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[ CAS No. 74457-86-6 ]

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Chemical Structure| 74457-86-6
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CAS No. :74457-86-6 MDL No. :MFCD00042290
Formula : C9H9FO2 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W :168.17 g/mol Pubchem ID :592821
Synonyms :

Safety of [ 74457-86-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 74457-86-6 ]

  • Upstream synthesis route of [ 74457-86-6 ]
  • Downstream synthetic route of [ 74457-86-6 ]

[ 74457-86-6 ] Synthesis Path-Upstream   1~11

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Reference: [1] Patent: WO2008/65508, 2008, A1,
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YieldReaction ConditionsOperation in experiment
90%
Stage #1: With hydrazine hydrate In ethanol for 6 h; Reflux
Stage #2: at 150℃; for 96 h;
To a solution of l-(2-fluoro-4-methoxyphenyl)ethanone (4.85 g, 28.8 mmol) in ethanol (50 mL) was added hydrazine hydrate (5.61 mL, 115 mmoi) and the mixture was heated at reflux temperature for 6 h.This mixture was evaporated to dryness. Then, ethylene glycol (24. 12 rnL, 433 mmol) was added and the mixture was heated at 150°C for 96 h. After cooling to room temperature, the mixture was diluted with water (75 mL). A solid was formed and the suspension was stirred for 30 minutes. After filtration, indazole INT-1A (4.20 g, 26 rnmol, 90percent) was isolated as an off white solid. LCMS: calculated for [M+[-I1: 163, found: 163.
78% With hydrazine hydrate In 1-methyl-pyrrolidin-2-one at 120℃; for 24 h; Inert atmosphere 1-(2-fluoro-4-methoxyphenyl)ethan-1-one (2 g, 11.9 mmol) was dissolved in 5 mL of a mixture of hydrazine hydrate (85percent) and NMP (15 mL). The mixture was stirred at 120 °C for 24 hours and purified by column chromatography to obtain 6-methoxy-3-methyl-1H-indazole (1.5 g, 78percent).
59% With hydrazine hydrate In ethanol; ethylene glycol Step A:
6-Methoxy-3-methyl-1H-indazole
To a solution of 2-fluoro-4-methoxyacetophenone (1.90 g, 11.3 mmol) in ethanol (20 ml) was added hydrazine hydrate (1.4 ml, 45.0 mmol) and heated at reflux temperature for 6 h.
This mixture was evaporated to a residue and ethylene glycol (10 ml) was added.
The mixture was heated at 150° C. for 18 h, cooled to room temperature, diluted with water (50 ml), and extracted with dichloromethane (3*60 ml).
The combined extracts were washed with brine (10 ml), dried (MgSO4) and evaporated to a residue, which was crystallized from ethyl acetate to give a solid (1.1 g, 59percent): MS(ES) m/z 163 (M+).
51% With hydrazine hydrate In ethylene glycol 6-Methoxy-3-methyl-1H-indazole
To a stirred solution of 2'-fluoro-4'-methoxyacetophenone (0.5 g, 3.0 mmol) in ethylene glycol (10 mL) was added dropwise hydrazine hydrate (0.1 g, 3.1 mmol).
The mixture was stirred for 24 h and partitioned between dichloromethane (20 mL) and water (3*20 mL).
The organic layer was dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:1)] to give an orange oil.
The oil was dissolved in ethylene glycol (10 mL) and heated at 165° C. for 24 h.
The solution was cooled to room temperature and partitioned between dichloromethane (20 mL) and water (3*20 mL).
The organic extract was dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:5)] to give the product (0.25 g, 51percent) as a colourless solid: IR νmax (Nujol/cm-1) 1624, 1519, 1458, 1295, 1208, 1170, 1024 and 821; NMR δH (400 MHz, CDCl3) 2.54 (3H, s), 3.86 (3H, s), 6.78-6.81 (2H, m) and 7.52 (1H, d, J 9 Hz).
32% for 48 h; Reflux Acid Preparation 14; 3-Methyl-1 H-indazole-5-carboxvlic acid; A solution of 2-fluoro-4-methoxyactophenone (2.0 g, 12 mmol) in hydrazine hydrate (30 mL) was heated at reflux for two days. The mixture was cooled to room temperature, poured into water and extracted with EtOAc (3x). The organic extracts were concentrated, dissolved in a minimal amount of CH2CI2 and filtered to afford 6-methoxy-3-methyl-1 H- <n="51"/>indazole (370 mg, 19percent). The filtrate was refiltered to provide additional product (250 mg, 13percent).
32% for 48 h; Heating / reflux A solution of 2-fluoro-4-methoxyacetophenone (2.0 g, 12 mmol) in hydrazine (30 mL) was heated at reflux for 2 days. The mixture was cooled to room temperature, poured into water and extracted with EtOAc (3x). The combined organic extracts were concentrated, dissolved in a minimum amount of CH2CI2, filtered to provide 6-methoxy-3-methyl-1 H-indazole as a yellow solid (620 mg, 32percent).To a solution of 6-methoxy-3-methyl-1 H-indazole (620 mg, 3.82 mol) in CH2CI2 (25 mL) at 0 0C was added a dichloromethane solution of boron tribromide (17 mL of 1 M solution). The mixture was stirred at room temperature overnight. The solution was carefully quenched by pouring slowly into iced saturated aqueous NaHCO3. The phases were separated and the aqueous phase was extracted with EtOAc (3x). The combined organic extracts were concentrated and the crude material was purified by Biotage chromatography (4OS column, acetone/heptane 45percent 500 mL and 60percent 150 mL) to provide 3-methyl-1H- . indazoJr6-ol as an orange, solid (458 mg, 81percent).A solution of 3-methyl-1 H-indazol-6:l (458 mg73.1 "mmol) in THF (30 mL) was treated with sodium hydride (0.50 g of 60percent oil dispersion). After the initial effervescence had subsided, the solution was heated to 50 0C for 1 hour before cooling to room temperature and adding N-phenyltrifluoromethane- sulphonimide (2.50 g, 7.0 mmol). The mixture was stirred at room temperature for 2 hours before pouring " into water.TheraqueTjus phase was extracted with EtOAc (3x). The combined organic extracts were concentrated and the crude material was purified by Biotage chromatography (4OM column, 12percent acetone/heptane). To provide 3-methyl-1-(trifluoromethylsulfonyi)-1H-indazol-6-yl trifluoromethanesulfonate (1.13 g, 89percent).A solution of 3-methyl-1-(trifluoromethylsulfonyl)-1 H-indazol-6-yl trifluoromethanesulfonate (0.61 g, 1.5 mmol) in DMF (6 mL) was flushed with carbon dioxide for 5 minutes. To this was added palladium acetate (68 mg, 0.30 mmol), 1,1 -bis(diphenylphosino)ferrocene (167 mg, 0.30 mmol), triethylamine (0.33 g, 0.45 mL, 3.2 mmol), and methanol (4 mL). The solution was stirred at room temperature overnight under one atmosphere of CO. The solution was poured into water and extracted with EtOAc (3x). The combined organic extracts were concentrated and purified by Biotage chromatography (4OS column, 8percent EtOAc/heptanes) to provide methyl 3-methyl-1-(trifluoromethylsulfonyl)-1 H-indazole-6-carboxylate (330 mg, 69percent). <n="32"/>To a solution of 3-methyl-1-(trifluoromethylsulfonyl)-1 H-indazole-6-carboxylate (590 mg, 1.83 mmol) in MeOH/water (3:1 , 72 mL) was added potassium carbonate (1.01 g, 7.31 mmol) and the mixture was heated at reflux for 2 hours. The mixture was cooled to room temperature and methanol was removed under reduced pressure. The aqueous solution was acidified with KHSO4 to pH 3 - 3.5. The white precipitate that formed was isolated by vacuum filtration, dissolved in EtOAc and washed with water. The organic extract was dried over MgSO4, filtered, concentrated and dried to yield the title compound as a white solid (259 mg, 80percent).
4.2 g at 140℃; for 20 h; To 2'-fluoro-4'-methoxyacetophenone (5.24 g) was added hydrazine monohydrate (20 mL) at room temperature, and then the reaction mixture was stirred at 140°C for 20 hours. The precipitated solid was filtered to give the titled compound (4.20 g) as a red solid. 1H-NMR (400 MHz, CDCl3) δ:7.52 (1H, d, J=9.3 Hz), 6.80-6.78 (2H, m), 3.86 (3H, s), 2.54 (3H, s).

Reference: [1] Patent: WO2016/8590, 2016, A1, . Location in patent: Page/Page column 50
[2] Patent: EP3205650, 2017, A1, . Location in patent: Paragraph 0106; 0365; 0366
[3] Patent: US6956036, 2005, B1,
[4] Patent: US6552062, 2003, B1,
[5] Patent: WO2009/144554, 2009, A1, . Location in patent: Page/Page column 49-50
[6] Patent: WO2008/65508, 2008, A1, . Location in patent: Page/Page column 30-31
[7] Patent: WO2005/26128, 2005, A1, . Location in patent: Page/Page column 14; 20-21
[8] Patent: US6303600, 2001, B1,
[9] Patent: EP2669270, 2013, A1, . Location in patent: Paragraph 0800-0801
[10] Patent: US2004/97575, 2004, A1, . Location in patent: Page 12; 21
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Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 36, p. 6331 - 6333
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Reference: [1] Archiv der Pharmazie, 1990, vol. 323, # 2, p. 73 - 78
[2] Journal of Medicinal Chemistry, 1990, vol. 33, # 9, p. 2535 - 2544
[3] Patent: EP1445249, 2004, A1, . Location in patent: Page 137
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YieldReaction ConditionsOperation in experiment
26.5 mg With hydrogenchloride; water In diethyl ether at 20℃; for 30 h; [3] A mixture of 2-fluoro-4-methoxyacetophenone oxime ether 39.4mg (0.2mmol), dissolved with 2ml 2ml of ether was added at a concentration of 37percent hydrochloric acid was stirred at room temperature for 30 hours.After completion of the reaction by TLC, the reaction solution was neutralized with saturated sodium carbonate solution to pH 7, the mixture was extracted with ether (10ml × 3), the organic phase was dried over anhydrous sodium sulfate and dried under reduced pressure to remove the solvent, purified by column chromatography (TLC) (eluent ratio: volume ratio of petroleum ether ethyl acetate 20: 1) separation of the product containing eluate was collected, the eluent solvent was distilled off to give 2-fluoro-4-methoxy ethanone 26.5mg (gas chromatography, 79percent yield).
Reference: [1] Patent: CN103922904, 2016, B, . Location in patent: Paragraph 0058; 0059; 0062
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Reference: [1] Journal of Medicinal Chemistry, 1984, vol. 27, # 7, p. 819 - 824
[2] Journal of Medicinal Chemistry, 1990, vol. 33, # 9, p. 2535 - 2544
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Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 36, p. 6331 - 6333
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Reference: [1] Patent: US5847008, 1998, A,
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Reference: [1] Patent: CN103922904, 2016, B,
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  • [ 883531-28-0 ]
Reference: [1] Patent: US5847008, 1998, A,
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  • [ 944317-92-4 ]
Reference: [1] Patent: EP2468735, 2012, A1,
[2] Patent: EP2468736, 2012, A1,
[3] Patent: EP2468735, 2012, A1,
[4] Patent: EP2468735, 2012, A1,
[5] Patent: WO2012/85133, 2012, A1,
[6] Patent: WO2012/85133, 2012, A1,
[7] Patent: WO2012/85133, 2012, A1,
[8] Patent: WO2013/66768, 2013, A1,
[9] Patent: WO2013/91696, 2013, A1,
[10] Patent: WO2013/91696, 2013, A1,
[11] Patent: WO2013/91696, 2013, A1,
[12] Patent: US2014/303380, 2014, A1,
[13] Patent: CN107365324, 2017, A,
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