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CAS No. : | 939412-86-9 | MDL No. : | MFCD09910171 |
Formula : | C5H7Cl2N3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YYVVOYJKQZWKFS-UHFFFAOYSA-N |
M.W : | 180.04 | Pubchem ID : | 42614233 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 41.68 |
TPSA : | 51.8 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.09 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.44 |
Log Po/w (WLOGP) : | 1.24 |
Log Po/w (MLOGP) : | -0.39 |
Log Po/w (SILICOS-IT) : | 1.18 |
Consensus Log Po/w : | 0.49 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.61 |
Solubility : | 4.4 mg/ml ; 0.0245 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.1 |
Solubility : | 14.4 mg/ml ; 0.0802 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.29 |
Solubility : | 0.923 mg/ml ; 0.00513 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.96 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 20℃; for 36 h; | To a solution of 3-chloropyrazine-2-carbonitrile (Compound 101) (6.00 g, 43.0 mmol, 1.0 equiv.) In acetic acid (50 mL) was added Raney nickel (4.00 g) In the hydrogen ball under the room temperature reaction for 1.5 days. The reaction solution was filtered and the filtrate was taken dry and the residue was spin-fed with toluene (40 mL), 1 N HCl (15 mL) and toluene (40 mL) The residue was dissolved in tetrahydrofuran (30 mL), filtered, the cake was spin dried, To give (3-chloropyrazin-2-yl) methanamine hydrochloride (8.75 g, yield: 100percent). Black solid; |
153.5 g | Stage #1: With hydrogen; acetic acid In water at 20℃; Stage #2: With hydrogenchloride In diethyl ether; ethyl acetate at 20℃; Cooling with ice |
To a solution of 3-chloropyrazine-2-carbonitrile (160 g, 1.147 mol) in acetic acid (1.5 L) was added Raney Nickel (50percent slurry in water, 70 g, 409 mmol). The resulting mixture was stirred under 4 bar hydrogen at room temperature overnight. Raney Nickel was removed by filtration over decalite and the filtrate was concentrated under reduced pressure and co-evaporated with toluene. The remaining brown solid was dissolved in ethyl acetate at 50°C and cooled on an ice-bath. 2M hydrogen chloride solution in diethyl ether (1.14 L) was added in 30 min. The mixture was allowed to stir at room temperature over weekend. The crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40°C. The product brown solid obtained was dissolved in methanol at 60°C. The mixture was filtered and partially concentrated, cooled to room temperature and diethyl ether (1000 ml) was added. The mixture was allowed to stir at room temperature overnight. The solids formed were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40°C to give 153.5 g of (3-chloropyrazin-2-yl)methanamine. hydrochloride as a brown solid (74.4 percent, content 77 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Into a round bottom 1-neck flask (5L), 3-oxo-cyclobutanecarboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (217.2 g, 0.937 mol), C-(3-chloro-pyrazin-2-yl)-methylamine hydrochloride salt (153.3 g, 0.852 mol), and THF (760 mL) were added. A solution of 10% NaHCO3 (1.07 kg) was then added and after 20 min, the layers were allowed to separate and the aqueous layer was removed. The aqueous layer was back extracted with EtOAc (1×700 mL, 1×300 mL). The combined organics were washed with brine (350 mL), dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound. This solid was resuspended in ethyl acetate (915 mL) and DMF (132 mL) and the solution was put under an atmosphere of nitrogen and cooled to 10.5 C. Phosphorus oxychloride (159 mL, 1.70 mol) was then added over 15 minutes and the reaction was allowed to stir for 45 min. The reaction solution was then poured slowly into a 22% aqueous Na2CO3 solution at 10IC. Water (1 L) was added and the layers were allowed to separate. The organic layer was removed and the aqueous was back extracted with EtOAc (1×1 L, 1×0.5 L). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo until about 0.5 L of solvent remained. Heptane was added and the slurry was concentrated in vacuo until most of the EtOAc was removed. The resultant slurry was filtered to give desired product. 1H NMR (400 MHz, CDCl3) delta 3.59-3.68 (m, 2H), 3.72-3.79 (m, 2H), 3.86-3.94 (m, 1H), 7.40 (d, 1H, J=5.2 Hz), 7.60 (d, 1H, J=5.2 Hz) and 7.85 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
C-(3-Chloro-pyrazin-2-yl)-methylamine hydrochloride (from 8a): To a suspension of 2-(3-chloro-pyrazin-2-ylmethyl)-iso indole-1,3-dione (90.0 g, 0.329 mol) in methanol (1800 mL) was added hydrazine (20.6 mL, 0.658 mol). After 3 min the mixture formed a thick white suspension, the mixture was gently heated to 60 C. A clear yellow solution formed which turned cloudy after 15 min. After 1 h the reaction was complete. The reaction mixture was cooled to 20 C. and filtered. The bulk of the fibrous residue was slurried in 6×450 mL toluene and this was also filtered. The combined filtrates were concentrated by evaporation to approx. 1.5 L. The resultant slurry was filtered and the cake was washed with 900 ml toluene. The combined solution was concentrated to 1 L, filtered and diluted to a total volume of 1.35 L. The solution was re-filtered and then hydrogen chloride gas was added to the rapidly stirring mixture. A cream colored solid which was collected by filtration and was washed with 100 ml toluene. The solid was dried under vacuum to give the title compound as the hydrochloride salt. 1H NMR (CD3OD, 400 MHz): delta 4.47 (s, 2H), 8.38-8.54 (m, 1H), 8.56-8.72 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
C-(3-Chloro-pyrazin-2-yl)-methylamine hydrochloride (from 8b): 1-(3-Chloro-pyrazin-2-ylmethyl)-3,5,7-triaza-1-azonia-tricyclo[3.3.1.1*3,7*]decane; chloride (6.0 g, 0.022 mol) was suspended in methanol and 37% hydrochloric acid (5.0 mL, 0.06 mol) was added. The mixture was heated to reflux to give a clear orange solution. After 5 min solid began to precipitate. After 1 h the heating was stopped and the reaction mixture was treated with sodium carbonate (3.2 g, 0.030 mol) and 10 mL of water. Toluene 50 mL was added and the mixture was concentrated by evaporation to remove water and methanol. A further 2×50 mL toluene was added and evaporated. Then IPA (50 mL) was added which caused salts to precipitate. The mixture was filtered and concentrated by evaporation followed by addition of further IPA (50 mL), it was again filtered to give a clear orange brown solution. The solution was treated with HCl gas until absorption has stopped. The resultant suspension was stirred for 30 minutes and the solid was collected by filtration. The cake was washed with IPA and the solid was dried under vacuum to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; water; In isopropyl alcohol; for 3h;Heating / reflux;Product distribution / selectivity; | C-(3-Chloro-pyrazin-2-yl)-methylamine (from 8c): A suspension of N-(3-Chloro-pyrazin-2-ylmethyl)-N-formyl-formamide (0.400 g, 0.002 mol) in isopropyl alcohol (4 mL) was treated with 37% hydrogen chloride (0.182 mL, 0.0022 mol) and was heated to reflux. After 1 h 13% of an intermediate (probably the formamide) remained. 37% Hydrogen chloride (33 muL, 0.00040 mol) was added and the reflux continued. After 1 h 3% of the intermediate remained. 37% Hydrogen chloride (6 muL, 0.0002 mol) was charged and the heating was continued for a further 1 h. The solvent was then removed by evaporation and the pale brown solid was dried under high vacuum to yield the title compound as the hydrochloride salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; for 0.5h; | 3-Oxo-cyclobutanecarboxylic acid (3-chloro-pyrazin-2-ylmethyl)-amide: 3-Oxo-cyclobutanecarboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (284 mg, 1.35 mmol), C-(3-chloro-pyrazin-2-yl)-methylamine hydrochloride salt (243 mg, 1.35 mmol), and NaHCO3 (298 mg, 3.55 mmol) were dissolved in THF (2.0 mL) and water (2.0 mL) and the reaction was stirred at rt. After 30 min, the layers were allowed to separate and the aqueous layer was removed. The aqueous layer was back extracted with EtOAc. The organics were dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound as a waxy pale yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 3.10-3.27 (m, 5H), 4.56 (d, 2H, J=5.6 Hz), 8.44 (d, 1H, J=3.2 Hz), 8.63 (d, 1H, J=2.4 Hz), 8.73 (t, 1H, J=5.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; In dichloromethane; at 0℃; for 0.5h; | (3-chloropyrazin-2-yl)methanamine.hydrochloride (5 g, 27.8 mmol) and triethylamine (11.61 mL, 83 mmol) dichloromethane (80 mL) was added acetic anhydride (2.63 mL, 27.8 mmol) and the reaction mixture was stirred at 0C for 30 min. The mixture was filtered and the filtrate concentrated in vacuo. The product was purified using silica gel chromatography (ethylacetate/ethanol = 5/1 v/v%) to give 4.45 g of N-((3-chloropyrazin-2-yl)methyl)acetamide (88%). |
72.9% | With triethylamine; In ethyl acetate; at 20℃; for 1h; | To a stirred suspension of <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (0092) (500 mg, 2.78mmol) in ethyl acetate (10 mL) was added acetic anhydride (315 pL, 3.33 mmol) dropwise, followed by triethylamine (1.16 mL, 8.34 mmol). The mixture was stirred at room temperature for 1 h, and the solvent was removed under reduced pressure. The obtained residue was dissolved in methylene chloride (150 mL) and washed with saturated NaHC03 (2 c 25 mL). The organic phase was evaporated under reduced pressure and was further dried under high vacuum to give the title compound as a beige solid (376 mg, 72.9% yield), which was directly used for the next reaction without further purification. MS (ESI) m/z 186.0507 [M + H]+. 1H NMR (500 MHz, Chloroform-d) d 8.5 (d, J = 2.51 Hz, 1H), 8.3 (d, J = 2.55 Hz, 1H), 4.7 - 4.7 (m, 2H), 2.1 (s, 3H)). |
1.66 g | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | Step-2: (0932) Preparation N-((3-chloropyrazin-2-yl)methyl)acetamide: (0933) [00353] To a solution of <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (3.5 g, 19.49 mmol) in dichloromethane (100 mL) was added diisopropylethylamine (10.18 mL, 38.99 mmol) followed by acetic anhydride (3.67 mL, 38.9 mmol) at room temperature. Then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ice water (100 mL), basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The crude product was purified by silica gel column chromatography using 3% methanol in dichloromethane to afford the title compound N-((3- chloropyrazin-2-yl)methyl)acetamide (1.66 g, 46% yield) as a brown solid. Calculated (M+H): 186.0; Found (M+H): 186.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 24h; | Example 3: Synthesis of 3-(4-Fluorophenyl)-imidazo[l,5-a]pyrazine-8-carboxylic acid (3);To a suspension of 2-aminomethyl-3-chloropyrazine hydrochloride (900 mg, 5 mmol) in dichloromethane (25 mL) is added 4-fluorobenzoyl chloride (730 lL, 6.1 mmol) followed by DIPEA (2.0 mL, 11 mmol). After 1 day, the mixture is concentrated and diluted with saturated aqueous ammonium chloride and extracted with EtOAc (3 x 40 mL). The combined organic layers are washed with brine (3 x 25 mL), dried over magnesium sulfate, filtered and concentrated. The residue is passed through a pad of silica gel using dichloromethane-heptane (1: 1) to load the sample and then eluting with dichloromethane to afford N-(3-chloro-pyrazin-2-ylmethyl)-4-fluoro-benzamide as an oil which partially solidified. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | (3-Chloropyrazin-2-yl)methanamine hydrochloride (content 77%, 1.634 g, 6.99 mmol) and 1 -methyl-5- oxopyrrolidine-3-carboxylic acid (1.000 g, 6.99 mmol) were suspended in dichloromethane (20 ml) and the reaction mixture was cooled to 0C under an argon atmosphere. N,N-diisopropylethylamine (3.05 ml, 17.48 mmol), 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide) hydrochloride (1.474 g, 7.69 mmol) and 1-hydroxy- 7-azabenzotriazole (0.476 g, 3.50 mmol) were added and the reaction mixture was stirred at room temperature overnight. Reaction was worked up by evaporting the solvents and a dark brown oil was obtained. This crude product was submitted to column chromatography (silica gel; dichloromethane / methanol 96/4) to yield impure material that was further purified by column chromatography (silica gel; dichloromethane / methanol 99/1 ) to give N-((3-chloropyrazin-2-yl)methyl)-1 -methyl-5-oxopyrrolidine-3- carboxamide (1.24 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To trichloromethyl chloroformate (4.19 mmol, 0.505 ml) in ethyl acetate (5 ml) at 0 C was added dropwise 1 ,4-dioxa-8-azaspiro[4.5]decane (6.98 mmol, 0.895 ml) in ethyl acetate (5ml) and N,N- diisopropylethylamine (6.98 mmol, 1.217 ml). After one hour the mixture was concentrated, the residue was dissolved in dichloromethane (25 ml) and 2-aminomethyl-3-chloropyrazine hydrochloride (content 60%; 10.00 mmol, 3 g) and triethylamine (27.9 mmol, 3.89 ml) were added. After stirring for 16 hours at room temperature the reaction mixture was diluted with water, filtered over decalite, washed with water, filtered over a phase separation filter and concentrated in vacuo. The crude product was dissolved in dichloromethane containing 1 % triethylamine and purification by column chromatography (silica gel; dichloromethane containing 1 % triethylamine) gave N-((3-chloropyrazin-2-yl)methyl)-1 ,4-dioxa-8- azaspiro[4.5]decane-8-carboxamide (1.5 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h; | 13a. Synthesis of N-((3-chloropyrazin-2-yl)methyl)-3-methyloxetane-3-carboxamideTo a stirred suspension of 2-aminomethyl-3-chloropyrazine hydrochloride (content 77%; 4.34 mmol, 0.81 g) in dichloromethane (150 ml) were added 3-methyl-3-oxetanecarboxylic acid (4.34 mmol, 0.504 g), triethylamine (9.56 mmol, 1.33 ml), 4-dimethylaminopyridine (0.434 mmol, 0.053 g) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.69 mmol, 1.67 g). After stirring for 16 hours at room temperature the suspension was filtered over decalite and the decalite was washed with dichloromethane. The combined filtrates were washed with 0.3 N hydrochloric acid (350 mL), 0.03 N hydrochloric acid (350 mL) and sodium hydrogencarbonate (aq). All aqueous layers were twice extracted with dichloromethane. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to give crude material. Solid sodium chloride was added to all aqueous layers and these were extracted five times with dichloromethane. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to give a second crop of crude material. The combined crude products were purified using chromatography (silica gel, ethyl acetate) to yield N-((3-chloropyrazin-2-yl)methyl)-3-methyloxetane- 3-carboxamide (0.58 g).H NMR (CDCl3, 400 MHz): delta 1.68 (s, 3H), 4.52 (d, J = 6 Hz, 2H), 4.76 (d, J = 5 Hz, 2H), 4.98 (d, J = 6 Hz, 2H), 7.13 (brs, 1 H), 8.35 (d, J = 2 Hz, 1 H), 8.47 (d, J = 2 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A stirred solution of trichloromethyl chloroformate (105 mmol, 12.68 mL) in tetrahydrofuran (100 mL) was cooled to 0 C and a solution of azetidine (88 mmol, 5 g) and N,N-diisopropylethylamine (193 mmol, 33.6 mL) in tetrahydrofuran (100 mL) was added slowly in 25 minutes. After stirring at 0 C for one hour the solids were removed by filtration and the filtrate was concentrated at 50 mbar (50C bath temperature). The residue was added to a solution of 2-aminomethyl-3-chloropyrazine hydrochloride (66.7 mmol, 12 g) and triethylamine (200 mmol, 27.9 mL) in dichloromethane (200 mL) and the reaction mixture was stirred for three hours. The solids were removed by filtration and the filtrate was concentrated in vacuo. Purification using column chromatography (silica gel; gradient dichloromethane / methanol 100:0 to 95:5) yielded 9.5 g of N-((3-chloropyrazin-2-yl)methyl)azetidine-1 -carboxamide. H NMR (CDCl3, 400 MHz): delta 2.30 (quintet, J = 9 Hz, 2H), 4.06 (t, J = 9 Hz, 4H), 4.66 (d, JJ = 2 Hz, 1 H), 8.45 (d, J = 2 Hz, 1 H). | ||
9.5 g | trichloromethyl chloroformate (105 mmol, 12.68 mL) in tetrahydrofuran (100 mL) was cooled to 0 C and a solution of azetidine (88 mmol, 5 g) and N,N-diisopropylethylamine (193 mmol, 33.6 mL) in tetrahydrofuran (100 mL) was added slowly in 25 minutes. After stirring at 0 C for one hour the solids were removed by filtration and the filtrate was concentrated at 50 mbar (50C bath temperature). The residue was added to a solution of 2-aminomethyl-3-chloropyrazine hydrochloride (66.7 mmol, 12 g) and triethylamine (200 mmol, 27.9 mL) in dichloromethane (200 mL) and the reaction mixture was stirred for three hours. The solids were removed by filtration and the filtrate was concentrated in vacuo. Purification using column chromatography (silica gel; gradient dichloromethane / methanol 100:0 to 95:5) yielded 9.5 g of N-((3-chloropyrazin-2-yl)methyl)azetidine-1-carboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A suspension of 3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a]piperazine hydrochloride (10.94 mmol, 2.5 g) in a mixture of tetrahydrofuran (50 ml) and N,N-diisopropylethylamine (32.8 mmol, 5.42 ml) was added to trichloromethyl chloroformate (13.12 mmol, 1.583 ml) in tetrahydrofuran (50 ml) at 0 C. After one hour at 0 C the reaction mixture was filtered over decalite and the filter washed with tetrahydrofuran. Then the filtrate was concentrated in vacuo. The residue (4.52 g, crude) was added to 2-aminomethyl-3- chloropyrazine hydrochloride (content 77%; 8.43 mmol, 1.97 g) in a mixture of dichloromethane (50 ml) and triethylamine (25.3 mmol, 3.52 ml) and the reaction mixture was stirred over night at room temperature. Then the reaction mixture was filtered over decalite and the filter washed with dichloromethane. The filtrate was washed with water. The aqueous layer was extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. The crude product was purification by column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) to give N-((3-chloropyrazin-2-yl)methyl)-3- (trifluoromethyl)-5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxamide (2.707g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; | The latter compound was added to 2-aminomethyl-3- chloropyrazine hydrochloride (content 69%; 3.49 mmol, 0.91 g) in dichloromethane (15 ml) and triethylamine (10.46 mmol, 1.458 ml) and the reaction mixture was stirred over night at room temperature. Then the reaction mixture was filtered over decalite (washed with dichloromethane). The filtrate was concentrated and the crude product was purified using column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) to give benzyl 4-((3-chloropyrazin-2- yl)methylcarbamoyl)piperazine-1 -carboxylate (1.15 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In dichloromethane; at 20℃; for 16h; | 2a. Synthesis of N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide To a stirred suspension of 2-aminomethyl-3-chloropyrazine hydrochloride (3.89 mmol, 0.70 g) in dichloromethane (25 mL) at room temperature was subsequently added triethylamine (7.78 mmol, 1.08 mL), 0-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluroniumhexafluorophosphate (4.67 mmol, 1.77 g) and finally 4-oxocyclohexanecarboxylate (3.89 mmol, 553 mg). After stirring for 16 hours, the suspension filtered over decalite. The decalite was washed with dichloromethane. The filtrate was washed with water, dried (sodium sulfate) and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel (ethyl acetate). The product was dissolved in dichloromethane, washed with water and concentrated in vacuo to afford 1.09 g of the title compound.H NMR (CDCl3, 400 MHz): delta 2.03 - 2.14 (m, 2H), 2.22-2.30 (m, 2H), 2.35 - 2.45 (m, 2H), 2.52 - 2.60 (m, 2H), 2.68 - 2.78 (m, 1 H), 4.73 (d, J = 4 Hz, 2H), 6.93 (brs, 1 H), 8.34 - 8.37 (m, 1 H), 8.46 (d, J = 2 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 2h; | To a solution of 2-aminomethyl-3-chloropyrazine hydrochloride (content 70%; 7.85 mmol, 1.7 g) in N,N- diisopropylethylamine (39.3 mmol, 6.84 ml) and dichloromethane (30 ml) at 0 C was added carefully 1- methylpiperidine-4-carbonyl chloride hydrochloride (9.42 mmol, 2.2 g). Then the cooling bath was removed. After two hours saturated aqueous sodium hydrogencarbonate solution (40 mL) was added and extracted five times with dichloromethane (30 mL). The organic extracts were combined, dried and concentrated and co-evaporated twice with toluene to give N-((3-chloropyrazin-2-yl)methyl)-1 - methylpiperidine-4-carboxamide (1.75 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h;pH 8.0; | To 2-aminomethyl-3-chloropyrazine hydrochloride (content 76%, 69.4 mmol, 16.43 g), cis-4- hydroxycyclohexanecarboxylic acid (69.4 mmol, 10 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (104 mmol, 19.95 g), 4-dimethylaminopyridine (6.94 mmol, 0.847 g) in dichloromethane (200 ml) was added N,N-diisopropylethylamine (173 mmol, 30.3 ml, 22.41 g) until pH became eight and the reaction mixture was stirred at room temperature for 18 hours. Then it was concentrated in vacuo, ethyl acetate and water were added and the organic layer separated. The water layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried (MgSC ) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient of 0% to 7% methanol). All fractions that contained product were combined and concentrated in vacuo. The residue was dissolved in dichloromethane (400 ml) and washed with 2 M sodium hydroxide (aq) (three times 100 ml), washed with brine, dried (MgSC ) and concentrated in vacuo to give (cis)-N-((3- chloropyrazin-2-yl)methyl)-4-hydroxycyclohexanecarboxamide (15.47 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h; | 2-Aminomethyl-3-chloropyrazine hydrochloride (content 77%; 34.7 mmol, 6.47 g), trans-4- hydroxycyclohexanecarboxylic acid (34.7 mmol, 5 g), N,N-diisopropylethylamine (104 mmol, 18.12 ml, 13.45 g), 4-dimethylaminopyridine (3.47 mmol, 0.424 g) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) hydrochloride (45.1 mmol, 8.64 g) in dichloromethane (100 ml) were stirred at room temperature. After 16 hours the reaction mixture was diluted with 2N hydrochloric acid and extracted with dichloromethane three times. The organic layer was dried (sodium sulfate) and concentrated in vacuo. The crude product was triturated with dichloromethane to give 2 g of solid (trans)-N-((3-chloropyrazin-2- yl)methyl)-4-hydroxycyclohexanecarboxamide. The mother liquor was dissolved in ethyl acetate and washed with aqueous sodium hydrogencarbonate solution, dried (sodium sulfate) and concentrated to give an additional crop of 0.7 g of (trans)-N-((3-chloropyrazin-2-yl)methyl)-4-hydroxycyclohexanecarboxamide. | |
31.1 g | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; | (3-chloropyrazin-2-yl)methanamine.hydrochloride (20 g, 108 mmol) and trans-4-hydroxycyclohexanecarboxylic Acid (15.54 g, 108 mmol) EDCl.HCl (22.72 g, 119 mmol), 1-hydroxy-7-azabenzotriazole (7.33 g, 53.9 mmol) in dichloromethane (250 mL) was added triethylamine (23.96 mL, 172 mmol) and the reaction mixture was stirred at room temperature over night. The mixture was washed with 0.1 M HCl-solution, 5% NaHCO3, water and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified using silica gel chromatography (dichloromethane/methanol = 9/1 v/v%) to give 31.1 g of (trans)-N-((3-chloropyrazin-2-yl)methyl)-4-hydroxycyclohexanecarboxamide (98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In dichloromethane; N,N-dimethyl-formamide; at 15 - 30℃; for 0.166667h;Inert atmosphere; | To a solution of 59 <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> 1a (0.9 g, 5.0 mmol) and 32 N,N-dimethyl formamide (0.02 mL) in 25 dichloromethane (20 mL) at room temperature, was added dropwise a solution of 60 benzyl 3-(chlorocarbonyl)azetidine-1-carboxylate (1.3 g, 5.0 mmol) in dichloromethane (5.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 10 min. The reaction mixture was quenched with saturated 33 sodium bicarbonate solution (30 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (30 mL×2). The combined organic phase was washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was purified by flash column chromatography (20:1 dichloromethane/methanol) to provide 61 benzyl-3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)azetidine-1-carboxylate 2a (1.20 g, 3.7 mmol, yellow oil). Yield: 75%.1H NMR (400 MHz, CDCl3) delta8.43 (d, J=2.4 Hz, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.35-7.27 (m, 5H), 6.91 (bs, 1H), 5.10 (s, 2H), 4.71 (d, J=4.4 Hz, 2H), 4.27-4.19 (m, 4H), 3.40 (dd, J=6.0 & 6.0 Hz, 1H). |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; | N,N-diisopropylethylamine (109 mmol, 18.01 ml) and a solution of benzyl 3-(chlorocarbonyl)azetidine-1- carboxylate (5.53 g) in dichloromethane (32.5 ml) were added to a stirred suspension of 2-aminomethyl-3- chloropyrazine hydrochloride (content 77%; 21.80 mmol, 5.10 g) in dichloromethane (55 ml) at room temperature to give a dark brown solution. After stirring at room temperature for two hours the reaction mixture was quenched with water and filtered over decalite. Layers were separated and to the aqueous layer saturated aqueous sodium hydrogencarbonate solution was added and the layer was extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried (sodium sulfate), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane / methanol gradient 10/0 to 9/1 ) to give benzyl 3-((3-chloropyrazin-2- yl)methylcarbamoyl)azetidine-1-carboxylate (6.46 g).NMR (CDCl3, 400 MHz): delta 3.37 -3.45 (m, 1 H), 4.16 - 4.30 (m, 4H), 4.71 (d, J = 5 Hz, 2H), 5.10 (s, 2H), 6.92 - 6.97 (m, 1 H), 7.28 - 7.47 (m, 5H), 8.33 (d, J = 2 Hz, 1 H), 8.44 (d, J = 2 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; | A mixture of <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (5 g, 21.38 mmol), (trans)-4- ((benzyloxycarbonylamino)methyl)cyclohexanecarboxylic acid (6.23 g, 21.38 mmol), 1 -ethyl-3-(3- dimethylaminopropyl) carbodiimide) hydrochloride (4.51 g, 23.52 mmol), 1 -hydroxy-7-azabenzotriazole (1.455 g, 10.69 mmol), and triethyl amine (4.76 ml, 34.2 mmol) in dichloromethane (60 ml) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane with gradient 0.5 to 5% of methanol) to yield benzyl ((trans)-4- ((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl)methylcarbamate (8.79 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 18h;Inert atmosphere; | To 2-aminomethyl-3-chloropyrazine hydrochloride (content 80%; 4.44 mmol, 1 g) and N,N- diisopropylethylamine (17.77 mmol, 3.10 ml) in dichloromethane (20 ml) under N2 at 0C was added N- methylpiperazin-4-carbamoyl chloride hydrochloride (4.89 mmol, 0.973 g). After stirring at room temperature for 18 hours water was added and the mixture extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) gave N-((3-chloropyrazin-2-yl)methyl)-4-methylpiperazine-1 -carboxamide (513 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen; acetic acid; at 20℃; for 36h; | To a solution of <strong>[55557-52-3]3-chloropyrazine-2-carbonitrile</strong> (Compound 101) (6.00 g, 43.0 mmol, 1.0 equiv.) In acetic acid (50 mL) was added Raney nickel (4.00 g) In the hydrogen ball under the room temperature reaction for 1.5 days. The reaction solution was filtered and the filtrate was taken dry and the residue was spin-fed with toluene (40 mL), 1 N HCl (15 mL) and toluene (40 mL) The residue was dissolved in tetrahydrofuran (30 mL), filtered, the cake was spin dried, To give (3-chloropyrazin-2-yl) methanamine hydrochloride (8.75 g, yield: 100%). Black solid; |
35% | (90 g, 645 mmol), CH3COOH (1 L) and Raney Ni (20 g) were added to a 2 Lautoclave successively. A reaction was carried out in the autoclave while the reaction solution was stirred under ahydrogen pressure of 1 MPa for 48 hours at atmospheric temperature. After the reaction was completed, the reactionsolution was filtered through diatomite, and a solution of HCl in MeOH (200mL, 6.0N) was used to wash diatomite The filtrate after being concentrated was poured into toluene and the obtained system was stirred, and was thenconcentrated again. The obtained mixture was stirred in MTBE (methyl tert-butyl ether) and was filtered. The filtercake was stirred in MTBE and MeOH and was then filtered to obtain intermediate 2 (40g, yield: 35%) as a brownsolid. LCMS showed a molecular ion peak (M+1) 144.0. | |
153.5 g | To a solution of <strong>[55557-52-3]3-chloropyrazine-2-carbonitrile</strong> (160 g, 1.147 mol) in acetic acid (1.5 L) was added Raney Nickel (50% slurry in water, 70 g, 409 mmol). The resulting mixture was stirred under 4 bar hydrogen at room temperature overnight. Raney Nickel was removed by filtration over decalite and the filtrate was concentrated under reduced pressure and co-evaporated with toluene. The remaining brown solid was dissolved in ethyl acetate at 50C and cooled on an ice-bath. 2M hydrogen chloride solution in diethyl ether (1.14 L) was added in 30 min. The mixture was allowed to stir at room temperature over weekend. The crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40C. The product brown solid obtained was dissolved in methanol at 60C. The mixture was filtered and partially concentrated, cooled to room temperature and diethyl ether (1000 ml) was added. The mixture was allowed to stir at room temperature overnight. The solids formed were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40C to give 153.5 g of (3-chloropyrazin-2-yl)methanamine. hydrochloride as a brown solid (74.4 %, content 77 %). |
Intermediate 1 (S)-Benzyl 2-(8-amino-1-bromoimidazo[1 ,5-alpyrazin-3-vnpyrrolidine-1-carboxylate (a) (3-Chloropyrazin-2-yl)methanamine. hydrochloride To a solution of <strong>[55557-52-3]3-chloropyrazine-2-carbonitrile</strong> (160 g, 1 .147 mol) in acetic acid (1.5 L) was added Raney Nickel (50% slurry in water, 70 g, 409 mmol). The resulting mixture was stirred under 4 bar hydrogen at room temperature overnight. Raney Nickel was removed by filtration over decalite and the filtrate was concentrated under reduced pressure and co-evaporated with toluene. The remaining brown solid was dissolved in ethyl acetate at 50C and cooled on an ice-bath. 2M hydrogen chloride solution in diethyl ether (1 .14 L) was added in 30 min. The mixture was allowed to stir at room temperature over weekend. The crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40C. The product brown solid obtained was dissolved in methanol at 60C. The mixture was filtered and partially concentrated, cooled to room temperature and diethyl ether (1000 ml) was added. The mixture was allowed to stir at room temperature overnight. The solids formed were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40C to give 153.5 g of (3-chloropyrazin-2- yl)methanamine. hydrochloride as a brown solid (74.4 %, content 77 %). | ||
<strong>[55557-52-3]3-chloropyrazine-2-carbonitrile</strong> (160 g, 1.147 mol) in acetic acid (1.5 L) was added Raney Nickel (50% slurry in water, 70 g, 409 mmol). The resulting mixture was stirred under 4 bar hydrogen at room temperature overnight. Raney Nickel was removed by filtration over decalite and the filtrate was concentrated under reduced pressure and co-evaporated with toluene. The remaining brown solid was dissolved in ethyl acetate at 50C and cooled on an ice-bath. 2M hydrogen chloride solution in diethyl ether (1.14 L) was added in 30 min. The mixture was allowed to stir at room temperature over weekend. The crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40C. The product brown solid obtained was dissolved in methanol at 60C. The mixture was filtered and partially concentrated, cooled to room temperature and diethyl ether (1000 ml) was added. The mixture was allowed to stir at room temperature overnight. The solids formed were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40C to give 153.5 g of (3-chloropyrazin-2-yl)methanamine.hydrochloride as a brown solid (74.4 %, content 77 %). | ||
(a). (3-Chloropyrazin-2-yl)methanamine hydrochloride was prepared as follows. To a solution of <strong>[55557-52-3]3-chloropyrazine-2-carbonitrile</strong> (160 g, 1 .147 mol) in acetic acid (1.5 L) was added Raney Nickel (50% slurry in water, 70 g, 409 mmol). The resulting mixture was stirred under 4 bar hydrogen at room temperature overnight. Raney Nickel was removed by filtration over decalite and the filtrate was concentrated under reduced pressure and co-evaporated with toluene. The remaining brown solid was dissolved in ethyl acetate at 50C and cooled on an ice-bath. 2M hydrogen chloride solution in diethyl ether (1 .14 L) was added in 30 min. The mixture was allowed to stir at room temperature over weekend. The crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40C. The product brown solid obtained was dissolved in methanol at 60C. The mixture was filtered and partially concentrated, cooled to room temperature and diethyl ether (1000 ml) was added. The mixture was allowed to stir at room temperature overnight. The solids formed were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40C to give 153.5 g of (3-chloropyrazin-2- yl)methanamine.hydrochloride as a brown solid (74.4 %, content 77 %). | ||
With hydrogen; acetic acid; In water; at 20℃; under 3000.3 Torr; for 15h; | Step-1: (0930) Preparation of (3-chloropyrazin-2-yl)methanamine hydrochloride: (0931) [00352] To a solution of <strong>[55557-52-3]3-chloropyrazine-2-carbonitrile</strong> (10 g) in acetic acid (100 mL) was added Raney Nickel (50% slurry in water, 10 g). The resulting mixture was stirred under 4 bar hydrogen pressure at room temperature for 15 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure and co-evaporated with toluene. The remaining brown solid was dissolved in ethyl acetate at 50 C and cooled on an ice-bath. 4M hydrochloric acid in dioxane (50 mL) was added and the reaction mixture was allowed to stir at room temperature for 18 h. The precipitate formed was collected by filtration, washed with diethyl ether and dried under reduced pressure. The product brown solid obtained was dissolved in methanol at 60 C and filtered. The filtrate was partially concentrated, cooled to room temperature and diethyl ether (500 mL) was added. The mixture was allowed to stir at room temperature 18 h. The solids formed were collected by filtration, washed with diethyl ether and dried under reduced pressure to afford the title compound (3-chloropyrazin-2- yl)methanamine hydrochloride (7.67 g, crude) as a brown solid. Calculated (M+H): 144.03; Found (M+H): 144.0 | |
23 g | <strong>[55557-52-3]3-chloropyrazine-2-carbonitrile</strong> (32 g) was dissolved in 300 ml of acetic acid and 14 g of Raney nickel in 50% slurry,Slowly add to the above solution, pass 4.5 bar of hydrogen, and stir overnight at room temperature.Filtered through diatomaceous earth, and the filtrate was spin-dried. The ethyl acetate was taken with water to obtain a solid. The solid was dissolved in 50 C ethyl acetate.A hydrogen chloride gas was passed into the ethyl acetate solution, and a solid was precipitated, filtered, and the filter cake was washed with ethyl acetate.Drying under vacuum at 50 C gave 23 g (3-chloropyrazin-2-yl) methylamine.hydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In dichloromethane; at 0 - 20℃; | (3-chloropyrazin-2-yl)methanamine.hydrochloride (1.85 g, 10.28 mmol), (R)-piperidine-1,3-dicarboxylic acid 1-benzylester (2.71 g, 10.28 mmol) and HATU (4.1 g, 10.79 mmol) in dichloromethane (75 mL) was added triethylamine (5.73 mL, 41.1 mmol) and the reaction mixture was stirred at 0C for 4 hr. and after warming up to room temperature over night. The mixture was washed with 0.1 M HCl-solution, 5% NaHCO3, water and brine, dried over sodium sulfate and concentrated in vacuo to give 5.03 g of crude (R)-benzyl 3-((3-chloropyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (126%) which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.4% | To a mixture of (3-chloropyrazin-2-yl)methanamine hydrochloride (3.9 g, 21.8 mmol, leq) and (S)-l-((benzyloxy)carbonyl)piperidine-2-carboxylic acid (5.73 g, 21.8 mmol, 1.0 eq) in DCM (50 mL), was added TEA (12.1 mL, 87.2 mmol, 4.0 eq). The reaction mixture was cooled to 0 C. After 10 min, HATU (9.94 g, 26.2 mmol, 1.2 eq) was added, and the reaction mixture was stirred at 0 C for 1 h and then at room temperature overnight. The mixture was washed subsequently with 0.1 M HCl-solution, 5% NaHC0 ; water and brine. It was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=200: l - 50: 1) to afford the desired product 1 (7.13 g, yield 84.4 %). LCMS: m/z = 389 [M+H]+. | |
73% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; | 2-Chloro-3-aminomethylpyrazine HCl (2 g; 11.1 minol), (5)-(-)-l-(carbobenzyloxy)-2- piperidine carboxylic acid (3.2 g; 12.2 minol) and N,N-diisopropylethylamine (7.7 mL; 44.4 minol) were dissolved in dichloromethane (100 mL). N-[(dimethylamino)-lH-l,2,3-triazolo- [4,5-6]pyridin-l -ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) (6.3 g; 16.7 minol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was washed with aqueous sodium bicarbonate solution and water. The organic layer was then dried over sodium sulfate, filtered and evaporated to dryness. The crude material was chromatographed over S1O2 using a gradient of 20 -80% ethyl acetate in heptane to give 4.4 g; 11.3 minol of benzyl (2<S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]piperidine-l- carboxylate (1-1) as a colorless oil (73%). Data: LCMS Rt = 5.85 min; m/z 389.2 (M+H)+; HPLC Rt = 8.30 min; NMR (400 MHz, CDCh, 300 K): delta = 8.35 (IH, d), 8.29 (IH, d), 7.35 (5H, bs), 5.20 (2H, s), 4.95 (IH, s), 4.76 (IH, d), 4.60 (IH, dd), 4.18 (IH, bs), 3.03 (IH, bs), 2.36 (IH, bd), 1.88 - 1.47 (6H, m). |
54.6% | With triethylamine; HATU; In dichloromethane; at 0 - 20℃; | (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate To a solution of (3-chloropyrazin-2-yl)methanamine.HCI (3.60 g, 19.98 mmol, 40% wt) and (S)- 1-N-Cbz-pipecolinic acid (2.63 g, 9.99 mmol) in dichloromethane (40 mL) was added triethylamine (2.78 mL, 19.98 mmol) and the reaction mixture was cooled to 0C. After 15 min stirring at 0C, HATU (4.18 g, 10.99 mmol) was added. The mixture was stirred for 1 hour at 0C and then overnight at room temperature. The mixture was washed with 0.1 M HCI-solution, 5% NaHC03, water and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified using silica gel chromatography (dichloromethane/methanol = 99/1 to 97/3 v/v% + triethylamine) to give 2.12 g of (S)-benzyl 2-((3-chloropyrazin-2- yl)methylcarbamoyl)piperidine-1-carboxylate (54.6%). |
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; | 2-Chloro-3- aminomethylpyrazine.HCl (2 g; 11.1 mmol), <strong>[28697-11-2](S)-(-)-1-(carbobenzyloxy)-2-piperidine carboxylic acid</strong> (3.2 g; 12.2 mmol) and N,N-diisopropylethylamine (7.7 mL; 44.4 mmol) were dissolved in dichloromethane (100 mL). HATU (6.3 g; 16.7 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was washed with aqueous sodium bicarbonate solution and water. The organic layer was then dried over sodium sulfate, filtered and evaporated to dryness. The crude material was chromatographed over SiO2 using a gradient of 20-80% ethyl acetate in heptane to give 4.4 g; 11.3 mmol of benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]piperidine- 1-carboxylate as a colorless oil (73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.7% | With triethylamine; HATU; In dichloromethane; at 0 - 20℃; | To a solution of (3-chloropyrazin-2-yl)methanamine.HCI (9.57 g, 21.26 mmol, 40% wt) and Z- Pro-OH (5.3 g, 21 .26 mmol) in dichloromethane (250 mL) was added triethylamine (1 1.85 mL, 85 mmol) and the reaction mixture was cooled to 0C. After 15 min stirring at 0C, HATU (8.49 g, 22.33 mmol) was added. The mixture was stirred for 1 hour at 0C and then overnight at room temperature. The mixture was washed with 0.1 M HCI-solution, 5% NaHC03, water and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified using silica gel chromatography (heptane/ethyl acetate = 1/4 v/v%) to give 5 g of (S)-benzyl 2-((3- chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (62.7%). |
60% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 12h;Inert atmosphere; | (3-Chloropyrazine-2-yl)methylamine hydrochloride (13.50 g, 30 mmol),Z-Pro-OH (7.48g, 30mmol)Triethylamine (11.85 mL, 85 mmol), HATU (11.98 g, 31.51 mmol) was added to dichloromethane (500 mL).Protected with nitrogen and stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was washed with 0.1 N hydrochloric acid 50 mL*3.The organic phase was dried over anhydrous sodium sulfate and concentrated.The yield was 60%. |
55.1% | At 0C To a solution of (3-chloropyrazin-2-yl) methanamine hydrochloride (compound 102) (2.48 g, 13.8 mmol, 1.0 equiv.) In dichloromethane (80 mL) was added triethylamine (5.58 g, 55.2 mmol , 4.0 equivalents) and ((benzyloxy) carbonyl) -L-proline (compound 103) (3.43 g, 13.8 mmol, 1.0 equiv) Stirred at 0 & lt; 0 & gt; C for 15 minutes, A solution of 2- (7-azobenzotriazole) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU, 5.50 g, 14.5 mmol, 1.05 equiv) was added and the reaction was allowed to react at 0 C to room temperature for 5 minutes. The reaction solution was diluted with dichloromethane (200 mL), washed successively with ammonium chloride solution (200 mL x 1), saturated sodium bicarbonate solution (200 mL x 1), saturated brine (200 mL x 1), and the organic phase was washed with anhydrous sulfuric acid The sodium was dried, filtered, the filtrate was dry and the residue was purified by column chromatography (eluent: Dichloromethane: methanol = 80: 1) to give benzyl (S) -2 - (((3-chloropyrazin-2-yl) methyl) carbamoyl) pyrrolidine-1-carboxylate (2.85 g , Yield: 55.1%). Light brown oil; |
14.7% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; for 14h;Inert atmosphere; | in a 3 L reaction flask, DCM (dichloromethane) (500 mL), intermediate 2 (39 g,217 mmol), 1148-11-4 (N-benzyloxycarbonyl-L-proline) (54 g, 217 mmol) and Et3N (87.7 g, 868 mmol) were addedsuccessively. Under nitrogen protection, the reaction solution was cooled to 0 C and HATU (2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate) (98.8 g, 260 mmol) was added in batches. The reaction solution wasnaturally warmed to room temperature, and the reaction was carried out for 14 hours under stirring. After the reactionwas completed, HCl (400 mL, 0.5 N H2O) was added, the obtained mixture was filtered through diatomite and wasextracted, the organic phase was washed with NaHCO3 (5%) and saturated saline solution, dried over Na2SO4 andconcentrated, then passed through column (PE (polyethylene): EA (ethyl acrylate) = 1:1) to obtain intermediate 3(12.7 g, yield: 14.7%) as a white solid. LCMS showed a molecular ion peak (M+1) 375.0. |
5 g | (b) (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate To a solution of (3-chloropyrazin-2-yl)methanamine.HCI (9.57 g, 21.26 mmol, 40% wt) and Z-Pro-OH (5.3 g, 21 .26 mmol) in dichloromethane (250 mL) was added triethylamine (1 1.85 mL, 85 mmol) and the reaction mixture was cooled to 0C. After 15 min stirring at 0C, HATU (8.49 g, 22.33 mmol) was added. The mixture was stirred for 1 hour at 0C and then overnight at room temperature. The mixture was washed with 0.1 M HCI-solution, 5% NaHC03, water and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified using silica gel chromatography (heptane/ethyl acetate = 1/4 v/v%) to give 5 g of (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (62.7%). | |
5 g | (b). (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate was prepared as follows. To a solution of (3-chloropyrazin-2-yl)methanamine HCI (9.57 g, 21.26 mmol, 40% wt) and Z-Pro-OH (5.3 g, 21.26 mmol) in dichloromethane (250 mL) was added triethylamine (11.85 mL, 85 mmol) and the reaction mixture was cooled to 0C. After 15 min stirring at 0C, HATU (8.49 g, 22.33 mmol) was added. The mixture was stirred for 1 hour at 0C and then overnight at room temperature. The mixture was washed with 0.1 M HCI- solution, 5% NaHC03, water and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified using silica gel chromatography (heptane/ethyl acetate = 1/4 v/v%) to give 5 g of (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (62.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0 - 20℃; for 1h; | HATU (15.91 g, 41.8 mmol) was added to a stirred, cooled 0 C mixture of (6R,8aS)-3-oxooctahydroindolizine-6-carboxylic acid (7.3 g, 39.8 mmol), (3- chloropyrazin-2-yl)methanamine hydrochloride (7.89 g, 43.8 mmol) and DIPEA (10.44 ml, 59.8 mmol) in CH2C12 (25 ml) and the mixture was stirred at room temperature for 1 h. and then concentrated. The residue was purified by column chromatography on silica gel (Isco 240 g silica gel), eluting with CH2Cl2/MeOH (50/1) to give (6R,8aS)-N- ((3-chloropyrazin-2-yl)methyl)-3-oxooctahydroindolizine -6-carboxamide (11.15g, 36.1 mmol, 91 % yield) as a white solid. LC-MS: Ret. time 1.09 min; m/z 309.11 (M+H)+; 1HNMR (CDCI3, 500 Hz): 8.38 (1H, d, J = 2 Hz), 8.25 (1H, d, J = 2 Hz), 7.37 (1H, dd, J = 4 and 4.5 Hz), 4.56-4.72 (2H, m,l), 4.29 (1H, dd, J = 13 and 4.5 Hz),3.42-3.47 (m,l), 2.81 (1H, t, J = 13 Hz), 2.35 (2H, t, J = 8 Hz), 2.17-2.23 (1H, m), 2.04 (1H, d, J = 13.5 Hz), 1.94-1.96 (1H, m), 1.74-1.82 (1H, m), 1.55-1.62 (1H, m), 1.16-1.24 (1H, m). |
91% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0℃; | (f) (6R,8aS)-N-((3-chloropyrazin-2-yl)methyl)-3-oxooctahydroindolizine-6-carboxamide HATU (15.91 g, 41.8 mmol) was added to a stirred, cooled 0 C. mixture of (6R,8aS)-3-oxooctahydroindolizine-6-carboxylic acid (7.3 g, 39.8 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (7.89 g, 43.8 mmol) and DIPEA (10.44 ml, 59.8 mmol) in CH2Cl2 (25 ml) and the mixture was stirred at room temperature for 1 h. and then concentrated. The residue was purified by column chromatography on silica gel (Isco 240 g silica gel), eluting with CH2Cl2/MeOH (50/1) to give (6R,8aS)-N-((3-chloropyrazin-2-yl)methyl)-3-oxooctahydroindolizine-6-carboxamide (11.15 g, 36.1 mmol, 91% yield) as a white solid. LC-MS: Ret. time 1.09 min; m/z 309.11 (M+H)+; 1HNMR (CDCl3, 500 Hz): 8.38 (1H, d, J=2 Hz), 8.25 (1H, d, J=2 Hz), 7.37 (1H, dd, J=4 and 4.5 Hz), 4.56-4.72 (2H, m, 1), 4.29 (1H, dd, J=13 and 4.5 Hz), 3.42-3.47 (m, 1), 2.81 (1H, t, J=13 Hz), 2.35 (2H, t, J=8 Hz), 2.17-2.23 (1H, m), 2.04 (1H, d, J=13.5 Hz), 1.94-1.96 (1H, m), 1.74-1.82 (1H, m), 1.55-1.62 (1H, m), 1.16-1.24 (1H, m). |
91% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0 - 20℃; for 1h; | HATU (15.91 g, 41.8 mmol) was added to a stirred, cooled 0 C mixture of (6R,8aS)-3-oxooctahydroindolizine-6-carboxylic acid (7.3 g, 39.8 mmol), (3- chloropyrazin-2-yl)methanamine hydrochloride (7.89 g, 43.8 mmol) and DIPEA (10.44 ml, 59.8 mmol) in CH2C12 (25 ml) and the mixture was stirred at room temperature for 1 h. and then concentrated. The residue was purified by column chromatography on silica gel (Isco 240 g silica gel), eluting with CH2Cl2/MeOH (50/1) to give (6R,8aS)-N- ((3-chloropyrazin-2-yl)methyl)-3-oxooctahydroindolizine -6-carboxamide (11.15g, 36.1 mmol, 91 % yield) as a white solid. LC-MS: Ret. time 1.09 min; m/z 309.11 (M+H)+; 1HNMR (CDCI3, 500 Hz): 8.38 (1H, d, J = 2 Hz), 8.25 (1H, d, J = 2 Hz), 7.37 (1H, dd, J = 4 and 4.5 Hz), 4.56-4.72 (2H, m,l), 4.29 (1H, dd, J = 13 and 4.5 Hz),3.42-3.47 (m,l), 2.81 (1H, t, J = 13 Hz), 2.35 (2H, t, J = 8 Hz), 2.17-2.23 (1H, m), 2.04 (1H, d, J = 13.5 Hz), 1.94-1.96 (1H, m), 1.74-1.82 (1H, m), 1.55-1.62 (1H, m), 1.16-1.24 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; HATU; In dichloromethane; at 13℃; for 12h; | To a solution of l-((benzyloxy)carbonyl)-2-cyanopiperidine-4-carboxylic acid (30 mg, 0.104 mmol) in anhydrous DCM (5 mL) was added HATU (43.5 mg, 0.114 mmol), Et3N (31.56 mg, 0.312 mmol) and <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (20.5 mg, 0.114 mmol). The reaction mixture was stirred at 13 C for 12 hrs. The reaction was quenched by the addtion of water (10 mL), then it was extracted with DCM (10 mL x 3), the combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford the crude product ,which was purified on silica gel column chromatograph (PE/THF = 100% ~ 50 %) to give benzyl 4-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-2-cyanopiperidine- 1 -carboxylate (40 mg, yeild 93%) .1H NMR (400MHz, METHANOL-d4) delta= 8.54 (d, J=2.5 Hz, 1H), 8.35 (d, J=2.5 Hz, 1H), 7.44 - 7.31 (m, 5H), 5.53 (d, J=4.0 Hz, 1H), 5.21 (d, J=2.5 Hz, 2H), 4.64 (s, 2H), 4.25 (d, J=13.1 Hz, 1H), 2.87 - 2.84 (m, 1H), 2.88 - 2.77 (m, 3H), 2.16 (d, J=12.5 Hz, 1H), 2.02 - 1.91 (m, 2H), 1.66 (dq, J=4.8, 12.9 Hz, 1H). |
93% | With triethylamine; HATU; In dichloromethane; at 13℃; for 12h; | (g) benzyl 4-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-2-cyanopiperidine-1-carboxylate To a solution of 1-((benzyloxy)carbonyl)-2-cyanopiperidine-4-carboxylic acid (30 mg, 0.104 mmol) in anhydrous DCM (5 mL) was added HATU (43.5 mg, 0.114 mmol), Et3N (31.56 mg, 0.312 mmol) and <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (20.5 mg, 0.114 mmol). The reaction mixture was stirred at 13 C. for 12 hrs. The reaction was quenched by the addition of water (10 mL), then it was extracted with DCM (10 mL*3), the combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford the crude product, which was purified on silica gel column chromatograph (PE/THF=100%?50%) to give benzyl 4-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-2-cyanopiperidine-1-carboxylate (40 mg, yield 93%) NMR (400 MHz, METHANOL-d4) delta=8.54 (d, J=2.5 Hz, 1H), 8.35 (d, J=2.5 Hz, 1H), 7.44-7.31 (m, 5H), 5.53 (d, J=4.0 Hz, 1H), 5.21 (d, J=2.5 Hz, 2H), 4.64 (s, 2H), 4.25 (d, J=13.1 Hz, 1H), 2.87-2.84 (m, 1H), 2.88-2.77 (m, 3H), 2.16 (d, J=12.5 Hz, 1H), 2.02-1.91 (m, 2H), 1.66 (dq, J=4.8, 12.9 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.4% | To a solution of (6R,8aS)-3-oxo-l-vinylhexahydro-lH-oxazolo[3,4-a]pyridine- 6-carboxylic acid (60 mg, 0.28 mmol) in DCM (5mL) was added (COCl)2 (54.1 mg, 0.43 mmol) at 0C and stirred at 20C for lh under N2 atmosphere. The mixture was concentracted in vacuo to give the resiude, which was dissloved in THF (2 mL) and followed by <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (76.7 mg, 0.43 mmol) and Et3N (86.2 mg, 0.85mmol). The mixture was stirred at 20C for 5h. TLC (PE: THF=1 : 1) showed the starting materials was consumed completely. Then the reaction mixture was poured into water (10 mL), extracted with EA (10mL><2). The organic layer was concentrated in vacuo and purified with pre-TLC to afford (6R,8aS)-N-((3- chloropyrazin-2-yl)methyl)-3-oxo-l-vinylhexahydro-lH-oxazolo[3,4-a]pyridine-6- carboxamide (30 mg, yied 31.4%) as a white soild. IHNMR (400MHz, Methanol-d4): delta= 8.53 (dd, J=1.0, 2.5 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 6.04 - 5.88 (m, 1H), 5.50 - 5.31 (m, 2H), 4.65 - 4.57 (m, 3H), 3.98 - 3.89 (m, 1H), 3.83 (ddd, J=3.4, 8.2, 11.8 Hz, 1H), 3.50 - 3.42 (m, 1H), 2.58 - 2.42 (m, 1H), 2.10 (dd, J=2.5, 12.8 Hz, 1H), 2.03 - 1.95 (m, 1H), 1.77 - 1.63 (m, 2H), 1.53 - 1.38 (m, 1H). | |
31.4% | (c) (6R,8aS)-N-((3-chloropyrazin-2-yl)methyl)-3-oxo-1-vinylhexahydro-1H-oxazolo[3,4-a]pyridine-6-carboxamide To a solution of (6R,8aS)-3-oxo-1-vinylhexahydro-1H-oxazolo[3,4-a]pyridine-6-carboxylic acid (60 mg, 0.28 mmol) in DCM (5 mL) was added (COCl)2 (54.1 mg, 0.43 mmol) at 0 C. and stirred at 20 C. for 1 h under N2 atmosphere. The mixture was concentrated in vacuo to give the residue, which was dissolved in THF (2 mL) and followed by <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (76.7 mg, 0.43 mmol) and Et3N (86.2 mg, 0.85 mmol). The mixture was stirred at 20 C. for 5 h. TLC (PE: THF=1:1) showed the starting materials was consumed completely. Then the reaction mixture was poured into water (10 mL), extracted with EA (10 mL*2). The organic layer was concentrated in vacuo and purified with pre-TLC to afford (6R,8aS)-N-((3-chloropyrazin-2-yl)methyl)-3-oxo-1-vinylhexahydro-1H-oxazolo[3,4-a]pyridine-6-carboxamide (30 mg, yield 31.4%) as a white solid. 1HNMR (400 MHz, Methanol-d4): delta=8.53 (dd, J=1.0, 2.5 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 6.04-5.88 (m, 1H), 5.50-5.31 (m, 2H), 4.65-4.57 (m, 3H), 3.98-3.89 (m, 1H), 3.83 (ddd, J=3.4, 8.2, 11.8 Hz, 1H), 3.50-3.42 (m, 1H), 2.58-2.42 (m, 1H), 2.10 (dd, J=2.5, 12.8 Hz, 1H), 2.03-1.95 (m, 1H), 1.77-1.63 (m, 2H), 1.53-1.38 (m, 111). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.1% | To a solution of (6R,8aS)-l,l-dimethyl-3-oxohexahydro-lH-oxazolo[3,4- a]pyridine-6-carboxylic acid (100 mg,0.468 mmol) in anhydrous DCM (40 mL) was added (COCl)2 (158.9 mg, 0.469mmol) at 0 C, then DMF (one drop) was added and the mixture was stirred at 25 C for 1.5 hrs. The mixture was concentrated in vacuo, which then diluted with DCM (5 mL) was added to a solution of (3-chloropyrazin-2- yl)methanamine hydrochloride (101.32 mg, 0.562 mmol), TEA (94.91 mg, 0.938 mmol) in DCM (10 mL). The mixture was stirred at 25 C for 3 hrs, The mixture was quenched by the addition of water (10 mL) at 0 C , the mixture was then extracted with DCM (50 mL x 3), the combined organic layers were washed with 1M HC1 (10 mL), brine (20mL), dried over sodium sulfate, filtered and concentrated to give (6R,8aS)-N- ((3 -chloropyrazin-2-yl)methyl)- 1 , 1 -dimethyl-3 -oxohexahydro- 1 H-oxazolo [3 ,4- a]pyridine-6-carboxamide (150 mg, 94.19%) as a colorless oil. 1H NMR (400MHz, CHLOROFORM-d) d = 8.46 (d, J=2.5 Hz, IH), 8.34 (d, J=2.5 Hz, IH), 6.94 (br. s., IH), 4.78 - 4.60 (m, 2H), 4.09 (dd, J=4.1, 12.7 Hz, IH), 3.26 (dd, J=3.3, 11.8 Hz, IH), 3.08 (dd, J=11.8, 13.1 Hz, IH), 2.43 (tt, J=4.1, 11.7 Hz, lH), 2.16 (d, J=12.5 Hz, IH), 1.86 - 1.70 (m, 2H), 1.46 (s, 3H), 1.44 - 1.38 (m, IH), 1.35 (s, 3H). | |
94.19% | Step 4: (6R,8aS)-N-((3-chloropyrazin-2-yl)methyl)-1,1-dimethyl-3-oxohexahydro-1H-oxazolo[3,4-a]pyridine-6-carboxamide To a solution of (6R,8aS)-1,1-dimethyl-3-oxohexahydro-1H-oxazolo[3,4-a]pyridine-6-carboxylic acid (100 mg, 0.468 mmol) in anhydrous DCM (40 mL) was added (COCl)2 (158.9 mg, 0.469 mmol) at 0 C., then DMF (one drop) was added and the mixture was stirred at 25 C. for 1.5 hrs. The mixture was concentrated in vacuo, which then diluted with DCM (5 mL) was added to a solution of <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (101.32 mg, 0.562 mmol), TEA (94.91 mg, 0.938 mmol) in DCM (10 mL). The mixture was stirred at 25 C. for 3 hrs, The mixture was quenched by the addition of water (10 mL) at 0 C., the mixture was then extracted with DCM (50 mL*3), the combined organic layers were washed with 1M HCl (10 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to give (6R,8aS)-N-((3-chloropyrazin-2-yl)methyl)-1,1-dimethyl-3-oxohexahydro-1H-oxazolo[3,4-a]pyridine-6-carboxamide (150 mg, 94.19%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) d=8.46 (d, J=2.5 Hz, 1H), 8.34 (d, J=2.5 Hz, 1H), 6.94 (br. s., 1H), 4.78-4.60 (m, 21-1), 4.09 (dd, J=4.1, 12.7 Hz, 1H), 3.26 (dd, J=3.3, 11.8 Hz, 1H), 3.08 (dd, J=11.8, 13.1 Hz, 1H), 2.43 (tt, J=4.1, 11.7 Hz, 1H), 2.16 (d, J=12.5 Hz, 1H), 1.86-1.70 (m, 2H), 1.46 (s, 3H), 1.44-1.38 (m, 1H), 1.35 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.8% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 25℃; | A mixture of (cis)-2-((benzyloxy)carbonyl)-4-oxooctahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic acid (0.7 g, 2.1 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (450 mg, 2.5 mmol), HATU (1.2 g, 3.1 mmol) and TEA (0.85 g, 8.4 mmol) in DMF (10 mL) was stirred at 25 C. for overnight. Then the reaction mixture was poured into water, the mixture was extracted with EA (50 ml*3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/THF=1/3) to give (cis)-benzyl 7-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-4-oxohexahydro-1H-pyrido[1,2-a]pyrazine-2(6H)-carboxylate (440 mg, yield 45.8%). |
35.3% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 25℃; | A mixture of (trans)-2-((benzyloxy)carbonyl)-4-oxooctahydro-l H-pyrido [1 ,2-a] pyrazine-7-carboxylic acid (1.3 g, 3.9 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (840 mg, 4.7 mmol), HATU (2.2 g, 5.8 mmol) and TEA (1.6 g, 15.6 mmol) in DMF (20 mL) was stirred at 25 C for overnight. Then the reaction mixture was poured into water and extracted with EA (50 ml*3). The combined organic phase was washed with brine (100 mL), dried over Na2S04, concentrated under vacuum to give the crude residue, which was purified by silica gel column chromatography (PE/THF = 1/3) to give (trans)-benzyl 7-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-4- oxohexahydro-1 H-pyrido [l ,2-a]pyrazine-2(6H)-carboxylate (600 mg, yield 35.3 %). 1H NMR (400MHz, CD3OD) delta= 8.52 (d, J=2.5 Hz, 1H), 8.33 (d, J=2.3 Hz, 1H), 7.40 - 7.29 (m, 5H), 5.15 (br. s., 2H), 4.77 - 4.67 (m, 1H), 4.12 (br. s., 1H), 3.96 - 3.85 (m, 1H), 3.48 (br. s., 2H), 2.71 (t, J=12.5 Hz, 1H), 2.52 - 2.36 (m, 1H), 2.1 1 - 1.97 (m, 2H), 1.90 - 1.71 (m, 2H). |
35.3% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 25℃; | (e) (trans)-benzyl 7-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-4-oxohexahydro-1H-pyrido[1,2-a]pyrazine-2(6H)-carboxylate A mixture of (trans)-2-((benzyloxy)carbonyl)-4-oxooctahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic acid (1.3 g, 3.9 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (840 mg, 4.7 mmol), HATU (2.2 g, 5.8 mmol) and TEA (1.6 g, 15.6 is mmol) in DMF (20 mL) was stirred at 25 C. for overnight. Then the reaction mixture was poured into water and extracted with EA (50 ml*3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, concentrated under vacuum to give the crude residue, which was purified by silica gel column chromatography (PE/THF=1/3) to give (trans)-benzyl 7-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-4-oxohexahydro-1H-pyrido[1,2-a]pyrazine-2(6H)-carboxylate (600 mg, yield 35.3%). 1H NMR (400 MHz, CD3OD) delta=8.52 (d, J=2.5 Hz, 1H), 8.33 (d, J=2.3 Hz, 1H), 7.40-7.29 (m, 5H), 5.15 (br. s., 2H), 4.77-4.67 (m, 1H), 4.12 (br. s., 1H), 3.96-3.85 (m, 1H), 3.48 (br. s., 2H), 2.71 (t, J=12.5 Hz, 1H), 2.52-2.36 (m, 1H), 2.11-1.97 (m, 2H), 1.90-1.71 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.35% | With triethylamine; HATU; In dichloromethane; at 25℃; | A mixture of (trans)-6-oxooctahydro-l H-quinolizine-3 -carboxylic acid (520 mg, 2.64 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (570 mg, 3.17 mmol), HATU (1.50 g, 3.95 mmol) and TEA (0.79 g, 7.91 mmol) in DCM (13 mL) was stirred at 25 C overnight. The mixture was quenched with H20 (40 mL) and extracted with DCM (15 mL*3).The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product.The crude product was purified by column chromatography on silica gel eluting with PE / THF (0-60%) to give (trans)- N-((3-chloropyrazin-2-yl)methyl)-6-oxooctahydro-l H-quinolizine-3 -carboxamide (0.7 g, 82.35%) as a light yellow solid. 1H NMR (400MHz, CDC13) delta = 8.53 - 8.41 (m, 1H), 8.33 (d, J=2.5 Hz, 1H), 6.96 (br. s., 1H), 5.08 - 4.88 (m, 1H), 4.73 - 4.61 (m, 2H), 3.40 - 3.26 (m, 1H), 2.72 - 2.57 (m, 1H), 2.47 - 2.28 (m, 3H), 2.12 - 2.00 (m, 2H), 1.89 - 1.77 (m, 4H), 1.73 - 1.62 (m, 1H), 1.58 - 1.47 (m, 1H). |
82.35% | With triethylamine; HATU; In dichloromethane; at 25℃; | A mixture of (trans)-6-oxooctahydro-l H-quinolizine-3 -carboxylic acid (520 mg, 2.64 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (570 mg, 3.17 mmol), HATU (1.50 g, 3.95 mmol) and TEA (0.79 g, 7.91 mmol) in DCM (13 mL) was stirred at 25 C overnight. The mixture was quenched with H20 (40 mL) and extracted with DCM (15 mL*3).The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product.The crude product was purified by column chromatography on silica gel eluting with PE / THF (0-60%) to give (trans)- N-((3-chloropyrazin-2-yl)methyl)-6-oxooctahydro-l H-quinolizine-3 -carboxamide (0.7 g, 82.35%) as a light yellow solid. 1H NMR (400MHz, CDC13) delta = 8.53 - 8.41 (m, 1H), 8.33 (d, J=2.5 Hz, 1H), 6.96 (br. s., 1H), 5.08 - 4.88 (m, 1H), 4.73 - 4.61 (m, 2H), 3.40 - 3.26 (m, 1H), 2.72 - 2.57 (m, 1H), 2.47 - 2.28 (m, 3H), 2.12 - 2.00 (m, 2H), 1.89 - 1.77 (m, 4H), 1.73 - 1.62 (m, 1H), 1.58 - 1.47 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.86 g | With triethylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h;Inert atmosphere; | (2R,5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(hydroxymethyl) morpholine-4-carboxylate (2g, 4.12 mmol) was dissolved in 100 mL CH2Cl2and cooled to 0 C. TEMPO(0.13 g, 0.82 mmol) was added, followed by (diacetoxyiodo)benzene (2.65 g, 8.24 mmol). The ice bath was removed, and the reaction was allowed to warm to room temperature and stirred overnight. The mixture was diluted with 200 mL ethyl acetate and washed with 10% Na2S203, aq. satd. NaHC03, and brine. The organic phase was dried with Na2S04, filtered and concentrated to give (2R,5R)-4-(tert- butoxycarbonyl)-5 -(((tert-butyl diphenylsilyl)oxy)methyl)morpholine-2-carboxylic acid (1.36g, 66%). LCMS: [M-H]+:498.23 Ret. time= 1.33 min, LC-MS method E). Used as such for the next step without any further purification. (2R,5R)-4-(tert-butoxycarbonyl)-5-(((tert- butyldiphenylsilyl)oxy)methyl)morpholine-2-carboxylic acid (1.5g, 3.0 mmol) and (3- chloropyrazin-2-yl)methanamine. HC1 salt (0.54g, 3.0 mmol) were dissolved in DMF 100 mL. To the reaction mixture was added Et3N (0.76g, 6.0 mmol) followed by slow addition of HATU (1.37g, 3.6 mmol) at 0 C. The reaction was stirred at rt for 1 day under a stream of nitrogen and then quenched with sat. NaHC03 (100 mL) and extracted with EtOAc(2xl50 mL). The combined organic layer was washed with water(200 mL) , brine(200mL), dried over anhydrous Na2S04, filtered, and evaporated. The crude residue was subjected to column purification using 20-50%) EtO Ac/Hex. to give (2R,5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy) methyl)-2-(((3-chloropyrazin- 2-yl)methyl)carbamoyl)morpholine-4-carboxylate (0.86g, 46%). LCMS: [M-Boc +H]+:525.25 Ret. time= 2.74 min, LC-MS method E). |
0.86 g | With triethylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h;Inert atmosphere; | (2R,5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(hydroxymethyl) morpholine-4-carboxylate (2g, 4.12 mmol) was dissolved in 100 mL CH2Cl2and cooled to 0 C. TEMPO(0.13 g, 0.82 mmol) was added, followed by (diacetoxyiodo)benzene (2.65 g, 8.24 mmol). The ice bath was removed, and the reaction was allowed to warm to room temperature and stirred overnight. The mixture was diluted with 200 mL ethyl acetate and washed with 10% Na2S203, aq. satd. NaHC03, and brine. The organic phase was dried with Na2S04, filtered and concentrated to give (2R,5R)-4-(tert- butoxycarbonyl)-5 -(((tert-butyl diphenylsilyl)oxy)methyl)morpholine-2-carboxylic acid (1.36g, 66%). LCMS: [M-H]+:498.23 Ret. time= 1.33 min, LC-MS method E). Used as such for the next step without any further purification. (2R,5R)-4-(tert-butoxycarbonyl)-5-(((tert- butyldiphenylsilyl)oxy)methyl)morpholine-2-carboxylic acid (1.5g, 3.0 mmol) and (3- chloropyrazin-2-yl)methanamine. HC1 salt (0.54g, 3.0 mmol) were dissolved in DMF 100 mL. To the reaction mixture was added Et3N (0.76g, 6.0 mmol) followed by slow addition of HATU (1.37g, 3.6 mmol) at 0 C. The reaction was stirred at rt for 1 day under a stream of nitrogen and then quenched with sat. NaHC03 (100 mL) and extracted with EtOAc(2xl50 mL). The combined organic layer was washed with water(200 mL) , brine(200mL), dried over anhydrous Na2S04, filtered, and evaporated. The crude residue was subjected to column purification using 20-50%) EtO Ac/Hex. to give (2R,5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy) methyl)-2-(((3-chloropyrazin- 2-yl)methyl)carbamoyl)morpholine-4-carboxylate (0.86g, 46%). LCMS: [M-Boc +H]+:525.25 Ret. time= 2.74 min, LC-MS method E). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.9% | To a solution of (3S,7R,9aS)-3-methyl-4-oxooctahydropyrido[2,l- c][l ,4]oxazine-7-carboxylic acid (55 mg, 0.26 mmol) in anhydrous DCM (1 mL) was added oxalyl dichloride (0.068 mL, 0.77 mmol) in DCM (0.5 mL) at 0C under N2 atmosphere, and followed by 1 drop of DMF. The resulting mixture was stirred at 0C for 2 hrs. The reaction mixture was evaporated, dissolved with DCM (0.5 mL), and added to a solution of <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (56.1 mg, 0.31 mmol), and triethylamine (0.079 mL, 0.57 mmol) in DCM (1 mL), at 0C under N2 atmosphere, and the mixture was stirred for 12 hrs at 15 C.Then the mixture was diluted with DCM (5 mL), and H20 (5 mL). The organic layer was washed with brine (5 mL), dried over Na2S04, evaporated to get the crude product, which was then purified by prep-TLC (PE/THF=1 : 1) to give (3S,7R,9aS)-N-((3-chloropyrazin-2- yl)methyl)-3-methyl-4-oxooctahydropyrido[2, 1 -c] [ 1 ,4]oxazine-7-carboxamide (55 mg, yield: 62.9 %). 1H NMR (400MHz, CDC13) delta = 8.42 (d, J=2.5 Hz, IH), 8.29 (d, J=2.5 Hz, IH), 7.17 (br. s., IH), 4.76 - 4.57 (m, 2H), 4.16 (q, J=6.9 Hz, IH), 3.92 (dd, J=4.1 , 12.2 Hz, IH), 3.74 (dd, J=2.5, 12.0 Hz, IH), 3.37 - 3.25 (m, IH), 2.73 (t, J=12.3 Hz, IH), 2.42 (tt, J=4.0, 1 1.8 Hz, IH), 2.18 - 2.03 (m, 2H), 1.99 - 1.84 (m, IH), 1.79 - 1.68 (m, 2H), 1.44 (d, J=7.0 Hz, 3H). | |
62.9% | (f) (3S,7R,9aS)-N-((3-chloropyrazin-2-yl)methyl)-3-methyl-4-oxooctahydropyrido[2,1-c][1,4]oxazine-7-carboxamide To a solution of (3S,7R,9aS)-3-methyl-4-oxooctahydropyrido[2,1-c][1,4]oxazine-7-carboxylic acid (55 mg, 0.26 mmol) in anhydrous DCM (1 mL) was added oxalyl dichloride (0.068 mL, 0.77 mmol) in DCM (0.5 mL) at 0 C. under N2 atmosphere, and followed by 1 drop of DMF. The resulting mixture was stirred at 0 C. for 2 hrs. The reaction mixture was evaporated, dissolved with DCM (0.5 mL), and added to a solution of <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (56.1 mg, 0.31 mmol), and triethylamine (0.079 mL, 0.57 mmol) in DCM (1 mL), at 0 C. under N2 atmosphere, and the mixture was stirred for 12 hrs at 15 C. Then the mixture was diluted with DCM (5 mL), and H2O (5 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4, evaporated to get the crude product, which was then purified by prep-TLC (PE/THF=1:1) to give (3S,7R,9aS)-N-((3-chloropyrazin-2-yl)methyl)-3-methyl-4-oxooctahydropyrido[2,1-c][1,4]oxazine-7-carboxamide (55 mg, yield: 62.9%). 1H NMR (400 MHz, CDCl3) delta=8.42 (d, J=2.5 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 7.17 (br. s., 1H), 4.76-4.57 (m, 2H), 4.16 (q, J=6.9 Hz, 1H), 3.92 (dd, J=4.1, 12.2 Hz, 1H), 3.74 (dd, J=2.5, 12.0 Hz, 1H), 3.37-3.25 (m, 1H), 2.73 (t, J=12.3 Hz, 1H), 2.42 (tt, J=4.0, 11.8 Hz, 1H), 2.18-2.03 (m, 2H), 1.99-1.84 (m, 1H), 1.79-1.68 (m, 2H), 1.44 (d, J=7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 50℃; | To a solution of trans-2-methyl-l -oxooctahydro- 1 H-pyrido [1, 2-c]pyrimidine-7- carboxylic acid (1.6 mmol) in DCM (20 mL) was added (3-chloropyrazin-2-yl) methanamine hydrochloride (356 mg, 2.0 mmol), EDC (477 mg, 2.5 mmol), HOBT (336 mg, 2.5 mmol) and TEA (670 mg, 6.6 mmol), and the resulting mixture was stirred at 50 C overnight. The volatiles were evaporated and the residue was purified by column chromatography on silica gel eluted with DCM/THF = 3/1 to give trans-N-((3- chloropyrazin-2-yl)methyl)-2 -methyl- 1 -oxooctahydro- 1 H- pyrido [ 1 ,2-c]pyramidine-7- carboxamide (90 mg, four steps: 17%).1H NMR (CDC13, 400 MHz) delta 1.24 - 1.34 (m, 1 H), 1.67 - 1.76 (m, 3 H), 1.92 - 2.08 (m, 3 H), 2.29 - 2.38 (m, 1 H), 2.64 (t, / = 12.0 Hz, 1 H), 2.87 (s, 3 H), 3.12 - 3.21 (m, 3 H), 4.59 - 4.69 (m, 3 H), 6.89 - 7.01 (m, 1 H), 8.24 (d, / = 4.0 Hz, 1 H), 8.37 (d, / = 4.0 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.8% | (f) (3R,8aR)-N-((3-chloropyrazin-2-yl)methyl)-6-oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-3-carboxamide To a solution of (3R,8aR)-6-oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-3-carboxylic acid (600 mg, 3.24 mmoL) in DCM (20 mL) was added isobutyl carbonochloridate (531 mg, 3.56 mmol) and TEA (0.53 mL, 3.78 mmol), the mixture was stirred at 0 C. for 1 hour, then <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (641 mg, 3.56 mmol) and TEA (1.1 mL, 7.56 mmol) was added at 0 C. The mixture was stirred at 25 C. for 3 hours. To the mixture was added water (20 mL) and DCM (50 mL), the mixture was then separated and the aqueous layer was extracted with DCM (50 mL*3), the combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford the crude product, which was purified on silica gel column chromatograph (MeOH/DCM=0?10%) to give (3R,8aR)-N-((3-chloropyrazin-2-yl)methyl)-6-oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-3-carboxamide (300 mg, yield 29.8%) as a sheer oil. 1H NMR (400 MHz, CHLOROFORM-d) d=8.50 (d, J=2.5 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 7.78 (br. s., 1H), 4.74 (d, J=5.0 Hz, 2H), 4.52 (dd, J=3.1, 13.4 Hz, 1H), 4.23 (dd, J=3.8, 11.3 Hz, 1H), 3.97 (dd, J=3.0, 11.0 Hz, 1H), 3.75 (dtd, J=4.0, 7.3, 10.8 Hz, 1H), 3.30 (t, J=11.0 Hz, 1H), 2.86 (t, J=12.3 Hz, 1H), 2.60-2.43 (m, 2H), 2.29-2.13 (m, 1H), 1.70-1.54 (m, 1H) | |
300 mg | With triethylamine; isobutyl chloroformate; In dichloromethane; at 0 - 25℃; for 4h; | To a solution of (3R,8aR)-6-oxohexahydro-lH-pyrrolo[2,l-c][l,4]oxazine-3- carboxylic acid (600 mg, 3.24 mmoL ) in DCM ( 20 mL) was added isobutyl carbonochloridate (531 mg, 3.56 mmol) and TEA (0.53 mL, 3.78 mmol), the mixture was stirred at 0C for 1 hour, then <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (641 mg, 3.56 mmol) and TEA (1.1 mL, 7.56 mmol) was added at 0C. The mixture was stirred at 25C for 3 hours. To the mixture was added water (20 mL) and DCM (50 mL), the mixture was then separated and the aqueous layer was extracted with DCM (50 mL x 3), the combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford the crude product, which was purified on silica gel column chromatograph (MeOH / DCM =0 ~ 10%) to give (3R,8aR)-N-((3- chloropyrazin-2-yl)methyl)-6-oxohexahydro- 1 H-pyrrolo [2, 1 -c] [ 1 ,4]oxazine-3 - carboxamide (300 mg, yield 29.8%) as a sheer oil. 1H NMR (400MHz, CHLOROFORM-d) d = 8.50 (d, J=2.5 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 7.78 (br. s., 1H), 4.74 (d, J=5.0 Hz, 2H), 4.52 (dd, J=3.1 , 13.4 Hz, 1H), 4.23 (dd, J=3.8, 1 1.3 Hz, 1H), 3.97 (dd, J=3.0, 1 1.0 Hz, 1H), 3.75 (dtd, J=4.0, 7.3, 10.8 Hz, 1H), 3.30 (t, J=1 1.0 Hz, 1H), 2.86 (t, J=12.3 Hz, 1H), 2.60 - 2.43 (m, 2H), 2.29 - 2.13 (m, 1H), 1.70 - 1.54 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
700 mg | With triethylamine; HATU; In tetrahydrofuran; at 20℃; for 4h; | To a solution of 2,2-dimethyl-3-oxooctahydroindolizine-6-carboxylic acid (500 mg, 2.4 mmol) and (3-chloropyrazin-2-yl) methanamine(509 mg, 2.83 mmol) in THF (20 mL) was added HATU(1.075 g, 2.8 mmol) and TEA (596 mg, 5.9 mmol). The mixture was stirred at room temperature for 4 hours. Removed the volatiles under reduced pressure, and the rest mixture was extracted with DCM, the combined organic layer was washed with water, brine and dried over anhydrous Na2S04. The organic layer was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/THF=10/1) to afford N-((3-chloropyrazin-2 -yl)methyl)-2,2- dimethyl-3-oxooctahydroindolizine-6-carboxamide (700 mg, 88.3%). MS-ESI (m/z): 337.2 (M+l) + (LC-MS method C; Ret. time: 0.935 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; HATU; In tetrahydrofuran; at 20℃; for 2h; | To a solution of l-oxooctahydropyrido[l,2-c][l,3]oxazine-7-carboxylic acid (3.13 g, 15.7 mmol) in THF (100 mL) was added <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (2.8 g, 15.7 mmol), TEA (4.8 g, 47.2 mmol) and HATU (6 g, 15.7 mmol). The mixture was stirred at room temperature for 2 h. The reaction was complete detected by LCMS. The reaction mixture was treated with DCM and water, the organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with DCM/THF = 5/1 to give N-((3-chloropyrazin-2-yl)methyl)-l- oxooctahydropyrido[l,2-c][l,3]oxazine-7-carboxamide (4.7 g, 92%).1H- NMR(CDC13,400 MHz) delta 1.40 - 1.49 (m, 1 H), 1.71 - 1.92 (m, 3 H), 2.04 - 2.26 (m, 2 H), 2.43 - 2.57 (m, 1 H), 2.81 - 2.97 (m, 1 H), 3.31 - 3.42 (m, 1 H), 4.13 - 4.27 (m, 2 H), 4.46 - 4.56 (m, 1 H), 4.64 (d, /= 4.70 Hz, 2 H), 8.29 (d, /= 2.35 Hz, 1 H), 8.44 (d, /= 2.35 Hz, 1 H). |
92% | With triethylamine; HATU; In tetrahydrofuran; at 20℃; for 2h; | (g) N-((3-chloropyrazin-2-yl)methyl)-1-oxooctahydropyrido[1,2-c][1,3]oxazine-7-carboxamide To a solution of 1-oxooctahydropyrido[1,2-c][1,3]oxazine-7-carboxylic acid (3.13 g, 15.7 mmol) in THF (100 mL) was added <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (2.8 g, 15.7 mmol), TEA (4.8 g, 47.2 mmol) and HATU (6 g, 15.7 mmol). The mixture was stirred at room temperature for 2 h. The reaction was complete detected by LCMS. The reaction mixture was treated with DCM and water, the organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with DCM/THF=5/1 to give N-((3-chloropyrazin-2-yl)methyl)-1-oxooctahydropyrido[1,2-c][1,3]oxazine-7-carboxamide (4.7 g, 92%). 1H-NMR (CDCl3, 400 MHz) delta 1.40-1.49 (m, 1H), 1.71-1.92 (m, 3H), 2.04-2.26 (m, 2H), 2.43-2.57 (m, 1H), 2.81-2.97 (m, 1H), 3.31-3.42 (m, 1H), 4.13-4.27 (m, 2H), 4.46-4.56 (m, 1H), 4.64 (d, J=4.70 Hz, 2H), 8.29 (d, J=2.35 Hz, 1H), 8.44 (d, J=2.35 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.8% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 25℃; | A mixture of (cis)-2-((benzyloxy)carbonyl)-4-oxooctahydro-l H-pyrido [1,2- a]pyrazine-7-carboxylic acid (0.7 g, 2.1 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (450 mg, 2.5 mmol), HATU (1.2 g, 3.1 mmol) and TEA (0.85 g, 8.4 mmol) in DMF (10 mL) was stirred at 25 C for overnight. Then the reaction mixture was poured into water, the mixture was extracted with EA (50 mix 3). The combined organic phase was washed with brine (100 mL), dried over Na2S04, concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/THF = 1/3) to give (cis)-benzyl 7-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-4-oxohexahydro-lH- pyrido[l,2-a]pyrazine-2(6H)-carboxylate (440 mg, yield 45.8 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.0% | (e) (2S,5R)-benzyl5-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-2-(hydroxymethyl)piperidine-1-carboxylate To a solution of (3S,6S)-1-((benzyloxy)carbonyl)-6-(hydroxymethyl)piperidine-3-carboxylic acid (0.78 g, 2.66 mmol) in 20 mL of DMF was added HATU (1.21 g, 3.2 mmol). After stirring for 30 min under N2, (3-Chloro-pyrazin-2-yl) methanamine hydrochloride (0.48 g, 2.66 mol) and Et3N (0.8 g, 7.98 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours under N2. The mixture was partitioned between EA and water. The organic layer was washed with 1 N HCl and water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford (2S,5R)-benzyl 5-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-2-(hydroxymethyl) piperidine-1-carboxylate (0.7 g, 63.0% yield). 1HNMR (400 MHz, CD3OD): delta=8.50?8.54 (m, 1H), 8.35 (d, J=2.4 Hz, 1H), 7.31?7.41 (m, 5H), 5.16 (s, 2H), 4.63 (s, 2H), 4.34?4.38 (m, 1H), 4.21?4.25 (m, 1H), 3.72?3.77 (m, 1H), 3.63?3.67 (m, 1H), 3.01?3.07 (m, 1H), 2.46?2.54 (m, 1H), 1.80?1.93 (m, 3H), 1.61?1.71 (m, 1H). MS (ESI): M/Z (M+1): 419.1. | |
63% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; | To a solution of (3S,6S)-l-((benzyloxy)carbonyl)-6-(hydroxymethyl)piperidine- 3-carboxylic acid (0.78 g, 2.66 mmol) in 20 mL of DMF was added HATU (1.21 g, 3.2 mmol). After stiring for 30 min under N2, (3-Chloro-pyrazin-2-yl) methanamine hydrochloride (0.48 g, 2.66 mol) and Et3N (0.8 g, 7.98 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours under N2. The mixture was partitioned between EA and water. The organic layer was washed with 1 N HCl and water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford (2S,5R)-benzyl 5-(((3- chloropyrazin-2-yl)methyl)carbamoyl)-2-(hydroxymethyl) piperidine-l-carboxylate (0.7 g, 63.0% yield). 1HNMR (400 MHz, CD3OD): delta= 8.50 - 8.54 (m, 1 H), 8.35 (d, J= 2.4 Hz, 1 H), 7.31 - 7.41 (m, 5 H), 5.16 (s, 2 H), 4.63 (s, 2 H), 4.34 - 4.38 (m, 1 H), 4.21 - 4.25 (m, 1 H), 3.72 - 3.77 (m, 1 H), 3.63 - 3.67 (m, 1 H), 3.01 - 3.07 (m, 1 H), 2.46 - 2.54 (m, 1 H), 1.80 - 1.93 (m, 3 H), 1.61 - 1.71 (m, 1 H). MS (ESI): M/Z (M+l): 419.1. |
60% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; | To a solution of(3S,6S)-l-((benzyloxy)carbonyl)-6-(hydroxymethyl)piperidine- 3-carboxylic acid (0.78 g, 2.66 mmol) in 20 mL of DMF was added HATU (1.21 g, 3.2 mmol). After stiring for 30 min under N2, (3-Chloro-pyrazin-2-yl) methanamine hydrochloride (0.48 g, 2.66 mol) and Et3N (0.8 g, 7.98 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours under N2. The mixture was partitioned between EA and water. The organic layer was washed with 1 N HC1 and water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford (2S,5R)-benzyl 5-(((3- chloropyrazin-2-yl)methyl)carbamoyl)-2-(hydroxymethyl)piperidine-l -carboxylate (0.7 g, 63.0% yield). 1HNMR (400 MHz, CD3OD): delta= 8.50 ~ 8.54 (m, 1 H), 8.35 (d, / = 2.4 Hz, 1 H), 7.31 ~ 7.41 (m, 5 H), 5.16 (s, 2 H), 4.63 (s, 2 H), 4.34 ~ 4.38 (m, 1 H), 4.21 ~ 4.25 (m, 1 H), 3.72 ~ 3.77 (m, 1 H), 3.63 ~ 3.67 (m, 1 H), 3.01 ~ 3.07 (m, 1 H), 2.46 ~ 2.54 (m, 1 H), 1.80 ~ 1.93 (m, 3 H), 1.61 ~ 1.71 (m, 1 H). MS (ESI): M/Z (M+l): 419.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.3% | With triethylamine; HATU; In dichloromethane; at 20℃; for 4h; | A mixture of trans-4-oxooctahydropyrido[2,l-c][l,4]oxazine-7-carboxylic acid (2.2 g, 11.0 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (2.2 g, 3.70 mmol), HATU (6.3 g, 16.6 mmol ) and triethylamine (4.7mL, 33.1 mmol ) in dichloromethane (100 mL) was stirred at room temperature for 4 hours. The reaction mixture was washed with water (150 mL) and extracted with dichloromethane (50 mLx 3) and the combined organic layers were concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (THF: PE = 10%~100%) to give trans-N-((3-chloropyrazin-2-yl)methyl)-4-oxooctahydropyrido[2,l- c][l,4]oxazine-7-carboxamide (2.1 g, 58.3% yield).1HNMR (400 MHz, CD3OD): delta =8.54 (d, J=2.4 Hz, 1H), 8.34 (d, J=2.3 Hz, 1H), 4.74 (dt, J=12.9, 1.9 Hz, 1H), 4.60-4.67 (m, 2H), 4.11 (s, 2H), 4.02 (dd, J=11.9, 4.3 Hz, 1H), 3.56-3.65 (m, 2H), 3.43-3.53 (m, 1H), 2.67-2.76 (m, 1H), 2.49 (tt, J=11.8, 3.7 Hz, 1H), 2.05-2.15 (m, 1H), 1.77-1.88 (m, 2H), 1.50 ppm (dd, J=l 1.8, 3.9 Hz, 1H). MS (ESI): M/Z (M+l): 325.1. |
58.3% | With triethylamine; HATU; In dichloromethane; at 20℃; for 4h; | d) trans-N-((3-chloropyrazin-2-yl)methyl)-4-oxooctahydropyrido[2,1-c][1,4]oxazine-7-carboxamide A mixture of trans-4-oxooctahydropyrido[2,1-c][1,4]oxazine-7-carboxylic acid (2.2 g, 11.0 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (2.2 g, 3.70 mmol), HATU (6.3 g, 16.6 mmol) and triethylamine (4.7 mL, 33.1 mmol) in dichloromethane (100 mL) was stirred at room temperature for 4 hours. The reaction mixture was washed with water (150 mL) and extracted with dichloromethane (50 mL*3) and the combined organic layers were concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (THF: PE=10%?100%) to give trans-N-((3-chloropyrazin-2-yl)methyl)-4-oxooctahydropyrido[2,1-c][1,4]oxazine-7-carboxamide (2.1 g, 58.3% yield). 1HNMR (400 MHz, CD3OD): delta=8.54 (d, J=2.4 Hz, 1H), 8.34 (d, J=2.3 Hz, 1H), 4.74 (dt, J=12.9, 1.9 Hz, 1H), 4.60-4.67 (m, 2H), 4.11 (s, 2H), 4.02 (dd, J=11.9, 4.3 Hz, 1H), 3.56-3.65 (m, 2H), 3.43-3.53 (m, 1H), 2.67-2.76 (m, 1H), 2.49 (tt, J=11.8, 3.7 Hz, 1H), 2.05-2.15 (m, 1H), 1.77-1.88 (m, 2H), 1.50 ppm (dd, J=11.8, 3.9 Hz, 1H). MS (ESI): M/Z (M+1): 325.1. |
58.3% | With triethylamine; HATU; In dichloromethane; at 20℃; for 4h; | A mixture of trans-4-oxooctahydropyrido[2,l-c][l,4]oxazine-7-carboxylic acid (2.2 g, 11.0 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (2.2 g, 3.70 mmol), HATU (6.3 g, 16.6 mmol ) and triethylamine (4.7mL, 33.1 mmol ) in dichloromethane (100 mL) was stirred at room temperature for 4 hours. The reaction mixture was washed with water (150 mL) and extracted with dichloromethane (50 mLx 3) and the combined organic layers were concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (THF: PE = 10%~100%) to give trans-N-((3-chloropyrazin-2-yl)methyl)-4-oxooctahydropyrido[2,l- c][l,4]oxazine-7-carboxamide (2.1 g, 58.3% yield).1HNMR (400 MHz, CD3OD): delta =8.54 (d, J=2.4 Hz, 1H), 8.34 (d, J=2.3 Hz, 1H), 4.74 (dt, J=12.9, 1.9 Hz, 1H), 4.60-4.67 (m, 2H), 4.11 (s, 2H), 4.02 (dd, J=11.9, 4.3 Hz, 1H), 3.56-3.65 (m, 2H), 3.43-3.53 (m, 1H), 2.67-2.76 (m, 1H), 2.49 (tt, J=11.8, 3.7 Hz, 1H), 2.05-2.15 (m, 1H), 1.77-1.88 (m, 2H), 1.50 ppm (dd, J=l 1.8, 3.9 Hz, 1H). MS (ESI): M/Z (M+l): 325.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.35% | With triethylamine; HATU; In dichloromethane; at 25℃; | (e) (trans)-N-((3-chloropyrazin-2-yl)methyl)-6-oxooctahydro-1H-quinolizine-3-carboxamide A mixture of (trans)-6-oxooctahydro-1H-quinolizine-3-carboxylic acid (520 mg, 2.64 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (570 mg, 3.17 mmol), HATU (1.50 g, 3.95 mmol) and TEA (0.79 g, 7.91 mmol) in DCM (13 mL) was stirred at 25 C. overnight. The mixture was quenched with H2O (40 mL) and extracted with DCM (15 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel eluting with PE/THF (0-60%) to give (trans)-N-((3-chloropyrazin-2-yl)methyl)-6-oxooctahydro-1H-quinolizine-3-carboxamide (0.7 g, 82.35%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) delta=8.53-8.41 (m, 1H), 8.33 (d, J=2.5 Hz, 1H), 6.96 (br. s., 1H), 5.08-4.88 (m, 1H), 4.73-4.61 (m, 2H), 3.40-3.26 (m, 1H), 2.72-2.57 (m, 1H), 2.47-2.28 (m, 3H), 2.12-2.00 (m, 2H), 1.89-1.77 (m, 4H), 1.73-1.62 (m, 1H), 1.58-1.47 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With sodium hydrogencarbonate; triethylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h;Inert atmosphere; | (2R,5R)-4-(tert-butoxycarbonyl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)morpholine-2-carboxylic acid (1.5 g, 3.0 mmol) and (3-chloropyrazin-2-yl)methanamine. HCl salt (0.54 g, 3.0 mmol) were dissolved in DMF 100 mL. To the reaction mixture was added Et3N (0.76 g, 6.0 mmol) followed by slow addition of HATU (1.37 g, 3.6 mmol) at 0 C. The reaction was stirred at rt for 1 day under a stream of nitrogen and then quenched with sat. NaHCO3 (100 mL) and extracted with EtOAc (2*150 mL). The combined organic layer was washed with water (200 mL), brine (200 mL), dried over anhydrous Na2SO4, filtered, and evaporated. The crude residue was subjected to column purification using 20-50% EtOAc/Hex. to give (2R,5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(((3-chloropyrazin-2-yl)methyl)carbamoyl)morpholine-4-carboxylate (0.86 g, 46%). LCMS: [M-Boc+H]+:525.25 Ret. time=2.74 min, LC-MS method E). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.56 g | With triethylamine; In dichloromethane; for 3h; | A stirred solution of trichloromethyl carbonochloridate (1.038 g, 5.25 mmol) in tetrahydrofuran (10 mL) was cooled to 0 C and a solution of 3-(trifluoromethyl)- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (1 g, 4.37 mmol, J. Med. Chem., 2005, 141) and N-ethyl-N-isopropylpropan-2-amine (1.131 g, 8.75 mmol) in tetrahydrofuran (10 mL) was added slowly in 25 minutes. After stirring at 0 C for one hour the solids were removed by filtration and the filtrate was concentrated in vaccuo (50C bath temperature). The residue was added to a solution of <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (0.788 g, 4.37 mmol) andtriethylamine (1.018 g, 10.06 mmol) in dichloromethane (20 mL) and the reaction mixture was stirred for three hours. The solids were removed by filtration and the filtrate was concentrated in vacuo. Purification using column chromatography (silica gel; gradient dichloromethane / methanol 100:0 to 95:5) to afford N-((3-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)- 5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxamide (1.56 g, 4.31 mmol, 99 % yield). LC-MS: C12H1 1C1F3N70: 361, found 362.04[M+H]+, RT = 0.42 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.8 g | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 60℃; for 1h; | To a solution of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (1.63 g, 6.93 mmol) in THF (35 mL) was added dropwise (COCl)2 (4.4 g, 34.66 mmol) and 0.1 mL of DMF at 0 C, the mixture was stirred at this temperature for 1 hours and then the solvent was removed. The resulting residue was dissolved in THF (35 mL), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (1.37 g, 7.63 mmol) and DIEA(2.68 g, 20.79 mmol) was added, the mixture was stirred at 60 C for 1 h. Remove the solvent in vacuo and the residue was extracted with DCM and the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/THF= 100/20) to afford N-((3-chloropyrazin- 2-yl)methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo [4,3-a]pyridine-7- carboxamide (0.8 g, yield 32%). MS-ESI (m/z): 361 (M+1) + (Acq Method: 10-80AB_2min;Rt: 0.81 min) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | To a solution of 1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxylic acid (6 g, 33 mmol) and <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (6 g, 33 mmol) in 200 mL of DCM was added TEA (9 g, 88 mmol) dropwise. The resulting mixture was stirred at room temperature for 5 mins, and then HATU (12.5 g, 33 mmol) was added to the solution in portions at 0 C. The mixture was stirred at room temperature for 2 hours. Water was added, the DCM layers was separated, and washed with brine, dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography on silica gel (PE/THF = 5/1 v/v%) to afford N-((3-chloropyrazin-2- yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxamide (1.5 g, 15 %). MS-ESI (m/z): 306 (M+1) + (Acq Method: 10-80AB_2min_220&254.1cm; Rt: 0.93 min) | |
15% | With triethylamine; HATU; In dichloromethane; at 0 - 20℃; for 2h; | To a solution of l-methyl-4,5,6,7-tetrahydro-lH-indazole-4-carboxylic acid (6 g, 33 mmol) and <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (6 g, 33 mmol) in 200 mL of DCM was added TEA (9 g, 88 mmol) dropwise. The resulting mixture was stirred at room temperature for 5 mins, and then HATU (12.5 g, 33 mmol) was added to the solution in portions at 0 C. The mixture was stirred at room temperature for 2 hours. Water was added, the DCM layers was separated, and washed with brine, dried over Na2S04. The solvent was removed and the residue was purified by column chromatography on silica gel (PE/THF = 5/1 v/v%) to afford N-((3-chloropyrazin-2- yl)methyl)-l-methyl-4,5,6,7-tetrahydro-lH-indazole-4-carboxamide (1.5 g, 15 %). MS-ESI (m/z): 306 (M+l) + (Acq Method: 10-80AB_2min_220&254.1cm; Rt: 0.93 min) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.5% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | HATU (377 mg, 0.991 mmol) was added to a stirred, mixture of cis-3- oxooctahydroindolizine-6-carboxylic acid (151 mg, 0.826 mmol) at C. DIPEA (0.433 ml, 2.478 mmol) in DMF (2ml) was then added followed by(3-chloropyrazin-2- yl)methanamine hydrochloride (164 mg, 0.909 mmol) and the mixture was stirred at room temperature for 1 h. and concentrated. The residue was purified by column chromatography on silica gel (Isco 40g column), eluting with CH2C12/MeOH (30/1) to give cis-N-((3-chloropyrazin-2-yl)methyl)-3-oxooctahydroindolizine -6-carboxamide (185 mg, 0.599 mmol, 72.5 % yield) as a white solid. LCMS data: Rt 1.08 min; m/z 309.10 (M+H)+; 1H MR (CDC13, 500 Hz): delta = 8.43 (1H, t, J = 4.5 and 2.5 Hz), 8.30 (1H, br s), 7.46 (1H, br s), 4.89-4.93 (1H, m), 4.52-4.57 (m, 2), 3.57-3.59 (m, l)? 3.00 (1H, br d, J = 14.5 Hz), 2.71 (1H, br s), 2.30-2.72 (4H, m), 1.69-1.82 (4H, m), 1.49-1.55 m, l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | To a solution of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyridine-7- carboxylic acid (1.63 g, 6.93 mmol) in THF (35 mL) was added dropwise (COCl)2 (4.4 g, 34.66 mmol) and 0.1 mL of DMF at 0 C, the mixture was stirred at this temperature for 1 hours and then the solvent was removed. The resulting residue was dissolved in THF (35 mL), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (1.37 g, 7.63 mmol) and DIEA(2.68 g, 20.79 mmol) was added, the mixture was stirred at 60 C for 1 h. Remove the solvent in vacuo and the residue was extracted with DCM and the combined organic layer was washed with water, brine and dried over anhydrous Na2S04. The organic layer was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/THF= 100/20) to afford N-((3-chloropyrazin-2- yl)methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo [4,3-a]pyridine-7- carboxamide (0.8 g, yield 32%). MS-ESI (m/z): 361 (M+l) + (Acq Method: 10-80AB_2min;Rt: 0.81 min) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | A stirred solution of trichloromethyl carbonochloridate (1.038 g, 5.25 mmol) in tetrahydrofiiran (10 mL) was cooled to 0 C and a solution of 3-(trifluoromethyl)- 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride (1 g, 4.37 mmol, J. Med. Chem., 2005, 141) and N-ethyl-N-isopropylpropan-2-amine (1.131 g, 8.75 mmol) in tetrahydrofiiran (10 mL) was added slowly in 25 minutes. After stirring at 0 C for one hour the solids were removed by filtration and the filtrate was concentrated in vaccuo (50C bath temperature). The residue was added to a solution of (3-chloropyrazin-2- yl)methanamine hydrochloride (0.788 g, 4.37 mmol) andtriethylamine (1.018 g, 10.06 mmol) in dichloromethane (20 mL) and the reaction mixture was stirred for three hours. The solids were removed by filtration and the filtrate was concentrated in vacuo. Purification using column chromatography (silica gel; gradient dichloromethane / methanol 100:0 to 95:5) to afford N-((3-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)- 5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxamide (1.56 g, 4.31 mmol, 99 % yield). LC-MS: C12H11C1F3N70: 361, found 362.04[M+H]+, RT = 0.42 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 30℃; for 12h; | Intermediate 17&18. Step 3: (6R.8aS)-N-((3-chloropyrazin-2-yl)methyl)-l-methyl-3-oxohexahydro-lH-oxazolor3.4- alpyridine-6-carboxamide To a solution of (6R,8aS)-l-methyl-3-oxohexahydro-lH-oxazolo[3,4-a]pyridine-6-carboxylic acid (600 mg, 3.02 mmol) in dry DCM (12 mL) at 5 C, Oxalyl dichloride (1.15 g, 9.04 mmol) was added drop wise and DMF (3 drops) was added. The reaction mixture was stirred at 30 C for 2 h. The reaction mixture was concentrated in vacuo to give crude acyl chloride. The solution of crude acyl chloride in DCM (3 ml) was added to a solution of (3-chloropyrazin-2- yl)methanamine hydrochloride (594 mg, 3.32 mmol), TEA (640 mg, 6.04 mmol) in DCM (10 ml), and then the reaction mixture was stirred at 30 C for 12h. The reaction was dulited with DCM (20 mL) and H20 (20 mL), the organic layer was washed with brine (20 mL), dried over Na2SC>4, The crude product was purified by column chromatography on silica gel eluted with PE/THF (100 %-40 %) to give (6R,8aS)-N-((3-chloropyrazin-2-yl)methyl)-l-methyl-3- oxohexahydro-lH-oxazolo[3,4-a]pyridine-6-carboxamide. l NMR (400MHz, CD3OD) delta = 8.55 (d, J=2.5 Hz, 1H), 8.36 (d, J=2.5 Hz, 1H), 4.77 (quin, J=6.8 Hz, 1H), 4.65 (s, 2H), 4.30 (quin, J=6.2 Hz, 1H), 3.98 - 3.90 (m, 1H), 3.78 - 3.70 (m, 1H), 3.12 - 3.00 (m, 1H), 2.51 (ttd, J=4.1, 12.1, 16.0 Hz, 1H), 2.19 - 2.07 (m, 1H), 2.00 (dd, J=3.5, 13.1 Hz, 1H), 1.81 - 1.66 (m, 2H), 1.55 - 1.39 (m, 3H), 1.35 (d, J=6.5 Hz, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 20. Step 7: (6R.8aS)-N-((3-chloropyrazin-2-yl)methyl)-2.2-dimethyl-3-oxooctahydroindolizine-6- carboxamide To a solution of (6R,8aS)-2,2-dimethyl-3-oxooctahydroindolizine-6-carboxylic acid (2.9 g, 13.74 mmol) in anhydrous DCM (137 mL) was added isopropyl carbonochloridate (2.02 g, 16.48 mmol) and Epsilon Nu (1.67 g, 16.48 mmol) at 0 C. The reaction mixture was stirred for 1 hour at room temperature. Then Epsilon Nu (2.78 g, 27.47 mmol) and <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (3.2 g, 17.86 mmol) was added , the reaction was stirred for 5 hours at room temperature. The solution was quenched with water, extracted with DCM and the combined organic layer was washed with water, brine and dried over anhydrous Na2SC>4. The organic layer was concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/THF = 3/1) to afford (6R,8aS)-N-((3-chloropyrazin-2-yl)methyl)-2,2-dimethyl-3- oxooctahydroindolizine-6-carboxamide. 1H NMR (400 MHz, CDC13) delta ppm 1.08 - 1.28 (m, 6 H), 1.40 - 1.55 (m, 1 H), 1.70 - 1.91 (m, 2 H), 1.95 - 2.21 (m, 3 H), 2.36 (t, J = 12.4 Hz, 1 H), 2.87 (t, J= 12.4 Hz, 1 H), 3.40 (d, J = 7.6 Hz, 1 H), 4.32 (dd, Ji = 13.2, J2 = 3.2 Hz, 1 H), 4.70 (m, 2 H), 7.05 (s, 1 H), 8.32 (s, 1 H), 8.44 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h; | Intermediate 25. Step 9: (trans) N-((3-chloropyrazin-2-yl)methyl)-2-ethyl-l-oxooctahvdro-lH-pyrido[1.2- clpyrimidine-7-carboxarnide To a solution of (trans) 2-ethyl-l-oxooctahydro-lH-pyrido[l,2-c]pyrimidine-7-carboxylic acid (700 mg, 3.09 mmol) in DMF (15 mL) was added HATU (1764 mg, 4.64 mmol) and Et3N (1.294 mL, 9.28 mmol) followed by <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (835 mg, 4.64 mmol). The mixture was stirred at 20 C for 3 h.. The mixture was quenched with water (10 mL), and extracted with DCM (20 mLx3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated in vacuum to give the crude, which was purified over combi-flash (20 g, DCM:THF=10: 1) to give (trans) N-((3-chloropyrazin-2-yl)methyl)-2- ethyl-l-oxooctahydro-lH-pyrido[l,2-c]pyrirnidine-7-carboxarnide. XH NMR (400 MHz, CDC13) delta 8.43 (d, J= 2.4 Hz, 1H), 8.31 (d, J= 2.4 Hz, 1H), 7.03 (s, 1Eta),4.73-4.63 (m, 3H), 3.42-3.31 (m, 2H), 3.27-3.16 (m, 3H), 2.69 (t, J= 12.4 Hz, 1H), 2.43-2.36 (m, 1H), 2.10-1.98 (m, 2H), 1.83- 1.69 (m, 3H), 1.38-1.32 (m, 1H), 1.09 (t, J= 7.2 Hz,3H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 12. Step 12: N-((3-chloropyrazin-2-yl)methyl)-2.3.3-trimethyl-l-oxooctahvdro-lH-pyrido[1.2- clpyrimidine-7-carboxamide (trans) To a solution of 2,3,3-trimethyl-l -oxooctahydro-lH-pyrido[l ,2-c]pyrirnidine-7-carboxylic acid (560 mg, 2.330 mmol) in DMF (25 mL) was added HATU (1329 mg, 3.50 mmol), the mixture was stirred at 20 C for 0.5 h. Then (3-chloropyrazin-2-yl)methanamine,HCl (503 mg, 2.80 mmol) was added, followed by Epsilon Nu (1.299 mL, 9.32 mmol). The mixture was stirred at 20 C - I l l - for 18 h. TLC showed the material was consumed completely, then the reaction mixture was poured into water (20 mL), extracted with DCM (20 mLx2). The organic layer was washed with brine (40 mL), dried over Na2SC>4, concentrated in vacuo to give N-((3-chloropyrazin-2- yl)methyl)-2,3,34rimethyl-l-oxooctahydro-lH-pyrido[l,2-c]pyrirnidine-7-carboxamide (trans) . XH NMR (400MHz, CD3OD) delta 8.52 (d, J = 2.3 Hz, 1H), 8.33 (s, 1H), 4.62 (s, 2H), 4.56 (d, J = 12.9 Hz, 1H), 3.26 - 3.21 (m, 1H), 2.86 (s, 3H), 2.65 (t, J= 12.3 Hz, 1H), 2.43 (t, J= 11.7 Hz, 1H), 2.03 - 1.82 (m, 4H), 1.67 (br. s., 1H), 1.31 (s, 3H), 1.29 - 1.24 (m, 1H), 1.21 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 25℃; for 12h; | Step 3: (7S.9aR)-benzyl 7-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-4-oxohexahvdro-lH- pyridor 1.2-al pyrazine-2(6H)-carboxylate To a solution of (7R,9aS)-2-((benzyloxy)carbonyl)-4-oxooctahydro-lH-pyrido[l,2-a]pyrazine-7- carboxylic acid (480 mg, 1.444 mmol) in anhydrous DMF (10 mL) was added EDC (415 mg, 2.166 mmol), DMAP (265 mg, 2.166 mmol), (3-chloropyrazin-2-yl)methanamine, HCl (312 mg, 1.733 mmol), and TEA (0.302 mL, 2.166 mmol) under N2, and the mixture was stirred at 25 C for 12 hrs. The mixture was poured into H20 (150 mL), and extracted with EtOAc (20 mL chi 5). The organic layer was washed with H20 (10 mL chi 6), brine (30 mL), dried over Na2SC>4, filtered, and evaporated in vacuo to give the crude product, which was then purified by flash chromatography (DCM/THF=85 ~ 70 %) to afford the title compound. 1H NMR (400MHz CDC13) delta = 8.44 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 6.98 (br. s., 1H), 5.20 - 5.10 (m, 2H), 4.88 (d, J=12.9 Hz, 1H), 4.68 (d, J=3.9 Hz, 2H), 4.29 - 4.18 (m, 1H), 4.16 - 4.05 (m, 1H), 3.94 (br. s., 1H), 3.41 (br. s., 2H), 2.73 (t, J=12.3 Hz, 1H), 2.39 (t, J=11.7 Hz, 1H), 2.08 (d, J=11.3 Hz, 1H), 1.95 - 1.86 (m, 2H), 1.41 - 1.32 (m, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; at 20℃; | Intermediate 11-14. Step 7 : N-((3-chloropyrazin-2-yl)methyl)-9.9-difluoro-6-oxooctahvdro-lH-quinolizine-3- carboxamide To a solution of 9,9-difluoro-6-oxooctahydro-lH-quinolizine-3-carboxylic acid (1.9 g, 8.15 mmol) in THF (40 ml) was added <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (2.2 g, 12.22 mmol), HATU (4.65 g, 12.22 mmol) and TEA (6.81 ml, 48.9 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was treated with EA (200 ml) and water (200 ml), the organic layer was dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluted with PE/DCM/THF = 1/1/1 to give N-((3-chloropyrazin-2-yl)methyl)-9,9-difluoro-6-oxooctahydro-lH-quinolizine-3-carboxamide. lH NMR (400 MHz, CDC13) delta ppm 1.63 - 1.85 (m, 2 H), 1.99 - 2.29 (m, 3 H), 2.32 - 2.81 (m, 5 H), 3.46 - 3.62 (m, 1 H), 4.33 - 4.98 (m, 3 H), 8.15 - 8.24 (m, 1 H), 8.30 - 8.40 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of bicyclo [3.2.2] nonane-1, 5-dicarboxylic acid (200 mg, 0.942 mmol) and TEA (0.328 ml, 2.356 mmol) in THF (10 ml) was added HATU (340 mg, 0.895 mmol) at 0. The mixture was stirred at this temperature for 10 mins and at 25 for another 20mins. (3-chloropyrazin-2-yl) methanamine hydrochloride (170 mg, 0.942 mmol) was added to above solution at 0 and the mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 30 mins. The mixture was treated with water (20 mL) and EA (20 mL). The EA layer was separated and was washed with brine (20mL) , dried over Na2SO4, filtered and concentrated. The residue was used next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of (1S, 3R) -3- (methoxycarbonyl) -2, 2, 3-trimethylcyclopentanecarboxylic acid (4.93 g, 23.01 mmol) and TEA (9.62 mL, 69.0 mmol) and HATU (13.12 g, 34.5 mmol) in DCM (100 mL) was stirred at 12 for 30 min. (3-chloropyrazin-2-yl) methanamine hydrochloride (4.97 g, 27.6 mmol) was added and the mixture was stirred at 12 for overnight. The mixture was added DCM (100 mL) and washed and brine. The organic layer was dried over Na2SO4, purified with silica gel to give the title compound. 1H NMR (400MHz, CDCl3) : delta 8.46 (d, J2.3 Hz, 1H) , 8.34 (s, 1H) , 6.70 (br. s., 1H) , 4.81 -4.66 (m, 2H) , 3.69 (s, 3H) , 2.74 (t, J9.2 Hz, 1H) , 2.65 (dt, J6.8, 12.6 Hz, 1H) , 2.34 -2.22 (m, 1H) , 1.91 -1.80 (m, 1H) , 1.54 (ddd, J4.1, 9.6, 13.7 Hz, 1H) , 1.32 (s, 3H) , 1.25 (s, 3H) , 0.81 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; at 20℃; | To a solution of 3-isopropyl-3- (methoxycarbonyl) cyclohexanecarboxylic acid (4.4 g, 19.3 mmol) in THF (100 mL) was added (3-chloropyrazin-2-yl) methanamine hydrochloride (5.2 g, 28.9 mmol) , HATU (11 g, 28.9 mmol) and TEA (11.7 g, 115.8 mmol) . The mixture was stirred at room temperature overnight. The reaction mixture was diluted with EA and water, the organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with PE/THF 5/1 to give methyl 3- ( ( (3-chloropyrazin-2-yl) methyl) carbamoyl) -1-isopropylcyclohexanecarboxylate. 1H NMR (400 MHz, CDCl3) delta ppm: 0.86 (t, J 6.65 Hz, 6 H) , 1.16 -1.32 (m, 2 H) , 1.36 -1.47 (m, 2 H) , 1.69 -1.87 (m, 3 H) , 2.07 -2.16 (m, 1 H) , 2.22 -2.42 (m, 2 H) , 3.69 (s, 3 H) , 4.56 -4.76 (m, 2 H) , 6.79 (s, 1 H) , 8.31 (d, J 2.74 Hz, 1 H) , 8.45 (d, J 2.74 Hz, 1 H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 15℃; for 12h; | To a solution of 5- (methoxycarbonyl) tricyclo [3.2.2.02, 4] nonane-1-carboxylic acid (440 mg, 1.962 mmol) in anhydrous CH2Cl2 (8 ml) was added Et3N (0.820 ml, 5.89 mmol) , (3-chloropyrazin-2-yl) methanamine, HCl (424 mg, 2.354 mmol) and HATU (895 mg, 2.354 mmol) . The reaction mixture was stirred at 15 for 12 hours. The reaction was quenched by the addtion of water (10 mL) , then it was extracted with DCM (20 mL x 3) , the combined organic layers were washed with brine (20 mL) , dried over sodium sulfate, filtered and concentrated to afford the crude product , which was purified on silica gel column chromatograph (PE /EA 100 50 ) to give methyl 5- ( ( (3-chloropyrazin-2-yl) methyl) carbamoyl) tricyclo [3.2.2.02, 4] nonane-1-carboxylate. 1H NMR (400MHz, CDCl3) delta 8.47 (d, J2.5 Hz, 1H) , 8.33 (s, 1H) , 4.70 (d, J4.8 Hz, 2H) , 3.72 (s, 3H) , 2.08 -1.83 (m, 4H) , 1.68 -1.59 (m, 4H) , 1.42 (br. s., 1H) , 1.25 (d, J7.3 Hz, 1H) , 0.84 -0.78 (m, 1H) , 0.68 -0.61 (m, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 4-isopropyl-3- (methoxycarbonyl) cyclohexanecarboxylic acid (11 g, 48.2 mmol) and TEA (12.19 g, 120 mmol) in THF (200 ml) was added isopropyl carbonochloridate (7.09 g, 57.8 mmol) at 0 . The mixture was stirred at 20 for 1 hour. <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (10.41 g, 57.8 mmol) was added to above solution. The mixture was stirred at 20 for another 2 hours. The mixture was treated with water (200 mL) and EA (200mL) . The oganic layer was washed with brine, dried, filtered and concentrated. The residue was purified by silica gel column chromatography (PE/THF 3/1) to afford methyl 5- ( ( (3-chloropyrazin-2-yl) methyl) carbamoyl) -2-isopropylcyclohexanecarboxylate as solid. MS354.0 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A 30 vial was charged with 8- (methoxycarbonyl) bicyclo [3.2.1] octane-3-carboxylic acid (830 mg, 3.91 mmol) , HATU (1784 mg, 4.69 mmol) , TEA (1.635 mL, 11.73 mmol) and DCM (20 mL) . The mixture was stirred at 30 for 30 minutes. Then (3-chloropyrazin-2-yl) methanamine hydrochloride (845 mg, 4.69 mmol) was added, the resulting mixture was stirred at 30 for 16 hours. The reaction mixture was diluted with EtOAc (50mL) and washed with brine (50mLx3) . The organic layer was evaporated to dryness and the residue was purified via combi flash (EtOAc in petroleum from 0to 50) to give the title compound. 1H NMR (400 MHz, CDCl3) : delta 8.46 (d, J 2.0 Hz, 1H) , 8.32 (brs, 1H) , 6.85 (brs, 1H) , 4.69-4.59 (m, 2H) , 3.72 (s, 3H) , 2.70-2.50 (m, 4H) , 2.05-1.93 (m, 2H) , 1.89-1.77 (m, 2H) , 1.70 (m, 2H) , 1.65-1.56 (m, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 30℃; for 18h;Inert atmosphere; | To a solution of 6- (ethoxycarbonyl) bicyclo [3.1.0] hexane-3-carboxylic acid (2.09 g, 10.54 mmol) in CH2Cl2 (60 mL) was added HATU (6.01 g, 15.82 mmol) under N2. Then <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (2.278 g, 12.65 mmol) and Et3N (2.94 mL, 21.09 mmol) was added. The resulting mixture was stirred at 30 for 18 hours. The mixture was diluted with H2O (100 mL) , extracted with CH2Cl2 (30 mL×3) . The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give crude product, which was purified by combi flash (0-50THF/Petroleum ether) to give ethyl 3- ( ( (3-chloropyrazin-2-yl) methyl) carbamoyl) bicyclo [3.1.0] hexane-6-carboxylate. 1H NMR (400MHz, CDCl3delta 8.45 (br. s., 1H) , 8.32 (br. s., 1H) , 6.95 -6.65 (m, 1H) , 4.67 (br. s., 2H) , 4.20 -4.02 (m, 2H) , 3.01 (d, J7.0 Hz, 1H) , 2.41 -2.30 (m, 1H) , 2.29 -2.22 (m, 1H) , 2.21 -2.13 (m, 2H) , 1.96 (br. s., 1H) , 1.90 (br. s., 1H) , 1.60 -1.43 (m, 1H) , 1.33 -1.19 (m, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of (l^S^-S-^ethoxycarbony^^^^-trimethylcyclopentanecarboxylic acid (4.93 g, 23.01 mmol) and TEA (9.62 mL, 69.0 mmol) and HATU (13.12 g, 34.5 mmol) in DCM (100 mL) was stirred at 12 C for 30 min. (3-chloropyrazin-2-yl) methanamine hydrochloride (4.97 g, 27.6 mmol) was added and the mixture was stirred at 12 C for overnight. The reaction was complete detected by LC-MS. The mixture was added DCM (100 mL) and washed and brine. The organic layer was dried over Na2S04, purified with silica gel to give the title compound. XH NMR (400MHz, CDC13): delta 8.46 (d, J=2.3 Hz, 1H), 8.34 (s, 1H), 6.70 (br. s., 1H), 4.81 - 4.66 (m, 2H), 3.69 (s, 3H), 2.74 (t, J=9.2 Hz, 1H), 2.65 (dt, J=6.8, 12.6 Hz, 1H), 2.34 - 2.22 (m, 1H), 1.91 - 1.80 (m, 1H), 1.54 (ddd, 3=4.1, 9.6, 13.7 Hz, 1H), 1.32 (s, 3H), 1.25 (s, 3H), 0.81 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; at 25℃; for 12h; | To a solution of 3-(l -methoxy-2-methyl-l -oxopropan-2-yl)cyclohexanecarboxylic acid (1500 mg, 6.57 mmol) in THF (20 ml) was added HATU (3748 mg, 9.86 mmol), DIEA (3.44 ml, 19.71 mmol) and<strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (1538 mg, 8.54 mmol) in one portion. After the addition was completed, the mixture was stirred at 25 C for 12h. The The reaction was quenched by addtion of water. The mixture was extracted with ethyl acetate several times. The combined organics was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residure was purified by column chromagrophy on silica gel (PE/THF=4) to afford methyl 2-(3-(((3-chloropyrazin-2- yl)methyl)carbamoyl)cyclohexyl)-2-methylpropanoate as a light solid. XH NMR (400 MHz, METHANOL-^) delta ppm 1.01 - 1.07 (m, 1 H) 1.12 (s, 6 H) 1.26 (d, J=12.13 Hz, 1 H) 1.32 - 1.38 (m, 2 H) 1.57 - 1.62 (m, 1 H) 1.69 - 1.77 (m, 2 H) 1.86 (br. s., 2 H) 2.30 - 2.36 (m, 1 H) 3.65 (s, 3 H) 4.60 (s, 2 H) 8.31 - 8.34 (m, 1 H) 8.50 - 8.52 (m, 1 H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 3h; | Preparation of benzyl N-[(15)-2-[(3-chloropyrazin-2-yl)methylamino]-l -methyl-2-oxo- ethyl]-N-methyl-carbamate. N,N-Diisopropylethylamine (19.35 mL, 111.09 mmol) was added dropwise in ten minutes to a mixture of (25)-2-[benzyloxycarbonyl(methyl)amino]propanoic acid (6.59 g, 27.77 mmol), (3-chloropyrazin-2-yl)methanamine hydrochloride (5.00 g, 27.77 mmol) and HATU (15.84 g, 41.66 mmol) in dichloromethane (250 mL) and the resulting mixture was stirred for three hours at 20 C. The mixture was washed once with aq. sat. sodium bicarbonate solution (200 mL) and once with aq. sat. ammonium chloride solution (200 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash column chromatography on silica gel (0-100% ethyl acetate in heptane) to give benzyl N-[(l<S -2-[(3-chloropyrazin-2-yl)methylamino]-l-methyl-2-oxo-ethyl]-N-methyl- carbamate (9.2 g, 91.3%) as a colorless oil. Data: LC-MS (Method A) : 5.32 min; m/z 363.2 (M+H)+ |
91.3% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 3h; | N,N-Diisopropylethylamine (19.35 mL, 111.09 mmol) was added dropwise in ten minutes to a mixture of (2S)-2-[benzyloxycarbonyl(methyl)amino]propanoic acid (6.59 g, 27.77 mmol), (3-chloropyrazin-2-yl)methanamine hydrochloride (5.00 g, 27.77 mmol) and HATU (15.84 g, 41.66 mmol) in dichloromethane (250 mL) and the resulting mixture was stirred for three hours at 20 C. The mixture was washed once with aqueous saturated. sodium bicarbonate solution (200 mL) and once with aqueous saturated ammonium chloride solution (200 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash column chromatography on silicagel (0-100% ethyl acetate in heptane) to give benzyl N-[(1S)-2-[(3-chloropyrazin-2-yl)methylamino]-1-methyl-2- oxo-ethyl]-N-methyl-carbamate (9.2 g, 91.3%) as a colorless oil. Data: LC-MS (Method A) Rt: 5.32 min; m/z 363.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 18h; | Step 2: (0988) Preparation of N-((3-chloropyrazin-2-yl)methyl)formamide: (0989) [00368] To a stirred solution <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (0.5 g, 2.77 mmol) in dichloromethane (20 mL) and N,N-dimethyl formamide (4 mL) were added N,N-diisopropylethylamine (0.72 mL, 4.16 mmol), 1-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (0.79 g, 4.16 mmol), 1-hydroxybenzotriazole (0.37 g, 2.77 mmol) , formic acid (0.135 mL, 3.60 mmol) and the reaction mixture was stirred at room temperature for 18 h. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (3 x 80 mL). The combined organic layer was washed with brine (40 mL), dried over anhydrous sodium sulfate and evaporated to get the crude product. The crude product was purified by silica gel column chromatography using 2% methanol in dichloromethane to afford the title compound N-((3-chloropyrazin-2- yl)methyl)formamide (0.21 g, 44% yield) as a yellow solid. Calculated (M+H): 172.0; Found (M+H): 172.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; | DIEA(43.6mmol) was added into a solution of Compound 1-2-1 (10.9 mmol) and <strong>[939412-86-9](3-chloropyrazin-2-yl)methylamine hydrochloride</strong> in dichloromethane (50ml).It was stirred at this temperature overnight. Pouedr into water (100 ml) and separated the organic phase. The aqueous phase was extracted with dichloromethane (2×30 mL).The organic phase was separated, dried over anhydrous Na2SO4, filtered and evaporated.The residue was purified by column chromatography by using with ethyl acetate / petroleum ether Elution = 1:5 to obtain 3.02 g of compound 1-2-2, yield 70% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;Inert atmosphere; | 2- (5-chloro-3- (6-chloropyridin-3-yl) -4-fluoro-2-isopropoxyphenyl) propanoic acid (770 mg, 2.07 mmol) , (3-chloropyrazin-2-yl) methanamine hydrochloride (356.4 mg, 2.48 mmol) , HOBt (335.42 mg, 2.48 mmol) , EDCI (475 mg, 2.48 mmol) and DIPEA (803 mg, 6.21 mmol) were dissolved in THF (15 mL) and stirred at room temperature for overnight under N 2. Water (20 mL) was added and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na 2SO 4. The product (680 mg, 66%yield) was received by chromatography column on silica gel (PE: EA = 1: 1) . MS (ESI) m/e [M+1] +497.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | The solution of 2- (5-chloro-2-isopropoxy-4-methyl-3- (6- (trifluoromethyl) pyridin-3-yl) phenyl) propanoic acid (680 mg, 1.6 mmol) , (3-chloropyrazin-2-yl) methanamine hydrochloride (366 mg, 2.56 mmol) , Benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.25 g, 2.4 mmol) and N, N-Diisopropylethylamine (413 mg, 3.2 mmol) in DMF (10 mL) was stirred at room temperature for overnight. After completed, the solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate. The mixture was washed with water, brine and dried over Na 2SO 4, filtered and evaporated in vacuo to give the product (850 mg) which was used directly for the next step without further purification. MS (M+H) + 527.1, 529.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | The reaction mixture of 2- (5-chloro-4-fluoro-2-isopropoxy-3- (6- (trifluoromethyl) pyridin-3-yl) phenyl) propanoic acid (520 mg, 1.28 mmol) , (3-chloropyrazin-2-yl) methanamine hydrochloride (293 mg, 2.05 mmol) , Benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (998 mg, 1.92 mmol) and N, N-Diisopropylethylamine (330 mg, 2.56 mmol) in DMF (20 mL) was stirred at room temperature for overnight. After completed, the solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate. The mixture was washed with water and brine, dried over Na 2SO 4, filtered and evaporated in vacuo to give the product which was used directly for the next step without further purification. MS (M+H) + 531.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.1% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;Inert atmosphere; | 2- (5-chloro-2-ethoxy-4-methyl-3- (6-methylpyridin-3-yl) phenyl) propanoic acid (2.7 g, 8.09 mmol) , (3-chloropyrazin-2-yl) methanamine hydrochloride (1.4 g, 9.71 mmol) , HOBt (1.32 g, 24.27 mmol) , EDCI (1.86 g, 9.71 mmol) and DIPEA (3.14 g, 24.27 mmol) were dissolved in THF (30 mL) and stirred at room temperature under N 2 for overnight, brine (20 mL) was added and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na 2SO 4. The product (3.2 g in 86.1 %yield) was got. MS (ESI) m/e (M+1) +459. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
130 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 25℃; | A mixture of compound 5 (270 mg, 1.28 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (277 mg, 1.54 mmol), HATU (632 mg, 1.66 mmol) and TEA (518 mg, 5.12 mmol) in DCM (13 mL) was stirred at 25C overnight. The mixture was quenched with H20 (40 mL) and extracted with DCM (15 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-TLC to give 6 (130 mg, 30 %). 1H NMR (400 MHz, CDC13): delta 8.45 (s, 1H), 8.32 (s, 1H), 7.06 (s, 2H), 4.74-4.69 (m, 3H), 3.23-3.22 (m, 3H), 2.93 (s, 3H), 2.74-2.71 (m, 1H), 2.53-2.40 (m, 1H), 2.13-2.02 (m, 2H), 1.81-1.77 (m, 2H). LCMS: m/z = 338 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.3 g | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 25℃; | A mixture of SM (1.4 g, crude, 7.8 mmol), <strong>[939412-86-9](3-chloropyrazin-2-yl)methanamine hydrochloride</strong> (1.4 g, 7.8 mmol), HATU (2.7 mg, 7.8 mmol) and TEA (3.2 mg, 31.2 mmol) in DCM (30 mL) was stirred at 25C overnight. The mixture was quenched with H20 (60 mL) and it was extracted with DCM (25 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by prep- TLC to give 1 (1.3 g, 50 %). LCMS: m/z = 309 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64 mg | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 110℃; for 0.333333h;Microwave irradiation; | (3-Chloropyrazin-2-yl)methanamine hydrochloride (157 mg, 0.873 mmol), 2-chloro-4- methoxyphenylboronic acid (325 mg, 1.75 mmol), potassium carbonate (482 mg, 3.49 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) in water (1.5 mL) and DME (4.5 mL) was microwave irradiated at 110 C for 30 min. After organic solvent was removed in vacuo, the residue was extracted with EtOAc and washed successively with water and brine. The organic layer was dried over Na2S04and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (MeOH/DCM) to obtain 64 mg of [3-(2-chloro-4-methoxy- phenyl)-pyrazin-2-yl]-methylamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; In dichloromethane; at 0 - 20℃; | To a mixture of compound V (49.8 g), DCM (500 mL) and DMF (5 mL) in a 500 mL three-neck flask, oxalyl chloride (38 g, 1.5 eq) was added at 0~10 C. The reaction mixture was warmed to RT. After completion of the reaction, the solvent was removed by concentration. DCM (200 mL) was added to obtain the compound VI solution in DCM. (0099) To a mixture of compound VII (30 g), DCM (240 mL) and TEA (6 eq) in a 1000 mL three-neck flask at 0~10 C, the solution of compound VI in DCM obtained from the above step was added dropwise, the reaction mixture was warmed to RT. After the reaction was completed, water (300 mL) was added to quench the reaction. The organic phase was washed with IN HCI aqueous solution (500 mL), saturated NaHC03 aqueous solution (500 mL) and water (500 mL). The organic phase was concentrated under vacuum. The crude product was recrystallized from IPAc/Heptane to afford compound VIII (61 g, 98% yield, 99.7% chiral purity). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 30℃; for 16h;Inert atmosphere; | To a solution of (3-chloropyrazin-2-yl)methanamine hydrochloride 22 1 a (3.1 g, 21.7 mmol), 23 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (7.1 g, 22 mmol) and 24 N,N-diisopropylethylamine (9.3 g, 72 mmol) in 25 dichloromethane (100 mL) at room temperature, 26 <strong>[192214-00-9](S)-1-((benzyloxy)carbonyl)pyrrolidine-3-carboxylic acid</strong> (4.5 g, 18 mmol) was added in several batches. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with 27 water (30 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (50 mL×2), the combined organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was purified by flash column chromatography (dichloromethane/methanol 20:1) to provide 28 benzyl-(S)-3-(((3-chloropyrazin-2-yl)methyl)carbamoyl) pyrrolidine-1-carboxylate 1b(4.85 g, 13.0 mmol, yellow oil). Yield: 72%1H NMR (400 MHz, CDCl3) delta8.43 (d, J=2.4 Hz, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.37-7.26 (m, 5H), 6.92-6.85 (bs, 1H), 5.14 (s, 2H), 4.71 (d, J=4.4 Hz, 2H), 3.88-3.51 (m, 3H), 3.22-3.05 (m, 2H), 2.31-2.07 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.9 g | 10g of (3-chloropyrazin-2-yl) methylamine. Hydrochloride and 10.5g of LN-Cbz-2-deuterated proline were suspended in 400ml of dichloromethane, and the reaction solution was cooled to 0-5 C and dropped Add 24ml of triethylamine and keep it at 0-5 C for 15min.17 g of O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate was added.The mixture was stirred at 0-5 C for 1 hour.The reaction solution was washed with 0.1M hydrochloric acid, sodium bicarbonate solution, saturated brine, dried and concentrated.Flash silica gel column chromatography gave 11.9 g of (S) -2-((3-chloropyrazin-2-yl) methylcarbamoyl) -2'-deuteropyrrolidine-1-carboxylic acid benzyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 6h; | 4- (benzyloxycarbonyl) bicyclo [2.2.1] heptane-1-carboxylic acid (2g, 6.9mmol), HATU (2.89g, 7.6mmol),DIEA (3.56g, 27.6mmol) and (3-chloropyrazin-2-yl) methylamine hydrochloride (1.3g, 7.24mmol)The DMF (20 mL) solution was stirred at room temperature for 6 hours.Pour into water (100 mL) and extract with ethyl acetate (2 × 30 mL). The organic phase was washed with saturated aqueous NaCl solution.The organic phase was separated, dried over Na 2 SO 4, filtered and evaporated.Purified by column chromatography with ethyl acetate / petroleum ether = 1: 1 ~ 1: 0 to obtain 2g of the desired compound A-1, yield: 70%. |
Tags: 939412-86-9 synthesis path| 939412-86-9 SDS| 939412-86-9 COA| 939412-86-9 purity| 939412-86-9 application| 939412-86-9 NMR| 939412-86-9 COA| 939412-86-9 structure
A363480[ 771581-15-8 ]
(3-Chloropyrazin-2-yl)methanamine
Reason: Free-salt
[ 21279-62-9 ]
3-Chloropyrazine-2-carboxamide
Similarity: 0.81
[ 55557-52-3 ]
3-Chloropyrazine-2-carbonitrile
Similarity: 0.76
[ 121246-96-6 ]
3-Chloropyrazine-2-carbaldehyde
Similarity: 0.75
[ 21279-62-9 ]
3-Chloropyrazine-2-carboxamide
Similarity: 0.81
[ 1023813-21-9 ]
3,6-Dichloropyrazine-2-carboxamide
Similarity: 0.70
[ 312736-50-8 ]
3,5-Dichloropyrazine-2-carboxamide
Similarity: 0.69
[ 39204-49-4 ]
Pyrazin-2-ylmethanamine hydrochloride
Similarity: 0.68
[ 21279-62-9 ]
3-Chloropyrazine-2-carboxamide
Similarity: 0.81
[ 55557-52-3 ]
3-Chloropyrazine-2-carbonitrile
Similarity: 0.76
[ 121246-96-6 ]
3-Chloropyrazine-2-carbaldehyde
Similarity: 0.75
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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 |
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