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Structure of 52099-72-6 * Storage: {[proInfo.prStorage]}
* 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 sodium hydroxide In o-xylene at 130℃; for 7 h;
50 grams of o-phenylenediamine,90 g of ethyl acetoacetate and 5 g of sodium hydroxide were dissolved in 300 ml of o-xylene.Warming up to 130 ° C,The water was refluxed for about 7 hours.Cooled to 80 ° C,Wash twice with 100 ml of water,Cooled to 0 ° C,Precipitating a white solid,filter,Drying gives 65 grams of compound (DOM-2),The yield was 94percent.
87.9%
With potassium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene; ethanol for 2 h; Reflux
In a three-necked reaction flask equipped with a water separator,54.0 g (0.5 mol) of o-phenylenediamine and 220 mL of xylene were added,5 mL of potassium hydroxide in ethanol (where the weight of potassium hydroxide was 1.0 g)After heating and stirring,A mixture of 71.5 g (0.55 mol) of ethyl acetoacetate and 20 mL of xylene was slowly added dropwise,After dripping, stir the mixture to azeotropic dehydration to the presence of no water,And then continue to stir reflux 2h.Reaction completed, cooling, precipitation crystallization, filtration,Dried to give 76.5 g of white granules (yield 87.9percent) of 1-isopropenylbenzimidazolone
18%
at 150℃; for 1 h;
1-(prop-1-en-2-yl)-1H-benzo[d]imidazol-2(3H)-one (Intermediate): [Show Image] A solution of benzene-1,2-diamine (1.0 g, 9.26 mmol) in ethyl acetoacetate (1.18 mL, 9.26 mol) was heated at 150°C for 1 h. The solvent was removed on vacuo and the residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 6/4) to afford a yellow solid (290 mg, 18percent). 1H NMR (400 MHz, CDCl3) δ 7.09 (m, 4H, Ar), 5.41 (s, 1H, H2C=C), 5.25 (s, 1H, H2C=C), 2.25 (s, 3H, C=CCH3).LC/MS (ES+) m/z 175.1 (M+H)+
Reference：
[1] Patent: CN108129396, 2018, A, . Location in patent: Paragraph 0022; 0023; 0033; 0034
[2] Bulletin des Societes Chimiques Belges, 1987, vol. 96, # 10, p. 787 - 792
[3] Patent: CN102816121, 2016, B, . Location in patent: Paragraph 0022-0024
[4] Journal of Chemical Research - Part S, 1996, # 2, p. 92 - 93
[5] Russian Journal of Physical Chemistry A, 2015, vol. 89, # 5, p. 807 - 811[6] Zh. Fiz. Khim.,
[7] Tetrahedron Letters, 1995, vol. 36, # 9, p. 1387 - 1390
[8] Organic Process Research and Development, 2016, vol. 20, # 9, p. 1576 - 1580
[9] European Journal of Medicinal Chemistry, 1992, vol. 27, # 8, p. 779 - 789
[10] Patent: EP1997381, 2008, A1, . Location in patent: Page/Page column 38
[11] Tetrahedron, 1992, vol. 48, # 37, p. 7863 - 7868
[12] Patent: US2008/103130, 2008, A1, . Location in patent: Page/Page column 7; 43
[13] Patent: WO2008/44127, 2008, A1, . Location in patent: Page/Page column 79
2
[ 105-45-3 ]
[ 95-54-5 ]
[ 52099-72-6 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1997, vol. 32, # 11, p. 843 - 868
[2] Patent: US5652246, 1997, A,
3
[ 30414-53-0 ]
[ 95-54-5 ]
[ 52099-72-6 ]
Reference：
[1] Patent: US5652246, 1997, A,
4
[ 609-14-3 ]
[ 95-54-5 ]
[ 52099-72-6 ]
Reference：
[1] Patent: US5652246, 1997, A,
5
[ 141-97-9 ]
[ 95-54-5 ]
[ 52099-72-6 ]
[ 81128-80-5 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1981, vol. 18, p. 85 - 89
6
[ 6276-48-8 ]
[ 52099-72-6 ]
Reference：
[1] Tetrahedron Letters, 1988, vol. 29, # 2, p. 195 - 199
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, p. 261 - 270
7
[ 141-97-9 ]
[ 95-54-5 ]
[ 6276-48-8 ]
[ 52099-72-6 ]
Reference：
[1] Helvetica Chimica Acta, 1960, vol. 43, p. 1298 - 1313
[2] Journal of the Chemical Society, 1942, p. 303
8
[ 56-23-5 ]
[ 141-97-9 ]
[ 95-54-5 ]
[ 52099-72-6 ]
Reference：
[1] Helvetica Chimica Acta, 1960, vol. 43, p. 1298 - 1313
[2] Journal of the Chemical Society, 1960, p. 308,312
9
[ 52099-72-6 ]
[ 28890-99-5 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1987, vol. 96, # 10, p. 787 - 792
Example V To a stirred solution of 8.5 parts of <strong>[52099-72-6]1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one</strong> in 45 Parts of N,N-dimethylformamide are added portionwise 1.7 parts of sodium hydride dispersion 78%. After stirring for 1 hour at room temperature, the whole is cooled to 0-5 C and 8.65 parts of 1-bromo-3-chloropropane are added dropwise (slowly). Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto crushed ice and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 5.5 parts (44%) of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one; mp. 115 C.
5.5 parts (44%)
In N,N-dimethyl-formamide;
EXAMPLE IX To a stirred solution of 8.5 parts of <strong>[52099-72-6]1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one</strong> in 45 parts of N,N-dimethylformamide are added portionwise 1.7 parts of a sodium hydride dispersion 78%. After stirring for 1 hour at room temperature, the whole is cooled to 0-5 C and 8.65 parts of 1-bromo-3-chloropropane are added dropwise (slowly). Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured into crushed ice and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 5.5 parts (44%) of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)2H-benzimidazol-2-one; mp. 115 C.
With sodium hydroxide; In o-xylene; at 130℃; for 7h;
50 grams of o-phenylenediamine,90 g of ethyl acetoacetate and 5 g of sodium hydroxide were dissolved in 300 ml of o-xylene.Warming up to 130 C,The water was refluxed for about 7 hours.Cooled to 80 C,Wash twice with 100 ml of water,Cooled to 0 C,Precipitating a white solid,filter,Drying gives 65 grams of compound (DOM-2),The yield was 94%.
90%
In 5,5-dimethyl-1,3-cyclohexadiene; for 6h;Reflux;
o-Phenylenediamine (1.0 g, 9 mmol) and ethyl acetoacetate (1.2 mL,9 mmol) were heated in xylene (10 mL) for 6 h. The mixturewas setaside for the growth of colourless crystals of N-isopropenyl benzimidazol-2-one (yield, 90%). 2.2.1.2. 1-Isopropenyl-1H-1,3-benzimidazol-2(3H)-one: 2. Yield(%) 90%; mp 392 K; 1H NMR (300 MHz, CDCl3): 22.24 (d, 3H,4JH-H 3 Hz, CH3),5.25 (d, 1H, 4JH-H 3 Hz, CH2), 5.40 (d, 1H, 4JHH 3 Hz, CH2), 7.05e7.14 (m, 4H, CHarom),10.00 (s, 1H, NH). 13C NMR(75 MHz, CDCl3): 154.44 (C]O), 137.84 (Cq), 130.27 (Cq), 128.27(Cq),121.93 (CHarom),121.43 (CHarom),113.93 (CH2),109.79 (CHarom),109.14 (CHarom), 20.22 (CH3).
87.9%
With potassium hydroxide; In 5,5-dimethyl-1,3-cyclohexadiene; ethanol; for 2h;Reflux;
In a three-necked reaction flask equipped with a water separator,54.0 g (0.5 mol) of o-phenylenediamine and 220 mL of xylene were added,5 mL of potassium hydroxide in ethanol (where the weight of potassium hydroxide was 1.0 g)After heating and stirring,A mixture of 71.5 g (0.55 mol) of ethyl acetoacetate and 20 mL of xylene was slowly added dropwise,After dripping, stir the mixture to azeotropic dehydration to the presence of no water,And then continue to stir reflux 2h.Reaction completed, cooling, precipitation crystallization, filtration,Dried to give 76.5 g of white granules (yield 87.9%) of 1-isopropenylbenzimidazolone
18%
at 150℃; for 1h;
1-(prop-1-en-2-yl)-1H-benzo[d]imidazol-2(3H)-one (Intermediate): [Show Image] A solution of benzene-1,2-diamine (1.0 g, 9.26 mmol) in ethyl acetoacetate (1.18 mL, 9.26 mol) was heated at 150C for 1 h. The solvent was removed on vacuo and the residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 6/4) to afford a yellow solid (290 mg, 18%). 1H NMR (400 MHz, CDCl3) delta 7.09 (m, 4H, Ar), 5.41 (s, 1H, H2C=C), 5.25 (s, 1H, H2C=C), 2.25 (s, 3H, C=CCH3).LC/MS (ES+) m/z 175.1 (M+H)+
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In xylene; at 120 - 150℃; for 60.5h;
To a solution of the compound of Preparation 102 (98.0 g, 0.9 mol) in xylene (420 ml), at 120 C., was added 1,8-diazobicylo[5.4.0]undec-7-ene (1.5 ml), followed by the compound of Preparation 125 (130.0 g, 1.0 mol), added over 30 min. The reaction mixture was heated at 150 C., using a Dean-Stark apparatus, for 60 h and then cooled to room temperature. The solid product was isolated by filtration, washing with cold xylene (250 ml), and dried in a vacuum oven to give the title compound (208.4 g). 1H-NMR (d6-DMSO): 2.08-2.11 (3H), 5.05-5.11 (1H), 5.34-5.37 (1H), 6.98-7.01 (3H), 7.01-7.06 (1H), 10.90-11.00 (1H)
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In xylene; at 120 - 150℃; for 60.5h;
Preparation 8; 1 -lsopropenyl-1 ,3-dihvdro-2H-benzimidazol-2-one; To a solution of the compound of Preparation 140 (98.0 g, 0.9 mol) in xylene (420 ml), at 12O0C, was added 1 ,8-diazobicylo[5.4.0]undec-7-ene (1.5 ml), followed by the compound of Preparation 141 (130.0 g, 1.0 mol), added over 30 min. The reaction mixture was heated at 15O0C, using a Dean-Stark apparatus, for 60 h and then cooled to room temperature. The solid product was isolated by filtration, washing with cold xylene (250 ml), and dried in a vacuum oven to give the title compound (208.4 g). 1H-NMR (d6-DMSO): 2.08 - 2.11 (3H), 5.05 - 5.11 (1 H), 5.34 - 5.37 (1 H), 6.98 - 7.01 (3H), 7.01 - 7.06 (1 H), 10.90 - 11.00 (1 H)
Step A: Ethyl 2,3-dihydro-3-(1-methyl-ethenyl)-2-oxo-1H-benzimidazol-1-butanoate A solution of 19 g of <strong>[52099-72-6]1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one</strong> [described in J. Chem. Soc. Perkins, 1982, p. 261] in 150 ml of dimethylformamide was added with stirring at 20 C.+-2 C. to 5.75 g of sodium hydride as a 50% suspension in oil and 10 ml of dimethylformamide and the mixture was stirred for another 30 minutes. 23.4 g of ethyl 4-bromo-butyrate were added to the mixture over 15 minutes and the mixture was stirred at room temperature for 4 hours and was poured into 800 ml of iced water. The mixture was extracted with ether and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure to obtain 33 g of ethyl 2,3-dihydro-3-(1-methyl-ethenyl)-2-oxo-1H-benzimidazol-1-butanoate.
With potassium carbonate; In acetone; for 18h;Heating / reflux;
A mixture of the compound of Preparation 8 (114.0 g, 0.7 mol), potassium carbonate (136 mg, 1.0 mol) and the compound of Preparation 130 (167.4 g, 0.9 mol) in acetone (500 ml) was heated at reflux for 18 h. The reaction mixture was then cooled to room temperature and filtered, washing through with acetone (250 ml). The filtrate was concentrated in vacuo and the residue was dried overnight at 40 C. to give the title compound (223.8 g). 1H-NMR (d6-DMSO): 1.10-1.20 (3H), 2.10-2.15 (3H), 3.95-4.07 (2H), 5.10-5.12 (1H), 5.35-5.39 (1H), 7.00-7.10 (3H), 7.20-7.26 (1H)
With potassium carbonate; In acetone; for 18h;Heating / reflux;
Preparation 7; Ethyl 4-(3-isopropenyl-2-oxo-2.3-dihydro-1H-benzimidazol-1-yl)butanoate; A mixture of the compound of Preparation 8 (114.0 g, 0.7 mol), potassium carbonate (136 mg, 1 mol) and the compound of Preparation 166 (167.4 g, 0.9 mol) in acetone (500 ml) was heated under reflux for 18 h. The reaction mixture was then cooled to room temperature and filtered, washing through with acetone (250 ml). The filtrate was concentrated in vacuo and the residue was dried overnight at 40C to give the title compound (223.8 g).1H-NMR (d6-DMSO): 1.10 - 1.20 (3H), 2.10 - 2.15 (3H), 3.95 - 4.07 (2H), 5.10 - 5.12 (1 H), 5.35 - 5.39 (1 H), 7.00 - 7.10 (3H), 7.20 - 7.26 (1 H)
PREPARATION A 1-(2-Chloroethyl)-3-isopropenyl-2(3H)-benzimidazolone 200 mmol of 1-bromo-2-chloroethane and 55 mmol of potassium carbonate are added to 50 mmol of 1-isopropenyl-2(3H)-benzimidazolone in 150 ml of dimethylformamide. The whole mixture is kept stirring for 48 hours. It is then poured into ice-cold water and extracted with dichloromethane. The organic phases are washed with water, dried and evaporated. The residue is then taken up in ether. The ether phase is washed with 2N potassium hydroxide and then with water, dried and evaporated and leads to the expected product.
With potassium hydroxide; In 5,5-dimethyl-1,3-cyclohexadiene; water;
PREPARATION B 3-Isopropenyl-2(3H)-benzimidazolone 1 ml of a 47% potassium hydroxide solution and then 530 mmol of methyl acetoacetate in solution in 20 ml of xylene are added to 500 mmol of 2-aminoaniline in 150 ml of xylene heated to 120 C. The whole mixture is heated and the water/methanol mixture formed is removed by means of a Dean and Stark apparatus. The whole mixture is then brought to reflux for 3 hours. After cooling to 40 C., 83 ml of 47% potassium hydroxide and 55 ml of water are added. The alkaline aqueous phase is neutralized with acetic acid. The expected product then crystallizes; it is filtered off, washed with water and dried. Melting point: 120 C.
1-Isopropyl-1,3-dihydro-benzoimidazol-2-one A mixture of 1-isopropenyl-1,3-dihydro-benzoimidazol-2-one (J. Davoll, J. Chem. Soc. 1960, 308) (6.90 g, 39.6 mmol) and 10% palladium on carbon (1.0 g) in MeOH (50 mL) was placed in a Parr shaker under hydrogen (40 psi) for 2 h. The reaction mixture was filtered through celite and evaporated to give 6.97 g (100%) of 1-isopropyl-1,3-dihydro-benzoimidazol-2-one as a white solid. 1H NMR (CDCl3) delta 1.57 (d, J=7.1 Hz, 6H), 4.70-4.81 (m, 1H), 7.02-7.10 (m, 2H), 7.10-7.20 (m, 2H); MS m/e 177 (MH+); Anal. Calcd for C10H12N2O: C, 68.16; H, 6.86; N, 15.90; Found: C, 68.05; H, 6.63; N, 15.77.
(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid methyl ester N-isopropenyl-2-benzimidazolone (15.0 g, 86.10 mmol), methyl bromoacetate (13.2 g, 86.1 mmol) and potassium carbonate (14.25 g, 103.26 mmol) were stirred in acetonitrile (300 ml) at room temperature overnight. The next day the reaction mixture was filtered and concentrated to give 21.0 g (99% yield) of (3-isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid methyl ester as a clear oil: 1H NMR (DMSO-d6) delta 2.13 (s, 3H), 3.69 (s, 3H), 4.74 (s, 2H), 5.17 (s, 1H), 5.38 (s, 1H), 7.05-7.23 (m, 4H); IR (KBr, cm-1) 2955, 1755, 1714, 1493, 757; MS m/e 247 (MH+).
With n-butyllithium; In tetrahydrofuran; N-methyl-acetamide; ice-water; hexane; isopropyl alcohol; mineral oil;
93.8 ml (150 mmol) of a n-butyllithium solution (about 1.6M in hexane) are added dropwise at 0-5 to 24.8 g (150 mmol) of 2-(N-benzyl-N-methylamino)ethanol dissolved in 250 ml of absolute tetrahydrofuran. After stirring at 0 for 15 minutes 11.7 ml (150 mmol) of methanesulphochloride in 50 ml of tetrahydrofuran are added dropwise at a temperature between 0 and 5 and the reaction mixture is stirred at 0 for 30 minutes. 5.8 g (133 mmol) of a 55% sodium hydride dispersion in mineral oil are washed oil-free with hexane and suspended in 40 ml of dimethylformamide. 23.1 g (132.5 mmol) of 1-(1-methylvinyl)benzimidazolin-2-one in 90 ml of dimethylformamide are subsequently added dropwise at room temperature and the reaction mixture is stirred for a further 15 minutes. This reaction mixture is added dropwise at 0 to the reaction solution described above. Thereafter, the mixture is heated to 70 and stirred for 3 hours. The reaction mixture is subsequently poured into 1 l of ice-water and extracted with 600 ml of methylene chloride. The extract is washed with water, dried over potassium carbonate and evaporated. The thus-obtained product is chromatographed on 500 g of silica gel with methylene chloride and 0-5% isopropanol as the elution agent, whereby there are obtained 26.8 g (63%) of 1-(1-methylvinyl)-3-[2-(N-benzyl-N-methylamino)ethyl]-2-benzimidazolinone as an oil.
EXAMPLE V To a stirred and hot (50 C.) mixture of 28.3 parts of <strong>[52099-72-6]1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one</strong>, 5 parts of N,N,N-triethylbenzenemethanaminium chloride and 225 parts of a sodium hydroxide solution 60% are added dropwise, during a 30 minutes-period, 33.7 parts of 1-bromo-4-chlorobutane. Upon completion, stirring is continued for 5 hours at 60 C. The reaction mixture is cooled, water is added and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 1-(4-chlorobutyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as a residue.
1-(4-aminophenyl)-3 -(prop-1-en-2-yl)-1H-benzo[d]imidazol-2(3H)-one (Intermediate): [Show Image] To a stirred solution of isopropylidene protected benzimidazolone derivative (80 mg, 0.46 mmol) in dimethylsulfoxide (DMSO) (0.6 mL) under N2 was added K2CO3 (32 mg, 0.23 mmol). The reaction mixture was heated at 80C for 20 min and 1-fluoro-4-nitrobenzene (49 muL, 0.46 mmol) was added. The mixture was heated at 80C overnight. K2CO3 (12 mg, 0.10 mmol) and 1-fluoro-4-nitrobenzene (16 muL, 0.15 mmol) were added and the solution was heated at 80C for 48h. Water (10 mL) was introduced and the mixture was extracted with ethyl acetate (3x15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. To a stirred solution of the crude material in MeOH (7 mL) under N2 were added HOAc (3 drops), decaborane (17 mg, 0.14 mmol) and 10% Pd/C (20 mg). The reaction mixture was refluxed for 3h. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuo and the residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 5/5) to afford a yellow oil (86 mg, 71%). LC/MS (ES+) m/z 266.10 (M+H)+
With potassium carbonate; In N,N-dimethyl acetamide; at 120 - 150℃; for 0.333333h;Microwave irradiation;
1-isopropenylbenzimidazolone (0.5 g, 2.9 mmol) in DMA (8 niL) was added and trimethyl-(4- methyl-benzo[&]thiophen-3-ylmethyl)-ammonium; iodide (1.0 g, 2.9 mmol) and K2CO3 (0.80 g, 5.74 mmol). The reaction mixture was heated to 120 0C for 15 min in a microwave and then 150 0C for another 5 min. The mixture was diluted with ethyl acetate and washed with water (x4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2CkMeOH as an eluent to afford 0.7 g of the desired product as a white solid
3-(3-isopropenyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-benzyl-trimethylammonium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 1.5h;
To a solution of l-Isopropenyl-2-benzimidazolidinone (2.5 g, 14.4 mmol) in DMF (10 inL) were added ethyl acrylate (1.7 mL, 15.8 mmol) and benzyltrimethyl ammonium hydroxide in MeOH (1.4 g, 8.6 mmol). The resulting mixture was stirred at room temperature for 1.5 h. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water (x4). The organic phase was dried over Na2SCH and concentrated. The resulting residue was purified by silica gel prep TLC using 1 : 1 Hexanes: Ethyl acetate as an eluent to afford 3.0 g (76%) of the desired product along with methyl ester. Since the methyl ester was the major product, this product was used for the next reaction.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 16h;
To a solution of 1-isopropenylbenzimidazolone (1.0 g, 5.7 mmol) in dry THF (80 inL) are added triphenylphosphine (1.8 g, 6.9 mmol) and naphthalen-1-yl-methanol (1.1 g, 6.9 mmol). Then diisopropyl azodicarboxylate (1.4 mL, 6.9 mmol) is added drop wise into the above solution at room temperature. The mixture is stirred for 16 hrs and then the solvent is removed under vacuum. The residue is purified by flash column chromatography using 10% EtOAc in hexanes to give 1.6 g (89%) of 1 -isopropenyl-3-naphthalen- 1 -ylmethyl- l,3-dihydro-benzimidazol-2-one.
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 2h;
To a solution of l-isopropenyl-2-benzimidazolidmone (200 mg, 1.1 mmol) in DMF (10 niL) were added methyl-2-bromomethyl-3-nitrobenzoate (472 mg, 1.7 mmol) and K2CO3 (317 mg, 2.3 mmol) at room temperature. The solution was heated to 80 C for 2 hours. The solution was cooled down and sat. NH4CI solution was added. The solution was extracted with EtOAc. The combined organic layer was dried with MgSO4 and was filtered. The filtrate was concentrated and the residue was purified by CombiFlash with 20% EtOAc m Hexane as the eluent to afford the desirable product 2-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-l-ylmethyl)-3-nitro- benzoic acid methyl ester (395 mg, 94%) as a pale yellow foam.
With N-benzyl-trimethylammonium hydroxide; In N,N-dimethyl-formamide; at 20℃;
To a stirred solution of l-Isopropenyl-l,3-dihydro-benzimidazol-2-one (5g, 28.7mmol) in DMF (20ml) was added methyl acrylate (2.8ml, 31.6mmol) followed by benzyltrimethylammonium hydroxide (Triton B, 40 wt% in MeOH, 3.2ml). The resulting solution was stirred at ambient temperature until the reaction was complete. After this time the reaction was poured into water <n="170"/>and ethyl acetate. The layers were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic layers were dried (MgSCH), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 30% ethyl acetate/hexanes). The product-containing fractions were combined and concentrated to give 4.8g (64%) of the desired product.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;
To a stirred solution of l-isopropenyl-l,3-dihydro-benzimidazol-2-one (Ig, 5.7mmol) in DMF (50ml) was added potassium carbonate (1.6g, 11.5mmol) followed by 2-fluorophenacyl bromide (1.5g, 6.9mmol). The resulting mixture was warmed to 8O0C for 2h and cooled to ambient <n="175"/>temperature. The reaction was poured into water and ethyl acetate and the layers were separated. The aqueous phase was extracted with ethyl acetate (2x) and the combined organics were dried (MgSCU). Filtration and concentration gave the crude product which was purified via column chromatography (silica gel, 50% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give 1.6g (90%) of the desired product.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 5h;
To a solution of 1-isopropenylbenzimidazolone (500 mg, 2.8 mmol) in dry THF (40 mL) are added triphenylphosphine (902 mg, 3.4 mmol) and (4-Methyl-benzo[>]thiophen-3-yl)-methanol (563 mg, 3.2 mmol). Then diisopropyl azodicarboxylate (0.70 mL, 3.4 mmol) is added drop wise into the above solution after it is cooled down to 0 0C. The mixture is then stirred at room temperature for 5 hr and then the solvent is removed under vacuum and the residue is purified by flash column chromatography using gradient EtOAc/Hexane from 0% to 20% to give 630mg (66%) of 1 -isopropenyl-3-(4-methyl-benzo[£]thiophen-3-ylmethyl)- 1 ,3-dihydro-benzimidazol- 2-one.
With N-benzyl-trimethylammonium hydroxide; In methanol; N,N-dimethyl-formamide; at 20 - 60℃; for 12h;
To a solution of l-isopropenyl-2-benzimidazolinone (2 g, 11.5 mmol) in DMF (10 niL) were added <strong>[27829-72-7]ethyl trans-2-hexenoate</strong> (2 g, 14 mmol) and the benzyltrimethylammonium hydroxide (40percent in MeOH) (0.4 mL, 2.3 mmol) at room temperature. The solution was heated to 60 C for 12 hours. The solution was cooled down and sat.NH4Cl sol was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4 and filtered. The filtrate was concentrated and the residue was purified by CombiFlash with 20percent EtOAc in Hexane to afford the desirable product 3-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-l- yl)-hexanoic acid ethyl ester (2 g, 55percent) as an colorless oil.
To a solution of 1-isopropenylbenzimidazolone (0.3 g, 1.72 mmol) in DMF (5 mL) was added 60% NaH (0.1 g, 2.6 mmol). The reaction mixture was stirred at room temperature for 15 min and added 3-(Bromomethyl)-5-chlorobenzo[b]thiophene (0.54 g, 2.07 mmol). The reaction mixture was heated to 65 0C and stirred at that temperature for 2 h. When the reaction was complete, the mixture was treated with water. The mixture was then diluted with ethyl acetate and washed with water (x4). The organic phase was dried over Na2SC>4 and concentarted. The resulting residue was purified by silica gel prep TLC to afford 0.53 g (87%) of the desired product.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 16h;
To a solution of 1-isopropenylbenzimidazolone (220 mg, 1.3 mmol) in dry THF (10 inL) are added triphenylphosphine (397 mg, 1.5 mmol) and (l,2-Dimethyl-lH-indol-7-yl)-methanol (220 mg, 1.3 mmol). Then diisopropyl azodicarboxylate (0.31 mL, 1.5 mmol) is added drop wise into the above solution at room temperature. The mixture is stirred for 16 hrs and then the solvent is removed under vacuum. The residue is purified by flash column chromatography using 10-30% EtOAc in hexanes to give 200 mg (48%) of l-(l,2-dimethyl-lH-indol-7-ylmethyl)-3- isopropenyl-l,3-dihydro-benzimidazol-2-one.
With sodium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 4h;
200 g of Intermediate 1 was added to 1 L of DMF, and 50 g of sodium hydroxide was added.187g of 1,2-dibromoethane was added dropwise; after the addition was completed,Stir at room temperature for 4 hours, concentrate, and add the residual liquid to water.Filtration, washing with water, drying, to obtain 284 g of intermediate 2, the yield was 87%;
86.2%
With sodium hydroxide; In N,N-dimethyl-formamide; at 25 - 30℃; for 4h;
1) added to the three-opening bottle -1 - 1, 3 - dihydro - 2H - (1 - methyl vinyl) benzimidazolone (10 g, 0.06 muM), N, N - dimethyl formamide (50 ml) and NaOH (4.6 g, 0 . 11 muM); dropwise 1, 2 - Dibromoethane (21.5 g, 0 . 11 muM), in the 25 - 30 C under stirring 4 hours; after the reaction is completed, water and ethyl acetate, separating the organic phase; the aqueous phase is extracted with ethyl acetate. The combined organic phase washing, drying, filtering, the concentrated oil of 1, 3 - dihydro -1 - (2 - bromomethyl) -3 - (isopropenyl) - 2H - benzimidazolone 13.9 g (purity 90.8%, yield is 86.2%)
A mixture of sodium hydroxide (47 gm) and i-(alpha-methylvinyl) benzimidazol-2-one (100 gm) in dimethylformamide (400 ml) was .stirred for 1 hour at room temperature. Dibromoethane (217 gm) was slowly added to the mixture and stirred at 1 hour 30 minutes. The resulting solution after addition water (500 ml) was extracted with ethyl acetate. The combined ethyl acetate extract washed with water. After drying the solvent was removed under vacuum to yield 132 gm of 1 ,3-dihydro-1-(2-bromoethyl)-3-isopropenyl-2H-benzimidazol- 2-one as a yellow oily liquid.
With phosgene; triethylamine; In dichloromethane; at 20℃;Cooling with ice;
1-isopropenylbenzimidazolone 1.74 g (0.01 mol)And 0.72 g (0.01 mol) of acrylic acid were placed in a 100 mL reaction flask,30 mL of dried methylene chloride was added,Stir to complete dissolution, add 0.2 mL of triethylamine.And then weighed three phosgene 1.19g (0.004moL) dissolved in dry 10mL dichloromethane,Ice bath slowly drop in the reaction bottle.After the dropwise addition, the reaction system was returned to room temperature,Continue to stir 5 ~ 8h, after the end of the reaction,To the reaction system was added 20 mL of a saturated aqueous solution of sodium hydrogencarbonate,Full shock after the static phase separation, the organic phase washed with water, magnesium chloride drying,Degassed under reduced pressure and purified by silica gel column chromatography (eluent petroleum ether / ethyl acetate = 4/1)To give 2.11 g of the title compound (yield 92.5%),
Multi-step reaction with 3 steps
1: potassium carbonate / N,N-dimethyl-formamide / 50 °C
2: potassium carbonate / acetonitrile / 70 °C
3: hydrogenchloride / isopropyl alcohol / 2 h / 70 °C
Multi-step reaction with 4 steps
1: tetrabutylammomium bromide; sodium hydroxide / 3 h / Reflux; Large scale
2: potassium carbonate; potassium iodide / N,N-dimethyl-formamide; water / 16 h / 120 °C
3: hydrogenchloride / water; methanol / 0.17 h / Reflux
4: potassium carbonate / water; ethanol / 2 h / 80 °C / Autoclave; Large scale
Multi-step reaction with 3 steps
1: sodium hydroxide / N,N-dimethyl-formamide / 4 h / 25 - 30 °C
2: sodium carbonate / ethanol / 18 h / 85 - 90 °C
3: hydrogenchloride / ethanol; water / 0 - 35 °C
Multi-step reaction with 4 steps
1: sodium hydroxide / N,N-dimethyl-formamide / 4 h / 20 °C
2: sodium hydroxide / dimethyl sulfoxide / 8 h / 20 °C
3: hydrogenchloride / water / 5 h / 100 °C
4: [2,2]bipyridinyl; nickel diacetate; sodium hydride / sulfolane / 10 h / 100 °C
Multi-step reaction with 4 steps
1.1: potassium carbonate / N,N-dimethyl-formamide / 9 h / 10 - 20 °C
2.1: triethylamine / dichloromethane / 3.5 h / 0 - 20 °C
3.1: ethyl acetate / 15 h / 20 °C
3.2: 12 h / Reflux
4.1: acetic acid / water / 6 h / 60 °C
With sodium sulfite; In ethylene glycol; at 40℃; for 8h;
Added to the reaction container 1-allyl benzimidazol-2-one (2) 0.19mol, glycol 140 ml, sodium sulfite 0.28mol, raising the temperature of the solution to 40 C, control the stirring speed 130rpm, dropwise 1-amino-3-bromo-propane 0.25mol, dropping time control in 3h, reaction 5h, the mass fraction of the reactants are poured into 25% sodium chloride solution, used for quality fraction of 65% cyclohexanol extracting 7 times, cyclohexanol extracted solution with calcium oxide drying, evaporate the solvent, get oily 1-allyl-3 - (3-chloro-propyl) benzimidazole-2-one
1-(3-chloropropionyl)-3-(prop-1-en-2-yl)-1H-benzimidazol-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With dmap; In dichloromethane; at 20℃;
1-isopropenylbenzimidazolone 1.74 g (0.01 mol)And 1.08 g (0.01 mol) of 3-chloropropionic acid,Placed in a 100 mL reaction flask, 30 mL of dried methylene chloride was added,Stir until completely dissolved.(DC) 2.48 g (0.012 mol) and p-dimethylaminopyridine (DMAP) were added, and the mixture was stirred at room temperature for 5 to 8 hours.After the reaction, the reaction liquid into the sand core funnel,Filter, filter with a small amount of ethyl acetate elution,The eluate was combined with the filtrate,And purified by silica gel column chromatography (eluent petroleum ether / ethyl acetate = 4/1)To obtain 2.27 g of the title compound (yield 86.0%),
With sodium hydroxide; In water; isopropyl alcohol; at 75℃; for 2h;
(1) A 250 ml reaction flask was charged with 1-isopropenyl-2-benzimidazolone (4.0 g, 0.023 mol), Intermediate I (9.8 g, 0.03 mol)45% NaOH (12.5 g, 0.14 mol),Isopropyl alcohol 25ml,Water 110ml,Heated to 75 degrees stirring reaction 2h;(2) the reaction is complete,Add concentrated hydrochloric acid to adjust PH = 1 or so,Continue stirring 1h,The resulting solid was filtered while cooling,Add to DCM and water,Adjust PH to alkaline,Separate the organic layer;(3) After drying and concentration,Concentration of the resulting material with acetone recrystallization available fluorine Ban Se Lin finished.
With potassium carbonate; In N,N-dimethyl-formamide; at 10 - 20℃; for 9h;
The 1-isopropenyl-2-benzimidazolone (10g, 0.057mol),Was added to DMF50mL,The ice bath was cooled to 10 C,Control the temperature below 20 slowly added 4g of potassium carbonate,After addition of 1 hour at room temperature, 2-bromoethanol (14.2g, 0.114mol) was added dropwise and stirred at room temperature for 8 hours.The reaction mixture was poured into ice-water, extracted with methylene chloride, and the extract was washed with water, dried, filtered and evaporated to dryness to give Intermediate 1 10g in a yield of 80%.
1-(2-chloro-ethyl)-4-(3-trifluoromethyl-phenyl)-piperazine; hydrochloride[ No CAS ]
[ 52099-72-6 ]
flibanserin[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In propan-1-ol; water; at 75℃; for 2h;
1-Isopropenyl-2-benzimidazolone (4.0 g, 0.023 mol), Intermediate I (9.8 g, 0.03 mol), 45% NaOH (12·5 g, 0·14 mol), was added to a 250 ml reaction flask. 25 ml of propanol and 110 ml of water were heated to 75 degrees and stirred for 2 hours. The reaction was completed, concentrated hydrochloric acid was added to adjust PHI, stirring was continued for 1 h, and the solid obtained by filtration was cooled.Adding to DCM and water, adjusting the pH to alkaline, separating the organic layer, drying and concentrating, and concentrating the obtained product by recrystallization from acetone to obtain the finished product of Flibanserin.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;
Compound III-1 (1.74 g, 10 mmol) represented by the following structural formulaPotassium carbonate (2.74 g), 1,4-dibromopropane (6.07 g, 30 mmol) was added to a solution of (20 ml) in DMF for 3 hours,Stir at 60 C. Water was added to the reaction solution, and extracted with ethyl acetate.The organic layer was washed with brine and dried over Na 2 SO 4. Filtration,After evaporation of the solvent, the residue is subjected to silica gel column chromatographyPurification by (AcOEt / n-hexane 1: 4) gave compound III-2 (1.961 g, 66%) as a colorless oil.
1-(6-bromohexyl)-3-(prop-1-en-2-yl)-1H-benzo[d]imidazol-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With tetrabutylammomium bromide; potassium carbonate; for 0.00833333h;Microwave irradiation;
General procedure: A mixture of heterocycle 2a, 2h-2p, 2x or sulfonamide 2q, 2r (0.001mol) with 0.414g of K2CO3 (0.003mol) and 0.032g of TBAB (0.0001mol) were triturated in a mortar. The triturated mixture was transferred to a round bottom flask, after which 0.46cm3 (0.003mol) of 1,6-dibromohexane (3) and 0.2cm3 of ACN or DMF was added. The reactions were carried out for 30s in a CEM Discover microwave reactor at 100 W output power. After the reaction had been completed, 40cm3 of water was added to the mixture and extracted with methylene chloride. After the distillation of methylene chloride, the product was macerated in 20cm3 of hexane to get rid of the excess 1,6-dibromohexane (3). The reaction yields for each product were calculated on the basis of the weight of the obtained product.
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