* 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.
The dry and clean 500mL coil was heated to 135 ° C, to take Compound 6 (standard atmospheric pressure boiling point of 117 to 119 ° C) 1000g (0.7eq.10.81mol) placed in a feeding bottle A, adding 4000g of toluene diluted trimethyl phosphite (standard large Pressure of boiling point 112 ° C) 1878g (1.0eq.15.13mol) placed in the bottle B, 3122g of toluene was added to be diluted to be coiled The batch was started after the temperature was stabilized, and pump A (toluene solution of compound 6): 12.5 g / min, pump B (trimethyl phosphite): 12.5 g / min. Residence time 20min, the reaction pressure is 0.5 ~ 2.0Mpa. The discharge port is directly connected to the thin-film evaporation device to control the pressure4 to 10 × 102 Pa and temperature of 60 to 70 ° C. Finally, 1230 g of product 7 (boiling point 85 to 88 ° C., 666 Pa) was obtained in a yield of 88percent.
45%
With potassium iodide In acetone; acetonitrile at 20 - 50℃; for 10 h;
Dimethyl 2-oxopropylphosphonate (52). A 2-liter eggplant type flask was charged with 179.2 g (1.08 1 mol) of potassium iodide, 300 ml of acetone and 250 ml of acetonitrile, to which 100 g (1.08 1 mol) of chloroacetone was added, thereby forming a whitesuspension. Further 134 g (1.08 1 mol) of trimethylphosphite was added and the resulting mixture was stirred for 6 hours at 20°C and 4 additional hours at 5 0°C. After that reaction mixture was filtered through the Celite pad and filtrate was distilled off to obtain a product in the form of brown oil. This oily product was subjected to fractional distillation under reduced pressure (8 1-85° C. and 0.02 mmHg) to obtain 127.5 g (45percent) of title compound
36%
Stage #1: With potassium iodide In acetone; acetonitrile at 20℃; for 0.833333 h; Stage #2: With triphenylphosphine In acetone; acetonitrile at 20 - 50℃; for 17 h;
To a stirred suspension of KI (33.2 g, 200 mmol) in acetone/CH3CN (120 mL, 3:4 v/v), chloroacetone SI-3 (15.9 mL, 200 mmol) was added and the obtained reaction mixture was stirred for 50 min at room temperature. Then, trimethylphosphite (23.6 mL, 200 mmol) was added and the obtained suspension was stirred overnight at room temperature. Finally, the reaction mixture was heated to 50°C, and stirring was continued for 1 h to ensure complete conversion. Then, the suspension was filtered over Celite and the residue was rinsed with acetone (2 × 20 mL). The filtrate was concentrated under reduced pressure and the SI-4residue was purified by vacuum distillation (product fraction was collected at 101 °C at 3.5 mbar). Ketone SI-4 was obtained as a colorless oil in 36percent yield (12.0 g). Rf 0.65 (CH2Cl2/MeOH 9:1 v/v);1H-NMR (300 MHz, CDCl3) δ = 2.32 (s, 3H, CH3), 3.11 (d (JH,P = 22.8 Hz), 2H, CH2), 3.80 (d (JH,P= 11.2 Hz), 6H, OCH3);13C-NMR (75 MHz, CDCl3): δ = 31.0, 41.0, 42.7, 52.7/52.8, 199.4 (two lines).
Reference：
[1] Patent: CN107163079, 2017, A, . Location in patent: Paragraph 0076; 0077; 0078
[2] Organic Letters, 2015, vol. 17, # 5, p. 1308 - 1311
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8765 - 8780
[4] Journal of the American Chemical Society, 1995, vol. 117, # 10, p. 2931 - 2932
[5] Organic and Biomolecular Chemistry, 2017, vol. 15, # 15, p. 3304 - 3309
[6] European Journal of Organic Chemistry, 2014, vol. 2014, # 17, p. 3622 - 3636
[7] Patent: WO2017/189553, 2017, A1, . Location in patent: Paragraph 0295; 0296
[8] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 19, p. 5345 - 5353
2
[ 141-78-6 ]
[ 756-79-6 ]
[ 4202-14-6 ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: With n-butyllithium In hexane; toluene at -80℃; for 0.166667 h; Inert atmosphere Stage #2: at -80℃; for 1 h; Inert atmosphere
Dimethyl methylphosphonate (119 mL, 1.10 mol) in abs. toluene (280 mL) was added at -80°C under nitrogen atmosphere to a solution of BuLi (660 mL, 1.10mol, 1.67 M/hexane) dissolved in abs. toluene (2.5 L). After stirring (10 min,-80°C) EtOAc (113 mL, 102 g, 1.16 mol) was added. After stirring (1 h, -80°C)the reaction mixture was poured into 1M NaHSO4 (1.2 L) solution. Thephases were separated after 0.5 h stirring, the organic phase was washed with brine (300 mL), the aqueous phase was extracted with chloroform (5 x 500 mL), the combined organic phase was dried over Na2SO4 and evaporated. The residue was purified by vacuum distillation, (distillation data: starting material: 40-45°C, 4-5 mbar, product: 87-90°C, 4-5 mbar) giving the title compound as a colourless liquid (92.07 g, 50percent)1H NMR (CDCl3, 500.15 MHz): δ = 2.30(s, 3H, CH3), 3.08 (d, 2JP,H = 22.7 Hz, 2H, CH2P),3.765 (d, 3JP,H = 11.2 Hz, 6H, OCH3). 13CNMR (CDCl3, 125.8 MHz): δ = 31.51 (CH3), 42.34 (d, 1JP,C= 127.8 Hz, CH2P), 53.14 (d, 2JP,C = 6.6 Hz,2C, OCH3), 199.78 (d, 2JP,C = 6.1 Hz). 31PNMR (CDCl3, 202.5 MHz): δ = 22.36 (m tsep, 3JP,H= 11.3 Hz, 2JP,H = 22.6 Hz).
Reference：
[1] Phosphorus, Sulfur and Silicon and the Related Elements, 2015, vol. 190, # 5-6, p. 677 - 680
[2] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 20, p. 2849 - 2854
With potassium iodide; phosphorous acid trimethyl ester In acetone; acetonitrile
(1) Synthesis of dimethyl 2-oxopropylphosphonate: A 2-liter eggplant type flask was charged with 179.2 g (1.081 mol) of potassium iodide, 300 ml of acetone and 250 ml of acetonitrile, to which 100 g (1.081 mol) of chloroacetone were added, thereby forming a white suspension. Further, 134 g (1,081 tool) of trimethylphosphite were added to stir the resulting mixture for 6 hours at 20° C. and for 4 hours at 50° C. After the thus-obtained solution was filtered through Celite, the solvent was distilled off to obtain a product in the form of a brown oil. This oily product was subjected to fractional distillation under reduced pressure (at 81-85° C. and 0.02 mmHg) to obtain 127.5 g (yield: 71percent) of dimethyl 2-oxopropylphosphonate.
Reference：
[1] Patent: US5532402, 1996, A,
5
[ 868-85-9 ]
[ 123-54-6 ]
[ 4202-14-6 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 35, p. 10539 - 10544[2] Angew. Chem., 2017, vol. 129, # 35, p. 10675 - 10680,6
6
[ 868-85-9 ]
[ 67-64-1 ]
[ 4202-14-6 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 35, p. 10539 - 10544[2] Angew. Chem., 2017, vol. 129, # 35, p. 10675 - 10680,6
7
[ 3019-04-3 ]
[ 121-45-9 ]
[ 4202-14-6 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 3, p. 518 - 522
[2] Journal of the American Chemical Society, 1963, vol. 85, p. 2394 - 2402
[3] Synthesis, 2006, # 24, p. 4266 - 4268
[4] MedChemComm, 2014, vol. 5, # 5, p. 603 - 608
8
[ 876-27-7 ]
[ 54731-75-8 ]
[ 4202-14-6 ]
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 12, p. 4815 - 4818
9
[ 103517-85-7 ]
[ 4202-14-6 ]
Reference：
[1] Synthesis, 1985, # 11, p. 1048 - 1051
10
[ 56504-60-0 ]
[ 4202-14-6 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 5, p. 2512 - 2523
11
[ 757-54-0 ]
[ 4202-14-6 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 5, p. 2512 - 2523
12
[ 90965-06-3 ]
[ 4202-14-6 ]
[ 26530-60-9 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1990, # 22, p. 1611 - 1613
13
[ 598-31-2 ]
[ 121-45-9 ]
[ 4202-14-6 ]
Reference：
[1] Tetrahedron, 1965, vol. 21, p. 1961 - 1970
[2] Chemical and Pharmaceutical Bulletin, 1987, vol. 35, # 9, p. 3898 - 3904
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1990, # 22, p. 1611 - 1613
16
[ 75-36-5 ]
[ 756-79-6 ]
[ 4202-14-6 ]
Reference：
[1] Tetrahedron, 1978, vol. 34, p. 649 - 654
17
[ 78-95-5 ]
[ 121-45-9 ]
[ 4185-82-4 ]
[ 4202-14-6 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1956, vol. 26, p. 1426,1430;engl.Ausg.S.1605,1608
18
[ 4202-14-6 ]
[ 90965-06-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil; benzene at 20℃; for 1 h; Inert atmosphere; Cooling with ice Stage #2: With 4-toluenesulfonyl azide In tetrahydrofuran; mineral oil; benzene at 20℃; Inert atmosphere
Sodium hydride (60percent in mineral oil) (1.214g, 50.61 mmol, 1 eq.) wassuspended in dry benzene (132 ml) and dry THF (43 ml) under Ar. This mixturewas cooled on ice. A solution of dimethyl (2-oxopropyl)-phosphonate (7.651g,46.06 mmol, 0.91 eq.) in dry benzene (132 ml) was added. A white solid wasformed. The reaction mixture was stirredfor 1h at room temperature. A solution of 4-methylbenzene-1-sulfonyl azide(9.582g, 48.59 mmol, 0.96 eq.) in dry benzene (23 ml)was added. The mixture was stirred over night at roomtemperature, then flitered through a celite pad and washed with toluene (100ml, x3) and EtOAC (132 ml, x14) and concentrated in vacuo. A dark orange oilwas obtained. This product was subjected directly into the next reactionwithout further purification. (11.02 g, Qtv).1H NMR (300 MHz, CDCl3): 2.22 (s, 3H), 3.81 (d, 6H, J= 11.9 Hz)ppm.13C NMR (75MHz, CDCl3):27.08, 53.51, 53.58 (d, J= 5.58 Hz), 16.33, 129.56, 189.85 (d, J= 12.98 Hz)ppm.
96%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: With 4-toluenesulfonyl azide In tetrahydrofuran at 0℃; for 0.5 h;
(ii) To a solution of compound Ill (18.00 g, 108.36 mmol) iu anhydrous THF (300 mL) was added NaH (5.2 g, 130.03 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour, theu compound 112 (25.64 g, 130.03 mmol) was added slowly into the mixture. The reaction mixture was stirred at 0 °C for 0.5 hour. The mixture was filtered, concentrated, aud purified by column chromatography ou silica gel (PE: EtOAc= 1:1) to give the desired product 113 (20 g, 96 percent).‘H NMR (400 MHz, CDCI3) 63.84 (s, 3H), 3.81 (s, 3H), 2.25 (s, 3H).
96%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: With 4-toluenesulfonyl azide In tetrahydrofuran at 0℃; for 0.5 h;
To a solution of compound 3 (18.00 g, 108.36 mmol) in anhydrous THF (300 mL) was added NaH (5.2 g, 130.03 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h, then compound 4 (25.64 g, 130.03 mmol) was added slowly into the mixture. The reaction mixture was stirred at 0 °C for 0.5 h. The mixture was filtered, concentrated, and purified by column chromatography on silica gel (PE: EtOAc= 1:1) to give the desired product (20 g, 96 percent).1H NMR (400 MHz, CDC13) 3.84 (s, 3H), 3.81 (s, 3H), 2.25 (s, 3H).
88%
With 4-toluenesulfonyl azide; sodium hydride In tetrahydrofuran at 20℃; for 12 h;
In the 1000ml counter In the bottle, 33.2 g (0.2 mol) of dimethyl acetylmethylphosphonate and 300 ml of tetrahydrofuran were added in sequence, and sodium hydride 8 g was added in batches.(0.2 mol), after the gas is completely discharged, a mixture of p-methylbenzenesulfonyl azide 47.3 g (0.24 mol) and 500 ml of tetrahydrofuran It was added to the reaction solution, and reacted at room temperature for 12 hours. After the reaction, it was diluted with petroleum ether, filtered, and the filter cake was washed with diethyl ether and evaporated under reduced pressure.In addition to the solvent, 33.7 g of a yellow liquid was obtained, yield 88percent.
85%
Stage #1: With potassium carbonate In acetonitrile at 40℃; for 1 h; Stage #2: With 4-toluenesulfonyl azide In acetonitrile at 18 - 25℃; for 2.75 h;
To a solution of dimethyl (2-oxopropyl)phosphonate (91.7 g, 0.552 mol) in acetonitrile (920 mL) was added potassium carbonate (91.6 g, 0.662 mol). The suspension was stirredat 40°C for 1 hr. A solution of tosyl azide (114.4 g, 0.58 mol) in acetonitrile (460 mL) was then added drop wise over 45 mm. The temperature was maintained between 18 °C and 24°C during the addition. The resulting mixture was stirred for an additional 2 hr at 20-25 °C and was then filtered over diatomaceous earth. The filer cake was rinsed with acetonitrile (2x100 mL) and the combined filtrates were evaporated under reduced pressure. Theresidue was purified by chromatography (silica, eluting with a mixture of ethyl acetate/heptanes) to yield dimethyl (1-diazo-2-oxopropyl)phosphonate (90.5g, 85 percent) as an oil. ‘H NMR (400 MHz, CDC13) 6 ppm 2.26 (s, 3 H), 3.82 (s, 3 H), 3.85 (s, 3 H).
81%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1 h; Inert atmosphere Stage #2: With p-toluenesulfonyl chloride In tetrahydrofuran; mineral oil at 0 - 20℃; for 2 h; Inert atmosphere
To a solution of dimethyl-2-oxopropylphosphonate (735.7 mg, 4.432 mmol) in THF (15.0 mL) at 0 °C was added 60percent NaH in mineral oil (186.1 mg, 4.654 mmol) and the reaction mixture was left to stir at 0 °C for 1 h. Tosyl azide (917.8 mg, 4.654 mmol) was added and the reaction was left to stir at rt for a further 2 h. The reaction mixture was filtered through a thin pad of Celite. The filtrate was evaporated to give a yellow oil. The oil was purified by column chromatography using gradient elution from EtOAc/petrol (1:1) to EtOAc/petrol (7:3) to give a yellow oil (686.3 mg, 3.574 mmol, 81percent yield). Rf = 0.12 in EtOAc/petrol (1:1). ESIMS m/z 193 (100percent) [M+H]+. 1H NMR d 3.84 (s, 3H, O-CH3), 3.82 (s, 3H, O-CH3), 2.26 (s, 3H, CH3). 13C NMR d 189.8 (C=N2), 189.7 (C=O), 53.5 (O-CH3), 27.0 (CH3).NMR data agreed with that reported.1
75%
With 4-toluenesulfonyl azide; potassium carbonate In acetonitrile at 0℃;
To a solution of dimethyl 2-oxopropylphosphonate(65.3g,331mmol) inacetonitrile (150 ml) at 0°C wasaddedK2C0 3 (45.8 g, 331 mmol) followed by the dropwise addition of 4-methylbenzenesulfonyl azide (50 g, 300 mmol)andthereactionmixturewas stirred overnight. It was dilutedwith EA (500 ml), washedwith water (3 x 300 ml), brine (3 x5 100 ml), dried (Na2S04 ), and filtered. Thefiltrate was concentrated under reduced pressure to a residue,which was dissolved in EhO (300 ml)and recrystallized with DCM and PE to remove4-methylbenzenesulfonamide as a white solid byproduct several times. Theremaining solutionwas concentrated under reducedpressureto give the Bestmann reagent as a yellow oil (43 g,75percent).1H NMR (400 MHz, CDCb) o2.28 (s, 3 H), 3.85 (d, J = 8.0 Hz, 6 H). G. Roth, B. Liepold, 10 S. Muller and H. J. Bestmann,Synthesis 2004,1, 59-62.
74%
Stage #1: With sodium hydride In tetrahydrofuran; benzene at 5 - 10℃; for 1 h; Stage #2: With 4-toluenesulfonyl azide In tetrahydrofuran; benzene at 5 - 20℃;
To an N2-FLUSHED, oven-dried round bottom flask equipped with a magnetic stir bar was added sodium hydride (303 mg, 12.64 MMOL). The flask was capped with a rubber septum and alternately evacuated and flushed with nitrogen. Freshly distilled THF (2 mL) was added via a syringe, and the mixture was stirred for 10 min at room temperature. THF (2 mL) and reagent grade benzene (5 mL) were added via a syringe, and the mixture was cooled to-5-10 °C. A solution of commercial (2-oxo- propyl)-phosphonic acid dimethyl ester (2000 mg, 12.04 MMOL) in benzene (5 mL) was added via a syringe, and the resulting mixture was stirred under a nitrogen atmosphere for 1 h. A solution of toluenesulfonyl azide (2612 mg, 13.24 MMOL) in benzene (5 mL) was added via a syringe. The solution was allowed to warm to room temperature and stirring under a nitrogen atmosphere was continued overnight. TLC analysis of the mixture, using straight ethyl acetate as eluent, revealed that all starting dimethyl ester has been consumed. The slurry was passed through a fritted filter funnel layered with celite. The residue was washed copiously with ethyl acetate. The eluate was washed with brine, dried over MgS04, concentrated and dried under high vacuum. The dry crude was passed through a silica gel column using straight ethyl acetate as eluent. The reaction yielded 1700 mg (74percent) of clear, yellow, viscous LIQUID. H-NMR (300 MHZ, CDCl3) : No. 3.75 (3H, s), 3.71 (3H, s), 2.14 (3H, S)."C- NMR (75.5 MHZ, CDCI3) : 5 189.73, 53.44, 26.98. MS (ES+) : 193 [M+H] +.
74%
Stage #1: With sodium hydride In toluene; mineral oil at 4 - 5℃; for 1 h; Stage #2: With 4-acetamidobenzenesulfonyl azide In tetrahydrofuran; toluene; mineral oil at 20℃; for 16 h;
This product was synthesized using the conditions described by Pietruszka and Witt3.To a solution of sodium hybride (2.74 g, 72.2 mmol, 60percent in dispersion in mineral oil) in 220mL of anhydrous toluene at 4-5°C (ice bath) was added dropwise a solution of dimethyl 2-oxopropylphosphonate 7 (10.50 g, 60.2 mmol) in 45 mL of anhydrous toluene. After 1h at 4-5°C, a solution of 4-acetamidobenzenesulfonyl azide (14.64 g, 60.2 mmol) in 45 mL ofanhydrous tetrahydrofuran was added dropwise. The yellow viscous solution was stirredduring 16h at ambient temperature. The mixture was filtered through Celite pad, washed with70 mL of tetrahydrofuran and the solvent was removed under reduce pressure. The residuewas purified by flash chromatography (silica gel, EtOAc/PE, 0/100 ramping to 100/0, v/v) togive compound 6 (8.55 g, 44.5 mmol) as a yellow oil in 74percent; Rf 0.30 (EtOAc). 1H NMR (300MHz, CDCl3) δ: 2.26 (s, 3H, CH3CO), 3.84 (d, 6H, 3JH-P = 11.9 Hz, CH3O). 13C NMR (75MHz, CDCl3) δ: 26.9 (CH3), 53.4 (d, 2JC-P = 5.4Hz, OCH3), 63.2 (d, 1JC-P = 220.3Hz, CN2),189.6 (d, 2JC-P = 12.9Hz, CH3CO). IR (cm-1): 2116, 1654, 1265, 1010.
74%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: With (p-aminobenzene)sulfonyl azide In tetrahydrofuran at 0℃; for 1.5 h;
Procedure and characterization according to: Cambeiro, X. C.; Perics, M. A., Adv. Synth. Catal. 2011, 353, 113. A three necked flask (500 mL) was charged with NaH (0.068 mol, 1.63 g). Dry THF (320 mL) was added and the rection cooled to 0 °C. Dimethyl 2-oxopropylphosphonate (0.039 mol, 6.48 g) in THF (20 mL) was slowly added by syringe pump. After 1 h p-ABSA (0.051 mol, 12.18 g) in THF (40 mL) was also added by syringe pump and the reaction stirred at 0 °C for 1.5 h. The ice-bath was then removed and the reaction mixture stirred overnight at RT. Diethyl ether (150 mL) was added and the mixture filtered. The filtrate was evaporated and the resulting oil purified by column chromatography hexane/ethyl acetate (1:1) to afford 3 (5.55 g, 74percent)
70%
With 4-toluenesulfonyl azide; sodium hydride In toluene at 20℃; for 16 h;
Step 3-Synthesis of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (2-oxo-propyl)-phosphonic acid dimethyl ester (20 g, 0.12 mol) was dissolved in toluene (500 mL) at 0° C. and NaH (4.8 g, 0.12 mol) was added in portions. After the gas evolution had ceased, a solution of 4-methyl-benzenesulfonyl azide (21.4 g, 1.1 mol) was added drop-wise and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with hexanes, filtered through a pad of celite and rinsed with TMBE. The filtrate was concentrated to afford the title compound (16 g, 70percent): 1H NMR (400 MHz, DMSO) delta 2.22 (s, 3H), 3.74 (s, 3H), 3.79 (s, 3H).
69%
Stage #1: With sodium hydride In toluene at 0℃; for 0.5 h; Stage #2: With 4-acetamidobenzenesulfonyl azide In tetrahydrofuran; toluene at 0℃; for 2.5 h;
Ketone SI-4 (11.8 g, 70.9 mmol) was dissolved in toluene (70 mL) and this solution was cooled to 0 °C (icebath), after which NaH (2.95 g, 65.5 mmol) was added to the mixture portion-wise and the obtained reaction mixture was stirred for 30 min. To this cooled (0 °C) mixture, a solution of pacetamidobenzenesulfonyl azide SI-2 (15.8 g, 65.5 mmol) in THF (23 mL) was added drop-wise. Initially, a highly viscous yellow suspension was obtained and the reaction mixture was stirred for 2.5 h at 0 °C. Then, the reaction mixture was allowed to warm up to room temperature and was subsequently diluted with Et2O (100 mL). The suspension was filtered over Celite and the filtratewas evaporated in vacuo. Finally, the residue was purified by silicagel column chromatography (EtOAc/hexane 1:1 v/v) to afford diazo compound SI-5 as a colorless oil in 69percent yield (9.40 g). Rf 0.74 (CH2Cl2/MeOH 9:1 v/v); 1H-NMR (300 MHz, CDCl3) δ = 2.28 (s, 3H, CH3), 3.85 (d (JH,P = 11.9 Hz), 6H, OCH3).
69.4%
Stage #1: With potassium carbonate In acetonitrile at 40℃; for 1 h; Stage #2: With 4-toluenesulfonyl azide In acetonitrile for 2 h;
To a solution of SM-2 (5.0g, 30 mmol) in CH3CN(50 ml) was addedK2C03 (5.0 g, 36 mmol), the suspensionwas stirredat 40°C for an hour and a solutionof TsN3(6.53 g, 33 mmol) in CH3CN (20 ml) was then added.The resulting mixture was stirred for an additional 2 hours and filteredover diatomaceous earth. The filtrate was concentratedin vacuum to give the crude whichwas purified by flash chromatography to give the desiredproduct SM-2A (4.0 g, 69.4percent). 1H-NMR (400MHz,CDC13): 3.75-3.80(m, 6H), 2.18-2.20(m, 3H). LC-MS:m/z=193.1 (M+1).
64%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: With 4-toluenesulfonyl azide In tetrahydrofuran
Dimethyl (2-oxopropyl)-phosphonate a (11.5 g, 69 mmol) was slowly added to a suspension of sodium hydride (3.3 g of a 60percent suspension, 83 mmol) in 200 mL of anhydrous THF at 00C. The mixture was stirred at 00C for 1 h. Then, toluenesulfonyl azide (15.0 g, 76 mmol), dissolved in 50 mL of THF, was added dropwise. The mixture was stirred for 30 min, filtered over celite and washed with ethyl acetate. The filtrate was concentrated, adsorbed on silica gel and purified by flash chromatography (SiO2, 40percent to 100percent ethyl acetate/hexanes) to afford 8.5 g (64percent) of compound b as a yellow oil. MS: m/z = 193 (M+H).
62%
Stage #1: With sodium hydride In tetrahydrofuran; toluene; mineral oil at 0℃; for 1 h; Inert atmosphere; Schlenk technique Stage #2: With 4-acetamidobenzenesulfonyl azide In tetrahydrofuran; toluene; mineral oil at 0 - 20℃; Inert atmosphere; Schlenk technique
Under an N2 atmosphere, a suspension of NaH (60percent in oil, 0.88 g, 22.0 mmol) in toluene (85 mL) and THF (18 mL) was stirred and cooled to 0 °C in an ice–water bath for 30 min. To this suspension was added slowly dimethyl 2-oxopropylphosphonate (3.32 g, 20.0 mmol). The mixture was stirred at 0 °C for 1 h, and p-acetamidobenzenesulfonyl azide (p-ABSA; 5.28 g, 22.0 mmol) was then added. The reaction was warmed to r.t. and stirring was continued overnight. The mixture was filtered through a Celite pad, and the filtrate was evaporated in vacuo to remove the volatile materials. The crude residue was purified by chromatography (silica gel, PE–EtOAc, 1:1) to give the product as a yellow oil; yield: 2.38 g (62percent).
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 436 - 441
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 6, p. 1693 - 1703
[3] Bioscience, Biotechnology and Biochemistry, 1999, vol. 63, # 7, p. 1253 - 1260
[4] Tetrahedron Letters, 2006, vol. 47, # 11, p. 1729 - 1731
[5] Chemistry - A European Journal, 2009, vol. 15, # 17, p. 4428 - 4436
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[7] Tetrahedron, 2006, vol. 62, # 28, p. 6673 - 6680
[8] Science China Chemistry, 2010, vol. 53, # 9, p. 1937 - 1945
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[10] Patent: WO2015/95124, 2015, A1, . Location in patent: Page/Page column 82
[11] Patent: WO2015/95223, 2015, A2, . Location in patent: Page/Page column 78; 79
[12] Journal of the American Chemical Society, 2017, vol. 139, # 23, p. 7872 - 7885
[13] Advanced Synthesis and Catalysis, 2011, vol. 353, # 1, p. 113 - 124
[14] Organic Letters, 2015, vol. 17, # 5, p. 1308 - 1311
[15] Organic and Biomolecular Chemistry, 2017, vol. 15, # 38, p. 8054 - 8058
[16] Organic Letters, 2006, vol. 8, # 17, p. 3837 - 3840
[17] Patent: CN108569969, 2018, A, . Location in patent: Paragraph 0035-0038
[18] Tetrahedron, 2003, vol. 59, # 10, p. 1719 - 1729
[19] Patent: WO2014/117274, 2014, A1, . Location in patent: Paragraph 217
[20] Synthesis, 2004, # 1, p. 59 - 62
[21] Tetrahedron, 2012, vol. 68, # 35, p. 7103 - 7115
[22] Synthetic Communications, 1984, vol. 14, # 2, p. 155 - 162
[23] Organic Letters, 2003, vol. 5, # 16, p. 2821 - 2824
[24] Synthesis, 2011, # 7, p. 1037 - 1044
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19
[ 941-55-9 ]
[ 4202-14-6 ]
[ 90965-06-3 ]
Yield
Reaction Conditions
Operation in experiment
88.35%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: at 0℃; for 0.5 h;
A 50 ml three-necked round-bottom flask was charged, After addition of re-evaporated tetrahydrofuran (25 ml), NaH (260 mg, 10 mmol) was then added slowly, Dimethyl acetonephosphonate (1.5 g, 9.0 mmol) was added dropwise at 0 degree C; In tetrahydrofuran, Dropping finished stirring continued 1h, A solution of 4-methylbenzenesulfonylazide (9) (1.96 g, 9.90 mmol)In tetrahydrofuran, After stirring at 0 degree C for 30 min; The progress of the reaction was monitored by TLC during the reaction. After completion of the reaction, the reaction solution was filtered through celite, concentrate, The crude product was concentrated with silica gel, The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) Isolation and purification(1-diazo-2-oxopropyl) phosphonic acid dimethyl ester (10) (1.53 g, yield: 88.35percent)As a yellow liquid,
81%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: at 0℃; for 0.166667 h;
To a suspension of NaH (60percent in mineral oil, 0.83 g, 20.8 mmols) in THF (50 ml) was added dropwise at 0 C (2-oxo-propyl)-phosphonic acid dimethyl ester (3.1 g, 18.7 mmols) in THF (50 ml), and the solution was stirred at 0 C for one hour. Tosyl azide (4g, 20 mmols) was added in one portion, stirred at 0 C for 10 minutes, filtered through Celite and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate to yield the title compound (2.9 g, 81percent) as oil. (Eur. J. Org. Chem. 2003, 821-832.)
81.5%
With sodium hydride In tetrahydrofuran at 0℃; for 3 h;
In a 250 ml three-necked flask was added anhydrous THF (tetrahydrofuran, 20 ml), NaH (608 mg, 25.3 mmol), and the mixture was stirred well at 0°C under mechanical stirring.Compound 3 (3.82 g, 23.0 mmol) was dissolved in 30 ml of THF, and the solution was slowly added dropwise. After the dropwise addition was completed, mechanical stirring at low temperature was continued for 1 hour, and the reaction solution turned milky white.A solution of compound 2 (4.994 g, 25.3 mmol) in THF (10 ml) was slowly added dropwise. After the addition was complete, mechanical stirring was carried out for 2 h. The color change sequence was: first yellow and then red.After the reaction was monitored by TLC, the filtrate was collected by filtration, dried over anhydrous Na2SO4, and the crude product of compound 4 was obtained by spin-drying the solvent. The product was purified by column chromatography and eluted with petroleum ether:ethyl acetate=2:1 to obtain 3.6 g of a pale yellow oily liquid. Yield: 81.5percent.
81%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: at 0℃; for 0.166667 h;
To a suspension of NaH (60percent in mineral oil, 0.83 g, 20.8 mmols) in THF (50 ml) was added dropwise at 0 C (2-oxo-propyl)-phosphonic acid dimethyl ester (3.1 g, 18.7 mmols) in THF (50 ml), and the solution was stirred at 0 C for one hour. Tosyl azide (4g, 20 mmols) was added in one portion, stirred at 0 C for 10 minutes, filtered through Celite and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate to yield the title compound (2.9 g, 81percent) as oil. (Eur. J. Org. Chem. 2003, 821-832.)
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20
[ 4202-14-6 ]
[ 2158-14-7 ]
[ 90965-06-3 ]
Reference：
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[2] Patent: US2009/275627, 2009, A1, . Location in patent: Page/Page column 9
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21
[ 4202-14-6 ]
[ 89711-08-0 ]
[ 92136-39-5 ]
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 3, p. 1254 - 1264
22
[ 177947-96-5 ]
[ 4202-14-6 ]
[ 287193-01-5 ]
Yield
Reaction Conditions
Operation in experiment
93%
Stage #1: With sodium azide; caesium carbonate; methanesulfonyl chloride In acetonitrile at 0 - 20℃; for 3 h; Stage #2: With caesium carbonate In methanol; acetonitrile at 0℃;
Sodium azide (2.4 g, 37 mmol) is suspended in ACN (14 mL) and methanesulfonyl chloride (2.7 mL, 35 mmol) is added over 45 seconds. The resulting mixture is stirred overnight at room temperature and is then cooled to 0 °C, at which point dimethyl (2-oxopropyi)phosphonate (4.3 mL, 31 mrnoi) is added over 30 seconds followed by Cs2CO3 (11 g, 34 mniol). This mixture is stirred for 30 minutes at 0 °C andthen at room temperature for 2.5 hours. The mixture is recooled to 0 °C and MeOH (15.5 mL) is added. After 1 hour, tert-butyl 3-fhmiyiazetidine- I -carboxylate (3.0 g, 16 mmol)added followed by additional Cs2CO3 (9.1 g, 28 mmol), and 25 minutes later the ice-water bath is removed and the reaction is stirred overnight. The solvent is removed under vacuum to give an orange oil that is purified by silica gel chromatography using 50percent MTBE/hexanes, The title compound is obtained as a light yellow oil (2.68 g, 93percent). MS (mlz): 181 (M±H).
Stage #1: dimethyl (2-oxopropyl)phosphonate With 4-toluenesulfonyl azide; potassium carbonate In toluene; acetonitrile at 20℃; for 2.5h;
Stage #2: tert-butyl N-(5-formyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamate In methanol; toluene; acetonitrile for 1.5h;
0-4 0-4. Scheme 4, tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan- 5-ylcarbamate) synthesis
To synthesize the tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate of Scheme 4, Dimethyl-2-oxo propyl-phosphonate (1.6) in an acetonitrile (50 ml) suspension containing K2CO3 (3.0 g, 2.25 eq) and p-toluenesulfonylazide (14% solution in toluene, 15.8 ml, 1.05 eq) g, 1.02eq) ml) was added and the mixture was vigorously stirred at room temperature for 2.5 hours. Formula 5 contained in methanol (40 ml) A solution of tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (2.5 g, 9.64 mmol) was added to the first reaction mixture. After addition of K2CO3 (2.7 g, 2.06eq), the mixture was stirred for 1.5 h, concentrated under reduced pressure, and the residue diluted with MC (200 ml) and H 2 O (200 ml). The organic layer was washed with H 2 O (200 ml), dried over MgSO 4 and concentrated under reduced pressure. The residue was subjected to SiO 2 column chromatography eluting with EA / n-hexane = 1/9 to give tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxane-5-ylcarrbarmate was obtained as a white solid (2.3 g, 93.4%).
93.4%
Stage #1: dimethyl (2-oxopropyl)phosphonate With 4-toluenesulfonyl azide; potassium carbonate In toluene; acetonitrile at 20℃; for 2.5h;
Stage #2: tert-butyl N-(5-formyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamate With potassium carbonate In methanol for 1.5h;
0-4 0-4. Scheme 4, Synthesis of tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate)
To synthesize tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate of Scheme 4, K2CO3 (3.0g, 2.25eq) and p-toluenesulfonylazide To a suspension of acetonitrile (50 ml) with (14 % solution in toluene, 15.8 ml, 1.05 eq) was added dimethyl (2-oxopropyl)phosphonate (1.6 g, 1.02 eq), and the mixture was stirred at room temperature for 2.5 hours. while vigorously stirring. A solution of tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (2.5 g, 9.64 mmol) of Formula 5 in methanol (40 ml) was first reacted with was added to After addition of K2CO3 (2.7g, 2.06eq), the mixture was stirred for 1.5 h, concentrated under reduced pressure and the residue was diluted with MC (200ml) and H2O (200ml). The organic layer was washed with H2O (200ml), dried over MgSO4 and concentrated under reduced pressure. The residue was subjected to SiO2 column chromatography eluting with EA/n-hexane = 1/9 to tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcar of formula 6 The barmate was obtained as a white solid (2.3 g, 93.4%).
84%
Stage #1: dimethyl (2-oxopropyl)phosphonate With 4-toluenesulfonyl azide; potassium carbonate In acetonitrile at 20℃; for 2h;
Stage #2: tert-butyl N-(5-formyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamate In methanol; acetonitrile at 20℃; for 8h;
A.64.2
2) (E)-4-(3-Methyl-4-trifluoromethyl-phenyl)-but-3-en-2-one: A mixture of the above described 3-methyl-4-trifluoromethyl-benzaldehyde (9.1 g, 48.3 mmol) and commercially available dimethyl-2-oxopropylphosphonate (8.46 mL, 58.0 mmol) was cooled at 0° C., then a mixture of K2CO3 (13.37 g, 96.7 mmol) in water (16 mL) was added and the mixture was stirred at 0° C. or 2 h. Poured onto sat. NaHCO3-sol. and extracted twice with EtOAc, washed with brine and dried over Na2SO4, filtered off and evaporated totally to give the (E)-4-(3-methyl-4-trifluoromethyl-phenyl)-but-3-en-2-one (12.7 g, 115%, ca. 80% purity) as a light yellow liquid, which was used without further purification. MS (ISP) 229.2 [(M+H)+].
With potassium carbonate; In water; at 23℃; for 1.5h;
To a vigourously stirred mixture of a carboxaldehyde compound of formula XVI (1.0 eq.), Rl-containing phosphonate compound of formula XVII (1.2 eq.) (optionally with additional THF (20 ml/50 mmol aldehyde) at 23 0C (waterbath) was added a solution of potassium carbonate (2.0 eq.) in water (25 ml/50 mmol aldehyde) within 5 min and stirring was continued at 23 0C for 1.5 h. Diluted with EtOAc, THF and water, separated phases, washed organic layer with brine, reextracted combined organic layer once with EtOAc, dried combined organic layer over Na2SO/t. Removal of the solvent in vacuum left the 3-aryl-prop-2-en-l -one-compound of formula XVIII, which was used without further purification; (E)-4-(6-Trifluoromethyl-pyridin-3-yl)-but-3-en-2-one: Prepared from commercially available <strong>[386704-12-7]6-(trifluoromethyl)pyridine-3-carboxaldehyde</strong> [CAS-no. 386704-12-7] (5 g, 29 mmol), commercially available dimethyl-2-oxopropylphosphonate (4.8 mL, 35 mmol) and K2CO3 (7.97 g, 58 mmol) in water (60 mL) according to the general procedure Ia step 1. MS (ISP) 216.1 [(MH-H)+].
With potassium hydroxide In ethanol; water at 5 - 20℃; for 7.16667h;
2.1
Dimethyl (2-oxopropyl)phosphonate (32.06 g, 193 mmol) is added to a chilled (ice-bath) solution of potassium hydroxide (10.83 g, 193 mmol) in water (30 ml) and ethanol (170 ml) and the mixture is stirred. Tetrahydrofuran-3-carboxaldehyde (50% wt. % solution in water, 25 ml, 138 mmol) is added dropwise and the reaction mixture is stirred at 5 0C for 10 minutes. The cooling bath is removed and the mixture is stirred at room temperature for 7 hours. Most of the solvent is removed in vacuo, water (100 ml) and diethyl ether (200 ml) are added, the mixture is poured into a separating funnel and the organic phase collected. The aqueous phase is extracted three times with diethyl ether, and the organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane to give 4- (tetrahydrofuran-3-yl)-3-buten-2-one as a pale yellow liquid.
Stage #1: dimethyl (2-oxopropyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h;
Stage #2: With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.333333h;
Stage #3: 1,3-diacetoxyacetone; allyl bromide In tetrahydrofuran; hexane at 0 - 20℃;
Stage #1: dimethyl (2-oxopropyl)phosphonate With n-butyllithium; sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h;
Stage #2: 1-Bromo-2-butyne In tetrahydrofuran; mineral oil for 2h;
Stage #3: 1,3-diacetoxyacetone With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃;
40%
Stage #1: dimethyl (2-oxopropyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere;
Stage #2: With n-butyllithium In tetrahydrofuran; hexane; mineral oil at 0℃; for 0.166667h; Inert atmosphere;
Stage #3: 1,3-diacetoxyacetone; 1-Bromo-2-butyne Further stages;
2-(Acetoxymethyl)-4-oxonon-2-en-7-yn-1-yl acetate 11
To a suspension of sodium hydride (1.8 eq., 108.4 mmol, 4.337 g of 60% dispersion in mineral oil) in THF (200 mL) was added dimethyl 2-oxopropylphosphonate 10 (10.00 g, 60.20 mmol) dropwise at 0 °C. After 30 minutes of stirring n-butyl lithium (1.35 eq., 81.3 mmol, 32.5 mL of 2.5 M solution in hexanes) was added dropwise. The suspension was stirred for 20 minutes before bromide 21 (1 eq., 60.20 mmol, 8.006 g) was added dropwise at 0 °C. After 10 minutes, 2-oxopropane-1,3-diyl diacetate 22 (1.5 eq., 90.30 mmol, 15.73 g) was added as a solid in one portion and the reaction was allowed to warm to rt. The suspension was stirred for 2 h before being quenched cautiously at 0 °C with saturated NH4Cl (100 mL). The organics were separated and the aqueous phase further extracted with CH2Cl2 (3 x 100 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was purified by column chromatography (PE:Et2O 5:1>3:1>Et2O) to afford enone 11 (6.417 g, 40%) as a yellow oil:
38%
Stage #1: dimethyl (2-oxopropyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h;
Stage #2: With n-butyllithium In tetrahydrofuran; hexane; mineral oil at 0℃; for 0.416667h;
Stage #3: 1,3-diacetoxyacetone; 1-Bromo-2-butyne Further stages;
To N-diazo-4-methyl-benzenesulfonamide (25.72 g, 130.4 mmol) and k2co3 (41.59 g, 300.9 mmol) in acetonitrile (800 mL) was added 1 - dimethoxyphosphorylpropan-2-one (21.66 g, 130.4 mmol) . After 2h, add tert- butyl (2S,4S)-2-formyl-4-methyl-pyrrolidine-1 -carboxylate (21.4 g, 100.3 mmol) in methanol (31 1.6 mL) . RT 12 h. Evap. add water (400 ml), extract with ether (3 x 200ml), wash with water (2) flash SiO2 with 20% EA to product: 14.7 g 1 H NMR
INTERMEDIATE 4: methyl 2-(2-acetylcyclopropyl)-2-methylpropanoateStep 1 : To a solution of dimethyl (2-oxopropyl)phosphonate (4.09 mL, 30.0 mmol) in tetrahydrofuran (200 mL) at 0 C was added potassium tert-butoxide (3.22 g, 28.7 mmol). After 15 minutes the reaction mixture was moved to room temperature, and after an additional 15 minutes <strong>[13865-20-8]methyl 2,2-dimethyl-3-oxopropanoate</strong> (3.39 g, 26.0 mmol) was added. The opaque reaction mixture was stirred for 21 hours and then partitioned between diethyl ether (100 ml) and water (100 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (100 mL, 50 mL). The combined organic layers were washed with aqueous saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-4% methanol/dichloromethane) to yield methyl (3E)-2,2-dimethyl-5-oxohex-3-enoate. lH NMR (500 MHz, CDCI3) delta 6.95 (d, J= 16.4 Hz, 1H), 6.09 (d, J= 16.4 Hz, 1H), 3.71 (s, 3H), 2.29 (s,3H), 1.37 (s, 6H).
tert-butyl [(1R)-1-isopropylprop-2-yn-1-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
148 mg
Stage #1: dimethyl (2-oxopropyl)phosphonate With 4-toluenesulfonyl azide; potassium carbonate In acetonitrile at 0℃; for 1h; Inert atmosphere;
Stage #2: (2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutylaldehyde In methanol; acetonitrile at 0 - 20℃;
Stage #1: dimethyl (2-oxopropyl)phosphonate With 4-toluenesulfonyl azide; potassium carbonate In acetonitrile at 20℃; for 2h;
Stage #2: 3-cyclohexylpropanal In methanol; acetonitrile at 20℃;
1 Step 1. But-3-ynylcyclohexane (24)
Step 1. But-3-ynylcyclohexane (24) To a suspension of K2CO3 (6.2 g, 44.86 mmol) in MeCN (76 mL) was added a solution of the 4-methylbenzenesulfonyl azide (3.6 g, 18.26 mmol) in MeCN (12 mL) followed by addition of the dimethyl 2-oxopropylphosphonate (3.0 g, 18.06 mmol) in MeCN (12 mL) (B. Liepold, et al. Synthesis, 2004, 1, 59-62). The reaction mixture was stirred at rt for 2 hours. A solution of the aldehyde 23 (2.0 g, 14.26 mmol) in MeOH (24 mL) was then added and the reaction mixture was stirred at rt overnight. The reaction mixture was filtered; the filtrate was collected, evaporated and partitioned between water and EtOAc. The organic phase was dried over anhydrous MgSO4, filtered and evaporated. The residue was suspended in a mixture EtOAc/hexanes, the white precipitate was discarded and the filtrate was collected and evaporated. The remained material was purified by flash column chromatography, eluent 10% EtOAc in hexanes to afford the title compound 24 as a light colorless oil (0.32 g, 16.5% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.22-2.17 (m, 2H), 1.93 (t, J=2.5 Hz, 1H), 1.73-1.62 (m, 5H), 1.46-1.11 (m, 6H), 0.92-0.82 (m, 2H).
With 4-toluenesulfonyl azide; potassium carbonate; In methanol; acetonitrile; for 18h;
Previously obtained p-toluenesulfonyl azide (2.48g, 12.6mmol) was dissolved in acetonitrile (50mL), was added commercially availableDimethylacetamidePhosphonate (1.94g, 11.7mmol) and potassium carbonate (3.23g, 23.9mmol), stirred at room temperature for 3 hours. Obtained in stage A of ((R) -1- benzyl-2-oxo - ethyl) - carbamic acid t- butyl ester (2.66g, 10.6mmol) was dissolved in methanol and slowly added to 50mL. After the addition of potassium carbonate (2.94g, 21.3mmol) was stirred for 18 hours. After the reaction, the Cellite filtered, washed with acetonitrile (100mL), the solvent was removed under reduced pressure. Using diethyl ether (100 mL) was diluted, added to water (100 mL) after organics were extracted with diethyl ether, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography the title compound were harvested (1.65g, 63%).
With potassium carbonate In methanol at 20℃; for 18h; Inert atmosphere;
6.1. Seyferth-Gilbert homologation
General procedure: To a solution of aldehyde in anhydrous methanol (0.1M), were added potassium carbonate (2 eq.) and dimethyl 1-diazo-2-oxopropylphosphonate (1.5 eq.). After 18h of stirring at room temperature, the reaction was quenched with a 5% solution of NaHCO3 and the aqueous layer was extracted 3 times with dichloromethane. The organic extracts were combined and washed with brine, dried over MgSO4 and filtered through a small pad of celite and concentrated in vacuo. The resulting residue was purified by flash column chromatography to afford the corresponding alkyne. 2-ethtnylnaphthalene (a4) [2]; The general procedure 1 applied to 2-naphthaldehyde (1.00 g, 6.4 mmol) which gave the product2as a white solid (0.812 g, 83% yield).1H NMR (300MHz, CDCl3): δ 3.15 (s, 1H), 7.46-7.55 (m, 3H), 7.76-7.82 (m, 3H), 8.03 (s, 1H) ppm.13C NMR (75MHz, CDCl3): δ 76.71, 77.14, 77.57, 84.13, 119.47, 126.69, 126.98, 127.84, 128.62, 132.39, 132.90, 133.11 ppm.
ethyl 3-(2-oxopropylidene)cyclobutane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
Stage #1: dimethyl (2-oxopropyl)phosphonate With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 0℃; for 0.5h;
Stage #2: ethyl 3-oxocyclobutanecarboxylate In acetonitrile at 0 - 20℃; for 0.5h;
195; 196 Ethyl 3-(2-oxopropylidene)cyclobutane-l -carboxylate (195 A)
To a stirred solution of dimethyl (2-oxopropyl)phosphonate (28.0 g, 169 mmol) in acetonitrile (140 mL) were added lithium chloride (7.16 g, 169 mmol) and l ,8-diazabicyclo[5.4.0]undec-7-ene (25.2 mL, 169 mmol) at 0°C and the resulting mixture was stirred for 30 minutes at same temperature. Ethyl 3-oxocyclobutane-l-carboxylate (20 g, 141 mmol) in acetonitrile (140 mL) was added drop wise at 0°C and the reaction mixture was stirred at RT for 30 minutes. Reaction mixture was concentrated under reduced pressure to get the crude product. The crude product was purified by combifiash chromatography (330 g, Redisep SiC column, eluting with 50% EtOAc in n-hexanes) to afford the title compound 195 A (10 g, 39%) as a colorless liquid. NMR (400MHz, CDCh) δ ppm 6.04 - 6.00 (m, 1H), 4.17 (m, 2H), 3.43 - 3.38 (m, 2H), 3.27 - 3.23 (m, 1H), 3.20 - 3.17 (m, 1H), 3.16 - 3.12 (m, 1H), 2.15 (s, 3H), 1.26 (t, J= 7.2 Hz, 3H).
1-(1-methoxy-4-piperidylidene)propan-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60 g
With potassium hydroxide In ethanol; water at 0 - 20℃;
1.1 Step 1 : Synthesis of 1-(1-methoxy-4-piperidylidene)propan-2-one
To a stirred solution of KOH (30.4 g, 542 mmol) in ethanol (440.0 ml.) and water (1 15.0 ml.) was added 1-dimethoxyphosphorylpropan-2-one (75.0 ml_, 542 mmol) dropwise at 0-5°C. Then 1-methoxypiperidin-4-one (50.0 g, 387 mmol) was added portionwise keeping internal temperature constant. The reaction mixture was stirred at room temperature overnight. Most of the solvent was evaporated under reduced pressure. The residue was diluted with DCM and water and the aqueous layer extracted twice with DCM. The combined organics were washed with brine, dried over Na2S04, filtered and evaporated under reduced pressure to obtain a crude residue, which was by flash column chromatography to obtain 1-(1-methoxy-4- piperidylidene)propan-2-one (60 g)1 H NMR (CDCIs) d 6.02 (s, 1 H), 3.53 (s, 3H), 3.44-3.16 (m, 3H), 2.69-2.62 (m, 3H), 2.36-2.35 (m, 2H), 2.17 (s, 3H).
Stage #1: 5-phenylpyridine-2-carboxaldehyde; dimethyl (2-oxopropyl)phosphonate With potassium carbonate In methanol at 0 - 20℃; for 2.5h;
Stage #2: With silica gel In methanol at 20℃; for 0.5h;
194.c
Step c. To a stirred solution of 5-phenylpicolinaldehyde (0.435 g, 2.38 mmol) in MeOH (15 ml) was added K2CO3 (0.656 g, 4.75 mmol) at 0° C. A solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (prepared in step a; 0.684 g, 3.565 mmol) in MeOH (5 ml) was added to the reaction mixture at 0° C. The reaction mixture was stirred at rt for 2.5 h. Silica gel (1.0 g) was added to the reaction mixture at rt. The reaction mixture was stirred at rt for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (7% EtOAc in hexane) to yield 2-ethynyl-5-phenylpyridine (0.300 g, 1.68 mmol). LCMS: Method C, 2.191 min, MS: ES+180.40; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (d, J=1.6 Hz, 1H), 8.12 (dd, J=8.0, 2.4 Hz, 1H), 7.76-7.78 (m, 2H), 7.66 (d, J=8.0 Hz, 1H), 7.51-7.54 (m, 2H), 7.45-7.47 (m, 1H), 4.40 (s, 1H).
Stage #1: dimethyl (2-oxopropyl)phosphonate With fluorosulfonyl azide; potassium carbonate In tetrahydrofuran; tert-butyl methyl ether at 20℃; for 1h;
Stage #2: 3-Cyanobenzaldehyde With potassium carbonate In tetrahydrofuran; methanol; tert-butyl methyl ether at 20℃; for 15h;
5 Example 5 Screening reaction conditions
Add acetonyl dimethyl phosphate [Compound 2] (332μL, 2.4mmol), Solvent (10.0mL) and Base A (5.0mmol), and finally add FSO2N3/MTBE solution (6.0mL, 485mM, 2.88mmol). Stir at room temperature for 60 minutes, and TLC monitors the completion of the reaction. Dissolve m-cyanobenzaldehyde (264.6 mg, 2.0 mmol) in methanol (10 mL), add the solution to the reaction, then add Base B (4.0 mmol), and react at room temperature for 15 hours. The completion of the reaction was monitored by LC-MS. The reaction was stopped, the reaction system was filtered, the filter cake was washed with dichloromethane, and the organic phase was concentrated to obtain a crude product. Purification by column chromatography (silica gel 300-400 mesh, dichloromethane: petroleum ether=1:4, product Rf=0.35) to obtain a pale yellow solid m-cyanophenylacetylene.The yield depends on the solvent used, Base A and Base B, as shown in Table 2. It can be seen from Table 2 that when the solvent is THF and both Base A and Base B are K2CO3, the yield is the highest at 88%
3-ethyl 5-methyl 4-(2-chlorophenyl)-6-methyl-2-((2-(4-(3-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: dimethyl (2-oxopropyl)phosphonate With fluorosulfonyl azide; potassium carbonate In tetrahydrofuran; tert-butyl methyl ether at 20℃; for 0.5h;
Stage #2: 3-(trifluoromethoxy)benzaldehyde In tetrahydrofuran; methanol; tert-butyl methyl ether at 20℃; for 15h;
Stage #3: 2-(2-azidoethoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine With phosphoric acid; copper(II) sulfate; sodium L-ascorbate In tetrahydrofuran; methanol; tert-butyl methyl ether; water at 50℃; for 3h;
7 Example 7 Preparation of 3-ethyl-5-methyl 4-(2-chlorophenyl)-6-methyl-2-((2-(4-(3-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diester
Add acetonyl dimethyl phosphate [Compound 2] (83μL, 0.6mmol),Tetrahydrofuran (2.5mL) and K2CO3 (310.5mg, 2.25mmol), and finally FSO2N3/MTBE solution (1.50mL, 479mM, 0.75mmol) was added.Stir at room temperature for 30 minutes, and TLC monitors the completion of the reaction.Dissolve m-trifluoromethoxybenzaldehyde [Compound 10] (95.3 mg, 0.5 mmol) in methanol (2.5 mL), add the solution to the reaction, and react at room temperature for 15 hours.The reaction was stopped, and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M).Take compound 5 (217.5mg, 0.5mmol) into the reaction system, take sodium ascorbate (98.4mg, 0.5mmol) dissolved in distilled water (2.5mL),And add copper sulfate solution (500μL, 100mM, 10%mmol), the solution changes from colorless to brown and then to egg-yellow, mix well and add to the reaction system.It was heated to 50°C and reacted for 3 hours. The completion of the reaction was monitored by LC-MS.The reaction was stopped, the reaction system was diluted with water (20 mL), extracted with dichloromethane (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.Purification by column chromatography (silica gel 300-400 mesh, dichloromethane: methanol = 50:1,Product Rf = 0.42) to obtain off-white solid 3-ethyl-5-methyl 4-(2-chlorophenyl)-6-methyl-2-((2-(4-(3-(trifluoromethoxy (Yl)phenyl)-1H-1,2,3-triazol-1-yl)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diester [Compound 11] (263.8mg, 85%)
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