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USD 0.00
Limited Quantity
USD 15-60
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Structure of 5460-31-1 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the Chemical Society, 1930, p. 1699,1707
[2] Patent: WO2011/69951, 2011, A1,
[3] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1441 - 1449
3
[ 603-83-8 ]
[ 5460-31-1 ]
Reference：
[1] Chemistry - A European Journal, 2009, vol. 15, # 12, p. 2742 - 2746
[2] Chemische Berichte, 1884, vol. 17, p. 1959
[3] Chemische Berichte, 1904, vol. 37, p. 1021
[4] Tetrahedron, 1968, vol. 24, p. 6093 - 6109
4
[ 95-48-7 ]
[ 5460-31-1 ]
[ 612-84-0 ]
[ 112036-07-4 ]
[ 112036-06-3 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1987, vol. 26, # 1-12, p. 272 - 273
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1987, vol. 26, # 1-12, p. 272 - 273
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1993, vol. 32, # 2, p. 266 - 274
[4] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1992, vol. 31, # 7, p. 464 - 466
[5] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1992, vol. 31, # 7, p. 464 - 466
5
[ 606-20-2 ]
[ 5460-31-1 ]
Reference：
[1] Chemische Berichte, 1904, vol. 37, p. 1021
6
[ 18102-30-2 ]
[ 5460-31-1 ]
Reference：
[1] Journal of the Chemical Society, 1915, vol. 107, p. 833
7
[ 143359-98-2 ]
[ 5460-31-1 ]
Reference：
[1] Journal of the Chemical Society, 1915, vol. 107, p. 833
8
[ 861548-37-0 ]
[ 5460-31-1 ]
Reference：
[1] Journal of the Chemical Society, 1915, vol. 107, p. 833
9
[ 861609-40-7 ]
[ 5460-31-1 ]
[ 4837-88-1 ]
Reference：
[1] Journal of the Chemical Society, 1915, vol. 107, p. 833
[2] Journal of the Chemical Society, 1915, vol. 107, p. 833
10
[ 7664-93-9 ]
[ 603-83-8 ]
[ 5460-31-1 ]
Reference：
[1] Chemische Berichte, 1884, vol. 17, p. 1959
11
[ 5460-31-1 ]
[ 74-88-4 ]
[ 4837-88-1 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2008, vol. 43, # 12, p. 2677 - 2687
[2] Heterocycles, 1981, vol. 16, # 7, p. 1119 - 1124
[3] Patent: WO2011/69951, 2011, A1, . Location in patent: Page/Page column 61
[4] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1441 - 1449
12
[ 5460-31-1 ]
[ 77-78-1 ]
[ 4837-88-1 ]
Reference：
[1] Journal of the Chemical Society, 1932, p. 1792,1795
[2] Journal of the Chemical Society, 1915, vol. 107, p. 833
[3] Helvetica Chimica Acta, 1924, vol. 7, p. 698
[4] Journal of the Chemical Society, 1930, p. 1699,1707
[5] Tetrahedron, 1968, vol. 24, p. 6093 - 6109
13
[ 861609-40-7 ]
[ 5460-31-1 ]
[ 4837-88-1 ]
Reference：
[1] Journal of the Chemical Society, 1915, vol. 107, p. 833
[2] Journal of the Chemical Society, 1915, vol. 107, p. 833
14
[ 5460-31-1 ]
[ 53967-73-0 ]
Reference：
[1] Journal of the Chemical Society, 1932, p. 1792,1795
15
[ 5460-31-1 ]
[ 53222-92-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 24 h;
A stirred mixture of 2-Methyl-3-nitrophenol 5 (2.0g, 13.1mmol) in MeOH (50mL) at room temperature was treated with 10wtpercent palladium on charcoal (100mg). Hydrogen gas was passed through the mixture for 24h, and then the palladium on charcoal was removed by filtration through Celite. The filtrate was concentrated in vacuo, and was obtained as darked solid (1.62g, 99percent). 1H NMR (CD3OD, δ=3.31ppm, 400MHz): 6.77–6.73, (t, 1H), 6.29–6.27 (d, 1H), 6.22–6.20 (d, 1H), 2.02 (s, 3H). 13C NMR (CD3OD, δ=49.00ppm, 100MHz): 156.7, 147.5, 127.2, 110.9, 108.8, 106.7, 9.2. HRMS (ESI) m/z: Anal. calcd. for [M+H]+ C7H10NO: 124.0757; found 124.0759.
99%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 24 h;
2-methyl-3-nitrophenol (2.0 g, 13.1 mmol) was dissolved in methanol (50 mL) at room temperature and then 10 wtpercent palladium on charcoal (100 mg) . The reaction mixture was stirred under hydrogen gas for 24 hours, then 10percent by weight palladium / charcoal was filtered through celite. The filtrate was concentrated in vacuo to give the desired compound (1.62 g, 99percent yield) as a solid.
Reference：
[1] Patent: US5952362, 1999, A,
[2] Patent: EP887346, 1998, A2,
[3] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 87 - 100
[4] Patent: KR2017/31307, 2017, A, . Location in patent: Paragraph 0182-0184
[5] Journal of Medicinal Chemistry, 2010, vol. 53, # 5, p. 1964 - 1978
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7170 - 7174
[7] Chemische Berichte, 1884, vol. 17, p. 1959
[8] Chemische Berichte, 1904, vol. 37, p. 1021
[9] Journal of Organic Chemistry, 1989, vol. 54, # 15, p. 3740 - 3744
[10] Chemical Communications, 2005, # 15, p. 2026 - 2028
[11] Patent: US4579951, 1986, A,
16
[ 5460-31-1 ]
[ 53600-33-2 ]
Reference：
[1] Journal of the Chemical Society, 1932, p. 1792,1795
17
[ 5460-31-1 ]
[ 100-39-0 ]
[ 20876-37-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3 h;
41.5 g (300 mmol) of potassium carbonate and 200 ml of N,N-dimethylformamide were added to 30.6 g (200 mmol) of 2-methyl-3-nitrophenol. Then, 23.8 ml (200 mmol) of benzyl bromide was added thereto in an argon stream with stirring and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into 1000 ml of water and the mixture was extracted with 800 ml of toluene and 500 ml of the same twice. The organic layer was successively washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, whereby 49.3 g of the title compound was obtained as yellow powder (yield: quantitative). Rf value: 0.48 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI, m/z): 244 (M++1) 1H-NMR spectrum (CDCl3, δppm): 2.42 (s, 3H), 5.13 (s, 2H), 7.08-7.11 (m, 1H), 7.21-7.27 (m, 1H), 7.32-7.44 (m, 6H)
87%
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 3 h;
A mixture of 2-methyl-3-nitrophenol (672 mg, 4.4 mmol), cesium carbonate (2.1 g, 6.44 mmol), and benzyl bromide (751 mg, 4.4 mmol) in DMF (6 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into ice water. The light yellow precipitation was filtered off, washed several times with water, and dried, to provide 1-nitro-2-methyl-3-[(phenylmethyl)oxy]benzene (930 mg, 87percent yield). (at)HNMR (400 MHz, d4-methanol): 8 7.47 (d, 1H), 7.45 (s, 1H), 7.40 (s, 1H), 7.39 (d, 1H), 7.37 (d, 1H), 7.34 (m, 1H), 7.32 (s, 1H), 7.29 (d, 1H), 4.90 (s, 2H), 2.35 (s, 3H).
8.6 g
With potassium carbonate In acetonitrile at 90℃; for 2 h;
To a 500-mL 3-necked round-bottom flask was placed a solution of 2-methyl-3-nitrophenol (10 g,65.30 mmol) and K2C03 (13 g,94.06 mmol) in CH3CN (100 mL) then BnBr (13 g,76.01 mmol) was added. The reaction was stirred at 90°C for 2 h,cooled to rt,filtered,and concentrated under reduced pressure. Thecrude product was purified by column chromatography eluting with EtOAc/petroleum ether (1:9) affording 8.6 g of the title compound as a yellow oil.
Reference：
[1] Patent: US2009/12123, 2009, A1, . Location in patent: Page/Page column 9-10
[2] Patent: WO2005/117909, 2005, A2, . Location in patent: Page/Page column 119
[3] Journal of the Chemical Society, 1948, p. 1605,1608
[4] Heterocycles, 1981, vol. 16, # 7, p. 1119 - 1124
[5] Patent: EP1870099, 2007, A1, . Location in patent: Page/Page column 14
[6] Patent: WO2017/62581, 2017, A1, . Location in patent: Paragraph 0209
18
[ 5460-31-1 ]
[ 100-44-7 ]
[ 20876-37-3 ]
Reference：
[1] Archiv der Pharmazie, 1988, vol. 321, # 8, p. 487 - 489
[2] Organic Syntheses, 1985, vol. 63, p. 214 - 214
[3] Tetrahedron, 1968, vol. 24, p. 6093 - 6109
Preparation of 2-methyl-3-aminophenol STR76 2-methyl-3-nitrophenol (25 g, 0.163 mol) was dissolved in 170 ml of absolute ethanol in a 1 l Parr hydrogenation flask. The flask was purged with nitrogen. 10% palladium on charcoal (1.73 g, 1.6 mmol) was added and the mixture was hydrogenated (40 psi H2) for 1.5 hr in a Parr apparatus. The flask was evacuated and purged with nitrogen. The catalyst was removed by filtration through a Whatman GF/F filter. After removal of the ethanol at reduced pressure, 20.1 g (100% yield) of 2-methyl-3-aminophenol was obtained as a lightly brown solid.
100%
palladium on charcoal; In ethanol;
1. Preparation of 2-methyl-3-aminophenol 2-methyl-3-nitrophenol (25 g, 0.163 mol) was dissolved in 170 ml of absolute ethanol in a 1l Parr hydrogenation flask. The flask was purged with nitrogen. 10% palladium on charcoal (1.73 g, 1.6 mmol) was added and the mixture was hydrogenated (40 psi H2) for 1.5 hr in a Parr apparatus. The flask was evacuated and purged with nitrogen. The catalyst was removed by filtration through a Whatman GF/F filter. After removal of the ethanol at reduced pressure, 20.1 g (100% yield) of 2-methyl-3-aminophenol was obtained as a lightly brown solid.
99%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 24h;
A stirred mixture of 2-Methyl-3-nitrophenol 5 (2.0g, 13.1mmol) in MeOH (50mL) at room temperature was treated with 10wt% palladium on charcoal (100mg). Hydrogen gas was passed through the mixture for 24h, and then the palladium on charcoal was removed by filtration through Celite. The filtrate was concentrated in vacuo, and was obtained as darked solid (1.62g, 99%). 1H NMR (CD3OD, delta=3.31ppm, 400MHz): 6.77-6.73, (t, 1H), 6.29-6.27 (d, 1H), 6.22-6.20 (d, 1H), 2.02 (s, 3H). 13C NMR (CD3OD, delta=49.00ppm, 100MHz): 156.7, 147.5, 127.2, 110.9, 108.8, 106.7, 9.2. HRMS (ESI) m/z: Anal. calcd. for [M+H]+ C7H10NO: 124.0757; found 124.0759.
99%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 24h;
2-methyl-3-nitrophenol (2.0 g, 13.1 mmol) was dissolved in methanol (50 mL) at room temperature and then 10 wt% palladium on charcoal (100 mg) . The reaction mixture was stirred under hydrogen gas for 24 hours, then 10% by weight palladium / charcoal was filtered through celite. The filtrate was concentrated in vacuo to give the desired compound (1.62 g, 99% yield) as a solid.
With hydrogen;palladium; In tetrahydrofuran; methanol;
Example 4 3-[(3,4-dihydro-2H-pyrrol-5-yl)amino]-2-methylphenol hydrochloride, Method B 2-Methyl-3-nitrophenol (70 g) in 100 ml of tetrahydrofuran and 400 ml of methanol at room temperature was hydrogenated under 5 psi of hydrogen gas using 3.5 g of 5% palladium on carbon as catalyst. After removal of catalyst by filtration, the filtrate was concentrated to give 56 g of analytically pure 3-amino-2-methylphenol.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3.0h;
41.5 g (300 mmol) of potassium carbonate and 200 ml of N,N-dimethylformamide were added to 30.6 g (200 mmol) of 2-methyl-3-nitrophenol. Then, 23.8 ml (200 mmol) of benzyl bromide was added thereto in an argon stream with stirring and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into 1000 ml of water and the mixture was extracted with 800 ml of toluene and 500 ml of the same twice. The organic layer was successively washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, whereby 49.3 g of the title compound was obtained as yellow powder (yield: quantitative). Rf value: 0.48 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI, m/z): 244 (M++1) 1H-NMR spectrum (CDCl3, deltappm): 2.42 (s, 3H), 5.13 (s, 2H), 7.08-7.11 (m, 1H), 7.21-7.27 (m, 1H), 7.32-7.44 (m, 6H)
87%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3.0h;
A mixture of 2-methyl-3-nitrophenol (672 mg, 4.4 mmol), cesium carbonate (2.1 g, 6.44 mmol), and benzyl bromide (751 mg, 4.4 mmol) in DMF (6 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into ice water. The light yellow precipitation was filtered off, washed several times with water, and dried, to provide 1-nitro-2-methyl-3-[(phenylmethyl)oxy]benzene (930 mg, 87% yield). (at)HNMR (400 MHz, d4-methanol): 8 7.47 (d, 1H), 7.45 (s, 1H), 7.40 (s, 1H), 7.39 (d, 1H), 7.37 (d, 1H), 7.34 (m, 1H), 7.32 (s, 1H), 7.29 (d, 1H), 4.90 (s, 2H), 2.35 (s, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3.0h;
(Reference Example 13) Synthesis of 2-benzyloxy-6-nitrotoluene (Reference compound 13) 41.5 g (300 mmol) of potassium carbonate and 200 ml of N,N-dimethylformamide were added to 30.6 g (200 mmol) of 2-methyl-3-nitrophenol. Then, 23.8 ml (200 mmol) of benzyl bromide was added thereto in an argon stream with stirring and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into 1000 ml of water and the mixture was extracted with 800 ml of toluene and 500 ml of the same twice. The organic layer was successively washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, whereby 49.3 g of the title compound was obtained as yellow powder (yield: quantitative). Rf value: 0.48 (n-hexane: ethyl acetate = 4: 1 (v/v)) Mass spectrum (CI, m/z): 244 (M++1) 1H-NMR spectrum (CDCl3, deltappm): 2.42 (s, 3H), 5.13 (s, 2H), 7.08-7.11 (m, 1H), 7.21-7.27 (m, 1H), 7.32-7.44 (m, 6H)
8.6 g
With potassium carbonate; In acetonitrile; at 90℃; for 2.0h;
To a 500-mL 3-necked round-bottom flask was placed a solution of 2-methyl-3-nitrophenol (10 g,65.30 mmol) and K2C03 (13 g,94.06 mmol) in CH3CN (100 mL) then BnBr (13 g,76.01 mmol) was added. The reaction was stirred at 90C for 2 h,cooled to rt,filtered,and concentrated under reduced pressure. Thecrude product was purified by column chromatography eluting with EtOAc/petroleum ether (1:9) affording 8.6 g of the title compound as a yellow oil.
Intermediate 57To a solution of 2-methyl-3-nitrophenol (15.3 g, 100 mmol) in DMF (150 mL) was added sodium hydride (60% in mineral oil, 2.6 g, 1 10 mmol) at 0C and the mixture was stirred for 30 minutes at room temperature. Methyl iodide (28.4 g, 200 mmol) was added and the mixture was heated to 80 C for 5 hours. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3 times 100 mL). The combined ethyl acetate phases were dried over sodium sulphate and concentrated under vacuum to give a residue, which was purified by column chromatography on silica gel (PE:EtOAc = 5: 1 ). Evaporation afforded the title compound as a yellow solid (14.4 g).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 14.0h;
Methyl iodide (8.13 mL, 130.6 mmol) was added dropwise to a solution of 8 (10 g, 65.29 mmol) ,and potassium carbonate (18.05 g, 130.6 mmol) in anhydrous DMF (130 mL). The reaction mixture was stirred at rt for 14 h and quenched by the addition of H2O (250 mL). The aqueous phase was extracted with EtOAc (3 × 200 mL), the combined organic layers washed with water (100 mL), saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give corresponding methyl ether as a colorless solid. Palladium on carbon (10%, 200 mg) was added to a solution of above product in EtOAc (130 mL). The suspension was stirred at rt for 6 h under a hydrogen atmosphere before it was filtered through a plug of celite and eluted with EtOAc (150 mL). The eluent was concentrated to afford 12 (8.59 g, 96% over two steps) as a colorless amorphous solid.
With aluminium trichloride In nitrobenzene 1.) 45 deg C, 1 h, 2.) 120 deg C, 16 h;
30.1%
With aluminum (III) chloride In nitrobenzene at 120℃; for 12h;
4.1 Step 1:1 -(2-Hydroxy-3-methyl-4-nitrophenyl)ethanone
10219] To a solution of 2-methyl-3-nitro-phenol (2 g,13.06 mmol, 1 eq) in nitrobenzene (30 mE) was added A1C13 (2.09 g, 15.67 mmol, 1.2 eq) and acetyl chloride (1.33 g, 16.98 mmol, 1.21 mE, 1.3 eq). The mixture was stirred at120° C. for 12 h. The reaction mixture was quenched by addition 1 N NaOH (80 mE) then filtered. The filtrate was extracted with ethyl acetate (50 mEx3). The combined aqueous layers were acidified with con. HC1 to adjusted to pH=3-4, extracted with DCM (50 mEx3). The combined organic layers were dried over anhydrous Na2504, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO; 24 g SepaFlash Silica Flash Column, Eluent of 8-10% Ethyl acetate/Petroleum ether gradient 50 mE/mm) to give 1 -(2-hydroxy-3-methyl-4-nitro-phenyl) ethanone (800 mg, 3.93 mmol, 30.1% yield, 96% purity) as yellow oil. ‘H NMR (400 MHz, DMSO) ö ppm 12.84 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 2.71 (s, 3H), 2.23 (s, 3H); ES-ECMS mlz 196.1 [M+H].
With hydrogenchloride; sodium chloride In dichloromethane; nitrobenzene
1 2-(Benzylamino-methyl)-3,4,7,9-tetrahydro-2H-pyrano-[2,3-e]indol-8-one
EXAMPLE 1 2-(Benzylamino-methyl)-3,4,7,9-tetrahydro-2H-pyrano-[2,3-e]indol-8-one To a 5L round-bottom flask equipped with a mechanical stirrer, nitrogen inlet and temperature controlled heating mantle was added 2-methyl -3-nitrophenol (210 g, 1.37 mol), nitrobenzene (1680 mL), and acetyl chloride (127 mL, 1.79 mol). The reaction mixture was warmed up to 45 °C and a small amount of aluminum chloride was added and the reaction was stirred at 45 °C for 1 hour. After another portion of aluminum chloride (183 g, 1.37 mol) was added, the temperature rose to 60 °C and the reaction mixture was slowly heated to 120 °C and stirred for 16 hours. The reaction mixture was cooled in an ice bath to 15°C and a saturated aqueous solution of sodium chloride (2 L) was added slowly, keeping the temperature below 25 °C. The organic layer separated and was diluted with toluene, filtered over Solka Floc to remove tar impurities, and washed with water. More tar impurties precipitated and the mixture was again filtered over Solka Floc. The organic layer was separated and washed with 0.5 N sodium hydroxide (4 x 1L). The combined aqueous layers were filtered over Solka Floc, and acidified by slow addition of concentrated hydrochloric acid (240 ml). The product was extracted in methylene chloride, dried with MgSO4, charcoalized, and the solvent was removed to afford 193 g of 2-hydroxy-3-methyl-4-nitro-acetophenone as a thick oil which solidified upon standing: mp 40-41 °C.
Stage #1: 3-nitro-o-cresol; tert-butyldimethylsilyl chloride In tetrahydrofuran at 20℃;
Stage #2: With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3h; Irradiation using a sun lamp;
4b
Step b: To a solution of 2-methyl-3-nitrophenol (10.0 g, 65.3 [MMOL)] in THF (300 mL) were added imidazole (5.8 g, 85 [MMOL)] and [TERT-BUTYLDIMETHYLSILYL] chloride (10.8 g, 71.8 [MMOL).] The reaction mixture was stirred at room temperature overnight. The mixture was diluted in EtOAc and washed successively with water and brine, dried [(MGS04),] filtered and concentrated under reduced pressure. The residue was filtered through a thin pad of silica gel [(HEXANE/ET2O).] The resulting yellow oil (13.3 g) was dissolved in CCI4, AIBN (350 mg) and NBS (10.2 g, 57.3 [MMOL)] was added. The reaction mixture was irradiated using a sun lamp (275 W) for 3 h, diluted in [ET2O,] filtered through a thin pad of silica gel, concentrated to dryness. The residue was purified by flash chromatography (hexane/EtOAc, 9/1) to give 4b (15 g, 66% yield over 2 steps).
66%
Stage #1: 3-nitro-o-cresol; tert-butyldimethylsilyl chloride With 1H-imidazole In tetrahydrofuran at 20℃; for 12h;
Stage #2: With N-Bromosuccinimide In tetrachloromethane for 3h; UV-irradiation;
A solution of 5a (10.0 g, 65.3 mmol), imidazole (5.8 g, 85 mmol) and tert-butyldimethylsilyl chloride (10.8 g, 71.8 mmol) in THF (300 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc and was washed successively with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was filtered through a thin pad of silica gel (hexane/Et2O). A solution of the resulting yellow oil (13.3 g), AlBN (350 mg, 2.13 mmol) and NBS (10.2 g, 57.3 mmol) in CCl4 (250 mL) was irradiated using a sun lamp (275 W) for 3 h. The reaction mixture was diluted with Et2O, filtered through a thin pad of silica gel and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc, 9/1) to give the bromide 5b (15 g, 66% yield).
With 1H-imidazole In dichloromethane at 20℃; for 3h; Inert atmosphere;
76%
With 1H-imidazole In tetrahydrofuran at 20℃; for 16h;
A solution of phenol 10a (10.0 g, 65.3 mmol), imidazole (5.78 g, 84.9 mmol) and tert-butyldimethylsilyl chloride (10.8 g, 71.6 mmol) in THF (300 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with Et2O and the solution was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/Et2O, 4/1) to give 10b (13.3 g, 76% yield) as an oil.
With 1H-imidazole In dichloromethane; N,N-dimethyl-formamide at 20℃;
1
Step 1:; To a solution of the 2-methyl-3-nitrophenol 16a (5.00 g, 32.6 mmol) in DCM (60 mL) and DMF (15 mL) is added imidazole (4.45 g, 65.3 mmol) followed by tert- butyldimethylchlorosilane (6.40 g, 42.4 mmol) slowly. The solution is left to stir at RT for the night. DCM is removed under vaccum. The solution is taken up in EtOAc, washed with 0.1 N HCI, sat NaHC03 and brine (2x). The organic phase is dried over MgS04, filtered and concentrated. The crude material is purified by combiflash (80 g column starting with 1 % EtOAc/hexane to 10% over 20 min) to afford 16b.
With 1H-imidazole In dichloromethane; N,N-dimethyl-formamide at 20℃;
1
Step 1:; To a solution of the 2-methyl-3-nitrophenol 16a (5.00 g, 32.6 mmol) in DCM (60 mL) and DMF (15 mL) is added imidazole (4.45 g, 65.3 mmol) followed by tert- butyldimethylchlorosilane (6.40 g, 42.4 mmol) slowly. The solution is left to stir at room temperature for the night. DCM is removed under vaccum. The solution is taken up in EtOAc, washed with 0.1 N HCI, saturated NaHC03 and brine (2x). The organic phase is dried over MgS04, filtered and concentrated. The crude is purified by combiflash with 80 g column starting with 1 % EtOAc/hexane to 10% over 20 minutes to afford 16b.
With caesium carbonate In acetonitrile at 20 - 60℃; for 18h;
78%
With caesium carbonate In acetonitrile at 20 - 70℃; for 19h;
1 Preparation of compound 1b : 5-METHYL-4- [2- (2-METHYL-3-NITROPHENOXY) ETHYL]-2-PHENYL- 1, 3-oxazol
To a solution of tosylate 1a (5.21 g, 14.6 MMOL) in acetonitrile (100 mL) at room temperature was added 3-methyl-2-nitrophenol (3.35 g, 21.9 MMOL) and then CS2CO3 (7.13 g, 21.9 MMOL). After 3 hour stirring at 70 C and an additional 16 hour at 60 C, the acetonitrile was removed under vacuum and the resulting residue was partitioned between ethyl acetate and H2O. The organic layer was washed with 1 N NAOH (x4), concentrated, and the crude residue was purified on silica gel eluting with a linear gradient elution of 0% to 30% ethyl acetate in hexanes to give the title compound as a pale yellow solid (3.83 g, 78%). 1H NMR (CDCI3) 6 : 7. 99-7. 96 (2H, m), 7.46-7. 36 (4H, m), 7.23 (1H, t, J = 7.8 Hz), 7.06 (1 H, d, J = 8. 1 Hz), 4.30 (2H, D, J = 6.3 Hz), 3.03 (2H, t, J = 6.6), 2.39 (3H, s), 2.33 (3H, s). HRMS calculated for C19H19N2O4 339.1340 (M+H) +, found 339.1352. Anal. Calcd. For C19H18N2O) : C, 67. 45; H, 5.36 ; N 8.28. Found: C, 67.20 ; H, 5.36 ; N 8. 27.
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 95℃; for 72h;
32 Preparation of compound 32a: methyl 2-METHYL-2- (2-METHYL-3-NITROPHENOXY) propanoate
To a solution OF 2-METHYL-3-NITROPHENOL (300 mg, 2 MMOL) in DMF (6 mL) were added potassium carbonate (0.55 g, 2 equiv) and methyl 2-bromo-2-methyl-proprionate (0.31 mL, 1.2 equiv). The resulting mixture was heated at 95 C for 3 days. After cooling to 23 C, the mixture was poured into water and extracted with ethyl acetate (3X20 mL). The combined organics were washed with water and saturated sodium chloride, dried over sodium sulfate and evaporated. The residue was purified by silica gel purification using 0-15% ethyl acetate in hexane to give the title compound (367 mg, 75%). LRMS (M/Z) 254 (M+H) +
39%
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 96h;
103A
.00 g (13.06 mmol) of 2-methyl-3-nitrophenol were dissolved in 40 ml of DMF, and 3.55 g (19.59 mmol) of methyl 2-bromo-2-methylpropanoate and 4.68 g (14.37 mmol) of cesium carbonate were added. The reaction mixture was stirred at 100° C. for 2 d, and a further 1.77 g (9.80 mmol) of methyl 2-bromo-2-methylpropanoate were then added. The mixture was stirred at 100° C. for another 1 d, a further 1.77 g (9.80 mmol) of methyl 2-bromo-2-methylpropanoate were then added and the mixture was stirred at 100° C. for another 1 d. After cooling, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted repeatedly with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC. This gave 1.33 g (39% of theory) of the target compound.1H-NMR (300 MHz, CDCl3, δ/ppm): 1.58 (s, 6H), 2.27 (s, 3H), 3.75 (s, 3H), 6.95 (d, 1H), 7.35 (t, 1H), 7.60 (d, 1H).
With boron trifluoride diethyl etherate In tetrahydrofuran; cyclohexane at 18 - 22℃; for 20h;
3K.1 EXAMPLE 3K; Synthesis of 7-tert-butyloxy-2-carbomethoxy-4-hydroxy-8-methylquinoline (K6); Step1:
To a solution of 2-methyl-3-nitrophenol K1 (1. 1 g; 7.18 MMOL) in THF (13 mL) was added cyclohexane (27 mL; a solution was maintained). TEFF-BUTYL TRICHLOROACETIMIDATE K2 (5.36 mL; 28. 73 MMOL) was added followed by a catalytic amount of boron TRIFLUORIDE etherate (143. 8 UL ; 1.14 MMO .) and the reaction was stirred at room temperature for 15 h. The reaction was incomplete (by analytical HPLC) and an additional amount OF FEFF-BUTYL TRICHLOROACETIMIDATE (1.4 mL; 7.51 MMOL) was added (reaction remains in solution). The reaction was complete after stirring at room temperature for 5 h. Solid sodium bicarbonate was added, and the mixture was filtered, rinsed with dichlormethane and evaporated to dryness to provide a white solid. The solid was triturated with dichloromethane, the white solid filtered and discarded (= trichloroacetimide). The filtrate was concentrated and loaded onto a flash column for purification (hexane: EtOAc 9: 1) to provide the pure 2-methyl-3-tert-butoxynitrobenzene K3 (1.17 g; 78%). Homogeneity by HPLC (TFA) 220nm: 96%
a.a
a) 4.5 g (26.38 mmol) 8 and 6.0 g (39.18 mmol) 2-methyl-3-nitrophenole are stirred together for 2 d at 150 °C. After customary workup, 4.7 g (61 %) 18, (Rt. = 2.84 min (method C) ) is obtained as a brown, resinous residue
(S)-(-)-1-tert-butoxycarbonyl)-2-pyrrolidinemethanol[ No CAS ]
[ 5460-31-1 ]
[ 1972-28-7 ]
[ 474000-39-0 ]
Yield
Reaction Conditions
Operation in experiment
91%
With triphenylphosphine In tetrahydrofuran
12 Preparation of t-Butyl (2S)-2-[(2-methyl-3-nitrophenoxy)methyl]pyrrolidine-1-carboxylate
EXAMPLE 12 Preparation of t-Butyl (2S)-2-[(2-methyl-3-nitrophenoxy)methyl]pyrrolidine-1-carboxylate A stirred solution of 2-methyl-3-nitrophenol (3.80 g, 24.84 mmol), (S)-(-)-1-tert-butoxycarbonyl)-2-pyrrolidinemethanol (5.0 g, 24.8 mmol) and triphenylphosphine (6.5 g, 24.8 mmol) in THF is treated with diethylazodicarboxylate (4.3 g, 24.8 mmol), stirred for 3 h at room temperature and concentrated in vacuo. The resultant residue is mixed with ether, stored at 0° C. overnight and filtered. The filtrate is concentrated in vacuo to give a residue which is purified by chromatography (silica gel, EtOAc:hexanes, 20:80) to afford the title compound as a light yellow semisolid, 7.73 g, (91% yield), identified by NMR and mass spectral analyses.
With N-chloro-succinimide; sulfuric acid; sodium sulfate; sodium nitrite; In water; acetonitrile;
4. Preparation of 4-chloro-2-methyl-3-nitrophenol A slurry of 4-chloro-2-methyl-3-nitroaniline (20.9 g), water (200 mL), and fluroboric acid (86 mL) was heated to boiling until almost complete solution took place, then cooled to 0-5 C. A solution of sodium nitrite (8.11 g) in water (20 mL) was then added dropwise to the above mixture, and then the mixture was stirred in the cold for an additional 30 min. The precipitated diazonium salt was filterd off and washed with a little cold water. The wet diazonium salt was added all at once to a hot (100-120 C.) solution of water (230 mL), concentrated sulfuric acid (115 mL), and sodium sulfate (35 g), and allowed to stir for 4 hr. The reaction mixture was cooled to room temperature and extracted with ethyl ether (700 mL in two portions). The combined ether extracts were washed with saturated sodium chloride solution, then dried over magnesium sulfate. Evaporation afforded crude product (17.5 g), which was purified by flash chromatography on silica, eluding with methylene chloride to afford 7.6 g as a yellow solid. The phenol was also prepared by the NCS chlorination of 2-methyl-3-nitrophenol, in a manner similar to that described in Oberhauser, J. Org. Chem. (1997) 62:4504-4506, as follows. STR72 2-Methyl-3-nitrophenol (25.5 g), N-chlorosuccinimide (44.5 g), and trifluormethanesulfonic acid (50.0 g) were combined in dry acetonitrile (500 mL) and allowed to stir under an atmosphere of nitrogen at 75 C. for 1.5 hr. The reaction mixture was cooled to room temperature, diluted with ethyl ether (650 mL), washed with water, 10% sodium bisulfite solution, water, and finally saturated sodium chloride solution. Evaporation of the solvent afforded a crude material which was flash chromatographed on silica and eluted with acetone:hexane (1:9) to afford 16.8 g as a yellow solid.
With N-chloro-succinimide; sulfuric acid; sodium sulfate; sodium nitrite; In water; acetonitrile;
4. Preparation of 4-chloro-2-methyl-3-nitrophenol A slurry of 4-chloro-2-methyl-3-nitroaniline (20.9 g), water (200 mL), and fluroboric acid (86 mL) was heated to boiling until almost complete solution took place, then cooled to 0-5C. A solution of sodium nitrite (8.11 g) in water (20 mL) was then added dropwise to the above mixture, and then the mixture was stirred in the cold for an additional 30 min. The precipitated diazonium salt was filterd off and washed with a little cold water. The wet diazonium salt was added all at once to a hot (100-120C) solution of water (230 mL), concentrated sulfuric acid (115 mL), and sodium sulfate (35 g), and allowed to stir for 4 hr. The reaction mixture was cooled to room temperature and extracted with ethyl ether (700 mL in two portions). The combined ether extracts were washed with saturated sodium chloride solution, then dried over magnesium sulfate. Evaporation afforded crude product (17.5 g), which was purified by flash chromatography on silica, eluding with methylene chloride to afford 7.6 g as a yellow solid. The phenol was also prepared by the NCS chlorination of 2-methyl-3-nitrophenol, in a manner similar to that described in Oberhauser, J. Org. Chem . (1997) 62 :4504-4506, as follows. 2-Methyl-3-nitrophenol (25.5 g), N-chlorosuccinimide (44.5 g), and trifluormethanesulfonic acid (50.0 g) were combined in dry acetonitrile (500 mL) and allowed to stir under an atmosphere of nitrogen at 75 C for 1.5 hr. The reaction mixture was cooled to room temperature, diluted with ethyl ether (650 mL), washed with water, 10% sodium bisulfite solution, water, and finally saturated sodium chloride solution. Evaporation of the solvent afforded a crude material which was flash chromatographed on silica and eluted with acetone:hexane (1:9) to afford 16.8 g as a yellow solid.
trans-6-benzyloxy-2-nitro-β-pyrrolindino -styrene[ No CAS ]
[ 5460-31-1 ]
[ 5585-96-6 ]
Yield
Reaction Conditions
Operation in experiment
69%
With 2-(Dimethylamino)pyridine; acetic anhydride; triethylamine;palladium-carbon; In ethyl acetate;
EXAMPLE 2 Synthesis of 4-acetoxyindole A suspension of 3.24 g of trans-6-benzyloxy-2-nitro-beta-pyrrolindino -styrene (prepared from 2-methyl-3-nitrophenol by a procedure reported in Organic Synthesis, Coll. Vol. 7, 34, 1990) and 648 mg of 10% pd/C catalyst in 30 ml of ethyl acetate was shaken under hydrogen atmosphere and at 50 psi, for 5 hours. To this reaction mixture were added acetic anhydride (1.4 ml), triethylamine (2.1 ml) and dimethylaminopyridine (324 mg). The resultant mixture was stirred for 1 hour at room temperature. The catalyst was removed over a layer of Celite and the filtrate was evaporated under reduced pressure to give an oily residue to which crushed ice was added. The resulting white precipitate was collected by filtration to give 1.2 g (69% yield) of 4-acetoxyindole: mp 97-98 C.; H-NMR (300 MHz, DMSO-d6)delta 2.32 (s,3H), 6.31 (s,1H), 6.71 (d,1H,J=8Hz), 7.05 (t, 1H, J=8 Hz), 7.28 (d,1H,J=8Hz), 7.32 (s,1H), 11.27 (s,1H).
With potassium carbonate In <i>N</i>-methyl-acetamide; water
1 3-(phenylmethoxy)-2-methylaniline STR6
Example 1 3-(phenylmethoxy)-2-methylaniline STR6 A mixture of 100 g of 2-methyl-3-nitrophenol, 113 g of benzyl bromide, and 100 g of potassium carbonate in 500 ml of dimethylformamide was stirred for three days at room temperature and then poured into 1500 ml of water. A solid was collected, washed with 5% aqueous sodium hydroxide and then water, and recrystallized from methanol, giving 156 g of the O-benzyl ether intermediate. Structure assignment of the intermediate was supported by the nmr spectrum (CDCl3): δ (ppm) 2.40 (s, 3H, phenyl CH3); 5.10 (s, 2H, benzyl CH2); 6.9-7.6 (m's, 8H, aromatic CH's).
Multi-step reaction with 2 steps
1: potassium carbonate / acetonitrile / 2 h / 90 °C
2: hydrogen / methanol / 16 h / 20 °C
2-methoxy-6-nitrophenylacetaldehyde semicarbazone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41.08 g (81.5%)
With hydrogenchloride In <i>N</i>-methyl-acetamide; hexane; water
1 EXAMPLE 1
EXAMPLE 1 A 1 liter flask equipped with reflux condenser and magnetic stirrer was flushed with argon and charged with 50% sodium hydride dispersion (9.6 g, 0.2 m). The dispersion was washed with two 100 ml portions of hexane, then suspended in dry dimethylformamide (100 ml) during the slow (foaming-) addition of 2-methyl-3-nitrophenol (30.62 g, 0.2 m). The red solution was cooled, and iodomethane (18.6 ml, 0.3 mole) was added rapidly. The solution was heated at 90° in an oil bath for 20 minutes. Tris(dimethylamino)methane (43.5 g, 0.3 m) was added followed by further heating at 115° for 3 hours. The mixture was cooled and a solution of semicarbazide hydrochloride (23.4 g, 0.21 m) and concentrated hydrochloric acid (18 ml, 0.22 m) in water (250 ml) was added. The tan mixture was cooled and filtered. The recovered precipitate was washed sequentially with water (500 ml), ice-cold ethanol (150 ml), and ether (250 ml), then dried to give 41.08 g (81.5%) of 2-methoxy-6-nitrophenylacetaldehyde semicarbazone as tan crystals, mp 205°-7°(d); mass spec. m/e 252 (M+).
21 3-[1-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)ethoxy]-2-methylbenzenamine hydrochloride STR27
EXAMPLE 21 3-[1-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)ethoxy]-2-methylbenzenamine hydrochloride STR27 A mixture of p-toluenesulfonic acid, dried by azeotroping the hydrate (0.1 mole) with benzene, N-methylethylenediamine (0.1 mole), and ethyl 2-(2-methyl-3-nitrophenoxy)propanoate (0.05 mole, prepared by the method of Example 1 using 2-methyl-3-nitrophenol) is heated to 240° to remove volatiles. After one hour at 230° the mixture is allowed to cool and then partitioned between 5% aqueous sodium hydroxide and diethyl ether. The organic layer is washed with two portions of water, dried over magnesium sulfate, concentrated to dryness, and purified by column chromatography on silica gel. The intermediate nitro compound is then converted to the title compound by the method of Example 3.
With potassium carbonate In <i>N</i>-methyl-acetamide
1 ethyl 2-(2-methyl-3-nitrophenoxy)butanoate STR7
EXAMPLE 1 ethyl 2-(2-methyl-3-nitrophenoxy)butanoate STR7 A mixture of 5.0 g (32 mmole) of 2-methyl-3-nitrophenol, 4.8 ml (ca. 32 mmole) of ethyl 2-bromobutanoate, and 4.5 g (32 mmole) of potassium carbonate in 50 ml of dimethylformamide was stirred for 18 hours at room temperature. The mixture was then poured over ice, diluted with water, and extracted twice with diethyl ether. The combined organic extract was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 8.0 g of the title compound as an analytically pure solid. Structure assignment was supported by nmr and infrared spectra and by elemental analysis. nmr (CDCl3): δ(ppm) 1.0-1.4 (m's, 6H, ethyl and propylidene CH3 's); 1.85-2.35 (m, 2H, propylidene CH2); 2.45 (s, 3H, phenyl CH3); 4.25 (q, 2H, ethyl CH2); 4.68 (t, 1H, propylidene CH); 6.8-7.6 (m, 3H, phenyl CH's) IR (KBr): 1750 cm-1 Analysis. Calcd. for C13 H17 NO5: C, 58.42; H, 6.41; N, 5.24. Found: C, 58.44; H, 6.41; N, 5.27.
With copper diacetate; triethylamine In dichloromethane at 23℃; for 76h; Molecular sieve;
20.1
Step 1 2-Methyl-3-nitrophenol (4.6 g, 30 mmol), phenylboronic acid (7.3 g, 60 mmol), copper (II) acetate (5.5 g, 30 mmol) and 4 A powdered molecular sieves (30 g, dried at 200° C.) were combined in dry dichloromethane (300 mL) at 23° C. Triethylamine (d 0.726, 21 mL, 150 mmol) was added and the mixture was stirred vigorously at 23° C. After 24 hours, additional phenylboronic acid (7.3 g, 60 mmol) was added. After 28 hours. (total), additional copper (II) acetate (2.3 g, 13 mmol) was added. After 48 hours, the mixture was filtered (Celite) and washed with dichloromethane. The filtrate was washed with saturated aqueous EDTA (disodium salt) solution (4*300 mL) and brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a tacky brown solid (6.9 g) that was dissolved in dichloromethane and pre-adsorbed on silica gel (15 g). Purification by flash column chromatography (silica 135 g, 1%, 2%, 5%, 10%, 20%, 40% ethyl acetate/hexanes) provided 2-methyl-1-nitro-3-phenoxybenzene (2.9 g, 91% based on recovered 2-methyl-3-nitrophenol) as a clear, light yellow oil. MS (EI) m/z 229 [M+].
With potassium carbonate In water; butan-1-ol at 80℃; for 13h;
19.A
To a slurry containing 5.0 g (33 mmol) of 2-methyl-3-nitrophenol, 9.4 g (65.2 mmol) of (2-chloroethyl)dimethylamine hydrochloride, 9.0 g (65.3 mmol) of K2CO3, and 100 mL of H2O was added 100 mL of butanol and the reaction mixture was heated at 80° C. for 13 h. The reaction mixture was extracted with EtOAc and the combined organic layers were dried over MgSO4 and filtered. The solvents were removed under reduced pressure and the residue was subjected to silica gel chromatography to give 7.4 g (100%) of dimethyl{2-[(2-methyl-3-nitrophenyl)oxy]ethyl}amine as a brown oil. 1HNMR (400 MHz, DMSO-d6) δ 7.29-7.42 (m, 3H), 4.11 (t, J=5.6 Hz, 2H), 2.66 (t, J=5.6 Hz, 2H), 2.22 (s, 3H), 2.20 (s, 6H). MS (ESI+) m/z 225 [M+H].
Stage #1: 3-nitro-o-cresol In methanol at 20℃;
Stage #2: acetic anhydride With pyridine In ethyl acetate for 2h; Heating / reflux;
320.a Example 320; Synthesis of 4-(piperidin-4-yloxy)-1H-indazole; (a) Synthesis of 3-(acetylamino)-2-methylphenyl acetate
Under a nitrogen atmosphere, 10% Pd-C (1.0 g) was added to a solution of 3-nitro-o-cresol (10.0 g, 65.3 mmol) in methanol (200 ml) at room temperature, and catalytic reduction was carried out at ordinary temperature and atmospheric pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, followed by adding thereto acetic anhydride (10.0 ml, 170 mmol) and pyridine (10.6 ml, 131 mmol), and the resulting mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was concentrated and hexane was added thereto. The resulting suspension was filtered and the precipitate was dried under reduced pressure to obtain 3-(acetylamino)-2-methylphenyl acetate (12.7 g, 94%).1H-NMR (DMSO-d6) δ; 1.96 (3H, s), 2.04 (3H, s), 2.29 (3H, s), 6.89 (1H, d, J=8.0Hz), 7.16 (1H, dd, J=8.0, 8.0Hz), 7.28 (1H, d, J=8.0Hz), 9.39 (1H, s).
Stage #1: 3-nitro-o-cresol With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.5h;
Stage #2: N-(2-chlorethyl)morpholine With sodium iodide In N,N-dimethyl-formamide; mineral oil at 60℃;
65.i
(i) Sodium hydride (0.44 g, 1 1.00 mmol, 60% dispersion in mineral oil) was added to a solution of 2-methyl-3-nitrophenol (0.77 g, 5.0 mmol) in N,N-dimethylformamide (10 ml) and stirred for 30 minutes. 4-(2-chloroethyl)morpholine (0.82 g, 5.5 mmol) and a catalytic amount of sodium iodide were then added and the reaction mixture stirred overnight at 600C. The reaction mixture was then partitioned between ethyl acetate and water. The aqueous layer was back extracted with three portions of ethyl acetate. The organic phases were combined and washed with three portions of water, brine and then dried over anhydrous magnesium sulphate. The mixture was filtered and concentrated in vacuo. The residue was then partitioned between ethyl acetate (100 ml) and 2 Molar sodium hydroxide (100 ml). The aqueous layer was back extracted with two portions of ethyl acetate and organic phases combined. These were then washed with two portions of water, brine and then dried over anhydrous magnesium sulphate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash-silica gel chromatography, eluting with a 0- 20% gradient of 2 Molar ammonia in methanol solution in dichloromethane. The clean fractions were concentrated in vacuo to afford 4-{2-[(2-methyl-3- nitrophenyl)oxy]ethyl}morpholine (0.93 g) as a yellow gum.
With potassium carbonate In acetonitrile at 120℃; for 0.05h; Microwave irradiation;
5.i
A mixture of 2-methyl-5-nitrophenol (1.53 g, 10 mmol), methyl bromoacetate (1.0 mL, 10.5 mmol) and potassium carbonate (1.9 g, 13.8 mmol) in acetonitrile (10 mL) was heated under microwave irradiation for 3 min at 1200C. The mixture was concentrated in vacuo, stirred with 0.1M aqueous sodium hydroxide (50 mL) for 5 min then extracted with DCM (50 mL). The organic layer was washed with water and brine, filtered through a PTFE membrane, then concentrated in vacuo to afford methyl 2- (2-methyl-3-nitrophenoxy) acetate as yellow needles (2.02 g, 90%). LCMS method A, (ES+) 226, RT = 2.76 min.
With triethylamine; In tetrahydrofuran; at 0℃;Inert atmosphere;
General procedure: 5-methyl-2-nitro phenol (0.14g, 0.91mmol) was dissolved in dry THF (10mL). <strong>[1498-51-7]Ethyl dichlorophosphate</strong> (0.11mL, 0.91mmol) was slowly added to the THF solution, followed by triethylamine (0.15mL, 1.10mmol). The reaction mixture was stirred under an atmosphere of nitrogen at 0C for 7 hours. The reaction was monitored by TLC (mobile phase petroleum ether/ethylacetate 5:1). Upon completion of the reaction as judged by TLC, the intermediate phosphorochloridates were reacted in situ with an appropriate amine as follows: To the reaction flask containing the phosphorochloridate, was added a further 10mL of THF. Isopropylamine (0.08mL, 0.91mmol) was injected into the flask along with triethylamine (0.15mL (1.10mmol). The reaction was stirred under an atmosphere of nitrogen at room temperature for 8 hours. The reaction was monitored by TLC (mobile phase petroleum ether/ethylacetate 5:1). Upon completion of the reaction as judged by TLC, the reaction mixture was filtered, the solvent removed in vacuo and the residue purified by flash column chromatography on silica gel (eluant: petroleum ether:ethyl acetate) to yield phosphoramidates (8-50). An analogous procedure was followed for phosphorothioamidates except the solvent used for the reaction was toluene.
With potassium carbonate In acetone for 10h; Reflux;
39.9 g
With potassium carbonate In acetone for 10h; Reflux;
25 Reference Preparation example 25
Reference Preparation example 25A mixture of 2-methyl-3-nitrophenol 33.5 g,iodoethane 41 g and potassium carbonate 90 g in acetone 400 mL was stirred with heating under ref lux for ten hours. The mixtures were cooled to room temperature and filteredand the resulting filtrates were concentrated. The resulting mixtures were extracted with ethyl acettae and the organic layers were washed with water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated uder reduced pressure. Theresulting residues were subjected to a silica gel column chromatography to give l-ethoxy-2--methyl-3-nitrobenzene 39.9 g.‘H NMR (CDC13) (ppm) : 7.39(1H, dd, J=8.2, 1.0Hz), 7.24(1H, t, J=8.3Hz), 7.02(1H, d, J=8.2Hz) , 4.0S(2H, q, J=7.OHz), 2.37(3H, 5), l.50-1.42(3H, m).
39.9 g
With potassium carbonate In acetone for 10h; Reflux;
13.1 Reference Production Example 13 Step (1)
Reference Production Example 13 Step (1) A mixture of 33.5 g of 2-methyl-3-nitrophenol, 41 g of iodoethane, 90 g of potassium carbonate, and 400 mL of acetone was stirred while heating under reflux for 10 hours. The mixture was cooled to room temperature and filtered, and the filtrate was concentrated. After extraction with ethyl acetate, the organic layer was washed in turn with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 39.9 g of 1-ethoxy-2-methyl-3-nitrobenzene. 1H-NMR (CDCl3) δ(ppm): 7.39 (1H, dd, J= 8.2, 1.0 Hz), 7.24 (1H, t, J = 8.3 Hz), 7.02 (1H, d, J = 8.2 Hz), 4.08 (2H, q, J= 7.0 Hz), 2.37 (3H, s), 1.50-1.42 (3H, m).
39.9 g
With potassium carbonate In acetone for 10h; Reflux;
13.1
A mixture of 33.5 g of 2-methyl-3-nitrophenol, 41 g of iodoethane, 90 g of potassium carbonate, and 400 mL of acetone was refluxed under heating with stirring for 10 hr. The mixture was cooled to ambient temperature, and filtered, and the filtrate was concentrated. The concentrated filtrate was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried by magnesium sulfate anhydride, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chrpmatography to obtain 39.9 g of 1-ethoxy-2-methyl-3-nitrobenzene. (0794) 1-ethoxy-2-methyl-3-nitrobenzene 1H-NMR (CDCl3) δ: 7.39 (1H, dd, J = 8.2, 1.0 Hz), 7.24 (1H, t, J = 8.3 Hz), 7.02 (1H, d, J = 8.2 Hz), 4.08 (2H, q, J = 7.0 Hz), 2.37 (3H, s), 1.50-1.42 (3H, m).
39.9 g
With potassium carbonate In acetone for 10h; Reflux;
46 Reference Production Example 46
Reference Production Example 46 (1400) A mixture of 33.5 g of 2-methyl-3-nitrophenol, 41 g of iodoethane, 90 g of potassium carbonate, and 400 ml of acetone was stirred with heating under reflux for 10 hours. The mixture was cooled to room temperature and filtered, and the filtrate was concentrated and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 39.9 g of 1-ethoxy-2-methyl-3-nitrobenzene (referred to as CA46). (1401) 1H-NMR (CDCl3) δ (ppm): 7.39 (1H, dd, J=8.2, 1.0 Hz), 7.24 (1H, t, J=8.3 Hz), 7.02 (1H, d, J=8.2 Hz), 4.08 (2H, q, J=7.0 Hz), 2.37 (3H, s), 1.50-1.42 (3H, m).
1-(difluoromethoxy)-2-methyl-3-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7.5 g
With potassium carbonate In acetonitrile at 20℃; for 24h;
7.5 g
With potassium hydroxide In water; acetonitrile at 20℃; for 24h;
16.1 Reference Production Example 16 Step (1)
Reference Production Example 16 Step (1) A mixture of 7.17 g of 2-methyl-3-nitrophenol, 27 g of potassium hydroxide, 25 g of bromodifluoromethyl-diethylphosphonate, 100 mL of water, and 100 mL of acetonitrile was stirred at room temperature for 24 hours. After extraction with ethyl acetate, the organic layer was washed in turn with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 7.50 g of 1-difluoromethoxy-2-methyl-3-nitrobenzene. 1H-NMR (CDCl3) δ(ppm): 7.74 (1H, dd, J = 7.6, 1.8 Hz), 7.40-7.32 (2H, m), 6.56 (1H, t, J = 72.4 Hz), 2.46 (3H, s).
7.50 g
With potassium hydroxide In water; acetonitrile at 20℃; for 24h;
16.1
A mixture of 7.17 g of 2-methyl-3-nitrophenol, 27 g of potassium hydroxide, 25 g of bromodifluoromethyl-diethylphosphonate, 100 mL of water, and 100 mL of acetanilile was stirred at ambient temperature for 24 hr. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried by magnesium sulfate anhydride, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 7.50 g of 1-difluoromethoxy-2-methyl-3-nitrobenzene. (0819) 1-difluoromethoxy-2-methyl-3-nitrobenzene 1H-NMR (CDCl3) δ: 7.74 (1H, dd, J = 7.6, 1.8 Hz), 7.40-7.32 (2H, m), 6.56 (1H, t, J = 72.4 Hz), 2.46 (3H, s).
1-(difluoromethoxy)-2-methyl-3-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate In water-d2; N,N-dimethyl-formamide at 110℃; for 19h;
5d.1d
Step 1d: A solution of 10 g of 2-methyl-3-nitrophenol in 20 ml of N,N-dimethylformamide is added to a mixture of 23.4 g of sodium chlorodifluoroacetate and 22 g of potassium carbonate in 30 ml of N,N-dimethylformamide and 6 ml of water. The reaction mixture is then heated at 110° C. for 3 hours and left to stand for 16 hours, and then treated with a mixture of water and ethyl acetate. The organic phase is washed with 1N sodium hydroxide, water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give the expected product in the form of a brown oil, used as it is in the next step.
With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 20℃;
6.1 Step 6.1 : Methyl (2-methyl-3-nitrophenoxy)acetate
To a solution of 2.0 g 2-methyl-3-nitrophenol in 12 ml DMF, 3.61 g K2C03, 7.24 g TBAI and 1.72 ml methyl chloroacetat were added and stirred until complete conversion at RT. The reaction mixture was quenched with water, extracted with EE, the combined organic layers washed with brine, dried with Na2S04, filtered and evaporated to dryness. The resulting material was purified by chromatography using silica gel (gradient: hexane/EE). Yield: 2.09 g. 1H NMR (400 MHz, DMSO-de) δ ppm 2.30 (s, 3 H) 3.71 (s, 3 H) 4.96 (s, 2 H) 7.27 (s, 1 H) 7.38 (s, 1 H) 7.48 (d, J=0.76 Hz, 1 H).
Stage #1: 3-nitro-o-cresol With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.25h;
Stage #2: diphenyliodonium chloride In tetrahydrofuran at 0 - 20℃;
1-4 Example 4
Add 30.6g (0.2mol) of 2-methyl-3-nitrophenol, 41.5g (0.3mol) of light potassium carbonate (120 mesh) and 54g (0.36mol) of 2-bromopentane into a 1000mL four-neck bottle , Add 200 mL of anhydrous ethanol, stir the reaction at reflux temperature (at reflux temperature of anhydrous ethanol), monitor the reaction progress by HPLC, and stop the reaction when the normalized content of the target substance is 90%.After the reaction solution was filtered, ethanol was evaporated, 200 mL of toluene and 50 mL of water were added to the residue, and the pH of the residue was adjusted to be strongly alkaline with a 20wt% aqueous NaOH solution, and then extracted and separated to remove unreacted raw materials in the water layer (re It can be recycled and used after acidification).The organic layer was washed with water and desolventized to obtain 41.8 g of the target product, which was quantified by HPLC internal standard method, and the content was >95%, the yield was ≥88.1%, and the phenol residue was ≤0.3%.A total of 220 g of wastewater was obtained.
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h;
2.1 Example 2: Synthesis of Compound 8(1) Synthesis of 1-(sec-butoxy)-2-methyl-3-nitrobenzene
2-bromobutane (2.14 g, 15.17 mmol) and potassium carbonate (2.16 g, 15.17 mmol) were added to the solution of 2-methyl-3-nitrophenol (2.00 g, 13.06 mmol) in N,N-dimethylformamide. The reaction mixture was heated to 90° C. for 2 hours. Then ethyl acetate and water was added, the organic layer was successively washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated by rotary evaporator. The residue was purified by silica gel column chromatography (Fluent: ethyl acetate/petroleum ether=1/100) to give the product (1.65 g) as a solid.
(2,5-dimethylphenyl)(6-oxa-3-azabicyclo[3.1.0]hex-3-yl)methanone[ No CAS ]
[ 74-88-4 ]
trans-(2,5-dimethylphenyl)(3-methoxy-4-(2-methyl-3-nitrophenoxy)pyrrolidin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
144 mg
Stage #1: 3-nitro-o-cresol; (2,5-dimethylphenyl)(6-oxa-3-azabicyclo[3.1.0]hex-3-yl)methanone With caesium carbonate In N,N-dimethyl-formamide at 80℃;
Stage #2: methyl iodide With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 3h;
103.A A) trans-(2,5-dimethylphenyl)(3-methoxy-4-(2-methyl-3-nitrophenoxy)pyrrolidin-1-yl)methanone
To a mixture of (2,5-dimethylphenyl) (6-oxa-3-azabicyclo[3.1.0]hex-3-yl)methanone (150 mg), 2-methyl-3-nitrophenol (159 mg) and DMF (3 ml) was added cesium carbonate (562 mg). The reaction mixture was stirred overnight at 80° C., and allowed to cool to room temperature, and iodomethane (294 mg) and 60% sodium hydride (55.2 mg) were added thereto. The mixture was stirred at room temperature for 3 days. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (144 mg). MS 385.1 [M+H]+.
With boron tribromide In dichloromethane at -5 - 20℃; for 12h; Inert atmosphere;
1.2
Compound 2 (72g, 1eq) was dissolved in 400ML DCM, the reaction system was reduced to -5°C, BBr3 (130g, 1.2eq) was slowly protected under N2, and the temperature was controlled at -5-0°C. After the addition is completed, the temperature is naturally raised to room temperature, and the reaction is carried out for 12 hours;(2) TLC monitors the completion of the reaction;(3) The reaction system was lowered to 0°C, 200ML of water was slowly added dropwise to quench the reaction, the pH of the system was adjusted to 8 with saturated Na2CO3, and the aqueous phase was extracted with DCM (400ML×2). Combined organicPhase, dry with anhydrous sodium sulfate, decolorize with 5g activated carbon, filter with 0.1kg silica gel;(4) Concentrate the organic phase to dryness, add petroleum ether (0.1L) to beaten, and dry to obtain 46 g of product, with a yield of 69.7%.
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