* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In tetrahydrofuran; ethyl acetate at 70℃; Inert atmosphere
To a solution of ketoxime (0.01 mol) in THF (10 mL) was added T3P (15 mol percent, 50percent soln in EtOAc) and the resulting reaction mixture was stirred at reflux for 1-4 h under nitrogen atmosphere. When the reaction was completed as confirmed by TLC, the solvent was removed under vacuum and the residue was diluted with water (20 mL). The product was extracted with ethyl acetate (2 .x. 20 mL) and the combined organic phase was washed with saturated NaHCO3 solution (1 .x. 10 mL) and brine. The organic phase was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford the desired amides in good purity.
48%
Stage #1: With sodium carbonate In water; acetone for 0.0833333 h; Stage #2: With p-toluenesulfonyl chloride In water; acetone at 20℃;
To a solution of intermediate I-49 (11 g, 50 mmol, 1.0 eq) in acetone (60 mL) was added a solution of Na2CO3 (16 g, 150 mmol, 3.0 eq) in water (80 mL) and the reaction mixture was stirred for 5 minutes. A solution of p-toluenesulfonyl chloride (14 g, 75 mmol, 1.5 eq) in acetone (20 mL) was added slowly and the reaction mixture was stirred at room temperature for 3 hours. Excess solvent was removed by evaporation, water was added and the reaction mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The crude reaction product was purified by silica gel column chromatography to give intermediate I-50 (5.0 g, 48percent). MS (ESI): m/z 159.1 (M+H+).
Intermediate 5 :tert-butyl 5-oxo-l,4-diazepane-l-carboxylate; To a stirred solution of commercially available l,4-diazepan-5-one (3.3 g, 28.94 mmol) in THF cooled to 10°C, was added di-tert-butyl dicarbonate(9.5 g, 43.42 mmol) and the resultant reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with n-pentane (50 mL) to afford the title compound as a solid (5.5 g, 89percent).:H NMR (300 MHz, DMSO) δ = 7.62 (s, 1H), 3.45-3.40 (m, 4H), 3.12-3.08 (m, 2H), 2.43-2.39 (m, 2H).
795 mg
With dmap In dichloromethane at 20℃; for 4 h;
6.01.22.04 5-Oxo-1,4-diazepane-1-carboxylic acid tert-butyl ester 3.26 g di-tert-butyl dicarbonate 160.5 mg DMAP were added to 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one in 50 mL dichlormethane. The reaction was stirred 4 h at RT and washed with 10percent citric acid, saturated sodium hydrogencarbonate and saturated sodium chloride solution and evaporated. The residue was purified by column chromatographie on silica gel (cyclohexane/ethylacetate: 1/1) and crystallized from diethylether/petrolether:3/1 to yield 795 mg of the desired product. Rt: 0.98 min (method B), (M+H)+: 215
795 mg
With dmap In dichloromethane at 20℃; for 4 h;
6.01.22.04 5-Oxo- 1 , 4-diazepane- 1 -carboxylic acid tert-butyl ester 3.26 g di-tert-butyl dicarbonate 160.5 mg DMAP were added to 2, 3, 6, 7-tetrahydro-(lH)-l, 4- diazepin-5 (4H)-one in 50 mL dichlormethane. The reaction was stirred 4 h at RT and washed with 10percent) citric acid, saturated sodium hydro gencarbonate and saturated sodium chloride solution and evaporated. The residue was purified by column chromatographie on silica gel (cyclohexane/ ethylacetate: 1/1) and crystallized from diethylether/petrolether: 3/1 to yield 795 mg of the desired product. Rt: 0.98 min (method B), (M+H)+: 215
With sodium hydroxide; sodium chloride In chloroform
Step B 1-(tert-Butoxycarbonyl)hexahydro-(5H)-1,4-diazepin-5-one A mixture of hexahydro-(5H)-1,4-diazepin-5-one acetic acid salt (200 mg, 1.15 mmol), di-tert-butyldicarbonate (277 mg, 1.27 mmol) and sodium chloride (460 mg, 7.93 mmol) in 2.0 mL of chloroform was stirred and 2.5 N aqueous sodium hydroxide (460 uL, 1.15 mmol) was added. The mixture was heated to reflux for 4 h, and then extracted with 3*10 mL of-ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, decanted and evaporated in vacuo to give 219 mg (89percent) of 1-(tert-butoxycarbonyl)hexahydro-(5H)-1,4-diazepin-5-one as a white solid. 1 H NMR (400 MHz, CD3 OD): δ3.60-3.53 (m, 4H), 3.28-3.25 (m, 2H), 2.61-2.56 (m, 2H), 1.47 (s, 9H). Mass spectrum: m/z=215 (M+1, 100percent). Anal. calcd for C10 H18 N2 O3: C, 56.32; H, 8.04; N, 13.14. Found: C, 55.92; H, 8.48; N, 13.00.
Reference：
[1] Patent: US6372733, 2002, B1, . Location in patent: Example 1
[2] Patent: US6043358, 2000, A,
Intermediate 5 :tert-butyl 5-oxo-l,4-diazepane-l-carboxylate; To a stirred solution of commercially available l,4-diazepan-5-one (3.3 g, 28.94 mmol) in THF cooled to 10°C, was added di-tert-butyl dicarbonate(9.5 g, 43.42 mmol) and the resultant reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with n-pentane (50 mL) to afford the title compound as a solid (5.5 g, 89percent).:H NMR (300 MHz, DMSO) delta = 7.62 (s, 1H), 3.45-3.40 (m, 4H), 3.12-3.08 (m, 2H), 2.43-2.39 (m, 2H).
795 mg
With dmap; In dichloromethane; at 20℃; for 4h;
6.01.22.04 5-Oxo-1,4-diazepane-1-carboxylic acid tert-butyl ester 3.26 g di-tert-butyl dicarbonate 160.5 mg DMAP were added to 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one in 50 mL dichlormethane. The reaction was stirred 4 h at RT and washed with 10percent citric acid, saturated sodium hydrogencarbonate and saturated sodium chloride solution and evaporated. The residue was purified by column chromatographie on silica gel (cyclohexane/ethylacetate: 1/1) and crystallized from diethylether/petrolether:3/1 to yield 795 mg of the desired product. Rt: 0.98 min (method B), (M+H)+: 215
795 mg
With dmap; In dichloromethane; at 20℃; for 4h;
6.01.22.04 5-Oxo- 1 , 4-diazepane- 1 -carboxylic acid tert-butyl ester 3.26 g di-tert-butyl dicarbonate 160.5 mg DMAP were added to 2, 3, 6, 7-tetrahydro-(lH)-l, 4- diazepin-5 (4H)-one in 50 mL dichlormethane. The reaction was stirred 4 h at RT and washed with 10percent) citric acid, saturated sodium hydro gencarbonate and saturated sodium chloride solution and evaporated. The residue was purified by column chromatographie on silica gel (cyclohexane/ ethylacetate: 1/1) and crystallized from diethylether/petrolether: 3/1 to yield 795 mg of the desired product. Rt: 0.98 min (method B), (M+H)+: 215
Step C 1-(tert-Butoxycarbonyl)-2,3,6,7-tetrahydro-5-methoxy-(1H)-1,4-diazepine Trimethyloxonium tetrafluoroborate (Meerwein's salt) (141 mg, 0.94 mmol) was added in one portion to a solution of <strong>[190900-21-1]1-(tert-butoxycarbonyl)hexahydro-(5H)-1,4-diazepin-5-one</strong> (200 mg, 0.94 mmol) in 2.0 mL of anhydrous methylene chloride. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned between 10 mL of saturated aqueous sodium bicarbonate and 20 mL of ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 3*10 mL of ethyl acetate. The combined ethyl acetate layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the organic solution was concentrated in vacuo to give 180 mg (85percent) of 1-(tert-butoxycarbonyl)-2,3,6,7-tetrahydro-5-methoxy-(1H)-1,4-diazepine as a yellow liquid. 1 H NMR(400 MHz, CD3 OD): delta3.58 (s, 3H), 3.53-3.45 (m, 6H), 2.63-2.59 (m, 2H), 1.46 (s, 9H). Mass spectrum: m/z=129.
100 mg
In dichloromethane; at 0 - 20℃;
6.01.22.05 5-Methoxy-2,3,6,7-tetrahydro-(1,4)-diazepine-1-carboxylic acid tert-butyl ester 77.5 mg trimethyloxonium tetrafluoroborate was added to 100 mg <strong>[190900-21-1]5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester</strong> in 2 mL dichlormethane at 0-5° C. The reaction mixture was stirred over night at RT. The reaction was washed with saturated sodium hydrogencarbonate solution and water and evaporated to yield 100 mg of the desired product. Rt: 0.79 min (method B), (M+H)+: 229
100 mg
In dichloromethane; at 0 - 20℃;
5-Methoxy-2, 3, 6, 7-tetrahydro-(l, 4)-diazepine-l-carboxylic acid tert-butyl ester 77.5 mg trimethyloxonium tetrafluoroborate was added to 100 mg 5-oxo-[l, 4] diazepane-1- carboxylic acid tert-butyl ester in 2 mL dichlormethane at 0-5 °C. The reaction mixture was stirred over night at RT. The reaction was washed with saturated sodium hydro gencarbonate solution and water and evaporated to yield 100 mg of the desired product. Rt: 0.79 min (method B), (M+H) : 229
With sodium hydroxide; sodium chloride; In chloroform;
Step B 1-(tert-Butoxycarbonyl)hexahydro-(5H)-1,4-diazepin-5-one A mixture of hexahydro-(5H)-1,4-diazepin-5-one acetic acid salt (200 mg, 1.15 mmol), di-tert-butyldicarbonate (277 mg, 1.27 mmol) and sodium chloride (460 mg, 7.93 mmol) in 2.0 mL of chloroform was stirred and 2.5 N aqueous sodium hydroxide (460 uL, 1.15 mmol) was added. The mixture was heated to reflux for 4 h, and then extracted with 3*10 mL of-ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, decanted and evaporated in vacuo to give 219 mg (89percent) of 1-(tert-butoxycarbonyl)hexahydro-(5H)-1,4-diazepin-5-one as a white solid. 1 H NMR (400 MHz, CD3 OD): delta3.60-3.53 (m, 4H), 3.28-3.25 (m, 2H), 2.61-2.56 (m, 2H), 1.47 (s, 9H). Mass spectrum: m/z=215 (M+1, 100percent). Anal. calcd for C10 H18 N2 O3: C, 56.32; H, 8.04; N, 13.14. Found: C, 55.92; H, 8.48; N, 13.00.
2-chloro-1,3-dimethyl imidazolium chloride[ No CAS ]
[ 150008-24-5 ]
[ 190900-21-1 ]
Yield
Reaction Conditions
Operation in experiment
To a solution of tert-butyl 4-(hydroxyimino)piperidinone carboxylate (32.70 g) in acetonitrile (250 mL), 2-chloro-1,3-dimethylimidazolynium chloride (30.96 g) was added, to which triethylamine (51 mL) was added dropwise at room temperature over 20 minutes. After dropwise addition, it was further stirred at room temperature for 30 minutes, and then water (50 mL) was added and stirred overnight. After the reaction mixture was diluted with ethyl acetate, the organic layer was separated. The organic layer was washed in 0.1 mol/L hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated saline in this order, and then dried on anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, dried under vacuum to obtain a crude title compound as a brown semi-solid compound. The product was used in the subsequent reaction without further purification.
To a solution of tert-butyl 5-oxo-1,4-diazaperhydroepin carboxylate in dichloromethane (400 mL), trimethyl tetrafluoroborate oxonium (33.86 g) was added and stirred overnight at room temperature. To the reaction mixture were added an aqueous solution of saturated sodium bicarbonate (200 mL) and water (100 mL), and then after stirring for 20 minutes, the aqueous layer was removed and the organic layer was dried on anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue dried under vacuum to obtain a crude title compound as a oily compound. The product thus obtained was used in the subsequent reaction without further purification.
The solid was dissolved in dichloromethane (20 mL), the solution was cooled to 0° C., and trifluoroacetic acid (10 ml, 0.1298 mol) was added. The reaction mixture was allowed to warm to room temperature. The solvent was evaporated under reduced pressure to afford 4-methyl-[1,4]diazepan-5-one monotrifluoroacetate as a brown oil ( 2.962 g, 0.01223 mol); 1H NMR (DMSO-d6, 400 MHz) delta 3.64 (m, 2H), 3.23 (m, 4H), 2.89 (s, 2H), 2.74 (m, 2H).
Preparation #11: 4-Methyl-[1,4]diazepan-5-one monotrifluoroacetate Di-tert-butyl dicarbonate (3.162 g, 0.01447 mol) was added to a suspension of <strong>[99822-50-1][1,4]diazepan-2-one</strong> (1.562 g, 0.01338 mol) in tetrahydrofuran (90 mL), and the mixture was stirred at ambient temperature for about 15 hours. The solvent was removed under reduced pressure. The residue was washed with ethyl acetate to give 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester as a white solid (2.866 g, 0.01338 mol).
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In tetrahydrofuran; ethyl acetate; at 70℃;Inert atmosphere;
To a solution of ketoxime (0.01 mol) in THF (10 mL) was added T3P (15 mol percent, 50percent soln in EtOAc) and the resulting reaction mixture was stirred at reflux for 1-4 h under nitrogen atmosphere. When the reaction was completed as confirmed by TLC, the solvent was removed under vacuum and the residue was diluted with water (20 mL). The product was extracted with ethyl acetate (2 .x. 20 mL) and the combined organic phase was washed with saturated NaHCO3 solution (1 .x. 10 mL) and brine. The organic phase was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford the desired amides in good purity.
48%
To a solution of intermediate I-49 (11 g, 50 mmol, 1.0 eq) in acetone (60 mL) was added a solution of Na2CO3 (16 g, 150 mmol, 3.0 eq) in water (80 mL) and the reaction mixture was stirred for 5 minutes. A solution of p-toluenesulfonyl chloride (14 g, 75 mmol, 1.5 eq) in acetone (20 mL) was added slowly and the reaction mixture was stirred at room temperature for 3 hours. Excess solvent was removed by evaporation, water was added and the reaction mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The crude reaction product was purified by silica gel column chromatography to give intermediate I-50 (5.0 g, 48percent). MS (ESI): m/z 159.1 (M+H+).
To a solution of tert-butyl 4-(hydroxyimino)piperidine-l-carboxylate (1 O g, 4.67 mmol) in acetone (20 mL) is added a solution OfNa2CO3 (1.48 g, 14 mmol) in water (20 mL), and the mixture is stirred for 5 minutes, then a solution of p- toluenesulfonyl chloride (1.33 g, 7 mmol) in acetone (5 mL) is added slowly. The reaction is stirred at room temperature for 3h, then the acetone is removed in vacuo, water is added, and the solution extracted with dichloromethane. The organic layer is dried over MgSO4, filtered, concentrated in vacuo, and purified by chromatography (6percent MeOH in dichloromethane) to afford the title compound.1H NMR (300 MHz, DMSO-ds): 1.41 (s, 9H), 2.40 (m, 2H), 3.09 (m, 2H), 3.39-3.44 (m, 4H), 7.62 (m, IH).
hexahydro-[1,4]diazepin-5-one; hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 2h;
A solution of HCl (20 mL, 2M in dioxane) is added to 5-oxo-l,4- diazepane-1-carboxylate (1.0 g, 4.67 mmol) and the reaction mixture is stirred at room temperature for 2h. The solvent is removed in vacuo to afford the title compound as the hydrochloride salt, which is used without further purification in the next step.1H NMR (300 MHz, DMSO-ds): 2.36 (m, 2H), 2.65-2.72 (m, 4H), 3.05 (m, 2H), 3.17 (s, IH), 7.47 (s, IH).
4-(4,4-dimethoxybutyl)-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester[ No CAS ]
(chloroform-a) δ[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In diethyl ether; chloroform; N,N-dimethyl-formamide; mineral oil;
5-Oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester To a suspension of 60percent sodium hydride in mineral oil (0.2 g, 5 mmole) in N,N-dimethylformamide (6 mL) was added <strong>[190900-21-1]5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester</strong> (1.0 g, 4.67 mmole). The reaction mixture was warmed at 50° C. for 5 minutes, and then at room temperature for 15 minutes. To the resulting solution was added 4-bromobutyraldehyde dimethyl acetal (0.99 g, 5 mmole). After the reaction mixture was stirred at room temperature for 16 hours, the solvent was removed, and the residue was partitioned between water and ethyl acetate. The organic phase was washed with water, dried (magnesium sulfate), and concentrated. The residue was dissolved in diethyl ether, and the suspension was filtered, and the filtrate was concentrated. Purification by silica gel chromatography, eluding with 2percent methanol in chloroform, gave 4-(4,4-dimethoxybutyl)-<strong>[190900-21-1]5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester</strong> (0.8 g,) as a heavy syrup. Nmr: (chloroform-a) delta (ppm) 1.49, s, (9H); 2.64, m, 3H; 3.32, s (3H); 4.37, m, (1H).
tert-Butyl 5-thioxo-l,4-diazepane-l-carboxylate tert-Butyl 5-oxo-l,4-diazepane-l-carboxylate, P4S10 (0.2 eq.), HMDO (2 eq.) and dichloromethane were combined and stirred magnetically at room temperature for 1 hour. The reaction mixture was then cooled to 00C and aqueous K2CO3 solution (1.26 mL of 5.3 M/mmol P4S10 taken) was added. A volume of acetone equal to one half of the reaction solvent was added to obtain a stirrable mixture, and the reaction mixture was stirred vigorously for 30 minutes at O0C. Volatiles were evaporated, water and ethyl acetate were added, layers were separated and the organic phase was washed with water and brine. The organic extract was dried over Nua2Spsi4 and evaporated, to afford the title EPO <DP n="76"/>compound. lH NMR (300 MHz, CDCI3) delta 8.7 (bs, 1 H), 3.68-3.60 (m, 4 H), 3.42-3.38 (m, 2 H), 3.15- 3.09 (m, 2 H), 1.43 (s, 9 H); MS (ES) Ci0Hi8N2O2S requires 230, found: 231 (M+H1).
4-(4-Chloro-benzyl)-5-oxo-[l,4]diazepane-l-carboxylic acid t-butyl ester5-Oxo-[l,4]diazepane-l-carboxylic acid t-butyl ester (70 mg, 0.33 mmol) was added to a solution of KHMDS (91 mg, 0.46 mmol) in dry THF (1.6 ml) at app. -70 0C. After stirring <n="39"/>for 15 min the/?-chlorobenzyl bromide (74 mg, 0.36 mmol) was added to the reaction mixture. The reaction was quenched after 6 h at -75 0C by addition OfH2O and diluted with CH2Cl2. The organic phase was washed with H2O and filtered through an Extrelut tube.(R)., which was rinsed with CH2Cl2. The resulting organic phase was evaporated and purified by flash chromatography (SiO2, CH2Cl2-EtOAc) to give 50 mg of the subtitled compound as a semisolid.1R NMR (CD3OD) delta 7.31 (m, 4H), 4.58 (s, 2H), 3.59 (m, 2H), 3.44-3.50 (m, 4H), 2.75 (m,2H), 1.45 (s, 9H).
The solid was dissolved in a mixture of tetrahydrofuran (80 mL) and N,N-dimethylformamide (30 mL), and sodium hydride (60% dispersion in mineral oil, 0.849 g, 0.0212 mol) was added. After about 1 hour, iodomethane (0.93 ml, 0.01835 mol) was added slowly to the reaction mixture. The mixture was stirred at ambient temperature for about 15 h, then the solvents were removed under reduced pressure. The residue was partitioned between saturated aqueous ammonium chloride solution (100 mL) and dichloromethane. The organic layer was separated and the aqueous layer was further extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate. The solvent was evaporated under reduced pressure to leave a dark brown solid which was purified by flash column chromatography on silica gel using ethyl acetate as a mobile phase to give 4-methyl-5-oxo (1,4]diazepane-1-carboxylic acid tert-butyl ester as a white solid (2.790 g, 0.0122 mol).
A) 5-Oxo-4-(3-piperidin-1-yl-propyl)-[1,4]diazepane-1-carboxylic Acid tert-butyl ester; A solution of 8.52 g (39.75 mmol) of <strong>[190900-21-1]5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester</strong> in 200 ml of DMA was treated at 0° C. with 2.60 g (59.6 mmol) of NaH (55percent dispersion in oil) in small portions. The reaction was stirred 1 h at this temperature, then the free 1-(3-chloropropyl)piperidine in 200 ml toluene was dropped in [49.62 g (250.42 mmol, 6.3 eq.) 1-(3-chloropropyl)piperidine hydrochloride were dissolved in 262 ml of 1 M aq. NaOH solution and extracted with toluene (200 ml). The organic phase was dried over Na2SO4]. The reaction was warmed up to RT and stirred overnight. After 2 h at 50° C. and cooling to RT, the reaction was neutralized with water (50 ml), evaporated and then dissolved in sat. aq. NaHCO3/Et2O. After reextraction with Et2O, the organic phase was dried (Na2SO4), evaporated and crystallized from pentane to yield 12.08 g (90percent) of the title compound as white crystals. MS: 340.2 (MH+).
90%
A) 5-Oxo-4-(3-piperidin-1-yl-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester; A solution of 8.52 g (39.75 mmol) of <strong>[190900-21-1]5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester</strong> in 200 ml of N,N-dimethylacetamide was treated at 0° C. with 2.60 g (59.62 mmol) of NaH (55percent in oil) in small portions. The reaction was stirred 1 h at this temperature, then the free 1-(3-chloropropyl)piperidine in 200 ml toluene was dropped in [49.6 g (250 mmol, 6.3 eq.) 1-(3-chloropropyl)piperidine hydrochloride were dissolved in 262 ml of 1 M aq. sodium hydroxide solution and extracted with toluene (200 ml). The organic phase was dried over Na2SO4]. The reaction was warmed up to room temperature and stirred over night. After 2 h at 50° C. and cooling to room temperature, the reaction was neutralized with water (50 ml), evaporated and then dissolved in sat. aq. sodium hydrogencarbonate solution/diethyl ether. After reextraction with diethyl ether, the organic phase was dried (Na2SO4), evaporated and crystallized from pentane to yield 12.08 g (90percent) of the title compound as white crystals. MS: 340.2 (MH+).
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;
A) 4-[2-(Methoxy-methyl-carbamoyl)-ethyl]-5-oxo-[1,4]diazepane-1-carboxylic Acid tert-butyl ester; To a cooled (0° C.) solution of <strong>[190900-21-1]5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester</strong> 5.9 g (28 mmol) and 4-bromo-N-methoxy-N-methyl-butyramide 5.4 g (28 mmol) in DMF (220 ml) was added NaH 1.3 g (30 mmol, 55percent dispersion in oil), the mixture allowed to reach RT and the mixture stirred for a further 2 h. The reaction was then concentrated, the residue redissolved in EtOAc and washed with 10percent aq. KHSO4solution, brine, dried (MgSO4) and concentrated affording the title compound 9.1 g (quant) as white foam. MS: 330.3 (MH+).
With trifluoroacetic acid; In dichloromethane; at 20℃; for 3h;
Intermediate I-50 (2.1 g, 10 mmol, 1.0 eq) was dissolved with dichloromethane (20 mL) and neat TFA (4 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and excess solvent and TFA were removed by evaporation. The resulting crude intermediate I-51 (MS (ESI): m/z 115.1 (M+H+)), cyclobutanone (1.1 g, 15 mmol, 1.5 eq) and acetic acid (0.5 mL, 0.8 eq) were dissolved in dichloromethane (20 mL) and the reaction mixture was stirred at room temperature for 60 minutes. Solid NaBH(OAc)3 (4.2 g, 20 mmol, 2.0 eq) was added and the reaction mixture was stirred at room temperature for additional 3 hours. The reaction mixture was neutralized by adding an aqueous solution of K2CO3 and extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4, the solids were removed by filtration and the filtrate was concentrated by evaporation to give the crude intermediate I-52 (1.6 g, 98percent) as white solid that was used in the following reaction without further purification. 1H-NMR (400 MHz, CDCl3) delta: 6.15 (s, 1H), 3.30 (q, J=4.8 Hz, 2H), 2.81 (q, J=4.4 Hz, 111), 2.61-2.63 (m, 2H), 2.45-2.50 (m, 4H), 2.03-2.10 (m, 2H), 1.79-1.88 (m, 2H), 1.62-1.74 (m, 2H). MS (ESI): m/z 169.1 (M+H+).
STEP A: To a stirred solution of ter/-butyl 5-oxo-l,4-diazepane-l-carboxylate (1000 mg, 4.67 mmol) in dichloromethane (10 mL) was added trimethyloxonium tetrafluoroborate (690 mg, 4.67 mmol) under nitrogen and the reaction mixture was stirred for 16 hours. At this point, formic hydrazine (280 mg, 4.67 mmol) indichloromethane (8 mL) was added, and the reaction was stirred for an additional 16 hours. The reaction mixture was then concentrated under reduced pressure, resuspended in methanol (10 mL), and heated to reflux for 16 hours. The reaction mixture was concentrated and purified via flash chromatography on silica gel (0-50percent 2N NH3 in methanol in CH2C12) to afford 4,5,7,8-tetrahydro-l,2,3a,6-tetraaza-azulene-6-carboxylic acid tert-butyl ester (680 mg, 61percent yield). MS [m/z; (M+l)+]: 319.3
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 3h;
Intermediate 6 :tert-butyl 4-benzyl-5-oxo-l,4-diazepane-l-carboxylate; To a suspension of sodium hydride (874 mg, 36.44 mmol) in THF (20 mL) cooled to 0°C was added tert-butyl 5-oxo-l,4-diazepane-l-carboxylate (Intermediate 5) (5.2 g, 24.29 mmol) and benzyl bromide (6.23 g, 36.44 mmol). The reaction mixture was warmed to RT, and stirred for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate layer was washed with water (50 mL) and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by n-pentane washings (3 x 10 mL)afforded the title compound as a solid (6.2 g, 84percent).Eta NMR (300 MHz, CDCI3) delta = 7.33-7.24 (m, 5H), 4.61 (s, 2H), 3.62-3.58 (m, 2H), 3.39-3.36 (m, 4H), 2.74-2.71 (m, 2H), 1.44 (s, 9H).
3-methyl-5,6,8,9-tetrahydro-imidazo[1,2-a][1,4]diazepine-7-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
468 mg
In methanol; for 5h;Reflux;
6.01.35.02 3-methyl-5,6,8,9-tetrahydro-imidazo[1,2-a][1,4]diazepine-7-carboxylic acid tert-butyl ester 0.6 mL propargylamin was added to 429 mg <strong>[190900-21-1]5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester</strong> in 20 mL methanol. The reaction was refluxed 5 h and evaporated to give 468 mg of the desired product. (M+H)+: 252, Rt: 0.88 min (method J)
tert-butyl 4-(4-methoxybenzyl)-5-oxo-1,4-diazepane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
To a solution of <strong>[190900-21-1]tert-butyl 5-oxo-1,4-diazepane-1-carboxylate</strong> (1.0 g, 4.67 mmol) in DMF (18 mL)cooled at 0 C, NaH (60% in mineral oil, 280 mg, 7.0 mmol) was added and the mixture was stirred at rt for 45 mi 4-Methoxybenzylchloride (1.1 g, 7.0 mmol) and TBAI (172 mg, 0.46 mmol) were added and the mixture was heated at 55 C for 16 h. The reaction mixture was cooled at rt, water was added and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and the solvent was removed under vacuum. Purificationby flash chromatography, silica gel, gradient Hex to 100% EtOAc afforded the title compound (944 mg, 60% yield). ESl-MS m/z, 357.1 (M+Na).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
