| 100% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h; |
A mixture of 1-benzhydrylazetidin-3-ol (20.0 g, 83.68 mmol) and Et3N (12.68 g, 125.52 mmol) in DCM (200 mL) at 0C, MsC1 (11.447 mg, 100.41 mmol) was added in portions and the resulting solution was stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer wasdried over anhydrous Na2504, filtered and concentrated in vacuo to afford the desired product (26.526 g, 100% yield). |
| 100% |
With triethylamine; In dichloromethane; for 1.5h;Cooling with ice; |
Example 8 N-(4-{4-[3-(4-hydroxymethylpiperidin-1-yl)azetidin-1-yl]phenylamino}-6-methoxypyridin-3-yl)acetamide (8a) 1-benzhydrylazetidin-3-yl methanesulfonate 1-Benzhydrylazetidin-3-ol (30.0 g, 125 mmol) was dissolved in methylene chloride (240 mL), triethylamine (26 mL, 0.19 mol) was added and, under ice-cooling, methanesulfonyl chloride (11.6 mL, 150 mmol) was added, and the mixture was stirred for 1.5 hr. Water (100 mL) was added, two layers were separated, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title object compound as a pale-yellow powder (40.1 g, yield 100%). 1H-NMR (CDCl3, 400 MHz) delta: 2.99 (3H, s), 3.15-3.23 (2H, m), 3.59-3.68 (2H, m), 4.39 (1H, s), 5.10 (1H, quintet, J=5.8 Hz), 7.16-7.22 (2H, m), 7.24-7.30 (4H, m), 7.36-7.41 (4H, m). |
| 100% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 1.5h; |
To a solution of l-(Diphenylmethyl)-3-hydroxyazetidine (1.087 g, 4.54 mmol) in (1381) dichloromethane (6.0 mL) was added Triethylamine (1.27 mL, 9.08 mmol) and the reaction mixture was cooled to 0 C. At that temperature, Methanesulfonyl chloride (425 pL, 5.45 mmol) was added dropwise. The reaction mixture was stirred at 0 C for 30 min and at room (1382) temperature for 1 h. The reaction mixture was poured into Water (5 mL) and extracted with dichloromethane (20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the title compound (1.563 g, 100 %) as a yellow oil, which was used without further purification. MS (ESI): 318.2 ([M+H]+). |
| 98% |
With triethylamine; In dichloromethane; at 0℃; for 1h; |
A solution of methanesulfonyl chloride (115 g, 1.01 mol) in CH2Cl2 (500 mL) was added dropwise to a solution of 1-benzhydrylazetidin-3-ol (Intermediate 31, 200 g, 0.84 mol) and triethylamine (119 g, 1.17 mmol) in CH2Cl2 (2 L) at 0C, and the mixture was stirred at 0C for1h. The reaction was quenched by the addition of aqueous NaHCO3. The phases were separated and the aqueous solution was extracted with CH2Cl2 (3 x 500 mL). The combined organic solutions were dried (Na2SO4) and concentrated in vacuo to give the title compound (260 g, 98%) as a white solid. |
| 91% |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -20 - 20℃; |
To a stirred solution of l-benzhydrylazetidin-3-ol (4.0 g, 16.7 mmol, CAS 18621-17-5) in CH2CI2 (40 mL) was added N,N-diisopropylethylamine (14.6 mL, 83.6 mmol). The reaction mixture was cooled to -20 C, followed by addition of methanesulfonyl chloride (1.95 mL, 25.1 mmol). After 30 min, the reaction mixture was allowed to warm to room temperature and stirred for further 16 hours. The mixture was diluted with CH2CI2 and the organic phrase washed with aqueous citric acid, aqueous NaHC03 then brine. Organic layers were collected, dried (Na2S04) and concentrated in vacuo to afford the title compound (4.85g, 91 ) as an orange solid. MS (ISP): 318.5 ([M+H]+). |
| 65% |
|
Step 2To a suspension of l-benzhydrylazetidin-3-ol [93] (5.0 g, 2 mmol) in DCM (50 ml), pyridine (8.26ml, 10 mmol) were slowly added at 0C under inert atmosphere. After the addition was complete, the suspension dissolved was stirred at 0 C for 20 min, then methane sulphonyl chloride (2.5 ml, 15 mmol) was added to the solution and stirred at RT for 2 h. The progress of the reaction was monitored by TLC. Reaction mixture was quenched with water (150 ml) and extracted with DCM (500 ml x 2). The DCM layer was washed with brine (100 ml x 2), dried over anhydrous Na2S04 and evaporated to yield a yellow gel. The product was purified by column chromatography over 100-200 silica mesh using 1% MeOH:DCM as eluent to give 1 - benzhydrylazetidin-3-yl methane sulfonate [94] as a white solid(4.3gm,65%).ESIMS: 318.1 (M+ + 1) |
| 56.7% |
With pyridine; at -20℃; for 61h; |
(Production Example 81) 1-Benzhydryl-3-(methanesulfonyloxy)azetidine A suspension of 1-benzhydrylazetidin-3-ol (15.0 g) in pyridine (100 ml) was cooled to -20 C under a nitrogen atmosphere, and methanesulfonyl chloride (6.33 ml) was added dropwise thereto. The reaction mixture was stirred under a nitrogen atmosphere at -20 C for 1 hr, then in a water bath for 2.5 days. The reaction mixture was partitioned after addition of water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. To the residue were added ethanol (10 ml) and hexane (50 ml) to suspend precipitated crystals. The crystals were collected by filtration and washed with hexane. This was dried under aeration at room temperature to provide the titled compound as pale yellow crystals (5.943 g, 44.8 %). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate = 2:1, 1:1, then heptane:ethyl acetate:methanol = 50:50:1, 40:60:1, then ethyl acetate:methanol = 100: 1). Fractions containing the target compound were concentrated to provide the titled compound as pale yellow crystals (1.58 g, 11.9 %). 1H-NMR Spectrum (CDCl3) delta (ppm): 2.99 (3H, s), 3.18-3.21 (2H, m), 3.62-3.66 (2H, m), 4.40 (1H, s), 5.11 (1H, m), 7.18-7.22 (2H, m), 7.26-7.31 (4H, m), 7.39 (4H, d, J = 7.2 Hz). |
| 11.9% |
With pyridine; at -20 - 0℃; for 61h; |
Water (7.2 ml) and sodium cyanate (3.48 g) were added to a solution of 1-benzhydryl-3-(methanesulfonyloxy)azetidine (7.52 g) in N,N-dimethylformamide (60 ml), followed by stirring at 65 C. for 9 hours. Water, sodium carbonate and ethyl acetate were added to the reaction mixture, which was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure, and the resultant crystals were suspended by addition of diethyl ether (10 ml). The crystals were collected by filtration, and washed with diethyl ether. This was dried under aeration to give the title compound (5.43 g, 92.3%) as pale yellow crystals.1H-NMR Spectrum (CDCl3) delta (ppm): 3.20-3.31 (3H, m), 3.47 (2H, m), 4.36 (1H, s), 7.19-7.23 (2H, m), 7.26-7.30 (4H, m), 7.39 (4H, m). |
| 11.9% |
In pyridine; at -20℃;Inert atmosphere; |
(Reference Example F-1) 1-Benzhydryl-3-(methanesulfonyloxy)azetidine A suspension of 1-benzhydrylazetidin-3-ol (15.0 g) in pyridine (100 ml) was cooled to -20 C under a nitrogen atmosphere, and methanesulfonyl chloride (6.33 ml) was added dropwise thereto. The reaction mixture was stirred under a nitrogen atmosphere at -20 C for 1 hr, then in a water bath for 2.5 days. The reaction mixture was partitioned after addition of water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. To the residue were added ethanol (10 ml) and hexane (50 ml) to suspend precipitated crystals. The crystals were collected by filtration and washed with hexane. This was dried under aeration at room temperature to provide the titled compound as pale yellow crystals (5.943 g, 44.8 %). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate = 2:1, 1:1, then heptane:ethyl acetate:methanol = 50:50:1, 40:60:1, then ethyl acetate:methanol = 100:1). Fractions containing the target compound were concentrated to provide the titled compound as pale yellow crystals (1.58 g, 11.9 %). 1H-NMR Spectrum (CDCl3) delta (ppm): 2.99 (3H, s), 3.18-3.21 (2H, m), 3.62-3.66 (2H, m), 4.40 (1H, s), 5.11 (1H, m), 7.18-7.22 (2H, m), 7.26-7.31 (4H, m), 7.39 (4H, d, J = 7.2 Hz). |
|
With pyridine; In dichloromethane; cyclohexane; ethyl acetate; |
1-Benzhydrylazetidin-3-yl methylsulfonate may be prepared by carrying out the procedure starting with 100 g of 1-benzhydrylazetidin-3-ol, 800 cm3 of dichloromethane, 31 cm3 of methylsulfonyl chloride and 35 cm3 of pyridine. The crude product obtained is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 50 cm, diameter 11 cm), eluding under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate ({fraction (80/20)}, {fraction (75/25)}, and then {fraction (70/30)} and {fraction (60/40)} by volume) and collecting 1-liter fractions. Fractions 12 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 66 g of 1-benzhydrylazetidine-3-yl methylsulfonate are obtained in the form of a yellowish white solid. 1-Benzhydrylazetidin-3-ol may be prepared by carrying out the procedure as described by Alan R. KATRITZKY et al., in J. Heterocyclic Chem.; 31, 271 (1994). |
|
With triethylamine; In dichloromethane; water; |
(b) 1-Diphenylmethyl-3-methanesulphonyloxyazetidine Triethylamine (57 ml, 1.5 mol equivalent) was added to a solution of 1-diphenylmethylazetidin-3-ol (65.9 g, 275.7 mmol) in dry dichloromethane (700 ml) at 0 C. under nitrogen. After five minutes, methanesulphonyl chloride (25.6 ml, 1.2 mol equivalent) was added and the mixture stirred for one hour. Water (300 ml) was added and the mixture extracted with dichloromethane (3*300 ml). The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was chromatographed on silica gel eluding with methanol:dichloromethane (1.49, by volume) to give the title product (73.4 g) as a solid. 1 H-NMR (CDCl3): delta=2.95(s,3H), 3.15-3.25(m,2H), 3.6-3.65(m,2H), 4.4(s,1H), 5.05-5.15(m,1H), 7.15-7.4(m,10H)ppm. |
|
With triethylamine; In dichioromethane; water; |
Preparation 11 1-Diphenylmethyl-3-methanesulphonyloxyazetidine To a solution of 1-diphenylmethylazetidin-3-ol (see Preparation 10) (65.9 g, 275.7 mmol) in dry dichioromethane (700 ml) at 0 C. under nitrogen was added triethylamine (57 ml, 1.2 mol. equiv.). After five minutes, methanesulphonyl chloride (25.6 ml, 1.5 mol. equiv.) was added and the mixture stirred for one hour. Water (300 ml) was then added and the mixture extracted with dichloromethane (3*300 ml). The combined organic layers were dried over magnesium sulphate. The solution was then filtered and the solvent removed from the filtrate under reduced pressure. The residue was chromatographed using silica gel eluding with methanol:dichloromethane (1:49, by volume) to give the title compound (73.4 g) as a solid. 1H-NMR (CDCl3): delta=2.95(s, 3H), 3.15-3.25(m, 2H), 3.6-3.65(m, 2H), 4.4(s, 1H), 5.05-5.15(m, 1H), 7.15-7.4(m, 10H). |
|
With triethylamine; In dichloromethane; water; |
(b) 1-Diphenylmethyl-3-methanesulphonyloxyazetidine To a solution of 1-diphenylmethylazetidin-3-ol (see Preparation 3(a)) (65.9 g, 275.7 mmol) in dry dichloromethane (700 ml) at 0 C. under nitrogen was added triethylamine (57 ml, 1.5 mol. equiv.). After five minutes, methanesulphonyl chloride (25.6 ml, 1.2 mol. equiv.) was added and the mixture stirred for one hour. Water (300 ml) was then added and the mixture extracted with dichloromethane (3*300 ml). The combined organic layers were dried over magnesium sulphate. The solution was then filtered and the solvent removed from the filtrate by evaporation under reduced pressure. The residue was chromatographed using silica gel eluding with methanol:dichloromethane (1:49, by volume) to give the title compound (73.4 g) as a solid. 1H-NMR (CDCl3): delta=2.95 (s,3H), 3.15-3.25 (m,2H), 3.6-3.65 (m,2H), 4.4 (s,1H), 5.05-5.15 (m,1H), 7.15-7.4 (m,10H) ppm. |
|
With triethylamine; In acetonitrile; at -5 - 5℃; for 0.25h; |
Example 1 : Preparation of Formula V; To a 5 L 3-neck round bottom flask was charged 632 g (2.64 mol) of 1-benzhydrylazetidin-3-ol, acetonitrile (1.9 L) and triethylamine (601 g, 1.5 eq.). The mixture was cooled in an ice-acetone bath (- 5C). Mesyl chloride (436 g, 1.20 eq.) was added by drop funnel while keeping the reaction temperature at < 50C. HPLC showed reaction completion after 15 min. Water (6.3 L) was added, and the reaction mixture was stirred for 2 h at room temperature, and filtered. The filter cake was rinsed with water (2 x 1 L), and dried under vacuum, and directly subjected to the aminolysis reaction in the next step (Example 2). |
|
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; |
Referential Example 1 Synthesis of 1-diphenylmethyl-3-mesyloxyazetidine Triethylamine (153 mL) was added to a methylene chloride solution (1 L) of 1-diphenylmethyl-3-hydroxyazetidine (239 g) at room temperature, and methanesulfonyl chloride (85 mL) was added dropwise to the mixture under cooling with ice. The mixture was returned to room temperature, and stirred for two hours. The reaction mixture was washed with water (1 L), and the organic layer was dried with sodium sulfate anhydrate, followed by removal of solvent under reduced pressure. The precipitated solid was dispersed in hexane and collected through filtration, to thereby yield 313 g of the title compound. Form: Colorless solid m.p.: 115-116C 1H-NMR(CDCl3) delta: 2.98(s, 3H), 3.20(m, 2H), 3.64(m, 2H), 4.40(s, 1H), 5.10(m, 1H), 7.20(t, J=7Hz, 2H), 7.28(dd, J=7Hz, 7Hz, 4H), 7.39(d, J=7Hz, 4H) |
|
With triethylamine; In chloroform; at 20℃; for 3h; |
1) Production of 1-(1-acetylazetidin-3-yl)-4-(4-nitrophenyl)piperazine 0.581 mL of triethylamine and 0.185 mL of methanesulfonyl chloride were added to chloroform (15 mL) solution of 500 mg of N-(diphenylmethyl)-3-hydroxyazetidine, and stirred at room temperature for 3 hours. Aqueous sodium carbonate solution was added to the reaction liquid, extracted with chloroform, dried with sodium sulfate, and evaporated under reduced pressure to obtain crude N-(diphenylmethyl)-3-(methanesulfonyloxy)azetidine. |
|
With triethylamine; In dichloromethane; at 0℃; for 2.08333h; |
Intermediate 40: 1-(Diphenylmethyl)-3-azetidinyl methanesulfonate. [Show Image] Under a nitrogen atmosphere, triethylamine (0.9 mL, 6.5 mmol) was added to a solution of 1-benzhydrylazetan-3-ol (MAYBRIDGE, 1.033 g, 4.3 mmol) in dry DCM (15 mL), previously cooled to 0 C. After 5 minutes, methanesulfonyl chloride (ALDRICH, 0.4 mL, 5.2 mmol) was added and the resulting reaction mixture was stirred at 0 C for 2 h. Water was then added and product was extracted with DCM. The combined organic layers were dried over anhydrous MgSO4 and solvent was removed in vacuo to yield the title compound. 1H NMR (300 MHz, DMSO-d6) delta ppm: 7.58- 7.10 (br., 10H), 5.19- 5.03 (br., 1 H), 4.60- 4.42 (br., 1 H), 3.53-3.42 (br., 2H), 3.17 (br.s, 3H), 3.15- 2.97 (br., 2H). |
|
With pyridine; at 0 - 20℃; for 3h; |
Example 2A1-Benzhydry[-N-methylazetidin-3-amineA solution of 1-benzhydry1-azetidin-3-o. (15 g, 62 J mmol) in pyridine (60 mL) was cooled to 0 0C, treated with mesy. chloride (6 3 mL, 81 mmo.) and stirred at room temperature for 3 hours. The mixture was partitioned between ether (300 mL) and H2O (150 mL), The ether layer was washed with H2O, washed with brine, dried (MgSO4), filtered and concentrated to provide a greenish solid. The solid (23.3 g) was mixed with methyl amine (40 % in H2O, 90 mL) in DMF (60 mL), heated at 85 0C for 48 hours, cooled to room temperature, and partitioned between H2O (200 mL) and EtOAc (400 mL). The aqueous was extracted with additional EtOAc. The combined organics were extracted twice with 2 N HCI (200 mL), The combined 2M HC. layers were basified with NaOH (50%) and extracted with diethyl ether. The ether layer was washed with brine, dried (MgSO4), filtered, <n="124"/>concentrated under reduced pressure and purified on a silica gel column eluting with NH4OH/MeOH/CH2CI2 (0,4/4/96) to provide the title compound. NMR (CDCl3). delta 2,26 (s, 3H), 2,83 (t, J = 6 Hz, 2H), 3 33 (m, 1 H), 3.46 (t, J = 6 Hz, 2H), 7.15-7,20 (m, 2H), 7,24-7,29 (m, 4H), 7.36-74 (m, 4H). MS (DCI-NH3) m/z 254 (M+H)+ |
|
With pyridine; at 0 - 20℃; |
A solution of 1-benzhydryl-azetidin-3-ol (15 g, 62.7 mmol) in pyridine (60 mL) was chilled to 0 C., then treated with methanesulfonyl chloride (6.3 mL, 81 mmol). The reaction was warmed to room temperature and stirred for 3 hours. The mixture was partitioned between ether (300 mL) and H2O (150 mL), and the ether layer was washed with H2O and brine, dried (MgSO4), and concentrated to provide the crude methanesulfonate. _ |
|
With triethylamine; In dichloromethane; at 20℃; for 2.33333h;Cooling with ice; |
(1) To a solution of 1-diphenylmethyl-3-hydroxyazetidine (1.0 g) and TEA (1.11 ml) in methylene chloride (5 ml) was added dropwise a solution of methanesulfonyl chloride (0.72 g) in methylene chloride (5 ml) over 20 minutes under ice-cooling. After the addition, the reaction solution was allowed to warm to room temperature, and stirred for 2 hours. To the reaction solution was added water, and the mixture was extracted with chloroform. The extract was sequentially washed with water and brine, then dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: hexane to hexane/ethyl acetate=7/3) to give 1-diphenylmethyl-3-methanesulfonyloxyazetidine (1.0 g) as a white powder. 1H-NMR (CDCl3, deltappm); 2.98 (3H, s), 3.14-3.25 (2H, m), 3.59-3.68 (2H, m), 4.40 (1H, s), 5.10 (1H, quint, J=5.9 Hz), 7.15-7.3, 7.3-7.4 (10H, m). LC-MS, m/z; 318 (MH+). |
|
With triethylamine; In dichloromethane; at 0℃; for 0.5h;Inert atmosphere; |
To a solution of 1-benzhydrylazetidin-3-ol (Step 1, 100.0 g, 360.0 mmol) and triethylamine (100.0 g, 1.08 mol) in dichloromethane (700 mL) was added Methanesulfonyl chloride (55.0 g, 432.0 mmol) slowly at 0 C under N2. The resulting mixture was stirred at 0 C for 0.5 hour and was poured into water (500 mL). The mixture was extracted with dichloromethane (3 ' 500 mL) and the organic layers were combined, washed with brine, dried over Magnesium sulfate and then evaporated to afford the crude compound (120.0 g) as a solid. The crude was used in the next step without further purification. |
|
With triethylamine; In toluene; at 0℃; for 1h; |
Description 19: 1-benzhydrylazetidin-3-yl methanesulfonate (D19) To a cooled solution of 1 -Benzhhydrylazetidin-3-ol (3.5 g, 14.624 mmol, available from Manchester No.A10473) and triethylamine (4.07ml, 29.25 mmol) in toluene (21 ml) Methanesulfonyl chloride (1 .13ml, 14.62 mmol) was added dropwise keeping the temperature at 0C. The reaction mixture was stirred 1 h at 0C then the solid was filtered off and washed with toluene (2x5ml). The yellow filtrate was evaporated in vacuo to afford the title compound (D19) (5 g).1 H NMR (400MHz ,CHLOROFORM-d) delta (ppm): 7.42 (d, J = 7.3 Hz, 4 H), 7.34 - 7.28 (m, 4 H), 7.24 - 7.17 (m, 2 H), 5.13 (quin, J = 5.9 Hz, 1 H), 4.43 (s, 1 H), 3.71 - 3.58 (m, 2 H), 3.27 - 3.19 (m, 2 H), 3.00 (s, 3 H) |
| 5 g |
With triethylamine; In toluene; at 0℃; for 1h; |
To a cooled solution of 1-Benzhhydrylazetidin-3-ol (3.5 g, 14.624 mmol, available from Manchester A10473) and triethylamine (4.07 ml, 29.25 mmol) in toluene (21 ml) Methanesulfonyl chloride (1.13 ml, 14.62 mmol) was added dropwise keeping the temperature at 0 C. The reaction mixture was stirred 1 h at 0 C. then the solid was filtered off and washed with toluene (2×5 ml). The yellow filtrate was evaporated in vacuo to afford the title compound (D19) (5g). |
|
With hydrogen; triethylamine; In ethanol; acetonitrile; at -10 - 0℃; for 1h; |
1) The synthesis of 1-(diphenylmethyl)-3-azidoazetidine 1-(diphenylmethyl)-3-hydroxyazetidine (5.5 g, 22.98 mmol) was dissolved in acetonitrile (16.5 mL), triethylamine (3.48 g, 34.45 mmol) was added. The reaction mixture was cooled to -10C, methylsulfonyl chloride (3.16 g, 27.59 mmol) was added dropwise slowly. After completion of dropwise addition, the reaction was performed at 0C for 1 h, The resultant reaction liquid was poured into water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a white solid. The resultant white solid was added to N,N-dimethyl formamide (25 mL), sodium azide (5.38 g, 82.73 mmol) was added. The reaction mixture was warmed to 100C and the reaction was performed overnight. The resultant reaction liquid was cooled to room temperature, poured into water, extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered; the filtrate was rotatedly concentrated to dryness to yield 1-(diphenylmethyl)-3-azidoazetidine. |
|
With triethylamine; In acetonitrile; at -10 - 0℃; for 1h; |
1-(diphenylmethyl)-3-hydroxyazetidine (5.5 g, 22.98 mmol) was dissolved in acetonitrile (16.5 mL), triethylamine (3.48 g, 34.45 mmol) was added. The reaction mixture was cooled to -10 C., methylsulfonyl chloride (3.16 g, 27.59 mmol) was added dropwise slowly. After completion of dropwise addition, the reaction was performed at 0 C. for 1 h, The resultant reaction liquid was poured into water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a white solid. The resultant white solid was added to N,N-dimethyl formamide (25 mL), sodium azide (5.38 g, 82.73 mmol) was added. The reaction mixture was warmed to 100 C. and the reaction was performed overnight. The resultant reaction liquid was cooled to room temperature, poured into water, extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered; the filtrate was rotatedly concentrated to dryness to yield 1-(diphenylmethyl)-3-azidoazetidine. |
|
With triethylamine; In dichloromethane; at 0℃; for 2.08333h; |
Intermediate 18: 1-(Diphenylmethyl)-3-azetidinyl methanesulfonate.Under a nitrogen atmosphere, TEA (0.9ml_, 6.5mmol) was added to a solution of 1- benzhydrylazetan-3-ol (Maybridge, 1.03g, 4.3mmol) in dry DCM (15ml_), previously cooled to 0 0C. After 5 min, methanesulfonyl chloride (Aldrich, 0.4ml_, 5.2mmol) was added and the resulting reaction mixture was stirred at 0 0C for 2 h. Water was then added and the mixture was extracted with DCM. The combined organic layers were dried over anhydrous MgSO4 and solvent was removed in vacuo to yield the title compound. 1H NMR (300 MHz, DMSO-d6) delta ppm: 7.58- 7.10 (br., 10H); 5.19- 5.03 (br., 1 H); 4.60- 4.42 (br., 1 H); 3.63- 3.42 (br., 2H); 3.17 (br.s, 3H); 3.15- 2.97 (br., 2H). |
| 11 g |
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; |
To a mixture of l-benzhydrylazeti din-3 -ol (10.0 g, 41.79 mmol) in DCM (100 mL) was added TEA (12.7 g, 125.37 mmol) and MsCl (8.6 g, 75.22 mmol) at 0C. Then the reaction mixture was warmed to r.t. and stirred for 3 hours. After the reaction was complete, the mixture was washed with water and the water layer was back-extracted with DCM. The combined organic layers were dried over Na2S04, and concentrated. The residue was purified by flash chromatography (silica gel, 2 % - 5 % MeOH in DCM) to give l-benzhydrylazetidin- 3-yl methanesulfonate (11.0 g) as a yellow solid. LC-MS (ESI) found: 318 [M+l]+. |
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