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[ CAS No. 40320-60-3 ] {[proInfo.proName]}

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Chemical Structure| 40320-60-3
Chemical Structure| 40320-60-3
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Product Details of [ 40320-60-3 ]

CAS No. :40320-60-3 MDL No. :MFCD00964539
Formula : C16H15NO Boiling Point : -
Linear Structure Formula :- InChI Key :AVUDXLOVIBJFQA-UHFFFAOYSA-N
M.W : 237.30 Pubchem ID :3735558
Synonyms :

Calculated chemistry of [ 40320-60-3 ]

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.19
Num. rotatable bonds : 3
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 75.21
TPSA : 20.31 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.55 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.39
Log Po/w (XLOGP3) : 3.1
Log Po/w (WLOGP) : 1.96
Log Po/w (MLOGP) : 2.45
Log Po/w (SILICOS-IT) : 3.38
Consensus Log Po/w : 2.66

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.56
Solubility : 0.0654 mg/ml ; 0.000276 mol/l
Class : Soluble
Log S (Ali) : -3.19
Solubility : 0.152 mg/ml ; 0.000639 mol/l
Class : Soluble
Log S (SILICOS-IT) : -5.02
Solubility : 0.00225 mg/ml ; 0.00000946 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.84

Safety of [ 40320-60-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 40320-60-3 ]

* 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.

  • Upstream synthesis route of [ 40320-60-3 ]
  • Downstream synthetic route of [ 40320-60-3 ]

[ 40320-60-3 ] Synthesis Path-Upstream   1~11

  • 1
  • [ 90604-02-7 ]
  • [ 40320-60-3 ]
YieldReaction ConditionsOperation in experiment
82% 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).

Reference: [1] Patent: US2010/190771, 2010, A1, . Location in patent: Page/Page column 38
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 16, p. 7029 - 7042
[3] Patent: WO2014/68527, 2014, A1, . Location in patent: Page/Page column 83; 84
[4] Chemistry Letters, 1999, # 7, p. 605 - 606
[5] Patent: EP1889836, 2008, A1, . Location in patent: Page/Page column 78
[6] Patent: WO2007/44515, 2007, A1, . Location in patent: Page/Page column 213
[7] Patent: WO2008/76415, 2008, A1, . Location in patent: Page/Page column 383
[8] Patent: WO2008/124085, 2008, A2, . Location in patent: Page/Page column 231
[9] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 5, p. 416 - 421
[10] Patent: US2008/214815, 2008, A1, . Location in patent: Page/Page column 12-13
  • 2
  • [ 18621-17-5 ]
  • [ 40320-60-3 ]
YieldReaction ConditionsOperation in experiment
92.4% With sulfur trioxide pyridine complex; triethylamine In dimethyl sulfoxide at 10 - 30℃; 1-(Diphenylmethyl)azetidin-3-ol (2.0 g) was dissolved in N,N-dimethyl sulfoxide (60 mL), and triethylamine (11.7 mL) was added.
The reaction solution was cooled to 10° C., a solution of pyridine sulfur trioxide complex (10.6 g) in N,N-dimethyl sulfoxide (20 mL) was added, and the mixture was stirred for 1 hr.
The mixture was warmed to room temperature and further stirred for 3 hr.
The reaction solution was poured into cold water, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, and dried over sodium sulfate.
The desiccant was filtered off, and the filtrate was concentrated.
The residue was purified by silica gel column chromatography (30percent to 50percent ethyl acetate/hexane) to give the object product as a white solid (1.83 g, 92.4percent).
1H NMR (300 MHz, CDCl3) δ ppm 4.00 (s, 4H) 4.59 (s, 1H) 7.17-7.35 (m, 6H) 7.44-7.52 (m, 4H)
88% With sulfur trioxide pyridine complex; triethylamine In dimethyl sulfoxide at 10 - 20℃; for 4.75 h; Step 1: l-Benzhydrylazetidin-3-oneTriethylamine (29.1 mL, 209 mmol) and a solution of sulphur trioxide pyridine complex (21.3 g, 134 mmol) in DMSO ( 100 mL) were added at 10°C to a solution of l-benzhydrylazetidin-3-ol (5.0 g, 20.9 mmol) in DMSO (60 mL) . The resulting mixture was stirred at 10°C for 45 minutes, then at room temperature for 4 hours, subsequently quenched by pouring onto crushed ice (~200 g) and extracted with ethyl acetate (3 x 200 mL) . The combined organic layers were washed with water (400 mL) and brine (400 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (80 : 20 to 70 : 30) as eluent. The title product was obtained as a yellowish solid (4.35 g, 88percent) .NM R (CDCI3, 400 M Hz) : δ (ppm) : 7.50-7.20 (m, 10H), 4.60 (s, 1 H), 4.01 (s,4H) .
88% With pyridine-SO3 complex; triethylamine In tetrahydrofuran; dimethyl sulfoxide for 2.16667 h; Step 1: l-Benzhydryl-azetidin-3-one; [00346] Sulfur trioxide pyridine complex (19.96, g, 125.40 mmol) was added over 10 min to a solution of l-benzhydryl-azetidin-3-ol (5.0 g, 21.0 mmol) and triethylamine (14.60 mL, 104.60 mmol) in THF (20 mL) and DMSO (50 mL). The yellow solution was stirred for 2 h then poured into water (50 mL). The aqueous phase was extracted with 1 :1 EtOAc:hexanes (4 x 50 mL). The combined organics were washed with water (50 mL), dried over MgSψ4 then concentrated in vacuo to give the product as a pale brown oil, which solidified on standing (18.56 mmol, 4.40 g, 88 percent). 1H NMR (400MHz, CDCl3): δ 7.50 - 7.45 (4H, m), 7.33 - 7.18 (6H, m), 4.59 (IH, s), 4.00 (s, 4H).
86%
Stage #1: With triethylamine In dimethyl sulfoxide at 20℃;
Stage #2: With sulfur trioxide-pyridine complex In dimethyl sulfoxide at 10 - 20℃; for 3 h;
Triethylamine (11.6 [ML,] 42 [MMOL)] was added to a solution of 1-benzhydryl- azetidin-3-ol (2.0 g, 4.2 [MMOL)] in dimethylsulfoxide (60 mL) at room temperature. The resulting mixture was cooled to 10 [°C,] then pyridine sulfur trioxide (8.64 g, 33.6 [MMOL)] in [DIMETHYLSULFOXIDE] was introduced. The mixture was stirred at 10 [°C] for 1 hour and then for 2 hours at room temperature. The reaction mixture was poured into water (100 mL) and extracted with methylene chloride (3 x 100 mL). The organic layer was washed with water (3 x 150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude oil was column chromatographed on silica gel (30percent ethyl acetate-hexane). The product-containing fractions were concentrated under vacuum to give 1.7 g (86percent) of the title compound as a yellow solid, m. p. [52-54°C.]
85% With sulfur trioxide pyridine complex; triethylamine In dimethyl sulfoxide at 0 - 10℃; for 8 h; Industrial scale 1- benzhydryl-3-hydroxy-azetidine (5kg) was dissolved in DMSO (15L) was added triethylamine (9L), cooled to 0-10 deg.] C, followed by sulfur trioxide pyridine were added in batches (10kg) (with added portionwise during 6h), was added after stirring for 2h, TLC the reaction was complete.Was slowly added ice-water (75L), stirred for two hours, stirred well, was added and extracted three times with ethyl acetate (40L), the organic phases were combined, dried over an appropriate amount of saturated brine (20L) washed three times, the organic phase was dried over anhydrous sodium sulfate, the filtrate under reduced pressure to remove the organic solvent, adding an appropriate amount of residual oil of petroleum ether (10L) beating yellowish solid precipitated was filtered to give 4.2kg product, yield 85percent.
74%
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78 - -70℃; for 1.66667 h;
Stage #2: With triethylamine In dichloromethane at -70 - 20℃; for 20.5 h;
Example 1 Preparation of 1-Benzhvdrvl-azetidin-3-one (1-1a) : Oxalyl chloride (145.2 g, 1.121 mol) was added to dichloromethane (3.75 liters) and the resulting solution was cooled to-78°C. Methyl sulfoxide (179.1 g, 2.269 mol) was then added over a duration of 20 minutes (maintained internal temperature <-70°C during addition). 1- Benzhydryl-azetidin-3-ol (250.0 g, 1.045 mol) was then added as a solution in dichloromethane (1.25 liter) to-78°C solution over a duration of 40 minutes (maintained internal temperature <-70°C during addition). The solution was stirred for 1 hour at-78°C followed by the addition of triethylamine (427.1 g, 4.179 mol) over 30 minutes (maintained internal temperature <-70°C during addition). Reaction was then allowed to come to room temperature slowly and stir for 20 hours. 1.0 M hydrochloric acid (3.2 liters, 3. 2 mol) was added to the crude reaction solution over 30 minutes, followed by stirring for 10 minutes at room temperature. The heavy dichloromethane layer (clear yellow in color) was then separated and discarded. The remaining acidic aqueous phase (clear, colorless) was treated with 50percent sodium hydroxide (150 mi, 2.1 mol) with stirring over a 30 minute period. The final aqueous solution had a pH=9. At this pH, the desired product precipitates from solution as a white solid. The pH=9 solution was stirred for 30 minutes and then the precipitated product was collected by filtration. The collected solid was washed with 1.0 liter of water and then air dried for 36 hr to give 1-benzhydryl-azetidin-3-one (1-1 a) (184.1 g, 74percent) as an off-white solid. +ESI MS (M+1) 256.3 (M+1 of hydrated ketone) ; 1H NMR (400 MHz, CD2CI2) 8 7.47-7. 49 (m, 4H), 7.27-7. 30 (m, 4H), 7.18-7. 22 (m, 2H), 4.60 (s, 1 H), 3.97 (s, 4H).
74%
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78 - -70℃; for 2 h;
Stage #2: at -70 - 20℃; for 20.5 h;
Oxalyl chloride (145.2 g, 1.121 mol) was added to dichloromethane (3.75 liters) and the resulting solution was cooled to -78° C. Dimethyl sulfoxide (179.1 g, 2.269 mol) was then added over a duration of 20 minutes (maintained internal temperature below -70° C. during addition). 1-Benzhydryl-azetidin-3-ol (250.0 g, 1.045 mol) was then added as a solution in dichloromethane (1.25 liter) to -78° C. solution over a duration of 40 minutes (maintained internal temperature below -70° C. during addition). The solution was stirred for 1 hour at -78° C. followed by the addition of triethylamine (427.1 g, 4.179 mol) over 30 minutes (maintained internal temperature below -70° C. during addition). The reaction was then allowed to come to room temperature slowly and stir for 20 hours. Aqueous 1.0 M hydrochloric acid (3.2 liters, 3.2 mol) was added to the crude reaction solution over 30 minutes, followed by stirring for 10 minutes at room temperature. The heavy dichloromethane layer (clear yellow in color) was then separated and discarded. The remaining acidic aqueous phase (clear, colorless) was treated with 50percent sodium hydroxide (150 ml, 2.1 mol) with stirring over a 30 minute period. The final aqueous solution had a pH=9. At this pH the desired product precipitates from solution as a colorless solid. The pH=9 solution was stirred for 30 minutes and then the precipitated product was collected by filtration. The collected solid was washed with 1.0 liter of water and then air dried for 36 hours to give 1-benzhydrylazetidin-3-one (184.1 g, 74percent) as an off-white solid: +ESI MS (M+1 of hydrated ketone) 256.3; 1H NMR (400 MHz, CD2Cl2) δ 7.47-7.49 (m, 4H), 7.27-7.30 (m, 4H), 7.18-7.22 (m, 2H), 4.60 (s, 1H), 3.97 (s, 4H)
74%
Stage #1: With oxalyl dichloride In hydrate; dichloromethane; dimethyl sulfoxide at -78 - -70℃; for 1 h;
Stage #2: at -70 - 20℃; for 20 h;
Oxalyl chloride (145.2 g, 1.121 mol) was added to dichloromethane (3.75 liters) and the resulting solution was cooled to -78° C. Dimethyl sulfoxide (179.1 g, 2.269 mol) was then added over a duration of 20 minutes while maintaining internal temperature of the reaction below -70° C. during addition. 1-Benzhydrylazetidin-3-ol (250.0 g, 1.045 mol) was then added as a solution in dichloromethane (1.25 liter) to the -780C solution of DMSO/oxalyl chloride over a duration of 40 minutes (note-internal temperature maintained below -70° C. during addition).
The solution was stirred for 1 hour at -78° C. followed by the addition of triethylamine (427.1 g, 4.179 mol) over 30 minutes (maintained internal temperature below -70° C. during addition).
The reaction mixture was then allowed to come to room temperature slowly and stir for 20 hours. 1.0 M hydrochloric acid (3.2 liters, 3.2 mol) was added to the crude reaction solution over 30 minutes, followed by stirring for 10 minutes at room temperature.
The heavy dichloromethane layer (clear yellow in color) was then separated and discarded.
The remaining acidic aqueous phase (clear, colorless) was treated with 50percent sodium hydroxide (150 ml, 2.1 mol) with stirring over a 30-minute period.
The final aqueous solution had a pH=9.
At this pH, the desired product precipitated from solution as a colorless solid.
The pH=9 solution was stirred for 30 minutes and then the precipitated product was collected by filtration.
The collected solid was washed with 1.0 liter of water and then air dried for 36 hr to give 1-benzhydrylazetidin-3-one (184.1 g, 74percent) as an off-white solid: +ESI MS (M+1 of hydrated ketone) 256.3; 1H NMR (400 MHz, CD2Cl2) δ 7.47-7.49 (m, 4H), 7.27-7.30 (m, 4H), 7.18-7.22 (m, 2H), 4.60 (s, 1H), 3.97 (s, 4H).
64%
Stage #1: With dimethyl sulfoxide; trifluoroacetic anhydride In dichloromethane at -78℃; for 1.25 h;
Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at -78 - 20℃; for 0.25 h;
Preparation 7; 1-Benzhydryl-azetidin-3-one; Trifluoroacetic anhydride (7.07 mL, 50.1 mmol) was added to a -780C solution of DMSO (4.75 mL, 66.9 mmol) in CH2CI2 (150 mL). After 15 min, 1-benzhydryl-azetidin-3-ol (27) (8.Og, 33.4 mmol) in CH2CI2 (150 mL) was added dropwise over 20 min. The mixture was stirred for 1hr, then diisopropylethylamiπe (25.7 mL, 147.0 mmol) was added, the mixture was stirred 15 min and subsequently warmed to it Saturated aq. NH4CI was added and the mixture was extracted into EtOAc and washed with brine. Concentration yielded an orange oil which was purified by chromatography using 10percent EtOAc/hexanes as elueπt to yield 5.11g (64percent) of the title compound as a yellow solid: mp 70-730C; NMR (CDCI3) δ 7.52-7.44 (m, 4H), 7.33-7.20 (m, 6H), 4.61 (s, 1H), 4.00 (s, 4H); 13C NMR (CDCI3) δ 201.28, 142.66, 128.99, 127.78, 127.52, 78.00, 74.47.
60% With pyridine-2-sulfonic acid; triethylamine In dimethyl sulfoxide at 0 - 50℃; for 0.666667 h; 1)
1-Benzhydrylazetidin-3-one
Under cooling on ice, pyridinesulfonic acid (19.7 g) in dimethyl sulfoxide (84 mL) was added dropwise to 1-benzhydrylazetidin-3-ol (4.79 g) in triethylamine (27.9 mL), and the mixture was stirred for 40 minutes at 50°C.
The reaction mixture was partitioned between ice-water and ethyl acetate.
The organic layer was washed with saturated brine and then dried over magnesium sulfate anhydrate.
After a filtration step, the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (hexane - ethyl acetate), to thereby give 1-benzhydrylazetidin-3-one as a solid product (2.85 g, 60percent).
1H-NMR(400MHz,CDCl3)δ:4.00(4H,s), 4.59 (1H,s), 7.19-7.49 (10H,m).
60% With pyridin-3-ylsulfonic acid; triethylamine In dimethyl sulfoxide at 50℃; for 0.666667 h; [Referential Example 100]; 1-Benzhydrylazetidin-3-one ; [] Under cooling with ice, pyridinesulfonic acid (19.7 g) in dimethyl sulfoxide (84 mL) was added dropwise to 1-benzhydrylazetidin-3-ol (4.79 g) in triethylamine (27.9 mL), and the resultant mixture was stirred at 50°C for 40 minutes. The reaction mixture was partitioned between ice-water and ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (hexane - ethyl acetate), to thereby give the title compound as a solid (2.85 g, 60percent) .1H-NMR(400MHz,CDCl3)δ: 4.00(4H,s), 4.59(1H,s), 7.19-7.49(10H,m).

Reference: [1] Organic Process Research and Development, 2012, vol. 16, # 5, p. 788 - 797
[2] Patent: US2010/69351, 2010, A1, . Location in patent: Page/Page column 42
[3] Patent: WO2011/61214, 2011, A1, . Location in patent: Page/Page column 151
[4] Patent: WO2008/55959, 2008, A1, . Location in patent: Page/Page column 106
[5] Patent: WO2004/24730, 2004, A1, . Location in patent: Page 46
[6] Patent: CN106905212, 2017, A, . Location in patent: Paragraph 0013; 0014-0015
[7] Patent: EP1213289, 2002, A1, . Location in patent: Page 11
[8] Patent: WO2005/54184, 2005, A1, . Location in patent: Page/Page column 8-9
[9] Patent: US2004/157839, 2004, A1, . Location in patent: Page 28
[10] Patent: US2004/214837, 2004, A1, . Location in patent: Page 27-28
[11] Patent: WO2006/72353, 2006, A1, . Location in patent: Page/Page column 47-48
[12] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 5, p. 797 - 817
[13] Tetrahedron, 2006, vol. 62, # 29, p. 6869 - 6875
[14] Patent: WO2007/60526, 2007, A1, . Location in patent: Page/Page column 42; 66
[15] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 2, p. 271 - 276
[16] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 48
[17] Patent: EP1591443, 2005, A1, . Location in patent: Page/Page column 65-66
[18] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 13, p. 2191 - 2194
[19] Patent: WO2004/112793, 2004, A1, . Location in patent: Page/Page column 126-127
[20] Patent: US5510362, 1996, A,
[21] Patent: US5567726, 1996, A,
[22] Patent: US2008/312209, 2008, A1, . Location in patent: Page/Page column 19
[23] Patent: WO2007/7018, 2007, A1, . Location in patent: Page/Page column 56
[24] Patent: EP1757582, 2007, A1, . Location in patent: Page/Page column 34-35
[25] Patent: WO2006/136830, 2006, A1, . Location in patent: Page/Page column 194-195
  • 3
  • [ 15103-48-7 ]
  • [ 18621-17-5 ]
  • [ 40320-60-3 ]
YieldReaction ConditionsOperation in experiment
60% With triethylamine In dimethyl sulfoxide at 50℃; for 0.666667 h; 1)
1-Benzhydrylazetidin-3-one
Pyridinesulfonic acid (19.7 g) in dimethyl sulfoxide (84 mL) was added dropwise to 1-benzhydrylazetidin-3-ol (4.79 g) in triethylamine (27.9 mL) under cooling on ice, followed by stirring at 50°C for 40 minutes.
The reaction mixture was partitioned between ice-water and ethyl acetate.
The organic layer was washed with saturated brine, followed by drying over magnesium sulfate anhydrate.
After a filtration step, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give 1-benzhydrylazetidin-3-one as a solid product (2.85 g, 60percent).
1H-NMR(400MHz,CDCl3)δ:4.00(4H,s), 4.59(1H,s), 7.19-7.49(10H,m).
Reference: [1] Patent: EP1762568, 2007, A1, . Location in patent: Page/Page column 37
  • 4
  • [ 18621-17-5 ]
  • [ 40320-60-3 ]
YieldReaction ConditionsOperation in experiment
89% With triethylamine In dimethyl sulfoxide 1.
1-Diphenylmethyl-3-azetidinone
A solution of 1-diphenylmethyl-3-hydroxyazetidine (3.3 g, 14 mmol; J. Org. Chem. 1972, 37, 3953) in dimethyl sulphoxide (20 ml) was treated with triethylamine (19.2 ml), cooled to 15° C. and treated with sulphur trioxide pyridine (13.8 g) in dimethyl sulphoxide (30 ml), keeping the temperature below 20° C.
The solution was stirred under an atmosphere of nitrogen at 15° C. for 45 minutes then at room temperature for 45 minutes.
The solution was poured into ice water and extracted twice with ethyl acetate.
The organic layer was collected, washed twice with water, dried (sodium sulphate), evaporated to dryness and the crude product purified using a plug of silica by eluding with dichloromethane to afford the ketone as a gum (2.9 g, 89percent), δ (360 MHz, CDCl3) 4.00 (4H, s), 4.59 (1H, s), 7.12-7.49 (10H, m).
Reference: [1] Patent: US6140347, 2000, A,
  • 5
  • [ 79-37-8 ]
  • [ 90604-02-7 ]
  • [ 40320-60-3 ]
Reference: [1] Patent: US6291457, 2001, B1,
  • 6
  • [ 686347-59-1 ]
  • [ 40320-60-3 ]
Reference: [1] Patent: WO2005/54184, 2005, A1, . Location in patent: Page/Page column 9-10
  • 7
  • [ 5267-34-5 ]
  • [ 40320-60-3 ]
Reference: [1] Chemistry Letters, 1999, # 7, p. 605 - 606
  • 8
  • [ 91-00-9 ]
  • [ 40320-60-3 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 5, p. 797 - 817
  • 9
  • [ 40320-60-3 ]
  • [ 18621-17-5 ]
YieldReaction ConditionsOperation in experiment
86.2% at 0 - 20℃; NaBH4 (2.39g, 0.063mol) was added portionwise to a solution of Compound 19-1 (15.0g, 0.063mol) in methanol (100mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours, the end of the reaction was monitored with TLC (petroleum ether/ethyl acetate = 3: 1). The reaction mixture was poured into ice water, and concentrated under reduced pressure, extracted with ethyl acetate (100mL × 3), washed with saturated brine, dried over anhydrous Na2SO4, the dried organic layer was concentrated under reduced pressure to give Compound 19-2 (13.0g, 86.2percent yield) as a white solid.
Reference: [1] Patent: EP2738156, 2014, A1, . Location in patent: Paragraph 0160-0162
  • 10
  • [ 40320-60-3 ]
  • [ 40432-52-8 ]
Reference: [1] Organic Process Research and Development, 2012, vol. 16, # 5, p. 788 - 797
  • 11
  • [ 40320-60-3 ]
  • [ 501-53-1 ]
  • [ 105258-93-3 ]
Reference: [1] Heterocycles, 1986, vol. 24, # 1, p. 25 - 28
[2] Patent: EP1757582, 2007, A1, . Location in patent: Page/Page column 34-35
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