* 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.
With potassium carbonate In ethyl acetate at 20℃; for 1.5 h;
General procedure: Powdered K2CO3(207 mg, 1.5 mmol) and 1,3-cyclohexanedione (8a) (56 mg, 0.50 mmol) were added to a suspension of sulfonium salt 13(332 mg, 0.75 mmol) in EtOAc (5 mL). After stirring at r.t. for 1.5 h, the reaction was quenched with water (10 mL) and the whole mixture was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (10 mL) and dried over anhydrous MgSO4. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, 30percent EtOAc in hexane) to provide 1a (60 mg, 87percent) as a colorless oil
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2016, vol. 64, # 12, p. 1763 - 1768
2
[ 141-97-9 ]
[ 106-93-4 ]
[ 32933-03-2 ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium carbonate In acetone
Step 1) ethyl 1-acetylcyclopropanecarboxylate To a solution of ethyl 3-oxobutanoate (26 g, 200 mmol) in acetone (500 mL) was added potassium carbonate (82.8 g, 600 mmol) followed by 1,2-dibromoethane (45.12 g, 240 mmol). The reaction was refluxed for 24 hrs, the reaction mixture was then filtered. The filtrate was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (1:50(v/v) EtOAc/n-hexane) to afford the title compound as colorless oil (18.7 g, 60percent). MS (ESI, pos. ion) m/z: 157 (M+1); 1H NMR (400 MHz, CDCl3): δ 1.25-1.29 (t, J=7.2 Hz, 3H), 1.45 (s, 4H), 2.45 (s, 3H), 4.18-4.20 (q, 2H).
60%
With potassium carbonate In acetone for 24 h; Reflux
To a solution of ethyl 3-oxobutanoate (26 g, 200 mmol) in acetone (500 mL) was added potassium carbonate (82.8 g, 600 mmol) followed by 1,2-dibromoethane (45.12 g, 240 mmol). The reaction was refluxed for 24 hrs, the reaction mixture was then filtered. The filtrate was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (1:50(v/v) EtOAc/n-hexane) to afford the title compound as colorless oil (18.7 g, 60 percent). MS (ESI, pos. ion) m/z: 157 (M+1); 1H NMR (400MHz, CDCl3): δ 1.25 - 1.29 (t, J=7.2 Hz, 3H), 1.45 (s, 4H), 2.45 (s, 3H), 4.18 - 4.20 (q, 2H).
60%
With potassium carbonate In acetone for 24 h; Reflux; Inert atmosphere
To a solution of ethyl 3-oxobutanoate (26 g, 200 mmol) in acetone (500 mL) was added potassium carbonate (82.8 g, 600 mmol) followed by 1 ,2-dibromoethane (45.12 g, 240 mmol). The reaction was refluxed for 24 hrs, then the reaction mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (l :50(v/v)EtOAc/n-hexane) to afford the title compound as colorless oil (18.7 g, 60 percent).MS (ESI, pos. ion) m/z: 157 (M+l);1H NMR (400MHz, CDCl3): δ 1.25 - 1.29 (t, J=7.2 Hz, 3H), 1.45 (s, 4H), 2.45 (s, 3H),4.18 - 4.20 (q, 2H).
52%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48 h;
Part A: Ethyl 1-acetylcyclopropanecarboxylate. To a stirred solution of ethyl 3-oxobutanoate (10 mL, 78.45 mmol) and 1 ,2- dibromoethane (6.5 mL, 78.45 mmol) in 150 mL of DMF was added potassium carbonate (22.7 g, 164.74 mmol). The resulting reaction mixture was stirred at room temperature for 2 days. The solution was diluted with 300 mL of water. The product was extracted into diethyl ether (2 x 200 mL), and the combined organic extracts were washed with water (1 x 1000 mL), and dried (MgSO4). Filtration and atmospheric distillation of the ether provided the crude product, which was distilled under reduced pressure (10 mBar) to provide ethyl 1-acetylcyclopropanecarboxylate (6.4273 g, 52percent). LCMS: (M+H) +: not detected. Part A: Ethyl 1 -acetylcyclopropanecarboxylateTo a solution of ethyl 3-oxobutanoate (10.0 g, 76.84 mmol) in DMF (150 mL) was added potassium carbonate (22.30 g, 161.3 mmol) and 1 ,2-dibromoethane (6.62 mL, 76.82 mmol). The mixture was stirred for 2 days, and then filtered. The solution was diluted with water (300 mL), and extracted with Et2O (2 x 200 mL). The combined organic phase was washed with a fresh portion of water (100 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was subjected to vacuum distillation at ca. 10 mbar, and the fraction boiling at 100 0C was collected to give ethyl 1- acetylcyclopropanecarboxylate (7.6482 g, 64percent) as a colorless oil.
51%
at 20℃;
Step 1 : ethyl 1-acetylcyclopropanecarboxylateA mixture of ethyl 3-oxobutanoate (100 g, 0.769 mol), 1 , 2-dibromoethane (215.7 g, 1.153 mol) and K2CO3 (424 g, 3.07 mol) was stirred at room temperature overnight. Water (800 mL) was added and the reaction mixture was extracted with ether (3 X 500 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo, and the residue was purified by column chromatography to give the title compound as a light yellow oil (51 g, 51 percent): 1H NMR (400 MHz, CDCI3) δ 4.10-4.16 (m, 3H), 2.40 (s, 2H), 1.39 (s, 3H), 1.18-1.24 (m, 4H); ES-LCMS m/z 157 (M+H)+.
50%
With potassium carbonate In dimethyl sulfoxide at 25℃; for 24 h; Inert atmosphere
The ethyl-3-oxobutanoate (10.0g, 76.8mmol) and 1,2-dibromoethane (21.7g, 115mmol) was dissolved in dimethyl sulfoxide (300mL), under nitrogen gas protection, and then was added portionwise potassium carbonate (42.5g, 307mmol).The reaction mixture was stirred for 24 hours at 25 °C. Adding water (10 ml) quenching the reaction, is filtered to remove insoluble matter, the filtrate is extracted with ethyl acetate (20mLx3). Combining the organic phase, dried with anhydrous sodium sulfate, filtered, concentrated filtrate under reduced pressure,purification by silica gel column chromatography (10: 1 petroleum ether / ethyl acetate, Rf = 0.4) to give ethyl 1-acetylcyclopropanoate (6.00 g, white oil). Yield: 50percent.
0.6 g
With potassium carbonate In dimethyl sulfoxide at 20℃; for 48 h;
To a stirred solution of ethyl 3-oxobutanoate (1 g, 7.68 mmol) in DMSO (10 mL) was added K2CO3(3.19 g, 23.05 mmol) at RT followed by drop-wise addition of 1, 2 dibromo ethane (3.61 g, 19.2 mmol). The reaction mixture was stirred at ambient temperature for 48 h and quenched with water (50 mL). The reaction mixture was extracted with EtOAc (200 mL), washed with brine (50 mL), dried over Na2S04, filtered and evaporated under reduced pressure. The crude was purified flash chromatography (Silica gel 230-400, 2percent EtOAc/petroleum ether) to give ketoester B-20a (0.6 g).XH NMR (CDC13, δ = 7.26 ppm, 400 MHz): 4.20 (q, d = 7.2, 2 H), 2.46 (s, 3 H), 1.46 (s, 4 H), 1.28 (t, J = 7.2, 3 H).
13 g
With potassium carbonate In N,N-dimethyl-formamide
13.0 g of ethyl acetoacetate was added to a 250 mL reaction flask. Then, added sequentially 130 mL of DMF, 37.6 g of 1,2-dibromoethane, 52.44 g of potassium carbonate. Stirring, reaction overnight. Was added to 650 mL of water. Ethyl acetate extraction. Dry. Concentration of the distillation yielded 13.0 g of compound 1.
152 g
With potassium carbonate In N,N-dimethyl-formamide at 35℃;
Ethylacetoacetate (130.2 g, 1.0 mol) was dissolved in DMF (400 mL)Anhydrous potassium carbonate (276.5 g, 2. Ommo 1), 1,2-dibromoethane (338 g, 1.8 mol) was added, heated to 35 ° C, and mechanically stirred overnight.The solvent was evaporated under reduced pressure to give ethyl 1-acetylcyclopropanecarboxylate (crude 152 g, 97percent)
Reference：
[1] Tetrahedron Letters, 2005, vol. 46, # 4, p. 635 - 638
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 2, p. 420 - 422
[3] Tetrahedron Asymmetry, 2010, vol. 21, # 5, p. 631 - 635
[4] Journal of Organic Chemistry, 2011, vol. 76, # 8, p. 2807 - 2813
[5] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1983, vol. 19, # 6, p. 644 - 650[6] Khimiya Geterotsiklicheskikh Soedinenii, 1983, vol. 19, # 6, p. 801 - 807
[7] European Journal of Organic Chemistry, 2005, # 19, p. 4167 - 4178
[8] Synlett, 2009, # 13, p. 2177 - 2179
[9] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 839 - 862
[10] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1988, vol. 27, p. 530 - 536
[11] Patent: US2010/239576, 2010, A1,
[12] Patent: EP2408300, 2016, B1, . Location in patent: Paragraph 0368
[13] Patent: WO2010/45095, 2010, A1, . Location in patent: Page/Page column 88
[14] Patent: WO2009/61879, 2009, A1, . Location in patent: Page/Page column 165, 177
[15] Patent: WO2010/141545, 2010, A1, . Location in patent: Page/Page column 24-25
[16] Patent: CN105566324, 2016, A, . Location in patent: Paragraph 0099; 0100; 0101; 0102
[17] Journal of the Chemical Society, 1885, vol. 47, p. 814[18] Chemische Berichte, 1884, vol. 17, p. 324
[19] Journal of the Chemical Society, 1887, vol. 51, p. 829
[20] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1925, vol. 145, p. 61[21] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1927, vol. 172, p. 234
[22] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 10, p. 3187 - 3194
[23] Russian Chemical Bulletin, 1994, vol. 43, # 1, p. 84 - 88[24] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1994, # 1, p. 89 - 93
[25] Patent: US5194431, 1993, A,
[26] Patent: US5286723, 1994, A,
[27] Patent: WO2015/5901, 2015, A1, . Location in patent: Page/Page column 638
[28] Patent: CN105906545, 2016, A, . Location in patent: Paragraph 0048; 0049
[29] Patent: CN104557871, 2017, B, . Location in patent: Paragraph 0143-0145
3
[ 141-97-9 ]
[ 107-06-2 ]
[ 32933-03-2 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 3.2, p. 631 - 633[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 3, p. 710 - 712
[3] Russian Chemical Bulletin, 1994, vol. 43, # 1, p. 84 - 88[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1994, # 1, p. 89 - 93
[5] Patent: US2003/65212, 2003, A1,
4
[ 64648-13-1 ]
[ 141-97-9 ]
[ 32933-03-2 ]
Reference：
[1] Organic Preparations and Procedures International, 1992, vol. 24, # 5, p. 548 - 552
5
[ 141-97-9 ]
[ 106-93-4 ]
[ 32933-03-2 ]
Reference：
[1] Patent: US5587386, 1996, A,
6
[ 141-97-9 ]
[ 106-93-4 ]
[ 32933-03-2 ]
Yield
Reaction Conditions
Operation in experiment
65.1%
With potassium carbonate In acetone
Referential Example 11-1 Ethyl 1-acetylcyclopropanecarboxylate Ethyl acetoacetate (100 g, 0.77 mol) was dissolved in acetone (500 ml). To the thus obtained solution was added dibromoethane (361 g, 1.92 mol) and potassium carbonate (266 g, 1.92 mol) and the mixture was heated under reflux for 4 days. After filtering off insoluble matter, the filtrate was distilled under reduced pressure (80° C./8 mmHg) to obtain 78.1 g (65.1percent) of the title compound as a colorless oily substance. 1 H-NMR (400 MHz, CDCl3) δ: 1.29 (3H, t, J=7.33 Hz), 1.47 (4H, s), 2.47 (3H, s), 4.21 (2H, q, J=7.33 Hz).
Reference：
[1] Patent: US6121285, 2000, A,
7
[ 141-97-9 ]
[ 106-93-4 ]
[ 2986-03-0 ]
[ 32933-03-2 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1983, vol. 19, p. 474 - 480[2] Zhurnal Organicheskoi Khimii, 1983, vol. 19, # 3, p. 541 - 548
8
[ 56692-06-9 ]
[ 141-97-9 ]
[ 32933-03-2 ]
Reference：
[1] Organic Preparations and Procedures International, 1992, vol. 24, # 5, p. 548 - 552
9
[ 14668-82-7 ]
[ 141-97-9 ]
[ 32933-03-2 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1972, vol. 45, p. 1884 - 1888
10
[ 141-97-9 ]
[ 106-93-4 ]
[ 75-21-8 ]
[ 32933-03-2 ]
[ 107-21-1 ]
Reference：
[1] Chemistry Letters, 1987, p. 2235 - 2238
11
[ 141-97-9 ]
[ 6307-04-6 ]
[ 32933-03-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1973, p. 65 - 68
Step 2: (R)-1-acetyl-Lambda/-(1-phenylethyl)cyclopropanecarboxamideTo a solution of <strong>[32933-03-2]ethyl 1-acetylcyclopropanecarboxylate</strong> (250 g, 1.60 mol) in EtOH (500 mL) was added aqueous NaOH solution (4 N, 2 L) at O0C. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was extracted with ether (3 X 500 mL). The aqueous layer was adjusted to pH 4 with concentrated HCI and extracted with CH2CI2 (3 X 2 L). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, and concentrated in vacuo to give 1- acetylcyclopropanecarboxylic acid as a light yellow oil (200 g, 92.8%).
With sodium hydroxide; In ethanol; dichloromethane; water;
1) 1-Acetylcyclopropane-1-carboxylic acid (compound 58) To a solution of 268.6 g of compound 2 in 400 ml of ethanol was added dropwise at room temperature an aqueous solution of 75.67 g of sodium hydroxide in 200 ml of water in 20 minutes. The mixture was stirred at room temperature for 2 hours. 1,500 ml of dichloromethane and 500 ml of water were added to the mixture. The mixture was shaken, then the aqueous layer was separated. The aqueous layer was washed with two 500 ml portions of dichloromethane. The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid under cooling, and the mixture was extracted with 1,500 ml of dichloromethane. The aqueous layer was extracted with 500 ml of dichloromethane, and the extracts were combined. The combined organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was distilled under reduced pressure to yield 232 g of title compound 58 as a colorless oil. 1 H-NMR (CDCl3) deltappm: 1.6-2.0 (4H, m), 2.21 (3H, s).
0.07 g
With methanol; lithium hydroxide; at 20℃; for 12h;
To a stirred solution of ketoester B-20a (0.3 g, 1.921 mmol) in MeOH (4 mL) was added LiOH (0.460 g, 19.21 mmol) and the resulting mixture was stirred at room temperature for 12 h. The volatile components were evaporated under reduced pressure and diluted with water (50 mL). The pH of the reaction mixture was adjusted to 3-4 with IN HC1 and extracted with DCM (250 mL). The organic layer was dried over Na2S04, filtered and evaporated under reduced pressure to give Cap B-20 (0.07 g). 'H NMR (CDCI3, delta = 7.26 ppm, 300 MHz): delta 2.12 (s, 3 H), 2.01-1.98 (m, 2 H), 1.76-1.73 (m, 2 H).
With hydrogenchloride; potassium iodide; potassium carbonate; In N,N-dimethyl acetamide;
Example 1 Production of Ethyl 1-Acetyl-1-cyclopropanecarboxylate A total of 165.6 g of potassium carbonate, 390.0 g of 1,2-dichloroethane, 234.0 g of N,N-dimethylacetamide, 5.0 g of potassium iodide, and 78.0 g of ethyl acetoacetate were mixed, followed by a reaction at 100 C. for 4 hours. The reaction mixture was cooled to room temperature and was filtrated, the resulting filtrate was washed with two portions of 5% by weight hydrochloric acid, and the organic layer was washed with water. The organic layer was then concentrated under a reduced pressure to distill off 1,2-dichloroethane, was subjected to distillation under a reduced pressure and thereby yielded 31.7 g of ethyl 1-acetyl-1-cyclopropanecarboxylate as a colorless liquid as a fraction at 80 C./20 mmHg. [Spectral data] 1H-NMR (CDCl3) delta: 1.27-1.32 (t, 3H, J=6.75, C3CH2O), 1.47 (s, 4H, CC2C2), 2.47 (s, 3H, C3COC), 4.17-4.25 (q, 2H, CH3C2O)
ethyl 3-(1-ethoxycarbonylcyclopropyl)-2-fluoro-2-butenoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; thionyl chloride; sodium chloride;iodine; In pyridine; dichloromethane; chloroform; benzene;
Referential Example 11-2 Ethyl 3-(1-ethoxycarbonylcyclopropyl)-2-fluoro-2-butenoate To a solution (1500 ml) of <strong>[32933-03-2]ethyl 1-acetylcyclopropanecarboxylate</strong> (124.5 g, 0.797 mmol) in benzene was added zinc powder (156.4 g, 2.39 mmol). While heating under reflux, a catalytic amount of iodine was added thereto. Subsequently, a solution of ethyl bromofluoroacetate (94.23 ml, 0.797 mol) in benzene (200 ml) was added dropwise thereinto over a period of 1 hour followed by heating under reflux for 1 hour. Under ice cooling, 1 N hydrochloric acid (1000 ml) was added to the liquid reaction mixture and the mixture was stirred for 1 hour. The organic layer taken up by phase separation was washed successively with 1 N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in pyridine (387 ml, 4.78 mol). After adding thionyl chloride (69.8 ml, 0.957 mol) at -10 C., the resultant mixture was stirred under ice cooling for 3 hours. Under ice cooling, the liquid reaction mixture was poured into 1 N hydrochloric acid (2000 ml) and ethyl acetate (1500 ml) was added thereto. The organic layer taken up by phase separation was washed successively with 1 N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in dichloromethane (500 ml). Under ice cooling, 1,8-azabicyclo[5.4.0]-7-undecene (131 ml, 0.877 mol) was added dropwise thereinto and then the resultant mixture was stirred at room temperature for 17 hours. After adding 1 N hydrochloric acid (2000 ml) and chloroform (1000 ml), the organic layer taken up by phase separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue thus obtained was subjected to flash silica gel column chromatography (eluent:n-hexane:ethyl acetate=4:1) 152.78 g (78.5%) of the title compound as an oily substance. The compound thus obtained, which was a mixture of geometrical isomers (about 1:1), was not separated but employed in the subsequent reaction as such.
Part B: 5-(Phenylmethyl)-5-azaspiro[2.4]heptane-4,7-dione. Ethyl 1-acetylcyclopropanecarboxylate (6.4273 g, 41.153 mmol) was dissolved in 46 mL of EtOH. Bromine (2.32 ml_, 45.2683 mmol) was slowly added to the solution. The resulting reaction mixture was stirred for 2 h, then concentrated in vacuo. The crude residue was dissolved in 46 ml. of EtOH and the mixture was cooled to O0C with an ice water bath. To this solution was slowly added benzyl amine (11.2 ml. 102.8825 mmol) and the reaction mixture was stirred at room temperature overnight, then concentrated in vacuo to dryness. The residue was dissolved in CH2CI2 (200 ml.) and 1 N aq HCI (100 ml_). The phases were separated, and the aqueous phase was extracted with CH2CI2 (100 ml_), the combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel using an eluting system of hexane/EtOAc (60:40) provided 5-(phenylmethyl)-5-azaspiro[2.4]heptane-4,7- dione (2.4283 g 27%) as an orange solid. LCMS: (M+H) +: not detected. Part B: 5-(Phenylmethyl)-5-azaspiro[2.4]heptane-4,7-dioneTo a solution of <strong>[32933-03-2]ethyl 1-acetylcyclopropanecarboxylate</strong> (7.6482 g, 48.97 mmol) in EtOH (54 ml.) was slowly added bromine (2.76 ml_, 53.87 mmol) via syringe. The orange solution was stirred for 2 h and then concentrated in vacuo. To a 0 0C solution of the residue in EtOH (54 ml.) was added benzylamine (13.4 ml_, 122.7 mmol) slowly via syringe, and the mixture was stirred and warmed to room temperature overnight. The mixture was concentrated in vacuo and partitioned between DCM (200 ml.) and 1 N aq. HCI (100 ml_). The aqueous phase was extracted with a fresh portion of DCM (100 ml_), and the combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (40% EtOAc in hexanes) to afford 5-(phenylmethyl)-5-azaspiro[2.4]heptane-4,7-dione (2.7842 g, 26%) as a yellow solid. LCMS: (M+H)+: 216.1.
With bromine; In ethanol; chloroform;
2) 5-Benzyl-4,7-dioxo-5-azaspiro[2,4]heptane (compound 4) In 50 ml of ethanol was dissolved 7 g of compound 2 and, then, 8.0 g of bromine was added dropwise thereto with stirring at room temperature. After 2 hours of stirring at this temperature, the excess bromine and the solvent were removed under reduced pressure to give ethyl 1-bromoacetyl-1-cyclopropanecarboxylate (compound 3). This product was dissolved as it was, i.e., without purification, in 50 ml of ethanol and 12 g of benzylamine was added dropwise thereto with stirring and ice-cooling. The mixture was then stirred at room temperature for 24 hours, after which the solvent was removed under reduced pressure. The residue was dissolved in 200 ml of chloroform and the solution was washed with 1N hydrochloric acid and saturated aqueous sodium chloride in that order and dried over anhydrous sodium sulfate. The solvent was then removed and the residue was subjected to silica gel chromatography using 2% methanol-chloroform as an eluent. The procedure gave 2.3 g of title compound 4 as light yellow crystals. 1 H-NMR (CDCl3) deltappm: 1.6-1.8 (4H, m), 3.78 (2H, s), 4.68 (2H, s), 7.2-7.45 (5H, br s).
5-[(1R)-Phenylethyl]-4.7-dioxo-5-azaspiro[2.4]-heptane[ No CAS ]
[ 32933-03-2 ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In water; N,N-dimethyl-formamide;
5-[(1R)-Phenylethyl]-4.7-dioxo-5-azaspiro[2.4]-heptane (19): To 10.4 g of ethyl acetoacetate were added 15 g of 1,2-dibromoethane, 23 g of potassium carbonate, and 150 ml of N,N-dimethylformamide (DMF), and the mixture was stirred at room temperature for 2 days. Any insoluble matter was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure. To the residue was added water, and the mixture was extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting pale yellow oily substance was subjected to distillation under reduced pressure to obtain 7.5 g of ethyl 1-acetyl-1-cyclopropanecarboxylate having a boiling point of 70 to 71 C./2 to 3 mmHg. 1 H-NMR (CDCl3) delta ppm: 1.30 (3H, t, J=7 Hz), 1.48 (4H, s), 2.49 (3H, s), 4.24 (2H, q, J=7 Hz)
1) 5-[(1R)-Phenylethyl]-4,7-dioxo-5-azaspiro[2.4]heptane 10: A mixture of 10.4 g of ethyl acetoacetate, 15 g of 1,2-dibromoethane, 23 g of potassium carbonate, and 150 ml of N,N-dimethylformamide (DMF) was stirred at room temperature for 2 days. An insoluble material was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting pale yellow oily substance was distilled under reduced pressure to give 7.5 g of ethyl 1-acetyl-1-cyclopropanecarboxylate as a fraction having a boiling point of 70 to 71 C./2-3 mmHg. 1 H-NMR (CDCl3) delta ppm: 1.30 (3H, t, J=7 Hz), 1.48 (4H, s), 2.49 (3H, s), 4.24 (2H, q, J=7 Hz)
46
[ 32933-03-2 ]
[ 105-36-2 ]
[ 7440-66-6 ]
[ 181941-61-7 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In ethyl bromoacetate benzene; benzene;
Reference Example D-2 Ethyl1-ethoxycarbonyl-beta-hydroxy-beta-methyl-cyclopropanepropanoate A 61.7 g (0.39 mol) portion of <strong>[32933-03-2]ethyl 1-acetylcyclopropanecarboxylate</strong> was dissolved in 500 ml of benzene to which were subsequently added 13 g of zinc powder and a catalytically effective amount of iodine. While heating under reflux, a solution of 56.2 ml (0.51 mol) of ethyl bromoacetate in 100 ml of benzene was added dropwise to the mixture above. When the reaction started to progress, the dropwise addition was suspended, 39 g of zinc powder was added in small portions and then the remaining ethyl bromoacetate benzene solution was added dropwise. After completion of the addition, the reaction solution was heated under reflux for another 2 hours. The reaction solution was cooled spontaneously, mixed with 500 ml of 1N hydrochloric acid and then filtered through celite. The organic layer was separated, washed with saturated brine (500 ml*2) and then dried over anhydrous sodium sulfate. By evaporating the solvent, 90.31 g (95%) of the title compound was obtained as an oily substance. 1 H-NMR (400 MHz, CDCl3) delta: 1.08-1.18 (4H, m), 1.23 (3H, t, J=6.84 Hz), 1.27 (3H, t, J=7.33 Hz), 1.43 (3H, s), 2.91 (1H, d, J=15.14 Hz), 2.98 (1H, d, J=15.14 Hz), 4.09 (2H, q, J=6.84 Hz), 4.19 (2H, dq, J=1.95 Hz, J=6.84 Hz).
(E)-ethyl 1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)cyclopropanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.26 g
solution of Lambda/,/V-diisopropylamine (2.51 g, 24.8 mmol) in tetrahydrofuran (150 mL) under argon was cooled in an ice water bath. A solution of n-butyllithium in hexanes (2.5 M, 9.7 mL, 24 mmol) was added dropwise over 2 min, and the resulting solution was stirred for 15 additional minutes. The solution was then cooled to -78C via C02(S):acetone bath, and ethyl 1- acetylcyclopropanecarboxylate (3.47 g, 22.2 mmol) was added dropwise over 2 min. The solution was stirred for an additional 20 min, and /V-Phenyl-bis(trifluoromethanesulfonimide) (8.4 g, 23.5 mmol) was added as a solution in tetrahydrofuran (24 mL) via canula over 5 min, washing with additional portions of tetrahydrofuran (2 x 5 mL). The resulting solution was removed from the cold bath. After an additional 30 min, the reaction mixture was concentrated in vacuo and was diluted with diethyl ether (200 mL). The organic phase was washed with 1 M aqueous sodium hydroxide (1 x 100 mL, 1 x 30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 6.6 g of a crude oil that was used without further purification. A solution of the crude material from the previous step in anhydrous pyridine (1 1 mL) was heated to 90C. After 16.5 h, the reaction mixture was diluted with diethyl ether (200 mL) and 3 M hydrochloric acid (100 mL) and the phases were separated. The organic phase was washed with 3 M hydrochloric acid (50 mL) and 1 M sodium hydroxide (50 mL), dried over magnesium sulfate, filtered, and concentrated to afford 2.2 g of a crude liquid that was used without further purification. To an argon-flushed vessel containing zirconocene dichloride (410 mg, 1 .6 mmol) was added a solution of the crude product from the previous step (2.2 g, ca. 16 mmol) and pinacolborane (3.1 g, 24 mmol) in dichloromethane (8 mL). After 1 16 h, the stirred reaction mixture was diluted with ethyl acetate (50 mL) and was quenched by dropwise addition of water. The mixture was further diluted with water (50 mL), and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to a crude residue that was purified by silica gel chromatography (5 to 20% ethyl acetate in /'so-hexanes, continuous gradient) to afford the title compound (1.26 g, 21 % over 3 steps) as an oil that crystallized on standing at -15C.
N-(4-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide[ No CAS ]
1-(N-(4-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide)-2-(tert-butoxycarbonylamino)acetate[ No CAS ]
1-(1,1,1-trifluoro-2-hydroxypropan-2-yl)cyclopropanecarboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
Ethyl 1-acetyl-cyclopropane (2.00g, 12.8mmol), cesium fluoride (195mg, 1.28mmol) was dissolved in tetrahydrofuran (30 mL), and then at 0C trifluoromethyl trimethylsilane (3.64g25.6mmol) was added. It was allowed to react at 20C under nitrogen gas protection for 6 hours. Then dilute 4N hydrochloric acid (7mL) was added . Reaction at room temperature under nitrogen gas protection for 6 hours. Saturated sodium bicarbonate solution (30 mL) was added to quench the reaction, extracted with ethyl acetate (100mLx3), organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography(10: 1 petroleum ether / ethyl acetate, Rf = 0.4) to give 1- (1,1,1-trifluoro-2-hydroxy-2-yl) cyclopropanecarboxylic acid (1.70 g, white oil). Yield: 59%.
(2-bromoethyl)(diphenyl)sulfonium trifluoromethanesulfonate[ No CAS ]
[ 32933-03-2 ]
Yield
Reaction Conditions
Operation in experiment
71%
With potassium carbonate; In ethyl acetate; at 20℃; for 1.5h;
General procedure: Powdered K2CO3(207 mg, 1.5 mmol) and 1,3-cyclohexanedione (8a) (56 mg, 0.50 mmol) were added to a suspension of sulfonium salt 13(332 mg, 0.75 mmol) in EtOAc (5 mL). After stirring at r.t. for 1.5 h, the reaction was quenched with water (10 mL) and the whole mixture was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (10 mL) and dried over anhydrous MgSO4. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, 30% EtOAc in hexane) to provide 1a (60 mg, 87%) as a colorless oil
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
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