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[ CAS No. 5291-32-7 ]

{[proInfo.proName]} (Synonyms:PRIMA-1MET) ,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 5291-32-7
Chemical Structure| 5291-32-7
Structure of 5291-32-7 * Storage: {[proInfo.prStorage]}

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Product Details of [ 5291-32-7 ]

CAS No. :5291-32-7 MDL No. :N/A
Formula : C10H17NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :N/A
M.W :199.25 g/mol Pubchem ID :52918385
Synonyms :

1. APR-246

Safety of [ 5291-32-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5291-32-7 ]

  • Downstream synthetic route of [ 5291-32-7 ]

[ 5291-32-7 ] Synthesis Path-Downstream   1~15

YieldReaction ConditionsOperation in experiment
3-Chinuclidinon-hydrochlorid, 5 mol 6 H2O in wss. Me., K2CO3, 64grad, 2 h;
(yield)16percent;
  • 2
  • [ 5291-32-7 ]
  • [ 13734-41-3 ]
  • (2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl (tert-butoxycarbonyl)-L-valinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 6h; 18 Synthesis of (2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl (tert- butoxycarbonyl)-L-valinate: Into a 50-mL round-bottom flask was placed 2- (hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one (500.0 mg, 2.51 mmol, 1.0 equiv). This was followed by the addition of (tert-butoxycarbonyl)-L-valine (545.2 mg, 2.51 mmol, 1.00 equiv), DCC (932.1 mg, 4.52 mmol), DMAP (61.3 mg, 0.51 mmol), DCM (15.0 mL). The resulting solution was stirred for 6 h at room temperature. The resulting solution was extracted with 3x10 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with DCM/MeOH (10; 1). This resulted in 420 mg (42.00%) of (2-(methoxymethyl)-3- oxoquinuclidin-2-yl)methyl (tert-butoxycarbonyl)-L-valinate as a white solid. LC-MS: (ES, m/z): M+l: 399
  • 3
  • [ 5291-32-7 ]
  • [ 13734-41-3 ]
  • (2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl L-valinate hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 6 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C
  • 4
  • [ 5291-32-7 ]
  • [2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methyl (2S)-2-amino-3-methylbutanoate [ No CAS ]
  • [ 530-62-1 ]
  • [2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methyl (2S)-2-[([[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methoxy]carbonyl)amino]-3-methylbutanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
10.15% Stage #1: 2-(hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one; 1,1'-carbonyldiimidazole In 1,2-dichloro-ethane at 50℃; for 3h; Stage #2: [2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methyl (2S)-2-amino-3-methylbutanoate With triethylamine at 50℃; for 5h; 18 Synthesis of (2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl (((2- (methoxymethyl)-3-oxoquinuclidin-2-yl)methoxy)carbonyl)-L-valinate: Into a 25mL round-bottom flask were added 2-(hydroxymethyl)-2-(methoxymethyl)-l- azabicyclo[2.2.2]octan-3-one (150.00 mg, 0.753 mmol, 1.00 equiv) DCE (3.00 mL) and CDI (0692) (146.48 mg, 0.903 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 3 h at 50 degrees C. To the above mixture was added [2-(methoxymethyl)-3-oxo-l- azabicyclo[2.2.2]octan-2-yl]methyl (2S)-2-amino-3-methylbutanoate (224.63 mg, 0.753 mmol, 1 equiv) and TEA (152.36 mg, 1.506 mmol, 2 equiv) at 50 °C. The resulting mixture was stirred for additional 5 h at 50 °C. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with CH2CI2 (2 x 10 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: Atlantis Prep T3 OBD Column, 19* 150mm 5um; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; (0693) Flow rate: 20 mL/min; Gradient: 10% B to 30% B in 7 min, 30% B; Wave Length: 202 nm;) and ACN (42% PhaseB up to 56% in 7 min); Detector, 254nm.) to afford [2- (methoxymethyl)-3-oxo-l-azabicyclo[2.2.2]octan-2-yl]methyl (2S)-2-[([[2-(methoxymethyl)- 3-oxo-l-azabicyclo[2.2.2]octan-2-yl]methoxy]carbonyl)amino]-3-methylbutanoate (40 mg, 10.15%) as a white solid. LC-MS: (ES, m/z ): M+l : 524. NMR (400 MHz, DMSO-d6) d 8.06 (dd, J= 19.3, 8.7 Hz, 1H), 4.84 - 4.33 (m, 4H), 4.06 (dd, J= 16.3, 7.9 Hz, 2H), 3.98 - 3.80 (m, 4H), 3.62 (d, J= 10.7 Hz, 4H), 3.32 (d, J= 10.7 Hz, 6H), 2.69 (d, J= 8.6 Hz, 2H), 2.34 - 2.00 (m, 9H), 0.90 (t, J= 6.5 Hz, 6H).
  • 5
  • [ 5291-32-7 ]
  • [ 100-21-0 ]
  • bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) terephthalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
29.32% With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3h; 19 Synthesis of bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) terephthalate: To a stirred solution of 2-(hydroxymethyl)-2-(methoxymethyl)-l- azabicyclo[2.2.2]octan-3-one (150 mg, 0.753 mmol, 2.0 equiv) and terephthalic acid (75.04 mg, 0.452 mmol, 1.00 equiv) in DCM was added DCC (279.59 mg, 1.355 mmol, 3.6 equiv) and DMAP (18.39 mg, 0.151 mmol, 0.4 equiv) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was extracted with CH2C12 (2 x 10 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. (0698) The crude product was purified by Prep-HPLC with the following conditions (Column: Atlantis Prep T3 OBD Column, 19*150mm 5um; Mobile Phase A: Water (0.05%TFA ), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 10% B to 30% B in 7 min, 30% B; Wave Length: 202 nm;) and ACN (42% PhaseB up to 56% in 7 min); Detector, 254nm.) to afford bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) terephthalate (70 mg, 29.32%) as a white solid. LC-MS: (ES, m/z): M+l : 529. NMR (300 MHz, Chloroform- ) d 8.27 (s, 4H), 4.85 (d, J = 3.4 Hz, 4H), 4.47 (d, J= 11.2 Hz, 2H), 4.12 (s, 2H), 4.01 (d, J= 11.2 Hz, 2H), 3.86 (s, 2H), 3.55 (s, 4H), 3.41 (s, 6H), 2.84 (s, 2H), 2.32 (d, J= 32.6 Hz, 8H).
  • 6
  • [ 676-97-1 ]
  • [ 5291-32-7 ]
  • bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) methylphosphonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
8.69% With triethylamine In dichloromethane at 0℃; for 4h; 21 Synthesis of bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) methylphosphonate: To a stirred solution of 2-(hydroxymethyl)-2-(methoxymethyl)-l- azabicyclo[2.2.2]octan-3-one (150 mg, 0.753 mmol, 1.0 equiv) and TEA (150.2 mg, 1.506 mmol, 2.00 equiv) in DCM was added methylphosphonic dichloride (60.0 mg, 0.452 mmol, 0.6 equiv) at 0 °C. The resulting mixture was stirred for 4 h at 0 °C. The resulting mixture was extracted with CH2CI2 (2 x 10 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO Cl 8 Column, 21.2*150, 5um; Mobile Phase A: Water(0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 13% B to 26% B in 8 min, 26% B; Wave Length: 220NM nm; RTl(min): 7.6;) to afford bis((2- (methoxymethyl)-3-oxoquinucli din-2 -yl)methyl) methylphosphonate (30 mg, 8.69%) as a white solid. LC-MS: (ES, m/z): M+l: 459. NMR (400 MHz, DMSO- is) d 4.75 - 4.61 (m, 1H), 4.47 (dd, J= 11.9, 5.7 Hz, 2H), 3.61 (t, J= 12.0 Hz, 5H), 3.53 - 3.39 (m, 5H), 3.32 (s, 6H), 2.76 - 2.65 (m, 3H), 2.19 (dd, J= 39.8, 12.1 Hz, 11H), 1.68 (d, J= 18.1 Hz, 3H).
  • 7
  • [ 67-56-1 ]
  • [ 50-00-0 ]
  • 3-quinuclidinone hydrochloride [ No CAS ]
  • [ 5291-32-7 ]
YieldReaction ConditionsOperation in experiment
13.82% With potassium carbonate In water at 20 - 75℃; 14 Synthesis of 2-(hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3- one: Into a 1000-mL round-bottom flask, was placed 3-Quinuclidinone hydrochloride (50 g, 310.56 mmol, 1.00 equiv), H2O (200.00 mL), MeOH (600.00 mL). This was followed by the addition of K2CO3 (50 g, 362.32 mmol, 1.17 equiv), 37% CH2O (105 mL). The resulting solution was stirred for 5 h at 75 degrees C. Then the resulting solution was stirred overnight at room temperature. The resulting solution was adjusted PH=12 with 2N NaOH, extracted with 3x500 mL of dichloromethane and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 11 g (13.82%) of 2- (hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one as a white solid. LC- MS: (ES, in z): M+l: 200; H-NMR (300 MHz, Chloroforms/, ppm ) 3.98 (d, .7=1 1.7Hz, 1H), 3.83-3.79 (m, 3H), 3.39-3.28 (m, 5H), 3.02-2.89 (m, 2H), 2.43-2.38 (m, 1H), 2.11-2.02 (m, 2H).
  • 8
  • [ 67-56-1 ]
  • [ 3731-38-2 ]
  • [ 5291-32-7 ]
YieldReaction ConditionsOperation in experiment
13.82% With potassium carbonate In water at 75℃; for 5h; 12-13; 18-19; 21-22 Synthesis of 2-(hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3- one: A 1000-mL round-bottom flask was placed quinuclidin-3-one (50.00g, 399.45 mmol). This was followed by the addition of K2CO3 (55.21 g, 399.45 mmol, 1.00 equiv), H2O (200.00 mL), MeOH (300.00 mL). The resulting solution was stirred for 5 h at 75 degrees C. Then the resulting solution was stirred for overnight at room temperature. The resulting solution was extracted with 3x500 mL of dichloromethane concentrated. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1: 1). This resulted in 11 g (13.82%) of 2- (hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one as a white solid. LC- MS: (ES, in z): M+l: 200. NMR (CDCh, 300 ppm ) 3.98 (d, J=11.7Hz, 1H), 3.83-3.79 (m, 3H), 3.39-3.28 (m, 5H), 3.02-2.89 (m, 2H), 2.43-2.38 (m, 1H), 2.11-2.02 (m, 2H).
  • 9
  • [ 5291-32-7 ]
  • tris((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) phosphate hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
7.17% With triethylamine; trichlorophosphate In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere; 22 Synthesis of Synthesis of tris((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) phosphate hydrochloride: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(hydroxymethyl)-2-(methoxymethyl)-l- azabicyclo[2.2.2]octan-3-one (389.84 mg, 1.956 mmol, 3 equiv), DCM (10 mL), TEA (263.98 mg, 2.608 mmol, 4 equiv). This was followed by the addition of POCb (100 mg, 0.652 mmol, 1.00 equiv) at 0 degrees C. The resulting solution was stirred for 16 h at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2x20 mL of dichloromethane/methanol (10:1) and washed with 2 x30 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: SunFire Prep Cl 8 OBD Column, 50*250mm 5um lOnm; mobile phase, phase A: H20 (0.05% TFA); phase B: CFECN (10% CFECN up to 40% CFECN in 12 min). This resulted in 30mg (7.17%) of tris((2-(methoxymethyl)-3-oxoquinuclidin-2- yl)methyl) phosphate hydrochloride as a white solid. LC-MS: (ES, m/z): M+l: 678. 1HNMR (400 MHz, DMSO-i/e) d 11.84 (s, 2H), 4.96 (dd, J= 12.0, 4.1 Hz, 3H), 4.58 (dt, J= 12.7, 3.9 Hz, 3H), 4.10-3.97 (m, 6H), 3.79-3.57 (m, 6H), 3.47 (s, 6H), 3.39- 3.25 (m, 9H), 2.70 (s, 3H), 2.27-2.14 (m, 12H).
  • 10
  • [ 5291-32-7 ]
  • 2-(iodomethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
38.67% With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 20℃; 14 Synthesis of 2-(iodomethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one: Into a 250-mL round-bottom flask, was placed 2-(hydroxymethyl)-2-(methoxymethyl)-l- azabicyclo[2.2.2]octan-3-one (2.00 g, 10.038 mmol, 1.00 equiv), DCM (30.00 mL), PPh3 (3.42 g, 13.039 mmol, 1.30 equiv), h (3.32 g, 13.081 mmol, 1.30 equiv), imidazole (923.00 mg, 13.558 mmol, 1.35 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 1.2 g (38.67%) of 2-(iodomethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one as yellow oil. LC-MS: (ES, m/z): M+l: 310; H-NMR (300 MHz, Chloroform-7, ppm ) d 3.77 - 3.50 (m, 3H), 3.45 - 3.28 (m, 5H), 3.15 (ddt, J= 14.5, 9.3, 4.1 Hz, 1H), 2.93 (dddd, 7= 31.6, 15.4, 10.2, 6.2 Hz, 2H), 2.58 - 2.44 (m, 1H), 2.05 (ddddt, J= 22.3, 18.7, 13.2, 5.4, 3.1 Hz, 4H).
  • 11
  • [ 5291-32-7 ]
  • 2-(methoxymethyl)-2-([[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methoxy]methyl)-1-azabicyclo[2.2.2]octan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triphenylphosphine; iodine; 1H-imidazole / dichloromethane / 20 °C 2: silver trifluoromethanesulfonate; 2,6-di-tert-butyl-4-methylpyridine / dichloromethane / -78 - 20 °C / Inert atmosphere
  • 12
  • [ 110-85-0 ]
  • [ 5291-32-7 ]
  • [ 530-62-1 ]
  • bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) piperazine 1,4-dicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
20 mg Stage #1: APR-246; 1,1'-carbonyldiimidazole In 1,2-dichloro-ethane at 50℃; for 4h; Stage #2: piperazine In 1,2-dichloro-ethane at 50℃; for 24h; 13 Synthesis of bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) piperazine- 1, 4-dicarboxylate A 50 ml round bottom flask was placed 2-(hydroxymethyl)-2- (methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one (300 mg, 1.5 mmol) ,CDI (317 mg, 1.95 mmol ) and DCE(10 ml). The resulting solution was stirred for 4 h at 50°C. Piperazine (77 mg, 0.9 mmol) was added and the mixture was stirred for 24 h at 50°C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO Cl 8 Column, 21.2*150, 5um; Mobile Phase A: Water(0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 13% B to 26% B in 8 min, 26% B; Wave Length: 220NM nm; RTl(min): 7.6;) to afford bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) piperazine- 1, 4-dicarboxylate (20 mg) as a white solid. LC-MS (ES, m/z ): M+l: 537. 1HNMR (300 MHz, Chloroform- ) d 4.57 (d, J= 11.7 Hz, 2H), 4.44 (d, J= 11.7Hz, 2H), 3.70 (s, 4H), 3.51 (s, 8H), 3.42 - 3.23 (m, 10H), 2.94 (dt, J= 15.2, 8.3 Hz, 4H), 2.47 - 2.38 (m, 2H), 2.04 (td, J= 7.8, 6.3, 3.3 Hz, 8H).
  • 13
  • [ 5291-32-7 ]
  • [ 26772-34-9 ]
  • [ 530-62-1 ]
  • bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) ((1R,3S)-cyclohexane-1,3-diyl)dicarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
20 mg Stage #1: 2-(hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one; 1,1'-carbonyldiimidazole In 1,2-dichloro-ethane at 50℃; for 4h; Stage #2: (1R,3S)-cyclohexane-1,3-diamine In 1,2-dichloro-ethane at 50℃; for 48h; 13 Synthesis of bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) ((1R,3S)- cyclohexane-l,3-diyl)dicarbamate: A 50 ml round bottom flask was placed 2- (hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one (300 mg, 1.5 mmol) ,CDI (317 mg, 1.95 mmol ) and DCE(10 ml). The resulting solution was stirred for 4 h at 50°C. (lR,3S)-cyclohexane-l,3-diamine(103mg, 0.9 mmol) was added and the mixture was stirred for 48 h at 50°C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column, 21.2*150, 5um; Mobile Phase A: Water(0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 13% B to 26% B in 8 min, 26% B; Wave Length: 220NM nm; RTl(min): 7.6;) to afford bis((2-(methoxymethyl)-3-oxoquinuclidin-2- yl)methyl) ((lR,3S)-cyclohexane-l,3-diyl)dicarbamate (20 mg) as a white solid. LC-MS: (0631) (ES, m/z ): M+l : 565. NMR (300 MHz, Chloroforms/) d 4.99 - 4.64 (m, 2H), 4.49 (d, J = (0632) 11.7 Hz, 2H), 4.30 (d, J= 11.7 Hz, 2H), 3.72 (s, 4H), 3.61 - 3.48 (m, 2H), 3.48 - 3.25 (m, 10H), 3.04 - 2.81 (m, 4H), 2.43 (q, 7= 3.1 Hz, 2H), 2.20 - 1.95 (m, 10H), 1.90 - 1.75 (m, 4H), 1.20 - 0.85(m, 2H).
  • 14
  • [ 5291-32-7 ]
  • 2-(iodomethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one [ No CAS ]
  • 2-(methoxymethyl)-2-([[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methoxy]methyl)-1-azabicyclo[2.2.2]octan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.75% With 2,6-di-tert-butyl-4-methylpyridine; silver trifluoromethanesulfonate In dichloromethane at -78 - 20℃; Inert atmosphere; 14 Synthesis of 2-(methoxymethyl)-2-([[2-(methoxymethyl)-3-oxo-l- azabicyclo[2.2.2]octan-2-yl]methoxy]methyl)-l-azabicyclo[2.2.2]octan-3-one: Into a 100- mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one (400.00 mg, 2.008 mmol, 1.00 equiv), DCM (20.00 mL). This was followed by the addition of 2-(iodomethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one (807.00 mg, 2.610 mmol, 1.30 equiv) at -78 degrees C. To this was added 2,6-di-tert-butyl-4-methylpyridine (935.00 mg, 4.553 mmol, 2.27 equiv) at -78 degrees C, then followed by AgSChCF3 (1.14 g, 4.453 mmol, 2.22 equiv) at -78 degrees C. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (32: 1). The crude product was purified by Prep-HPLC with the following conditions (2 SHIM ADZU (HPLC-01)): Column, X Bridge Shield RP18 OBD Column, 5um,19*150mm; mobile phase, Water (0.05% NH3.H2O) and ACN (14% Phase B up to 36% in 7 min); Detector, UV. This resulted in 21 mg (2.75%) of 2-(methoxymethyl)-2-([[2- (methoxymethyl)-3-oxo-l-azabicyclo[2.2.2]octan-2-yl]methoxy]methyl)-l- azabicyclo[2.2.2]octan-3-one as a white solid. LC-MS: (ES, m/z): M+l: 381; H-NMR (300 MHz, Chloroform -7, ppm ) d 4.00 (dd, J= 44.8, 10.0 Hz, 1H), 3.75 - 3.37 (m, 8H), 3.34 (s, 6H), 3.18 - 2.73 (m, 7H), 2.58 - 2.32 (m, 2H), 2.14 - 1.59 (m, 8H).
  • 15
  • [ 261909-49-3 ]
  • [ 5291-32-7 ]
  • isopropyl (2S)-2-([[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methoxy(phenoxy)phosphoryl]amino)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
8.51% With NMI In tetrahydrofuran at 0 - 20℃; for 1h; 1 Synthesis of isopropyl (2S)-2-([[2-(methoxymethyl)-3-oxo-l- azabicyclo[2.2.2]octan-2-yl]methoxy(phenoxy)phosphoryl]amino)propanoate: Into a 50- mL 3 -necked round-bottom flask, was placed 2-(hydroxymethyl)-2-(methoxymethyl)-l- azabicyclo[2.2.2]octan-3-one (100 mg, 1.00 equiv), THF (5 mL), NMI (82.4 mg, 2.0 equiv). (0484) This was followed by the addition of a solution of isopropyl (2S)-2- (0485) [[chloro(phenoxy)phosphoryl]amino]propanoate (230 mg, 1.5 equiv) in THF (1 mL) dropwise with stirring at 0 degrees C. The resulting solution was stirred for 1 hr at room temperature. The resulting mixture was concentrated under lower temperature. The residue was dissolved in 4 mL of CH3CN. The crude was purified by Prep-HPLC with the following conditions (IntelFlash-1): Column, C18; mobile phase, CH3CN:H20 (0.5%CF3COOH); Detector, 220. 20 mg product was obtained. This resulted in 20 mg (8.51%) of isopropyl (2S)-2-([[2-(methoxymethyl)-3-oxo-l-azabicyclo[2.2.2]octan-2- yl]methoxy(phenoxy)phosphoryl]amino)propanoate as colorless oil. LC-MS: (ES, m/z ): [M+l]=469. H-NMR: (300 MHz, Chloroform- ) d 7.34 (t, J= 7.8 Hz, 2H), 7.28 - 7.12 (m, 3H), 5.12 - 4.90 (m, 1H), 4.78 - 4.36 (m, 3H), 4.15 - 3.83 (m, 4H), 3.76 - 3.46 (m, 2H), 3.31 (d, J= 9.3 Hz, 3H), 2.74 (d, J= 3.4 Hz, 1H), 2.47 - 1.97 (m, 4H), 1.42 (dd, J= 7.1, 5.2 Hz, 2H), 1.36 - 1.14 (m, 6H).
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