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[ CAS No. 450-91-9 ] {[proInfo.proName]}

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Chemical Structure| 450-91-9
Chemical Structure| 450-91-9
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Product Details of [ 450-91-9 ]

CAS No. :450-91-9 MDL No. :MFCD00077536
Formula : C7H8FNO Boiling Point : -
Linear Structure Formula :- InChI Key :BNRRMRUVYDETQC-UHFFFAOYSA-N
M.W :141.14 Pubchem ID :13532228
Synonyms :

Calculated chemistry of [ 450-91-9 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 37.3
TPSA : 35.25 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.22 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.67
Log Po/w (XLOGP3) : 1.33
Log Po/w (WLOGP) : 1.84
Log Po/w (MLOGP) : 1.58
Log Po/w (SILICOS-IT) : 1.53
Consensus Log Po/w : 1.59

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.93
Solubility : 1.65 mg/ml ; 0.0117 mol/l
Class : Very soluble
Log S (Ali) : -1.67
Solubility : 3.01 mg/ml ; 0.0213 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.42
Solubility : 0.538 mg/ml ; 0.00381 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.19

Safety of [ 450-91-9 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P305+P351+P338 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 450-91-9 ]

* 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.

  • Upstream synthesis route of [ 450-91-9 ]
  • Downstream synthetic route of [ 450-91-9 ]

[ 450-91-9 ] Synthesis Path-Upstream   1~16

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YieldReaction ConditionsOperation in experiment
4 g at 20℃; 2-methoxy-4-fluoro-nitrobenzene (10g, 58.44mmol) was dissolved in methanol, was added 1g of palladium / carbon, substituted with hydrogen, the reaction under a hydrogen atmosphere for three days. Filtered and the filtrate was collected, methanol was distilled off to give an oily crude product. Was added at 0 crude product concentrated sulfuric acid was dissolved solid mixture, in batches added potassium nitrate (5.91g). The reaction solution was slowly warmed to room temperature and stirred overnight. The reaction solution was poured into ice water and NaHC03, adjustment pH6.0-8.0. The aqueous phase was thrice extracted with dichloromethane, the organic phase was collected, dried. The organic solvent was distilled off, the residue was purified by column chromatography to give 4-fluoro-2-methoxy-5-nitroaniline (4.0g).
Reference: [1] Patent: CN105503827, 2016, A, . Location in patent: Paragraph 0070; 0071
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YieldReaction ConditionsOperation in experiment
100% With hydrogen In ethanol for 1 h; Paladium/carbon(Pd/C, 5percent, 0.5 g) was added to a solution of 4-fluoro-2-methoxynitrobenzene (1.65 g, 9.6 mmol) in ethanol, which was then stirred for 1 hour under 30 psi of hydrogen pressure. The reaction mixture was filtered to remove paladium/carbon, and concentrated to give 1.35 g of the titled compound. (Yield 100percent).
NMR (CDCl3): 3.8 (s, 3H), 6.5 (m, 3H).
100% With hydrogen In methanol at 20℃; for 12 h; 2-methoxy-4-fluoronitrobenzene (50.0 g, 0.29 mol) was added to a one-necked flask,Add 650 mL of methanol and 10 g of Raney nickelAt room temperature, a pressure of 1.5 atm hydrogen gas was allowed to react for 12 h.After the reaction is complete,The reaction solution was filtered through celite,A light pink solution was obtained,Concentrated under reduced pressure to get brown liquid,Is 2-methoxy-4-fluoroaniline (41.2 g)
100% With hydrogen In methanol at 15 - 26℃; for 12 h; 2-methoxy-4-fluoronitrobenzene (50.0 g, 0.29 mol) was added to a 1 L vial,Add 650mL methanol, stirring at 15 ~ 26 , then add 10g Raney nickel and pass 1.1atm of hydrogen, after 12h reaction. The reaction solution was filtered through celite to give a pale pink solution,The filtrate was concentrated under reduced pressure to give 41.2 g of 2-methoxy-4-fluoroaniline in 100percent yield.
98% With hydrogen In methanol at 20℃; for 6 h; Example 2294-fluoro-2-methoxyanilineA solution of 5-fluoro-2-nitroanisole (5.0 g, 29.22 mmol, 1 equiv) in the presence of 250 mg of Pd/C (5percent) in MeOH (60 mL) was hydrogenated at room temperature for 6 hours. The reaction mixture was filtered over a pad of Celite and then concentrated to give a brown oil (4.06 g, 98percent) which was directly used in the next step. m/z=142 (M+H)+.
98% With hydrogen In methanol at 25 - 30℃; Autoclave In an autoclave methanol (4000 ml) and 4-fluoro-2-methoxy-l -nitrobenzene (470 gms) were added. A mixture of Raney Ni (47 gms) and methanol (470 ml) was added to the reaction mass under nitrogen atmosphere. The reaction mass was stirred at 25-30°C for 10-15 minutes. Hydrogen gas was slowly fed into the autoclave upto 3.0 kgs (slight exothermic temperature observed). The reaction mass was stirred at 25-30°C for 8-10 hrs till there was no hydrogen consumption. The reaction mass was filtered through celite and the celite bed was washed with methanol (250 ml). Organic solvent was distilled under vacuum to give black color liquid (Yield - 380 gms; 98.0percent).
94.3% With palladium on activated charcoal; hydrogen In methanol for 16 h; 4-fluoro-2-methoxy-1-nitrobenzene (15.00 g, 87.67 mmol) was added to methanol (200 mL)Palladium carbon (200 mg) was added under nitrogen atmosphere,Hydrogen atmosphere for 16 hours, suction filtration,The filtrate was concentrated to give the title compound (11.67 g, yield 94.3percent).
93% With iron; ammonium chloride In tetrahydrofuran; water at 25 - 65℃; for 3 h; Step a: Compound 1a1 (10.6 g, 58 mmol) was added into a 500 ml reaction flask, and THF/water (100 ml/60 ml) mixed solution was added to dissolve the compound. Ammonium chloride (15.5 g, 292 mmol) and reduced iron powder (26 g, 467 mmol) were sequentially added with stirring at room temperature, and then the reaction system was heated to 65° C. and stirred continually for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the excess iron powder was removed by filtration, and the filter cake was washed for three times with EA. Filtrate was extracted with EA/water system for three times, and the organic layer was separated, washed with water, saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 1a2 (8.0 g) which was used directly in the next reaction. Yield: 93percent; purity: 90percent; MS m/z (ESI): 142.0 [M+H]+.
93.28% With palladium 10% on activated carbon; hydrogen In methanol at 40℃; for 12 h; Inert atmosphere 2-Methoxy-4-fluoronitrobenzene (100.00g, 584.35mmol) was dissolved in methanol (400mL), Pd/C (10percent, 10g) was added after sweeping with nitrogen.
The mixture was heated to 40°C under H2 (50Psi) and stirred for 12 hours. TLC showed the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated to dryness to deliver the title compound (red oil, 83.00g, yield 93.28percent). LCMS (ESI) (10-80CD): m/z: 142.1 [M+1].
92% With 5%-palladium/activated carbon; hydrogen In ethyl acetate at 30 - 35℃; Autoclave; Inert atmosphere In a 1L autoclave, ethyl acetate 600 g, 4-fluoro-2-methoxynitrobenzene (257.5 g, 1.50 mol), 5percent Pd / C 3g were added, and the autoclave was closed. Nitrogen was purged 3-4 times, and maintained in a hydrogen pressure at 0.5-1.0MPa, temperature between 30-35°C for 7-8 hours. Sampling of GC analysis was carried out, 4-fluoro-2-methoxy nitrobenzene <0.5percent. After completion of the reaction, the hydrogen in the kettle was replaced with nitrogen. After the nip with nitrogen, filtered, and Pd / C was recovered. The filtrate was recovered with ethyl acetate. The residual material was distilled under reduced pressure, and the liquid was collected as a pale yellow oily liquid 4-fluoro-2-methoxyaniline 195 g. GC content of 98.5percent. Yield 92percent.
91% With iron; ammonium chloride In ethanol; water at 55 - 85℃; for 2 h; 2-methoxy-4-fluoro-1-nitrobenzene (Intermediate 101) (20 g, 0.12 mol, 1.0 eq), ammonium chloride (13 g, 0.24 mol, 2.0 eq) and water (50 mL) were dissolved in ethanol (200 mL). After heated to 55°C, iron powder (13 g, 0.24 mol, 2.0 eq) was added portionwise. The temperature was raised to 85 °C and after reaction for 2 hours, the temperature was lowered to room temperature, filtration was performed and the solvent was rotary evaporated. The residue was dissolved in ethyl acetate which was then washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated to obtain 4-fluoro-2-methoxyaniline as a light green product (15 g, yield: 91percent). LCMS (ESI): m/z 142 [M + H]+.
7 g With ammonium chloride; zinc In water; acetone at 0 - 20℃; To a suspension of 5-fluoro-2-nitroanisole (50 mmol, 8.5 g) and zinc powder (3.5 eq, 11.4 g) in acetone (45 mL) and water (5 mL) was added ammonium chloride (11 eq, 29.3 g) at 0 °C in multiple portions. After the mixture was stirred at r.t. overnight, HPLC indicated a complete conversion. Acetone was removed on rotavap and the residue was suspended in DCM and water. Filtration was carried out and the filtrate was extracted with DCM. Concentration of combined organic layers gave crude aniline (~ 7.0 g), which was used in the next step without purification.
8.0 g With iron; ammonium chloride In tetrahydrofuran; water at 65℃; for 3 h; The reaction substrate 2-a-1 (10.6g, 58mmol) is placed in the 500mL reaction flask, was dissolved in a mixed solution oftetrahydrofuran / water (100mL / 60mL) . At room temperature, to the stirred reaction flask were sequentially added ammonium chloride (15.5g, 292mmol) and reduced iron powder (26g, 467mmol), then the reaction system was heated to 65 deg. C and stirring was continued for 3 hours. The progress of the reaction by TLC, until complete reaction substrate, the excess iron was removed by filtration, the filter cake rinsed three times with ethyl acetate. Filtrate was washed with ethyl acetate / water system was extracted three times, the organic layer was separated, washed with water, saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2-a-2 (8.0g), was used directly in the next reaction step. Yield: 93percent ; purity: 90percent.

Reference: [1] Patent: US6352993, 2002, B1, . Location in patent: Page column 30
[2] Patent: CN106366072, 2017, A, . Location in patent: Paragraph 0062; 0063; 0064; 0090; 0091; 0092
[3] Patent: CN106366022, 2017, A, . Location in patent: Paragraph 0051; 0052; 0056
[4] Patent: US2011/130415, 2011, A1, . Location in patent: Page/Page column 102
[5] Patent: WO2018/207120, 2018, A1, . Location in patent: Page/Page column 11; 12
[6] Journal of the American Chemical Society, 2009, vol. 131, # 38, p. 13860 - 13869
[7] Patent: CN105884695, 2016, A, . Location in patent: Paragraph 0230; 0231; 0232
[8] Patent: US2017/8889, 2017, A1, . Location in patent: Paragraph 0135; 0136; 0137
[9] Patent: EP3290419, 2018, A1, . Location in patent: Paragraph 0074; 0075
[10] Patent: CN106083536, 2016, A, . Location in patent: Paragraph 0037; 0038
[11] Patent: EP3345900, 2018, A1, . Location in patent: Paragraph 0042
[12] Journal of the American Chemical Society, 2018, vol. 140, # 14, p. 4893 - 4904
[13] Journal of the Chemical Society, 1940, p. 1268,1270
[14] Journal of the Chemical Society, 1931, p. 981
[15] Heterocycles, 1992, vol. 34, # 12, p. 2301 - 2311
[16] Organic Mass Spectrometry, 1992, vol. 27, # 6, p. 720 - 723
[17] Journal of Medicinal Chemistry, 1997, vol. 40, # 17, p. 2674 - 2687
[18] Patent: US2009/23773, 2009, A1, . Location in patent: Page/Page column 59
[19] Patent: WO2012/151561, 2012, A1, . Location in patent: Page/Page column 60
[20] Patent: WO2013/169401, 2013, A1, . Location in patent: Page/Page column 61-62
[21] Journal of Chemical Research, 2015, vol. 39, # 6, p. 318 - 320
[22] Patent: WO2015/175632, 2015, A1, . Location in patent: Paragraph 447
[23] Patent: WO2015/195228, 2015, A1, . Location in patent: Paragraph 454
[24] Patent: CN105524068, 2016, A, . Location in patent: Paragraph 0181; 0182
[25] Patent: CN105503827, 2016, A, . Location in patent: Paragraph 0070; 0071
[26] Patent: WO2016/183278, 2016, A1, . Location in patent: Paragraph 00394; 00395
[27] Patent: US2017/57957, 2017, A1, . Location in patent: Paragraph 0209-0210
[28] Patent: CN106083736, 2016, A, . Location in patent: Paragraph 0096; 0103
[29] Patent: EP3173412, 2017, A1, . Location in patent: Paragraph 0112; 0113
[30] Patent: CN108558835, 2018, A, . Location in patent: Paragraph 0048; 0049
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Reference: [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 17, p. 2674 - 2687
[2] Heterocycles, 1992, vol. 34, # 12, p. 2301 - 2311
[3] Patent: CN106083536, 2016, A,
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Reference: [1] Patent: US6455528, 2002, B1,
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Reference: [1] Patent: CN106083536, 2016, A,
[2] Patent: WO2018/207120, 2018, A1,
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Reference: [1] Organic Mass Spectrometry, 1992, vol. 27, # 6, p. 720 - 723
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Reference: [1] Journal of the Chemical Society, 1931, p. 981
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YieldReaction ConditionsOperation in experiment
93%
Stage #1: With sodium nitrite In water at -5 - 0℃;
Stage #2: With hydrogen bromide; copper(I) bromide In water at 105℃;
In a 1L four-necked flask, 48percent hydrobromic acid 660 g was added, stirred, and slowly poured into 4-fluoro-2-methoxyaniline 195 g (1.38 mol), stirred for 30 min, and large number of solids were precipitated. The mixture was cooled to -5°C, 300 g (1.45 mol) of a 33percent aqueous solution of sodium nitrite was added dropwise, the temperature was controlled to below -5 ° C for 1 hour. The temperature was maintained at 0 ° C for 15-30 minutes to obtain diazo solution. In another 2L four-necked flask, 48 g of hydrobromic acid was added, water 200 g, cuprous bromide 80 g were added, heated to boil for about 105°C. The diazo liquid was began to drop through the dropping funnel for about 30-60 min. After completion of dropping, steam distillation was carried out, the product was distilled out. Diazo liquid was dropped, steam distillation was carried out for 5 hours, until the distillate does not have oil beads. The layer separation was carried out, the oil layer was separated to obtain 263 g of 4-fluoro-2-methoxybromobenzene, light yellow oily liquid. GC content of 98.30percent, yield 93percent.
Reference: [1] Patent: CN106083536, 2016, A, . Location in patent: Paragraph 0039; 0040
[2] Journal of the Chemical Society, 1931, p. 981
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Reference: [1] Patent: CN106083536, 2016, A,
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YieldReaction ConditionsOperation in experiment
82% at 0 - 25℃; for 16 h; 4-Fluoro-2-methoxy-5-nitroaniline. 4-Fluoro-2-methoxyaniline (50.0 g, 354 mmol) was added to stirred sulfuric acid (300 mL) at 0 C in portions, ensuring that the temperature did not rise above 10 C. When all of the solid had dissolved up, potassium nitrate (36 g 354 mmol) was added in portions keeping the temperature below 10 C. The reaction mixture allowed to warm to 25 C, and stirred for 16 hr. It was then poured onto was poured onto ice- water (1 L) with vigorous stirring, and the solid was collected by vacuum filtration, rinsed with water (2 x250 mL), and dried to give 4-fluoro-2-methoxy-5-nitroaniline (54 g, 82percent) as a light yellow solid. 1H NMR: (CDCl3) 7.35, (1H, d, J = 8 Hz), 7.03 (1H, d, J = 11 Hz), 5.21, (2H, brs), 3.91 (3H, s).
80% at -20℃; for 0.0833333 h; The compound 2-a-2 (8.0g, 43mmol) in 500mL reaction flask, under stirring concentrated sulfuric acid was added (100 mL) to dissolve the substrate. At -20 deg. C condition, to the stirred reaction flask was slowly added dropwise concentrated nitric acid (6.15 mL, 48mmol), and held at that temperature for 5 minutes. The progress of the reaction by TLC, until complete reaction of the substrate, poured into ice water. -20 deg. C kept ice bath, was slowly added to the reaction system sodium hydroxide / water solution (150mL / 300 mL), adjusted to pH 8-9. After completion of the reaction solution with ethyl acetate / water system was extracted three times, the organic layer was separated, washed with water, saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-fluoro-2-methoxy -5-nitroaniline compound 2-a-3 (8.7g), was used directly in the next reaction. Yield: 80percent; purity: 100percent;
80%
Stage #1: for 0.5 h; Cooling with ice
Stage #2: at 20℃; for 12 h;
Ice bath,4-Fluoro-2-methoxyaniline (6.5 g, 46 mmol) was dissolved in concentrated sulfuric acid (50 mL)After stirring for 30 minutes in an ice bath,Potassium nitrate (5.2 g, 51 mmol) was added portionwise,After the addition, the reaction was allowed to proceed to room temperature and the reaction was stirred for 12 hours.After completion of the reaction,The reaction was poured into ice and the pH was adjusted to 8 with the addition of ammonia, Ethyl acetate (200 mL × 3), dried over anhydrous sodium sulfate,Concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to give the title compound (6.9 g, yield 80percent).
80% at -20℃; for 0.0833333 h; Step b: Compound 1a2 (8.0 g, 43 mmol) was added into a 500 ml reaction flask, and concentrated sulfuric acid (100 ml) was added to dissolve the substrate under constant agitation. At −20° C., concentrated nitric acid (6.15 ml, 48 mmol) was slowly added dropwise with stirring, and the reaction mixture was stirred for 5 mins at this temperature. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was poured into ice water. Sodium hydroxide/water solution (150 ml/300 ml) were added slowly to the reaction system at −20° C. in an ice-water bath, and the mixture was adjusted to pH 8-9. The reaction solution was extracted with EA/water system for three times, the organic layer was separated, washed with water, saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 1a (8.7 g) which was used directly in the next reaction. Yield: 80percent; purity: 100percent; MS m/z (ESI): 187.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 7.34 (d, J=7.8 Hz, 1H), 7.04 (d, J=13.4 Hz, 1H), 5.25 (brs, 2H), 3.90 (s, 3H).
77% at 15℃; Cooling with ice 4-Fluoro-2-methoxyaniline (2.4 g, 17.00 mmol) was added portionwise to concentrated H2SO4 (15 mL) which was cooled in a ice/water bath, and where the temperature was kept below 15°C during the addition. The mixture was stirred until all the solid that formed had dissolved. KNO3 (0.815 mL, 17.00 mmol) was added portionwise such that the temperature was maintained below 10°C. The mixture was stirred overnight and then poured onto ice/water. The mixture was basified with concentrated NH4OH. The resulting solid was filtered off and then dissolved in CH2Cl2, washed with water, dried (Na2SO4) and concentrated onto silica. Purification by FCC, eluting with 50-0percent heptane in CH2Cl2 gave the title compound (2.450 g, 77percent) as a yellow crystalline solid; 1H NMR: 3.91 (3H, s), 5.21 (2H, s), 7.03 (1H, d), 7.35 (1H, d); m/z: ES+ MH+ 187.4.
77% at 15℃; 4-Fluoro-2-methoxyaniline (2.4 g, 17.00 mmol)Was added portionwise to concentrated H2SO4 (15 mL) cooled in an ice / water bath,The temperature was maintained below 15 & lt; 0 & gt; C during the addition.The mixture was stirred until all of the formed solids had dissolved.KNO3 (0.815 mL, 17.00 mmol) was added in portions,So as to keep the temperature below 10 ° C. The mixture was stirred overnight and then poured onto ice / water.The mixture was basified with concentrated NH4OH. The resulting solid was filtered off,Then dissolved in CH2Cl2, washed with water, dried (Na2SO4),Concentrated on silica gel. Using FCC for purification,Eluting with 50percent by weight of heptane in CH2Cl2,The title compound was obtained as a yellow crystalline solid (2.450 g, 77percent).
77% at 10 - 15℃; 4-fluoro-2-methoxyaniline (2.4 g, 17.00 mmol) was added portionwise to a concentrated H2SO4(15 mL)cooled in an ice / water bath andthe temperature was maintained below 15 ° C during the addition TheThe mixture was stirred until all of the formed solidshad dissolved.Was added portionwise a KNO. 3(0.815mL, 17.00mmol), so that the temperature was kept below 10 .The mixture was stirredovernight and then poured onto ice / water.The mixture was basified with concentrated NH4OH.The resulting solid was filtered off, then dissolved inCH2CI2, washed with water, dried (of Na2SO. 4), concentrated onto silica gel.Using the FCC, eluting with 50-0percent in CH2CI2iseluted heptane to give the title compound as a yellow crystalline solid (2.450g, 77percent).m / z: 186
77% at 0℃; for 1 h; Under an ice bath condition, 4-fluoro-2-methoxyaniline (Intermediate 102) (15 g, 106.4 mmol, 1.0 eq) was added dropwise to a concentrated sulfuric acid (150 mL) while controlling the temperature around 0°C during the course of addition. After the forming solid was dissolved completely, potassium nitrate (11 g, 106.4 mmol, 1.0 eq) was added portionwise and the reaction was continued for 1 hour under this condition. The reaction was poured into ice water and the pH was adjusted to basic by sodium hydroxide. A vast amount of solid was precipitated out which was filtered and washed with water, petroleum ether, dried in air to give 4-fluoro-2-methoxy-5-nitroaniline as a brown solid (18 g, yield: 77percent). LCMS (ESI): m/z 187 [M + H]+.
75.2% at 5 - 20℃; for 2 h; Take 98wtpercent sulfuric acid (200 mL) was added to a 500mL three-necked flask,Ice bath cooling to 5 ~ 10 ,2-methoxy-4-fluoroaniline (41.0 g, 0.29 mol) was added in portions;Then divided into batches at 15 was added KNO3 (34.4g, 0.34mol),After adding the natural temperature to room temperature reaction 2h.The reaction solution was slowly poured into 1 L of ice water,Filter out the resulting solid,The filtrate was neutralized with 40 wtpercent NaOH to pH 10.5,Then stir for 1 h,,The resulting solid was filtered off and washed with water until neutral,The solid was dried to give 40.5 g of terephthalic solid 2-methoxy-4-fluoro-5-nitroaniline in a yield of 75.2percent.
75.2% at 0 - 25℃; for 2 h; Taking 200 ml 98 wt percent sulfuric acid is added to a 500 ml three-port flask, ice water bath cooled to 5 - 10 °C, then addition of 2 - methoxy -4 - fluoro aniline (41.0g, 0 . 29 µM), control of speed of addition, the reaction solution maintained at a temperature of 0 - 20 °C; then adding KNO batch3(34.4g, 0 . 34 µM), keep the temperature of the reaction solution is 0 - 20 °C, after adding the reaction liquid natural temperature to 25 °C, reaction 2h end after. The reaction liquid slowly poured into the 1L the ice water, stirring after filtering out the solid, the filtrate 40 wt percent NaOH to pH=9 and in, dropwise lye process is maintained in the temperature not higher than 40 °C, after adding stirring 1h, separating solid, after the solid is filtered, washed with water solid to neutral, then dried to obtain the brown body solid 2 - methoxy -4 - fluoro -5 - nitroaniline 40.5g, yield is 75.2percent.
70% Cooling with ice 4-Fluoro-2-methoxyaniline (1.4g, 10mmol) was added portion-wise to concentrated H2SO4 (10mL) in ice-water bath. After the solid dissolved, concentrated nitric acid (10 mmol) was added portion-wise, stirred overnight and poured into cooled water. The mixture was basified by NH4OH, the solid was filtered off and dissolved in ethyl acetate, washed with water and purified by silica chromatography to afford 20b (1.3g, 70percent) as a yellow crystalline solid. 1H NMR (600MHz, DMSO-d6) δ (ppm): 7.337 (d, J=7.8Hz, 1H, Ar-H), 7.028 (d, J=13.8Hz, 1H, Ar-H), 5.233 (s, 2H, -NH2), 3.902 (s, 3H, -OCH3). ESI-MS m/z: 187.3 (M+H)+, calcd for C7H7FN2O3: 186.04.
60% at 0 - 20℃; Inert atmosphere Under nitrogen, to a 2000mL three necked flask successively add 001-1 (100g, 708.5mmol) and 800mL sulfuric acid (H2SO4),cooled to 0 deg.C, at 0-10 portionwise added potassium nitrate (KNO3)(71.6g, 708.19mmol), used time 1h, and finally react overnight at room temperature (rt). After completion of the reaction, three-necked flask was added 2000mL of ice water to quench the reaction. At a low temperature the reaction mixture was adjusted to pH 10 with aqueous ammonia, washed with 1 liter (L) in dichloromethane (DCM) and extracted 3 times. The organic layers were combined and backwashed with saturated brine 3000mL three times, dried over anhydrous sodium sulfate, and spin dry. The resulting crude product ispurified by silica gel column chromatography (eluent: ethyl acetate (EA):petroleum ether (PE) = 1: 4-1: 1), after the spin dry eluent to give 79g (60percent)001-2, as a yellow solid.
60%
Stage #1: at 0 - 10℃; Inert atmosphere
Stage #2: at 20℃; Inert atmosphere
5. Synthesis of Intermediate 001-8 The intermediate 001-7 (100 g, 708.5 mmol) and 800 mL of concentrated sulfuric acid (H2SO4) were added sequentially to a 2000 mL three-necked flask under nitrogen protection and cooled to 0°C, and the reaction temperature was maintained at a temperature between 0 and 10°C. Potassium nitrate (KNO3) (71.6 g, 708.19 mmol) was added in batches for 1 hour, and then the reaction was stirred overnight at room temperature. After completion of the reaction, 2 L of ice water was added to the three-necked flask to quench the reaction. The reaction mixture was adjusted to pH = 10 with aqueous ammonia at low temperature and extracted three times with 1 L of dichloromethane (DCM). Then, the organic phases were combined, washed three times with 3 L of saturated brine, dried over anhydrous sodium sulfate and rotovapped. The crude product was purified by silica gel column chromatography (the used eluent, ethyl acetate (EA) : petroleum ether (PE) = 1: 4 - 1:1) and eluent was rotovapped to give 79 g of the intermediate 001-8 (yield: 60percent) as a yellow solid. LCMS: 187.0.
60% at 0 - 20℃; Inert atmosphere Under nitrogen protection, add 122-3 (100 g, 709 mmol) and 800 mL of concentrated sulfuric acid (H2SO4) to a 2000 mL three-necked bottle in sequence, and cool down to 0°C to maintain the temperature at 0-10°C.Potassium nitrate (KNO3) (71.6 g, 708 mmol) was added in portions over 1 hour.Finally, react overnight at room temperature. After the reaction is completed, add 2 liters (L) to three bottlesIce water quenches the reaction. The reaction mixture was adjusted to pH 10 with aqueous ammonia at low temperature.Extract 3 times with 1 L dichloromethane (DCM). After the organic phase is merged, it is saturated with 3LThe saline was backwashed 3 times, dried over anhydrous sodium sulfate, and spin-dried.The resulting crude product was subjected to silica gel column chromatography (eluent ethyl acetate (EA): petroleum ether (PE) = 1:4:1:1).After spin-drying the eluate, 79 g of 122-4 (yield: 60percent) was obtained as a yellow solid.
54.81% at 0 - 10℃; for 3 h; Embodiment A1
(83.00g, 558.67mmol) was slowly added dropwise to concentrated H2SO4 (415mL) at 0°C and then KNO3 (56.48g, 558.67mmol) was added in batches.
The mixture was stirred at 0 to 10°C for 3 hours. TLC showed the reaction was complete, NH3·H2O was added until the pH of the reaction mixture was 8, and the temperature was controlled below 10°C.
The resulting mixture was filtered and the filter cake was washed with water (500mL) and dissolved in DCM (1L).
The solution was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (PE: DCM = 5: 1, 1: 10) to deliver the title compound (yellow solid, 60.00 g, yield 54.81percent).
1H NMR (400 MHz, CDCl3): δ 7.40 (d, J=7.2 Hz, 1 H), 6.64 (d, J=12.4 Hz, 1 H), 3.86-3.97 (m, 5 H).
4.72 g for 0.5 h; Cooling with ice To a suspension of 4-fluoro-2-methoxyaniline (5.1 g, 36.1 mmol) in concentrated sulfuric acid (55mL) was added guanidine nitrate (4.38g, 36.1 mmol) in portion wise under ice cooling over 15 min. The mixture was stirred at the same temperature for additional 15 min. The reaction was then poured into a saturated cold NaHCC solution and the precipitated solid were collected by filtration. The residue was taken up in EtOAc and dried over anhydrous Na2SC>4. The solvent was stripped off to afford the B (4.72g).
8.7 g at -20℃; Compound 2 (8.0 g, 43 mmol) was placed in a 500 ml one-necked reaction flask, and concentrated sulfuric acid (100 ml) was added to dissolve the substrate with constant agitation. At −20° C., concentrated nitric acid (6.15 ml, 48 mmol) was slowly added dropwise with stirring, and the reaction mixture was stirred for 5 mins at this temperature. The reaction progress was monitored by TLC. After the substrate was completely consumed, the mixture was poured into ice water. Sodium hydroxide/water solution (150 ml/300 ml) were added slowly to the reaction system which was kept in an ice-water bath at −20° C., and the pH of the mixture was adjusted to 8-9. After the neutralization, the reaction mixture was extracted with ethyl acetate/water system for three times, and the organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound a1 (8.7 g) which was used directly in the next reaction. Yield: 80percent; purity: 100percent; MS m/z(ESI): 187.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 7.34 (d, J=7.8 Hz, 1H), 7.04 (d, J=13.4 Hz, 1H), 5.25 (brs, 2H), 3.90 (s, 3H).
44 g at 10 - 20℃; 39 g of crude compound b2-2 was added to 500 ml of concentrated sulfuric acid (ice salt bath)Stirring at T less than 10 °C is stirred under the condition completely dissolved, maintained at this temperature by adding 1ep potassium nitrate, stir at room temperature overnight; the next day the reaction liquid is poured into ice water, adjusted with ammonia water PH7, ethyl acetate extraction, drying, column chromatography separation, obtained 44g product, that is, compound b2-3.
8.7 g at -20℃; for 0.0833333 h; Compound a1-2 (8.0 g, 43 mmol) was placed in a 500 mL single-necked reaction flask and concentrated sulfuricacid (100 mL) was added under stirring at a constant rate to dissolve the substrate. Concentrated nitric acid (6.15 mL,48 mmol) was slowly added dropwise to the stirred reaction flask at -20 °C and stirred at that temperature for 5 minutes.The progress of the reaction was checked by TLC. After the reaction of the substrate was complete, the reaction mixturewas poured into iced water. In -20 °C ice bath, the aqueous solution of hydroxide/water (150 mL/300 mL) was slowly added to the reaction system and pH was adjusted to 8-9. After neutralization, the reaction solution was extracted threetimes with ethyl acetate/water system. The organic layer was separated, washed with water and then saturated brine,dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the compound 4-fluoro-2-methoxy-5-nitroaniline a1 (8.7 g) which was directly used in the next step. Yield: 80percent; purity: 100percent; MS m/z(ESI): 187.0 [M+H]+;1HNMR (400 MHz, DMSO-d6): δ 7.34 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 13.4 Hz, 1H), 5.25 (brs, 2H), 3.90 (s, 3H).
18.6 g at 10℃; for 2 h; Cooling with ice Under ice bath, will be 4 - fluoro -2 - anisidine (2 A) (17.1 g, 0.1 mmol) is dissolved in concentrated sulfuric acid (100 ml) in, slowly adding potassium nitrate (10.1 g, 0.1 mmol), 10 °C reaction under 2 hours. In the reaction liquid is poured into the ice, regulated by ammonia water to the reaction solution to pH 8, ethyl acetate (400 ml × 2) extraction, the combined organic phase, the organic phase dried with anhydrous sodium sulfate, concentrated, to obtain 4 - fluoro -2 - methoxy -5 - nitroaniline (intermediate 2), a yellow solid (18.6 g, crude product).

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Reference: [1] Patent: WO2013/14448, 2013, A1,
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