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[ CAS No. 1153949-11-1 ]

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CAS No. :1153949-11-1 MDL No. :MFCD12761241
Formula : C10H14N2O2 Boiling Point : 309.7±35.0°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :194.23 g/mol Pubchem ID :45789216
Synonyms :

Safety of [ 1153949-11-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
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Application In Synthesis of [ 1153949-11-1 ]

  • Upstream synthesis route of [ 1153949-11-1 ]
  • Downstream synthetic route of [ 1153949-11-1 ]

[ 1153949-11-1 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 398489-26-4 ]
  • [ 50586-62-4 ]
  • [ 1153949-11-1 ]
YieldReaction ConditionsOperation in experiment
91%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at -15 - -5℃; for 3 h; Inert atmosphere
Stage #2: for 18 h; Inert atmosphere
24.8 g of diethyl cyanomethyl phosphate and 300 ml of anhydrous tetrahydrofuran were added to a 1000 ml four-necked flask under nitrogen.Slowly cool down to -15 ~ -10 ° C, under the protection of nitrogen, slowly add 128.5 ml of 1.0N potassium t-butoxide potassium tetrahydrofuran solution,At the same time, the temperature is controlled below -5 ° C, after the end of the addition,The reaction temperature was continued to be stirred at -10 to -5 ° C for 3 hours;The temperature of the control was below -5 ° C, and a solution of the intermediate 6 in tetrahydrofuran (20.0 g of the intermediate 6 dissolved in 67 ml of tetrahydrofuran) was slowly added dropwise.After the completion of the dropwise addition, the temperature was controlled to continue stirring at -10 to -5 ° C for 2 hours;The reaction solution was slowly warmed to 25 to -30 ° C and stirred at this temperature for 16 hours.After the reaction was completed, 300 ml of a 12.5percent aqueous sodium chloride solution was slowly added, and the layers were separated.The aqueous phase was extracted with 300 mL of ethyl acetate.The organic phases were combined and washed with brine (200 mL)A product of 20.65 white solid was obtained in a yield of 91percent.
61%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at -14 - 5℃; for 3 h;
Stage #2: at -10 - 20℃;
Step 4. tert-Butyl 3-(cyanomethylene)azetidine-l-carboxylate (13) Diethyl cyanomethyl phosphate (12, 745 g, 4.20 mol, 1.20 equiv) and anhydrous tetrahydrofuran (THF, 9 L) was added to a four-neck flask equipped with a thermowell, an addition funnel and the nitrogen protection tube at room temperature. The solution was copied with an ice-methanol bath to - 14 °C and a l .O M solution of potassium teri-butoxide (f-BuO ) in anhydrous tetrahydrofuran (THF, 3.85 L, 3.85 mol, 1.1 equiv) was added over 20 minutes keeping the reaction temperature below - 5 °C. The resulting reaction mixture was stirred for 3 hours at - 10 °C and a solution of l -/er/-butoxycarbonyl-3-azetidinone (11, 600 g, 3.50 mol) in anhydrous tetrahydrofuran (THF, 2 L) was added over 2 h keeping the internal temperature below - 5 °C. The reaction mixture was stirred at - 5 to - 10 °C over 1 hour and then slowly warmed up to room temperature and stirred at room temperature for overnight. The reaction mixture was then diluted with water (4.5 L) and saturated aqueous sodium chloride solution (NaCl, 4.5 L) and extracted with ethyl acetate (EtOAc, 2 x 9 L). The combined organic layers were washed with brine (6 L) and dried over anhydrous sodium sulfate (Na2S04). The organic solvent was removed under reduced pressure and the residue was diluted with dichloromethane (CH2CI2, 4 L) before being absorbed onto silica gel (S1O2, 1.5 Kg). The crude product, which was absorbed on silica gel, was purified by flash column chromatography (Si02, 3.5 Kg, 0 - 25percent EtOAc/hexanes gradient elution) to afford terf-butyl 3-(cyanomethylene)azetidine-l - carboxylate (13, 414.7 g, 679.8 g theoretical, 61 percent yield) as white solid. For 13: NMR (CDC , 300MHz), 6 5.40 (m, 1H), 4.70 (m, 2H), 4.61 (m, 2H), 1.46 (s, 9H) ppm; C,oH, N202 (MW, 194.23), LCMS (EI) mle 217 (M+ + Na).
4.3 g With potassium <i>tert</i>-butylate In tetrahydrofuran at -7 - 20℃; Inert atmosphere Dissolving cyanomethyl diethyl phosphate in THF (75 mE), cooling to —7-—5° C. under the protection of nitrogen, dropwise adding potassium tert-butoxide/THF (3.6 g is dissolved in 35 mE of THF), keeping for 3 h after addition, dropwise adding 1 -l3oc-3-azetidinone/THF solution (5 g is dissolved in 15 mE of THF), keeping for 1 hand then stirring overnight at room temperature, using EAH20 for extraction afier adding water for quenching, spinning it dry to obtain 8 g of crude product, and putting the product into the column to obtain 4.3 g of white solid productCF0726Y.
Reference: [1] Patent: CN108752254, 2018, A, . Location in patent: Paragraph 0097-0099
[2] Patent: WO2013/36611, 2013, A1, . Location in patent: Page/Page column 28; 29
[3] Patent: US2016/333015, 2016, A1, . Location in patent: Paragraph 0055; 0056; 0081; 0082; 0105; 0106; 0134; 0135
  • 2
  • [ 398489-26-4 ]
  • [ 2537-48-6 ]
  • [ 1153949-11-1 ]
YieldReaction ConditionsOperation in experiment
99%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃;
To a suspension of sodium hydride (60percent dispersion in mineral oil, 0.257 g, 6.42 mmol) in tetrahydrofuran (32 mL) at 0° C. under a nitrogen atmosphere was added diethyl cyanomethylphosphonate (1.19 g, 6.72 mmol) (purchased from Aldrich).
The reaction was then stirred for 45 minutes at room temperature.
A solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.00 g, 5.84 mmol) (purchased from Alfa Aesar) in tetrahydrofuran (8.8 mL) was introduced dropwise and the mixture was stirred for 16 hours.
Brine and ethyl acetate were added and the layers separated.
The aqueous layer was extracted with three portions of ethyl acetate.
The combined extracts were dried over sodium sulfate, filtered and concentrated to afford product, used without further purification in Step 2 (1.12 g, 99percent).
1H NMR (300 MHz, CDCl3): δ 5.38 (p, 1H), 4.73-4.68 (m, 2H), 4.64-4.59 (m, 2), 1.46 (s, 9H).
98%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃;
Stage #2: at 0℃;
Stage #3: With water In tetrahydrofuran
Step A: Preparation of tert-butyl 3-(cyanomethylene)azetidine-l -carboxylate:In a 5L flask, a suspension of NaH (24.531 g, 613.34 mmol) in 500 mL of THF was cooled in an ice bath. A solution of diethyl cyanomethylphosphonate (104.08 mL, 648.39 mmol) in THF (200 mL) was added dropwise. After addition, another 120 mL of THF was added to aid stirring. The reaction was warmed to ambient temperature for 1 hour then cooled back to 0 °C for 1 hour to give a milky yellow solution. Then a solution of tert-butyl 3-oxoazetidine- 1-carboxylate (100.00 g, 584.13 mmol) in THF (400 mL) was added dropwise over an hour. The resultant reaction mixture was stirred for 15 hours, then quenched with water and concentrated to remove THF. The resultant aqueous solution was extracted with EtOAc. The combined organic layers were washed with brine and dried with MgS04. The filtrate was concentrated down to a yellow oil, which precipitated out a yellow solid after sitting overnight. This solid was diluted in cold EtOAc, sonicated, filtered and washed with cold EtOAc and hexanes to afford 82.09 g of a cream colored solid (80percent). Additional product was isolated by concentrating the filtrate in vacuo and purifying by silica chromatography using a gradient of 20-30percent EtOAc/Hexanes to afford an additional 18.6 g (18percent>) of tert-butyl 3-(cyanomethylene)azetidine-l-carboxylate. lH NMR (CDC13) δ 5.38 (m, 1H), 4.69-4.72 (m, 2H), 4.60-4.63 (m, 2H), 1.46 (s, 9H).
95%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 30℃;
Stage #2: at 0 - 30℃;
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (30.7 mL) at 0 0C was added dropwise a solution of diethyl cyanomethylphosphonate (5.20 mL, 0.0322 mol) in tetrahydrofuran (39.12 mL). The reaction was warmed to room temperature and then cooled to 0 0C again. To the reaction mixture was added a solution of tert-butyl 3-oxoazetidine-l-carboxylate (5.0 g, 0.029 mol) in tetrahydrofuran (7.82 mL). The reaction was allowed to warm up to room temperature and stirred at room temperature overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 70percent EtOAc in hexanes, to give the desired product (5.40 g, 95percent). LCMS (M+Na) 217.1.
95% With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; Step 2: tert-butyl 3-(cyanomethylene)azetidine-l-carboxylateTo a solution of 1.0 M potassium tert-butoxide in tetrahydrofuran (30.7 mL, 0.0307 mol) at 0 °C was added dropwise a solution of diethylcyanomethylphosphonate (5.20 mL, 0.0322 mol) in tetrahydrofuran (39.12 mL). The reaction was warmed to room temperature and then cooled at 0 °C again. To the reaction mixture was added a solution of tert-butyl 3-oxoazetidine-l-carboxylate (5.0 g, 0.029 mol, Aldrich: Cat.No.696315) in tetrahydrofuran (7.82 mL). The reaction was allowed to warm to room temperature and stirred overnight. After quenched with water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgS04 and evaporated under reduced pressure. The crude mixture was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0 - 70percent) to give the desired product (5.40 g, 95percent). LCMS (M+Na)+: m/z = 217.1.
95% With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; To a solution of 1.0 M potassium tert-butoxide in tetrahydrofuran (30.7 mL, 30.7 mmol) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (5.20 mL, 32.2 mmol) in tetrahydrofuran (39 mL). The reaction was warmed to room temperature and then cooled at 0° C. again. To the reaction mixture was added a solution of tert-butyl 3-oxoazetidine-1-carboxylate (5.0 g, 0.029 mol, from Aldrich) in tetrahydrofuran (8 mL). The reaction was allowed to warm to room temperature and stirred overnight. After quenched with water, the mixture was extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over MgSO4, and evaporated under reduced pressure. The crude mixture was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-70percent) to give the desired product (5.40 g, 95percent). LCMS cacld. for C10H14N2O2Na (M+Na)+: m/z=217.1. Found: 217.1
84%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2 h;
Stage #2: at 0℃;
A suspension of NaH (260 mg, 11 mmol) in 25 mL of THF was cooled in a 100 mL flask in an ice bath. A solution of diethyl cyanomethylphosphonate (1.1 mL, 6.72 mmol, 1.15 equiv.) in THF (20 mL) was added dropwise. The reaction was warmed to room temperature for 1 h then cooled back to 0 °C for 1 h to give a milky yellow solution. Then a solution of tert-butyl 3-oxoazetidine-1-carboxylate (1) (1.0 g, 5.84 mmol) in THF (10 mL) was added drop-wise over 1 h. The resulting reaction mixture was stirred overnight, then quenched with water and concentrated to remove THF. The resulting aqueous solution was extracted with EtOAc. The combined organic layers were washed with brine and dried with MgSO4. The filtrate was concentrated down to a yellow oil which was purified by silica chromatography using a gradient of 20–30percent EtOAc/hexanes to afford compound 2: Yield 939 mg (84percent); m.p. 75–77 °C; IR (KBr): 2987, 2222,1684, 1406, 1162 cm–1. Anal. calcd for C10H14N2O2: C, 61.84; H, 7.27; N, 14.42; found: C, 61.95; H, 7.46; N, 14.38percent. MS (m/z): 217 [M + Na]+; 1H NMR (300 MHz, CDCl3): δ 1.46 (s, 9H), 4.62 (t, J = 1.9 Hz, 2H),4.70 (t, J = 3.2 Hz, 2H), 5.38 (t, J = 2.3 Hz, 1H); 13C NMR (75 MHz, DMSO-d6): δ 27.9, 39.5, 79.4, 92.8, 115.2, 155.6, 158.4.
83%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 25℃; for 2 h; Inert atmosphere
Stage #2: at 0 - 25℃;
Sodium hydride (0.260 g, 0.011 mol) was dissolved in a tetrahydrofuran solvent in a nitrogen-sealed three-necked flask, Cooled to 0 ° C, and compound 7 (1100 ml, 6.72 mmol, 1.15 equiv) was dissolved in tetrahydrofuran solvent,Slowly added to the preceding solution. The mixture was allowed to warm to room temperature (25 ° C) for 1 hour,The reaction was further cooled to 0 ° C and reacted for 1 hour.Compound 1 (1.0 g, 5.84 mmol)Dissolved in tetrahydrofuran solvent,The above mixed solution was slowly added,And the mixture was stirred for 1 hour. To room temperature (25 & lt; 0 & gt; C)The reaction was run overnight (12 h).Cold water quenching, rotary steam solvent in addition to tetrahydrofuran. Extracted with ethyl acetate, the aqueous layer was separated and the organic layer was washed with brine. Dried over anhydrous magnesium sulphate, filtered, concentrated and purified by column chromatography to give 0.939 g of a white solid in 83percent yield.
73%
Stage #1: With sodium hydride In tetrahydrofuran at 4℃; for 0.75 h; Inert atmosphere
Stage #2: at 20℃; for 16 h;
0.81 g sodiumhydride (55percent purity, 18.6 mmol, 1.1 eq.) was suspended in 96 mL THE under argon atmosphere. At 4 C bath temperature 3. 45 g diethyl (cyanomethyl)phosphonate (19.5 mmol, 1.15 eq.) was added drop wise. After 45 minutes at room temperature 2.90 g of the commercial available starting material tert-butyl 3-oxoazetidine-1-carboxylate (16.9 mmol, 1.0 eq.), dissolved in 15 mL THE, were added drop wise. It was stirred at room temperature for 16 hours. The reaction mixture was poured into half concentrated sodium chloride solution and extracted three times with EE, dried over sodium sulfate and was concentrated under reduced pressure. The crude product was purified by flash chromatography to provide 2.40 g of the target compound:12.36 mmol, 73percent.1H NMR (400 MHz, DMSO-d6) 6 [ppm]= 1.34-1.43 (m, 9 H) 4.57 (br. s., 2 H) 4.64 (br. s.,2 H) 5.79 - 5.86 (m, 1 H).
66.1%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 3 - 18.2℃; for 1.58333 h; Inert atmosphere
Stage #2: for 24 h;
An oven-dried 1 L 4-neck round bottom flask fitted with stir bar, septa, nitrogen inlet, 250 ml addition funnel and thermocouple was charged with sodium hydride (5.6 g, 0.14 mol) and tetrahydrofuran (THF) (140 mL) under a nitrogen atmosphere. The mixture was chilled to 3° C., and then charged with diethyl cyanomethylphosphonate (22.4 mL, 0.138 mol) dropwise via a syringe over 20 minutes. The solution became a light yellow slurry. The reaction was then stirred for 75 minutes while warming to 18.2° C. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (20 g, 0.1 mol) in tetrahydrofuran (280 mL) was prepared in an oven-dried round bottom, charged to the addition funnel via canula, then added to the reaction mixture dropwise over 25 minutes. The reaction solution became red in color. The reaction was allowed to stir overnight. The reaction was checked after 24 hours by TLC (70percent hexane/EtOAc) and found to be complete. The reaction was diluted with 200 mL of 20percent brine and 250 mL of EtOAc. The solution was partitioned and the aqueous phase was extracted with 250 mL of EtOAc. The combined organic phase was dried over MgSO4 and filtered, evaporated under reduced pressure, and purified by flash chromatography (0percent to 20percent EtOAc/hexanes, 150 g flash column) to give the desired product, tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (15 g, 66.1percent yield).
66.1%
Stage #1: With sodium hydride In tetrahydrofuran at 3 - 18.2℃; for 1.58333 h; Inert atmosphere
Stage #2: Inert atmosphere
An oven-dried 1 L 4-neck round bottom flask fitted with stir bar, septa, nitrogen inlet, 250 ml addition funnel and thermocouple was charged with sodium hydride (5.6 g, 0.14 mol) and tetrahydrofuran (THF) (140 mL) under a nitrogen atmosphere.
The mixture was chilled to 3° C., and then charged with diethyl cyanomethylphosphonate (22.4 mL, 0.138 mol) dropwise via a syringe over 20 minutes.
The solution became a light yellow slurry.
The reaction was then stirred for 75 minutes while warming to 18.2° C. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (20 g, 0.1 mol) in tetrahydrofuran (280 mL) was prepared in an oven-dried round bottom, charged to the addition funnel via canula, then added to the reaction mixture dropwise over 25 minutes.
The reaction solution became red in color.
The reaction was allowed to stir overnight.
The reaction was checked after 24 hours by TLC (70percent hexane/EtOAc) and found to be complete.
The reaction was diluted with 200 mL of 20percent brine and 250 mL of EtOAc.
The solution was partitioned and the aqueous phase was extracted with 250 mL of EtOAc.
The combined organic phase was dried over MgSO4 and filtered, evaporated under reduced pressure, and purified by flash chromatography (0percent to 20percent EtOAc/hexanes, 150 g flash column) to give the desired product, tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (15 g, 66.1percent yield).
62%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 73 h;
Stage #2: With water In tetrahydrofuran; mineral oil at 20℃;
To a suspension of NaH (60percent in mineral oil) (1.4g 35 mmol) in THF (100 mL) at 0 °C was added dropwise diethyl phosphonate (6.45 mL, 41 mmol) and stirred at room temperature for 1 h. A solution of l-boc-3-one-azetidine (45a) (5g, 29.2 mmol) in THF (45 mL) was added to the anion at room temperature and stirred for 72 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel 80 g, eluting with ethylacetate/hexanes, 0-100percent) to furnish tert-butyl 3 -(cyanomethylene)azetidine-l -carboxylate (45b) (3.52 g, 62percent) as a white solid.1H NMR (300 MHz, DMSO) δ 5.84 (s, J= 2.5, IH), 4.74 - 4.51 (m, 4H), 1.53 - 1.30 (s, 9H); MS (ES-) 193.4 (M-l); IR (KBr) 2222 cm"1; Analysis; Calcd for C10H14N2O2: C, 61.84; H, 7.27; N, 14.42; Found C, 61.94; H, 7.28; N, 14.38.
414.7 g
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at -14 - -5℃; for 3 h; Inert atmosphere
Stage #2: at -5 - 20℃;
tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (2) [0157] Diethyl cyanomethyl phosphate (745 g, 4.20 mol, 1.20 equiv) and anhydrous tetrahydrofuran (THF, 9 L) were added to a four-neck flask equipped with a thermowell, an addition funnel and the nitrogen protection tube at room temperature. The solution was cooled with an ice-methanol bath to −14° C. and a 1.0 M solution of potassium tert-butoxide (t-BuOK) in anhydrous tetrahydrofuran (THF, 3.85 L, 3.85 mol, 1.1 equiv) was added over 20 min keeping the reaction temperature below −5° C. The resulting reaction mixture was stirred for 3 h at −10° C. and a solution of 1-tert-butoxycarbonyl-3-azetidinone (600 g, 3.50 mol) in anhydrous tetrahydrofuran (THF, 2 L) was added over 2 h keeping the internal temperature below −5° C. The reaction mixture was stirred at −5 to −10° C. over 1 h and then slowly warmed up to room temperature and stirred at room temperature for overnight. The reaction mixture was then diluted with water (4.5 L) and saturated aqueous sodium chloride solution (NaCl, 4.5 L) and extracted with ethyl acetate (EtOAc, 2×9 L). The combined organic layers were washed with brine (6 L) and dried over anhydrous sodium sulfate (Na2SO4). The solvent was removed under reduced pressure and the residue was diluted with dichloromethane (CH2Cl2, 4 L) before being absorbed onto silica gel (SiO2, 1.5 Kg). The crude product, which was absorbed on silica gel, was purified by flash column chromatography (SiO2, 3.5 Kg, 0-25percent EtOAc/hexanes gradient elution) to afford tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 414.7 g, 679.8 g theoretical, 61percent yield) as a white solid. For 2: 1H NMR (300 MHz, CDCl3) δ 5.40 (m, 1H), 4.70 (m, 2H), 4.61 (m, 2H), 1.46 (s, 9H) ppm; C10H14N2O2 (MW, 194.23), LCMS (EI) m/e 217 (M++Na).

Reference: [1] Patent: US2009/233903, 2009, A1, . Location in patent: Page/Page column 26-27; 58
[2] Patent: WO2011/130146, 2011, A1, . Location in patent: Page/Page column 84-85
[3] Patent: WO2009/64835, 2009, A1, . Location in patent: Page/Page column 44
[4] Patent: WO2012/177606, 2012, A1, . Location in patent: Page/Page column 57-58
[5] Patent: US2014/343030, 2014, A1, . Location in patent: Paragraph 0420; 0421; 0422
[6] Journal of Chemical Research, 2016, vol. 40, # 4, p. 205 - 208
[7] Patent: CN105541891, 2016, A, . Location in patent: Paragraph 0070; 0071; 0072; 0073; 0074; 0075
[8] Patent: WO2016/41925, 2016, A1, . Location in patent: Page/Page column 255; 256
[9] Patent: US2011/224190, 2011, A1, . Location in patent: Page/Page column 36-37
[10] Patent: US2015/246046, 2015, A1, . Location in patent: Paragraph 0131
[11] Patent: WO2011/31554, 2011, A2, . Location in patent: Page/Page column 154
[12] Patent: WO2013/55645, 2013, A1, . Location in patent: Paragraph 00368
[13] Patent: US2014/256941, 2014, A1, . Location in patent: Paragraph 0157
[14] European Journal of Organic Chemistry, 2017, vol. 2017, # 31, p. 4530 - 4542
[15] Patent: EP3290418, 2018, A1, . Location in patent: Paragraph 0081
  • 3
  • [ 398489-26-4 ]
  • [ 15898-47-2 ]
  • [ 1153949-11-1 ]
YieldReaction ConditionsOperation in experiment
37% With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 1 h; Inert atmosphere Under nitrogen, a suspension of (cyanomethyl)triphenylphosphanium bromide (13.4 g, 35.09 mmol) in anhydrous THF (100 mL) was cooled to 0° C., a solution of 2.5 M n-BuLi in n-hexane (15.5 mL, 38.59 mmol) was added dropwise. The mixture tert-butyl-3-oxoazetidine-1-carboxylate (6.0 g, 35.09 mmol) was added, and the mixture was warmed to room temperature and stirred for further 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (150 mL×3). The organic layers were combined, washed with water (100 mL×3) and saturated brine (100 mL) in sequence, dried over anhydrous sodium sulfate. The resultant mixture was filtrated, the filtrate was concentrated in vacuum, and the residue was purified by silica column chromatography (petroleum ether:ethyl acetate=5:1) to give a white solid 5-c (2.5 g, yield: 37percent). LC-MS (ESI): m/z=217 [M+Na]+.
Reference: [1] Patent: US2015/336982, 2015, A1, . Location in patent: Paragraph 0134; 0135
  • 4
  • [ 141699-55-0 ]
  • [ 1153949-11-1 ]
Reference: [1] Patent: US2011/224190, 2011, A1,
[2] Patent: WO2013/36611, 2013, A1,
[3] Patent: US2014/256941, 2014, A1,
[4] Patent: US2015/246046, 2015, A1,
[5] Patent: CN108752254, 2018, A,
  • 5
  • [ 1153949-11-1 ]
  • [ 1187595-85-2 ]
Reference: [1] Patent: WO2013/40863, 2013, A1,
[2] Journal of Chemical Research, 2016, vol. 40, # 4, p. 205 - 208
[3] Patent: US2016/333015, 2016, A1,
[4] Patent: CN105541891, 2016, A,
[5] Patent: EP3290418, 2018, A1,
  • 6
  • [ 1153949-11-1 ]
  • [ 1187594-09-7 ]
Reference: [1] Journal of Chemical Research, 2016, vol. 40, # 4, p. 205 - 208
[2] Patent: CN105541891, 2016, A,
  • 7
  • [ 1153949-11-1 ]
  • [ 1314910-43-4 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogenchloride In 1,4-dioxane for 2.5 h; Inert atmosphere; Cooling with ice General procedure: Compound 1d (1.0 g, 5.15 mmol) and a 4M solution of HCI in dioxane (10 mL) were added to a 50 mL reaction flask, argon atmosphere protection was applied, and the reaction was stirred in an ice bath for 2.5 h, while white solid gradually precipitated.
The reaction was monitored by thin layer chromatography.
After the reaction was complete, the reaction solution was filtered with suction, and the filter cake was washed with anhydrous ether and dried, to afford 2-(azetidin-3-ylidene) acetonitrile hydrochloride salt (1e) (600 mg, yield: 90.0percent, white solid), which was used directly in the next reaction.
75% With hydrogenchloride In methanol; waterReflux Aqueous hydrochloric acid (6N, 10 mL) and montmorillonite K-10 (2 g) were added into a reaction vessel at ambient temperature. The contents were stirred for 1 hour, and then filtered under reduced pressure to obtain activated montmorillonite K-10. The activated montmorillonite K-10 was added into another reaction vessel containing tert- butyl 3-(cyanomethylidene)azetidine-l-carboxylate (2 g; Formula VI) and methanol (20 mL) at ambient temperature. The reaction mixture was refluxed for about 12 hours to about 15 hours. On completion, the reaction mixture was filtered under reduced pressure followed by recovery of methanol under reduced pressure at about 40°C to about 45°C to obtain 3-(cyanomethylene)azetidine hydrochloride. Yield: 75percent
67.8% With hydrogenchloride In isopropyl alcohol at 20℃; for 18 h; Inert atmosphere 2-(Azetidin-3-ylidene)acetonitrile hydrochloride (2a) [0145] To a 0.5-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were added tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 30 g, 154.46 mmol) and methylenechloride (300 mL) at ambient temperature. The solution was then treated with a solution of 5 M hydrogen chloride (HCl) in isopropanol solution (294.2 mL, 1.54 mol, 10 equiv) at ambient temperature and the resulting reaction mixture was stirred at ambient temperature for 18 hours. After the reaction was complete as monitored by HPLC, the suspension was added tert-butyl methyl ether (TBME, 150 mL), and the mixture was stirred at ambient temperature for 2 hours. The solids was collected by filtration, washed with n-heptane (2×100 mL), and dried on the filtration funnel at ambient temperature for 3 hours to afford 2-(azetidin-3-ylidene)acetonitrile hydrochloride (2a, 13.7 g, 20.2 g theoretical, 67.8percent) as a white solid. For 2a: 1H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 2H), 5.94 (p, J=2.5 Hz, 1H), 4.85-4.80 (m, 2H), 4.77-4.71 (m, 2H) ppm; 13C NMR (126 MHz, DMSO-d6) δ 155.65, 114.54, 94.78, 55.26, 54.63 ppm; C5H7ClN2 (MW 130.58; C5H6N2 for free base, MW 94.11), LCMS (EI) m/e 95 (M++H).
Reference: [1] Patent: EP3360878, 2018, A1, . Location in patent: Paragraph 0082; 0085; 0151; 0154; 0158; 0161; 0165; 0168
[2] Patent: WO2016/125080, 2016, A2, . Location in patent: Page/Page column 10; 11
[3] Patent: US2014/256941, 2014, A1, . Location in patent: Paragraph 0145
[4] Patent: US2009/233903, 2009, A1, . Location in patent: Page/Page column 63-64
[5] Patent: WO2013/40863, 2013, A1, . Location in patent: Page/Page column 109-110
[6] Patent: US2016/333015, 2016, A1, . Location in patent: Paragraph 0055; 0057; 0081; 0083; 0105; 0107; 0134; 0136
  • 8
  • [ 1153949-11-1 ]
  • [ 1314910-43-4 ]
  • [ 1379208-59-9 ]
Reference: [1] Patent: US2009/233903, 2009, A1, . Location in patent: Page/Page column 58-60
  • 9
  • [ 1153949-11-1 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: WO2013/36611, 2013, A1,
[2] Patent: US2014/256941, 2014, A1,
[3] Patent: US2015/246046, 2015, A1,
  • 10
  • [ 1153949-11-1 ]
  • [ 142253-58-5 ]
YieldReaction ConditionsOperation in experiment
98% With palladium 10% on activated carbon; hydrogen In methanol; water at 20℃; for 2 h; 2.60 g of tert-butyl 3-(cyanomethylidene)azetidine-1-carboxylate 1-8-1 (13.9 mmol, 1.0 eq.) was dissolved in 130 mL methanol and treated with 513mg palladium 10percent on carbonand 50percent water (0.48 mmol, 0.036 eq.). It was stirred for two hours at room temperatureunder hydrogen atmosphere. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure to provide 2.63 g of the target compound. 13.3mmol, 98percent.1HNMR (400MHz, chloroform-d): 6 [ppm]=. 1.47(s,9 H) 2.66 (d, J=7.07 Hz, 2 H) 2.83-2.93 (m, 1 H) 3.71 (dd, J=9.09, 5.05 Hz, 2 H) 4.15 (t, J=8.59 Hz, 2 H).
Reference: [1] Patent: WO2016/41925, 2016, A1, . Location in patent: Page/Page column 254; 255
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