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[ CAS No. 367-12-4 ]

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Chemical Structure| 367-12-4
Chemical Structure| 367-12-4
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CAS No. :367-12-4 MDL No. :MFCD00002155
Formula : C6H5FO Boiling Point : 151.5°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :112.10 g/mol Pubchem ID :9707
Synonyms :

Safety of [ 367-12-4 ]

Signal Word:Danger Class:3
Precautionary Statements:P501-P261-P270-P240-P210-P233-P243-P241-P242-P271-P264-P280-P370+P378-P337+P313-P305+P351+P338-P362+P364-P303+P361+P353-P332+P313-P301+P312+P330-P304+P340+P312-P403+P235 UN#:1993
Hazard Statements:H302+H312+H332-H315-H319-H225 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 367-12-4 ]

  • Upstream synthesis route of [ 367-12-4 ]
  • Downstream synthetic route of [ 367-12-4 ]

[ 367-12-4 ] Synthesis Path-Upstream   1~47

  • 1
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YieldReaction ConditionsOperation in experiment
90% With bromine In dichloromethane; water EXAMPLE 5
Preparation of 2-[4-(4-bromo-2-fluorophenoxy)phenoxy]propionic acid methyl ester STR29
To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mol) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mol).
The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour.
The mixture was poured into water (600 ml) containing excess sodium bisulfite.
The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml).
The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90percent).
The NMR (CDCl3) was consistent with the assigned structure.
90% With bromine In dichloromethane; water EXAMPLE 5
Preparation of 2-[4-(4-bromo-2-fluorophenoxy)phenoxy propionic acid methyl ester STR29
To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mmol) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mol).
The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour.
The mixture was poured into water (600 ml) containing excess sodium bisulfite.
The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml).
The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90percent).
The NMR (CDCl3) was consistent with the assigned structure.
90% With bromine In dichloromethane; water STR34
To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mole) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mole).
The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour.
The mixture was poured into water (600 ml) containing excess sodium bisulfite.
The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml).
The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90percent).
The NMR (CDCl3) was consistent with the assigned structure.
The gc of this material showed that it contained only a trace of the 2,6-isomer.
This material was used directly in the following step without additional purification.
90% With bromine In dichloromethane; water EXAMPLE 5
Preparation of α[4(4'-bromo-2'-fluorophenoxy)phenoxy]propionic acid methyl ester STR30
To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mole) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mole).
The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour.
The mixture was poured into water (600 ml) containing excess sodium bisulfite.
The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml).
The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90percent).
The NMR (CDCl3) was consistent with the assigned structure.

Reference: [1] Patent: US4642338, 1987, A,
[2] Patent: US4725683, 1988, A,
[3] Patent: US4808750, 1989, A,
[4] Patent: US4550192, 1985, A,
[5] Chemistry - A European Journal, 2017, vol. 23, # 5, p. 1044 - 1047
[6] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
[7] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
[8] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 3112 - 3129
[9] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[10] Patent: WO2005/123748, 2005, A1, . Location in patent: Page/Page column 84 - 85
[11] Patent: WO2006/135316, 2006, A1, . Location in patent: Page/Page column 58
[12] Patent: WO2006/137770, 2006, A1, . Location in patent: Page/Page column 33
[13] Canadian Journal of Chemistry, 2011, vol. 89, # 3, p. 364 - 384
  • 2
  • [ 367-12-4 ]
  • [ 2105-94-4 ]
  • [ 576-86-3 ]
Reference: [1] Tetrahedron, 2012, vol. 68, # 46, p. 9456 - 9463
  • 3
  • [ 367-12-4 ]
  • [ 2105-94-4 ]
Reference: [1] Patent: US5225607, 1993, A,
[2] Patent: EP240121, 1991, B1,
  • 4
  • [ 367-12-4 ]
  • [ 2105-94-4 ]
Reference: [1] Patent: US4829074, 1989, A,
  • 5
  • [ 367-12-4 ]
  • [ 2105-94-4 ]
  • [ 576-86-3 ]
  • [ 2040-89-3 ]
Reference: [1] Dalton Transactions, 2013, vol. 42, # 33, p. 11926 - 11940
  • 6
  • [ 367-12-4 ]
  • [ 1526-17-6 ]
Reference: [1] Chinese Chemical Letters, 2010, vol. 21, # 11, p. 1283 - 1286
[2] Patent: WO2013/28474, 2013, A1, . Location in patent: Page/Page column 83
[3] Patent: WO2014/126944, 2014, A2, . Location in patent: Page/Page column 54
[4] Patent: EP2744499, 2016, B1, . Location in patent: Paragraph 0192
  • 7
  • [ 367-12-4 ]
  • [ 7440-44-0 ]
  • [ 1526-17-6 ]
  • [ 403-19-0 ]
YieldReaction ConditionsOperation in experiment
30 % With nitric acid In hexane; dichloromethane A.
2-Fluoro-4-nitrophenol
To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylene chloride which was cooled to -10° C. (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period.
During the addition, the temperature was maintained at about -5° C.
After the addition was complete, stirring was continued at 0° C. for an additional hour.
At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction.
This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated.
The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p.=119°-121° C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol.
The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated.
The solid which resulted was triturated with boiling hexane (3*150 ml).
This effectively removed all of the least polar-more volatile reaction product.
This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of by-product 2-fluoro-6-nitrophenol as a yellow solid: m.p.=70°-86° C.
30 % With nitric acid In hexane; dichloromethane A.
2-Fluoro-4-nitrophenol
To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylenechloride which was cooled to -10°C (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period.
During the addition, the temperature was maintained at about -5°C.
After the addition was complete, stirring was continued at 0°C for an additional hour.
At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction.
This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated.
The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p. = 119-121°C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol.
The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated.
The solid which resulted was triturated with boiling hexane (3 x 150 ml).
This effectively removed all of the least polar - more volatile reaction product.
This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of 2-fluoro-6-nitrophenol as a yellow solid: m.p. = 70-86°C.
Reference: [1] Patent: US4750931, 1988, A,
[2] Patent: EP142328, 1991, B1,
  • 8
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  • [ 1526-17-6 ]
  • [ 403-19-0 ]
  • [ 123871-61-4 ]
Reference: [1] Tetrahedron, 1989, vol. 45, # 5, p. 1299 - 1310
[2] Tetrahedron, 1989, vol. 45, # 5, p. 1299 - 1310
  • 9
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  • [ 1526-17-6 ]
  • [ 403-19-0 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
  • 10
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  • [ 1526-17-6 ]
  • [ 681227-38-3 ]
Reference: [1] Journal of the Chemical Society, 1940, p. 810
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  • [ 1526-17-6 ]
  • [ 351-49-5 ]
Reference: [1] Journal of the Chemical Society, 1940, p. 810
  • 12
  • [ 50-00-0 ]
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  • [ 394-50-3 ]
Reference: [1] Organic Syntheses, 2005, vol. 82, p. 64 - 68
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 13, p. 1823 - 1832
[3] Tetrahedron Letters, 2005, vol. 46, # 19, p. 3357 - 3358
[4] Tetrahedron Letters, 2005, vol. 46, # 32, p. 5285 - 5287
[5] Organic Letters, 2018, vol. 20, # 10, p. 2880 - 2883
  • 13
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  • [ 394-50-3 ]
  • [ 405-05-0 ]
Reference: [1] Journal of the American Chemical Society, 1946, vol. 68, p. 2502
  • 14
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  • [ 394-50-3 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[2] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[3] Journal of the American Chemical Society, 2013, vol. 135, # 10, p. 3964 - 3970
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  • [ 367-27-1 ]
YieldReaction ConditionsOperation in experiment
41 %Spectr. With Selectfluor; 1-(n-butyl)-3-methylimidazolium triflate In methanol at 80℃; for 5 h; Inert atmosphere General procedure: A mixture of phenol (20 mg), F‐TEDA‐BF4 (1.1 equivalents), IL(0‐15 equivalents) and the organic solvent (5 mL) was stirred for 5 h at various temperatures under an argo atmosphere (Tables 1‐5). The mixture was evaporated at a reduced pressure and analysed by 1H, 19F NMR assolution in CDCl3 or CDCl3‐DMSO‐d6. Cl2CHCHCl2 and PhCF3 were used as internal standards for peakintegration.
Reference: [1] Journal of the American Chemical Society, 1990, vol. 112, # 23, p. 8563 - 8575
[2] Tetrahedron Letters, 1986, vol. 27, # 37, p. 4465 - 4468
[3] Tetrahedron Letters, 1986, vol. 27, # 37, p. 4465 - 4468
[4] Journal of Organic Chemistry, 1998, vol. 63, # 10, p. 3379 - 3385
[5] Tetrahedron Letters, 1986, vol. 27, # 37, p. 4465 - 4468
[6] Journal of Organic Chemistry, 1998, vol. 63, # 10, p. 3379 - 3385
[7] Journal of Organic Chemistry, 1998, vol. 63, # 10, p. 3379 - 3385
[8] Russian Journal of Organic Chemistry, 2009, vol. 45, # 10, p. 1468 - 1473
[9] Arkivoc, 2017, vol. 2018, # 2, p. 60 - 71
  • 16
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  • [ 371-41-5 ]
  • [ 367-12-4 ]
  • [ 367-27-1 ]
  • [ 28177-48-2 ]
Reference: [1] Patent: CN105753655, 2016, A, . Location in patent: Paragraph 0028; 0030; 0038; 0054-0058
  • 17
  • [ 367-12-4 ]
  • [ 2040-90-6 ]
Reference: [1] ACS Catalysis, 2018, vol. 8, # 5, p. 4033 - 4043
[2] Journal of the American Chemical Society, 1959, vol. 81, p. 5904,5905
[3] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
[4] Synthesis, 2006, # 10, p. 1578 - 1589
[5] Tetrahedron Letters, 2008, vol. 49, # 31, p. 4575 - 4578
  • 18
  • [ 29650-44-0 ]
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  • [ 403-14-5 ]
  • [ 699-92-3 ]
YieldReaction ConditionsOperation in experiment
58% With aluminum (III) chloride In chlorobenzene at 120℃; Inert atmosphere; Large scale A solution of 2-fluorophenyl acetate (3, 1.070 Kg, 6.94 moles) and monochlorobenzene (5.34 Lit.) was heated to 120oC. Aluminum trichloride (1.39 Kg, 10.42 moles) was added lot wise at 120 °C over 70–75min. The rise in temperature (~5oC) was controlled by rate of addition. The reaction was maintained at the same temperature for additional 3 h. The reaction mass was cooled to 0 – 5oC. Water (1.07 Lit.) followed by 3.5percent aq. HCl (2.14 Lit.) was added gradually by maintaining internal temperature <30oC using ice bath with vigorous stirring. The mixture was stirred vigorously at 5–10oC for 1 h and filtered, washed the solid cake with water (1 Lit.), suck dried the cake to get beige solid which gave para-isomer 4 (416 g, 38.8percent, >98percent HPLC purity). The organic layers was separated from the filtrate and washed with water (2 Lit.). Concentration of organic layer at normal pressure provided the crude product (530 g) which was then purified by steam distillation. The first fraction was a liquid enriched with 2-fluorophenol (45.2 g, LC: 70 percent 2-fluorophenol, 4 percent 4, 21 percent 5) and second fraction of pale yellow solid as ortho-isomer 5. The product 5 was then isolated by filtration, washed with water (80 mL) and dried under vacuum to yield the title compound (257.6 g, 24percent, > 98.2 percent HPLC) as a pale yellow solid. Steam distillation residue (HPLC: 92.7 percent 4,3.63 percent 5) crystallized from MTBE:Hexane to furnish compound 4 (205.4g, 19.2percent, >98percent HPLC purity). 3-fluoro-4-hydroxyacetophenone (4).1H NMR (CDCl3, 400 MHz) δ: 7.75-7.67 (m, 2H, ArH), 7.06 (t, 1H, J = 8.4 Hz, ArH), 5.98 (d,1H, J = 4 Hz, Ar-OH), 2.56 (s, 3H, Ac). Observed LCMS 153.00. 3-fluoro-2-hydroacetophenone (5).1HNMR (CDCl3, 400 MHz) δ:12.29 (s, 1H, OH), 7.56-7.51 (m, 1H, ArH), 7.32-7.25 (m, 1H, ArH), 6.88-6.81 (m, 1H, ArH), 2.66 (s, 3H, CH3). Observed LCMS 153.00. 
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 15, p. 2426 - 2429
  • 19
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  • [ 75-36-5 ]
  • [ 403-14-5 ]
Reference: [1] Journal of Medicinal Chemistry, 1980, vol. 23, # 7, p. 738 - 744
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  • [ 403-14-5 ]
Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 3, p. 1018 - 1025
[2] Journal of Fluorine Chemistry, 1994, vol. 67, # 1, p. 47 - 52
[3] Journal of the Indian Chemical Society, 1985, vol. 62, # 5, p. 388 - 390
[4] Helvetica Chimica Acta, 1989, vol. 72, p. 594 - 607
[5] Journal of Organic Chemistry, 1952, vol. 17, p. 1425,1429
[6] Patent: US6124323, 2000, A,
[7] Tetrahedron Letters, 2014, vol. 55, # 15, p. 2426 - 2429
[8] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 1, p. 132 - 140
[9] Patent: US2002/28832, 2002, A1,
  • 21
  • [ 367-12-4 ]
  • [ 29650-44-0 ]
  • [ 403-14-5 ]
Reference: [1] Patent: US5516931, 1996, A,
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  • [ 367-12-4 ]
  • [ 7440-44-0 ]
  • [ 1526-17-6 ]
  • [ 403-19-0 ]
YieldReaction ConditionsOperation in experiment
30 % With nitric acid In hexane; dichloromethane A.
2-Fluoro-4-nitrophenol
To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylene chloride which was cooled to -10° C. (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period.
During the addition, the temperature was maintained at about -5° C.
After the addition was complete, stirring was continued at 0° C. for an additional hour.
At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction.
This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated.
The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p.=119°-121° C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol.
The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated.
The solid which resulted was triturated with boiling hexane (3*150 ml).
This effectively removed all of the least polar-more volatile reaction product.
This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of by-product 2-fluoro-6-nitrophenol as a yellow solid: m.p.=70°-86° C.
30 % With nitric acid In hexane; dichloromethane A.
2-Fluoro-4-nitrophenol
To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylenechloride which was cooled to -10°C (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period.
During the addition, the temperature was maintained at about -5°C.
After the addition was complete, stirring was continued at 0°C for an additional hour.
At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction.
This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated.
The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p. = 119-121°C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol.
The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated.
The solid which resulted was triturated with boiling hexane (3 x 150 ml).
This effectively removed all of the least polar - more volatile reaction product.
This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of 2-fluoro-6-nitrophenol as a yellow solid: m.p. = 70-86°C.
Reference: [1] Patent: US4750931, 1988, A,
[2] Patent: EP142328, 1991, B1,
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  • [ 403-19-0 ]
  • [ 123871-61-4 ]
Reference: [1] Tetrahedron, 1989, vol. 45, # 5, p. 1299 - 1310
[2] Tetrahedron, 1989, vol. 45, # 5, p. 1299 - 1310
  • 24
  • [ 367-12-4 ]
  • [ 1526-17-6 ]
  • [ 403-19-0 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
  • 25
  • [ 108-95-2 ]
  • [ 371-41-5 ]
  • [ 367-12-4 ]
  • [ 28177-48-2 ]
Reference: [1] Patent: CN105753655, 2016, A, . Location in patent: Paragraph 0028; 0030; 0038; 0044-0048
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  • [ 108-95-2 ]
  • [ 371-41-5 ]
  • [ 367-12-4 ]
  • [ 367-27-1 ]
  • [ 28177-48-2 ]
Reference: [1] Patent: CN105753655, 2016, A, . Location in patent: Paragraph 0028; 0030; 0038; 0054-0058
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  • [ 363-52-0 ]
YieldReaction ConditionsOperation in experiment
45%
Stage #1: With triethylamine; magnesium chloride In acetonitrile for 0.333333 h; Molecular sieve; Inert atmosphere
Stage #2: With formaldehyd In acetonitrile at 50℃; for 6 h; Inert atmosphere; Molecular sieve
Stage #3: With dihydrogen peroxide; sodium hydroxide In water; acetonitrile at 20 - 30℃; for 1.5 h; Cooling with ice; Inert atmosphere; Molecular sieve
O-fluorophenol (20 g, 0.2 mol) was dissolved in acetonitrile (500 mL, dried over molecular sieves) and protected by argon. Anhydrous magnesium chloride (68 g, 0.72 mol) was added with stirring. Triethylamine (150 mL, 1.08 mol) was added and the mixture was exothermic. After stirring for 20 min, paraformaldehyde (42 g) was added and reacted at 50 ° C for 6 h. TLC showed that some of the starting material remained and the reaction time was not changed significantly. The temperature was lowered to room temperature, and a mixture of sodium hydroxide and water (22.8 g of sodium hydroxide dissolved in 80 mL of 7 jO) was added under ice-water bath. Hydrogen peroxide (30 wtpercent, 140 mL) was then slowly added dropwise with significant exotherm to keep the temperature below The reaction mixture was stirred at 30 ° C for 1.5 h, concentrated hydrochloric acid (12 mol / L) was added to adjust the pH value to 1, and the mixture was extracted with ethyl acetate (4 × 100 mL). The combined organic phases were added with saturated aqueous sodium thiosulfate (200 mL) The mixture was stirred for 1 h. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (1 × 100 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (PE / EtOAc 15: 1 by volume as Eluent) to give 10.3 g of the pale yellow oily liquid (intermediate C-1a) in 45percent yield and recovery of o-fluorophenol 4.3goC-1a: 6H (300MHζ; CDC13) 6.63-6.45 (3H, m) (D, J = 15.5Ηζ), 120.3 (d, J = 15.5Ηζ) J = 8.9Hz), 111.6 (d, J = 2.6Hz), 108.1 (d, J = 18.4Hz)
7.21 g
Stage #1: With formaldehyd; triethylamine; magnesium chloride In tetrahydrofuran for 4 h; Inert atmosphere; Reflux
Stage #2: With dihydrogen peroxide; sodium hydroxide In tetrahydrofuran at 20℃; for 8 h;
Under a nitrogen atmosphere, 600 mL of anhydrous tetrahydrofuran was added 16.2 mL of o-fluorophenol, 35 g of MgCl2,50 mL of triethylamine and 16.2 g of paraformaldehyde were added and heated under reflux for 4 h.Cooled to room temperature, dropping 500mL0.05mol / L NaOH solution, all the components dissolved after the drop of 72mL 30percent hydrogen peroxide, the reaction 2h; then add 72mL 30percent H2O2, stirring reaction 6h.Then add 1.0mol / L hydrochloric acid, adjust the pH 4-5, extracted with methylene chloride,The extract was washed three times with 80percent aqueous Na2S2O3 and dried over anhydrous sodium sulfate overnight.The organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography,Eluting with methylene chloride and collecting the desired fractions and evaporated to dryness under reduced pressure to give 7.21 g of a crystalline solid as white
7.5 g
Stage #1: With formaldehyd; triethylamine; magnesium chloride In tetrahydrofuran for 4 h; Inert atmosphere; Reflux
Stage #2: With dihydrogen peroxide In tetrahydrofuran for 8 h;
Under the protection of nitrogen,Add 16 mL of o-fluorophenol to 600 mL of anhydrous tetrahydrofuran.35g MgCl2,50mL of triethylamine and 16g of paraformaldehyde,The reaction was heated to reflux for 4 h.Cool to room temperature,Add 500mL of 0.05mol/L NaOH solution dropwise.After all the components were dissolved, 72 mL of 30percent hydrogen peroxide was added dropwise.Reaction 2h;Add 70mL of 30percent H2O2,The reaction was stirred for 6 h.Then add 1.0 mol/L hydrochloric acid dropwise.Adjust the pH to 4-5,Extracted with dichloromethane,The extract was washed 3 times with an 80percent Na2S2O3 aqueous solution.It was dried over anhydrous sodium sulfate overnight.Evaporating the organic solvent under reduced pressure,The residue was separated by silica gel column chromatography.Elution with dichloromethane,Collect the required components,Evaporation to dryness under reduced pressure gave 7.5 g of white crystals.Intermediate 2.
Reference: [1] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[2] Patent: CN104557654, 2017, B, . Location in patent: Paragraph 0091-0093
[3] Tetrahedron Letters, 2005, vol. 46, # 19, p. 3357 - 3358
[4] Tetrahedron Letters, 2014, vol. 55, # 15, p. 2426 - 2429
[5] Patent: CN102850335, 2017, B, . Location in patent: Paragraph 0018-0019
[6] Patent: CN108947989, 2018, A, . Location in patent: Paragraph 0010; 0011; 0012
  • 28
  • [ 367-12-4 ]
  • [ 363-52-0 ]
  • [ 120-80-9 ]
Reference: [1] Angewandte Chemie, International Edition, 2014, vol. 53, # 36, p. 9608 - 9612,5[2] Angewandte Chemie, 2014, vol. 53-126, # 36, p. 9762 - 9766,5
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  • [ 367-12-4 ]
  • [ 348-62-9 ]
Reference: [1] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
  • 30
  • [ 367-12-4 ]
  • [ 2713-28-2 ]
YieldReaction ConditionsOperation in experiment
42% at 20℃; To a stirred solution of 2-fluorophenol (0.47 g;4.18 mmol) in concentrated NH4OH (22 ml) a solution of 12 (1.06 g; 4.18 mmol) was added at once at room temperature. After stirring overnight at room temperature themixture was evaporated to dryness under reduced pressure and the residue was partitioned between EtOAc (100 ml) and H20 (40 ml). The organic phase was washed with 5percent NaHSO3, brine (10 ml), dried over anhydrous MgSO4, filtered and the filtrate evaporated to dryness, The residue was purified by FCC (SiC2, CH2CI2 /EtOAc 9:1) to give the title compound (0.42 g; 42percent), as colourless solid. 1H-NMR (CDCI3) 7.3—7.4 (m,2H); 6.75 (tr, 8.8 Hz); 5.17 (m, 1 H).
5.7 g With tert.-butylhydroperoxide; potassium iodide In methanol at 20℃; for 12 h; 10523] A mixture of 2-fluorophenol (5 g, 44 mmol) and potassium iodide (8.i4 g, 49 mmol) in methanol (150 mE) was added tert-butyl hydroperoxide (6.43 mE, 66.9 mmol) and stirred at room temperature for i 2 h. Afier completion of reaction, reaction mixture was quenched with sodium thiosulphate and extracted with EtOAc. Organic layer was washed water followed by brine, concentrated under reduced pressure to obtain the crude compound. Crude material was purified by column chromatography over 230- 400 mesh silica gel using i 5percent EtOAc in n-hexane to give the title compound (5.7 g)
Reference: [1] Tetrahedron Letters, 2010, vol. 51, # 16, p. 2170 - 2173
[2] Patent: WO2014/63199, 2014, A1, . Location in patent: Page/Page column 94
[3] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
[4] Patent: EP409634, 1991, A2,
[5] Patent: EP409634, 1991, A2,
[6] Patent: US2012/101039, 2012, A1,
[7] Patent: US2016/347717, 2016, A1, . Location in patent: Paragraph 0522; 0523
  • 31
  • [ 367-12-4 ]
  • [ 2040-89-3 ]
YieldReaction ConditionsOperation in experiment
65% With bromine; <i>tert</i>-butylamine In toluene at -78 - 20℃; Starting from 2-fluorophenol (86-1, 33.8 g, 302 mmol), Boc-T86 was prepared utilizing the five step process shown in 26percent yield (corrected for recovered starting materials in step 3).TLC: Rf: 0.33 (50/50 AcOEt/Hex), detection: UV, ninhydrin1H NMR (CDCl3): δ 6.94 (m, 2H), 5.09 (m, 1H), 4.15 (m, 2H), 3.94 (m, 2H), 3.08 (m, 2H), 2.70 (m, 2H), 1.78 (m, 1H), 1.61 (m, 2H), 1.44 (s, 9H)LC-MS (Grad A4) tR: 6.81 min L. Standard Procedure for the Synthesis of Tether T109 This tether required a five (5) step procedure in order to prepare Ddz-T109 in an overall yield of 34percent starting from 2-fluorophenol (109-1, 11.2 g, 100 mmol). The corresponding (S)-isomer, Boc-T109b, can be constructed analogously, but using (R)-methyl lactate in place of (S)-methyl lactate (109-3) in the second step.TLC: Rf: 0.25 [Et2O:hexane, (1:1)]Boc-T109 was synthesized similarly in an overall yield of 15-25percent.1H NMR (CDCl3, 300 MHz): δ 6.94 (m, 3H), 4.45 (m, 1H), 3.85 (dd, J=12, 3.2, 1H), 3.72 (m, 1H), 3.05 (m, 2H), 2.72 (m, 2H), 2.52 (s, br, 1H), 1.76 (m, 2H), 1.45 (s, 9H), 1.24 (dd, J=6.5, 1.1, 3H).13C NMR (CDCl3, 75 MHz): δ 136.97, 125.26, 125.22, 123.81, 123.70, 122.78, 114.62, 114.36, 79.82, 79.75, 66.31, 39.55, 30.58, 28.41, 26.66, 16.08.MS: 328 (M+H)+
Reference: [1] Patent: US2008/194672, 2008, A1, . Location in patent: Page/Page column 36; 44
[2] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
[3] Synthesis, 2006, # 10, p. 1578 - 1589
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  • [ 2040-89-3 ]
Reference: [1] Dalton Transactions, 2013, vol. 42, # 33, p. 11926 - 11940
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Reference: [1] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
[2] Synthesis, 2006, # 10, p. 1578 - 1589
  • 34
  • [ 367-12-4 ]
  • [ 100-39-0 ]
  • [ 368-21-8 ]
Reference: [1] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[2] Patent: CN104557654, 2017, B, . Location in patent: Paragraph 0076-0078
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Reference: [1] Journal of the Chemical Society, 1938, p. 1414[2] Journal of the Chemical Society, 1942, p. 418
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Reference: [1] Journal of the American Chemical Society, 1943, vol. 65, p. 1555
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 16, p. 4597 - 4601
[3] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 1, p. 183 - 187
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Reference: [1] Journal of Fluorine Chemistry, 2006, vol. 127, # 2, p. 291 - 295
[2] Journal of Fluorine Chemistry, 2012, vol. 142, p. 24 - 28
[3] Phosphorus, Sulfur and Silicon and the Related Elements, 2013, vol. 188, # 6, p. 663 - 671
[4] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 1, p. 173 - 179
[5] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5601 - 5603
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Reference: [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
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Reference: [1] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
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Reference: [1] Organic and Biomolecular Chemistry, 2004, vol. 2, # 7, p. 963 - 964
[2] Canadian Journal of Chemistry, 2001, vol. 79, # 11, p. 1541 - 1545
[3] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915
[4] Journal of the American Chemical Society, 1946, vol. 68, p. 2502
[5] Patent: US4140769, 1979, A,
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[2] Journal of Medicinal Chemistry, 1986, vol. 29, # 10, p. 1982 - 1988
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[2] Patent: US2008/119496, 2008, A1,
[3] Patent: WO2008/60301, 2008, A1,
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[2] Patent: WO2014/22569, 2014, A1,
[3] Patent: US8673925, 2014, B1,
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