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CAS No. : | 16681-70-2 | MDL No. : | MFCD00039676 |
Formula : | C3H3N3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GTODOEDLCNTSLG-UHFFFAOYSA-N |
M.W : | 113.07 | Pubchem ID : | 140120 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 23.34 |
TPSA : | 78.87 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.32 cm/s |
Log Po/w (iLOGP) : | -0.23 |
Log Po/w (XLOGP3) : | -0.47 |
Log Po/w (WLOGP) : | -0.5 |
Log Po/w (MLOGP) : | -1.28 |
Log Po/w (SILICOS-IT) : | 0.2 |
Consensus Log Po/w : | -0.46 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -0.64 |
Solubility : | 25.8 mg/ml ; 0.228 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.72 |
Solubility : | 21.6 mg/ml ; 0.191 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.18 |
Solubility : | 75.1 mg/ml ; 0.664 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.43 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
4.18 g | at 300℃; | 3-Bromo-1-propyne (1a, 23.8 g, 0.200mol) was dissolved in methanol (100 mL), charged with sodium azide (11.8 g, 0.1815 mol) inwater (50 mL), and stirred at room temperature for 14 h. The mixture was added to a solution of sodium hydroxide (36.3 g, 0.908 mol) in methanol (700 mL) and heated under reflux for 2 h. Themethanol was evaporated and the residue diluted with water (400 mL). Potassium hydroxide (17.7g, 0.315 mol) was added to the solution, which was charged in portions with potassium permanganate (41.1 g, 0.259 mol). The mixture was stirred for 12 h at room temperature and,thereafter, heated at 70 °C for 3 h. The suspension was filtered and the clear filtrate dissolved in hydrochloric acid. During the evaporation of the volatiles, carboxylic acid 1269 crystallized in thecold solution. The solid was separated by filtration and heated at 300 °C in an open apparatus of recondensation to remove carbon dioxide. The triazole 13 (4.18 g, 60.5 mmol, 33percent, based onsodium azide) was isolated by recondensation (5·10−3 mbar) at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; acetone; | Preparation of N'-t-butyl-N-(1,2,3-triazole-4-carbonyl)-N'-(3-methylbenzoyl)hydrazine <strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong> (1.0 g) and triethylamine (0.9 g) were dissolved in 40 ml methylene chloride and cooled in an ice bath. Methanesulfonylchloride (1.0 g) was added dropwise. After addition was complete, the reaction mixture was stirred for 0.5 hours. N'-t-butyl-N'-(3-methylbenzoyl)hydrazine (1.84 g) in 10 ml CH2 Cl2 was added dropwise. The resulting mixture was allowed to stand for 14 hours. Aqueous sodium bicarbonate was added. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to give a yellow oil. Chromatography on silica gel using acetone as eluant afforded N'-t-butyl-N-1,2,3-triazole-4-carbonyl-N'-(3-methylbenzoyl)hydrazine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of 9-3 (2.Og, 3.6mMol), HOBT (0.5g, 3.9mMol), and 1H-1,2,3- triazole-4-carboxylic acid (0.4g, 3.9mMol) in anhydrous DMF (2OmL) was added DIEA (1.2mL, 7.2mMol) followed by EDC (0.76g, 3.9mMol). The solution was stirred at ambient temperature overnight. The solution was then treated with 2mL of acetic acid and was heated to 800C for 3hrs. Upon cooling to room temperature, the solution was filtered through a syringe filter and purified on a C18 reverse phase HPLC to give 9-4 as a solid. Mass (M+l) calculated: 631.2789 observed: 631.2778 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of 11-3 (0.2g, 0.36mMol), HOBT (0.05g, 0.4mMol), and IH-1, 2,3- triazole-4-carboxylic acid (0.05g, 0.4mMol) in anhydrous DMF (2mL) was added DIEA (0.18mL, 1. ImMoI) followed by EDC (0.08g, 0.4mMol). The solution was heated in the microwave reactor for 30 minutes at 800C. Solution was then treated with 0.5mL of acetic acid and was heated to 800C in the microwave reactor for lOmin. Upon cooling to room temperature, the solution was passed through a EPO <DP n="104"/>syringe filter and purified on a C18 reverse phase HPLC to give 11-4 as a solid. Mass (M+l) calculated: 632.2742 observed: 632.274 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of 21-3 (0.2g, 0.36mMol), HOBT (0.05g, 0.4mMol), and 1H-1,2,3- triazole-4-carboxylic acid (0.05g, 0.4mMol) in anhydrous DMF (2mL) was added DIEA (0.18mL,1. ImMoI) followed by EDC (0.08g, 0.4mMol). The solution was heated in the microwave reactor for 12 minutes at 800C. The solution was then treated with 0.5mL of acetic acid and was heated to 800C in the microwave reactor for and additional 10 minutes. Upon cooling to room temperature, the solution was passed through a syringe filter and purified on a Cl 8 reverse phase HPLC to yield 21-4 as the HCl salt. Mass (M+l) calculated: observed: LC/MS (M+l) calculated: 554.6; observed: 554.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With DIPEA; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; | B. (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (R7=H) (R)-4-Amino-5-biphenyl-4-yl-2-hydroxy-2-methyl-pentanoic acid ethyl ester (300 mg, 916 mumol, 1.0 eq.), <strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong> (114 mg, 1.0 mmol, 1.1 eq.), and DIPEA (479 muL, 2.8 mmol, 3.0 eq.) were dissolved in DMF (6.0 mL). HATU (383 mg, 1.0 mmol, 1.1 eq.) was added and the mixture was stirred at room temperature overnight. The mixture was split 50/50 and the two solutions were concentrated. One portion was purified by preparative HPLC (10-70% MeCN/water), followed by isomer separation by preparative HPLC to yield compound A (27 mg, 96% purity). MS m/z [M+H]+ calc'd for C23H26N4O4, 423.20; found 423.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (R4=H; R7=H) 1,2,3-Triazole-4-carboxylic acid (130 mg, 1.2 mmol, 1.2 eq.) and HATU (400 mg, 1.1 mmol, 1.1 eq.) were dissolved in DIPEA (167 muL) and the resulting mixture was stirred for 5 minutes at room temperature in DMF (0.2 mL). DIPEA (3 eq.) and (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (300 mg, 957 nmol, 1.0 eq.) dissolved in DMF (0.2 mL) was added, and the resulting mixture was stirred for 15 minutes. The reaction was quenched with AcOH and the product was purified by preparative HPLC then lyophilized to yield the title compound (120 mg, 95% purity). MS m/z [M+H]+ calc'd for C22H24N4O4, 409.18. found 409.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 muL, 969 mumol) and HATU (92 mg, 242 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-dimethylamino-ethyl ester (93 mg, 240 mumol), predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (30 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H33N5O4, 480.25. found 480.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 muL, 969 mumol) and HATU (92 mg, 242 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-piperidin-1-yl-ethyl ester (103 mg, 242 mumol), predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (40 mg; purity 95%). MS m/z [M+H]+ calc'd for C29H37N5O4, 520.28. found 520.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 muL, 969 mumol) and HATU (92 mg, 242 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid oxetan-3-yl ester (89.5 mg, 242 mumol), predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (17 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H28N4O5, 465.21. found 465.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 mumol), DIPEA (86.3 muL, 496 mumol) and HATU (47.1 mg, 124 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-morpholin-4-yl-2-oxo-ethyl ester (54 mg, 120 mumol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (35 mg; purity 95%). MS m/z [M+H]+ calc'd for C28H33N5O6, 536.24. found 536.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 mumol), DIPEA (86.3 muL, 496 mumol) and HATU (47.1 mg, 124 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid dimethylcarbamoylmethyl ester (49 mg, 120 mumol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (51 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H31N5O5, 494.23. found 494.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 mumol), DIPEA (86.3 muL, 496 mumol) and HATU (47.1 mg, 124 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid methoxycarbonylmethyl ester (47.8 mg, 124 mumol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (18 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H28N4O6, 481.20. found 481.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 mumol), DIPEA (86.3 muL, 496 mumol) and HATU (47.1 mg, 124 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid acetoxymethyl ester (47.8 mg, 124 mumol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (3 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H28N4O6, 481.20. found 481.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 mumol), DIPEA (86.3 muL, 496 mumol) and HATU (47.1 mg, 124 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid butyryloxymethyl ester (51 mg, 120 mumol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (1 mg; purity 95%). MS m/z [M+H]+ calc'd for C27H32N4O6, 509.23. found 509.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 mumol), DIPEA (86.3 muL, 496 mumol) and HATU (47.1 mg, 124 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid benzyloxycarbonylmethyl ester (57.2 mg, 124 mumol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (19 mg; purity 95%). MS m/z [M+H]+ calc'd for C31H32N4O6, 557.23. found 557.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 mumol), DIPEA (86.3 muL, 496 mumol) and HATU (47.1 mg, 124 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-(2-oxo-pyrrolidin-1-yl)-ethyl ester (52.6 mg, 124 mumol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (13 mg; purity 95%). MS m/z [M+H]+ calc'd for C28H33N5O5, 520.25. found 520.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 mumol), DIPEA (86.3 muL, 496 mumol) and HATU (47.1 mg, 124 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid ethoxycarbonyloxymethyl ester (51 mg, 120 mumol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (5 mg; purity 90%). MS m/z [M+H]+ calc'd for C26H30N4O2, 511.21. found 511.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 mumol), DIPEA (86.3 muL, 496 mumol) and HATU (47.1 mg, 124 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid benzyl ester (50 mg, 120 mumol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (13 mg; purity 95%). MS m/z [M+H]+ calc'd for C29H30N4O4, 499.23. found 499.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (45.2 mg, 400 mumol), DIPEA (209 muL, 1.2 mmol) and HCTU (165 mg, 400 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (S)-2-methoxycarbonylamino-3-methyl-butyryloxymethyl ester (200 mg, 400 mumol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (15 mg; purity 95%). MS m/z [M+H]+ calc'd for C30H37N5O8, 596.26. found 596.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (18 mg, 156 mumol), DIPEA (81.6 muL, 468 mumol) and HATU (59.3 mg, 156 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (S)-2-benzyloxycarbonylamino-3-methyl-butyryloxymethyl ester (90 mg, 160 mumol) dissolved in DMF (1 mL). The resulting mixture was stirred for 20 minutes and the solvent was evaporated. The remaining solid was dissolved in degassed 4.4% formic acid-methanol (5 mL) in a flask containing palladium black (~100 mg) under nitrogen. The mixture was continuously stirred at room temperature. The mixture was filtered and washed with MeOH. The solvent was evaporated and the product purified by preparative HPLC to yield the title compound (25 mg; purity 95%). MS m/z [M+H]+ calc'd for C28H35N5O6, 538.26. found 538.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1,2,3-Triazole-4-carboxylic acid (45.2 mg, 400 mumol), DIPEA (209 muL, 1.2 mmol) and HCTU (165 mg, 400 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester (193 mg, 400 mumol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The products were purified and separated by preparative HPLC, then lyophilized to yield to yield compound ZC (20 mg; purity 95%), MS m/z [M+H]+ calc'd for C31H38N4O2, 579.27. found 579.6, and compound ZD (15 mg; purity 95%), MS m/z [M+H]+ calc'd for C31H38N4O2, 579.27. found 579.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B. (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]-triazole-4-carbonyl)-amino]-pentanoic acid (R7=H) 1,2,3-Triazole-4-carboxylic acid (87.3 mg, 772 mumol, 1.5 eq.) was combined with HATU (293 mg, 772 mumol, 1.5 eq.) and DIPEA (179 muL, 2.0 eq.) and stirred for 5 minutes at room temperature in DCM (3 mL) to yield the activated acid. (2S,4S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-pentanoic acid ethyl ester (220 mg, 514 mumol, 1.0 eq.) was combined with DCM and TFA (1 mL each), and stirred at room temperature for 1 hour. The mixture was evaporated and azeotroped with toluene (2*). The activated acid was added and the resulting mixture was stirred for 2 hours. The reaction was quenched with water and extracted with DCM. The layers were separated, and the organic layer was dried and evaporated. Two-thirds of the product was purified by preparative HPLC to yield compound A (R7=-CH2CH3) (60 mg, 98% purity), MS m/z [M+H]+ calc'd for C23H26N4O4, 423.40. found 423.2. One-third of the product was hydrolyzed by adding 1 M of NaOH in water (619 muL) in THF (1 mL). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the resulting material purified by preparative HPLC to yield compound B (R7=H) (35 mg, 99% purity), MS m/z [M+H]+ calc'd for C21H22N4O4, 395.16. found 395.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide;Inert atmosphere; | C. (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]-triazole-4-carbonyl)-amino]-pentanoic acid 5-methyl-2-oxo-[1,3]-dioxol-4-ylmethyl ester (R7=-CH2-5-methyl-[1,3]-dioxol-2-one) (2S,4S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-pentanoic acid (75 mg, 190 mumol, 1.0 eq.), HOBt (76 mg, 560 mumol, 3.0 eq.), and EDCI (100 muL, 560 mumol, 3.0 eq.) were dissolved in DCM (2 mL). After stirring for 10 minutes, 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one (0.2 g, 1.5 mmol, 8.0 eq.) and 4-methylmorpholine (82 muL, 4.0 eq.) were added. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with DCM, and washed with water and saturated aqueous NaCl. The organic layer was collected and concentrated. MeCN (1.9 mL) and 4 M of HCl in dioxane (190 muL, 4.0 eq.) were added and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed to provide the intermediate HCl salt, which was used in the following coupling step. 1,2,3-Triazole-4-carboxylic acid (25 mg, 220 mumol, 1.2 eq.) and HATU (71 mg, 190 mumol, 1.0 eq.) were dissolved in DMF (1.5 mL), and the resulting solution was stirred for 5 minutes, followed by the addition of DIPEA (650 muL) and the intermediate HCl salt. The reaction was monitored and after 1 hour an additional equivalent of <strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong>, HATU, and DIPEA was added. The reaction was quenched with water and the product purified by preparative HPLC to yield the title compound (39.5 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H26N4O7, 507.18. found 507.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
F. (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester (R7=-CH(CH3)OCOO-cyclohexyl) (2S,4S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-pentanoic acid (50 mg, 120 mumol, 1.0 eq.), DMA (1 mL), DIPEA (0.13 mL, 0.75 mmol) and 1-chloroethyl cyclohexyl carbonate (52 mg, 250 mumol, 2.0 eq.) were combined. The reaction vessel was capped and microwaved at 80 C. for 2 hours. The mixture was dried under vacuum, dissolved in MeCN (2 mL), and combined with 4 M of HCl in dioxane (500 muL). The resulting mixture was stirred at room temperature for 30 minutes. The precipitate was filtered and discarded, and the filtrate containing the intermediate was concentrated down and submitted to next step. <strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong> (14 mg, 120 mumol, 0.5 eq.) and HATU (48 mg, 120 mumol, 1.0 eq) were dissolved in DMF (1 mL) and the resulting solution was stirred for 5 minutes, followed by the addition of DIPEA (44 muL) and the intermediate from last step. The mixture was stirred for 5 minutes. The reaction was quenched with water and the product dried under vacuum. The product was then purified by preparative HPLC to yield the title compound (4.8 mg, 95% purity. MS m/z [M+H]+ calc'd for C30H36N4O7, 565.26. found 565.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
G. (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid 1-isopropoxycarbonyloxy-ethyl ester (R7=-CH(CH3)OCOO-CH(CH3)2) (2S,4S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-pentanoic acid (50 mg, 120 mumol, 1.0 eq.), DMA (1 mL), DIPEA (0.13 mL) and 1-chloroethyl isopropyl carbonate (83 mg, 0.5 mmol, 4.0 eq.) were combined. The reaction vessel was capped and microwaved at 80 C. for 2 hours. The mixture was dried under vacuum, dissolved in MeCN (2 mL), and combined with 4 M of HCl in dioxane (500 muL). The resulting mixture was stirred at room temperature for 30 minutes. The precipitate was filtered and discarded, and the filtrate containing the intermediate was concentrated down and submitted to the next step. 1,2,3-Triazole-4-carboxylic acid (14 mg, 120 mumol, 0.5 eq.) and HATU (48 mg, 120 mumol, 1.0 eq) were dissolved in DMF (1 mL) and the resulting solution was stirred for 5 minutes, followed by the addition of DIPEA (44 muL) and the intermediate from last step. The mixture was stirred for 5 minutes. The reaction was quenched with water and the product dried under vacuum. The product was then purified by preparative HPLC to yield the title compound (6 mg; purity 95%). MS m/z [M+H]+ calc'd for C27H32N4O7, 525.23. found 525.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
H. (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]-triazole-4-carbonyl)-amino]-pentanoic acid 2-methanesulfonyl-ethyl ester (R7=-(CH2)2SO2CH3) (2S,4S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-pentanoic acid (100 mg, 250 mumol, 1.0 eq.), HOBt (0.1 g, 750 mumol, 3.0 eq.), and EDCI (130 muL, 3.0 eq.) were dissolved in DCM (2 mL). After stirring for 10 minutes, 2-(methylsulfonyl)-ethanol (250 mg, 2.0 mmol, 8.0 eq.) and 4-methylmorpholine (110 muL, 4.0 eq.) were added. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with water. The DCM layer was separated, concentrated, and the product purified by flash chromatography (70-100% EtOAc/hexanes over 15 minutes). The clean fractions were combined and concentrated. MeCN (2.5 mL) and 4 M of HCl in dioxane (250 muL, 4.0 eq.) were added and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed to provide the intermediate HCl salt, which was used in the following coupling step. 1,2,3-Triazole-4-carboxylic acid (28.3 mg, 250 mumol, 1.0 eq.) and HATU (95.2 mg, 250 mumol, 1.0 eq.) were dissolved in DMF (2.0 mL) and the resulting solution was stirred for 5 minutes, followed by the addition of DIPEA (131 muL) and the intermediate HCl salt. After 5 minutes, the reaction was quenched with water and the product purified by preparative HPLC to yield the title compound (64 mg; purity 95%). MS m/z [M+H]+ calc'd for C24H28N4O6S, 501.17. found 501.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
I. (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]-triazole-4-carbonyl)-amino]-pentanoic acid 2-morpholin-4-yl-ethyl ester (R7=-O-(CH2)2-morpholine)(2S,4S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-pentanoic acid (100 mg, 250 mumol, 1.0 eq.), HOBt (0.2 g, 1.5 mmol, 6.0 eq.), and EDCI (260 muL, 6.0 eq.) were dissolved in DCM (2 mL). After stirring for 10 minutes, 4-morpholineethanol (330 mg, 2.5 mmol) was added. The mixture was stirred at room temperature until the reaction was complete (3 hours). The mixture was then diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was separated, dried, and concentrated. MeCN (2.5 mL) and 4 M of HCl in dioxane (250 muL) were added and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed to provide the intermediate HCl salt, which was used in the following coupling step. 1,2,3-Triazole-4-carboxylic acid (28.3 mg, 250 mumol, 1.0 eq.) and HATU (95 mg, 250 mumol, 1.0 eq.) were dissolved in DMF (2.0 mL) and the resulting solution was stirred for 5 minutes, followed by the addition of DIPEA (87.2 muL) and the intermediate HCl salt. After 5 minutes, the mixture was diluted with EtOAc then washed with saturated aqueous NaHCO3. The organic layer was separated, concentrated and purified by preparative HPLC to yield the title compound (60 mg; purity 95%). MS m/z [M+H]+ calc'd for C27H33N5O5, 508.25. found 508.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid ethyl ester (R4=H; R7=-CH2CH3) 1,2,3-Triazole-4-carboxylic acid (11.5 mg, 102 nmol, 1.2 eq.) and HATU (38.6 mg, 102 nmol, 1.2 eq.) were dissolved in DMF (0.9 mL) and stirred at room temperature for 5 minutes. DIPEA (29.5 muL, 2.0 eq.) was added to yield the activated acid. (2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (35 mg, 85 mumol, 1.0 eq.) was dissolved in EtOH and 4 M of HCl in dioxane (423 muL) was added. The mixture was heated to 60 C. overnight, then concentrated to dryness and purified by reverse phase chromatography (5-60% MeCN in water over 18 minutes. The clean fractions were combined and dried under vacuum to dryness, then combined with the activated acid. After 20 minutes, the reaction was quenched with water and the product was dried under vacuum and purified by preparative HPLC to yield the title compound (4 mg, >95% purity. MS m/z [M+H]+ calc'd for C24H28N4O4, 437.21. found 437.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
D. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbon)-amino]-pentanoic acid 2-morpholin-4-yl ethyl ester (R4=H; R7=-(CH2)2-morpholine) (2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (300 mg, 726 mumol, 1.0 eq.), EDCI (770 muL, 6.0 eq.) and HOBt (590 mg, 4.4 mmol, 6.0 eq.) were dissolved in DCM (6 mL). After stirring for 2 minutes, 4-morpholineethanol (879 muL, 10.0 eq.) was added, and the resulting mixture was stirred for 3 hours at room temperature. The mixture was diluted with DCM and washed with saturated sodium bicarbonate. The organic layer was separated, dried and concentrated. The material was purified (reverse phase column: 5-60% MeCN in water with 0.05% TFA over 30 min; compound eluted between 35-45% MeCN in water) and the clean fractions were combined and lyophilized. MeCN (7.2 mL) and 4 M of HCl in dioxane (720 muL) were added to the lyophilized material. The resulting mixture was stirred at room temperature for 0.5 hour and then the solvent was removed to yield the intermediate. 1,2,3-Triazole-4-carboxylic acid (82 mg, 726 mumol, 1.0 eq.), HATU (280 mg, 720 mumol, 1.0 eq.) and DMF (5.8 mL) were combined and the resulting mixture was stirred for 5 minutes. DIPEA (505 muL, 4.0 eq.) and the intermediate were added, and the mixture was stirred for 30 minutes. The reaction was quenched with AcOH and the product was purified by preparative HPLC to yield the title compound (60 mg, 95% purity). MS m/z [M+H]+ calc'd for C28H35N5O5, 522.26. found 522.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
G. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid 2-methanesulfonyl-ethyl ester (R4=H; R7=-(CH2)2-SO2CH3) (2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (207 mg, 501 mumol, 1.0 eq.), HOBt (0.2 g, 1.5 mmol, 3.0 eq.), and EDCI (260 muL, 3.0 eq.) were dissolved in DCM (4 mL). After stirring for 2 minutes, 2-(methylsulfonyl)ethanol (0.5 g, 4.0 mmol, 8.0 eq.) and 4-methylmorpholine (220 muL) were added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water. The DCM layer was separated and concentrated, then purified by flash chromatography (10-100% EtOAc/hexanes). MeCN (2 mL) and 4 M of HCl in dioxane (0.5 mL) were added and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed to provide the intermediate HCl salt, which was used in the following coupling step. 1,2,3-Triazole-4-carboxylic acid (56.6 mg, 501 mumol, 1.0 eq.), HATU (190 mg, 501 mumol, 1.0 eq.) were dissolved in DMF (1 mL) and the resulting solution was stirred for 5 minutes, followed by the addition of DIPEA (262 muL) and the intermediate HCl salt. After 10 minutes, the reaction was quenched with AcOH and the product was purified by preparative HPLC to yield the title compound (28 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H30N4O6S, 515.19. found 515.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
H. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid isopropyl ester (R4=H; R7=-CH(CH3)2) (2S,4R)-4-Amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (76 mg, 242 mumol) in MeCN (0.4 mL, 8 mmol) and 4 M HCl in 1,4-dioxane (242 muL, 969 mumol) was combined with propan-2-ol (0.5 mL) at 60 C. The resulting mixture was stirred until solid precipitation was observed (~30 minutes). The solvent was evaporated under vacuum and the solids were azeotroped in toluene and dried under vacuum. 1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 muL, 969 mumol) and HATU (92 mg, 242 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with the dried solids, predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (38 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H30N4O4, 451.23. found 451.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
J. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid butyl ester (R4=H; R7=-(CH2)3CH3) (2S,4R)-4-Amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (76 mg, 242 mumol) in MeCN (0.4 mL, 8 mmol) and 4 M HCl in 1,4-dioxane (242 muL, 969 mumol) was combined with butan-1-ol (0.5 mL) at 60 C. The resulting mixture was stirred until solid precipitation was observed (~30 minutes). The solvent was evaporated under vacuum and the solids were azeotroped in toluene and dried under vacuum. 1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 muL, 969 mumol) and HATU (92 mg, 242 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with the dried solids, predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (30 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H32N4O4, 465.24. found 465.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
K. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid propyl ester (R4=H; R7=-(CH2)2CH3) (2S,4R)-4-Amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (76 mg, 242 mumol) in MeCN (0.4 mL, 8 mmol) and 4 M HCl in 1,4-dioxane (242 muL, 969 mumol) was combined with propan-1-ol (0.5 mL) at 60 C. The resulting mixture was stirred until solid precipitation was observed (~30 minutes). The solvent was evaporated under vacuum and the solids were azeotroped in toluene and dried under vacuum. 1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 muL, 969 mumol) and HATU (92 mg, 242 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with the dried solids, predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (24 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H30N4O4, 451.23. found 451.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
M. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid 3-methyl-butyl ester (R4=H; R7=-(CH2)2-CH(CH3)2) (2S,4R)-4-Amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (76 mg, 242 mumol) in MeCN (0.4 mL, 8 mmol) and 4 M HCl in 1,4-dioxane (242 muL, 969 mumol) was combined with 3-methyl-butan-1-ol (0.5 mL) at 60 C. The resulting mixture was stirred until solid precipitation was observed (~30 minutes). The solvent was evaporated under vacuum and the solids were azeotroped in toluene and dried under vacuum. 1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 muL, 969 mumol) and HATU (92 mg, 242 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with the dried solids, predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (28 mg; purity 95%). MS m/z [M+H]+ calc'd for C27H34N4O4, 479.26. found 479.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
N. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid pentyl ester (R4=H; R7=-(CH2)4CH3) (2S,4R)-4-Amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (76 mg, 242 mumol) in MeCN (0.4 mL, 8 mmol) and 4 M HCl in 1,4-dioxane (242 muL, 969 mumol) was combined with pentan-1-ol (0.5 mL) at 60 C. The resulting mixture was stirred until solid precipitation was observed (~30 minutes). The solvent was evaporated under vacuum and the solids were azeotroped in toluene and dried under vacuum. 1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 muL, 969 mumol) and HATU (92 mg, 242 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with the dried solids, predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (30 mg; purity 95%). MS m/z [M+H]+ calc'd for C27H34N4O4, 479.26. found 479.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
O. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid isobutyl ester (R4=H; R7=-CH2CH(CH3)2) (2S,4R)-4-Amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (76 mg, 242 mumol) in MeCN (0.4 mL, 8 mmol) and 4 M HCl in 1,4-dioxane (242 muL, 969 mumol) was combined with 2-methyl-propan-1-ol (0.5 mL) at 60 C. The resulting mixture was stirred until solid precipitation was observed (~30 minutes). The solvent was evaporated under vacuum and the solids were azeotroped in toluene and dried under vacuum. 1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 muL, 969 mumol) and HATU (92 mg, 242 mumol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with the dried solids, predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (36 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H32N4O4, 465.24. found 465.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | cyanopyrrolidin-1 -yl)-2-oxoethyl)-1 H-1 ,2,3-triazole-5-carboxamide 1 H-1 ,2,3-triazole-4-carboxylic acid (0,092 g, 0,814 mmol) was dispersed in dry dioxane (3m L) in a round bottom flask with nitrogen. To this 1 -chloro-N,N,2-trimethylprop-1 -en-1 -amine (0,151 ml, 1 ,139 mmol) was added and the reaction was stirred for 30 minutes at room temperature. The starting material dissolves over time, Then (S)-1 -(2-aminoacetyl)pyrrolidine-2-carbonitrile hydrochloride (0,247 g, 1 ,302 mmol) with N-ethyl-N-isopropylpropan-2-amine (0,307 ml, 1 ,709 mmol) was added and the mixture was stirred for 2h, evaporated to dryness and redissolved in ethyl acetate. Followed by washing with 0.1 N citric acid and saturated sodium bicarbonate and - - brine. After drying over sodium sulfate, filtration and evaporation, the product was purified using column chromatography. Yield: 34mg, 40% 1 H NMR (400 MHz, DMSO) (9/1 mixture of trans/cis amide rotamers) delta 15.53 (s, 1 H), 8.58 - 8.44 (s, 1 H), 8.39 (s, 1 H), 5.28 - 5.22 (m, 0.1 H), 4.77 (dd, J = 3.76, 7.32 Hz, 1 H), 4.30 (dd, J = 5.61 , 16.77 Hz, 0.2H), 4.10 (d, J = 5.76 Hz, 2H), 3.68 (ddd, J = 4.04, 7.68, 9.39 Hz, 1 H), 3.50 (td, J = 6.84, 9.09 Hz, 1 H), 2.31 - 1 .88 (m, 4H). UPLC I (ESI) Rt 0.72 min, m/z 249.6 [M+H]+ (96%) ; LC-MS (l-B) Rt 4.0 min, m/z 249.0 [M+H]+ (96%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
120 mg | 1,2,3-Triazole-4-carboxylic acid (130 mg, 1.2 mmol, 1.2 eq.) and HATU (400 mg, 1.1 mmol, 1.1 eq.) were dissolved in DIPEA (167 muL) and the resulting mixture was stirred for 5 minutes at room temperature in DMF (0.2 mL). DIPEA (3 eq.) and Compound 5 (300 mg, 957 mumol, 1.0 eq.) dissolved in DMF (0.2 mL) was added, and the resulting mixture was stirred for 15 minutes. The reaction was quenched with AcOH and the product was purified by preparative HPLC then lyophilized to yield Compound 6 as a TFA salt (120 mg, 95% purity). MS m/z [M+H]+ calc'd for C22H24N4O4, 409.18. found 409.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.5 g | With pyridine; In N,N-dimethyl-formamide; at 0 - 23℃; for 24h; | Preparation 1 1-Trityl-1H-<strong>[16681-70-2]1,2,3-triazole-4-carboxylic Acid</strong> <strong>[16681-70-2]1H-1,2,3-Triazole-4-carboxylic acid</strong> (20.0 g, 177 mmol) was combined with DMF (200 mL, 2.6 mol) and pyridine (100 mL, 1.2 mol), and the resulting mixture was cooled to 0 C. Triphenylmethyl chloride (54 g, 190 mmol) was added in portions and the mixture was stirred at room temperature for 24 hours. The resulting slurry was filtered and the filter cake was washed with water (2*200 mL) and air-dried yield an off white solid (60 g). The solid was slurried in THF (800 mL) at room temperature for 4 hours, then filtered. The filtrate was then concentrated by rotary evaporation, yielding a thick oil. EtOAc (500 mL) was added and the volume was reduced to 200 mL. The resulting thick slurry was filtered and dried to yield the title compound (35.5 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
287 mg | Preparation 14 (2S,4R)-5-(4-Bromophenyl)-2-hydroxymethyl-2-methyl-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic Acid (2S,4R)-5-(4-bromophenyl)-4-t-butoxycarbonylamino)-2-(hydroxymethyl)-2-methylpentanoic acid (1.0 g, 2.4 mmol) was combined with MeCN (20 mL). 4N HCl in dioxane 1.8 mL, 7.2 mmol) was added. The resulting mixture was stirred for 30 minutes then concentrated under reduced pressure. 1H-[1,2,3]Triazole-4-carboxylic acid (272 mg, 2.4 mmol) and HATU (959 mg, 2.5 mmol) were combined in DMF (2 mL) and stirred for 10 minutes. DIPEA (1.3 mL, 7.2 mmol) and Compound 1 in DMF (2 mL) were added and the resulting mixture was stirred for 30 minutes then concentrated. The residue was purified by reverse phase chromatography (20-100% MeCN in water) to yield the title compound (287 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 2h; | Compound 2 (35 mg, 83 mumol) was combined with HATU (38 mg, 100 mumol), <strong>[16681-70-2]1H-[1,2,3]triazole-4-carboxylic acid</strong> (12.3 mg, 108 mumol) in DMF (0.5 mL). DIPEA (43.7 muL, 250 mumol) was added and the mixture was stirred for 2 hours. EtOAc was added, followed by a saturated aqueous NH4Cl solution. The mixture was stirred for 10 minutes then concentrated under reduced pressure to yield Compound 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In 1,4-dioxane; acetonitrile; for 0.166667h; | Compound 1 (26.3 mg, 49 mumol) in MeCN (0.3 mL) was combined with 4N HCl in dioxane (0.3 mL). The mixture was stirred for 10 minutes then concentrated under reduced pressure to yield Compound 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 0.5h; | Compound 2 (18 mg, 47 mumol) was dissolved in DMF (0.3 mL) and <strong>[16681-70-2]1H-<strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong></strong> (5.3 mg, 47 mumol). HATU (18 mg, 47 mumol) was added, followed by DIPEA (25 muL, 141 mumol). The mixture was stirred for 30 minutes then concentrated under reduced pressure to yield Compound 3, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30 mg | 3A: (2S,4R)-5-(3'-Fluorobiphenyl-4-O-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)amino]pentanoic Acid 1,2,3-Triazole-4-carboxylic acid (27.3 mg, 241 mumol) was combined with EDC (42.7 muL, 241 mumol), 4-methylmorpholine (1 eq.) and HOBt (32.6 mg, 241 mumol) in DMF (0.2 mL). The resulting mixture was stirred for 5 minutes at room temperature. A solution (2S,4R)-4-amino-5-(3'-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (80 mg, 240 mumol) and 4-methylmorpholine (53.1 muL, 483 mumol) in DMF (0.3 mL) was added, and the resulting mixture was stirred for 15 minutes. The reaction was quenched with ACOH and the product was purified by preparative HPLC and lyophilized to yield the title compound (30 mg). MS m/z [M+H]+ calc'd for C22H23FN4O4, 427.17. found 427.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16 mg | 3B: (2S,4R)-5-(2'-Fluorobiphenyl-4-O-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]-triazole-4-carbonyl)amino]pentanoic Acid 1,2,3-Triazole-4-carboxylic acid (30 mg, 260 mumol) was combined with DIPEA (92.4 muL, 531 mumol) and HATU (101 mg, 265 mumol) in DMF (0.2 mL). The resulting mixture was stirred for 5 minutes at room temperature. A solution (2S,4R)-4-t-butoxycarbonylamino-5-(2'-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (114 mg, 265 mumol) and DIPEA (3 eq.) in DMF (0.2 mL) was added, and the resulting mixture was stirred for 15 minutes. The reaction was quenched with ACOH and the product was purified by preparative HPLC and lyophilized to yield the title compound (16 mg). MS m/z [M+H]+ calc'd for C22H23FN4O4, 427.17. found 427.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; | Step 3: 3,5-Dichlorobenzyl 4-(3-(1H-1,2,3-triazole-4-carboxamido)propyl)piperazine-1-carboxylate To <strong>[16681-70-2]1H-<strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong></strong> (32.7 mg, 0.289 mmol) in DMF (2 ml) was added HATU (110 mg, 0.289 mmol) and DIPEA (0.050 ml, 0.289 mmol). The resulting yellow solution was stirred for 10 mins and treated with 3,5-dichlorobenzyl 4-(3-amino propyl)piperazine-1-carboxylate (step 2) (100 mg, 0.289 mmol). After stirring at ambient temperature for 4 hrs, the mixture was diluted with EtOAc (50 ml) and washed with water (2*10 ml). The organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in DCM and applied to a 20 g silica cartridge eluting with 10% MeOH/DCM containing 1% aqueous 880 ammonia. The product fractions were concentrated to give 3,5-dichlorobenzyl 4-(3-(1H-1,2,3-triazole-4-carboxamido)propyl) piperazine-1-carboxylate as a white foam; LCMS: Rt=0.74 mins; MS m/z 439.2 and 441.2 [M-H] for chlorine isotopes; Method 2minLowpHv01 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | Step 2: Tert-butyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate To <strong>[16681-70-2]1H-<strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong></strong> (150 mg, 1.327 mmol) and tert-butyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (step 1) (322 mg, 1.327 mmol) in DMF (6 ml) was added DIPEA (0.695 ml, 3.98 mmol) and 50% T3P in DMF (1.549 ml, 2.65 mmol). The resulting orange solution was stirred for 4 hrs. The mixture was diluted with EtOAc (200 ml) and washed with 1M HCl (2*50 ml). The organics were dried (MgSO4) and concentrated under reduced pressure. The crude residue in was dissolved in DCM and applied to a 12 g silica cartridge eluting with 0-100% EtOAc/iso-hexane. The product fractions were concentrated to give tert-butyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate as a gum. LCMS: Rt=1.01 mins; MS m/z 338.5 [M+H]+; Method 2minLowpHv01 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 35 3,5-Dichlorobenzyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate The title compound was prepared analogously to Example 34, step 3 from <strong>[16681-70-2]1H-<strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong></strong> and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) (200 mg, 0.579 mmol); LCMS: Rt=1.23 mins; MS m/z 440.5 and 442.5 [M+H]+ for Cl isotopes; Method 2minLowpHv01 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Example 41 (S)-N-(2-(2-cyanopyrrolidine-1-yl)-2-oxoethyl)-1H-1,2,3-triazole-5-carboxamide <strong>[16681-70-2]1H-<strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong></strong> (0.092 g, 0.814 mmol) was dispersed in dry dioxane (3 mL) in a round bottom flask with nitrogen. To this 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.151 ml, 1.139 mmol) was added and the reaction was stirred for 30 minutes at room temperature. The starting material dissolves over time. Then (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile hydrochloride (0.247 g, 1.302 mmol) with N-ethyl-N-isopropylpropan-2-amine (0.307 ml, 1.709 mmol) was added and the mixture was stirred for 2 h, evaporated to dryness and redissolved in ethyl acetate. Followed by washing with 0.1N citric acid and saturated sodium bicarbonate and brine. After drying over sodium sulfate, filtration and evaporation, the product was purified using column chromatography. Yield: 34 mg, 40% 1H NMR (400 MHz, DMSO) (9/1 mixture of trans/cis amide rotamers) delta 15.53 (s, 1H), 8.58-8.44 (s, 1H), 8.39 (s, 1H), 5.28-5.22 (m, 0.1H), 4.77 (dd, J=3.76, 7.32 Hz, 1H), 4.30 (dd, J=5.61, 16.77 Hz, 0.2H), 4.10 (d, J=5.76 Hz, 2H), 3.68 (ddd, J=4.04, 7.68, 9.39 Hz, 1H), 3.50 (td, J=6.84, 9.09 Hz, 1H), 2.31-1.88 (m, 4H). UPLC I (ESI) Rt 0.72 min, m/z 249.6 [M+H]+ (96%); LC-MS (I-B) Rt 4.0 min, m/z 249.0 [M+H]+ (96%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of (E)-3-(4-chloro-2-((5-methyl-2 H-tetrazol-2-yl)methyl)phenyl)- 1 -(4-(pi peridi n-4- yl)piperazin-i-yl)prop-2-en-i-one, dihydrochloride salt (Example 149, step 2)(130 mg, 0.259 mmol), DIPEA (0.316 ml, 1.810 mmol) and 1H-i ,2,3-triazole-4-carboxylic acid (38.0 mg, 0.336 mmol) in DMF (1.5 ml) was added T3P, 50% solution in EtOAc (0.302 ml, 0.517mmol). The resultant mixture was stirred at room temperature over the weekend. Water (0.5 ml) was added and the solvent removed in vacuo. The residue was purified by reverse phase preparative HPLC to afford the title compound as the trifluoroacetate salt;LC-MS: Rt 0.87 mins; MS mlz 525.3 (M+H)+; Method 2minLowpHvo2 |
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 ethyl acetate; N,N-dimethyl-formamide; at 20℃; for 5h; | To a solution of (E)-1-(4-(2-aminoethyl)piperidin-1-yl)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2- yl)methyl)phenyl)prop-2-en-1-one (Example 145, step 2)(53 mg, 0.136 mmol), DIPEA (0.095ml, 0.545 mmol) and <strong>[16681-70-2]1H-<strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong></strong> (17 mg, 0.150 mmol) in DMF (2 ml)was added T3P, 50% solution in EtOAc (0.159 ml, 0.273 mmol). The resultant mixture was stirred at room temperature for 5 hours. Water (0.5 ml) was added and the mixture wasconcentrated in vacuo. The residue was purified by reverse phase preparative HPLC to afford the the title compound.LC-MS: Rt 1.01 mins; [M+H]+ 484.6 Method 2minLowpHvol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 22 1-Acetyl-3-{(R)-3-(5?-chloro-2?-fluorobiphenyl-4-yl)-2-[(3H-[1,2,3]triazole-4-carbonyl)amino]propyl}pyrrolidine-3-carboxylic Acid (isomers a and b) [0464] 1-Acetyl-3-[(R)-2-amino-3-(5?-chloro-2?-fluorobiphenyl-4-yl)propyl]pyrrolidine-3-carboxylic Acid (isomer a; 10 mg) dissolved in DMF. <strong>[16681-70-2]1H-<strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong></strong> (2 eq.), DIPEA (2 equiv.), and HATU (1 equiv.) were also dissolved in DMF and stirred at room temperature for a few minutes. The solutions were then combined and the resulting mixture stirred at room temperature until the reaction was complete (as seen by LCMS). The mixture was concentrated in vacuo and purified by preparative HPLC to yield the title compound (isomer a; 4.1 mg). LCMS (ESI): calc. C25H25ClFN5O4=513; obs. M+H=514.3. Retention time: 2.24 min. [0466] 1-Acetyl-3-[(R)-2-amino-3-(5?-chloro-2?-fluorobiphenyl-4-yl)propyl]pyrrolidine-3-carboxylic Acid (isomer b; (40 mg, 88 mumol, 1.0 eq.) and DIPEA (50 muL, 170 mumol, 2.0 eq.) were dissolved in DMF (0.2 mL). <strong>[16681-70-2]1H-<strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong></strong> (30 mg, 260 mumol, 3.0 eq.), DIPEA (90 muL, 340 mumol, 4.0 eq.) and HATU (65 mg, 170 mumol, 1.9 eq.), were dissolved in DMF (0.6 mL) and stirred at room temperature for 30 minutes. The solutions were then combined and the resulting mixture stirred at room temperature for ten minutes. The mixture was stirred for 20 minutes with an excess of 2N NaOH in MeOH and concentrated to dryness. It was then acidified to pH 3 with HCl and extracted with EtOAc. The organic phase was concentrated in vacuo and purified by preparative HPLC to yield the title compound (isomer b; 30 mg). LCMS (ESI): calc. C25H25ClFN5O4=513; obs. M+H=514.3. Retention time: 2.24 min. [0467] LC/MS Method: flow rate: 1.5 mL/min; Buffer A: 0.1% TFA/H2O; Buffer B 0.1% TFA/MeCN; gradient elution from 5-100% B over 3.6 minutes, then 100% B for 1.0 minute, detection at 254 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70 mg | [0664] To a solution of 3H-[1,2,3]triazole-4-carboxylicacid (77 mg, 688 flillOl) and HATU (130 mg, 344 f.tmol) inDMF (1.5 mL) was added DIPEA (160 f.LL, 920 flillOl). Themixture was stirred at room temperature for 20 minutes, followedby the addition of Compound 11 (140 mg, 210 f.tmol).The mixture was stirred at room temperature for 20 minutes,then the reaction was quenched with 10% aqueous citric acid(15 mL) to pH 4. The mixture was extracted with EtOAc(3x20 mL ), washed with saturated aqueous NaCl (1 0 mL) anddried over MgS04 . The mixture was filtered and the filtratewas evaporated. The residue was purified by flash chromatography(10-100% hexanes/EtOAc gradient over 45 minutes).The fractions containing the desired product were combinedand evaporated. The residue was dried in vacuo at roomtemperature overnight to yield Compound 12 (70 mg). LCMS(ESI): calc. C33H33ClFN50 5 =634.1; obs. rn/z 634.2[M+Ht. Retention time 5.96 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11 mg | 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 20℃; for 0.666667h;Inert atmosphere; | [0674] Compound 10 (32 mg, 75 fllllOl, 1.0 eq.) was dissolvedinDMF(500 f.LL). lH-<strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong>(25 mg, 221 f.tmol, 3.0 eq.) was dissolved in DMF (500 f.LL),followed by the additionofDIPEA (51 f.LL, 297 f.tmol, 4.0 eq.)and HATU ( 42 mg, 111 f.tmol, 1.5 eq.). The solutions werestirred at room temperature for 20 minutes, then combinedand stirred at room temperature for an additional 20 minutesand when the reaction was complete (as determined byLC/MS analysis), the mixture was diluted with water (0.5mL), the pH adjusted to 4 with 10% citric acid, then washedwith EtOAc (2x20 mL). The aqueous phase was discardedand the combined organics were extracted with saturatedaqueous NaCl (10 mL). The aqueous phase was discarded andthe organic phase was dried over Na2S04 , filtered, and concentratedin vacuo, and purified by preparative HPLC to yieldthe title compound (11 mg; purity 99.6% ). LCMS (ESI): calc.C27H31N50 4=489; obs. M+H=490.2. Retention time: 4.23mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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; for 0.5h;Inert atmosphere; | [0680] Compound 3a (7.0 mg, 16 f.tmol) was combinedwithDMF (0.5 mL), lH-1,2,3-triazole-5-carboxylic acid (2.0mg, 18 flillOl), HATU (6.8 mg, 18 flillOl) and DIPEA (8.5 f.LL,49 f.tmol). The mixture was stirred for 30 minutes after whichtime LCMS showed the desired product formation. The solutionwas concentrated in vacuo to yield Compound 4a whichwas used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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; for 0.5h;Inert atmosphere; | [0683] Compound 3b (7.0 mg, 16 f.tmol) was combinedwithDMF (0.5 mL), lH-1,2,3-triazole-5-carboxylic acid (2.0mg, 18 f.tmol), HATU (6.8 mg, 18 flillOl) and DIPEA (8.5 f.LL,49 f.tmol). The mixture was stirred for 30 minutes after whichtime LCMS showed the desired product formation. The solutionwas concentrated in vacuo to yield Compound 4b whichwas used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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; for 0.5h;Inert atmosphere; | [0688] Compound 3 (7 .0 mg, 16 f.tmol) was combined withDMF (0.5 mL), 1H-1,2,3-triazole-5-carboxylic acid (2.0 mg,18 f.tmol), HATU (6.8 mg, 18 f.tmol) and DIPEA (8.5 f.LL, 49f.tmol). The mixture was stirred for 30 minutes after whichtime LCMS showed the desired product formation, Compound4, which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0708] 18-1,2,3-triazole-5-carboxylic acid (1.1 mg, 10.0f.tmol) was combined with HATU (3.0 mg, 7.8 flillOl) in DMF(0.5 mL) and stirred for 10minutes; DIPEA (1 eq.)was addedand the mixture was stirred for 1 minute. Compound 2 (5.0mg, 11 f.tmol) was dissolved in DMF (1 mL) and DIPEA (5.8f.LL, 33 flillOl) was added, followed by addition of the activatedacid solution. The mixture was stirred for 30 minutes to yieldCompound3. | ||
lH-l,2,3-triazole-5-carboxylic acid (1.1 mg, 10.0 muiotaetaomicron) was combined with HATU (3.0 mg, 7.8 muiotaetaomicron) in DMF (0.5 mL) and stirred for 10 minutes; DIPEA (1 eq.) was added and the mixture was stirred for 1 minute. Compound 2 (5.0 mg, 11 muiotaetaomicron) was dissolved in DMF (1 mL) and DIPEA (5.8 mu^, 33 muiotaetaomicron) was added, followed by addition of the activated acid solution. yield Compound 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0713] <strong>[16681-70-2]3H-1,2,3-triazole-5-carboxylic acid</strong> (2.5 mg, 22f.tmol) was combined with HATU (8.4 mg, 22 fllllOl) in DMF(0.3 mL) and stirred for 10 minutes; Et3N (1 eq.) was addedand the mixture was stirred for 1 minute. Compound 2 (22f.tmol) was dissolved in DMF (0.5 mL) and Et3N (3.1 f.LL, 22f.tmol) was added, followed by addition of the activated acidsolution. The mixture was stirred for 30 minutes, concentrated,and purified by preparative HPLC to yield the titlecompound. MS m/z [M + Ht calc' d for C27H31 ClFN 50 4 , 544.21; found 544.2. | ||
3H-l,2,3-triazole-5-carboxylic acid (2.5 mg, 22 muiotaetaomicron) was combined with HATU (8.4 mg, 22 muiotaetaomicron) in DMF (0.3 mL) and stirred for 10 minutes; Et3N (1 eq.) was added and the mixture was stirred for 1 minute. Compound 2 (22 muiotaetaomicron) was dissolved in DMF (0.5 mL) and Et3N (3.1 mu, 22 muiotaetaomicron) was added, followed by addition of the activated acid solution. The mixture was stirred for 30 minutes, concentrated, and purified by preparative HPLC to yield the title compound. MS m/z [M+H]+ calc'd for C27H31CIFN5O4, 544.21 ; found 544.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0725] lH-1,2,3-triazole-5-carboxylic acid (2.3 mg, 20f.tmol) was combined with HATU (5.9 mg, 15 flillOI) in DMF(0.5 mL) and stirred for lOminutes; DIPEA (1 eq.)was addedand the mixture was stirred for 1 minute. Compound 2 (10.0mg, 22 f.tmol) was dissolved in DMF (1 mL) and DIPEA (11.6f.LL, 66 flillOI) was added, followed by addition of the activatedacid solution. The mixture was stirred for 30 minutes and thenconcentrated in vacuo to yield Compound 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.9 mg | [0734] A solution of Compound 1 (8.9 mg, 18 flillOI) in HCI(88 f.LL, 351 flillOI) was stirred at room temperature for 20minutes. After this time, LCMS indicated that the BOC grouphad been cleaved so the solution was concentrated in vacuo.In a separate flask, a solution of 3H-[1,2,3]triazole-4-carboxylicacid (2.4 mg, 21 f.tmol) and HATU (8.0 mg, 21 flillOI)in DMF (180 f.LL) was stirred at room temperature for 30minutes. After this time, a solution of the crude amine inDMF(180 f.LL) was added, followed by DIPEA (9.2 f.LL, 53 f.tmol).The resulting solution was stirred overnight at room temperature.LCMS indicated that the reaction was complete and thesolution was concentrated in vacuo to yield Compound 2 (8.9mg), which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.6 mg | [0738] To a solution of Compound 1 (9.7 mg, 18 f.tmol) indioxane (180 f.LL) was added HCI (92 f.LL, 368 flillOI). Theresulting solution was stirred at room temperature for 2 hours,and then concentrated in vacuo. In a separate flask, a solutionof 3H-[1,2,3]triazole-4-carboxylic acid (2.5 mg, 22 f.tmol)andHATU (8.4 mg, 22 f.tmol) inDMF (180 f.LL) was stirred atroom temperature for 30 minutes. After this time, a solution ofthe crude amine in DMF (180 f.LL) was added, followed byDIPEA (9.6 f.LL, 55 f.tmol). The resulting solution was stirredfor 1 hour at room temperature then concentrated in vacuowhen the reaction was deemed complete by LCMS to yieldCompound 2 (9.6 mg), which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16 mg | [0742] To a solution of Compound 1 (15.9 mg, 30 f.tmol) indioxane (0.3 mL) was added HCI (149 f.LL, 598 fllllOI). Theresulting solution was stirred at room temperature for 2 hours,and then concentrated in vacuo. In a separate flask, a solutionof 3H-[1,2,3]triazole-4-carboxylic acid (4.1 mg, 36 f.tmol)and HATU (14 mg, 36 f.tmol) in DMF (0.3 mL) was stirred atroom temperature for 30 minutes. After this time, a solution ofthe crude amine in DMF (0.3 mL) was added, followed byDIPEA (16 f.LL, 90 f.tmol). The resulting solution was stirredfor 1 hour at room temperature then concentrated in vacuowhen the reaction was deemed complete by LCMS to yieldCompound 2 (16 mg), which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0752] Compound 1 (4 mg, 50 f.tmol) was dissolved inMeCN (1 mL) and dry 4N HCI in dioxane (0.5 mL). Themixture was stirred for 1 0 minutes and then concentratedunder reduced pressure to yield Compound 2, which wascarried to the next step without purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.8 mg | [0760] lH-<strong>[16681-70-2]1,2,3-triazole-4-carboxylic acid</strong> (2.6 mg, 23f.tmol) was combined with HATU (9.6 mg, 25 flillOl) in DMF(3.0 mL) and stirred at room temperature for 15 minutes.Compound 2 (13 mg, 29 f.tmol) was dissolved in DIPEA (12f.LL, 69 f.tmol) and combined with the activated acid solution.The mixture was stirred at room temperature for 15 minutes,after which time LCMS indicated desired product formation.The solvent was removed in vacuo and the crude residue waspurified by reverse phase chromatography to yield Compoundb (0.8 mg) as a TFA salt. MS m/z [M+Ht calc'd forC25H27ClF3N50 3 , 538.18. found 538. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0758] <strong>[16681-70-2]3H-1,2,3-triazole-5-carboxylic acid</strong> (2.5 mg, 22f.tmol) was combined with HATU (8.4 mg, 22 flillOl) in DMF(0.3 mL) and stirred for 10 minutes; Et3N (1 eq.) was addedand the mixture was stirred for 1 minute. Compound 2 (22f.tmol) was dissolved in DMF (0.5 mL) and Et3N (3.1 f.LL, 22f.tmol) was added, followed by addition of the activated acidsolution. The mixture was stirred for 30 minutes and concentratedto yieldCompound3, which was carried to the next stepwithout purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7 mg | [0764] <strong>[16681-70-2]3H-1,2,3-triazole-5-carboxylic acid</strong> (2.5 mg, 22f.tmol) was combined with HATU (8.4 mg, 22 flillOI) in DMF(0.3 mL) and stirred for 10 minutes; Et3N (1 eq.) was addedand the mixture was stirred for 1 minute. Compound 2 (22f.tmol) was dissolved in DMF (0.5 mL) and Et3N (3.1 f.LL, 22f.tmol) was added, followed by addition of the activated acidsolution. The mixture was stirred for 30 minutes, concentrated,and purified by preparative HPLC to yield Compounda (7 mg) as a TFA salt. MS m/z [M+Ht calc'd forC26H29CIFN50 4 , 530.19. found 530.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8 mg | [0769] <strong>[16681-70-2]3H-1,2,3-triazole-5-carboxylic acid</strong> (2.5 mg, 22f.tmol) was combined with HATU (8.4 mg, 22 flillOI) in DMF(0.3 mL) and stirred for 10 minutes; Et3N (1 eq.) was addedand the mixture was stirred for 1 minute. Compound 2 (22f.tmol) was dissolved in DMF (0.5 mL) and Et3N (3.1 f.LL, 22f.tmol) was added, followed by addition of the activated acidsolution. The mixture was stirred for 30 minutes, concentrated,and purified by preparative HPLC to yield Compounda (8 mg) as a TFA salt. MS m/z [M+Ht calc'd forC26H29CIFN50 3 , 514.19. found 514.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8 mg | [0776] 38-1,2,3-triazole-5-carboxylic acid (3.0 mg, 27f.tmol) was combined with HATU (1 0.1 mg, 27 flillOl) in DMF(0.5 mL); DIPEA ( 4.7 f.LL, 27 f.tmol) was added and the mixturewas stirred for 5 minutes. Compound 2 (12 mg, 27 f.tmol)was dissolved in DMF (0.5 mL) and DIPEA (13.9 f.LL, 80f.tmol) and combined with the activated acid solution. Themixture was stirred for 10 minutes, at which time LCMSindicated the mass of the desired compound. The solvent wasremoved under reduced pressure and the residue was purifiedby reverse phase chromatography to yield Compound b (8mg) as a TFA salt. MS m/z [M+Ht calc'd forC22H33ClFN50 4 , 546.22. found 546. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0774] <strong>[16681-70-2]3H-1,2,3-triazole-5-carboxylic acid</strong> (2.5 mg, 22f.tmol) was combined with HATU (8.4 mg, 22 flillOI) in DMF(0.3 mL) and stirred for 10 minutes; Et3N (1 eq.) was addedand the mixture was stirred for 1 minute. Compound 2 (22f.tmol) was dissolved in DMF (0.5 mL) and Et3N (3.1 f.LL, 22f.tmol) was added, followed by addition of the activated acidsolution. The mixture was stirred for 30 minutes and concentratedto yieldCompound3, which was carried to the next stepwithout purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0780] <strong>[16681-70-2]3H-1,2,3-triazole-5-carboxylic acid</strong> (2.5 mg, 22f.tmol) was combined with HATU (8.4 mg, 22 f.tmol) in DMF(0.3 mL) and stirred for 10 minutes; Et3N (1 eq.) was addedand the mixture was stirred for 1 minute. Compound 2 (22f.tmol) was dissolved in DMF (0.5 mL) and Et3N (3.1 f.LL, 22f.tmol) was added, followed by addition of the activated acidsolution. The mixture was stirred for 30 minutes, concentrated,and purified by preparative HPLC to yield the titlecompound. MS m/z [M + Ht calc' d for C24H27CIFN 50 3 , 488.18; found 488.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 mg | [0784] 1H-1,2,3-triazole-5-carboxylic acid (3.4 mg, 30f.tmol) was combined with HATU (11 mg, 30 f.tmol) in DMF(0.3 mL) stirred at room temperature for 10 minutes; DIPEA(1 eq.) was added and the mixture was stirred for 1 minute.Compound 2 (10 mg, 30 f.tmol) was dissolved in DMF (0.5mL) and DIPEA (5.2 f.LL, 30 f.tmol) was added, followed byaddition of the activated acid solution. The mixture wasstirred at room temperature for 30 minutes, after which timeLCMS indicated desired product formation. Half of the crudeproduct was purified using reverse phase chromatography toyield Compound a as a TFA salt (1 mg). MS m/z [M+Htcalc'd for C26H31CIFN50 4 , 532.21. found 532. Half of thecrude product was carried to the next step without furtherpurification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.7 mg | [0789] lH-1,2,3-triazole-5-carboxylic acid (3.4 mg, 30f.tmol) was combined with HATU (11 mg, 30 f.tmol) in DMF(0.3 mL) and stirred at room temperature for 10 minutes;DIPEA (1 eq.) was added and the mixture was stirred for 1minute. Compound 2 (1 0 mg, 30 f.tmol) was dissolved in DMF(0.5 mL) and DIPEA (5.2 f.LL, 30 fllllOI) was added, followedby addition of the activated acid solution. The mixture wasstirred at room temperature for 30 minutes, after which timeLCMS indicated desired product formation. Half of the crudeproduct was purified using reverse phase chromatography toyield Compound a (7.7 mg) as a TFA salt. MS m/z [M+Hrcalc'd for C22H28CIFN60 3 , 539.19; found 539. Half of thecrude product was carried to the next step without furtherpurification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.1 mg | [0794] IH-1,2,3-triazole-5-carboxylic acid (3.4 mg, 30f.tmol) was combined with HATU (II mg, 30 f.tmol) in DMF(0.3 mL) stirred at room temperature for 10 minutes; DIPEA(I eq.) was added and the mixture was stirred for I minute.Compound 2 (10 mg, 30 f.tmol) was dissolved in DMF (0.5mL) and DIPEA (5.2 f.LL, 30 f.tmol) was added, followed byaddition of the activated acid solution. The mixture wasstirred at room temperature for 30 minutes, after which timeLCMS indicated desired product formation. Half of the crudeproduct was purified using reverse phase chromatography toyield Compound a (12.1 mg) as a TFA salt. MS m/z [M+Hrcalc'd for C28H33CIFN50 3 , 542.23. found 542. Half of thecrude product was used in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.4 mg | [0799] lH-1,2,3-triazole-5-carboxylic acid (3.4 mg, 30f.tmol) was combined with HATU (11 mg, 30 f.tmol) in DMF(0.3 mL) and stirred at room temperature for 10 minutes;DIPEA (1 eq.) was added and the mixture was stirred for 1minute. Compound 2 (1 0 mg, 30 f.tmol) was dissolved in DMF(0.5 mL) and DIPEA (5.2 f.LL, 30 fllllOI) was added, followedby addition of the activated acid solution. The mixture wasstirred at room temperature for 30 minutes, after which timeLCMS indicated desired product formation. Half of the crudeproduct was purified using reverse phase chromatography toyield Compound a (1.4 mg) as a TFA salt. MS m/z [M+Hrcalc'd for C26H22CIF3N50 3 , 550.18; found 550. Half of thecrude product was used in the next step without further purification. |
Tags: 16681-70-2 synthesis path| 16681-70-2 SDS| 16681-70-2 COA| 16681-70-2 purity| 16681-70-2 application| 16681-70-2 NMR| 16681-70-2 COA| 16681-70-2 structure
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