Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 345954-83-8 | MDL No. : | MFCD09749828 |
Formula : | C4H7ClN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MJZQSPDYIKSJCN-UHFFFAOYSA-N |
M.W : | 118.56 | Pubchem ID : | 45072465 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 32.66 |
TPSA : | 35.82 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 : | Yes |
Log Kp (skin permeation) : | -6.95 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.1 |
Log Po/w (WLOGP) : | 0.15 |
Log Po/w (MLOGP) : | -0.31 |
Log Po/w (SILICOS-IT) : | 0.57 |
Consensus Log Po/w : | 0.1 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.64 |
Solubility : | 27.3 mg/ml ; 0.23 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.41 |
Solubility : | 46.4 mg/ml ; 0.392 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.5 |
Solubility : | 37.3 mg/ml ; 0.315 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.29 |
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 |
---|---|---|
98% | With triethylamine In dichloromethane for 16 h; | Step 1 3-Cyanoazetidine hydrochloride (3.64 g, 30.7 mmol) was suspended in 77 mL of dichloromethane. Triethylamine (4.3 mL, 30.7 mmol) was added, followed by portionwise addition of di-tert-butyl dicarbonate (8.0 g, 36.8 mmol). The reaction mixture was stirred for 16 h then diluted with aqueous hydrochloric acid and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 5.5 g (98percent) of tert-butyl 3-cyanoazetidine-1-carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 2h; | l-(3.4-Dichloro-benzyl)-azetidine-3-carbonitrile:A solution of l-Benzhydryl-azetidine-3-carbonitrile (0.25 g, 1.0 mmol) in dichloromethane(2ml) is treated with 1-chloroethylchloroformate (0.12 ml, 1.1 mmol). The reaction mixtureis stirred at room temperature for 3 hours, the solvent evaporated and the residue taken-upin methanol and refluxed for 1 hour. The reaction mixture is cooled to room temperatureand stirred for a further 18 hours. The solvent is evaporated to afford crude <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong>. The crude azetidine-3-carbonitrile is dissolved indichloromethane (3 ml) and treated with triethylamine (0.25 ml, 2.0 mmol) and 3,4-dichlorobenzylbromide (0.24 g, 1.0 mmol). The reaction mixture is stirred at ambienttemperature for 2 hours, then washed with water, the organic phase dried over magnesiumsulphate and evaporated. The crude product is purified by chromatography over flash silicausing hexanetethylacetate 2:1 as eluent to afford l-(3,4-Dichloro-benzyl)-azetidine-3-carbonitrile. [MH]+ 240.97 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1-(3.4-Dichloro-benzyl)-azetidine-3-carbonitrile:A solution of l-Benzhydryl-azetidine-3-carbonitrile (0.25 g, 1.0 mmol) in dichloromethane(2ml) is treated with 1-chloroethylchloroformate (0.12 ml, 1.1 mmol). The reaction mixtureis stirred at room temperature for 3 hours, the solvent evaporated and the residue taken-upin methanol and refluxed for 1 hour. The reaction mixture is cooled to room temperatureand stirred for a further 18 hours. The solvent is evaporated to afford crude azetidine-3-carbonitrile hydrochloride. The crude azetidine-3-carbonitrile is dissolved indichloromethane (3 ml) and treated with triethylamine (0.25 ml, 2.0 mmol) and 3,4-dichlorobenzylbromide (0.24 g, 1.0 mmol). The reaction mixture is stirred at ambienttemperature for 2 hours, then washed with water, the organic phase dried over magnesiumsulphate and evaporated. The crude product is purified by chromatography over flash silicausing hexanetethylacetate 2:1 as eluent to afford l-(3,4-Dichloro-benzyl)-azetidine-3-carbonitrile. [MH]+ 240.97 | ||
With carbonochloridic acid 1-chloro-ethyl ester; In 1,2-dichloro-ethane; at 70℃; for 1.5h; | Step 1: Azetidine-3-carbonitrile hydrochlorideA 50 ml_ flask was charged with l-benzhydrylazetane-3-carbonitrile (500 mg, 2.01 mmol) and 1,2-dichloroethane (8.9 ml_). 1-chloroethyl chloroformate (285 muIota_, 2.61 mmol) was added and the reaction mixture was stirred at 70 C for 1.5 h. After cooling to room temperature, methanol (8.9 ml_) was added and the reaction mixture was stirred at 70 C for 1.5h. The reaction mixture was concentrated to dryness. The crude mixture was triturated in pentane to give a dark solid (250 mg, quantitative) which was used without further purification. | |
[Reference Example 7]; 3-Azetidinecarbonitrile hydrochloride; [Show Image] [Show Image] 1,2-Dichloroethane (16 ml) was added with 1-benzhydrylazetidine-3-carbonitrile (1.24 g), and added with 1-chloroethyl chloroformate (0.82 ml) at room temperature, and the mixture was refluxed for 0.5 hour by heating. The reaction mixture was concentrated, then the resulting residue was added with methanol (16 ml), and the mixture was refluxed for 1 hour by heating, and left to cool. The mixture was concentrated again, and then the resulting residue was added with ethyl acetate, and the deposited solid was collected by filtration, and dried to obtain the title compound (360 mg) as colorless solid. 1H-NMR (400MHz, d6-DMSO) delta : 3.94-4.02 (1H, m), 4.14 (2H, s), 4.16 (2H, s), 9.61 (2H, br). EI-MS; m/z: 82 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 2h; | To 0.3 g (1.64 mmol) 1-N-boc-3-cyanoazetidine, was added 8.23 ml. (32.9 mmol) HCI in dioxane (4 M), and the reaction was stirred at room temperature for 2 hours. The solvent was evaporated to give the desired product as a HCI salt, which was used in the next step without further purification. | |
195 g | With hydrogenchloride; In 1,4-dioxane; at 0 - 20℃; for 4h; | Step 1: Preparation of azetidine-3-carbonitrile Hydrochloride To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (300 g, 1.65 mol, Pharma Blocks) in 1,4-dioxane (300 mL) at 0 C. was added 4M HCl in dioxane (1.25 L, 5.0 mol). The mixture was allowed to warm to rt and stirred for an additional 4 h. The reaction mixture was then concentrated under reduced pressure and azeotroped with toluene (3*250 mL). The residue was slurried with hexanes (500 mL) and dried under high vacuum to give azetidine-3-carbonitrile hydrochloride (195 g) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 9.87 (bs, 2H), 4.22-4.08 (m, 4H), 4.05-3.95 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.7% | With 4-methyl-morpholine; dmap; HATU; In tetrahydrofuran; at 25℃; for 1h;Inert atmosphere; | EXAMPLE 41 : (i?)-l-(2-(6-chloro-3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin- 4(lH,3H,5H)-yl)-3,3-dimethylbutanoyl)azetidine-3-carbonitrile[0384] To an 8 niL scintillation vial equipped for stirring was added (i?)-2-(6-chloro-3- oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-4(lH,3H,5H)-yl)-3,3-dimethylbutanoic acid (25 mg, 0.078 mmol) under nitrogen. THF (0.5 mL), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (18.45 mg, 0.155 mmol), HATU and 4-methylmorpholine (11.79 mg, 0.117 mmol) were added and the solution was stirred at 25C for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCNZH2O, 15-40%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow semi-solid (4.1 mg, 13.7%). 1H NMR (400 MHz, CD3OD) delta 1.17 (s, 9 H) 3.50 - 3.78 (m, 1 H) 4.17 (br. s., 1 H) 4.25 - 4.37 (m, 1 H) 4.41 - 4.69 (m, 2 H) 5.17 - 5.30 (m, 2 H) 5.44 (s, 1 H) 7.87 (br. s., 1 H) 8.25 (s, 1 H). [M+H] calc'd for Ci9H20ClN5O2, 386; found, 386.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.4% | With dmap; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 25℃; for 4h; | EXAMPLE 42: (i?)-l-(2-(6-fluoro-3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin-4(lH,3H,5H)-yl)-3-methylbutanoyl)azetidine-3-carbonitrile[0406] To an 8 rnL scintillation vial equipped for stirring was added (i?)-2-(6-fluoro-3- oxopyrrolo[4,3,2-fe][2,6]naphthyridin-4(l/f,3/f,5H)-yl)-3-methylbutanoic acid (60 mg, 0.206 mmol). DMF (0.5 mL), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (0.309, 36.6 mg), HOBt (47.3 mg, 0.309 mmol), EDC (59.2 mg, 0.309 mmol) and JV,JV-dimethylpyridin-4- amine (37.7 mg, 0.309 mmol) were added and the solution was stirred at 25C for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCNZH2O, 20-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a TFA salt. The residue was further purified using silica column chromatography (MeOH/DCM, 0-10%) which gave the title compound as a white solid (free base, 25.2 mg, 34.4%). 1H NMR (400 MHz, DMSO-Je) delta 0.78 (dd, J=6.57, 3.79 Hz, 3 H) 0.95 (dd, J=13.01, 6.44 Hz, 3 H) 1.09 (t, J=6.95 Hz, 1 H) 3.53 - 3.86 (m, 1 H) 3.94 - 4.10 (m, 1 H) 4.10 - 4.29 (m, 2 H) 4.29 - 4.48 (m, 1 H) 4.87 (dd, J=18.82, 8.21 Hz, 1 H) 4.96 - 5.14 (m, 2 H) 7.99 (dd, J=5.43, 2.40 Hz, 1 H) 8.25 (t, J=2.78 Hz, 1 H) 12.39 (br. s., 1 H). [M+H] calc'd for Ci8Hi8FN5O2, 356; found, 356.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃; for 2h; | EXAMPLE 81 : (i?)-l-(3-methyl-2-(3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin- 4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile[0519] (i?)-3-Methyl-2-(3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin-4(l/f,3H,5H)- yl)butanoic acid (80 mg, 0.29 mmol), HOBt (54 mg, 0.35 mmol) and EDC (84 mg, 0.44 mmol) were combined in DMF (2 rnL). Azetidine-3-carbonitrile HCl salt (52 mg, 0.44 mmol) and JV-methylmorpholine (130 muL, 1.17 mmol) were added, and the solution was stirred at room temperature for 2 h. Purification by preparative HPLC (10-45% AcCN/water with 0.035% TFA) followed by purification by silica gel chromatography (8% MeOH/DCM) gave the title compound as a white solid (28 mg, 28%). 1H NMR (500 MHz, DMSO-J6) delta 0.90 (dd, J=6.5, 2.0 Hz, 3H), 1.06 (dd, J=6.5, 2.0 Hz, 3H), 2.42-2.51 (m, IH), 3.61-3.75 (m, IH), 4.15-4.68 (m, 4H), 4.95-5.21 (m, 3H), 7.09 (t, J=5.0 Hz, IH), 7.81 (d, J=12.5 Hz, IH), 8.27 (t, J=5.0 Hz, IH). [M+H] calc'd for Ci8Hi9N5O2, 338; found, 338. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 2h; | EXAMPLE 82: (i?)-l-(3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin-4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile[0528] (i?)-3,3-Dimethyl-2-(3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin-4(l/f,3/f,5H)- yl)butanoic acid (80 mg, 0.278 mmol), HOBt hydrate (51.2 mg, 0.334 mmol), and EDC hydrochloride (80 mg, 0.418 mmol) were combined in DMF (2 mL). Azetidine-3- carbonitrile hydrochloride (49.5 mg, 0.418 mmol) and 4-methylmorpholine (0.124 mL, 1.114 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-50% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and purified by flash column chromatography (8% MeOH/DCM) to afford the title compound (38 mg, 39%). 1H NMR (500 MHz, CD3OD) delta 1.17 (s, 9H), 3.58-3.72 (m, IH), 4.13-4.65 (m, 4H), 5.35-5.45 (m, 3H), 7.28-7.38 (m, IH), 7.95 (d, J=15.5 Hz, IH), 8.33-8.40 (m, IH). [M+H] calc'd for Ci9H2IN5O2, 352; found, 352. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With 4-methyl-morpholine; dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere; | EXAMPLE 87: (i?)-l-(3,3-dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2- fe][2,6]naphthyridin-4(l/f,3/f,5H)-yl)butanoyl)azetidine-3-carbonitrile[0543] (i?)-3,3-Dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-fe][2,6]naphthyridin- 4(l/f,3/f,5H)-yl)butanoic acid (10 mg, 0.033 mmol), DMAP (6 mg, 0.05 mmol), 4- methylmorpholine (0.015 niL, 0.13 mmol), EDC hydrochloride (10 mg, 0.050 mmol), HOBt hydrate (8 mg, 0.050 mmol) and <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (6 mg, 0.050 mmol) were dissolved in DMF (2 mL). The reaction mixture was stirred under nitrogen at room temperature for 3 h. The solution was concentrated and purified by preparative HPLC (10-30% AcCN/H2O with 0.035% TFA) to give the title compound (1.4 mg, 12%). 1H NMR (500 MHz, CD3OD) delta 1.18 (s, 9H), 2.35 (d, J=8.8 Hz, 3H) 4.17-4.18 (m, IH), 4.29-4.31 (m, 2H), 4.52-4.62 (m, IH), 4.64-4.69 (m, IH), 5.19-5.23 (m, 2H), 5.45 (s, IH), 7.83 (d, J=16.1 Hz, 3H), 8.19 (s, IH). [M+H] calc'd for C20H23N5O2, 366; found, 366 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; In dichloromethane; for 16h; | Step 1 3-Cyanoazetidine hydrochloride (3.64 g, 30.7 mmol) was suspended in 77 mL of dichloromethane. Triethylamine (4.3 mL, 30.7 mmol) was added, followed by portionwise addition of di-tert-butyl dicarbonate (8.0 g, 36.8 mmol). The reaction mixture was stirred for 16 h then diluted with aqueous hydrochloric acid and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 5.5 g (98%) of tert-butyl 3-cyanoazetidine-1-carboxylate. |
With triethylamine; In dichloromethane; at 5 - 20℃; | Step 2: tert- Butyl 3-cyanoazetidine-l-carboxylateTo a solution of <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (250 mg, 2.01 mmol theoretical; which may be prepared as described in Step 1) and triethylamine (1.12 ml_, 8.04 mmol) in dichloromethane (10.2 mL) was added di-tert-butyldicarbonate (482 mg, 2.21 mmol) portionwise at 5 C. After stirring at room temperature for 16 h, the reaction mixture was washed with HCI 0.5N and brine then dried over Na2S04. The solvent was removed under reduced pressure and the crude mixture purified on column chromatography (eluent: Pentane/EtOAc 95/5 to 4/1) to give the compound (190 mg, 52%) as a clear oil.*H NMR (CDCIs, 300 MHz) : delta (ppm) : 4.29-4.05 (m, 4H), 3.48-3.29 (m, 1H), 1.44 (s, 9H). | |
With triethylamine; In tetrahydrofuran; at 20℃; for 4h; | Step 1 : To a stirred solution of 3-cyano azetidine hydrochloride (Oakwood) (10.0 g, 0.084 mol) in THF (100 mL) containing Et3N (25.5 g, 0.252 mol, 3.0 eq) is added di-tert-butyl dicarbonate (27.6 g, 0.126 mol, 1 .5 eq). The mixture is stirred at RT for 4 h, then water (100 mL) is added followed by EtOAc (50 mL). The aqueous phase is extracted with EtOAc (3 x 50 mL). The organic layers are combined and washed with brine, dried over Na2S04, filtered and concentrated. The crude residue is purified by silica gel flash chromatography (eluent: petroleum ether / EtOAc, 10%) to afford intermediate 8004A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;Product distribution / selectivity; | Step 1 In a round-bottomed flask were combined Boc-D-alanine (500 mg, 2.64 mmol), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (376 mg, 3.17 mmol), HOBT (445 mg, 2.91 mmol) and HATU (1.11 g, 2.91 mmol). Then added DMF (5 mL) followed by N,N-diisopropylethylamine (1.38 mL, 7.93 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then quenched with water and extracted with EtOAc (3*). The combined organics were washed with water (3*) dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (50% to 100% EtOAc/hexanes) to afford 493 mg (74%) of [(R)-2-(3-cyanoazetidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a white solid. |
74% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h; | Step 4[(R)-2-(3-Cyanoazetidin-l-yl)-l-methyl-2-oxo-ethyl]-carbamic acid tert-butyl esterIn a round-bottomed flask were combined Boc-D-alanine (500 mg, 2.64 mmol), azetidine-3- carbonitrile hydrochloride (376 mg, 3.17 mmol), HOBT (445 mg, 2.91 mmol) and HATU (1.11 g, 2.91 mmol). Then added DMF (5 mL) followed by N,N-diisopropylethylamine (1.38 mL, 7.93 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then quenched with water and extracted with EtOAc (3x). The combined organics were washed with water (3x) dried over MgSC^ and concentrated. The residue was purified by Si02 chromatography (50% to 100% EtOAc/hexanes) to afford 493 mg (74%) of [( )-2-(3 -cyanoazetidin- 1 -yl)- 1 -methyl-2- oxo-ethyl]-carbamic acid tert-butyl ester as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 5h; | Step 1 (R)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (2.25 g, 10.5 mmol) and O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (3.69 g, 11.5 mmol) were dissolved in dichloromethane (105 mL). 3-Cyanoazetidine hydrochloride (1.36 g, 11.5 mmol) and then N,N-diisopropylethylamine (4.5 mL, 26.1 mmol) were added and the mixture was stirred at room temperature for 5 h. Water, dilute HCl and more dichloromethane were added, the layers were separated and the aqueous layer was extracted once more with dichloromethane. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give 2.45 g (83%) of [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester. |
59% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | Example 21.2- (6-Chloro-l-methyl-lH-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3- cyano-azetidin- 1 -yl)- 1 -cyclopropyl-2-oxo-ethyl]-amide Step 1[(R)-2-(3-C ano-azetidin-l-yl)-l-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl esterIn a round-bottomed flask Boc-D-cyclopropylglycine (500 mg, 2.32 mmol) and azetidine-3- carbonitrile hydrochloride (441 mg, 3.72 mmol) were dissolved in DMF (10 ml). N,N- Diisopropylethylamine (1.2 ml, 6.87 mmol) was added followed by HATU (972 mg, 2.56 mmol). The reaction mixture was stirred at room temperature ovemight then quenched with water and extracted with diethyl ether (2x). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether to afford 384 mg (59%) of [(R)-2-(3-cyano-azetidin-l-yl)-l- cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Step 2 To a solution of (R)-cyclopropyl-[2-(7-methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-acetic acid (27 mg, 0.049 mmol) in DMF (2 mL) at room temperature was added triethylamine (34.0 muL, 0.24 mmol), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (6 mg, 0.049 mmol and PyBOP (31 mg, 0.059 mmol). The reaction mixture was stirred for 16 h at the same temperature then poured into EtOAc (25 mL) and washed with water (4×30 mL). The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (SiO2, 23 g, hex:EtOAc, 9:1 to 100% in 30 min) to give 26 mg (64%) of 2-(7-methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 3h;Product distribution / selectivity; | EXAMPLE 2: (R)-ierf-Butyl 1 -(3 -cyanoazetidin-l-yl)-3 -methyl- l-oxobutan-2- ylcarbamate; Method A:; To (i~)-2-(tert-Butoxycarbonylamino)-3-methylbutanoic acid (100 g, 460 mmol) in DCM (1.08 L) was added <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (54.6 g, 46 mmol), lH-benzo[d][l,2,3]triazol-l-ol (6.22 g, 46.0 mmol), Et3N (64.2 mL, 460 mmol), and -((ethylimino)methylene)-N3,N3-dimethylpropane- 1 ,3 -diamine hydrochloride (97 g, 506 mmol). The resulting white suspension was stirred at room temperature for 3 hours. The reaction was subsequently quenched with water (360 mL). The organic layer was washed with water (360 mL), concentrated, and dried in a vacuum oven at 40C for 16 hours. The crude material was suspended in isopropyl acetate (360 mL) at 65C for 90 minutes. The suspension was cooled and stirred at room temperature for 1 hour. Hexanes (180 mL) were added to the suspension over a 15 minute period, and the reaction mixture was stirred for 2 hours at 0C. The solid was filtered and washed with isopropyl acetate/hexanes (1 :1, 100 mL) and dried in a vacuum oven at 40C for 16 hours to give the title compound as a white solid (119.2 g, 92%). 1H NMR (400 MHz, DMSO-d6) delta ppm 0.75-0.94 (m, 6H), 1.30-1.47 (m, 9H), 1.74-1.95 (m, 1H), 3.64 (m, J=8.0 Hz, 1H), 3.73-3.89 (m, 1H), 4.00 (ddd, J=12.3, 9.7, 6.1 Hz, 1H), 4.15 (dt, J=18.6, 9.3 Hz, 1H), 4.34 (dd, J=8.5, 5.9 Hz, 1H), 4.40-4.60 (m, 1H), 7.05 (dd, J=12.9, 8.3 Hz, 1H). [M+H] calc'd for C14H23N3O3, 282; found, 282. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Step 2. 1-[(3'-Acetyl-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-yl)carbonyl]azetidine-3-carbonitrile To a solution of 3'-acetyl-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-carboxylic acid (70 mg, 0.2 mmol), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (30 mg, 0.25 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.11 g, 0.25 mmol) in N,N-dimethylformamide (0.42 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.46 mmol). After being stirred at room temperature for 2 h, the mixture was diluted with ethyl acetate, washed with water, brine, dried and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired product (25 mg, 30% in 3 steps). LCMS calculated for C21H19ClFN2O3 (M+H)+: m/z=401.1. found: 401.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15%; 17% | To a vial charged with a scalemic mixture enriched, in (1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanecarbaldehyde and (1R,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanecarbaldehyde (0.350 g, 1.304 mmol) and <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (0.309 g, 2.61 mmol) was added MeOH (9 mL). The mixture was stirred at rt for about 1 h. Sodium cyanoborohydride (0.246 g, 3.91 mmol) was added in one portion. The mixture was stirred at rt for about 1 h. Solvent was removed under reduced pressure. The residue was purified by mass triggered HPLC (Table 1, method f). The desired fractions were concentrated under reduced pressure and the residue was purified by chiral chromatography (Table 2, Method 5) Detection methods were evaporative light scattering (ELSD) detection and optical rotation. The desired fractions were combined and concentrated under reduced pressure to yield 1-(((1R,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)methyl)azetidine-3-carbonitrile (0.0675 g, 15%). LC/MS (Table 1, Method b) Rt=1.40 min; MS m/z: 335 (M+H)+) and 1-(((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)methyl)azetidine-3-carbonitrile (0.0764 g, 17%) both as white solids. LC/MS (Table 1, Method b) Rt=1.38 min; MS m/z: 335 (M+H)+. Jak3 IC50=C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 48h; | Example 20.2-(6-Chloro-l -methyl- 1 H-indazol-3 -yl)-5H-pyrrolo [2,3 -b]pyrazine-7-carboxylic acid [(R)- 1 -(3 - cyano-azetidine- 1 -carbonyl)-prop l]-amideStep 1[(R)-l -(3 -C ano-azetidine- l-carbonyl)-propyl]-carbamic acid tert-butyl esterIn a round-bottomed flask Boc-D-2-aminobutyric acid (400 mg, 1.97 mmol) and azetidine-3- carbonitrile hydrochloride (373 mg, 3.15 mmol) were dissolved in DMF (9 ml). N,N- Diisopropylethylamine (1.0 ml, 5.73 mmol) was added followed by HATU (823 mg, 2.16 mmol). The reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2x). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to provide 410 mg (70%) of [(R)-l-(3-cyano-azetidine-l-carbonyl)-propyl]-carbamic acid tert-butyl ester white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
458 mg | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 48h; | Example 43.2-(6-Chloro-l -methyl- 1 H-indazol-3 -yl)-5H-pyrrolo [2,3 -b]pyrazine-7-carboxylic acid [(R)- 1 -(3 - cyano-azetidine-1 -carbonyl)-2,2-dimethyl-propyl]-amideStep 1[(R)-l-(3-C ano-azetidine-l-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl esterA round-bottomed flask was charged with Boc-D-tert-leucine (300 mg, 1.3 mmol) and azetidine- 3-carbonitrile hydrochloride (231 mg, 1.95 mmol). DMF (6 ml) was added followed by N,N- diisopropylethylamine (0.68 ml, 3.9 mmol) and HATU (543 mg, 1.43 mmol). The light yellow solution was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2x). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 458 mg of [(R)-l-(3- cyano-azetidine-l-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester as a light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In ethanol; at 100℃; for 18h; | Step 4: Intermediate 6009C (50 mg, 0.1 1 mmol) is charged in a round-bottom flask and suspended in EtOH (1 .0 mL). Diisopropylethylamine (48 mg, 0.26 mmol, 2.5 eq) and azetidine- 3-carbonitrile hydrochloride (Fluorochem) (19 mg, 0.16 mmol, 1 .5 eq) are added and the solution is heated at 100 C for 18 h. The solution is diluted with EtOAc and washed with brine (3x). The organic layer is dried over MgS04, filtered and concentrated under reduced pressure. The crude mixture is purified by flash chromatography (EtOAc/hexanes) to provide intermediate 6009D. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.5 mg | Prepared according to the method of Example 1 using <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (13 mg, 0.1 1 mmol, Oakwood) and N,N-diisopropylethyamine (23 , 0.13 mmol) in the displacement step which was carried out at room temperature overnight, and the product was afforded as the free base (7.5 mg, 55%). 'H NMR (400 MHZ, d6-DMSO) delta 12.1 1 (br s, 1 H), 8.83 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.60 (d, = 3.6 Hz, 1H), 7.31 (s, 1H), 7.08 (d, J= 3.6 Hz, 1H), 6.96 (s, 1H), 5.28 - 4.71 (m, 1 H), 3.66 (s, 2H), 3.56 - 3.46 (m, 3H), 3.42 (s, 2H), 3.38 - 3.24 (m, 2H), 3.09 - 2.95 (m, 2H), 2.81 (p, 7= 7.4 Hz, 1H), 2.73 - 2.56 (m, 2H), 2.40 - 2.27 (m, 2H), 2.23 - 2.08 (m, 2H), 2.08 - 1.93 (m, 2H), 1.76 - 1.59 (m, 2H). 19F NMR (376 MHz, de-DMSO) delta -67.38 (s). LCMS (M+H)+: 617.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 135℃; for 8h; | The following Examples were prepared according to Method 5 (Example 54) above using 8-chloro-A/-(2-methoxy-4-(1 -methyl-1 H-pyrazol-4-yl)phenyl)pyrido[3,4- d]pyrimidin-2-amine (Example 94) and the appropriate amine as described. The crude reaction residues were purified as above or according to one of the following methods: Method A: Silica gel column chromatography eluting with 0-5% or 0-10% MeOH in DCM. Method B: Silica gel column chromatography eluting with 0-5% MeOH in EtOAc. Method C: Silica gel column chromatography eluting with 0-70% EtOAc in cyclohexane followed by reverse phase preparative HPLC eluting with 10-90% MeOH in water (0.1 % formic acid). Method D: Silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane followed by a second chromatography eluting with either 0-5% or 0-20% MeOH in either DCM or EtOAc. Method E: Silica gel column chromatography eluting with between 0-20% MeOH in DCM. Method F: Elution through an SCX-2 column followed by silica gel column chromatography eluting with 0-5% MeOH in EtOAc. Method G: Elution through an SCX-2 column followed by silica gel column chromatography eluting with 1 -10% MeOH/aq NH3 (10/1 ) in DCM. Method I: Elution through an SCX-2 column using 1 M followed by 7M methanolic ammonia followed by trituration with MeOH. Method J: Elution through an SCX-2 column followed by silica gel column chromatography eluting with 0-10% EtOH in DCM. Method K: Trituration with ether. Method L: Elution thorugh an SCX column using 50% MeOH in chloroform followed by 50% chloroform in 7N NH3/MeOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -20 - 20℃; | To a stirred solution of isovaleric acid (0.90 g, 8.85 mmol) in DCM (20 mL) was added 0.1 mL of N,N-Dimethylformamide. The solution was cooled to 0C, followed by the addion of oxalyl chloride (1.45 g, 1 1.5 mmol). The reaction mixture was warmed to room temperature and stirred for 4.0 h. Then the solution was evaporated to remove the solvent at below 50C. The residue and <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (0.94 g, 7.96 mmol) were dissolved in 20 mL DCM. The solution was cooled to -20C, followed by the addion of DIPEA (3.83 mL, 26.55 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The resultant was quenched by addition of saturated aqueous NaHC03. The mixture was extracted with DCM (3 X 100 mL), and the combined extracts were washed with brine, dried by Na2S04 and filtered, concentrated under vacuum at below 40C. The crude product was purified by flash chromatography (20% Petrolium ether/ethyl acetate) to give 833 mg of Compound 9a (Yield: 63%) as a light yellow oil. [M+H] found 167. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.2% | With caesium carbonate; In acetonitrile; at 20℃; for 18h; | A mixture of <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (1.51 g, 12.7 mmol) , 1, 2-dibromoethane (9 mL, 8.20 mmol) and cesium carbonate (8 g, 104 mmol) in acetonitrile (15 mL) was stirred at rt for 18 h. The reaction mixture was diluted with water (30 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were washed with saturated aqueous NaCl (15 mL) , dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with DCM/MeOH (v/v) 40/1 to give a light yellow liquid product (1.16 g, 48.2) .[1878]MS (ESI, pos. ion) m/z: 189.05 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.86% | With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In dimethyl sulfoxide; at 70℃; for 5h; | To a solution of 1-bromo-4-iodobenzene (1.0 g, 3.53 mmol) in DMSO (16 mL) were added <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (420 mg, 3.54 mmol) , cesium carbonate (1.7 g, 5.2 mmol) , N, N-dimethylglycine (400 mg, 3.80 mmol) and cuprous iodide (675 mg, 3.54 mmol) in turn. The mixture was stirred at 70 for 5 h and quenched with water (30 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 3/1 to give a light yellow solid product (200 mg, 23.86) .[1006]MS (ESI, pos. ion) m/z: 237.1, 238.9 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | The 1H- pyrrolo [2,3-b] pyridine-4-carboxylic acid (250mg, 1.54mmol) was dissolved in N, N- dimethylformamide (5mL) added successively HATU (879.6mg, 2.31mmol), diisopropylethyl amine (403muL, 2.3mmol) and D- valine (270.9mg, 2.31mmol), stirred at rt for 12h, and then continue to add HATU (879.6mg, 2.31mmol), DIPEA (403muL, 2.31mmol) and 3-cyano-ring butylamine hydrochloride (273mg, 2.31mmol), stirred at room temperature 12h, was added a saturated brine (10 mL) quenched and extracted with dichloromethane (15mL × 3), dried, concentrated and subjected to column chromatography separation (eluent: CH2Cl2/ MeOH (v / v) = 30/1), and then by preparative thin layer chromatography to give 10mg of white solid, yield: 2.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃; for 2h; | Compound BB-30-1 (0.200g, 1.10mmol) was dissolved in dichloromethane (2mL), followed by addition of hydrogen chloride in dioxanesix rings solution (1mL, 4M).The reaction was stirred at 20 2 hours.The reaction mixture was concentrated to give the title compound BB-30-30a and the BB(white solid, 0.130 g, yield: 99%), was used directly in the next step synthesis without isolation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 70℃; for 16h; | Example 110 l-(2 3-chloro-lH^yrrolo[2,3-b]pyridin-5-yl)-6,6-dimethyl-8,9-dihydro-6H-[l,4]oxazino[4,3- e]purin-4-yl)azetidine-3-carbonitrile To a solution of 2,4-dichloro-6,6-dimethyl-8,9-dihydro-6H-[l,4]oxazino[4,3-e]purine (80.0 mg, 0.293 mmol) in N,N-dimethylformaldehyde (1 mL) was added <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (34.7 mg, 0.293 mmol) and N,N-diisopropylethylamine (0.153 mL, 0.879 mmol). The reaction mixture was shaken at 70 C for 16 h and concentrated to dryness in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In acetonitrile; at 20℃; | To a solution of azetidine-3-carbonitrile, HC1 (1.5 g, 12.65 mmol) and (bromomethyl)benzene (1.503 mL, 12.65 mmol) in ACN (20 mL) was added TEA (5.29 mL, 38.0 mmol) and stirred at ft for overnight. The reaction mixture was thenconcentrated under vacuum and diluted with EtOAc (15 mL). The organic layer is then washed with brine (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography afforded 1-benzylazetidine-3-carbonitrile (2.01 g, 92% yield) as a pale yellow solid. MS (ESI) m/z: 201.1 (M+H)t |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 1h; | A solution of 4,6-diiodo-2-methoxypyrimidine (1.00 g, 2.76 mmol), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (0.52 g, 4.42 mmcl) and DIPEA (1.78 g, 13.8 mmcl) in NMP (5 mL) was heated to 100 C and stirred for 1 h. The mixture was partitioned with EtOAc (100 mL) and water (100 mL). The organic layer was washed with water (100 mL) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by column (DCM) to give thetitle compound (600 mg, yield 69%) as a white solid.1H NMR (300 MHz, CDCI3): 6 6.36 (s, 1 H), 4.40-4.27 (m, 4H), 3.91 (s, 3H), 3.66-3.58 (m,1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃;Inert atmosphere; | Step 1 : tert-butyl 3-(3-cyanoazetidin-l-yl)propylcarbamate [00286] To a solution of tert-butyl 3 -oxopropyl carbamate (0.30 g, 1.73 mmol) in 1,2- dichloroethane (19 mL) was added <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (0.205 g, 1.73 mmol), followed by addition of NaBH(OAc)3 (0.55 g, 2.6 mmol). The reaction mixture was stirred at room temperature under argon overnight and a solution of saturated NaHC03 (20 mL) added. The organic phase was separated, and the aqueous phase was further extracted with CH2C12 (20 mL x 2). The combined organic phase was washed with saturated NaHC03 (20 mL) and brine (20 mL), dried over MgS04, and finally was concentrated under reduced pressure. Purification by silica-gel column chromatography with CH3OH/CH2Cl2/NH4OH (180:9: 1) yielded the desired product (0.24 g, 58 %) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of tert-butyl 4-oxopiperidine-l-carboxylate (1.00 g, 5.02 mmol) in methanol (10 mL) was added NaOAc (412 mg, 5.02 mmol) and <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (714 mg, 6.02 mmol). The mixture was stirred overnight at room temperature, then NaBH3CN (315 mg, 5.02 mmol) was added. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The residue was dissolved in EtOAc and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloride methane /methanol (95/5). This resulted in 1.41 g (crude) of tert-butyl 4- (3- cyanoazetidin-l-yl)piperidine- l-carboxylate as a white solid. LC/MS (Method I, ESI): [M+H]+= 266.4, RT= 0.71 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In 1,4-dioxane; at 95℃; for 3h;Inert atmosphere; | To a degassed (argon, 10 mm) suspension of 1,3-dibromobenzene (2.98 g, 12.65 mmol, 1.5mL), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (1.0 g, 8.43 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.49 g, 0.84 mmol) and sodium tert-butoxide (3.2 g, 33.70mmol) in dry 1 ,4-dioxane (70 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.39 g,0.42 mmol). The reaction mixture was stirred at 95C for 3 h and was allowed to cool to room temperature. Water (20 mL) and ethyl acetate (100 mL) were added. Layers were separated and aqueous layer was extracted with ethyl acetate (2x50 mL). Combined organic extracts were dried with sodium sulfate and solvents were removed in vacuo. Purification by flashcolumn chromatography (Method L7; 500 g; heptane, 10%-30% ethyl acetate) afforded 1.25 g(5.28 mmol; 62% of theory) of 1-(3-bromophenyl)azetidine-3-carbonitrile.GC-MS (Method A) R1 = 4.87 mm; m/z = 236/238 M1H NMR (300 MHz, DMSO-d6, Method M2) 67.14 (t, J = 8.0 Hz, 1H), 6.97-6.82 (m, 1H), 6.66(t, J = 2.0 Hz, 1H), 6.51 -6.42 (m, 1H), 4.10 (dd, J = 8.4, 7.5 Hz, 2H), 3.99 (dd, J = 7.5, 5.4 Hz,2H), 3.90-3.77 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 60℃; for 6h;Sealed tube; | To a solution of octan-3-yl 3-((3-chloro-2-fluoropyridin-4-yl)thio)propanoate in DMA (862 mu.), was added <strong>[345954-83-8]3-azetidinecarbonitrile hydrochloride</strong> (152 mg, 1.29 mmol) and DIPEA (298 mu^, 1.72 mmol). Reaction mixture was stirred in a capped vial at 60 C for 6 hours. The resulting reaction mixture was concentrated in vacuo and the residue, octan-3-yl 3- ((3-chloro-2-(3-cyanoazetidin-l-yl)pyridin-4-yl)thio)propanoate, was carried onto the next step without any further purification and assuming quantitative yield. LC-MS (ESI) m/z: [M + H] calculated for C20H28CIN3O2S : 410.17; found 409.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Compound 17k (30 mg, 0.08 mmol) was added to a solution of HATU (30 mg, 0.08 mmol) and DIPEA (30 mg 0.24 mmol) in DMF (4 mL). After stirring for 5 min, <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (13 mg, 0.09 mmol) was added to the mixture. The mixture was stirred at room temperature for 24 h and then the reaction was quenched with saturated ammonium chloride (15 mL). The solution was extracted with EtOAc (3*15 mL). The combined organic layer was washed with saturated sodium bicarbonate (15 mL), water and brine and dried using anhydrous sodium sulfate. The residue obtained after evaporation of the organic layer was purified using silica gel column chromatography (CH2Cl2:MeOH 9.8:0.2) to give compound 20a as a white solid (28 mg, 60%): mp 257-260 C. IR (thin film) 3313, 2957, 1649, 1609, 1572, 1514, 1464, 1421, 1385, 1310, 1262, 1209, 1152, 1040 cm-1; 1H NMR (500 MHz, DMSO) delta 12.26 (s, 1H), 9.47 (s, 1H), 8.09 (s, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.06 (s, 1H), 5.77 (s, 1H), 4.08 (s, 3H), 3.99 (t, J=8.9 Hz, 1H), 3.94 (s, 3H), 3.88 (d, J=8.4 Hz, 1H), 3.54 (s, 1H), 2.47-2.36 (m, 2H), 2.21 (d, J=7.6 Hz, 1H), 0.81 (t, J=7.6 Hz, 3H); MALDIMS m/z (rel intensity) 446 (MH)+; HRESIMS calcd for C24H23N5O4 (MH)+ 446.1823, found 446.1828; C18 HPLC purity, 96.72% (MeOH-H2O, 85:15). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
475 g | With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; | Step 2: Preparation of 3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic Acid, Intermediate 3.1 To a suspension of <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (275 g, 2.32 mol) in DCM (2.8 L) at 0 C. was added triethylamine (1.3 L, 9.28 mol). The mixture was stirred for 10 min at 0 C. then 3-(chlorosulfonyl)benzoic acid (563 g, 2.56 mol, Arbor Chemicals) was slowly added in portions over the period of 1 h (Caution: Exotherm). The reaction mixture was stirred at rt for 3 h and then cooled to 0 C. and quenched with 1N aqueous HCl (4 L). The precipitate was collected by filtration, washed with water (2 L) and dried under vacuum to give 3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic acid (475 g) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 13.65 (bs, 1H), 8.33 (d, J=7.8 Hz, 1H), 8.26 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.87 (dd, J=8.1, 7.8 Hz, 1H), 4.02 (dd, J=8.5, 5.8 Hz, 2H), 3.89 (dd, J=8.5, 5.8 Hz, 2H), 3.68-3.60 (m, 1H). LCMS-ESI (NEG) m/z: 265.0 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
349 mg | With triethylamine; In dichloromethane; at 20℃; for 2h; | 3-((3-cyanoazetidin-1-yl)sulfonyl)-5-fluorobenzoic Acid, Intermediate 6.0 A 40 mL pressure vial was charged with 3-(chlorosulfonyl)-5-fluorobenzoic acid (500 mg, 2.10 mmol, Enamine) and <strong>[345954-83-8]3-cyanoazetidine hydrochloride</strong> (497 mg, 4.19 mmol, Synthonix, Inc.). To that mixture was added DCM (10.5 mL) followed by triethylamine (1.17 mL, 8.38 mmol). After 2 hours at rt, the mixture was transferred to a separatory funnel and the pH was adjusted to ?10 using saturated aqueous solution NaHCO3. The layers were separated and the aqueous was carefully acidified with concentrated HCl (pH=3) upon which a white solid precipitated from the solution. The solid was collected by filtration and lyophilized to give 3-((3-cyanoazetidin-1-yl)sulfonyl)-5-fluorobenzoic acid (349 mg) as a white solid. 1H NMR (500 MHz, DMSO-d6) delta ppm 3.64 (tt, J=8.94, 5.86 Hz, 1H) 3.96 (dd, J=8.69, 5.84 Hz, 2H) 4.06 (t, J=8.82 Hz, 2H) 8.03 (dt, J=7.85, 1.98 Hz, 1H) 8.07-8.11 (m, 2H) 13.92 (br s, 1H). LCMS-ESI (POS.) m/z: 285.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With methanesulfonic acid(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); caesium carbonate; at 90℃; for 16h;Inert atmosphere; | A mixture of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole (200 mg, 0.71 mmol), [2-(2-aminophenyl)phenyl]palladium; dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane; methanesulfonate (60 mg, 0.07 mmol), cesiumcarbonate (693 mg, 2.13 mmol) and <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (168 mg, 1.42 mmol) was stirred at 90 C for 16 h under nitrogen atmosphere. The mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60% / 0.05% ammonia hydroxide in water) to afford l-[(5S,7S)-7-fluoro- 5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]azetidine-3-carbonitrile (15.3 mg, 8%) as a red solid. XH NMR (400 MHz, CDCI3) delta 7.42 - 7.35 (m, 3H), 7.23 - 7.21 (m, 2H), 5.98 - 5.81 (m, 1H), 5.30 - 5.29 (m, 1H), 4.35 - 4.22 (m, 4H), 3.63 - 3.51 (m, 2H), 2.81 - 2.70 (m, 1H). LCMS RT = 1.852 min, m/z = 283.9 [M+H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoacetic acid over 7 mins) retention time 1.852 min, ESI+ found [M+H] = 283.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In dimethyl sulfoxide; at 20℃; | A solution of 2-(2-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-fluoropiperidin-1-yl)-5,6-d^ benzo d|imidazol-1-yl)acetic acid (0.015 g, 0.035 mmol), <strong>[345954-83-8]3-cyanoazetidine hydrochloride</strong> (4.15 mg, 0.035 mmol) and 2-(1H-benzotriazole-1-yl)-l,l,3,3-tetramethyluronium hexaflurophosphate (0.013 g, 0.035 mmol) in dimethyl sulfoxide (0.117 ml) and DIPEA (0.024 ml, 0.140 mmol) was shaken at ambient temperature. The reaction mixture was purified by reverse phase HPLC to obtain tert-butyl {( 3 .. R - j -i j -(2-(3-cyanoazetidin-1-yl -2-oxoethyl)-5,6-diyl)carbamate. MS: (ESI pos. ion) m/z: 493.2 fM+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; | To a solution of N-[(li?)-8-[8-(2,3-dichlorophenyl)-7-methylimidazo[l,2- c]pyrimidin-5-yl]-3-oxo-8-azaspiro[4.5]decan-l-yl]-2-methydpropane-2-sulfinamide (20 mg, 36 mhio, 1 eq.), N,N-diisopropylethylamine (7 mg), and azetidine-3-carbonitriie hydrochloride (6 mg, 47 umol, 1.3 eq.) in DMC (0.3 mL) was added sodium triacetoxyborohydnde (12 rng, 55 mhio) at room temperature. The reaction was stirred at room temperature for 2 h and then filtered. The filtrate was concentrated under reduced pressure and the remaining residue was purified by column chromatography to afford crude N-[(ii?)-3-(3-cyanoazetidin-l-yl)~8-[8-(2,3- dichlorophenyl)-7-methylimidazo[l ,2-c]pyrimidin-5-yl]-8-azaspiro[4.5]decan-l -yl]-2- methylpropane-2-sulfinamide. To a solution of this material in MeOH (0.3 mL) was added HCL (4M solution in dioxane, 0.1 mL) dropwise at room temperature. The mixture was let stirred at room temperature for 2 h. The solution was concentrated under reduced pressure and purified by reverse phase HPLC to afford l-[(4R)-4-amino-8-[8-(2,3-dichlorophenyl)-7-methylimidazo[l ,2- c]pyrimidin-5-yl]-8-azaspiro[4.5]decan-2-yl]azetidine-3-carbonitrile (3 mg) as a white solid.jH NMR (500 MHz, Methanol-A) d 8.36 (s, 3H), 7.74 - 7.70 (m, 1 1 1 ). 7.68 (dd, .1 8 1. 1.5 Hz,1 1 1 ). 7.48 (d, J = 1.5 Hz, i l l ). 7.45 (t, J = 7.9 Hz, 1 I ) 7 33 (dd, I = 7 7, 1.6 Hz, i l l ). 3.95 (d, .1 = 10.3 Hz, I I I). 3.88 (d, J = 9.0 Hz, 1 1 1). 3.62 Lid. J = 19.9, 6.5 Hz, 21 1 ). 3.49 - 3.38 (m, 31 1 ). 3.24 (t, J = 12.6 Hz, 3H), 3.12 (dq, J = 6.7, 3.3 Hz, I I I). 2.26 (dd, J = 14.0, 6.5 Hz, }. 2.21 (s, 3H), 1.99 (dtd, J = 36.6, 13.2, 12.5, 5.7 Hz, 31 1). 1.83 (d, J = 12.8 Hz, H i ). 1.76 (d, J = 13.8 Hz, 1 1 1 ). 1.70 (d, J = 14.0 Hz, 21 1). LC-MS (ESI): m/z [M + i f ] calculated for C26H30CI2N? 510.2; found 510.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of Int 94 (43 mg, 0.090 mmol, 1 eq.) in dry DMSO (0.5 mL) is added HATU (41 mg, 0.179 mmol, 2 eq.) and DIPEA (47 pL, 0.269 mmol, 3 eq.). The mixture is stirred at RT for 5 min and then <strong>[345954-83-8]3-cyanoazetidine hydrochloride</strong> (CAS 345954-83-8; 21 mg, 0.178 mmol, 2.0 eq.) is added. The mixture is stirred at RT for 2 h and then purified by preparative HPLC to afford Cpd 357. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In dimethyl sulfoxide; acetonitrile; at 70℃; for 18h; | General procedure: To a stirred suspension of 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4- yl]methyl]pyridazin-3-one (building block A, 300 mg, 0.947 mmol) and (R)-3- hydroxypyrrolidine (0.14 mL, 1.73 mmol) in DMSO (0.5 mL) and acetonitrile (3 mL) was added potassium carbonate (393 mg, 2.84 mmol) Then the reaction mixture was stirred at 70 C for 18 h. After cooling to room temperature the reaction mixture was diluted with EtOAc (80 mL) was washed three times with water (10 mL) and brine (10 mL). The aqueous layers were back extracted twice with EtOAc (80 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH2CI2) afforded the title compound (341 mg, 93 %) as an off-white foam. MS (ESI): 368.2 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In 1,4-dioxane; at 100℃; | The <strong>[6945-67-1]2-bromo-4-nitropyridine</strong> (1.00g, 4.93mmol),3-acetonitrile cyclobutylamine hydrochloride(759.30mg, 6.40mmol) and cesium carbonate (4.82g, 14.78mmol) were placed in the reaction flask,50mL 1,4-dioxane was added, and the reaction was carried out at 100C overnight.After LC-MS detection, the reaction was completed, cooled to room temperature, filtered to obtain a filtrate, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound. |
Tags: 345954-83-8 synthesis path| 345954-83-8 SDS| 345954-83-8 COA| 345954-83-8 purity| 345954-83-8 application| 345954-83-8 NMR| 345954-83-8 COA| 345954-83-8 structure
[ 1153950-49-2 ]
(S)-Pyrrolidine-3-carbonitrile hydrochloride
Similarity: 0.72
[ 1187930-86-4 ]
Pyrrolidine-3-carbonitrile hydrochloride
Similarity: 0.72
[ 1205750-61-3 ]
3-Cyano-3-methylpyrrolidine hydrochloride
Similarity: 0.69
[ 1199773-75-5 ]
Piperidine-3-carbonitrile hydrochloride
Similarity: 0.69
[ 935669-28-6 ]
3-Methylazetidine hydrochloride
Similarity: 0.74
[ 1153950-49-2 ]
(S)-Pyrrolidine-3-carbonitrile hydrochloride
Similarity: 0.72
[ 1187930-86-4 ]
Pyrrolidine-3-carbonitrile hydrochloride
Similarity: 0.72
[ 221095-80-3 ]
Azetidin-3-ylmethanamine dihydrochloride
Similarity: 0.70
[ 89381-03-3 ]
3,3-Dimethylazetidine hydrochloride
Similarity: 0.70
[ 935669-28-6 ]
3-Methylazetidine hydrochloride
Similarity: 0.74
[ 221095-80-3 ]
Azetidin-3-ylmethanamine dihydrochloride
Similarity: 0.70
[ 89381-03-3 ]
3,3-Dimethylazetidine hydrochloride
Similarity: 0.70
[ 321890-22-6 ]
1-(Azetidin-3-yl)-N,N-dimethylmethanamine dihydrochloride
Similarity: 0.64
[ 928038-44-2 ]
Azetidin-3-ylmethanol hydrochloride
Similarity: 0.58
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :