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CAS No. : | 867-13-0 | MDL No. : | MFCD00009177 |
Formula : | C8H17O5P | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GGUBFICZYGKNTD-UHFFFAOYSA-N |
M.W : | 224.19 | Pubchem ID : | 13345 |
Synonyms : |
|
Chemical Name : | Ethyl 2-(diethoxyphosphoryl)acetate |
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.88 |
Num. rotatable bonds : | 8 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 52.69 |
TPSA : | 71.64 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) : | -7.32 cm/s |
Log Po/w (iLOGP) : | 1.85 |
Log Po/w (XLOGP3) : | 0.49 |
Log Po/w (WLOGP) : | 1.82 |
Log Po/w (MLOGP) : | 0.51 |
Log Po/w (SILICOS-IT) : | 0.52 |
Consensus Log Po/w : | 1.04 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.01 |
Solubility : | 21.9 mg/ml ; 0.0976 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.56 |
Solubility : | 6.12 mg/ml ; 0.0273 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.86 |
Solubility : | 3.12 mg/ml ; 0.0139 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.69 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P330-P362+P364-P403+P233-P501 | UN#: | 3082 |
Hazard Statements: | H302-H315-H318-H335-H411 | Packing Group: | Ⅲ |
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% | With potassium hydroxide In ethanol; water at 20℃; | After dissolving triethyl phosphonoacetate (1.7 g, 7.5 mmol, Sigma-Aldrich T61391) in ethanol / water (15 mL ie 14: 1) at room temperature, potassium hydroxide (424.2 mg, 7.56 mmol, ) 6597-4400) was added and stirred at room temperature. The reaction was neutralized with 1N HCl to pH 4, the ethanol was removed by distillation under reduced pressure, diluted with chloroform (20 mL), washed with water (10 mL) and saturated brine (10 mL). The separated organic layer was dried over anhydrous sodium sulfate (product number (Daejeong) 7630-4400), filtered and distilled under reduced pressure to obtain 2-(diethoxyphosphoryl)acetic acid 4 (1.48 gm, 100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1 h; Stage #2: at -20 - 20℃; for 3 h; |
To a solution of NaH (60percent mineral oil suspension, 33.3 g, 832.38 mmol) in anhydrous THF (1 L) was added dropwise a solution of l,4-dioxaspiro[4.5]decan-8-one (100 g, 640.29 mmol) in anhydrous THF (500 mL) at 0 °C for 1 hour. The reaction was stirred at 0 °C for 1 hour, then triethyl phosphonoacetate (172.26 g, 768.35 mmol) was added dropwise at -20 °C for 1 hour. The reaction was allowed to warm to room temperature and stirred for 2 hours. The mixture was diluted with H2O (1 L) and extracted with EtOAc (1 L x 3). The combined organic phases were washed with brine (1 L), dried over anhydrous Na2SO i, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtAOc (v/v) = 10/1) to give the title compound as light yellow oil (145 g, 100 percent). 1H M (600 MHz, CDCI3): δ (ppm) 5.62 (s, 1H), 4.10 (qd, / = 7.1, 2.9 Hz, 2H), 3.94 (d, J = 13.8 Hz, 4H), 2.99-2.89 (m, 2H), 2.37-2.27 (m, 2H), 1.77-1.66 (m, 4H), 1.23 (td, J = 7.1, 2.7 Hz, 3H). |
100% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 2 h; Stage #2: at -20 - 20℃; for 3 h; |
Step 1) ethyl 2-(l,4-dioxaspiro[4.51decan-8-ylidene)acetate [0342] To a suspension of NaH (60percent mineral oil suspension, 33.3 g, 832.38 mmol) in anhydrous THF (1 L) was added a solution of l,4-dioxaspiro[4.5]decan-8-one (100 g, 640.29 mmol) in anhydrous THF (500 mL) dropwise at 0 °C for 1 h and continued to stir for 1 h. Then triethyl phosphonoacetate (203.23 g, 832.38 mmol) was added to the above suspension dropwise at -20 °C in 1 h. The resulting mixture was allowed to warm to rt, stirred for 2 h, quenched with H20 (1 L) and extracted with EtOAC (1 L x 3). The combined organic phases were washed with brine (1 L), dried over anhydrous Na2S04, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v) = 1/10) to give the title compound as pale yellow oil (157 g, 100 percent). FontWeight="Bold" FontSize="10" H NMR (600 MHz, CDCI3): δ (ppm) 5.64 (s, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.95 (s, 4H), 2.97 (m, 2H), 2.36 (m, 2H), 1.74 (m, 4H), 1.25 (t, J= 7.2 Hz, 4H). |
100% | Stage #1: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.166667 h; Stage #2: at 20℃; for 1 h; |
Potassium tert-butylate (10.7 g, 95.6 mmol) was added to a solution of phosphonoacetic acid triethyl ester (21.4 g, 19 ml, 95.6 mmol) in anhydrous N,N-dimethylformamide (90 ml) underargon and the mixture was stirred for 10 mm at room temperature. A solution of 1,4- dioxaspiro[4.5]decan-8-one (10.0 g, 64 mmol) in anhydrous N,N-dimethylformamide (160 ml) was then added to the mixture and the mixture was stirred for 1 h at room temperature and then poured into ice-water (240 g). The aqueous suspension was extracted with diethyl ether (4 x 100 ml). The combined organic extracts were dried with sodium sulfate andconcentrated i. vac.Yield: 14.4 g (100 percent), yellowish oil.1H-NMR (CDCI3): 1.27 (3 H, t, J = 7.1 Hz): 1.73—1.80 (4 H, m); 2.35—2.40 (2 H, m); 2.92—3.02(2 H, m): 3.97 (4 H, s): 4.15 (2 H, q, J = 7.1 Hz): 5.66(1 H, s). |
100% | Stage #1: With sodium hydride In tetrahydrofuran; water; mineral oil at -20 - 0℃; Stage #2: at 20℃; for 3 h; |
The NaH (60percent mineral oil suspension, 33.3g, 832 . 38mmol) THF suspended water-free (1L) in, in 0 °C lower, added to the 1,4-dioxaspiro [4.5] decane-8-one (100g, 640.29mmol) anhydrous THF (500 ml) solution, 1-hour internal dropping end. Furthermore, at -20 °C lower, the phosphoryl acetic acid triethyl ester (203.23g, 832 . 38mmol) is dripped into the in the above-mentioned suspension system, 1-hour internal dropping end. The resulting system is moved to the room temperature, is continuously stirred for 2 hours, then water (1L) quenching the reaction, and using ethyl acetate (1Lx3) extraction. Combined with the phase, saturated salt water for (1L) washing, anhydrous Na2SO4drying, concentrated filtrate under reduced pressure, the resulting residue by a silica gel column chromatography (PE/EtOAc = 10/1 (v/v)) purification, to obtain the title compound as of bombycinous (157g, 100percent). |
100% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 2 h; Stage #2: at -20 - 20℃; for 3 h; |
Step 1) ethyl 2-(l ,4-dioxaspiror4.51decan-8-ylidene)acetate [0350] To a suspension of NaH (60percent mineral oil suspension, 33.3 g, 832.38 mmol) in anhydrous THF (1 L) was added a solution of l ,4-dioxaspiro[4.5]decan-8-one (100 g, 640.29 mmol) in anhydrous THF (500 mL) dropwise at 0 °C for 1 h and the reaction mixture was stirred for another 1 h. Then, triethyl phosphonoacetate was added dropwise to the above suspension at -20 °C in 1 h. The resulting mixture was allowed to warm to rt, and stirred for another 2 h, then quenched with 0 (1 L) and extracted with EtOAc (1 L x 3). The combined organic phases were washed with brine (1 L), then dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v) = 1/10) to give the title compound as pale yellow oil (157 g, 100 percent). NMPv (600 MHz, CDCb): δ (ppm) 5.64 (s, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.95 (s, 4H), 2.97 (m, 2H), 2.36 (m, 2H), 1.74 (m, 4H), 1.25 (t, J= 7.2 Hz, 4H). |
100% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 20℃; for 2 h; |
To a suspension of NaH (60percent suspension in oil) (1.42 g, 35.45 mmol) in THF (190mL) at 0 °C, under N2, ethyl 2-(diethoxyphosphoryl)acetate (7 mL, 35.45 mmol) was addeddrop-wise. The mixture was stirred for 30’, then 1,4-dioxaspiro[4.5]decan-8-one (5g, 32 mmol)in THF (20 mL) was added drop-wise. The resulting mixture was stirred at RT for 2 hrs and thenconcentrated under vacuum. The residue was taken up with Et20, washed with water and Brine, dried over Na2SO4 and concentrated to obtain 7.58 g of title compound (p121, y= quant) as colourless oil. MS (m/z): 227.2 [IVIH]t |
100% | With sodium hydride In tetrahydrofuran; mineral oil at -20 - 20℃; for 2 h; | NaH (60percent suspended in mineral oil, 33.3 g, 832.38 mmol) was suspended in dry THF (1 L), and then the suspension was placed at 0 ° C, 1,4-dioxaspiro[4.5]decan-8-one (100 g, 640.29 mmol) in dry THF (500 mL) dropwise over 1 hour to give a suspension. Then, triethyl phosphonoacetate (203.23 g, 832.38 mmol) was added dropwise to the above suspension at -20 ° C, and the mixture was dropwise added in 1 hour to obtain a reaction system. The resulting reaction was moved to room temperature and stirring continued for 2 hours, then the reaction was quenched with water (1 L) and extracted with ethyl acetate (1 L x 3). The combined organic phases were washed with brine (1 L), then dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a pale yellow oil (157 g, 100percent). |
100% | With sodium hydride In tetrahydrofuran; kerosene at -20 - 20℃; for 4 h; | At 0 ° C, NaH (60percent [w / w], 33.3 g, 832.38 mmol) suspended in kerosene was added to dry tetrahydrofuran (500 mL) and 1,4-dioxaspiro[4.5]decan-8-one (100 g, 640.29 mmol) was added dropwise over 1 hour. Then triethyl phosphonoacetate (172.26 g, 768.35 mmol) was added dropwise at -20 ° C for 1 hour. The reaction was warmed to room temperature and stirred for 2 hours before it was diluted with water (1 L), extracted with ethyl acetate (1 L × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10/1) to give the title compound as a pale yellow oil (145 g, 100percent). |
96% | Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5 h; Stage #2: at 0 - 20℃; for 0.5 h; |
Triethyl phosphonoacetate (21.79 ml, 109 mmol) was added to a suspension of sodium hydride (3.84 g, 96 mmol) in THF (64.0 ml) and 0 °C. Reaction was stirred at room temperature for 30 minutes. After 30 minutes, the reaction was recooled to 0 °C and a solution of 1,4-dioxaspiro[4.5]decan-8-one (10 g, 64.0 mmol) in 5 mL THF wasadded. The reaction was then stirred at room temperature for 30 minutes prior to quenching with water. The mixture was extracted with DCM three times. Combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. Crude residue was purified via silica gel chromatography to give Intermediate 71A (13.88 g, 61.3 mmol, 96percent yield). TLC: product stains as purple spot in anisaldehyde (Rf= 0.75in 1:1 Hex/EtOAc). ‘H NMR (400 MHz, chloroform-d) ö: 5.65 (s, 1H), 4.13 (q, J=7.2 Hz,2H), 3.92-3.99 (m, 4H), 2.94-3.02 (m, 2H), 2.3 1-2.40 (m, 2H), 1.71-1.79 (m, 4H), 1.26 (t, J=7.2 Hz, 3H). |
96% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.5 h; Stage #2: at 0 - 20℃; for 0.5 h; |
Triethyl phosphonoacetate (21.79 ml, 109 mmol) was added to a suspension of sodium hydride (3.84 g, 96 mmol) in THF (64.0 ml) and 0 °C. Reaction was stirred at room temperature for 30 minutes. After 30 minutes, the reaction was recooled to 0 °C and a solution of l,4-dioxaspiro[4.5]decan-8-one (10 g, 64.0 mmol) in 5 mL THF was added. The reaction was then stirred at room temperature for 30 minutes prior to quenching with water. The mixture was extracted with DCM three times. Combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. Crude residue was purified via silica gel chromatography to give Intermediate 83A (13.88 g, 61.3 mmol, 96percent> yield). TLC: product stains as purple spot in anisaldehyde (Rf = 0.75 in 1 : 1 Hex/EtOAc). 1H NMR (400 MHz, chloroform-d) δ: 5.65 (s, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.92-3.99 (m, 4H), 2.94-3.02 (m, 2H), 2.31-2.40 (m, 2H), 1.71-1.79 (m, 4H), 1.26 (t, J=7.2 Hz, 3H) |
96% | Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1 h; Stage #2: at 0 - 20℃; for 0.5 h; |
Triethyl phosphonoacetate (21.79 ml, 109 mmol) was added to a suspension ofsodium hydride (3.84 g, 96 mmol) in THF (64.0 ml) and 0 °C. Reaction was stirred atroom temperature for 30 minutes. After 30 minutes, the reaction was recooled to 0 °C and a solution of 1,4-dioxaspiro[4.5]decan-8-one (10 g, 64.0 mmol) in 5 mL THF was added. The reaction was then stirred at room temperature for 30 minutes prior to quenching with water. The mixture was extracted with DCM three times. Combinedorganic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. Crude residue was purified via silica gel chromatography to give Intermediate 305A (13.88 g, 61.3 mmol, 96percent yield). TLC: product stains as purple spot in anisaldehyde (Rf = 0.75 in 1:1 Hex/EtOAc). ‘H NMR (400 MHz, chloroform-d) ö: 5.65 (s, 1H), 4.13 (q, J7.2 Hz, 2H), 3.92-3.99 (m, 4H), 2.94-3.02 (m, 2H), 2.3 1-2.40 (m, 2H), 1.7 1-1.79 (m,4H), 1.26 (t, J7.2 Hz, 3H). |
96% | Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5 h; Stage #2: at 0 - 20℃; for 0.5 h; |
[00187] Tri ethyl phosphonoacetate (21.79 ml, 109 mmol) was added to a suspension of sodium hydride (3.84 g, 96 mmol) in THF (64.0 ml) and 0 °C. Reaction was stirred at room temperature for 30 minutes. After 30 minutes, the reaction was recooled to 0 °C and a soution of l,4-dioxaspiro[4.5]decan-8-one (10 g, 64.0 mmol) in 5 mL THF was added. The reaction was then stirred at room temperature for 30 minutes prior to quenching with water. The mixture was extracted with DCM three times. Combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. Crude residue was purified via silica gel chromatography to give intermeduate 3A (13.88 g, 61.3 mmol, 96 percent yield). TLC: product stains as purple spot in anisaldehyde (Rf = 0.75 in 1 : 1 Hex/EtOAc). NMR (400 MHz, CHLOROFORM-d) δ: 5.65 (s, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.92-3.99 (m, 4H), 2.94-3.02 (m, 2H), 2.31 -2.40 (m, 2H), 1.71 -1.79 (m, 4H), 1.26 (t, J=7.2 Hz, 3H) |
96% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.5 h; Stage #2: at 0 - 20℃; for 0.5 h; |
Triethyl phosphonoacetate (21.79 ml. 109 mmoi) was added to a suspension of sodium hydride (3.84 g, 96 mrnol) in TI-iF (64.0 ml) and 0 °C. Reaction was stirred at room temperature for 30 minutes. After 30 minutes, the reaction was recooled to 0 C and a soution of 1,4-dioxaspiro[4.5Idecan-8-one (10 g, 64.0 mmol) in 5 mL THF was added. The reaction was then stirred at room temperature for 30 minutes prior to quenching with water, The mixture was extracted with DCM three times. Combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. Crude residue was purified via silica gel chromatography to give intermediate 13A (13.88 g, 61.3 mmoi, 96 percent yield). TLC: product stains as purple spot in anisaldeliyde (RI 0 7 in 11 He [tO’\.c) ‘HMR(400 MHz (HLOROH)RNI-d) 5 565 (1H), 4.13 (q, J=7.2 Hz, 2Ff), 3.92-3.99 (m, 4H), 2.94-3.02 (in, 2H), 2.31-2.40 (m, 2H). 1.71-1.79 (in, 4H), 1.26 (t, J=7.2 Hz, 3H) |
94% | Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: at -20 - 20℃; |
Step-1: Ethyl 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate A solution of compound 1 (10.05 g, 64.04 mmol, 1.0 eq.) in THF (30 ml) was added dropwise to a suspension NaH (1.84 g, 76.85 mmol, 1.2 eq.) in THF (90 ml) at 0° C. and the mixture was stirred at same temperature for 1 h. Triethyl phosphonoacetate (16.5 ml, 83.25 mmol, 1.3 eq.) was added to the reaction mixture at -20° C. and the reaction mixture was allowed to warm to RT and stir for 2 h. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (2*100 ml) and the organic layer dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel; 5percent ethyl acetate/hexanes) to yield compound 2. Yield: 94percent (17.28 g, 60.2 mmol). |
93% | Stage #1: With lithium hydride In tetrahydrofuran at 20℃; for 1 h; Stage #2: at 65℃; for 16 h; |
To a solution of THF (18 mL) under argon was added 0.38 g (47.8 mmol, 5 equiv) of LiH, followed by slow addition of 8.78 G (47.8 mmol, 5 equiv) of triethyl phosphonoacetate. The solution was stirred at rt for 1 h and 1.49 g (9.6 mmol, 1 equiv) of 1, 4-cyclohexanedione mono-ethylene ketal was added and the solution was heated at 65 °C for 16 h. Upon cooling the solution was treated with MeOH (10 mL) and water (5 mL) and concentrated in vacuo. The resulting yellow oil was purified by silica gel chromatography eluting with 4: 1 Hex/EtOAc to yield 1.89 g (93percent) of a clear oil.'H-NMR (CDCI3-D) 8 5.67 (s, 1H), 4.16 (t, 2H), 3.99 (m, 4H), 3.02 (m, 2H), 2.39 (m, 2H), 1.78 (m, 4H), 1.29 (t, 3H); LCMS RT = 2.56 min; [M+H] + = 226.9. |
93% | Stage #1: With lithium hydride In tetrahydrofuran at 20℃; for 1 h; Stage #2: at 65℃; for 16 h; |
Example 1; Preparation of ethyl [4-({3-chloro-4-[(3-fluorobenzyl)oxy] phenyl )amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]acetate; Step 1. Preparation of ethyl 1,4-dioxaspiro[4.5]dec-8-ylideneacetate; To a solution of THF (18 mL) under argon was added 0.38 g (47.8 mmol, 5 equiv) of LiH, followed by slow addition of 8.78 g (47.8 mmol, 5 equiv) of triethyl phosphonoacetate. The solution was stirred at rt for 1 h and 1.49 g (9.6 mmol, 1 equiv) of l,4-dioxa-spiro[4.5]decan-8-one was added and the solution was heated at 65°C for 16 h. Upon cooling the solution was treated with MeOH (10 mL) and water (5 mL) and concentrated in vacuo. The resulting yellow oil was purified by silica gel chromatography eluting with 4: 1 Hex/EtOAc to yield 1.89 g (93percent) of a clear oil. 1H- NMR (CDCl3-d) δ 5.67 (s, 1H), 4.16 (t, 2H), 3.99 (m, 4H), 3.02 (m, 2H), 2.39 (m, 2H), 1.78 (m, 4H), 1.29 (t, 3H); LCMS RT = 2.56 min, [M+H]+ = 226.9. |
93% | Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 0 - 25℃; for 3 h; Inert atmosphere |
Triethyl phosphonoacetate (12.2g, 54.4mmol) was dissolved in tetrahydrofuran (100mL), at 0 °C was added sodium hydride (1.92g, 48.0mmol), the reaction mixture was stirred under nitrogen atmosphere for 30 minutes.Then at 0 °C dissolved in tetrahydrofuran (15mL) 1,4-cyclohexanedione monoethylene ketal (5.00g, 32.0mmol) was added dropwise to the reaction mixture, the reaction solution was stirred at 25 °C for 3 hours. Water was added (25mL) to quench the reaction and extracted with dichloromethane (20mLx3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrousOver sodium sulfate, and concentrated under reduced pressure, the residue was residue was purified by silica gel column chromatography (5: 1 petroleum ether / acetic acidEthyl ester, Rf = 0.3), give ethyl 2-(1,4-dioxa-spiro[4.5]decane-8-ylidene)acetate (6.30g, Colorless oil). Yield: 93percent. |
90% | Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: at 0℃; for 16 h; |
A solution of triethyl phosphonoacetate (11 mmol) in THF (50 ml) was added slowly to a suspension, cooled to 0° C., of NaH (10 mmol) in THF (50 ml), and the reaction mixture was stirred for 30 min. 1,4-Dioxa-spiro[4.5]decan-8-one (10 mmol) in THF (50 ml) was then added dropwise at 0° C., and stirring was carried out for 16 h. After addition of ice and aqueous saturated NaCl solution, the aqueous phase was washed with ethyl acetate and the organic phase with water and aqueous saturated NaCl solution. The combined organic phases were dried over Na2SO4 and, after filtration, the solvent was removed in vacuo. The product was purified by column chromatography (20percent ethyl acetate/hexane). Yield: 90percent. |
83% | With sodium hydride In tetrahydrofuran at 0℃; | Into a 250-mL round-bottom flask, was placed ethyl 2-(diethoxyphosphoryl)acetate (14.4 g, 64.23 mmol, 1 equiv), tetrahydrofuran (150 mL), sodium hydride (5.12 g, 213.33 mmol, 3.33 equiv), l,4-dioxaspiro[4.5]decan-8-one (10 g, 64.03 mmol, 1 equiv). The resulting solution was stirred overnight at 0 °C. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5). This resulted in 12 g (83percent) of as a yellow liquid. Analytical Data: 1H NMR (300 MHz, Chloroform-d) δ 5.67 (p, J= 1.1 Hz, 1H), 4.15 (q, J= 7.1 Hz, 2H), 3.98 (s, 4H), 3.00 (ddd, J= 7.8, 5.1, 1.2 Hz, 2H), 2.44 - 2.32 (m, 2H), 1.84 - 1.70 (m, 4H), 1.28 (t, J= 7.1 Hz, 3H). |
69% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1 h; Stage #2: at 0 - 20℃; |
To a solution of commercially available ethyl 2-diethoxyphosphorylacetate(9.5 g, 42.3 mmol) in THE (20 mL) was added NaH (1 .7 g, 42.3 mmol) at 0°C. The mixture solution was stirred at 0°C for 1 h. Then a solution ofcommercially available 1 ,4-dioxaspiro[4.5]decan-8-one (6 g, 38.5 mmol) in THE (5 mL) was added at 000. The solution was stirred at r.t overnight. The mixture was quenched with aqueous NH4CI and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give the crude product which was purified by column to givereagent KR-46 (6.6 g, 69 percent yield) as a white solid. ESI-MS (Mi-i): 227.2; calc. for C12H1804: 226.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: With sodium hydride In tetrahydrofuran at 0 - 5℃; for 1 h; Stage #2: at 20℃; for 16 h; |
Step 1: (1,4-Dioxa-spiro[4.5]dec-8-ylidene)-acetic acid ethyl ester Triethyl phosphonoacetate (1.14 ml, 7.04 mmol) was dissolved in 15 ml THF and cooled to 0-5° C. Sodium hydride (310 mg, 7.04 mmol, 55percent) was added and the reaction mixture stirred for 1 hour at 0-5° C. 1,4-Cyclohexanedione (1.0 g, 6.40 mmol) dissolved in 10 ml THF was added drop wise and stirred for 16 hours at room temperature. The reaction mixture was quenched with saturated NaHCO3-solution and extracted two times with ethyl acetate. The organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10-->0:100 gradient). The desired compound was obtained as a colourless liquid (1.10 g, 76percent), MS: m/e=227.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 10℃; for 1.16667 h; Inert atmosphere Stage #2: at 0 - 10℃; for 2.5 h; Inert atmosphere |
To a slurry of NaH (8.0 g, 60percent in oil) in THF (150mL), was added triethyl phosphonoacetate (44.8 g)in 25 mL of THF dropwise at 0-10 oC over 40 min. The reactionmixture was stirred at 0-10 oC for another 0.5 h. Then cyclobutanone(5, 14.0 g) in 25 mL of THF was added dropwise at 0-10 oCover 30 min. The reaction mixture was stirred at 0-10 oC for 2 h. Atotal of 50 mL of water was then added slowly at 20-30 oC. Theorganic solvent was removed under reduced pressure followed by addition of 150mL of water. The aqueous solution was extracted with MTBE (3 x 100 mL). Thecombined organic phase was washed with water (100 mL). It was then dried overanhydrous MgSO4. Filtration followed by evaporation gave the crudeproduct, which was purified by fractional distillation at 81-82 oC/19mbar to give 22.2 g (79percent yield) of Compound 9 as a colorless liquid. 1HNMR (500 MHz,CDCl3) δ 5.58 (m, 1H), 4.13(q, 2H, J = 7.1 Hz), 3.15-3.12 (m, 2H),2.85-2.82 (m, 2H),2.12-2.06 (m, 2H),1.26 (t, 3H, J = 7.1 Hz); 13C NMR (125 MHz, CDCl3) δ 167.60, 166.60, 112.38, 59.53, 33.75, 32.32, 17.66, 14.36; MS (m/z)140.1; ESI-HRMS m/zcalcd for C8H12O2 [M + H]+ 141.0910, found 141.0911. |
79% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 10℃; for 1.16667 h; Stage #2: at 0 - 10℃; for 2.5 h; |
To a slurry of NaH (8.0 g, 60 in oil) in THF (150 mL) , was added triethyl phosphonoactate (44.8 g) in 25mL of THF dropwise at 0-10 over 40 min. The reaction mixture was stirred at 0-10 for another 0.5 h. Then cyclobutanone (14.0 g) in 25 mL of THF was added dropwise at 0-10 over 30 min. The reaction mixture was stirred at 0-10 for 2 h. A total of 50 mL of water was then added slowly at 20-30 . The organic solvent was removed under reduced pressure followed by addition of 150 mL of water. The aqueous solution was extracted with MTBE (3 x 100 mL) . The combined organic phase was washed with water (100 mL) . It was then dried over anhydrous MgSO4. Filtration followed by evaporation gave the crude product, which was purified by fractional distillation at 81-82 /19 mbar to give 22.2 g (79 yield, 99 purity) of Compound 12 as a colorless liquid.1HNMR(400 MHz, CDCl3) δ 5.56 (m, 1H) , 4.13 (q, 2H, J 7.2 Hz) , 3.12 (m, 2H) , 2.81 (m, 2H) , 2.08 (m, 2H) , 1.25 (t, 3H, J 7.2 Hz) 13CNMR(100 MHz, DMSO-d6) δ167.2, 165.3, 111.8, 58.9, 33.3, 31.8, 17.1, 14.0 MS (m/z) 140.1. |
75% | Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.166667 h; Stage #2: at 20℃; for 4 h; |
(0203) Triethyl phosphonoacetate (3.32 g, 1.0 equiv) was dissolved in abs. tetrahydrofuran and added to a suspension, cooled down to 0° C., of sodium hydride (0.58 g, 1.02 equiv, 60percent dispersion) in abs. tetrahydrofuran (5 mL). The resulting reaction mixture was stirred at a temperature of 0° C. for 10 minutes and then admixed with a solution of cyclobutanone (1.0 g, 1.0 equiv) in abs. tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for a further 4 h. After the cautious addition of water, the reaction mixture was concentrated under reduced pressure and admixed with dichloromethane. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), ethyl cyclobutylideneacetate (1.5 g, 75percent of theory) was isolated. Ethyl cyclobutylideneacetate (1.0 g, 1.0 equiv) was dissolved in methanol and admixed with a 1 M solution of KOH in aq. methanol. The resulting reaction mixture was stirred at room temperature for 16 h, then neutralized with dil. HCl, admixed with water, concentrated under reduced pressure and then admixed with dichloromethane. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), cyclobutylideneacetic acid (0.40 g, 51percent of theory) was isolated. Aniline (0.26 g, 1 equiv.) was dissolved in dichloromethane (5 mL) and cooled down to a temperature of 0° C., and diisopropylethylamine (1.98 mL, 4.0 equiv.), cyclopentylideneacetic acid (0.30 g, 1.0 equiv.) and N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (0.97 g, 1.1 equiv.) were added. The resulting reaction mixture was stirred at room temperature for 3 h, and water and dichloromethane were then added. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 2-cyclobutylidene-N-phenylacetamide (0.27 g, 54percent of theory) was isolated. In the next step, aluminum trichloride (0.42 g, 3.0 equiv.) was initially charged in abs. dichloroethane (5 mL) under argon in a baked-out round-bottom flask and then, while cooling with ice, a solution of 2-cyclobutylidene-N-phenylacetamide (0.20 g, 1.0 equiv.) in abs. dichloroethane (5 mL) was added. The resulting reaction mixture was stirred at room temperature for a further 4 h and then added cautiously to ice-water. After adding aqueous HCl and dichloromethane, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated cautiously under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one was isolated as a colorless solid. 1′H-Spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (0.2 g, 1 equiv.) was added to conc. acetic acid (1.5 mL) and then cautiously admixed at 0° C. with fuming nitric acid (0.5 mL). The resulting reaction mixture was then stirred at 90° C. for 2 h and, after cooling to room temperature, cautiously diluted with ice-water. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6′-nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (100 mg, 78percent of theory) was isolated as a colorless solid. 6′-Nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (100 mg, 1.0 equiv.) was dissolved under argon in abs. dioxane (2 mL) and admixed with fine cesium carbonate powder (400 mg, 3.0 equiv.). After stirring at room temperature for 5 min, cyclobutylmethyl bromide (110 mg, 2.0 equiv.) and potassium iodide (35 mg, 0.1 equiv.) were added at room temperature. The resulting reaction mixture was stirred at 150° C. under microwave conditions for 1 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1-(cyclopropylmethyl)-6′-nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (70 mg, 60percent of theory) was isolated as a colorless solid. In the next step, 1-(cyclopropylmethyl)-6′-nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (50 g, 1 equiv.) was added together with zinc dust (55 mg, 5 equiv.) and ammonium chloride (90 mg, 10 equiv.) to methanol/water (5:1) and the mixture was stirred under argon at a temperature of 70° C. for 2 h. After cooling to room temperature, the reaction mixture was poured onto ice-water and then adjusted to pH 12 with 6 N NaOH. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6′-amino-1-(cyclopropylmethyl)-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (35 mg, 70percent of theory) was isolated as a colorless solid. 6′-Amino-1-(cyclopropylmethyl)-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (100 mg, 1.0 equiv.) was dissolved together with 4-methylphenylsulfonyl chloride (81 mg, 1.1 equiv) in abs. dichloromethane (5 mL) in a baked-out round-bottom flask under argon, then pyridine (0.15 mL, 5 equiv.) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure, the remaining residue was admixed with dil. HCl and dichloromethane, and the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 4-methyl-N-[1′-(cyclopropylmethyl)-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutyl-1,4′-quinolin]-6′-yl]phenylsulfonamide (70 mg, 43percent of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 10.05 (s, 1H, NH), 7.62 (d, 2H), 7.36 (d, 2H), 7.12 (m, 2H), 6.96 (m, 1H), 3.76 (m, 2H), 2.61 (s, 2H), 2.33 (s, 3H), 2.03-1.92 (m, 5H), 1.79 (m, 1H), 0.97 (m, 1H), 0.36 (m, 2H), 0.22 (m, 2H). |
16% | Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.0833333 h; Stage #2: at 27℃; for 2 h; |
To a stirred suspension of 60percent NaH (1.23 g, 51.35 mmol) in THF (50 mL), ethyl 2-(diethoxyphosphoryl)acetate (6.23 mL, 31.38 mmol) in 10 mL THF was added at 0°C and stirred for 5 mm at same temperature. Then cyclobutanone 75 (2 g, 28.53 mmol) in THF (10 mL) was added to it and allowed to stir at room temperature for 2h. Then the reaction mixture was quenched with cold water and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain ethyl 2-cyclobutylideneacetate 76 as colorless liquid (0.65 g, 16percent yield). 1HNMR (400 MHz, CDC13): ö 5.57 (s, 1H), 4.13 (q, 2H), 3.12 (t, 2H), 2.82 (t, 2H), 2.12-2.04 (m, 2H), 1.26 (t, 3H). |
96% | With NaH In tetrahydrofuran | Synthesis of Cyclobutylidene-acetic acid ethyl ester (2) NaH (60percent dispersion in oil, 1.80 g, 44.94 mmol) was suspended in dry tetrahydrofuran (80 mL) and cooled to 0° C. Triethylphosphonoacetate (9.33 mL, 47.08 mmol) was added and the mixture stirred at 0° C. for 15 minutes. Cyclobutanone (1) (3.0 g, 42.8 mmol) in THF (20 mL) was then added and the mixture allowed to warm to room temperature. After 2 hours, the mixture was partitioned between diethyl ether (200 mL) and water (150 mL). The organic phase was separated, washed with brine, dried (MgSO4), and the solvent removed in vacuo at 600 mm Hg. The residue was purified by flash chromatography (silica, ethyl acetate:pentane 1:19) to give 5.81 g (96percent) of (2) as a colorless oil. 1H NMR, 400 MHz (CDCl3): δ1.27 (3H, t, J=6 Hz), 2.09 (2H, m), 2.82 (2H, m,) 3.15 (2H, m), 4.14 (2H, q, J=6 Hz), 5.58 (1H, s). MS (ES+) m/e: 141 ([MH+], 100percent). IR (film) ν cm-1: 1088, 1189, 1336, 1673, 1716, 2926. |
80% | With ammonium chloride; sodium hexamethyldisilazane In tetrahydrofuran | Step A Ethyl 3,3-trimethylene acrylate A solution of triethylphosphonoacetate (17 mL, 85.6 mmol), in 150 mL dry THF was cooled to -78° C. A solution of sodium hexamethyldisilazide (86 mL, 1.0M in THF, 86 mmol) was added. The mixture was warmed to 0 C for 30 min and cyclobutanone (5 grams, 71.3 mmol) was added. The mixture was warmed to room temperature and stirred overnight. Sat'd ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic was dried over sodium sulfate and concentrated. Flash chromatography (30/1 hexane/ether) afforded 8.0 grams (80percent) of the desired compound. 1H NMR (300 MHz, CDCl3). δ1.25 (t, 3H), 2.0-2.2 (p, 2H), 2.8-2.9 (t, 2H), 3.1-3.2 (t, 2H), 4.1-4.2 (q, 2H), 5.58 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: at 20℃; for 22 h; |
Reference Example 1-1 t-Butyl 4-(2-ethoxy-2-oxoethylidene)-1-piperidine carboxylate To a solution of ethyl diethylphosphoryl acetate (28.3g) in tetrahydrofuran (200 ml) was added 60percent sodium hydride (4.82g) under ice cooling and the mixture was stirred for 30 minutes, and then a solution of N-butoyxcarbonyl-4-piperidone (20g) in tetrahydrofuran (200 ml) was added dropwise thereto. The mixture was stirred for 22 hours at room temperature. After the completion of the reaction, water (200 ml) was added and extraction was carried out with ethyl acetate. After the extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, the concentrated residue obtained was then purified using silica gel column chromatography and eluted with hexane/ethyl acetate (6/1) to obtain the title compound (27.3 g, 100percent) as a colorless powder. 1H NMR (CDCl3) δ 1.28 (3H, t, J=7.4Hz), 1.47 (9H, s), 2.24-2.33 (2H, m), 2.90-2.98 (2H, m), 3.43-3.55 (4H, m), 4.16 (2H, q, J=7.4Hz), 5.70-5.73 (1H, m). |
97% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1 h; Inert atmosphere Stage #2: at 20℃; for 18 h; |
the NaH(60percentin οil, 500mg, 12.5mml) added to 10 mL of tetrahydrofuran, under argon protection the reaction was cool inan ice bath then added Triethylphosphonoacetate(2.2ml,12.5mmol), ice bath was removed and the reaction was carriedout at room temperature for 1 hour. The reaction mixture was cooled again to 0° C in an ice bath and N-Boc-piperidone (997 mg, 5 mmol) was dissolved in 1 mLof tetrahydrofuran and then slowly added dropwise into the reaction system, Theice bath was removed and the reaction was carried out at room temperature for18 hours until the reaction was complete. addition of saturated NH4Clsolution to quench the reaction and extracted three times with ethyl acetate.combined organic phases then it was washed sequentially with saturated NaHCO3solution, saturated NaCl solution and dried over anhydrous Na2SO4.After concentration, carried out columnchromatography separation to obtain 1.3g of a white solid,yield 97percent. |
89% | Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 5 - 10℃; for 2 h; Stage #2: at 5 - 20℃; for 2 h; |
Potassium tert-butoxide (720 mmol) was added to THF (600 mL), A solution of triethyl phosphonoacetate (600 mmol) in THF (120 mL) was added dropwise at 5 to 10°C. After stirring, add 2h A solution of starting material 1 (540 mmol) in THF (100 mL) was added dropwise at 5 to 10°C. After the addition, Room temperature reaction 2h, Stop the reaction, The reaction was quenched by the dropwise addition of water (100 mL). The reaction solution was extracted with ethyl acetate (200 mL×3). Combine the ethyl acetate layers, Followed by water (100mL×2), Saturated brine (100mL × 2) wash, Drying with anhydrous sodium sulfate, filter, Concentrated 130 g of white solid (Intermediate 2), Yield 89percent |
81% | Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 1 h; Stage #2: at 20℃; |
To a solution of t-BuOK (11.52 g, 120 mmol) in dry THF (200 mL) was added ethyl 2- (diethoxyphosphoryl) acetate (23.6 g, 105 mmol) at 0. After stirring for 1h at 0, tert-butyl 4-oxopiperidine-1-carboxylate (20 g, 100 mmol) in 50 mL of dry THF was added dropwise to the mixture, and the resulting solution was stirred at rt for 2h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) , extracted with EtOAc (200 mL × 3) . The organic layer was collected, washed with saturated aqueous solution of Na2CO3 (50 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (silica gel: 300-400 mesh, PE/EtOAc 20/1) to afford tert-butyl 4- (2-ethoxy-2-oxoethylidene) piperidine-1-carboxylate (22 g, 81) . LRMS m/z (M-100) 170.1 found, 170.1 required. |
78% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h; Stage #2: at 0 - 20℃; for 2 h; Stage #3: With water In tetrahydrofuran; mineral oil |
Stage (i): tert-Butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate A solution of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.25 mmol, 1 eq) in THF (50 ml) was slowly added dropwise to an ice-cold (0° C.) suspension of NaH (1.56 g, 65.32 mmol, 1.3 eq) in THF (50 ml), and stirring was carried out for 30 min. Triethyl phosphonoacetate (12.96 ml, 65.32 mmol, 1.3 eq), dissolved in THF (50 ml), was added and stirring was carried out for 2 h at RT. The reaction mixture was hydrolyzed with water (5 ml) and concentrated. The residue was taken up in water (150 ml) and extracted with ethyl acetate (2*300 ml). The combined organic phases were washed with sat. NaCl solution (200 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 3percent ethyl acetate in hexane), the desired product was obtained in the form of a white solid. Yield: 78percent (10.5 g, 39.03 mmol). |
73% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1 h; Stage #2: at 0℃; for 12 h; |
At 0 deg. C, ethyl 2- (diethoxyphosphoryl)acetate (6.18 g, 27.6 mmol) in anhydrous THF (100mL) solution was added slowly portionwise NaH (1.2 g, 30.1 mmol, 60percent), and the mixture was stirred at 0 deg.C for 1 hour. And then tert-butyl-4-oxo-piperidine-1-carboxylate (5 g, 25.1 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at 0 deg.C for 12 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed the reaction was complete. To the reaction mixture was added water (50mL) to quench the reaction, and extracted with EtOAc (100mL), the organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness to give the title compound (4.95 g, yield 73percent) as a white solid. |
62% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; | Step 1 . tert-Butyl 4-(2-ethoxy-2-oxoethylidene)piperidine- l -carboxylate. A mixture of tert-buty I 4-oxopiperidine- l -carboxylate (300 g, 1 .51 mol, 1 .00 equiv), ethyl 2-(diethoxyphosphoryl)acetate (405 g, 1 .8 1 mol, 1 .20 equiv) and potassium carbonate (31 4 g, 2.26 mol, 1 .50 equiv) in DMF (4.5 L) was stirred overnight at 80°C. The reaction was cooled to rt and then quenched by the addition of 5 L of water/ice. The precipitate was col lected by fi ltration and air-dried to give 252 g (62percent) of tert- butyl 4-(2-ethoxy-2-oxoethylidene)piperidine- l -carboxylate as a wh ite solid. TLC: ethyl acetate/petroleum ether = 1 2. t- = 0.6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 5℃; for 1 h; Stage #2: at 0 - 20℃; for 2 h; Stage #3: With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 24 h; |
General procedure: A solution of triethyl phosphonoacetate (52.0g, 232.0mmol) in THF (200mL) was added dropwise while stirring to a solution of potassium tert-butanolate (43.4g, 386.6mmol) in THF (400mL) at 0–5°C and continuously stirred for 1h. Then a suspension of N-(4-oxocyclohexy)acetamide (30.0g, 193.3mmol) in THF (150mL) was added dropwise to the solution at 0–5°C. The resulting solution was stirred for another 2hat room temperature and subsequently quenched with water (100mL). The resultant mixture was extracted with acetic ether (2×20mL) after separation. Palladium 10percent on carbon (1.5g) was then added to the organic layer and hydrogenation was conducted at ambient temperature and pressure conditions. The resulting solution was stirred for 24h and then filtered. The filtrate evaporated in vacuo to give a colorless oil. The residue was partitioned between water (100mL) and dichloromethane (2×100mL), and the combined extracts were dried (MgSO4) and evaporated in vacuo to afford 1 (40.7g, 92.6percent) as a colorless semi-solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.6% | With sodium t-butanolate In water; toluene at 100℃; for 4 h; | Add (115.2 g, 1.2 mol) sodium tert-butoxide, (269.0, 1.2 mol) triethyl phosphonoacetate and 150 g tolueneInto a 2L three-necked flask, warmed to 100°C, and added (S)-2-(3,4-difluorophenyl) ethylene oxide toluene solution dropwise to control the temperatureAfter reacting at 100°C for 4 hours, the temperature is lowered, 500 g water is added, and the mixture is dried and dried over anhydrous sodium sulfate. The concentration is 203.9 g (1R, 2R)-Ethyl 2-(3,4-difluorophenyl)cyclopropanecarboxylate, yield 90.6percent, ee value 99.2percent, purity 99.2percent. |
81% | With sodium t-butanolate In toluene at 60 - 80℃; for 11 h; | Example 2; Preparation of ethyl (Ii?, 2i?)-2-(3,4-difluorophenyl)- 1-cyclopropanecarboxylate; Sodium t-butoxide (32.22 g, 1.25 molar equivalents) and toluene (243.0 g) were charged into a reaction vessel. Triethyl phosphonoacetate (78.06 g, 1.04 molar equivalents to sodium t-butoxide) was added to the mixture with stirring. A toluene solution of (25)-2- (3,4-difluorophenyl) oxirane (32.8 wt percent solution, net 41.83 g, 267.9 mmol) was added drop-wise to the mixture keeping the internal temperature between 60 to 80 0C. After completion of addition, stirring was continued for 11 hours at 8O0C. After cooling to room temperature, the mixture was washed with water, and the organic layer was concentrated under reduced pressure. Ethyl (Ii?, 2i?)-2-(3,4-difluorophenyl)- 1-cyclopropanecarboxylate was obtained as resultant concentrate (net 49.11 g, yield: 81percent). 1H-NMR in (400MHz, CDC13) δ 1.22 - 1.26(1H, m), 1.26 - 1.3O(3H, t, J=7.1Hz), 1.57 - 1.62(1H, m), 1.82 - 1.87(1H, m), 2.45 - 2.5O(1H, m), 4.14 - 4.20(2H, q, J=7.1Hz), 6.82 - 6.91(2H, m), 7.02 - 7.09(1H, m) |
0.83 g | With sodium t-butanolate In toluene at 60 - 80℃; for 11 h; | Sodium t-butoxide (0.38 g, 4.0 mmol, 1.25 eq) and toluene (3 mL) were charged into a reaction vessel. Triethyl phosphonoacetate (0.93 g, 1.04 eq to sodium t-butoxide) was added to the mixture with stirring. A solution of 24 (0.50 g, 3.2 mmol, 1 eq) in toluene was added dropwise to the mixture with keeping the internal temperature between 60~80 °C. After completion of the addition, stirring was continued for 11 h at 80 °C. After cooling to room temperature, the mixture was washed with water, and the organic layer was concentrated under reduced pressure to give the title product as a yellow oil (0.83 g). 1H NMR (300 MHz, CDCl3) δ 1.21~1.23 (m, 1 H), 1.23~1.30 (t, 3 H), 1.49~1.62 (m, 1 H), 1.81~1.87 (m, 1 H), 2.44~2.50 (m, 1 H), 4.13~4.21 (q, 2 H), 6.81~7.26 (m, 3 H). |
A837323[ 61203-67-6 ]
Ethyl 2-(diethoxyphosphoryl)acetate-1-13C
Reason: Stable Isotope
A502838[ 100940-60-1 ]
Ethyl 2-(diethoxyphosphoryl)acetate-13C2
Reason: Stable Isotope
A609705[ 82426-28-6 ]
Ethyl 2-(diethoxyphosphoryl)acetate-2-13C
Reason: Stable Isotope