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CAS No. : | 1228675-18-0 | MDL No. : | MFCD17480504 |
Formula : | C10H18N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MALCQJIQWIWGOV-UHFFFAOYSA-N |
M.W : | 198.26 | Pubchem ID : | 50986452 |
Synonyms : |
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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: |
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* 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 |
---|---|---|
1: 45.3% 2: 37.7% | Stage #1: tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate; 4-((2-fluoro-4-(methylsulfonyl)phenoxy)methyl)cyclohexanone With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 45℃; for 2h; Inert atmosphere; Stage #2: With sodium hydrogencarbonate In water; 1,2-dichloro-ethane | 1.83 To a solution of tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (0.11 g, 0.56 mmol) and 4-((2-fluoro-4-(methylsulfonyl)phenoxy)methyl)cyclohexanone (0.18 g, 0.61 mmol) in DCE (5 mL) at room temperature under nitrogen was added acetic acid (63.0 μ, 1.10 mmol) and sodium triacetoxyborohydride (0.29 g, 1.4 mmol). The mixture was heated at 45 °C for 2 h. The reaction was quenched with saturated NaHC03 (aq.). The organic layer was separated and the aqueous layer was extracted once with DCM. The combined organic phases were concentrated under reduced pressure and purified by Biotage column chromatography to afford the more polar title compound as an off-white solid (101.0 mg, 37.7%). Exact mass calculated for C24H35FN2O5S: 482.2, found: LCMS mlz = 483.2 [M+H]+; lU NMR (400 MHz, CDCI3) δ ppm 0.44-0.57 (m, 1H), 0.58-0.82 (m, 1H), 1.10-1.24 (m, 2H), 1.29-1.44 (m, 2H), 1.48 (s, 9H), 1.78-1.95 (m, 1H), 2.01 (d, J = 13.64 Hz, 2H), 2.07-2.22 (m, 2H), 2.35-2.52 (m, 3H), 2.66-2.87 (m, 2H), 2.96-3.16 (m, 1H), 3.03 (s, 3H), 3.44-3.73 (m, 1H), 3.92 (d, J = 6.32 Hz,2H), 7.06 (t, J = 8.21 Hz, 1H), 7.61-7.66 (m, 1H), 7.68 (d, J = 9.35 Hz, 1H). The less polar cis analog was also obtained (121.2 mg, 45.3%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In dichloromethane at 0 - 25℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: pyridine / dichloromethane / 0 - 25 °C / Inert atmosphere 2.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C 3.1: hydrogenchloride / water; ethyl acetate; 1,4-dioxane / 1 h / 25 °C 4.1: triethylamine; acetic acid / methanol / 25 °C 4.2: 24 h / 25 °C 5.1: ammonia / methanol / Resolution of racemate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 0 - 25 °C / Inert atmosphere 2: potassium carbonate / N,N-dimethyl-formamide / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 0 - 25 °C / Inert atmosphere 2: potassium carbonate / N,N-dimethyl-formamide / 25 °C 3: hydrogenchloride / water; ethyl acetate; 1,4-dioxane / 1 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 0 - 25 °C / Inert atmosphere 2.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C 3.1: hydrogenchloride / water; ethyl acetate; 1,4-dioxane / 1 h / 25 °C 4.1: triethylamine; acetic acid / methanol / 25 °C 4.2: 24 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / acetonitrile / 2 h / 60 °C 1.2: 18 h / 0 °C 2.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / acetonitrile / 2 h / 60 °C 1.2: 18 h / 0 °C 2.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 90 °C / Inert atmosphere 3.1: trifluoroacetic acid / dichloromethane / 0.25 h / 20 °C 3.2: 0.75 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: (M)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione With N-ethyl-N,N-diisopropylamine; trichlorophosphate In acetonitrile at 60℃; for 2h; Stage #2: tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 18h; | 222.1 Step 1: (M)-tert-Butyl 5-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate DIPEA (0.19 mL, 1.1 mmol) and POCl3 (0.10 mL, 1.11 mmol) were sequentially added to a room temperature solution of (M)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Intermediate 73B, 270 mg, 0.74 mmol) in acetonitrile (3.5 mL). The homogenous bright-yellow solution was heated at 60° C. After 2 h, the reaction mixture was concentrated under reduced pressure and azeotropically dried with heptane. The resulting dark-orange residue was dissolved in DCM (2.0 mL) and cooled to 0° C. DIPEA (0.65 mL, 3.7 mmol) was added, followed by a solution of tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (Aurum Pharmatech LLC, Franklin Park, N.J., USA, 250 mg, 1.3 mmol) in DCM (1.5 mL). After 18 h, the reaction was diluted with EtOAc (70 mL) and water (70 mL). The layers were partitioned and the aqueous phase was extracted with EtOAc (2*30 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to afford an orange oil which was purified by silica gel chromatography (eluent: 0-50% (3:1 EtOAc-EtOH)/heptane) to afford (M)-tert-butyl 5-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (390 mg, 0.72 mmol, 97% yield) as a bright yellow-orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
400 mg | With 4-dimethylaminopyridine In 1-methyl-pyrrolidin-2-one at 120℃; for 12h; Inert atmosphere; | 15.a; 37.f f)5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicycl o[4.1.0]heptan-2-carboxylate Under the protection of nitrogen, (R)-4-chloro-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (300 mg), tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (455 mg) and 4-dimethylaminopyridine (600 mg) were dissolved in N-methylpyrrolidone (5 mL). The reaction solution was stirred at 120°C for 12 hours, then poured into 50 mL of water, extracted with ethyl acetate (20 mL×2), and washed with 15 mL of saturated sodium chloride solution. The organic phase was dried and desolventized to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (PE:EA=1:1-1:2) to obtain 400 mg of a yellow solid. |
0.28 g | With 4-dimethylaminopyridine In 1-methyl-pyrrolidin-2-one at 22 - 140℃; for 3h; Inert atmosphere; | 2.a a) 5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-carboxylate tert-butyl ester Under nitrogen protection, (R)-4-chloro-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (0.21 g), 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate tert-butyl ester (0.31 g) and 4-dimethylaminopyridine (0.39 g) were dissolved in N-methylpyrrolidone (5 mL) at 22°C,then heated to 140°C,The reaction was carried out for 3 hours.After the reaction is complete,The reaction solution was cooled to 20°C,Pour into 20mL ice water,Ethyl acetate (20mL×2) extraction,Washed with saturated brine (10mL×3),The solvent was evaporated under reduced pressure,Silica gel column chromatography (petroleum ether:ethyl acetate=3:11:1) separated,0.28 g of pale yellow liquid was obtained. |
0.28 g | With 4-dimethylaminopyridine In 1-methyl-pyrrolidin-2-one at 22 - 140℃; for 3h; Inert atmosphere; | 2.a a) 5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-carboxylate tert-butyl ester Under nitrogen protection, (R)-4-chloro-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (0.21 g), 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate tert-butyl ester (0.31 g) and 4-dimethylaminopyridine (0.39 g) were dissolved in N-methylpyrrolidone (5 mL) at 22°C,then heated to 140°C,The reaction was carried out for 3 hours.After the reaction is complete,The reaction solution was cooled to 20°C,Pour into 20mL ice water,Ethyl acetate (20mL×2) extraction,Washed with saturated brine (10mL×3),The solvent was evaporated under reduced pressure,Silica gel column chromatography (petroleum ether:ethyl acetate=3:11:1) separated,0.28 g of pale yellow liquid was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile / 6 h / 95 °C / Inert atmosphere; Sealed tube 2: hydrogenchloride / isopropyl alcohol / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile / 6 h / 95 °C / Inert atmosphere; Sealed tube 2: hydrogenchloride / isopropyl alcohol / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile / 6 h / 95 °C / Inert atmosphere; Sealed tube 2: hydrogenchloride / isopropyl alcohol / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 12 h / 20 °C 4: hydrogenchloride / methanol; 1,4-dioxane / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.2 g | With N-ethyl-N,N-diisopropylamine In acetonitrile at 95℃; for 6h; Inert atmosphere; Sealed tube; | 34.e e) tert-butyl 5-((S)-4-methyl-2-oxo-1,4-dihydro-2H-pyrimidin[4,5-d][1,3]oxazin-5-yl)-2,5-diazabicy clo[4.1.0]heptane-2-carboxylate (Compound 34-5a) Compound 34-4a (2g) and tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (3.58 g) were dissolved in anhydrous MeCN (20 mL), and DIEA (3.89g) was added, and the reaction solution was purged with nitrogen, and the tube was sealed and stirred at 95°C for 6 hours. After the reaction was completed, the reaction solution was concentrated to obtain the crude product of the target product. The crude product was dissolved in DCM, washed with water and concentrated to obtain the crude product, which was separated and purified by column chromatography (EA: PE=1:1) to obtain 3.2 g of a pale brown solid. |