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Structure of 110-52-1 * 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 caesium carbonate In N,N-dimethyl-formamide at 60℃;
Step 82a: l-(4-Bromophenyl)pyrrolidine (Compound 0601-155)A mixture of 4-bromoaniline (1 g, 5.81 mmol), Cs2C03 (5.68 g, 17.44 mmol), 1,4- dibromobutane (1.88 g, 8.72 mmol) in DMF (20 mL) was stirred at 60 °C overnight. After cooled to room temperature, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with water (3 x 100 mL) and brine (100 mL), dried over Na2S04, concentrated and purified by columnchromatography on silica gel (petroleum ether) to give compound 0601-155 (720 mg, 46percent) as a colorless oil. LCMS: 226 [M+l]+. 1H NMR (400 MHz, DMSO-<3/4) δ 1.94 (t, J= 6.4 Hz, 4H), 3.18 (t, J= 6.4 Hz, 4H), 6.47 (d, J= 9.2 Hz, 1H), 7.27 (d, J= 9.2 Hz, 1H).
46%
With caesium carbonate In N,N-dimethyl-formamide at 60℃;
Step 82a: 1-(4-Bromophenyl)pyrrolidine (Compound 0601-155)[0550]A mixture of 4-bromoaniline (1 g, 5.81 mmol), Cs2CO3 (5.68 g, 17.44 mmol), 1,4-dibromobutane (1.88 g, 8.72 mmol) in DMF (20 mL) was stirred at 60° C. overnight. After cooled to room temperature, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (3×100 mL) and brine (100 mL), dried over Na2SO4, concentrated and purified by column chromatography on silica gel (petroleum ether) to give compound 0601-155 (720 mg, 46percent) as a colorless oil. LCMS: 226 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 1.94 (t, J=6.4 Hz, 4H), 3.18 (t, J=6.4 Hz, 4H), 6.47 (d, J=9.2 Hz, 1H), 7.27 (d, J=9.2 Hz, 1H).
46%
With caesium carbonate In N,N-dimethyl-formamide at 60℃;
DMF (20mL) in, 4-bromo-aniline (1g, 5.81mmol), Cs2CO3 (5.68g, 17.44mmol), 1,4- dibromobutane (1.88g, 8.72mmol) was stirred overnight in a mixture of 60 of, after cooling to room temperature, the mixture was diluted with water (200mL), and extracted with ethyl acetate (2x100mL). The organic layer was washed with water (3 × 100 mL) and brine (100 mL), dried over Na2SO4, and purified by column chromatography on silica gel (petroleum ether) and concentrated to give the compound 0601-155 as a colorless oil It was (720mg, 46percent).
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 33, p. 11602 - 11605
[2] Journal of Organic Chemistry, 2006, vol. 71, # 1, p. 135 - 141
[3] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 221
[4] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0550
[5] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0468
[6] Patent: WO2015/42397, 2015, A1, . Location in patent: Paragraph 0001009
[7] Angewandte Chemie - International Edition, 2018, vol. 57, # 18, p. 5110 - 5114[8] Angew. Chem., 2018, vol. 130, # 18, p. 5204 - 5208,5
5
[ 110-52-1 ]
[ 586-77-6 ]
[ 22090-26-2 ]
Reference：
[1] Synthesis, 2002, # 1, p. 34 - 38
6
[ 110-52-1 ]
[ 136918-14-4 ]
[ 5394-18-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium carbonate In acetone for 2 h; Reflux
Phthalimide 6a (148mg, 1mmol), 124 1,4-dibromobutane (1.080g, 5mmol), 12 potassium carbonate (276mg, 2mmol) was added to 115 acetone (3mL), and the reaction mixture was refluxed for 2h. After cooling to room temperature, the reaction mixture was purified by column chromatography using 125 PE: acetone (40:1) as eluent to give 126 7a (260mg, 92percent) as a white solid.
86%
With potassium carbonate In acetone at 50℃; for 12 h;
Phthalimide (3.20 g, 0.05 mmol) was dissolved in acetone (40 mL), potassium carbonate (10.4 g, 0.15 mmol), 1,4-dibromobutane (9.1 mL, 0.15 mmol), 50 The reaction was carried out at ° C for 12 h, and the reaction was complete by TLC.The reaction mixture was concentrated under reduced vacuo.The organic layer was combined, dried over anhydrous sodium sulfateColumn chromatography (petroleum ether: ethyl acetate = 3:1) gave N-(4-bromobutyl)phthalimide (6.10 g, 86percent).
83%
With 18-crown-6 ether; potassium carbonate In toluene at 111℃; for 24 h; Inert atmosphere
General procedure: To the solution of an imide of general structure B in dry toluene anhydrous K2CO3 (2.5 equiv), 18-crown-6 (1 mol percent) and 1,4-dibromobutane (4 equiv) were added. The reaction mixture was stirred under reflux for 24 h under inert gas. Then, the reaction mixture was filtered off and the filter cake washed with dichloromethane. The combined filtrates were evaporated under reduced pressure and crude product was distilled under reduced pressure.
83%
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In acetone at 20℃; for 24 h;
Phthalimide (1.176 g, 7.98 mmol), K2CO3 (3.316 g, 24 mmol) and benzyltriethylammonium chloride (200 mg, 0.88 mmol) were dissolved in acetone (20 mL), A mixture of 1,4-dibromobutane (2.9 mL, 24 mmol) was added and stirred for 24 h at room temperature. The solvent was evaporated off, the residue was dissolved in water and DCM, the organic phase was separated, the aqueous layer was extracted twice more with DCM, and the organic layers were combined. It was dried over anhydrous sodium sulfate and concentrated by filtration. The residue was purified by column chromatography to give the title compound (1.861 g, yield: 83percent) as a colorless solid.
83%
With potassium carbonate In acetonitrile for 24 h; Reflux
General procedure: Compound 6–9 was prepared according the literature reported by Cheng L etal. [34] and with some modifications. Namely, phthalimide (2.9g, 20mmol) and the appropriate dibromoalkanes (80mmol) were added into MeCN (50mL). After an addition of K2CO3 (11g, 80mmol), the mixture was refluxed for 24h and followed by TLC (Thin Layer Chromatography). The solvent was evaporated under reduced pressure, and then the residuum was dissolved in ethyl acetate (200mL) and washed by water (3×100 mL). The organic phase was dried by MgSO4, and then was evaporated. The crude product was purified by column chromatography (PE/EtOAc=10:1, Rf=0.4) to give 6–9.
62.3%
With potassium carbonate In acetone at 20℃; for 10 h;
0.1 part of 1,4-dibromobutane, 0.1 part of benzoxazole carboxylate and 0.3 part of potassium carbonatewere mixed into the reacion flask. 20 parts of acetine was added and reacted at room temperature for 10 hours.Filtration and drying were carried out to collect compound 1 in 62.3 percent yield.
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 18, p. 6094 - 6099
[2] Angewandte Chemie - International Edition, 2018, vol. 57, # 6, p. 1532 - 1536[3] Angew. Chem., 2018, vol. 130, # 6, p. 1548 - 1552,5
[4] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 74 - 85
[5] Journal of the Chinese Chemical Society, 2013, vol. 60, # 12, p. 1431 - 1436
[6] Patent: CN108383892, 2018, A, . Location in patent: Paragraph 0088; 0089
[7] European Journal of Medicinal Chemistry, 2012, vol. 49, p. 200 - 210
[8] Advanced Synthesis and Catalysis, 2015, vol. 357, # 5, p. 1013 - 1021
[9] Patent: CN103570683, 2018, B, . Location in patent: Paragraph 0819; 0829-0832
[10] Journal of Organometallic Chemistry, 2018, vol. 868, p. 154 - 163
[11] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 1, p. 198 - 210
[12] Patent: CN106749407, 2017, A, . Location in patent: Paragraph 0009; 0035; 0036
[13] Journal of Medicinal Chemistry, 1989, vol. 32, # 6, p. 1147 - 1156
[14] Tetrahedron Letters, 1996, vol. 37, # 15, p. 2577 - 2580
[15] European Journal of Medicinal Chemistry, 2011, vol. 46, # 12, p. 5885 - 5893
[16] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2976 - 2979
[17] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 9, p. 3038 - 3048
[18] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1548 - 1552
[19] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 2035 - 2039
[20] European Journal of Organic Chemistry, 2016, vol. 2016, # 17, p. 2944 - 2953
[21] ChemMedChem, 2016, vol. 11, # 20, p. 2327 - 2338
7
[ 110-52-1 ]
[ 1074-82-4 ]
[ 5394-18-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 115℃; for 15 h;
Into a Sovirel type reactor mechanically stirred, provided with a condenser, an opening for introduction of solids, a system for inerting with nitrogen, and a temperature probe, are loaded 5 mol (1081 g) of 1,4-dibromobutane and 1 mol (188 g; 98.5percent pure) of potassium phthalimide. The reaction medium is brought under stirring to 115° C. and then kept at this temperature for 15 h. It is verified that the conversion is complete by a measurement of the potassium bromide in the reaction medium. [0048] After cooling of the reaction medium to 80° C., 200 g of water are added. After 15 min of stirring and then decantation, the aqueous phase containing the potassium bromide is removed and then a second washing is carried out (still at 80° C.) with 50 g of water. [0049] The ascending condenser is then replaced by a distillation column and then the excess 1,4-dibromobutane is distilled under reduced pressure (8-10 mbar) with a bottom temperature from 80 to 120° C. Thus, 815 g of 1,4-dibromobutane are recovered corresponding to a recovery rate of 1,4-dibromobutane of 94percent. This latter with a purity greater than 99.8percent may be directly recycled into a later operation. [0050] At the end of the distillation, the reaction medium is left to cool to 75-80° C. and then 325 g of ethanol are added. After homogenization and obtention of a clear organic solution at reflux of ethanol, the reaction medium is left to cool under stirring to room temperature (20° C.). [0051] After crystallization of the N-(4-bromobutyl)phthalimide, the ethanolic suspension of the product is filtered on frit at room temperature. The moist cake is washed with 35 g of ethanol and then dried at 50° C. under reduced pressure (20 mmHg). Thus, 268 g of N-(4-bromobutyl)phthalimide are obtained that correspond to a molar yield of 92percent compared with the potassium phthalimide provided.
92.4%
at 20℃; for 26 h;
The phthalimide potassium salt (2.0g, 10 . 7mmol) with 1, 4 - dibromo butane (2.8g, 12 . 9mmol) dissolved in 25 ml dry N,N-dimethylformamide in, for pH 10, room temperature stirring 26h. Dichloromethane is used for extraction three times (100 ml × 3), washed with distilled water, combined with the organic layer, drying by anhydrous magnesium sulphate, concentrated, dichloromethane/distilled water recrystallization, filtering, drying to obtain the white solid, yield of 92.4percent.
85%
at 30℃;
General procedure: Potassium phthalimide (0.93 g, 5 mmol) was added to a solution of 1,2-dibromoethane (1.3 mL, 15 mmol) in DMF (8 mL). The mixture was stirred at room temperature overnight and evaporated the solvent in vacuo, the residue dissolved in H2O and extracted with ethyl acetate. The organic layer was washed by brine and dried by MgSO4. Filtered and the solvent evaporated in vacuo, recrystallized from ethyl acetate to give white solid (566 mg, 45 percent).
84%
With tetrabutylammomium bromide In N,N-dimethyl-formamide at 78℃; for 6 h;
Potassium phthalimide (18.62 g, 0.10 mol) and tetrabutylammoniumbromide (TBAB, 5.00 g) were added to a solutionof 1,4-dibromobutane (35.5 mL, 0.30mol) in N, N-Dimethylformamide (DMF, 240 mL) at room temperature and then the mixture was stirred at 78 °C for 6 h. After the completion of the reaction (monitored by TLC analysis), the mixture was filtered, and washed with DMF (20 mL × 2).The filtrate was evaporated under vacuum to removed DMF,the residual liquid was poured into ice-water bath, immediately a large amount of white solid generated. The white solid was collected by filtration, washed on the filter withwater and dried in vacuum. The crude residue was purifiedby recrystallization from methanol to afford pure N-(4-Bromobutyl) phthalimide 2 (23.60 g, 84percent, m.p. 79-81oC aswhite solid. 1H NMR (CDCl3, 400 MHz), δ: 1.82-1.95 (m,4H, C13H, C14H), 3.45 (t, J=6.3 Hz, 2H, C15H), 3.73 (t,J=6.6 Hz, 2H, C16H), 7.27-7.74 (m, 2H, C3H, C6H), 7.83-7.86 (m, 2H, C1H, C2H); 13C NMR (CDCl3, 100 MHz), δ:27.3 (C13), 29.9 (C14), 32.8 (C15), 37.0 (C12), 123.3 (C3,C6), 132.1 (C4, C5), 134.0 (C1, C2), 168.4 (C7, C9). KunHu has reported the same compound in 2013 [17], the NMRcharacterization in the literature is described as follows: 1HNMR (CDCl 3, 500 MHz): d 1.84-1.94 (m, 4H), 3.45 (t,2H, J = 6.0 Hz), 3.73 (t, 2H, J = 6.5 Hz), 7.73 (dd, 2H, J =3.0, 5.5 Hz), 7.85 (dd, 2H, J = 3.0, 5.0 Hz); 13 C NMR(CDCl 3, 125 MHz): d 27.27, 29.89, 32.73, 36.99, 123.27,132.11, 133.99, 168.36.
82.5%
With tetrabutylammomium bromide In N,N-dimethyl-formamide at 70℃; for 2 h;
50 mL DMF, 0.025 mol potassium salt of phthalimide,0.10 mol 1,4-dibromobutane and 0.5 g TBAB,70 reaction 2.0h;Cool to room temperature,Pour ice waterEthyl acetate extraction,Washed,dry,De-soluble,Stand overnight,5.82 g of N- (4-bromobutyl) phthalimide precipitated as a white solid,m.p. 78-81 ° C, yield 82.5percent.
82%
for 24 h; Reflux
General procedure: A mixture of phthalimide10(6.8 mmol) dissolved in EtOH (20 mL) was gently boiled for about 1h. The hot solution was decanted from any solid into 1.25 mL of a specially prepared solution of KOH (15.25 g KOH dissolved in 15 mL of H2O and 45 mL of EtOH). A precipitate of potassium phthalimide separates at once. The mixture was stirred and cooled quickly to room temperature, and the precipitate was filtered under vacuum. To the alcoholic mother liquors a second 1 g portion of phthalimide was added, and the entire process was repeated. The two crops of crystals were united and washed with acetone to remove any unchanged phthalimide. After air-dried pure potassium phthalimidewas obtained as white crystals (yield 30percent). In a second step, a mixture of potassium phthalimide (2.2 mmol),the appropriate dibromoalkane derivative (2.9 mmol) and 2.5 mL of acetone was stirred and refluxed for 24h, and then cooled to 15 °C. After filtering off the precipitated potassium bromide, the cake was washed with acetone and the solvent evaporated to give pure compound.
82.5%
With tetrabutylammomium bromide In N,N-dimethyl-formamide at 70℃; for 2 h;
50 mL of DMF, 0.025 mol of the potassium salt of phthalimide, 0.10 mol of 1,4-dibromobutane and 0.5 g of TBAB, reaction at 70° C. for 2.0 h; cooling to room temperature, pouring into ice water, extraction with ethyl acetate, After washing with water, drying and desolvation, the mixture was allowed to stand overnight to precipitate 5.82 g of N-(4-bromobutyl)phthalimide as a white solid, mp 78-81°C, yield 82.5percent.
78.2%
With potassium carbonate In acetone at 60 - 65℃; Inert atmosphere
General procedure: The appropriate dibromoalkane derivative 2a-2e (11.9 mmol) was added slowly to a mixture of the starting material phthalimide potassium salt (1) (1g, 5.4 mmol) and anhydrous K2CO3 (0.82 g, 5.94 mmol) in acetone (15 mL). The reaction mixture was heated to 60-65 °C and stirred for 6-10 h under an argon atmosphere. After complete reaction, the solvent was evaporated under reduced pressure. Water (50 mL) was added to the residue and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated aqueous NaCl, dried over Na2SO4, and filtered. The solvent was evaporated to dryness under reduced pressure. The crude product was purified on a silica gel chromatography using dichloromethane/acetone (50:1) as eluent to give the intermediates 3a-3e.
76%
With potassium carbonate; potassium iodide In acetone at 100℃; for 6 h;
General procedure: To a solution of 1.6g (10.0mmol) of (R,S) 4-phenyloxazolin-2-one (13), 3.4g (25.0mmol) of K2CO3 and a catalytic amount of KI in acetonitrile, 5.4g (25.0mmol) of 1,4-dibromobutane were slowly added drop by drop stirring at rt. The mixture was then heated under reflux for 6–12h, monitored by TLC (CH2Cl2/EtOH 9:1). The hot solution was filtered and evaporated under reduced pressure. The yellow oil residue of (R,S) 3-(4-bromobutyl)-4-phenyloxazolidin-2-one 23 was used without further purification. (0045) Yield: 96percent;
75%
for 10.25 h; Reflux
General procedure: Acetone (150mL) and dibromoalkyl (30mol) were added to a 250mL three-necked round-bottom flask fitted with a mechanical stirrer and reflux condenser. Potassium phthalimide (11.85g, 10 mol) was added slowly over a 15-min period, and then the reaction mixture was heated under reflux for 10h. The reaction mixture was filtered via suction, and the acetone was removed via rotary evaporation. The crude product was purified by flash chromatography on silica gel (EtOAc:petroleum ether=1:14) to afford 2–5 as white solid.
72.3%
at 90℃; for 18.5 h;
To a stirred solution of 1,4-dibromobutane (2j) (9,7 mL, 27,0 mmoi) (100 mL), was added potassIum phthaiate (i—) (5.0 g, 27,0 mrnol) portion—wise over 30 mm at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 rnL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 rnL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5.40percent EtOAc / hexanes to afford 3j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 2.3.9(M+1)
72.3%
at 20 - 90℃; for 18.5 h;
To a stirred solution of 1,4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 min at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).
72.3%
at 20 - 90℃; for 18.5 h;
To a stirred solution of 1,4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 mm at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).
72.3%
at 90℃; for 18 h;
To a stirred solution of 1,4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 min at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).
72.3%
at 20 - 90℃; for 18.5 h;
To a stirred solution of 1,4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 mm at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).
72.3%
at 20 - 90℃;
Production Example 25a: Synthesis of (R)-N-(1-(3-(cyclopropylmethoxy)-4- fluorophenyl) ethyl)-4-(2,4-dioxoimidazolidin-1-yl)butane-1-sulfonamideScheme 11. [0697] Step 1: Synthesis of 2-(4-bromobutyl)isoindoline-1,3-dione (3-j) To a stirred solution of 1,4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 min at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).
68.3%
With potassium carbonate In acetoneReflux
General procedure: A mixture of dibromoalkane (23 mmol) and potassium carbonate (12 mmol)was added in acetone (30 mL), and potassium phthalimide (10 mmol) was added slowly over a 15-min period, and then the reaction was heated under reflux for 8-10 h. The reaction mixture was filtered,and the acetone was evaporated in vacuo. The crude product was purified by column chromatography on silica gel using mixtures of petroleum/acetone as eluent) to obtain the white solid compounds 2-4.
66%
at 0 - 20℃; for 18 h;
Syntheses of D,L-Sulforaphane and Erysolin; Compound 9; 2-(4-bromobutyl)isoindoline-l,3-dione; The following procedure was adapted from that previously reported by Vermeulen, et al (25) 1 ,4-Dibromobutane (4 400 mL, 36 457 mmols) was dissolved in anhydrous DMF (52 mL) and the resulting solution was chilled to 0°C under argon After 15 min, potassium phthahmide (3 459 g, 18 672 mmols) was slowly added to the stirring solution and the reaction was allowed to warm to ambient temperature under argon over 18 h The reaction was concentrated in vacuo and co-stπpped with anhydrous THF several times Products were dissolved in 1 1 H2O EtOAc (200 mL) and the aqueous phase was extracted with EtOAc (3 x 100 mL) Combined organics were washed with brine, dried over Na2SO4, and filtered through a celite plug prior to concentration in vacuo Silica gel chromatography (3 1 Hexane EtOAc) and subsequent concentration afforded 3 466 g 9 as a white solid (66percent yield) 1H NMR (CDCl3) 5 7 85 (dd, J = 5 4, 3 1 Hz, 2H), 7 73 (dd, J = 5 4, 3 0 Hz, 2H), 3 73 (t, J = 6 7 Hz, 2H), 3 45 (t, J = 6 4 Hz, 2H), 1 89 (m, 4H) 13C NMR (CDCl3) δ 168 5, 134 1, 132 2, 123 4, 37 1, 32 9, 30 0, 27 4 HRMS (ESI-EMM) calc'd for [M + Na]+ m/z 303 9949, found 303 9936
66%
at 0 - 20℃; for 18 h; Inert atmosphere
Compound 9: 2-(4-bromobutyl)isoindoline-1,3-dione. The following procedure was adapted from that previously reported by Vermeulen, et al. (25). 1,4-Dibromobutane (4.400 mL, 36.457 mmols) was dissolved in anhydrous DMF (52 mL) and the resulting solution was chilled to 0° C. under argon. After 15 min, potassium phthalimide (3.459 g, 18.672 mmols) was slowly added to the stirring solution and the reaction was allowed to warm to ambient temperature under argon over 18 h. The reaction was concentrated in vacuo and co-stripped with anhydrous THF several times. Products were dissolved in 1:1 H2O:EtOAc (200 mL) and the aqueous phase was extracted with EtOAc (3×100 mL). Combined organics were washed with brine, dried over Na2SO4, and filtered through a celite plug prior to concentration in vacuo. Silica gel chromatography (3:1 Hexane:EtOAc) and subsequent concentration afforded 3.466 g 9 as a white solid (66percent yield). 1H NMR (CDCl3) δ 7.85 (dd, J=5.4, 3.1 Hz, 2H), 7.73 (dd, J=5.4, 3.0 Hz, 2H), 3.73 (t, J=6.7 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 1.89 (m, 4H). 13C NMR (CDCl3) δ 168.5, 134.1, 132.2, 123.4, 37.1, 32.9, 30.0, 27.4. HRMS (ESI-EMM) calc'd for [M+Na]+m/z 303.9949. found 303.9936.
61%
at 115 - 120℃; for 12 h;
Into a Sovirel type reactor mechanically stirred, provided with a condenser, an opening for introduction of solids, a system inerting with nitrogen, and a temperature probe, are loaded 655 g of 1,4-dibromobutane at 99percent purity (3 mol) and 187 g of potassium phthalimide at 99percent purity (1 mol). The reaction medium is brought under stirring between 115° C. and 120° C. and then kept at this temperature for 12 h. It is verified that the transformation of potassium phthalimide is completed by a measurement of the KBr in the reaction medium and then the excess 1,4-dibromobutane is evaporated under reduced pressure (10 to 18 mmHg). The recovery rate of the 1,4-dibromobutane is near 90percent and this latter may be recycled directly into a later operation. [0052] At the end of the distillation, the heterogeneous reaction medium is 120° C.-130° C. Its temperature is lowered to 70° C. and then 320 g of ethanol are introduced. The medium is kept at 70° C. [0053] The contents of the reactor are filtered at 70° C. on a frit kept at this temperature. The moist cake is dried. It essentially contains KBr and diphthalimidobutane. [0054] The ethanolic filtrate is left to cool to 20° C., which causes crystallization of the N-(4-bromobutyl)phthalimide. The ethanolic suspension of the product is filtered on the frit. The moist cake is washed with 2 ethanol fractions and then dried at 50° C. under reduced pressure (20 to 30 mmHg). Thus, 173 g of N-(4-bromobutyl)phthalimide are obtained or an isolated yield of 61percent compared with the potassium phthalimide provided.
61%
for 12 h; Heating / reflux
Potassium phthalimide (65 g, 350 mmol, 1.00 eq.) and tetramethylene dibromide (200 g, 930 mmol, 2.66 eq.) were combined (neat) and heated for 12 hours. The excess tetramethylene dibromide was removed via rotary-evaporation (rotovap). The resulting residue was digested with ethanol and filtered. The material that crystallized on standing was filtered, washed with ethanol, and dried in vacuo. A second crop was obtained by concentration of combined filtrate and washings. The combined mass of crops was 60.5 g (61percent yield).
48.6%
With tetra-(n-butyl)ammonium iodide In acetone for 18 h; Reflux
(3) N-(4-bromobutyl)phthalimide 93.6g (0.43mol) 1,4-dibromobutane was weighed, and added to 380mL acetone. The mixture was added with 72.5g (0.39mol) phthalimide potassium salt and 2.1g tetrabutylammonium iodide under stirring, subjected to refluxing for 18h, cooled, filtrated to remove solid, and washed with acetone. All acetone solutions are combined, subjected to recovering the solvent under a reduced pressure, and added with petroleum ether for crystallization while the reaction mixture was hot. A solid was filtered out, washed with with petroleum ether and dried to obtain a product 48.0g(43.6percent),mp 75∼78°C. The mother liquor was concentraed to precipitate crystal, cooled in an ice-bath to obtain a solid 5.5g (5.0percent), mp 73∼76°C.
48.6%
With tetra-(n-butyl)ammonium iodide In acetone for 18 h; Reflux
(3) N-(4-bromobutyl)phthalimide 93.6 g (0.43 mol) 1,4-dibromobutane was weighed, and added to 380 mL acetone. The mixture was added with 72.5 g (0.39 mol) phthalimide potassium salt and 2.1 g tetrabutylammonium iodide under stirring, subjected to refluxing for 18 h, cooled, filtrated to remove solid, and washed with acetone. All acetone solutions are combined, subjected to recovering the solvent under a reduced pressure, and added with petroleum ether for crystallization while the reaction mixture was hot. A solid was filtered out, washed with petroleum ether and dried to obtain a product 48.0 g (43.6percent), mp 75~78° C. The mother liquor was concentrated to precipitate crystal, cooled in an ice-bath to obtain a solid 5.5 g (5.0percent), mp 73~76° C.
17.3 g
at 20℃; for 48 h;
A mixture of 1,4-dibromobutane (22 mL, 185 mmol) and potassium phthalimide (11.35 g, 61.4 mmol) in 60 mL of DMF was mixed at room temperature for 1 day. Then, the reaction mixture was extracted with hexane (3x150 mL). The hexane fractions were dried over MgS04, filtered, and concentrated to give 30 g of a 1:2.2 molar mixture of recovered 1,4-dibromobutane and DMF. This mixture was diluted with 30 mL of DMF and retreated with potassium phthalimide (4.80 g, 26 mmol) at room temperature for 1 day. The two reaction mixtures in DMF were partitioned between 1: 1 EA/Hex (3x150 mL) and H20 (2x100 mL), 0.1M HCl (100 mL), and brine (100 mL).The organic phases were dried over MgS04 and concentrated. SPE, eluting with 0percent and 10percent EA/Hex, gave 17.3 g of colorless solid. R 0.55 (40percent EA/Hex); 1H NMR (CDC13) δ 7.86-7.81 (m, 2H), 7.73-7.69 (m, 2H), 3.71 (t, 2H), 3.43 (t, 2H), 1.94-1.80 (m, 4H); 13C NMR (CDC13) δ 168.5, 134.2, 132.3, 123.5, 37.2, 32.9, 30.1, 27.4.
5.6 g
at 20℃; for 15 h;
7.8ml (6. 5 X 10 2 mol) of 1,4-dibromobutane with 6 g (3. 2 X 10 2 moles) Phthalimide potassium salt dissolved in 100ml of N, N- dimethylformamide andunder room temperatureit was stirred for 15hours.The solvent was distilled off under reduced pressure The residue usingn-hexane: ethyl acetate with a volumeratio of 10: 1 eluent to carry out column chromatography, gradually increasingthe polarity to hexane: ethyl acetate with a volume ratio of 5: 1 to give aproduct of 5.6g (2.0X102mole) a bromo group substituted by Phthalimide. The product with 5. 0g (5. 0X 10 2 mol) ofsodium sulfite, 140ml water and 85ml95percent ethanol mixed reaction was heated to 95° C for 18h, the remaining solvent was drained, and the resulting residue was mixed with 73ml ofconcentrated hydrochloric acid then was heated to 110 ° C the for 18H, itwas drained, with water - 95percent ethanol on the residue to carry out recrystallization to give 2. 5g of4-amino-1-Butanesulfonic acid (total yield 50percent).
Reference：
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[4] Organic Letters, 2011, vol. 13, # 4, p. 764 - 767
[5] Chinese Chemical Letters, 2016, vol. 27, # 2, p. 185 - 189
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[7] Patent: CN107382980, 2017, A, . Location in patent: Paragraph 0041; 0042; 0043; 0044
[8] European Journal of Medicinal Chemistry, 2018, vol. 149, p. 69 - 78
[9] Patent: CN107540647, 2018, A, . Location in patent: Paragraph 0056-0059
[10] Angewandte Chemie, International Edition, 2009, vol. 48, # 36, p. 6675 - 6677[11] Angewandte Chemie, 2009, vol. 121, # 36, p. 6803 - 6805
[12] Archiv der Pharmazie, 2012, vol. 345, # 7, p. 509 - 516
[13] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 22, p. 5053 - 5059
[14] European Journal of Medicinal Chemistry, 2016, vol. 121, p. 712 - 726
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[52] Patent: CN101948412, 2016, B, . Location in patent: Paragraph 0031; 0032
[53] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3464 - 3471
[54] Patent: CN103833623, 2016, B, . Location in patent: Paragraph 0058; 0059; 0061
[55] Patent: US2018/193330, 2018, A1, . Location in patent: Paragraph 0011; 0140
8
[ 110-52-1 ]
[ 33081-78-6 ]
[ 5394-18-3 ]
Yield
Reaction Conditions
Operation in experiment
68.3%
With potassium carbonate In acetoneReflux
General procedure: To a suspension of the appropriate dibromoalkane (33mmol) and potassium carbonate (18mmol) in anhydrous acetone (30mL), and potassium phthalimide (15mmol) was added slowly over a 15min period, and then the reaction mixture was heated under reflux for 8–10h. The reaction mixture was filtered, and the acetone was evaporated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum/acetone as eluent) to obtain 2a-d as white solid.#10;#10;
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 307 - 323
Reference：
[1] Russian Journal of Applied Chemistry, 2000, vol. 73, # 12, p. 2106 - 2108
[2] Helvetica Chimica Acta, 1948, vol. 31, p. 1497,1500
[3] Journal of the Chemical Society, 1952, p. 3334,3337
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[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1981, vol. 30, # 12, p. 2304 - 2307[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1981, # 12, p. 2767 - 2771
14
[ 110-52-1 ]
[ 829-85-6 ]
[ 7688-25-7 ]
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[2] Phosphorus, Sulfur and Silicon and the Related Elements, 2004, vol. 179, # 2, p. 277 - 283
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[1] Journal of Organic Chemistry, 1957, vol. 22, p. 834
17
[ 110-52-1 ]
[ 5162-44-7 ]
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[2] Journal of Chemical Research, Miniprint, 1992, # 9, p. 2409 - 2446
[3] Journal of Organic Chemistry, 1993, vol. 58, # 24, p. 6807 - 6813
[4] Synthesis, 1984, # 10, p. 885
[5] Chemistry of Heterocyclic Compounds, 2012, vol. 48, # 3, p. 412 - 421
[6] Journal of Organic Chemistry, 2006, vol. 71, # 4, p. 1736 - 1738
[7] Organometallics, 2015, vol. 34, # 13, p. 3335 - 3357
[8] Patent: US4833262, 1989, A,
[9] Chemistry - A European Journal, 2009, vol. 15, # 34, p. 8533 - 8541
[10] Dalton Transactions, 2017, vol. 46, # 1, p. 221 - 226
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[ 110-52-1 ]
[ 4549-32-0 ]
[ 3344-70-5 ]
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19
[ 110-52-1 ]
[ 4457-67-4 ]
Reference：
[1] Patent: US5608069, 1997, A,
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[ 110-52-1 ]
[ 124-41-4 ]
[ 4457-67-4 ]
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[1] Chemical and pharmaceutical bulletin, 1980, vol. 28, # 5, p. 1422 - 1431
[2] Bulletin de la Societe Chimique de France, 1957, p. 789
[3] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1950, vol. 231, p. 151
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, p. 1303 - 1310
21
[ 110-52-1 ]
[ 67-56-1 ]
[ 4457-67-4 ]
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[2] Journal of the American Chemical Society, 1968, vol. 90, p. 4675 - 4678
[3] Journal of Chemical Ecology, 1995, vol. 21, # 6, p. 815 - 832
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[1] Organic Process Research and Development, 2007, vol. 11, # 1, p. 60 - 63
24
[ 110-52-1 ]
[ 106-95-6 ]
[ 4117-09-3 ]
Reference：
[1] Journal of Organometallic Chemistry, 2001, vol. 628, # 2, p. 169 - 182
25
[ 110-52-1 ]
[ 106-95-6 ]
[ 1647-16-1 ]
[ 592-42-7 ]
[ 4117-09-3 ]
[ 21964-49-8 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1968, p. 3893 - 3903
26
[ 110-52-1 ]
[ 151-50-8 ]
[ 5414-21-1 ]
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[1] Journal of the American Chemical Society, 2001, vol. 123, # 13, p. 3157 - 3158
[2] Journal of the American Chemical Society, 1949, vol. 71, p. 3100
[3] Journal of the American Chemical Society, 1934, vol. 56, p. 2144
[4] Canadian Journal of Chemistry, 1979, vol. 57, p. 831 - 834
[5] Canadian Journal of Chemistry, 1960, vol. 38, p. 1099 - 1103
27
[ 110-52-1 ]
[ 143-33-9 ]
[ 5414-21-1 ]
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[1] Synthesis, 2003, # 14, p. 2155 - 2160
[2] Helvetica Chimica Acta, 1983, vol. 66, # 7, p. 2294 - 2307
[3] Journal of Natural Products, 2001, vol. 64, # 3, p. 341 - 344
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[1] Justus Liebigs Annalen der Chemie, 1960, vol. 631, p. 180 - 184
30
[ 110-52-1 ]
[ 996-82-7 ]
[ 5802-65-3 ]
Reference：
[1] Journal of the Indian Institute of Science, 1923, vol. 6, p. 54[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 997
[3] Journal of the Chemical Society, 1929, p. 1478
31
[ 110-52-1 ]
[ 108-95-2 ]
[ 1200-03-9 ]
Yield
Reaction Conditions
Operation in experiment
96.1%
at 20 - 80℃;
In 500mL round-bottom flask was added phenol (50g, 1eq) at room temperature and 1,4-dibromobutane (137.7 g, 1.2 eq), potassium carbonate (110.5g, 1.5eq, 70 degrees bake about 2h, grind was added crushed), was added 5.5g of potassium iodide (5percent by mass of potassium carbonate) with mechanical stirring.Then warmed to 80 °C, at this temperature the reaction 4 ~ 6h.To detect the liquid phase reaction process.The resulting reaction solution was cooled to room temperature and filtered off with suction, the filtrate is combined at a temperature of 40-45 degrees, and concentrated under pressurized pressure 0.09-0.1MPa.The crude product purity after concentration reached 90.6percent, and crude product was distilled under reduced pressure at 120-130 °, collecting distillate products.1,4-dibromobutane recovery was 64.1percent, net yield was 96.1percent.
50%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1 h; Stage #2: With potassium iodide In N,N-dimethyl-formamide at 20℃; for 16 h;
1.1 1-(4-Bromobutoxy) benzenePotassium carbonate (22.0 g, 159.5 mmol, 1.5 equiv.) was added to a stirred solution of phenol (10.0 g, 106.3 mmol, 1.0 equiv.) in dimethylformamide (DMF) (15 ml_). The mixture was stirred at room temperature for 1 h. 1 ,4-Dibromobutane (45.9 g, 212.7 mmol, 2.0 equiv.) was added dropwise to the reaction mixture, followed by the addition of potassium iodide (176 mg, 1.06 mmol, 0.01 equiv.) in one portion. Stirring at room temperature was continued for 16 h; then the solids were filtered off and rinsed with ethyl acetate (EtOAc) (2x150 ml_). The filtrate was washed with water (3x100 ml_), brine (1 x100 ml_), dried over anhydrous Na2SU4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 1 percent EtOAc/hexanes) to afford the title bromide in a yield of 12.1 g (50percent).1H NMR (400 MHz, CDCI3) δ 7.32-7.27 (m, 2H), 6.98-6.89 (m, 3H), 4.01 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 6.4 Hz, 2H), 2.12-2.05 (m, 2H), 1.99-1.92 (m, 2H).
Reference：
[1] Patent: CN104447220, 2016, B, . Location in patent: Paragraph 0024-0026
[2] Archiv der Pharmazie, 2009, vol. 342, # 12, p. 732 - 739
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 3, p. 1244 - 1251
[4] Tetrahedron Letters, 2010, vol. 51, # 35, p. 4612 - 4616
[5] Chemical Communications, 2014, vol. 50, # 39, p. 5017 - 5019
[6] Organic Preparations and Procedures International, 2003, vol. 35, # 5, p. 501 - 507
[7] Chemistry - A European Journal, 2017, vol. 23, # 60, p. 15041 - 15045
[8] Patent: WO2010/146112, 2010, A1, . Location in patent: Page/Page column 111
[9] Journal of Organic Chemistry, 1956, vol. 21, p. 61,63
[10] Patent: US2603656, 1951, ,
[11] Bulletin de la Societe Chimique de France, 1950, p. 1062
[12] Annales Pharmaceutiques Francaises, 1952, vol. 10, p. 181,186
[13] Journal of Medicinal Chemistry, 1965, vol. 8, p. 271 - 273
[14] Journal of Organic Chemistry, 1962, vol. 27, p. 1288 - 1294
[15] Chemistry of Heterocyclic Compounds, 2003, vol. 39, # 9, p. 1218 - 1226
[16] Pharmacy and Pharmacology Communications, 1999, vol. 5, # 8, p. 491 - 494
[17] European Journal of Medicinal Chemistry, 2009, vol. 44, # 10, p. 4218 - 4226
[18] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 17, p. 5145 - 5153
[19] Chinese Journal of Chemistry, 2015, vol. 33, # 3, p. 384 - 388
[20] Inorganica Chimica Acta, 2015, vol. 433, p. 63 - 71
[21] Chemico-Biological Interactions, 2016, vol. 259, p. 154 - 159
[22] Patent: WO2017/9651, 2017, A1, . Location in patent: Page/Page column 84
32
[ 110-52-1 ]
[ 71-43-2 ]
[ 1200-03-9 ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium carbonate; potassium hydroxide In acetoneReflux
General procedure: 1,4-Dibromobutane, 1-bromo-4-fluorobutane, (2E)-1,4-dibromo-2-butene or 1-bromo-3-methyl-2-butene(3.0 mmol) was added to a solution of benzene (3a–d) or aniline (4a–d) (3.5 mmol), KOH(1 mmol), and K2CO3 (4 mmol) in acetone (20 mL), respectively. The reaction was heated atreflux detected with TLC. Then, the crude products were further purified by silica chromatography(CHCl3/MeOH 50/1) to give compounds 3a–d and 4a–d (Scheme 2).(4-Bromobutoxy) benzene (3a): White oil; yield: 75percent; m.p., 40–41 °C; 1H-NMR (CHCl3-d, 400 MHz) δ:1.74–1.78 (m, 2H), 1.80–1.86 (m, 2H), 3.51 (t, 2H, J = 8.0 Hz), 4.08 (t, 2H, J = 8.0 Hz), 6.99 (dd, 2H,mboxemphJ = 8.0 Hz, 2.4 Hz), 7.03 (dd, 1H, J = 8.0 Hz, 2.4 Hz), 7.37–7.40 (m, 2H).
Reference：
[1] Molecules, 2018, vol. 23, # 11,
33
[ 110-52-1 ]
[ 120-92-3 ]
[ 108-95-2 ]
[ 1200-03-9 ]
Reference：
[1] Patent: US4380546, 1983, A,
[2] Patent: US4456608, 1984, A,
34
[ 1927-71-5 ]
[ 110-52-1 ]
[ 1200-03-9 ]
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[1] Journal of the Indian Institute of Science, 1923, vol. 6, p. 54[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 997
[3] Journal of the American Chemical Society, 1922, vol. 44, p. 2649
35
[ 110-52-1 ]
[ 139-02-6 ]
[ 1200-03-9 ]
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[3] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 16, p. 2329 - 2336
[4] Molecular Pharmacology, 2005, vol. 68, # 5, p. 1254 - 1270
36
[ 110-52-1 ]
[ 105-53-3 ]
[ 4167-77-5 ]
Yield
Reaction Conditions
Operation in experiment
84%
With tetrabutyl ammonium fluoride; potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere
To a solution of 1 ,4-dibromobutane, diethylmalonate in DMF at r.t. under N2 were added K2CO3 and TBAF. The reaction mixture was then stirred at r.t. overnight. The reaction mixture was then quenched with cold water ((200. mL) and extracted with 10percent EtOAc/hexanes (3 x 150mL). The combined organic layers were washed with half- saturated brine (150 mL x 2) then brine (150 mL), dried over Na2S04 and filtered. The filtrate was concentrated to dryness and the residue was purified by flash silica gel column eluted with 2percent EtOAc/hexanes to give 36.7g (84percent yield) colorless oil.
75%
With potassium carbonate; 1-butyl-3-methylimidazolium Tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 16 h;
Step 1. To a solution of compound 16-1 (10 g, 62.4 mmol) in DMF (50 mL) was added 1,4- dibromobutane (14.8 g, 68.6 mmol), K2C03 (21.5 g, 155.8 mmol) and compound 16-2 (1.4 g, 6.2 mmol) at r.t. and stirred at r.t. for 16 h. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc (200 mL) and H20 (80 mL), the combined organic phase was dried and concentrated to give compound 16-3 as oil (10.0 g, Yield: 75percent). 'IT NMR (400 MHz, CDC13)
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[1] Tetrahedron Letters, 2005, vol. 46, # 4, p. 635 - 638
[2] Patent: WO2013/185202, 2013, A1, . Location in patent: Paragraph 00280; 00281
[3] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 96; 97
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[9] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7709 - 7717
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[12] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 10, p. 3187 - 3194
[13] Patent: US5453423, 1995, A,
[14] Patent: US4792563, 1988, A,
[15] Patent: EP2103592, 2009, A2, . Location in patent: Page/Page column 41-42
[16] Organic Process Research and Development, 2014, vol. 18, # 1, p. 26 - 35
[17] Organic and Biomolecular Chemistry, 2017, vol. 15, # 12, p. 2647 - 2654
[18] New Journal of Chemistry, 2017, vol. 41, # 15, p. 6991 - 6994
37
[ 110-52-1 ]
[ 105-53-3 ]
[ 132525-49-6 ]
[ 4167-77-5 ]
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[1] Zhurnal Obshchei Khimii, 1952, vol. 22, p. 1944,1951; engl. Ausg. S. 1993, 1998, 1999
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38
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[ 4167-77-5 ]
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[1] Journal of the American Chemical Society, 1987, vol. 109, p. 6825
39
[ 110-52-1 ]
[ 105-53-3 ]
[ 109-99-9 ]
[ 110-63-4 ]
[ 4167-77-5 ]
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[1] Chemistry Letters, 1987, p. 2235 - 2238
[2] Chemistry Letters, 1987, p. 2235 - 2238
40
[ 110-52-1 ]
[ 64-17-5 ]
[ 996-82-7 ]
[ 132525-49-6 ]
[ 4167-77-5 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1952, vol. 22, p. 1944,1951; engl. Ausg. S. 1993, 1998, 1999
41
[ 110-52-1 ]
[ 36589-61-4 ]
Reference：
[1] Journal of the American Chemical Society, 1936, vol. 58, p. 488
[2] Chemische Berichte, 1941, vol. 74, p. 1532
[3] Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases, 1982, vol. 78, p. 1331 - 1344
[4] Antimicrobial Agents and Chemotherapy, 2002, vol. 46, # 8, p. 2619 - 2626
42
[ 110-52-1 ]
[ 1123-40-6 ]
[ 20980-22-7 ]
[ 83928-76-1 ]
Reference：
[1] Archiv der Pharmazie, 1992, vol. 325, # 5, p. 313 - 315
43
[ 110-52-1 ]
[ 70500-72-0 ]
[ 203395-59-9 ]
Yield
Reaction Conditions
Operation in experiment
41%
With potassium carbonate In ethanolReflux
Intermediate 14:[0130] AICI3 (11.5 g, 86.3 mmol) was added portion-wise to a suspension of intermediate 13 (4.2 g, 16.6 mmol) in chlorobenzene (90 mL) at 0°C. The reaction mixture was gradually warmed to 120°C and stirred for 3 h. The mixture was poured into ice water and the resulting precipitate was collected by filtration, washed with water, and purified by flash chromatography on silica gel column (elution with DCM/MeOH = 60:1) to give 7-hydroxyquinolin-2(lH)-one (intermediate 14) (1.41 g, 53percent) as a white solid. Intermediate 15:
Reference：
[1] Organic Process Research and Development, 2018, vol. 22, # 11, p. 1471 - 1480
[2] Patent: WO2012/3418, 2012, A2, . Location in patent: Page/Page column 51
[3] Journal of Medicinal Chemistry, 1998, vol. 41, # 5, p. 658 - 667
[4] Patent: WO2008/24481, 2008, A2, . Location in patent: Page/Page column 42
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 16, p. 7141 - 7153
44
[ 110-52-1 ]
[ 22246-18-0 ]
[ 129722-34-5 ]
Yield
Reaction Conditions
Operation in experiment
80.95%
With potassium carbonate In N,N-dimethyl-formamide at 30 - 45℃; for 6 - 7 h;
Example-l; <n="10"/>Preparation of 7-(4-bromobutoxy)- 3,4- dihydro carbostyril [ BBQ]:In a 3 -Liter capacity multi necked flask equipped with mechanical stirrer, condenser, thermometer, were charged 100 gm of 7 - HQ, 397.5 gm of 1,4- dibromobutane, 42.33 gm of potassium carbonate and 300 ml of N,N-dimethyl formamide at RT (30 - 35°C).The reaction mass was heated up to 40-45 0C and maintained for 1 hour at 40 - 450C. After that second lot of potassium carbonate (42.33 gm) was added. The reaction mass was further maintained for 1 hour. After that third lot of potassium carbonate (42.33 gm) was added and further maintained at 40 - 450C for 4 - 5 hours. The reaction mass was cooled to room temperature and dumped into 1500 ml of water. The reaction mass was stirred for 30 minutes and to it were added 500 ml of chloroform , layers were separated and aq. phase is further extracted with 500 ml of chloroform. Layers were separated and organic phases were combined and washed with 10 percent NaOH solution. Layers were separated and chloroform layer was washed with 1500 ml water and organic phase was distilled out under vacuum. The traces were swapped with 2x250 ml of cyclohexane. To the reaction mass were added 300 ml of cyclohexane and stirred for 3 hours. The solid material was filtered and washed with 200 ml of cyclohexane. T he material was dried in tray dryer at about 65-700C for about 10 to 12 hours till loss on diying was less than 1 percentWeight of product: 148 gms Yield is 80.95percent; Purity 86.09 percent by HPLC
75.5%
With potassium carbonate In propan-1-ol for 6 h; Heating / reflux
Example 10; Preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (7-BBQ) by Reaction of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone with 1,4-dibromobutane in 1-propanol in the Presence of potassium carbonate; A mixture of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (10 g, 0.061 mole), 1,4-dibromobutane (22.2 ml, 39.75 g, 0.184 mole. 3 eq.) and potassium carbonate (9.32 g, 0.067 mole, 1.1 eq.) in 1-propanol (100 ml) was heated under reflux for 6 hours (the reaction mixture contained 9.6percent of BQB after reaction completion). The hot reaction mixture was then filtered and the solid was washed with hot 1-propanol (3.x.20 ml). The solvent and the excess of 1,4-dichlorobutane were removed to dryness by evaporation in vacuum. 2-Propanol (50 ml) was added to the residue thus obtained and the mixing was maintained at 5-10° C. for 3 hours. A precipitate was then collected by filtration and dried at 50° C. under reduced pressure overnight to give crude 7-BBQ (16.5 g, 90.7percent yield, containing 11.0percent of BQB). The crude 7-BBQ (16.5 g) was slurried in ethyl acetate (230 ml) at room temperature for 8 hours. A precipitate (BQB) was collected by filtration and washed with ethyl acetate (3.x.15 ml). The ethyl acetate was removed to dryness by evaporation under reduced pressure to give 7-BBQ (13.72 g, 75.5percent total yield, containing 1.8percent of BQB). Melting point=110-111° C.
74%
With potassium carbonate In ethanolReflux
Intermediate 4:[0118] 7-hydroxy-3,4-dihydroquinolin-2(lH)-one (163 mg, 1.0 mmol), 1,4- dibromobutane (0.36 mL, 3.0 mmol) and anhydrous K2C03 (138 mg, 1.0 mmol) were dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated NaHC03, brine, dried over anhydrous Na2S04, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE EtOAc = 2: 1) to give 7-(4-bromobutoxy)-3,4-dihydroquinolin- 2(lH)-one (intermediate 4) (220 mg, 74percent) as a white solid, mp: 106-109°C.
73.3%
With potassium carbonate In water; acetonitrile for 4 h; Reflux
40 g of acetonitrile was added to 82 g (0.5 mol) of 7-hydroxy-3,4-dihydrocarbostyril,to this,After adding a potassium carbonate aqueous solution (a solution obtained by dissolving 69 g (0.5 mol) of potassium carbonate in 204 g of water)further,324 g (1.5 mol) of 1,4-dibromobutane was added,Refluxed for 6 hours.This reaction solution was concentrated under reduced pressure,408 g of 2-propanol was added to the residue,After stirring at 10 ° C. or less for 1 hour,204 g of water was added,The mixture was stirred at 10 ° C. or less for 1 hour for crystallization and filtration.The obtained crystals were dried at 80 ° C.,109 g (yield: 73.3percent) of 7- (4-bromobutoxy) -3,4-dihydrocarbostyril was obtained.
72%
With potassium carbonate; sodium sulfate In toluene for 2 h; Heating / reflux
Example 11; Preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (7-BBQ) by reaction of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone with 1,4-dibromobutane in the Presence of Phase Transfer Catalyst; A reactor was charged with 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (50 g, 0.307 mole), 1,4-dibromobutane (98percent purity, 110.8 ml, 198.7 g, 0.92 mol, 3 eq.), potassium carbonate (55.1 g, 0.399 mole, 1.3 eq.), tricaprylylmethylammonium chloride (Aliquat.(R). 336) (5 g), sodium sulfate (30 g), water (250 ml) and toluene (75 ml) and the mixture was heated under reflux for 2 hours (the reaction mixture contained 12.1percent of BQB after reaction completion). The organic phase was collected and the solvent and an excess of 1,4-dibromobutane were removed from to dryness by evaporation in vacuum. 2-Propanol (270 ml) was added to the residue thus obtained and the mixture was stirred at 5-10° C. for 5 hours. A precipitate was then collected by filtration, washed with cold 2-propanol (2.x.35 ml) and dried at 50° C. overnight to give crude 7-BBQ (82.3 g, 90.0percent yield, containing 14.3percent of BQB). The crude 7-CBQ (82.3 g) was slurried in ethyl acetate (1150 ml) at room temperature for 8 hours. A precipitate (BQB) was collected by filtration and washed with ethyl acetate (2.x.100 ml). The ethyl acetate was removed from the filtrate to dryness by evaporation under reduced pressure and the colorless solid thus obtained was dried at 60° C. overnight to give 7-BBQ (65.9 g, 72.0percent total yield, containing 1.9percent of BQB). Melting point=110-111° C.
72%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 12 h;
Example 1; 7-(4-Bromobutoxy)-3,4-dihydroquinolinone-2(1H)-one (3) (Scheme 1); To a stirred suspension of anhydrous potassium carbonate (K2CO3) (10.50 g, 0.075 mol) in 100 mL of anhydrous N,N-dimethylformamide (DMF) was added 7-hydroxyquinolinone 1 (10.00 g, 0.06 mol) followed by 1,4-dibromobutane 2 (25.91 g, 0.12 mol). The resulting mixture was heated at 60° C. for 12 h. The progress of the reaction was monitored by thin layer chromatography (TLC) technique. After cooling to room temperature, the reaction mixture was filtered through a sintered funnel and the precipitate was washed with ethyl acetate (25 mL.x.2). The combined filtrate was concentrated on a rotavapor. The residue was diluted with 250 mL of ethyl acetate, washed with water (100 mL.x.2), dried over anhydrous magnesium sulfate and evaporated the solvent. The residue was triturated with hexane and then filtered the precipitate to give the pure title compound 3. White solid, 12.88 g (72percent). 1H NMR (400 MHz, CDCl3): δ 1.92-1.97 (m, 2H); 2.05-2.10 (m, 2H); 2.64 (t, J=9.2 Hz, 2H); 2.92 (t, J=9.2 Hz, 2H); 3.50 (t, J=7.6 Hz, 2H); 3.98 (t, J=7.6 Hz, 2H); 6.37 (d, J=3.2 Hz, 1H); 6.50-6.54 (m, 1H); 7.04 (d, J=11.2 Hz, 1H), 8.61 (broad s, 1H).
68.7%
With potassium carbonate In acetonitrile at 60 - 65℃; Inert atmosphere
General procedure: The appropriate dibromoalkane derivative 2a–2d (4.4 mmol)was added to a mixture of the starting material 7-hydroxy-3,4-dihydro-2(1H)-quinoline (1) (2.0 mmol), anhydrous K2CO3(290 mg, 2.1 mmol) in CH3CN (8 mL). The reaction mixture washeated to 60–65 C and stirred for 8–10 h under an argon atmosphere.After complete reaction, the solvent was evaporated underreduced pressure. Water (30 mL) was added to the residue and themixture was extracted with dichloromethane (30 mL 3). Thecombined organic phases were washed with saturated aqueoussodium chloride, dried over sodium sulfate, and filtered. The solventwas evaporated to dryness under reduced pressure. The residuewas purified on a silica gel chromatography usingdichloromethane/acetone (50:1) as eluent to give the intermediates3a–3d.
55%
With potassium hydroxide In isopropyl alcohol for 16 h; Reflux
Potassium hydroxide (0.120 g, 2.139 mmol) was added to a solution of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (0.200 g, 1.226 mmol) in 2-propanol (3 mL). After a clear solution was obtained, 1,4-dibromobutane (0.44 mL, 3.685 mmol) was added and the mixture was refluxed for 16 h. It was then cooled, diluted with ethyl acetate and filtered. The filtrate was concentrated to provide a crude residue which was purified by chromatography on neutral alumina (20percent acetone in dichloromethane) to give the title compound as a white solid (0.200 g, 55percent). 1H NMR (400 MHz, CDCl3) δ 1.87-1.98 (m, 2H), 2.00-2.10 (m, 2H), 2.62 (t, J=7.7 Hz, 2H), 2.90 (t, J=7.5 Hz, 2H), 3.49 (t, J=6.8 Hz, 2H), 3.97 (t, J=6.0 Hz, 2H), 6.29 (d, J=2.1 Hz, 1H), 6.52 (dd, J=8.3, 2.5 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 7.69 (br, exchangeable with D2O, 1H); IR (KBr) υ 2928, 1677, 1631, 1594, 1383 cm-1; MS 298, 300 [(M+1), (M+3)].
32%
With potassium carbonate In N,N-dimethyl-formamide at 50℃;
To a mixture of 7-hydroxy-3,4-dihydroquinolin-2(lH)-one (23-1) (14.0 g, 85.9 mmol, 1.0 eq) and potassium carbonate (17.8 g, 129 mmol, 1.5 eq) in N,N-dimethylformamide (200 mL) was added 1,4-dibromobutane (46.0 g, 215 mmol, 2.5 eq). The mixture was stirred at 50 °C overnight. The reaction mixture was poured into 500 mL of water, extracted with ethyl acetate (200 mL x 2), dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5: 1) to give compound 23-2 as a white solid (8.2 g, yield: 32 percent). MS (ESI): m/z 298, 300 [M+H]+.
93 g
With potassium carbonate In water; N,N-dimethyl-formamide at 25 - 30℃; for 19 h;
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (75 gm), 1 ,4-dibromobutane (196.6 gm), potassium carbonate (90 gm), dimethylformamide (375 ml) and water (37.5 ml) was stirred for 19 hrs at 25-30°C. Dichloromethane was added to the reaction mixture at 25- 30°C and stirred for 30 min at the same temperature. Filtered the unwanted solid and extracted the desired compound trapper in the unwanted solid by using dichloromethane. Combined the obtained dichloromethane solution with the above obtained filtrate. Water was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer and co-distilled with cyclohexane. Cyclohexane (75 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the solid, washed with cyclohexane and dried the material to get the title compound. Yield: 93.0 gm.
Reference：
[1] Asian Journal of Chemistry, 2011, vol. 23, # 4, p. 1655 - 1660
[2] Arzneimittel-Forschung/Drug Research, 2006, vol. 56, # 10, p. 673 - 677
[3] Patent: WO2008/1188, 2008, A2, . Location in patent: Page/Page column 8-9
[4] Journal of Medicinal Chemistry, 1998, vol. 41, # 5, p. 658 - 667
[5] Patent: US2006/79689, 2006, A1, . Location in patent: Page/Page column 11
[6] Patent: WO2012/3418, 2012, A2, . Location in patent: Page/Page column 45
[7] Patent: JP2016/69349, 2016, A, . Location in patent: Paragraph 0019; 0020
[8] Patent: US2006/79689, 2006, A1, . Location in patent: Page/Page column 11
[9] Patent: US2008/293736, 2008, A1, . Location in patent: Page/Page column 24
[10] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 12, p. 3006 - 3017
[11] Heterocyclic Communications, 2005, vol. 11, # 6, p. 485 - 490
[12] Patent: US2010/69399, 2010, A1, . Location in patent: Page/Page column 26
[13] Patent: WO2013/169964, 2013, A1, . Location in patent: Paragraph 00287; 00288; 00367; 00368
[14] Patent: US5006528, 1991, A,
[15] Patent: US2010/113784, 2010, A1, . Location in patent: Page/Page column 4-5
[16] Patent: US2010/130744, 2010, A1, . Location in patent: Page/Page column 3
[17] Patent: WO2011/30213, 2011, A1, . Location in patent: Page/Page column 8
[18] Asian Journal of Chemistry, 2013, vol. 25, # 14, p. 7959 - 7966
[19] Journal of Labelled Compounds and Radiopharmaceuticals, 2015, vol. 58, # 7, p. 304 - 307
[20] Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2890 - 2907
[21] Patent: WO2018/87775, 2018, A1, . Location in patent: Page/Page column 36-37
[22] Monatshefte fur Chemie, 2018, vol. 149, # 11, p. 2069 - 2084
45
[ 110-52-1 ]
[ 129722-34-5 ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate In acetoneReflux
General procedure: 1,3-dibromopropane (1,4-dibromobutane; 1,5-dibromopentane; 1,6-dibromohexane; 20 mmol) was added to asolution of compounds 6 (10 mmol) and potassium carbonate(20 mmol) in acetone (100 mL), and the mixture was refluxed for4e6 h. The progress of the reaction was monitored by TLC. Aftercooling to room temperature, the mixture was filtered, the solventwas evaporated under reduced pressure. The crude product waspurified by means of chromatography (petroleum ether/EtOAc 10/1) to yield compounds 8ae8d. 6.1.1.2. 7-(4-Bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (8b).Yield: 91percent. White solid, m. p. 110e112 C. 1H NMR (400 MHz, CDCl3)d 10.05 (s, 1H), 7.01 (d, J 8.2 Hz, 1H), 6.49 (dd, J 8.2, 2.3 Hz, 1H),6.45 (d, J 2.2 Hz, 1H), 3.91 (t, J 6.0 Hz, 2H), 3.45 (t, J 6.6 Hz, 2H),2.87 (t, J 7.5 Hz, 2H), 2.61 (t, J 7.5 Hz, 2H), 2.05e1.98 (m, 2H),1.91e1.84 (m, 2H). 13C NMR (100 MHz, CDCl3) d 173.00, 158.47,138.41, 128.55, 115.75, 108.71, 102.35, 66.94, 33.65, 31.04, 29.45,27.89, 24.53. MS (ESI) m/z 298.1 ([M H]).
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 79, p. 216 - 230
46
[ 110-52-1 ]
[ 22246-18-0 ]
[ 129722-34-5 ]
Yield
Reaction Conditions
Operation in experiment
66.8%
With sodium hydroxide In ISOPROPYLAMIDE at 36 - 40℃; for 4 h;
1,4-dibromo butane (509 ml) was added to a stirred solution of 7-hydroxy-3,4-dihydrocarbostyril (100 gm) in dimethylacetamide (500 ml) at ambient temperature. The reaction mixture was heated at 36° to 40° C. Sodium hydroxide (33.1 gm) was added to the reaction mixture at the interval of 30 min (Complete the addition of sodium hydroxide in 9 equal fractions in 4.0 hours). The reaction mixture was cooled at ambient temperature and D.M Water was added to it. The reaction mixture was extracted with ethylacetate. Organic layer was separated and washed with 5percent brine and finally dried over sodium sulphate. The organic layer was evaporated to dryness under reduced pressure (10 mm) at 45° C. to obtain residue. To the residue cyclohexane (1000 ml) was added to give of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril. Yield: 122.0 gms (66.8percent) Dimer content: 5.0-8.0percent
66%
Stage #1: With potassium carbonate In acetonitrile for 2 h; Heating / reflux Stage #2: With tetra-(n-butyl)ammonium iodide In acetonitrile for 2 - 4 h; Heating / reflux
Example 1; A mixture of 7-hydroxy 3,4-dihydrocarbostyril (5Og, 0.306 mole, 1 eq.), anhydrous potassium carbonate (50.7 g, 0.367 mole, 1.2 eq.) in acetonitrile (750 ml) was heated under reflux for 2 hours, the hot reaction mixture cooled to 25-3O0CA mixture of dibromo butane (20Og, 0.926 mole, 3.02 eq.), tetrabutylammonium iodide (2.2g, 0.006 mole, 0.02eq.) in acetonitrile (250 ml) was heated under reflux for 15 min, the <n="10"/>0003109above potassium salt of 7-hydroxy 3,4-dihydrocarbostyril added to it. The resultant mixture was heated under reflux for 2-4 hrs, monitored by HPLC till 7-hydroxy 3,4- dihydrocarbostyril is present less than 1.0percent, (the reaction mixture contained 14-15 percent of the dimer impurity), mixture was cooled to 25-3O0C1 filtered, residue washed with acetonitrile (250 ml), the filtrate was concentrated, dichloromethane (750 ml) was added to it, Hydrogen chloride gas was purged into it, the filtrate was monitored by HPLC for dimer content to be less than 0.5 percent, carbon (5g) was added to the solution, filtered through celite bed .water (250 ml) was added to the filtrate, pH of the solution was adjusted to 6.8-7.5 using 20percent potassium carbonate solution, the organic layer separated , washed with water (250 ml), washed with 20percent brine solution (250 ml). The organic layer further concentrated, cyclohexane (500 ml) was added to it, stirred for 15 minutes, then cooled to 5-100C, the solid was filtered, washed with cyclohexane (100 ml), dried under vacuum at 40-450C, for 5-6 hours, to give 7-(4- Bromo butoxy)-3,4-dihydro carbostyril (62 g, yield 66percent, purity by HPLC 97.4 percent, dimer impurity 0.28percent).
55%
Stage #1: With potassium carbonate In acetonitrile for 2 h; Heating / reflux Stage #2: With tetra-(n-butyl)ammonium iodide In acetonitrile for 2 - 4 h; Heating / reflux
Example 2; A mixture of 7-hydroxy 3,4-dihydrocarbostyril (5Og, 0.306 mole, 1 eq.), anhydrous potassium carbonate (50.7 g, 0.367 mole, 1.2 eq.) in acetonitrile (750 ml) was heated under reflux for 2 hours, the hot reaction mixture cooled to 25-300CA mixture of dibromo butane (20Og, 0.926 mole, 3.02 eq.), tetrabutylammonium iodide (2.2g, 0.006 mole, 0.02eq.) in acetonitrile (250 ml) was heated under reflux for 15 min, the above potassium salt of 7-hydroxy 3,4-dihydrocarbostyril added to it. The resultant mixture heated under reflux for 2-4 hrs, monitored by HPLC till 7-hydroxy 3,4- dihydrocarbostyril is present less than 1.0percent, (the reaction mixture contained 14-15 percent of the dimer impurity), mixture was cooled to 25-300C, filtered, residue washed with acetonitrile (250 ml), the filtrate was concentrated, dichloromethane (750 ml) was added to it, sulphuric acid (55g) was added to it, the filtrate was monitored by HPLC for dimer content to be less than 0.5 percent, carbon (5g) was added to the <n="11"/>N2007/00031010solution, filtered through celite bed .water (250 ml) was added to the filtrate, pH of the solution was adjusted to 6.8-7.5 using 20percent potassium carbonate solution, the organic layer separated , washed with water (250 ml), washed with 20percent brine solution (250 ml). The organic layer further concentrated, cyclohexane (500 ml) was added to it, stirred for 15 minutes, then cooled to 5-100C, the solid was filtered, washed with cyclohexane (100 ml), dried under vacuum at 40-450C, for 5-6 hours, to give 7-(4- Bromo butoxy)-3,4-dihydro carbostyril (52 g, yield 55percent, purity by HPLC 98.05 percent, dimer impurity 0.08percent).
Reference：
[1] Patent: US2006/258869, 2006, A1, . Location in patent: Page/Page column 3-5
[2] Patent: WO2008/26220, 2008, A1, . Location in patent: Page/Page column 8-9
[3] Patent: WO2008/26220, 2008, A1, . Location in patent: Page/Page column 9-10
[4] Patent: WO2008/146156, 2008, A2, . Location in patent: Page/Page column 6-10
[5] Journal of Labelled Compounds and Radiopharmaceuticals, 2015, vol. 58, # 7, p. 304 - 307
47
[ 110-52-1 ]
[ 129722-34-5 ]
Yield
Reaction Conditions
Operation in experiment
73.8%
Stage #1: With sodium hydroxide In isopropyl alcohol at 25 - 30℃; for 0.5 h; Stage #2: With tetrabutylammomium bromide In isopropyl alcohol at 80 - 85℃; for 3 h;
EXAMPLE-XIII: Preparation of Aripiprazole p-toluenesulfonate; Step-1; Sodium hydroxide (29.5 g, 0.737 mole) is added to a suspension of 7-Hydroxy carbostyril (100 g, 0.613 mole) in isopropyl alcohol (1850 ml) and mixed at 250C to 300C for about 30 min. Tetra butyl ammonium bromide is added (5 g, 0.015 mole) followed by 1,4-Dibromo butane (530 g, 2.45 mole), raised to reflux and maintained at reflux temperature 8O0C - 850C for 3 hrs. The insolubles are filtered in hot condition, and isopropyl alcohol is distilled off from the filtrate under vacuum at temperature up to 1100C - 115°C. The reaction mass is .cooled and isopropyl alcohol (300 ml) is added to the reaction mass, maintained at 300C - 35°C for 1 hr. The mass is further cooled and maintained at 2O0C- 22°C for 2 hrs, filtered, washed with isopropyl alcohol (50 ml) to give the wet cake of about 250 g. The wet cake (250 g) is suspended in n- hexane (300 ml) , raised the temperature to reflux and maintained for about 60min. The reaction mass is cooled to a temperature of 250C - 35°C and maintained for 1 hr. The mass is filtered; washed and dried the wet cake at 40°C to 500C till becomes constant weight.The dry weight of 7- (4-bromobutoxy) -3, 4-dihydrocarbostyril is 135 g (Yield: 73.8percent) .
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 27, p. 8700 - 8703
[2] Synthetic Communications, 2012, vol. 42, # 17, p. 2512 - 2525
[3] Chemical Communications, 2018, vol. 54, # 50, p. 6939 - 6942
[4] Chemistry - A European Journal, 2018, vol. 24, # 52, p. 13778 - 13782
49
[ 110-52-1 ]
[ 1989-33-9 ]
[ 373-88-6 ]
[ 182438-98-8 ]
Yield
Reaction Conditions
Operation in experiment
155 g
Stage #1: With sodium t-butanolate In toluene at 5 - 30℃; for 3 h; Inert atmosphere Stage #2: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 25 - 30℃; for 2 h; Stage #3: With sodium carbonate In dichloromethane; water at 5 - 10℃; for 0.75 h;
A mixture of 9H-fluorene-9-carboxylic acid compound of formula-2a (100 gm), 1,4-dibromobutane (308 gm) and toluene (1000 ml) was stirred for 15 mm at 25-30°C undernitrogen atmosphere. Cooled the reaction mixture to 5-10°C, sodium tert.butoxide (100.5 gm) was slowly added to it and stirred the reaction mixture for 3 hrs at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 15 mm at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with water. Both the organic and aqueous layers were separated and washed the aqueouslayer with toluene. Acidified the aqueous layer using aqueous hydrochloric acid solution at25-30°C aiid stirred the reaction mixture for 20 mm at the same temperature. Dichioromethane was added to the reaction mixture at 25-30°C and stirred for 15 mm at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous citric acid solution. Distilled off the solvent completely from theorganic layer. Dichioromethane (500 ml) was added to the reaction mixture at 25-30°C and stirred for 15 mm at the same temperature. N,N-dimethylformamide (6.9 gm) followed by oxalyl chloride (66.4 gm) were slowly added to the reaction mixture at 25-30°C and stirred for 2 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under nitrogen atmosphere and co-distilled with dichloromethane under reducedpressure. Dichloromethane (500 ml) was added to the obtained compound at 25-30°C and stirred for .15 mm at the same temperature. The obtained compound was slowly added to a pre-cooled mixture of water (500 ml), 2,2,2-trifluoroethylamine hydrochloride (64.4 gm) and sodium carbonate (75.6 gm) at 5-10°C and stirred the reaction mixture for 45 mm at the same temperature. Both the organic and aqueous layers were separated and washed the organiclayer with aqueous hydrochloric acid solution followed by with aqueous sodium bicarbonate solution and then finally washed with water. Distilled off the solvent completely from the organic layer and then co-distilled with n-heptane under reduced pressure. n-Heptane (100 ml) and isopropanol (5 ml) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 1 hr at the same temperature. Cooled the reaction ttiture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the precipitatedsolid, washed with n-heptäne and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-5.Yield: 155.0 gm; M.R: 95-102°C.
With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride; In water; toluene; at 0 - 20℃;
(1) 1-(Aminomethyl)cyclopentylamine dihydrochloride To a mixture of benzyltriethylammonium chloride (500 mg, 2.20 mmol) and 50% aqueous sodium hydroxide solution (18.2 g, 22.7 mmol) was added dropwise a solution of <strong>[70591-20-7]N-(diphenylmethylene)aminoacetonitrile</strong> (5.00 g, 22.7 mmol) and 1,4-dibromobutane (5.88 g, 27.3 mmol) in toluene (10 mL) under ice-cooling. After stirring at room temperature overnight, the mixture was added with water, and extracted three times with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1). 1-Cyano-1-[N-(diphenylmethylene)amino]cyclopentane was dissolved in THF (200 mL), and the solution was added with 2 mol/L hydrochloric acid (4 mL) and stirred at room temperature overnight. After the reaction mixture was washed twice with chloroform, the aqueous layer was concentrated to obtain a solid (1.58 g). The obtained solid was dissolved in ethanol (200 mL), and platinum dioxide (270 mg) and concentrated hydrochloric acid (5.35 mL) were added to the solution. And the mixture was allowed to react under hydrogen (50 psi) at 36 DEG C overnight. The reaction mixture was filtered using Celite as a filtration aid. The filtrate was concentrated, and the obtained product was recrystallized from 2-propanol to obtain the title compound (1.21 g, 6.44 mmol).yield: 28%<1>H NMR (D2O) delta (ppm): 3.28 (2H, s), 1.85-1.72 (8H, m).APCIMS (m/z): 115 (M + H)<+>
With potassium iodide; sodium hydroxide; In acetonitrile; at 30℃; for 16h;
5 mmol of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one,5mmol 1,4-dibromobutane,5mmol sodium hydroxide,0.2 mmol of potassium iodide was added to acetonitrile and stirred at 30 ° C for 16 h.After the reaction is filtered,The filtrate is concentrated,85percent by column chromatography7-(4-Bromobutoxy)-3,4-dihydroquinolin-2(1H)-one.
80.95%
With potassium carbonate; In N,N-dimethyl-formamide; at 30 - 45℃; for 6 - 7h;
Example-l; <n="10"/>Preparation of 7-(4-bromobutoxy)- 3,4- dihydro carbostyril [ BBQ]:In a 3 -Liter capacity multi necked flask equipped with mechanical stirrer, condenser, thermometer, were charged 100 gm of 7 - HQ, 397.5 gm of 1,4- dibromobutane, 42.33 gm of potassium carbonate and 300 ml of N,N-dimethyl formamide at RT (30 - 35°C).The reaction mass was heated up to 40-45 0C and maintained for 1 hour at 40 - 450C. After that second lot of potassium carbonate (42.33 gm) was added. The reaction mass was further maintained for 1 hour. After that third lot of potassium carbonate (42.33 gm) was added and further maintained at 40 - 450C for 4 - 5 hours. The reaction mass was cooled to room temperature and dumped into 1500 ml of water. The reaction mass was stirred for 30 minutes and to it were added 500 ml of chloroform , layers were separated and aq. phase is further extracted with 500 ml of chloroform. Layers were separated and organic phases were combined and washed with 10 percent NaOH solution. Layers were separated and chloroform layer was washed with 1500 ml water and organic phase was distilled out under vacuum. The traces were swapped with 2x250 ml of cyclohexane. To the reaction mass were added 300 ml of cyclohexane and stirred for 3 hours. The solid material was filtered and washed with 200 ml of cyclohexane. T he material was dried in tray dryer at about 65-700C for about 10 to 12 hours till loss on diying was less than 1 percentWeight of product: 148 gms Yield is 80.95percent; Purity 86.09 percent by HPLC
75.5%
With potassium carbonate; In propan-1-ol; for 6h;Heating / reflux;Product distribution / selectivity;
Example 10; Preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (7-BBQ) by Reaction of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone with 1,4-dibromobutane in 1-propanol in the Presence of potassium carbonate; A mixture of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (10 g, 0.061 mole), 1,4-dibromobutane (22.2 ml, 39.75 g, 0.184 mole. 3 eq.) and potassium carbonate (9.32 g, 0.067 mole, 1.1 eq.) in 1-propanol (100 ml) was heated under reflux for 6 hours (the reaction mixture contained 9.6percent of BQB after reaction completion). The hot reaction mixture was then filtered and the solid was washed with hot 1-propanol (3.x.20 ml). The solvent and the excess of 1,4-dichlorobutane were removed to dryness by evaporation in vacuum. 2-Propanol (50 ml) was added to the residue thus obtained and the mixing was maintained at 5-10° C. for 3 hours. A precipitate was then collected by filtration and dried at 50° C. under reduced pressure overnight to give crude 7-BBQ (16.5 g, 90.7percent yield, containing 11.0percent of BQB). The crude 7-BBQ (16.5 g) was slurried in ethyl acetate (230 ml) at room temperature for 8 hours. A precipitate (BQB) was collected by filtration and washed with ethyl acetate (3.x.15 ml). The ethyl acetate was removed to dryness by evaporation under reduced pressure to give 7-BBQ (13.72 g, 75.5percent total yield, containing 1.8percent of BQB). Melting point=110-111° C.
74%
With potassium carbonate; In ethanol;Reflux;
Intermediate 4:[0118] 7-hydroxy-3,4-dihydroquinolin-2(lH)-one (163 mg, 1.0 mmol), 1,4- dibromobutane (0.36 mL, 3.0 mmol) and anhydrous K2C03 (138 mg, 1.0 mmol) were dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated NaHC03, brine, dried over anhydrous Na2S04, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE EtOAc = 2: 1) to give 7-(4-bromobutoxy)-3,4-dihydroquinolin- 2(lH)-one (intermediate 4) (220 mg, 74percent) as a white solid, mp: 106-109°C.
73.3%
With potassium carbonate; In water; acetonitrile; for 4h;Reflux;
40 g of acetonitrile was added to 82 g (0.5 mol) of 7-hydroxy-3,4-dihydrocarbostyril,to this,After adding a potassium carbonate aqueous solution (a solution obtained by dissolving 69 g (0.5 mol) of potassium carbonate in 204 g of water)further,324 g (1.5 mol) of 1,4-dibromobutane was added,Refluxed for 6 hours.This reaction solution was concentrated under reduced pressure,408 g of 2-propanol was added to the residue,After stirring at 10 ° C. or less for 1 hour,204 g of water was added,The mixture was stirred at 10 ° C. or less for 1 hour for crystallization and filtration.The obtained crystals were dried at 80 ° C.,109 g (yield: 73.3percent) of 7- (4-bromobutoxy) -3,4-dihydrocarbostyril was obtained.
72%
With potassium carbonate; sodium sulfate;Aliquat 336; In toluene; for 2h;Heating / reflux;Product distribution / selectivity;
Example 11; Preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (7-BBQ) by reaction of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone with 1,4-dibromobutane in the Presence of Phase Transfer Catalyst; A reactor was charged with 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (50 g, 0.307 mole), 1,4-dibromobutane (98percent purity, 110.8 ml, 198.7 g, 0.92 mol, 3 eq.), potassium carbonate (55.1 g, 0.399 mole, 1.3 eq.), tricaprylylmethylammonium chloride (Aliquat.(R). 336) (5 g), sodium sulfate (30 g), water (250 ml) and toluene (75 ml) and the mixture was heated under reflux for 2 hours (the reaction mixture contained 12.1percent of BQB after reaction completion). The organic phase was collected and the solvent and an excess of 1,4-dibromobutane were removed from to dryness by evaporation in vacuum. 2-Propanol (270 ml) was added to the residue thus obtained and the mixture was stirred at 5-10° C. for 5 hours. A precipitate was then collected by filtration, washed with cold 2-propanol (2.x.35 ml) and dried at 50° C. overnight to give crude 7-BBQ (82.3 g, 90.0percent yield, containing 14.3percent of BQB). The crude 7-CBQ (82.3 g) was slurried in ethyl acetate (1150 ml) at room temperature for 8 hours. A precipitate (BQB) was collected by filtration and washed with ethyl acetate (2.x.100 ml). The ethyl acetate was removed from the filtrate to dryness by evaporation under reduced pressure and the colorless solid thus obtained was dried at 60° C. overnight to give 7-BBQ (65.9 g, 72.0percent total yield, containing 1.9percent of BQB). Melting point=110-111° C.
72%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 12h;
Example 1; 7-(4-Bromobutoxy)-3,4-dihydroquinolinone-2(1H)-one (3) (Scheme 1); To a stirred suspension of anhydrous potassium carbonate (K2CO3) (10.50 g, 0.075 mol) in 100 mL of anhydrous N,N-dimethylformamide (DMF) was added 7-hydroxyquinolinone 1 (10.00 g, 0.06 mol) followed by 1,4-dibromobutane 2 (25.91 g, 0.12 mol). The resulting mixture was heated at 60° C. for 12 h. The progress of the reaction was monitored by thin layer chromatography (TLC) technique. After cooling to room temperature, the reaction mixture was filtered through a sintered funnel and the precipitate was washed with ethyl acetate (25 mL.x.2). The combined filtrate was concentrated on a rotavapor. The residue was diluted with 250 mL of ethyl acetate, washed with water (100 mL.x.2), dried over anhydrous magnesium sulfate and evaporated the solvent. The residue was triturated with hexane and then filtered the precipitate to give the pure title compound 3. White solid, 12.88 g (72percent). 1H NMR (400 MHz, CDCl3): delta 1.92-1.97 (m, 2H); 2.05-2.10 (m, 2H); 2.64 (t, J=9.2 Hz, 2H); 2.92 (t, J=9.2 Hz, 2H); 3.50 (t, J=7.6 Hz, 2H); 3.98 (t, J=7.6 Hz, 2H); 6.37 (d, J=3.2 Hz, 1H); 6.50-6.54 (m, 1H); 7.04 (d, J=11.2 Hz, 1H), 8.61 (broad s, 1H).
68.7%
With potassium carbonate; In acetonitrile; at 60 - 65℃;Inert atmosphere;
General procedure: The appropriate dibromoalkane derivative 2a?2d (4.4 mmol)was added to a mixture of the starting material 7-hydroxy-3,4-dihydro-2(1H)-quinoline (1) (2.0 mmol), anhydrous K2CO3(290 mg, 2.1 mmol) in CH3CN (8 mL). The reaction mixture washeated to 60?65 C and stirred for 8?10 h under an argon atmosphere.After complete reaction, the solvent was evaporated underreduced pressure. Water (30 mL) was added to the residue and themixture was extracted with dichloromethane (30 mL 3). Thecombined organic phases were washed with saturated aqueoussodium chloride, dried over sodium sulfate, and filtered. The solventwas evaporated to dryness under reduced pressure. The residuewas purified on a silica gel chromatography usingdichloromethane/acetone (50:1) as eluent to give the intermediates3a?3d.
55%
With potassium hydroxide; In isopropyl alcohol; for 16h;Reflux;
Potassium hydroxide (0.120 g, 2.139 mmol) was added to a solution of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (0.200 g, 1.226 mmol) in 2-propanol (3 mL). After a clear solution was obtained, 1,4-dibromobutane (0.44 mL, 3.685 mmol) was added and the mixture was refluxed for 16 h. It was then cooled, diluted with ethyl acetate and filtered. The filtrate was concentrated to provide a crude residue which was purified by chromatography on neutral alumina (20percent acetone in dichloromethane) to give the title compound as a white solid (0.200 g, 55percent). 1H NMR (400 MHz, CDCl3) delta 1.87-1.98 (m, 2H), 2.00-2.10 (m, 2H), 2.62 (t, J=7.7 Hz, 2H), 2.90 (t, J=7.5 Hz, 2H), 3.49 (t, J=6.8 Hz, 2H), 3.97 (t, J=6.0 Hz, 2H), 6.29 (d, J=2.1 Hz, 1H), 6.52 (dd, J=8.3, 2.5 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 7.69 (br, exchangeable with D2O, 1H); IR (KBr) upsilon 2928, 1677, 1631, 1594, 1383 cm-1; MS 298, 300 [(M+1), (M+3)].
32%
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;
To a mixture of 7-hydroxy-3,4-dihydroquinolin-2(lH)-one (23-1) (14.0 g, 85.9 mmol, 1.0 eq) and potassium carbonate (17.8 g, 129 mmol, 1.5 eq) in N,N-dimethylformamide (200 mL) was added 1,4-dibromobutane (46.0 g, 215 mmol, 2.5 eq). The mixture was stirred at 50 °C overnight. The reaction mixture was poured into 500 mL of water, extracted with ethyl acetate (200 mL x 2), dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5: 1) to give compound 23-2 as a white solid (8.2 g, yield: 32 percent). MS (ESI): m/z 298, 300 [M+H]+.
With potassium carbonate; In water;
Reference Example 6 To a solution of 4.06 g of potassium carbonate with 400 ml of water was added 40 g of 7-hydroxy-3,4-dihydrocarbostyril and 158 g of 1,4-dibromobutane, then the mixture was refluxed for 3 hours. The reaction mixture thus obtained was extracted with dichloromethane, dried with anhydrous magnesium sulfate, then the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane), and recrystallized from n-hexane-ethanol to yield 50 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril.
With potassium carbonate; In acetone; at 60 - 65℃; for 16h;
Example-1 Preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyryl The solution of 7-(4-hydroxy)-3,4-dihydrocarbostyryl (125 g), potassium carbonate (158.75 g) and 1,4-dibromobutane (662.5 g) was prepared in acetone (1375 mL) and refluxed at 60° C.-65° C. for 16 hours. After the completion of the reaction, the reaction mixture was cooled to 15° C.-20° C. and stirred for 1.0 h. Isolated solid was filtered and washed with chilled acetone (250 mL). The filtrate was distilled under vacuum at 60° C. to remove access of acetone and at 120° C. to remove traces of 1,4-dibromobutane. The oily residue were cooled at 40° C.-45° C. and treated with methylene dichloride and stirred for 15-20 minutes till clear solution was obtained. The reaction mixture was treated with 5percent NaOH and process water at 25° C.-35° C. and the organic layer was separated. The organic layer was further charcoalized and filtered through cilete bed. The filtrate was subjected to distillation under vacuum to remove excess of methylene dichloride. The resulting mass was treated with ethyl acetate (125 mL) and cyclohexane (500 mL) at 25° C.-35° C. and stirred for 1 h. The solid thus obtained was filtered, washed with cyclohexane and suck dried. The product was dried in hot air oven at 55° C.-60° C.
Example-1Step A:Preparation of Pure 7-(4-Bromobutoxy)-3,4-Dihydro-2(1H)-Quinolinone; (IV):7-Hydroxy-3,4-dihydro-2(1H)-quinolinone (20 g, 0.153 mol) was added to a solution of potassium carbonate (25 g, 0.181 mol) in DM water (400 ml) at 25-35° C. and the contents were heated to 80-90° C. to obtain a clear solution. 1,4-Dibromobutane (200 ml) was added to the reaction mass, heated to reflux temperature (100-105° C.) and stirred for 7 hours at the same temperature. After completion of reaction, reaction mass was cooled to ambient temperature and organic layer was separated. Organic layer containing 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone having 5percent 1,4-bis[3,4-dihydro-2(1H)quinolinon-7-oxy]butane (by HPLC, by area normalization) was washed with precooled 5percent w/v aqueous sodium hydroxide (75 ml) at 15-20° C., to remove unreacted 7-hydroxy-3,4-dihydro-2(1H)-quinolinone. Organic layer was concentrated at 90-105° C. under reduced pressure varying from 50 to 5 mm of Hg to dryness. The concentrated mass was diluted with toluene (2000 ml) and heated to 60° C. Silica gel (50 g) was added and stirred for 30 min at 60-70° C. Silica gel was removed by filtration and the filtrate was concentrated at 60-80° C. under reduced pressure varying from 200 to 10 mm of Hg. The resulting concentrated mass having 0.3percent of 1,4-bis[3,4-dihydro-2(1H)quinolinon-7-oxy]butane (by HPLC, by area normalization) was diluted with hexanes (50 ml) and stirred for 30 minutes to crystallize the product. Product was filtered and washed with hexanes.Yield: 18 gChromatographic purity: 97.89percent (by HPLC, by area normalization)1,4-Bis[3,4-dihydro-2(1H)quinolinone-7-oxy]butane content: 0.33percent
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In acetonitrile; at 40 - 45℃; for 24h;Product distribution / selectivity;
Example 1Preparation of 7-(4-bromobutoxy)-3,4-dihvdrocarbostyril7-Hydroxy-3,4-dihydrocarbostyril (60gm) and potassium carbonate (76.3 gm) were taken in acetonitrile (1200ml) at room temperature. To this tetra butyl ammonium iodide (13.7 gm) and 1 ,4-dibromobutane (238.5gm) were added and heated at 40- 45°C for 24 hours. Reaction mass was cooled upto room temperature and was filtered off. The resulting filtrate was distilled off under vacuum. The resultant mass was cooled to 25-30°C and cyclohexane (300 ml) was added under stirring. The resulting solid was filtered off and was dried. The resulting solid was taken in water and was stirred for few minutes. The solid was filtered and dried under vacuum at 55-60°C for 20 hours to obtain title compound.Yield: 73-75percent; Purity: 93-95percent
93 g
With potassium carbonate; In water; N,N-dimethyl-formamide; at 25 - 30℃; for 19h;
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (75 gm), 1 ,4-dibromobutane (196.6 gm), potassium carbonate (90 gm), dimethylformamide (375 ml) and water (37.5 ml) was stirred for 19 hrs at 25-30°C. Dichloromethane was added to the reaction mixture at 25- 30°C and stirred for 30 min at the same temperature. Filtered the unwanted solid and extracted the desired compound trapper in the unwanted solid by using dichloromethane. Combined the obtained dichloromethane solution with the above obtained filtrate. Water was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer and co-distilled with cyclohexane. Cyclohexane (75 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the solid, washed with cyclohexane and dried the material to get the title compound. Yield: 93.0 gm.
With potassium carbonate; In acetonitrile; for 15h;Heating / reflux;
The solution of N+-benzyloxycarbonyl-N-ter-butyloxycarbonyl hydrazine (4 g, 15 mmol) and 1,4-diabromobutane (5.8 g, 25.9 mmol) in acetonitrile (50 ml) was refluxed for 15 hrs in presence of potassium carbonate (4.2 g, 30 mmol). Reaction mixture was filtered, evaporated to dryness, purified by column chromatography (10percent ethylacetate-hexane, 4 g, yield: 83percent). The solution of obtained solid in 50percent methanol-water (100 ml) was stirred with 5percent palladium-charcoal (400 mg) at 50 psi for 6 hrs, filtered evaporated, and purified by column chromatography (ethylacetate 1.9 g, yield: 82percent). The solution of obtained N-ter-butyloxypyridazine (1 g, 5.3mmol) was stirred with 3-chloroacyl-4-cyanothiazolidine (1.5 g, 7.8 mmol) in tetrahydrofuran (60 ml) at room temperature for 5 hrs in presence of cesium carbonate (2.6 g, 7.8 mmol) and then heated at 55° C. for 30 hrs. Reaction mixture was filtered, evaporated, column chromatographed (35percent ethylacetate-hexane) yielded desired product (0.4 g, yield: 20percent). Obtained product stirred with trifluoroacetic acid for 10 minutes at 5-10° C. Trifluoroacetic acid removed in vacuo neutralised with aqueous sodium carbonate, extracted with ethylacetate. Dried organic layer was evaporated to dryness, purified by column chromatography (2percent methanol/dichloromethane) yielded 90 ml final compound (yield: 30percent).
In ethyl acetate; N,N-dimethyl-formamide;
EXAMPLE 8 STR35 Step A. Preparation of 1-Boc-2-Cbz-hexahydropyridazine 1.5 g (37.5 mmol) of 60percent sodium hydride in oil was suspended in 50 mL of DMF to which was added 5.0 g (18.7 mmol) of 1-Boc-2-Cbz-hydrazine dissolved in 20 mL of dry DMF slowly over 30 minutes. The reaction mixture was stirred for 1 hour until H2 evolution had ceased. To this mixture was added 2.24 mL (18.77 mmol) of 1,4-dibromobutane neat. The reaction mixture was stirred at room temperature over 3 days. The mixture was concentrated in vacuo and the residue was suspended in 150 mL of EtOAc. The mixture was washed with water twice, 5percent citric acid twice, saturated aqueous NaHCO3 solution, water and brine. The solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluding with 30percent EtOAc/hexanes to give the desired product as a white solid. 1 H-NMR (CDCl3, 400 MHz):1.45 (bs, 9H); 1.62 (bm, 4H); 2.90 (bs, 2H); 4.15 (bm, 2H); 5.00-5.30 (m, 2H); 7.20-7.40 (bm, 5H).
With sodium hydroxide; tetrabutylammomium bromide; In water;
Preparation Example 2 Into a 2 liter glass flask, 317 g of <strong>[3452-97-9]3,5,5-trimethylhexanol</strong>, 216 g of 1,4-dibromobutane, 14.3 g of tetrabutylammonium bromide and 442 g of a 52percent by mass aqueous solution of sodium hydroxide were placed, and the reaction was allowed to proceed at 70° C. for 8 hours under stirring. After the reaction was completed, the reaction mixture was transferred to a separatory funnel, and the aqueous phase was removed by filtration. The remaining organic phase was washed with 500 ml of water 5 times. From the organic phase, 1,4-bis(3,5,5-trimethylhexoxy)butane was separated by distillation under a reduced pressure.
With sodium hydroxide; tetrabutylammomium bromide; In hexane; water; at 80℃; for 6h;
Into a 2 L egg plant type flask were charged 46.3 g (0.40 mol) of 3-hydroxymethyl-3-ethyloxetane (product name: OXT-101 manufactured by Toagosei Co., Ltd.), 250.3 g (1.16 mol) of 1,4-dibromobutane (reagent, manufactured by Tokyo Kasei Kogyo Co., Ltd.), and 275 ml of hexane. 500 ml of a 33 percent sodium hydroxide aqueous solution containing 2 g of tetra-n-butylammonium bromide (reagent, manufactured by Tokyo Kasei Kogyo Co. , Ltd.) was added to the mixture and vigorously stirred for 5 hours. After the mixture was refluxed at a temperature of 80 °C for one hour, 500 ml of deionized water was added thereto so as to separate the mixture into an organic phase and an aqueous phase. The aqueous phase was extracted three times with 160 ml of hexane. After the organic phase and the extracted phase were dried over magnesium sulfate, the solvent was distilled out in a vacuum. The resulting transparent liquid was distilled in a vacuum thereby obtaining 44.5 g (0.18 mol) of 3-[(4-bromobutoxy)methyl]-3-ethyloxetane as a distillate at 109 °C/532 Pa (yield: 44percent, identified with 1H-NMR). In a 300 ml three neck flask, 5.2 g (31 mmol) of ethyl p-hydroxybenzoate, 4.7 g (34 mmol) of potassium carbonate anhydride, and 7.8 g (31 mmol) of the 3-[(4-bromobutoxy)methyl]-3-ethyloxetane were dissolved in 50 ml of dimethylformamide. After the solution remained turbid was heated to a temperature of 80 °C and stirred for 4 hours, the solvent was completely distilled out in a vacuum. To the resulting yellow oily substance were added 15 ml of a 7 percent sodium hydroxide aqueous solution and 15 ml of methanol. The mixture was refluxed for two and half hours. 1 N (normality) of hydrochloric acid was added to the mixture such that the pH is adjusted to about 3. The resulting white precipitate was filtered and dried in a vacuum thereby obtaining 8.6 g (28 mmol)of 4-[7-(3-ethyl-3-oxetanyl)-1,6-dioxaheptyl)benzoic acid (yield: 89percent, identified with 1H-NMR). The resulting compound was no more purified and used in the following reaction. Into a 100 ml three neck flask were charged 1.1 g (9.6 mmol) of methanesulfonyl chloride, 0.1 g of nitrobenzene, and 10 ml of tetrahydrofuran. To the mixture was added a solution obtained by dissolving 3.1 g (10 mmol) of the 4-[7-(3-ethyl-3-oxetanyl)-1,6-dioxaheptyl]benzoic acid in 1.3 g (10 mmol) of diisopropylethylamine and 10 ml of tetrahydrofuran, while the mixture was cooled with ice. The mixture was stirred for 2 hours after the temperature thereof had been returned to ordinary temperature. To the mixture were added a solution obtained by dissolving 0.54 g (4.8 mmol) of hydroquinone in 8 ml of tetrahydrofuran, 0.3 g of dimethylaminopyridine, and 1.0 g of triethylamine. The mixture was refluxed for 3 hours. After the mixture was cooled, the resulting white precipitate was recrystallized from methanol thereby obtaining 1.9 g (2.8 mmol) of the intended liquid crystalline oxetane compound 1 represented by the following formula (yield: 55 percent, identified with 1H-NMR).[Liquid crystalline oxetane compound 1] The 1H-NMR spectrum of the resulting liquid crystalline oxetane compound 1 is shown in Fig. 1. The phase behavior and phase transition temperature of the resulting liquid crystalline oxetane compound were as follows:[Liquid crystal phase behavior and phase transition temperature] C-65 °C-Nm-94 °C-Iso
With sodium hydroxide;tetrabutylammomium bromide; In hexane; water; at 20℃; for 6h;Heating / reflux;
[Reference Example 2 (synthesis of intermediate compound 2 having an oxetanyl group)]; In accordance with Scheme 2 below, an intermediate compound 2 having an oxetanyl group was synthesized. [Show Image] Intermediate Compound 2 having an oxetanyl group
With sodium hydroxide; tetrabutylammomium bromide; In hexane; water; at 20℃; for 6h;Heating / reflux;
In accordance with Scheme 2 below, an acrylic compound having an oxetanyl group (acrylic compound 2) was synthesized using 3-ethyl-3-hydroxymethyloxetane (OXT-101, manufactured by Toagosei Co., Ltd). The 1H-NMR spectrum of the acrylic compound 2 is shown in Fig. 2.
With sodium hydroxide; In ethanol; for 5h;Heating / reflux;
A 0.16g (4mmol) of sodium hydroxide was dissolved in 120ml of anhydrous ethanol, and 0.8g (1.92mmol) of <strong>[3681-99-0]puerarin</strong> was added and dissolved completely by heating and refluxing. After slightly cooling, 0.25ml (2mmol) of 1,4-dibromobutane was added dropwisely. And the reaction was continued for 5 hours under reflux. When the reaction was finished, the solvent was removed by distillation, and the resultant residue was separated by silica gel column chromatography (methylenechloride: methanol = 8:1) to give 0.53g of the title compound in the form of a white solid, yield 47.2percent. mp:198°C. FAB-MS, m/z(percent): 552.1(M++1,22). 1H-NMR(d6DMSO)delta(ppm): 8.36 (1H,s,C2-H), 7.96 (1H,d,J=9,C5-H), 7.52 (2H,d,J=9,C2',5'-H), 7.01 (2H,d,J=9,C3',6'-H), 6.99 (1H,d,J=9,C6-H), 4.86 (1H,d,J=10,C1''-H), 4.06 (3H,m,-OCH2-,C3''-H), 3.62 (2H,t,J=7,-CH2Br), 2.02 (2H,m,-CH2-), 1.99 (2H,m,-CH2-).
With sodium hydroxide; tetrabutylammomium bromide; In water; toluene;
Synthesis of 4-bromobutoxymethylstyrene An amount of 20 g (0.5 mol) of sodium hydroxide and 20 ml of water were placed into a four-necked flask of 300 ml in capacity and then stirred to prepare a homogeneous solution. The temperature of this solution was reverted to room temperature, and then thereto a solution as prepared by dissolving 13.42 g (0.1 mol) of vinylbenzyl alcohol (mixture of m-isomer and p-isomer), 32.39 g (0.15 mol) of 1,4-dibromobutane, and 3.22 g (0.01 mol) of tetrabutylammonium bromide into 100 ml of toluene was added. While being vigorously stirred, the resultant mixed solution was allowed to react at 40° C. for 6 hours. Thereafter, the solution was separated and then sufficiently washed with water. The resultant organic layer was dried by adding thereto magnesium sulfate, and then toluene was distilled off under reduced pressure. The resultant solution was distilled in the presence of DPPH (diphenylpicryl-2-hydrazyl) under vacuum (boiling point: 125~128° C./16 Pa) to obtain a colorless transparent liquid of 4-bromobutoxymethylstyrene. The yield amount was 15.0 g, and the yield ratio was 56 mol percent.
With potassium tert-butylate; In tetrahydrofuran; water;
1.1. 43.7 g of potassium tert-butylate (0.39 mol) were added portionwise at -78° C. to a solution of 32.0 g of 7-fluoro-l,2,3,4-tetrahydro-naphthalen-1-one (0.19 mol) in 320 ml of THF while gassing with argon. The mixture was stirred at -78° C. for 2 hrs. and then a solution of 40 ml of 1,4-dibromobutane (73 g, 0.338 mol) in 40 ml of THF was added dropwise. The cooling bath was removed and the mixture was stirred at RT for 16 hrs. Water was added, the mixture was extracted with ether, the organic phase was washed with a saturated aqueous sodium chloride solution, dried over MgSO4, filtered, concentrated and the residue was chromatographed over silica gel with toluene. The product was distilled through a 20 cm Vigreux column. Yield: 29.4 g (76percent) of 7'-fluoro-3'4'-dihydro-spiro[cyclopentan-1,2'(1'H)-naphthalen]-1'-one as a colourless liquid; b.p. 98°-102° C./0. 11 Torr.
1,4-Dibromobutane (20.9 ml), tetrabromobutylammonium bromide (1 g), water (150 ml) and aqueous 50% sodium hydroxide solution (50 ml) were successively added to a stirred solution of <strong>[3610-02-4]benzo[b]thiophen-4-ol</strong> (5.25 g) in dichloromethane (200 ml) and the mixture was vigorously stirred at laboratory temperature for 2 days. The organic layer was separated and evaporated to dryness and the excess of dibromobutane was removed by distillation. The residue was purified by chromatography on a silica gel column using dichloromethane as eluant and there was thus obtained 4-(4-bromobutyloxy)benzo[b]thiophen as an oil.
EXAMPLE 12 (R) -1-(2-(((5-Methoxy-1-phenyl-1-pentylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid hydrochloride A mixture of 1,4-dibromobutane (216 g, 1 mol), methanol (45 ml) and toluene (45 ml) was heated at reflux under an inert atmosphere. A solution of sodium methoxide prepared from sodium (15.3 g, 0.7 mol) and methanol (225 ml) was added over a period of 3 hours while the mixture was kept at reflux. When addition was complete the reaction mixture was kept at reflux for an additional hour and the solvent then distilled off. Water (200 ml) was added, the resulting mixture extracted with diethylether (2*300 ml) and the combined organic phases were dried (Na2 SO4). The solvent was evaporated in vacuo and the residue was submitted to fractional distillation to give 33.7 g of 1-bromo-4-methoxybutane. B.p. 76°-78° C./35 mmHg.
EXAMPLE-XIII: Preparation of Aripiprazole p-toluenesulfonate; Step-1; Sodium hydroxide (29.5 g, 0.737 mole) is added to a suspension of 7-Hydroxy carbostyril (100 g, 0.613 mole) in isopropyl alcohol (1850 ml) and mixed at 250C to 300C for about 30 min. Tetra butyl ammonium bromide is added (5 g, 0.015 mole) followed by 1,4-Dibromo butane (530 g, 2.45 mole), raised to reflux and maintained at reflux temperature 8O0C - 850C for 3 hrs. The insolubles are filtered in hot condition, and isopropyl alcohol is distilled off from the filtrate under vacuum at temperature up to 1100C - 115°C. The reaction mass is .cooled and isopropyl alcohol (300 ml) is added to the reaction mass, maintained at 300C - 35°C for 1 hr. The mass is further cooled and maintained at 2O0C- 22°C for 2 hrs, filtered, washed with isopropyl alcohol (50 ml) to give the wet cake of about 250 g. The wet cake (250 g) is suspended in n- hexane (300 ml) , raised the temperature to reflux and maintained for about 60min. The reaction mass is cooled to a temperature of 250C - 35°C and maintained for 1 hr. The mass is filtered; washed and dried the wet cake at 40°C to 500C till becomes constant weight.The dry weight of 7- (4-bromobutoxy) -3, 4-dihydrocarbostyril is 135 g (Yield: 73.8percent) .
With potassium carbonate; potassium iodide; In acetonitrile; at 80℃; for 18h;
To a mixture of (f?)-2-aminopropanamide hydrochloride (685 mg, 5.50 mmol), K2C03 (760 mg, 5.50 mmol), and Kl (2.74 mg, 0.016 mmol) in acetonitrile (17 ml_) was added 1 ,4-dibromobutane (0.657 ml_, 5.50 mmol). After heating to 80 °C for 18 h, the reaction was cooled to RT and 2N HCI (15 ml_) and DCM (20 ml_) were added. The aqueous layer was basified with aq NaOH, and extracted sequentially with DCM, EtOAc and CHCI3-IPA (4: 1). The combined organic extracts were dried (Na2S04) and concentrated in vacuo to give the title compound (362 mg, 46percent) as a white solid. 1H NMR (400 MHz, CDCI3): delta 6.85 (br s, 1 H), 5.25 (br s, 1 H), 2.90 (br m, 1 H), 2.50-2.70 (br m, 4H), 1.40-1.60 (br m, 4H), 1.35 (d, 3H).
With potassium carbonate; potassium iodide; In acetonitrile; for 14h;Heating / reflux;
Method 5; (R)-2-pyrrolidin- 1 -yl-propylaminea) (R)-2-pyrrolidin- 1 -yl-propionamide2 g (16.06 mmol) R-alaninamine hydrochloride, 6.67 g (16.08 mmol) potassium carbonate and 8 mg (0.05 mmol) potassium iodide are suspended in 50 mL acetonitrile and then the mixture is combined with 1.92 mL (16.08 mmol) 1,4-dibromobutane. This reaction mixture is stirred for 14 h under reflux conditions. 100 mL of 1 N hydrochloric acid and <n="25"/>100 mL dichloromethane are added to the reaction mixture. The organic phase is separated off and discarded. The aqueous phase is made basic with sodium hydroxide solution and extracted 3 times with dichloromethane. The organic phases are combined, dried and freed from the solvent in vacuo. Yield: 1.31 gMS (ESI): 143 (M+H)+
7-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-oxy)butoxy)-3,4-dihydroquinoline-2(1H)-one[ No CAS ]
[ 129722-34-5 ]
Yield
Reaction Conditions
Operation in experiment
5.0 - 8.0%; 66.8%
With sodium hydroxide; In ISOPROPYLAMIDE; at 36 - 40℃; for 4h;Product distribution / selectivity;
1,4-dibromo butane (509 ml) was added to a stirred solution of 7-hydroxy-3,4-dihydrocarbostyril (100 gm) in dimethylacetamide (500 ml) at ambient temperature. The reaction mixture was heated at 36° to 40° C. Sodium hydroxide (33.1 gm) was added to the reaction mixture at the interval of 30 min (Complete the addition of sodium hydroxide in 9 equal fractions in 4.0 hours). The reaction mixture was cooled at ambient temperature and D.M Water was added to it. The reaction mixture was extracted with ethylacetate. Organic layer was separated and washed with 5percent brine and finally dried over sodium sulphate. The organic layer was evaporated to dryness under reduced pressure (10 mm) at 45° C. to obtain residue. To the residue cyclohexane (1000 ml) was added to give of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril. Yield: 122.0 gms (66.8percent) Dimer content: 5.0-8.0percent
66%
Example 1; A mixture of 7-hydroxy 3,4-dihydrocarbostyril (5Og, 0.306 mole, 1 eq.), anhydrous potassium carbonate (50.7 g, 0.367 mole, 1.2 eq.) in acetonitrile (750 ml) was heated under reflux for 2 hours, the hot reaction mixture cooled to 25-3O0CA mixture of dibromo butane (20Og, 0.926 mole, 3.02 eq.), tetrabutylammonium iodide (2.2g, 0.006 mole, 0.02eq.) in acetonitrile (250 ml) was heated under reflux for 15 min, the <n="10"/>0003109above potassium salt of 7-hydroxy 3,4-dihydrocarbostyril added to it. The resultant mixture was heated under reflux for 2-4 hrs, monitored by HPLC till 7-hydroxy 3,4- dihydrocarbostyril is present less than 1.0percent, (the reaction mixture contained 14-15 percent of the dimer impurity), mixture was cooled to 25-3O0C1 filtered, residue washed with acetonitrile (250 ml), the filtrate was concentrated, dichloromethane (750 ml) was added to it, Hydrogen chloride gas was purged into it, the filtrate was monitored by HPLC for dimer content to be less than 0.5 percent, carbon (5g) was added to the solution, filtered through celite bed .water (250 ml) was added to the filtrate, pH of the solution was adjusted to 6.8-7.5 using 20percent potassium carbonate solution, the organic layer separated , washed with water (250 ml), washed with 20percent brine solution (250 ml). The organic layer further concentrated, cyclohexane (500 ml) was added to it, stirred for 15 minutes, then cooled to 5-100C, the solid was filtered, washed with cyclohexane (100 ml), dried under vacuum at 40-450C, for 5-6 hours, to give 7-(4- Bromo butoxy)-3,4-dihydro carbostyril (62 g, yield 66percent, purity by HPLC 97.4 percent, dimer impurity 0.28percent).
55%
Example 2; A mixture of 7-hydroxy 3,4-dihydrocarbostyril (5Og, 0.306 mole, 1 eq.), anhydrous potassium carbonate (50.7 g, 0.367 mole, 1.2 eq.) in acetonitrile (750 ml) was heated under reflux for 2 hours, the hot reaction mixture cooled to 25-300CA mixture of dibromo butane (20Og, 0.926 mole, 3.02 eq.), tetrabutylammonium iodide (2.2g, 0.006 mole, 0.02eq.) in acetonitrile (250 ml) was heated under reflux for 15 min, the above potassium salt of 7-hydroxy 3,4-dihydrocarbostyril added to it. The resultant mixture heated under reflux for 2-4 hrs, monitored by HPLC till 7-hydroxy 3,4- dihydrocarbostyril is present less than 1.0percent, (the reaction mixture contained 14-15 percent of the dimer impurity), mixture was cooled to 25-300C, filtered, residue washed with acetonitrile (250 ml), the filtrate was concentrated, dichloromethane (750 ml) was added to it, sulphuric acid (55g) was added to it, the filtrate was monitored by HPLC for dimer content to be less than 0.5 percent, carbon (5g) was added to the <n="11"/>N2007/00031010solution, filtered through celite bed .water (250 ml) was added to the filtrate, pH of the solution was adjusted to 6.8-7.5 using 20percent potassium carbonate solution, the organic layer separated , washed with water (250 ml), washed with 20percent brine solution (250 ml). The organic layer further concentrated, cyclohexane (500 ml) was added to it, stirred for 15 minutes, then cooled to 5-100C, the solid was filtered, washed with cyclohexane (100 ml), dried under vacuum at 40-450C, for 5-6 hours, to give 7-(4- Bromo butoxy)-3,4-dihydro carbostyril (52 g, yield 55percent, purity by HPLC 98.05 percent, dimer impurity 0.08percent).
With potassium carbonate; In water; at 25 - 105℃; for 5 - 7h;Heating / reflux;Product distribution / selectivity;
7-Hydroxy-3,4-dihydro-2(lH)-quinolinone (2Og, 0.153mol) was added to a solution of potassium carbonate (25g, O.l Slmol) in DM water (400ml) at 25-350C and the contents <n="8"/>were heated to 80-900C to obtain a clear solution. 1 ,4-Dibromobutane (200ml) was added to the reaction mass, heated to reflux temperature (100-1050C) and stirred for 7 hours at the same temperature. After completion of reaction, reaction mass was cooled to ambient temperature and organic layer was separated. Organic layer containing 7-(4- bromobutoxy)-3,4-dihydro-2(lH)-quinolinone having 5percent l,4-bis[3,4-dihydro- 2(lH)quinolinon-7-oxy]butane (by HPLC, by area normalization) was washed with precooled 5percentw/v aqueous sodium hydroxide (75ml) at 15-200C, to remove unreacted 7- hydroxy-3?4-dihydro-2(lH)-quinolinone. Organic layer was concentrated at 90-1050C under reduced pressure varying from 50 to 5 mm of Hg to dryness. The concentrated mass was diluted with toluene (2000ml) and heated to 6O0C. Silica gel (50g) was added and stirred for 30 min at 60-700C. Silica gel was removed by filtration and the filtrate was concentrated at 60-800C under reduced pressure vaiying from 200 to 10 mm of Hg. The resulting concentrated mass having 0.3percent of l,4-bis[3,4-dihydro-2(lH)quinolinon-7- oxy]butane (by HPLC, by area normalization) was diluted with hexanes (50ml) and stirred for 30 minutes to crystallize the product. Product was filtered and washed with hexanes. Yield: 18gChromatographic purity: 97.89percent (by HPLC, by area nopinalization) EXAMPLE-2PREPARATION OFPURE 7-(4-BROMOBUTOXY)-SJ-DIHYDROOUINOLINONE7-Hydroxy-3,4-dihydroquinolinone (2Og, 0.153mol) was added to a solution of potassium carbonate (25g, O.ldeltalmol) in DM water (140ml) at 25-35°C and the contents were heated to 65-7O0C to obtain a clear solution. 1,4-Dibromobutane (200ml) was added to the reaction mass and again heated to reflux temperature (95-1000C) and stirred for 5 hours at the same temperature. After completion of reaction, reaction mass was cooled to ambient temperature and organic layer was separated. Organic layer containing l,4-bis[3,4- dihydro-2(lH)quinolinon-7-oxy]butane was washed with precooled 5percentw/v aqueous sodium hydroxide (75ml) at 10-150C, to remove unreacted 7-hydroxy-3,4- dihydroquinolinone. Organic layer was concentrated at 100-1200C under reduced pressure varying from 50 to 5 mm of Hg. The concentrated mass was diluted with toluene (500ml) and heated to 6O0C. Silica gel (6Og) was added and stirred for 30 min at 60-700C. Silica gel was removed by filtration and treated again with preheated toluene (l x400ml, lx200ml, 60-700C). The combined filtrate was concentrated at 60-700C under reduced pressure vary ing from 200 to 10 mm of Hg. Thus, obtained concentrated mass was diluted with hexanes (150ml) and stirred for 30 minutes upon which the product crystallized out. Product was filtered and washed with hexanes. Yield: 17g Chromatographic purity: 97.31percent (by HPLC, by area normalization) l,4-Bis[3,4-dihydiO-2(lH)quinolinon-7-oxy]butane content: 0.44percentEXAMPLE-3PREPARATION OFPURE 7-(4-BROMOBUTOXY)-3,4-DIHYDROOUINOLINONE7-Hydroxy-3,4-dihydroquinolinone (50g, 0.306mol) was added to a solution of potassium carbonate (62.5g, 0.453mol) in DM water (350ml) at 25-350C and the contents were heated to 65-7O0C to obtain a clear solution. 1,4-Dibromobutane (500ml) was added to the <n="10"/>reaction mass and again heated to reflux temperature (95-100°C) and stirred for 5 hours at the same temperature. After completion of reaction, reaction mass was cooled to ambient temperature and organic layer was separated. Organic layer containing l,4-bis[3,4- dihydro-2(lH)quinolinon-7-oxy]butane was washed with precooled 5percentw/v aqueous sodium hydroxide (195ml) at 10~15°C, to remove unreacted 7-hydroxy-3,4- dihydroquinolinone. Organic layer was concentrated at 100-120°C under reduced pressure varying from 50 to 5 mm of Hg. The concentrated mass was diluted with toluene (1000ml) and heated to 600C. Silica gel (165g) was added and stirred for 30 min at 60-700C. Silica gel was removed by filtration and treated again with preheated toluene (2x750ml, 60- 7O0C). The combined filtrate was concentrated at 60-700C under reduced pressure varying from 200 to 10 mm of Hg. Thus, obtained concentrated mass was diluted with cyclohexane (150ml) and stirred for 30 minutes to crystallize the product. Product was filtered and washed with cyclohexane. Yield: 42.5g Chromatographic purity: 97.5percent (by HPLC, by area normalization) l,4-Bis[3,4-dihydro-2(lH)quinolinon-7-oxy]butane content: 0.55percentEXAMPLE-4PREPARATION OFPURE 7-(4-BROMOBUTOXY)-3,4-DIHWROQUINOUNONE7-Hydroxy-3,4-dihydroquinolinone (30g, 0.184mol) was added to a solution of potassium carbonate (37g, 0.268mol) in DM water (1200ml) at 25-35°C and the contents were heated to 65-700C to obtain a clear solution. 1 ,4-Dibromobutane (150ml) was added to the reaction mass and again heated to reflux temperature (95-1000...
With potassium carbonate; In N,N-dimethyl-formamide;
1). 2,4,6-Trimethyl-3-pyrrolidin-1-yl-phenylamine (2). To a solution of 2,4,6-trimethyl-1,3-phenylenediamine (15.0 g, 99.8 mmol) in anhydrous DMF (300 mL) were sequentially added potassium carbonate (30.4 g, 219.7 mmol) and 1,4-dibromobutane (11.9 mL, 99.8 mmol). The reaction was stirred overnight and then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed eluding with hexanes:ethyl acetate (20:1) to give the desired product (10.8 g, 53%). The titled compound was synthesised as shown in scheme 2 using 2 to give a white solid (ESI [M+H+])=315.21.
Sodium hydride (60% in oil, 1.07 g, 26.8 mmol) is added to a solution of (3-bromo-phenyl)- acetic acid ethyl ester [2.59 g, 10.7 mmol] and 18-crown-6 (catalytic amount) in N,N'- <n="198"/>dimethylformamide (50 mL). The mixture is stirred for 25 minutes and 1 ,4-dibromobutane (1.41 mL, 11.8 mmol) is added dropwise via syringe. The mixture is stirred for 18 hours at ambient temperature, diluted with water (100 mL) and extracted thrice with EtOAc (60 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 1 -(3-bromo-phenyl)- cyclopentanecarboxylic acid ethyl ester [2.9 g, 91%] as an oil, which is used without further purification.
poly(4-(dimethylamino)phenyldiphenylphosphonium-alt-butane)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In DMF (N,N-dimethyl-formamide); for 168h;
4- (DIMETHYLAMINO) phenyldiphenylphosphine (1.73 mmoles, 0.529 g) and 1,4-dibromobutane (1.73 mmoles, 0.207 g) were dissolved in DMF (1 ml) and shaken for 1 week. A viscous liquid was obtained.
General procedure: The method adopted for the synthesis of 1-(4-bromobutyl)indole (3a) is described. Potassium hydroxide (3.83 g, 68.3 mmol) and tetrabutylammonium iodide (0.2 g, 0.54 mmol) were added, under mechanical stirring, to a solution of indole (2a) (2 g, 17.1 mmol) in anhydrous DMF (25 mL). The reaction mixture was stirred at room temperature for 45 min and cooled to 0 °C. 1,4-Dibromobutane was then added and the mixture was stirred for 15 min at 0 °C and for 1 h at room temperature. The mixture was poured into 70 mL of water, extracted with methylene chloride (3 .x. 50 mL), and the combined organic layers were washed with brine and dried. The solvent was removed in vacuo, and the residue was chromatographed on a silica gel column using a gradient of hexanes/ethyl acetate (10:0 to 9:1) as the eluent to give 2.92 g (68percent) of 1-(4-bromobutyl)indole as a pale yellow oil.
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 50℃; for 4h;
(q) l-(4-Bromobutyl)-4-phenyl-lH-imidazole -2 -carbaldehyde[00403] A mixture of 4-phenyl-l H-imidazole -2 -carbaldehyde (1.79 g, 10.4 mmol), potassium carbonate (2.87 g, 20.8 mmol), potassium iodide (2.94 g, 17.7 mmol) and1 ,4-dibromobutane (4.49 g, 20.8 mmol) in dry DMF (35 mL) were heated to 50 C and stirred for 4 hours. The mixture was poured into ice -water (100 mL), and washed with EtOAc(2 x 80 mL). The combined organic layers were washed with brine (2 x 100 mL). The organic layer was dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to give l-(4-bromobutyl)-4- phenyl- lH-imidazole-2-carbaldehyde as a colorless oil (2.1 g). MS (ESI): m/z 308 (M+H)+.
With potassium carbonate; In acetone; for 6h;Reflux;
General procedure: The corresponding coumarin derivatives (4.21mmol) 5a-k and potassium carbonate (0.872 g, 6.31 mmol) were suspended in dry acetone, and then the corresponding dibromoalkyl derivative (84.12 mmol) was added. The mixture was refluxed for 6 h. After cooling to room temperature, the solid was filtered and washed with acetone. The filtrate was concentrated under reduced pressure and purified by column chromatography using petroleum ether/ethy actate (5 : 1 to 8:1) as eluent to get the intermediates of 6a-n
With potassium carbonate; In acetonitrile; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (foralkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyldibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
58.6%
With potassium carbonate; In acetonitrile; at 60℃; for 18h;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in CH3CN (75 mL)were added K2CO3 (1.80 g, 13 mmol) and 1,3-dibromopropane or 1,4-dibromobutane (30 mmol). The resulting mixture was warmed to 60C and stirred for 18 h at the same temperature. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure to dryness. The residue was dissolved in ethyl acetate (60 mL) and the organic layer was washed consecutively with saturated K2CO3 solution (2 x 5mL), water (2 x 10 mL) and brine (2 x 10 mL). The washed organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to dryness. The residue was purified by flash chromatography (petroleum ether/ethylacetate, 1:1) to give compounds 9 and 10 in yields of 64.5% and 66.5%, respectively.
General procedure: Acetone (8 ml) was added to a mixture of 2 (0.82, 0.005mol) and K2CO3 (2.07 g, 0.015 mol) and was stirred for 15minutes. Dihalogenoalkane (ethylene dibromide, propanedibromide or butyl hydride dibromide, 0.015 mol) was addedand the mixture was stirred at refluxing temperature in theabsence of light for 24 h. The mixture was diluted with waterand extracted with ethyl acetate. After pooling the organiclayers and evaporating to dryness, the crude compound 3a-cwere obtained and they were further purified by columnchromatography
With potassium carbonate; In acetonitrile;Reflux;
General procedure: A mixture of methyl ferulicate 2 (2.1 g, 10 mmol), K2CO3 (3.5 g, 25 mmol) and various dibromoalkanes (30 mmol) in acetonitrile (80mL) was refluxed for 4-6 h. The solvent was evaporated under vacuum and water was added. The solution was neutralized with 2mol/L HCl solution to pH 7?8, and then extracted with CH2Cl2 (60mL×3). The organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether-ethyl acetate=10:1?6:1, v/v as the eluent) to yield 3a-c as yellowish oil (63-77%).
With potassium carbonate; In ethanol; for 3h;Reflux;
4-(2-fluoro-5-methylphenoxy)butyldiethanolamine: A solution of 150 g (1.19 moles) 2- fluoro-5-methylphenol, 770.4 g (3.57 moles) of 1,4-dibromobutane and 600 mL of ethanol was treated with 180.6 g (1.31 moles) of potassium carbonate and heated to reflux for 3 hours. After cooling to 25C, the solids were removed by filtration. The solvent from the filtrate was stripped off and re-filtered. This filtrate was vacuum distilled to remove the excess dibromobutane. The product was used as is from the distillation pot. The crude 4-(2-fluoro-5-methylphenoxy)butyl bromide (295.0 g) was mixed with 1 kg of diethanolamine and heated slowly to 70C. After 3 hours at 70C, the reaction mixture was cooled to 25C and treated with 1.0 L of IN sodium hydroxide. This mixture was washed with ethyl acetate (3 X 330 mL). The combined organic phases were washed with water. After drying over sodium sulfate the organic layer was treated with gaseous hydrogen chloride. The solvents were stripped off and the product crystallized from ethanol and methyl t- butyl ether. The solid was dried in a vacuum oven to yield the hydrochloride salt of 4-(2-fluoro- 5-methylphenoxy)butyldiethanolamine. Melting point: 83-86C. 1H NMR Analysis: (d6- DMSO): delta 9.77, bs, 1H (R3N+H); delta 7.01, d, 1H (arylH); delta 6.95, d, 1H (arylH); delta 6.69, dd, H (arylH); delta 5.30, bs, 2H (OH); delta 4.01, t, 2H, (CH2 a to ArO); delta 3.74, t, 4H, (CH2's a to OH); delta 3.20, m, 6H, (CH2's a to N); delta 2.23, s, 3H, CH3); delta 1.84, m, 2H (CH2 in chain); delta 1.73, m, 2H (CH2 in chain). 13C NMR (d6-DMSO): 151.2, 148.71, 145.86, 134.06, 121.06, 115.51, 67.95, 55.23, 54.75, 52.86, 25.82, 20.63, 19.93.
1,4-bis(3-dodecylimidazolium-1-yl) butane bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92.4%
In isopropyl alcohol; at 60℃; for 48h;Inert atmosphere;
General procedure: A mixture of 10 mmol of N-dodecyl imidazole or Ntetradecylimidazole, 1,4-dibromobutane (4 mmol,0.856 g) and isopropanol (20 mL) was stirred for 48 h at60° C under nitrogen atmosphere. After removal ofisopropanol, the residue was washed with ethyl acetate,further purified four times by recrystallization in acetoneand then dried under vacuum for 48 h. [C12C4C12im]Br2and [C14 C4C14im]Br2 as the white powder were gained.The respective yields of [C12C4C12im]Br2 and [C14 C4-C14im]Br2 are 92.4 percent and 93.3 percent. 1H NMR (500 MHz,CDCl3) [C12C4C12im]Br2: delta 10.19 (s, 2H, ?NCHN?),8.05 (s, 2H, ?NCHCHN?), 7.21 (s, 2H, ?NCHCHN?),4.58 (t, 4H, ?N+?CH2?), 4.24 (t, 4H, ?NCH2?), 2.19 (m,4H, ?N+?CH2CH2?), 1.88 (m, 4H, ?NCH2CH2?),1.20?1.35 (m, 36H, ?N+?CH2CH2(CH2)9?), 0.86 (t, 6H,?CH2CH3); MS (ESI) [M-2Br]2+: 264.27.
In isopropyl alcohol; at 80℃; for 24h;
Dicationic imidazolium ionic liquids were prepared by refluxing N?dodecylimidazole (4.72 g, 20 mmol) and 1,4? dibromobutane (2.16 g, 10 mmol) in isopropanol (25 mL) at 80 °C for 24 h. Then, the products were washed with diethyl ether four times under vacuum.
In isopropyl alcohol; at 80℃; for 24h;
General procedure: Dicationic imidazolium ionic liquids were prepared by refluxing-N-hexadecylimidazole (5.85 g, 20 mmol) and 1,4-dibromobutane (2.16 g, 10 mmol) in isopropanol (50 mL) at 80 °C for 24 h. Then, the products were washed with diethyl ether four times under vacuum.
General procedure: Dicationic imidazolium ionic liquids were prepared by refluxing-N-hexadecylimidazole (5.85 g, 20 mmol) and 1,4-dibromobutane (2.16 g, 10 mmol) in isopropanol (50 mL) at 80 °C for 24 h. Then, the products were washed with diethyl ether four times under vacuum.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;
General procedure: To a solution of compound 2 (1.12 g, 5 mmol) and K2CO3 (2.07 g,15 mmol) in DMF (15 mL), an appropriate amount of a,x-dibromoalkanewas added. After stirring at 80 C for 2?10 h until thematerial 2 disappeared, the solvent was poured into ice water(100 mL), extracted with EtOAc (2 70 mL) and washed with saturatedaq NaCl solution (2 80 mL). The organic layer was driedover anhydrous Na2SO4 and concentrated in vacuum. Then the residuewas purified by a silica-gel column chromatography to affordproduct.
To a stirred solution of <strong>[7321-93-9]4,6-dichloropyridin-3-amine</strong> (3.9 g, 0.0239 mol) in dry DMF (35 mL) was added sodium hydride (1.914 g, 0.0478 mol, 60 percent suspension in mineral oil) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at this temperature for 30 min. Then 1 ,4-dibromobutane (4.134 g, 0.0191 mol) was added dropwise. The reaction mixture was stirred at RT overnight. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction was quenched by addition of ice-water (50 mL) and the product was extracted with EtOAc (2x150 mL). The organic layer was again washed with water (2x50 mL) and brine solution (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afforded an oily residue that was purified by column chromatography on silica gel (100-200 mesh) using 0.5-1percent EtOAc-hexane to afford 2,4-dichloro-5-pyrrolidin-l-yl-pyridine (3.711 g) as an off- white solid.
1-tert-butyl 1-methylcyclopentane-1,1-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With caesium carbonate; 1-butyl-3-methylimidazolium Tetrafluoroborate; In acetonitrile; at 20℃;
1,4-Dibromobutane (2.4 mL, 20. mmol) was added to a mixture of <strong>[42726-73-8]tert-butyl methyl malonate</strong> (1.74 g, 10.0 mmol), cesium carbonate (9.8 g, 30. mmol) and 1-butyl-3-methyl-1H-imidazol-3-ium tetrafluoroborate (0.4 g, 2 mmol) in acetonitrile (20 mL). The resulting mixture was stirred at room temperature overnight then diluted with diethyl ether and filtered. The filtrate was concentrated and the residue was dissolved in diethyl ether then washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified via flash chromatography on a silica gel column eluting with 0 to 10percent EtOAc in hexanes to give the desired product (1.7 g, 75percent). LC-MS calculated for C8H13O4 (M-tBu+2H)+: m/z=173.1. found 173.1.
With potassium carbonate; In N,N-dimethyl-formamide; at 75℃;
General procedure: Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate 2 (1.0 mmol), dimethyl formamide (4 mL) as a solvent media and potassium carbonate (1.05 mmol)was taken in RBF and heated to 75°C for 15 to 20 min and then dibromoethane (2.0 mmol) solution in dimethylformamide (1 mL) was added and reaction continued for 4-5 hr. The completion of reaction was checked by TLC. Heating was stopped after the completion of reaction and reaction mixture was gradually cooled to RT. It was filtered and washed with dimethyl formamide (1 mL). The reaction mass was collected and poured onto water (20 mL), stirred for 30 min, filtered and washed with water. The product ethyl 2-(4-(2-bromoethoxy)-3-formylphenyl)-4-methylthiazole-5-carboxylate 5 was purified by recrystallization from IPA at RT.
1,4-bis(1-propylimidazol-3-ium-3-yl)butane*2Br-[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
In toluene; at 100℃; for 24h;Reflux;
General procedure: A solution of N-alkylimidazole (10 mmol, 2 equivalents) and Dibromoalkane (5 mmol, 1 equivalent) was refluxed in toluene (20 mL) for 24?30 h. The reaction mixture was allowed to cool and toluene was decanted leaving a sticky solid behind. The sticky solid was washed three times with dry THF and finally with diethyl ether once. Solvent was removed under vacuum to get a white amorphous hygroscopic powder (88?94 percent yield). NMR spectra were recorded in D2O and/or DMSO-d6.
methyl 5-(4-bromobutoxy)-2-chlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With potassium carbonate; In acetone; for 2.5h;Reflux;
General procedure: A mixture of compound10a (144 mg, 0.5 mmol), 1,4-dibromobutane (300 muL, 2.5 mmol), and potassium carbonate (138 mg, 1 mmol) in acetone (4mL) was refluxed for 150 min. After cooled to room temperature, the reactionmixture was poured into water, extracted with DCM (15 mL). The organic layer waswashed with water, saturated brine, dried and concentrated, and the crudeproduct was chromatographed (petroleum ether : DCM=2 : 1) to give titlecompound as colorless oil (86% yield). Spectroscopic data are identical tothose reported in the literature. 1
methyl 3-(4-bromobutoxy)-4-chlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate; In acetone; for 2.5h;Reflux;
General procedure: A mixture of compound10a (144 mg, 0.5 mmol), 1,4-dibromobutane (300 muL, 2.5 mmol), and potassium carbonate (138 mg, 1 mmol) in acetone (4mL) was refluxed for 150 min. After cooled to room temperature, the reactionmixture was poured into water, extracted with DCM (15 mL). The organic layer waswashed with water, saturated brine, dried and concentrated, and the crudeproduct was chromatographed (petroleum ether : DCM=2 : 1) to give titlecompound as colorless oil (86% yield). Spectroscopic data are identical tothose reported in the literature. 1
1-(4-bromobutyl)-3-dodecylimidazoliumbromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.3%
In acetone; at 50℃;Inert atmosphere;
General procedure: 1,4-dibromobutane (36.0 mmol, 7.70 g) was dissolved indry acetone (50 mL) and the obtained N-alkyl imidazole(9.0 mmol of N-hexyl imidazole, N-octyl imidazole, Ndecylimidazole, or N-dodecyl imidazole) was addedgradually. The reaction mixture was refluxed at 50° Cunder nitrogen atmosphere and the reaction was monitoredby TLC analysis. After the reaction finished, the solventwas removed under reduced pressure, and subsequently theun-reacted 1, 4-dibromobutane was washed thoroughlywith hexane. The collected viscous liquid was purified bysilica column chromatography with mixtures of acetone/methanol (10:1, by vol) as eluent to afford 1-(4-bromobutyl)-3-alkylimidazolium bromide. The yields of 1-(4-bromobutyl)-3-hexylimidazolium bromide, 1-(4-bromobutyl)-3-octylimidazolium bromide, 1-(4-bromobutyl)-3-decylimidazolium bromide and 1-(4-bromobutyl)-3-dodecylimidazoliumbromide are 72.5, 74.1, 76.8 and 80.3 percent,respectively.
1-(4-bromobutyl)-3-octylimidazolium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.1%
In acetone; at 50℃;Inert atmosphere;
General procedure: 1,4-dibromobutane (36.0 mmol, 7.70 g) was dissolved indry acetone (50 mL) and the obtained N-alkyl imidazole(9.0 mmol of N-hexyl imidazole, <strong>[21252-69-7]N-octyl imidazole</strong>, Ndecylimidazole, or N-dodecyl imidazole) was addedgradually. The reaction mixture was refluxed at 50° Cunder nitrogen atmosphere and the reaction was monitoredby TLC analysis. After the reaction finished, the solventwas removed under reduced pressure, and subsequently theun-reacted 1, 4-dibromobutane was washed thoroughlywith hexane. The collected viscous liquid was purified bysilica column chromatography with mixtures of acetone/methanol (10:1, by vol) as eluent to afford 1-(4-bromobutyl)-3-alkylimidazolium bromide. The yields of 1-(4-bromobutyl)-3-hexylimidazolium bromide, 1-(4-bromobutyl)-3-octylimidazolium bromide, 1-(4-bromobutyl)-3-decylimidazolium bromide and 1-(4-bromobutyl)-3-dodecylimidazoliumbromide are 72.5, 74.1, 76.8 and 80.3 percent,respectively.
5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-bromobutyl)-3-methyl-1H-indole[ No CAS ]
6-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-(4-bromobutyl)-3-methyl-3H-indole[ No CAS ]
1,4-bis(5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)butane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%; 17%; 20%
General procedure: The indole (5) dissolved in THF (10 mL) was added dropwise toa stirring mixture of NaH in THF (10 mL) at 0 C under N2 atmosphere.The mixture was stirred for 10 min, at which point theappropriate dibromoalkane (6)-(10) was added and the mixturewas stirred for 30 min at 0 C. The reaction was refluxed for a further30 min under N2 atmosphere, the mixture was allowed to coolat which point water was added dropwise until the solutionbecame clear. The solvent was then evaporated under reducedpressure to obtain a brown oil. The resin was dissolved in DCM(50 mL) and washed with water (3 50 mL), brine (50 mL) anddried over Na2SO4. The solvent was evaporated under reducedpressure to obtain a brown oil. The material was purified via flashchromatography over silica gel to afford the desired product.
5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-bromobutyl)-3-methyl-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60.6%
Sodium hydride (1.1g, 0.048mol) placed in 250mL round bottom flask was added N, N- dimethylformamide (15mL), under ice-cooling with stirring 10min, was added dropwise a solution of 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl -1H- indole (10.0g, 0.024mol) in N, N- dimethylformamide solution was dropwise completion, stirring was continued under ice 30min. Was added dropwise at the same temperature containing 1,4-dibromobutane (7.7g, 0.036mol) in N, N- dimethylformamide solution was dropwise Bi, warmed to room temperature, the reaction 2.5h. The reaction mixture was poured into ice water, and extracted with dichloromethane (3 × 50mL), saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, by column chromatography to give a pale yellow solid 8.0g. Yield 60.6%.
With potassium carbonate; In acetonitrile; for 10h;Reflux;
To a solution containing 3- (1-piperazinyl) -1,2_ benzisothiazole hydrochloride (100g) and potassium carbonate (136g) in acetonitrile (800ml) added 1,4_ dibromobutane suspension ( 110g). Vigorous stirring mixture was refluxed for 10 hours, the solvent was distilled off pressure acetonitrile was added water (100ml) and toluene (300ml) to the reaction mixture was distilled net was effected under stirring to break up the product mixture, refluxing under stirring operation , the net after the water addition, cooling down, the suspension was filtered to give a white inorganic salts and organic salts of a mixture of the crude quaternary spiro ammonium base (280g).
With potassium carbonate; In acetonitrile; at 90.0℃; for 12.0h;
Raw <strong>[6681-15-8]jatrorrhizine</strong> V(0.1 mol) was dissolved in 50 ml of acetonitrile and (0.2 mol) of 1,4-dibromohexane, (0.3 mol K2CO3)The reaction was carried out at 90 ° C for 12 hours, filtered, concentrated and purified by column chromatography (methanol-chloroform mixture in a volume ratio of 1 to 6: 100 The eluent was collected and the solvent was evaporated under reduced pressure to give Intermediate VII
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h;
A mixture of <strong>[42523-29-5]2,7-dihydroxyfluorenone</strong> (1) (23.34 g, 0.11 mol), 1,4-dibromobutane (216 g, 1.00 mol) and anhydrous K2CO3 (64 g,0.46 mol) in DMF (150 mL) was stirred at 80 °C for one day. Upon completion of reaction, the mixture was diluted with H2O (600 mL).The precipitate was filtered and recrystallized from EtOH to give a solid; (39.25 g, yield: 74percent); mp 109-110° C.
2-[(4-bromobutyl)thio]-5-chlorobenzo[d]oxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With potassium carbonate; In acetone; at 20℃; for 24h;
General procedure: Commercially available 5-chloro-2-mercapto benzoxazole or benzothiazole (10 mmol) and K2CO3 (15mmol) were added to 50 mL of acetone. After 10 min, appropriate 1-bromo--bromoalkane (12 mmol) was added and the mixture was stirred at room temperature for 24 h. After this time the suspension was filtered from inorganic material and the solvent was evaporated under reduced pressure. The residue was suspended in water and extracted with diethyl ether (3 × 50 mL). The combined extracts were washed with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure to givein termediates 9-12 that were used without further purification for the final step. For analytical purpose,a little amount was purified by means of flash chromatography, using cyclohexane/ethyl acetate 9.5:0.5v/v as eluent. Analytical and spectral data are reported for novel compounds 9-12
3-(4-bromobutyl)-6-nitrobenzo[d]thiazol-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 2h;
To a solution of 1d (3.0 g, 15.3 mmol) in 35 mL DMF were added potassium carbonate (6.30 g, 45.65mmol) and 1,4-dibromobutane (13.20 g, 61.1 mmol). The reaction mixture was heated at 65 C for 2hr, then the mixture was poured into water and extracted with EtOAc. The organic phase was dried over sodium sulfate, filtered and evaporated under vacuum. The crude compound was purified by column chromatography (EtOAc/Hexane 1:1) to afford 2d as yellow oil (3.30 g, 66%).
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