* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sulfur trioxide pyridine complex; triethylamine In dimethyl sulfoxide at 0 - 20℃;
To a solution of pyridine sulfur trioxide (29.95 g, 188 mmol) in DMSO (100 mL) at 0° C., was added triethylamine (26.2 mL) and C48 (15.0 g, 62.7 mmol) in DMSO (50 mL). The mixture was warmed to room temperature after 5 mins and stirred for 3 h. The reaction was quenched with saturated aqueous sodium chloride solution and extracted with EtOH; the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (Eluant: 1:1:100:200 MeOH: triethylamine: EtOAc: hexane) to afford C74 as a yellow solid. Yield: 12.2 g, 51.4 mmol, 82percent. 1H NMR (400 MHz, CDCl3) δ4.02 (s, 4H), 4.61 (s, 1H), 7.23 (m, 2H), 7.32 (m, 4H), 7.49 (m, 4H).
66%
With sulfur trioxide pyridine complex; triethylamine In dimethylsulfoxide-d6 for 2 h;
Example 95-amino-I -(I -cyanoazetidi n-3-yl)-3-(4-phenoxyphenyl)-I H-pyrazole-4-carboxamide Step i: preparation of i-(diphenylmethyl)azetidin-3-one. To a stirred solution of sulfur trioxide-pyridine complex (69 g, 432.95 mmol) in dimethylsulfoxide (i 72.6 mL) was added a solution of i-(diphenylmethyl)azetidin-3-ol hydrochloric acid (20 g, 72.52 mmol) and triethylamine (50.5 mL, 362.6 mmol) in tetrahydrofuran (69 mL) drop wise over 10 minutes. The solution was allowed to stir for 2h. The reaction mixture was then poured into water and extracted into 50percent ethyl acetate hexanes. The organic layers were combined and washed with brine, dried over sodium sulfate, and concentrated invacuo to afford the title compound (11.4 g, 66percent).
43.2%
at 20 - 50℃; for 0.5 h;
(Production Example 78) 1-Benzhydrylazetidin-3-one To a mixture of 1-benzhydrylazetidin-3-ol hydrochloride (5.52 g) and triethylamine (27.9 ml) was added dropwise a solution of pyridine sulfur trioxide complex (19.7 g) in dimethyl sulfoxide (80 ml) at room temperature. The reaction mixture was stirred at 50 °C for 30 min. The reaction was allowed to cool down to room temperature. This was poured into ice water. This was extracted with ethyl acetate, and the organic layer was washed with brine. Activated carbon (5 g) was added to the organic layer, followed by stirring at room temperature for 3 days. Activated carbon was removed by filtration and the filtrate was concentrated. The residue was dissolved in methanol (200 ml), and activated carbon (10 g) was added thereto, followed by stirring at room temperature for 3 days. Activated carbon was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate = 4:1, then 2:1). Fractions containing the target compound were concentrated to provide the target compound as a pale yellow oil (3.21 g). Hexane was added thereto to precipitate crystals, which were collected by filtration. Drying under aeration provided the titled compound (1.11 g, 23.4 percent). To the residue obtained by concentrating the filtrate was added hexane, and allowed to stand at room temperature. After crystals precipitated, supernatant was removed by a pipette. This was dried under reduced pressure to provide the titled compound as pale yellow crystals (940 mg, 19.8 percent). 1H-NMR Spectrum (CDCl3) δ (ppm): 4.01 (4H, s), 4.60 (1H, s), 7.22 (2H, m), 7.30 (4H, m), 7.48 (4H, m).
37%
With 4-methyl-morpholine; tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In dichloromethane at 0 - 20℃; for 24 h; Molecular sieve
l-(Diphenylmethyl)azetidin-3-ol hydrochloride (2.75 g, 9.98 mmol), prepared using procedures similar to those described for Scheme 1 of the General Synthetic Section, 3 A molecular sieves and 4-methylmorpholine (1.1 niL, 10.0 mmol) were suspended in dichloromethane (20 mL) at 0 0C. 4-Methylmorpholine N-oxide (2.93 g, 25.0 mmol) and tetrapropylammonium perruthenate (140 mg, 0.399 mmol) were added and the mixture was stirred at ambient for 24 h. The mixture was filtered through a plug of silica using 5percent triethylamine in ethyl acetate as eluent. The filtrate was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 8:1 hexanes:ethyl acetate) gave l-(diphenylmethyl)azetidin-3-one (871 mg, 3.68 mmol, 37percent yield): 1H NMR (400 MHz, CDCl3): 7.50-7.46 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 4.59 (s, IH), 4.01 (s, 4H); MS (EI) for CJ6H15NO: 238 (MH+).
37%
With 4-methyl-morpholine; tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In dichloromethane at 0 - 20℃; for 24 h; Molecular sieve
l-(Diphenylmethyl)azetidin-3-ol hydrochloride (2.75 g, 9.98 mmol), prepared using procedures similar to those described for Scheme 1 of the General Synthetic Section, 3 A molecular sieves and 4-methylmorpholine (1.1 mL, 10.0 mmol) were suspended in dichloromethane (20 mL) at 0 0C. 4-Methylmorpholine N-oxide (2.93 g, 25.0 mmol) and tetrapropylammonium perruthenate (140 mg, 0.399 mmol) were added and the mixture was stirred at ambient for 24 h. The mixture was filtered through a plug of silica using 5percent triethylamine in ethyl acetate as eluent. The filtrate was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 8:1 hexanes:ethyl acetate) gave 1- (diphenylmethyl)azetidin-3-one (871 mg, 3.68 mmol, 37percent yield): 1H NMR (400 MHz, CDCl3): 7.50-7.46 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 4.59 (s, IH), 4.01 (s, 4H); MS (EI) for C16H15NO: 238 (MH+).
37%
With 4-methyl-morpholine; tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In dichloromethane at 0 - 20℃; for 24 h; 3A molecular sieves
l-(Diphenylmethyl)azetidin-3-ol hydrochloride (2.75 g, 9.98 mmol), prepared using procedures similar to those described for Scheme 1 of the General Synthetic Section, 3 A molecular sieves and 4-methylmorpholine (1.1 mL, 10.0 mmol) were suspended in dichloromethane (20 mL) at 0 0C. 4-Methylmorpholine N-oxide (2.93 g, 25.0 mmol) and tetrapropylammonium perruthenate (140 mg, 0.399 mmol) were added and the mixture was stirred at ambient for 24 h. The mixture was filtered through a plug of silica using 5percent triethylamine in ethyl acetate as eluent. The filtrate was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 8:1 hexanes:ethyl acetate) gave l-(diphenylmethyl)azetidin-3-one (871 mg, 3.68 mmol, 37percent yield): 1H NMR (400 MHz, CDCl3): 7.50-7.46 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 4.59 (s, IH), 4.01 (s, 4H); MS (EI) for C16H15NO: 238 (MH+).
19.8%
With pyridine-SO3 complex; triethylamine In dimethyl sulfoxide at 20 - 50℃; for 0.5 h;
A solution of pyridine sulfur trioxide complex (19.7 g) in dimethyl sulfoxide (80 ml) was added dropwise to a mixture of 1-benzhydrylazetidin-3-ol hydrochloride (5.52 g) and triethylamine (27.9 ml) at room temperature. The reaction mixture was stirred at 50° C. for 30 minutes. The reaction mixture was allowed to cool down to room temperature, and poured into ice water. This was extracted with ethyl acetate, and the organic layer was washed with brine. Activated carbon (5 g) was added to the organic layer, followed by stirring at room temperature for 3 days. The activated carbon was removed by filtration, and the filtrate was concentrated. The residue was dissolved in methanol (200 ml), and activated carbon (10 g) was added thereto, followed by stirring at room temperature for 3 days. The activated carbon was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=4:1, then 2:1). The fractions containing the target compound were concentrated to give the target compound (3.21 g) as a pale yellow oil. Hexane was added thereto to precipitate crystals, and the crystals were collected by filtration. Drying under aeration gave the title compound (1.11 g, 23.4percent) as white crystals. Hexane was added to the residue obtained by concentration of the filtrate, which was allowed to stand at room temperature. After crystals precipitated, the supernatant was removed using a pipette. These were dried under reduced pressure to give the title compound (940 mg, 19.8percent) as pale yellow crystals.1H-NMR Spectrum (CDCl3) δ (ppm): 4.01 (4H, s), 4.60 (1H, s), 7.22 (2H, m), 7.30 (4H, m), 7.48 (4H, m).
C. Preparation of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (C49). Methanesulfonyl chloride (180 g, 1.57 mol) was added to a solution of C48 (360 g, 1.31 mol) and triethylamine (330 g, 3.26 mol) in dichloromethane (3 L) at 0° C. The reaction mixture was stirred at room temperature for 3 h, quenched with saturated aqueous sodium bicarbonate solution, then extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford C49. Yield: 360 g, 1.14 mol, 87percent. B. Preparation of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (C49). Compound C49 was prepared according to the procedure described in Preparation 1 to afford C49 as a yellow solid. Yield: 303 g, 0.96 mol, 91percent. 1H NMR (400 MHz, CDCl3) δ 2.91 (s, 3H), 3.13 (m, 2H), 3.55 (m, 2H), 4.31 (s, 1H), 4.02 (m, 1H), 7.14 (m, 2H), 7.20 (m, 4H), 7.31 (m, 4H).
Reference：
[1] Patent: US2010/190771, 2010, A1, . Location in patent: Page/Page column 28-29
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 21, p. 9055 - 9068
5
[ 90604-02-7 ]
[ 18621-18-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
With hydrogen In ethanol at 20℃; for 12 h;
A solution of l-(diphenylmethyl)-3-hydroxyazetidine hydrochloride (11.8 g) in absolute ethanol (700 mL) was hydrogenated at room temperature over Pd(OH)2/C in a Parr shaker at 4 atm. After 12 hr the catalyst was filtered off and the filtrate evaporated to dryness to give3-hydroxyazetidine hydrochloride (4.20 g, 94percent). 1H-NMR (300 MHz, DMSO-de, ppm from TMS): δ 9.07 (2H, bb), 6.19 (IH, bb), 4.49 (IH, m), 3.99 (2H, m), 3.71 (2H, m).
52%
With hydrogen In methanol for 48 h;
A reaction mixture of N-benzhydrylazetidin-3-ol HCl salt (2.76 g, 10.0 mmol) with palladium hydroxide, 20percent Pd (dry base) on C (400 mg) in 50 mL of MeOH was hydrogenated at 55 psi for 48 h. The reaction mixture was filtered through Celite pad and washed well with MeOH. The filtrate was concentrated under vacuum at room temperature water bath. The residue was treated with ether (3x30 ml) and the solvent is decanted. The solid was air dried to give 571 mg of HCl salt product (2) as white solid (52percent yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.33 (s, 1H) 3.63-3.80 (m, 2H) 3.93-4.09 (m, 2H) 4.40-4.58 (m, 1H) 6.18 (d, J=6.32 Hz, 1H).
52%
With hydrogen In methanol for 48 h;
A reaction mixture of N-benzhydrylazetidin-3-ol HCI salt (2.76 g, 10.0 mmol) with palladium hydroxide, 20percent Pd (dry base) on C (400 mg) in 50 mL of MeOH was hydrogenated at 55 psi for 48 h. The reaction mixture was filtered through Celite pad and washed well with MeOH. The filtrate was concentrated under vacuum at room temperature water bath. The residue was treated with ether (3x30ml) and the solvent is decanted. The solid was air dried to give 571 mg of HCI salt product (2-2) as white solid (52percent yield). 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.33 (s, 1 H) 3.63 - 3.80 (m, 2 H) 3.93 -4.09 (m, 2 H) 4.40 - 4.58 (m, 1 H) 6.18 (d, J=6.32 Hz, 1 H).
Reference：
[1] Journal of Antibiotics, 2006, vol. 59, # 4, p. 241 - 247
[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4601 - 4608
[3] Patent: WO2007/118830, 2007, A1, . Location in patent: Page/Page column 91
[4] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 57-58
[5] Patent: WO2006/21881, 2006, A2, . Location in patent: Page/Page column 62; 63
[6] Heterocycles, 1992, vol. 33, # 2, p. 523 - 528
[7] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 2, p. 271 - 276
6
[ 18621-17-5 ]
[ 90604-02-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrogenchloride In ethyl acetate at 20℃; for 0.166667 h;
1-(Diphenylmethyl) -3 -hydroxy azetidine (9.70 g) was suspended in 4.5M HCl in EtOAc (35 niL) at room temperature and stirred for 10 min. The solvent was then evaporated to dryness to give l-(diphenylmethyl)- 3-hydroxyazetidine hydrochloride (12.0 g, 100percent). 1H-NMR (300 MHz, DMSO-de, ppm from TMS): δ 7.30-7.70 (1OH, m), 5.85 (IH, s), 5.80 (IH, d), 4.46 (IH, m), 3.70-4.20 (4H, m).
Reference：
[1] Journal of Antibiotics, 2006, vol. 59, # 4, p. 241 - 247
11
[ 91-00-9 ]
[ 90604-02-7 ]
Reference：
[1] Journal of Antibiotics, 2006, vol. 59, # 4, p. 241 - 247
12
[ 24424-99-5 ]
[ 90604-02-7 ]
[ 141699-55-0 ]
Yield
Reaction Conditions
Operation in experiment
357 g
Stage #1: With sodium carbonate In dichloromethane; water at 20℃; Stage #2: With palladium on carbon; hydrogen In tetrahydrofuran at 20℃; for 18 h;
Step 2. tert-Butyl 3-hydroxyazetidine-l -carboxylate (10) A suspension of l-benzhydrylazetidin-3-ol hydrochloride (9, 625 g, 2.27 mol) in a 10 percent solution of aqueous sodium carbonate (Na2C03, 5 L) and dichloromethane (CH2CI2, 5 L) was stirred at room temperature until all solids were dissolved. The two layers were separated, and the aqueous layer was extracted with dichloromethane (CH2CI2, 2 L). The combined organics extracts were dried over sodium sulfate (Na2SC>4) and concentrated under reduced pressure. This resulting crude free base of 9 was then dissolved in THF (6 L) and the solution was placed into a large Parr bomb. Di-teri-butyl dicarbonate (BOC20, 545 g, 2.5 mol, 1.1 equiv) and 20 percent palladium (Pd) on carbon (125 g, 50 percent wet) were added to the Parr bomb. The vessel was charged to 30 psi with hydrogen gas () and stirred under steady hydrogen atmosphere (vessel was recharged three times to maintain the pressure at 30 psi) at room temperature for 18 h. When HPLC showed that the reaction was complete (when no more hydrogen was taken up), the reaction mixture was filtered through a Celite pad and the Celite pad was washed with THF (4 L). The filtrates were concentrated under reduced pressure to remove the solvent and the residue was loaded onto a Biotage 150 column with a minimum amount of dichloromethane (CH2CI2). The column was eluted with 20 - 50 percent ethyl acetate in heptane and the fractions containing the pure desired product (10) were collected and combined. The solvents were removed under reduced pressure to afford terr-butyl 3-hydroxyazetidine-l - carboxylate (10, 357 g, 393.2 g theoretical, 90.8percent yield) as colorless oil, which solidified upon standing at room temperature in vacuum. For 10: 'iTNMR (CDCI3, 300 MHz), δ 4.56 (m 1 H), 4.13 (m, 2H), 3.81 (m, 2H), 1.43 (s, 9H) ppm.
With hydrogen;palladium hydroxide on carbon; In ethanol; at 20℃; under 3040.2 Torr; for 12h;
A solution of l-(diphenylmethyl)-3-hydroxyazetidine hydrochloride (11.8 g) in absolute ethanol (700 mL) was hydrogenated at room temperature over Pd(OH)2/C in a Parr shaker at 4 atm. After 12 hr the catalyst was filtered off and the filtrate evaporated to dryness to give3-hydroxyazetidine hydrochloride (4.20 g, 94%). 1H-NMR (300 MHz, DMSO-de, ppm from TMS): delta 9.07 (2H, bb), 6.19 (IH, bb), 4.49 (IH, m), 3.99 (2H, m), 3.71 (2H, m).
52%
With hydrogen;palladium(II) hydroxide/carbon; In methanol; under 2844.39 Torr; for 48h;
A reaction mixture of N-benzhydrylazetidin-3-ol HCl salt (2.76 g, 10.0 mmol) with palladium hydroxide, 20% Pd (dry base) on C (400 mg) in 50 mL of MeOH was hydrogenated at 55 psi for 48 h. The reaction mixture was filtered through Celite pad and washed well with MeOH. The filtrate was concentrated under vacuum at room temperature water bath. The residue was treated with ether (3x30 ml) and the solvent is decanted. The solid was air dried to give 571 mg of HCl salt product (2) as white solid (52% yield). 1H NMR (400 MHz, DMSO-D6) delta ppm 3.33 (s, 1H) 3.63-3.80 (m, 2H) 3.93-4.09 (m, 2H) 4.40-4.58 (m, 1H) 6.18 (d, J=6.32 Hz, 1H).
52%
With hydrogen;palladium hydroxide on carbon; In methanol; under 2844.39 Torr; for 48h;
A reaction mixture of N-benzhydrylazetidin-3-ol HCI salt (2.76 g, 10.0 mmol) with palladium hydroxide, 20% Pd (dry base) on C (400 mg) in 50 mL of MeOH was hydrogenated at 55 psi for 48 h. The reaction mixture was filtered through Celite pad and washed well with MeOH. The filtrate was concentrated under vacuum at room temperature water bath. The residue was treated with ether (3x30ml) and the solvent is decanted. The solid was air dried to give 571 mg of HCI salt product (2-2) as white solid (52% yield). 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.33 (s, 1 H) 3.63 - 3.80 (m, 2 H) 3.93 -4.09 (m, 2 H) 4.40 - 4.58 (m, 1 H) 6.18 (d, J=6.32 Hz, 1 H).
Step 1: Preparation of 1-diphenylmethyl-3-hydroxy-azetidine hydrochloride This compound is obtained according to the procedure of Example 2, Step B, starting with 88 g (0.480 mol) of diphenylmethylamine and 1 equivalent of epichlorohydrin. 68 g of 1-diphenylmethyl-3-hydroxy-azetidine hydrochloride are obtained, i.e. a yield of 51%.
45%
In methanol;
410.1)1-(diphenylmethyl)-3-hydroxyazetidine hydrochloride: Aminodiphenylmethane (55 g; 0.3 mol) and epichlorhydrin (23.5 ml; 0.3 mol) are mixed in methanol (200 ml). The mixture is heated under reflux for 5 days. The methanol is then evaporated off in order to produce a beige solid. The latter is filtered and washed with ether in order to produce a white solid with a yield of 45%. Melting point: 186.0-186.4 C.
In methanol; at 20℃;Reflux;
A solution of diphenylmethanamine (21, 2737 g, 15.0 mol, 1.04 equiv) in methanol (MeOH, 6 L) was treated with 2-(chloromethyl)oxirane (22, 1330 g, 14.5 mol) from an addition funnel at room temperature. During the initial addition a slight endotherm was noticed. The resulting reaction mixture was stirred at room temperature for 3 days before being warmed to reflux for an additional 3 days. When TLC showed that the reaction was deemed complete, the reaction mixture was first cooled down to room temperature and then to 0-5 C. in an ice bath. The solids were collected by filtration and washed with acetone (4 L) to give the first crop of the crude desired product (23, 1516 g).The filtrate was concentrated under reduced pressure and the resulting semisolid was diluted with acetone (1 L). This solid was then collected by filtration to give the second crop of the crude desired product (23, 221 g). The crude product, 1-benzhydrylazetidin-3-ol hydrochloride (23, 1737 g, 3998.7 g theoretical, 43.4% yield), was found to be sufficiently pure to be used in the subsequent reaction without further purification.
In methanol; for 96h;Reflux;
A solution of 2-(chloromethyl)oxirane (260 g, 2.81 mol) and C47 (500 g, 2.73 mol) in MeOH (1 L) was heated at reflux for 4 days. Solvent was removed under reduced pressure to provide a white precipitate, which was collected by filtration. The solid was washed with acetone and dried to provide C48, which was used in the next step without further purification.
In methanol; at 20℃; for 144h;Reflux; Large scale;
Step 1. 1 -Benzhydrylazetidin-3-ol hydrochloride (9) A solution of diphenylmethanamine (7, 2737 g, 15.0 mol, 1.04 equiv) in methanol (MeOH, 6 L) was treated with 2-(chloromethyl)oxirane (8, 1330 g, 14.5 mol) from an addition funnel at room temperature. During the initial addition a slight endotherm was noticed. The resulting reaction mixture was stirred at room temperature for 3 days before being warmed to reflux for an additional 3 days. When TLC showed that the reaction was deemed complete, the reaction mixture was first cooled down to room temperature and then to 0 - 5 C in an ice bath. The solids were collected by filtration and washed with acetone (4 L) to give the first crop of the crude desired product (9, 1516 g). The filtrate was concentrated under reduced pressure and the resulting semisolid was diluted with acetone (1 L). This solid was then collected by filtration to give the second crop of the crude desired product (9, 221 g). The crude product, l -benzhydrylazetidin-3-ol hydrochloride (9, 1737 g, 3998.7 g theoretical, 43.4 % yield), was found to be sufficiently pure to be used in the subsequent reaction without further purification. For 9: 'H MR (DMSO-C/6, 300 MHz), delta 12.28 (br. d, 1 H), 7.7 (m, 5H), 7.49 (m, 5H), 6.38 (d, 1H), 4.72 (br. s, 1 H), 4.46 (m, 1 H), 4.12 (m, 2H), 3.85 (m, 2H) ppm; C,6H,8ClNO (free base of 9, Ci6Hi7NO MW, 239.31 ), LCMS (EI) m/e 240 (M+ +. H).
In methanol; at 20℃; for 144h;Reflux;
1-Benzhydrylazetidin-3-ol hydrochloride (16) [0154] A solution of diphenylmethanamine (2737 g, 15.0 mol, 1.04 equiv) in methanol (MeOH, 6 L) was treated with 2-(chloromethyl)oxirane (1330 g, 14.5 mol) from an addition funnel at ambient temperature. During the initial addition a slight endotherm was noticed. The resulting reaction mixture was stirred at room temperature for 3 days before being warmed to reflux for an additional 3 days. When TLC showed that the reaction was deemed complete, the reaction mixture was first cooled down to room temperature and then to 0-5 C. in an ice bath. The solids were collected by filtration and washed with acetone (4 L) to give the first crop of the crude desired product (1516 g). The filtrate was concentrated under reduced pressure and the resulting semisolid was diluted with acetone (1 L). This solid was then collected by filtration to give the second crop of the crude desired product (221 g). The crude product, 1-benzhydrylazetidin-3-ol hydrochloride (1737 g, 3998.7 g theoretical, 43.4% yield), was found to be sufficiently pure to be used in the subsequent reaction without further purification. 1HNMR (300 MHz, DMSO-d6) delta 12.28 (br. d, 1H), 7.7 (m, 5H), 7.49 (m, 5H), 6.38 (d, 1H), 4.72 (br. s, 1H), 4.46 (m, 1H), 4.12 (m, 2H), 3.85 (m, 2H) ppm; C16H18ClNO (MW 275.77; C16H17NO for free base, MW, 239.31), LCMS (EI) m/e 240 (M++H).
With methanol; at 20℃; for 144h;Reflux; Large scale;
1-Benzhydrylazetidin-3-ol hydrochloride (16) A solution of diphenylmethanamine (2737 g, 15.0 mol, 1.04 equiv) in methanol (MeOH, 6 L) was treated with 2-(chloromethyl)oxirane (1330 g, 14.5 mol) from an addition funnel at ambient temperature. During the initial addition a slight endotherm was noticed. The resulting reaction mixture was stirred at room temperature for 3 days before being warmed to reflux for an additional 3 days. When TLC showed that the reaction was deemed complete, the reaction mixture was first cooled down to room temperature and then to 0-5 C. in an ice bath. The solids were collected by filtration and washed with acetone (4 L) give the first crop of the crude desired product (1516 g). The filtrate was concentrated under reduced pressure and the resulting semisolid was diluted with acetone (1 L). This solid was then collected by filtration to give the second crop of the crude desired product (221 g). The crude product, 1-benzhydrylazetidin-3-ol hydrochloride (1737 g, 3998.7 g theoretical, 43.4% yield), was found to be sufficiently pure to be used in the subsequent reaction without further purification. 1HNMR (300 MHz, DMSO-d6) delta 12.28 (br. d, 1H), 7.7 (m, 5H), 7.49 (m, 5H), 6.38 (d, 1H), 4.72 (br. s, 1H), 4.46 (m, 1H), 4.12 (m, 2H), 3.85 (m, 2H) ppm; C16H18ClNO (MW 275.77; C16H17NO for free base, MW, 239.31), LCMS (EI) m/e 240 (M++H).
With sulfur trioxide pyridine complex; triethylamine; In dimethyl sulfoxide; at 0 - 20℃;
To a solution of pyridine sulfur trioxide (29.95 g, 188 mmol) in DMSO (100 mL) at 0 C., was added triethylamine (26.2 mL) and C48 (15.0 g, 62.7 mmol) in DMSO (50 mL). The mixture was warmed to room temperature after 5 mins and stirred for 3 h. The reaction was quenched with saturated aqueous sodium chloride solution and extracted with EtOH; the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (Eluant: 1:1:100:200 MeOH: triethylamine: EtOAc: hexane) to afford C74 as a yellow solid. Yield: 12.2 g, 51.4 mmol, 82%. 1H NMR (400 MHz, CDCl3) delta4.02 (s, 4H), 4.61 (s, 1H), 7.23 (m, 2H), 7.32 (m, 4H), 7.49 (m, 4H).
66%
With sulfur trioxide pyridine complex; triethylamine; In dimethylsulfoxide-d6; for 2h;
Example 95-amino-I -(I -cyanoazetidi n-3-yl)-3-(4-phenoxyphenyl)-I H-pyrazole-4-carboxamide Step i: preparation of i-(diphenylmethyl)azetidin-3-one. To a stirred solution of sulfur trioxide-pyridine complex (69 g, 432.95 mmol) in dimethylsulfoxide (i 72.6 mL) was added a solution of i-(diphenylmethyl)azetidin-3-ol hydrochloric acid (20 g, 72.52 mmol) and triethylamine (50.5 mL, 362.6 mmol) in tetrahydrofuran (69 mL) drop wise over 10 minutes. The solution was allowed to stir for 2h. The reaction mixture was then poured into water and extracted into 50% ethyl acetate hexanes. The organic layers were combined and washed with brine, dried over sodium sulfate, and concentrated invacuo to afford the title compound (11.4 g, 66%).
43.2%
With sulfur trioxide pyridine complex; dimethyl sulfoxide; triethylamine; at 20 - 50℃; for 0.5h;
(Production Example 78) 1-Benzhydrylazetidin-3-one To a mixture of 1-benzhydrylazetidin-3-ol hydrochloride (5.52 g) and triethylamine (27.9 ml) was added dropwise a solution of pyridine sulfur trioxide complex (19.7 g) in dimethyl sulfoxide (80 ml) at room temperature. The reaction mixture was stirred at 50 C for 30 min. The reaction was allowed to cool down to room temperature. This was poured into ice water. This was extracted with ethyl acetate, and the organic layer was washed with brine. Activated carbon (5 g) was added to the organic layer, followed by stirring at room temperature for 3 days. Activated carbon was removed by filtration and the filtrate was concentrated. The residue was dissolved in methanol (200 ml), and activated carbon (10 g) was added thereto, followed by stirring at room temperature for 3 days. Activated carbon was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate = 4:1, then 2:1). Fractions containing the target compound were concentrated to provide the target compound as a pale yellow oil (3.21 g). Hexane was added thereto to precipitate crystals, which were collected by filtration. Drying under aeration provided the titled compound (1.11 g, 23.4 %). To the residue obtained by concentrating the filtrate was added hexane, and allowed to stand at room temperature. After crystals precipitated, supernatant was removed by a pipette. This was dried under reduced pressure to provide the titled compound as pale yellow crystals (940 mg, 19.8 %). 1H-NMR Spectrum (CDCl3) delta (ppm): 4.01 (4H, s), 4.60 (1H, s), 7.22 (2H, m), 7.30 (4H, m), 7.48 (4H, m).
37%
With 4-methyl-morpholine; tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; at 0 - 20℃; for 24h;Molecular sieve;
l-(Diphenylmethyl)azetidin-3-ol hydrochloride (2.75 g, 9.98 mmol), prepared using procedures similar to those described for Scheme 1 of the General Synthetic Section, 3 A molecular sieves and 4-methylmorpholine (1.1 niL, 10.0 mmol) were suspended in dichloromethane (20 mL) at 0 0C. 4-Methylmorpholine N-oxide (2.93 g, 25.0 mmol) and tetrapropylammonium perruthenate (140 mg, 0.399 mmol) were added and the mixture was stirred at ambient for 24 h. The mixture was filtered through a plug of silica using 5% triethylamine in ethyl acetate as eluent. The filtrate was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 8:1 hexanes:ethyl acetate) gave l-(diphenylmethyl)azetidin-3-one (871 mg, 3.68 mmol, 37% yield): 1H NMR (400 MHz, CDCl3): 7.50-7.46 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 4.59 (s, IH), 4.01 (s, 4H); MS (EI) for CJ6H15NO: 238 (MH+).
37%
With 4-methyl-morpholine; tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; at 0 - 20℃; for 24h;Molecular sieve;
l-(Diphenylmethyl)azetidin-3-ol hydrochloride (2.75 g, 9.98 mmol), prepared using procedures similar to those described for Scheme 1 of the General Synthetic Section, 3 A molecular sieves and 4-methylmorpholine (1.1 mL, 10.0 mmol) were suspended in dichloromethane (20 mL) at 0 0C. 4-Methylmorpholine N-oxide (2.93 g, 25.0 mmol) and tetrapropylammonium perruthenate (140 mg, 0.399 mmol) were added and the mixture was stirred at ambient for 24 h. The mixture was filtered through a plug of silica using 5% triethylamine in ethyl acetate as eluent. The filtrate was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 8:1 hexanes:ethyl acetate) gave 1- (diphenylmethyl)azetidin-3-one (871 mg, 3.68 mmol, 37% yield): 1H NMR (400 MHz, CDCl3): 7.50-7.46 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 4.59 (s, IH), 4.01 (s, 4H); MS (EI) for C16H15NO: 238 (MH+).
37%
With 4-methyl-morpholine; tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; at 0 - 20℃; for 24h;3A molecular sieves;
l-(Diphenylmethyl)azetidin-3-ol hydrochloride (2.75 g, 9.98 mmol), prepared using procedures similar to those described for Scheme 1 of the General Synthetic Section, 3 A molecular sieves and 4-methylmorpholine (1.1 mL, 10.0 mmol) were suspended in dichloromethane (20 mL) at 0 0C. 4-Methylmorpholine N-oxide (2.93 g, 25.0 mmol) and tetrapropylammonium perruthenate (140 mg, 0.399 mmol) were added and the mixture was stirred at ambient for 24 h. The mixture was filtered through a plug of silica using 5% triethylamine in ethyl acetate as eluent. The filtrate was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 8:1 hexanes:ethyl acetate) gave l-(diphenylmethyl)azetidin-3-one (871 mg, 3.68 mmol, 37% yield): 1H NMR (400 MHz, CDCl3): 7.50-7.46 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 4.59 (s, IH), 4.01 (s, 4H); MS (EI) for C16H15NO: 238 (MH+).
19.8%
With pyridine-SO3 complex; triethylamine; In dimethyl sulfoxide; at 20 - 50℃; for 0.5h;
A solution of pyridine sulfur trioxide complex (19.7 g) in dimethyl sulfoxide (80 ml) was added dropwise to a mixture of 1-benzhydrylazetidin-3-ol hydrochloride (5.52 g) and triethylamine (27.9 ml) at room temperature. The reaction mixture was stirred at 50 C. for 30 minutes. The reaction mixture was allowed to cool down to room temperature, and poured into ice water. This was extracted with ethyl acetate, and the organic layer was washed with brine. Activated carbon (5 g) was added to the organic layer, followed by stirring at room temperature for 3 days. The activated carbon was removed by filtration, and the filtrate was concentrated. The residue was dissolved in methanol (200 ml), and activated carbon (10 g) was added thereto, followed by stirring at room temperature for 3 days. The activated carbon was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=4:1, then 2:1). The fractions containing the target compound were concentrated to give the target compound (3.21 g) as a pale yellow oil. Hexane was added thereto to precipitate crystals, and the crystals were collected by filtration. Drying under aeration gave the title compound (1.11 g, 23.4%) as white crystals. Hexane was added to the residue obtained by concentration of the filtrate, which was allowed to stand at room temperature. After crystals precipitated, the supernatant was removed using a pipette. These were dried under reduced pressure to give the title compound (940 mg, 19.8%) as pale yellow crystals.1H-NMR Spectrum (CDCl3) delta (ppm): 4.01 (4H, s), 4.60 (1H, s), 7.22 (2H, m), 7.30 (4H, m), 7.48 (4H, m).
With hydrogenchloride; In ethyl acetate; at 20℃; for 0.166667h;
1-(Diphenylmethyl) -3 -hydroxy azetidine (9.70 g) was suspended in 4.5M HCl in EtOAc (35 niL) at room temperature and stirred for 10 min. The solvent was then evaporated to dryness to give l-(diphenylmethyl)- 3-hydroxyazetidine hydrochloride (12.0 g, 100%). 1H-NMR (300 MHz, DMSO-de, ppm from TMS): delta 7.30-7.70 (1OH, m), 5.85 (IH, s), 5.80 (IH, d), 4.46 (IH, m), 3.70-4.20 (4H, m).
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 25℃; for 15.1667h;
Preparation 13; To a solution of <strong>[90604-02-7]1-(diphenylmethyl)-3-azetidinol hydrochloride</strong> (5.0 g) in DMF (25 ml), was added sodium hydride under ice-bath cooling. After 10 minute stirring at the same temperature, the mixture was allowed to warm to 25C and then stirred for 15 hours. EtOAc (500 ml) and water (200 ml) were poured into the mixture. The organic layer was separated, washed with water and brine, and dried over MgSO. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel; 200 ml, toluene : EtOAc=15 : 1 - 8 : 1) to give 1-(diphenylmethyl)-3-methoxyazetidine (3*41 g). 1H-NMR (DMSO-d6 No.) : 2.7-2. 9 (2H, m), 3. 12 (3H, s), 3. 3-3. 5 (211, m), 3.99 (1H, m), 4. 40 (1H, s), 7.1-7. 4 (6H, m), 7.3-7. 5 (4H, m) MS (ESI+) : 254 [M+H]+
1-(diphenylmethyl)-3-methane sulfonyl azetidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With methanesulfonyl chloride; triethylamine; In dichloromethane; at 20℃; for 1h;
To a suspension of the commercially available HCl salt of N-diphenylmethyl-3-hydroxazetidine (3.31 mmol, 1.0 equiv) in CH2Cl2 (20 mL) was added Et3N (1.15 mL, 2.5 equiv.). After dissolution of the amine, methanesulfonyl chloride (0.513 mL, 3.97 mmol) was added and the resulting solution was stirred at ambient temperatures for 1 h. The solution was then partitioned between an aqueous sat. NaHCO3 solution and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic portions were washed with water, brine, dried over Na2SO4, and concentrated in vacuo to furnish the mesylate as a light yellow oil which gradually solidified on standing. The crude mesylate (280 mg, 1.0 equiv) was mixed with cycloalkylamine (5.0 equiv) and toluene (3.0 mL) in a microwavable tube and heated at 160 C. for 45 min under microwave irradiation. The resulting mixture was directly purified by flash column chromatography to afford the product in 42% yield isolated as a clear oil: MS Calcd for C22H28N2 [M+H]: 321. Found: 321.
With hydrogenchloride; H2;palladium dihydroxide; In methanol; dimethyl sulfoxide; acetonitrile;
Step 1 3-fluoro-4-(3-hydroxy-1-azetidinyl)nitrobenzene 1-(Diphenylmethyl)-3-azetidinol hydrochloride (2.000 g, 7.29 mmol) was dissolved in methanol (75 mL) and treated with 6N HCl (1.20 mL, 7.29 mmol). Palladium hydroxide on carbon (0.200 g) was then added under a nitrogen stream. The reaction mixture was then shaken on a Parr apparatus under 40 psi of H2. After 16 h, TLC analysis (5% methanol/chloroform) revealed the starting material was consumed. The reaction mixture was filtered through Celite and concentrated under reduced pressure to an amber oil. This material was dissolved in dimethylsulfoxide (29 mL) and the atmosphere replaced with nitrogen. Dipotassium hydrogen phosphate (5.07 g, 29.2 mmol) was added followed by 3,4-difluoronitrobenzene (0.966 mL, 8.75 mmol). The mixture was stirred at ambient temperature under nitrogen. After 3 h, TLC analysis (5% methanol/chloroform) revealed the reaction to be complete. The reaction mixture was diluted with water (250 mL) and extracted with chloroform (4*50 mL). The combined organic extracts were washed with water (2*50 mL) and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow solid. Chromatography over silica gel (100 g), eluding with a gradient of 3-7% acetonitrile/chloroform afforded, after concentration of appropriate fractions, 1.00 g (65%) of the title compound as an orange solid with mp 130.5-132 C. and MS(EI) 212 (M+).
With tetrabutylammomium bromide; sodium; oxalic acid; potassium carbonate; triethylamine;palladium dihydroxide; In ethanol; chloroform; water; methanesulfonyl chloride; toluene;
Preparation 7 3-(3-Fluorophenoxy)azetidine oxalate [1:1] A mixture of 55.1 g (0.2 mole) of 1-diphenylmethyl-3-azetidinol hydrochloride [1:1] (prepared by the Method of Andersen and Lok, J. Org. Chem. 37: 3953 (1972)) and 50.5 g (0.5 mole) of triethylamine in 1.2 liters of toluene was stirred at ambient temperature under a nitrogen atmosphere for 5 hr, then cooled to 5 C. in an ice water bath and methanesulfonyl chloride added dropwise with stirring. The reaction mixture was allowed to warm to ambient temperature while stirring for approximately 18 hr. The reaction mixture was diluted with 600 ml of isopropyl ether and the solid removed by filtration. The filtrate was then treated with 22.5 g (0.2 mole) of 3-fluorophenol and 24 g (0.6 mole) of sodium in 50 ml of water. Tetrabutylammonium bromide, 1 gm, was added to the reaction mixture and the reaction mixture was stirred rapidly and heated at reflux for approximately 16 hr. The toluene layer was separated and washed with water twice (200 ml*2). Then while stirring, 20 g (0.22 mole) of oxalic acid was added as a solution in 100 ml of isopropyl alcohol and the mixture was allowed to stir for approximately 16 hr. Filtration yielded 61.6 g of white granular solid 1-diphenylmethyl-3-(3-fluorophenoxy)azetidine oxalate. A slurry of 55 g of this white granular solid in 350 ml of ethanol was treated with 5.5 g (10% w/w) of 20% palladium hydroxide on carbon under nitrogen atmosphere and hydrogenated on a Parr apparatus at 70 C. with an initial hydrogen pressure of 45 psi for 18 hr. The hydrogen uptake could not be obtained since some leakage had occurred. The product was an insoluble solid which had to be converted to the free base in warm water with potassium carbonate. This mixture was stirred with chloroform and then filtered through Celite to remove the catalyst. The chloroform portion was separated and the aqueous basic solution extracted with 400 ml of chloroform. The chloroform portions were combined, dried over magnesium sulfate and concentrated on a rotary evaporator to yield 36.45 g of oil. The oil was dissolved in ethanol and treated with 10 g of oxalic acid, yielding 15.5 g (46.4%) of crude title compound. A sample was recrystallized from ethanol, m.p. 170-171 C. Analysis: Calculated for C9 H10 FNO.C2 H2 O: C,51.37; H,4.70; N,5.45 Found: C,51.41; H,4.72; N,5.47
With tetrabutylammomium bromide; sodium; oxalic acid; potassium carbonate; triethylamine;palladium dihydroxide; In ethanol; chloroform; water; methanesulfonyl chloride; toluene;
PREPARATION 7 3-(3-Fluorophenoxy)azetidine oxalate [1:1] A mixture of 55.1 g (0.2 mole) of 1-diphenylmethyl-3-azetidinol hydrochloride [1:1] (prepared by the Method of Andersen and Lok, J. Org. Chem. 37: 3953 (1972)) and 50.5 g (0.5 mole) of triethylamine in 1.2 liters of toluene was stirred at ambient temperature under a nitrogen atmosphere for 5 hr, then cooled to 5 C. in an ice water bath and methanesulfonyl chloride added dropwise with stirring. The reaction mixture was allowed to warm to ambient temperature while stirring for approximately 18 hr. The reaction mixture was diluted with 600 ml of isopropyl ether and the solid removed by filtration. The filtrate was then treated with 22.5 g (0.2 mole) of 3-fluorophenol and 24 g (0.6 mole) of sodium in 50 ml of water. Tetrabutylammonium bromide, 1 gm, was added to the reaction mixture and the reaction mixture was stirred rapidly and heated at reflux for approximately 16 hr. The toluene layer was separated and washed with water twice (200 ml*2). Then while stirring, 20 g (0.22 mole) of oxalic acid was added as a solution in 100 ml of isopropyl alcohol and the mixture was allowed to stir for approximately 16 hr. Filtration yielded 61.6 g of white granular solid 1-diphenylmethyl-3-(3-fluorophenoxy)azetidine oxalate. A slurry of 55 g of this white granular solid in 350 ml of ethanol was treated with 5.5 g (10% w/w) of 20% palladium hydroxide on carbon under nitrogen atmosphere and hydrogenated on a Parr apparatus at 70 C. with an initial hydrogen pressure of 45 psi for 18 hr. The hydrogen uptake could not be obtained since some leakage had occurred. The product was an insoluble solid which had to be converted to the free base in warm water with potassium carbonate. This mixture was stirred with chloroform and then filtered through Celite to remove the catalyst. The chloroform portion was separated and the aqueous basic solution extracted with 400 ml of chloroform. The chloroform portions were combined, dried over magnesium sulfate and concentrated on a rotary evaporator to yield 36.45 g of oil. The oil was dissolved in ethanol and treated with 10 g of oxalic acid, yielding 15.5 g (46.4%) of crude title compound. A sample was recrystallized from ethanol, m.p. 170-171 C. Analysis: Calculated for C9 H10 FNO.C2 H2 O: C,51.37; H,4.70; N,5.45. Found: C,51.41; H,4.72; N,5.47.
With hydrogenchloride; sodium hydroxide; tetrabutylammomium bromide; triethylamine; In water; methanesulfonyl chloride; toluene;
Preparation 2 1-(Diphenylmethyl)-3-azetidinol methanesulfonate (ester) hydrochloride [1:1] A mixture of 60.02 g (0.22 mole) of 1-diphenylmethyl-3-azetidinol hydrochloride (prepared by the Method of Anderson and Lok, J. Org. Chem., 37: 3953 (1972)) and 48.94 g (0.484 mole) of triethylamine in 800 ml of toluene was stirred for 24 hr, then cooled to 5 C. in an ice bath and treated with 27.7 g (0.24 mole) of methanesulfonyl chloride added at a rate which maintained the temperature below 15 C. The reaction mixture was stirred for 3 hr and filtered to remove the triethylamine hydrochloride. The filtrate was treated with 40 g (0.242 mole) of 4-trifluoromethylphenol followed by 19.35 g (0.484 mole) of sodium hydroxide and 1.6 g (0.005 mole) of tetrabutylammonium bromide in 60 ml of water. The reaction mixture was stirred rapidly at reflux for 18 hr, then stirred for 72 hr while it cooled to ambient temperature. The reaction mixture was transferred to a separatory funnel and washed with 4*200 ml of water (emulsion). The toluene phase was dried over magnesium sulfate and concentrated in vacuo to 82 g of oil. This residue was dissolved in 200 ml of isopropyl alcohol and treated with 20 ml of concentrated hydrochloric acid. Upon cooling, a solid separated and was removed by filtration (5.1 g). The filtrate was treated with isopropyl ether to give an oil which was worked up later. The solid was identified by spectral analysis as the methylsulfonate of the starting azetidinol. Recrystallization from isopropyl alcohol gave 3.3 g of fine white crystalline material, m.p. 172-173 C., (shrinks 167 C.). Analysis: Calculated for C17 H19 NO3 S.HCl: C,57.70; H,5.70; N,3.96 Found: C,57.80; H,5.86; N,3.92
With hydrogenchloride; sodium hydroxide; tetrabutylammomium bromide; triethylamine; In water; methanesulfonyl chloride; toluene;
PREPARATION 2 1-(Diphenylmethyl)-3-azetidinol methanesulfonate (ester) hydrochloride [1:1] A mixture of 60.02 g (0.22 mole) of 1-diphenylmethyl-3-azetidinol hydrochloride and 48.94 g (0.484 mole) of triethylamine in 800 ml of toluene was stirred for 24 hr, then cooled to 5 C. in an ice bath and treated with 27.7 g (0.24 mole) of methanesulfonyl chloride added at a rate which maintained the temperature below 15 C. The reaction mixture was stirred for 3 hr and filtered to remove the triethylamine hydrochloride. The filtrate was treated with 40 g (0.242 mole) of 4-trifluoromethylphenol followed by 19.35 g (0.484 mole) of sodium hydroxide and 1.6 g (0.005 mole) of tetrabutylammonium bromide in 60 ml of water. The reaction mixture was stirred rapidly at reflux for 18 hrs, then stirred for 72 hr while it cooled to ambient temperature. The reaction mixture was transferred to a separatory funnel and washed with 4*200 ml of water (emulsion). The toluene phase was dried over magnesium sulfate and concentrated in vacuo to 82 g of oil. This residue was dissolved in 200 ml of isopropyl alcohol and treated with 20 ml of concentrated hydrochloric acid. Upon cooling, a solid separated and was removed by filtration (5.1 g). The filtrate was treated with isopropyl ether to give an oil which was worked up later. The solid was identified by spectral analysis as the methylsulfonate of the starting azetidinol. Recrystallization from isopropyl alcohol gave 3.3 g of fine white crystalline material, m.p. 172-173 C., (shrinks 167 C.). Analysis: Calculated for C17 H19 NO3 S.HCl: C,57.70; H,5.70; N,3.96. Found: C,57.80; H,5.86; N,3.92.
With sodium hydroxide; triethylamine; In dichloromethane; water; ethyl acetate; isopropyl alcohol; toluene;
Preparation 6 1-(Diphenylmethyl)-3-[3-(trifluoromethyl)phenoxy] azetidine N-Diphenylmethyl-3-hydroxyazetidine hydrochloride (I) was prepared from benzhydrylamine and epichlorohydrin according to Anderson and Lok, J. Org. Chem., 37:3953 (1972). I (41.33 g, 0.15 mole) and triethylamine (42 ml, 0.30 mole) were stirred in toluene (250 ml) while methane sulfonylchloride (12 ml, 0.15 m) was added dropwise over 10 minutes with stirring and the temperature was maintained between 4 and 12 C. TLC (silica gel, 10% ethyl acetate in methylene chloride) at one hour showed all starting materials had reacted. The mixture was filtered to remove the triethylamine hydrochloride which was rinsed twice with toluene. The filtrate and washings combined to about 450 ml of solution. To this solution was added m-trifluoromethylphenol (27.5 g, 0.17 mole), tetrabutyl ammonium bromide (2.4 g), 50% sodium hydroxide (24 g, 0.3 mole) and water (24 ml) and the mixture was stirred vigorously and heated to reflux under nitrogen for 2.5 hr. The toluene layer of the mixture was separated and washed once with water, dried over sodium sulfate and evaporated to an oil. This oil was seeded and pumped on an oil pump overnight. A solid cake weighing 49.7 was obtained. Some of this solid was dissolved in isopropanol with brief heating. Water was then added to cause slight cloudiness.
With sodium hydroxide; triethylamine; In dichloromethane; water; ethyl acetate; isopropyl alcohol; toluene;
PREPARATION 6 1-(Diphenylmethyl)-3-[3-(trifluoromethyl)phenoxy]azetidine N-Diphenylmethyl-3-hydroxyazetidine hydrochloride (I) was prepared from benzhydrylamine and epichlorohydrin according to Anderson and Lok, J. Org. Chem., 37:3953 (1972). I (41.33 g, 0.15 mole) and triethylamine (42 ml, 0.30 mole) were stirred in toluene (250 ml) while methane sulfonylchloride (12 ml, 0.15 m) was added dropwise over 10 minutes with stirring and the temperature was maintained between 4 and 12 C. TLC (silica gel, 10% ethyl acetate in methylene chloride) at one hour showed all starting materials had reacted. The mixture was filtered to remove the triethylamine hydrochloride which was rinsed twice with toluene. The filtrate and washings combined to about 450 ml of solution. To this solution was added m-trifluoromethylphenol (27.5 g, 0.17 mole), tetrabutyl ammonium bromide (2.4 g), 50% sodium hydroxide (24 g, 0.3 mole) and water (24 ml) and the mixture was stirred vigorously and heated to reflux under nitrogen for 2.5 hr. The toluene layer of the mixture was separated and washed once with water, dried over sodium sulfate and evaporated to an oil. This oil was seeded and pumped on an oil pump overnight. A solid cake weighing 49.7 g was obtained. Some of this solid was dissolved in isopropanol with brief heating. Water was then added to cause slight cloudiness.
With sodium hydroxide; triethylamine; In dichloromethane; water; ethyl acetate; isopropyl alcohol; toluene;
PREPARATION 6 1-(Diphenylmethyl)-3-[3-(trifluoromethyl)phenoxy] azetidine. N-Diphenylmethyl-3-hydroxyazetidine hydrochloride (I) was prepared from benzhydrylamine and epichlorohydrin according to Anderson and Lok, J. Org. Chem., 37:3953 (1972). I (41.33 g, 0.15 mole) and triethylamine (42 ml, 0.30 mole) were stirred in toluene (250 ml) while methane sulfonylchloride (12 ml, 0.15 m) was added dropwise over 10 minutes with stirring and the temperature was maintained between 4 and 12 C. TLC (silica gel, 10% ethyl acetate in methylene chloride) at one hour showed all starting materials had reacted. The mixture was filtered to remove the triethylamine hydrochloride which was rinsed twice with toluene. The filtrate and washings combined to about 450 ml of solution. To this solution was added m-trifluoromethylphenol (27.5 g, 0.17 mole), tetrabutyl ammonium bromide (2.4 g), 50% sodium hydroxide (24 g, 0.3 mole) and water (24 ml) and the mixture was stirred vigorously and heated to reflux under nitrogen for 2.5 hr. The toluene layer of the mixture was separated and washed once with water dried over sodium sulfate and evaporated to an oil. This oil was seeded and pumped on an oil pump overnight. A solid cake weighing 49.7 was obtained. Some of this solid was dissolved in isopropanol with brief heating. Water was then added to cause slight cloudiness.
With hydrogenchloride; sodium hydroxide; tetrabutylammomium bromide; triethylamine; In water; methanesulfonyl chloride; isopropyl alcohol; toluene;
PREPARATION 1 1-(Diphenylmethyl)-3-azetidinol methanesulfonate (ester) hydrochloride A mixture of 60.02 g (0.22 mole) of 1-diphenylmethyl-3-azetidinol hydrochloride and 48.94 g (0.484 mole) of triethylamine in 800 mL of toluene was stirred for 24 hrs, then cooled to 5 C. in an ice bath and treated with 27.7 g (0.24 mole) of methanesulfonyl chloride added at a rate which maintained the temperature below 15 C. The reaction was stirred for 3 hrs. and filtered to remove the triethylamine hydrochloride. The filtrate was treated with 40 g (0.242 mole) of 4-trifluoromethylphenol followed by 19.35 g (0.484 mole) of sodium hydroxide and 1.6 g (0.005 mole) of tetrabutylammonium bromide in 60 mL of water. The reaction mixture was stirred rapidly at reflux for 18 hrs., then stirred for 72 hrs. at ambient temperature. The reaction mixture was transferred to a separatory funnel and washed with 4*200 mL of H2 O. The toluene layer was dried over MgSO 4 and concentrated in vacuo to an oil (82 g). This residue was dissolved in 200 mL 2-propanol and treated with 20 mL of concentrated hydrochloric acid. Upon cooling, a solid separated and was removed by filtration (5.1 g). Recrystallization from isopropyl alcohol gave 3.3 g of fine white crystalline material, mp 172-173 C. Analysis: Calculated for C17 H19 NO3 S·HCl: C, 57.70; H, 5.70; N, 3.96. Found: C, 57.80; H, 5.86; N, 3.92.
With hydrogenchloride; sodium hydroxide; tetrabutylammomium bromide; In water; methanesulfonyl chloride; toluene;
PREPARATION 2 1-(Diphenylmethyl)-3-azetidinol methanesulfonate (ester) hydrochloride [1:1] A mixture of 60.02 g (0.22 mole) of 1-diphenylmethyl-3-azetidinol hydrochloride (prepared by the Method of Anderson and Lok, J. Org. Chem., 37: 3953 (1972)) and 48.94 g (0.484 mole) of triethylene in 800 ml of toluene was stirred for 24 hr, then cooled to 5 C. in an ice bath and treated with 27.7 g (0.24 mole) of methanesulfonyl chloride added at a rate which maintained the temperature below 15 C. The reaction mixture was stirred for 3 hr and filtered to remove the triethylamine hydrochloride. The filtrate was treated with 40 g (0.242 mole) of 4-trifluoromethylphenol followed by 19.35 g (0.484 mole) of sodium hydroxide and 1.6 g (0.005 mole) of tetrabutylammonium bromide in 60 ml of water. The reaction mixture was stirred rapidly at reflux for 18 hr, then stirred for 72 hr while it cooled to ambient temperature. The reaction mixture was transferred to a separatory funnel and washed with 4*200 ml of water (emulsion). The toluene phase was dried over magnesium sulfate and concentrated in vacuo to 82 g of oil. This residue was dissolved in 200 ml of isopropyl alcohol and treated with 20 ml of concentrated hydrochloric acid. Upon cooling, a solid separated and was removed by filtration (5.1 g). The filtrate was treated with iospropyl ether to give an oil which was worked up later. The solid was identified by spectral analysis as the methylsulfonate of the starting azetidinol. Recrystallization from isopropyl alcohol gave 3.3 g of fine white crystalline material, m.p. 172-173 C., (shrinks 167 C.). Analysis: Calculated for C17 H19 NO3 S.HCl: C,57.70; H,5.70; N,3.96. Found: C,57.80; H,5.86; N,3.92.
[Referential Example 192] 1-Benzhydryl-3-(tert-butyldiphenylsilyloxy)azetidine: The title compound was obtained from 1-benzhydryl-3-hydroxyazetidine hydrochloride in a similar manner to Referential Example 191. 1H-NMR (CDCl3) delta: 1.01(9H,s), 2.90-3.00(2H,m), 3.40-3.50(2H,m), 4.36(1H,s), 4.40-4.50(1H,m), 7.10-7.20(2H,m), 7.20-7.30(4H,m), 7.30-7.40(10H,m), 7.55-7.65(4H,m). MS (ESI) m/z: 478(M+H)+.
With triethylamine; In dichloromethane; dimethyl sulfoxide; ethyl acetate;
Step 3B (1-Benzhydryl-azetidin-3-ylidene)-acetic Acid Ethyl Ester To a stirring solution of DMSO (5.3 mL, 75 mmol) in methylene chloride (100 mL) at -78 C. under argon was added oxalyl chloride (4.6 mL, 53 mmol) dropwise. After stirring for 30 min., a solution of 1-benzhydryl-azetidin-3-ol hydrochloride (12) (10 g, 36 mmol) in methylene chloride (10 mL) was added dropwise. The reaction mixture was stirred for 1 hr at -78 C. before triethylamine (18 mL, 128 mmol) was added. The ice bath was removed and the reaction quenched with saturated ammonium chloride (75 mL) at 0 C., then extracted with ethyl acetate (3*150 mL). The combined ethyl acetate layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was stirred in ethyl acetate and hexane, filtered to give 1-benzhydrylazetidin-3-one (9 g, 33 mmol, 92%).
With sodium carbonate; In dichloromethane; water; at 20℃;
A suspension of <strong>[90604-02-7]1-benzhydrylazetidin-3-ol hydrochloride</strong> (23, 625 g, 2.27 mol) in a 10% solution of aqueous sodium carbonate (Na2CO3, 5 L) and dichloromethane (CH2Cl2, 5 L) was stirred at room temperature until all solids were dissolved. The two layers were separated, and the aqueous layer was extracted with dichloromethane (CH2Cl2, 2 L). The combined organics extracts were dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. This resulting crude free base of 23 was then dissolved in THF (6 L) and the solution was placed into a large Parr bomb. Di-tert-butyl dicarbonate (BOC2O, 545 g, 2.5 mol, 1.1 equiv) and 20% palladium (Pd) on carbon (125 g, 50% wet) were added to the Parr bomb. The vessel was charged to 30 psi with hydrogen gas (H2) and stirred under steady hydrogen atmosphere (vessel was recharged three times to maintain the pressure at 30 psi) at room temperature for 18 h. When HPLC showed that the reaction was complete (when no more hydrogen was taken up), the reaction mixture was filtered through a Celite pad and the Celite pad was washed with THF (4 L). The filtrates were concentrated under reduced pressure to remove the solvent and the residue was loaded onto a Biotage 150 column with a minimum amount of dichloromethane (CH2Cl2). The column was eluted with 20-50% ethyl acetate in heptane and the fractions containing the pure desired product (24) were collected and combined. The solvents were removed under reduced pressure to afford tert-butyl 3-hydroxyazetidine-1-carboxylate (24, 357 g, 393.2 g theoretical, 90.8% yield) as colorless oil, which solidified upon standing at room temperature in vacuum. For 24: 1HNMR (CDCl3, 300 MHz), delta 4.56 (m 1H), 4.13 (m, 2H), 3.81 (m, 2H), 1.43 (s, 9H) ppm.
With sodium carbonate; In dichloromethane; water; at 20℃;
tert-Butyl 3-hydroxyazetidine-1-carboxylate (17) [0155] A suspension of <strong>[90604-02-7]1-benzhydrylazetidin-3-ol hydrochloride</strong> (625 g, 2.27 mol) in a 10% solution of aqueous sodium carbonate (Na2CO3, 5 L) and dichloromethane (CH2Cl2, 5 L) was stirred at room temperature until all solids were dissolved. The two layers were separated, and the aqueous layer was extracted with dichloromethane (CH2Cl2, 2 L). The combined organics extracts were dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The resulting crude 1-benzhydrylazetidin-3-ol free base was then dissolved in THF (6 L) and the solution was placed into a large Parr bomb. Di-tert-butyl dicarbonate (BOC2O, 545 g, 2.5 mol, 1.1 equiv) and 20% palladium (Pd) on carbon (125 g, 50% wet) were added to the Parr bomb. The vessel was charged to 30 psi with hydrogen gas (H2) and stirred under steady hydrogen atmosphere (vessel was recharged three times to maintain the pressure at 30 psi) at room temperature for 18 h. When HPLC showed that the reaction was complete (no more hydrogen was taken up), the reaction mixture was filtered through a Celite pad and the Celite pad was washed with THF (4 L). The filtrates were concentrated under reduced pressure to remove the solvent and the residue was loaded onto a Biotage 150 column with a minimum amount of dichloromethane (CH2Cl2). The column was eluted with 20-50% ethyl acetate in n-heptane and the fractions containing the pure desired product, tert-butyl 3-hydroxyazetidine-1-carboxylate, were collected and combined. The solvents were removed under reduced pressure to afford tert-butyl 3-hydroxyazetidine-1-carboxylate (357 g, 393.2 g theoretical, 90.8% yield) as a colorless oil, which solidified upon standing at ambient temperature in vacuum. 1HNMR (300 MHz, CDCl3), delta 4.56 (m 1H), 4.13 (m, 2H), 3.81 (m, 2H), 1.43 (s, 9H) ppm.
With triethylamine; In dichloromethane; at 0 - 20℃;Product distribution / selectivity;
C. Preparation of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (C49). Methanesulfonyl chloride (180 g, 1.57 mol) was added to a solution of C48 (360 g, 1.31 mol) and triethylamine (330 g, 3.26 mol) in dichloromethane (3 L) at 0 C. The reaction mixture was stirred at room temperature for 3 h, quenched with saturated aqueous sodium bicarbonate solution, then extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford C49. Yield: 360 g, 1.14 mol, 87%. B. Preparation of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (C49). Compound C49 was prepared according to the procedure described in Preparation 1 to afford C49 as a yellow solid. Yield: 303 g, 0.96 mol, 91%. 1H NMR (400 MHz, CDCl3) delta 2.91 (s, 3H), 3.13 (m, 2H), 3.55 (m, 2H), 4.31 (s, 1H), 4.02 (m, 1H), 7.14 (m, 2H), 7.20 (m, 4H), 7.31 (m, 4H).
Step 2. tert-Butyl 3-hydroxyazetidine-l -carboxylate (10) A suspension of l-benzhydrylazetidin-3-ol hydrochloride (9, 625 g, 2.27 mol) in a 10 % solution of aqueous sodium carbonate (Na2C03, 5 L) and dichloromethane (CH2CI2, 5 L) was stirred at room temperature until all solids were dissolved. The two layers were separated, and the aqueous layer was extracted with dichloromethane (CH2CI2, 2 L). The combined organics extracts were dried over sodium sulfate (Na2SC>4) and concentrated under reduced pressure. This resulting crude free base of 9 was then dissolved in THF (6 L) and the solution was placed into a large Parr bomb. Di-teri-butyl dicarbonate (BOC20, 545 g, 2.5 mol, 1.1 equiv) and 20 % palladium (Pd) on carbon (125 g, 50 % wet) were added to the Parr bomb. The vessel was charged to 30 psi with hydrogen gas () and stirred under steady hydrogen atmosphere (vessel was recharged three times to maintain the pressure at 30 psi) at room temperature for 18 h. When HPLC showed that the reaction was complete (when no more hydrogen was taken up), the reaction mixture was filtered through a Celite pad and the Celite pad was washed with THF (4 L). The filtrates were concentrated under reduced pressure to remove the solvent and the residue was loaded onto a Biotage 150 column with a minimum amount of dichloromethane (CH2CI2). The column was eluted with 20 - 50 % ethyl acetate in heptane and the fractions containing the pure desired product (10) were collected and combined. The solvents were removed under reduced pressure to afford terr-butyl 3-hydroxyazetidine-l - carboxylate (10, 357 g, 393.2 g theoretical, 90.8% yield) as colorless oil, which solidified upon standing at room temperature in vacuum. For 10: 'iTNMR (CDCI3, 300 MHz), delta 4.56 (m 1 H), 4.13 (m, 2H), 3.81 (m, 2H), 1.43 (s, 9H) ppm.
357 g
tert-Butyl 3-hydroxyazetidine-1-carboxylate (17) A suspension of <strong>[90604-02-7]1-benzhydrylazetidin-3-ol hydrochloride</strong> (625 g, 2.27 mol) in a 10% solution of aqueous sodium carbonate (Na2CO3, 5 L) and dichloromethane (CH2Cl2, 5 L) was stirred at room temperature until all solids were dissolved. The two layers were separated, and the aqueous layer was extracted with dichloromethane (CH2Cl2, 2 L). The combined organics extracts were dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The resulting crude 1-benzhydrylazetidin-3-ol free base was then dissolved in THF (6 L) and the solution was placed into a large Parr bomb. Di-tert-butyl dicarbonate (BOC2O, 545 g, 2.5 mol, 1.1 equiv) and 20% palladium (Pd) on carbon (125 g, 50% wet) were added to the Parr bomb. The vessel was charged to 30 psi with hydrogen gas (H2) and stirred under steady hydrogen atmosphere (vessel was recharged three times to maintain the pressure at 30 psi) at room temperature for 18 h. When HPLC showed that the reaction was complete (no more hydrogen was taken up), the reaction mixture was filtered through a Celite pad and the Celite pad was washed with THF (4 L). The filtrates were concentrated under reduced pressure to remove the solvent and the residue was loaded onto a Biotage 150 column with a minimum amount of dichloromethane (CH2Cl2). The column was eluted with 20-50% ethyl acetate in n-heptane and the fractions containing the pure desired product, tert-butyl 3-hydroxyazetidine-1-carboxylate, were collected and combined. The solvents were removed under reduced pressure to afford tert-butyl 3-hydroxyazetidine-1-carboxylate (357 g, 393.2 g theoretical, 90.8% yield) as a colorless oil, which solidified upon standing at ambient temperature in vacuum. 1HNMR (300 MHz, CDCl3), delta 4.56 (m 1H), 4.13 (m, 2H), 3.81 (m, 2H), 1.43 (s, 9H) ppm.
1-benzhydryl-3-((tetrahydro-2H-pyran-2-yl)oxy)azetidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃; for 16h;
To a solution of 1-benzhydrylazetidin-3-oI, hydrochloride (5 g, 18.13 mmol) in DCM (50 mL) was added PPTS (2.278 g, 9.07 mmol) and DHP (6.63 mL, 72.5 mmcl). The reactionsolution was stirred at room temperature for 16 hours. After concentration, the residue waspurified by silica gel column chromatography (30-50% MeOH in PE)to give 1-benzhydryl-3-((tetrahydro-2H-pyran-2-yl)oxy)azetidine (5 g, 15.46 mmol, 85 % yield).LCMS: (mobile phase: 5-95% Acetonitrile), Rt = 2.76 mm in 5 mm; MS Calcd: 323; MSFound: 324 [M+1].
4-(4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide[ No CAS ]
Chemistry
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