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[ CAS No. 110-52-1 ]

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Chemical Structure| 110-52-1
Chemical Structure| 110-52-1
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CAS No. :110-52-1 MDL No. :MFCD00000261
Formula : C4H8Br2 Boiling Point : 63-65°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :215.91 g/mol Pubchem ID :8056
Synonyms :

Safety of [ 110-52-1 ]

Signal Word:Danger Class:8,6.1
Precautionary Statements:P261-P280-P301+P310-P305+P351+P338 UN#:2922
Hazard Statements:H301-H315-H318-H335-H412 Packing Group:
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Application In Synthesis of [ 110-52-1 ]

  • Upstream synthesis route of [ 110-52-1 ]
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[ 110-52-1 ] Synthesis Path-Upstream   1~49

  • 1
  • [ 110-52-1 ]
  • [ 64-17-5 ]
  • [ 107-15-3 ]
  • [ 7154-73-6 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1939, vol. 58, p. 1105,1106
  • 2
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  • [ 1455-20-5 ]
Reference: [1] Patent: US2018/201697, 2018, A1,
  • 3
  • [ 110-52-1 ]
  • [ 126-33-0 ]
  • [ 24308-29-0 ]
Reference: [1] Monatshefte fuer Chemie, 1982, vol. 113, p. 37 - 42
  • 4
  • [ 110-52-1 ]
  • [ 106-40-1 ]
  • [ 22090-26-2 ]
YieldReaction ConditionsOperation in experiment
46% 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
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  • [ 586-77-6 ]
  • [ 22090-26-2 ]
Reference: [1] Synthesis, 2002, # 1, p. 34 - 38
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  • [ 136918-14-4 ]
  • [ 5394-18-3 ]
YieldReaction ConditionsOperation 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
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  • [ 1074-82-4 ]
  • [ 5394-18-3 ]
YieldReaction ConditionsOperation 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).

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YieldReaction ConditionsOperation 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;
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YieldReaction ConditionsOperation 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).
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  • [ 1200-03-9 ]
YieldReaction ConditionsOperation 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 ]
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  • [ 108-95-2 ]
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Reference: [1] Patent: US4380546, 1983, A,
[2] Patent: US4456608, 1984, A,
  • 34
  • [ 1927-71-5 ]
  • [ 110-52-1 ]
  • [ 1200-03-9 ]
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 American Chemical Society, 1922, vol. 44, p. 2649
  • 35
  • [ 110-52-1 ]
  • [ 139-02-6 ]
  • [ 1200-03-9 ]
Reference: [1] Chemische Berichte, 1983, vol. 116, # 1, p. 323 - 347
[2] Journal of Organic Chemistry, 1974, vol. 39, p. 2598 - 2600
[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 ]
YieldReaction ConditionsOperation 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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[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
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[5] Journal of the American Chemical Society, 2010, vol. 132, # 41, p. 14409 - 14411
[6] Journal of Organic Chemistry USSR (English Translation), 1983, vol. 19, p. 474 - 480[7] Zhurnal Organicheskoi Khimii, 1983, vol. 19, # 3, p. 541 - 548
[8] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 141 - 146
[9] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7709 - 7717
[10] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 11, p. 2399 - 2401[11] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 11, p. 2646 - 2648
[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
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  • [ 132525-49-6 ]
  • [ 4167-77-5 ]
Reference: [1] Zhurnal Obshchei Khimii, 1952, vol. 22, p. 1944,1951; engl. Ausg. S. 1993, 1998, 1999
[2] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 11, p. 2399 - 2401[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 11, p. 2646 - 2648
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Reference: [1] Journal of the American Chemical Society, 1987, vol. 109, p. 6825
  • 39
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  • [ 109-99-9 ]
  • [ 110-63-4 ]
  • [ 4167-77-5 ]
Reference: [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 ]
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  • 41
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  • [ 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 ]
  • [ 70500-72-0 ]
  • [ 203395-59-9 ]
YieldReaction ConditionsOperation 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
  • 43
  • [ 110-52-1 ]
  • [ 22246-18-0 ]
  • [ 129722-34-5 ]
YieldReaction ConditionsOperation 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.

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[6] Patent: WO2012/3418, 2012, A2, . Location in patent: Page/Page column 45
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  • 44
  • [ 110-52-1 ]
  • [ 129722-34-5 ]
YieldReaction ConditionsOperation 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]).
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  • 45
  • [ 110-52-1 ]
  • [ 22246-18-0 ]
  • [ 129722-34-5 ]
YieldReaction ConditionsOperation 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
  • 46
  • [ 110-52-1 ]
  • [ 129722-34-5 ]
YieldReaction ConditionsOperation 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] Patent: WO2006/30446, 2006, A1, . Location in patent: Page/Page column 22-26; 28
  • 47
  • [ 110-52-1 ]
  • [ 591-19-5 ]
  • [ 219928-13-9 ]
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
  • 48
  • [ 110-52-1 ]
  • [ 1989-33-9 ]
  • [ 373-88-6 ]
  • [ 182438-98-8 ]
YieldReaction ConditionsOperation 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.
Reference: [1] Patent: WO2017/98522, 2017, A1, . Location in patent: Page/Page column 18; 19; 24; 25
  • 49
  • [ 110-52-1 ]
  • [ 753-90-2 ]
  • [ 1989-33-9 ]
  • [ 182438-98-8 ]
Reference: [1] Patent: US2017/57917, 2017, A1,
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