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Product Details of [ 1075705-01-9 ]

CAS No. :1075705-01-9 MDL No. :MFCD23098941
Formula : C7H7FN2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :FYSIGSQCZXQTIH-UHFFFAOYSA-N
M.W : 186.14 Pubchem ID :57429072
Synonyms :

Calculated chemistry of [ 1075705-01-9 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 46.12
TPSA : 81.07 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.63 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.11
Log Po/w (XLOGP3) : 1.14
Log Po/w (WLOGP) : 1.75
Log Po/w (MLOGP) : 0.49
Log Po/w (SILICOS-IT) : -0.59
Consensus Log Po/w : 0.78

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.92
Solubility : 2.23 mg/ml ; 0.012 mol/l
Class : Very soluble
Log S (Ali) : -2.44
Solubility : 0.681 mg/ml ; 0.00366 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.83
Solubility : 2.77 mg/ml ; 0.0149 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 3.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.04

Safety of [ 1075705-01-9 ]

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

Application In Synthesis of [ 1075705-01-9 ]

* 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 [ 1075705-01-9 ]
  • Downstream synthetic route of [ 1075705-01-9 ]

[ 1075705-01-9 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 450-91-9 ]
  • [ 1075705-01-9 ]
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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[4] Patent: CN105884695, 2016, A, . Location in patent: Paragraph 0233; 0234; 0235
[5] Patent: US2017/8889, 2017, A1, . Location in patent: Paragraph 0135; 0138
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[9] Patent: CN106995435, 2017, A, . Location in patent: Paragraph 0305-0308
[10] Patent: EP3345900, 2018, A1, . Location in patent: Paragraph 0043
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[15] Patent: EP3216786, 2017, A1, . Location in patent: Paragraph 0052-0053
[16] Patent: CN106478605, 2017, A, . Location in patent: Paragraph 0120; 0121; 0122; 0123
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  • 2
  • [ 124-41-4 ]
  • [ 123344-02-5 ]
  • [ 1075705-01-9 ]
YieldReaction ConditionsOperation in experiment
87.6% at 20℃; for 48 h; Dissolve 2,4-difluoro-5-nitroaniline (3.48 g, 20 mmol) in anhydrous methanol (50 mL).Sodium methoxide (1.30 g, 24 mmol) is added at room temperatureAnd stir for 48 hours.After the reaction is over,Add water (100 mL),Extract with dichloromethane (100 mL x 3).Combine the organic phase,The organic phase was washed with saturated brine (100 mL).Drying with anhydrous sodium sulfateConcentrate under reduced pressure,The crude product was isolated and purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 6:1).A red solid (3.26 g, yield: 87.6percent) was obtained.
Reference: [1] Patent: CN107793413, 2018, A, . Location in patent: Paragraph 0168; 0169; 0172; 0173
  • 3
  • [ 448-19-1 ]
  • [ 1075705-01-9 ]
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[2] Patent: WO2013/169401, 2013, A1,
[3] Journal of Chemical Research, 2015, vol. 39, # 6, p. 318 - 320
[4] Patent: WO2015/175632, 2015, A1,
[5] Patent: WO2015/195228, 2015, A1,
[6] Patent: CN105524068, 2016, A,
[7] Patent: CN105884695, 2016, A,
[8] Patent: WO2016/183278, 2016, A1,
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[10] Patent: CN106366022, 2017, A,
[11] Patent: US2017/8889, 2017, A1,
[12] Patent: US2017/57957, 2017, A1,
[13] Patent: CN106083736, 2016, A,
[14] Patent: EP3173412, 2017, A1,
[15] Patent: EP3290419, 2018, A1,
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  • 4
  • [ 367-25-9 ]
  • [ 1075705-01-9 ]
Reference: [1] Patent: CN107793413, 2018, A,
  • 5
  • [ 1075705-01-9 ]
  • [ 935288-20-3 ]
YieldReaction ConditionsOperation in experiment
69.57% With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 50℃; for 2.5 h; Inert atmosphere Under nitrogen atmosphere, cupric bromide (3.568 g, 16 mmol, 1.5 eq) and tert-Butyl nitrite (3.399 g, 33 mmol, 3 eq) were mixed in acetonitrile (250 mL) and heated to 50 °C. A solution of 4-fluoro-2-methoxy-5-nitroaniline (103) (2 g, 11 mmol, 1 eq) in acetonitrile (20mL) was added dropwise to the system and stirred for reaction for additional 2.5 hours. The reaction temperature was lowered to room temperature and extraction was performed with ethyl acetate and water. The organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the crude product as a brown oil which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give 1-bromo-4-fluoro-2-methoxy-5-nitrobenzene as a yellow solid (1.87g, yield: 69.57percent).
Reference: [1] Patent: EP3345900, 2018, A1, . Location in patent: Paragraph 0044
  • 6
  • [ 1075705-01-9 ]
  • [ 1421373-98-9 ]
Reference: [1] Patent: WO2013/14448, 2013, A1,
  • 7
  • [ 1075705-01-9 ]
  • [ 1421372-66-8 ]
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  • 8
  • [ 1032452-86-0 ]
  • [ 1075705-01-9 ]
  • [ 1421372-94-2 ]
YieldReaction ConditionsOperation in experiment
99% at 80℃; for 6 h; in room temperature,1000 ml of 2-pentanol was added to a 2 L reaction flask,50 g of 3- (2-chloro-4-pyrimidinyl) -1-methyl -1H- indole,42 g of 4-fluoro-2-methoxy-5-nitroaniline,3.54 g p-toluenesulfonic acid,The mixture was heated to 80 ° C and reacted for 6 hours.The mixture was cooled to 25 ° C to 28 ° C,Filter,The filter cake was washed with 50 ml of 2-pentanol.After the filter cake is dry,Dried in a vacuum oven to give 80.1 g of a yellow solid,Yield: 99.0percent.
97% With toluene-4-sulfonic acid In 1,4-dioxane at 85℃; for 7 h; 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (10.00 g, 41.15 mmol), 4-fluoro-2-methoxy-5-nitroaniline (8.42 g, 45.27 mmol) and 4-methyl-benzenesulfonic acidmonohydrate (8.60 g, 45.27 mmol) were heated at 85 °C in 1,4-dioxane (200 mL) for 7 h.The reaction was cooled to room temperature and diluted with water (150 mL) and 40percent aqNaOH added until pH = 9. The solid was collected by filtration and washed with EtOH (40mL) to afford the yellow solid (15.70 g, 97.0 percent yield): 1H NMR (400 MHz, DMSO-d6)δ9.72 (s, 1H), 8.82 (s, 1H), 8.67 (s, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H),7.48 (dd, J = 20.7, 9.2 Hz, 2H), 7.32 (s, 1H), 7.14 (s, 1H), 4.01 (s, 3H), 3.93 (s, 3H). MS(ESI) m/z 394.3 [M+H]+.
95% at 105℃; for 2.5 h; p-Toluenesulfonic acid hydrate (22.73 g, 119.5 mmol) was added in one portion to a mixture of 3-(2-chloropyrimidin-4-yl)-1-methylindole (Intermediate 130, 24.27 g, 99.58 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 18.54 g, 99.58 mmol) in 2-pentanol (500 mL). The resulting mixture was stirred at 105°C for 2.5h. and then cooled to r.t. The resulting precipitate was collected by filtration, washed with 2-pentanol (50 mL) and dried under vacuum to give some of the desired product as a yellow solid. The filtrate was cooled and the resulting precipitate was collected by filtration and washed with 2-pentanol (10 mL). The two crops of product were combined and triturated with CH3CN to give a solid which was collected by filtration and dried under vacuum to give the title compound (37.4 g, 95percent) as a yellow solid; 1H NMR: 3.92 (3H, s), 4.01 (3H, s), 7.13 (1H, dd), 7.27-7.36 (1H, m), 7.40-7.51 (2H, m), 7.59 (1H, d), 8.26 (1H, t), 8.35 (1H, d), 8.61 (1H, s), 8.85 (1H, d), 9.46 (1H, s); m/z: ES- M- 392.
95% at 105℃; for 2.5 h; P-Toluenesulfonic acid hydrate (22.73 g, 119.5 mmol)Was added to a solution of 3- (2-chloropyrimidin-4-yl) -1-methyl-indole (Intermediate 20, 24.27 g, 99.58 mmol)And 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 22, 18.54 g, 99.58 mmol)In a mixture of 2-pentanol (500 mL).The resulting mixture was stirred at 105 ° C for 2.5 hours.Then cooled to room temperature.The resulting precipitate was collected by filtration,Washed with 2-pentanol (50 mL), dried under vacuum,Some of the desired product was obtained as a yellow solid. The filtrate was cooled,The resulting precipitate was collected by filtration,Washed with 2-pentanol (10 mL).The two batches were combined and ground with CH? CN to obtain a solid,The solid was collected by filtration, dried under vacuum,The title compound was obtained as a yellow solid (37.4 g, 95percent).
94.6% at 105℃; for 3 h; 4-fluoro-2-methoxy-5-nitroaniline (1.40 g, 7.52 mmol),3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (1.83 g, 7.52 mmol) was dissolved in 2-pentanol (50 mL).Then p-toluenesulfonic acid monohydrate (1.55 g, 9.0 mmol) was added.The reaction solution was stirred at 105°C for 3 hours.After the reaction is over,Cool to room temperatureFilter through a suction funnel.The solid was washed with 2-pentanol (50 mL).It was washed with a mixed solvent of dichloromethane (50 mL) and petroleum ether (50 mL).It was then dried in vacuo to give a yellow solid (2.80 g, yield: 94.6percent).
91.5% With toluene-4-sulfonic acid In ethanol at 120℃; Large scale The starting material 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole 2.5 kg (10.26 mol)2 kg (10.74 mol) of 4-fluoro-2-methoxy-5-nitroaniline was added to a 50 L ethanol reactor under stirring.After stirring evenly, the oil bath was heated at 120 ° C, and 2.34 kg (12.31 mol) of p-toluenesulfonic acid was slowly added.Then reflux overnight, the reaction is completed, the heating is stopped, the temperature is lowered to room temperature, and suction filtration is performed.The filter cake was rinsed with 5 L of isopropanol and dried to give a yellow solid 3.7 kg, yield 91.5percent.(HPLC purity >95percent).
87% at 80℃; for 2.5 h; To a 250 mL three-necked flask was added 3- (2-chloropyrimidin-4-yl) -1-methylindole (2.430 g, 10 mmol)4-fluoro-2-methoxy-5-nitroaniline (2.418 g, 13 mmol)And p-toluenesulfonic acid monohydrate (2.850 g, 15 mmol)And 80 mL of 2-pentanol was added,Start stirring and heating,80 reflux 2.5h,After completion (CHCl3:MeOH = 8:1, Rf = 0.5 ) detection reaction, TLC Turn off heating,From a bottle of three bottles with a needle through the plastic plug and slowly into the amount of ethanol,As the temperature decreases,Precipitation of yellow solid,Ice bath to continue to precipitate solid,Filtration, ethanol washing,Dried to give 3.431 g of compound 3 as a yellow solid,Yield 87percent.
85% With toluene-4-sulfonic acid In 2-methyl-propan-1-ol for 6 h; Reflux 40 g (0.164 mol) of SM1, 30.6 g (0.164 mol) of SM2 and 62.3 g (0.328 mol) of mono-p-toluenesulfonic acid monohydrate were added to 200 ml of isobutyl alcohol and warmed to reflux for 6 h. A yellow solid precipitated and dropped to After washing at room temperature, filtration, isopropanol and vacuum drying at 50 ° C 54.8 g of a yellow solid was obtained with a yield of 85.0percent.
76% at 110℃; for 2 h; Microwave irradiation 3-(2-chloropyrimidin-4-yl)-1-methyl-indole (2g, 8.21 mmol) and 4-fluoro-2- methoxy-5-nitro-aniline (1833 mg, 9.85 mmol) were suspended in 2-pentanol. Para- toluenesulfonic acid (1873 mg, 9.85 mmol) was added and the reaction heated to 110 °C for 2 hours under microwave conditions. The reaction mixture was allowed to cool to r.t. and the resulting precipitate collected by filtration, washed with 2-pentanol, triturated with acetonitrile and dried in vacuo to a yellow solid (2453 mg, 76percent). NMR and LC-MS conform to structure and match literature reports.
74% With toluene-4-sulfonic acid In 1,4-dioxane at 95 - 102℃; for 3 h; Intermediate 6: N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine
To a 1 L three-neck flask equipped with mechanical agitation, were added 500 mL 1,4-dioxane and 30 g 3-(2-chloropyrimidin-4-yl)-1-methylindole (intermediate 7), 30 g p-toluenesulfonic acid and 46 g 4-fluoro-2-methoxy-5-nitroaniline were added while stirring, then the resultant solid-liquid suspension was heated to 95 to 102°C and reacted for 3 h.
After the result of TLC showed that the reaction was complete, the mixture was cooled to 60°C, diluted conc. aqueous ammonia was added dropwise, pH was adjusted, then cooled to 10 to 15°C and stirred for 30 min, filtered, the filter cake was washed with 5percent NaHCO3 solution once, then cold ethanol once, filtered out and dried at 50°C to deliver 47 g product, yield 74percent, which was used directly in the next step without purification.
62% With toluene-4-sulfonic acid In isopropyl alcohol at 105℃; for 5 h; Inert atmosphere 3. Synthesis of intermediate 006-5 The intermediates 006-2 (75 mg, 307.8 mmol) and 006-4 (57.4 g, 308.4 mmol), 975 mL of isopropyl alcohol, and p-toluenesulfonic acid (63.7 g, 369.9 mmol) were sequentially added into a 2 L four-necked flask under nitrogen atmosphere, and the reaction was heated and maintained at 105°C for 5 h. The reaction mixture was cooled to room temperature and filtered, and the filter cake was washed with 750 mL of isopropanol three times. The filter cake was washed three times with 750 mL of acetonitrile and dried to give 75 g of the intermediate 006-5 (62percent) as a yellow solid. LC-MS: 394.1.
62% With toluene-4-sulfonic acid In isopropyl alcohol at 105℃; for 2.5 h; To a solution of 3-(2-chloropyrimidin-4-yl)-l -methyl- IH-indole (50 mg, 0.205 mmol), and 4-fluoro-2-methoxy-5-nitroaniline (40 mg, 0.215 mmol) in isopropyl alcohol (10 mL) was added 4-methylbenzenesulfonic acid (45 mg, 0.261 mmol). The resulting mixture was heated at 105 °C for 2.5 h. The mixture was cooled to RT. The precipitate was collected by filtration, washed with 2-pentanol (50 mL), and dried under vacuum to afford N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3- yl)pynmidin-2-amine as a yellow solid (51 mg, 62percent). LC/MS (ESI) m/z 394.1 [M+H]+.
15.5 g With toluene-4-sulfonic acid In butan-1-ol for 1 h; Reflux 4-Methylbenzenesulfonic acid hydrate (8.7 g) was added in one portion to 3-(2- chloropyrimidin-4-yl)-1-methylindole (9.3 g) and 4-fluoro-2-methoxy-5-nitroaniline (7.1 g) in nbutanol (200 mL). The resulting mixture was stirred at reflux for 1 h. The mixture was cooled to room temperature. The precipitate was collected by filtration, washed with n-butanol (50 mL), and dried under vacuum to afford N-(4-fluoro-2-methoxy-5-nitrophenyl)- 4-(1- methylindol-3- yl)pyrimidin-2-amine as a yellow solid (CompoundS, 15.5 g).

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[2] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 12 - 23
[3] Patent: WO2013/14448, 2013, A1, . Location in patent: Page/Page column 138
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8249 - 8267
[5] Patent: CN107043369, 2017, A, . Location in patent: Paragraph 0395; 0396; 0397; 0398
[6] Patent: CN107793413, 2018, A, . Location in patent: Paragraph 0168; 0169; 0174; 0175
[7] Patent: CN108623567, 2018, A, . Location in patent: Paragraph 0056; 0057; 0058
[8] Patent: CN106967050, 2017, A, . Location in patent: Paragraph 0020; 0021
[9] Patent: CN107216313, 2017, A, . Location in patent: Paragraph 0053; 0054
[10] Patent: WO2018/119441, 2018, A1, . Location in patent: Paragraph 00892; 00893
[11] Patent: EP3181559, 2017, A1, . Location in patent: Paragraph 0047
[12] Patent: EP3216786, 2017, A1, . Location in patent: Paragraph 0102-0103
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[12] Patent: CN107188888, 2017, A,
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[2] Patent: WO2013/14448, 2013, A1,
[3] Patent: WO2013/14448, 2013, A1,
[4] Patent: CN106543060, 2017, A,
[5] Patent: CN107188888, 2017, A,
[6] Patent: CN108623567, 2018, A,
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