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USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 619-08-9 * 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 Organic Chemistry, 2013, vol. 78, # 10, p. 4834 - 4839
[2] Journal of Organic Chemistry, 2008, vol. 73, # 5, p. 1925 - 1934
2
[ 619-08-9 ]
[ 77-78-1 ]
[ 4920-79-0 ]
Reference：
[1] Tetrahedron Letters, 1998, vol. 39, # 27, p. 4883 - 4886
[2] Journal of the Chemical Society, 1930, p. 2166,2168
3
[ 619-08-9 ]
[ 74-88-4 ]
[ 4920-79-0 ]
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 4, p. 1551 - 1554
[2] Bulletin of the Chemical Society of Japan, 1994, vol. 67, # 10, p. 2639 - 2646
4
[ 95-57-8 ]
[ 619-08-9 ]
[ 603-86-1 ]
Yield
Reaction Conditions
Operation in experiment
92%
With silica supported Al(NO3)3*9H2O In acetone at 20℃; for 0.416667 h;
General procedure: To a solution of phenol (1 mmol) in acetone (5 mL) wasadded silica supported Al(NO3)3·9H2O (1 mmol) and theresulting mixture stirred at room temperature. After completionof the reaction, as indicated by TLC, the reaction masswas filtered and the residue (silica) was washed with ethylacetate (2 5 mL). The filtrate and the washing were collectivelyconcentrated under reduced pressure, and the crudecompound was purified by column chromatography oversilica gel (100-200 mesh) to afford the pure ortho-nitro phenol(95percent) and para- nitro phenol (3percent).
36%
With nickel(II) nitrate hexahydrate In tetrahydrofuran at 50℃; for 4 h;
General procedure: A suspension of 2-methylphenol(18.5 mmol, 1.0 eq) and Cu(NO3)2.3H2O (27.7 mmol, 1.5 eq) in THF was stirred magnetically at 60°C or reflux for several hours. Then after the solvent was removed under vacuum, the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (5mL), dried over anhydrous MgSO4 and concentrated under vacuum. The crude residue was purified by column chromatography to afford the product (67-90percent).
Reference：
[1] Letters in Organic Chemistry, 2015, vol. 12, # 2, p. 129 - 135
[2] Bulletin de la Societe Chimique de France, 1996, vol. 133, # 10, p. 973 - 977
[3] International Journal of Chemical Kinetics, 2016, vol. 48, # 4, p. 171 - 196
[4] Synthetic Communications, 2003, vol. 33, # 6, p. 961 - 966
[5] European Journal of Organic Chemistry, 2005, # 11, p. 2379 - 2384
[6] Tetrahedron, 1989, vol. 45, # 5, p. 1415 - 1422
[7] Tetrahedron, 2005, vol. 61, # 46, p. 10861 - 10867
[8] Tetrahedron, 2005, vol. 61, # 46, p. 10861 - 10867
[9] Bulletin de la Societe Chimique de France, 1996, vol. 133, # 10, p. 973 - 977
[10] Bulletin de la Societe Chimique de France, 1996, vol. 133, # 10, p. 973 - 977
[11] Journal of Organic Chemistry, 2005, vol. 70, # 22, p. 9071 - 9073
[12] Arkivoc, 2014, vol. 2014, # 5, p. 64 - 71
[13] Journal of the American Chemical Society, 1982, vol. 104, # 23, p. 6470 - 6471
[14] Roczniki Chemii, 1930, vol. 10, p. 761,765,771[15] Chem. Zentralbl., 1931, vol. 102, # I, p. 1427
[16] Chemische Berichte, 1872, vol. 5, p. 778[17] Justus Liebigs Annalen der Chemie, 1874, vol. 173, p. 306
[18] Tetrahedron, 1989, vol. 45, # 5, p. 1299 - 1310
[19] Journal of the American Chemical Society, 1934, vol. 56, p. 1787,1790
[20] Quarterly Journal of Pharmacy and Pharmacology, 1945, vol. 18, p. 41,43
[21] Journal of the American Chemical Society, 1934, vol. 56, p. 1787,1790
[22] Quarterly Journal of Pharmacy and Pharmacology, 1945, vol. 18, p. 41,43
[23] Chemische Berichte, 1872, vol. 5, p. 778[24] Justus Liebigs Annalen der Chemie, 1874, vol. 173, p. 306
[25] Tetrahedron, 1989, vol. 45, # 5, p. 1299 - 1310
[26] South African Journal of Chemistry, 2006, vol. 59, p. 93 - 96
[27] Synthetic Communications, 2013, vol. 43, # 19, p. 2672 - 2677
5
[ 121-73-3 ]
[ 619-08-9 ]
[ 89-64-5 ]
[ 603-86-1 ]
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 17, p. 4979 - 4981
[2] Journal of Organic Chemistry USSR (English Translation), 1986, vol. 22, p. 720 - 726[3] Zhurnal Organicheskoi Khimii, 1986, vol. 22, # 4, p. 806 - 814
[4] Journal of Organic Chemistry, 1998, vol. 63, # 13, p. 4199 - 4208
6
[ 88-75-5 ]
[ 619-08-9 ]
[ 603-86-1 ]
Reference：
[1] Roczniki Chemii, 1930, vol. 10, p. 761,765,771[2] Chem. Zentralbl., 1931, vol. 102, # I, p. 1427
7
[ 121-73-3 ]
[ 619-08-9 ]
[ 89-64-5 ]
[ 603-86-1 ]
[ 139-24-2 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1986, vol. 22, p. 720 - 726[2] Zhurnal Organicheskoi Khimii, 1986, vol. 22, # 4, p. 806 - 814
8
[ 95-57-8 ]
[ 7697-37-2 ]
[ 619-08-9 ]
[ 603-86-1 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1874, vol. 173, p. 303
9
[ 99-54-7 ]
[ 619-08-9 ]
[ 39224-65-2 ]
[ 28165-60-8 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 13, p. 4199 - 4208
10
[ 619-08-9 ]
[ 3964-52-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 22, p. 5864 - 5869
[2] Molecular crystals and liquid crystals, 1982, vol. 80, # 1-4, p. 105 - 118
[3] Journal of the American Chemical Society, 1923, vol. 45, p. 2191,2193
[4] Journal of the American Chemical Society, 1923, vol. 45, p. 2191,2193
[5] Chemische Berichte, 1925, vol. 58, p. 664
[6] Quarterly Journal of Pharmacy and Pharmacology, 1945, vol. 18, p. 41,43
[7] Justus Liebigs Annalen der Chemie, 1886, vol. 234, p. 3
[8] Zeitschrift fuer Chemie, 1871, p. 339
[9] Inorganic Chemistry, 2014, vol. 53, # 11, p. 5692 - 5697
[10] RSC Advances, 2015, vol. 5, # 16, p. 11913 - 11916
[11] Journal of the Brazilian Chemical Society, 2016, vol. 27, # 2, p. 372 - 381
[12] ACS Catalysis, 2016, vol. 6, # 7, p. 4110 - 4116
[13] RSC Advances, 2016, vol. 6, # 98, p. 96431 - 96435
[14] Langmuir, 2018, vol. 34, # 46, p. 13897 - 13904
11
[ 619-08-9 ]
[ 3964-52-1 ]
Reference：
[1] Patent: US5866611, 1999, A,
12
[ 619-08-9 ]
[ 30880-72-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1970, vol. 13, p. 1165 - 1170
13
[ 619-08-9 ]
[ 202197-26-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691
[2] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 175 - 194
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
[4] Patent: US2015/366868, 2015, A1,
[5] Archiv der Pharmazie, 2016, vol. 349, # 11, p. 827 - 847
[6] Patent: CN103483324, 2016, B,
[7] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 330 - 348
[8] Patent: CN105085496, 2018, B,
[9] Patent: US2016/214964, 2016, A1,
[10] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 316 - 336
[11] Patent: US2018/208584, 2018, A1,
[12] Patent: WO2006/55268, 2006, A2,
14
[ 619-08-9 ]
[ 524955-09-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 11, p. 3090 - 3104
[2] Research on Chemical Intermediates, 2013, vol. 39, # 7, p. 3105 - 3110
[3] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 330 - 348
[4] Patent: US2016/214964, 2016, A1,
[5] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 316 - 336
With potassium carbonate In acetone at 30℃; for 16 h;
A mixture of 2-chloro-4-nitrophenol (35 g, 0.2 mol), m-furobenzylbromide (45.4 g, 0.24 mol), K2CO3 (55.2 g, 0.4 mol) and acetone (800 mL) was stirred at 30 0C for 16h. The resulting mixture was filtered and washed with acetone. The filtrate was concentrated to give the crude product which was washed with petroleum ether and dried to give the product 1502 as a yellow solid (55.0 g, 99percent yield). 1H NMR (DMSO-J6): δ 8.33 (d, J = 3.3 Hz, IH), 8.21-8.26 (m, IH), 7.42-7.50 (m, 2H), 7.29- 7.33 (m, 2H), 7.16-7.22 (m, IH), 5.39 (s, 2H). LC-MS: 282 (M+l).
95%
With potassium carbonate In acetonitrile
(c) 4-(3-fluorobenzyloxy)-3-chloro Nitrobenzene 2-chloro-4-nitrophenol (9.02 g, 52 mmol)), 3-fluorobenzyl bromide (9.85 g, 52 mmol) and acetonitrile (90 mL) was combined at room temperature under nitrogen. Potassium carbonate (7.9 g, 57 mmol)) was added and the reaction mixture stirred at 60° C. for 2 hours and then cooled to room temperature. After cooling the reaction mixture was poured into water. The solids were collected by filtration and washed with diethyl ether to afford the desired product (13.98 g, 95percent yield). [TLC system=1:1 EtOAc:Hexanes, Rf=0.76]
95%
With potassium carbonate In acetonitrile at 20 - 60℃; for 2 h; Inert atmosphere
2-chloro-4-nitrophenol (9.02 g, 52 mmol)), 3-fluorobenzyl bromide (9.85 g, 52 mmol) and acetonitrile (90 mL) was combined at room temperature under nitrogen. Potassium carbonate (7.9 g, 57 mmol)) was added and the reaction mixture stirred at 60° C. for 2 hours and then cooled to room temperature. After cooling the reaction mixture was poured into water. The solids were collected by filtration and washed with diethyl ether to afford the desired product (13.98 g, 95percent yield). [TLC system=1:1 EtOAc:Hexanes, Rf=0.76]
95%
Stage #1: With potassium carbonate In acetonitrile at 20℃; for 0.5 h; Stage #2: Reflux
Compound 1 was weighed 100g in 2L three-necked flask, mechanical stirring, 1000mLCH3CN 76gK2CO3Reacting at room temperature, after half an hour the reaction was slowly added dropwise 104g of compound 2. After the addition, the reaction was heated at reflux for 4 hours.After the reaction was cooled to room temperature, the reaction flask was added a lot of water, stirred, suction filtered, washed with ethanol and a small amount of solid, Compound 3, quality 134g, 95percent yield
95%
With potassium carbonate In acetonitrile at 60℃; for 2 h; Inert atmosphere
2-Chloro-4-nitrophenol (9.02 g, 52 mmol), 3-fluorobenzyl bromide (9.85 g, 52 mmol)90 ml of acetonitrile was added to the reaction flask while potassium carbonate (7.0 g, 57 mmol) was addedThe reaction was added to it under a nitrogen atmosphere at 60°C for two hours and then the reaction was allowed to come to room temperature.Pour 80 ml of water into the reaction flask and filter under reduced pressure to obtain a solid.The filter cake was washed twice with ethyl acetate (50 ml x 2) to give a final solid product (13.16 g, yield 95percent).
94%
With potassium carbonate In acetonitrile at 70℃; for 18 h;
Step 8; Preparation of 3-chloro-4-f3-fluoro-benzvloxv)-phenvlamine; To 90 mL CH3CN was added 2-chloro-4-nitrophenol (15 g, 86.4 mmol) followed by potassium carbonate (17.9 g, 129.6 mmol). To the stirring suspension was added via dropping funnel a 10 mL CH3CN solution of 3-fluoro-benzylbromide(16.3 g, 86.4 mmol). The contents were stirred and heated at 70°C for 18 h, after which time the bright yellow mixture was allowed to cool to it. The yellow contents were poured onto water (200 mL) and stirred, upon which solid formation occurs. The solid was filtered and filter cake washed with additional water (50 mL). The collected solid was dried in vacuo, yielding 2-chloro-1-(3-fluoro-benzoyloxy)-4- nitro-benzene (23 g, 94percent) as a white solid.2-Chloro-1-(3-fluoro-benzoyloxy)-4-nitro-benzene (10 g, 35.5 mmol) was suspended in 50 mL acetic acid and 150 mL EtOAc in a 500 mL flask. Iron (9.9 g (177.5 mmol) was added to this suspension, and the mixture stirred at rt overnight. The reaction mixture was filtered through a thin pad of Celite.(R).. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 aq solution, followed by EtOAc extraction. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 15percent EtOAc/hexanes yielding 3-chloro-4-(3-fluoro- benzyloxy)-phenylamine as a brown solid [8.5 g, 95percent, TLC Rf = 0.4, 30percentEtOAc/Hex.(3:7)]. 1H-NMR (DMSO-d6) δ 4.94 (s, 2H), 5.00 (s, 2H), 6.40 (dd, 1H), 6.60 (s, 1H), 6.87 (d, 1H), 7.10-7.18 (m, 1H), 7.20-7.28 (m, 2H), 7.37-7.44 (m, 1H).
94%
With potassium carbonate In acetonitrile at 70℃; for 18 h;
To 90 mL CH3CN was added 2-chloro-4-nitrophenol (15 g, 86.4 mmol) followed by potassium carbonate (17.9 g, 129.6 mmol). To the stirring suspension was added via EPO <DP n="33"/>dropping funnel a 10 niL CH3CN solution of 3-fluoro-benzylbromide (16.3 g, 86.4 mmol). The contents were stirred and heated at 70 0C for 18 h, after which time the bright yellow mixture was allowed to cool to rt. The yellow contents were poured onto H2O (200 mL) and stirred, upon which solid formation occurs. The solid was filtered and filter cake washed with additional H2O (50 mL). The collected solid was dried in vacuo, yielding 2- chloro-l-(3-fluoro~benzoyloxy)-4-nitro-benzene (23 g, 94percent) as a white solid.
87.5%
With potassium carbonate In acetone at 30℃; for 12 h;
A mixture of 2-chloro-4-nitrophenol (2.00 g, 11.6 mmol), m-fluorobenzylbromide (2.60 g, 13.8 mmol), K2CO3 (3.19 g, 23.1 mmol) and acetone (50 mL) was stirred at 30° C. for 12 hours. The resulting mixture was filtered and washed with acetone. The filtrate was concentrated to give the crude product which was washed with petroleum ether and dried to produce the product as a yellow solid (2.80 g, yield 87.5percent). 1H-NMR (300 MHz, DMSO-d6): δ 8.35 (d, J=2.8 Hz, 1H), 8.25 (dd, J1=9.6 Hz, J2=2.8 Hz, 1H), 7.49-7.45 (m, 2H), 7.31-7.34 (m, 2H), 7.20-7.21 (m, 1H), 3.32 (s, 2H)
87.5%
With potassium carbonate In acetone at 30℃; for 12 h;
A mixture of 2-chloro-4-nitrophenol (2.00 g, 11.6 mmol), m-fluorobenzylbromide (2.60 g, 13.8 mmol), K2CO3 (3.19 g, 23.1 mmol) and acetone (50 mL) was stirred at 30° C. for 12 hours. The resulting mixture was filtered and washed with acetone. The filtrate was concentrated to give the crude product which was washed with petroleum ether and dried to produce the product as a yellow solid (2.80 g, yield 87.5percent). 1H-NMR (300 MHz, DMSO-d6): δ 8.35 (d, J=2.8 Hz, 1H), 8.25 (dd, J1=9.6 Hz, J2=2.8 Hz, 1H), 7.49-7.45 (m, 2H), 7.31-7.34 (m, 2H), 7.20-7.21 (m, 1H), 3.32 (s, 2H); MS (ES) m/e 280 [M-H]+.
Step 1: 2-chloro-1-(3-fluorobenzyloxy)-4-nitrobenzene 2-chloro-4-nitrophenol (3.4 g, 20 mmol), 3-fluorobenzyl chloride (2.8 g, 20 mmol) and potassium carbonate (3.3 g, 24 mmol) was refluxed in acetonitrile (30 mL) overnight. The reaction mixture was poured into 100 mL of H2O, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated in vacuo to obtain the crude product. The crude product was washed with petroleum ether, filtered and dried, and the compound shown in the title (3.2 g, 57percent) was obtained. 1H NMR (CDCl3): δ 8.35 (1H, d, J=2.8 Hz), 8.17-8.14 (1H, m), 7.44-7.38 (1H, m), 7.25-7.19 (2H, m), 7.10-7.06 (1H, m), 7.03 (1H, d, J=9.2 Hz), 5.26 (2H, s).
53%
With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 23 h; Inert atmosphere
The synthesis was performed as described by Shiao et al. for similar compounds [60]. The work-up was performed as described by Fontana et al. [61]. 2-Chloro-4-nitrophenol (1.50 g, 8.64 mmol) was mixed with K2CO3 (3.58 g, 25.9 mmol), before DMF (90 mL) was added under nitrogen atmosphere. The mixture was heated to 75 °C, and 3-fluorobenzyl chloride (1.87 g, 13.0 mmol) dissolved in DMF (60 mL) was added slowly. The reaction mixture was stirred at 75 °C for 23 h, cooled to rt, quenched into cold water (150 mL, 5 °C) and filtered. The isolated solid was washed with an ACN/water mixture (1/1, 50 mL), and n-hexane (30 mL). The obtained white solid was dried under reduced pressure. This yielded 1.29 g (4.58 mmol, 53percent) of 2-chloro-1-((3-fluorobenzyl)oxy)-4-nitrobenzene as a white solid, mp. 90–96 °C; 1H NMR (400 MHz, DMSO-d6) δ: 8.35 (d, J=2.8, 1H), 8.25 (dd, J=8.8, 2.8, 1H), 7.52–7.44 (m, 2H), 7.35–7.30 (m, 2H), 7.24–7.17 (m, 1H), 5.42 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ: 162.2 (d, J=243.7), 158.6, 140.9, 138.4 (d, J=8.1), 130.7 (d, J=8.1), 125.4, 124.6, 123.5 (d, J=2.9), 122.0, 115.1 (d, J=20.6), 114.3 (d, J=22.0), 113.8, 70.1 (d, J=2.1); 19F NMR (564 MHz, DMSO-d6, C6F6) δ: −115.15 (s, dec.); 1H NMR findings are in accordance with literature [59].
Reference：
[1] Patent: US2016/214964, 2016, A1, . Location in patent: Paragraph 0124
[2] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 175 - 194
[3] Patent: EP3181553, 2017, A1, . Location in patent: Paragraph 0198; 0199
[4] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 330 - 348
[5] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 316 - 336
18
[ 619-08-9 ]
[ 456-47-3 ]
[ 443882-99-3 ]
Yield
Reaction Conditions
Operation in experiment
93%
With tributylphosphine; diamide In tetrahydrofuran at 10 - 40℃; for 1.5 h;
To a 1000 ml reaction flask was added 350 ml of tetrahydrofuran, 75 g of 2-chloro-4-nitrophenol, 58.0 g 3-fluorobenzyl alcoholAnd 106gTributylphosphine,Turn agitated, cool to 10 ° C, slowly drop 90 g of tetramethylazodicarbonamide (TMAD) and 200 mlTetrahydrofuran, the solution was added dropwise and the temperature was stirred at 10 ° C for 1.5 hours. The reaction was carried out at a temperature of 40 ° CThe reaction solution was concentrated under reduced pressure to dryness, and the residue was stirred with N, N-dimethylformamide (200 ml), and the mixture was cooled to 0 ° C.The resulting solid was dried at 55-60 ° C to give 113.2 g of a pale yellow solid, 99.82percent purity and a yield of 93.0percent.
Reference：
[1] Patent: CN106543007, 2017, A, . Location in patent: Paragraph 0017; 0018; 0019; 0020; 0021; 0022
19
[ 619-08-9 ]
[ 848139-78-6 ]
Reference：
[1] Research on Chemical Intermediates, 2013, vol. 39, # 7, p. 3105 - 3110
20
[ 619-08-9 ]
[ 6959-47-3 ]
[ 179687-79-7 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: With potassium iodide In N,N-dimethyl-formamide at 60℃; for 12 h;
2-(Chloromethyl)pyridine hydrochloride (16.4 g, 0.1 mol) and K2CO3 (27.6 g, 0.2 mol) were suspended in DMF (100 mL) and stirred at room temperature for 30 min. 2-Chloro-4-nitrophenol (17.4 g, 0.1 mol) and KI (0.83 g, 5 mol percent) were added in and the reaction mixture was stirred at 60 °C for 12 h. The reaction suspension was diluted with water (400 mL) and the resulting solid was filtered, washed with water and dried to give 2-((2-chloro-4-nitrophenoxy)methyl)pyridine (26 g, 98percent) as a white solid. Mp 149.2–149.9 °C; MS-EI (m/z): 92, 229, 263(M+).
74%
With potassium carbonate; sodium iodide In acetonitrileReflux
Step 1: 2-((2-chloro-4-nitrophenoxy)methyl)pyridine 2-chloro-4-nitrophenol (3.4 g, 20 mmol), 2-(chloromethyl)pyridine hydrochloride (3.4 g, 21 mmol), potassium carbonate (3.3 g, 24 mmol) and sodium iodide (3.0 g, 20 mmol) were refluxed in acetonitrile (30 mL) overnight. The reaction mixture was poured into 100 mL of H2O, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, evaporated with rotary evaporator, to obtain the crude product. The crude product was washed with petroleum ether, filtered and dried, and the compound shown in the title (3.9 g, 74percent) was obtained. 1H NMR (CDCl3): δ 8.63 (1H, d, J=4.8 Hz), 8.34 (1H, d, J=2.8 Hz), 8.16-8.14 (1H, m), 7.79-7.76 (1H, m), 7.62-7.60 (1H, m), 7.31-7.27 (1H, m), 7.11 (1H, d, J=9.2 Hz), 5.49 (2H, s).
52%
With caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h;
2-CHLORO-4-NITRO PHENOL 10G (57.6 MMOL, 1EQ), 2-PYCOLYL CHLORIDE hydrogen chloride 9.45g (57.6 mmol, 1 eq) cesium carbonate 41.3 (126.8 mmol, 2.2 eq) and sodium iodide 8. 64G (57.6 mmol, 1 eq) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with 400 mL water, YIELDING 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8G, 52percent) as a red solid. 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8 g, 30. 2MMOL, 1 eq) and 8. 44g iron (151.1 mmol, 5 eq) were mixed in 100 mL acetic acid and 50 mL ethyl acetate and were stirred at rt overnight. The reaction mixture was filtered through celite pad. The filtrate was concentrated in vacuo and neutralized with sat. NA2CO3 solution. The solution was extracted with ethyl acetate and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 30percent ethyl acetate/hexane yielding 3. 2G of 3-Chloro-4- (pyridin-2-ylmethoxy)-phenylamine as a white solid (52percent). 1H-NMR (CDCL3) No. 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H),. 6.80 (d, 1H), 7.22 (m, 1 H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H) ; LCMS RT = 0.89 min; [M+H]+= 235.1.
52%
With caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h;
2-chloro-4-nitro phenol 1Og (57.6 mmol, leq), 2-pycolyl chloride hydrogen chloride 9.45g (57.6 mmol, 1 equiv) cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide 8.64g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8g, 52percent) as a red solid. 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2mmol, 1 equiv) and 8.44g iron (151.1 mmol, 5 equiv) were mixed in 100 mL acetic acid and 50 mL EtOAc and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52percent) as a white solid. 1H-NMR (CDCl3) δ 5.18 (s, 2H), 6.50 (dd, IH), 6.76 (d, IH),. 6.80 (d, IH), 7.22 (m, IH), 7.64 (d, IH), 7.73 (td, IH), 8.55 (m, IH); LCMS RT = 0.89 min; [M+H]+ = 235.1.
52%
With caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h;
2-chloro-4-nitro phenol (10 g, 57.6 mmol, 1 equiv), 2-pycolyl chloride hydrogen chloride (9.45 g, 57.6 mmol, 1 equiv), cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide (8.64 g, 57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60° C. for 5 h. The resulted suspension was filtered and washed with water (400 mL), yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 52percent) as a red solid.
52%
With caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h;
2-Chloro-4-nitro phenol 10 g (57.6 mmol, 1 eq), 2-(chloromethyl)pyridine hydrogen chloride 9.45 g (57.6 mmol, 1 equiv), cesium carbonate (41.3 g, 126.8 mmol, 2.2 equiv) and sodium iodide 8.64 g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60 0C for 5 h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g,52percent) as a red solid.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 11, p. 3090 - 3104
[2] Patent: US2016/214964, 2016, A1, . Location in patent: Paragraph 0138
[3] Patent: WO2005/10008, 2005, A1, . Location in patent: Page/Page column 114-115
[4] Patent: WO2006/23843, 2006, A2, . Location in patent: Page/Page column 64
[5] Patent: US2010/298297, 2010, A1, . Location in patent: Page/Page column 14
[6] Patent: WO2006/55268, 2006, A2, . Location in patent: Page/Page column 32
[7] Research on Chemical Intermediates, 2013, vol. 39, # 7, p. 3105 - 3110
[8] Patent: EP3181553, 2017, A1, . Location in patent: Paragraph 0209; 0210
[9] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 316 - 336
21
[ 4377-33-7 ]
[ 619-08-9 ]
[ 179687-79-7 ]
Yield
Reaction Conditions
Operation in experiment
52%
With hydrogenchloride; caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h;
Example 71; 4-f [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino) [1]benzothieno[2,3-d] pyrimidin-7-ol; Step 1. Preparation of 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine; EPO <DP n="84"/> 2-chloro-4-nitro phenol (10 g, 57.6 mmol, 1 equiv), 2-pycolyl chloride hydrogen chloride (9.45 g, 57.6 mmol, 1 equiv) cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide (8.64 g, 57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with water (400 mL), yielding 2-(2-chloro-4- nitro-phenoxymethyl)-pyridine (8 g, 52percent) as a red solid.2-(2-chloro-4-nitro-phenoxyrnethyl)-pyridine (8 g, 30.2mmol, 1 equiv) and iron (8.44 g, 151.1 mmol, 5 equiv) were mixed in acetic acid (100 mL ) and EtOAc (50 mL ) and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro- 4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52percent) as a white solid. 1H-NMR (CDCl3) δ 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H),. 6.80 (d, 1H), 7.22 (m, 1H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H); LCMS RT = 0.89 min, [M+H]+ = 235.1.
Reference：
[1] Patent: WO2006/44524, 2006, A1, . Location in patent: Page/Page column 82-83
[2] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 330 - 348
p-nitrophenol (69.55 g, 0.5 mole) was dissolved in 10 N HCl (200 ml) in a 1000 ml flask with heating and then cooled down. To the mixture was added 600 ml potassium chlorate (61.25 g, 0.5 mole) solution, gradually with stirring. Stirring was continued for 1 hour after completion of addition and mixture was left overnight at room temperature. After filtration with vacuuming, the filtrate was washed with distilled water and recrystallized with dilute acetic acid solution to yield pale yellow acicular crystal, 2-chloro4-nitro-phenol (80.2 g, m.p. 110-111 C., yield rate 91%).2-chloro-4-nitro-phenol (64.44 g, 0.4 mole) and 300 ml 4M NaOH solution were refluxed with heating for 6 hours. After cooling down and filtration with vacuuming, the filtrate (crystal) was dissolved in a little warm water (60 C.). The solution was adjusted to pH 2.0 with 10% HCl and cooled down while stirring. After filtration, the filtrate was recrystallized with water to yield 4-nitro-1,2-benzenediol (52.1 g, yield rate 84%).To a 1000 ml flask was added 4-nitro-1,2-benzenediol (49.6 g, 0.32 mole), and then 403 ml water and 16 ml 10 N HCl (0.16 mole). While stirring 83.2 g zinc dust (1.28 mole) was added gradually and reaction mixture refluxed with heating for 8 hours. After cooling down and filtration with vacuuming, the filtrate was washed thoroughly with 95% ethanol and decolorized by active carbon. Filtration again and evaporation of ethanol was carried out until the solution just started to become turbid. After cooling in freezer and filtration with vacuuming, filtrate was collected as 4-amino-1,2-benzenediol (30.0 g, yield rate 75%).Dissolve 4-amino-1,2-benzenediol (23.2 g, 0.18 mole) in 95% ethanol. Under salt ice bath 140 ml 2M NaOH solution and 150 ml dichloromethane solution of 13-methyltetradecanoyl chloride (23.2 g, 0.18 mole) were added simultaneously to the benzenediol solution. Stir at room temperature for 6 hours. Adjust pH to 3.0 with HCl, freeze, and filtrate. Wash the filtrate to neutral with water and recrystallize with 50% ethanol to yield N-(3,4dihydroxyl-phenyl)-13-methyl-tetradecanamide (55.8 g, m.p. 85-86 C., yield rate 85%).
45%
With ammonium persulfate; N-chloro-succinimide; oxygen; methylene green; In acetonitrile; at 20℃; for 24h;Irradiation;
General procedure: To an oven-dried flask was added a magnetic stir bar, methylene green (9.1 mg, 0.05 equiv, 0.025 mmol), ammonium peroxodisulfate (11.4 mg, 0.1 equiv, 0.05 mmol), arene/heteroarene (1 equiv, 0.5 mmol), acetonitrile (2.5 mL), and then N-chlorosuccinimide (73.4 mg, 1.1 equiv, 0.55 mmol). The reaction mixture was stirred open to air at room temperature (20 C) in a white LED chamber for 24 h. For substrates that produced a mixture of mono- and dibrominated products upon full conversion, 2.2 equivalents (1.1 mmol) of N-chlorosuccinimide was employed. Upon completion of the reaction, the crude mixture was evaporated under pressure and the chlorinated product was isolated via column chromatography on silica gel.
With copper(II) nitrate trihydrate; In tetrahydrofuran; at 50℃; for 4h;
General procedure: A suspension of 2-methylphenol(18.5 mmol, 1.0 eq) and Cu(NO3)2.3H2O (27.7 mmol, 1.5 eq) in THF was stirred magnetically at 60C or reflux for several hours. Then after the solvent was removed under vacuum, the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (5mL), dried over anhydrous MgSO4 and concentrated under vacuum. The crude residue was purified by column chromatography to afford the product (67-90%).
82%
With nitric acid; vanadia; silica gel; at 150℃; for 0.025h;Microwave irradiation;Catalytic behavior;
General procedure: The microwave (MW) reactor used was of CEM make, which was equipped with temperature, pressure, and MW power control units. An oven-dried MW vial was charged with a mixture containing aromatic compound, V2O5 (9 mg, 0.005 mmol) and 69% HNO3 (0.063 mL, 1 mmol) and silica gel slurry, and irradiated in a MW (power input 140 W) at 150 C for few minutes. After completion of the reaction, as as certained by TLC, the reaction mixture was treated with sodium bicarbonate; the organic layer was diluted with dichloromethane (DCM) and separated from aqueous layer. The crude product mixture was purified with ethyl acetate DCM mixture. The purity was checked with TLC. The products were identified by characteristic spectroscopic data.
75%
With potassium hydrogensulfate; sodium perborate hexahydrate; sodium nitrite; In neat (no solvent); for 0.025h;Molecular sieve; Microwave irradiation;
General procedure: Reactants such as sodium nitrite (12 mmol), with aromatic or heteroaromatic compound (10 mmol), KHSO4 (1 mmol), and SPB (1 mmol), were thoroughly mixed with silica gel and placed in MW oven. Reaction progress was monitored by thin-layer chromatography (TLC) until completion. The reaction mixture was then treated with NaHCO3 solution and extracted with ethyl acetate (30 mL). Final product was obtained by using the same workup steps as detailed in the preceding section. Sodium perborate/NaNO2/KHSO4-initiated nitration reactions with several other compounds also afforded corresponding nitroderivatives (Scheme 1) via both conventional and MW-assisted reactions.
With silica supported Al(NO3)3*9H2O; In acetone; at 20℃; for 0.416667h;
General procedure: To a solution of phenol (1 mmol) in acetone (5 mL) wasadded silica supported Al(NO3)3·9H2O (1 mmol) and theresulting mixture stirred at room temperature. After completionof the reaction, as indicated by TLC, the reaction masswas filtered and the residue (silica) was washed with ethylacetate (2 5 mL). The filtrate and the washing were collectivelyconcentrated under reduced pressure, and the crudecompound was purified by column chromatography oversilica gel (100-200 mesh) to afford the pure ortho-nitro phenol(95%) and para- nitro phenol (3%).
28%; 36%
With nickel(II) nitrate hexahydrate; In tetrahydrofuran; at 50℃; for 4h;
General procedure: A suspension of 2-methylphenol(18.5 mmol, 1.0 eq) and Cu(NO3)2.3H2O (27.7 mmol, 1.5 eq) in THF was stirred magnetically at 60C or reflux for several hours. Then after the solvent was removed under vacuum, the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (5mL), dried over anhydrous MgSO4 and concentrated under vacuum. The crude residue was purified by column chromatography to afford the product (67-90%).
With sodium hydroxide; In water; for 6h;Heating / reflux;
p-nitrophenol (69.55 g, 0.5 mole) was dissolved in 10 N HCl (200 ml) in a 1000 ml flask with heating and then cooled down. To the mixture was added 600 ml potassium chlorate (61.25 g, 0.5 mole) solution, gradually with stirring. Stirring was continued for 1 hour after completion of addition and mixture was left overnight at room temperature. After filtration with vacuuming, the filtrate was washed with distilled water and recrystallized with dilute acetic acid solution to yield pale yellow acicular crystal, 2-chloro4-nitro-phenol (80.2 g, m.p. 110-111 C., yield rate 91%).2-chloro-4-nitro-phenol (64.44 g, 0.4 mole) and 300 ml 4M NaOH solution were refluxed with heating for 6 hours. After cooling down and filtration with vacuuming, the filtrate (crystal) was dissolved in a little warm water (60 C.). The solution was adjusted to pH 2.0 with 10% HCl and cooled down while stirring. After filtration, the filtrate was recrystallized with water to yield 4-nitro-1,2-benzenediol (52.1 g, yield rate 84%).To a 1000 ml flask was added 4-nitro-1,2-benzenediol (49.6 g, 0.32 mole), and then 403 ml water and 16 ml 10 N HCl (0.16 mole). While stirring 83.2 g zinc dust (1.28 mole) was added gradually and reaction mixture refluxed with heating for 8 hours. After cooling down and filtration with vacuuming, the filtrate was washed thoroughly with 95% ethanol and decolorized by active carbon. Filtration again and evaporation of ethanol was carried out until the solution just started to become turbid. After cooling in freezer and filtration with vacuuming, filtrate was collected as 4-amino-1,2-benzenediol (30.0 g, yield rate 75%).Dissolve 4-amino-1,2-benzenediol (23.2 g, 0.18 mole) in 95% ethanol. Under salt ice bath 140 ml 2M NaOH solution and 150 ml dichloromethane solution of 13-methyltetradecanoyl chloride (23.2 g, 0.18 mole) were added simultaneously to the benzenediol solution. Stir at room temperature for 6 hours. Adjust pH to 3.0 with HCl, freeze, and filtrate. Wash the filtrate to neutral with water and recrystallize with 50% ethanol to yield N-(3,4dihydroxyl-phenyl)-13-methyl-tetradecanamide (55.8 g, m.p. 85-86 C., yield rate 85%).
With sodium tetrahydroborate; In tetrahydrofuran; water; at 20℃; for 0.5h;
General procedure: A mixture of 3 mL of 0.015 mol L-1 aromatic nitro compound dissolved in tetrahydrofuran (THF), an aliquot of palladium nanoparticles, 300 muL of 2.0 mol L-1 NaCl solution and an aliquot of water were added into a reaction flask, totalizing 9 mL. Then, 900 muL of 0.5 mol L-1 NaBH4 solution freshly prepared was added to the above solution under continuous stirring. The final ratio H2O:THF was 2.3:1. The mixture was stirred at room temperature for 30 min. After this time, diethyl ether was added and the organic phase was separated and analyzed by gas chromatography (GC/MS) (chromatograph AgilentTechnologies model 7820A coupled to mass spectrometer Agilent Technologies model 5975, operating with acolumn HP5-ms).
With potassium carbonate; In acetonitrile; at 70℃; for 2h;
To 90 mL CH3CN was added 2-Cl-4-nitrobenzene (15 g, 86.4 mmol), followed by potassium carbonate (17.9 g, 129.64 mmol), and benzyl bromide (14.78 g, 86.4 mmol) as a 10 mL CH3CN solution. The suspension was stirred and heated at 70 0C for 2 h, after which time the bright yellow mixture was allowed to cool to rt. The contents were poured onto 200 mL water with stirring, upon which a solid crashes out of solution. The contents were filtered, and washed with water, and dried in vac. ven at ca. 40 0C yielding 1- Benzyloxy-2-chloro-4-nitro-benzene (4.87 g, 61%) as white solid. l-Benzyloxy-2-chloro-4-nitrobenzene (10.0 g, 37.9 mmol) and iron powder (10.6 g, 189.6 mmol) were mixed in 250 mL acetic acid and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite, and washed with EtOAc. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The contents were extracted with EtOAc (6 x 300 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude material was triturated with Hex/EtOAc (2:1) to furnish 4-Benzyloxy-3-chloro- phenylamine (7.8 g, 88%) as a white solid. 1H-NMR (DMSO-^6) delta 7.43-7.30 (m, 5H), 6.90 (d, IH), 6.63 (d, IH), 6.46 (dd, IH), 4.99 (s, 2H), 4.92 (s, 2H); LCMS RT = 2.09 min; [M+H]+ = 234.5.
With potassium carbonate; In acetone; for 1h;Reflux;
The synthesis of l-(tert-butoxycarbonyl) -5-(tert-butyldimethylsiloxy) -4-chloro-lH-indol-2- yl boronic acid (Compound 7-7) is shown in Scheme 7. 4-Nitro-2-chlorophenol (cpd. 4-1) is protected as the benzyl ether, and converted to the mixture of compounds 7-2 and 7-3. Treatment with palladium on carbon under a hydrogen atmosphere reduces the nitro functionality, cyclizes the indole heterocyclic ring and removes the O-benzyl protection, to obtain compound 7-4. The hydroxyl is reprotected as the tert-butyldimethylsilyl ether 7-5, the indole nitrogen is protected with Boc (Cpd. 7-6), and subsequently treated with treated with lithium diispropylamide and triisopropylborate to produce the protected substituted boronic acid 7-7.
With potassium carbonate; In N,N-dimethyl-formamide;Heating / reflux;
Example 2 3-chloro-4-benzyloxy-aniline In a 250 mL flask equipped with a reflux condenser, <strong>[619-08-9]2-chloro-4-nitrophenol</strong> 4.65 g (26.6 mmol), benzyl bromide 2.97 mL (27.0 mmol, 1 eq), K2CO3 9.4 g (54 mmol, 2 eq) and DMF (60 mL) were added and then heated to reflux. The procedure was conducted as Example 1, the residue was purified by column chromatography to obtain the title compound as brown solid, total yield: 73%. 1H-NMR (400 MHz, CDCl3): delta7.38-7.29 (1H, m), 7.23-7.16(2H, m), 7.04-6.96 (1H, m), 6.79-6.74 (2H, m), 6.50 (1H, dd, J=2.75 Hz, 8.61 Hz), 5.03 (2H, s), 3.50 (2H, br).
With potassium carbonate; In acetonitrile; at 50℃; for 12h;
General procedure: 10145] Aniline Synthesis. Anilines 17 were synthesized using general procedure 13. In a 20 mE glass vial, a solution of substituted 4-nitrophenol (1.5 mmol) in 5 mE of acetonitrile was combined with potassium carbonate (3 mmol) and the appropriate benzyl bromide (1.5 mmol) at 25C. The reaction mixture was stirred at 50 C. for 12 h. After completion of the alkylation reaction, the reaction mixture was triturated with 10 mE of 10% MeOH/DCM and was filtered through a silica gel plug. The organic filtrate was evaporated and redissolved inS mE of MeOH:H20 (5:1). To this solution was added zinc (0.29 g, 4.5 mmol), followed by ammonium chloride (0.48 g, 9 mmol) at 25 C. The temperature was raised to 50 C., and the stirring was continued for 6 h. Progress of the reaction was followed by EC-MS. Upon completion of the reaction, 15 mE of DCM:MeOH (1:1) was added to the reaction mixture and inorganic residues were removed by filtration. The filtrate was evaporated, and the residue was purified via flash chromatography (0-50% EtOAc/hexanes) to afford the desired substituted anilines.
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃;
A mixture of <strong>[619-08-9]2-chloro-4-nitro-phenol</strong> (3.6 g, 21.0 mMol), 2C03 (5.76 g, 41.6 mMol) and 1 ,2-dibromoethane (4.0 g, 21.2 mMol) in dimethylformamide (10 mL) was stirred at room temperature overnight and then on 80 C for 3 hours. The mixture was filtered and evaporated. The residue was diluted with ethylacetate and washed with I M NaOH (30 mL) and water (30 mL), dried over Na2S04, filtered and the ethylacetate was evaporated. The residue was chiOmatographed on silica gel eluting with cyclohexane and ethylacetate (65:35) to yield 4.14 g (70.2%) of the title compound.
68%
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 3h;
36.6 mL (416 mmol) of 1,2-dibromoethane is dissolved in 200 mL of DMF and 11.5 g (83.3 mmol) of potassium carbonate is added. 7.20 g (41.6 mmol) of <strong>[619-08-9]2-chloro-4-nitrophenol</strong> in 40 mL of DMF is slowly added dropwise to this mixture. The mixture is stirred for 3 hours at ambient temperature. The solvent is eliminated, the residue is taken up in ethyl acetate and washed with saturated saline solution. The organic phase is dried over sodium sulfate. The solvent is eliminated and the residue is purified through a silica gel column with a gradient of petroleum ether/ethyl acetate (4:1 to 9:1). Yield: 7.9 g (68% of theory); Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate=3:1); C8H7BrClNO3.
With potassium carbonate; In acetone; at 30℃; for 16h;
A mixture of 2-chloro-4-nitrophenol (35 g, 0.2 mol), m-furobenzylbromide (45.4 g, 0.24 mol), K2CO3 (55.2 g, 0.4 mol) and acetone (800 mL) was stirred at 30 0C for 16h. The resulting mixture was filtered and washed with acetone. The filtrate was concentrated to give the crude product which was washed with petroleum ether and dried to give the product 1502 as a yellow solid (55.0 g, 99% yield). 1H NMR (DMSO-J6): delta 8.33 (d, J = 3.3 Hz, IH), 8.21-8.26 (m, IH), 7.42-7.50 (m, 2H), 7.29- 7.33 (m, 2H), 7.16-7.22 (m, IH), 5.39 (s, 2H). LC-MS: 282 (M+l).
95%
With potassium carbonate; In acetonitrile;
(c) 4-(3-fluorobenzyloxy)-3-chloro Nitrobenzene 2-chloro-4-nitrophenol (9.02 g, 52 mmol)), 3-fluorobenzyl bromide (9.85 g, 52 mmol) and acetonitrile (90 mL) was combined at room temperature under nitrogen. Potassium carbonate (7.9 g, 57 mmol)) was added and the reaction mixture stirred at 60 C. for 2 hours and then cooled to room temperature. After cooling the reaction mixture was poured into water. The solids were collected by filtration and washed with diethyl ether to afford the desired product (13.98 g, 95% yield). [TLC system=1:1 EtOAc:Hexanes, Rf=0.76]
95%
With potassium carbonate; In acetonitrile; at 20 - 60℃; for 2h;Inert atmosphere;
2-chloro-4-nitrophenol (9.02 g, 52 mmol)), 3-fluorobenzyl bromide (9.85 g, 52 mmol) and acetonitrile (90 mL) was combined at room temperature under nitrogen. Potassium carbonate (7.9 g, 57 mmol)) was added and the reaction mixture stirred at 60 C. for 2 hours and then cooled to room temperature. After cooling the reaction mixture was poured into water. The solids were collected by filtration and washed with diethyl ether to afford the desired product (13.98 g, 95% yield). [TLC system=1:1 EtOAc:Hexanes, Rf=0.76]
95%
Compound 1 was weighed 100g in 2L three-necked flask, mechanical stirring, 1000mLCH3CN 76gK2CO3Reacting at room temperature, after half an hour the reaction was slowly added dropwise 104g of compound 2. After the addition, the reaction was heated at reflux for 4 hours.After the reaction was cooled to room temperature, the reaction flask was added a lot of water, stirred, suction filtered, washed with ethanol and a small amount of solid, Compound 3, quality 134g, 95% yield
95%
With potassium carbonate; In acetonitrile; at 60℃; for 2h;Inert atmosphere;
2-Chloro-4-nitrophenol (9.02 g, 52 mmol), 3-fluorobenzyl bromide (9.85 g, 52 mmol)90 ml of acetonitrile was added to the reaction flask while potassium carbonate (7.0 g, 57 mmol) was addedThe reaction was added to it under a nitrogen atmosphere at 60C for two hours and then the reaction was allowed to come to room temperature.Pour 80 ml of water into the reaction flask and filter under reduced pressure to obtain a solid.The filter cake was washed twice with ethyl acetate (50 ml x 2) to give a final solid product (13.16 g, yield 95%).
94%
With potassium carbonate; In acetonitrile; at 70℃; for 18h;
Step 8; Preparation of 3-chloro-4-f3-fluoro-benzvloxv)-phenvlamine; To 90 mL CH3CN was added 2-chloro-4-nitrophenol (15 g, 86.4 mmol) followed by potassium carbonate (17.9 g, 129.6 mmol). To the stirring suspension was added via dropping funnel a 10 mL CH3CN solution of 3-fluoro-benzylbromide(16.3 g, 86.4 mmol). The contents were stirred and heated at 70C for 18 h, after which time the bright yellow mixture was allowed to cool to it. The yellow contents were poured onto water (200 mL) and stirred, upon which solid formation occurs. The solid was filtered and filter cake washed with additional water (50 mL). The collected solid was dried in vacuo, yielding 2-chloro-1-(3-fluoro-benzoyloxy)-4- nitro-benzene (23 g, 94%) as a white solid.2-Chloro-1-(3-fluoro-benzoyloxy)-4-nitro-benzene (10 g, 35.5 mmol) was suspended in 50 mL acetic acid and 150 mL EtOAc in a 500 mL flask. Iron (9.9 g (177.5 mmol) was added to this suspension, and the mixture stirred at rt overnight. The reaction mixture was filtered through a thin pad of Celite. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 aq solution, followed by EtOAc extraction. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 15% EtOAc/hexanes yielding 3-chloro-4-(3-fluoro- benzyloxy)-phenylamine as a brown solid [8.5 g, 95%, TLC Rf = 0.4, 30%EtOAc/Hex.(3:7)]. 1H-NMR (DMSO-d6) delta 4.94 (s, 2H), 5.00 (s, 2H), 6.40 (dd, 1H), 6.60 (s, 1H), 6.87 (d, 1H), 7.10-7.18 (m, 1H), 7.20-7.28 (m, 2H), 7.37-7.44 (m, 1H).
94%
With potassium carbonate; In acetonitrile; at 70℃; for 18h;
To 90 mL CH3CN was added 2-chloro-4-nitrophenol (15 g, 86.4 mmol) followed by potassium carbonate (17.9 g, 129.6 mmol). To the stirring suspension was added via EPO <DP n="33"/>dropping funnel a 10 niL CH3CN solution of 3-fluoro-benzylbromide (16.3 g, 86.4 mmol). The contents were stirred and heated at 70 0C for 18 h, after which time the bright yellow mixture was allowed to cool to rt. The yellow contents were poured onto H2O (200 mL) and stirred, upon which solid formation occurs. The solid was filtered and filter cake washed with additional H2O (50 mL). The collected solid was dried in vacuo, yielding 2- chloro-l-(3-fluoro~benzoyloxy)-4-nitro-benzene (23 g, 94%) as a white solid.
87.5%
With potassium carbonate; In acetone; at 30℃; for 12h;
A mixture of 2-chloro-4-nitrophenol (2.00 g, 11.6 mmol), m-fluorobenzylbromide (2.60 g, 13.8 mmol), K2CO3 (3.19 g, 23.1 mmol) and acetone (50 mL) was stirred at 30 C. for 12 hours. The resulting mixture was filtered and washed with acetone. The filtrate was concentrated to give the crude product which was washed with petroleum ether and dried to produce the product as a yellow solid (2.80 g, yield 87.5%). 1H-NMR (300 MHz, DMSO-d6): delta 8.35 (d, J=2.8 Hz, 1H), 8.25 (dd, J1=9.6 Hz, J2=2.8 Hz, 1H), 7.49-7.45 (m, 2H), 7.31-7.34 (m, 2H), 7.20-7.21 (m, 1H), 3.32 (s, 2H)
87.5%
With potassium carbonate; In acetone; at 30℃; for 12h;
A mixture of 2-chloro-4-nitrophenol (2.00 g, 11.6 mmol), m-fluorobenzylbromide (2.60 g, 13.8 mmol), K2CO3 (3.19 g, 23.1 mmol) and acetone (50 mL) was stirred at 30 C. for 12 hours. The resulting mixture was filtered and washed with acetone. The filtrate was concentrated to give the crude product which was washed with petroleum ether and dried to produce the product as a yellow solid (2.80 g, yield 87.5%). 1H-NMR (300 MHz, DMSO-d6): delta 8.35 (d, J=2.8 Hz, 1H), 8.25 (dd, J1=9.6 Hz, J2=2.8 Hz, 1H), 7.49-7.45 (m, 2H), 7.31-7.34 (m, 2H), 7.20-7.21 (m, 1H), 3.32 (s, 2H); MS (ES) m/e 280 [M-H]+.
84%
a 2-Chloro-1-(3-fluoro-benzyloxy)-4-nitro-benzene Prepared in analogy to example 8 from 2-chloro-4-nitrophenol and 3-fluoro-benzylbromide. Colorless solid. Yield=84%. MS: m/e=281.0 (M+).
With potassium carbonate; acetic acid; In N,N-dimethyl-formamide; for 4h;Heating / reflux;
Example 1 3-chloro-4-(3-fluorobenzyloxy)-aniline In a 250mL flask equipped with a reflux condenser, 2-chloro-4-nitropheno 14.65 g (26.6mmol), 1-(bromomethyl)-3-fluorobenzene 3.31mL(27.0mmol, 1eq), K2CO3 9.4g(54mmol, 2eq) and 50 mL of DMF were added and then heated to reflux. The mixture was stirred for 4h, and then filtered without cooling to remove the solid. The filtrate was cooled to room temperature. 300mL of ethyl acetate was added to dilute the solution, and washed with water for 3 times. The organic phases were combined, dried and concentrated. The resulting residue was purified by column chromatography to obtain a solid product.
With potassium carbonate; In N,N-dimethyl-formamide;Reflux;
4.65 g (26.6 mmol) of 2-chloro-4-nitrophenol, 3.31 ml (27.0 mmol, 1 eq) of m-fluorobenzyl bromide, 9.4 g (54 mmol, 2 eq) of potassium carbonate and 50 ml of dimethyl formamide were added to a flask of 250 ml equipped with a reflux condenser, and then heated and refluxed. The solid was removed by filtration while it was still warm after 4 hours of reaction. The filtrate was cooled to room temperature, diluted with 300 ml of ethyl acetate, and washed with water for three times. The organic phase was dried, concentrated and purified by column chromatography to obtain a solid product. Said solid product was placed in a flask of 250 ml equipped with a refluxing condenser and 4.7 g (87 mmol) of Fe powders, 10 ml of glacial acetic acid and 50 ml of absolute ethyl alcohol were added thereto. The resulting mixture was heated and refluxed for 5 hours, cooled to the room temperature, and then extracted with a large amount of the mixed solvent of water-ethyl acetate. The organic phases were combined; washed with the sodium bicarbonate solution for twice, dried, concentrated and purified by column chromatography to obtain a light brown solid with a yield of 75%, which was identified as 4-(3-fluorobenzyloxy)-3-chloroaniline. 1H-NMR(400MHz, CDCl3): delta7.38-7.29 (1H, m), 7.23-7.16 (2H, m), 7.04-6.96 (1H, m), 6.79-6.74 (2H, m), 6.50 (1H, dd, J=2.75 Hz, 8.61 Hz), 5.03 (2H, s), 3.50 (2H, br).
With potassium carbonate; In N,N-dimethyl-formamide; for 4h;Heating / reflux;
Example 1 3-chloro-4-(3-fluorobenzyloxy)-aniline In a 250 mL flask equipped with a reflux condenser, 2-chloro-4-nitrophenol 4.65 g (26.6 mmol), 1-(bromomethyl)-3-fluorobenzene 3.3 mL (27.0 mmol, 1 eq), K2CO3 9.4 g (54 mmol, 2 eq) and 50 mL of DMF were added and then heated to reflux. The mixture was stirred for 4 h, and then filtered without cooling to remove the solid. The filtrate was cooled to room temperature. 300 mL of ethyl acetate was added to dilute the solution, and washed with water for 3 times. The organic phases were combined, dried and concentrated. The resulting residue was purified by column chromatography to obtain a solid product.
With potassium carbonate; In N,N-dimethyl-formamide;Reflux;
2) 4.65 g (26.6 mmol) of 2-chloro-4-nitrophenol, 3.31 ml (27.0 mmol, 1 eq) of m-fluorobenzyl bromide, 9.4 g (54 mmol, 2 eq) of potassium carbonate and 50 ml of dimethyl formamide were added to a flask of 250 ml equipped with a reflux condenser, and then heated and refluxed. The solid was removed by filtration while it was still warm after 4 hours of reaction. The filtrate was cooled to room temperature, diluted with 300 ml of ethyl acetate, and washed with water for three times. The organic phase was dried, concentrated and purified by column chromatography to obtain a solid product. Said solid product was placed in a flask of 250 ml equipped with a refluxing condenser and 4.7 g (87 mmol) of Fe powders, 10 ml of glacial acetic acid and 50 ml of absolute ethyl alcohol were added thereto. The resulting mixture was heated and refluxed for 5 hours, cooled to the room temperature, and then extracted with a large amount of the mixed solvent of water-ethyl acetate. The organic phases were combined; washed with the sodium bicarbonate solution for twice, dried, concentrated and purified by column chromatography to obtain a light brown solid with a yield of 75%, which was identified as 4-(3-fluorobenzyloxy)-3-chloroaniline.1H-NMR (400 MHz, CDCl3): delta7.38-7.29 (1H, m), 7.23-7.16 (2H, m), 7.04-6.96 (1H, m), 6.79-6.74 (2H, m), 6.50 (1H, dd. J=2.75 Hz, 8.61 Hz), 5.03 (2H, s), 3.50 (2H, br).
3-(2-Chloro-4-nitro-phenoxy)-1-methyl-pyrrolidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 1.5h;
To a solution of 2-chloro-4-nitrophenol (2.0 g) in tetrahydrofuran (60 mL) is added <strong>[13220-33-2]1-methyl-3-pyrrolidinol</strong> (2.3 g), triphenyl phosphine (6.0 g), and diethylazodicarboxylate (3.6 mL) and the mixture is stirred at room temperature under an atmosphere of argon for 1.5 hours. The solution is then concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 10percent aqueous sodium hydroxide, water, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is chromatographed over silica gel (ethyl acetate then 10percent methanol in dichloromethane is used as the eluant). Pooled product fractions are then recrystallized from hexanes to provide the desired product as a yellow solid.
With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 0 - 20℃; for 18h;
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (3.32 g), <strong>[619-08-9]2-chloro-4-nitrophenol</strong> (2.36 g) and triphenylphosphine (5.11 g) in dichloromethane (60 ml), diethyl azodicarboxylate (3.10 ml) was added dropwise with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 18 hours and then evaporated in vacuo.. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:2) as the eluent to afford the title compound (3.90 g, yield: 76%) as a pale yellow solid. 1H NMR (500MHz, CDCl3) delta ppm: 1.48 (9H, s), 1.84-1.98 (4H, m) 3.54 (2H, m), 3.62 (2H, m), 4.73 (1H, m), 7.00 (1H, d, J=9.0), 8.14 (1H, dd, J=9.0, 3.0), 8.31 (1H, d, J=3.0).
59.6%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 4.66667h;
a. Preparation of 4-(1-butoxycarbonyl-piperidin-4-yloxy)-3-chloro-nitrobenzene; The reaction was carried out in a 5 L 3-necked flask provided with a mechanical stirrer, thermometer, CaCI2 tube, N2 atmosphere and chilling facility. Di-isopropylazodicarboxylate (DIAD, 489.7 g, 2.42 mol) was added over 45 mins to a solution of <strong>[619-08-9]2-chloro-4-nitrophenol</strong> (300 g, 1.729 mol), N-Boc-4-hydroxypiperidine (382.8 g, 1.902 mol) and triphenylphosphine (Ph3P, 634.5 g, 2.47 mol) in tetrahydrofuran (THF, 2,160 ml) at 0 to 5C. After stirring for a further 10 mins at 50C, the temperature was gradually allowed to rise to 200C. After 3.75 hours from the end of the addition, the batch was vacuum concentrated to a residual oil (1921 g). EPO <DP n="61"/>On digestion with 9 : 1 hexane-ethyl acetate (4.3 I) and stirring, the resulting solid (largely Ph3PO contaminated with product) was filtered and washed with 9 : 1 hexane : EtOAc (2 L).The filtrate was vacuum concentrated to an oil (292 g), dissolved in DCM (500 ml) and washed with 0.08 N NaOH (1.5 I), 0.005 N NaOH (1.0 I) and saturated brine (200 ml). The DCM liquors were then dried with MgSO4, filtered and vacuum concentrated to an oil (264 g). On dissolution in hexane (400 ml) and standing, a crystalline crop separated and this was filtered, washed with hexane (500 ml) and dried to yield 51.0 g of material, M. Pt. 95-98C. The hexane mother and wash liquors were combined and charged onto a silica column (1 ,600 g). Flash chromatography was carried out, eluting with 100% hexane through to 25% EtOAc-hexane to yield 71.8 g of good quality intermediate, M.Pt. 105.0-105.5C.The impure "Ph3PO" crop was further extracted with 50 % EtOAc - hexane (total 1.8 L) until TLC indicated that the residual solid comprised only Ph3PO. Evaporation of the extract yielded an orange oil (533 g), which was dissolved in DCM (1.5 I) and washed with 0.2 N NaOH (2.6 I), 0.1 N NaOH (1 I). After brine (1 x 500 ml) washing of the DCM solution, drying, filtration and vacuum evaporation, an orange oil (420 g) was obtained. This oil was flash chromatographed on two columns (total SiO2 3,060 g), eluting as previously. Fractions containing product were obtained by vacuum concentration and filtration from a small volume of hexane. The combined column fractions yielded 71.7 g of M.Pt. 106-108.80C and 172.9 g of M.Pt. 94-96C.Total batch yield: 367.4 g (59.6 % theory on 2-CI-4-NO2-phenol input)1 ) 143.5 g, M.Pt. 105-1080C. Clean TLC (50 % EtOAc : hexane - detection by exposure with TFA and iodoplatinate spray, Rf 0.692) 223.9 g, M.Pt. 94-96C. Similar TLC main product spot, but "ghosting" with probably di-isopropyl hydrazodicarboxylate deriv.
With triphenylphosphine; diethylazodicarboxylate In dichloromethane at 0 - 20℃;
85 Reference example 85; 4-(1-t-Butoxycarbonyl-2-methylpiperidin-4-yloxy)-3-chloronitrobenzene
To a solution of the high polar compound of 1-t-butoxycarbonyl-4-hydroxy-2-methylpiperidine (1.02 g) obtained in reference example 84, 2-chloro-4-nitrophenol (0.83 g) and triphenylphosphine (1.62 g) in dichloromethane (60 ml), diethyl azodicarboxylate (0.97 ml) was added dropwise with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 8 hours.. Because of the slow progress of the reaction, to the reaction mixture were successively added triphenylphosphine (1.62 g) and diethyl azodicarboxylate (0.97 ml), and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuo.. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (4:1) as the eluent to afford the title compound (1.15 g, yield: 76 %) as a yellow oil. 1H NMR (500MHz, CDCl3) δ ppm: 1.35 (3H, d, J=7.0), 1.48 (9H, s), 1.75-1.85 (1H, m), 1.95-2.05 (3H, m), 3.25-3.35 (1H, m), 3.90-4.00 (1H, m), 4.35-4.45 (1H, m), 4.87 (1H, m), 6.97 (1H, d, J=9.0), 8.15 (1H, dd, J=9.0, 2.5), 8.32 (1H, d, J=2.5).
2-(Chloromethyl)pyridine hydrochloride (16.4 g, 0.1 mol) and K2CO3 (27.6 g, 0.2 mol) were suspended in DMF (100 mL) and stirred at room temperature for 30 min. 2-Chloro-4-nitrophenol (17.4 g, 0.1 mol) and KI (0.83 g, 5 mol %) were added in and the reaction mixture was stirred at 60 C for 12 h. The reaction suspension was diluted with water (400 mL) and the resulting solid was filtered, washed with water and dried to give 2-((2-chloro-4-nitrophenoxy)methyl)pyridine (26 g, 98%) as a white solid. Mp 149.2-149.9 C; MS-EI (m/z): 92, 229, 263(M+).
74%
With potassium carbonate; sodium iodide; In acetonitrile;Reflux;
Step 1: 2-((2-chloro-4-nitrophenoxy)methyl)pyridine <strong>[619-08-9]2-chloro-4-nitrophenol</strong> (3.4 g, 20 mmol), 2-(chloromethyl)pyridine hydrochloride (3.4 g, 21 mmol), potassium carbonate (3.3 g, 24 mmol) and sodium iodide (3.0 g, 20 mmol) were refluxed in acetonitrile (30 mL) overnight. The reaction mixture was poured into 100 mL of H2O, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, evaporated with rotary evaporator, to obtain the crude product. The crude product was washed with petroleum ether, filtered and dried, and the compound shown in the title (3.9 g, 74%) was obtained. 1H NMR (CDCl3): delta 8.63 (1H, d, J=4.8 Hz), 8.34 (1H, d, J=2.8 Hz), 8.16-8.14 (1H, m), 7.79-7.76 (1H, m), 7.62-7.60 (1H, m), 7.31-7.27 (1H, m), 7.11 (1H, d, J=9.2 Hz), 5.49 (2H, s).
52%
With caesium carbonate; sodium iodide; In acetonitrile; at 60℃; for 5h;
2-CHLORO-4-NITRO PHENOL 10G (57.6 MMOL, 1EQ), 2-PYCOLYL CHLORIDE hydrogen chloride 9.45g (57.6 mmol, 1 eq) cesium carbonate 41.3 (126.8 mmol, 2.2 eq) and sodium iodide 8. 64G (57.6 mmol, 1 eq) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60C for 5h. The resulted suspension was filtered and washed with 400 mL water, YIELDING 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8G, 52%) as a red solid. 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8 g, 30. 2MMOL, 1 eq) and 8. 44g iron (151.1 mmol, 5 eq) were mixed in 100 mL acetic acid and 50 mL ethyl acetate and were stirred at rt overnight. The reaction mixture was filtered through celite pad. The filtrate was concentrated in vacuo and neutralized with sat. NA2CO3 solution. The solution was extracted with ethyl acetate and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 30% ethyl acetate/hexane yielding 3. 2G of 3-Chloro-4- (pyridin-2-ylmethoxy)-phenylamine as a white solid (52%). 1H-NMR (CDCL3) No. 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H),. 6.80 (d, 1H), 7.22 (m, 1 H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H) ; LCMS RT = 0.89 min; [M+H]+= 235.1.
52%
With caesium carbonate; sodium iodide; In acetonitrile; at 60℃; for 5h;
2-chloro-4-nitro phenol 1Og (57.6 mmol, leq), 2-pycolyl chloride hydrogen chloride 9.45g (57.6 mmol, 1 equiv) cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide 8.64g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60C for 5h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8g, 52%) as a red solid. 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2mmol, 1 equiv) and 8.44g iron (151.1 mmol, 5 equiv) were mixed in 100 mL acetic acid and 50 mL EtOAc and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52%) as a white solid. 1H-NMR (CDCl3) delta 5.18 (s, 2H), 6.50 (dd, IH), 6.76 (d, IH),. 6.80 (d, IH), 7.22 (m, IH), 7.64 (d, IH), 7.73 (td, IH), 8.55 (m, IH); LCMS RT = 0.89 min; [M+H]+ = 235.1.
52%
With caesium carbonate; sodium iodide; In acetonitrile; at 60℃; for 5h;
2-chloro-4-nitro phenol (10 g, 57.6 mmol, 1 equiv), 2-pycolyl chloride hydrogen chloride (9.45 g, 57.6 mmol, 1 equiv), cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide (8.64 g, 57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60 C. for 5 h. The resulted suspension was filtered and washed with water (400 mL), yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 52%) as a red solid.
52%
With caesium carbonate; sodium iodide; In acetonitrile; at 60℃; for 5h;
2-Chloro-4-nitro phenol 10 g (57.6 mmol, 1 eq), 2-(chloromethyl)pyridine hydrogen chloride 9.45 g (57.6 mmol, 1 equiv), cesium carbonate (41.3 g, 126.8 mmol, 2.2 equiv) and sodium iodide 8.64 g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60 0C for 5 h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g,52%) as a red solid.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h;
General procedure: A mixture of <strong>[619-08-9]2-chloro-4-nitrophenol</strong> (1 equiv., 2.88 mmol, 0.5 g), the respective substituted benzyl chloride (viz; 3-fluorobenzyl chloride, 3-chlorobenzyl chloride, 3,4-dichlorobenzyl chloride) or 2-picolyl chloride HCl (1 equiv., 2.88 mmol) and anhydrous K2CO3 (1.66 equiv., 4.78 mmol, 0.66 g) in dry DMF (10 mL) was heated at 80 oC for 24 hours. After cooling, the reaction mixture was poured into ice/water (100 mL). The precipitated solid was filtered, washed with water, and then washed with cold n-hexane to afford the designated compounds (1a-d). [1,2]
With potassium carbonate; In acetonitrile; at 70 - 80℃; for 12h;
12A. Preparation of 2-(2-chloro-4-nitro-phenoxymethyl)-quinoline A mixture of 2-chloro-4-nitro-phenol (202 mg, 1.16 mmol), <strong>[3747-74-8]2-chloromethyl-quinoline hydrochloride</strong> (224 mg, 1.04 mmol), K2CO3 (354 mg, 2.55 mmol) in CH3CN (3.6 ml) was heated at 70 C. for 8 h. DMA (2 ml) was added, and the mixture was heated at 80 C. for 4 h. The mixture was cooled to rt, diluted with EtOAc (120 ml), washed with H2O (6*80 ml) and brine (1*80 ml), dried (MgSO4) and filtered. The filtrate was concentrated to give 12A (280 mg, 85%).
With hydrogenchloride; caesium carbonate; sodium iodide; In acetonitrile; at 60℃; for 5h;
Example 71; 4-f [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino) [1]benzothieno[2,3-d] pyrimidin-7-ol; Step 1. Preparation of 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine; EPO <DP n="84"/> 2-chloro-4-nitro phenol (10 g, 57.6 mmol, 1 equiv), 2-pycolyl chloride hydrogen chloride (9.45 g, 57.6 mmol, 1 equiv) cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide (8.64 g, 57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60C for 5h. The resulted suspension was filtered and washed with water (400 mL), yielding 2-(2-chloro-4- nitro-phenoxymethyl)-pyridine (8 g, 52%) as a red solid.2-(2-chloro-4-nitro-phenoxyrnethyl)-pyridine (8 g, 30.2mmol, 1 equiv) and iron (8.44 g, 151.1 mmol, 5 equiv) were mixed in acetic acid (100 mL ) and EtOAc (50 mL ) and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro- 4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52%) as a white solid. 1H-NMR (CDCl3) delta 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H),. 6.80 (d, 1H), 7.22 (m, 1H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H); LCMS RT = 0.89 min, [M+H]+ = 235.1.
2-chloro-5-(2-chloro-4-nitrophenoxy)methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
EXAMPLE 5 2-Chloro-4-nitrophenol (17.4 mmol) in 15 ml of THF is slowly added to a stirring suspension of sodium hydride (17.4 mmol) in 25 ml of THF. After gas evolution has ceased, 2-chloro-5-bromomethylpyridine is added and the mixture is heated under reflux overnight. The reaction is diluted with water, extracted with chloroform, washed with water, dried and stripped to give 2-chloro-5-(2-chloro-4-nitrophenoxy)methylpyridine.
With potassium carbonate; In acetonitrile; at 70℃; for 18h;
To 90 rriL CH3CN was added 2-chloro-4-nitrophenol (15 g, 86.4 mmol) followed by potassium carbonate (17.9 g, 129.6 mmol). To the stirring suspension was added via dropping funnel a 10 mL CH3CN solution of 3-fluoro-benzylbromide (16.3 g, 86.4 mmol). The contents were stirred and heated at 7O0C for 18 h, after which time the bright yellow mixture was allowed to cool to rt. The yellow contents were poured onto H2O (200 mL) and stirred, upon which solid formation occurs. The solid was filtered and filter cake washed with additional H2O (50 mL). The collected solid was dried in vacuo, yielding 2- chloro-l-(3-fluoro-benzoyloxy)-4-nitro-benzene (23 g, 94%) as a white solid. 2-chloro-l-(3-fluoro-benzoyloxy)-4-nitro-benzene (10 g, 35.5 mmol) was suspended in 50 mL acetic acid and 150 mL EtOAc in a 500 mL flask. Iron (9.9 g (177.5 mmol) was added to this suspension, and the mixture stirred at rt overnight. The reaction mixture was filtered through a thin pad of Celite. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 aq solution, followed by EtOAc extraction. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 15% EtOAc/hexanes yielding 3-Chloro-4-(3-fluoro-benzyloxy)-phenylamine as a brown solid [8.5 g, 95%, TLC Rf = 0.4, 30% EtOAc/HEX.(3:7)]. 1H-NMR (DMSOd6) delta 4.94 (s, 2H), 5.00 (s, 2H), 6.40 (dd, IH), 6.60 (s, IH), 6.87 (d, IH), 7.10-7.18 (m, IH), 7.20-7.28 (m, 2H), 7.37-7.44 (m, IH).
94%
With potassium carbonate; In acetonitrile; at 70℃; for 18h;
To 90 mL CH3CN was added 2-chloro-4-nitrophenol (15 g, 86.4 mmol) followed by potassium carbonate (17.9 g, 129.6 mmol). To the stirring suspension was added via dropping funnel a 10 mL CH3CN solution of 3-fluoro-benzylbromide (16.3 g, 86.4 mmol). The contents were stirred and heated at 70 C. for 18 h, after which time the bright yellow mixture was allowed to cool to rt. The yellow contents were poured onto water (200 mL) and stirred, upon which solid formation occurs. The solid was filtered and filter cake washed with additional water (50 mL). The collected solid was dried in vacuo, yielding 2-chloro-1-(3-fluoro-benzoyloxy)-4-nitro-benzene (23 g, 94%) as a white solid.
(1R,3S,5S)-3-(2-chloro-4-nitrophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triphenylphosphine on polystyrene; di-tert-butyl-diazodicarboxylate; In dichloromethane; at 20℃; for 12h;
((lR,3S,5S)-3-(2-Chloro-4-nitrophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane: A solution of 2-chloro-4-nitrophenol (3.0 g) and tropine (2.69 g) in dichloromethane (100 mL) was mixed with triphenylphosphine (polymer; 6.8 g), and then di-tert-butyl azodicarboxylate(4.78 g) was added dropwise. After stirring at room temperature for 12 hours, the polymer was filtered off with suction and the filtrate was concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 266.77 (C14H19C1N2O) was obtained in this way; MS (ESI): 267 (M+H+).)
With potassium carbonate; In N,N-dimethyl acetamide; at 60℃; for 16h;
A mixture of <strong>[619-08-9]2-chloro-4-nitrophenol</strong> (0.05 mol), 6-bromohexanoic acid, ethyl ester (0.055 mol) and K2CO3 (0.055 mol) in DMA (50 ml) was stirred for 16 hours at 60 C. The mixture was cooled. H2O was added. This mixture was extracted with EtOAc (3x). The combined organic layers were washed with water (2x), then dried (MgSO4), filtered and the solvent was evaporated. Yield: 15.8 g of intermediate 78 (quantitative yield; used in next reaction step, without further purification).
With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; at 20 - 45℃; for 2h;Inert atmosphere;
To a stirred solution of 2-chloro-4- nitrophenol (17.3 grams, 0.10 mol) and NaH (60% in oil, 5 grams, 0.125 mol) in THF (200 mL) and DMF (30 mL) is added (3-trifluoromethyl)benzyl bromide (17 mL) at room temperature (r.t). The reaction mixture is stirred for 2 hours at 45 0C under argon. The resulted mixture is concentrated to give an oily residue, which is dissolved in dichloromethane (50 mL), washed successively with 10 mL each of water, 0.1 M hydrochloric acid (HCl), water, saturated sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. Sample was isolated by column chromatography using silica gel (CH2CVEt2O = 1 -3) in 86% yield 1H NMR (300 MHz, DMSO-d6) delta ppm 5 49 (s, 2H), 7 49 (, J = 9.1 Hz, IH), 7 66-7.79 (m, 2H), 7.79-7 84 (m, IH), 7 89 (s, IH), 8 27 (dd, J = 9 1, 2.7 Hz, IH), 8.32- 8.36 (m, IH). 13C NMR (75 MHz, DMSO-d6) delta ppm 70 1, 113 8, 122 1, 124 1, 124.1, 124.6, 125.0, 125 4, 129 8, 131.6, 137.1, 141 0, 158.6
A solution of phenyl dichlorophosphate (60 g, 42.5 mL, 284 mmol) indichloromethane (300 mL) was cooled to 0C and then treated with (S)-isopropyl 2- aminopropanoate hydrochloride (47.7 g, 284 mmol). The mixture was further cooled to - 78C and treated dropwise with a solution of triethylamine (57.6 g, 79 mL, 569 mmol) in methylene chloride (300 mL) over a 1 h period. The reaction mixture was warmed to 0C for 30 min and then treated with a preformed mixture of 2-chloro-4-nitrophenol (46.9 g, 270 mmol) and triethylamine (28.8 g, 39.6 mL, 284 mmol) in dichloromethane (120 mL) over a 20 min period. After 2 h at 0C, the mixture was filtered through a fritted funnel, and the collected filtrate concentrated to dryness. The crude gum was dissolved MTBE (500 mL) and washed with 0.2 M K2CO3 (2 x 100 mL) followed by 10% brine (3 x 75 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness by rotary evaporator to give a diastereomeric mixture (100 g, 93%) as a pale yellow oil.
3.2 g; 4.2 g
Example 92. Synthesis of 2-chloro-4-nitrophenyl phosphoramidate: A solution of phenyl dichlorophosphate (60 g, 42.5 mL, 284 mmol) in dichloromethane (300 mL) was cooled to 0oC and then treated with (S)-isopropyl 2- aminopropanoate hydrochloride (47.7 g, 284 mmol). The mixture was further cooled to - 78oC and treated dropwise with a solution of triethylamine (57.6 g, 79 mL, 569 mmol) in methylene chloride (300 mL) over a 1 h period. The reaction mixture was warmed to 0oC for 30 min and then treated with a preformed mixture of 2-chloro-4-nitrophenol (46.9 g, 270 mmol) and triethylamine (28.8 g, 39.6 mL, 284 mmol) in dichloromethane (120 mL) over a 20 min period. After 2 h at 0oC, the mixture was filtered through a fritted funnel, and the collected filtrate concentrated to dryness. The crude gum was dissolved MTBE (500 mL) and washed with 0.2 M K2CO3 (2 x 100 mL) followed by 10% brine (3 x 75 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness by rotary evaporator to give a diastereomeric mixture (100 g, 93%) as a pale yellow oil. 1H NMR (400 MHz, Chloroform-d) delta 8.33 (dd, J = 2.7, 1.1 Hz, 1H, diastereomer 1), 8.31 (dd, J = 2.7, 1.1 Hz, 1H, diastereomer 2), 8.12 (dd, J = 9.1, 2.7 Hz, 1H), 7.72 (dt, J = 9.1, 1.1 Hz, 1H), 7.40- 7.31 (m, 2H), 7.28- 7.19 (m, 6H), 5.01 (pd, J = 6.3, 5.2 Hz, 1H), 4.22- 4.08 (m, 1H), 3.96 (td, J = 10.7, 9.1, 3.6 Hz, 1H), 1.43 (dd, J = 7.0, 0.6 Hz, 3H), 1.40 (dd, J = 7.2, 0.6 Hz, 3H, diastereomer 2), 1.25- 1.20 (m, 9H). Example 93. Separation of compound 253 diastereomers: The diastereomeric mixture 253 (28 g, 63.2 mmol) was dissolved in 2:3 ethyl acetate:hexanes (100 mL) and cooled to -20oC. After 16 h, the resulting white solid was collected by filtration and dried under high vacuum to give a 16:1 Sp:Rp-diastereomeric mixture (5.5 g, 19.6%). The mother liquor was concentrated and the resulting residue dissolved in 2:3 ethyl acetate:hexanes (50 mL). After 16h at -10oC, the resulting white solid was collected and dried under high vacuum to give a 1:6 Sp:Rp-diastereomeric mixture (4g, 14%). The 16:1 Sp:Rp-diastereomeric mixture (5.5 g, 12.4 mmol) was suspended in hot hexanes (50 mL) and treated slowly with ethyl acetate (approximately 10 mL) until complete dissolution. After cooling to 0oC, the resulting white solid was collected by filtration, washed with hexanes, and dried under high vacuum to give the Sp-diastereomer of 254 (4.2 g, 76%) as a single isomer. 1H NMR (Sp-diastereomer, 400 MHz, Chloroform-d) delta 8.33 (dd, J = 2.7, 1.1 Hz, 1H), 8.12 (dd, J = 9.1, 2.7 Hz, 1H), 7.71 (dd, J = 9.1, 1.2 Hz, 1H), 7.41- 7.30 (m, 2H), 7.29- 7.11 (m, 3H), 5.00 (m, 1H), 4.25- 4.07 (m, 1H), 3.97 (dd, J = 12.7, 9.4 Hz, 1H), 1.43 (d, J = 7.0 Hz, 3H), 1.23 (d, J = 2.2 Hz,3H), 1.21 (d, J = 2.2 Hz, 3H). The 1:6 Sp:Rp-diastereomeric mixture (4 g, 12.4 mmol) was suspended in hot hexanes (50 mL) and treated slowly with ethyl acetate (approximately 5 mL) until complete dissolution. After cooling to 0oC, the resulting white solid was collected by filtration, washed with hexanes, and dried under high vacuum to give the Rp-diastereomer of 255 (3.2g, 80%) as a single isomer. Absolute stereochemistry was confirmed by X-ray analysis. 1H NMR (Rp-diastereomer , 400 MHz, Chloroform-d) delta 8.31 (dd, J = 2.7, 1.1 Hz, 1H), 8.11 (dd, J = 9.1, 2.7 Hz, 1H), 7.72 (dd, J = 9.1, 1.2 Hz, 1H), 7.42- 7.30 (m, 2H), 7.31- 7.14 (m, 3H), 5.01 (p, J = 6.3 Hz, 1H), 4.15 (tq, J = 9.0, 7.0 Hz, 1H), 4.08- 3.94 (m, 1H), 1.40 (d, J = 7.0 Hz, 3H), 1.24 (d, J = 3.5 Hz, 3H), 1.22 (d, J = 3.5 Hz, 3H).
3.2 g; 4.2 g
A solution of phenyl dichlorophosphate (60 g, 42.5 mL, 284 mmol) in (0564) dichloromethane (300 mL) was cooled to 0C and then treated with (S)-isopropyl 2- aminopropanoate hydrochloride (47.7 g, 284 mmol). The mixture was further cooled to - 78C and treated dropwise with a solution of triethylamine (57.6 g, 79 mL, 569 mmol) in methylene chloride (300 mL) over a 1 h period. The reaction mixture was warmed to 0C for 30 min and then treated with a preformed mixture of 2-chloro-4-nitrophenol (46.9 g, 270 mmol) and triethylamine (28.8 g, 39.6 mL, 284 mmol) in dichloromethane (120 mL) over a 20 min period. After 2 h at 0C, the mixture was filtered through a fritted funnel, and the collected filtrate concentrated to dryness. The crude gum was dissolved MTBE (500 mL) and washed with 0.2 M K2CO3 (2 x 100 mL) followed by 10% brine (3 x 75 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness by rotary evaporator to give a diastereomeric mixture (100 g, 93%) as a pale yellow oil. (0565) Example 4: Separation of compound 5 diastereomers (0566) The diastereomeric mixture 5 (28 g, 63.2 mmol) was dissolved in 2:3 ethyl acetate: hexanes (100 mL) and cooled to -20C. After 16 h, the resulting white solid was collected by filtration and dried under high vacuum to give a 16: 1 SP:RP-diastereomeric mixture (5.5 g, 19.6%). The mother liquor was concentrated and the resulting residue dissolved in 2:3 ethyl acetate: hexanes (50 mL). After 16h at -10C, the resulting white solid was collected and dried under high vacuum to give a 1 :6 SP:RP-diastereomeric mixture (4g, 14%). The 16: 1 SP:RP-diastereomeric mixture (5.5 g, 12.4 mmol) was suspended in hot hexanes (50 mL) and treated slowly with ethyl acetate (approximately 10 mL) until complete dissolution. After cooling to 0C, the resulting white solid was collected by filtration, washed with hexanes, and dried under high vacuum to give the SP -diastereomer of 6 (4.2 g, 76%) as a single isomer. (0567) The 1 :6 SP:RP-diastereomeric mixture (4 g, 12.4 mmol) was suspended in hot hexanes (50 mL) and treated slowly with ethyl acetate (approximately 5 mL) until complete dissolution. After cooling to 0C, the resulting white solid was collected by filtration, washed with hexanes, and dried under high vacuum to give the RP -diastereomer of 7 (3.2g, 80%) as a single isomer.
With potassium carbonate; In acetonitrile; at 60℃; for 2h;Inert atmosphere;
In a glass flask provided with a condenser, thermometer, mechanical stirrer and nitrogen inlet, - under nitrogen flow - 22.9 g of 2-Chloro-4-nitrophenol of formula (VI), 25.0 g of 1-(bromomethyl)-2-fluorobenzene of formula (VII) and 230 mL of Acetonitrile are introduced. Stirring is carried out at 20-25 C and 20.1 g of Potassium carbonate are added. The mixture is stirred at 60 C for 2 hours. Upon completing the reaction cooling is carried out and the reaction mixture is poured into 230 mL of purified water pre-cooled at 0-5 C. The precipitation of a yellowish solid is observed. The formed solid is filtered thoroughly draining the mother liquors and washing with 2x46 mL of water/acetonitrile 1:1 mixture pre-cooled at 0-5 C. Washing is then carried out with 46 mL of n-Hexane pre-cooled at 0-5 C. The product is dried in an oven under vacuum for 4-5 hours at 45 C. 33.9 g of product as an almost white solid equivalent to a 91.2% yield are obtained.
91.2%
With potassium carbonate; In acetonitrile; at 60℃; for 2h;Inert atmosphere;
In a glass flask provided with a condenser, thermometer, mechanical stirrer and nitrogen inlet, -under nitrogen flow-22.9 g of 2-Chloro-4-nitrophenol of formula (VI), 25.0 g of 1-(bromomethyl)-2-fluorobenzene of formula (VII) and 230 mL of Acetonitrile were introduced. Stirring was carried out at 20-25 C. and 20.1 g of potassium carbonate were added. The mixture was stirred at 60 C. for 2 hours. Upon completing the reaction cooling was carried out and the reaction mixture was poured into 230 mL of purified water pre-cooled at 0-5 C. The precipitation of a yellowish solid was observed. The formed solid was filtered thoroughly draining the mother liquors and washing with 2×46 mL of water/acetonitrile 1:1 mixture pre-cooled at 0-5 C. Washing was then carried out with 46 mL of n-Hexane pre-cooled at 0-5 C. The product was dried in an oven under vacuum for 4-5 hours at 45 C. 33.9 g of product as an almost white solid equivalent to a 91.2% yield were obtained.
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;
a) 6- 3-(2-Chl0ro-4-nitro-phenoxy)-propyll-2-oxa-6-aza-spiro[3.31heptaneTo a mixture 3-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-propan-l -ol (0.22 g 1.44 mmol), 2-chloro- 4-nitro-phenol (0.25 g, 1.44 mmol), triphenylphosphine (0.75 g, 2.88 mmol) in dry tetrahydrofurane (30 mL) was added droppwise at 0 C di-tert-butyl-azo-dicarboxylate (0.66 g, 2.88 mmol) in tetrahydrofurane (10 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was diluted with dichloromethane (30 mL) and washed with water (100 mL), and 2 M NaOH (2 x 20 mL) and dried over Na2S04. After filtration the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane and methanol (95:5) to yield 0.39 g (86%) of the title compound.
Stage #1: 2-chloro-4-nitrophenol With potassium hydroxide In methanol; water for 0.5h;
Stage #2: trifluoromethan In methanol; water; acetonitrile at 20℃; for 3h;
4.3 4.3 Preparation of 1-(difluoromethoxy)-4-nitrobenzene (2a)
General procedure: Using the apparatus previously described for method B [21] , potassium hydroxide (2.52 g, 45 mmol, 15 equiv), water (2.52 g), and methanol (1 g) were added to the reaction vessel and the mixture was allowed to stir until the potassium hydroxide was almost completely dissolved. Then, 4-nitrophenol (0.52 g, 3 mmol) was added and the mixture stirred for 30 min, after which acetonitrile (10 mL) was added via syringe and the mixture stirred at room temperature. Fluoroform was then bubbled slowly into the mixture for 2 h, after which the resulting mixture was stirred for one additional hour. After being quenched with water and extracted with ethyl acetate, the ethyl acetate layer was washed with a saturated solution on sodium hydroxide, separated and concentrated. Additional impurities were removed via column chromatography on silica gel using an 80:20 mixture of hexanes/methylene chloride to give an 83% yield of the liquid product, 1-(difluoromethoxy)-4-nitrobenzene (2a):
(2S)-isopropyl 2-(((2-chloro-4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
A solution of phenyl dichiorophosphate (60 g, 42.5 mL, 284 mmol) indichloromethane (300 mL) was cooled to 0C and then treated with <strong>[39613-92-8](S)-isopropyl 2-aminopropanoate hydrochloride</strong> (47.7 g, 284 mmol). The mixture was further cooled to -78C and treated dropwise with a solution of triethylamine (57.6 g, 79 mL, 569 mmol) inmethylene chloride (300 mL) over a 1 h period. The reaction mixture was warmed to 0C for30 mm and then treated with a preformed mixture of 2-chloro-4-nitrophenol (46.9 g, 270mmol) and triethylamine (28.8 g, 39.6 mL, 284 mmol) in dichloromethane (120 mL) over a20 mm period. After 2 h at 0C, the mixture was filtered through a fitted funnel, and thecollected filtrate concentrated to dryness. The crude gum was dissolved MTBE (500 mL) andwashed with 0.2 M K2C03 (2 x 100 mL) followed by 10% brine (3 x 75 mL). The organicphase was dried over sodium sulfate, filtered and concentrated to dryness by rotary evaporator to give a diastereomeric mixture (100 g, 93%) as a pale yellow oil.?H NMR (400 MHz, Chloroform-d) oe 8.33 (dd,J=2.7, 1.1 Hz, 1H, diastereomer 1), 8.31 (dd, J= 2.7, 1.1 Hz, 1H, diastereomer 2), 8.12 (dd, J= 9.1, 2.7 Hz, 1H), 7.72 (dt, J= 9.1, 1.1Hz, 1H), 7.40- 7.31 (m, 2H), 7.28 -7.19 (m, 6H), 5.01 (pd, J= 6.3, 5.2 Hz, 1H), 4.22-4.08(m, 1H), 3.96 (td, J= 10.7, 9.1, 3.6 Hz, 1H), 1.43 (dd, J 7.0, 0.6 Hz, 3H), 1.40 (dd, J 7.2,0.6 Hz, 3H, diastereomer 2), 1.25 - 1.20 (m, 9H).
93%
A solution of phenyl dichlorophosphate (60 g, 42.5 mL, 284 mmol) in dichloromethane (300 mL) was cooled to 0C and then treated with <strong>[39613-92-8](S)-isopropyl 2-aminopropanoate hydrochloride</strong> (47.7 g, 284 mmol). The mixture was further cooled to -78C and treated dropwise with a solution of triethylamine (57.6 g, 79 mL, 569 mmol) in methylene chloride (300 mL) over a 1 h period. The reaction mixture was warmed to 0C for 30 min and then treated with a preformed mixture of 2-chloro-4-nitrophenol (46.9 g, 270 mmol) and triethylamine (28.8 g, 39.6 mL, 284 mmol) in dichloromethane (120 mL) over a 20 min period. After 2 h at 0C, the mixture was filtered through a fritted funnel, and the collected filtrate concentrated to dryness. The crude gum was dissolved MTBE (500 mL) and washed with 0.2 M K2CO3 (2 x 100 mL) followed by 10% brine (3 x 75 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness by rotary evaporator to give a diastereomeric mixture (100 g, 93%) as a pale yellow oil. 1H NMR (400 MHz, Chloroform-d) delta 8.33 (dd, J = 2.7, 1.1 Hz, 1H, diastereomer 1), 8.31 (dd, J = 2.7, 1.1 Hz, 1H, diastereomer 2), 8.12 (dd, J= 9.1 , 2.7 Hz, 1H), 7.72 (dt, J = 9.1, 1.1 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.28 - 7.19 (m, 6H), 5.01 (pd, J= 6.3, 5.2 Hz, 1H), 4.22 - 4.08 (m, 1H), 3.96 (td, J = 10.7, 9.1 , 3.6 Hz, 1H), 1.43 (dd, J = 7.0, 0.6 Hz, 3H), 1.40 (dd, J= 7.2, 0.6 Hz, 3H, diastereomer 2), 1.25 - 1.20 (m, 9H).
93%
A solution of phenyl dichlorophosphate (60 g, 42.5 mL, 284 mmol) in (1077) dichloromethane (300 mL) was cooled to 0C and then treated with (S)-isopropyl 2- aminopropanoate hydrochloride (47.7 g, 284 mmol). The mixture was further cooled to - 78C and treated dropwise with a solution of triethylamine (57.6 g, 79 mL, 569 mmol) in methylene chloride (300 mL) over a 1 h period. The reaction mixture was warmed to 0C for 30 min and then treated with a preformed mixture of 2-chloro-4-nitrophenol (46.9 g, 270 mmol) and triethylamine (28.8 g, 39.6 mL, 284 mmol) in dichloromethane (120 mL) over a 20 min period. After 2 h at 0C, the mixture was filtered through a fritted funnel, and the collected filtrate concentrated to dryness. The crude gum was dissolved MTBE (500 mL) and washed with 0.2 M K2CO3 (2 x 100 mL) followed by 10% brine (3 x 75 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness by rotary evaporator to give a diastereomeric mixture (100 g, 93%) as a pale yellow oil. NMR (400 MHz, Chloroform-c delta 8.33 (dd, J = 2.7, 1.1 Hz, 1H, diastereomer 1), 8.31 (dd, J = 2.7, 1.1 Hz, 1H, diastereomer 2), 8.12 (dd, J = 9.1, 2.7 Hz, 1H), 7.72 (dt, J = 9.1, 1.1 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.28 - 7.19 (m, 6H), 5.01 (pd, J = 6.3, 5.2 Hz, 1H), 4.22 - 4.08 (m, 1H), 3.96 (td, J = 10.7, 9.1, 3.6 Hz, 1H), 1.43 (dd, J = 7.0, 0.6 Hz, 3H), 1.40 (dd, J = 7.2, 0.6 Hz, 3H, diastereomer 2), 1.25 - 1.20 (m, 9H).
93%
A solution of phenyl dichlorophosphate (60 g, 42.5 mL, 284 mmol) in dichloromethane (300 mL) was cooled to 0C and then treated with (S)-isopropyl 2- aminopropanoate hydrochloride (47.7 g, 284 mmol). The mixture was further cooled to - 78C and treated dropwise with a solution of triethylamine (57.6 g, 79 mL, 569 mmol) in methylene chloride (300 mL) over a 1 h period. The reaction mixture was warmed to 0C for 30 min and then treated with a preformed mixture of 2-chloro-4-nitrophenol (46.9 g, 270 mmol) and triethylamine (28.8 g, 39.6 mL, 284 mmol) in dichloromethane (120 mL) over a 20 min period. After 2 h at 0C, the mixture was filtered through a fritted funnel, and the collected filtrate concentrated to dryness. The crude gum was dissolved MTBE (500 mL) and washed with 0.2 M K2CO3 (2 x 100 mL) followed by 10% brine (3 x 75 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness by rotary evaporator to give a diastereomeric mixture (100 g, 93%) as a pale yellow oil. 'H NMR (400 MHz, Chloroform-6/) d 8.33 (dd, J= 2.7, 1.1Hz, 1H, diastereomer 1), 8.31 (dd, = 2.7, 1.1Hz, 1H, diastereomer 2), 8.12 (dd, J= 9.1, 2.7 Hz, 1H), 7.72 (dt, = 9.1, 1.1Hz, 1H), 7.40 - 7.31 (m, 2H), 7.28 - 7.19 (m, 6H), 5.01 (pd, J= 6.3, 5.2 Hz, 1H), 4.22 - 4.08 (m, 1H), 3.96 (td, J= 10.7, 9.1, 3.6 Hz, 1H), 1.43 (dd,.7= 7.0, 0.6 Hz, 3H), 1.40 (dd, J = 7.2, 0.6 Hz, 3H, diastereomer 2), 1.25 - 1.20 (m, 9H).
A solution of phenyl dichlorophosphate (60 g, 42.5 mL, 284 mmol) in dichloromethane (300 mL) was cooled to 0C and then treated with (S)-isopropyl 2-aminopropanoate (2081) hydrochloride (47.7 g, 284 mmol). The mixture was further cooled to -78C and treated dropwise with a solution of triethylamine (57.6 g, 79 mL, 569 mmol) in methylene chloride (300 mL) over a 1 h period. The reaction mixture was warmed to 0C for 30 min and then treated with a preformed mixture of 2-chloro-4-nitrophenol (46.9 g, 270 mmol) and triethylamine (28.8 g, 39.6 mL, 284 mmol) in dichloromethane (120 mL) over a 20 min period. After 2 h at 0C, the mixture was filtered through a fritted funnel, and the collected filtrate concentrated to dryness. The crude gum was dissolved MTBE (500 mL) and washed with 0.2 M K2CO3 (2 x 100 mL) followed by 10% brine (3 x 75 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness by rotary evaporator to give a diastereomeric mixture (100 g, 93%) as a pale yellow oil.
Step 1: 2-chloro-1-(3-fluorobenzyloxy)-4-nitrobenzene 2-chloro-4-nitrophenol (3.4 g, 20 mmol), <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (2.8 g, 20 mmol) and potassium carbonate (3.3 g, 24 mmol) was refluxed in acetonitrile (30 mL) overnight. The reaction mixture was poured into 100 mL of H2O, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated in vacuo to obtain the crude product. The crude product was washed with petroleum ether, filtered and dried, and the compound shown in the title (3.2 g, 57%) was obtained. 1H NMR (CDCl3): delta 8.35 (1H, d, J=2.8 Hz), 8.17-8.14 (1H, m), 7.44-7.38 (1H, m), 7.25-7.19 (2H, m), 7.10-7.06 (1H, m), 7.03 (1H, d, J=9.2 Hz), 5.26 (2H, s).
53%
With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 23h;Inert atmosphere;
The synthesis was performed as described by Shiao et al. for similar compounds [60]. The work-up was performed as described by Fontana et al. [61]. 2-Chloro-4-nitrophenol (1.50 g, 8.64 mmol) was mixed with K2CO3 (3.58 g, 25.9 mmol), before DMF (90 mL) was added under nitrogen atmosphere. The mixture was heated to 75 C, and <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (1.87 g, 13.0 mmol) dissolved in DMF (60 mL) was added slowly. The reaction mixture was stirred at 75 C for 23 h, cooled to rt, quenched into cold water (150 mL, 5 C) and filtered. The isolated solid was washed with an ACN/water mixture (1/1, 50 mL), and n-hexane (30 mL). The obtained white solid was dried under reduced pressure. This yielded 1.29 g (4.58 mmol, 53%) of 2-chloro-1-((3-fluorobenzyl)oxy)-4-nitrobenzene as a white solid, mp. 90-96 C; 1H NMR (400 MHz, DMSO-d6) delta: 8.35 (d, J=2.8, 1H), 8.25 (dd, J=8.8, 2.8, 1H), 7.52-7.44 (m, 2H), 7.35-7.30 (m, 2H), 7.24-7.17 (m, 1H), 5.42 (s, 2H); 13C NMR (100 MHz, DMSO-d6) delta: 162.2 (d, J=243.7), 158.6, 140.9, 138.4 (d, J=8.1), 130.7 (d, J=8.1), 125.4, 124.6, 123.5 (d, J=2.9), 122.0, 115.1 (d, J=20.6), 114.3 (d, J=22.0), 113.8, 70.1 (d, J=2.1); 19F NMR (564 MHz, DMSO-d6, C6F6) delta: -115.15 (s, dec.); 1H NMR findings are in accordance with literature [59].
a. synthesis of 3-chloro-4-(3-fluorobenzyloxy)aniline (0198) (0199) 1-(Chloromethyl)-3-fluorobenzene (4.9 g, 34.6 mmol) was added into DMF (48 mL) and stirred to dissolve completely, K2CO3 (9.6 g, 69 mmol) was added and stirred for 30 min. 2-Chloro-4-nitrophenol (6 g, 34.6 mmol), KI (0.29 g, 1.7 mmol) were added at 60C under an oil bath, then reacted for 3 h. The reaction solution was added into ice-water, a large amount of solid was precipitated after stirring, filtrated to deliver the product 2-chloro-1-(3-fluorobenzyloxy)-4-nitrobenzene, which was used in the next step directly. (0200) According to a method similar to the preparation of compound 4, taking 2-chloro-1-(3-fluorobenzyloxy)-4-nitrobenzene obtained in the previous step as the starting material, 3-chloro-4-(3-fluorobenzyloxy)aniline (81% yield) can be synthesized. ESI-MS (m/z): 252.1 [M+H]+.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h;
General procedure: A mixture of 2-chloro-4-nitrophenol (1 equiv., 2.88 mmol, 0.5 g), the respective substituted benzyl chloride (viz; <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong>, 3-chlorobenzyl chloride, 3,4-dichlorobenzyl chloride) or 2-picolyl chloride HCl (1 equiv., 2.88 mmol) and anhydrous K2CO3 (1.66 equiv., 4.78 mmol, 0.66 g) in dry DMF (10 mL) was heated at 80 oC for 24 hours. After cooling, the reaction mixture was poured into ice/water (100 mL). The precipitated solid was filtered, washed with water, and then washed with cold n-hexane to afford the designated compounds (1a-d). [1,2]
2-(2-chloro-4-nitrophenoxy)-N-cyclohexyl-3-methylbutanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With 1,4-diaza-bicyclo[2.2.2]octane; In neat (no solvent); at 55℃; for 12h;
General procedure: To 1.0 equiv. of phenol were added successively 1.0 equiv. of DABCO, 2.0 equiv. of aldehyde, and 1.0 equiv. of isocyanide. The resulting mixture was stirred neat at 80 C for 12 h. The crude product was dissolved in dichloromethane. The organic layer was washed with 1 M NaOH, water, dried over MgSO4 and then concentrated. The crude product was purified by flash chromatography on silica gel.
With potassium hydroxide In methanol; water at 50℃; for 1h;
Stage #1: 2-chloro-4-nitrophenol; ethyl bromoacetate With potassium carbonate In dimethyl sulfoxide at 50℃; for 6h;
Stage #2: With water; sodium hydroxide In acetone at 50℃; for 3h;
Stage #3: With hydrogenchloride In water at 25℃;
With tributylphosphine; diamide; In tetrahydrofuran; at 10 - 40℃; for 1.5h;
To a 1000 ml reaction flask was added 350 ml of tetrahydrofuran, 75 g of <strong>[619-08-9]2-chloro-4-nitrophenol</strong>, 58.0 g 3-fluorobenzyl alcoholAnd 106gTributylphosphine,Turn agitated, cool to 10 C, slowly drop 90 g of tetramethylazodicarbonamide (TMAD) and 200 mlTetrahydrofuran, the solution was added dropwise and the temperature was stirred at 10 C for 1.5 hours. The reaction was carried out at a temperature of 40 CThe reaction solution was concentrated under reduced pressure to dryness, and the residue was stirred with N, N-dimethylformamide (200 ml), and the mixture was cooled to 0 C.The resulting solid was dried at 55-60 C to give 113.2 g of a pale yellow solid, 99.82% purity and a yield of 93.0%.
With sodium hydride; In N,N-dimethyl-formamide; at 140℃;pH 8.0;
General procedure: The solution of N-substituted-2-chloroacetamide 2 (5.0 mmol, 1.0 equiv.) and 2-chloro-4-nitro -phenol (5.0 mmol, 1.0 equiv.) was heated at 140 C and generated the desired product by the slowly addition of appropriate amounts NaH (12.5 mmol, 2.5 equiv.) in DMF (40 mL). The reaction was monitored by TLC and pH indicator (maintain the value at pH 8.0). After completion of the reaction, the solvent was removed under vacuum and water (40 mL) was added into the residue. The mixture was then extracted with ethyl acetate (4 × 40 mL). The organic layers were combined, dried over anhydrous MgSO4, and evaporated under vacuum to give the crude product. The residue obtained was purified by silica gel column chromatography (elute: ethyl acetate: petroleum = 1: 10) to obtain the corresponding compound 3.
With sodium hydride; In N,N-dimethyl-formamide; at 140℃;pH 8.0;
General procedure: The solution of N-substituted-2-chloroacetamide 2 (5.0 mmol, 1.0 equiv.) and 2-chloro-4-nitro -phenol (5.0 mmol, 1.0 equiv.) was heated at 140 C and generated the desired product by the slowly addition of appropriate amounts NaH (12.5 mmol, 2.5 equiv.) in DMF (40 mL). The reaction was monitored by TLC and pH indicator (maintain the value at pH 8.0). After completion of the reaction, the solvent was removed under vacuum and water (40 mL) was added into the residue. The mixture was then extracted with ethyl acetate (4 × 40 mL). The organic layers were combined, dried over anhydrous MgSO4, and evaporated under vacuum to give the crude product. The residue obtained was purified by silica gel column chromatography (elute: ethyl acetate: petroleum = 1: 10) to obtain the corresponding compound 3.
(3S,3aR,6S,6aR)-6-(2-chloro-4-nitrophenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
To a solution of triphenylphosphine (7.87 g, 30 mmol) in THF (200 mL) in a 500 mL 3- neck RB flask was added di-isopropylazodicarboxylate (6.06 g, 5.9 mL, 30 mmol) at 0-5C (ice + water) for 10 minutes under an argon atmosphere. The resulting light yellow suspension was stirred for 10-15 minutes at this temperature. Then, a clear solution of <strong>[619-08-9]2-chloro-4-nitrophenol</strong>(3.47 g, 20 mmol) in THF (100 mL) was added drop-wise over 10-15 minutes. After 2 minutes,the cooling bath was removed to allow the reaction mixture to warm to room temperature where it was stirred for 10-15 minutes.Then, a solution of isosorbide (3.51 g, 24 mmol) in THF (60 mL) was slowly addedfollowed by the neat DIPEA (3.87 g, 5.22 mL, 30 mmol) at room temperature. It produced a light yellow color solution after the addition of isosorbide solution. Then, the resulting light yellowsolution was stirred for 36 h and the cloudy reaction mixture was heated to 65C and stirred for 4h by which time TLC (1:1, Hex:EA) analysis of the reaction mixture indicated the appearance of a new spot.Then, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The crude residue was dissolved in a minimum amount of EA at hot conditionand then diluted with hexanes. The resulting solution was stored in the freezer over the weekend. The resulting off-white solids were collected by filtration and washed with hexanes. After air drying, 20.05 g of solid was isolated as a mixture of the desired product and triphenylphosphine oxide based on the TLC. This solid was dissolved in acetonitrile (-3O mL) in hot conditions and then stored in the freezer. The resulting triphenylphosphine oxide solids were collected byfiltration and the filtration was removed under vacuum which mostly contained the desired product. Then, the residue was again dissolved in minimum EA at hot condition and diluted with hexanes and the clear solution was stored in the freezer. The remaining triphenylphosphine oxide precipitated which was removed by filtration under vacuum to obtain 5.56 g (92%) of(3S ,3aR,6S ,6aR)-6-(2-chloro-4-nitro-phenoxy)-2,3 ,3a,5,6,6a-hexahydrofuro[3 ,2-bjfuran-3-ol asa light brown paste. 1H-NMR (DMSO-d6): 8.34 (d, 1=2.3 Hz, 1H), 8.23 (dd, 1=8.4, 2.8 Hz,1H), 7.46 (d, 1=8.4 Hz, 1H), 5.30 (d, 1=3.9 Hz, 1H), 5.16 (d, 2.8 Hz, 1H), 4.64 (d, 1=3.9 Hz, 1H),4.48 (d, 1=3.9 Hz, 1H), 4.15 (br, s, 1H), 4.02 (dd, 1=10.1, 3.9 Hz, 1H), 3.93 (d, 1=10.1 Hz, 1H),3.81 (dd, 1=8.4, 3.4 Hz, 1H), 3.74 (d, 1=9.0 Hz, 1H). LC/MS calcd. for C12H12C1N06 [(M-H)j300, obsd. 300.
(3S,3aR,6S,6aR)-3-benzyloxy-6-(2-chloro-4-nitrophenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
To a solution of triphenylphosphine (5.9 g, 22.5 mmol) in THF (150 mL) in a 500 mL 3- neck RB flask was added di-isopropylazodicarboxylate (4.55 g, 4.43 mL, 22.5 mmol) at 0-5C(ice + water) for 5-10 minutes under an argon atmosphere. The resulting light yellow suspension was stirred for 10-15 minutes at this temperature. Then, a clear solution of 2-chloro-4- nitrophenol (2.6 g, 15 mmol) in THF (100 mL) was added drop-wise over 5-10 minutes. After 2 minutes, the cooling bath was removed to allow the reaction mixture to warm to room temperature where it was stirred for 10-15 minutes. Then, a solution of isosorbide 2-benzyl ether (4.25 g, 18 mmol) (prepared following the literature procedure, Carbohydrate Research 1994, 26], 255-266) in THF (100 mL) was slowly added followed by the neat triethylamine (2.28 g, 3.2 mL, 22.5 mmol) at room temperature. The resulting light yellow suspension was stirred for 48 h by which time TLC (1:1, Hex:EA) analysisof the reaction mixture indicated the appearance of a new spot. Then, the solvent was removed under vacuum and the crude residue was purified using an ISCO (330 g) column chromatography to afford 5.29 g (90%) of (3 S ,3 aR,6S ,6aR)-3 -benzyloxy-6-(2-chloro-4- nitrophenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-bjfuran as a light brown viscous oil. LC/MS calcd. for C19H18C1N06 [(M-H)j 390, obsd. 390.
With potassium hydroxide; In water; at 150℃; for 4h;Sealed tube; Inert atmosphere;
86.3 g (0.5 mol) of the starting material 2-chloro-4-nitroaniline, 33.7 g (0.6 mol) of potassium hydroxide, 150 ml of deionized water, and 10 g of polyethylene glycol (PEG400) were mixed and added to the reaction vessel.The reaction vessel was sealed by replacing the air several times with nitrogen, and the temperature was raised to 150 C for 4 h. After the reaction was completed, the reaction vessel was cooled to room temperature and then opened, and the reaction solution was adjusted to pH=2 with 20% by volume of sulfuric acid.Thus, crude 2-chloro-4-nitrophenol was precipitated, filtered, and the filter cake was washed three times with deionized water (30 ml of deionized water per wash).Drying (drying to constant weight at 80 C) gave 71.7 g of 2-chloro-4-nitrophenol (fine), the yield was 82.6%, and the purity was 99%
With potassium carbonate; In acetonitrile; at 65℃;Inert atmosphere;
General procedure: Substituted phenol (0.1 mol), anhydrous CH3CN (20 mL) and K2CO3 (0.11 mol) were added to a 100 mL dry eggplant flask. With stirring, methyl chloroacetate (0.11 mol)was added dropwise 3-6 h at 65 . The reaction progress was tracked using TLC.After the reaction completion, the reaction mixture was filtered and the filtrate was evaporated to give the compound C. The analytical data corresponded to the literature[1-8].
With sodium carbonate; In acetonitrile; at 25℃; for 5h;
Add 40g of 2-bromomethylpyridine, 44g of <strong>[619-08-9]2-chloro-4-nitrophenol</strong> to a 1000ml three-necked bottle, add 300ml of acetonitrile and 24.6g of sodium carbonate, start stirring, and control the temperature in the reaction bottle at 25 C to stir for 5 hoursThen add 500ml of drinking water, stir for 10 minutes, then cool to 10 C and stir for 30 minutes, filter, wash the filter cake with 200ml of drinking water, the obtained wet product solid is placed in a hot air circulation oven, and the temperature is controlled at 60-65 C and dried for 6 hours. Off-white solid 59.68g, yield 96.98%, purity 99.83%.
2-chloro-4-nitrophenyl 5-chloro-2-hydroxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With trichlorophosphate In toluene at 180℃; for 1h; Microwave irradiation;
1 General procedure A: Microwave assisted amide formation.
General procedure: In an oven dried microwave vial, the required carboxylic acid (1.5 equiv), aniline (R3 = NH2) or phenol (R3 = OH) (1 equiv), and POCI3 (1.5 equiv) were combined in anhydrous toluene (6 mL/mmol) and heated under microwave irradiation conditions at 180 °C for 1 hr. The solvent was removed In vacuo and the crude residue was subsequently purified via silica gel chromatography to give the desired product.
With thionyl chloride at 80℃; for 3h;
4 5-chloro-O-(2-chloro-4-nitrophenyl)-2-hydroxybenzoate
Synthesis method: Weigh 173 mg of 5-chloro-2-hydroxybenzoic acid and 173 mg of 2-chloro-4-nitrophenol into a flask, 15 ml of thionyl chloride as solvent, heat to 80 degrees and reflux for 3 hours. After the TLC detection reaction is completed, turn off the heating and cool to room temperature. Prepare a beaker of ice-water mixture for post-reaction treatment, reversely quench the remaining thionyl chloride, transfer the post-treatment solution to a separatory funnel, extract 3 times with ethyl acetate, take the organic layer, and wash with saturated sodium chloride solution. Dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and separate by silica gel column chromatography (ethyl acetate: petroleum ether=1: 5, v/v) to obtain compound I-04.
With thionyl chloride for 3h; Reflux;
4.2.11 2-Chloro-4-nitrophenyl-5-chloro-2-hydroxybenzoate (11)
To a solution of 5-chloro-2-hydroxybenzoic acid (200mg, 1.2mmol, 1.0 eq.) in SOCl2 (10mL) was added 2-chloro-4-nitrophenol (201mg, 1.2mmol, 1.0 eq.) and the mixture was heated to reflux for 3h. TLC (PE:EA=3:1) showed that the reaction was complete. Then, the reaction was quenched with ice water (20mL) and extracted three times with EA (40mL). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO2, EA:PE=1:5) to yield 11 as a white solid. 1H NMR (400MHz, DMSO-d6) δ 13.46 (s, 1H), 8.45 (d, J=2.7Hz, 1H), 8.11 (dd, J=9.1, 2.7Hz, 1H), 7.96 (d, J=2.6Hz, 1H), 7.80 (dd, J=8.7, 2.6Hz, 1H), 7.39 (d, J=8.7Hz, 1H), 6.88 (d, J=9.2Hz, 1H). 13C NMR (101MHz, DMSO-d6) δ 164.73, 159.27, 151.72, 142.65, 134.70, 132.03, 130.91, 126.74, 126.41, 125.53, 124.89, 123.04, 116.54. HRMS (EI) m/z calcd for C13H7Cl2NO5 [M]+ 326.9701, found 326.9703.
With thionyl chloride for 3h; Reflux;
4.2.11 2-Chloro-4-nitrophenyl-5-chloro-2-hydroxybenzoate (11)
To a solution of 5-chloro-2-hydroxybenzoic acid (200mg, 1.2mmol, 1.0 eq.) in SOCl2 (10mL) was added 2-chloro-4-nitrophenol (201mg, 1.2mmol, 1.0 eq.) and the mixture was heated to reflux for 3h. TLC (PE:EA=3:1) showed that the reaction was complete. Then, the reaction was quenched with ice water (20mL) and extracted three times with EA (40mL). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO2, EA:PE=1:5) to yield 11 as a white solid. 1H NMR (400MHz, DMSO-d6) δ 13.46 (s, 1H), 8.45 (d, J=2.7Hz, 1H), 8.11 (dd, J=9.1, 2.7Hz, 1H), 7.96 (d, J=2.6Hz, 1H), 7.80 (dd, J=8.7, 2.6Hz, 1H), 7.39 (d, J=8.7Hz, 1H), 6.88 (d, J=9.2Hz, 1H). 13C NMR (101MHz, DMSO-d6) δ 164.73, 159.27, 151.72, 142.65, 134.70, 132.03, 130.91, 126.74, 126.41, 125.53, 124.89, 123.04, 116.54. HRMS (EI) m/z calcd for C13H7Cl2NO5 [M]+ 326.9701, found 326.9703.
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