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[ CAS No. 19463-48-0 ]

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Chemical Structure| 19463-48-0
Chemical Structure| 19463-48-0
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CAS No. :19463-48-0 MDL No. :MFCD00016982
Formula : C8H7ClO3 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W :186.59 g/mol Pubchem ID :-
Synonyms :

Safety of [ 19463-48-0 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P305+P351+P338 UN#:
Hazard Statements:H315-H319-H335-H413 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 19463-48-0 ]

  • Downstream synthetic route of [ 19463-48-0 ]

[ 19463-48-0 ] Synthesis Path-Downstream   1~16

  • 1
  • [ 141-82-2 ]
  • [ 19463-48-0 ]
  • [ 5438-40-4 ]
YieldReaction ConditionsOperation in experiment
75.9% With pyridine; aniline In toluene for 2h; Reflux;
With piperidine; pyridine Lichtausschluss;
  • 2
  • [ 19463-48-0 ]
  • [ 2051-53-8 ]
  • 2-chloro-4-[(5-isopropyl-2-methyl-phenylimino)-methyl]-6-methoxy-phenol [ No CAS ]
  • 3
  • [ 19463-48-0 ]
  • [ 20624-92-4 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; sodium tetrahydroborate
With sodium hydroxide; sodium tetrahydroborate
With sodium tetrahydroborate; water In acetonitrile
  • 4
  • [ 19463-48-0 ]
  • [ 62936-23-6 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; silver(l) oxide
With potassium permanganate In water; acetonitrile
  • 5
  • [ 19463-48-0 ]
  • [ 108-24-7 ]
  • [ 63055-10-7 ]
YieldReaction ConditionsOperation in experiment
With acetic acid
1.05 g In pyridine at 20℃; for 18h;
  • 6
  • [ 19463-48-0 ]
  • [ 108-24-7 ]
  • 5-chloro-3-methoxy-4-acetoxy-<i>trans</i>-cinnamic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium acetate
With sodium acetate Reflux; 2. Synthesis of compounds II 1-8 General procedure: In a round flask, hydroxybenzaldehyde derivative (10 mmol) and sodium acetate (15 mmol) were disslolved acetic anhydride (0.1 mol). The mixture was refluxed for 5-12h. After cooled to the room temperature, the mixture was poured into 100 m lwater and the solution stirred 0.5 h. The solution was left overnight in the freezer and the acetylhydroxycinnamic derivatives (VI) was obtained by filtration and washed.
  • 7
  • [ 19463-48-0 ]
  • [ 100-44-7 ]
  • [ 37687-67-5 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide
With sodium iodide; potassium carbonate In ethanol 3 EXAMPLE 3 EXAMPLE 3 5-Chlorovanillin (60 g., 0.32 m.), 46.8 g. of potassium carbonate (0.34 m.), 1.9 g. of sodium iodide in 1.4 l. of ethanol and 46.8 g. (0.37 m.) of benzyl chloride in 200 ml. of ethanol are reacted to give 4-benzyloxy-5-chloro-3-methoxybenzaldehyde as an orange liquid which is employed for conversion of the epoxide without purification.
With caesium carbonate In DMF (N,N-dimethyl-formamide) for 1h; Heating / reflux; 100 Intermediate 100; 3-chloro-5-(methyloxy)-4-[(phenylmethyl)oxy]benzaldehyde Intermediate 100 3-chloro-5-(methyloxy)-4-[(phenylmethyl)oxy]benzaldehyde. To a stirring solution of [3-CHLORO-4-HYDROXY-5-METHOXYBENZALDEHYDE] (599 mg, 3.21 [MMOL)] in DMF (5 mL) under nitrogen was added [CS2CO3] (1.10 g, 3.38 [MMOL)] followed by benzyl chloride (0.40 mL, 3.48 [MMOL)] and the mixture heated at reflux for 1 h. After allowing the mixture to cool to ambient temperature the reaction was quenched by the addition of aqueous [NAOH] (2N, 30 mL) and the mixture concentrated under vacuum. The residue was then partitioned between [NAOH] (2N, 30 mL) and EtOAc (50 mL) and the layers separated. The aqueous layer was then re- extracted with EtOAc (50 mL), the layers separated and the combined organic layer washed with brine and then concentrated under vacuum. Purification by SPE (silica, 20 [G] cartridge) eluting with cyclohexane : EtOAc (gradient 50: 1 to 10: 1) afforded the title compound (632 mg). LC/MS: m/z 277.1 [M+H] [+,] [RT] 3.47 min.
  • 8
  • [ 121-33-5 ]
  • [ 19463-48-0 ]
YieldReaction ConditionsOperation in experiment
91% With N-chloro-succinimide; dimethyl sulfoxide In chloroform at 25℃; for 12h; Schlenk technique; 39.a-39.b Example 39: Preparation of chlorovanillin (Compound 39) a) Take a 25 mL Schlenk reaction tube, add 76.1 mg of vanillin, 79.8 mg of N-chlorosuccinimide, 7 μL of dimethyl sulfoxide, and 2 mL of chloroform, and stir for 12 hours at 25°C.After the reaction, the solvent was removed by rotary evaporation and column chromatography was separated to obtain 84.9 mg of chlorovanillin with a yield of 91%.
88% With chlorine In glacial acetic acid at 25℃; for 0.5h;
88% Stage #1: vanillin With chlorine In glacial acetic acid at 25℃; for 0.5h; Stage #2: With chlorine In glacial acetic acid for 0.5h; 3.1 Step 1 To a solution of 2.50 g (16.4 mmol) of vanillin in 15 mL of glacial acetic acid was added chlorine gas through a glass tubing over 30 minutes (with a slow gas flow) at 25° C. White solid product was collected by filtration, washed with 50 mL of hexane, and dried in vacuo to give 2.033 g of 12. The acetic acid filtrate was again treated with chlorine gas as above for 30 minutes to give another 0.659 g of 12. A total of 2.691 g (88% yield) of 12 was obtained. The white solids were used in next step without purification. 1H NMR (CDCl3) δ 10.04 (s, 1H, OH), 9.76 (s, 1H, CHO), 7.56 (d, J=1.6 Hz, 1H, Ar), 7.37 (d, J=1.6Hz, 1H, Ar), 3.91 (s, 3H, OMe); 13C NMR (CDCl3) δ 190.5 (C=O), 149.0 (s, 2C), 128.2 (s), 125.6 (d), 120.1 (s), 109.2 (d), 56.3 (q).
85% With sulfuryl dichloride In glacial acetic acid at 0 - 2℃; for 2h; 5-Chloro-vanillin (3-chloro-4-hydroxy-5-methoxybenzaldehyde). Neat sulfuryl chloride (14.85 g, 8.89mL, 110 mmol, 1.1 eq.) was added dropwise over a 5 minute period to a solution of 15.00 g (100 mmol,1 eq. ) of vanillin (4-hydroxy-3-methoxybenzaldehyde) in 120 mL of glacial acetic acid in an ice waterbath (0- 2°C). After two hours of stirring with ice bath cooling, the reaction mixture was vacuum filtered,rinsed with chilled glacial acetic acid and dried under vacuum to afford a clumpy white solid. HPLC and1H-NMR indicate the presence of vanillin starting material. The solid was dissolved in hot ethanol,recrystallized, vacuum filtered, rinsed with cold ethanol and dried under vacuum to yield to product as12.59 g (85%) of a chunky, white, crystalline solid (mp =163.0-170.0 °C). Product was 98% pure by asestimated by 1H-NMR. Minor contaminating species included ~1% each of vanillin and di-chloro-vanillin.1H-NMR (300 MHz, DMSO-d6): 10.54 (s, 1H, OH), 9.79 (s, 1H, CHO), 7.60 (s, 1H, Ar-H), 7.40 (s, 1H,Ar-H), 3.91 (s, 3H, OMe); EI-MS m/z: 187 (M+2), 185 (M+, 100%), 173, 171, 157, 143, 115, 107, 99, 79,65, 51. UV-Vis: 237.2, 278.3, 302.3 nm.
80% With chlorine In chloroform for 1h;
78% With N-chloro-succinimide; sodium hydride In tetrahydrofuran
64% With N-chloro-succinimide; sodium hydride In tetrahydrofuran at 20℃; for 16h; 4.1.2 3-Chloro-4-hydroxy-5-methoxy-benzaldehyde (8) A solution of vanillin (0.50 g, 3.3 mmol) in THF (10 mL) was cooled to 0 °C and NaH (0.25 g, 6.6 mmol) and N-chlorosuccinimide (0.53 g, 4.0 mmol) was added. The reaction mixture was stirred for 16 h at room temperature and diluted with EtOAc. The mixture was acidified with 1 N HCl and extracted with EtOAc several times. The combined organic layers were washed with water and brine and dried over Na2SO4. The layer was filtered and the filtrate was concentrated in vacuo. The residue was purified by recrystallization to afford 8 as a white solid (0.4 g, 64%).
61.15% With thionyl chloride; glacial acetic acid at 20 - 25℃; for 12h; 11.A Step A At 25 °C, to a solution of the compound 11-1 (20 g, 131.45 mmol, 1 eq) in acetic acid (100 mL) was added thionyl chloride (19.52 g, 144.60 mmol, 1.1 eq), and the reaction was stirred at 20 °C for 12 hours. The reaction solution was filtered, and the filter cake was collected to obtain compound 15-a (15 g, yield: 61.15%).
58% With chlorine In glacial acetic acid at 25℃; for 1h; 3-Chloro-4-hydroxy-5-methoxy-benzaldehyde 3-Chloro-4-hydroxy-5-methoxy-benzaldehyde To a solution of 50.0 g (330 mmol) of vanillin in 250 mL of glacial acetic acid was added chlorine gas through a glass tubing over 60 minutes (with a slow gas flow) at 25°C. White solid product was collected by filtration, washed with 300 mL of hexane, and dried in vacuum to give the title compound (36.0 g; 58%). Characterization by H-NMR (400 MHz, CDCI3): 5[delta] = 9.51 (s, 1 H), 7.52 (s, 1 H), 7.36 (s, 1 H), 4.01 (s, 3H).
53% With 1,4-diaza-bicyclo[2.2.2]octane; N-chloro-succinimide In dichloromethane at 20℃;
53% With 1,4-diaza-bicyclo[2.2.2]octane; N-chloro-succinimide In dichloromethane at 25℃; for 6h; 7 Synthesis of compound 2g In a 25mL reaction tube,vanillin (0.5 mmol) was added,N-chlorosuccinimide (0.55 mmol),triethylenediamine (0.025 mmol) and dichloromethane (2 mL),Stir at 25°C for 6 hours,After the reaction is completed,concentrate,The product was isolated by column chromatography to give 2 g (53%).
49% With N-chloro-succinimide; sodium hydride In tetrahydrofuran
47% With N-chloro-succinimide; glacial acetic acid at 20℃; for 16h; Inert atmosphere; 1 4.1.1. Synthesis of halogenated vanillin 1a-1c 4.1.1.1. Synthesis of 3-chloro-4-hydroxy-5-methoxybenzaldehyde(1a). To a solution of vanillin (2.00 g, 13.1 mmol) in glacial acetic acid (20 mL), N-chlorosuccinimide (NCS) (1.76 g, 13.1 mmol) wasadded. The reaction was stirred at room temperature for 16 h. Thereaction was extracted with CH2Cl2. An organic layer was washed withH2O followed by saturated NaCl solution. The resulting organic layerwas dried over anhydrous Na2SO4 and concentrated to dryness to affordan off-white solid. The solid was washed with CHCl3. Upon filtration, anoff-white precipitated crystal product (1a) was obtained (1.14 g, 47%).1H NMR (300 MHz, DMSO-d6) δ: 3.89 (s, 3H), 6.45 (s, 1H), 7.38 (d, J = 1.77 Hz, 1H), 7.57 (d, J = 1.79 Hz, 1H), 9.76 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 56.32, 109.16, 120.05, 125.64, 128.18, 148.79, 148.94, 190.49; ESI-MS calc for C8H7ClNaO3 [M+Na+]+: 208.9976, found 208.9975.
With sodium chlorine monoxide; lithium hydroxide monohydrate
With glacial acetic acid durch Chlorierung;
With anhydrous Sodium acetate; glacial acetic acid durch Chlorierung;
With chloroform; chlorine
5 g Stage #1: vanillin With sodium hydride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: With N-chloro-succinimide In tetrahydrofuran at 20℃;
With chlorine In glacial acetic acid

Reference: [1]Current Patent Assignee: PEKING UNIVERSITY - CN112573978, 2021, A Location in patent: Paragraph 0250-0254
[2]Hua, Duy H.; Huang, Xiaodong; Chen, Yi; Battina, Srinivas K.; Tamura, Masafumi; Noh, Sang K.; Koo, Sung I.; Namatame, Ichiji; Tomoda, Hiroshi; Perchellet, Elisabeth M.; Perchellet, Jean-Pierre [Journal of Organic Chemistry, 2004, vol. 69, # 18, p. 6065 - 6078]
[3]Current Patent Assignee: KANSAS STATE UNIVERSITY - US6727277, 2004, B1 Location in patent: Page/Page column 32
[4]Maresh, Justin J.; Ralko, Arthur A.; Speltz, Tom E.; Burke, James L.; Murphy, Casey M.; Gaskell, Zachary; Girel, Joann K.; Terranova, Erin; Richtscheidt, Conrad; Krzeszowiec, Mark [Synlett, 2014, vol. 25, # 20, p. 2891 - 2894]
[5]Oliver, D.W.; Haasbroek, P.P.; Leger, J.M.; Carpy, A.J.M. [Journal of Chemical Crystallography, 1994, vol. 24, # 10, p. 665 - 668]
[6]Kang, Dong Wook; Ryu, HyungChul; Lee, Jeewoo; Lang, Krystle A.; Pavlyukovets, Vladimir A.; Pearce, Larry V.; Ikeda, Tetsurou; Lazar, Jozsef; Blumberg, Peter M. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 1, p. 214 - 219]
[7]Lim, Kwang Su; Lee, Hobin; Kim, Sung Eun; Ha, Tae-Hwan; Ann, Jihyae; Son, Karam; Choi, Sun; Sun, Wei; Pearce, Larry V.; Deandrea-Lazarus, Ian A.; Blumberg, Peter M.; Lee, Jeewoo [European Journal of Medicinal Chemistry, 2013, vol. 68, p. 233 - 243]
[8]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD; WUXI APPTEC CO., LTD. - EP3766883, 2021, A1 Location in patent: Paragraph 0146
[9]Current Patent Assignee: BASF SE - WO2013/164295, 2013, A1 Location in patent: Page/Page column 100
[10]Hu, Lanping; Huang, Weichun; Wang, Yang; Wu, Zheng-Guang; Xu, Haiyan; Zhu, Guanghua; Zhu, Yueping; Zi, You [RSC Advances, 2022, vol. 12, # 12, p. 7115 - 7119]
[11]Current Patent Assignee: UNIV NANTONG - CN114292153, 2022, A Location in patent: Paragraph 0052-0054
[12]Location in patent: scheme or table Lim, Kwang Su; Kang, Dong Wook; Kim, Yong Soo; Kim, Myeong Seop; Park, Seul-Gi; Choi, Sun; Pearce, Larry V.; Blumberg, Peter M.; Lee, Jeewoo [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 299 - 302]
[13]Nilchan, Napon; Phetsang, Wanida; Nowwarat, Taechin; Chaturongakul, Soraya; Jiarpinitnun, Chutima [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 19, p. 5343 - 5348]
[14]Hopkins; Chisholm [Canadian Journal of Research, Section B: Chemical Sciences, 1946, vol. 24, p. 208]
[15]Hann; Spencer [Journal of the American Chemical Society, 1927, vol. 49, p. 537]
[16]Menke; Bentley [Journal of the American Chemical Society, 1898, vol. 20, p. 316] Peratoner [Gazzetta Chimica Italiana, 1898, vol. 28 I, p. 235] Hann; Markley [Journal. Washington Academy of Sciences, Washington, D. C, vol. 16, p. 171][Chemisches Zentralblatt, 1926, vol. 97, # I, p. 3401] Hann [Journal of the American Chemical Society, 1925, vol. 47, p. 2000][Chemisches Zentralblatt, 1924, vol. 95, # I, p. 2110]
[17]Raiford; Lichty [Journal of the American Chemical Society, 1930, vol. 52, p. 4576,4582]
[18]Appendino, Giovanni; Daddario, Nives; Minassi, Alberto; Moriello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2005, vol. 48, # 14, p. 4663 - 4669]
[19]Location in patent: scheme or table Xia, Chun-nian; Li, Hai-bo; liu, Feng; Hu, Wei-xiao [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6553 - 6557]
  • 9
  • [ 19463-48-0 ]
  • [ 105-56-6 ]
  • 3-(3-chloro-4-hydroxy-5-methoxy-phenyl)-2-cyano-acrylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With piperidine at 70℃;
  • 11
  • [ 19463-48-0 ]
  • [ 34098-18-5 ]
YieldReaction ConditionsOperation in experiment
94% With boron tribromide In dichloromethane at 0 - 25℃; for 4.3h;
91% Stage #1: 5-chlorovanillin With boron tribromide In dichloromethane at 0 - 20℃; for 3.5h; Inert atmosphere; Stage #2: With methanol In dichloromethane at 0℃;
89% Stage #1: 5-chlorovanillin With boron tribromide In dichloromethane at -40℃; for 5h; Stage #2: With water In dichloromethane at 0℃; 18 To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde (10 g, 54 mmol) in dichloromethane (300 mL) was added BBr3 (26.7 g, 107 mmol) dropwise at -40° C. under N2. After addition, the mixture was stirred at this temperature for 5 h and then was poured into ice water. The precipitated solid was filtered and washed with petroleum ether. The filtrate was evaporated under reduced pressure to afford 3-chloro-4,5-dihydroxybenzaldehyde (9.8 g, 89%), which was directly used in the next step.
89% With boron tribromide In dichloromethane at -40℃; for 5h; 6.a Step a: 3-Chloro-4,5-dihydroxybenzaldehyde To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde (10 g, 54 mmol) in dichloromethane (300 mL) was added BBr3 (26.7 g, 107 mmol) dropwise at -40° C. under N2. After addition, the mixture was stirred at this temperature for 5 h and then was poured into ice water. The precipitated solid was filtered and washed with petroleum ether. The filtrate was evaporated under reduced pressure to afford 3-chloro-4,5-dihydroxybenzaldehyde (9.8 g, 89%), which was directly used in the next step.
89% With boron tribromide In dichloromethane 18 3-Chloro-4,5-dihydroxybenzaldehyde 3-Chloro-4,5-dihydroxybenzaldehyde To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde (10 g, 54 mmol) in dichloromethane (300 mL) was added BBr3 (26.7 g, 107 mmol) dropwise at -40° C. under N2. After addition, the mixture was stirred at this temperature for 5 h and then was poured into ice water. The precipitated solid was filtered and washed with petroleum ether. The filtrate was evaporated under reduced pressure to afford 3-chloro-4,5-dihydroxybenzaldehyde (9.8 g, 89%), which was directly used in the next step.
89% In dichloromethane 6.a Step a: Step a: 3-Chloro-4,5-dihydroxybenzaldehyde To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde (10 g, 54 mmol) in dichloromethane (300 mL) was added BBr3 (26.7 g, 107 mmol) dropwise at -40° C. under N2. After addition, the mixture was stirred at this temperature for 5 h and then was poured into ice water. The precipitated solid was filtered and washed with petroleum ether. The filtrate was evaporated under reduced pressure to afford 3-chloro-4,5-dihydroxybenzaldehyde (9.8 g, 89%), which was directly used in the next step.
89% With boron tribromide In dichloromethane at -40℃; for 5h; Inert atmosphere; 6.a; 18 3-Chloro-4,5-dihydroxybenzaldehyde To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde (10 g, 54 mmol) in dichloromethane (300 mL) was added BBr3 (26.7 g, 107 mmol) dropwise at -40° C. under N2. After addition, the mixture was stirred at this temperature for 5 h and then was poured into ice water. The precipitated solid was filtered and washed with petroleum ether. The filtrate was evaporated under reduced pressure to afford 3-chloro-4,5-dihydroxybenzaldehyde (9.8 g, 89%), which was directly used in the next step.
86% With boron tribromide In dichloromethane at 20℃; for 4h;
78% With boron tribromide In dichloromethane at 0 - 20℃; for 3.5h; Inert atmosphere; 3-chloro-4,5-dihydroxybenzaldehyde A-21 A solution of BBr3 1M in DCM (9.65 mL; 9.65 10-3 mol) was added to a stirred solution of 3-chloro-4-hydroxy-5-methoxybenzaldehyde (1.49 g; 8.04 10-3mol) in dry DCM (20 mL) at 0°C under nitrogen atmosphere. After stirring at 0°Cfor 0,5h and at room temperature for 3h, the mixture was cooled to 0°C and MeOH(20 mL) was added carefully. The solvent concentrated in vacuo, and the residue was added MeOH (20 mL). This process was repeated three times. The titlecompound was obtained by column chromatography (DCM - EtOAc: 9-1) as a whitesolid (1.08 g; 78%). IR (ATR): 3411,3028, 2968, 2921, 2857, 2757, 2689, 2617, 2562, 1655, 1584, 1502 cm-1.1H NMR(300 MHz, DMSO D6) δ ppm 10.41 (s, 2H), 9.71(s, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.22 (d, J = 1.8 Hz, 1H). 13CNMR (75 MHz, DMSO D6) δ ppm 190.6, 148.2, 146.8,128.3, 124.2, 120.2, 112.4.
73% With boron tribromide In dichloromethane at 0 - 20℃; 39 3-Chloro-4,5-dihydroxybenzaldehyde. To a stirred solution of 3-chloro-4-hydroxy-5-methoxybenzaldehyde (5 mmol, 972 mg) in dichloromethane (20 mL) at 0°C was added drop-wise (10-15 minutes) a solution of boron tribromide in dichloromethane (1M, 15 mmol, 15 mL), the reaction mixture being stirred, under moisture exclusion conditions, at 0 °C for one hour and then at room temperature overnight. After cooling to 0 °C, the crude product mixture was carefully washed with distilled water and the organic layer was evaporated under reduced pressure. The pinkish solid that precipitated was filtered under reduced pressure, washed with distilled water and dried at room temperature under vacuum, yielding 3- chloro-4,5-dihydroxybenzaldehyde as a pale-pink solid. Yield: 73%, 630 mg; mp (°C): 219-221; ‘H NMR (400 MHz, (CD3)2SO/CCL): ö, ppm = 10.10 (1H, bs, OH), 9.97 (1H, bs, OH), 9.66 (1H, s, CH), 7.31 (1H, s, ArH), 7.19 (1H, s, ArH); ‘3C NMR (100 MHz, (CD3)2SO/CCL): ö,ppm= 189.3, 148.3, 146.6, 128.1, 123.7, 120.4, 112.7; GC-MS (El):mlz (tR, mm) = 172 (9.49) Mt
With boron trichloride
With boron tribromide In dichloromethane at 0 - 20℃;
Stage #1: 5-chlorovanillin With boron tribromide In dichloromethane at 20℃; Cooling with ice; Stage #2: With hydrogenchloride; water In dichloromethane Cooling with ice; 1.1 Stcpl : 3-chloro-4,5-dihydroxy benzaldchyde: A solution of 19.1 g 3-chloro-4- hydroxy-5-mcthoxy benzaldchyde in dichloromethane (1600 ml) was cooled in ice water bath. Boron tribromide (53.8 g) in dichloromethane (80 ml) were added and the mixture was stirred for two hours at ambient temperature and then was concentrated. The residue was cooled again with ice water bath and precipitated with ice-cold aqueous hydrochloric acid (IN, 500 ml). Solid residue was received upon filtration, then washed with ice water (500 ml) and dried in the air to obtain 19.3 g crude product of 3-chloro-4,5-dihydroxy benzaldehyde, which was used for the following step.
With boron tribromide In dichloromethane at -40℃; Inert atmosphere; 3-Chloro-4,5-dihydroxy-benzaldehyde 3-Chloro-4,5-dihydroxy-benzaldehyde To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde (36.0 g, 193 mmol) in dichloromethane (1000 mL) was added BBr3 (97.0 g, 387 mmol) dropwise at -40°C under N2. After addition, the mixture was stirred at this temperature for 5 h and then was poured into ice water. The precipitated solid was filtered and washed with petroleum ether. The solid was dried under reduced pressure to afford the title compound (30.0 g; 91 %), which was directly used in the next step. Characterization by H-NMR (400 MHz, DMSO): 5[delta] = 10.41 (s, 1 H), 9.70 (s, 1 H), 7.44 (s, 1 H), 7.23 (s, 1 H).
In methanol; dichloromethane 4 EXAMPLE 4 EXAMPLE 4 To a stirred solution of 12.0 g. (0.064 m.) of 5-chlorovanillin in 40 ml. of methylene chloride at 0°C. is added dropwise, 25 g. (0.1 m.) of boron tribromide. The mixture is stirred at 25°C. for 3 hours. Methanol (100 ml.) is added and the solution is concentrated. The residue is dissolved in ether, the ether solution is washed with water, dried and concentrated to give 10.3 g. of 5-chloroprotocatechualdehyde, m.p. 231°C. dec.
With boron tribromide In dichloromethane at -40 - 25℃; for 12h; 11.B Step B At -40 °C, to a solution of the compound 15-a (15 g, 80.39 mmol, 1 eq) in dichloromethane (150 mL) was added boron tribromide (40.28 g, 160.78 mmol, 2 eq), and the reaction system was stirred at -40 °C for 3 hours and then heated to 25 °C and stirred for another 9 hours. Water (200 mL) was added to the reaction solution and filtered, and the filter cake was collected to obtain compound 11-b (13 g, the crude product was directly used in the next step).

Reference: [1]Hua, Duy H.; Huang, Xiaodong; Chen, Yi; Battina, Srinivas K.; Tamura, Masafumi; Noh, Sang K.; Koo, Sung I.; Namatame, Ichiji; Tomoda, Hiroshi; Perchellet, Elisabeth M.; Perchellet, Jean-Pierre [Journal of Organic Chemistry, 2004, vol. 69, # 18, p. 6065 - 6078]
[2]Location in patent: experimental part Wang, Min; Gao, Mingzhang; Miller, Kathy D.; Zheng, Qi-Huang [Synthetic Communications, 2011, vol. 41, # 8, p. 1127 - 1140]
[3]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2007/244159, 2007, A1 Location in patent: Page/Page column 93
[4]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2008/9524, 2008, A1 Location in patent: Page/Page column 385
[5]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2011/98311, 2011, A1
[6]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2011/98311, 2011, A1
[7]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2015/231142, 2015, A1 Location in patent: Paragraph 1132; 1584
[8]Hyotylainen [Chemosphere, 1994, vol. 28, # 9, p. 1641 - 1656]
[9]Pallandre, Jean-René; Borg, Christophe; Rognan, Didier; Boibessot, Thibault; Luzet, Vincent; Yesylevskyy, Semen; Ramseyer, Christophe; Pudlo, Marc [European Journal of Medicinal Chemistry, 2015, vol. 103, p. 163 - 174]
[10]Current Patent Assignee: BSIM THERAPEUTICS - WO2016/80853, 2016, A1 Location in patent: Paragraph 00316; 00317
[11]Jong, Ting-Ting; Williard, Paul G.; Porwoll, Joseph P. [Journal of Organic Chemistry, 1984, vol. 49, # 4, p. 735 - 736]
[12]Lin, Shuangjun; Van Lanen, Steven G.; Shen, Ben [Journal of the American Chemical Society, 2007, vol. 129, # 41, p. 12432 - 12438]
[13]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2010/77976, 2010, A2 Location in patent: Page/Page column 26
[14]Current Patent Assignee: BASF SE - WO2013/164295, 2013, A1 Location in patent: Page/Page column 100
[15]Current Patent Assignee: GLAXOSMITHKLINE PLC - US3976695, 1976, A
[16]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD; WUXI APPTEC CO., LTD. - EP3766883, 2021, A1 Location in patent: Paragraph 0146
  • 12
  • [ 19463-48-0 ]
  • [ 67-64-1 ]
  • 4-(5-chloro-4-hydroxy-3-methoxyphenyl)-buten-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% With sodium hydroxide In water for 1h;
  • 13
  • [ 20624-92-4 ]
  • [ 19463-48-0 ]
YieldReaction ConditionsOperation in experiment
95% With potassium carbonate In n-heptane at 80℃; for 24h; S4. Procedure for the synthesis of aldehydes and ketones General procedure: A magnetic stir bar, 0.5 mmol alcohol and 3 mL n-heptane solvent were added to 20 mL glass tube. Then, 35mg catalyst and 10 mol% of K2CO3 were added. The glass tube containing reaction mixture was f itted withseptum and connected to a balloon containing one bar of air. Then the glass tube was placed into a preheatedaluminum block at 85°C. Temperature inside the reaction tube was measured to be 80 oC and this temperaturehas been taken as the reaction temperature. The reaction was allowed to progress under continuous stirringfor the required time at 80 °C. Af ter completion of the reaction, the glass tube was cooled down to roomtemperature. Afterwards, the catalyst was f iltered-off and washed with ethyl acetate. The solvent f rom thef iltrate containing the reaction products was removed in vacuum and the corresponding aldehyde/ketone waspurif ied by column chromatography. All products were analyzed by GC-MS and NMR spectroscopy analysis.In the case of yields determined the by GC, 100 μL n-hexadecane was added to the reaction vial containingthe products and diluted with ethyl acetate. Then, the reaction mixture containing catalyst and products wasf iltered through a plug of silica and the filtrate containing product was analyzed by GC.
With oxygen; copper(l) chloride In dimethyl sulfoxide
  • 14
  • [ 19463-48-0 ]
  • [ 62936-23-6 ]
  • 15
  • [ 19463-48-0 ]
  • [ 20624-92-4 ]
  • [ 62936-23-6 ]
  • 16
  • [ 19463-48-0 ]
  • [ 106-93-4 ]
  • [ 219685-39-9 ]
YieldReaction ConditionsOperation in experiment
86% With potassium carbonate In acetonitrile Reflux;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
9.33 g (59%) With potassium carbonate In N,N-dimethyl-formamide Preparation of 4-(2-Bromoethoxy)-3-chloro-5-methoxybenzaldehyde Preparation of 4-(2-Bromoethoxy)-3-chloro-5-methoxybenzaldehyde 1,2-Dibromoethane (46 mL, 0.54 moles) was added to a mixture of 3-chloro-4-hydroxy-5-methoxybenzaldehyde (10 g, 54 mmoles) and potassium carbonate (37 g, 0.27 moles) in DMF (180 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2*100 mL). The combined organic phases were washed with saturated sodium chloride (150 mL), dried over MgSO4 and evaporated in vacuo to afford 9.33 g (59%) of 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde. M.p. 52-54° C.
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