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CAS No. :162012-70-6 MDL No. :MFCD08063159
Formula : C8H3ClFN3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W :227.58 Pubchem ID :-
Synonyms :

Safety of [ 162012-70-6 ]

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

Application In Synthesis of [ 162012-70-6 ]

* 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 [ 162012-70-6 ]
  • Downstream synthetic route of [ 162012-70-6 ]

[ 162012-70-6 ] Synthesis Path-Upstream   1~6

  • 1
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  • [ 162012-67-1 ]
YieldReaction ConditionsOperation in experiment
100% for 4 h; Reflux Example 1; (5*,i^-N-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6- yl)-4-(D6-dimethylamino)but-2-enamide; N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroqunazolin-4-amine (2).; 230 mg of 1 (1.0 mmol) and 146 mg 3-chloro-4-fluoroaniline (1.0 equivalent) were suspended in 5 ml isopropanol and heated to reflux for 4 h. The mixture was cooled to room temperature and sovent was evaporated under vacuum to give crude product. The crude product was dissolved in dichlormethane and basified by 10percent NaOH solution. The organic layer was separated and dried to give pure product 2 as yellow solid, yield 100percent.HPLC-MS: m/z: 337[M+1]+.
100% With triethylamine In isopropyl alcohol for 1.5 h; 4-Chloro-7-fluoro-6-nitroquinazoline 1f (7.15 g, 0.031 mol), 4-fluoro-3-chloroaniline (4.58 g, 0.031 mol), triethylamine (3.52 g, 0.035 mol ) Was added to 70 mL of isopropanol and stirred for 1.5 hours.The reaction solution was concentrated under reduced pressure, 30 mL of dichloromethane was added, filtered and the filtrate was concentrated under reduced pressure to give the title compound N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitroquinazoline-Amine (10.50 g, yellow solid), yield: 100percent.
91% With triethylamine In isopropyl alcohol at 20℃; for 1.5 h; 7-fluoro-6-nitro-4-chloroquinazoline (14.73,g, 65 mmol) was combined with 3-choro-4-fluoroaniline (9.49 g, 65 mmol) and triethylamine (10 mL, 72 mmol) in 150 mL of isopropanol. The reaction was stirred at room temperature for 1.5 hours, resulting in a yellow slurry. The solid was collected by filtration, rinsing with isopropanol and then water. The solid was dried in a 40 deqC. vacuum oven overnight to give 19.83 g (91percent) of the product as an orange solid. MS (APCI, m/z, M+1): 337.0 NaH (60percent in mineral oil, 3.55 g, 88 mmol) was added, in portions, to a solution of 2-fluoroethanol (5.19 g, 80 mmol) in 200 mL THF. The reaction was stirred for 60 minutes at room temperature. To the reaction was added 7-fluoro-6-nitro-4-(3-chloro-4-fluoroaniline)quinazoline (18.11 g, 54 mmol) as a solid, rinsing with THF. The reaction was heated to 65deq C. for 26 hours. The reaction was cooled to room temperature and quenched with water. THF was removed in vacuo. The resulting residue was sonicated briefly in water then the solid collected by filtration. The solid was triturated with MeOH, filtered and dried in a 40deq C. vacuum oven overnight to 12.63 g of the product. Additional product was obtained by concentrating the MeOH filtrate to dryness and chromatography eluting with 50percent EtOAc/hex. The isolated material was triturated with MeOH (2times), filtered and dried. 3.90 g Total yield: 16.53 g, 81percent MS (APCI, m/z, M+1): 381.0 7-(2-fluoroethoxy)-6-nitro-4-(3-chloro-4-fluoroaniline)quinazoline (0.845 g, 2.2 mmol) in 50 mL THF was hydrogenated with Raney nickel (0.5 g) as the catalyst over 15 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.77 g of product. (99percent) MS (APCI, m/z, M+1): 351.2 Methyl 4-bromocrotonate (85percent, 20 mL, 144 mmol) was hydrolyzed with Ba(OH)2 in EtOH/H2O as described in J.Med.Chem. 2001, 44(17), 2729-2734. MS (APCI, m/z, M-1): 163.0 To a solution of 4-bromocrotonic acid (4.17 g, 25 mmol) in CH2Cl2 (20 mL) was added oxalyl chloride (33 mL, 38 mmoL) and several drops of DMF. The reaction was stirred at room temperature for 1.5 hours. The solvent and excess reagent was removed in vacuo. The resulting residue was dissolved in 10 mL THF and added to a 0deq C. mixture of 6-amino-7-(2-fluoroethoxy)-4-(3-chloro-4-fluoroaniline)quinazoline (5.28 g, 15 mmol) and triethylamine (5.2 mL, 37 mmol). The reaction was stirred at 0deq C. for 1 hour. Water was added to the reaction and the THF removed in vacuo. The product was extracted into CH2Cl2 (400 mL). The organic layer was dried over MgSO4, filtered and concentrated. The crude material was chromatographed on silica gel eluting with 0-4percent MeOH/CH2Cl2. An isolated gold foam was isolated. Yield: 4.58 g, 61percent MS (APCI, m/z, M-1): 497.1 Piperidine (0.75 mL, 6.7 mmol) was added to a solution of the above compound (3.35 g, 6.7 mmol) and TEA (2.80 mL, 20 mmol) in 10 mL DMA at 0deq C. The reaction was stirred at 0deq C. for 17 hours. Water was added to the reaction until a precipitate was evident. The reaction was sonicated for 40 minutes and the liquid decanted. The residue was dissolved in CH2Cl2, dried over MgSO4, filtered and concentrated. The material was chromatographed on silica gel eluting with 4-10percent MeOH/CH2Cl2. The isolated residue was triturated with acetonitrile (2times) and collected by filtration. Impurity found: Michael addition of piperidine (2.2percent in first trituration of acetonitrile). Additional material can be obtained from the acetonitrile filtrates. Yield: 0.95 g, 27percent MS (APCI, m/z, M+1): 502.3
90% for 1 h; Reflux Step 1:
N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazoline-4-amine
4-chloro-7-fluoro-6-nitroquinazoline (2.28 g, 10 mmol) and 3-chloro-4-fluoroaniline (1.46 g, 10 mmol) were dissolved in acetonitrile (50 mL), refluxed under heating for 1 h.
The solution was concentrated in vacuo and the solvent was removed.
Saturated sodium carbonate and ethyl acetate were added into the residue.
The solution was stirred for 10 min, then separated.
The aqueous phase was extracted with ethyl acetate.
The organic phases were combined, and dried over anhydrous sodium sulfate.
The solution was concentrated in vacuo and the solvent was removed.
The residue was made into slurry with diethyl ether, filtered, and the compound shown in the title (3.01 g, 90percent) was obtained.
1H NMR (DMSO-d6): δ 10.51 (1H, s), 9.58 (1H, d, J=8.0 Hz), 8.73 (1H, s), 8.13 (1H, dd, J=6.8 Hz, 2.8 Hz), 7.85 (1H, d, J=12.4 Hz), 7.77-7.61 (1H, m), 7.49 (1H, t, J=9.2 Hz).
87.8% With triethylamine In isopropyl alcohol at 20℃; for 1.5 h; To the solution of compound 3 (50.0 g, 0.220 mol), isopropanol (400 mL), triethylamine (34 mL), 3-choro-4-fluoroaniline was added at room temperature.
The reaction mixture then was stirred at room temperature for 1.5 h.
After completion of reaction as indicated by TLC, the mixture was then filtered, washed with isopropanol and water, dried to yield N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine 4 as orange solid
16
(65.0 g, 87.8percent).
Mp 261.4-262.5 °C. 1H NMR (400 MHz, DMSO) δ 10.43 (s, 1H), 9.51 (d, J = 7.8 Hz, 1H), 8.68 (s, 1H), 8.08 (d, J = 6.4 Hz, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.76 (s, 1H), 7.45 (t, J = 9.0 Hz, 1H).
87.8% With triethylamine In isopropyl alcohol at 20℃; for 1.5 h; Sequentially to 400 ml of isopropanol by adding 50.0g of 7-fluoro-6-nitro-4-chloriquine oxazoline (IV), 32.3g of 4-fluoro-3-chloroaniline, to the reaction liquid to carry out polyreaction 34.0 ml triethylamine, room temperature stirring 1.5h. After the reaction, filtration, with isopropanol and water washing, drying, the filtrate water enlarges the quantity solid precipitation, filtration, washing, drying, merging, shall be 65.0g crocatus solid, in other words, 4 - [(3-chloro-4-fluoro-phenyl) amino] - 6-nitro-7- [...] (V), yield: 87.8percent.
87.8% With triethylamine In isopropyl alcohol at 20℃; for 1.5 h; To 40 mL of isopropyl alcohol was added 50.0 g of 7-fluoro-6-nitro-4-chloroquinazoline,32.3 g of 4-fluoro-3-chloroaniline, 34.0 mL of triethylamine was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1.5 h.After completion of the reaction, the filter cake was washed with isopropyl alcohol and water, dried, and the filtrate was stirred with a large amount of water to precipitate a solid, suction, washed with water, dried and combined to give 65.0 g of a dark yellow solid,4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7-fluoroquinazoline in a yield of 87.8percent.

Reference: [1] Patent: WO2011/84796, 2011, A2, . Location in patent: Page/Page column 55-56
[2] Patent: CN103987700, 2016, B, . Location in patent: Paragraph 0178-0180
[3] Patent: US2005/250761, 2005, A1, . Location in patent: Page/Page column 13-14
[4] Patent: US2016/214964, 2016, A1, . Location in patent: Paragraph 0098
[5] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 7, p. 1495 - 1503
[6] Patent: CN106008480, 2016, A, . Location in patent: Paragraph 0079; 0080; 0081
[7] Patent: CN106892907, 2017, A, . Location in patent: Paragraph 0083; 0084; 0085
[8] Journal of Medicinal Chemistry, 2000, vol. 43, # 7, p. 1380 - 1397
[9] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 22, p. 5916 - 5919
[10] Patent: EP2612860, 2013, A1, . Location in patent: Paragraph 0063; 0064
[11] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 974 - 978
[12] Patent: WO2014/89546, 2014, A1, . Location in patent: Sheet 16
[13] Patent: WO2015/7219, 2015, A1, . Location in patent: Page/Page column 24
[14] European Journal of Medicinal Chemistry, 2015, vol. 102, p. 445 - 463
[15] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3359 - 3370
[16] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 12, p. 3148 - 3157
[17] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1740 - 1750
[18] Patent: US2018/297989, 2018, A1, . Location in patent: Paragraph 0210
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  • [ 267243-68-5 ]
YieldReaction ConditionsOperation in experiment
77.7%
Stage #1: for 24 h; Heating / reflux
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran; <i>tert</i>-butyl alcohol at 15 - 20℃; for 0.5 h;
Example 2
One-pot Reaction for the Preparation of (3-chloro-4-fluorophenyl)-r7-(3-morpholin-4-yl-propoxy)-6-aminoquinazolin-4-yl1-amine (VII).
20 g 7-fluoro-6-nitroquinazolin-4-(3H)-one (III) are suspended in 80 ml thionyl chloride and, after addition of 20 drops of DMF, boiled under reflux for 24 hrs..
A clear solution hereby results..
About 60 ml thionyl chloride are distilled off in a vacuum..
The resulting coarsely crystalline suspension is mixed with about 60 ml toluene..
About 60 ml are distilled off in a vacuum..
This distillation is repeated 3 times with, in each case, 60 ml fresh toluene..
In the last distillation, the toluene is distilled off as far as possible..
There results a coarsely crystalline suspension which at all times remains well stirrable.
The almost dry residue is mixed with 160 ml of a tetrahydrofuran/tert.-butanol mixture..
The resulting suspension is cooled to about 10C.
With good stirring and cooling, a solution of 15.2 g 3-chloro-4-fluoroaniline and 34.4 g 3-morpholin-4-yl-propan-1-ol (VI) in 40 ml THF/tert.-butanol (7:3) is added dropwise over the course of about 20 min. so that the temperature in the reactor remains between 10° C. and 15° C.
The initially yellow suspension becomes thinner during the addition and turns orange.
One allows the reaction mixture to come slowly to room temperature and subsequently stirs for at least 24 hrs. at room temperature.
To the yellow-orange suspension is added dropwise, with good stirring and gentle cooling over the course of about 20 min., a solution of 43.2 g potassium tert.-butylate in 250 ml tetrahydrofuran so that the temperature in the reactor remains between 15° C. and 20° C.
After addition of about 1/3 of the potassium tert.-butylate/THF solution, the whole reaction mixture becomes dark red coloured.
After stirring for about 30 minutes further, the reaction mixture is mixed at 0° C.-5° C.
with a mixture of 20 ml hydrochloric acid and 30 ml water and diluted with a further 200 ml THF.
After stirring for 20 minutes in an ice bath, the reaction mixture is filtered clear over 50 g Celite.
The filter cake is rinsed with 100 ml THF.
The filtrate is mixed with 31 g Raney nickel and hydrogenated at room temperature for 3 hrs. at 3.5 bar with hydrogen..
After filtering off the catalyst with suction, the filtrate is evaporated to dryness and the residue stirred with 80 ml ethanol at about 2° C.
The precipitated product is filtered off with suction and washed with a little cold ethanol..
After drying in a circulating air drying cabinet at 60° C., there are obtained 32.1 g (77.7percent) of product.
Reference: [1] Patent: US6664390, 2003, B2, . Location in patent: Page column 8-9
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Reference: [1] Journal of Medicinal Chemistry, 2000, vol. 43, # 7, p. 1380 - 1397
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3359 - 3370
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1740 - 1750
  • 4
  • [ 162012-70-6 ]
  • [ 179552-74-0 ]
Reference: [1] Patent: WO2015/7219, 2015, A1,
[2] European Journal of Medicinal Chemistry, 2015, vol. 102, p. 445 - 463
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 7, p. 1495 - 1503
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3359 - 3370
[5] Patent: CN106008480, 2016, A,
[6] Patent: CN103987700, 2016, B,
[7] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 12, p. 3148 - 3157
[8] Patent: CN106892907, 2017, A,
[9] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1740 - 1750
  • 5
  • [ 162012-70-6 ]
  • [ 1012057-52-1 ]
Reference: [1] Patent: WO2014/177038, 2014, A1,
[2] European Journal of Medicinal Chemistry, 2015, vol. 102, p. 445 - 463
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  • [ 162012-70-6 ]
  • [ 179552-75-1 ]
Reference: [1] European Journal of Medicinal Chemistry, 2015, vol. 102, p. 445 - 463
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 7, p. 1495 - 1503
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3359 - 3370
[4] Patent: CN103987700, 2016, B,
[5] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 12, p. 3148 - 3157
[6] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1740 - 1750
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