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[ CAS No. 84388-68-1 ] {[proInfo.proName]}

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Chemical Structure| 84388-68-1
Chemical Structure| 84388-68-1
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Product Details of [ 84388-68-1 ]

CAS No. :84388-68-1 MDL No. :MFCD06739497
Formula : C7H4Cl2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :RZVJTHXDHLQJIK-UHFFFAOYSA-N
M.W :191.01 Pubchem ID :528389
Synonyms :

Safety of [ 84388-68-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 84388-68-1 ]

* 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.

  • Downstream synthetic route of [ 84388-68-1 ]

[ 84388-68-1 ] Synthesis Path-Downstream   1~80

  • 1
  • [ 95-77-2 ]
  • [ 100-97-0 ]
  • [ 84388-68-1 ]
YieldReaction ConditionsOperation in experiment
58% With methanesulfonic acid at 105℃; for 1h; 4,5-dichloro-2-hydroxybenzaldehyde (61b). To a solution of 3,4-dichlorophenol (7.5 g, 46.3 mmol) in methane sulfonic acid (45 mL) was added hexamethylenetetramine (7.14 g, 50.9 mmol) in small portions. The mixture was slowly heated to 105 °C and kept at 105 °C for 1 h before being cooled to room temperature and poured into ice-water. The mixture was extracted with EtOAc, and the extracts were combined, washed with brine, dried over Na2SO4, and recrystallized to give a yellow solid (5.1g, 58%).
23% With methanesulfonic acid at 110℃; for 0.5h; 1.a Step a: To a stirred solution of 3,4-dichlorophenol (50.00 g, 306.75 mmol) in methanesulfonic acid (35 mL) was added hexamethyltetramine (47.50 g, 337.40 mmol) at room temperature. The reaction solution was stirred at 110 °C for 30 min. The reaction solution was allowed to cool down to room temperature and quenched with water (500 mL). The resulting solution was extracted with DCM (3 x 500 mL) and dried over anhydrous Na2SC>4. After the filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/DCM (10/1) to afford 4,5-dichloro-2- hydroxybenzaldehyde as a yellow solid (13.50 g, 23%): NMR (300 MHz, CDCh) d 10.96 (s, 1H), 9.84 (d, J= 0.7 Hz, 1H), 7.64 (s, 1H), 7.15 (s, 1H).
15% Stage #1: 3,4-dichlorophenol; hexamethylenetetramine In trifluoroacetic acid Heating / reflux; Stage #2: With sulfuric acid In water; trifluoroacetic acid at 25℃; for 4h; 2 Example 1-3; Preparation of salicylaldehydes (27a, 27b, 28b) via formylation of 4-sabstituted phenoles (duff formylation); Preparation of 4,5-dichloro-2-hydroxy-benzaldehyde (27b) General procedure. To a solution of the appropriately substituted phenol (10.0 g) in TFA (100 mL) was added HMTA (1.1 equivalent) in small portions. The reaction solution was heated at reflux overnight. After cooling, the solution was treated with 50% H2SO4 solution (40 mL) for 4 h at room temperature, and then was extracted with ether (3?100 mL). The combined ether phases were washed with 5 M HCl solution and water, and then dried over anhydrous MgSO4. After filtration, the filtrate was evaporated and purified. 2-Hydroxy-5-trifluoromethyl-benzaldehyde (27a). Following the general procedure and FCC purification with 30% ethyl acetate-hexane, 4-trifluoromethyl phenol (10.0 g, 61.7 mmol) gave 2-hydroxy-5-trifluoromethyl-benzaldehyde 27 (3.9 g, 34%) as a pink solid. Rf (20% ethyl acetate-hexane): 0.47. 1H NMR (300 MHz, CDCl3) ? 11.31 (s, 1H, OH), 9.96 (s, 1H, CHO), 7.87 (d, J=1.6 Hz, 1H, C6-H (Ph)), 7.76 (dd, J=2.0 and 8.5 Hz, 1H, C4-H (Ph)) and 7.11 (d, J=8.8 Hz, 1H, C3-H (Ph)). 13C NMR (75 MHz, CDCl3) ? 195.8, 163.8, 133.4(d), 131.0(d), 125.3, 122.1 (m), 119.8 and 118.6. 4,5-Dichloro-2-hydroxy-benzaldehyde (27b) and 5,6-dichloro-2-hydroxy-benzaldehyde (28). Following the general procedure and FCC purification with 5-10% ethyl acetate-hexane, 3,4-dichlorophenol (10.0 g, 61.1 mmol) gave 5,6-dichloro-2-hydroxy-benzaldehyde 28 (2.2 g, 19%) as a light yellow solid. Rf (40% ethyl acetate-hexane): 0.63. 1H NMR (300 MHz, CDCl3) ? 11.98 (s, 1H, OH), 10.44 (s, 1H, CHO), 7.55 (d, J=9.4 Hz, 1H, C4-H (Ph)) and 6.89 (d, J=9.3 Hz, 1H, C3-H (Ph)). 13C NMR (75 MHz, CDCl3) ? 195.4, 162.4, 137.8 (2C), 135.6, 123.8 and 118.1. From the same reaction continuous FCC purification with 10% ethyl acetate-hexane gave 4,5-dichloro-2-hydroxy-benzaldehyde 27b (1.8 g, 15%) as a light yellow solid. Rf (40% ethyl acetate-hexane): 0.47. 1H NMR (300 MHz, CDCl3) ? 10.97 (s, 1H, OH), 9.84 (s, 1H, CHO), 7.64 (s, 1H, C3-H (Ph)) and 7.15 (s, 1H, C6-H (Ph)). 13C NMR (75 MHz, CDCl3) ? 194.7, 160.0, 149.9, 141.5, 134.0, 123.6 and 119.9.
18.2 g With methanesulfonic acid at 105℃;
In methanesulfonic acid at 105℃; for 0.25h; 33.A 4,5-Dichloro-2-hydroxybenzaldehyde 3,4-Dichlorophenol (20.0 g, 0.123 mol) was added to methylsulfonic acid (120 mL) and stirred for 15 min to give a clear solution. To this solution was added slowlyhexamethylenetetramine (18.8 g, 0.134 mol) in small portions. The mixture was then heated to 105 °C and stirred for 15 min before being cooled to room temperature and poured into a mixture of ice and water (1.2 L). The mixture was extracted with DCM (200 mL *3) and the combined extracts were dried over sodium sulfate and concentrated to give the subtitle intermediate as a crude yellow solid (18.2 g, 77%).

  • 2
  • [ 1205681-42-0 ]
  • [ 84388-68-1 ]
  • [ 1205681-23-7 ]
YieldReaction ConditionsOperation in experiment
Stage #1: biphenyl-2-yl-carbamic acid 1-{2-[4-(2-amino-ethyl)-phenyl]-ethyl}-piperidin-4-yl ester; 4,5-dichloro-2-hydroxybenzaldehyde With acetic acid In ethanol for 1h; Stage #2: With sodium tris(acetoxy)borohydride In ethanol at 20℃; for 18h; Stage #3: With water In ethanol for 0.0833333h; 22 Example 22 Biphenyl-2-yl-carbamic acid 1-(2-{4-[2-(4,5-dichloro-2-hvdroxy-benzylamino)-ethyl1-phenyl)-ethvD- piperidin-4-yl ester; Biphenyl-2-yl-carbamic acid 1-{2-[4-(2-amino-ethyl)-phenyl]-ethyl}-piperidin-4-yl ester (Preparation 5, 40mg, 90μmol) was dissolved in ethanol (0.5ml) and added to a reaction vessel containing 4,5-dichloro-2- hydroxybenzaldehyde (17.2mg, 90μmol). To the reaction mixture was then added acetic acid (5.1 μl, 90μmol) and sodium sulphate (drying agent). The resulting mixture was allowed to stir for 1 hour. Sodium tri(acetoxy)borohydride (38mg, 178μmol) was then added, and the reaction allowed to stir at room temperature for 18h. The reaction was quenched with water (20μl) and stirred for 5 minutes. The solvents were removed in vacuo and the residue partitioned between dichloromethane (2ml) and saturated aqueous sodium hydrogen carbonate solution (2ml). The aqueous phase was separated and extracted with further dichloromethane (1 ml). The combined organic layers were concentrated in vacuo and the crude residue purified using an Isolute SCX-2 cartridge, eluting with methanol, followed by 1 M ammonia in methanol. The basic fractions were evaporated under reduced pressure and the residue purified by HPLC method E to afford the title compound. LCMS Method E: RT 2.27 min (100%area) ES m/z 618 [M+H]+.
  • 3
  • [ 1427594-56-6 ]
  • [ 84388-68-1 ]
  • [ 1427594-95-3 ]
YieldReaction ConditionsOperation in experiment
80.5% With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; 60 2-((4-(6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperazin-1 -yl)methyl)-415- dichlorophenol ("60") 2-((4-(6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperazin-1 -yl)methyl)-415- dichlorophenol ("60")A reaction mixture of 5-(4-fluoro-phenyl)-6-piperazin-1 -yl-pyrimidin-4-ylamine (400.0 mg; 1 .46 mmol; 1 .00 eq.), 4,5-dichloro-2-hydroxy-benzaldehyde (279.5 mg; 1 .46 mmol; 1 .00 eq.), Acetic acid (87.8 mg; 1 .46 mmol; 1 .00 eq.) and sodium triacetoxy borohydride (926.1 mg; 4.39 mmol; 3.00 eq.) in DCE (1 0 ml ) was stirred overnight at RT. The reaction solution was diluted with DCM and washed with brine. The organic layer was dried and concentrated, which was added 10ml of ether and stirred for 5mins. The precipitate was filtered to afford the title asd white off solid (528mg, yield 80.5%). LC-MS: (M+1 =448, obsd. = 448/450).
  • 4
  • [ 141-97-9 ]
  • [ 84388-68-1 ]
  • [ 1087738-71-3 ]
YieldReaction ConditionsOperation in experiment
92% With ziconium(IV) oxychloride octahydrate at 20℃; for 0.333333h; Milling; Green chemistry;
  • 5
  • [ 84388-68-1 ]
  • [ 105-53-3 ]
  • ethyl 6,7-dichloro-2-oxo-2H-chromene-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With ziconium(IV) oxychloride octahydrate at 20℃; for 0.666667h; Milling; Green chemistry;
  • 6
  • [ 84388-68-1 ]
  • [ 95-54-5 ]
  • C20H12Cl4N2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With formaldehyd EXPERIMENTAL General procedure: Modified salen ligands were synthesized by a single-step Mannich condensation between the phenylene diamine, ethylene diamine, formaldehyde and the substituted phenol. The synthesized salen compounds are shown in Scheme 1 the structures of synthetic compounds are confirmed with the spectroscopic data.
  • 7
  • [ 84388-68-1 ]
  • [ 107-15-3 ]
  • C16H12Cl4N2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With formaldehyd EXPERIMENTAL General procedure: Modified salen ligands were synthesized by a single-step Mannich condensation between the phenylene diamine, ethylene diamine, formaldehyde and the substituted phenol. The synthesized salen compounds are shown in Scheme 1 the structures of synthetic compounds are confirmed with the spectroscopic data.
  • 8
  • [ 14741-71-0 ]
  • [ 84388-68-1 ]
  • [ 1333341-00-6 ]
  • 9
  • 3-ethyl-1-isopentyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride [ No CAS ]
  • [ 84388-68-1 ]
  • 8-[(4,5-dichloro-2-hydroxyphenyl)methyl]-3-etyl-1-(3-methylbutyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
46.82% Stage #1: 3-ethyl-1-isopentyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride; 4,5-dichloro-2-hydroxybenzaldehyde In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In N,N-dimethyl-formamide at 20℃; for 24h; Stage #3: With hydrogenchloride In diethyl ether 8-[(4,5-dichloro-2-hydroxyphenyl)methyl]-3-etyl-1-(3-methylbutyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (12k) A mixture of 12n (30.3 mg, 0.10mmol, 1 equiv) and 4,5-dichloro-2-hydroxybenzaldehyde (38.2 mg, 0.20 mmol, 2 equiv) was dissolved in DMF (2 mL) and stirred at room temperature for 30 minutes before the addition of sodium triacetoxyborohydride (50.8 mg, 0.24 mmol, 2.4 equiv). The reaction stirred at room temperature under anhydrous conditions for 24 h. It was then quenched with water (1 mL) then purified by reverse phase HPLC (10% to 75% acetonitrile/water/0.05% TFA). The product was treated with 2 M HCl in diethyl either (0.1 mL) and stirred for 15 minutes before being filtered and dried to yield 66.7 mg product as a HCl salt. The solid was then dissolved in minimum amount of DCM and loaded onto an SCX column (2 g). The residual impurities were eluted with 1:1 MeOH/DCM (10 mL). The product was eluted with 2 M Ammonia/MeOH (10 mL). The ammonia eluent was then condensed yielding 30.2 mg final compound. The ammonia product was then condensed and dissolved in diethyl ether (1 mL). The product was then treated with 2M HCl in diethyl ether (0.05 mL) to make an HCl salt. The salt was filtered, yielding the final compound as an off white HCl salt (25.6 mg, 0.0532 mmol, 46.82% yield). 1H NMR (400 MHz,DMSO-d6) δ 7.42 (s, 1 H), 7.00 (s, 1 H), 3.66 (br. s., 1 H), 3.38 (q, J=7.2 Hz, 4 H), 3.09 - 3.25(m, 2 H), 2.78 (br. s., 4 H), 1.89 - 2.08 (m, 2 H), 1.69 (br. s., 2 H), 1.53 - 1.65 (m, 1 H), 1.34 -1.51 (m, 2 H), 1.07 (t, J=7.2 Hz, 3 H), 0.91 (d, J=6.6 Hz, 6 H). ES-MS m/z 443.84 (M+H).
  • 10
  • [ 84388-68-1 ]
  • tert-butyl [[2-[2-(allyloxy)-4,5-dichlorophenyl]cyclopropyl]methyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 11 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: boron tribromide / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.1: caesium carbonate / N,N-dimethyl-formamide / 80 °C / Microwave irradiation
  • 11
  • [ 84388-68-1 ]
  • tert-butyl [[2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl]methyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: RegisPack chiral column / ethanol; hexane / Resolution of racemate
  • 12
  • [ 84388-68-1 ]
  • tert-butyl [[2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl]methyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: RegisPack chiral column / ethanol; hexane / Resolution of racemate
  • 13
  • [ 84388-68-1 ]
  • tert-butyl [[2-[4,5-dichloro-2-(2-fluoroethoxy)phenyl]cyclopropyl]methyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 12 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: boron tribromide / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 1 h / 0 - 60 °C / Microwave irradiation 12.1: RegisPack chiral column / ethanol; hexane / Resolution of racemate
  • 14
  • [ 84388-68-1 ]
  • tert-butyl [[2-[4,5-dichloro-2-(2-fluoroethoxy)phenyl]cyclopropyl]methyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 12 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: boron tribromide / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 1 h / 0 - 60 °C / Microwave irradiation 12.1: RegisPack chiral column / ethanol; hexane / Resolution of racemate
  • 15
  • [ 84388-68-1 ]
  • tert-butyl [[2-[2-(allyloxy)-4,5-dichlorophenyl]cyclopropyl]methyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 12 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: boron tribromide / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.1: caesium carbonate / N,N-dimethyl-formamide / 80 °C / Microwave irradiation 12.1: RegisPack chiral column / ethanol; hexane / Resolution of racemate
  • 16
  • [ 84388-68-1 ]
  • tert-butyl [[2-[2-(allyloxy)-4,5-dichlorophenyl]cyclopropyl]methyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 12 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: boron tribromide / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.1: caesium carbonate / N,N-dimethyl-formamide / 80 °C / Microwave irradiation 12.1: RegisPack chiral column / ethanol; hexane / Resolution of racemate
  • 17
  • [ 84388-68-1 ]
  • (-)-[2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl]-methanamine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 10 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: RegisPack chiral column / ethanol; hexane / Resolution of racemate 10.1: hydrogenchloride / diethyl ether / 20 °C
  • 18
  • [ 84388-68-1 ]
  • (+)-[2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl]-methanamine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 10 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: RegisPack chiral column / ethanol; hexane / Resolution of racemate 10.1: hydrogenchloride / diethyl ether / 20 °C
  • 19
  • [ 84388-68-1 ]
  • (-)-[2-[4,5-dichloro-2-(2-fluoroethoxy)phenyl]cyclopropyl]-methanamine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 13 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: boron tribromide / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 1 h / 0 - 60 °C / Microwave irradiation 12.1: RegisPack chiral column / ethanol; hexane / Resolution of racemate 13.1: hydrogenchloride / diethyl ether / 20 °C
  • 20
  • [ 84388-68-1 ]
  • (+)-[2-[4,5-dichloro-2-(2-fluoroethoxy)phenyl]cyclopropyl]-methanamine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 13 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: boron tribromide / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 1 h / 0 - 60 °C / Microwave irradiation 12.1: RegisPack chiral column / ethanol; hexane / Resolution of racemate 13.1: hydrogenchloride / diethyl ether / 20 °C
  • 21
  • [ 84388-68-1 ]
  • (E)-3-(4,5-dichloro-2-methoxyphenyl)-N-methoxy-N-methylacrylamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2: dichloromethane / 20 °C
  • 22
  • [ 84388-68-1 ]
  • (-)-[2-[2-(allyloxy)-4,5-dichlorophenyl]cyclopropyl]-methanamine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 13 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: boron tribromide / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.1: caesium carbonate / N,N-dimethyl-formamide / 80 °C / Microwave irradiation 12.1: RegisPack chiral column / ethanol; hexane / Resolution of racemate 13.1: hydrogenchloride / diethyl ether / 20 °C
  • 23
  • [ 84388-68-1 ]
  • (+)-[2-[2-(allyloxy)-4,5-dichlorophenyl]cyclopropyl]-methanamine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 13 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: boron tribromide / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.1: caesium carbonate / N,N-dimethyl-formamide / 80 °C / Microwave irradiation 12.1: RegisPack chiral column / ethanol; hexane / Resolution of racemate 13.1: hydrogenchloride / diethyl ether / 20 °C
  • 24
  • [ 84388-68-1 ]
  • C11H10Cl2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere
  • 25
  • [ 84388-68-1 ]
  • 2-(4,5-dichloro-2-methoxyphenyl)-N-methoxy-N-methylcyclopropanecarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C
  • 26
  • [ 84388-68-1 ]
  • [2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl]methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C
  • 27
  • [ 84388-68-1 ]
  • 2-[[2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl]methyl]isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C
  • 28
  • [ 84388-68-1 ]
  • C11H13Cl2NO [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux
  • 29
  • [ 84388-68-1 ]
  • (rac-trans)-tert-butyl ((2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl)methyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C
  • 30
  • [ 84388-68-1 ]
  • C10H11Cl2NO [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: boron tribromide / dichloromethane / 3 h / -78 °C / Inert atmosphere
  • 31
  • [ 84388-68-1 ]
  • tert-butyl [[2-(4,5-dichloro-2-hydroxyphenyl)cyclopropyl]methyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 10 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: boron tribromide / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C
  • 32
  • [ 84388-68-1 ]
  • tert-butyl [[2-[4,5-dichloro-2-(2-fluoroethoxy)phenyl]cyclopropyl]methyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 11 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.1: dichloromethane / 20 °C 3.1: sodium hydride / dimethyl sulfoxide / 20 °C 3.2: 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / -78 °C / Inert atmosphere 5.1: sodium tetrahydroborate / methanol / 0 - 20 °C 6.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0 - 20 °C 7.1: hydrazine hydrate / ethanol / 3 h / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.1: boron tribromide / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 1 h / 0 - 60 °C / Microwave irradiation
  • 33
  • [ 84388-68-1 ]
  • [ 74-88-4 ]
  • 4,5-dichloro-2-methoxybenzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With potassium carbonate In 1,2-dimethoxyethane at 20 - 30℃; for 2h; 2.a Step a: To a stirred solution of Intermediate 1 (4,5-dichloro-2-hydroxybenzaldehyde) (10.00 g, 52.35 mmol) and K2CO3 (21.70 g, 157.06 mmol) in DMF (100 mL) was added CH3I (11.10 g, 78.53 mmol) at room temperature. The resulting mixture was stirred at 30 C for 2 h. The reaction was diluted with water (500 mL). The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) to afford 4,5-dichloro-2-methoxybenzaldehyde as an off-white solid (10.30 g, 96%): 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.85 (s, 1H), 7.08 (s, 1H), 3.91 (s, 3H).
96% With potassium carbonate In N,N-dimethyl-formamide at 30℃; for 2h; 1.b Step b: To a stirred solution of 4,5-dichloro-2-hydroxybenzaldehyde (10.00 g, 52.35 mmol) and K2CO3 (21.70 g, 157.06 mmol) in DMF (100 mL) was added CH3I (11.10 g, 78.53 mmol) at room temperature. The resulting mixture was stirred at 30 °C for 2 h. The reaction was diluted with water (500 mL). The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) to afford 4,5-dichloro-2- (0282) - 58 - (0283) 5UB5TITUTE SHEET (RULE 26) methoxybenzaldehyde as an off-white solid (10.30 g, 96%): 'H NMR (300 MHz, CDCb) d 10.32 (s, 1H), 7.85 (s, 1H), 7.08 (s, 1H), 3.91 (s, 3H).
76% With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 2h; 19.b Step b: To a stirred mixture of 4,5-dichloro-2-hydroxybenzaldehyde (2.00 g, 10.47 mmol) and K2CO3 (2.90 g, 20.94 mmol) in DMF (10 mL) was added MeI (2.20 g, 15.71 mmol) dropwise at 0oC. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was diluted with water (30 mL) and extracted with EA (3 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) to afford 4,5-dichloro-2-methoxybenzaldehyde as a light yellow solid (2.00 g, 76%):1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.86 (s, 1H), 7.09 (s, 1H), 3.92 (s, 3H).
22% With potassium carbonate In N,N-dimethyl-formamide at 20℃;
5.6 g With potassium carbonate In N,N-dimethyl-formamide at 20℃; 33.B 4,5-Dichloro-2-methoxybenzaldehyde The crude product from Step A (18.2 g, 95 mmol) was dissolved in DMF (100 mL) and K2CO3(26.2 g, 0.19 mol) and iodomethane (27.0 g, 0.19 mol) was added. The mixture was stirred at room temperature overnight. Water (500 mL) was then added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, concentrated and purified with flash chromatography to give the subtitle intermediate as a white solid (5.6 g, 22%). 1H NMR (CDC13, 400 MHz) 10.34 (s, 1H), 7.87 (s, lH), 7.10 (s, 1H), 3.94 (s, 3H).

  • 34
  • [ 6287-38-3 ]
  • [ 84388-68-1 ]
YieldReaction ConditionsOperation in experiment
55% With palladium diacetate; toluene-4-sulfonic acid; 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate; acetic acid; 2-Amino-4-chlorobenzoic acid at 90℃; for 24h; Sealed tube;
  • 35
  • [ 84388-68-1 ]
  • [ 536-74-3 ]
  • [ 4105-21-9 ]
  • 3-(2-benzyl-5,6-dichlorobenzofuran-3-yl)-2-phenylimidazo[1,2-a]pyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With piperidine; copper(II) acetate monohydrate; zinc(II) iodide In 1,2-dichloro-benzene at 120℃; for 4h; regioselective reaction;
  • 36
  • [ 113826-06-5 ]
  • [ 84388-68-1 ]
  • (R)-4,5-dichloro-2-(oxiran-2-ylmethoxy)benzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; 5-methoxy-2-(oxiran-2-ylmethoxy)benzaldehyde (22a). General procedure: To a DMF (25mL) solution of 2-hydroxy-5-methoxybenzaldehyde (2.0g, 13.2mmol) were added potassium carbonate powder (2.2g, 15.8mmol) and epichlorohydrin (1.34mL, 17.2mmol). The resulting suspension was heated to 80°C for 3h. The reaction mixture was cooled to ambient temperature and added AcOEt and water. The extracts are combined, and washed by brine, then dried over anhydrous Na2SO4. The mixture was concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether=1:10) to give compound 22a (1.6g, 58%) as a colorless oil.
  • 37
  • [ 84388-68-1 ]
  • [ 871824-63-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 80 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / Reflux 2.2: 4 h / 20 °C
  • 38
  • [ 84388-68-1 ]
  • methyl (S)-3-(4-(((S)-6,7-dichloro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methoxy)phenyl)hex-4-ynoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 80 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / Reflux 2.2: 4 h / 20 °C 3.1: tributylphosphine; 1,1'-azodicarbonyl-dipiperidine / toluene / 5 h / 40 °C
  • 39
  • [ 84388-68-1 ]
  • (S)-3-(4-(((S)-6,7-dichloro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methoxy)phenyl)hex-4-ynoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 3 h / 80 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / Reflux 2.2: 4 h / 20 °C 3.1: tributylphosphine; 1,1'-azodicarbonyl-dipiperidine / toluene / 5 h / 40 °C 4.1: lithium hydroxide / methanol; tetrahydrofuran; water / 5 h / 20 °C
  • 40
  • [ 24395-14-0 ]
  • [ 84388-68-1 ]
  • 7,8-dichloro-2-phenyl-4-tosyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With tetrakis(actonitrile)copper(I) hexafluorophosphate; 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone; 2-(2,4,6-tribromophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-4-ium tetrafluoroborate; caesium carbonate; 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine In dimethyl sulfoxide at 35℃; for 10h; Schlenk technique; Sealed tube; Inert atmosphere; regioselective reaction;
  • 41
  • [ 75-75-2 ]
  • [ 95-77-2 ]
  • [ 84388-68-1 ]
YieldReaction ConditionsOperation in experiment
23% With hexamethylenetetramine at 20 - 110℃; for 0.5h; 1.a Step a: To a stirred solution of 3,4-dichlorophenol (50.00 g, 306.75 mmol) in methanesulfonic acid (35 mL) was added hexamethylenetetramine (47.50 g, 337.40 mmol) at room temperature. The reaction solution was stirred at 110 C for 30 min. The reaction solution was allowed to cool down to room temperature and quenched with water (500 mL). The resulting solution was extracted with DCM (3 x 500 mL) and dried over anhydrous Na2SO4. After the filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/DCM (10/1) to afford Intermediate 1 (4,5-dichloro-2-hydroxybenzaldehyde) as a yellow solid (13.50 g, 23%): 1H NMR (400 MHz, CDCl3) δ 10.98 (s, 1H), 9.85 (s, 1H), 7.66 (s, 1H), 7.16 (s, 1H).
15% With hexamethylenetetramine at 110℃; for 0.5h; 19.a Step a: To a solution of 3,4-dichlorophenol (10 g, 61.35 mmol) in methylsulfonic acid (70 mL) was added hexamethylenetetramine (9.46 g, 67.48 mmol) in small portions. The mixture was then heated to 110oC and stirred for 30 min. After cooling to room temperature, the reaction was poured into iced-water (500 mL). The mixture was extracted with DCM (3 x 100 mL) and the combined organic layer was washed with brine (2 x 80 mL) and dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/DCM (10/1) to afford 4,5-dichloro-2-hydroxybenzaldehyde as a light yellow solid (1.8 g, 15%):1H NMR (300 MHz, CDCl3) δ 10.96 (s, 1H), 9.83 (s, 1H), 7.64 (s, 1H), 7.15 (s, 1H).
  • 42
  • 2,2,2-trifluoro-N-[[4-(2,2,2-trifluoroacetamido)piperidin-4-yl]methyl]acetamide [ No CAS ]
  • [ 84388-68-1 ]
  • N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(trifluoroacetamido)piperidin-4-yl]methyl)-2,2,2-trifluoroacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
27% With sodium tris(acetoxy)borohydride; acetic acid In methanol at 20℃; for 2h; 4.c Step c: To a stirred solution of 2,2,2-trifluoro-N-[[4-(trifluoroacetamido)piperidin-4- yl]methyl]acetamide (0.12 g, 0.38 mmol) and Intermediate 1 (87 mg, 0.46 mmol) in MeOH (2 mL) were added HOAc (25 mg, 0.42 mmol) and NaBH(OAc)3 (0.24 g, 1.14 mmol) at room temperature. After stirring for 2 h at room temperature, the resulting mixture was quenched with water (10 mL) and extracted with EA (3 x 30 mL). Then the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with PE/EA (3/1) to afford N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4- (trifluoroacetamido)piperidin-4-yl]methyl)-2,2,2-trifluoroacetamide as a light yellow solid (63 mg, 27%): LCMS (ESI) calculated for C17H17Cl2F6N3O3 [M + H]+: 496, 498 (3 : 2), found 496, 498 (3 : 2); 1H NMR (300 MHz, DMSO-d6) δ 9.45 (d, J = 5.9 Hz, 1H), 8.56 (s, 1H), 7.36 (s, 1H), 6.90 (s, 1H), 3.56 (s, 2H), 3.15 (s, 2H), 2.67-2.54 (m, 2H), 2.29-2.00 (m, 4H), 1.61-1.42 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ -73.84, 74.00.
  • 43
  • tert-butyl N-[4-(hydroxymethyl)piperidin-4-yl]carbamate [ No CAS ]
  • [ 84388-68-1 ]
  • tert-butyl-N-[1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% With sodium tris(acetoxy)borohydride; acetic acid In methanol at 20℃; for 0.5h; Inert atmosphere; 14.a Step a: To a stirred solution of Intermediate 1 (0.23 g, 1.20 mmol), HOAc (60 mg, 1.00 mmol) and tert-butyl-N-[4-(hydroxymethyl)piperidin-4-yl]carbamate (0.29 g, 1.00 mmol) in MeOH (5 mL) was added NaBH(OAc)3 (0.64 g, 3.00 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere, and then quenched with water (5 mL). The mixture was concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and washed with water (3 x 20 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA to afford tert-butyl-N-[1-[(4,5-dichloro-2- hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]carbamate as a yellow oil (0.10 g, 25%): LCMS (ESI) calculated for C18H26Cl2N2O4 [M + H]+: 405, 407 (3 : 2), found 405, 407 (3 : 2); 1H NMR (400 MHz, CD3OD) δ 7.23 (d, J = 2.2 Hz, 1H), 6.89 (d, J = 1.9 Hz, 1H), 3.74 (s, 2H), 3.61 (s, 2H), 2.80 (d, J = 11.8 Hz, 2H), 2.45 (t, J = 11.8 Hz, 2H), 2.12 (d, J = 13.9 Hz, 2H), 1.73-1.62 (m, 2H), 1.45 (s, 9H).
  • 44
  • [ 6457-49-4 ]
  • [ 84388-68-1 ]
  • 4,5-dichloro-2-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
22% With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 3h; Inert atmosphere; 28.a Step a: To a solution of piperidin-4-ylmethanol (63 mg, 0.55 mmol), Intermediate 1 (0.10 g, 0.53 mmol), acetic acid (30 mg, 0.50 mmol) in DCE (3 mL) was added NaBH(OAc)3 (0.32 g, 1.51 mmol) at room temperature under nitrogen atmosphere. After stirring for 3 h at room temperature under nitrogen atmosphere, the reaction mixture was quenched with water (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 190 mm x 150 mm, 5 μm; Mobile Phase A: water with 10 mmoL/L NH4HCO3, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 55% B in 7 min; Detector: UV 254/220 nm; Retention time: 6.33 min. The fractions containing desired product were collected and concentrated under reduced pressure to afford Compound 65 (4,5-dichloro-2-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenol) as an off-white solid (34 mg, 22%): LCMS (ESI) calculated for C13H17Cl2NO2 [M + H]+: 290, 292 (3 : 2), found 290, 292 (3 : 2); 1H NMR (400 MHz, DMSOd6 + D2O) δ 7.32 (s, 1H), 6.93 (s, 1H), 3.61 (s, 2H), 3.25 (d, J = 6.4 Hz, 2H), 2.84 (d, J = 11.2 Hz, 2H), 2.04 (t, J = 9.6 Hz, 2H), 1.69 (d, J = 11.2 Hz, 2H), 1.40- 1.36 (m, 1H), 1.17 (q, J = 8.0 Hz, 2H).
  • 45
  • [ 925-90-6 ]
  • [ 84388-68-1 ]
  • C9H10Cl2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; diethyl ether at 20℃; for 2h; Inert atmosphere; 18.a Step a: To a stirred solution of Intermediate 1 (0.15 g, 0.79 mmol) in THF (3 mL) was added bromo(ethyl)magnesium (0.6 mL, 1.74 mmol, 3 M in ether) at room temperature under nitrogen atmosphere. After stirring for 2 h at room temperature under nitrogen atmosphere, the resulting solution was quenched with water (30 mL) at 0 C and extracted with EA (3 x 35 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford 2-(1-bromopropyl)-4,5- dichlorophenol as an off-white solid (72 mg, crude), which was used in next step directly without further purification: LCMS (ESI) calculated for C9H10Cl2O2 [M - H]+: 219, 221 (3 : 2), found 219, 221 (3 : 2).
  • 46
  • [ 926-62-5 ]
  • [ 84388-68-1 ]
  • 4,5-dichloro-2-(1-hydroxy-3-methylbutyl)phenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; 21.a Step a: To a stirred solution of Intermediate 1 (0.10 g, 0.52 mmol) in THF (2 mL) was added bromo(2-methylpropyl)magnesium (0.6 mL, 1.14 mmol, 2 M in ether) at room temperature under nitrogen atmosphere. After stirring for 1 h, the resulting solution was quenched with water (20 mL) and extracted with EA (2 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After the filtration, the filtrate was concentrated under reduced pressure to afford 4,5-dichloro-2-(1-hydroxy-3-methylbutyl)phenol as a yellow oil (0.14 g, crude), which was used in next step directly without further purification: LCMS (ESI) calculated for C11H14Cl2O2 [M - H]+: 247, 249 (3 : 2), found 247, 249 (3 : 2).
  • 47
  • [ 84388-68-1 ]
  • [ 168986-49-0 ]
  • methyl 2-(1-(4,5-dichloro-2-hydroxybenzyl)piperidin-4-yl)acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With sodium tris(acetoxy)borohydride; acetic acid In methanol at 20℃; for 2h; Inert atmosphere; 22.a Step a: To a stirred solution of methyl 2-(piperidin-4-yl)acetate (0.25 g, 1.29 mmol) and Intermediate 1 (0.20 g, 1.05 mmol) in MeOH (3 mL) were added HOAc (62 mg, 1.03 mmol) and NaBH(OAc)3 (0.66 g, 3.12 mmol) at room temperature under nitrogen atmosphere. After stirring for 2 h at room temperature under nitrogen atmosphere, the resulting solution was quenched with water (3 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (7/1) to afford methyl 2-(1-(4,5- dichloro-2-hydroxybenzyl)piperidin-4-yl)acetate as a light brown solid (0.19 g, 55%): LCMS (ESI) calculated for C15H19Cl2NO3 [M + H]+: 332, 334 (3 : 2), found 332, 334 (3 : 2); 1H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 0.9 Hz, 1H), 6.94 (s, 1H), 3.69 (s, 3H), 3.67 (s, 2H), 3.00 (d, J = 11.7 Hz, 2H), 2.29 (d, J = 6.9 Hz, 2H), 2.24-2.13 (m, 2H), 1.96-1.75 (m, 3H), 1.44-1.31 (m, 2H).
  • 48
  • [ 1207177-75-0 ]
  • [ 84388-68-1 ]
  • 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With sodium tris(acetoxy)borohydride; acetic acid In methanol at 20℃; for 1h; Inert atmosphere; 7.b; 25.c Step b: To a stirred solution of 4-(hydroxymethyl)piperidine-4-carbonitrile (0.20 g, 1.43 mmol) and Intermediate 1 (0.27 g, 1.43 mmol) in MeOH (3.5 mL) were added HOAc (85 mg, 1.43 mmol) and NaBH(OAc)3 (0.90 g, 4.28 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/3) to afford 1-[(4,5- dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carbonitrile as a yellow solid (0.20 g, 60%): LCMS (ESI) calculated for C14H16Cl2N2O2 [M + H]+: 315, 317 (3 : 2), found 315, 317 (3 : 2); 1H NMR (300 MHz, CDCl3) δ 7.07 (s, 1H), 6.89 (s, 1H), 3.72 (s, 2H), 3.60 (s, 2H), 3.07-2.97 (m, 2H), 2.54-2.39 (m, 3H), 2.08-1.96 (m, 2H), 1.72-1.56 (m, 2H).
  • 49
  • [ 1464153-65-8 ]
  • [ 84388-68-1 ]
  • N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-hydroxypiperidin-4-yl]methyl)-2,2,2-trifluoroacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
22% With sodium tris(acetoxy)borohydride; acetic acid In methanol at 20℃; for 1h; Inert atmosphere; 10.c Step c: To a solution of 2,2,2-trifluoro-N-[(4-hydroxypiperidin-4-yl)methyl]acetamide (0.27 g, 1.19 mmol), HOAc (72 mg, 1.20 mmol) and Intermediate 1 (0.23 g, 1.21 mmol) in MeOH (10 mL) was added NaBH(OAc)3 (0.76 g, 3.52 mmol) at room temperature under nitrogen atmosphere. The reaction solution was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting solution was quenched with water (2 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20/1) to afford N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4- hydroxypiperidin-4-yl]methyl)-2,2,2-trifluoroacetamide as a yellow semi-solid (0.10 g, 22%): LCMS (ESI) calculated for C15H17Cl2F3N2O3 [M + H]+: 401, 403 (3 : 2), found 401, 403 (3 : 2); 1H NMR (300 MHz, CD3OD) δ 7.37 (s, 1H), 6.96 (s, 1H), 3.99 (s, 2H), 3.28 (d, J = 1.6 Hz, 2H), 3.13-2.87 (m, 4H), 1.89-1.61 (m, 4H).
  • 50
  • [ 84388-68-1 ]
  • (1-(4,5-dichloro-2-hydroxybenzyl)piperidine-2,4-diyl)dimethanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2: sodium tetrahydroborate; ethanol / tetrahydrofuran / 1 h / 20 °C 3: phosphorus tribromide / dichloromethane / 1 h / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 - 45 °C 5: boron tribromide / dichloromethane / 1 h / 20 °C
  • 51
  • [ 84388-68-1 ]
  • methyl 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-4-(hydroxymethyl)piperidine-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2: sodium tetrahydroborate; ethanol / tetrahydrofuran / 1 h / 20 °C 3: phosphorus tribromide / dichloromethane / 1 h / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 3 h / 20 - 45 °C
  • 52
  • [ 84388-68-1 ]
  • methyl 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2: sodium tetrahydroborate; ethanol / tetrahydrofuran / 1 h / 20 °C 3: phosphorus tribromide / dichloromethane / 1 h / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 3 h / 20 - 45 °C 5: boron tribromide / dichloromethane / 2 h / 20 °C / Inert atmosphere
  • 53
  • [ 84388-68-1 ]
  • 2-[[4-(aminomethyl)-4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dichlorophenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: acetic acid / methanol / 1 h / 20 °C 1.2: 2 h / 20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 2 h / 20 °C
  • 54
  • [ 84388-68-1 ]
  • 1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidine-4-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: acetic acid; sodium tris(acetoxy)borohydride / methanol / 1 h / 20 °C / Inert atmosphere 2: hydrogenchloride / water / 2 h / 80 °C
  • 55
  • [ 84388-68-1 ]
  • 4,5-dichloro-2-[[4-(hydroxymethyl)-4-[(pyrrolidin-1-yl)carbonyl]piperidin-1-yl]methyl]phenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: acetic acid; sodium tris(acetoxy)borohydride / methanol / 1 h / 20 °C / Inert atmosphere 2: hydrogenchloride / water / 2 h / 80 °C 3: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 20 °C
  • 56
  • [ 84388-68-1 ]
  • N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)prop-2-enamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: acetic acid / methanol / 1 h / 20 °C 1.2: 2 h / 20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 2 h / 20 °C 3.1: triethylamine / dichloromethane / 1.5 h / 20 °C / Inert atmosphere
  • 57
  • [ 84388-68-1 ]
  • 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-2-phenylpiperidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2: sodium tetrahydroborate; ethanol / tetrahydrofuran / 1 h / 20 °C 3: phosphorus tribromide / dichloromethane / 1 h / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 - 40 °C
  • 58
  • [ 84388-68-1 ]
  • (4E)-1-[(4,5-dichloro-2-methoxyphenyl)methyl]-4-(methoxymethylidene)-2-phenylpiperidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2.1: sodium tetrahydroborate; ethanol / tetrahydrofuran / 1 h / 20 °C 3.1: phosphorus tribromide / dichloromethane / 1 h / 20 °C 4.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 - 40 °C 5.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.5 h / 20 °C / Inert atmosphere 5.2: 2 h / 20 °C / Inert atmosphere
  • 59
  • [ 84388-68-1 ]
  • 1-[(4,5-dichloro-2-methoxyphenyl)methyl]-2-phenylpiperidine-4-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2.1: sodium tetrahydroborate; ethanol / tetrahydrofuran / 1 h / 20 °C 3.1: phosphorus tribromide / dichloromethane / 1 h / 20 °C 4.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 - 40 °C 5.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.5 h / 20 °C / Inert atmosphere 5.2: 2 h / 20 °C / Inert atmosphere 6.1: hydrogenchloride / tetrahydrofuran; water / 4 h / 20 °C
  • 60
  • [ 84388-68-1 ]
  • (1-(4,5-dichloro-2-methoxybenzyl)-2-phenylpiperidin-4-yl)methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2.1: sodium tetrahydroborate; ethanol / tetrahydrofuran / 1 h / 20 °C 3.1: phosphorus tribromide / dichloromethane / 1 h / 20 °C 4.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 - 40 °C 5.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.5 h / 20 °C / Inert atmosphere 5.2: 2 h / 20 °C / Inert atmosphere 6.1: hydrogenchloride / tetrahydrofuran; water / 4 h / 20 °C 7.1: sodium tetrahydroborate; methanol / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere
  • 61
  • [ 84388-68-1 ]
  • N-[1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: acetic acid; sodium tris(acetoxy)borohydride / methanol / 0.5 h / 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.1: dichloromethane / 3 h / 20 °C 3.2: 3 h / 20 °C
  • 62
  • [ 84388-68-1 ]
  • 2-[[4-amino-4-(hydroxymethyl)piperidin-1-yl]methyl]-4,5-dichlorophenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: acetic acid; sodium tris(acetoxy)borohydride / methanol / 0.5 h / 20 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
  • 63
  • [ 84388-68-1 ]
  • (4,5-dichloro-2-methoxyphenyl)methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2: sodium tetrahydroborate; ethanol / tetrahydrofuran / 1 h / 20 °C
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 0 - 20 °C 2: ethanol; sodium tetrahydroborate / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 30 °C 2: sodium tetrahydroborate; ethanol / tetrahydrofuran / 1 h / 20 °C
  • 64
  • [ 84388-68-1 ]
  • 2-(1-bromopropyl)-4,5-dichlorophenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrahydrofuran; diethyl ether / 2 h / 20 °C / Inert atmosphere 2: phosphorus tribromide / dichloromethane / 2 h / 20 °C / Inert atmosphere
  • 65
  • [ 84388-68-1 ]
  • 4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]propyl]phenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tetrahydrofuran; diethyl ether / 2 h / 20 °C / Inert atmosphere 2: phosphorus tribromide / dichloromethane / 2 h / 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C
  • 66
  • [ 84388-68-1 ]
  • [ 37420-52-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2: sodium tetrahydroborate; ethanol / tetrahydrofuran / 1 h / 20 °C 3: phosphorus tribromide / dichloromethane / 1 h / 20 °C
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 0 - 20 °C 2: ethanol; sodium tetrahydroborate / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 3: boron tribromide / dichloromethane / 1 h / 20 °C
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 30 °C 2: sodium tetrahydroborate; ethanol / tetrahydrofuran / 1 h / 20 °C 3: phosphorus tribromide / dichloromethane / 1 h / 20 °C
  • 67
  • [ 84388-68-1 ]
  • 2-(1-bromo-3-methylbutyl)-4,5-dichlorophenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 2: phosphorus tribromide / dichloromethane / 2 h / 20 °C / Inert atmosphere
  • 68
  • [ 84388-68-1 ]
  • 4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]-3-methylbutyl]phenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 2: phosphorus tribromide / dichloromethane / 2 h / 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C
  • 69
  • [ 84388-68-1 ]
  • 4,5-dichloro-2-(hydroxymethyl)phenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium tetrahydroborate; ethanol at 0℃; for 0.5h; Inert atmosphere; 23.a Step a: To a stirred solution of Intermediate 1 (0.20 g, 1.05 mmol) in EtOH (10 mL) was added NaBH4 (79 mg, 2.09 mmol) at 0 C under nitrogen atmosphere. The reaction mixture was stirred at 0 C for 30 min under nitrogen atmosphere. The resulting mixture was quenched with water (10 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford 4,5-dichloro-2-(hydroxymethyl)phenol as an off-white solid (0.20 g, crude), which was directly used in the next step without further purification: LCMS (ESI) calculated for C7H6Cl2O2 [M - H]-: 191, 193 (3 : 2), found 191, 193 (3 : 2).
  • 70
  • [ 84388-68-1 ]
  • 2-(bromomethyl)-4,5-dichlorophenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; ethanol / 0.5 h / 0 °C / Inert atmosphere 2: phosphorus tribromide / dichloromethane / 0.5 h / 20 °C / Inert atmosphere
  • 71
  • [ 84388-68-1 ]
  • 1-(4,5-dichloro-2-methoxyphenyl)ethan-1-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2: tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere
  • 72
  • [ 84388-68-1 ]
  • 1-(1-bromoethyl)-4,5-dichloro-2-methoxybenzene [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2: tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 3: phosphorus tribromide / dichloromethane / 0.25 h / 20 °C
  • 73
  • [ 84388-68-1 ]
  • [1-[1-(4,5-dichloro-2-methoxyphenyl)ethyl]piperidin-4-yl]methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2: tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 3: phosphorus tribromide / dichloromethane / 0.25 h / 20 °C 4: potassium carbonate / acetone / 2 h / 20 - 40 °C
  • 74
  • [ 84388-68-1 ]
  • 4,5-dichloro-2-[1-[4-(hydroxymethyl)piperidin-1-yl]ethyl]phenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2: tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 3: phosphorus tribromide / dichloromethane / 0.25 h / 20 °C 4: potassium carbonate / acetone / 2 h / 20 - 40 °C 5: boron tribromide / dichloromethane / 2 h / 20 °C
  • 75
  • [ 84388-68-1 ]
  • (1-(4,5-dichloro-2-methoxybenzyl)piperidine-2,4-diyl)dimethanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 30 °C 2: sodium tetrahydroborate; ethanol / tetrahydrofuran / 1 h / 20 °C 3: phosphorus tribromide / dichloromethane / 1 h / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 - 45 °C
  • 76
  • 2,2,2-trifluoro-N-((4-(hydroxymethyl)piperidin-4-yl)methyl)acetamide [ No CAS ]
  • [ 84388-68-1 ]
  • N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)-2,2,2-trifluoroacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% Stage #1: 2,2,2-trifluoro-N-((4-(hydroxymethyl)piperidin-4-yl)methyl)acetamide; 4,5-dichloro-2-hydroxybenzaldehyde With acetic acid In methanol at 20℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In methanol at 20℃; for 2h; Inert atmosphere; 13.c Step c: To a stirred solution of 2,2,2-trifluoro-N-[[4-(hydroxymethyl)piperidin-4- yl]methyl]acetamide (0.11 g, 0.45 mmol) and Intermediate 1 (86 mg, 0.45 mmol) in MeOH (1 mL) was added HOAc (3 mg, 0.04 mmol) at room temperature. The resulting solution was stirred at room temperature for 1 h. To the stirred solution was added NaBH(OAc)3 (0.29 g, 1.35 mmol) at room temperature under nitrogen atmosphere. The resulting solution was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL) at room temperature and extracted with EA (5 x 30 mL). The combined organic layers were washed with brine (2 x 25 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column 100 Å, 10 µm, 19 mm x 250 mm; Mobile Phase A: water with 20 mmol/L NH4HCO3, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 10% B to 90% B in 9 min; Detector: UV 254/210 nm; Retention time: 8.10 min. The fractions containing desired product were collected and concentrated under reduced pressure to afford Compound 13 (N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4- (hydroxymethyl)piperidin-4-yl]methyl)-2,2,2-trifluoroacetamide) as an off-white solid (82 mg, 43%): LCMS (ESI) calculated for C16H19Cl2F3N2O3 [M + H]+: 415, 417 (3 : 2), found 415, 417 (3 : 2); 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.39 (s, 1H), 6.98 (s, 1H), 4.70 (br, 1H), 3.72 (s, 2H), 3.30 (s, 2H), 3.25 (d, J = 6.0 Hz, 2H), 2.28-2.50 (m, 4H), 1.61-1.55 (m, 2H), 1.47- 1.30 (m, 2H).
  • 77
  • N-((4-(hydroxymethyl)piperidin-4-yl)methyl)acetamide [ No CAS ]
  • [ 84388-68-1 ]
  • N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4-yl]methyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% With sodium tris(acetoxy)borohydride; acetic acid In methanol at 20℃; for 2h; Inert atmosphere; 20.c Step c: To a stirred solution of N-[[4-(hydroxymethyl)piperidin-4-yl]methyl]acetamide (0.12 g, 0.58 mmol) and Intermediate 1 (0.11 g, 0.58 mmol) in MeOH (1 mL) was added HOAc (35 mg, 0.6 mmol) and NaBH(OAc)3 at room temperature under nitrogen atmosphere. The reaction solution was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting solution was quenched with water (5 mL) at room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column 100 Å, 10 µm, 19 mm x 250 mm; Mobile Phase A: water with 20 mmol/L NH4HCO3, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 80% B in 9 min; Detector: UV 254/210 nm; Retention time: 8.14 min. The fractions containing desired product were collected and concentrated under reduced pressure to afford Compound 21 (N-([1-[(4,5-dichloro-2-hydroxyphenyl)methyl]-4-(hydroxymethyl)piperidin-4- yl]methyl)acetamide) as an off-white solid (97 mg, 46%): LCMS (ESI) calculated for C16H22Cl2N2O3 [M + H]+: 361, 363 (3 : 2), found 361, 363 (3 : 2); 1H NMR (400 MHz, DMSO- d6) δ 7.89-7.76 (m, 1H), 7.34 (s, 1H), 6.95 (s, 1H), 4.94-4.29 (m, 1H).3.64 (s, 2H), 3.07 (d, J = 6.3 Hz, 2H), 2.49-2.40 (m, 4H), 1.86 (s, 3H), 1.47-1.26 (m, 4H).
  • 78
  • [ 84388-68-1 ]
  • [ 37420-53-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 0 - 20 °C 2: ethanol; sodium tetrahydroborate / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 3: boron tribromide / dichloromethane / 1 h / 20 °C 4: ethanol / 5 h / 90 °C
  • 79
  • [ 84388-68-1 ]
  • tert-butyl 4-cyano-4-(4,5-dichloro-2-methoxyphenyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 0 - 20 °C 2.1: ethanol; sodium tetrahydroborate / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 3.1: boron tribromide / dichloromethane / 1 h / 20 °C 4.1: ethanol / 5 h / 90 °C 5.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 20 °C / Inert atmosphere 5.2: 5 h / 80 °C / Inert atmosphere
  • 80
  • [ 84388-68-1 ]
  • 4-(4,5-dichloro-2-hydroxyphenyl)piperidine-4-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 0 - 20 °C 2.1: ethanol; sodium tetrahydroborate / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 3.1: boron tribromide / dichloromethane / 1 h / 20 °C 4.1: ethanol / 5 h / 90 °C 5.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 20 °C / Inert atmosphere 5.2: 5 h / 80 °C / Inert atmosphere 6.1: boron tribromide / dichloromethane / 48 h / 20 °C
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