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CAS No. : | 13139-12-3 | MDL No. : | MFCD00037903 |
Formula : | C9H13NO5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VTGFSVGZCYYHLO-UHFFFAOYSA-N |
M.W : | 215.20 | Pubchem ID : | 83168 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 53.27 |
TPSA : | 72.91 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.17 cm/s |
Log Po/w (iLOGP) : | 2.07 |
Log Po/w (XLOGP3) : | 0.62 |
Log Po/w (WLOGP) : | 0.62 |
Log Po/w (MLOGP) : | 0.34 |
Log Po/w (SILICOS-IT) : | 0.16 |
Consensus Log Po/w : | 0.76 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.3 |
Solubility : | 10.8 mg/ml ; 0.05 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.73 |
Solubility : | 4.05 mg/ml ; 0.0188 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.75 |
Solubility : | 38.2 mg/ml ; 0.177 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.42 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P270-P272-P280-P301+P312-P302+P352-P330-P333+P313-P363-P403-P501 | UN#: | N/A |
Hazard Statements: | H302-H317 | 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 |
---|---|---|
54% | at -78 - 20℃; for 4.16667 - 4.25 h; | Example 26 2-R (AMINOCARBONYL) AMINOL-N-R (3S)-AZEPAN-3-VLL-5-(4-METHOXD7PHENVL) THIOPHENE-3 carboxamide hydrochloride (S)-3-AMINO-AZEPANE-1-CARBOXYLIC acid tert-butyl ester. (S)-Azepan-3-ylamine (5g ; 43.8 mmol) was dissolved in 100 mL of anhydrous CH2C12 and cooled to-78 °C while stirring with a magnetic stirring bar. In another flask N-(TERT-BUTOXYCARBONYLOXY) SUCCINIMIDE [BOC-OSU] (9.7 g; 45 mmol) was dissolved in 50 ML of anhydrous CH2C12. To the stirred solution of the amine was added the solution of the SUCCINIMIDE over a period of 10-15 minutes so as to keep the reaction mixture at-78 °C while stirring. After the addition was complete, the reaction was allowed to warm to room temperature and then stirred for an additional 4h or until the reaction was complete by TLC (Ninhydrin; Rf 0.3 ; 0.1 : 1: 10 NH4OH, MeOH ; CH2C12). The reaction mixture was washed with 50 mL of H20. The aqueous layer was brought to a pH >13 by the addition of 6N NAOH and extracted with CH2C12 (3 x 100 mL). The organic layer was dried over Na2C03, filtered, and concentracted in a vacuum to yield pure (S)-3-AMINO-AZEPANE-L-CARBOXYLIC acid tert- butyl ester as a viscous oil (5.1 g, 54percent). |
54% | at -78℃; for 4.16667 - 4.25 h; | tert-butyl (3S)-3-aminoazepane-1-carboxylate.; (3S)-azepan-3-amine (5g ; 43.8 mmol) was dissolved in 100 mL of anhydrous CH2Cl2 and cooled to-78 °C while stirring with a magnetic stirring bar. In another flask N- (tert-Butoxycarbonyloxy) succinimide [Boc-OSu] (9.7g ; 45 mmol) was dissolved in 50 mL of anhydrous CH2Cl2. To the stirred solution of the amine was added the solution of the succinimide over a period of 10-15 minutes so as to keep the reaction mixture at-78 °C while stirring. After the addition was complete, the reaction was allowed to warm to room temperature and then stirred for an additional 4h or until the reaction was complete by TLC (Ninhydrin; Rf 0. 3; 0.1 : 1 : 10 NH40H, MeOH ; CH2C12). The reaction mixture was washed with 50 mL of H20. The aqueous layer was brought to a pH >13 by the addition of 6N NaOH and extracted with CH2Cl2 (3 x 100mL). The organic layer was dried over Na2C03, filtered, and concentrated in vacuo to yield pure title compound as a viscous oil (5. 1g, 54percent). 1H NMR (d6-DMSO, d 3.4, m, 2H; d 2.89, m, 1H; d 2.71, m, 1H ; d 2.54, m, 1H; d 1.54, m, 3H; d 1.34, m, 3H ; d 1.27, s, 9H; d 1.12, m, 2H), LC/MS (APCI, ES, M+H=215). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at -40 - 20℃; | To a pre-cooled solution of (3-amino-1 -ethylpropyl)amine (1.27 mL, 10.6 mmol) in CH2CI2 (50 mL) at -40 0C was dropwisely added a pre-cooled solution of 1-([(1 ,1- dimethylethyl)oxy]carbonyl}oxy)-2,5-pyrrolidinedione (2.22 g, 10.3 mmol) in CH2CI2 (50 mL) via a cannula ) at -40 0C. After stirring for 3.5 hr at -40 0C, the reaction mixture was warmed up to rt and stirred overnight. The reaction was quenched with 1 N aqueous HCI (30 mL) and extracted with CH2CI2 (30 ml_ x 2). The aqueous solution was basified to pH 1 1-12 with cold 1 N aqueous NaOH followed by extraction with EtOAc (50 mL x 2). The combined organic solution was dried over K2CO3, filtered, and concentrated to provide the title compound which was used for the next reaction without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In chloroform; at 20℃; for 31h; | N-(tert-Butoxycarbonyloxy)succinimide (2.50 g, 11.62 mmol) inchloroform (30 mL) was added dropwise into the solution of1,4,7,10-tetraazacyclododecane (1.00 g, 5.80 mmol) in CHCl3(50 mL) during 7 h. The reaction mixture was stirred 24 h at roomtemperature and the solvent was removed under reduced pressure. The residue was suspended in aqueous NaOH (3 M, 50 mL) and theaqueous phase was extracted with CHCl3 (3 50 mL). The combinedextracts were dried with K2CO3 and evaporated to drynessto give 1,7-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane(10) in quantitative yield.1,3,5-Tris(bromomethyl)benzene (7.65 g, 21.62 mmol) was dissolvedin CHCl3 (150 mL) and Na2CO3 (1.71 g, 16.15 mmol) wasadded. Compound 10 (1.08 g, 2.90 mmol) in CHCl3 (50 mL) wasadded dropwise into the reaction mixture during 11 hours at52 C. The reaction mixture was refluxed for 3 days at 62 C,filtrated, and evaporated to dryness. The residue was purified bysilica gel chromatography (40-70% EtOAc in hexane), giving 11 in27% yield (0.722 g). 1H NMR (500 MHz, CDCl3) d 7.33 (s, 6H), 4.45(s, 8H), 3.71 (s, 4H), 3.21-3.57 (m, 8H), 2.55-2.68 (m, 8H), 1.27(s, 18H). 13C NMR (100 MHz, CDCl3) dppm 155.8, 140.8, 138.5,129.9, 128.3, 79.3, 59.5, 55.2, 46.1, 32.9, 28.4. HRMS(ESI): obsd.921.0840 [M+H]+, Calcd. 921.0795 [M+H]+. |
With sodium hydroxide; In chloroform; | Synthesis of 1,7-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane Cyclen (1.05 g) was dissolved in chloroform (50 mL), to which <strong>[13139-12-3]N-(tert-butoxycarbonyloxy)succinimide</strong> (2.62 g) was added, followed by stirring at room temperature. After 48 hours of stirring, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in chloroform (50 mL), washed with an aqueous solution of sodium hydroxide, and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the resulting product was dried in a vacuum to give the title compound (2.27 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In methanol; at 20℃; for 2h; | Crude (3i?,4i?)-4-aminopiperidin-3-ol (12 mmol) was dissolved in DCM (50 ml), methanol (10 ml) and DIEA (2.3 grams; 3 ml; 18 mmol; 3 equiv.). Boc-OSu (-[(tert- butoxycarbonyl)oxy]pyrrolidine-2,5-dione) (2.7 grams; 12.6 mmol; 1.05 equiv.) was added in a single portion. The reaction mixture was stirred at room temperature for 2 hours and monitored by TLC (90: 10: 1 CHCl3 / methanol / NH4OH). The reaction mixture was concentrated to an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In DMF (N,N-dimethyl-formamide); | 2-AMINO-6-BENZYLOXYCARBONYLAMINO-HEXANOATE (1.0 g, 2.68 mmol) was dissolved in N, N-DIMETHYLFORMAMIDE (50 mL) and then triethylamine (5.35 mmol, 0.75 ML) followed by N-(tert-butoxycarbonyloxy) succinimide (0.72 g, 3. 35 mmol) was added to the solution. The mixture was stirred overnight and then concentrated. The product was purified from the residue by silica gel chromatography (20% MEOH/CHLOROFORM) to give tert-butyl 6-BENZYLOXYCARBONYLAMINO-2-TERT-BUTOXYCARBONYLAMINO-HEXANOATE. The tri- protected product was reduced on a Parr hydrogenator (50 psi) to remove the benzyloxycarbonyl protecting group. The solvents were removed to give tert-butyl 6- amino-2-tert-butoxycarbonylamino-hexanoate (0.65 g, 80%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | In dichloromethane; at -78 - 20℃; for 4.16667 - 4.25h; | Example 26 2-R (AMINOCARBONYL) AMINOL-N-R (3S)-AZEPAN-3-VLL-5-(4-METHOXD7PHENVL) THIOPHENE-3 carboxamide hydrochloride (S)-3-AMINO-AZEPANE-1-CARBOXYLIC acid tert-butyl ester. (S)-Azepan-3-ylamine (5g ; 43.8 mmol) was dissolved in 100 mL of anhydrous CH2C12 and cooled to-78 C while stirring with a magnetic stirring bar. In another flask N-(TERT-BUTOXYCARBONYLOXY) SUCCINIMIDE [BOC-OSU] (9.7 g; 45 mmol) was dissolved in 50 ML of anhydrous CH2C12. To the stirred solution of the amine was added the solution of the SUCCINIMIDE over a period of 10-15 minutes so as to keep the reaction mixture at-78 C while stirring. After the addition was complete, the reaction was allowed to warm to room temperature and then stirred for an additional 4h or until the reaction was complete by TLC (Ninhydrin; Rf 0.3 ; 0.1 : 1: 10 NH4OH, MeOH ; CH2C12). The reaction mixture was washed with 50 mL of H20. The aqueous layer was brought to a pH >13 by the addition of 6N NAOH and extracted with CH2C12 (3 x 100 mL). The organic layer was dried over Na2C03, filtered, and concentracted in a vacuum to yield pure (S)-3-AMINO-AZEPANE-L-CARBOXYLIC acid tert- butyl ester as a viscous oil (5.1 g, 54%). |
54% | In dichloromethane; at -78℃; for 4.16667 - 4.25h; | tert-butyl (3S)-3-aminoazepane-1-carboxylate.; (3S)-azepan-3-amine (5g ; 43.8 mmol) was dissolved in 100 mL of anhydrous CH2Cl2 and cooled to-78 C while stirring with a magnetic stirring bar. In another flask N- (tert-Butoxycarbonyloxy) succinimide [Boc-OSu] (9.7g ; 45 mmol) was dissolved in 50 mL of anhydrous CH2Cl2. To the stirred solution of the amine was added the solution of the succinimide over a period of 10-15 minutes so as to keep the reaction mixture at-78 C while stirring. After the addition was complete, the reaction was allowed to warm to room temperature and then stirred for an additional 4h or until the reaction was complete by TLC (Ninhydrin; Rf 0. 3; 0.1 : 1 : 10 NH40H, MeOH ; CH2C12). The reaction mixture was washed with 50 mL of H20. The aqueous layer was brought to a pH >13 by the addition of 6N NaOH and extracted with CH2Cl2 (3 x 100mL). The organic layer was dried over Na2C03, filtered, and concentrated in vacuo to yield pure title compound as a viscous oil (5. 1g, 54%). 1H NMR (d6-DMSO, d 3.4, m, 2H; d 2.89, m, 1H; d 2.71, m, 1H ; d 2.54, m, 1H; d 1.54, m, 3H; d 1.34, m, 3H ; d 1.27, s, 9H; d 1.12, m, 2H), LC/MS (APCI, ES, M+H=215). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In pyridine; water; | EXAMPLE 20 The 1,1-dioxide of tert.-butyl 7-(tert.-butoxycarbonylamino)cephalosporanate Stage 1: 4.5 g (0.021 mole) of N-(tert.-butoxycarbonyloxy)succinimide are added to 6.6 g (0.02 mole) of tert.-butyl 7-aminocephalosporanate, dissolved in 25 ccs of pyridine. The mixture is stirred at room temperature for 7 hours, the pyridine is stripped off in vacuo and the residue is triturated in water with the addition of 2 N HCl and filtered off. 8.4 g of crude product are obtained which, after recrystallization from methanol/H2 O with the addition of active charcoal, gives 6.5 g of tert.-butyl 7-(tert.-butoxycarbonylamino)-cephalosporanate of melting point 145-146. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In dichloromethane; at 20℃; for 24h;Inert atmosphere; | N-(tert-Butoxycarbonyloxy)succinimide (36 mg, 0.15 mmol) was added to a solution of diprotected macrocycle 28a (50 mg, 0.1 mmol) in dichloromethane (7 mL). The solution was stirred at room temperature under an inert atmosphere. The reaction progress was monitored by TLC. After 24 hours, the reaction was complete. The solution was washed directly with saturated aqueous sodium chloride solution (3×10 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on a column of alumina (dichloromethane/methanol 90:10 to 70:30 in 5% increments) to give the desired compound 29a in the form of a brown oil (44 mg, 72%). 1H NMR (400 MHz, CDCl3) delta: 7.30-7.19 (m, 4H), 6.88-6.83 (m, 4H), 5.06-4.92 (m, 4H), 3.77 (s, 6H), 3.46-3.39 (m, 12H), 1.55 (s, 9H). 13C NMR (100 MHz, CDCl3) delta: 159.65; 156.56; 155.76; 130.04; 128.98; 114.00; 80.01; 67.15; 55.38; 49.74; 49.64; 49.47; 49.37; 49.12; 48.92; 48.80; 28.53; 27.75; 25.60. HMRS (ESI) calculated for C29H39N3O8 [M+H+], m/z 558.2815. found: 558.2808. |
72% | In dichloromethane; at 20℃; for 24h;Inert atmosphere; | N-(tert-Butoxycarbonyloxy)succinimide (Boc-OSu) (36 mg, 0.15 mmol) was added to a solution of diprotected macrocycle 5 (50 mg, 0.1 mmol) in dichloromethane (7 mL). The solution was stirred at room temperature under inert atmosphere. The progress of the reaction was monitored by TLC. After 24 h, reaction was complete. The solution was washed directly with water saturated with sodium chloride (3×10 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by alumina column chromatography (dichloromethane/methanol 90:10 to 70:30 in increments of 5%) to give compound 6 in the form of a brown-colored oil (44 mg, 72%). 1H NMR (400 MHz, CDCl3) delta: 7.30-7.19 (m, 4H), 6.88-6.83 (m, 4H), 5.06-4.92 (m, 4H), 3.77 (s, 6H), 3.46-3.39 (m, 12H), 1.55 (s, 9H). 13C NMR (100 MHz, CDCl3) delta: 159.65, 156.56, 155.76, 130.04, 128.98, 114.00, 80.01, 67.15, 55.38, 49.74, 49.64, 49.47, 49.37, 49.12, 48.92, 48.80, 28.53, 27.75, 25.60. HRMS (ESI+) calculated for C29H39N3O8 [M+H]+, m/z 558.2815. found: 558.2808. Rf=0.28 (silica; cyclohexane-ethyl acetate 50:50). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Synthesis oftert-butyl ((3R.4S.5S -l-(3-aminopyridin-4-vn-5-methyl-4-(N- methylacetamido)piperidin-3-yl)carbamate To a solution of di-tert-butyl 4-((3R,4S,5S)-3-(tert-butoxycarbonylamino)-5- methyl-4-(methylamino)piperidin-l-yl)pyridin-3-yliminodicarbonate (1.0 equiv.) in DCM (0.10 M) was added DIEA (3.0 equiv.) the reaction mixture was then cooled to 0 C. To this solution was added acetic anhydride (1.2 equiv.). The resulting mixture was at RT for 50 min. The reaction mixture was quenched with NaHC03 and diluted with EtOAc. The aqeuous layer was separated and extracted with EtOAc, the combined organics were then dried over MgS04 and concentrated in vacuo. 4 M HC1 (43.0 equiv.) in Dioxane was added to the residue. After lhr, the volatile was removed in vacuo. To the solution of the residue in DCM (0.10 M) at 0 C was added DIEA (3.0 equiv.) and BocOSu (1.0 equiv.). After 60 min at rt, The reaction mixture was quenched with NaHC03 and diluted with EtOAc. The aqeuous layer was seperated and extracted with EtOAc, the combined organics were then dried over MgS04 and concentrated in vaccuo to yield a yellow residue, which was purified by Si02 chromatography to yield tert-butyl ((3R,4S,5S)-l-(3- aminopyridin-4-yl)-5-methyl-4-(N-methylacetamido)piperidin-3-yl)carbamate in 60% yield. LC/MS (m/z) = 378.2 (MH+), R, = 0.50 min. 1HNMR (400 MHz, <cdcl3>) delta ppm 1.06 (d, J=7.83 Hz, 3 H), 1.39 - 1.50 (m, 9 H), 2.20 (br. s., 3 H), 2.34 - 2.48 (m, 1 H), 2.84 - 3.28 (m, 6 H), 3.77(d, J=18.00 Hz, 2 H), 4.19 - 4.62 (m, 1 H), 6.82 (d, J=5.09 Hz, 1 H), 7.97 (br. s., 1 H), 8.05 (br. s., 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8%; 9%; 14%; 15% | Synthesis of tert-butyl ((lR,2S.3S.5R -5-(3-aminopyridin-4-vn-3-methyl-2-(2- oxopyridin-l(2H)-yl)cyclohexyl)carbamate, tert-butyl ((l S,2R,3R,5S)-5-(3- aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin- 1 (2H)-yl)cyclohexyl)carbamate, tert-butyl ((lR,2S,3S,5R -5-(3-aminopyridin-4-vn-3-methyl-2-(pyridin-2- yloxy)cyclohexyl)carbamate and tert-butyl ((l S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3- methyl-2-(pyridin-2-yloxy)cyclohexyl)carbamate Single Enantiomer Single Enantiomer Single Enantiomer Single Enantiomer To a solution of (lR,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert- butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate (1.0 equiv.) CS2CO3 (3.0 equiv.) in DMF (0.15 M) was added pyridin-2-ol (1.0 equiv). The mixture was stirred at 70 C for 5 hrs. The reaction was worked up with EtOAc and Brine. The organic layer was concentrated and was treated with 4N HCl (30.0 equiv.) in Dioxane for 2 hrs at which time the volatiles were removed in vacuo. The redisue was dissolved in THF (0.15 M) and tert-butyl 2,5-dioxopyrrolidin-l-yl carbonate (1.5 equiv.) was added, followed by DIEA (3.0 equiv.). After stirring at rt for 3 hrs, the reaction was quenched with sat. NaHC03 and extracted with EtOAc. The organic layer was washed with Brine, dried over Na2S04 and concentrated. The crude was purified by prep HPLC to yield two major peaks. The fractions of the first product peak was combined and neutralized with sat. NaHC03 and extrtcted with EtOAc. The organic layer was washed with Brine, dried over Na2S04 and concentrated. Purification was completed via SFC (20% (MeOH with 10% DEA), 100 mL/min, AD column) to yield tert-butyl ((lR,2S,3S,5R)-5-(3- aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin-l(2H)-yl)cyclohexyl)carbamate (8% yield, 99%ee) and tert-butyl ((lS,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2- oxopyridin-l(2H)-yl)cyclohexyl)carbamate (9% yield, 99%ee). LC/MS (m/z) = 399.2 (MH+), R, = 0.60 min. 1H NMR (400 MHz, <dmso>) delta ppm 0.72 (s, 3 H), 1.30 (s, 9 H), 1.63 - 1.81 (m, 2 H), 1.89 - 2.00 (m, 2 H), 2.02 - 2.18 (m, 2 H), 3.04 - 3.13 (m, 1 H), 4.03 - 4.12 (m, 1 H), 4.91 - 5.02 (m, 1 H), 5.04 - 5.13 (m, 2 H), 6.17 - 6.26 (m, 1 H), 6.31 - 6.41 (m, 1 H), 6.98 - 7.07 (m, 1 H), 7.32 - 7.41 (m, 2 H), 7.68 - 7.74 (m, 1 H), 7.74 - 7.82 (m, 1 H), 7.85 - 7.90 (m, 1 H). The fractions of the second product peak was combined and neutralized with sat. NaHC03 and extrtcted with EtOAc. The organic layer was washed with Brine, dried over Na2S04 and concentrated. Purification was completed via SFC (20% (MeOH with 10% DEA), 100 mL/min, AD column) to yield tert-butyl ((lR,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(pyridin-2- yloxy)cyclohexyl)carbamate (14% yield, 99%ee) and tert-butyl ((lS,2R,3R,5S)-5-(3- aminopyridin-4-yl)-3-methyl-2-(pyridin-2-yloxy)cyclohexyl)carbamate (15% yield, 99%ee). LC/MS (m/z) = 399.2 (MH+), R, = 0.65 min. 1H NMR (400 MHz, <cdcl3>) delta ppm 0.95 (d, J=6.65 Hz, 3 H), 1.35 - 1.78 (m, 12 H), 1.97 - 2.08 (m, 2 H), 2.76 (t, J=1 1.93 Hz, 1 H), 3.72 (br. s., 2 H), 3.88 (d, J=4.70 Hz, 1 H), 5.43 (d, J=7.43 Hz, 1 H), 5.59 (br. s., 1 H), 6.79 - 6.94 (m, 2 H), 7.08 (d, J=5.09 Hz, 1 H), 7.56 - 7.65 (m, 1 H), 7.98 - 8.17 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In 1,4-dioxane; water; for 3h; | Synthesis of (+/- tert-butyl (Y lR,2S,3S,5R -5-(3-aminopyridin-4-vn-3-methyl-2- (methylsulfonvOcyclohexyOcarbamate To a solution of (+/-)S-((lS,2R,4R,6S)-2-((tert-butoxycarbonyl)amino)-4-(3-((tert- butoxycarbonyl)amino)pyridin-4-yl)-6-methylcyclohexyl) ethanethioate (1.0 equiv.) in MeOH (0.09 M) was added potassium carbonate (3.0 equiv.). The mixture was stirred for 15 minutes at which time methyl iodide (1.1 eq.) was added and the solution was stirred at rt for 15 minutes. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H20. The organic layer was washed with H20, NaCl(sa ), dried over MgS04, filtered, concentrated and purified by ISCO Si02 chromatography to yield the methyl sulfide product in 99% yield. LC/MS (m/z) = 452.3 (MH+), R, = 0.87 min. To a solution of methyl sulfide (1.0 eq.) in THF (0.05 M) at rt was added an aqueous solution of oxone (2.2 eq.) dropwise over 10 minutes. After stirring at rt for 1 hour the solution was partitioned between EtOAc and H20. The organic layer was washed with H20, NaCl(sat.), dried over MgS04, filtered, concentrated to yield the bis Boc protected methyl sulfone product in 95% yield. LC/MS (m/z) = 484.2 (MH+), R, = 0.77 min. The bis boc procteced cyclohexyl sulfone (1.0 equiv) was treated with 4M HC1 in dioxane for 3 hours to removed both Boc groups. Upon removal of the volatiles in vacuo, the residue was suspended in 1 : 1 dioxane/Na2C03 (sat.) and N-(tert- Butoxycarbonyloxy)succinimide (1.2 eq.) was added. After stirring for 1 hour, additional N-(tert-Butoxycarbonyloxy)succinimide (1.2 eq.) was added. After stirring for an additional 2 hours the solution was extracted with CH2C12, the combined organic layers were washed with H20, NaCl(sa ), dried over MgS04, filtered, concentrated and purified by ISCO Si02 chromatography to yield the (+/-)tert-butyl ((lR,2S,3S,5R)-5-(3- aminopyridin-4-yl)-3-methyl-2-(methylsulfonyl)cyclohexyl)carbamate in 56% yield. LC/MS (m/z) = 384.3 (MH+), R, = 0.57 min. Chiral purification was completed via SFC (20% EtOH/80% n-heptanes, 20 mL/min, OJ column) to isolate the pure enantiomers. The second peak correlated with tert-butyl ((lR,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3- methyl-2-(methylsulfonyl)cyclohexyl)carbamate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Synthesis of (+/-)-methyl (Yl S.2R.4R.6S)-4-(3-aniinopyridin-4-yl)-2-((tert- butoxycarbonyl)amino)-6-methylcyclohexyl)(methyl)carbamate To a solution of (+/-)-tert-butyl ((lR,2S,3S,5R)-5-(3-((tert- butoxycarbonyl)amino)pyridin-4-yl)-3-methyl-2-(methylamino)cyclohexyl)carbamate (1.0 equiv.) in DCM (0.05 M) at 0 C was added DIEA (3.0 equiv.) and then methyl chloroformate (1.5 equiv.). The homogeneous solution was left standing at 0 C at for 4 hrs. The reaction was quenched partitioned between NaHC03 solution and EtOAc. The organic layer was washed with Brine, dried over Na2S04, concentrated and purified by ISCO chromatography. The product was treated with 4 M HCl in dioxane (30.0 equiv.) at rt for 1 hour. The volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2CI2 (0.15 M DIEA (5.0 equiv.) and tert-butyl 2,5-dioxopyrrolidin-l-yl carbonate (1.6 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H20. The organic layer was washed with Na2C03(sat.)? NaCl(sat), dried over MgSC^, filtered, concentrated and purified by ISCO Si02 chromatography to yield (+/-)-methyl ((lS,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert- butoxycarbonyl)amino)-6-methylcyclohexyl)(methyl)carbamate in 20% yield. LC/MS (m/z) = 393.2 (MH+), R, = 0.60 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Synthesis of methyl ((3R.4S.5S -l-(3-aminopyridin-4-vn-3-((tert- butoxycarbonyl)amino)-5-methylpiperidin-4-yl)(methyl)carbamate To a solution of di-tert-butyl 4-((3R,4S,5S)-3-(tert-butoxycarbonylamino)-5- methyl-4-(methylamino)piperidin-l-yl)pyridin-3-yliminodicarbonate (1.0 equiv.) in DCM (0.10 M) was added DIEA (3.0 equiv.) the reaction mixture was then cooled to 0 C. To this solution was added methyl chloroformate (1.2 equiv.). The resulting mixture was at RT for 50 min. The reaction mixture was quenched with NaHC03 and diluted with EtOAc. The aqeuous layer was separated and extracted with EtOAc, the combined organics were then dried over MgS04 and concentrated in vaccuo. 4 M HC1 (43.0 equiv.) in dioxane was added to the residue. After lhr, the volatile was removed in vacuo. To the solution of the residue in DCM (0.10 M) at 0 C was added DIEA (3.0 equiv.) and BocOSu (1.0 equiv.). After 60 min at rt, The reaction mixture was quenched with NaHC03 and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc, the combined organics were then dried over MgS04 and concentrated in vaccuo to yield a yellow residue, which was purified by ISCO Si02 chromatography to yield methyl ((3R,4S,5S)- 1 -(3-aminopyridin-4-yl)-3-((tert-butoxycarbonyl)amino)-5- methylpiperidin-4-yl)(methyl)carbamate in 44 % yield. LC/MS (m/z) = 394.2 (MH+), R, = 0.59 min. 1H NMR (400 MHz, <cdcl3>) delta ppm 1.06 (d, J=7.04 Hz, 3 H), 1.40 - 1.52 (m, 10 H), 2.28 - 2.42 (m, 1 H), 2.89 (d, J=4.70 Hz, 2 H), 3.08 (dd, J=11.93 Hz, 4.50 Hz, 1 H), 3.15 (s, 3 H), 3.47 (dd, J=11.15, 4.11 Hz, 1 H), 3.67 - 3.79 (m, 5 H), 4.13 - 4.23 (m, 1 H), 4.56 - 4.77 (m, 1 H), 6.80 (d, J=5.09 Hz, 1 H), 7.97 (d, J=5.48 Hz, 1 H), 8.04 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Synthesis of tert-butyl (3S,4S,5R)-l-(3-aminopyridin-4-yl)-4-cyano-5-methylpiperidin-3- ylcarbamate Tert-butyl ((3S,4S,5R)-l-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-cyano- 5-methylpiperidin-3-yl)carbamate (1.0 equiv.) was treated with 4 M HC1 in dioxane (30.0 equiv.) at rt for 1 hour. The volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2C12 (0.05 M), DIEA (5.0 equiv.) and Boc-OSu (1.6 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H20. The organic layer was washed with Na2C03(sat.)? NaCl(sat), dried over MgSC^, filtered, concentrated to yield tert-butyl (3S,4S,5R)-l-(3-aminopyridin-4-yl)-4-cyano-5- methylpiperidin-3-ylcarbamate in 100% yield. LC/MS (m/z) = 332.1 (MH+), R, = 0.59 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Synthesis of tert-butyl (3R,4S,5S)-l-(3-aminopyridin-4-yl)-4-(4-(hvdroxymethyl)- 1H- 1 ,2,3-triazol- 1 -yl)-5-methylpiperidin-3-ylcarbamate To di-tert-butyl 4-((3R,4S,5S)-3-(tert-butoxycarbonylamino)-4-(4- (hydroxymethyl)- 1 H- 1 ,2,3-triazol- 1 -yl)-5 -methylpiperidin- 1 -yl)pyridin-3 - yliminodicarbonate (1.0 equiv.) was added 4 M HC1 (30.0 equiv.) in dioxane. After lhr, the volatile was removed in vacuo. To the solution of the residue in DCM (0.10 M) at 0 C was added DIEA (30.0 equiv.) and BocOSu (1.0 equiv.). After 4 hrs at rt, the reaction mixture was quenched with NaHC03 and diluted with EtOAc. The aqeuous layer was seperated and extracted with EtOAc, the combined organics were then dried over MgS04 and concentrated in vacuo to yield a yellow residue, which was purified by ISCO Si02 chromatography to yield tert-butyl (3R,4S,5S)-l-(3-aminopyridin-4-yl)-4-(4- (hydroxymethyl)-lH-l,2,3-triazol-l-yl)-5-methylpiperidin-3-ylcarbamate in 57% yield. LC/MS (m/z) = 404.3 (MH+), R, = 0.47 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at -78 - 20℃; | Step C: To a solution of I-lb (32.83 g, 0.288 mol) in CH2C12 (1300 mL) at -78C was added dropwise a solution of BocOSu (51.13 g, 1.345 mol) in CH2C12 (400 mL). The mixture was stirred at room temperature overnight, treated with H20 (400 mL) and the organic phase was separated and discarded. The aqueous layer was basified to pH-13with solid NaOH and extracted with CH2C12. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (Intermediate 1) as a yellow oil. 1H-NMR (400 MHz, CDC13): 3.74-3.42 (m, 2H), 3.28-3.18 (m, 1H), 3.11-3.01 (m, 1H), 2.97-2.88 (m, 1H), 1.88-1.50 (m, 4H), 1.48 (s, 9H),1.45-1.23 (m, 4H); MS calculated for C11H23N202 (M+H) 215.17, found 215.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In 1,4-dioxane; for 3h; | Synthesis of (+/-)-tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(methylsulfonyl)cyclohexyl)carbamate To a solution of (+/-)S-((lS,2R,4R,6S)-2-((tert-butoxycarbonyl)amino)-4-(3-((tert- butoxycarbonyl)amino)pyridin-4-yl)-6-methylcyclohexyl) ethanethioate (1.0 equiv.) in MeOH (0.09 M) was added potassium carbonate (3.0 equiv.). The mixture was stirred for 15 minutes at which time methyl iodide (1.1 eq.) was added and the solution was stirred at rt for 15 minutes. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H20. The organic layer was washed with H20, NaCl(sat.), dried over MgS04, filtered, concentrated and purified by ISCO Si02 chromatography to yield the methyl sulfide product in 99% yield. LC/MS (m/z) = 452.3 (MH+), R, = 0.87 min. To a solution of methyl sulfide (1.0 eq.) in THF (0.05 M) at rt was added an aqueous solution of oxone (2.2 eq.) dropwise over 10 minutes. After stirring at rt for 1 hour the solution was partitioned between EtOAc and H20. The organic layer was washed with H20, NaCl(sat), dried over MgS04, filtered, concentrated to yield the bis Boc protected methyl sulfone product in 95% yield. LC/MS (m/z) = 484.2 (MH+), R, = 0.77 min. The bis boc procteced cyclohexyl sulfone (1.0 equiv) was treated with 4M HC1 in dioxane for 3 hours to removed both Boc groups. Upon removal of the volatiles in vacuo, the residue was suspended in 1 : 1 dioxane/Na2C03 (sat.) and N-(tert- Butoxycarbonyloxy)succinimide (1.2 eq.) was added. After stirring for 1 hour, additional N-(tert-Butoxycarbonyloxy)succinimide (1.2 eq.) was added. After stirring for an additional 2 hours the solution was extracted with CH2C12, the combined organic layers were washed with H20, NaCl(sa ), dried over MgS04, filtered, concentrated and purified by ISCO Si02 chromatography to yield the (+/-)tert-butyl ((lR,2S,3S,5R)-5-(3- aminopyridin-4-yl)-3-methyl-2-(methylsulfonyl)cyclohexyl)carbamate in 56% yield. LC/MS (m/z) = 384.3 (MH+), R, = 0.57 min. Chiral purification was completed via SFC (20% EtOH/80% n-heptanes, 20 mL/min, OJ column) to isolate the pure enantiomers. The second peak correlated with tert-butyl ((lR,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3- methyl-2-(methylsulfonyl)cyclohexyl)carbamate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | Synthesis of (+/- -methyl ( ( 1 S.2R,4R,6SV4-(3-aminopyridin-4-yr)-2-( (tert- butoxycarbonyl)amino)-6-methylcvclohexyl)(methyl)carbamate To a solution of (+/-)-tert-butyl ((lR,2S,3S,5R)-5-(3-((tert- butoxycarbonyl)amino)pyridin-4-yl)-3-methyl-2-(methylamino)cyclohexyl)carbamate (1.0 equiv.) in DCM (0.05 M) at 0 C was added DIEA (3.0 equiv.) and then methyl chloroformate (1.5 equiv.). The homogeneous solution was left standing at 0 C at for 4 hrs. The reaction was quenched partitioned between NaHC03 solution and EtOAc. The organic layer was washed with Brine, dried over Na2S04, concentrated and purified by ISCO chromatography. The product was treated with 4 M HCl in dioxane (30.0 equiv.) at rt for 1 hour. The volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2C12 (0.15 M), DIEA (5.0 equiv.) and tert-butyl 2,5-dioxopyrrolidin-l-yl carbonate (1.6 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H20. The organic layer was washed with Na2C03(sat.), NaCl(Sat), dried over MgS04, filtered, concentrated and purified by ISCO Si02 chromatography to yield (+/-)-methyl ((lS,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert- butoxycarbonyl)amino)-6-methylcyclohexyl)(methyl)carbamate in 20% yield. LC/MS (m/z) = 393.2 (MH+), R, = 0.60 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of methyl ((3R.4S.5S -l-(3-aminopyridin-4-vn-3-((tert- butoxycarbonyl)amino)-5-methylpiperidin-4-yl)(methyl)carbamate To a solution of di-tert-butyl 4-((3R,4S,5S)-3-(tert-butoxycarbonylamino)-5- methyl-4-(methylamino)piperidin-l-yl)pyridin-3 -yliminodicarbonate (1.0 equiv.) in DCM (0.10 M) was added DIEA (3.0 equiv.) the reaction mixture was then cooled to 0 C. To this solution was added methyl chloro formate (1.2 equiv.). The resulting mixture was at RT for 50 min. The reaction mixture was quenched with NaHC03 and diluted with EtOAc. The aqeuous layer was separated and extracted with EtOAc, the combined organics were then dried over MgS04 and concentrated in vaccuo. 4 M HC1 (43.0 equiv.) in dioxane was added to the residue. After lhr, the volatile was removed in vacuo. To the solution of the residue in DCM (0.10 M) at 0 C was added DIEA (3.0 equiv.) and BocOSu (1.0 equiv.). After 60 min at rt, The reaction mixture was quenched with NaHC03 and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc, the combined organics were then dried over MgS04 and concentrated in vaccuo to yield a yellow residue, which was purified by ISCO Si02 chromatography to yield methyl ((3R,4S ,5 S)- 1 -(3 -aminopyridin-4-yl)-3 -((tert-butoxycarbonyl)amino)-5 - methylpiperidin-4-yl)(methyl)carbamate in 44 % yield. LC/MS (m/z) = 394.2 (MH+), R, = 0.59 min. 1H NMR (400 MHz, <cdcl3>) delta ppm 1.06 (d, J=7.04 Hz, 3 H), 1.40 - 1.52 (m, 10 H), 2.28 - 2.42 (m, 1 H), 2.89 (d, J=4.70 Hz, 2 H), 3.08 (dd, J=1 1.93 Hz, 4.50 Hz, 1 H), 3.15 (s, 3 H), 3.47 (dd, J=1 1.15, 4.1 1 Hz, 1 H), 3.67 - 3.79 (m, 5 H), 4.13 - 4.23 (m, 1 H), 4.56 - 4.77 (m, 1 H), 6.80 (d, J=5.09 Hz, 1 H), 7.97 (d, J=5.48 Hz, 1 H), 8.04 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of tert-butyl (Y3R.4S.5 S 1 -(3-aminopyridin-4-ylV5-methyl-4-(N- methylacetamido)piperidin-3-yl)carbamate To a solution of di-tert-butyl 4-((3R,4S,5S)-3-(tert-butoxycarbonylamino)-5- methyl-4-(methylamino)piperidin-l-yl)pyridin-3-yliminodicarbonate (1.0 equiv.) in DCM (0.10 M) was added DIEA (3.0 equiv.) the reaction mixture was then cooled to 0 C. To this solution was added acetic anhydride (1.2 equiv.). The resulting mixture was at RT for 50 min. The reaction mixture was quenched with NaHC03 and diluted with EtOAc. The aqeuous layer was separated and extracted with EtOAc, the combined organics were then dried over MgS04 and concentrated in vacuo. 4 M HC1 (43.0 equiv.) in Dioxane was added to the residue. After lhr, the volatile was removed in vacuo. To the solution of the residue in DCM (0.10 M) at 0 C was added DIEA (3.0 equiv.) and BocOSu (1.0 equiv.). After 60 min at rt, The reaction mixture was quenched with NaHC03 and diluted with EtOAc. The aqeuous layer was seperated and extracted with EtOAc, the combined organics were then dried over MgS04 and concentrated in vaccuo to yield a yellow residue, which was purified by Si02 chromatography to yield tert-butyl ((3R,4S,5S)-l-(3- aminopyridin-4-yl)-5-methyl-4-(N-methylacetamido)piperidin-3-yl)carbamate in 60% yield. LC/MS (m/z) = 378.2 (MH+), R, = 0.50 min. 1HNMR (400 MHz, <cdcl3>) delta ppm 1.06 (d, J=7.83 Hz, 3 H), 1.39 - 1.50 (m, 9 H), 2.20 (br. s., 3 H), 2.34 - 2.48 (m, 1 H), 2.84 - 3.28 (m, 6 H), 3.77(d, J=18.00 Hz, 2 H), 4.19 - 4.62 (m, 1 H), 6.82 (d, J=5.09 Hz, 1 H), 7.97 (br. s., 1 H), 8.05 (br. s., 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | In dichloromethane; at 20℃; for 24h; | N-(tert-Butoxycarbonyloxy)succinimide (630 mg, 2.93 mmol) was added to a solution of diMOZ macrocycle 28b (980 mg, 1.96 mmol) in dichloromethane (40 mL). The reaction mixture was stirred at room temperature for 24 hours. The reaction progress was monitored by TLC. After this period, the reaction was complete. The solution was washed with saturated aqueous sodium chloride solution (2×20 mL). The aqueous phases were combined and extracted with dichloromethane (2×30 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on a column of alumina (cyclohexane/ethyl acetate 100:0 to 70:30 in 5% increments) to give the desired compound 29b in the form of an oil (507 mg, 42%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h; | S nthesis of intermediatesTo a solution of 5' trifluoroacetate salt (380 mg, 0.387 mmol) in DMF (5 mL) and diisopropylethylamine (0.50 mL) was added a solution of BocOSu (91.5 mg, 0.425 mmol) in DMF (2 mL). The reaction was stirred at room temperature for 4 h, then the reaction mixture loaded onto a 50 g C 18 Isco column. Eluting with 5% to 75% acetonitrile in water with 0.1% AcOH yielded 6' (338 mg, 0.349 mmol, 90% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at -40 - 20℃; for 2h; | Synthesis of intermediatesTo a solution of octreotide acetate (545 mg, 0.505 mmol) in DMF (10 mL) was added diisopropylethylamine (0.50 mL). The solution was then cooled to -40 C, and a solution of BocOSu (119 mg, 0.553 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred at -40 C for 1 h, then gradually warmed up to room temperature over 1 h. Most of the DMF was removed in vacuo, and the remaining residue was loaded onto a 50 g C18 Isco column. Elution with 15% to 60% acetonitrile in water with 0.1% AcOH gave Lys-Boc octreotide acetate (54', 440 mg, 0.373 mmol, 74% yield) with >95% regioselectivity by XH NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at -40 - 20℃; for 3h; | EXAMPLE 1 : Synthesis of Conjugate 1To a solution of octreotide acetate (2.08 g, 1.93 mmol) in DMF (20 mL) and diisopropylethylamine (2.0 mL), cooled to -40 C, was added a solution of BocOSu (419 mg, 1.95 mmol) in DMF (5 mL) dropwise. The reaction was gradually warmed to room temperature, over 3 hours. Most of the DMF was removed, and the reaction mixture loaded onto a CI 8 column, eluting with 15% to 60% acetonitrile in water with 0.1% AcOH, to give the product as the acetate salt (1.53 g, 1.30 mmol,- Boc + 2H)/2. |
67% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at -40 - 20℃; for 3h; | [00629j To a solution of octreotide acetate (2.08 g, 1.93 mmoi) in DMF (20 itT.) and diisopropyiethyianiine (2.0 niL). cooled to -40 C, was added a solution of BocOSu (419 mg, 1,95 mmol) in DMF (5 mL) dropwise. The reaction was gradually warmed to room teniperature, over 3 hours. Most of the DMF was removed, and the reaction mixture loaded onto a Cl 8 column, eluting with 15% to 60% acetonitrile it water with 0.1% AeOH, to give the product as the acetate salt (1.53 g, 1.30 mmol, 67% yield). LCMS mIz: 510.3 (M Boc f 2H)/2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | 7.0 g of (S,E)-7-tert-butyl 1-methyl 6-(bis(tert-butoxycarbonyl)amino)hept-2-enedioate (15.8 mmol) are dissolve in 40 mL of dichloromethane and added into the solution of 70 mL of trifluoroacetic acid. It is stirred at RT for 4 h. The solvent is removed in vacuo and the green residue is dried under high vacuum. The obtained oil is further used without purification. By successive addition of DIPEA the pH value is adjusted to ca. 7. The oil is taken up in 50 mL of DMF and treated with 5.37 mL of DIPEA. 4.08 g of Boc-OSu (18.9 mmol, 1.2 eq) are added and stirred at RT overnight. The solvent is removed in vacuo and the residue is suspended in 130 mL of 5% KHSO4 solution. It is extracted with ethyl acetate (1×150 mL, 2×100 mL) and the corrected organic phases are washed with brine (75 mL). After drying of the organic phase over Na2SO4 the solvent is removed in vacuo. The residue is purified by chromatography on silica gel (column: 13*6.0 cm, toluene/ethyl acetate 65:35, 0.5% acetic acid). Colorless oil is obtained.Column chromatography: collected in 200 mL fractions, product: fractions 2-5, first running 500 mLTLC control: toluene/ethyl acetate 1:1, 0.5% acetic acid, Rf=0.35Yield: 4.04 g, 14.1 mmol, 89% (purity 88.6%)ESI-MS: 310.1 [M+Na]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
201 mg | 590 mg of (S,E)-methyl 7-(1-(2-tert-butoxy-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl-amino)-6-(tert-butoxycarbonylamino)-7-oxohept-2-enoate (ZED1209, 1.20 mmol) are dissolved in 10 mL of dichloromethane and to this solution 10 mL of trifluoroacetic acid is added. It is stirred at RT for 1 h. The solvent is removed in vacuo and the residue is dried under high vacuum. The obtained oil is further reacted without purification. The oil is taken up in 15 mL of DMF and treated with 173 muL of DIPEA. By successive addition of DIPEA the pH value is adjusted to ca. 7. To this solution, 285 mg of Boc-OSu (1.1 eq) are added and stirred at RT overnight. The solvent is removed in vacuo and the residue is purified by preparative HPLC (30% ACN in water, 8 mL/min, gradient 1% pro min).Yield: 201 mg, 0.46 mmol, 38%ESI-MS: 438.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | 972 mg of (S,E)-7-tert-butyl 1-ethyl 6-(bis(tert-butoxycarbonyl)amino)hept-2-enedioate (ZED724, 2.12 mmol) are dissolve in 15 mL of dichloromethane and to this solution 15 mL of trifluoroacetic acid is added. It is stirred at RT for 2 h. The solvent is removed in vacuo and the residue is dried under high vacuum. The obtained oil is further reacted without purification.The oil is taken up in 30 mL DMF and treated with 361 muL of DIPEA. By successive addition of DIPEA the pH value is adjusted to ca. 7. 502 mg of Boc-OSu (2.33 mmol, 1.1 eq) are added and stirred at RT overnight. The solvent is removed in vacuo and the residue is purified by chromatography on silica gel (column: 23*6.0 cm, dichloromethane/methanol 9:1). Colorless oil is obtained.Column chromatography: corrected in 50 mL fractions, product: fractions 35-80TLC control: Dichloromethane/Methanol 9:1, Rf=0.21Yield: 249 mg, 0.83 mmol, 39%ESI-MS: 302.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | 518 mg of (S,E)-7-tert-butyl 1-isopropyl 6-(bis(tert-butoxycarbonyl)amino)hept-2-enedioate (ZED855, 1.10 mmol) are dissolve in 10 mL of dichloromethane and to this solution 10 mL of trifluoroacetic acid is added. It is stirred at RT for 2 h. The solvent is removed in vacuo and the residue is dried under high vacuum. The obtained oil is further reacted without purification.The oil is taken up in 2.5 mL DMF and treated with 185 muL of DIPEA. By successive addition of DIPEA the pH value is adjusted to ca. 7. 259 mg of Boc-OSu (1.21 mmol, 1.1 eq) are added and stirred at RT overnight. The solvent is removed in vacuo and the residue is taken up in 75 mL of ethyl acetate and washed two times with 10% citric acid and once with brine. After drying of the organic phase over Na2SO4, the solvent is removed in vacuo. The residue is purified by preparative HPLC (40% ACN in water, 8 mL/min, gradient 1% pro min).Yield: 267 mg, 0.85 mmol, 77%ESI-MS: 316.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | 356 mg of (S,E)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-6-(methylsulfonyl)hex-5-enoate (ZED865, 0.77 mmol) are dissolve in 10 mL of dichloromethane and to this solution 10 mL of trifluoroacetic acid is added. It is stirred at RT for 1 h. The solvent is removed in vacuo and the residue is dried under high vacuum. The obtained oil is further reacted without purification.The oil is taken up in 5 mL of DMF and treated with 131 muL of DIPEA. By successive addition of DIPEA the pH value is adjusted to ca. 7. 182 mg of Boc-OSu (0.85 mmol, 1.1 eq) are added and stirred at RT overnight. The solvent is removed in vacuo and the residue is purified by preparative HPLC (5% ACN in water, 8 mL/min, gradient 1% pro min).Yield: 148 mg, 0.48 mmol, 63%ESI-MS: 308.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | 94 mg of (S,E)-1-benzyl 7-tert-butyl 6-(bis(tert-butoxycarbonyl)amino)hept-2-enedioate (ZED818, 0.18 mmol) are dissolve in 2 mL of dichloromethane and to this solution 2 mL of trifluoroacetic acid is added. It is stirred at RT for 1.5 h. The solvent is removed in vacuo and the residue is dried under high vacuum. The obtained oil is further reacted without purification.The oil is taken up in 2 mL DMF and treated with 61 muL of DIPEA (2 eq). By successive addition of DIPEA the pH value is adjusted to ca. 7. 43 mg of Boc-OSu (0.20 mmol, 1.1 eq) are added and stirred at RT overnight. The solvent is removed in vacuo and the residue is purified by preparative HPLC (35% ACN in water, 8 mL/min, gradient 1% pro min).Yield: 60 mg, 0.16 mmol, 91%ESI-MS: 364.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.24 g | With 20% palladium hydroxide-activated charcoal; hydrogen; In methanol; | A 1 L Buchi hydrogenation reactor was charged with 20% Pd(OH)2/ C, (300 mg, 1 wt%), (S)-methyl-5-(4-(benzyloxy)phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate, (which may be prepared as described herein for Description 2), (30.00 g, 97.0 mmol), N-(tert- butoxycarbonyloxy)succinimide, (21.52 g, 102 mmol, 1.00 eq based on 97% purity) and methanol (360 ml_). The mixture was pressurized with hydrogen gas (4 bar), agitated at -1000 rpm and maintained at < 23 C; the reaction was sampled periodically for completion (HPLC). Upon completion, Celite (5 g) was charged to the reactor and stirring was continued for an additional 5 - 10 min. The mixture was filtered through a pad of Celite (5 g). The reactor was charged with methanol (60 ml_) and this rinse was used to wash the filter cake. One-quarter of the combined filtrate and wash was concentrated by rotary evaporation to low volume. Following charging of methanol (15 ml_), water (7.5 ml_) was added slowly over 15 - 20 min at ambient temperature with good stirring. After aging for ~ 35 min at ambient temperature, the slurry was aged at -5 C overnight, filtered, washed with cold (-5 C) 1 :4 (v/v) methanol - water (2 X 7.5 ml_) and dried to constant weight in vacuo at 35 C to afford (D3) as a crystalline solid, (6.24 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In N,N-dimethyl-formamide; at 30℃; for 3h;Inert atmosphere; | To a solution of 37 (1.74 g, 3.41 mmol) and Et3N (1.43 mL, 10.2 mmol) in DMF (20.0 mL) was added <strong>[13139-12-3]N-(tert-butoxycarbonyloxy)succinimide</strong> (1.47 g, 6.82 mmol) at r.t. and the solution was heated at 40 C for 3 h. After cooling to 0 C, EtOAc and aq NaHCO3 were added. The resulting solution was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography(SiO2; n-hexane-EtOAc, 5:1) to give 38 (1.91 g, 92%) as a white amorphous solid; [alpha]D27 +17.9 (c = 1.00, CHCl3).IR (film): 2932, 2857, 2362, 2238, 1695, 1508, 1472, 1394, 1232,1174, 1130, 1045, 884, 835, 776 cm-1.1H NMR (400 MHz, CDCl3): delta = 6.82 (s, 4 H), 5.67 (dddd, J = 18.4, 13.4,7.3, 2.3 Hz, 1 H), 5.05 (d, J = 15.6 Hz, 1 H), 5.04 (d, J = 12.4 Hz, 1 H),4.43 (ddd, J = 8.2, 4.1, 2.3 Hz, 1 H), 4.04 (ddd, J = 13.2, 8.2, 7.3 Hz, 2 H),3.91 (t, J = 6.0 Hz, 2 H), 3.76 (s, 3 H), 3.58 (dd, J = 3.2, 2.7 Hz, 1 H), 2.68 (dddd, J = 12.4, 12,4, 3.0, 3.0 Hz, 1 H), 2.36-2.20 (m, 2 H), 2.07 (dd, J =7.3, 2.3 Hz, 1 H), 2.02-1.90 (m, 2 H), 1.85-1.70 (m, 3 H), 1.69-1.54 (m,6 H), 1.47 (s, 9 H), 0.89 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H).13C NMR (100 MHz, CDCl3): delta = 153.9 (C), 153.5 (C), 152.8 (C), 134.7(CH), 123.0 (C), 117.2 (CH2), 115.4 (CH), 114.6 (CH), 79.7 (C), 72.6(CH), 68.5 (CH2), 60.5 (CH), 57.0 (CH), 55.7 (CH3), 53.6 (CH), 50.2 (C),39.2 (CH2), 38.6 (CH2), 36.7 (CH), 34.8 (CH2), 29.3 (CH2), 29.0 (CH2),28.4 (CH3), 25.8 (CH2), 25.8 (CH3), 19.1 (CH), 18.0 (C), -4.6 (CH3), -4.9(CH3).HRMS (ESI+): m/z calcd for C35H54N2O5SiNa: 633.3700; found:633.3719. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | To a solution of 1,4,7,10-tetraazacyclododecane free base 1(714 mg, 4.067 mmol) in chloroform (35 mL), N-(tert-Butoxycarbonyloxy)succinimide (8.134 mmol) was added. The reaction mixture was stirred at room temperature for 28 h. Solvent was removed by rotary evaporation and 30 mL of NaOH 3 M was added to the remaining residue. The aqueous phase was extracted with chloroform (3.3 mL). The extracts were combined and dried (over K2CO3). The solvent was removed by rotary evaporation and the residue was dried in vacuum for several hours. 513 mg of the unpurified compound from the preceding reaction (1.3761 mmol)was solubilized in acetonitrile. 0.67 mL (2.87 mmol) of benzyl bromoacetate and 0.474 g (3.412 mmol) K2CO3 were added to this solution at room temperature, after which the mixture was heated under reflux for 8 h. The solids were discarded by filtration over Celite and the solvent was removed under vacuum. Chromatographic purification (alumina, 98/2 DCM/MeOH) yielded 2 as aslowly solidifying colourless oil (736 mg, 87% over all for two steps). 1H NMR (500 MHz, CDCl3) d (ppm): 7.31 (m, 10H), 5.11 (s,4H), 3.54 (s, 4H), 3.49 (m, 8H), 2.86 (m, 8H), 1.41 (s, br 18H). 13C(500 MHz, CDCl3) d (ppm): 171.48, 157.11, 136.02, 79.33, 66.04,55.04, 54.51, 46.68, 28.46. ESI-MS (C36H52N4O8); m/z = 668 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 19 (0780) Synthesis of NalphaB1-propargyl-C5 NepsilonB29C14 RHI (INS22). (0781) (0782) Step 1: NepsilonB29C14 RHI (2.74 g, 0.472 mmol) is dissolved in DMSO (50 mL) and the mixture is stirred at RT until homogeneous (about 45 minutes). To the solution is added 1,1,3,3-tetramethylguanidine (0.19 mL, 1.179 mmol) and followed by slow addition of a solution of Boc-OSu (0.216 g, 1.005 mmol) DMSO ( 2.1 mL, plus 0.4 mL wash) over 30 minutes. The reaction is further stirred for 1.5 hours for NalphaA1 Boc RHI to be formed. To the reaction mixture is added a solution of 2,5-dioxopyrrolidin-1-yl pent-4-ynoate in DMSO (1 mL) using a syringe pump over 30 minutes. After stirring for two hours, the reaction mixture is dropwise added to a stirred 275 mL of IPAc to precipitate the product. The white solids are filtered, washed with IPAc and dried under N2 and vacuum for one hour. (0783) Step 2: TFA (15 mL, 195 mmol) is added to the above crude material (3 g, 0.493 mmol) and the reaction is stirred and sonicated until solids fully dissolved (about 30 minutes). The reaction mixture is dropwise added to water (75mL) and the precipitated solids are filtered and dried under N2 and vacuum. The crude material is purified using RP- HPLC to give the NalphaB1-propargyl-C5 NepsilonB29C14 RHI |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 20 (0784) Synthesis of NalphaB1-propargyl-C5 NepsilonB29gammaE-C16 RHI (INS23). (0785) Step 1: NepsilonB29gammaE-C16 RHI (2.74 g, 0.472 mmol) is dissolved in DMSO (50 mL) and the mixture is stirred at RT until homogeneous (about 45 minutes). To the solution is added 1,1,3,3-tetramethylguanidine (0.19 mL, 1.179 mmol) and followed by slow addition of a solution of Boc-OSu (0.216 g, 1.005 mmol) DMSO ( 2.1 mL, plus 0.4 mL wash) over 30 minutes. The reaction is further stirred for 1.5 hours for NalphaA1 Boc RHI to be formed. To the reaction mixture is added a solution of 2,5-dioxopyrrolidin-1-yl pent-4-ynoate in DMSO (1 mL) using a syringe pump over 30 minutes. After stirring for two hours, the reaction mixture is dropwise added to a stirred 275 mL of IPAc to precipitate the product. The white solids are filtered, washed with IPAc and dried under N2 and vacuum for one hour. (0786) Step 2: TFA (15 mL, 195 mmol) is added to the above crude material (3 g, 0.493 mmol) and the reaction is stirred and sonicated until solids fully dissolved (about 30 minutes). The reaction mixture is dropwise added to water (75mL) and the precipitated solids are filtered and dried under N2 and vacuum. The crude material is purified using RP- HPLC to give the NalphaB1-propargyl-C5 NepsilonB29gammaE-C16 RHI |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,2,6,6-tetramethyl-piperidine; In dimethyl sulfoxide; at 20℃; for 4h; | RHI (10 g) is dissolved in DMSO (200 mL) at RT the mixture is stirred at RT until homogeneous. To the solution is added 2,2,6,6-tetramethylpiperidine (5.8 mL) followed slow addition of a solution of <strong>[13139-12-3]tert-butyl (2,5-dioxopyrrolidin-1-yl) carbonate</strong> (Boc-OSu, 0.8 g) in DMSO (10 mL). The reaction is agitated for four hours and the mixture is transferred to IPAc (1 L) over 20 minutes. The slurry is centrifuged for two hours and the solid is filtered, washed with IPAc (20ml X 3) and dried under vacuum to give bis-Boc RHI. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 21 (0787) Synthesis of NalphaB1-propargyl-PEG13 NepsilonB29gammaE-C16 RHI (INS24). (0788) Step 1: NepsilonB29gammaE-C16 RHI (2.74 g, 0.472 mmol) is dissolved in DMSO (50 mL) and the mixture is stirred at RT until homogeneous (about 45 minutes). To the solution is added 1,1,3,3-tetramethylguanidine (0.19 mL, 1.179 mmol) and followed by slow addition of a solution of Boc-OSu (0.216 g, 1.005 mmol) DMSO ( 2.1 mL, plus 0.4 mL wash) over 30 minutes. The reaction is further stirred for 1.5 hours for NalphaA1 Boc RHI to be formed. To the reaction mixture is added a solution of 2,5-dioxopyrrolidin-1-yl pent-4-ynoate in DMSO (1 mL) using a syringe pump over 30 minutes. After stirring for two hours, the reaction mixture is dropwise added to a stirred 275 mL of IPAc to precipitate the product. The white solids are filtered, washed with IPAc and dried under N2 and vacuum for one hour. (0789) Step 2: TFA (15 mL, 195 mmol) is added to the above crude material (3 g, 0.493 mmol) and the reaction is stirred and sonicated until solids fully dissolved (about 30 minutes). The reaction mixture is dropwise added to water (75mL) and the precipitated solids are filtered and dried under N2 and vacuum. The crude material is purified using RP- HPLC to give the NalphaB1-propargyl-PEG13 NepsilonB29gammaE-C16 RHI. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In N,N-dimethyl-formamide; at 20℃; for 3h; | To a stirred solution of compound 6 (200 mg, 1.62 mmol) in DMF(4 mL), Boc-OSu (1 eq, 349 mg, 1.62 mmol) was added at room temperature.Upon completion of the reaction after 3 h, the solvent wasremoved under high vacuo and the residue, dissolved in AcOEt, waswashed with brine and H2O. The organic phase was dried with Na2SO4,the solvent was evaporated and the crude product was purified usingcolumn chromatography with AcOEt-petroleum ether (40-60 C) 1:1 aseluent. White solid; yield 350 mg (97%); mp: 83.2-84.8 C (mplit 6987 C); Rf [AcOEt-petroleum ether (40-60 C] 1:1) 0.63; 1H NMR(CDCl3) delta 7.23 (1H, br s, NH), 7.09-7.05 (2H, d, J = 8.0 Hz, Ar-H),6.79-6.75 (2H, d, J = 8,4 Hz, Ar-H), 4.96 (1H, br s, OH), 4.22-4.19(2H, d, J = 5,8 Hz, CH2), 1.46 (9H, s, 3xCH3); 13C NMR (CDCl3) delta156.46, 155.74, 129.79, 128.90, 115.60, 80.07, 44.25, 28.47; MS (ESI)m/z (%) 222.21 [(Mu - H-), 100]. |
Tags: 13139-12-3 synthesis path| 13139-12-3 SDS| 13139-12-3 COA| 13139-12-3 purity| 13139-12-3 application| 13139-12-3 NMR| 13139-12-3 COA| 13139-12-3 structure
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