Acetic acid, 2-(1,4-dioxaspiro[4.5]dec-8-ylidene)-, ethyl ester

A solution of triethyl phosphonate (44.8 g, 200 mmol) in THF (30 ml) at 0° C. was treated with a 1M solution (200 ml) of sodium bis(trimethylsilylamide) in THF. The resulting mixture was stirred at room temperature for 0.5 hour, and then cooled to 0° C. A solution of 1, 4-cyclohexanedione mono ethylene ketal (15.6 g, 200 mmol) in THF (50 ml) was added dropwise, and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was then cooled to 0° C., treated with cold aqueous citric acid, and the mixture was extracted with EtOAc. The extract was washed with satd. aqueous NaHCOTo 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). 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 HPotassium 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).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 NaStep 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).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]tNaH (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).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).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).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)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).[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)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)Step-1: 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. 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. 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.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 NaInto 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 HTo 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.Triethylphosphono acetate (6lmL, 0.3Omol) was added to a suspention KOBu-t(33g, 0.3Omol) in DMF (200mL) at 0 00, stirred for lh at RT. A solution of 1, 4- dioxaspiro[4.5]decan-8-one (40g, 0.25mo1) in DMF (200mL) was added at 0 C and the whole then stirred for 16h at RT. The reaction mixture was quenched with sat NH4CI solutionand extracted with ethyl acetate (2X500mL). The combined organic layer was washed with water, brine, dried over Na2SO4 and distilled under reduced pressure to afford crude, which was purified by column chromatography (silica gel; 60-l20mesh); the product eluted with 10- 15percentethyl acetate in hexane to yield 50.Og (86percent) of Ethyl-2-(1, 4-dioxaspiro-[4.5]-decan-8- ylidene)-acetate as liquid.Step 1: Preparation of (l, 4-Dioxa-spiro[4.5]dec-8-ylidene)-acetic acid ethyl ester 22; A solution of 1, 4-cycloliexanedionemonoetliylketal 20 (6g, 40mmol) and ethyl- (triphenylphosphoranylidene)acetate 22 (15g, 44mmol) in dry benzene (80ml) were refluxed under argon for 24hours. The solvent was removed under vacuum and product purified by flash chromatography to give the product in 90percent.

Molecular Weight:226.27
XLogP3:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:226.12050905
Monoisotopic Mass:226.12050905
Topological Polar Surface Area:44.8
Heavy Atom Count:16
Complexity:277
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes