* 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.
Reference：
[1] European Journal of Pharmaceutical Sciences, 2016, vol. 88, p. 166 - 177
2
[ 91-00-9 ]
[ 53871-06-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 20, p. 6031 - 6035
3
[ 91-00-9 ]
[ 3060-50-2 ]
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 294
4
[ 7664-41-7 ]
[ 91-00-9 ]
[ 3060-50-2 ]
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 294
5
[ 91-00-9 ]
[ 40320-60-3 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 5, p. 797 - 817
6
[ 91-00-9 ]
[ 106-89-8 ]
[ 18621-17-5 ]
Yield
Reaction Conditions
Operation in experiment
88.2%
With sodium carbonate In isopropyl alcohol for 12 h; Reflux
183 g of diphenylmethylamine and 92.5 g of epichlorohydrin,Add about 400mlIsopropyl alcohol, stir well,Then add 63gSodium carbonate, heated to reflux for 12 hours, and the reaction was complete by HPLC monitoring. filter,Isopropanol washing filter cake, the filtrate recovery isopropyl alcohol, the residue added ethyl acetate dissolved,Add concentrated hydrochloric acid to adjust the pH of 3 to 4, precipitation of large amounts of solid, filter detergent cake. Filter cake added to the water,And then slowly add the liquid alkaline solution, adjust the pH 10 to 11, filter out the solid,Dry to a white solidProduct III 210.9 g, yield 88.2percent, purity 99.98percent.
83%
for 72 h; Inert atmosphere
Production Example 191 1-Benzhydrylazetidin-3-ol Benzhydrylamine (12 g, 64 mmol), epichlorohydrin (5.9 g, 64 mmol), and 30 mL of methanol were stored under argon in a light-shielded state for 3 days. Next, the mixture was heated under reflux for 3 days in an oil bath. After the completion of the reaction was confirmed by TLC, the solvent was distilled off. To the resulting residue was added acetone, and the mixture was filtrated. The matter separated by filtration was dissolved in ether and washed with a 6-N sodium hydroxide aqueous solution. The organic layer was dried over sodium sulfate, the solvent was distilled off. Thus the title compound (1.3 g, 83percent) was obtained. 1H-NMR (CDCl3, δ): 2.38 (1H,brs), 2.8-3.0 (2H,m), 3.4-3.7 (2H,m), 4.34 (1H,s), 4.3-4.5 (1H,m), 7.1-7.5 (10H,m) MS (m/z): 238 (M+-1)
74%
With hydrogenchloride In N,N-dimethyl-formamide
Example 9(a) 1-benzhydrylazetidin-3-ol A mixture of (diphenylmethyl)amine (2.2 ml, 12.8 mmole), 2-chloromethyloxirane (2.0 ml, 25.6 mmole) in DMF (25 ml) were heated at 95° C. for 72 hours. The resultant yellow solution was cooled to 0° and treated with 0.5 M HCl (250 ml). The aqueous layer was washed with methyl tert-butyl ether (3*150 ml), and the organic layers were discarded. The aqueous layer was made basic with NaOH and the resultant milky white suspension was extracted with methyl tert-butyl ether (3*150 ml). The combined organic layers were washed with brine, dried over MgSO4 and concentrated, in vacuo, to a clear oil (3.1 g). The oil was triturated with cyclohexane and methyl tert-butyl ether and provided a white solid (2.3 g, 74percent): TLC (4percent methanol-chloroform with 0.1percent ammonium hydroxide) Rf 0.3; 1H-NMR (DMSO-d6, 400 MHz) δ7.40-7.38 (4H, m), 7.27-7.23 (4H, m), 7.17-7.13 (2H, m), 5.28 (1H, d, J=6.3 Hz), 4.34 (1H, s), 4.22-4.18 (1H,m), 3.36-3.34 (2H,m), 2.69-2.66 (2H,m).
51.82%
Stage #1: at 0 - 28℃; for 10 h; Inert atmosphere Stage #2: With N-ethyl-N,N-diisopropylamine In ethanol at 90℃; for 10 h;
Step 1: 2-(chloromethyl)ethylene oxide (5.05 g, 54.58 mmol) was dropwise added to a methanol solution (55 mL) of benzhydryl amine (10.00 g, 54.58 mmol) under nitrogen protection at 0°C, then the reaction solution was warmed up to 28°C and stirred for 10 h. LCMS showed that the reaction was completed. The mixture was concentrated under reduced pressure to obtain 1-(benzylaminopyridine)-3-chloropropyl-2-ol (15.00 g, crude product) which was yellow liquid and directly used in next step.
41%
at 20 - 70℃;
Step lTo a stirred solution of epichlorohydrin [91] (1 1.3 g, 13.9 mmol) in methanol (50 ml), a-amino- diphenylmethane [92] (25 g, 13.9 mmol) was added dropwise under at room temperature. The resulting solution was refluxed at 70 °C for 72 h. The progress of the reaction was monitored by TLC. After 72 h, the solvent was evaporated under vacuum. The residual solid was washed with 1000 ml of diethyl ether. The resulting residue was purified by column chromatography over 100-200 mesh silica using 2percent MeOH:DCM as eluent to gave l-benzhydrylazetidin-3-ol [93] as a white solid (14.1g,41percent).ESIMS: 240 (M+ + 1)
38%
at 90 - 100℃; for 72 h;
The solution of 2-(chloromethyl)oxirane (10 mL, 128 mmol) and Ph2CHNH2 (1 1 mL, 64 mmol) in DMF (80 mL) was heated at 90-100 0C under N2 for 3 d. The mixture was cooled to r.t. and evaporated under vacuum to give a yellow oil, which was dissolved in DCM (200 mL), washed with water (200 mL x 2), and extracted with IN HCl (200 mL x 2). The aq. solution was made basic with 10percent aq. NaOH, the mixture was extracted with Et2O (200 mL x 3), dried (Na2SO4), and evaporated under vacuum to give l-benzhydrylazetidin- 3-ol (5.74 g, 38percent yield).
Reference：
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[2] Patent: US2013/85127, 2013, A1, . Location in patent: Paragraph 0373; 0374; 0375; 0376
[3] Patent: US2004/9965, 2004, A1,
[4] Journal of Organic Chemistry, 1991, vol. 56, # 24, p. 6729 - 6730
[5] Patent: EP3248980, 2017, A1, . Location in patent: Paragraph 0289; 0290; 0291
[6] Patent: EP1213289, 2002, A1, . Location in patent: Page 11
[7] Patent: WO2012/101654, 2012, A2, . Location in patent: Page/Page column 63
[8] Patent: WO2008/108988, 2008, A1, . Location in patent: Page/Page column 70
[9] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 5, p. 797 - 817
[10] Patent: US5968923, 1999, A,
[11] Patent: US5741790, 1998, A,
[12] Patent: US5846965, 1998, A,
[13] Patent: US4183923, 1980, A,
[14] Patent: US6242438, 2001, B1,
[15] Patent: US6262075, 2001, B1,
[16] Patent: US5510362, 1996, A,
[17] Heterocycles, 2008, vol. 75, # 12, p. 2981 - 2988
[18] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 20, p. 6031 - 6035
[19] Organic Letters, 2014, vol. 16, # 10, p. 2744 - 2747
With potassium carbonate In methanol; water; toluene
EXAMPLE 1 N-Benzhydrylazetidine To A solution of 6.9 kg (50 moles) of potassium carbonate in 7.5 liters of water was added 18.5 liters of 1-butanol, 7.85 kg (50 moles) of 1-bromo-3-chloropropane and 5.18 kg (25 moles) of benzhydrylamine (97percent purity with 10percent toluene as a residual solvent). The reaction mixture was heated to 100° C. externally with steam and stirred slowly under a nitrogen gas atmosphere overnight. About 12 liters of water was added to the mixture to dissolve some inorganic salt precipitate. The layers were separated and organic layer was distilled under reduced pressure to remove about 18 liters of butanol and water. To the residue was added 1.5 liters of methanol and the resulting mixture was stirred slowly while cooling down to room temperature. The white solid was collected by filtration, rinsed twice with 700 ml portions of methanol and dried in a vacuum oven to give 4.2 kg (75percent) of product, m.p. 107°-109°
Reference：
[1] Patent: US4870189, 1989, A,
17
[ 63256-90-6 ]
[ 91-00-9 ]
[ 107128-00-7 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 20, p. 7885 - 7887
Reference Example 23 N-diphenylmethyl-2-chloroacetamide A solution of N-diphenylmethylamine (1103 mg) in methylene chloride (20 ml) was stirred at 0 C. Triethylamine (1.70 ml) and chloroacetyl chloride (0.72 ml) were added to the solution, and the mixture was stirred at 0 C. for 40 minutes. After water (20 ml) was added to the reaction mixture, the mixture was extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (developing solvent:n-hexane/ethyl acetate=5/1) to obtain the object compound (1522 mg, yield 97%). 1H-NMR (300 MHz, CDCl3) delta4.13 (2H, s), 6.26 (1H, d, J=8.1 Hz), 7.13-7.40 (11H, m). IR (KBr method) 3204, 3042, 1554, 1495, 1454, 1420, 1237, 1090, 1060, 1031, 987, 925, 857, 786, 762, 748, 703 cm-1 Mass (EI, m/e) 259 (M+)
With sodium carbonate; In methanol; at 20℃; for 16h;
Step 1: (E)-N-(4-methoxybenzvIidene)-1,1-diphenylmethanamine (39). To a solution of diphenylmethanamine (3.00 g, 16.4 mniol) in methanol (80 mL) was added 4-methoxybenzaldehyde (2.45 g, 18.0 mmol) and sodium carbonate (2.60 g, 24.6 mmol). The reaction mixture was stirred at room temperature for 16 h prior to removal of all solvents under vacuum. The residue was then diluted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford compound 39 as a white solid (3.62 g, 73%). LRMS (ESI): (calc.) 301.4 (found) 302.4 (MH)+
Synthesis of the Acid Unit AC-23: 2-[2-(Benzhydryl-methylsulfonyl-amino)-ethoxy]-acetic acid (AC-23) 3. The sulfonyl chloride 1 (9.76 g, 85.2 mmol) and Et3N (11.8 ml, 85.2 mmol) were dissolved in CH2Cl2 (100 ml), and a solution of diphenylmethanamine (2, 15.61 g, 85.2 mmol) in CH2Cl2 (40 ml) was added dropwise in the course of 10 min. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was washed with aqueous 0.5 M KHSO4 (2×200 ml) and sat. NaCl solution (100 ml), dried over Na2SO4 and concentrated to dryness. Recrystallization from CH2Cl2 at 0-5 C. gave 17.63 g (79%) of the sulfonamide 3.
79%
With triethylamine; In dichloromethane; at 20℃;
Synthesis of Acid Building Block S-23l; 2-[2-(Benzhydryl-methylsulfonyl-amino)-ethoxy]-acetic acid (S-23) 3. Sulfonyl chloride 1 (9.76 g, 85.2 mmol) and Et3N (11.8 ml, 85.2 mmol) were dissolved in CH2Cl2 (100 ml) and a solution of diphenylmethanimine (2, 15.61 g, 85.2 mmol) in CH2Cl2 (40 ml) was added dropwise over 10 min. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was washed with aqueous 0.5 M KHSO4 (2×200 ml), brine (100 ml), dried over Na2SO4 and evaporated to dryness. Crystallisation from CH2Cl2 at 0-5 C. afforded 17.63 g (79%) of sulfonamide 3.
With triethylamine; In dichloromethane;
a) N-(diphenylmethyl)methanesulfonamide To a solution of 4 g (0.02 mol) of (diphenylmethyl)amine in 50 mL of anhydrous dichloromethane, 10 mL (0.072 mol) of triethylamine were added. The mixture was cooled with an ice bath and 1.8 mL (0.024 mol) of methanesulfonyl chloride were added under nitrogen atmosphere and the mixture was stirred at room temperature for 18 h. The resulting solution was diluted with dichloromethane, washed with water and 0.1 N hydrochloric acid and the organic phase was dried over sodium sulfate. Evaporation of the solvent afforded 5.22 g of a crude that was purified by chromatography on silica gel (hexane: ethyl acetate, 30%), to give 3.36 g of the product (64% yield). IR(KBr) nu: 3290, 3054, 3018, 2920, 1595, 1487, 1446, 1317, 1147, 742, 698 cmmin1; 1H NMR (80MHz, CDCl3) delta (TMS): 7.32 (s, 10H, Ph), 5.73 (broad s, 1H, NH), 5.19 (s, 1H, CH), 2.63 (s, 3H, CH3).
With 5-nitroso-1,3-diphenyltetrazolium tetrafluoroborate; In acetonitrile; at 20℃; for 0.166667h;
General procedure: To a solution of benzhydrylamine (18.4 mg, 0.101 mmol) inMeCN (1.0 mL) was added a solution of 1 (34.1 mg, 0.101 mmol) in MeCN (1.0 mL) dropwise. Theresulting mixture was stirred under argon at room temperature for 10 min and concentrated in vacuo.The residue was separated by chromatography on NH-SiO2 (eluting with 2:8 CH2Cl2/hexane,gradually changing to pure CH2Cl2, then acetone) to give benzophenone benzhydrylimine (9.4 mg,54%), benzophenone (0.6 mg, 3%), 2 (3.4 mg, 13%), 3 (6.5 mg, 27%), and crude 4, which waswashed with Et2O to give pure 4 (14.4 mg, 60%).
With sodium carbonate; In isopropyl alcohol; for 12h;Reflux;
183 g of diphenylmethylamine and 92.5 g of epichlorohydrin,Add about 400mlIsopropyl alcohol, stir well,Then add 63gSodium carbonate, heated to reflux for 12 hours, and the reaction was complete by HPLC monitoring. filter,Isopropanol washing filter cake, the filtrate recovery isopropyl alcohol, the residue added ethyl acetate dissolved,Add concentrated hydrochloric acid to adjust the pH of 3 to 4, precipitation of large amounts of solid, filter detergent cake. Filter cake added to the water,And then slowly add the liquid alkaline solution, adjust the pH 10 to 11, filter out the solid,Dry to a white solidProduct III 210.9 g, yield 88.2%, purity 99.98%.
83%
In methanol; for 72h;Inert atmosphere;
Production Example 191 1-Benzhydrylazetidin-3-ol <strong>[91-00-9]Benzhydrylamine</strong> (12 g, 64 mmol), epichlorohydrin (5.9 g, 64 mmol), and 30 mL of methanol were stored under argon in a light-shielded state for 3 days. Next, the mixture was heated under reflux for 3 days in an oil bath. After the completion of the reaction was confirmed by TLC, the solvent was distilled off. To the resulting residue was added acetone, and the mixture was filtrated. The matter separated by filtration was dissolved in ether and washed with a 6-N sodium hydroxide aqueous solution. The organic layer was dried over sodium sulfate, the solvent was distilled off. Thus the title compound (1.3 g, 83%) was obtained. 1H-NMR (CDCl3, delta): 2.38 (1H,brs), 2.8-3.0 (2H,m), 3.4-3.7 (2H,m), 4.34 (1H,s), 4.3-4.5 (1H,m), 7.1-7.5 (10H,m) MS (m/z): 238 (M+-1)
74%
With hydrogenchloride; In N,N-dimethyl-formamide;
Example 9(a) 1-benzhydrylazetidin-3-ol A mixture of (diphenylmethyl)amine (2.2 ml, 12.8 mmole), 2-chloromethyloxirane (2.0 ml, 25.6 mmole) in DMF (25 ml) were heated at 95 C. for 72 hours. The resultant yellow solution was cooled to 0 and treated with 0.5 M HCl (250 ml). The aqueous layer was washed with methyl tert-butyl ether (3*150 ml), and the organic layers were discarded. The aqueous layer was made basic with NaOH and the resultant milky white suspension was extracted with methyl tert-butyl ether (3*150 ml). The combined organic layers were washed with brine, dried over MgSO4 and concentrated, in vacuo, to a clear oil (3.1 g). The oil was triturated with cyclohexane and methyl tert-butyl ether and provided a white solid (2.3 g, 74%): TLC (4% methanol-chloroform with 0.1% ammonium hydroxide) Rf 0.3; 1H-NMR (DMSO-d6, 400 MHz) delta7.40-7.38 (4H, m), 7.27-7.23 (4H, m), 7.17-7.13 (2H, m), 5.28 (1H, d, J=6.3 Hz), 4.34 (1H, s), 4.22-4.18 (1H,m), 3.36-3.34 (2H,m), 2.69-2.66 (2H,m).
51.82%
Step 1: 2-(chloromethyl)ethylene oxide (5.05 g, 54.58 mmol) was dropwise added to a methanol solution (55 mL) of benzhydryl amine (10.00 g, 54.58 mmol) under nitrogen protection at 0C, then the reaction solution was warmed up to 28C and stirred for 10 h. LCMS showed that the reaction was completed. The mixture was concentrated under reduced pressure to obtain 1-(benzylaminopyridine)-3-chloropropyl-2-ol (15.00 g, crude product) which was yellow liquid and directly used in next step.
41%
In methanol; at 20 - 70℃;
Step lTo a stirred solution of epichlorohydrin [91] (1 1.3 g, 13.9 mmol) in methanol (50 ml), a-amino- diphenylmethane [92] (25 g, 13.9 mmol) was added dropwise under at room temperature. The resulting solution was refluxed at 70 C for 72 h. The progress of the reaction was monitored by TLC. After 72 h, the solvent was evaporated under vacuum. The residual solid was washed with 1000 ml of diethyl ether. The resulting residue was purified by column chromatography over 100-200 mesh silica using 2% MeOH:DCM as eluent to gave l-benzhydrylazetidin-3-ol [93] as a white solid (14.1g,41%).ESIMS: 240 (M+ + 1)
38%
In N,N-dimethyl-formamide; at 90 - 100℃; for 72h;
The solution of 2-(chloromethyl)oxirane (10 mL, 128 mmol) and Ph2CHNH2 (1 1 mL, 64 mmol) in DMF (80 mL) was heated at 90-100 0C under N2 for 3 d. The mixture was cooled to r.t. and evaporated under vacuum to give a yellow oil, which was dissolved in DCM (200 mL), washed with water (200 mL x 2), and extracted with IN HCl (200 mL x 2). The aq. solution was made basic with 10% aq. NaOH, the mixture was extracted with Et2O (200 mL x 3), dried (Na2SO4), and evaporated under vacuum to give l-benzhydrylazetidin- 3-ol (5.74 g, 38% yield).
In methanol;
Preparation 53 1-Diphenylmethylazetidin-3-ol A solution of benzhydrylamine (200 ml, 1.16 mol) and epichlorohydrin (186 ml, 1 mol. equiv.) in methanol (600 ml) was stirred at room temperature for five days and then heated at 40 C. for two days. The solvent was then removed under reduced pressure, the residue dissolved in isopropyl alcohol (500 ml) and the solution heated under reflux for six hours. The solution was cooled to room temperature and the precipitate filtered off. This solid was partitioned between dichloromethane (400 ml) and saturated aqueous sodium bicarbonate solution (500 ml). The aqueous phase was extracted with dichloromethane (2*400 ml) and the combined organic phases dried over magnesium sulphate. The solution was then filtered and the solvent removed from the filtrate under reduced pressure to give the title compound (86 g) as a crystalline solid. 1 H-NMR (CDCl3):delta=1.8-2.3 (s,br,1H), 2.85-2.9 (m,2H), 3.5-3.55 (m,2H), 4.35 (s,1H), 4.4-4.5 (m,1H), 7.15-7.4 (m,10H) ppm.
In methanol;
1(a) 1-Diphenylmethylazetidin-3-ol A solution of benzhydrylamine (200 ml, 1.16 mol) and epichlorohydrin (186 ml, 1 mol equiv) in methanol (600 ml) was stirred at room temperature for 5 days and then heated to 40 C. for 2 days. The solvent was then removed in vacuo, the residue dissolved in isopropyl alcohol (500 ml) and the solution heated under reflux for 6 hours. The solution was cooled to room temperature and the precipitate filtered off. The solid was partitioned between dichloromethane (400 ml) and saturated NaHCO3 solution (500 ml). The aqueous phase was extracted with dichloromethane (2*400 ml) and the combined organic phases dried over anhydrous MgSO4. The solvent was then removed in vacuo to give the title compound (86 g) as a crystalline solid. 1 H NMR (CDCl3): 1.8-2.3 (s,br, 1H); 2.85-2.9 (m,2H); 3.5-3.55 (m,2H); 4.35 (s,1H); 4.4-4.5 (m,1H); 7.15-7.4 (m, 10H) ppm.
In methanol;
(a) 1-Diphenylmethylazetidin-3-ol A solution of benzhydrylamine (200 ml, 1.6 mol) and epichlorohydrin (186 ml, 1 mol equivalent) in methanol (600 ml) was stirred at room temperature for five days and then heated at 40 C. for two days. The solvent was then removed under reduced pressure, the residue dissolved in isopropyl alcohol (500 ml) and the solution heated under reflux for six hours. The solution was cooled to room temperature and the precipitate filtered off. This solid was partitioned between dichloromethane (400 ml) and saturated aqueous sodium bicarbonate solution (500 ml). The aqueous phase was extracted with dichloromethane (2*400 ml), the combined organic extracts dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure to give the title product (86 g) as a crystalline solid. 1 H-NMR (CDCl3): delta=1.8-2.3(s,br,1H), 2.85-2.9(m,2H), 3.5-3.55(m,2H), 4.35(s,1H), 4.4-4.5(m, 1H), 7.15-7.4(m,10H)ppm.
With hydrogenchloride; sodium hydroxide; In diethyl ether; N,N-dimethyl-formamide;
EXAMPLE 1 1-Isopropyl-3-Methanesulfonyloxyazetidine Hemimaleate Heat a mixture of 1.0 mole 1-chloro-2,3-epoxypropane and 0.5 mole diphenylmethylamine in N,N-dimethylformamide at about 95 C. for 48 hours. Cool the solution with agitation to less than 10 C. and slowly add 6 N hydrochloric acid at such a rate as to maintain the temperature below 25 C. Filter the resultant precipitate, wash it several times with diethyl ether and air dry. Dissolve the hydrochloride salt in a 1:1 mixture of sodium hydroxide and diethyl ether. Separate the ether layer and extract the water layer several times with diethyl ether. Dry the combined ether extract over anhydrous sodium sulfate and remove the ether by distillation to afford 1-benzhydryl-3-hydroxyazetidine.
In methanol;
Preparation 10 1-Diphenylmethylazetidin-3-ol A solution of benzhydrylamine (200 ml, 1.16 mol) and epichlorohydrin (186 ml, 1 mol. equiv.) in methanol (600 ml) was stirred at room temperature for five days and then heated at 40 C. for two days. The solvent was then removed under reduced pressure, the residue dissolved in isopropyl alcohol (500 ml) and the solution heated under reflux for six hours. The solution was cooled to room temperature and the precipitate filtered off. This solid was partitioned between dichloromethane (400 ml) and saturated aqueous sodium bicarbonate solution (500 ml). The aqueous phase was extracted with dichloromethane (2*400 ml) and the combined organic phases dried over magnesium sulphate. The solution was then filtered and the solvent removed from the filtrate under reduced pressure to give the title compound (86 g) as a crystalline solid. 1H-NMR (CDCl3): delta=1.8-2.3 (s, br, 1H), 2.85-2.9 (m, 2H), 3.5-3.55 (m, 2H), 4.35 (s, 1H), 4.4-4.5 (m, 1H), 7.15-7.4 (m, 10H).
In methanol;
(a) 1-Diphenylmethylazetidin-3-ol A solution of benzhydrylamine (200 ml, 1.16 mol) and epichlorohydrin (186 ml, 1 mol. equiv.) in methanol (600 ml) was stirred at room temperature for five days and then heated at 40 C. for two days. The solvent was removed under reduced pressure, the residue dissolved in isopropyl alcohol (500 ml) and the solution heated under reflux for six hours. The solution was cooled to room temperature and the precipitate filtered off. This solid was partitioned between dichloromethane (400 ml) and saturated aqueous sodium bicarbonate solution (500 ml). The aqueous phase was extracted with dichloromethane (2*400 ml) and the combined organic phases dried over magnesium sulphate. The solution was then filtered and the solvent removed from the filtrate by evaporation under reduced pressure to give the title compound (86 g) as a crystalline solid. 1H-NMR (CDCl3): delta=1.8-2.3 (s,br,1H), 2.85-2.9 (m,2H), 3.5-3.55 (m,2H), 4.35 (s,1H), 4.4-4.5 (m,1H), 7.15-7.4 (m,10H) ppm.
With sodium hydroxide; In dimethyl sulfoxide;
1. N-Diphenylmethylazetidin-3-ol Aminodiphenylmethane (100 g, 0.54 mols) was added to a solution of epichlorohydrin (50 g, 0.54 mols) in DMSO (135 ml) and stirred at 25 C. for 3 days. The solution was then heated at 70 C. for 3 days before cooling to room temperature, adding 10% NaOH solution, and extracting with Et2 O (2*800 ml). The combined extracts were washed with water (2*1), dried (Na2 SO4) and evaporated. The crude product was chromatographed on silica-gel eluding with CH2 Cl2 /MeOH (98:2) to give the title-azetidinol (33.5 g); delta (360 MHz, CDCl3) 2.30 (1H, br s, OH), 2.87-2.91 (2H, m, 2 of CH of CH2), 3.51-3.55 (2H, m, 2 of CH of CH2), 4.34 (1H, s, CH), 4.41-4.48 (1H, m, CH--OH), 7.13-7.39 (10H, m, Ar--H).
In ethanol; at 20℃; for 144h;Reflux;
A mixture of diphenylmethanamine (437.0 g, 2.39 mol) and 2-(chloromethyl)oxirane (215.0 g, 2.33 mol) in ethanol (1 L) was stirred at ambient temperature for 3 days and then heated at reflux for 3 days. The volume of the solution was reduced to ca 200 mL and the resulting precipitate was filtered and washed with ethyl acetate, to afford 1-benzhydrylazetidin-3-ol (335.0 g, 51%) as a white solid. It was used crude in the next step.
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).
(1-{Benzhydryl-[1-benzylcarbamoyl-2-(4-hydroxy-phenyl)-1-methyl-ethyl]-carbamoyl}-1-methyl-2-phenyl-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester[ No CAS ]
With triethylamine; In N,N-dimethyl-d6-formamide; at 10 - 20℃; for 12h;
General procedure: 3.24 mL (23 mmol, 0.77 equiv.) of Et3N was added to 30 mmol (1 equiv.) of substituted amine in 30 mL of dry DMF. 32 mmol (1.1 equiv.) of 4-acetylamino benzenesulfonyl chloride were then added in small portions (5 portions for 1 h) under stirring and cooling in a water bath (10-15 C). The reaction mixture was stirred for 12 h at room temperature. After the end of the reaction, the reaction mixture was poured into 100 mL of 1 M HCl and 50 mL of a saturated NaCl solution were added under cooling(10 C). The precipitate was separated, washed with 200 mL H2O and dried in vacuum under KOH.
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1h;Inert atmosphere;
General procedure: To a solution of bromoacetyl chloride (1.40g, 8.17mmol) in10mL of dry THF cooled at 0C, under argon atmosphere, was added dropwise, under vigorous stirring, a solution of the appropriate amine (5.45mmol) and triethylamine (0.276g, 2.72mmol) in dry THF (10mL). After 30min at 0 and 30min at room temperature the reaction mixture was quenched by the addition of 50ml of H2O and extracted with dichloromethane (3×50ml). The combined organic extracts were washed with saturated NaHCO3 and brine, and then dried over anhydrous Na2SO4. Evaporation under reduced pressure gave the crude 3-bromopropanamide derivatives (1-3) which were purified by flash chromatography on silica gel, using CH2Cl2 and cyclohexane as eluent.
tert-butyl (2S)-2-(benzhydrylcarbamoyl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
To a stirred solution of N-t-butyloxycarbonyl-l-proline (1.075 g, 5 mmol) in dry dichloromethane (15 mL) was added DMAP (210 mg, 1.5 mmol). The mixture was allowed to stir for 15 min and then cooled to 0 C after which EDCI (1.22 g, 5.5 mmol) was added. After 20 min, a solution of 1,1-diphenylmethylamine (676 mg,4 mmol) in dichloromethane (15 mL) was added to the above reaction mixture. The resulting solution was stirred at room temperature until complete consumption of the nitroalkene (monitored by TLC). The reaction was quenched with water and extracted with dichloromethane (3 * 50 mL). The combined organic layers were washed with saturated brine solution (20 mL), followed by drying over Na2SO4 and evaporation in vacuo. The crude product was purified by column chromatography to give pure tert-butyl (S)-2-(benzhydrylcarbamoyl)pyrrolidine-1-carboxylate 3a as an amorphous powder, 97% yield. [alpha]D20 = -78.6 (c 1.0, CHCl3); IR (KBr) 698, 1160, 1245, 1384, 1540, 1654, 1699, 2974, 3288 cm-1; HRMS (EI) calcd for C23H28N2O3 [M+Na]+ 403.1992, found 403.1993. 1H NMR (400 MHz, CDCl3, TMS): delta 7.97 (s, 1H), 7.38-7.24 (m, 10H), 6.24 (d, J = 27.2 Hz, 1H), 4.35 (d, J = 26.8 Hz, 1H), 3.39 (d, J = 59.2 Hz, 1H), 2.42 (s, 1H), 2.19 (s, 1H), 1.88 (s, 3H), 1.46 (s, 5H), 1.32 (s, 4H); 13C NMR (100 MHz, CDCl3, TMS): delta 170.8, 156.1, 141.8, 128.6, 128.5, 127.5, 127.2, 127.0, 126.9, 80.5, 61.3, 59.7, 56.7, 47.2, 31.1, 28.3, 27.5, 24.7, 23.9.
General procedure: A solution of sulfonyl chloride B (10 mmol) in dichloromethane (25 mL) was slowlyadded to a stirred solution of diamine A (10 mmol), NEt3 (11 mmol) in dichloromethane(25 mL). The resulting mixture was stirred for another 3 hr, washed twice with water (25mL) and dried over Na2SO4. The solvent was removed in vacuo to give a white solid C. Toa solution of D in CH2Cl2 (40 mL) was added NEt3 (11 mmol), isobutyl carbonochloridate(11 mmol) at 0 oC under stirring. After 10 min, C was added. The reaction was allowed towarm to room temperature for another 3 hr. The mixture was washed with 1 M KHSO4solution, saturated NaHCO3 solution, and brine, dried over anhydrous Na2SO4 andconcentrated to get a white solid E. Then, TFA (10 mL) was added to the CH2Cl2 (10 mL)solution of E, and stirred until the reaction finished (1 hr). The pH value of the mixture wasbrought into the range of 10-12 by the addition of 2 N NaOH solution. The aqueousphase was extracted with CH2Cl2 (3 × 30 mL). The combined organic phase was washedwith brine, dried over anhydrous Na2SO4, and concentrated and purified through flashchromatograph as a white solid F (70% yield).
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In xylene; at 135℃; for 16h;
A mixture of a portion (5 g) of the material so obtained, diphenylmethyleneamine (3.75 g), cesium carbonate (25.67 g) and xylene (200 ml) was stirred at ambient temperature for 30 minutes.. racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.227 g) and palladium diacetate (0.221 g) were added and the mixture was stirred and heated to 135 C. for 16 hours.. The mixture was cooled to ambient temperature and diethyl ether (600 ml) was added.. The mixture was filtered and the filtrate was evaporated.. There was thus obtained N-diphenylmethylene-6-acetoxy-7-methoxyquinazolin-4-amine (7.12 g); Mass Spectrum: M+H+ 398.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃;
EXAMPLE 24 : N-Benzhydryl-4-phenyl-2 (S)-phenylmethane-sulphonylamino- butyramide A solution of N-BOC-L-HOMOPHENYLALANINE (Intermediate 7,0. 21 mmol), AMINODIPHENYLMETHANE (0.25 MMOL), N-HYDROXYBENZOTRIAZOLE (0.25 mmol), N, N- DIISOPROPYLETHYLAMINE (0.84 MMOL) and EDC (0.25 MMOL) in DMF (0.6 mi) was allowed to stand overnight at room temperature. The reaction mixture was then worked up as described in Example 8 Step 1 to give a crude amide, 68 mg, tic Rf 0.59 (ethyl acetate/hexane 1: 1).
With xantphos; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 100℃; for 2h;
The product of Example 24D (360 mg, 1 mmol) was coupled with benzhydrylideneamine (Aldrich, 270 mg, 1.5 mmol) under the catalysis of Pd2(dba)3 (Aldrich, 18.3 mg, 0.02 mmol) and Xantphos (Strem Chemicals, 36 mg, 0.06 mmol) with t-BuONa (Aldrich, 150 mg, 1.5 mmol) in toluene (anhydrous, Aldrich, 10 mL) at 100 C. for 2 h. The mixture was then cooled down to ambient temperature and diluted with EtOAc (50 mL), washed with water (2×5 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2: MeOH:NH3.H2O, 90:10:1, Rf. 0.4) as a solid (360 mg, yield, 78%). 1H NMR (300 MHz, CD3OD) delta 1.45-1.63 (m, 1 H), 1.64-1.94 (m, 2 H), 1.94-2.13 (m, 1 H), 2.23-2.41 (m, 1 H), 2.71-3.06 (m, 5 H), 3.39-3.55 (m, 1 H), 5.10-5.37 (m, 1 H), 6.82-6.93 (m, 2 H), 7.12-7.23 (m, 3 H), 7.25-7.35 (m, 3 H), 7.39-7.57 (m, 3 H), 7.67-7.74 (m, 2 H), 7.74-7.83 (m, 2 H), 7.96 (d, J=9.2 Hz, 1 H) ppm. MS (DCl/NH3): 461 (M+H)+.
1-t-Butoxycarbonyl-semicarbazid-4-yl Diphenylmethane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With hydrogenchloride; In N-methyl-acetamide; water; N,N-dimethyl-formamide;
Part I Synthesis of 1-t-Butoxycarbonyl-semicarbazid-4-yl Diphenylmethane A solution of carbonyidiimidazole (16.2 g, 0.10 mole) in 225 mL of dimethylformamide was prepared at room temperature and allowed to stir under nitrogen. A solution of t-butyl carbazate (13.2 g, 0.100 mol) in 225 mL DMF was then added dropwise overa 30 min. period. Diphenylmethylamine (18.3 g, 0.10 mol) was added next over a 30 min. period. The reaction was allowed to stir at room temperature under nitrogen for one hour. Water (10 mL) was added and the mixture was concentrated to about 150 mL under reduced pressure. This solution was poured into 500 mL water and extracted with 400 mL of ethyl acetate. The ethylacetate phase was extracted two times each with 75 mL 1N HCl, H2O, saturated sodium bicarbonate solution and sodium chloride, and dried with magnesium sulfate. The mixture was filtered and the solution was concentrated to give 29.5 g (85% yield) of a white foam. This material could be purified by recrystallization from ethyl acetate/hexane, but was pure enough to use directly in the next step: mp 142-143 C. 1H NMR (CDCl3) d 1.45 (s, 9H), 6.10 (dd, 2H), 6.42 (S, 1H), 6.67 (bs, 1H), 7.21-7.31 (m, 10H). Anal: Calcd. for C19H23N3O3: C, 66.84; H, 6.79; N, 12.31. Found: C, 66.46; H, 6.75; N; 12.90.
85%
With hydrogenchloride; 1,1'-carbonyldiimidazole; In N-methyl-acetamide; water; N,N-dimethyl-formamide;
e1) Synthesis of 1-t-Butoxycarbonyl-semicarbazid-4-yl diphenylmethane A solution of carbonyldiimidazole (16.2 g, 0.10 mole) in 225 mL of dimethylformamide was prepared at room temperature and allowed to stir under nitrogen. A solution of t-butyl carbazate (13.2 g, 0.100 mol) in 225 mL DMF was then added dropwise over a 30 min. period. Diphenylmethylamine (18.3 g, 0.10 mol) was added next over a 30 min. period. The reaction was allowed to stir at room temperature under nitrogen for one hour. Water (10 mL) was added and the mixture was concentrated to about 150 mL under reduced pressure. This solution was poured into 500 mL water and extracted with 400 mL of ethyl acetate. The ethylacetate phase was extracted two times each with 75 mL 1N HCl, H2O, saturated sodium bicarbonate solution and sodium chloride, and dried with magnesium sulfate. The mixture was filtered and the solution was concentrated to give 29.5 g (85% yield) of a white foam. This material could be purified by recrystallization from ethyl acetate/hexane, but was pure enough to use directly in the next step: mp 142-143 C. 1H NMR (CDCl3) d 1.45 (s, 9H), 6.10 (dd, 2H), 6.42 (s, 1H), 6.67 (bs, 1H), 7.21-7.31 (m, 10H). Anal: Calcd. for C19H23N3O3: C, 66.84; H, 6.79; N, 12.31. Found: C, 66.46; H, 6.75; N; 12.90.
85%
With hydrogenchloride; 1,1'-carbonyldiimidazole; In N-methyl-acetamide; water;
Step 1 A solution of carbonyldiimidazole (16.2 g, 0.10 mole) in 225 mL of dimethylformamide was prepared at room temperature and allowed to stir under nitrogen. A solution of t-butyl carbazate (13.2 g, 0.100 mole) in 225 mL dimethylformamide was then added dropwise over a 30 minute period. Next, diphenylmethylamine (18.3 g, 0.10 mole) was added over a 30 minute period. The reaction mixture was allowed to stir at room temperature under nitrogen for one hour. Water (10 mL) was added and this mixture was concentrated to about 150 mL under vacuum. This solution was poured into 500 mL water and then extracted with 400 mL of ethyl acetate. The ethyl acetate phase was extracted two times each with 75 mL 1N HCl, water, saturated sodium bicarbonate and brine, and then was dried with anhydrous magnesium sulfate. The mixture was filtered and the solution was concentrated to give 29.5 g (85% yield) of 1-t-butoxycarbonyl-semicarbazid-4-yl diphenylmethane as a white foam. This material may be purified by recrystalization from ethyl acetate/hexane, but was pure enough to use directly in step 2: mp 142-143 C. 1H NMR (CDCl3) delta 1.45 (s, 9H), 6.10 (dd, 2H), 6.42 (s, 1H), 6.67 (bs, 1H), 7.21-7.31 (m, 10H). Analysis calculated for C19H23N3O3: C, 66.84; H, 6.79; N, 12.31. Found: C, 66.46; H, 6.75; N; 12.90.
85%
With hydrogenchloride; 1,1'-carbonyldiimidazole; In N-methyl-acetamide; water;
STR47 Step 1: A solution of carbonyldiimidazole (16.2 g, 0.10 mole) in 225 mL of dimethylformamide was prepared at room temperature and allowed to stir under nitrogen. A solution of t-butyl carbazate (13.2 g, 0.100 moles) in 225 mL dimethylformamide was then added dropwise over a 30 minute period. Next, diphenylmethylamine (18.3 g, 0.10 moles) was added over a 30 minute period. The reaction was allowed to stir at room temperature under nitrogen for one hour. Water (10 mL) was added and this mixture was concentrated to about 150 mL under vacuum. This solution was poured into 500 mL water and extracted with 400 mL of ethyl acetate. The ethyl acetate phase was extracted two times each with 75 mL 1N HCl, water, saturated sodium bicarbonate and brine, and then was dried with anhydrous magnesium sulfate. The mixture was filtered and the solution was concentrated to give 29.5 g (85% yield) of 1-t-butoxycarbonyl-semicarbazid-4-yl diphenylmethane as a white foam. This material may be purified by recrystallization from ethyl acetate/hexane, but was pure enough to use directly in step 2: mp 142-143 C. 1 H NMR (CDCl3) delta 1.45 (s, 9H), 6.10 (dd, 2H), 6.42 (s, 1H), 6.67 (bs, 1H), 7.21-7.31 (m, 10H). Anal. Calc'd. for C19 H23 N3 O3: C, 66.84; H, 6.79; N, 12.31. Found: C, 66.46; H, 6.75; N; 12.90.
85%
With hydrogenchloride; 1,1'-carbonyldiimidazole; In N-methyl-acetamide; water;
Step 1 A solution of carbonyldiimidazole (16.2 g, 0.10 mole) in 225 mL of dimethylformamide was prepared at room temperature and allowed to stir under nitrogen. A solution of t-butyl carbazate (13.2 g, 0.100 moles) in 225 mL dimethylformamide was then added dropwise over a 30 minute period. Next, diphenylmethylamine (18.3 g, 0.10 moles) was added over a 30 minute period. The reaction was allowed to stir at room temperature under nitrogen for one hour. Water (10 mL) was added and this mixture was concentrated to about 150 mL under vacuum. This solution was poured into 500 mL water and extracted with 400 mL of ethyl acetate. The ethyl acetate phase was extracted two times each with 75 mL 1N HCl, water, saturated sodium bicarbonate and brine, and then was dried with anhydrous magnesium sulfate. The mixture was filtered and the solution was concentrated to give 29.5 g (85% yield) of 1-t-butoxycarbonyl-semicarbazid-4-yl diphenylmethane as a white foam. This material may be purified by recrystallization from ethyl acetate/hexane, but was pure enough to use directly in step 2: mp 142-143 C. 1 H NMR (CDCL3) delta 1.45 (s, 9H), 6.10 (dd, 2H), 6.42 (s, 1H), 6.67 (bs, 1H), 7.21-7.31 (m, 10H). Anal. Calc'd. for C19 H23 N3 O3: C, 66.84; H, 6.79; N, 12.31. Found: C, 66.46; H, 6.75; N; 12.90.
(Diphenylmethyl)[(4-chloro-3-nitrophenyl)sulfonyl]amine. To a stirred solution of aminodiphenylmethane (1.9 g, 11 mmol) and 4-chloro-3-nitrobenzenesulfonyl chloride (2.56 g, 10 mmol) in 75 mL of dichloromethane was added triethylamine (2 mL, 14.4 mmol). The solution was stirred for 16 h. The reaction mixture was washed successively with 1M HCl and brine. The organic layer was dried over MgSO4, filtered and evaporated. The resulting yellow solid was recrystallized from ethyl acetate/hexane to give 2.98 g of product in (74%) yield as pale yellow crystals: 1H NMR (400 MHz, CDCl3) delta5.34 (d, 1H, J=7.0 Hz), 5.73 (d, 1H, J=7.0 Hz), 7.11-7.14 (m, 4H), 7.23-7.26 (m, 6H), 7.43 (d, 1H, J=8.5 Hz), 7.67 (dd, 1H, J=2.0, 8.5 Hz), 7.93 (d, 1H, J=2.0 Hz).
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.
EXAMPLE 49 STR65 Ethyl 2[(diphenylmethyl)amino]-4-(trifluoromethyl)-5thiazolecarboxylate A reaction vessel was charged with 120 ml of toluene and 11.0 g (42.4 mmol) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506). Then, 15.5 g (86 mmol) of aminodiphenylmethane was added in one portion. The resulting yellowish-orange solution was refluxed under nitrogen for 9 days. Then, solvent was removed from the mixture under reduced pressure to yield a yellowish-orange solid material, which was flash chromatographed (~38 ml/min) on silica gel using 10% ethyl acetate in hexane solvent. There was obtained 13.2 g of a thick yellow oil which solidified upon standing to a yellow solid product (m.p.=92-95 C.) identified in Table I.
With N-ethyl-N,N-diisopropylamine; In hexane; water; ethyl acetate; N,N-dimethyl-formamide;
PREPARATION 9 N-(Diphenylmethyl)-1H-imidazole-4-carboxamide A mixture of 11.7 g of 4-imidazolecarboxylic acid, 18.7 g of 1,1'-carbonyldiidmidazole, 20 ml of diisopropylethylamine and 600 ml of DMF was heated at 35° C. for approximately 18 hours. Twenty milliters of aminodiphenylmethane were added and the solution stirred at 35° C. for approximately 21/2 days. The mixture was concentrated in vacuo and the residue added to 400 ml of water. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Two crystallizations from hot ethyl acetate/hexane provided 11 grams of the desired titled intermediate, m.p. 201°-202° C. Analysis for C17 H15 N3 O: Calc.: C, 73.63; H, 5.45; N, 15.15; Found: C, 73.90; H, 5.58; N, 15.12.
With potassium carbonate; In methanol; water; toluene;
EXAMPLE 1 N-Benzhydrylazetidine To A solution of 6.9 kg (50 moles) of potassium carbonate in 7.5 liters of water was added 18.5 liters of 1-butanol, 7.85 kg (50 moles) of 1-bromo-3-chloropropane and 5.18 kg (25 moles) of benzhydrylamine (97% purity with 10% toluene as a residual solvent). The reaction mixture was heated to 100 C. externally with steam and stirred slowly under a nitrogen gas atmosphere overnight. About 12 liters of water was added to the mixture to dissolve some inorganic salt precipitate. The layers were separated and organic layer was distilled under reduced pressure to remove about 18 liters of butanol and water. To the residue was added 1.5 liters of methanol and the resulting mixture was stirred slowly while cooling down to room temperature. The white solid was collected by filtration, rinsed twice with 700 ml portions of methanol and dried in a vacuum oven to give 4.2 kg (75%) of product, m.p. 107-109
With sodium methylate; In water; isopropyl alcohol;
EXAMPLE 8 N-benzhydryl-2,2-dimethoxy-acetamide Into a 50 ml. round-bottomed flask equipped with a magnetic stirrer and surmounted by a bent tube leading to a sulfuric acid trap, there are introduced 3.5 g. (0.019 mole) benzhydrylamine, 2.68 g (0.02 mole) methyl 2,2-dimethoxy-acetate and 1.5 g. (0.03 mole) sodium methylate. The reaction mixture is stirred for 90 minutes. The reaction is slightly exothermal and the reaction mixture becomes colored. 40 ml. of a mixture of isopropanol and water are added and the mixture is left to crystallize in the cold. Crystals are thus formed which are filtered off and recrystallized from petroleum ether. There are obtained 3.3 g. (61% of theory) N-benzhydryl-2,2-dimethoxyacetamide in the form of fine white needles. A sample for analysis is obtained by sublimation at 70 C./0.03 mm.Hg. and recrystallization from petroleum ether. Yield without the use of sodium methylate: nil Yield with the use of sodium methylate: 61% of theory The product melts at 74.6-77 C. Infrared spectroscopy (KBr) (cm-1): 3340 (NH), 2870 (OCH3), 1655 + 1525 (CONH), 1115 + 1060 (CO), 690 NMR (CDCl3): 7.2 (11H, singlet, 2 C6 H5 + NH, Ha); 6.23 (1H, doublet, J = 8Hz, Hb); 4.7 (1H, singlet, Hc); 3.36 (6H, singlet, Hd) STR13 Mass spectrum: m/e 285 (M+), 253 (--CH3 OH) (M+ 225), 222 (--OCH3), 182 (amine) 167 (tropylium), 121, 104, 75, 47, M* 29.5 Analysis: C17 H19 NO3 (M.W. 285.346): calculated: C 71.55%; H 6.71%; N 4.90%; found: 71.50%; 6.74%; 4.86%
With sodium sulfate; triethylamine; In dichloromethane; at 20℃; for 1h;
Preparation of Amino Acids Method A: A 100-mL round-bottomed flask containing a stir bar was charged with Na2SO4 (8.0 g) and CH2Cl2 (40 mL). Trimethylacetaldehyde (8) (7.65 mL, 52 mmol, 1.3 equiv) and aminodiphenylmethane (9) (6.89 mL, 40 mmol, 1.0 equiv) were added sequentially via syringe while stirring. The flask was capped with a plastic stopper, and the mixture was stirred at room temperature. The mixture became cloudy after 5 min. After stirring for 1 h, the solution was decanted into a 200-mL round-bottomed flask, rinsing with CH2Cl2 (4*5 mL) and concentrated to 8-10 mL using a rotary evaporator. The flask was then maintained at 1 torr for 10 min. A 5-cm diameter fritted disk funnel was filled with a 2-cm high layer of silica gel. The funnel was rinsed with a solution of 20:1:0.5 hexanes/Et2O/triethylamine (50 mL) under reduced pressure, followed by a solution of 20:1 hexanes/Et2O (50 mL). The oil prepared above was dissolved in 20:1 hexanes/Et2O (25 mL) and rinsed through the frit into a tared 250-mL round-bottomed flask under reduced pressure, rinsing with 20:1 hexanes/Et2O (4*25 mL). The mixture was concentrated (30 torr?1 torr) to provide a clear, pale yellow oil that solidified into a white solid. The solid was broken up into approximately 1-cm diameter pieces using a spatula, and was maintained at 1 torr for another 15 min to provide N-(2,2-dimethyl propylidene)diphenylmethanamine (2a) as a white solid in approximately 98% 1H-NMR purity. The product was used in the next step without further purification. Yield: 9.93 g (39.6 mmol, 99%).
(i) Methyl 2-(2-(2-benzhydrylamino)-2-oxoethoxy)acetamido-5-bromobenzoate2.18 g (6.3 mmol) of 2-(2-(4-bromo-2-(methoxycarbonyl)phenylamino)-2-oxoethoxy)acetic acid obtained in Example 44-(i), 37 mg (0.51 mmol) of DMF, and 0.65 ml (7.56 mmol) of oxalyl chloride were stirred in 19 ml THF at 0 C. for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure and dried. 1.09 ml (6.3 mmol) of diphenylmethylamine was added to this residue, and the mixture was stirred in 19 ml of DMA at room temperature overnight. After completion of the reaction, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution, and the obtained organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography to give 2.55 g of methyl 2-(2-(2-benzhydrylamino)-2-oxoethoxy)acetamido-5-bromobenzoate (yield: 79%).1H-NMR (CDCl3) delta: 3.33 (3H, s), 4.20 (2H, s), 4.24 (2H, s), 6.48 (1H, d, J=9.1 Hz), 7.21-7.35 (10H, m), 7.65 (1H, dd, J=9.0, 2.4 Hz), 7.88 (1H, d, J=9.1 Hz), 8.13 (1H, d, J=2.4 Hz), 8.69 (1H, d, J=9.0 Hz), 11.9 (1H, s).
General procedure: At r.t., benzhydrylamine (18.3 g, 100 mmol) was added to a solution of the aldehyde (100 mmol) in EtOH (400 mL) and the reaction mixture was stirred overnight. Product precipitation was observed in most cases and could be further promoted by cooling with an ice bath or by adding a few drops of water. The solids were filtered off, washed with cold Et2O and recrystallised from EtOH to yield analytically pure imines.
In methanol; at 20℃; for 24h;
General procedure: Furfural (2.5 mmol, 0.24 g) was dissolved in methanol (15 mL) and to this solution, aniline derivative 1a-e (2.5 mmol) was added. The mixture was stirred at room temperaturefor 24 h, then solvent was evaporated to obtain almost pure Schiff base (1a-e).
In dichloromethane; at 20℃;
General procedure: The arylaldehyde 2a or 2b (0.50 mol) was added to a solution ofbenzhydrylamine (0.50 mol) in CH2Cl2 (230 mL) at room temperature.After completion of the reaction, (TLC), the solvent was removed underreduced pressure. The residue was dissolved in DMSO (850 mL) andheated to 40 C and portions of potassium tert-butoxide (0.13 mol) wereadded over 10 min with stirring. After 10 min, the reaction mixture washeated to 55 C for about 12 h, evaporated in vacuo and treated with H2SO4(1.40 M, 885 mL) at room temperature. After completion of the hydrolysis(TLC), the aqueous phase was extracted with CH2Cl2, and separated intoorganic and aqueous layers. The aqueous phase was adjusted to a basic pHby sodium hydroxide solution (40%), extracted with CH2Cl2 and then theorganic phase was distilled under reduced pressure to yield the expectedproducts 5a and 5b.
To a solution of 1 IB (0.63g, 3.3mmol) in acetonitrile (10 mL) was added aminodiphenylmethane (0.7 Ig, 3.9mmol), and the solution was heated to 80 0C for 2.5 hours. The reaction was allowed to cool to room temperature, then partitioned between EtOAc (4OmL) and 5% aqueous citric acid (40 mL). The EtOAc layer was separated, washed with H2O, washed with saturated aqueous NaHCO3, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to yield compound 11C as a tan solid (0.86g, 78%).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;Cooling with ice;
General procedure: To a stirred solution of thiophosgene (15.18 g, 132 mmol) in dried CH2Cl2 (150 mL) cooled in anice-water bath was added dropwise a solution prepared by dissolving 2c-2k, 2m-2n or 2ha-2hi (120mmol) and DIPEA (46.53 g, 360 mmol) in dried CH2Cl2 (150 mL). The resulting mixture was stirredfor 1 h in an ice-water bath and for another 1 h at room temperature. The reaction mixture was thenpoured into ice-water (300 mL) while stirring. The organic phase was separated, and the aqueousphase was back-extracted with CH2Cl2 (200 mL × 2). The combined organic phases were washedsuccessively with 5% hydrochloric acid (100 mL × 2; for 3f and 3n, the washing with 5% hydrochloricacid is omitted) and saturated brine (300 mL), dried (Na2SO4) and evaporated on a rotary evaporatorto give a residue, which was purified by column chromatography to afford 3c-3k, 3m-3n or3ha-3hi.
Example 3: 1,1 -diphenyl-Lambda/-((2-phenylquinolin-7-yl)methylene)methanamine; 7-Bromo-2-phenyl-quinoline (40.0 g, 0.141 mol) was added to a 1000 mL three-neck round bottom flask (rbf). The flask was degassed and filled with N2. THF (400 mL) was added. The solid dissolved. The flask was kept in a cooling bath (at -62 0C). The off-white solid crashed out at low temperature. 1.4 M of sec-butyllithium in cyclohexane (125.7 rnL, 0.176 mol) was added within 15 min, and the internal temperature was kept at around -50 0C. After addition was complete, the reaction was stirred at -50 0C (internal temperature) for 5 min. DMF (13.6 mL, 0.176 mol) was added within 10 min and the internal temperature was always kept at around -50 0C and the cooling bath was kept at around at -62 0C. After 35 min, the reaction was quenched by NF^Cl/water (200 mL), and EtOAc (200 mL) was added. The organic layer was washed with water (300 mL x 2) and brine (150 mL), dried over MgSO4, filtered and concentrated in vacuo. After evaporating to almost dryness, EtOAc (200 mL) was added and heated in a 70 0C oil bath to dissolve the solid. Half of the aminodiphenylmethane (26.2 mL, 0.148 mol) was added and the reaction was stirred at 58 0C (internal temperature) for 5 min. The reaction was seeded and the solid came out of solution slowly. After 5 min, the remaining aminodiphenylmethane was added within 3 min. The oil bath temperature was kept at 70 0C, the internal temperature increased to 67 0C. After 10 min, the reaction mixture was cooled in an ice bath. The off-white solid was collected by vacuum filtration and dried in vacuo at 40-60 0C for 2 hours. The title compound was isolated as an off-white solid (37.42 g, 67% yield).
With triethylamine; In butan-1-ol; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation;
2-Chloro- V-(2,2-diphenylethyl)-9-methyl-9H-purin-6-amine (16i). To a solution of 15b (68.0 mg, 0.335 mmol) in n-BuOH (1.0 mL) was added aminodiphenylmethane (66.2 mg, 0.350 mmol) and triethylamine (55.1 mg, 0.539 mmol) under an N2 atmosphere. The reaction mixture was heated under microwave irradiation at 120 C for 30 min. n-BuOH was evaporated, and the residue was dissolved in EtOAc and washed with water. The aqueous phase was further extracted with EtOAc, and the combined organic extracts were dried (MgS04) and concentrated to yield a colorless solid. The solid was resuspended (hexanes/Et20, 2: 1), filtered, triturated (hexanes/Et20, 2: 1), and dried under high-vacuum to yield 16i (83.0 mg, 0.237 mmol, 71%) as an off-white, crude solid that was used without further purification: Characteristic signals: NMR (CDCI3, 600 MHz) delta 7.40-7.20 (m, 12 H), 6.75 (bs, 1 H), 3.69 (s, 3 H); 13C NMR (CDCb, 150 MHz) delta 154.5, 154.2, 150.7, 141.3, 140.9, 128.5, 127.6, 127.4, 118.4, 57.3, 29.9.
trans-N-benzhydryl-4-phenylcyclohexanamine[ No CAS ]
cis-N-benzhydryl-4-phenylcyclohexanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19.0%; 75%
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 1.5h;Cooling with ice;
Cis-4-phenylcyclohexanamine -benzhydryl-4-phenylcyclohexanamine[00190] To a solution of 4-phenylcyclohexanone (500 mg, 2.87 mmol) and diphenylmethanamine (526 mg, 2.87 mmol) in DCE (4 mL) at 0 C was slowly added sodium triacetoxyborohydride (912 mg, 4.30 mmol) portionwise. A white suspension formed and was stirred for 5 min before the ice-water bath was removed. The reaction mixture was stirred at rt for 1.5 h, quenched with water carefully, then saturated aHC03 was added carefully and the aqueous layer was extracted with DCM three times. The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography (hexane/EtOAc) to give Intermediate 14A (734 mg, 2.15 mmol, 75.0 % yield) and trans-N-benzhydryl-4-phenylcyclohexanamine (191 mg, 0.560 mmol, 19.0 % yield). HPLC/MS (Method L), retention time = 1.76 min, [M+l 342.1; 'H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.37 (4 H, d, J=7.33 Hz), 7.23 - 7.31 (6 H, m), 7.11 - 7.23 (5 H, m), 4.91 (1 H, s), 2.80 - 2.88 (1 H, m), 2.46 - 2.56 (1 H, m), 1.74 - 1.90 (4 H, m), 1.60 - 1.70 (2 H, m), 1.47 - 1.59 (2 H, m).
19.49%; 74.9%
With sodium tris(acetoxy)borohydride; In monoethylene glycol diethyl ether; at 0℃;
00194] To a solution of 4-phenylcyclohexanone (500 mg, 2.87 mmol) and diphenylmethanamine (526 mg, 2.87 mmol) in DCE (4 mL) at 0 C was added sodium triacetoxyborohydride (912 mg, 4.30 mmol) by portions slowly. A white suspension resulted and was stirred for 5 min before the ice-water bath was removed. The reaction was stirred at rt for 1.5 h. The reaction was quenched with water carefully, then saturated NaHCC^ was added carefully and the aqueous was extracted with DCM (3x). The organic layers were combined, washed with brine, dried over a2S04, and concentrated. The residue was purified by ISCO flash chromatography (0-100% hexane/EtOAc) to give Intermediate 30A (734 mg, 2.149 mmol, 74.9 % yield) and trans-N-benzhydryl-4-phenylcyclohexanamine (191 mg, 0.559 mmol, 19.49 % yield), LC-MS (ESI) m/z 342.1 (M+H), RT = 1.76 min (Method B). ¾ NMR (400 MHz, chloroform-d) delta ppm 7.37 (4 H, d, J=7.33 Hz), 7.23 - 7.31 (6 H, m), 7.1 1 - 7.23 (5 H, m), 4.91 (1 H, s), 2.80 - 2.88 (1 H, m), 2.46 - 2.56 (1 H, m), 1.74 - 1.90 (4 H, m), 1.60 - 1.70 (2 H, m), 1.47 - 1.59 (2 H, m
19.49%; 74.9%
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 0℃; for 1.5h;Cooling with ice;
Intermediate 14A. Cis-N-benzhydryl-4-phenylcyclohexanamine and Intermediate -N-benzhydryl-4-phenylcyclohexanamine. [00169] To a solution of 4-phenylcyclohexanone (500 mg, 2.87 mmol) and diphenylmethanamine (526 mg, 2.87 mmol) in DCE (4 mL) at 0 C was added sodium triacetoxyborohydride (912 mg, 4.30 mmol) by portions slowly. A white suspension resulted and was stirred for 5 min before the ice-water bath was removed. The reaction was stirred at rt for 1.5 h. The reaction was quenched with water carefully, then saturated aHC03 was added carefully and the aqueous layer was extracted with DCM (3x). The organic layers were combined, washed with brine, dried over Na2S04, and concentrated. The residue was purified by ISCO flash chromatography (0-100% hexane/EtOAc) to give cis-N-benzhydryl-4- phenylcyclohexanamine (Intermediate 14A) (734 mg, 2.15 mmol, 74.9 % yield) LC- MS (ESI) m/z 342.1 (M+H), RT = 1.76 min (Method B); XH NMR (400 MHz, CHLOROFORM-d) delta ppm 7.37 (4 H, d, J=7.33 Hz), 7.23 - 7.31 (6 H, m), 7.11 - 7.23 (5 H, m), 4.91 (1 H, s), 2.80 - 2.88 (1 H, m), 2.46 - 2.56 (1 H, m), 1.74 - 1.90 (4 H, m), 1.60 - 1.70 (2 H, m), 1.47 - 1.59 (2 H, m); and trans-N-benzhydryl-4- phenylcyclohexanamine (Intermediate 14B) (191 mg, 0.559 mmol, 19.49 % yield), LC-MS (ESI) m/z 342.1 (M+H), RT = 1.76 min (Method B).
19.5%; 74.9%
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 0 - 20℃; for 1.5h;
Intermediate 1A. Czs-N-benzhydryl-4-phenylcyclohexanamine: To a solution of 4-phenylcyclohexanone (500 mg, 2.87 mmol) and diphenylmethanamine (526 mg, 2.87 mmol) in DCE (4 mL) at 0 C was added sodium triacetoxyborohydride (912 mg, 4.30 mmol) by portions slowly. A white suspension resulted and was stirred for 5 min before the ice-water bath was removed. The reaction was stirred at rt for 1.5 h. The reaction was quenched with water carefully, then saturated NaHCC^ was added carefully and the aqueous portion was extracted with DCM (3 x). The organic layers were combined, washed with brine, dried over a2S04, filtered and concentrated. The residue was purified by flash chromatography (0-100% hexane/EtOAc) to give Intermediate 1A (734 mg, 2.15 mmol, 74.9% yield) and trans-N-benzhydryl-4-phenylcyclohexanamine (191 mg, 0.559 mmol, 19.5% yield), LC-MS (ESI) m/z 342.1 (M+H), RT = 1.76 min (Method B). NMR (400 MHz, chloroform-d) delta ppm 7.37 (4 H, d, J=7.33 Hz), 7.23 - 7.31 (6 H, m), 7.11 - 7.23 (5 H, m), 4.91 (1 H, s), 2.80 - 2.88 (1 H, m), 2.46 - 2.56 (1 H, m), 1.74 - 1.90 (4 H, m), 1.60 - 1.70 (2 H, m), 1.47 - 1.59 (2 H, m).
With dihydroxy-methyl-borane; In water; toluene; for 8h;Reflux; Molecular sieve;
EXPERIMENTAL EXAMPLES 62 to 82] [0047] The amide condensation between various alpha-hydroxycarboxylic acids and various amines was performed with use of methylboronic acid catalyst. The synthesis procedures were similar to those in Experimental Example 59. The results are described in Table 7 and Table 8. The amide bond formation in (S)-3-phenyllactic acid took place without any racemization, and the corresponding amide was obtained in a high yield (Experimental Examples 62 to 68). The amide condensation of (R)-mandelic acid proceeded favorably but slight racemization occurred (Experimental Examples 69 to 75). This racemization was suppressed to some degree by using dichloroethane (boiling point 83C) as the reaction solvent. The condensation reactions involving high-reactive amines proceeded favorably even when the amount of the catalyst was decreased to 1 mol%. In the amide condensation reactions involving 2-hydroxyoctanoic acid, the corresponding amides were obtained in high yields (Experimental Examples 76 to 79). The amide condensation reactions between 2-hydroxyisobutyric acid having a quaternary carbon atom at the alpha position and a primary amine also afforded the corresponding amides in a high yield (Experimental Examples 80 to 82). Experimental Examples 62 to 82 correspond to Inventive Examples.
(3) Synthesis of N-(9-fluorenylmethoxycarbonyl)-2,3,4-tris(2,3-dihydrophytyloxy)benzhydryl amine Under an argon atmosphere, 2,3,4-tris(2,3-dihydrophytyloxy)benzhydryl alcohol (3.56 g, 3.31 mmol) synthesized in Preparation Example 24-(2) and <strong>[84418-43-9]9-fluorenylmethyl carbamate</strong> (1.42 g, 5.96 mmol) were dissolved in anhydrous toluene (40 ml) at 50 C., methanesulfonic acid (64 mul, 993 mumol) was added and the mixture was stirred at 100 C. for 2 hr. The reaction mixture was allowed to cool to room temperature, washed with 5% aqueous sodium hydrogen carbonate solution (20 ml) and saturated brine (20 ml), and dried over sodium sulfate. The solvent in the filtrate was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-90/10 (v/v)). The object fractions were collected and concentrated to give the title compound (4.00 g, 93.3%) as an oil.
With copper(l) iodide; 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine; oxygen; In toluene; at 100℃; under 760.051 Torr; for 18h;
General procedure: Copper(I) iodide (1.9 mg, 0.01 mmol) and1,5,7-triazabicyclo[4.4.0] dec-5-ene (TBD, 7.0 mg, 0.05 mmol) was added to a solution of p-OMe-benzyl amine 1a (131 mul, 1.0 mmol) and thiophenol 1b (52 mul, 0.5 mmol) in toluene(0.5 M, 1 ml). A slow stream of O2 was passed through this solution for 10 min. Then, thereaction mixture was stirred at 100 C for 18 h under O2 atmosphere. The solvent wasremoved under vacuum, and the residue was purified by flash silica gel columnchromatography by using 1% ether/hexane as an eluent to obtain sulfenylimine 1c (82.7 mg,68 %).
(2S)-1-(diphenylmethyl)-2-methylazetidinium-[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
Assemble a 2000 mL 3-neck RBF with an addition funnel, nitrogen inlet and a thermometer adapter. Purge the vessel with nitrogen and add (3R)-butane-1,3-diol (25 g, 277.4 mmol), DIPEA (127 ml, 731 mmol) and ACN (556 ml). Cool to -30 C. Add trifluoromethanesulfonic anhydride (101 mL, 601 mmol) dropwise over 3 h such that the internal temperature is maintained between -35 and -30 C. After the completion of the addition, stir for 10 min at -35 to -30 C. Add trifluoromethanesulfonic anhydride (1.9 mL, 11 mmol) dropwise over 5 min such that the internal temperature is maintained between -35 and -30 C. After the completion of the addition, stir for 10 min at -35 to -30 C. Add DIPEA (127 mL, 731 mmol) dropwise over 15 min such that the internal temperature is maintained between -35 and -30 C. After the completion of the addition, stir for 10 min at -35 to -30 C. In a separate flask under nitrogen, dissolve aminodiphenylmethane (48.0 mL, 270 mmol) in ACN (49 mL, 935 mmol) and transfer the resulting solution to the addition funnel. Add the amine solution to the cold triflate dropwise over 40 min such that the internal temperature is maintained between -20 to -35 C. After the completion of the addition, stir for 30 min at -35 to -30 C. Transfer the reaction to a water bath and allow it to slowly warm over 30 min. Remove the bath and allow the reaction to warm to RT over 30 min. Transfer the vessel to a heating mantle and warm the reaction to 45 C. for 30 min, then cool to RT. Pour the resulting mixture into 1200 mL of water and extract with toluene (400 mL×3). Combine the extracts, wash with water, sat. aq. NaCl solution, dry over anhydrous Na2SO4, filter and concentrate on a rotary evaporator. Dry the material under vacuum overnight. Dissolve the residue in DCM (400 mL). Prepare a silica pad on a fritted funnel and equilibrate it with 1:1 heptane/EtOAc. Load the product solution onto the silica pad and wash with 1600 mL of 1:1 heptane/EtOAc. Concentrate the filtrate to give a red oil. Dissolve the oil in MeOH (250 mL) and place the flask in a water bath (10 C.). Add L(-)-camphorsulfonic acid (61.6 g, 265 mmol) portion-wise keeping the internal temperature below 20 C. Stir the resulting mixture for 15 min and then concentrate on a rotary evaporator to give a brown foam. Dry the foam on a vacuum pump for 2 h. Dissolve the foam in 130 mL of DCM. Attach an addition funnel to the flask. Use the funnel to slowly add 1100 mL of EtOAc to the stirring solution. Transfer the resulting mixture to a 4000 mL beaker and stir open to the atmosphere overnight. Cool the beaker in an ice bath for 10 min. Collect the precipitate in a fritted funnel by vacuum filtration washing with a minimal amount of ice-cold EtOAc. Dry the solid on the frit for 2 h. Dissolve the resulting white solid in a minimal amount of DCM, transfer to a 2000 mL beaker and then dilute slowly with EtOAc until the clear solution starts to become cloudy. Stir the suspension for 4 h while open to the atmosphere. Collect the solids by vacuum filtration using a fritted funnel and dry on the frit overnight to give the title compound (111.8 g, 238.06 mmol, 86% Yield) as a white solid. 1H NMR (400 MHz, d6-DMSO): 10.54-10.47 (m, 1H), 7.61 (d, J=7.3 Hz, 5H), 7.47-7.37 (m, 7H), 5.85 (d, J=10.3 Hz, 1H), 4.68-4.61 (m, 1H), 3.91-3.83 (m, 2H), 3.37 (s, 8H), 2.99 (d, J=14.6 Hz, 1H), 2.77-2.68 (m, 1H), 2.51-2.44 (m, 4H), 2.30-2.16 (m, 2H), 1.91-1.81 (m, 2H), 1.42-1.28 (m, 3H), 1.08 (s, 3H), 1.01 (d, J=6.6 Hz, 3H), 0.77 (s, 4H); >98% ee [HPLC: Chiralcel OJ (10 cm×4.6 mm, 5 [mum), 5 mL/min, 40 C. isocratic 10% EtOH (0.2% iPrNH2)/CO2].
65%
A solution of R-(-)-1,3-butanediol (20.0 g, 222 mmol) and DIPEA (101.5 mL, 585.0 mmol) in acetonitrile (444 mL) was cooled to -30 C. and treated with trifluoromethanesulfonic anhydride (81.2 mL, 480 mmol) dropwise via addition funnel over 90 min, maintaining the internal reaction temperature between -30 and -35 C. After the addition was complete, the reaction mixture was stirred for 10 min at -30 C. and then treated with additional trifluoromethanesulfonic anhydride (1.5 mL) dropwise and stirred at -30 C. for an additional 15 min. The reaction mixture was then treated with additional DIPEA (101.5 mL, 585.0 mmol) over the course of 15 min while maintaining the internal temperature at -30 C. After an additional 10 min at -30 C. the reaction mixture was treated with a solution of benzhydrylamine (38 mL) in acetonitrile (40 mL) dropwise over 30 min via an addition funnel, maintaining the internal reaction temperature below -30 C. The reaction mixture was stirred at -30 C. for 20 min then placed in an ice water bath for 30 min. The reaction was then stirred at rt for 30 min, followed by heating at 45 C. for 30 min. The reaction mixture was cooled to rt, poured into deionized water (900 mL) and extracted with toluene (1 L). The aqueous phase was back-extracted with toluene (300 mL) and the combined organic layers were washed with water (2*250 mL), dried over Na2SO4, filtered and evaporated. The crude product was dissolved in DCM (300 mL) and loaded onto a plug of silica gel (300 mL SiO2, preflushed with 1:1 heptane/EtOAc). The plug was flushed with 1:1 heptane/EtOAc (1.2 L) and the filtrate was evaporated to give a red oil (50.2 g). The crude product was dissolved in methanol (200 mL), placed in a water bath at 10 C., and treated with [(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid (49 g) in batches over 5 minutes. The solution was stirred at rt for 2 h, the solvent was evaporated and the solids were dried under high vacuum for 15 h to give a solid (99.2 g). The solid was dissolved in DCM (100 mL) and stirred at rt for 10 min to give a dark solution. EtOAc (850 mL) was added slowly with stirring and solids precipitated from solution after ?5 min. The suspension was stirred at rt for 2 h, and the solids were collected by filtration and washed with EtOAc (50 mL). The solids were dissolved in DCM (100 mL) and EtOAc (700 mL) was added. The mixture was stirred at rt and solids immediately precipitated from solution. The suspension was stirred at rt for 15 h, then the solids were collected by filtration, washed with EtOAc (50 mL) and dried under reduced pressure to give the title compound (66.7 g, 65% yield) as a white solid. 1H NMR (500 MHz, CD3OD) delta: 7.54-7.59 (m, 4H), 7.43-7.53 (m, 6H), 5.67 (s, 1H), 4.69-4.76 (m, 1H), 3.97-4.02 (m, 2H), 3.36 (d, 1H), 2.81 (d, 1H), 2.70-2.75 (m, 1H), 2.58-2.64 (m, 1H), 2.31-2.39 (m, 2H), 2.03-2.09 (m, 2H), 1.91 (d, 1H), 1.62-1.66 (m, 1H), 1.41-1.47 (m, 1H), 1.16 (s, 3H), 1.11 (d, 3H), 0.88 (s, 3H); Elemental analysis: Calculated for C27H35NO4S: C=69.05%, H=7.51%, N=2.98%; Found: C=68.90%, H=7.59%, N=2.91%.
A mixture of benzhydrylamine (0.50 mol), CH3CN (838 mL), <strong>[40412-06-4]2-(2-thienyl)ethyl toluene-p-sulfonate</strong> 6a (0.50 mol) and Na2CO3 (0.91 mol) was heatedto 70 C. After completion of the reaction, the reaction mixture was cooled,filtered and evaporated in vacuo. The residue was dissolved in benzene(1.03 L) and stirred at room temperature for 10 min, under a stream of N2,and then portions of DDQ (1.09 mol) were added over 10 min with stirring.The reaction mixture was heated under reflux for 5 h, evaporated in vacuoand treated with H2SO4 (1.40 M, 885 mL) at room temperature. Aftercompletion of the hydrolysis, the aqueous phase was extracted with CH2Cl2,followed by separation of organic and aqueous layers. The aqueous phasewas adjusted to a basic pH by sodium hydroxide solution (40%), extractedwith CH2Cl2 and then the organic phase was distilled under reducedpressure to yield the expected product 9a. 2-Thiophenylethylamine (9a): Colourless liquid; yield 91%; FTIR (KBr)(nmax cm-1): 3369, 3285 (N-H); 1H NMR (400 MHz, CDCl3): delta 7.11 (m,1H), 6.94-6.90 (m, 1H), 6.81 (s, 1H), 2.94 (m, 4H), 1.24 (s, 2H).
General procedure: A mixture of benzhydrylamine (0.50 mol), CH3CN (838 mL), 2-(2-thienyl)ethyl toluene-p-sulfonate 6a (0.50 mol) and Na2CO3 (0.91 mol) was heatedto 70 C. After completion of the reaction, the reaction mixture was cooled,filtered and evaporated in vacuo. The residue was dissolved in benzene(1.03 L) and stirred at room temperature for 10 min, under a stream of N2,and then portions of DDQ (1.09 mol) were added over 10 min with stirring.The reaction mixture was heated under reflux for 5 h, evaporated in vacuoand treated with H2SO4 (1.40 M, 885 mL) at room temperature. Aftercompletion of the hydrolysis, the aqueous phase was extracted with CH2Cl2,followed by separation of organic and aqueous layers. The aqueous phasewas adjusted to a basic pH by sodium hydroxide solution (40%), extractedwith CH2Cl2 and then the organic phase was distilled under reducedpressure to yield the expected product 9a.
General procedure: A mixture of benzhydrylamine (0.50 mol), CH3CN (838 mL), 2-(2-thienyl)ethyl toluene-p-sulfonate 6a (0.50 mol) and Na2CO3 (0.91 mol) was heatedto 70 °C. After completion of the reaction, the reaction mixture was cooled,filtered and evaporated in vacuo. The residue was dissolved in benzene(1.03 L) and stirred at room temperature for 10 min, under a stream of N2,and then portions of DDQ (1.09 mol) were added over 10 min with stirring.The reaction mixture was heated under reflux for 5 h, evaporated in vacuoand treated with H2SO4 (1.40 M, 885 mL) at room temperature. Aftercompletion of the hydrolysis, the aqueous phase was extracted with CH2Cl2,followed by separation of organic and aqueous layers. The aqueous phasewas adjusted to a basic pH by sodium hydroxide solution (40percent), extractedwith CH2Cl2 and then the organic phase was distilled under reducedpressure to yield the expected product 9a.
With titanium(IV) isopropylate; C25H30NO2P*Ir; hydrogen; trifluoroacetic acid; In dichloromethane; at 50℃; under 45603.1 Torr; for 20h;Molecular sieve;
Compound 3 (0.2 mmol), 4 (0.26 mmol, 1.3 equiv.) and TFA (0.8 equiv.) in CH2Cl2 were added toa small vial, followed by Ti(OiPr)4 (0.06 mmol, 0.3 equiv.) and the Ir?L1 (1 molpercent) solution in CH2Cl2,which was in situ generated from stirring the solution of [Ir(cod)Cl]2 and L1 in CH2Cl2 for 20 min.The resulting vial was transferred to an autoclave, which was charged with 60 atm of H2, and stirredat 50 °C for 20 h. The reaction was quenched with aqueous sodium bicarbonate solution and extractedwith CH2Cl2 (2 mL 3). The organic phase was dried over anhydrous Na2SO4, concentrated andpurified by column chromatography (EtOAc/Hex) to give the chiral amine product 5, which wasanalyzed by chiral HPLC determine the enantiomeric excess (Yield: 93percent, ee: 96percent). 1H-NMR (500 MHz,Chloroform-d): 7.41?7.36 (m, 7H, ArH), 7.33?7.30 (m, 3H, ArH), 7.25 (t, J = 6.5 Hz, 1H, ArH), 7.14 (d,J = 6.5 Hz, 1H, ArH), 7.09 (s, 2H, ArH), 4.75 (s, 1H, ?CH(Ph)2), 3.76 (d, J = 6.0 Hz, 1H, ?CHCH3C6H4?),3.54 (dd, J = 5.5, 2H, ?CH2CH3), 3.13 (d, J = 35 Hz, 3H, ?NCH3), 1.44 (d, J = 6.5 Hz, 3H, ?CHCH3),1.31?1.27 (m, 3H, ?CH2CH3).
2.1 g of compound 1 was dissolved into 15mL of DMF, add 1.39 g of potassium carbonate, stir at 50 C with heating, add the drops of chlorotoluene (1.27g), heat to reflux, and react for 3 h, and then cool at 60 C, added the drops of Diphenyl methylamine (1.83g), heat again to reflux, carry on reaction for 1.5h, after the reaction, filter, filter cake washed with a small amount of DMF, the filtrate is distilled off under reduced pressure, add 15 g of ice water, stir, and filter and obtained a crude product, adding the crude product to methanol and then, it is made into salt with concentrated hydrochloric acid, by filter obtained hydrochloride salt of compound I-1, hydrochloride added into 6mL of water, adjust adjusting the pH at 8 with ammonia hydroxide and obtain a large amount of white powder, filter, dry, i.e. obtained Compound I-1 (2.15g, yield 48.1%).
2.1 g of compound 1 was dissolved into 15mL of DMF, add 1.39 g of potassium carbonate, stir at 50 C with heating, add the drops of alpha-chloroethylbenzene (1.41g), heat to reflux, and react for 3h, and then cool at 60 C, added the drops of Diphenyl methylamine (1.83g), heat again to reflux, carry on reaction for 1.5h, after the reaction, filter, filter cake washed with a small amount of DMF, the filtrate is distilled off under reduced pressure, add 15g of ice water, stir, and filter and obtained a crude product, adding the crude product to methanol and then, it is made into salt with concentrated hydrochloric acid, by filter obtained hydrochloride salt of compound I-2, hydrochloride added into 6mL of water, adjust adjusting the pH at 8 with ammonium hydroxide and obtain a large amount of white powder, filter, dry, i.e. obtained Compound I-2 (2.07g, yield 44.9%).
2.1 g of compound 1 was dissolved into 15mL of DMF, add 1.39 g of potassium carbonate, stir at 50 C with heating, add the drops of 3-phenylpropyl chloride (1.55g), heat to reflux, and react for 2h, and then cool at 60 C, added the drops of Diphenyl methylamine (1.83g), heat again to reflux, carry on reaction for 1.5h, after the reaction, filter, filter cake washed with a small amount of DMF, the filtrate is distilled off under reduced pressure, add 15g of ice water, stir, and filter and obtained a crude product, adding the crude product to methanol and then, it is made into salt with concentrated hydrochloric acid, by filter obtained hydrochloride salt of compound I-3, hydrochloride added into 6mL of water, adjust adjusting the pH at 8 with ammonium hydroxide and obtain a large amount of white powder, filter, dry, i.e. obtained Compound I-3 (3.34g, yield is 70.3%).
With triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20.0℃;Large scale;
Solid a,e-(t-Boc)2-(L)-lysine p-nitrophenol ester (2.787 kg, 5.96 mol) was added to a solution of aminodiphenylmethane (benzhydrylamine) (0.99 kg, 5.4 mol) in anhydrous acetonitrile (4.0 L), DMF (1 .0 L) and triethylamine (1 .09 kg) over a period of 15 min. The reaction mixture was agitated at 20C overnight. The reaction mixture was then warmed to 35C and aqueous sodium hydroxide (0.5 N, 10 L) was added slowly over 30 min. The mixture was stirred for an additional 30 min then filtered. The solid cake was washed with water and dried to a constant weight (2.76 kg, 5.4 mol) in 100% yield. 1 H NMR (CD3OD) d 7.3 (m, 10H, Ph Calc 10H); 6.2 (s, 1 H, CH-Ph2 Calc 1 H); 4.08 (m, a-CH, 1 H), 3.18 (br, e-CH2) and 2.99 (m, e-CH2 2H); 1.7-1 .2 (br, b,g,d-H2) and 1.43 (s, tBu) total for ,y,6-CH2 and tBu 25H Calc 24H. MS (ESI +ve) found 534.2 [M+Na]+ calc for C29H4i N305Na [M+Na]+ 534.7.
100%
With triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20.0℃;Large scale;
Solid a,e-(t-Boc)2-(L)-lysine p-nitrophenol ester (2.787 kg, 5.96 mol) was added to a solution of aminodiphenylmethane (benzhydrylamine) (0.99 kg, 5.4 mol) in anhydrous acetonitrile (4.0 L), DMF (1.0 L) and triethylamine (1.09 kg) over a period of 15 min. The reaction mixture was agitated at 20C overnight. The reaction mixture was then warmed to 35C and aqueous sodium hydroxide (0.5 N, 10 L) was added slowly over 30 min. The mixture was stirred for an additional 30 min then filtered. The solid cake was washed with water and dried to a constant weight (2.76 kg, 5.4 mol) in 100% yield. NMR (CD3OD) d 7.3 (m, 10H, Ph Calc 10H); 6.2 (s, 1H, CH-Ph2 Calc 1H); 4.08 (m, a-CH, 1H), 3.18 (br, e- CH2) and 2.99 (m, e-CH2 2H); 1.7-1.2 (br, b,g,d-OT2) and 1.43 (s, tBu) total for b,g,d-OT2 and tBu 25H Calc 24H. MS (ESI +ve) found 534.2 [M+Na]+ calc for CwHiiN^OsNa [M+Na]+ 534.7.
100%
With triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20.0℃;Inert atmosphere; Large scale;
Solid a,s-(t-Boc)2-(L)-lysine p-nitrophenol ester (2.787 kg, 5.96 mol) was added to a solution of aminodiphenylmethane (benzhydrylamine) (0.99 kg, 5.4 mol) in anhydrous acetonitrile (4.0 L), DMF (1 .0 L) and triethylamine (1 .09 kg) over a period of 15 min. The reaction mixture was agitated at 20C overnight. The reaction mixture was then warmed to 35C and aqueous sodium hydroxide (0.5 N, 10 L) was added slowly over 30 min. The mixture was stirred for an additional 30 min then filtered. The solid cake was washed with water and dried to a constant weight (2.76 kg, 5.4 mol) in 100% yield. 1 H NMR (CD3OD) d 7.3 (m, 10H, Ph Calc 10H); 6.2 (s, 1 H, CH-Ph2 Calc 1 H); 4.08 (m, a-CH, 1 H), 3.18 (br, s-CH2) and 2.99 (m, s-CH2 2H); 1.7-1 .2 (br, b,g,d-H2) and 1.43 (s, tBu) total for ,y,6-CH2 and tBu 25H Calc 24H. MS (ESI +ve) found 534.2 [M+Na]+ calc for C^i NsOsNa [M+Na]+ 534.7.
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