed with 20 mL portions of 1 M HCl, saturated NaHCO3 solution and saturated NaCl solution, then dried with anhydrous MgSO4, filtered and concentrated in vacuo. The obtained compounds were purified by crystallization with EtOAc/hexane o MeOH/Et2O. All stages of the synthesis were controlled by TLC. The purity of the final compound was determined by HPLC and identity by 1H NMR. The pathway for the synthesis of the obtained compounds is shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.65 g | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h; | To a solution of (lR,3R)-ter?-butyl 1-((R)-1,1- dimethylethylsulfinamido)-3-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (3.0 g, 8.01 mmol), triphenylphosphine (4.2 g, 16.02 mmol), and isoquinoline-l-carboxylic acid (4.16 g, 24.03 mmol) in THF (80 mL) was added DIAD (3.1 mL, 16.02 mmol). The resulting mixture was stirred for 1 h at RT. The reaction was diluted with EtOAc (50 mL), filtered through a pad of Celite, poured into a separation funnel containing sat. aq NaHCC^ and extracted with EtOAc (3 x 25 mL). The combined organic phases were dried over MgS04, filtered and the volatiles were removed under reduced pressure. The resulting residue was purified by silica chromatography (0 to 4% gradient of MeOH/DCM) to give (2S,4R)-8-(?ert-butoxycarbonyl)-4-((R)-l,l-dimethylethylsulfinamido)-8- azaspiro[4.5]decan-2-yl isoquinoline-l-carboxylate (3.65 g, 6.89 mmol) as orange solid. MS m/z 530.3 (M+H)+. |
3.65 g | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h; | Step a: To a solution of (1R,3R)-tert-butyl 1-((R)-1,1- dimethylethylsulfinamino)-3-hydroxy-8-azaspiro[4.Sjdecane-8-carboxylate (3.0 g, 8.01 mmol), triphenylphosphine (4.2 g, 16.02 mmol), and isoquinoline-1-carboxylic acid (4.16 g, 24.03 mmol) in THF (80 mL) was added DIAD (3.1 mL, 16.02 mmol). The resulting mixture was stirred for 1 h at RT. The reaction was diluted with EtOAc (50 mL), filtered through a pad of Celite, poured into a separation funnel containing sat. aq. NaHCO3 and extracted with EtOAc (3 x 25 mL). The combined organic phases were dried over Mg504, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica chromatography (0 to 4% gradientof MeOHJDCM) to give (2S,4R)-8-(tert-butoxycarbonyl)-4-((R)- 1,1 -dimethylethylsulfinamino)-8- azaspiro[4.5jdecan-2-yl isoquinoline-1-carboxylate (3.65 g, 6.89 mmol) as an orange solid. MS m/z 530.3 (M+H). |
3.65 g | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h; | Intermediate B-12 (R3S)-tert -butyl l-((R)-l,l-dimethylethylsulfinamino)-3-hvdroxy-8-azaspiror4.51decane-8- carboxylate Step a: To a solution of (lR,3R)-ferf-butyl 1 -((R)-1,1- dimethylethylsulfinamino)-3-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (3.0 g, 8.01 mmol), triphenylphosphine (4.2 g, 16.02 mmol), and isoquinoline-l-carboxylic acid (4.16 g, 24.03 mmol) in THF (80 mL) was added DIAD (3.1 mL, 16.02 mmol). The resulting mixture was stirred for 1 h at RT. The reaction was diluted with EtOAc (50 mL), filtered through a pad of Celite, poured into a separation funnel containing sat. aq. NaHC( and extracted with EtOAc (3 x 25 mL). The combined organic phases were dried over MgSC, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica chromatography (0 to 4% gradient of MeOH/DCM) to give (25,4R)-8-(rerf-butoxycarbonyl)-4-((R)-l,l-dimethylethylsulfinamino)-8- azaspiro[4.5]decan-2-yl isoquinoline-l-carboxylate (3.65 g, 6.89 mmol) as an orange solid. MS m/z, 530.3 (M+H)+. |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h; | To a solution of (1R,3R)-tert-butyl 1-((R)-1,1 -dimethylethylsulfinamido)-3-hydroxy-8-azaspiro[4.5] decane-8-carboxylate (3.0 g, 8.01 mmol), triphenylphosphine (4.2 g, 16.02 mmol), and isoquinoline-1-carboxylic acid (4.16 g, 24.03 mmol) in THF (80 mE) was added DIAD (3.1 mE, 16.02 mmol). The resulting mixture was stirred for 1 h at RT. The reaction was diluted with EtOAc (50 mE), filtered through a pad of Celite, poured into a separation funnel containing sat. aq NaHCO3 and extracted with EtOAc (3x25 mE). The combined organic phases were dried over Mg504, filtered and the volatiles were removed under reduced pressure. The resulting residue was purified by silica chromatography (0 to 4% gradient of MeOH/DCM) to give (25,4R)-8-(tert-butoxycarbonyl)-4-((R)- 1,1 -dimethylethylsulfinamido)-8-azaspiro[4.5]decan-2-yl isoquinoline1-carboxylate (3.65 g, 6.89 mmol) as orange solid. MS mlz530.3 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | General procedure: To a suspension of the acid(0.25 mmol, 1.00 equiv) and N,N,N0 ,N0-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (0.25 mmol,1.00 equiv) in CH2Cl2 (2.5 mL), under an air atmosphere, at ambienttemperature, was added diisopropylethylamine (0.1 mL,0.58 mmol, 2.34 equiv) and the mixture was stirred for 25 min.2-((5-(Trifluoromethyl)pyridin-2-yl)sulfonyl)ethan-1-aminiumchloride(14) (0.26 mmol, 1.05 equiv) and CH2Cl2 (5 mL) were thenadded and the mixture was stirred for 48 h. The reaction wasquenched with aqueous HCl (1 M, 2 mL), followed by H2O(10 mL) and EtOAc (20 mL). The mixture was transferred to a separatoryfunnel and the flask rinsed with EtOAc (10 mL). The organicphase was separated, washed with saturated aqueous NaHCO3(15 mL) and dried over anhydrous Na2SO4. The solvent was thenremoved under reduced pressure, at or below 40 C, to afford thecrude product. Purification was performed as indicated for eachcompound below5.3.6.17 N-(2-((5-(Trifluoromethyl)pyridin-2-yl)sulfonyl)ethyl)isoquinoline-1-carboxamide (47) The title compound was prepared from isoquinoline-1-carboxylic acid (98%, 0.044 g, 0.25 mmol). The crude product was purified by flash chromatography on silica gel (0:100-30:70/EtOAc:Heptane) affording a colourless solid (0.060 g, 0.15 mmol, 59%). 1H NMR (600 MHz, DMSO-d6) delta 9.08 (br d, J = 8.7 Hz, 1H), 9.04 (m, 1H), 8.81 (t, J = 5.7 Hz, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.43 (dd, J = 8.2, 2.4 Hz, 1H), 8.27 (br d, J = 8.2 Hz, 1H), 8.02 (br d, J = 8.2 Hz, 1H), 7.99 (br d, J = 5.6 Hz, 1H), 7.81 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.72 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 3.94 (t, J = 6.4 Hz, 2H), 3.80 (q, J = 6.2 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) delta 165.4, 159.9 (q, J = 1.4 Hz), 148.7, 146.9 (q, J = 4.0 Hz), 140.1, 136.6 (q, J = 3.7 Hz), 136.5, 130.3, 128.2, 128.0 (q, J = 33.1 Hz), 126.8, 126.4, 123.6, 122.4 (q, J = 273.4 Hz), 122.0, 50.7, 33.1 (d, J = 1.4 Hz). HRMS (ESI) Calcd for C18H14F3N3NaO3S [M+Na]+: 432.0600; found 432.0602 (-0.5 ppm). HPLC (CH3OH:H2O/55:45, 1 mL/min, 254 nm) tr(major) 15.57 min (>99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.4 mg | To a mixture of isoquinoline-1 -carboxylic acid (150 mg, 0.87 mmol) in DMF (1 mL) was added CDI (140 mg, 0.87 mmol). After 10 mins, Intermediate 31 (195 mg, 0.79 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 hrs and was then partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (10 mL) and the combined organics were washed with water (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by dry flash chromatography (50 to 100% EtOAc in heptane) to afford the title compound as a solid (76.4 mg). LCMS (Method B): Two peaks at 2.23 and 2.28 min, 404 [M+H]+.1H NMR (400 MHz, CDCI3) 8.56 (d, 0.85 H), 8.53-8.45 (m, 1 .3 H), 8.43 (bs, 0.85 H), 8.35 (bs, 0.85 H), 8.13 (d, 0.85 H), 7.90-7.82 (m, 1 H), 7.77-7.68 (m, 2 H), 7.68-7.65 (d, 0.15 H), 7.65-7.60 (td, 0.85 H), 7.50 (tt, 0.15 H), 6.24 (m, 0.15 H), 5.1 1 (m, 0.15 H), 3.91 -3.61 (m, 1.85 H), 3.24 (m, 0.85 H), 3.07 (s, 2.55 H), 2.67 (s, 0.45 H), 1 .75 (m, 0.3 H), 1 .70- 1.62 (m, 0.85 H), 1 .42 (m, 0.85 H), 1 .15 (t, 0.45 H), 0.78 (m, 2.7 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diphenyl phosphoryl azide; triethylamine; In 1-methyl-pyrrolidin-2-one; at 0 - 35℃; for 1h;Schlenk technique; Inert atmosphere; | General procedure: 2-Pyridinecarboxylic, 2-quinolinecarboxylic or <strong>[486-73-7]1-isoquinolinecarboxylic acid</strong> (1.5 mmol) and NEt3 (1.5 mmol,152 mg, 209 mL) were added to dry NMP (2.1 mL) in a Schlenk flaskunder Ar atmosphere. At 0 C, diphenyl phosphoryl azide(1.6 mmol, 440 mg, 345 mL) was added drop-wise and the reactionmixture was stirred at 35 C for 1 h. N-Oxide (1 mmol) was thenadded in one portion and the reaction mixture was stirred at 70 Cfor 20 h. The mixture was then poured into water (50 mL) andextracted with AcOEt (3 x 20 mL). Combined organic extracts werewashed with brine (5 x 30 mL) dried over anhyd. Na2SO4 andevaporated. Products 2 were purified by column chromatographyon silica gel using hexaneseAcOEt 2:1 or tolueneeAcOEt 2:1, thenAcOEt as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In acetonitrile; for 6h;Reflux; | General procedure: Starting complex mer-[Re(p-NC6H4CH3)X3(PPh3)2] (0.54 mmol) was added to the corresponding N-heterocyclic carboxylic acid(0.60 mmol) in acetonitrile (60 mL) and the reaction mixture was refluxed for 6 h. The resulting solution was reduced in volume to 10 mL and allowed to cool to room temperature. A crystalline precipitateof 1-4 was filtered off and dried in the air. X-ray quality brown crystals of 1-4 were obtained by slow recrystallization from acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In methanol; for 6h;Reflux; | General procedure: Complex trans-(X,X)-[Re(p-NC6H4CH3)X2(OMe)(PPh3)2](0.54 mmol) was added to the corresponding N-heterocyclic carboxylic acid (0.60 mmol) in methanol (60 mL) and the reaction mixture was refluxed for 6 h. The resulting solution was reduced in volume to 10 mL and allowed to cool to room temperature. A crystalline precipitate of mixture of 5-8 was filtered off and dried in the air. The mixture of X-ray quality green crystals of 5-8 was obtained by slow recrystallization from methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In methanol; for 6h;Reflux; | General procedure: Complex trans-(X,X)-[Re(p-NC6H4CH3)X2(OMe)(PPh3)2](0.54 mmol) was added to the corresponding N-heterocyclic carboxylic acid (0.60 mmol) in methanol (60 mL) and the reaction mixture was refluxed for 6 h. The resulting solution was reduced in volume to 10 mL and allowed to cool to room temperature. A crystalline precipitate of mixture of 5-8 was filtered off and dried in the air. The mixture of X-ray quality green crystals of 5-8 was obtained by slow recrystallization from methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In acetonitrile; for 6h;Reflux; | General procedure: Starting complex mer-[Re(p-NC6H4CH3)X3(PPh3)2] (0.54 mmol) was added to the corresponding N-heterocyclic carboxylic acid(0.60 mmol) in acetonitrile (60 mL) and the reaction mixture was refluxed for 6 h. The resulting solution was reduced in volume to 10 mL and allowed to cool to room temperature. A crystalline precipitateof 1-4 was filtered off and dried in the air. X-ray quality brown crystals of 1-4 were obtained by slow recrystallization from acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: 4-methyl-morpholine / dichloromethane / 0.25 h / Inert atmosphere 1.2: 0.5 h / -15 - 20 °C / Inert atmosphere 1.3: 1 h / -15 - 20 °C / Inert atmosphere 2.1: triethylamine; dmap; p-toluenesulfonyl chloride / dichloromethane / 3 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The compounds 1-9 were synthesized using themixed anhydrides method of peptide synthesis (18).The suitable acid (10 mM) was dissolved in DMF(15 mL) and THF (15 mL) was added. Next N-methylmorpholine (10 mM, 1.1 mL) was added andthe mixture was stirred under nitrogen and chilled to-15 O C. Isobutyl chloroformate (10 mM, 1.3 mL) wasadded dropwise to keep the temperature below -15 O C. Then, the suitable amine: 2- or 4-fluorobenzy-lamine (2-F-BZA, 4-F-BZA); 2- or 4-methoxyben-zylamine (2-OMe-BZA, 4-OMe-BZA); 3- or 4-methylbenzylamine (3-Me-BZA, 4-Me-BZA) or 1-naphthylmethylamine (10 mM) in THF was added insmall portions and the reaction mixture was stirred at -15 O C for 30 min and at room temperature for 1 h.The solution was concentrated in vacuo and theresidue was dissolved in CHCl 3 (40 mL). This solu-tion was washed with 20 mL portions of 1M HCl,saturated NaHCO 3 solution and saturated NaCl solu-tion, then dried with anhydrous MgSO 4 , filtered andconcentrated in vacuo. The obtained compoundswere purified by crystallization with EtOAc/hexaneor MeOH/Et 2 O. All stages of the synthesis were con-trolled by TLC. The purity and identity of the finalcompounds were determined by HPLC, elementalanalyses, 1 H NMR, MS. The elemental analyses werewithin ± 0.4% of the theoretical value. The analyticaldata confirmed that the purity of the products was ?95%. The general procedure for the synthesis of theobtained compounds is shown in Schemes 1 and 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The compounds 1-9 were synthesized using themixed anhydrides method of peptide synthesis (18).The suitable acid (10 mM) was dissolved in DMF(15 mL) and THF (15 mL) was added. Next N-methylmorpholine (10 mM, 1.1 mL) was added andthe mixture was stirred under nitrogen and chilled to-15 O C. Isobutyl chloroformate (10 mM, 1.3 mL) wasadded dropwise to keep the temperature below -15 O C. Then, the suitable amine: 2- or 4-fluorobenzy-lamine (2-F-BZA, 4-F-BZA); 2- or 4-methoxyben-zylamine (2-OMe-BZA, 4-OMe-BZA); 3- or 4-methylbenzylamine (3-Me-BZA, 4-Me-BZA) or 1-naphthylmethylamine (10 mM) in THF was added insmall portions and the reaction mixture was stirred at -15 O C for 30 min and at room temperature for 1 h.The solution was concentrated in vacuo and theresidue was dissolved in CHCl 3 (40 mL). This solu-tion was washed with 20 mL portions of 1M HCl,saturated NaHCO 3 solution and saturated NaCl solu-tion, then dried with anhydrous MgSO 4 , filtered andconcentrated in vacuo. The obtained compoundswere purified by crystallization with EtOAc/hexaneor MeOH/Et 2 O. All stages of the synthesis were con-trolled by TLC. The purity and identity of the finalcompounds were determined by HPLC, elementalanalyses, 1 H NMR, MS. The elemental analyses werewithin ± 0.4% of the theoretical value. The analyticaldata confirmed that the purity of the products was ?95%. The general procedure for the synthesis of theobtained compounds is shown in Schemes 1 and 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The compounds 1-9 were synthesized using themixed anhydrides method of peptide synthesis (18).The suitable acid (10 mM) was dissolved in DMF(15 mL) and THF (15 mL) was added. Next N-methylmorpholine (10 mM, 1.1 mL) was added andthe mixture was stirred under nitrogen and chilled to-15 O C. Isobutyl chloroformate (10 mM, 1.3 mL) wasadded dropwise to keep the temperature below -15 O C. Then, the suitable amine: 2- or 4-fluorobenzy-lamine (2-F-BZA, 4-F-BZA); 2- or 4-methoxyben-zylamine (2-OMe-BZA, 4-OMe-BZA); 3- or 4-methylbenzylamine (3-Me-BZA, 4-Me-BZA) or 1-naphthylmethylamine (10 mM) in THF was added insmall portions and the reaction mixture was stirred at -15 O C for 30 min and at room temperature for 1 h.The solution was concentrated in vacuo and theresidue was dissolved in CHCl 3 (40 mL). This solu-tion was washed with 20 mL portions of 1M HCl,saturated NaHCO 3 solution and saturated NaCl solu-tion, then dried with anhydrous MgSO 4 , filtered andconcentrated in vacuo. The obtained compoundswere purified by crystallization with EtOAc/hexaneor MeOH/Et 2 O. All stages of the synthesis were con-trolled by TLC. The purity and identity of the finalcompounds were determined by HPLC, elementalanalyses, 1 H NMR, MS. The elemental analyses werewithin ± 0.4% of the theoretical value. The analyticaldata confirmed that the purity of the products was ?95%. The general procedure for the synthesis of theobtained compounds is shown in Schemes 1 and 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The compounds 1-9 were synthesized using themixed anhydrides method of peptide synthesis (18).The suitable acid (10 mM) was dissolved in DMF(15 mL) and THF (15 mL) was added. Next N-methylmorpholine (10 mM, 1.1 mL) was added andthe mixture was stirred under nitrogen and chilled to-15 O C. Isobutyl chloroformate (10 mM, 1.3 mL) wasadded dropwise to keep the temperature below -15 O C. Then, the suitable amine: 2- or 4-fluorobenzy-lamine (2-F-BZA, 4-F-BZA); 2- or 4-methoxyben-zylamine (2-OMe-BZA, 4-OMe-BZA); 3- or 4-methylbenzylamine (3-Me-BZA, 4-Me-BZA) or 1-naphthylmethylamine (10 mM) in THF was added insmall portions and the reaction mixture was stirred at -15 O C for 30 min and at room temperature for 1 h.The solution was concentrated in vacuo and theresidue was dissolved in CHCl 3 (40 mL). This solu-tion was washed with 20 mL portions of 1M HCl,saturated NaHCO 3 solution and saturated NaCl solu-tion, then dried with anhydrous MgSO 4 , filtered andconcentrated in vacuo. The obtained compoundswere purified by crystallization with EtOAc/hexaneor MeOH/Et 2 O. All stages of the synthesis were con-trolled by TLC. The purity and identity of the finalcompounds were determined by HPLC, elementalanalyses, 1 H NMR, MS. The elemental analyses werewithin ± 0.4% of the theoretical value. The analyticaldata confirmed that the purity of the products was ?95%. The general procedure for the synthesis of theobtained compounds is shown in Schemes 1 and 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The compounds 1-9 were synthesized using themixed anhydrides method of peptide synthesis (18).The suitable acid (10 mM) was dissolved in DMF(15 mL) and THF (15 mL) was added. Next N-methylmorpholine (10 mM, 1.1 mL) was added andthe mixture was stirred under nitrogen and chilled to-15 O C. Isobutyl chloroformate (10 mM, 1.3 mL) wasadded dropwise to keep the temperature below -15 O C. Then, the suitable amine: 2- or 4-fluorobenzy-lamine (2-F-BZA, 4-F-BZA); 2- or 4-methoxyben-zylamine (2-OMe-BZA, 4-OMe-BZA); 3- or 4-methylbenzylamine (3-Me-BZA, 4-Me-BZA) or 1-naphthylmethylamine (10 mM) in THF was added insmall portions and the reaction mixture was stirred at -15 O C for 30 min and at room temperature for 1 h.The solution was concentrated in vacuo and theresidue was dissolved in CHCl 3 (40 mL). This solu-tion was washed with 20 mL portions of 1M HCl,saturated NaHCO 3 solution and saturated NaCl solu-tion, then dried with anhydrous MgSO 4 , filtered andconcentrated in vacuo. The obtained compoundswere purified by crystallization with EtOAc/hexaneor MeOH/Et 2 O. All stages of the synthesis were con-trolled by TLC. The purity and identity of the finalcompounds were determined by HPLC, elementalanalyses, 1 H NMR, MS. The elemental analyses werewithin ± 0.4% of the theoretical value. The analyticaldata confirmed that the purity of the products was ?95%. The general procedure for the synthesis of theobtained compounds is shown in Schemes 1 and 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
436 mg | Stage #1: 1,2,3,4,6-penta-O-benzoyl-α,β-D-mannopyranoside With hydrogen bromide; acetic acid In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere; Stage #2: 1-isoquinolinecarboxylic acid With silver carbonate In dichloromethane at 20℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With polyphosphoric acid; at 180℃; for 6h;Inert atmosphere; | General procedure: A mixture of isoquinoline-1-carboxylic acid (20.00mmol, 3.46g) and 1,2-phenylenediamine (20.00mmol, 2.16g) in polyphosphoric acid (PPA, 20mL) was heated at 180C under nitrogen for 6h. The reaction mixture was then cooled down to 80C and added deionized water (500mL) with stirring. The mixture was filtered and the residue was washed with water (100mL). The crude product was purified by silica gel column chromatography using an ethyl acetate-dichloromethane mixture (2:1, v/v) as eluent to afford Hbisq in 75% yield (3.68g, 15.00mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.3% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 0 - 20℃;pH 8 - 9; | General procedure: To a solution of carboxylic acid (1.0 mmol) in anhydrous THF (20 mL) were added (2S,3R)-2-amino-3-hydroxy-N-alkylbutanamide 4a-d (1.0 mmol) and HOBt (1.0 mmol, 0.135 g) at 0 C. After the reaction mixture was stirred for 5 min, EDC·HCl (0.220 g, 1.1 mmol) was added. The pH value of the solution was adjusted to 8-9 with 4-methylmorpholine. The reaction mixture was stirred at 0 C for 2 h and overnight at room temperature. After evaporation of the mixture in vacuo, the residue was dissolved in ethyl acetate (50 mL). The solution was washed successively with saturated NaHCO3, 5% KHSO4, and saturated NaCl. The organic phase was separated and dried over anhydrous MgSO4. After filtration and evaporation in vacuo, residue was purified by recrystallization in petroleum ester/ethyl acetate to give the desired ceramide analogues 5xa-xj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.6% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 0 - 20℃;pH 8 - 9; | General procedure: To a solution of carboxylic acid (1.0 mmol) in anhydrous THF (20 mL) were added (2S,3R)-2-amino-3-hydroxy-N-alkylbutanamide 4a-d (1.0 mmol) and HOBt (1.0 mmol, 0.135 g) at 0 C. After the reaction mixture was stirred for 5 min, EDC·HCl (0.220 g, 1.1 mmol) was added. The pH value of the solution was adjusted to 8-9 with 4-methylmorpholine. The reaction mixture was stirred at 0 C for 2 h and overnight at room temperature. After evaporation of the mixture in vacuo, the residue was dissolved in ethyl acetate (50 mL). The solution was washed successively with saturated NaHCO3, 5% KHSO4, and saturated NaCl. The organic phase was separated and dried over anhydrous MgSO4. After filtration and evaporation in vacuo, residue was purified by recrystallization in petroleum ester/ethyl acetate to give the desired ceramide analogues 5xa-xj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.3% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 0 - 20℃;pH 8 - 9; | General procedure: To a solution of carboxylic acid (1.0 mmol) in anhydrous THF (20 mL) were added (2S,3R)-2-amino-3-hydroxy-N-alkylbutanamide 4a-d (1.0 mmol) and HOBt (1.0 mmol, 0.135 g) at 0 C. After the reaction mixture was stirred for 5 min, EDC·HCl (0.220 g, 1.1 mmol) was added. The pH value of the solution was adjusted to 8-9 with 4-methylmorpholine. The reaction mixture was stirred at 0 C for 2 h and overnight at room temperature. After evaporation of the mixture in vacuo, the residue was dissolved in ethyl acetate (50 mL). The solution was washed successively with saturated NaHCO3, 5% KHSO4, and saturated NaCl. The organic phase was separated and dried over anhydrous MgSO4. After filtration and evaporation in vacuo, residue was purified by recrystallization in petroleum ester/ethyl acetate to give the desired ceramide analogues 5xa-xj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 27℃; for 16h;Inert atmosphere; | Compound 34-d (60.00 mg, 129.19 mmol, 1.00 eq) was dissolved in dichloromethane (8.00 mL), and compound 34-e (22.37 mg, 129.19 mmol, 1.00 eq), EDCI (33.93 mg, 176.98 mmol, 1.37 eq), HOBt (23.91 mg, 176.98 mmol, 1.37 eq) and NMM (39.20 mg, 387.56 mmol, 42.61 mL, 3.00 eq) were added thereto. The reaction solution was stirred at 27C for 16 hours under the protection of nitrogen gas. After the reaction was completed, the reaction solution was added with 80 mL of water, and extracted with dichloromethane (80 mL 3 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was subjected to column chromatography (dichloromethane/methanol; 0-10%) to give the product of compound 34-f (61.00 mg, yield: 59%) as a colorless oil. LCMS m/z = 620.3 [M+H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; | General procedure: To a solution of oridonin (36.4mg, 0.1mmol) in 10mL dry CH2Cl2 and different carboxyl compounds (0.15mmol), the solution was treated with EDCI (0.3mmol) and 4-dimethylaminopyridine (DMAP) (10mg). The mixture was stirred at 25C for 2-8h and monitored by TLC. After completion of the reaction, water was added and the mixture was extracted with dichloromethane and the organic phase was washed with saturated sodium bicarbonate solution and brine, and dried over Na2SO4. The evaporation of the solvents gave the crude products, which were purified by silica gel column (CH2Cl2/MeOH, 100:1) to afford compounds A1-9, B1-3, C1-9, D1, E, F. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | General procedure: Carboxylic acid (1 mmol) was dissolved in 10 mL acetonitrile. The reaction mixture was cooled to 0 C and chlorosulfonyl isocyanate (CSI, 1.1 mmol) and triflic acid (TfOH, 1.0 mmol) were added and resulting solution was stirred for 4 h. Then, the reaction mixture was added 2mL MeOH and stirred for 2 h. The reaction mixture was extracted with dichloromethane. The organic phase was dried over sodium sulphate and concentrated. Purification was performed through thin-layer chromatography (TLC) on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 22℃; for 16h; | General procedure: The respective carboxylic acid (1.00 eq), the coupling reagent HATU (1.00 eq) and DIPEA (2.00 eq)were dissolved in 10 mL of DMF and stirred for 10 minutes at ambient temperature. Subsequently,the hydroxylamine 3 (1.00 eq) was added and the resulting mixture stirred for 16 h at rt. Purification method AThe solution was diluted with 50 mL of ethyl acetate and washed with a 10% (w/w)-solution (3x), sat.K2CO3-solution (3x) brine (1x). After drying over Na2SO4 the solvent removed under reducedpressure. The product was obtained after flash column chromatography (hexane/ethyl acetate). Purification method BThe reaction mixture was diluted with 50 mL of dH2O and the resulting precipitate collected byfiltration. The product was obtained after washing with dH2O (3x). |
Tags: 486-73-7 synthesis path| 486-73-7 SDS| 486-73-7 COA| 486-73-7 purity| 486-73-7 application| 486-73-7 NMR| 486-73-7 COA| 486-73-7 structure
[ 1214363-66-2 ]
[3,4'-Bipyridine]-6-carboxylic acid
Similarity: 0.90
[ 203626-75-9 ]
Isoquinoline-3-carboxylic acid hydrate
Similarity: 0.87
[ 203626-75-9 ]
Isoquinoline-3-carboxylic acid hydrate
Similarity: 0.87
[ 27104-73-0 ]
Methyl isoquinoline-3-carboxylate
Similarity: 0.79
[ 50458-79-2 ]
Ethyl 3-isoquinolinecarboxylate
Similarity: 0.76
[ 1416713-22-8 ]
6-Bromoisoquinoline-3-carboxylic acid
Similarity: 0.73
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 :