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Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
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Structure of 867-13-0 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Archiv der Pharmazie, 1984, vol. 317, # 12, p. 1010 - 1017
3
[ 867-13-0 ]
[ 400-53-3 ]
[ 372-31-6 ]
Reference：
[1] Journal of the Chinese Chemical Society, 2007, vol. 54, # 3, p. 749 - 757
[2] Phosphorus, Sulfur and Silicon and Related Elements, 1997, vol. 126, p. 1 - 10
4
[ 867-13-0 ]
[ 3095-95-2 ]
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).
Reference：
[1] Patent: KR2018/71069, 2018, A, . Location in patent: Paragraph 0090; 0091; 0093; 0156-0158
[2] Synthesis, 1981, # 4, p. 283 - 285
[3] Journal of Medicinal Chemistry, 1995, vol. 38, # 15, p. 2906 - 2921
[4] Organic Letters, 2010, vol. 12, # 7, p. 1460 - 1463
[5] Organic Letters, 2015, vol. 17, # 4, p. 816 - 819
[6] Journal of Fluorine Chemistry, 2005, vol. 126, # 11-12, p. 1467 - 1475
[7] Journal of Medicinal Chemistry, 1994, vol. 37, # 14, p. 2216 - 2223
[8] Australian Journal of Chemistry, 1987, vol. 40, # 9, p. 1511 - 1518
[9] Organic and Biomolecular Chemistry, 2011, vol. 9, # 8, p. 2702 - 2714
[10] Journal of Organic Chemistry, 2001, vol. 66, # 15, p. 5217 - 5231
[11] J. Gen. Chem. USSR (Engl. Transl.), 1971, vol. 41, p. 1432 - 1439[12] Zhurnal Obshchei Khimii, 1971, vol. 41, p. 1426 - 1434
[13] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1978, p. 1130 - 1134
[14] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1979, p. 308 - 313
[15] Chemistry Letters, 1988, p. 211 - 214
[16] Phosphorus and Sulfur and the Related Elements, 1983, vol. 14, p. 285 - 294
[17] Monatshefte fur Chemie, 1997, vol. 128, # 10, p. 995 - 1008
[18] Organic Letters, 2004, vol. 6, # 20, p. 3477 - 3480
[19] Journal of Organic Chemistry, 2013, vol. 78, # 11, p. 5401 - 5409
[20] Research on Chemical Intermediates, 2013, vol. 39, # 7, p. 3105 - 3110
[21] Patent: KR101653677, 2016, B1, . Location in patent: Paragraph 0090-0093
5
[ 867-13-0 ]
[ 3095-95-2 ]
Reference：
[1] Patent: EP1336611, 2003, A1,
6
[ 867-13-0 ]
[ 3095-95-2 ]
[ 4408-78-0 ]
[ 35752-46-6 ]
Reference：
[1] Phosphorus and Sulfur and the Related Elements, 1983, vol. 14, p. 285 - 294
7
[ 4746-97-8 ]
[ 867-13-0 ]
[ 51656-91-8 ]
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.
Reference：
[1] Tetrahedron, 1994, vol. 50, # 4, p. 1093 - 1104
[2] Organic Letters, 2005, vol. 7, # 19, p. 4185 - 4188
[3] Patent: WO2015/94803, 2015, A1, . Location in patent: Paragraph 340
[4] Patent: WO2015/148868, 2015, A1, . Location in patent: Paragraph 0342
[5] Patent: WO2016/8582, 2016, A1, . Location in patent: Page/Page column 125
[6] Patent: CN105367555, 2016, A, . Location in patent: Paragraph 0488; 0489; 0490
[7] Patent: WO2016/190847, 2016, A1, . Location in patent: Paragraph 0350; 0374
[8] Patent: WO2017/21920, 2017, A1, . Location in patent: Paragraph 1102; 1103
[9] Patent: CN104974163, 2017, B, . Location in patent: Paragraph 0551; 0552; 0553; 0644; 0645; 0646
[10] Patent: CN104672250, 2017, B, . Location in patent: Paragraph 0520; 0521; 0522
[11] Synthesis (Germany), 2012, vol. 44, # 23, p. 3623 - 3632
[12] Tetrahedron Asymmetry, 2008, vol. 19, # 2, p. 176 - 185
[13] Patent: WO2016/73774, 2016, A2, . Location in patent: Paragraph 0341
[14] Patent: WO2016/73770, 2016, A1, . Location in patent: Paragraph 0334
[15] Patent: WO2016/73738, 2016, A2, . Location in patent: Paragraph 0567
[16] Patent: WO2017/192840, 2017, A1, . Location in patent: Paragraph 00187
[17] Patent: WO2018/39512, 2018, A1, . Location in patent: Paragraph 00175; 00188
[18] Tetrahedron, 1999, vol. 55, # 36, p. 11095 - 11108
[19] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 23, p. 6309 - 6323
[20] Patent: US2010/249095, 2010, A1, . Location in patent: Page/Page column 128-129
[21] Patent: WO2005/10008, 2005, A1, . Location in patent: Page/Page column 104-105
[22] Patent: WO2006/44524, 2006, A1, . Location in patent: Page/Page column 45
[23] Patent: CN105566324, 2016, A, . Location in patent: Paragraph 0303; 0304; 0305; 0306
[24] Patent: US2008/153843, 2008, A1, . Location in patent: Page/Page column 47-48
[25] Patent: WO2017/181177, 2017, A1, . Location in patent: Paragraph 0568-0571
[26] Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8967 - 9004
[27] Patent: WO2014/131855, 2014, A1, . Location in patent: Page/Page column 65; 66
[28] Tetrahedron Letters, 1992, vol. 33, # 32, p. 4581 - 4584
[29] Journal of the Chemical Society, Chemical Communications, 1988, # 6, p. 425 - 426
[30] Patent: US2010/222324, 2010, A1, . Location in patent: Page/Page column 58
[31] Patent: WO2010/103429, 2010, A1, . Location in patent: Page/Page column 33
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[34] Patent: WO2011/146371, 2011, A1, . Location in patent: Page/Page column 24-25
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8
[ 867-13-0 ]
[ 637-88-7 ]
[ 51656-91-8 ]
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+).
Reference：
[1] Chemische Berichte, 1924, vol. 57, p. 1030[2] Chemische Berichte, 1926, vol. 59, p. 1120
[3] Roczniki Chemii, 1963, vol. 37, p. 949 - 954
11
[ 867-13-0 ]
[ 5464-68-6 ]
Reference：
[1] Chemische Berichte, 1924, vol. 57, p. 1030[2] Chemische Berichte, 1926, vol. 59, p. 1120
12
[ 67-56-1 ]
[ 867-13-0 ]
[ 1067-74-9 ]
Reference：
[1] Synlett, 2007, # 3, p. 491 - 493
[2] Synlett, 2010, # 14, p. 2141 - 2145
13
[ 867-13-0 ]
[ 2356-16-3 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 15, p. 4730 - 4737
[2] Journal of Fluorine Chemistry, 2005, vol. 126, # 11-12, p. 1467 - 1475
[3] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 8, p. 1051 - 1056
14
[ 867-13-0 ]
[ 17843-01-5 ]
[ 2356-16-3 ]
Reference：
[1] Journal of Fluorine Chemistry, 1998, vol. 92, # 1, p. 45 - 52
15
[ 867-13-0 ]
[ 1191-95-3 ]
[ 27741-65-7 ]
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).
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 3, p. 1057 - 1074
[2] Journal of the Chemical Society. Perkin Transactions 2, 1999, # 5, p. 937 - 945
[3] Tetrahedron Letters, 2015, vol. 56, # 45, p. 6287 - 6289
[4] Patent: WO2016/37534, 2016, A1, . Location in patent: Page/Page column 19
[5] Patent: US2017/27172, 2017, A1, . Location in patent: Paragraph 0203
[6] Patent: WO2015/25197, 2015, A1, . Location in patent: Paragraph 000149
[7] Journal of Medicinal Chemistry, 2005, vol. 48, # 15, p. 5025 - 5037
[8] Patent: US6635673, 2003, B1,
[9] Patent: US6248755, 2001, B1,
[10] European Journal of Organic Chemistry, 2017, vol. 2017, # 31, p. 4530 - 4542
[11] Molecules, 2018, vol. 23, # 11,
Reference：
[1] Chemical Communications, 2015, vol. 51, # 2, p. 342 - 345
19
[ 867-13-0 ]
[ 7396-44-3 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 11, p. 5401 - 5409
20
[ 867-13-0 ]
[ 2426-87-1 ]
[ 38157-08-3 ]
Reference：
[1] Synthetic Communications, 2001, vol. 31, # 15, p. 2357 - 2364
[2] Patent: EP1577290, 2005, A1, . Location in patent: Page/Page column 93-94
[3] Patent: EP1640360, 2006, A1, . Location in patent: Page/Page column 66
[4] European Journal of Medicinal Chemistry, 2019, vol. 161, p. 78 - 92
[5] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 21, p. 5672 - 5681
21
[ 867-13-0 ]
[ 4660-80-4 ]
[ 3999-55-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 24, p. 4567 - 4574
22
[ 867-13-0 ]
[ 79099-07-3 ]
[ 135716-08-4 ]
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
Reference：
[1] Heterocycles, 2001, vol. 54, # 2, p. 747 - 755
[2] Patent: EP1498125, 2005, A1, . Location in patent: Page/Page column 84-85
[3] Patent: WO2018/152329, 2018, A1, . Location in patent: Page/Page column 48
[4] Patent: CN102952072, 2016, B, . Location in patent: Paragraph 0109
[5] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 707 - 710
[6] Patent: CN107793408, 2018, A, . Location in patent: Paragraph 0168; 0171
[7] Patent: WO2018/68297, 2018, A1, . Location in patent: Page/Page column 135
[8] Journal of Organic Chemistry, 2016, vol. 81, # 3, p. 1057 - 1074
[9] Patent: US2012/71461, 2012, A1, . Location in patent: Page/Page column 123; 131
[10] Russian Journal of Organic Chemistry, 2014, vol. 50, # 7, p. 953 - 959[11] Zh. Org. Khim., 2014, vol. 50, # 7, p. 973 - 978,6
[12] Patent: CN105330698, 2016, A, . Location in patent: Paragraph 0220; 0221; 0222; 0223
[13] Patent: WO2013/127269, 2013, A1, . Location in patent: Page/Page column 189
[14] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 13, p. 2167 - 2172
[15] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 167 - 170
[16] Patent: WO2005/33108, 2005, A1, . Location in patent: Page/Page column 48
[17] Patent: US2003/191316, 2003, A1, . Location in patent: Page/Page column 32
[18] Organic Letters, 2011, vol. 13, # 7, p. 1698 - 1701
[19] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1880 - 1886
[20] Patent: EP2444402, 2012, A1, . Location in patent: Page/Page column 47
[21] Chemistry Letters, 2012, vol. 41, # 12, p. 1703 - 1705
[22] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8597 - 8601[23] Angew. Chem., 2013, vol. 125, # 33, p. 8759 - 8763,5
[24] Patent: WO2014/15495, 2014, A1, . Location in patent: Page/Page column 37; 38
[25] Patent: WO2014/18764, 2014, A1, . Location in patent: Page/Page column 40
[26] Russian Journal of Organic Chemistry, 2014, vol. 50, # 1, p. 54 - 58[27] Zh. Org. Khim., 2014, vol. 50, # 1, p. 61 - 65,5
[28] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 23, p. 5502 - 5506
[29] Patent: WO2015/17305, 2015, A1, . Location in patent: Page/Page column 61; 62
[30] Patent: WO2016/65582, 2016, A1, . Location in patent: Page/Page column 44-45
[31] Patent: WO2016/122994, 2016, A1, . Location in patent: Page/Page column 43
[32] Patent: WO2016/60941, 2016, A1, . Location in patent: Page/Page column 51
[33] Angewandte Chemie - International Edition, 2017, vol. 56, # 33, p. 9868 - 9871[34] Angew. Chem., 2017, vol. 129, p. 10000 - 10003,4
[35] Patent: CN107540659, 2018, A, . Location in patent: Paragraph 0190
Reference：
[1] Russian Journal of Organic Chemistry, 2014, vol. 50, # 1, p. 54 - 58[2] Zh. Org. Khim., 2014, vol. 50, # 1, p. 61 - 65,5
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 6, p. 641 - 644
[4] European Journal of Organic Chemistry, 2014, vol. 2014, # 33, p. 7413 - 7425
25
[ 867-13-0 ]
[ 79099-07-3 ]
[ 135716-09-5 ]
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.
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 332 - 353
[2] European Journal of Organic Chemistry, 2014, vol. 2014, # 33, p. 7413 - 7425
[3] Patent: US2004/2504, 2004, A1, . Location in patent: Page/Page column 30-31
26
[ 872-85-5 ]
[ 867-13-0 ]
[ 24489-96-1 ]
Reference：
[1] Bioorganic & Medicinal Chemistry, 2000, vol. 8, # 6, p. 1423 - 1432
[2] Chemical Communications, 2014, vol. 50, # 98, p. 15631 - 15633
27
[ 6704-31-0 ]
[ 867-13-0 ]
[ 922500-91-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2017, vol. 2017, # 31, p. 4530 - 4542
28
[ 867-13-0 ]
[ 54450-20-3 ]
[ 200204-85-9 ]
Reference：
[1] Patent: US6127388, 2000, A,
29
[ 867-13-0 ]
[ 1006376-63-1 ]
[ 1006376-61-9 ]
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).
Reference：
[1] Patent: CN107686447, 2018, A, . Location in patent: Paragraph 0024; 0029; 0030; 0034
[2] Patent: WO2008/18823, 2008, A1, . Location in patent: Page/Page column 30
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602
30
[ 867-13-0 ]
[ 1006376-60-8 ]
[ 1006376-61-9 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 10, p. 1595 - 1601
[2] Patent: CN104974017, 2017, B, . Location in patent: Paragraph 0115-0118
[3] Patent: CN107892693, 2018, A, . Location in patent: Paragraph 0035; 0040; 0044; 0084; 0125
EXAMPLE 1 Preparation of N-acetyl-4-piperidineacetaldehyde A 55 percent dispersion of sodium hydride in mineral oil containing 3.24 g. of a 55percent dispersion of sodium hydride in mineral oil was washed with three 50 ml portions of dry pentane and then the sodium hydride was suspended in 100 ml of anhydrous 1,2-dimethoxyethane (to be referred to hereinafter as DME). 16.58 g. of triethylphosphonoacetate in 50 ml of anhydrous DME were added to the sodium hydride suspension under a nitrogen atmosphere slowly with stirring and cooling to about 0° C. After the addition had been completed, the ice bath was removed and the mixture stirred for an additional hour at ambient temperature. The ice bath was then replaced and a solution of 10 g. of N-benzoyl-4-piperidone in 25 ml of anhydrous DME was added in dropwise fashion with stirring. After this addition had been completed, the ice bath was again removed and stirring continued for about three hours. Excess solvents were removed in vacuo from the reaction mixture. About 100 ml of an ice-water mixture were added. The resulting aqueous mixture was extracted with three 100 ml portions of ether, and the ether extracts separated, combined and dried. Removal of the ether therefrom in vacuo yielded a residue comprising N-benzoyl-4-(carbethoxymethylene) piperidine formed in the above reaction. Recrystallization of the residue from hexane yielded about 11.7 g. of colorless prisms of N-benzoyl-4-(carbethoxymethylene) piperidine melting at about 102°-103° C. N-benzoyl-4-(carbethoxymethylene) piperidine thus prepared had the following physical characteristics. Boiling point = 178°-180° C. at 0.03 mm Hg. nmr (CDCL3): delta1.28 (5, 3), 2.38 (broad m, 2), 3.05 (broad m, 2), 3.67 (broad m, 4), 4.18 (q, 2), 5.78 (broad s, 1), 7.41 (s,5). ir (KBr): 1715, 1660, 1620 cm-1. Anal: Calcd. for C16 H19 NO3: C, 70.31; H, 7.01; N, 5.13. Found: C, 70.42; H, 7.10; N, 5.07.
Reference Example 16 To a mixture of 60% sodium hydride and THF were added dropwise ethyl diethylphosphonoacetate and further <strong>[197638-83-8]4-[4-(t-butoxycarbonyl)piperazin-1-yl]benzaldehyde</strong> under cooling to 0C, followed by stirring.. Then, post-treatment and purification were carried out in a usual way to obtain ethyl 3-{4-[4-(t-butoxycarbonyl)piperazin-1-yl]phenyl}acrylate.. Further, catalytic reduction was carried out using palladium/carbon to obtain an objective compound.
ethyl (2E)-3-(1,5-dimethyl-1H-pyrazol-4-yl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20℃; for 1h;
A mixture of 1, 5-DIMETHYL-LH-PYRAZOLE-4-CARBALDEHYDE (400 mg), sodium hydride (60% in oil, 155 mg), ethyl diethylphosphonoacetate (795 mg) and N, N-dimethylformamide (5 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave ethyl (2E)-3- (1, 5-DIMETHYL-LH-PYRAZOL-4-YL) acrylate (304 mg, 49%) as colorless prism crystals. melting point: 82-83C.
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 0-5C 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 0-5C. 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 10% 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, 92.6%) as a colorless semi-solid.
With triethylamine; lithium chloride; In acetonitrile; for 7h;
To compound 1.2 (-19 g, -111 mmol) in CH3CN (300 mL) was added (diethoxy-phosphoryl)-acetic acid ethyl ester (28.3 g, 122 mmol), LiCl (9.24 g, 220 mmol), and Et3N (18.2 mL, 130 mmol). After 7 hours, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3X); the combined organic layer was extracted with H2O, dried over Na2SO4, and concentrated in vacuo to provide a brown solid. The resulting solid was suspended in toluene and then filtered to give compound 1.3 (15.6 g, 62% from compound 1.1).
PREPARATION 9 A mixture of 4-formyl-1-methylimidazole (3.0 g) and triethylphosphonoacetate (6.3 g) in N,N-dimethylformamide (30 ml) was stirred under ice-cooling. After several minutes, sodium hydride (1.63 g, 60% in mineral oil) was added to the mixture, which was stirred for 30 minutes at the same temperature. The resulting mixture was poured into ice-water, neutralized with aqueous ammonium acetate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give ethyl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate (4.63 g). IR (Nujol): 2900, 1700, 1625 cm-1 NMR (CDCl3, delta): 1.31 (3H, t, J=7.1Hz), 3.70 (3H, s), 4.23 (2H, q, J=7.1Hz), 6.53 (1H, d, J=15.6Hz), 7.07 (1H, s), 7.45 (1H, s), 7.54 (1H, d, J=15.6Hz) MASS: 181 (M+H)+
Step A (E)-{3-[3-(4'-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic Acid Ethyl Ester (E)-3-(4'-Bromo-biphenyl-4-yl)-but-2-enoic acid ethyl ester was prepared from 4-(4-bromophenyl)acetophenone (12.0 g, 0.044 mol), sodium (1.25 g, 0.052 mol) and triethyl phosphonoacetate (11.73 g, 0.052 mol) by a procedure analogous to that described in example 11 step A, yielding 11.97 g (80%). 1H NMR (300 MHz, CDCl3) delta: 1.32 (3H, t), 2.61 (3H, d), 4.23 (2H, q), 6.19 (1H, d), 7.40-7.58 (8H, m).
11.97 g (80%)
With sodium;
a) (E)-3-(4'-Bromo-biphenyl-4-yl)-but-2-enoic acid ethyl ester was prepared from 4-(4-bromophenyl)acetophenone (12.0 g, 0.044 mol), sodium (1.25 g, 0.052 mol) and triethyl phosphonoacetate (11.73 g, 0.052 mol) by a procedure analogous to that described in example 1a yielding 11.97 g (80%). 1H NMR (300 MHz, CDCl3) delta: 1.32 (3H, t), 2.61 (3H, d), 4.23 (2H, q), 6.19 (1H, d), 7.40-7.58 (8H, m).
b) Preparation of Ethyl 3-(4-fluorophenyl)hexenoate A solution of butyllithium, 2.5M in hexanes (166 ml, 0.416 mol, Aldrich) was added dropwise over 0.5 hr, with rapid mechanical stirring, to a solution of triethyl phosphonoacetate (93.2 g, 0.416 mol, Aldrich) in tetrahydrofuran (700 ml, anhydrous,Aldrich) at <5 C. while blanketed with a nitrogen atmosphere. This solution was stirred for an additional 0.25 hr and cooled to -5 C. with a methanol:ice bath and a solution of <strong>[582-83-2]4'-fluorobutyrophenone</strong> (69 g, 0.416 mol, Aldrich) in tetrahydrofuran (150 ml) was then added in one portion. Stirring was continued for 18 hr without additional cooling. The solution was concentrated to a dark camel sludge by spin evaporation in vacuo and diluted to 600 ml with deionized water. The aqueous solution was extracted with dichloromethane (5*500 ml) and the dichloromethane was concentrated by spin evaporation in vacuo. Distillation at reduced pressure gave 58.5 g (60%) of ethyl 3-(4-fluorophenyl) hexenoate as a mixture of (E) and (Z) isomers (ratio 1:1) as clear liquid, b.p. 140-150 C. at aspirator pressure;
With sodium hydroxide; In tetrahydrofuran; ethyl acetate;
a) Preparation of 4-(ethoxycarbonylmethylidene)piperidine To a suspension of sodium hydride (2.6 g) in 30 ml of tetrahydrofuran, cooled to 0 C. and kept under nitrogen atmosphere, 13 ml of triethylphosphonoacetate, dissolved in 10 ml of tetahydrofuran, are added dropwise. The temperature is then brought to room temperature and the stirring is continued for 30 minutes. The mixture is again cooled to 0 C. and it is added dropwise with a solution obtained by adding portionwise to a solution of <strong>[40064-34-4]4-piperidone monohydrate hydrochloride</strong> (10 g) in THF 2.6 g of sodium hydride filtered to eliminate the sodium chloride which formed. At the end of the addition, the temperature is brought to room temperature and the stirring is continued for 20 hours. The solvent is then evaporated under reduced pressure and the residue is redissolved in ethyl acetate and washed with 1 N hydrochloric acid. The aqueous phase is extracted with ethyl acetate and chloroform, then it is basified to pH=9-10 by adding 20% sodium hydroxide and it is extracted with chloroform. The aqueous phase is then salted and extracted again with chloroform three times. The pooled extracts are dried over sodium sulfate and evaporated to give 7.1 g of the product as a yellow oil.
With potassium hexamethylsilazane; In tetrahydrofuran; dichloromethane; ethyl acetate; toluene;
Step 3 5-Bromobenzofuran-3-ylacetic acid ethyl ester To a solution of triethyl phosphonoacetate (6 ml, 30.2 mmol) in dry tetrahydrofuran (200 ml) at -78 C. was added a solution of potassium bis(trimethylsilyl)amide in toluene (58 ml of a 0.5M solution). After stirring for 2 hours at -78 C., <strong>[54450-20-3]5-bromobenzofuran-3-one</strong> (5.5 g, 26 mmol) was added dropwise. The resulting solution was stirred 1 hour at -78 C. and overnight at room temperature. Saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was separated and evaporated to dryness to give the crude title compound which was purified by column chromatography on silica using dichloromethane, followed by column chromatography on alumina using dichloromethane. 5-Bromobenzofuran-3-ylacetic acid ethyl ester was obtained as a low melting solid (4.2 g, 57%). mp 38-40 C. 1 H NMR (250 MHz, CDCl3) delta 1.28 (3H, t, J=7 Hz), 3.65 (2H, d, J=1 Hz), 4.20 (2H, q, J=7 Hz), 7.36 (1H, s), 7.38 (1H, d, J=2 Hz), 7.63 (1H, s), 7.71 (1H, d, J=2 Hz).
b) Preparation of Ethyl 3-(4-fluorophenyl)hexenoate A solution of butyllithium, 2.5M in hexanes (166 ml, 0.416 mol, Aldrich) was added dropwise over 0.5 hr, with rapid mechanical stirring, to a solution of triethyl phosphonoacetate (93.2 g, 0.416 mol, Aldrich) in tetrahydrofuran (700 ml, anhydrous, Aldrich) at <5 C. while blanketed with a nitrogen atmosphere. This solution was stirred for an additional 0.25 hr and cooled to -5 C. with a methanol:ice bath and a solution of <strong>[582-83-2]4'-fluorobutyrophenone</strong> (69 g, 0.416 mol, Aldrich) in tetrahydrofuran (150 ml) was then added in one portion. Stirring was continued for 18 hr without additional cooling. The solution was concentrated to a dark camel sludge by spin evaporation in vacuo and diluted to 600 ml with deionized water. The aqueous solution was extracted with dichloromethane (5*500 ml) and the dichloromethane was concentrated by spin evaporation in vacuo. Distillation at reduced pressure gave 58.5 g (60%) of ethyl 3-(4-fluorophenyl)hexenoate as a mixture of (E) and (Z) isomers (ratio 1:1) as clear liquid b.p. 140-150 C. at aspirator pressure:
With sodium hydroxide;palladium; In ethanol; water; benzene;
EXAMPLE 27 Preparation of 4-tetrahydropyranylacetic acid To a stirred, cooled suspension of 0.9 g of sodium hydride (60percent oil dispersion) in 5 mL of benzene was added 5.32 g of triethylphosphonoacetate in 3 mL of benzene, keeping the temperature below 30°C. After 1 hour at 25°C, a solution of 2 g of tetrahydro-4H-pyran-4-one in 3 mL of benezene was added slowly. After 1 hour at 25°C, 20 mL of water and 50 mL of ether were added. The organic layer was dried over MgSO4 and concentrated to dryness. Evaporative distillation at 5 mm, oven temperature 130°C, gave 1.8 g of product as a fragrant liquid. Hydrogenation in 20 mL of ethanol with 0.5 g of 10percent palladium on carbon under 1 atmosphere of hydrogen for 10 days gave 1.8 g of saturated product, after filtration and concentration. Saponification using 20 mL of ethanol, 10 mL of 10percent NaOH for 4 hours followed acidification (H2SO4) and ether extraction gave 1.5 g of product. Evaporative distillation at 0.1 mm, oven temperature 160-8°C gave 1.1 g of product as a crystalline solid, mp 61-2°C.
(E)-ethyl 3-(2-isopropyl-4-thiazolyl)propenoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.61 g (81%)
With NaH; In tetrahydrofuran; hexane; ethyl acetate; mineral oil;
35B. (E)-Ethyl 3-(2-Isopropyl-4-thiazolyl)propenoate A slurry of 60% NaH (18 mmol) in mineral oil was washed with hexane, decanted under N2 atmosphere, and diluted with 25 ml of THF. The resulting mixture was cooled to 0 C., treated portionwise with 3.24 ml (16.4 mmol) of triethylphosphonoacetate. After addition, the solution was stirred for 10 minutes, treated with 1.37 g (8.84 mmol) of <strong>[133047-46-8]2-isopropylthiazole-4-carboxaldehyde</strong> in 25 ml of THF, allowed to warm to ambient temperature for 25 minutes, and quenched with 100 ml of saturated aqueous NH4Cl. The mixture was extracted with three 100 ml portions of ethyl acetate, dried over Na2SO4, and concentrated in vacuo. Silica gel chromatography of the residue using 5-10% ethyl acetate in hexane provided 1.61 g (81%) of the desired compound, Rf 0.64 (20% ethyl acetate in hexane). 1H NMR (CDCl3) d 1.33 (t, J=7 Hz, 3H), 1.42 (d, J=7 Hz, 6H), 3.32 (heptet, J=7 Hz, 1H), 4.26 (q, J=7 Hz, 2H), 6.75 (d, J=15 Hz, 1H), 7.29 (s, 1H), 7.57 (d, J=15 Hz, 1H).
A solution of ethyl diethylphosphonoacetate (2.34 g, 10.4 mml) and 60% sodium hydride (0.38 g, 9.50 mmol) in tetrahydrofuran (40 ml) was stirred under ice-cooling for 10 min. <strong>[256417-10-4]2,6-Difluoro-4-methoxybenzaldehyde</strong> (1.5 g, 8.71 mmol) was added, and the mixture was stirred while elevating the temperature to room temperature for 4 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate:hexane=1:10-1:5), and then subjected to catalytic reduction in the same manner as in Reference Example 172 to give the title compound (1.17 g) as a colorless oil. yield 52%. MS 245.0 (MH+).
To a solution of triethyl phosphonoacetate (26.9 g) in tetrahydrofuran (200 ml) was added sodium hydride (60% dispersion in mineral oil, 4.8 G) by portions under ice- cooling. The mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 1-METHYL-LH-PYRAZOLE- 5-carbaldehyde (33.0 g) in tetrahydrofuran (165 ml) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. To the resulting solution was added 10% aqueous potassium hydrogen sulfate solution. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated sodium hydrogen carbonate solution and brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give ethyl (2E)-3-(1-METHYL-LH-PYRAZOL-5-YL)-2-PROPENOATE (33.4 g) as an oil. IR (neat) 2981,2943, 1713,1703, 1180,781 CM~1. H-NMR (DMSO-d6) 8 1. 26 (3H, t, J = 7.1 Hz), 3.88 (3H, s), 4.20 (2H, q, JAZZ 7.1 Hz), 6.54 (1H, d, J = 15.8 Hz), 6.88 (1H, d, J = 1.8 Hz), 7.45 (1H, d, J = 1.8 Hz), 7.60 (1H, d, J = 15.8 Hz). MS (APCI) 181 (M+H+).
Example 9:Synthesis of Intermediate X:A 60percent suspension of sodium hydride in mineral oil (34.4 g, 1.43 mol) was added to dry toluene (3000 ml) under a nitrogen atmosphere, cooled, and stirred at 0- 50C for 15-20 minutes. Triethyl phosphonoacetate (257.1 g, 1.148 mol) was added dropwise at 0-50C and stirred for 2 hr at room temperature. Compound VIII (100.0 g, 0.5740 mol) was added, and the reaction mixture was heated to 90-1000C and stirred under a nitrogen atmosphere for 15-18 hr. The reaction was monitored by HPLC. After completion of the reaction, the mixture was cooled and water was added slowly with striring. The organic layer was separated, washed with brine, and concentrated under vacuum at 50-60° C to leave crude product. Yield: 80-85percent, Purity: 92-95percent.
Example-1; Synthesis of Intermdiate-IIA 60percent suspension of sodium hydride in mineral oil (34.4 g, 1.43 mol) was added to dry toluene (3000 ml) under a nitrogen atmosphere, cooled, and stirred at 0-5° C. for 15-20 minutes. Triethyl phosphonoacetate (257.1 g, 1.148 mol) was added dropwise at 0-5° C. and stirred for 2 hr at room temperature. <strong>[196597-78-1]1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one</strong> (100.0 g, 0.5740 mol) was added, and the reaction mixture was heated to 90-100° C. and stirred under a nitrogen atmosphere for 15-18 hr. The reaction was monitored by HPLC. After completion of the reaction, the mixture was cooled and water was added slowly with stirring. The organic layer was separated, washed with brine, and concentrated under vacuum at 50-60° C. to leave crude product. Yield: 80-85percent, Purity: 92-95percent (By HPLC).
Triethylphosphonoacetate (1.33 [G)] was added to a suspension of sodium hydride (60% suspension in mineral oil-200 mg) in anhydrous THF (7.4 mL) previously cooled to [0C] under a Nitrogen atmosphere. The mixture was allowed to warm to r. t. and stirred at [23C] for 20 minutes. Then, a solution of intermediate 10 (58 mg) in anhydrous THF (7.4 mL) was added and the resulting solution was heated to reflux for 48 hours. The solution was allowed to cool to r. t. , diluted with water and extracted with Et20. The organic layer was washed with water and brine, dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH/AcOEt 9: 1) to give: intermediate [11A] (181 mg) as yellow oil ; intermediate [11 B] (267 mg) as yellow oil. Intermediate 11a : [T. I.] c.: CH/AcOEt 7: 3, Rf=0.64 (detection with ninhydrine). NMR [(D6-DMSO)] : 8 (ppm): 7.2 (m, 4H); 5.67 (s, [1H)] ; 4.13 (q, 2H); 3.76 (t, [1H)] ; 3.97-2. 7 (m, 4H); 1.34 (s, 9H); 1.22 (t, 3H). MS (ES/+): m/z=378 [M+H] +, 400 [M+Na] +. Intermediate [11 B] : T. [I. C.] : CH/AcOEt 7: 3, Rf= 0.53 (detection with ninhydrine). NMR [(DE-DMSO)] : [8] (ppm): 7.2 (m, 4H); 5.83 (d, [1H)] ; 3.87 (q, 2H); 3.96-2. 63 (m, 4H); 3.6 (m, [1H)] ; 1.63-1. 17 (m, 4H); 1.36 (s, 9H); 0.97 (t, 3H). MS (ES/+): m/z=378 [[M+H]] +, 400 [M+Na] +.
To a solution of ethyl 2- (diethoxyphosphoryl) acetate (2.1 g, 1.86 mL, 9.36 mmol, cas RN 867-13-0) in l,4-dioxane (9.73 mL) was added dropwise LiHMDS 1.0 M in hexanes (15 mL, 15 mmol) and the solution was stirred for 15 minutes. A solution of tert-butyl 4-(4- fluorobenzoyl)piperidine- 1 -carboxylate (2.878 g, 9.36 mmol, CAS RN 160296-40-2) in l,4-dioxane (9.73 mL) was added dropwise to the mixture and stirring was continued at reflux over two days. The reaction mixture was poured on saturated aqueous NH4CI solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed once with H20, dried over MgS04, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 40 g column using an MPLC system eluting with a gradient of n-heptane : EtOAc (100 : 0 to 50 : 50) to yield the desired compound as a colorless liquid (1.74 g; 49.4%). MS (ESI): m/z = 278.2 [M-Boc+H]+.
To sodium hydride (1.593 g, 39.8 mmol) was added THF (39 mL) dropwise and the reaction mixture cooled to -10 0C. Triethyl phosphonoacetate (7.90 mL, 39.8 mmol) was added dropwise to give a colourless solution, maintaining the temperature at -10 0C. The reaction mixture was allowed to warm to RT. and the reaction mixture stirred for 30 mins. A solution of <strong>[20357-22-6]4-methyl-2-nitrobenzaldehyde</strong> D140 (2.192 g, 13.27 mmol) in THF (39 mL) was added to give a dark yellow solution and the reaction mixture was heated at reflux for 90 mins. The solution turned a dark red/brown. After this time, the reaction mixture was allowed to cool to RT. TLC showed all s.m. disappeared, product and a baseline impurity (DCM). The reaction mixture was diluted with water (32 mL) and extracted into diethyl ether (3 x 30 mL) and the organic layer dried over MgSO4. The reaction mixture was filtered and evaporated to dryness. The crude product was purified by flash chromatography and was eluted with DCM to give the title compound as a yellow oil. Oil was triturated with iso-hexane to give a pale yellow solid (1.18 g, 37.8%).1H-NMR (CDCI3) delta: 1.31-1.39 (t, 3H), 2.47 (s, 3H), 4.26 (q, 2H), 6.32-6.36 (d, 1 H), 7.25 - 7.26 (d, 1 H), 7.43-7.45 (d, 1 H), 7.83-7.84 (d, 1 H), 8.04-8.09 (d, 1 H).
Production Example 1 Under ice-cooling, sodium hydride (about 40% mineral oil was added, 7.0 g) was added to a THF (120 ml) solution of ethyl diethylphosphonoacetate (38 ml) and stirred under ice-cooling for 30 minutes. A THF (200 ml) solution of <strong>[146137-80-6]2-fluoro-4-methylbenzaldehyde</strong> (20 g) was added dropwise under ice-cooling to the reaction mixture and stirred under ice-cooling for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and then dried with anhydrous magnesium sulfate. The desiccant was removed, the solvent was evaporated under a reduced pressure, and then the residue was purified by a silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl (2E)-3-(2-fluoro-4-methylphenyl)acrylate (30 g) as a colorless oil.
Step 1 To a suspension of NaH (60percent in mineral oil, 3.0 g, 75.7 mmol) in dry tetrahydrofuran (460 mL) was added triethyl phosphonoacetate (16.97 g, 75.7 mmol) at room temperature. After stirring for 1 hour, <strong>[90390-49-1]3-chloro-5-fluorobenzaldehyde</strong> (10.0 g, 63.07 mmol) in tetrahydrofuran (20 mL) was added dropwise. The reaction was stirred for 12 hours, quenched with water (30 mL) and concentrated. The crude residue was then taken up in ethyl acetate, washed with water, and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6 g (96percent) of ethyl (2E)-3-(3-chloro-5-fluorophenyl)acrylate as a white solid. HRMS: calculated for C11H10ClFO2, 228.0353; found (EI, [M+], 228.0340.
Based on a procedure by Z-C Duan, X-P Hu, C Zhang and Z Zheng in Org Chem (2010) 75(23), 8319 - 8321. Neat ethyl 2-(diethoxyphosphoryl)acetate ( 10.98 g, 49 mmol) was added dropwise under nitrogen to an ice-cold, stirred suspension of 60percent sodium hydride in mineral oil ( 1.96 g, 49 mmol) in dry tetrahydrofuran (80 mL), taking care to maintain the temperature below 3 °C. The reactants were stirred for 30 minutes before addition of l-(4-(trifluoromethoxy)phenyl)ethanone (8.0 g, 39.2 mmol). The reaction mixture was allowed to warm slowly to ambient temperature under nitrogen to give a thick, yellow gum. Saturated aqueous ammonium chloride (80 mL) was added dropwise under rapid stirring . This mixture was extracted with ethyl ether (2 x 170 mL) . The combined organic extracts was washed with water (400 mL) and brine (200 ml_), dried over magnesium sulfate, and purified by silica gel chromatography, eluting with a gradient of ethyl acetate in hexane. Two closely eluting fractions were obtained. The desired product was obtained from the faster eluting fraction as a colorless liquid (9.0 g, 84percent) after drying in vacuo at 42 °C for 14 hours : 'H NM R (400 MHz, CDCb) delta 7.50 (dt, J = 8.9, 2.1 Hz, 2H), 7.21 (dd, J = 8.9, 0.9 Hz, 2H), 6.11 (d, J = 1.3 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.56 (d, J = 1.3 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H) ; 13C NMR ( 101 MHz, CDCb) delta 166.58, 153.79, 149.63, 149.61, 140.82, 127.82, 124.26, 121.70, 120.81, 119.14, 117.95, 116.58, 60.02, 17.95, 14.33; l9F NM R (376 MHz, CDCb) delta -57.82 ; IR (thin film) 1712, 1253, 1161 cm 1 ; EIMS m/z 274.
tert-butyl 4-(2-ethoxy-2-oxoethylidene)-3,3-dimethylpiperidine-1-carboxylate At 0 C., to a solution of ethyl (diethoxyphosphoryl)formate (950 mg, 4.52 mmol) in THF (50 mL) was added sodium hydride (102 mg, 4.25 mmol) at 0 C. The resulting mixture was stirred for 15 min and then was added by <strong>[1215071-17-2]tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate</strong> (798 mg, 3.39 mmol) at 0 C. The reaction mixture was stirred for 0.5 h at 0 C., warmed up to room temperature and stirred for 3 h at room temperature. When the reaction was done, it was quenched by the addition of water (20 mL). The resulting mixture was extracted with ethyl acetate (40 mL*3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 50% gradient) to yield tert-butyl 4-(2-ethoxy-2-oxoethylidene)-3,3-dimethylpiperidine-1-carboxylate as colorless oil (560 mg, 35%). MS: m/z=205.9 [M-100+1]+.
ferf-Butyl 4-(2-ethoxy-2-oxoethylidene)-3,3-difluoropiperidine-1 -carboxylate: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of ferf-butyl 3,3-difluoro-4-hydroxypiperidine-1- carboxylate (2.40 g, 10.00 mmol) in dry CH2CI2 (50 ml.) was added a solution of Dess- Martin periodinane (50 ml. of a 15% solution in CH2CI2, 24.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. Sat. aq. NaHC03 (50 ml.) was then added followed by 10% aq. Na2S03 (50 ml_). The mixture was stirred at rt for 1 h, the layers separated and the aq. layer extracted with CH2CI2 (3x). The combined org. extracts were dried over MgS04, filtered, and concentrated under reduced pressure. The crude residue was redissolved in CH2CI2 (30 ml.) and stirred in the presence of molecular sieves for 24 h, filtered and concentrated under reduced pressure to give ferf-butyl 3,3-difluoro-4- oxopiperidine-1 -carboxylate as a yellow solid. In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to NaH (45 mg, 1 .12 mmol, 60% dispersion in oil washed with heptane) was added a solution of triethyl phosphonoacetate (262 mg, 1.17 mmol) in dry THF (10 ml.) at 0 C. The reaction mixture was stirred at 0 C for 30 min. Molecular sieves were then added followed by a solution of ferf-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (220 mg, 0.93 mmol) in THF (5 ml_). The reaction mixture was stirred at 0 C for 30 min and at rt for 1 h. Water was then added and the mixture extracted with EA (3x). The combined org. extracts were dried over MgS04, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil (mixture of E and Z isomers). LC-MS- conditions 08: tR = 0.88 and 0.93 min; [M-CH3+H]+ = 291.27.
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to NaH (45 mg, 1.12 mmol, 60% dispersion in oil washed with heptane) was added a solution of triethyl phosphonoacetate (262 mg, 1.17 mmol) in dry THF (10 mL) at 0 C. The reaction mixture was stirred at 0 C. for 30 min. Molecular sieves were then added followed by a solution of <strong>[1215071-17-2]tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate</strong> (220 mg, 0.93 mmol) in THF (5 mL). The reaction mixture was stirred at 0 C. for 30 min and at rt for 1 h. Water was then added and the mixture extracted with EA (3*). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil (mixture of E and Z isomers). LC-MS-conditions 08: tR=0.88 and 0.93 min; [M-CH3+H]+=291.27.
ethyl (2Z)-dihydrofuran-3(2H)-ylideneacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
General procedure: Preparation 36Eth yl (2Z)-d i h yd rof u ra n -3(2/-/)- yl id e n eacetateMETHOD HSodium hydride (60percent dispersion in oil, 0.65 g, 16.3 mmol) was cooled to 0°C under nitrogen before adding anhydrous THF (20 mL). Triethyl phosphonoacetate (3 mL, 15.1 mmol) was added slowly over 40 minutes to control gas evolution. A solution of 3-oxo- tetrahydrofuran (1 g, 11 .62 mmol) in anhydrous THF (2 mL) was added and the reaction gradually warmed to room temperature and stirred for 18 hours. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (3 x 50 mL) and water (30 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-50percent ethyl acetate in heptane gradient elution) to afford the title compound as an oil (1 .29 g, 71 percent yield).1HNMR (CDCI3): ? 1 .3 (m, 3H), 2.7 (m, 1 H), 3.05 (m, 0.7H), 3.2 (m, 0.3H), 3.9 (t, 1 H), 3.95 (t, 0.7H), 4.15 (m, 2H), 4.4 (m, 0.7H), 4.6-4.7 (m, 0.6H), 4.75 (m, 1 H), 5.7-5.85 (m, 1 H).LCMS ( 2 min) Rt = 1 .23 min MS m/z 157 [MH]+
(E)-ethyl 3-(2-bromo-1,3-thiazol-5-yl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
General procedure: To a stirred solution of triethyl phosphonoacetate (24.4 mmol) in THF (30 mL) at 0oC was added sodium hydride (24.4 mmol) portionwise. The mixture was stirred for 1 h before addition of aldehyde (12.2 mmol). The reaction mixture was allowed to warm to r.t. and stirred for 17 h, before quenching with water (50 mL) and extracting into EtOAc (2 x 50 mL). The organic layers were combined and washed with water (2 x 50 mL), dried (MgS04), filtered and concentrated.
Triethyl phosphonoacetate (2.46 g) was stirred in an ice bath, and NaH powder (480 mg, 50% mineral oil) was added portionwise.After stirring for half an hour, <strong>[400822-47-1]4-bromo-3,5-dimethylbenzaldehyde</strong> (2.12 g) was added to the reaction mixture, and the mixture was stirred at room temperature overnight.. After the reaction was completed, poured into 20 mL of water and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate.After filtration and concentration under reduced pressure, using silica gel column chromatography to obtain an oily liquid (2.1 g of), 74% yield,
Step A: (E)-ethyl 3 -(4-bromo-3 ,5 -dimethylphenyl)acrylate (19-2)To a solution of triethyl phosphonoacetate (2.1 g, 9.4 mmol) in THF (20 mL) was added NaH(0.38 g, 9.4 mmol) in portions at 0C. The mixture was stirred at 0C for 30 minutes, thencompound 19-1 (1 g, 4.7 mmol) was added and the reaction was stirred at 0C for another 30minutes. The reaction mixture was poured into 100 mL of water, and extracted with ethyl acetate (50 ml x 2). The ethyl acetate layer was concentrated in vacuo, and the resulting residue waspurified by column chromatography on silica gel eluted with petroleum ether:ethyl acetate (10:1)to give compound 19-2. MS (ESI) m/z: 283 (M+H).
To a solution of triethyl phosphonoacetate (2.1 g, 9.4 mmol) in THF (20 mL) was added NaH (0.38 g, 9.4 mmol) in portions at 0C. The mixture was stirred at 0C for 30 minutes, then compound 19-1 (1 g, 4.7 mmol) was added and the reaction was stirred at 0C for another 30 minutes. The reaction mixture was poured into 100 mL of water, and extracted with ethyl acetate(50 ml x 2). The ethyl acetate layer was concentrated in vacuo, and the resulting residue waspurified by column chromatography on silica gel eluted with petroleum ether:ethyl acetate (10:1)to give compound 19-2. MS (ESI) m/z: 283 (M+H).
(E)-ethyl 3-(3-chloropyridin-4-yl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium tert-butylate; In benzene; at 20℃;
Preparation example 412: (E)-ethyl 3-(3-chl or opyr idiii-4-yl ) aery late <strong>[72990-37-5]3-chloroisonicotinaldehyde</strong> (Preparation example 411, 0.54g, 3.79mmol) was dissolved in benzene. At the room temperature, triethyl phosphoacetate (753 f , 3.79mmol) and potassium tert-but oxide (468 mg, 4.17 mmol) were added and stirred. When the reaction was completed, the obtained product was washed with water and ethylacetate (EA) . Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgS04), filtrated, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (0.57g, 70~90%) . LH NMR (400MHz, CDC13) delta 1.40 (t, J = 12, 3H) 4.13 (q, J = 6.6, 2H) 6.61(d, J = 16.0, 1H).7.46 (cl, J = 16.0, 1H) 7.97 (d J = 8.0, 1H) 8.51 (d, J - 4.0, 1H) 8.66 (s, 1H)
To a stirred suspension of sodium hydride (1.2 mmol) in THF was added triethyl phosphonoacetate (1.2 mmol) drop wise. The mixture was allowed to stir until it became colorless and a solution of <strong>[27514-08-5]N-(4-oxocyclohexyl)acetamide</strong> (1.0 mmol) in THF (1 mL) was added. The solution was allowed to stir at rt until the reaction was complete (by TLC). The solvent was removed under reduced pressure and the crude residue was filtered through a small plug of silica gel to afford the desired product, which was used directly in the next synthetic step. (1195) To a stirred solution of the ester (225.6 mg, 1.0 mmol) in THF (5 mL) at 0 C. was added LiAlH4 (56.9 mg, 1.5 mmol) portion wise carefully. The reaction was allowed to stir for an additional 3 h at 0 C. The excess LiAlH4 was destroyed with ethyl acetate and the solvent removed under reduced pressure. The crude residue was adsorbed on silica gel and was purified by flash column chromatography on silica gel to afford the desired alcohol in 66% yield. 1H NMR: 1.50-1.67 (m, 2H), 1.78-2.11 (m, 4H), 1.94 (s, 3H), 2.18 (t, 2H, J=6.0 Hz), 2.34 (d, 1H, J=12.9 Hz), 3.64 (t, 2H, J=6.4 Hz), 3.78-4.09 (m, 1H), 5.39 (br s, 1H), 5.73 (d, 1H, J=6.8 Hz).
Potassium tert.butoxide (187.8 gm) was slowly added lot wise to pre-cooled methanol (1000 ml) at 0-5C. Ethyl 2-(diethoxyphosphoryl)acetate compound of formula-3a (404.5 gm) was slowly added to the reaction mixture at 0-5C and stirred the reaction mixture for 1 hr at the same temperature. <strong>[27514-08-5]N-(4-oxocyclohexyl)acetamide</strong> compound of formula-2a (200 gm) was slowly added lot wise to the reaction mixture at 0-5 C and stirred the reaction mixture for 1 hr at the same temperature. Raised the temperature of the reaction mixture to 10-15C and stirred for 4 hr at the same temperature. Water (2000 ml) was slowly added to the reaction mixture at 10-15C. Cooled the reaction mixture to 0-5C and stirred for 2 hr at the same temperature. Filtered the solid, washed with water and suck dried the material. The obtained solid was transferred to an autoclave vessel, methanol (2600 ml) was added to it at 25-30C and stirred the reaction mixture for 15 min at the same temperature. 5% Pd-C (10 gm) was added to the reaction mixture under nitrogen atmosphere. 2-3 Kg/Cm hydrogen gas pressure was applied to the reaction mixture at 25-30C and stirred the reaction mixture for 3 hr at the same temperature. Released the hydrogen gas from the autoclave vessel and purged the reaction mixture twice with nitrogen gas pressure. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure. Aqueous sodium hydroxide solution (dissolve 103.1 gm of sodium hydroxide in 600 ml of water) was added to the obtained compound at 25-30C and stirred the reaction mixture for 5 hr at the same temperature. Cooled the reaction mixture to 5-10C, slowly acidified with aqueous hydrochloric acid solution and stirred for 2 hr at the same temperature. Filtered the solid, washed with water and dried the material. Methanol (1800 ml) and isopropyl alcohol (1200 ml) were added to the obtained compound at 25-30C and stirred the reaction mixture for 15 min at the same temperature. Heated the reaction mixture to 65-70C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30C and stirred for 20 min at the same temperature. Further cooled the reaction mixture to 0-5C and stirred for 2 hr at the same temperature. Filtered the solid, washed with a mixture of methanol and isopropyl alcohol and dried the material to get the title compound. Yield: 105.0 gm; Melting Range: 238.4C-239.0C.
In a round bottom flask, 2,2-diethoxy-N,N-dimethylethanamine (Formula III, 200 g) and deionized water (100 mL) were added at about 20°C to about 25°C. To the solution, concentrated hydrochloric acid (240 mL) was added at about 25°C to about 50°C. The temperature of the reaction mixture was raised to about 70°C. The reaction mixture was stirred at about 60°C to about 70°C for about 12 hours. The reaction mixture was cooled to about 0°C. To the reaction mixture, about 200 mL of aqueous potassium hydroxide (240 g in 250 mL water) was added at about 0°C to about 10°C to attain a pH of 9.0. To the reaction mixture, ethyl(diethoxyphosphoryl) acetate (200 g) and 2- methyltetrahydrofuran (600 mL) were added at about 0°C to about 5°C. Further, 50 mL of aqueous potassium hydroxide was added to the reaction mixture at about -5°C to about 0°C to attain a pH of about 13.5. The reaction mixture was stirred at about -5°C to about 0°C for about 1 hour. The reaction mixture was filtered, and then the filtrate was recovered under vacuum at about 45°C to about 50°C to obtain ethyl-4- (dimethylamino)crotonate as an oily mass. Yield: 89percent
Step 1: Synthesis of (E)-ethyl 3-(4-bromo-3-methoxyphenyl)acrylate (6*)NaH (60percent in mineral oil, 85mg, 21.3mmol) was suspended in THE at 0 00 andtriethylphosphonoacetate (4.38 g, 19.6mmol) was added. The mixture was stirred for30mm, then <strong>[43192-34-3]4-bromo-3-methoxybenzaldehyde</strong> (3.9g, 18.lmmol) in THE was added. The reaction was stirred for lh, quenched with a sat. aq. NH4OI solution and extracted with TBME. The combined organic phases were dried on Mg504, filtered, and evaporated in vacuo to yield desired product 6* as a white solid (5.16g, 100percent)which was used in the following step without further purification. MS (ES) C12H13BrO3 requires: 284/286, (M-f-H) not found.
ethyl 2-(trans/cis)-(4-acetamidocyclohexyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92.6%
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 0-5C 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 0-5C. 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 10% 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, 92.6%) as a colorless semi-solid. MS (ESI) m/z: 228.2 ([M+ H]+).
90%
A solution of triethyl phosphonoacetate (50.0 g, 223.1 mmol) in THF (190 mL) was added dropwise while stirring to a solution of potassium tert-butoxide (41.7 g, 371.7 mmol) in THF (380 mL) at 0-5 C and the solution was continuously stirred for 1 h. A suspension of N-(4-oxocyclohexy)acetamide (28.8 g, 186.9 mmol) in THF (130 mL) was added dropwise to the solution at 0-5 C. The resulting solution was stirred for 2 h at r.t. and the reaction was subsequently quenched with H2O (80 mL). The resultant mixture was extracted with EtOAc (3 × 20 mL) and the layers were separated. 10% Pd/C (1.4 g) was added to the organic layer and hydrogenation was conducted at ambient temperature and pressure conditions. The resulting solution was stirred for 24 h and filtered. The filtrate was evaporated in vacuo to give a colorless oil. The residue was partitioned between H2O (100 mL) and CH2Cl2 (2 × 90 mL), and the combined extracts were dried (MgSO4) and evaporated in vacuo to afford 8a. Yield: 38 g (90%); colorless semisolid. MS (ESI): m/z = 228.2 [M + H]+.
4-Propylbenzaldehyde(si) (10.0 g), ethyl diethylphosphonoacetate (18.2g) and toluene (200 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to 0° C. Sodium ethoxide in ethanol solution(20percent; 27.6 g) was added at the same temperature, and the stirring was continued for another 2 hours. After the reaction mixture had been returned to 25° C, thestirring was continued for another 2hours. The reaction mixture was treated with water, and the aqueous layer wasextracted with toluene. The combined organic layers were washed with water, andthen dried over anhydrous magnesium sulfate. The solution was concentratedunder reduced pressure, and the residue was purified by col- 50 umn chromatography with a mixed solvent of toluene and heptane(toluene:heptane=2:l by volume) as an eluent and silica gel as a stationaryphase powder. The purified product was dissolved in 2-propanol (150 ml), towhich Pd/C (0.91 g) was added. The mixture was stirred at room temperature 55 under a hydrogen atmosphere until hydrogen absorption had ceased. Afterthe reaction had been completed, Pd/C was removed, and then solvent wasdistilled off. The residue was purified by column chromatography with tolueneas an eluent and silica gel as a stationary phase powder to give ethyl 60 3-(4-propylphenyl) propionate (s2) (14.2 g). The yield based on thecompound (si) was 95.5percent.
General procedure: To a stirred suspension of NaH (133 mg, 3.32 mmol) in THF(5 mL) was added triethyl phosphonoacetate (0.66 mL, 3.32 mmol)at 0 C, and the resulting mixture was stirred at 0 C. After stirringfor 30 min., a solution of aldehyde 5g, h (2.77 mmol) in THF (5 mL)was added to the reaction mixture, and the resulting mixture wasstirred at room temperature for 18 h. The reaction was quenchedby adding H2O, and the aqueous mixture was extracted with CH2Cl2, and the organic phase was separated, the aqueous mixturewas extracted with CH2Cl2. The organic phase and extracts werecombined, dried over Na2SO4, and concentrated in vacuo. Theresidue was chromatographed on SiO2 (Hexane:Acetone =90:1 80:1) to give corresponding ethyl ester 6g, h. To a stirredsolution of 6g, h (2.69 mmol), obtained above, in the mixed solvent(20 mL) with MeOH-H2O (3: 1) was added LiOHH2O (226 mg,5.38 mmol), and the resulting mixture was refluxed for 2 h. Aftercooling, the solvent was removed, and then the residue was acidifiedwith 10% HCl aq. The aqueous mixture was extracted withAcOEt, and the organic extracts were dried over Na2SO4, and evaporatedto give the carboxylic acid 7g, h.
General procedure: Compound 1a-9a (1.0mmol) was dissolved in toluene (70mL) in a flask which was wrapped with tin foil, sodium hydride (1.5mmol) and triethyl phosphonoacetate (1.0mmol) was added respectively. Then the reaction solution was stirred at room temperature under dark until TLC analysis showed complete conversion. Extracted with EtOAc, the combined organic phase was washed with saturated brine (50mL×3), and dried over anhydrous sodium sulfate. Concentrated and purified by column chromatography (PE/EA=8: 1) to give a pale yellow solid (1b-9b). The synthetic routes are similar to PL [7,12].
1-(3-Methoxyphenyl)propan-2-one (CAS registry number: 3027-13-2) (15 g) was dissolved in THF (1,000 mL),and to the mixture, sodium hydride (4.4 g) was added little by little at 0C. While being left at 0C, after the mixture wasstirred for 15 minutes, ethyl (2-diethoxyphosphoryl)acetate (24.57 g) was added, and the mixture was warmed to roomtemperature and was stirred for 8 hours. After being diluted with ethyl acetate, the mixture was washed sequentially withtap water and saturated saline, was dried over anhydrous magnesium sulfate, and thereafter, the solvent was distilledoff. The residue was diluted with ethyl acetate (1,000 mL), and to the residue, 5% palladium carbon (100 mg) was added,and the mixture was stirred under hydrogen atmosphere at room temperature for 4 hours. The reaction liquid was filteredthrough Celite and the solvent was distilled off. The product was purified by silica gel column chromatography (hexane :ethyl acetate = 10 :1) to give the title compound (5.7 g) having the following physical properties.1 H-NMR (CDCl3): delta 7.19, 6.75, 4.11, 3.80, 2.50, 2.49, 2.38-2.20, 2.18, 1.26, 0.94.
With sodium ethanolate; In ethanol; toluene; at 0 - 20℃; for 6h;
The compound (T-69) (20.0 g), phosphonoethyl acetate (22.5 g) and toluene (300 ml) were placed in a reactor and cooled to 0 ° C.Sodium ethoxide (20percent ethanol solution) (34.2 g) was slowly added thereto, returned to room temperature and stirred for 6 hours.After the insolubles were removed, the reaction mixture was poured into water and the aqueous layer was extracted with toluene.The organic layer formed simultaneously with water washing was dried over anhydrous magnesium sulfate.The solution was concentrated under reduced pressure and the residue was purified with silica gel chromatography using toluene to obtain compound (T-70) (23.3 g; 90percent).
(Z)-ethyl 2-(5H-cyclopenta[b]pyridin-7(6H)-ylidene)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.32 g
A. To a solution of sodium hydride (0.23 g, 5.64 mmol) in THF (8 mL) was added ethyl 2- (diethoxyphosphoryl)acetate (1.69 g, 7.52 mmol) in THF (1 mL) slowly at 0 °C under N2. The mixture was stirred at ambient temperature for 30 min. Then <strong>[31170-78-2]5H-cyclopenta[b]pyridin-7(6H)-one</strong> (500 mg, 3.76 mmol) in THF (10 mL) was added. The reaction was stirred at 50 °C for 2 h. Saturated aqueous NH4Cl (5 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2 x 15 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of petroleum ether (90percent) and EtOAc (10percent) to petroleum ether (85percent) and EtOAc (15percent) to provide (Z)-ethyl 2-(5H- cyclopenta[b]pyridin-7(6H)-ylidene)acetate (0.32 g, 1.57 mmol) as a yellow oil.
With lithium hydroxide; In tetrahydrofuran;Molecular sieve;
To a solution of <strong>[90905-33-2]2-methylpyrimidine-5-carbaldehyde</strong> (1.0 g, 8.19 mmol) in THF (15 mL) was added 5 g of molecular sieves (4 A) followed by ethyl 2- (diethoxyphosphoryl)acetate (1.967 mL, 9.83 mmol) and LiOH (0.235 g, 9.83 mmol). After stirring overnight at room temperature, the reaction was filtered over CELITE® and the volatiles were removed. The residue was dissolved in EtOAc and sequentially washed with 10percent NaHCC aq solution and brine. The organic layer was dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (0 to 50percent EtOAc/Hexanes) to give Example 22A (0.841 g, 4.38 mmol, 53percent yield) as a white solid. LCMS (ESI) m/z 193.1 (M+H)+. NMR (400MHz, CDC13) delta 8.79 (s, 1H), 7.61 (d, J = 16.3 Hz, 1H), 7.28 (s, 1H), 6.56 (d, J = 16.3 Hz, 1H), 4.31 (d, J = 7.2 Hz, 2H), 2.79 (s, 3H), 1.37 (t, J = 12 Hz, 3H).
Tetrahydrofuran (100 mL) was cooled to 0 ° C under nitrogen, and sodium hydride (1.95 g, 48.8 mmol, 60 mass percent) was added portionwise.Subsequently, triethyl phosphonoacetate (10.9 g, 48.6 mmol) was added.After the obtained reaction mixture was stirred at this temperature for 20 minutes, a solution of <strong>[31191-08-9]5-hydroxypyridine-2-carbaldehyde</strong> 30a (2.00 g, 16.2 mmol) in tetrahydrofuran (10 mL) was added dropwise.After adding water (100 mL), the mixture was quenched with hydrochloric acid (1 mol/L), and the organic solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate (100 mL×4).The combined organic layers were dried over anhydrous sodium[ethyl acetate / petroleum ether (v / v) = 1 / 1] purified to give the title compound30b (2.66 g, 85percent yield) as a white solid.
114 kg of dichloromethane and 3.05 kg of 60% sodium hydride were added to a 300 L reactor and stirred well, and the mixture was cooled by freezing brine. 7.66 kg of triethyl phosphonoacetate was slowly added dropwise, and the addition was completed within about 30 min. The mixture was stirred at room temperature until no bubbles were produced. A solution of 6.4 kg of compound 2 obtained in the previous step in dichloromethane (85 kg) was added slowly dropwise, and the addition was completed within about 1 h. Then the reaction was carried out at room temperature for 1.5-2 h. After the completion of the reaction was determined by TLC detection, the mixture was cooled by freezing brine. An aqueous solution of ammonium chloride (1.26 kg of ammonium chloride dissolved in 4.0 kg of water) was added slowly until no bubbles were produced. The mixture was stirred for about 0.5 h. Purified water was then slowly added dropwise until the mixture was clear. Two phases were separated, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude ester product. The crude ester product was subjected to column chromatography (the eluent was ethyl acetate: petroleum ether =1:8). The main fraction was collected and concentrated to obtain 4.82 kg of compound 3, yield: 45.0%. (The TLC condition was petroleum ether: ethyl acetate =3:1, the Rf of the product =0.7, the Rf of the starting material =0.6). (0065) Compound 3: 1H NMR (400 MHz, CDCl3) delta=6.85-6.80 (dd, 1H), 5.84-5.80 (d, 1H), 4.40 (br, 1H), 4.22-4.17 (q, 2H), 3.42 (s, 2H), 2.08-2.06 (m, 1H), 1.89-1.82 (m, 2H), 1.79-1.73 (m, 1H), 1.44 (s, 9H), 1.31-1.27 (t, 3H) ppm. (0066) MS (M+Na): 292.1
To a suspension of sodium hydride (80 mg, 1 .998 mmol) in dry Tetrahydrofuran (10 mL) cooled to 0 C with an ice bath was added dropwise a solution of ethyl 2- (diethoxyphosphoryl)acetate (448 mg, 1 .998 mmol) in Tetrahydrofuran (10 mL). The bath was removed and the mixture was stirred for 1 h at rt. The mxiture was then re-cooled to 0 C with an ice bath and a solution of <strong>[20249-16-5]3-oxocyclobutanecarbonitrile</strong> (190 mg, 1 .998 mmol) in Tetrahydrofuran (2 mL) was then was added dropwise. The resulted mixture was then stirred overnight at rt. Water (20 ml) and diethyl ether (50 ml) were added, the aqueous phase was extracted with diethyl ether (2x20 ml), the combined extracts were washed with water and brine, dired over anhydrous Na2S04 and concentrated to give the title compound ethyl 2-(3- cyanocyclobutylidene)acetate (200 mg, 1 .21 1 mmol, 60.6 % yield) as a clorless oil. m/z: [M + H]+ Calcd for C9H12NO2 166.2; Found 166.
ethyl (2E)-3-(1-methyl-1H-pyrazol-3-yl)prop-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.11%
To a suspension of sodium hydride (60percent in mineral oil, 0.44 g, 10.9 mmol, 1.2 eq) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (2.44 g, 10.9 mmol, 1.2 eq) dropwise at 0°C and the mixture was allowed to stir at the same temperature for 30 minutes. To this mixture was added a solution of <strong>[27258-32-8]1-methyl-1H-pyrazole-3-carbaldehyde</strong> (1.0 g, 9.09 mmol,1.0 eq) in THF (5 mL) and the resulting mixture was allowed to stir at room temperature for 2 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with saturated aq. NH4C1 (100 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness under vacuum to afford crude which was purified by Combi-Flash on silica gel using ethyl acetate15 hexane system as eluent to afford ethyl (2E)-3-(1-methyl-1H-indol-3-yl)prop-2-enoate (0.70 g,61.11percent).LCMS: 181 [M+1]
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