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CAS No. : | 25458-45-1 | MDL No. : | MFCD00457268 |
Formula : | C8H9BrO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BDRBSCRINVJXKW-UHFFFAOYSA-N |
M.W : | 217.06 | Pubchem ID : | 10465919 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 46.53 |
TPSA : | 18.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.83 cm/s |
Log Po/w (iLOGP) : | 2.41 |
Log Po/w (XLOGP3) : | 2.53 |
Log Po/w (WLOGP) : | 2.43 |
Log Po/w (MLOGP) : | 2.36 |
Log Po/w (SILICOS-IT) : | 2.36 |
Consensus Log Po/w : | 2.42 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.99 |
Solubility : | 0.225 mg/ml ; 0.00103 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.56 |
Solubility : | 0.592 mg/ml ; 0.00273 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.53 |
Solubility : | 0.0642 mg/ml ; 0.000296 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.8 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In acetone for 2h; Heating; | |
96% | Stage #1: 4-bromo-phenol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25h; Inert atmosphere; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide at 0℃; for 1.16667h; Inert atmosphere; | 1-Bromo-4-(methoxymethoxy)benzene (5): To stirred solution of NaH (1.67 g, 0.07 mmol), in dimethylformamide (50 mL) under N2 atmosphere was added 4-bromophenol (10.0 g, 0.0581 mmol) slowly at 0 °C over 15 min and then MOMCl (7.02 g, 0.087 mmol) was added dropwise manner over 10 min at the same temperature. The mixture was allowed to stir for 1h at the same temperature and the progress of the reaction was monitored by TLC. After completion as shown by TLC, the reaction was quenched with ice cold water (100 mL) at 0 °C and then extracted with EtOAc (3x100 mL). The combined organic layers were washed with 10% brine solution (50 mL) followed by dried over sodium sulphate and then evaporated under reduced pressure to give the crude (12.6 g) of 1-bromo-4-(methoxymethoxy)benzene (5), which was then purified by column chromatography on silica gel (60-120 mesh) using 3% EtOAc in pet.ether to afford the pure product, 1-bromo-4-(methoxymethoxy)benzene (5) as a colour less liquid (12.0 g, Yield: 96%). Colourless oil; 1H NMR (500 MHz, CDCl3): δ 7.36 (d, J = 9.1 Hz 2H), 6.92 (d, J = 9.1 Hz 2H), 5.14 (s, 2H), 3.46 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 156.3, 132.2, 118.0, 114.1, 94.4, 55.9; IR (KBr): ν 2922, 2858, 1588, 1487, 1456, 1395, 1292, 1233, 1157, 1080, 995, 927, 827. |
93% | With sodium hydride In N,N-dimethyl-formamide for 2h; Ambient temperature; |
93% | Stage #1: 4-bromo-phenol With sodium hydride In DMF (N,N-dimethyl-formamide) at -5℃; for 1.33333h; Stage #2: chloromethyl methyl ether In DMF (N,N-dimethyl-formamide) at -5℃; for 3h; | 3 PREPARATION 3 Preparation of 1-BROMO-4-METHOXYMETHOXY-BENZENE Add sodium hydride (2.78 g of 95% dry, 0.116 mol) in portions to a 500 mL three- necked flask equipped with a nitrogen inlet, magnetic stir bar and DMF (200 mL) at-10 TO-15 °C. Add a solution of 4-bromophenol (20.00 g, 0.116 mol) in DMF (100 mL) over about 20 minutes, maintaining the internal temperature of the reaction BELOW-5 °C. Stir the reaction for 1 hour and then add MOMCI (8.81 mL, 0.116 mol) in portions to maintain the internal temperature BELOW-5 °C. Stir the mixture for 3 hours and then add ice until gas evolution ceases. Pour the reaction into ICE-H20 (500 mL) and extract with EtOAc (2 x 300 mL). Wash the combined organic extracts with 1 N NAOH (500 mL), H20 (500 ML) and brine (400 mL). Dry the solution (MgS04), filter and concentrate to obtain the title product (23.94 g, 93%) as an oil which may be used without further PURIFICATION. H NMR (CDC13) 5 3.46 (s, 3H), 5.14 (s, 2H), 6.92 (D,. J = 9.0 Hz, 2H), 7.37 (d, J = 9. 0 Hz, 2H). |
92% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; | |
92% | Stage #1: 4-bromo-phenol With sodium hydride In N,N-dimethyl-formamide at 20℃; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide at 20℃; for 0.5h; | |
92% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1.83333h; | 4.1 To a suspension of 60% NaH in mineral oil (12.7 g, 31.8 MMOL) in anhydrous THF (300 mL) at 0 °C was added 4-bromophenol (50.0 g, 28.9 MMOL) dissolved in THF (100 mL) dropwise over 1 h. The reaction mixture was stirred at 0 °C for 30 min, and chloromethylmethyl ether (24.8 mL, 32.6 MMOL) dissolved in THF (30 mL) was added dropwise over 20 min. The reaction mixture was stirred overnight at RT. H20 (250 mL) was added, and the mixture was extracted with ET20 (2 x 250 mL). The combined ethereal extracts were washed with brine (500 mL), dried over MGS04, and concentrated. The residue was distilled under vacuum to afford 57.6 g (92%) of 13 as a colorless OIL. H NMR (400 MHz, DMSO-D6) : No. 3.33 (s, 3H), 5.15 (s, 2H), 6.96 (d, J = 9. 0 HZ, 2H), 7.43 (d, J = 9. 0 HZ, 2H). Step 2: N-METHOXY-N-METHYL-2-PHENYLBUTANAMIDE (14 To a stirred solution of pyridine (33.1 mL, 40.9 MMOL) and N, O- dimethylhydroxylamine hydrochloride (26.0 g, 26.7 MMOL) in anhydrous CH2CI2 (300 mL) at 0 °C was added dropwise 2-phenylbutyryl chloride (37.4 g, 20.5 MMOL) dissolved in THF (100 mL). The reaction mixture was stirred overnight at RT. H20 (300 mL) was added, and the mixture was extracted with CH2CI2 (2 x 200 mL). The combined extracts were washed successively with 5% aqueous HCI (300 mL), 5% aqueous NAHC03 (300 mL), H20 (300 mL), and brine (300 mL). The mixture was dried over NA2SO4, filtered, and concentrated to afford 41.6 g (98%) of 14 as a colorless oil which was used without further purification.'HNMR (400 MHz, CDCI3) : 8 0.87 (t, J = 7. 3 Hz, 3H), 1.74 (h, J = 7. 1 Hz, 1H), 2. 08 (h, J = 7. 1 Hz, 1H), 3.14 (s, 3H), 3.46 (s, 3H), 3. 88 (br s, 1H), 7.19-7. 33 (m, 5H). Step 3-1- [4- (METHOXYMETHOXY) PHENYL]-2-PHENYLBUTAN-1-ONE (J 5 To a stirred solution of 13 (99.0 g, 0.46 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 310 mL, 0.50 mol) dropwise at-78 °C. The reaction mixture was stirred for 30 min and 14 (90.1 g, 0.43 mol) dissolved in THF (500 mL) was added dropwise. The reaction mixture was stirred at-78 °C for 1 h and then slowly warmed to 0 °C. H20 (500 mL) was added and the volatiles were removed under reduced pressure. The residue was extracted with ET20 (3 x 500 mL) and the combined extracts were washed with water (500 mL) and brine (500 mL). The mixture was dried over MGS04 and concentrated. The residue was recrystallized from hexanes to afford 97.6 g (80%) of 15 as white needles.'HNMR (400 MHz, DMSO-d6) : 8 0. 79 (t, J = 7. 3 Hz, 3H), 1.68 (h, J = 7. 0 HZ, 1 H), 2.03 (h, J = 7. 0 Hz, 1H), 3.32 (s, 3H), 4.65 (t, J=7. 3HZ, 1H), 5.21 (s, 2H), 7.03 (d, J=8. 8HZ, 2H), 7.15 (t, J = 7. 1 Hz, 1H), 7.23-7. 30 (m, 4H), 7.98 (d, J=8. 8HZ, 2H). Step 4: 1- [4- (DIETHOXYMETHYL) PHENYL]-1- [4- (METHOXYMETHOXY) PHENYL]-2- PHENYLBUTAN-1-OL () To a stirred solution of 4-bromobenzaldehyde diethyl acetal (107 g, 0.41 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 268 mL, 0.43 mol) dropwise at-78 °C. After stirring for 1 h at-78 °C, a solution of 15 (97.6 g, 0.34 mol) in THF (750 mL) was cannulated into the reaction mixture portionwise. The mixture was stirred overnight at RT, H20 (500 mL) was added, and the volatiles were removed under reduced pressure. The residue was extracted with ET20 (3 x 500 mL) and the combined extracts washed with H20 (500 mL) and brine (500 mL). The mixture was dried over MGS04 and concentrated to afford 194 g of 16 that was used without further purification.'HNMR (400 MHz, DMSO-d6) : 8 0.58 (t, J = 7.3 Hz, 3H), 1.12 (m, 6H), 1.52 (m, 1H), 1.70 (m, 1 H), 3.23 (s, 3H), 3.40-3. 65 (m, 5H), 4.98 (s, 2H), 5.41 (s, 1H), 5.51 (s, 1H), 6.62 (d, J = 8.8 Hz, 2H), 6.96-7. 06 (m, 3H), 7.17- 7.23 (m, 4H), 7.31 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H). Step 5: 4- [ (1)-1- (4-HYDROXYPHENYL)-2-PHENYLBUT-1-ENYL] BENZALDEHYDE (10 To a solution of 16 (194 g, 0.42 mol) in ETOH (1.25 L) was added 12 M HCI (250 mL). The reaction mixture was refluxed for 3 h, cooled to RT, and the volatiles were removed under reduced pressure. H2O (750 mL) was added and the mixture was extracted with ether (3 x 500 mL). The combined ethereal extracts were washed with H20 (750 mL), brine (750 mL), and dried over MGS04. CONCENTRATION followed by recrystallization from hexanes afforded 52.8 g (38%) of 10 as a white solid.'HNMR (400 MHz, DMSO-d6) : 8 0.83 (t, J = 7.3 Hz, 3H), 2.33 (q, J = 7.3 Hz, 2H), 6.40 (d, J = 8. 4 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 7.10-7. 20 (m, 5H), 7.40 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 8. 1 Hz, 2H), 9.23 (s, 1H), 9.98 (s, 1H). Step 6: TERT-BUTYL (2E)-3- (4- [ (121-1- (4-HYDROXYPHENYL)-2-PHENYLBUT-L- enyl] phenyl} prop-2-enoate (12 To a stirred solution of (TERT-BUTOXYCARBONYLMETHYLENE) triphenylphosphorane (5.19 g, 13.8 MMOL) in CH2CI2 (200 mL) was added 10 (2.29 g, 7.0 MMOL) dissolved in CH2CI2 (100 mL) dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h. Silica gel (12.0 g) was added, and the volatiles were removed under reduced pressure. Flash chromatography (20: 1 to 4: 1 hexane: EtOAc), followed by recrystallization (hexane/EtOAc) afforded 2.0 g (67%) of 12 as a white solid.'HNMR (400 MHz, DMSO-d6) : 8 0. 83 (t, J = 7. 3 Hz, 3H), 1.46 (s, 9H), 2.35 (q, J = 7. 3 Hz, 2H), 6.39 (d, J = 8. 4 Hz, 2H), 6.48 (d, J = 16.0 Hz, 1H), 6.59 (d, J = 8. 4 Hz, 2H), 7.07-7. 20 (m, 7H), 7.53 (d, J = 16. 0 Hz, 1H), 7.66 (d, J = 8. 1 Hz, 2H), 9.19 (s, 1H) ; MS, m/z, 425 (M-H)- This material was contaminated with up to 25% of the undesired E-isomer, tert-Butyl (2E)-3- {4- [ (1E)-1- (4-HYDROXYPHENYL)-2-PHENYLBUT-1-ENYL] PHENYL} PROP-2-ENOATE (17). HNMR (400 MHz, DMSO-d6) : 8 0.83 (t, J = 7.5 Hz, 3H), 1.42 (s, 9H), 2.40 (q, J = 7.5 Hz, 2H), 6.32 (d, J=15. 9HZ, 1H), 6.74 (d, J=8. 4HZ, 2H), 6.80 (d, J=8. 4HZ, 2H), 6. 98 (d, J = 7. 4 Hz, 2H), 7.06-7. 17 (m, 5H), 7.31 (d, J = 8. 4 Hz, 2H), 7.34 (d, J = 16 Hz, 1 H), 9.44 (s, 1 H). The pure (>95% by HPLC) 12 (Z-isomer) was prepared by recrystallization from EtOAc or by separation by RP-HPLC using a C18 Luna column (150 x 21.2 mm, 5 1 particle size) with 77: 33 CH3CN/H2O (0.1% TFA) for 20 min at a flow rate of 20 ML/MIN (Tr = 15.08 min). |
91% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | |
91.7% | With N-ethyl-N,N-diisopropylamine In toluene for 3h; Cooling with ice; | 1.1 Step 1 4-Bromophenol (T-1)(50.0g, 289.01mmol; Tokyo Chemical Industry Co., Ltd.)And diisopropylethyl amine (56.03g, 433.5mmol)In toluene (250ml) solution was ice-cooled,Dropwise methyl ether (34.9g, 433.51mmol).After stirring for 3 hours,The reaction mixture was poured into saturated aqueous ammonium chloride solution (200ml), andExtracted with ethyl acetate.The extract was water (300ml) and saturated brine (200ml) washedDried over anhydrous magnesium sulfate,Concentrated under reduced pressure.By column chromatography(The eluent: toluene / heptane = 2/1 (volume ratio))The residue was purifiedTo obtain the compound (T-2) (57.6g, 265.1mol, 91.7%). |
91.7% | With N-ethyl-N,N-diisopropylamine In toluene for 3h; Cooling with ice; | 1.1 A toluene (250 mL) solution of 4-bromophenol (T-1) (50.0 g, 289.01 mmol; Tokyo Chemical Industry Co., Ltd.) and diisopropylethylamine (56.03 g, 433.5 mmol) was ice-cooled, and chloromethyl methyl ether (34.9 g, 433.51 mmol) was added dropwise thereto. The resulting mixture was stirred for 3 hours, and then the reaction mixture was poured into a saturated aqueous solution of ammonium chloride (200 mL), and subjected to extraction with ethyl acetate. The extracted liquid was washed with water (300 mL) and saturated brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent:toluene:heptane=2:1 (volume ratio)) to obtain compound (T-2) (57.6 g, 265.1 mol, 91.7%). |
90% | Stage #1: 4-bromo-phenol With potassium carbonate In acetone for 0.166667h; Stage #2: chloromethyl methyl ether In acetone Reflux; | |
90% | Stage #1: 4-bromo-phenol With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: chloromethyl methyl ether In tetrahydrofuran at 20℃; for 19h; Inert atmosphere; | |
88% | Stage #1: 4-bromo-phenol With sodium hydride In tetrahydrofuran at 0℃; Stage #2: chloromethyl methyl ether In tetrahydrofuran at 0℃; for 1h; | |
88% | Stage #1: 4-bromo-phenol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1h; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | 1 Step 1: l-Bromo-4-(methoxymethoxy)benzene To a solution of 4-bromophenol (50 g, 289 mmol) in DMF (500 mL) at 0°C, NaH (23.1 g, 578 mmol, 60% purity) was added. The mixture was stirred at 0°C for 1 h. MOM-C1 (58.1 g, 722 mmol) was added at 0°C and the reaction warmed to room temperature overnight. The mixture was poured into water (1L) and extracted with EtOAc (2 x 800 mL). The organic layers were combined, washed with H20 (1 L), brine (1.5 L), dried (Na2S04), filtered, concentrated, and then purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=5/l) to give l-bromo-4- (methoxymethoxy)benzene (55 g, 88%) as an oil. 1H NMR (400 MHz, CDCl3): d 7.49 (d, 2H), 6.93 (d, 2H), 5.15 (s, 2H), 3.47 (s, 3H). |
87% | With sodium hydroxide; tetrabutyl-ammonium chloride In diethyl ether; dichloromethane | 7.a Preparation of 3-(4-methoxymethoxyphenyl-ONN-azoxy)-2-butanol (a) 5.2 g (30 mmol) of 4-bromophenol was dissolved in 20 ml of anhydrous methylene chloride, and 1.6 g (5.9 mmol) of tetrabutylammonium chloride and 20 ml (50 mmol) of 2.5N sodium hydroxide solution were added successively under ice cooling and stirring. Further, 3.4 ml (45 mmol) of chloromethyl methyl ether was added, and the mixture was brought back to room temperature and stirred for 30 minutes. After the reaction, diethyl ether was added to the reaction solution to carry out extraction, and the organic layer was washed successively with water, 1N sodium hydroxide solution, saturated saline, saturated ammonium chloride solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Thereby, 5.7 g of 4-methoxymethoxybromobenzene was obtained as a colorless oil (yield 87%). 1 H-NMR (CDCl3:δ) 3.46 (3H, s, OCH3), 5.15 (2H, s, OCH2 O), 6.94.(2H, d,J=9 Hz, Aromatic 3, 5-H), 7.38 (2H, d,J=9 Hz, Aromatic 2, 6-H). |
86% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 48h; Inert atmosphere; | |
84% | Stage #1: 4-bromo-phenol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 9h; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide at 20℃; for 1h; | |
83% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 2.16667h; Inert atmosphere; | |
83% | Stage #1: 4-bromo-phenol With potassium carbonate In acetone at 20℃; Inert atmosphere; Schlenk technique; Stage #2: chloromethyl methyl ether In acetone at 60℃; for 20h; Inert atmosphere; Schlenk technique; | |
80% | Stage #1: 4-bromo-phenol With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: chloromethyl methyl ether In tetrahydrofuran at 0 - 20℃; for 2.5h; | 178.1 [00386] Intermediate 20: Synthesis of l-(4-(methoxymethoxy)phenyl)-2- phenylethanone[00387] Step 1: To a solution of 4-bromophenol (1.0 g, 5.8 mmol) in anhydrous THF(10 mL) was added NaH (60%, 254 mg, 6.4 mmol) at 0°C. After being stirred at the temperature for 0.5 h, MOM-Cl (698 mg, 8.7 mmol) was added to the mixture. The mixture was stirred at 0°C for 0.5 h, warmed to room temperature for 2 h, quenched with water, and extracted with EtOAc. The organic layer was dried over Na2S04, concentrated in vacuo, and purified by column chromatography (PE:EtOAc=50: l) to give l-bromo-4- (methoxymethoxy)benzene (1 g, yield 80%). |
67% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | 1 Example 1; The Preparation of a Representative Electron Acceptor Compound and Representative NLO Chromophore Made From the Acceptor: AJL7; In this example, the preparation of a representative chromophore of the invention, AJL7, is described. In the following preparations, yields are based on 1H NMR of clean separated compounds after purification by column chromatography. The preparation is described in reference to FIG. 7. Preparation of compound 2; To a stirred solution of 17.3 g (100 mmol) of 1 and 10.47 g (130 mmol) of chloromethyl methyl ether in 120 ml of methylene chloride was added 14.2 g (110 mmol) of diisopropylethyl amine slowly with stirring at 0° C. The resulting solution was stirred for one hour and the mixture was left to warm up to room temperature overnight with stirring. The reaction solution was washed with 5% NaHCO3 aqueous solution, dried, and the solvent was removed via rotary evaporation. Compound 2 was purified via a flash chromatography over silica gel with 5% ethyl acetate in hexane to give a yellow oil (15 g, 67%). 1H NMR (CDCl3): δ 7.36 (d, 2H, 9.3 Hz), 6.90 (d, 2H, 9.3 Hz), 5.12 (s, 2H), 3.45 (s, 3H). |
48% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; | |
With ethanol; sodium ethanolate | ||
With methanol; sodium methylate | ||
With sodium hydroxide; tetrabutylammomium bromide In water; benzene for 4h; Heating; | ||
With potassium hydroxide 1.) methanol, 2.) acetonitrile, RT, 30 min; Yield given. Multistep reaction; | ||
With sodium hydride | ||
15.a 4-(Methoxymethoxy-2'-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1';4',1"terphenyl-4"-carboxylic Acid (a) 4-Methoxymethoxybromobenzene. In a manner similar to that of Example 7(a), by reaction of 48.84 g (282.3 mmol) of 4-bromophenol with 25.0 ml (310.5 mmol) of chloromethyl methyl ether, 63.85 g (100%) of the expected product are obtained in the form of a beige-coloured oil. 1H NMR (CDCl3) δ 3.46 (s, 3H), 5.14 (s, 2H), 6.92 (d, 2H, J=9.0 Hz), 7.38 (d, 2H, J=9.0 Hz). | ||
In tetrahydrofuran; N,N-dimethyl-formamide | 28.a (a) (a) 4-Methoxymethoxybromobenzene: 48.84 g (282.3 mmol) of 4-bromophenol, 150 ml of THF and 150 ml of DMF are introduced into a three-necked flask. The solution obtained is cooled to 0° C., 11.74 g (366.9 mmol) of 75% sodium hydride are added portionwise and the mixture is stirred at 0° C. for one hour. 25.0 ml (310.5 mmol) of methyl chloromethyl ether are added dropwise and the reaction medium is stirred for two hours at room temperature. The reaction medium is poured into a 1N HCl/ethyl acetate mixture and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, and dried over magnesium sulphate. After evaporating the solvents, 63.85 g (100%) of the expected compound are collected in the form of a beige-coloured oil. 1 H NMR (CDCl3) δ 3.46 (s, 3H), 5.14 (s, 2H), 6.92 (d, 2H, J=9.0 Hz), 7.57 (d, 2H, J=9.0 Hz). | |
774 mg (61.7%) | With N-ethyl-N,N-diisopropylamine In dichloromethane | 10.a Sodium [4-[2-[[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]amino]-1-(pyridin-3-yl)ethyl]phenyl]oxyacetic acid (a) 4-Bromophenol (1 g) was dissolved in methylene chloride (10 ml). Diisopropylethylamine (1.1 ml) and chloromethyl methyl ether (475 μl) were added to the solution under ice cooling, and the mixture was stirred for one hr. Methylene chloride was further added thereto, and the mixture was extracted. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (50 g, n-hexane: ethyl acetate = 5: 1) to give 774 mg (61.7%) of bromo-4-methoxymethyloxybenzene. 1H-NMR (CDCl3) δ: 3.43 (3H, s), 5.11 (2H, s), 6.90 (2H, d, J = 8.6 Hz), 7.35 (2H, d, J = 8.6 Hz) EIMS (m/z): 216 (M+- 1), 218 (M++ 1) |
Stage #1: 4-bromo-phenol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.25h; Inert atmosphere; Schlenk technique; Stage #2: chloromethyl methyl ether In tetrahydrofuran; mineral oil Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.1% | With pyridine In toluene at 30 - 50℃; for 2h; Cooling with ice; | 2.1 A preparation method: 4-(4-hydroxyphenyl)cyclohexanone: step one, 346 g of p-bromophenol and 237.3 g of pyridine were placed in a 3000 ml three-necked flask.Add 1038mL of toluene, stir well, add the toluene solution of methylal (182.6g methylal dissolved in 913mL of toluene) under ice salt bath condition, the temperature control does not exceed 50 °C, after the 60min drop, the system appears white Salt, stir the reaction at 30 ° C for 1 h,Add 600 ml of water to the system and stir for 30 min.Post-treatment can obtain 417.07g of a colorless transparent liquid of p-methoxymethoxybromobenzene as shown in Formula I.Yield 96.1%, purity 99.5%; |
90% | With phosphorus pentoxide In dichloromethane | |
90% | With phosphorus pentoxide In dichloromethane at 20℃; |
87% | With phosphorus pentoxide In dichloromethane at 20℃; for 12h; | 1 6.1.1. 1-Bromo-4-(methoxymethoxy)benzene (2) 6.1.1 1-Bromo-4-(methoxymethoxy)benzene (2) To a solution of 4-bromophenol (1) (1.7 g, 10 mmol) and CH2(OCH3)2 (7.6 g, 100 mmol) in dichloromethane (200 mL) was added P2O5 (5.0 g, 35 mmol). The reaction mixture was stirred at room temperature for 12 h and the insoluble precipitate was filtered off. Excess solid Na2CO3 was added to the filtrate. The suspension was stirred for an additional 10 min and filtered. The filtrate was concentrated under reduced pressure to give 2 (1.9 g, 87%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 5.15 (s, 2H), 3.47 (s, 3H). |
87% | With phosphorus pentoxide In dichloromethane at 20℃; for 12h; | 1.6.1 Synthesis of Intermediate B6-1 to the bromophenol (1.7 g, 10 mmol) and CH2 (OCH3 )2 (7.6 g, 100 mmol) dissolved in dichloromethane (200 ml) in, adding P2 O5 (5.0 g, 35.2 mmol), stirring at room temperature 12 hours, in the filtrate after filtering and adding excessive sodium carbonate solid, stirring 10 minutes after filtering, the filtrate is concentrated under reduced pressure to obtain a colorless oily matter (1.9 g, 87%). |
85% | With 3 A molecular sieve; toluene-4-sulfonic acid In dichloromethane for 48h; Heating; 3A molecular sieves; | |
With phosphorus pentoxide In dichloromethane for 1h; | 96.A Step A: 1-bromo-4-(methoxymethoxy)benzene; To a solution of 4-bromophenol (0.50 g, 2.89 mmol) and dimethoxymethane (2.6 mL, 29.39 mmol) in DCM (60 mL) was added P2O5 (1.50 g, 10.57 mmol). The reaction mixture was stirred at for 1 h and insoluble precipitate was filtered off. Solid Na2CO3 was added to the solution and stirred for additional 10 min. The solid was filtered off and the solution was concentrated. Purification on a silica gel column gave the desired product as a clear oil (363 mg). NMR (CDCl3): 7.38 (d, 2H), 6.93 (d, 2H), 5.15 (s, 2H), 3.47 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.6% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In benzene for 0.5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium 1.) THF, 2.) THF; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: p-methoxymethoxybromobenzene With magnesium In tetrahydrofuran Stage #2: allyl bromide In tetrahydrofuran at 20℃; for 2.5h; Reflux; | 1-Allyl-4-(methoxymethoxy)benzene (6): Arylmagnesium bromide was prepared from 1-bromo-4-(methoxymethoxy)benzene (5) (6.2 g, 0.029 mmol) and Magnesium metal (0.76 g, 0.031 mmol) in anhydrous THF (60 mL). To a solution of arylmagnesium bromide was added allyl bromide (2.9 mL, 0.043 mmol) at room temperature over 30 min. The resulting suspension was heated under reflux for 2h and then quenched with aqueous NH4Cl solution at room temperature. The product was extracted with EtOAc (2x100 mL) and organic layer was washed with water (100 mL) followed by brine solution (50 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the crude (5.8 g) of 1-allyl-4-(methoxymethoxy)benzene (6), which was then purified by column chromatography on silica gel (60-120 mesh) using 3%EtOAc in pet.ether to furnish the pure product, 1-allyl-4-(methoxymethoxy)benzene (6) as a colourless liquid (4.6 g, Yield: 91%). Colourless oil ; 1H NMR (500 MHz, CDCl3): δ 7.14 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.05 (ddt, 1H, J = 17.0, 10.2, 6.5 Hz ), 5.14 (s, 2H), 5.11 (dd, J = 17.0, 2.3 Hz, 1H), 5.08 (dd, J = 10.2, 2.3 Hz, 1H), 3.32 (d, J = 6.5 Hz, 2H), 3.50 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 155.6, 137.7, 133.4, 129.5, 116.2, 115.5, 94.5, 55.8, 39.4;IR (KBr): ν 3401, 2923, 2856, 1608, 1512, 1451, 1308, 1237, 1159, 1081, 1006. |
With magnesium 1.) THF, 2.) THF, reflux, 3 h; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With palladium diacetate; N-ethyl-N,N-diisopropylamine; triphenylphosphine at 100℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With tetrabutyl-ammonium chloride; potassium acetate; triphenylphosphine In N,N-dimethyl-formamide at 80℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With scandium tris(trifluoromethanesulfonate); trimethyleneglycol In acetonitrile at 50℃; for 2h; | |
91% | With carbon tetrabromide; triphenylphosphine In 1,2-dichloro-ethane at 40℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran; diethyl ether; hexane at -90℃; for 0.25h; Stage #2: methyl pyridine-2-carboxylate In various solvents at -110 - 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In diethyl ether; hexane at 0 - 20℃; Stage #2: chloro-diphenylphosphine In diethyl ether; hexane at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
662 mg | Stage #1: p-methoxymethoxybromobenzene With iodine; magnesium In tetrahydrofuran Heating; Stage #2: With tributyltin chloride In tetrahydrofuran at 20℃; for 4h; Stage #3: 2-furancarbonyl chloride In chloroform for 11h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: p-methoxymethoxybromobenzene With iodine; magnesium In tetrahydrofuran Heating; Stage #2: With tributyltin chloride In tetrahydrofuran at 20℃; for 4h; Stage #3: 4-(trifluoromethoxy)benzoyl chloride In chloroform for 11h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: p-methoxymethoxybromobenzene With magnesium In tetrahydrofuran Stage #2: p-tert-butylphenyl 4,6-di-O-tert-butyl(dimethyl)silyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride In tetrahydrofuran at -40℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: p-methoxymethoxybromobenzene With iodine; magnesium In tetrahydrofuran Heating; Stage #2: With tributyltin chloride In tetrahydrofuran at 20℃; for 4h; Stage #3: 4-cyanobenzoyl chlorIde In chloroform for 11h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: p-methoxymethoxybromobenzene With iodine; magnesium In tetrahydrofuran Heating; Stage #2: With tributyltin chloride In tetrahydrofuran at 20℃; for 4h; Stage #3: 4-trifluoromethyl-phenyl acetyl chloride In chloroform for 11h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: p-methoxymethoxybromobenzene With iodine; magnesium In tetrahydrofuran Heating; Stage #2: With tributyltin chloride In tetrahydrofuran at 20℃; for 4h; Stage #3: 4-methyl-benzoyl chloride In chloroform for 11h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: p-methoxymethoxybromobenzene With iodine; magnesium In tetrahydrofuran Heating; Stage #2: With tributyltin chloride In tetrahydrofuran at 20℃; for 4h; Stage #3: 4-nitro-benzoyl chloride In chloroform for 11h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With caesium carbonate In tetrahydrofuran Heating; | |
80% | With caesium carbonate In tetrahydrofuran Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: With Triisopropyl borate In tetrahydrofuran; hexane at -78 - 20℃; for 5h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water at 0℃; for 0.5h; | |
71% | Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: With Triisopropyl borate In tetrahydrofuran; hexane at -78 - 20℃; for 5h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane at 0℃; for 0.5h; | |
15.b 4-(Methoxymethoxy-2'-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1';4',1"terphenyl-4"-carboxylic Acid (b) 4-Methoxymethoxyphenylboronic Acid. In a manner similar to that of Example 1(a), starting with 63.81 g (293.0 mmol) of 4-methoxymethoxybromobenzene, 35.42 g (80%) of the expected product are obtained in the form of a white solid with a melting point of 122° C. 1H NMR (CDCl3) δ 3.52 (s, 3H), 5.27 (s, 2H), 7.15 (d, 2H, J=8.6 Hz), 8.16 (d, 2H, J=8.6 Hz). |
28.b (b) (b) 4-Methoxymethoxybenzeneboronic acid: In a similar manner to that of Example 2(a), starting with 63.81 g (293.0 mmol) of 4-methoxymethoxybromobenzene obtained in Example 28(a), 35.42 g (80%) of the expected compound are obtained in the form of a white powder with a melting point of 122° C. 1 H NMR (CDCl3) δ 3.52 (s, 3H), 5.27 (s, 2H), 7.14 (d, 2H, J=8.6 Hz), 8.16 (d, 2H, J=8.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; Stage #2: N-methoxy-3-[3-methoxy-4-[2-(methoxymethoxy)-5-(2-(N-methoxy-N-methylcarbamoyl)ethyl)phenoxy]phenyl]-N-methylpropanamide In tetrahydrofuran; hexane for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: p-methoxymethoxybromobenzene With sec.-butyllithium In tetrahydrofuran; cyclohexane at -78℃; for 0.5h; Stage #2: (1SR,2RS)-2-(2,5-bis-methoxymethoxyphenyl)cyclopentanecarboxylic acid methoxymethylamide In tetrahydrofuran; cyclohexane at 0℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: n-BuLi / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: triisopropyl borate / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 1.3: 71 percent / aq. HCl / tetrahydrofuran; hexane / 0.5 h / 0 °C 2.1: 69 percent / Cu(OAc)2; Et3N; pyridine / 4 Angstroem molecular sieves / CH2Cl2 / 20 °C 3.1: 96 percent / HCl / ethyl acetate / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-BuLi / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: triisopropyl borate / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 1.3: 71 percent / aq. HCl / tetrahydrofuran; hexane / 0.5 h / 0 °C 2.1: 69 percent / Cu(OAc)2; Et3N; pyridine / 4 Angstroem molecular sieves / CH2Cl2 / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 82 percent / Cs2CO3 / Pd(PPh3)4 / tetrahydrofuran / Heating 2: 81 percent / aq. HCl / 16 h / 20 °C 3: 65 percent / acetone / 4 h / Heating 4: 72 percent / NBu4OH / propan-2-ol; methanol / 0.03 h | ||
Multi-step reaction with 4 steps 1: 80 percent / Cs2CO3 / Pd(PPh4)4 / tetrahydrofuran / Heating 2: 94 percent / aq. HCl 3: 65 percent / acetone 4: 85 percent / tetrabutylammonium hydroxide / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 82 percent / Cs2CO3 / Pd(PPh3)4 / tetrahydrofuran / Heating 2: 81 percent / aq. HCl / 16 h / 20 °C 3: 65 percent / acetone / 4 h / Heating | ||
Multi-step reaction with 3 steps 1: 80 percent / Cs2CO3 / Pd(PPh4)4 / tetrahydrofuran / Heating 2: 94 percent / aq. HCl 3: 65 percent / acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 82 percent / Cs2CO3 / Pd(PPh3)4 / tetrahydrofuran / Heating 2: 81 percent / aq. HCl / 16 h / 20 °C 3: 67 percent / acetone / 4 h / Heating 4: 35 percent / NBu4OH / propan-2-ol; methanol / 0.03 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 82 percent / Cs2CO3 / Pd(PPh3)4 / tetrahydrofuran / Heating 2: 81 percent / aq. HCl / 16 h / 20 °C 3: 67 percent / acetone / 4 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 82 percent / Cs2CO3 / Pd(PPh3)4 / tetrahydrofuran / Heating 2: 81 percent / aq. HCl / 16 h / 20 °C | ||
Multi-step reaction with 2 steps 1: 80 percent / Cs2CO3 / Pd(PPh4)4 / tetrahydrofuran / Heating 2: 94 percent / aq. HCl |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: triisopropyl borate / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 1.3: 71 percent / HCl / tetrahydrofuran; hexane; H2O / 0.5 h / 0 °C 2.1: 32 percent / pyridine; copper(II) acetate; ethyldiisopropylamine / molecular sieves 4 Angstroem / CH2Cl2 / 20 °C 3.1: 58 percent / diisobutylaluminum hydride / toluene; tetrahydrofuran / 1 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: triisopropyl borate / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 1.3: 71 percent / HCl / tetrahydrofuran; hexane; H2O / 0.5 h / 0 °C 2.1: 32 percent / pyridine; copper(II) acetate; ethyldiisopropylamine / molecular sieves 4 Angstroem / CH2Cl2 / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: triisopropyl borate / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 1.3: 71 percent / HCl / tetrahydrofuran; hexane; H2O / 0.5 h / 0 °C 2.1: 48 percent / copper(II) acetate; ethyldiisopropylamine; pyridine / molecular sieves 4 Angstroem / CH2Cl2 / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: triisopropyl borate / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 1.3: 71 percent / HCl / tetrahydrofuran; hexane; H2O / 0.5 h / 0 °C 2.1: 73 percent / pyridine; copper(II) acetate; ethyldiisopropylamine / molecular sieves 4 Angstroem / CH2Cl2 / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: triisopropyl borate / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 1.3: 71 percent / HCl / tetrahydrofuran; hexane; H2O / 0.5 h / 0 °C 2.1: 32 percent / pyridine; copper(II) acetate; ethyldiisopropylamine / molecular sieves 4 Angstroem / CH2Cl2 / 20 °C 3.1: 58 percent / diisobutylaluminum hydride / toluene; tetrahydrofuran / 1 h / -78 °C 4.1: ammonium acetate / methanol; tetrahydrofuran / 3 h / 20 °C 4.2: [3H3]sodium cyanoborohydride / methanol; tetrahydrofuran / 2 h / 20 °C 4.3: HCl / ethyl acetate / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: triisopropyl borate / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 1.3: 71 percent / HCl / tetrahydrofuran; hexane; H2O / 0.5 h / 0 °C 2.1: 73 percent / pyridine; copper(II) acetate; ethyldiisopropylamine / molecular sieves 4 Angstroem / CH2Cl2 / 20 °C 3.1: 94 percent / HCl / ethyl acetate / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 4-bromo-phenol With sodium hydride In acetonitrile at 0 - 20℃; for 0.333333h; Stage #2: chloromethyl methyl ether In acetonitrile at 20℃; for 0.333333h; | 38.a EXAMPLE 38; Preparation of 8-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-8-(4-methoxymethoxyphenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine; Step a) Preparation of Compound 2; A mixture of 4-bromophenol (4.00 g, 23.1 mmol) in acetonitrile (100 mL) at 0° C. was treated portionwise with sodium hydride (1.10 g of a 60% dispersion in oil, 27.7 mmol). The mixture was stirred for 5 min, then warmed to room temperature and stirred for an additional 15 min. Chloromethyl methyl ether (2.23 g, 27.7 mmol) was added dropwise and the mixture stirred for 20 min. The solvents were evaporated and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2 (5.30 g, 106%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J=8.9 Hz, 2H), 6.92 (d, J=8.9 Hz, 2H), 5.14 (s, 2H), 3.46 (s, 3H). |
92% | Stage #1: 4-bromo-phenol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1.5h; Stage #2: chloromethyl methyl ether In tetrahydrofuran; mineral oil at 20℃; | 29.1 To a suspension of 60% NaH in mineral oil (12.7 g, 31.8 mmol) in anhydrous THF (300 mL) at 0 °C was added 4-BROMOPHENOL (50.0 g, 28.9 mmol) dissolved in THF (100 mL) dropwise over 1 h. The reaction mixture was stirred at 0 °C for 30 min, and chloromethylmethyl ether (24.8 mL, 32.6 mmol) dissolved in THF (30 mL) was added dropwise over 20 min. The reaction mixture was stirred overnight at RT Water (250 mL) was added, and the mixture was extracted with ether (3 x 250 mL). The combined ethereal extracts were washed with brine, dried (MgSO4), and concentrated. The residue was distilled under vacuum to afford 57.6 G (92%) of 86 as a colorless oil.'H NMR (400 MHz, DMSO-D6) : 8 3.33 (s, 3H), 5.15 (s, 2H), 6.96 (d, J = 9.0 Hz, 2H), 7.43 (d, J = 9.0 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With n-butyllithium In tetrahydrofuran; hexane at -78 - 0℃; for 1.5h; | 4.C; 4.3 To a suspension of 60% NaH in mineral oil (12.7 g, 31.8 MMOL) in anhydrous THF (300 mL) at 0 °C was added 4-bromophenol (50.0 g, 28.9 MMOL) dissolved in THF (100 mL) dropwise over 1 h. The reaction mixture was stirred at 0 °C for 30 min, and chloromethylmethyl ether (24.8 mL, 32.6 MMOL) dissolved in THF (30 mL) was added dropwise over 20 min. The reaction mixture was stirred overnight at RT. H20 (250 mL) was added, and the mixture was extracted with ET20 (2 x 250 mL). The combined ethereal extracts were washed with brine (500 mL), dried over MGS04, and concentrated. The residue was distilled under vacuum to afford 57.6 g (92%) of 13 as a colorless OIL. H NMR (400 MHz, DMSO-D6) : No. 3.33 (s, 3H), 5.15 (s, 2H), 6.96 (d, J = 9. 0 HZ, 2H), 7.43 (d, J = 9. 0 HZ, 2H). Step 2: N-METHOXY-N-METHYL-2-PHENYLBUTANAMIDE (14 To a stirred solution of pyridine (33.1 mL, 40.9 MMOL) and N, O- dimethylhydroxylamine hydrochloride (26.0 g, 26.7 MMOL) in anhydrous CH2CI2 (300 mL) at 0 °C was added dropwise 2-phenylbutyryl chloride (37.4 g, 20.5 MMOL) dissolved in THF (100 mL). The reaction mixture was stirred overnight at RT. H20 (300 mL) was added, and the mixture was extracted with CH2CI2 (2 x 200 mL). The combined extracts were washed successively with 5% aqueous HCI (300 mL), 5% aqueous NAHC03 (300 mL), H20 (300 mL), and brine (300 mL). The mixture was dried over NA2SO4, filtered, and concentrated to afford 41.6 g (98%) of 14 as a colorless oil which was used without further purification.'HNMR (400 MHz, CDCI3) : 8 0.87 (t, J = 7. 3 Hz, 3H), 1.74 (h, J = 7. 1 Hz, 1H), 2. 08 (h, J = 7. 1 Hz, 1H), 3.14 (s, 3H), 3.46 (s, 3H), 3. 88 (br s, 1H), 7.19-7. 33 (m, 5H). Step 3-1- [4- (METHOXYMETHOXY) PHENYL]-2-PHENYLBUTAN-1-ONE (J 5 To a stirred solution of 13 (99.0 g, 0.46 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 310 mL, 0.50 mol) dropwise at-78 °C. The reaction mixture was stirred for 30 min and 14 (90.1 g, 0.43 mol) dissolved in THF (500 mL) was added dropwise. The reaction mixture was stirred at-78 °C for 1 h and then slowly warmed to 0 °C. H20 (500 mL) was added and the volatiles were removed under reduced pressure. The residue was extracted with ET20 (3 x 500 mL) and the combined extracts were washed with water (500 mL) and brine (500 mL). The mixture was dried over MGS04 and concentrated. The residue was recrystallized from hexanes to afford 97.6 g (80%) of 15 as white needles.'HNMR (400 MHz, DMSO-d6) : 8 0. 79 (t, J = 7. 3 Hz, 3H), 1.68 (h, J = 7. 0 HZ, 1 H), 2.03 (h, J = 7. 0 Hz, 1H), 3.32 (s, 3H), 4.65 (t, J=7. 3HZ, 1H), 5.21 (s, 2H), 7.03 (d, J=8. 8HZ, 2H), 7.15 (t, J = 7. 1 Hz, 1H), 7.23-7. 30 (m, 4H), 7.98 (d, J=8. 8HZ, 2H). Step 4: 1- [4- (DIETHOXYMETHYL) PHENYL]-1- [4- (METHOXYMETHOXY) PHENYL]-2- PHENYLBUTAN-1-OL () To a stirred solution of 4-bromobenzaldehyde diethyl acetal (107 g, 0.41 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 268 mL, 0.43 mol) dropwise at-78 °C. After stirring for 1 h at-78 °C, a solution of 15 (97.6 g, 0.34 mol) in THF (750 mL) was cannulated into the reaction mixture portionwise. The mixture was stirred overnight at RT, H20 (500 mL) was added, and the volatiles were removed under reduced pressure. The residue was extracted with ET20 (3 x 500 mL) and the combined extracts washed with H20 (500 mL) and brine (500 mL). The mixture was dried over MGS04 and concentrated to afford 194 g of 16 that was used without further purification.'HNMR (400 MHz, DMSO-d6) : 8 0.58 (t, J = 7.3 Hz, 3H), 1.12 (m, 6H), 1.52 (m, 1H), 1.70 (m, 1 H), 3.23 (s, 3H), 3.40-3. 65 (m, 5H), 4.98 (s, 2H), 5.41 (s, 1H), 5.51 (s, 1H), 6.62 (d, J = 8.8 Hz, 2H), 6.96-7. 06 (m, 3H), 7.17- 7.23 (m, 4H), 7.31 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H). Step 5: 4- [ (1)-1- (4-HYDROXYPHENYL)-2-PHENYLBUT-1-ENYL] BENZALDEHYDE (10 To a solution of 16 (194 g, 0.42 mol) in ETOH (1.25 L) was added 12 M HCI (250 mL). The reaction mixture was refluxed for 3 h, cooled to RT, and the volatiles were removed under reduced pressure. H2O (750 mL) was added and the mixture was extracted with ether (3 x 500 mL). The combined ethereal extracts were washed with H20 (750 mL), brine (750 mL), and dried over MGS04. CONCENTRATION followed by recrystallization from hexanes afforded 52.8 g (38%) of 10 as a white solid.'HNMR (400 MHz, DMSO-d6) : 8 0.83 (t, J = 7.3 Hz, 3H), 2.33 (q, J = 7.3 Hz, 2H), 6.40 (d, J = 8. 4 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 7.10-7. 20 (m, 5H), 7.40 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 8. 1 Hz, 2H), 9.23 (s, 1H), 9.98 (s, 1H). Step 6: TERT-BUTYL (2E)-3- (4- [ (121-1- (4-HYDROXYPHENYL)-2-PHENYLBUT-L- enyl] phenyl} prop-2-enoate (12 To a stirred solution of (TERT-BUTOXYCARBONYLMETHYLENE) triphenylphosphorane (5.19 g, 13.8 MMOL) in CH2CI2 (200 mL) was added 10 (2.29 g, 7.0 MMOL) dissolved in CH2CI2 (100 mL) dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h. Silica gel (12.0 g) was added, and the volatiles were removed under reduced pressure. Flash chromatography (20: 1 to 4: 1 hexane: EtOAc), followed by recrystallization (hexane/EtOAc) afforded 2.0 g (67%) of 12 as a white solid.'HNMR (400 MHz, DMSO-d6) : 8 0. 83 (t, J = 7. 3 Hz, 3H), 1.46 (s, 9H), 2.35 (q, J = 7. 3 Hz, 2H), 6.39 (d, J = 8. 4 Hz, 2H), 6.48 (d, J = 16.0 Hz, 1H), 6.59 (d, J = 8. 4 Hz, 2H), 7.07-7. 20 (m, 7H), 7.53 (d, J = 16. 0 Hz, 1H), 7.66 (d, J = 8. 1 Hz, 2H), 9.19 (s, 1H) ; MS, m/z, 425 (M-H)- This material was contaminated with up to 25% of the undesired E-isomer, tert-Butyl (2E)-3- {4- [ (1E)-1- (4-HYDROXYPHENYL)-2-PHENYLBUT-1-ENYL] PHENYL} PROP-2-ENOATE (17). HNMR (400 MHz, DMSO-d6) : 8 0.83 (t, J = 7.5 Hz, 3H), 1.42 (s, 9H), 2.40 (q, J = 7.5 Hz, 2H), 6.32 (d, J=15. 9HZ, 1H), 6.74 (d, J=8. 4HZ, 2H), 6.80 (d, J=8. 4HZ, 2H), 6. 98 (d, J = 7. 4 Hz, 2H), 7.06-7. 17 (m, 5H), 7.31 (d, J = 8. 4 Hz, 2H), 7.34 (d, J = 16 Hz, 1 H), 9.44 (s, 1 H). The pure (>95% by HPLC) 12 (Z-isomer) was prepared by recrystallization from EtOAc or by separation by RP-HPLC using a C18 Luna column (150 x 21.2 mm, 5 1 particle size) with 77: 33 CH3CN/H2O (0.1% TFA) for 20 min at a flow rate of 20 ML/MIN (Tr = 15.08 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium In tetrahydrofuran at -78℃; for 0.5h; | ||
With magnesium In tetrahydrofuran; water | 15.1 4-(3,4-diethoxyphenyl)-N-{4-[4-(methoxymethoxy)phenyl]quinolin-2-yl}-4-oxobutanamide (1) [4-(methoxymethoxy)phenyl](2-nitrophenyl)methanol 1-Bromo-4-(methoxymethoxy)benzene (11 g) was dissolved in THF (60 mL), and magnesium (1.6 g) was added. The reaction mixture was cooled to -78°C, 2-nitrobenzaldehyde (6.4 g) was added, and the mixture was stirred for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and vacuum-dried to give [4-(methoxymethoxy)phenyl](2-nitrophenyl)methanol (4.9 g) as yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran | 2 Preparation of the compounds of formula (I), where X=--OH EXAMPLE 2 Preparation of the compounds of formula (I), where X=--OH 4-Methoxymethoxy-1-bromobenzene was prepared from formaldehyde dimethyl acetal and 4-bromophenol by the method of Y. P. Yardley and H. Fletcher, Synthesis 1976, p. 244. The boiling point of this derivative is 54° to 56° C. at 0.1 hPa, and the yield is 49 percent theory. About 4.6 g (0.19 Mol) of magnesium turnings were moistened with absolute tetrahydrofuran under nitrogen, warmed to 60° C. and treated with a few drops of 4-methoxy-methoxy-1-bromobenzene and a few drops of ethyl iodide as initiator. After the reaction had commenced, the remainder of a total of 35 g (0.16 Mol) of the bromine compound, dissolved in 150 ml of tetrahydrofuran (THF), was added at such a rate that the mixture continued to boil, and the mixture was subsequently refluxed for an additional 2.5 hours. A catalytic amount of a solution of dilithium tetrachlorocuprate (containing 5 percent of dilithium tetrabromocuprate) and 16.2 ml (0.16 Mol) of 4-bromo-1-butene, dissolved in 200 ml of THF, were then added. | |
With magnesium In tetrahydrofuran | 2.a Preparation of pentamethyl-penta-(4-(4-biphenylylcarbonyloxy)phenylbutyl)cyclopentasiloxane (a) 4-Methoxymethoxy-1-bromobenzene was prepared from formaldehyde dimethyl acetal and 4-bromophenol by the method of Y. P. Yardley and H. Fletcher, Synthesis 1976, p. 244. The boiling point of this derivative is 54°-56° C. at 0.1 hPa, and the yield is 49% of theory. About 4.6 g (0.19 mol) of magnesium turnings were moistened under nitrogen with absolute tetrahydrofuran, warmed to 60° C. and treated with a few drops of ethyl iodide as initiator. After the reaction had commenced, the remainder of a total of 35 g (0.16 mol) of the bromine compound, dissolved in 150 ml of tetrahydrofuran, was metered in at such a rate that the mixture continued to boil, and the mixture was subsequently refluxed for an additional 2.5 hours. A catalytic amount of a solution of dilithium tetrachlorocuprate (containing 25% of dilithium tetrabromocuprate) and a solution of 16.2 ml (0.16 mol) of 4-bromo-1-butene in 200 ml of THF were then added. The mixture was refluxed for 16 hours, then cooled and poured onto ice. After acidification and phase separation, the aqueous phase was extracted twice with 400 ml of methyl tert-butyl ether. The organic phases were dried and evaporated. The residue was fractionated under reduced pressure, giving 16.5 g (corresponding to 53.6% of theory) of 4-(methoxymethoxy)-1-(3-butenyl)benzene with a boiling point of 118°-120° C. and a pressure of 15 hPa. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium sulfate In tetrahydrofuran | 1.1 EXAMPLE 1 (1) In an atmosphere of nitrogen, 2.03 g of magnesium was suspended in 5 ml of dry tetrahydrofuran, and 16.45 g of bromo-4-methoxymethyloxybenzene which has been dissolved in dry tetrahydrofuran was added dropwise to the thus prepared suspension to form Grignard reagent. The resulting reaction mixture was diluted with 150 ml of dry tetrahydrofuran and cooled down to 0° C. To this was added dropwise 7.96 g of pyridine-3-aldehyde which has been dissolved in 20 ml of dry tetrahydrofuran. After 24 hours of stirring, saturated aqueous sodium chloride solution was added to the resulting reaction mixture. Thereafter, the organic layer was separated and the water layer was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution and dried using anhydrous magnesium sulfate, followed by the removal of solvents by distillation under a reduced pressure. The thus prepared residue was subjected to silica gel column chromatography to obtain 14.09 g of α-(4-methoxymethyloxyphenyl)-3-pyridylmethyl alcohol from a methanol-methylene chloride (5:95 v/v) elude fraction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With ammonium chloride In tetrahydrofuran | 7.b Preparation of 3-(4-methoxymethoxyphenyl-ONN-azoxy)-2-butanol (b) A small quantity of iodine was put in a vessel containing 2.5 g (103 mmol) of metal magnesium and 90 ml of anhydrous tetrahydrofuran, and a solution of 20 g (92 mmol) of 4-methoxymethoxybromobenzene obtained in the above (a) in 90 ml of anhydrous tetrahydrofuran was gradually added dropwise under stirring. Reaction progressed rapidly, and after the reaction somewhat calmed down, the mixture was stirred at 50° C. for further 3 hours. Thereafter, the rector was cooled to 0° C., 22 g (110 mmol) of trimethyltin chloride was added thereto, and the mixture was heated again to 50° C. and refluxed for 2 hours. After the reaction, the reaction solution was cooled again to 0° C., saturated ammonium chloride solution was added, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) and vacuum distillation to give 24.6 g of 4-methoxymethoxyphenyltrimethyltin as a colorless oil (yield 89%, bp. 97°-102° C./0.9 mmHg). 1 H-NMR (CDCl3:δ) 0.27 (9H, s, SnCH3), 3.48 (3H, s, OCH3), 5.19 (2H, s, OCH2 O), 7.05 (2H, d, J=9 Hz, Aromatic 3, 5-H), 7.42 (2H, d, J=9 Hz, Aromatic 2, 6-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium In tetrahydrofuran; methanol; hexane; water | R.104 Reference Example 104 In ether (240 ml) was dissolved 1-bromo-4-(methoxymethoxy)benzene (30 g). To the mixture was added dropwise at -78° C. 1.6M n-butyllithium/hexane (90.7 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (43.1 g) in THF (43 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added water (150 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was stirred in methanol/water (2/1, 1000 ml) for 3 days. Under reduced pressure, methanol was removed, and the residue was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(methoxymethoxy)phenyl borate (2.4 g). 1H-NMR (200 MHz, CDCl3) δ 3.51 (3H, s), 5.26 (2H, s), 7.14 (2H, d, J=8.4 Hz), 8.15 (2H, d, J=8.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In water; N,N-dimethyl-formamide | R.104 Reference Example 104 Reference Example 104 In DMF (255 ml) was dissolved 4-bromophenol (51.0 g). To the mixture was added at room temperature potassium carbonate (81.5 g) and then was added dropwise chloromethylmethyl ether (44.8 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-4-(methoxymethoxy)benzene (61.4 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide; magnesium In tetrahydrofuran | 32.1 N-(5-benzyl-4-phenyl-1,3-thiazol-2-yl)-4-oxo-4-[4-(methoxymethoxy)phenyl]butanamide (1) 4-[4-(methoxymethoxy)phenyl]-4-oxobutanoic acid Under ice-cooling, to a solution of succinic anhydride (4.5 g) in THF (100 mL) was added dropwise a solution of 4-(methoxymethoxy)phenylmagnesium bromide (prepared from magnesium (1.23 g) and 4-bromo-(methoxymethoxy) benzene (10 g)) in THF (50 mL), and the mixture was stirred for 2 hr. Diluted hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 1N Aqueous sodium hydroxide solution was added to the obtained residue, and the mixture was washed with ether. The aqueous layer was acidified with diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-[4-(methoxymethoxy)phenyl]-4-oxobutanoic acid (1.2 g) as crystals. 1H-NMR (CDCl3) δ: 2.74(2H, t, J=6.6Hz), 3.26(2H, t, J=6.6Hz), 3.49(3H, s), 5.24(2H, s), 7.07(2H, d, J=8.7Hz), 7.96(2H, d, J=8.7Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; pentane at -78 - 0℃; | 1 Preparation of compound 3; To a solution of 6.51 g (30 mmol) of 2 in 100 ml of diethyl ether was added 35.3 ml (60 mmol) of solution of t-BuLi in pentane (1.7M) at -78° C. over 30 min and the mixture was stirred for additional 3 hours at -78° C. under nitrogen. The temperature of the reaction mixture was raised to 0° C. until the formation of white solid (lithiated 2) and recooled to -78° C. before the addition of 5.68 g (40 mmol) of ethyl trifluoroacetate in 30 ml of diethylether slowly over the period of 30 min, and the mixture was stirred for 3 hours at -78° C. The reaction was poured into 100 ml of sat. NH4Cl aqueous solution and the mixture was extracted with diethyl ether (100 ml×2). The combined organic layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was chromatographed over silica gel using 8% ethyl acetate in hexane to give 3 as a yellow oil (6.3 g, 90%). 1H NMR (CDCl3): δ 8.04 (d, 2H, 8.8 Hz), 7.12 (d, 2H, 8.8 Hz), 5.25 (s, 2H), 3.47 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 3,5-dibromo-2-methylthiophene With n-butyllithium; boric acid tributyl ester In tetrahydrofuran; hexane at -78℃; for 1.5h; Inert atmosphere; Stage #2: p-methoxymethoxybromobenzene With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-formyl-4-methylphenyl]-5-thio-D-glucopyranose; p-methoxymethoxybromobenzene; ammonium chloride With n-butyllithium In tetrahydrofuran; hexane at -78 - -60℃; for 0.166667h; Stage #2: With water; ammonium chloride In tetrahydrofuran; hexane Saturated solution; | 11.1 (1) Preparation of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-{hydroxy[4-(methoxymethoxy)phenyl]methyl}-4-methylphenyl]-5-thio-α-D-glucopyranose To a solution of 1-bromo-4-(methoxymethoxy)benzene (1.55 g, 7.13 mmol) in tetrahydrofuran (7.5 mL), 2.67 M n-butyllithium in hexane (2.58 mL, 6.9 mmol) was added dropwise at -60°C under a nitrogen atmosphere. Then, a solution of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-formyl-4-methylphenyl]-5-thio-D-glucopyranose (1.80 g, 2.30 mmol) in tetrahydrofuran (10 mL) was added dropwise and stirred at -78°C for 10 minutes. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1 → 1:1) to give the titled compound (1.2 g, 57%) as a yellow amorphous substance. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.19 (br. s., 3 H) 3.46 (s, 7 H) 3.89-4.03 (m, 2 H) 4.47-4.56 (m, 2 H) 4.64 (d, J=11.35 Hz, 1 H) 4.73-4.97 (m, 4 H) 4.99-5.22 (m, 5 H) 5.79-5.95 (m, 1 H) 6.66-7.39 (m, 31 H). ESI m/z = 942 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: 6,11-diphenyl-5,12-naphthacenequinone In tetrahydrofuran; hexane at -78 - 20℃; for 24h; Stage #3: With ammonium chloride In tetrahydrofuran; hexane; water | 29 20 mL of a THF solution containing 3.96 g (18.25 mmol) of 4-methoxymethoxybromobenzene, which was cooled to -78° C. with dry ice/acetone, was added dropwise with 7 mL (17.5 mmol) of a 2.5 M hexane solution of normal-butyllithium (n-BuLi), and the mixture was stirred for 30 minutes to obtain a solution. Then, the solution thus obtained was transferred, using a cannula, into 80 mL of a THF solution containing 1.50 g (3.65 mmol) of 6,11-diphenyl-5,12-naphthacenequinone, which was cooled to -78° C. with dry ice/acetone. Thereby, a mixed solution was obtained. Subsequently, the temperature of the mixed solution was gradually brought to room temperature with stirring for 24 hours. A saturated NH4Cl aqueous solution was added to suppress the reaction. The aqueous phase in the mixed solution was extracted with ether. Thereafter, the organic phase thus obtained was washed with a saturated NH4 Cl aqueous solution and a saturated NaCl aqueous solution, and dried with anhydrous magnesium sulfate. After that, magnesium sulfate was removed by filtration, and the filtrate was concentrated. Then, the filtrate thus obtained was added with hexane, and a precipitate thus formed was recovered by suction filtration. Subsequently, the obtained precipitate was thoroughly washed with hexane, and thus vacuum-dried. Thereby, 5,12-bis(4-methoxymethoxyphenyl)-6,11-diphenyl-5,12-naphthacenediol expressed by the following general formula (106) was obtained (a slightly yellowish white solid: a yield of 1.45 g and 58%). The 5,12-bis(4-methoxymethoxyphenyl-6,11-diphenyl-5,12-naphthacenediol thus obtained was subjected to 1H NMR measurement. Note that, the NMR spectrum was measured with a JOEL JNM EX270 spectrometer (270 MHz for 1H). Moreover, TMS was used as a reference for the chemical shifts in 1H NMR. The measurement result is shown below.1H NMR (CDCl3) δ7.72 (dd, J=5.60, 3.03 Hz, 2H), 7.57 (dd, J=6.39, 3.35 Hz, 2H), 7.49 (d, J=8.75 Hz, 4H), 7.29 (dd, J=6.39, 3.35 Hz, 2H), 7.14-7.25 (m, 10H), 6.95 (d, J=8.25 Hz, 2H), 6.72 (d, J=8.75 Hz, 4H), 5.10 (s, 4H), 3.44 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 16h; | |
With caesium carbonate In tetrahydrofuran at 80℃; | 96.B Step B: 4-(4-(methoxymethoxy)phenyl)pyridine; To a degassed solution of 1-bromo-4-(methoxymethoxy)benzene (360 mg, 1.66 mmol), pyridin-4-ylboronic acid (307 mg, 2.50 mmol), and Cs2CO3 (1.09 g, 3.35 mmol) in THF (5 mL) was added Pd(PPh3)4 (190 mg, 0.16 mmol). The reaction mixture was heated at 80° C. overnight and diluted with EtOAc (50 mL). It was washed with H2O (2×25 mL), dried over Na2SO4, and concentrated. Purification on a silica gel column gave the desired product as a white solid (265 mg). NMR (CDCl3): 8.63 (d, 2H), 7.67 (d, 2H), 7.47 (d, 2H), 7.16 (d, 2H), 5.24 (s, 2H), 3.52 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tetrabutylammomium bromide; palladium diacetate; potassium carbonate In N,N-dimethyl-formamide at 170℃; for 0.5h; Inert atmosphere; Microwave irradiation; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.7% | Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran at -40℃; for 2h; Stage #2: Trimethyl borate In tetrahydrofuran at 20℃; for 8h; | 1.2 Step 2 The compound obtained in Step 1(T-2) (57.6g, 265.1)Tetrahydrofuran (THF) (290ml)The solution was cooled to -40 ,Was added dropwise n-BuLi (1.59M, 200.3ml, 318.4mmol).At -40 for 2 hours,Dropwise trimethoxy boron (35.85g, 344.97mmol).Stirring at room temperature for 8 hoursThe reaction mixture was poured into saturated aqueous ammonium chloride(300ml), andExtracted with ethyl acetate.The extract was water (300ml) and saturated brine (200ml) washedDried over anhydrous magnesium sulfate,Concentrated under reduced pressure,To give the compound (T-3) (32.7g, 179.69mol, 67.7%). |
Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2.5h; Inert atmosphere; Stage #2: Trimethyl borate In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With palladium diacetate; caesium carbonate; tricyclohexylphosphine In 1,4-dioxane at 160℃; for 0.333333h; Microwave irradiation; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran; hexane at -85℃; for 0.833333h; Stage #2: N-tert-butyloxycarbonylpiperidin-4-one In tetrahydrofuran; hexane at -85 - -25℃; for 6.16667h; Stage #3: With ammonium chloride In tetrahydrofuran; hexane; water | 1.1 Reference Example 1Production of 1-(t-butoxycarbonyl)-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine(Step 1)•Production of 1- (t-butoxycarbonyl) -4- [ (4-methoxymethoxy)phenyl]-4-hydroxypiperidineA solution of l-bromo-4-methoxymethoxybenzene(5.43 g, 25.0 mmol) in tetrahydrofuran (THF) (100 mL)was stirred at -85°C, and a 2.46 M .n-butyllithium hexanesolution (10.2 mL, 25.0 mmol) was added dropwise to thestirred solution over 10 minutes. The resultingsolution was stirred at the same temperature for 40minutes. To the reaction solution was added dropwisefor 10 minutes a solution of 1-(t-butoxycarbonyl)-4-piperidone (5.20 g, 26.0 mmol) in THF (30 mL). Thetemperature of the resulting solution was raised to -25°C over 4 hours, and then the solution was stirred atthat temperature for 2 hours. An aqueous solution ofsaturated ammonium chloride was then added to thissolution. The reaction solution was extracted withethyl acetate and dried over anhydrous magnesiumsulfate, after which the solvent was evaporated. Theresidue was purified by silica gel columnchromatography (ethyl acetate: n-hexane =2 : 3, inratio by volume; hereinafter the same), to therebyyield 7.63 g of the title compound.Appearance: Colorless oilXH NMR (CDC13) 6 1.49(9H, s) , 1.73(2H, d, J = 12.0 Hz),1.97(2H, brs), 3.24(2H, brs), 3.48(3H, s), 4.00(2H,brs), 5.17(2H, s), 7.03(2H, d, J = 9.0 Hz), 7.39(2H, d,J = 9.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: p-methoxymethoxybromobenzene With tert.-butyl lithium In tetrahydrofuran; pentane at -78℃; for 0.166667h; Inert atmosphere; Stage #2: (1R,2R,3R)-1-(3,4-dimethoxyphenyl)-2,3-dimethyl-1-(tertbutyldimethylsiloxy)-4-butanal In tetrahydrofuran; pentane at -78 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate for 12h; Inert atmosphere; Reflux; | 5 3.5 1-(Methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (11) Under argon atmosphere, a solution of 1-bromo-4-(methoxymethoxy)benzene (10)13 (410 mg, 1.889 mmol) in dioxane (6 mL) was added to bis(pinacolato)diboron (500 mg, 1.969 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (146 mg, 0.179 mmol), and potassium acetate (527 mg, 5.370 mmol) at room temperature. After being refluxed for 12 h, the reaction mixture was evaporated. The residue was chromatographed over silica gel eluted by hexane/ EtOAc (19:1) to give 11 (442 mg, 1.672 mmol, 88%). Data for 11: colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.75 (2H, d, J=8.8 Hz), 7.02 (2H, d, J=8.8 Hz), 5.20 (2H, s), 3.47 (3H, s), 1.33 (12H, s); 13C NMR (100 MHz, CDCl3) δ 159.7, 136.4 (2C), 115.4 (2C), 94.0, 83.6 (2C), 56.0, 24.8 (4C) (because a boron atom was bonded to C-4, the C-4 signal was highly broadened and not observed); LREIMS m/z 264 [M]+ (100%), 234 (35%), 219 (11%); HREIMS m/z 264.1527 [M]+ (264.1533 calcd for C14H21O4B). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; for 24h;Inert atmosphere; Reflux; | Under argon atmosphere, a solution of 16 (71.2 mg, 0.291 mmol) and 10 (70.8 mg, 0.268 mmol) in dioxane (2 mL) was added to [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (22.1 mg, 0.027 mmol), and tripotassium phosphate (175 mg, 0.824 mmol) at room temperature. After being refluxed for 24 h, the reaction mixture was evaporated. The residue was chromatographed over silica gel eluted by hexane-EtOAc (9:1) to give 17 (75.4 mg, 0.249 mmol, 93%). Data for 17: colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.98-8.02 (2H, m), 7.46 (2H, d, J=8.9 Hz), 7.09 (2H, d, J=8.9 Hz), 6.97 (1H, d, J=9.1 Hz), 5.21 (2H, s), 3.89 (3H, s), 3.86 (3H, s), 3.50 (3H, s); 13C NMR (100 MHz, CDCl3) δ 166.8, 160.1, 156.6, 132.2, 131.0, 130.6 (2C), 130.4, 130.0, 122.6, 115.8 (2C), 110.5, 94.4, 55.9, 55.7, 51.8; LREIMS m/z 302 [M]+ (100%), 272 (36%), 226 (11%); HREIMS m/z 302.1141 [M]+ (302.1154 calcd for C17H18O5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: p-methoxymethoxybromobenzene With magnesium In tetrahydrofuran at 20℃; for 2h; Stage #2: With N,N-dimethyl-formamide In tetrahydrofuran at 0℃; for 2h; Stage #3: With ammonia; iodine In tetrahydrofuran; water at 20℃; for 2h; | 3.2 Typical experimental procedure for conversion of aromaticbromides into aromatic nitriles with Mg, DMF, I2, and aqNH3 General procedure: To a flask containing Mg turnings (0.29 g, 12 mmol) was added1-bromo-4-methylbenzene (1.37 g, 8.0 mmol) in THF (8 mL) at room temperature. After being stirred for 2 h, DMF (1.3 mL,12 mmol) was added to the reaction mixture. The obtained mixturewas stirred for 2 h at 0 ° C. Then, aq NH3 (7 mL, 28-30%) and I2 (4.06 g, 16 mmol) were added to the reaction mixture. After beingstirred for 2 h at room temperature, the reaction mixture waspoured into satd aq Na2SO3 solution and was extracted with CHCl3 (3*30 mL). The organic layer was dried over Na2SO4 and filtered.After removal of the solvent, the residue was purified by shortcolumn chromatography on silica gel (eluent: hexane/ethylacetate=9:1, v/v) to provide pure 4-methyl-1-benzonitrile (0.77 g) in 82% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With copper(l) iodide; N,N-dimethylglycine hydrochoride; caesium carbonate In 1,4-dioxane at 110℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In tetrahydrofuran; at 85℃; for 12h;Inert atmosphere; | The B6 - 1 (1.5 g, 6 . 91 mmol) and 2 - methyl pyridine -4 - boric acid pinacone ester (3.3 g, 55%, 8.29 mmol) dissolved in tetrahydrofuran (30 ml) in, adding Pd (PPh3 )4 (635 mg, 0 . 55 mmol) and cesium carbonate (2.7 g, 8 . 29 mmol). Under the protection of nitrogen, replace the nitrogen five times, heating to 85 C, reaction 12 hours. After cooling to room temperature the filtering, the filtrate is concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate=5:1) to obtain colorless oily matter (1.3 g, 82%). |
1.3 g | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In tetrahydrofuran; at 75℃; for 12h;Inert atmosphere; | 6.1.3 4-(4-(Methoxymethoxy)phenyl)-2-methylpyridine (5) To a solution of the above crude oil 4 (3.3 g), 2 (1.5 g, 6.91 mmol) and Pd(PPh3)4 (635 mg, 0.55 mmol) in THF (10 mL) was added Cs2CO3 (2.7 g, 8.29 mmol). The mixture was stirred at 75 C under N2 for 12 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1) to give 5 (1.3 g, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3): delta 8.48 (d, J = 5.2 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.32 (s, 1H), 7.27 (d, J = 5.2 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 5.22 (s, 2H), 3.49 (s, 3H), 2.60 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.7% | Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran at -40℃; for 2h; Stage #2: Trimethyl borate In tetrahydrofuran at 20℃; for 8h; | 1.2 A THF (290 mL) solution of compound (T-2) (57.6 g, 265.1) obtained in the first step was cooled to -40° C., and n-BuLi (1.59 M, 200.3 mL, 318.4 mmol) was added dropwise thereto. The resulting mixture was stirred at -40° C. for 2 hours, and then trimethoxyboron (35.85 g, 344.97 mmol) was added dropwise thereto. The resulting mixture was stirred at room temperature for 8 hours, and then the reaction mixture was poured into a saturated aqueous solution of ammonium chloride (300 mL), and subjected to extraction with ethyl acetate. Then, the extracted liquid was washed with water (300 mL) and saturated brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound (T-3) (32.7 g, 179.69 mol, 67.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iodine; magnesium; lithium chloride In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: lithium chloride; magnesium; iodine / tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 2: Li2CoCl4 / tetrahydrofuran / 8 h / -20 - 20 °C / Inert atmosphere; Schlenk technique | ||
Multi-step reaction with 2 steps 1: lithium chloride; magnesium / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere; Schlenk technique 2: iron(II) chloride / tetrahydrofuran / 16 h / -20 - 25 °C / Inert atmosphere; Schlenk technique |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: lithium chloride; magnesium; iodine / tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 2: Li2CoCl4 / tetrahydrofuran / 8 h / -20 - 20 °C / Inert atmosphere; Schlenk technique | ||
Multi-step reaction with 2 steps 1: lithium chloride; magnesium / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere; Schlenk technique 2: iron(II) chloride / tetrahydrofuran / 16 h / -20 - 25 °C / Inert atmosphere; Schlenk technique |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: p-methoxymethoxybromobenzene With magnesium In tetrahydrofuran; ethylene dibromide for 0.166667h; Reflux; Stage #2: C11H14O3 With copper(l) iodide In tetrahydrofuran; ethylene dibromide at 0 - 20℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: cyclopent-2-enone; p-methoxymethoxybromobenzene With palladium diacetate In toluene at 20℃; for 0.25h; Stage #2: With triethanolamine In toluene at 110℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.333333h; Stage #2: [13C]methyl iodide In tetrahydrofuran; hexane at -78 - 20℃; for 2h; Stage #3: With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione | |
275 mg | Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.333333h; Stage #2: [13C]methyl iodide In tetrahydrofuran; hexane at -78 - 20℃; for 2h; Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium; lithium chloride In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Schlenk technique; | Typical procedure 1 (TP1): Preparation of di(hetero)arylmanganese reagents by magnesiuminsertion and transmetalation1 General procedure: LiCl (1.2 equiv) was flame dried under high vacuum and allowed to cool to room temperature, then Mg turnings(1.2 equiv) and THF (1 M solution relating to the aryl bromide) were added. The reaction mixture was cooled to0 °C and the corresponding aryl bromide (1.0 equiv) was added dropwise. The progress of the insertion reactionwas monitored by GC-analysis of reaction aliquots quenched with I2. Then a solution of MnCl2·2LiCl (0.55 equiv,1 M in THF) was added dropwise at 0 °C and the solution was stirred for 1 h to afford the correspondingdiarylmanganese reagent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With sodium t-butanolate; XPhos In tetrahydrofuran at 100℃; for 4h; Sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran; hexane at -80℃; for 0.166667h; Inert atmosphere; Stage #2: p-methoxymethoxybromobenzene; di-tert-butylsilyl bis(trifluoromethanesulfonate) With n-butyllithium In tetrahydrofuran; hexane; dibutyl ether at 20℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With caesium carbonate In toluene at 120℃; for 24h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 0.5 h / -50 °C / Inert atmosphere 1.2: 1 h / -50 - 20 °C / Inert atmosphere 1.3: 2 h / 20 °C / Inert atmosphere 2.1: diphenylphosphoranyl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 110 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran; hexane at -50℃; for 0.5h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -50 - 20℃; for 1h; Inert atmosphere; Stage #3: With hydroxylamine hydrochloride; potassium carbonate In tetrahydrofuran; hexane at 20℃; for 2h; Inert atmosphere; | 4.1 4.2.Typical experimental procedure for preparation of 5-aryltetrazoles 3 from aryl bromides 1 General procedure: n-BuLi (1.55 M solution in hexane, 2.32 mL, 3.6 mmol) was added dropwise to a solution of 4-methylphenyl bromide (513 mg, 3.0 mmol) in THF (6.0 mL) at -50 °C under Ar atmosphere. After 30 min, DMF (278 μL, 3.6 mmol) was added and the obtained mixture was gradually warmed to r.t. After 1 h at the same temperature, NH2OHxHCl (313 mg, 4.5 mmol) and K2CO3 (622 mg, 4.5 mmol) were added and the obtained mixture was stirred for 2 h at r.t. Then, after removal of the solvent under reduced pressure, toluene (3.0 mL), DPPA (1.61 mL, 7.5 mmol), and DBU (1.57 mL, 10.5 mmol) were added to the obtained residue under Ar atmosphere. After being stirred for 16 h under refluxing conditions, the mixture was cooled to r.t. and then, saturated NaHCO3 aq. (15.0 mL) was added. After being stirred for 5 min, the mixture was diluted with water (5.0 mL). The aqueous layer was then washed with AcOEt (25.0 mL) and acidified with 1.0 M HCl aq. to pH 2. The aqueous layer was extracted with AcOEt (2 x 25.0 mL). Removal of the solvent, followed by purification of the residue by short column chromatography on neutral silica gel (AcOEt: hexane = 1:3-1:1) gave 5-(4′-methylphenyl)tetrazole 3A (336.1 mg, 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 66% 2: 24% | Stage #1: p-methoxymethoxybromobenzene With magnesium In tetrahydrofuran at 50℃; for 0.75h; Inert atmosphere; Schlenk technique; Stage #2: With copper(l) iodide In tetrahydrofuran for 0.416667h; Cooling with ice; Inert atmosphere; Schlenk technique; Stage #3: C20H33NO4Si In tetrahydrofuran at 45℃; for 20h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100 - 120℃; for 18h; Sealed tube; Inert atmosphere; | 1.2 Step 2: Preparation of N-(4-(methoxymethoxyphenyl)pyridine-3-amine The compound prepared in step 1 (1.4 g, 11.53 mmol), pyridine-3-amine (0.92 mL, 9.61 mmol), Pd2(bda)3(0.437 g, 0.321 mmol), X-Phos (1.364 g, 1.364 mmol) and NaOtBu (1.318 g, 9.61 mmol) were dissolved in 10 mL ofanhydrous toluene, which was added in a seal tube filled with argon gas, followed by stirring at 100 ∼ 120°C for 18 hours.The temperature was lowered to room temperature and the reaction was terminated with distilled water. The generated reaction mixture was diluted with ethyl acetate and then washed with water and saturated brine. The organic phase wasdried over sodium sulfate, followed by concentration in vacuo. The crude product was purified by using silica gel columnchromatography (flash column chromatography) using EtOAc:Hex (1:4) as a moving phase to give the target compound.[0124] 1H NMR (600 Hz, CDCl3): δ 8.27 (d, J = 2.6 Hz, 1 H), 8.08 (dd, J = 4.5, 0.94 Hz, 1 H), 7.26-7.23 (m, 1 H),7.12-7.09 (m, 1 H), 7.06 (d, J = 9.0 Hz, 2 H), 7.01 (d, J = 9.0 Hz, 2 H), 5.87-5.85 (bs, 1 H), 5.15 (s, 2 H), 3.49 (s, 3 H),13C NMR (125 MHz, CDCl3): δ 153.0, 141.2, 140.6, 138.5, 135.7, 123.6, 121.8 (3 C), 121.4, 117.4 (2 C), 94.8, 55.9 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydride for 12h; | 1.1 Step 1: Preparation of 1-bromo-4-(methoxymethoxy)benzene 50 mL of 4-bromophenol (5 g, 28.9 mmol) was dissolved in anhydrous tetrahydropyran, to which bromo(methoxy)methane (MOM-Br, 2.8 mL, 34.68 mmol) and sodium hydride (1.387 g, 34.68 mmol) were added, followed by stirringfor 12 hours. The reaction was terminated by using methanol drop and distilled water. The reaction mixture was dilutedwith ethyl acetate and then washed with water and saturated brine. The organic phase was dried over sodium sulfate,followed by concentration in vacuo. The crude product was purified by using silica gel column chromatography (flashcolumn chromatography) using EtOAc:Hex (1:9) as a moving phase to give the target compound (5.35 g, 85%).[0122] 1H NMR (600 Hz, CDCl3) : δ 7.41 (d, J = 8.6 Hz, 2 H), 6.92 (d, J = 8.24 Hz, 2 H), 5.17 (s, 2H), 3.49 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 20 - 100℃; for 12h; Inert atmosphere; Schlenk technique; Sealed tube; | 5.2.2. 4-(Methoxymethoxy)eN-phenyl aniline (5) The oven dried resalable schlenk tube was charged withrequired amounts of Pd2(dba)3 (0.949 g, 1.03 mmol), BINAP(3.873 g, 6.22 mmol), NaOtBu (2.849 g, 9.61 mmol) then adddegassed anhydrous Toluene (40 mL), degas through pumpingArgon, then add Aniline (8) (2.26 mL, 24.88 mmol) and compound 7(4.5 gr, 20.73 mmol) the schlenk tube was capped with a septumand then evacuated and back filled with Argon, the resultingmixture stirred for 5e10 min at rt. The septum was replaced with aTeflon screwcap. The schlenk tube was sealed and the mixture wasstirred at 80e100 for 12 h, monitored with TLC, after completion ofcompound 7 the reaction mixturewas cooled to room temperature,diluted with DCM (50 mL), filtered through celite. Filtrate waswashed with brine then concentrated under reduced pressure andthe crude product was purified by column chromatography (10%ethyl acetate-hexane) to give compound 5 (5.828 g, 94%) as lightbrown liquid; IR (neat): 2962, 2954, 2900, 2818, 1597, 1511, 1304,1149, 1077, 1015, 744 cm1; 1H NMR (600 MHz, CDCl3) d 7.28e7.24(m, 3H), 7.08 (t, J 9.0 Hz, 1H), 7.02e6.98 (m, 2H), 6.92 (dd, J 10.6,4.1 Hz, 1H), 6.87 (dd, J 12.7, 2.7 Hz, 1H), 6.74 (ddd, J 8.8, 2.6,1.4 Hz, 1H), 5.62e5.85 (bs, 1H), 5.14 (s, 2H), 3.54 (s, 3H); 13C NMR(150 MHz, CDCl3) d 154.57, 152.95, 142.99, 138.64, 129.24, 120.88,119.84, 117.24, 114.05, 114.03, 106.86, 106.72, 96.45, 56.15 ppm; ESIMS:m/z 229 [M]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 4-bromo-phenol With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: bromethyl methyl ether In tetrahydrofuran at 20℃; for 4h; Inert atmosphere; | 5.2.1. Bromo-4-(methoxymethoxy) benzene (7) To suspension of sodium hydride (0.887 g, 23.12 mmol, 60%dispersion in paraffin oil) in dry THF (30 mL) at 0 °C was slowlyadded a solution of 4-bromophenol (9) (4.0 g, 60.78 mmol) in dryTHF (20 mL) under nitrogen atmosphere and mixture was allowedto stir for 30 min at which point the hydrogen gas evolution hadstopped. The resultant mixture was cooled to 0 C and, bromomethylmethyl ether (27.74 mL, 66.87 mmol) was added dropwiseand stirred for an additional 4 h at rt. After completion of reaction,the reaction mixturewas quenched with Ice-cold water and extractwith Ethyl acetate and the organic layerwaswashed with brine anddried over Na2SO4. The solvent was removed under reduced pressure,and the crude product was subjected to flash column chromatography(5% ethyl acetate-hexane) to give compound 7 (4.61 gr,92%) as colour less oil; IR (neat): 2956, 2902, 2826,1590,1487,1233,1152, 997, 824 cm1; 1H NMR (600 MHz, CDCl3) δ 7.38 (d, J 9.0 Hz,1H), 6.93 (d, J 9.0 Hz, 1H), 5.14 (s, 1H), 3.47 (s, 2H); 13C NMR(150 MHz, CDCl3) d 156.13, 132.12 (2 C), 117.88 (2 C), 114.01, 94.30,55.85 ppm; ESI-MS: m/z 217 [M]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: p-methoxymethoxybromobenzene With magnesium In diethyl ether at 0 - 30℃; for 3h; Inert atmosphere; Stage #2: cyclohexanedione monoethylene ketal In tetrahydrofuran; diethyl ether; toluene at 66℃; for 10h; Inert atmosphere; | 2.2; 2.3 Step 2, Under nitrogen protection, 7.56 g of magnesium dust is placed in a 500 mL three-necked flask, and the ice salt bath is 0 ° C.65.1 g of p-methoxymethoxybromobenzene obtained in the above preparation was dissolved in 148 mL of diethyl ether, and added dropwise to a three-necked flask. After 30 minutes, the mixture was added dropwise to a water bath at 30 ° C, and stirred for 2.5 h to obtain p-methoxymethoxy bromide. Magnesium oxide solution;Step 3. Under nitrogen protection, add toluene solution of cyclohexanedione ethylene glycol monoketal to the crude solution of p-methoxymethoxymagnesium bromide(60.84g 1,4-cyclohexanedione monoethylene ketal dissolved in 127ml tetrahydrofuran), the addition time is 10min, after the addition is completed, it is heated to 66 ° C, reflux reaction for 10h,After falling to normal temperature, the whole reaction solution was added to dilute sulfuric acid (51 g of concentrated sulfuric acid dissolved in 100 g of ice water), the temperature was controlled at 10 ° C, and stirred for ten minutes.Dispensing, the aqueous phase is discarded, and the crude product of p-methoxymethoxycyclohexanol ethylene glycol monoketide is obtained 89g; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos In 1,4-dioxane; water at 100℃; Inert atmosphere; | 3 Step 3: 2-(4-(4-(Methoxymethoxy)phenyl)-3, 5-dimethyl- Lif-pyrazol-l-yl) acetamide A mixture of 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1 H- pyrazol-l-yl) acetamide (640 mg, 2.29 mmol), l-bromo-4-(methoxymethoxy)benzene (597 mg, 2.75 mmol), K2C03 (951 mg, 6.88 mmol), Pd2(dba)3 (210 mg, 0.23 mmol), XPhos (219 mg, 0.46 mmol), dioxane (30 mL) and H20 (6 mL) was stirred at 100 °C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, poured into water (30 mL) and extracted with EtOAc (2 x50 mL). The organic layers were combined, washed with water (2 x30 mL), brine (30 mL), dried (Na2S04), filtered, concentrated and then purified by chromatography on silica gel (petroleum ether/EtOAc = 10/1) to give 2-(4-(4-(methoxymethoxy )phenyl)-3,5-di methyl - 1 //- pyrazol-l-yl) acetamide (400 mg, 60 %) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 7.15 (d, 2H), 7.09 (d, 2H), 6.17 (s, 1H), 5.55 (s, 1H), 5.22 (s, 2H), 4.72 (s, 2H), 3.51 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H); LCMS: 290.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | To a solution of l-bromo-4-(methoxymethoxy)benzene (1.0 g, 4.61 mmol) in THF (40 mL) at -78C, n- BuLi (2.5 M in -hexane, 1.9 mL) was added under a nitrogen atmosphere. The mixture was stirred at -78C for 0.5 h. A solution of 3-benzyl-3-azabicyclo[3.2. l]octan-8-one (661 mg, 3.07 mmol) in THF (10 mL) was added at -78C under a nitrogen atmosphere and warmed to room temperature overnight. The reaction mixture was poured into water (35 mL) and then extracted with EtOAc (2 x 35 mL). The combined organic layers were washed with H20 (35 mL), brine (35 mL), dried over Na2S04, filtered, concentrated, and then purified by column (1250) chromatography (Si02, Petroleum ether/Ethyl acetate=3/l) to give 3-benzyl-8-(4- (methoxymethoxy)phenyl)-3-azabicyclo[3.2. l]octan-8-ol (800 mg, 74%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 7.44 (d, 2H), 7.41-7.37 (m, 2H), 7.34-7.31 (m, 2H), 7.26-7.22 (m, 1H), 7.03 (d, 2H), 5.19 (s, 2H), 3.62 (s, 2H), 3.49 (s, 3H), 2.89 (d, 2H), 2.67-2.58 (m, 2H), 2.40 (m, 2H), 1.81 (d, 2H), 1.52-1.38 (m, 3H); LCMS: 354.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | To a solution of Mg (1.12 g, 46.1 mmol) and LiCl (1.95 g, 46.07 mmol) in THF (60 mL) at room temperature, 1 M DIBAL-H in toluene (0.58 mL) was added and stirred at room (1297) temperature for 30 min. l-Bromo-4-(methoxymethoxy)benzene (5.0 g, 23.0 mmol) was added dropwise at room temperature and then stirred at room temperature for 2 h. A solution of 9-benzyl- 3-oxa-9-azabicyclo[3.3. l]nonan-7-one (1.3 g, 5.62 mmol) in THF (60 mL) was added dropwise at room temperature and then stirred at room temperature overnight. The mixture was poured into aqueous sat. NH4Cl (200 mL) and filtered through celite pad. The filtrate was extracted with EtOAc (2 x300 mL). The organic layers were combined, washed with water (2 x l00 mL), brine (100 mL), dried (Na2S04), filtered, concentrated, and then purified by chromatography on silica gel (petoleum ether/EtOAc = 5/1) to give 9-benzyl-7-(4-(methoxymethoxy)phenyl)-3-oxa-9- azabicyclo[3.3. l]nonan-7-ol (1.2 g, 28%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) d 7.61- 747 (m, 2H), 7.44-7.13 (m, 5H), 7.00-6.91 (m, 2H), 5.12 (s, 2H), 3.81-3.70 (m, 2H), 4.03-3.69 (m, 4H), 3.32 (s, 3H), 3.28 (s, 2H), 2.79-2.71 (m, 2H), 1.61-1.51 (m, 2H). LCMS: 370.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran; hexane at -80℃; for 1h; Inert atmosphere; Stage #2: (N-morpholin-4-yl)butan-1-one In tetrahydrofuran; hexane at -80 - 25℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: p-methoxymethoxybromobenzene With n-butyllithium In tetrahydrofuran; hexane at -80℃; for 1h; Inert atmosphere; Stage #2: 2-methyl-1-(4-morpholinyl)propan-1-one In tetrahydrofuran; hexane at -80 - 25℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; cesium pivalate In N,N-dimethyl acetamide at 140℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; cesium pivalate In N,N-dimethyl acetamide at 140℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; cesium pivalate In N,N-dimethyl acetamide at 140℃; for 24h; Inert atmosphere; |
Tags: 25458-45-1 synthesis path| 25458-45-1 SDS| 25458-45-1 COA| 25458-45-1 purity| 25458-45-1 application| 25458-45-1 NMR| 25458-45-1 COA| 25458-45-1 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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