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CAS No. : | 124931-12-0 | MDL No. : | MFCD00134233 |
Formula : | C8H18NO5P | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WYLRYBDGIILFIR-UHFFFAOYSA-N |
M.W : | 239.21 | Pubchem ID : | 2773719 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
94% | With sodium hydride In diethyl ether for 1h; 0 deg C to room temperature; | |
50% | With sodium hydride In tetrahydrofuran at -78 - 20℃; for 17h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With n-butyllithium In tetrahydrofuran; hexane for 24h; Ambient temperature; | |
With sodium hydride In tetrahydrofuran at -78 - 20℃; Inert atmosphere; | ||
1.43 g | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In 1,4-dioxane at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2,6,6-trimethylcyclohex-1-enecarbaldehyde In 1,4-dioxane at 100℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 73% 2: 4.6% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: (2R)-1-(tert-butyloxycarbonyl)-2-((tert-butyldiphenylsilyl)oxymethyl)-3-azetidinone In tetrahydrofuran at 20℃; for 14h; | |
1: 67% 2: 7.7% | In methanol at -78 - 20℃; for 25h; | |
With sodium hydride In tetrahydrofuran at 0℃; Yield given. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydride In diethyl ether for 1h; 0 deg C to room temperature; | |
With n-butyllithium 1.) THF, -78 deg C, 2.) 0 deg C, 1 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: benzaldehyde In tetrahydrofuran at -78 - 20℃; | HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent. |
91% | With sodium hydride In diethyl ether for 1h; 0 deg C to room temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | at 100℃; for 18h; | A solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (2.48 g,17.7 mmol) and triethyl phosphite (3.00 mL, 17.7 mmol) was heated to 100 °C for 18 h. The crude product was purified by flash column chromatography (0?2percent MeOH in CH2Cl2) to give 1 as a colorless oil; yield: 3.31 g (13.8 mmol; 78percent); Rf = 0.42 (2percent MeOH in CH2Cl2); HPLC purity (method b): >95percent (210 nm), >95percent (254 nm). IR (ATR): 2985, 2940, 2908, 1659, 1381, 1253, 1050, 1020, 998, 961 cm?1. 1H NMR (400 MHz, CDCl3): delta = 4.26?4.07 (m, 4 H, 2 × OCH2CH3), 3.76(s, 3 H, OCH3), 3.20 (s, 3 H, NCH3), 3.15 (d, J = 22.1 Hz, 2 H, 1-H), 1.33(td, J = 7.1, 0.6 Hz, 6 H, 2 × OCH2CH3). 13C NMR (101 MHz, CDCl3): delta = 166.2 (C-2), 62.7 (2 × OCH2CH3), 61.6(OCH3), 32.3 (NCH3), 30.9 (C-1), 16.5 (2 × OCH2CH3). HRMS (ESI): m/z [M + H]+ calcd for C8H19NO5P+: 240.0995; found: 240.0996. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium <i>tert</i>-butylate | |
80% | With potassium <i>tert</i>-butylate In tetrahydrofuran 1.) 0 deg C, 30 min, 2.) -78 deg C, 1 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With n-butyllithium In tetrahydrofuran at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium methylate In tetrahydrofuran at 20℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 4-methoxy-benzaldehyde In tetrahydrofuran at -78 - 20℃; | HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent. |
97% | With sodium methylate In tetrahydrofuran at 20℃; for 0.333333h; | |
93% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at -10 - 0℃; Inert atmosphere; Stage #2: 4-methoxy-benzaldehyde In tetrahydrofuran at -10 - 20℃; Inert atmosphere; |
66% | With sodium hydride In tetrahydrofuran at -78 - 20℃; for 17h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: (2R)-2-benzyloxycarbonylamino-3-(4-methoxybenzylsulfanyl)-succinic acid 1-methyl ester 4-tert-butyl ester With diisobutylaluminium hydride In tetrahydrofuran; hexane; toluene at -78 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With methyllithium In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 3,6-diphenyl-3,6-dihydro-1,2-dioxine In tetrahydrofuran for 3h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With methyllithium In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 3-phenyl-3,6-dihydro-1,2-dioxine In tetrahydrofuran for 3h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydride In tetrahydrofuran at 20℃; | |
92% | With sodium hydride In tetrahydrofuran at 20℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 57% 2: 35% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: (2S,4RS)-5-(tert-butyldimethylsilyloxy)-2-methyl-4-(trimethoxymethylphenyl)pentanal In tetrahydrofuran at 20℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.171 g | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: C28H44O10 In tetrahydrofuran at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1.16667h; Stage #2: (5Z,7E)-(3R,4R)-4-(tert-butyldimethylsilanyloxy)-10-(tert-butyldiphenylsilanyloxy)-3-methyldeca-5,7-dienal In tetrahydrofuran at 20℃; for 1.16667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: [6-fluoro-1-(4-toluenesulfonyl)indol-3-yl]carboxaldehyde In tetrahydrofuran at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: [4-fluoro-1-(4-toluenesulfonyl)indol-3-yl]carboxaldehyde In tetrahydrofuran at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: [7-fluoro-1-(4-toluenesulfonyl)indol-3-yl]carboxaldehyde In tetrahydrofuran at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 3-formyl-1-(4-toluenesulfonyl)-1H-indole-6-carbonitrile In tetrahydrofuran at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 3-formyl-1-(4-toluenesulfonyl)-1H-indole-4-carbonitrile In tetrahydrofuran at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; for 1h; Stage #2: 3-formyl-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile In tetrahydrofuran at 0℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 3-formyl-1-(4-toluenesulfonyl)-1H-indole-7-carbonitrile In tetrahydrofuran at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 5-fluoro-1-(p-tolylsulfonyl)indole-3-carboxaldehyde In tetrahydrofuran at 0℃; | |
88% | In tetrahydrofuran | 2 Trans-1-(N,N-dimethylaminomethyl)-2-[5-fluoroindol-3-yl]cyclopropane A solution of diethyl (N-methoxy-N-methylcarbamoylmethyl) phosphonate (5.64 ml, 6.54 g, 27.4 mmol) in anhydrous tetrahydrofuran (25 ml) was added to a stirred suspension of oil free sodium hydride (1.05 g, 27.4 mmol) in anhydrous tetrahydrofuran (350 ml) maintained at 0° C. The reaction was warmed to room temperature and was stirred for 2 h. After cooling to 0° C., [5-fluoro-1-(p-toluenesulfonyl)indol-3-yl]carboxaldehyde (7.24 g, 22.8 mmol) was added. The resulting mixture was stirred at 0° C. for 30 min. The reaction was quenched with aqueous hydrochloric acid (0.1 N) and poured into water (150 ml). After being made acidic with hydrochloric acid (1.0 N), the aqueous portion was extracted with ethyl acetate (3*100 ml). The combined organic layers were washed with brine (50 ml) and dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo. The crude product was purified by recrystallization from ethyl acetate to afford a total of 8.03 g (88% yield) of (E)-[5-fluoro-1-(p-toluenesulfonyl)indol-3-yl]-N-methoxy-N-methylacrylamide as a white solid: mp 199-200° C. (dec.); 1H NMR (400 MHz, DMSO-d6) 8.56 (1 H, s), 7.99 (1 H, m), 7.93 (2 H, d, J=8.4 Hz), 7.68 (2 H, m), 7.42 (2 H, d, J=8.1 Hz), 7.28 (1 H, t, J=9.2 Hz), 7.12 (1 H, d, J=16 Hz), 3.77 (3 H, s), 3.22 (3 H, s), 2.33 (3 H, s); MS m/e 403 (M+H)+. Anal. Calcd. For C20H19FN2O4S: C, 59.69; H, 4.75; N 6.96. Found: C, 59.60; H, 4.70; N, 6.86. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; for 1h; Stage #2: Cyclopropanecarboxaldehyde In tetrahydrofuran at 20℃; for 2h; Further stages.; | |
79% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Stage #2: Cyclopropanecarboxaldehyde In tetrahydrofuran at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NaH In tetrahydrofuran | 63.3 (2-{2,3-Difluoro-4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]phenyl}cyclopropyl)acetic acid Trifluoroacetate. Step 3: (2E)-3-(2,3-Difluoro-4-methoxyphenyl)-N-methoxy-N-methylprop-2-enamide. Diethyl (N-methoxy-N-methylcarbamoylmethyl)-phosphonate (4.8 g) was added to a suspension of 95% NaH (550 mg) in THF (40 mL) under nitrogen atmosphere. The mixture was stirred at an ambient temperature for 10 minutes, and was treated with the product of step 2 (3.44 grams). The mixture was stirred at room temperature for 1 hour and was quenched with water (10 mL). The mixture was concentrated in vacuoo afforded an oily residue. The residue was extracted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated to yield 3.2 grams of the title compound as white solid. 1H-NMR(CDCl3): 7.72 (d, 1H), 7.22(m, 1H), 7.15(d, 1H), 6.75(m,1H), 3.92(s, 3H), 3.78(s, 3H), 3.3(s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.4 g | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; Stage #2: (S)-2-(2,2-dimethyl-1,3-dioxan-4-yl)ethanal In tetrahydrofuran at 0 - 20℃; Further stages.; | |
13.4 g | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 24℃; Inert atmosphere; Stage #2: (S)-2-(2,2-dimethyl-1,3-dioxan-4-yl)ethanal In tetrahydrofuran; mineral oil at 0℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.75h; | |
86% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: (2R,3R,4S)-5-(tert-butyldimethylsilyloxy)-2,4-dimethyl-3-hydroxy-pentanal In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 18h; | Diethyl (N-methoxy-N-methyl-carbamoylmethyl) phosphonate (4.0 g, 16.7 mmol) was added dropwise to a suspension of sodium hydride (671 mg, 60% dispersion in mineral oil, 16.7 mmol) in THF (75 mL) at 0C. A solution of <strong>[209256-42-8]2,3-dihydrobenzofuran-4-carboxaldehyde</strong> (3.0 g, 15.2 mmol) in THF (25 mL) was added dropwise. The resulting suspension was allowed to warm to room temperature. After 18 h, water (60 mL) was added and the solution was extracted three times with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over K2CO3, and concentrated to give a pale red oil, 3.5 g (100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium In tetrahydrofuran; water; pentane | 12 (E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-N-methoxy-N-methylacrylamide EXAMPLE 12 (E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-N-methoxy-N-methylacrylamide 0.465 g (10.65 mmol) of sodium hydride (55%) are introduced into a 100 ml three-necked, round-bottomed flask, equipped with a magnetic stirrer, thermometer, dropping funnel and nitrogen delivery line, and washed twice with 5 ml of pentane. The pentane is removed using a pipette and the sodium hydride is blown dry with nitrogen. 10 ml of THF, rendered absolute using sodium, are added, and 1.84 g (7.46 mmol) of diethyl (N-methoxy-N-methylcarbamoyl-methyl)phosphonate dissolved in 5 ml of THF are slowly added dropwise so that the temperature does not exceed 30° C. 1 g (3.55 mmol) of 3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde dissolved in 10 ml of THF is then added dropwise and the clear, slightly yellow solution is stirred overnight. The reaction mixture is poured into 100 ml of water and extracted 3 times with 50 ml of ethyl acetate. The combined organic phases are washed twice with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. Flash chromatography (hexane/ethyl acetate=2:1) and crystallisation from 94% ethanol yields slightly yellow crystals having a melting point of from 123 to 124° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.75h; Stage #2: (1R,2R,3aS,6aS)-2-(tert-butyldimethylsilyloxy)-5-(5-(4-methoxybenzyloxy)pentyl)-1,2,3,3a,6,6a-hexahydropentalene-1-carbaldehyde In tetrahydrofuran at 20℃; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With lithium hydroxide; 4 A molecular sieve In tetrahydrofuran at 40℃; for 0.333333h; Stage #2: 2-tert-butyldimethylsilyloxypropanal In tetrahydrofuran at 0 - 20℃; Stage #3: With hydrogenchloride In isopropyl alcohol at 20℃; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydride In tetrahydrofuran at -78 - 20℃; Inert atmosphere; | |
80% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at -10 - 0℃; Inert atmosphere; Stage #2: 4-methyl-benzaldehyde In tetrahydrofuran at -10 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at -10 - 0℃; Inert atmosphere; Stage #2: 4-chlorobenzaldehyde In tetrahydrofuran at -10 - 20℃; Inert atmosphere; | |
74% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 4-chlorobenzaldehyde In tetrahydrofuran at -78 - 20℃; | HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at -10 - 0℃; Inert atmosphere; Stage #2: 2-methylphenyl aldehyde In tetrahydrofuran at -10 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 23℃; | 2 To the solution of the ester prepared in the precedent procedure (5.85 g, 20.4 mmol) in CH2CI2 (100 mL) under nitrogen atmosphere, DIBAL (24.5 mL, IM in toluene, 1.2 equiv.) was added at -78 0C and the reaction was kept stirring at the same temperature for half an hour. Then saturated tartrate salt solution (100 mL) was added to the reaction and stirred for 2 hrs until the system turned clear. The two phases were separated and extracted by CH2CI2 (100 mL x 2), washed by brine, dried over Na2SO4. After removal of the solvent, the residue (4.33 g) obtained was used for the next step without further purification. To the solution of the aldehyde (4.33 g) in CH2Cl2 (100 mL) was added Wittig reagent (7.33g, 20.2 mmol, 1.0 equiv.) at 23 0C. The reaction was stirred overnight. After removal of the solvent under reduced vacuum, the residue underwent flash chromatography (PE/EA = 20: 1, then 10/1, 3/1) afforded the desired compound (4.25 g) in the yield of 71 % for the two steps. 1H (CDCI3, 400 MHz, 25 0C) δ 6.89-6.96 (dt, IH); 6.41 (d, IH); 5.77-5.85 (m, IH); 5.18 (dd, IH); 5.05 (dd, IH); 4.23 (dd, IH); 3.67 (s, 3H); 3.22 (s, 3H); 2.42 (dd, 2H); 0.88 (s, 9H); 0.03 (d, 6H).13C (CDCl3, 400 MHz, 25 0C) δ 166.6, 143.5, 140.6, 120.9, 114.3, 72.7, 61.6, 41.4, 32.3, 25.8, 18.2, -4.5, -4.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: 2,3-difluoro-4-methoxy-benzaldehyde In tetrahydrofuran at 20℃; for 1h; | 63.3 Diethyl (N-methoxy-N-methylcarbamoylmethyl)-phosphonate (4.8 g) was added to a suspension of 95% NaH (550 mg) in THF (40 mL) under nitrogen atmosphere. The mixture was stirred at an ambient temperature for 10 minutes, and was treated with the product of step 2 (3.44 grams). The mixture was stirred at room temperature for 1 hour and was quenched with water (10 mL). The mixture was concentrated in vacuoo afforded an oily residue. The residue was extracted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated to yield 3.2 grams of the title compound as white solid. 1HNMR(CDCl3): 7.72 (d, 1H), 7.22(m, 1H), 7.15(d, 1H), 6.75(m,1H), 3.92(s, 3H), 3.78(s, 3H), 3.3(s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 23℃; for 0.75h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; Inert atmosphere; Stage #2: 7-(4-methoxyphenylmethoxy)heptanal In tetrahydrofuran; mineral oil at 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Stage #2: 10-Undecenal In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.75h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With barium(II) hydroxide In tetrahydrofuran at 20℃; for 0.666667h; Inert atmosphere; Stage #2: 3-(tert-butyldimethylsilanyloxy)-2,2-dimethylpropionaldehyde In tetrahydrofuran; water at 20℃; for 24h; Inert atmosphere; | |
Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: 3-(tert-butyldimethylsilanyloxy)-2,2-dimethylpropionaldehyde In tetrahydrofuran; mineral oil at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: (R)-4-hydroxy-1-undecene With ozone In dichloromethane at -78℃; for 0.0833333h; Stage #2: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In dichloromethane; acetonitrile at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane at 20℃; for 12h; | |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
491 mg | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 0℃; for 0.333333h; Stage #2: C11H12O2 In acetonitrile at 20℃; for 4h; | (S,2E,6E)-5-hydroxy-N-methoxy-N-methyl-7-phenylhepta-2,6-dienamide (21). To a stirred solution of 10 (1 g, 2.61 mmol) in dry THF (20 mL) was added asolution of DIBAL-H in toluene (4.4 mL, 7.83 mmol, 25% solution in toluene) at -78 oC, and allowed to stir for 30 min at same temperature. Then the reaction was quenched by adding saturated sodiumpotassiumtartarate solution (10 mL). The resultant mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and evaporated. The resulting crude product 390 mg was employed in next step without further purification. To a stirred solution of (OEt)2P(O)CH2C(O)NMe(OMe) (794 mg, 3.32 mmol) in CH3CN (15 ml) was added LiCl (140 mg, 3.32 mmol) and DBU (0.494 ml, 3.32 mmol) at 0 oC and the mixture was stirred for 20 minutes and the aldehyde (390 mg, 2.215 mmol ) in CH2Cl2 (5 mL) was added dropwise at 0 oC and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, evaporated under reduced pressure and purified by column chromatography (60-120 silica gel) using EtOAc/hexane (40%) as an eluent to afford 21 (491 mg, 78%) as yellow liquid. Rf = 0.5 (60% EtOAc/hexane). IR (neat) υmax : 3405, 2931, 1659, 1618, 1448, 1387, 970 cm-1; 1H NMR (500 MHz, CDCl3) : δ 7.32-7.13 (m, 5H), 6.92 (dt, J = 15.0, 7.0 Hz, 1H), 6.54 (d, J = 16.0 Hz, 1H), 6.44 (d, J = 15.0 Hz, 1H), 6.17 (dd, J = 15.0, 6.0 Hz, 1H), 4.38 (q, J = 13.0, 6.0 Hz, 1H), 3.58 (s, 3H), 3.15 (s, 3H), 2.50 (m, 2H); 13C NMR (75 MHz, CDCl3) : δ 166.5, 143.1, 136.4, 131.2, 130.4, 128.4, 127.6, 126.4, 121.4, 71.3, 61.6, 40.5, 32.2; Mass (ESI-MS) m/z : 284 [M + Na]+; HRMS (ESI) : Calcd. for C15H19NO3Na 284.1262, found 284.1280. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 20℃; for 0.333333h; Inert atmosphere; Stage #2: (3R,5R,6E)-3,5--butyl(dimethyl)silyl]oxy}-7-phenylhept-6-enal In dichloromethane; acetonitrile at 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 75% 2: 24% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 3-(tert-butyldimethylsilyloxy)-20-((oxomethyl)methylene)pregn-5-ene In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; | 4.2.1. (20E,23E)-N-Methoxy-N-methyl-24-(3β-(tert-butyldimethylsilyloxy)-chola-5,20(22),23-triene)carboxamide and [(20E,23E)-17] and (20Z,23E)-N-methoxy-N-methyl-24-(3β-(tert-butyldimethylsilyloxy)-chola-5,20(22),23-triene)carboxamide [(20Z,23E)-17] NaH (60% dispersion in mineral oil, 190 mg, 4.75 mmol) was added portion-wise to a solution of diethyl 2-(methoxy(methyl)amino)-2-oxoethylphosphonate30 (16) (1.030 g, 4.31 mmol) in anhydrous THF (15 mL) stirring under a N2 atmosphere at 0 °C. The mixture was stirred for a further 10 min following the completion of effervescence of H2 then a solution of isomeric aldehydes (20E)-15 and (20Z)-15 (∼75%:25%, 912 mg, 2.00 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. Saturated aqueous NH4Cl solution (10 mL) was added to quench the reaction and the aqueous and organic layers were separated. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic extract was washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 100% CH2Cl2 to 2% EtOAc in CH2Cl2) to afford the major unsaturated Weinreb amide (20E,23E)-17 (810 mg, 1.49 mmol, 75%) and the minor isomer (20Z,23E)-17 (261 mg, 0.48 mmol, 24%; total 99% yield) as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium hydride In tetrahydrofuran at -78 - -40℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: C39H53FN4O10 In tetrahydrofuran at 20℃; for 2h; | 13 To a solution of diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (91 mg, 0.368 mmol) in THF (5.0 mL) was added NaH (2.8 mg, 0.1 104 mmol) in anhydrous THF (0.2 mL) at 0 °C with stirring. The solution was then stirred at 20°C until it became clear. Then 23-3 (70 mg, 0.092 mmol) was added to the clear solution and the mixture stirred at 20 °C for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with brine and dried over Na2S04, filtered and reduced in vacuo. The residue was purified by preparative HPLC to obtained 23 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: C39H52F2N4O10 In tetrahydrofuran at 20℃; for 2h; | 20 xample 20 - preparation of compound 30 xample 20 - preparation of compound 30 To a solution of diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (37 mg, 0.155 mmol) in THF (1.0 mL) was added NaH (2.3 mg, 0.0575 mmol) in anhydrous THF (0.2 mL) at 0 °C with stirring. The solution was then stirred at 20 °C until it became clear. Then 28-3 (30 mg, 0.0387 mmol) was added to the clear solution and the mixture stirred at 20 °C for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with brine and dried over Na2S04, filtered, evaporated. The residue was purified by preparative HPLC to obtained 30 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 2h; | 13 Example 13 Preparation of Compound 23 To a solution of diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (91 mg, 0.368 mmol) in THF (5.0 mL) was added NaH (2.8 mg, 0.1104 mmol) in anhydrous THF (0.2 mL) at 0° C. with stirring. The solution was then stirred at 20° C. until it became clear. Then 23-3 (70 mg, 0.092 mmol) was added to the clear solution and the mixture stirred at 20° C. for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was washed with brine and dried over Na2SO4, filtered and reduced in vacuo. The residue was purified by preparative HPLC to obtained 23 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 2h; | 20 Example 20 Preparation of Compound 30 To a solution of diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (37 mg, 0.155 mmol) in THF (1.0 mL) was added NaH (2.3 mg, 0.0575 mmol) in anhydrous THF (0.2 mL) at 0° C. with stirring. The solution was then stirred at 20° C. until it became clear. Then 28-3 (30 mg, 0.0387 mmol) was added to the clear solution and the mixture stirred at 20° C. for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, evaporated. The residue was purified by preparative HPLC to obtained 30 as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; Stage #2: C15H30O4Si In tetrahydrofuran; mineral oil at 20℃; for 3h; Inert atmosphere; | To a solution of phosphate 19 (23.9 g, 100.1 mmol) in THF (130 mL) was slowly added NaH (4.17g, 95.6 mmol, 55% dispersion in mineral oil) at 0 C, and the mixture was stirredfor 1 h. To this was added a solution of aldehyde 18 (27.5 g, 91.0 mmol) in THF (100 mL), and the mixture was stirredfor 3 h at room temperature. A saturated aqueous NH4Cl solution wasadded, and the mixture was separated. The aqueous layer was extracted with ethylacetate, and the combined organic layers were washed with brine, dried overanhydrous MgSO4, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethyl acetate/hexane)to afford amide 20 (32.6 g, 92%) as acolorless oil: IR (neat) νmax 2970,2891, 1664, 1634, 1462, 1381, 1161, 1105, 1068, 1037, 928, 683 cm-1;1H NMR (500 MHz, CDCl3)δ 6.77 (d, J = 16.0 Hz, 1H), 6.60 (d,J = 16.0 Hz, 1H), 4.94 (d, J = 6.3 Hz, 1H), 4.71 (d, J = 6.3 Hz, 1H), 4.01 (d, J = 11.5 Hz, 2H), 3.94 (s, 2H),3.70-3.67 (m, 5H, involving a singlet at 3.69), 3.25 (s, 3H), 1.16-1.05 (m,21H); 13C NMR (125 MHz, CDCl3) δ 145.83,119.88, 93.97, 70.34, 64.18, 61.69, 42.15, 17.97, 11.88 (2C missing); HRMS (FI+) calcd for C19H37NO5Si [M]+: 387.2441, found: 387.2431. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1.08333h; Inert atmosphere; Darkness; Stage #2: trans,trans-2,4-Hexadienal In tetrahydrofuran; hexane at 0℃; for 1h; Inert atmosphere; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1.08333h; Inert atmosphere; Darkness; Stage #2: (2E,4E,6E)-2,4,6-octatrienal In tetrahydrofuran; hexane at 0℃; for 1h; Inert atmosphere; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In diethyl ether; mineral oil at 0℃; for 0.5h; Stage #2: 3,6-difluoro-2-methoxybenzaldehyde In diethyl ether; mineral oil at 0 - 20℃; for 18h; | AN.AN1 Step AN1. A 60 % dispersion of sodium hydride in mineral oil (0.906 g, 37.8 mmol) was added to a chilled 0 °C solution of diethyl (2-(methoxy(methyl)amino)-2- oxoethyl)phosphonate (7.64 g, 32.0 mmol) in diethyl ether (250 mL). After 30 minutes, 3,6-difluoro-2-methoxybenzaldehyde (5.0 g, 29.0 mmol) was slowly added. The resulting mixture was allowed to warm to rt and stir for 18 h. The reaction was quenched with IN HC1 (10 mL), then poured into water. The aqueous layer was made acidic with IN HC1 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product mixture was purified by silica-gel column chromatography (0-50% EtOAc/hexanes) to afford (E)-3-(3,6-difluoro-2-methoxyphenyl)-N-methoxy- N-methylacrylamide (4.96 g, 66 % yield). LC-MS (M+H)+ 258.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: methyl iodide In tetrahydrofuran; mineral oil at 0 - 20℃; for 18h; | Diethyl 1-mehtyl-(N-methoxy-N-methylcarbamoylmethyl)phosphonate (S5) A solution of S49 (1.08 g, 4.53 mmol) in THF (2.0 mL) was added dropwise to a suspension of NaH (60% in mineral oil, 217.6 mg, 5.44 mmol) in THF (6.5 mL) at 0 °C. After the reaction mixture was stirred for 30 min, methyl iodide (0.85 mL, 13.7 mmol) was added dropwise to the reaction mixture at 0 °C. The mixture was stirred 0 °C to room temperature for 18 h and quenched with sat. NH4Cl, and extracted with CH2Cl2. The combined organic layer was washed with water and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was distilled by bulb to bulb distillation to give S510 (770.3 mg,72%) as a colorless oil. 1H NMR (500 MHz, CDCl3) 4.18-4.12 (m, 4H), 3.77 (s, 3H), 3.73-3.62 (m, 1H), 3.23 (bs, 3H), 1.43 (dd, J = 18.4, 7.2 Hz, 3H), 1.34 (t, J = 7.1 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium hydride In tetrahydrofuran at -78 - 20℃; for 17h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium hydride In tetrahydrofuran at -78 - 20℃; for 17h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With sodium hydride In tetrahydrofuran at -78 - 20℃; for 17h; Inert atmosphere; | |
53% | With sodium hydride In tetrahydrofuran at -78 - 20℃; for 17h; |