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Chemical Structure| 1421372-66-8
Chemical Structure| 1421372-66-8
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Product Details of [ 1421372-66-8 ]

CAS No. :1421372-66-8 MDL No. :MFCD28167800
Formula : C25H31N7O Boiling Point : -
Linear Structure Formula :- InChI Key :HTNTZPBKKCORTP-UHFFFAOYSA-N
M.W : 445.56 Pubchem ID :78358313
Synonyms :
Chemical Name :N1-(2-(Dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine

Calculated chemistry of [ 1421372-66-8 ]

Physicochemical Properties

Num. heavy atoms : 33
Num. arom. heavy atoms : 21
Fraction Csp3 : 0.28
Num. rotatable bonds : 8
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 136.19
TPSA : 84.47 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.7 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.66
Log Po/w (XLOGP3) : 3.27
Log Po/w (WLOGP) : 3.98
Log Po/w (MLOGP) : 1.62
Log Po/w (SILICOS-IT) : 2.12
Consensus Log Po/w : 2.93

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.61
Solubility : 0.0111 mg/ml ; 0.0000248 mol/l
Class : Moderately soluble
Log S (Ali) : -4.72
Solubility : 0.00852 mg/ml ; 0.0000191 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -7.48
Solubility : 0.0000148 mg/ml ; 0.0000000332 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.67

Safety of [ 1421372-66-8 ]

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 [ 1421372-66-8 ]

* 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 [ 1421372-66-8 ]
  • Downstream synthetic route of [ 1421372-66-8 ]

[ 1421372-66-8 ] Synthesis Path-Upstream   1~21

  • 1
  • [ 1421372-67-9 ]
  • [ 1421372-66-8 ]
YieldReaction ConditionsOperation in experiment
97.3% With palladium on activated charcoal; hydrogen In methanol at 25℃; for 4 h; In a nitrogen atmosphere, 28.5 (0.060 mol) of the intermediate 2 and 2.5 g of palladium carbon were added to 500 ml of methanol and passed at 25C Hydrogen atmospheric reaction 4h, filtered, the filtrate was concentrated to dryness under reduced pressure to give a brown solid, 26g, a yield of 97.3percent.
96.9% With hydrogen In ethyl acetate at 40℃; Autoclave A 125 ml autoclave was taken, and after replacing nitrogen three times, a compound F (1.50 g, 3.15 mmol) and a Raney nickel catalyst (0.70 g) were added and dissolved in ethyl acetate (30 ml), and the hydrogen was replaced twice and then charged with 2.0 MPa of hydrogen.The temperature was raised to 40 ° C to stir the reaction.Filter off and wash the filter cake twice with ethyl acetate (10 ml x 2).The filtrate was concentrated under reduced pressure at 40 ° C to give a dark green solid: 1.36 g.The molar yield was 96.90percent.
95% With hydrogen In methanol at 25℃; for 6 h; Under nitrogen protection,928 ml of methanol was added to a 2 L four-necked flask,Then, 92.8 g of the compound represented by the formula (III)Stirring,18.6g was added Raney nickel (water-wet product)8 at atmospheric pressure under hydrogenation,Reaction temperature 25 ,The reaction was carried out for 6 hours.Filtered by rotary evaporation to yield 82.6 g of gray solid, yield: 95.0percent
88.6% With iron; ammonium chloride In ethanol for 2 h; Reflux N1-(2-(Dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidine(Hydroxy-2-yl)-2-nitrobenzene-1,4-diamine (666 mg, 1.4 mmol)Soluble in ethanol (40mL),Iron powder (470mg,8.4 mmol) and ammonium chloride (241 mg, 4.5 mmol).The reaction was stirred at reflux for 2 hours.After the reaction is over,The reaction solution was concentrated under reduced pressure.The crude product was isolated and purified by silica gel column chromatography (eluent: dichloromethane:methanol=20:1) to give a brown oil (552 mg, yield: 88.6percent).
85% With iron; ammonium chloride In ethanol; water for 2 h; Reflux A mixture of N'-(2-dimethylaminoethyl)-2-methoxy-N’-methyl-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine (Intermediate 101, 220 mg, 0.46 mmol), iron (155 mg, 2.78 mmol) and NH4Cl (17.32 mg, 0.32 mmol) in ethanol (12 mL) and water (4 mL) was heated at reflux for 2h. The crude mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and appropriate fractions were combined and concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5percent 7N methanolic ammonia in CH2Cl2 gave the title compound (175 mg, 85percent) as a beige foam; 1H NMR: 2.17 (6H, s), 2.36 (2H, t), 2.63 (3H, s), 2.88 (2H, t), 3.74 (3H, s), 3.88 (3H, s), 4.58 (2H, br s), 6.76 (1H, s), 7.12-7.19 (2H, m), 7.21-7.27 (1H, m), 7.48 (1H, s), 7.51 (1H, d), 7.78 (1H, s), 8.27 (1H, d), 8.30 (1H, s), 8.42 (1H, d); m/z: ES+ MH+ 446.32.
85.9% With palladium 10% on activated carbon; hydrogen In tetrahydrofuran at 30℃; for 16 h; Solvent is tetrahydrofuran B, catalyst for A 10percent Pd/C, the pressure of the hydrogen is charged into the is 30bar, in 30 °C stirring under the temperature condition of 16h. The specific process: in 500 ml dry reaction flask, 5gN-(2-dimethyl amino-ethyl) - 2-methoxy-N-methyl-N-[ 4 - (1-methyl -1H-Indol-3-yl)-pyrimidin-2-yl] - 5-nitro-benzene -1,4-diamine with tetrafuran 140 ml dissolved, add 0.01g10percent Pd/C, access 30bar hydrogen, in the 30 °C stirring under 16h. Filtering, to obtain the product solvent is removed by the spin vaporization N-(2-dimethyl amino-ethyl) - 2-methoxy-N-methyl-N-[ 4 - (1-methyl -1H-Indol-3-yl)-pyrimidin-2-yl] - 5-amino-benzene -1,4-diamine a kind of white solid powder. The product purity 98.4percent, yield 85.9percent.
85.73% With hydrogenchloride; palladium 10% on activated carbon; hydrogen In methanol at 90℃; for 0.00694444 h; 1) Weigh 200g of the raw material hydrogenation precursor nitro compound, and then add it to a mixture of 4L of methanol and 100g of concentrated hydrochloric acid, stir and dissolve, then add 10g of Pd/C catalyst with Pd content of 10percent, stir well and mix to form Material I, the material I is sent to the preheating module 1 of the microchannel reactor for preheating, and after preheating, enters the reaction module group of the microchannel reactor.2) The reaction module group that delivers hydrogen to the microchannel reactor and the step 1) the preheated material I reacts in the reaction module group, wherein: the flow rate of the slurry pump is adjusted so that the flow rate of the material I is 40.0 g/min. The flow rate of the H2 gas flow meter is adjusted to 500 ml/min, the molar ratio of the raw material hydrogenation precursor nitro compound to hydrogen is 1:3.5, the reaction temperature is 90 ° C, the temperature of the cooling module is 20 ° C, and the residence time of the reaction is 25s, the reaction pressure is 1.5Mpa, and the collection flows out from the outlet of the cooling module.The reaction solution is subjected to post-treatment, which means that the catalyst is recovered by filtration, and the solvent is distilled off under reduced pressure. The residue is added to 1 L of water, stirred and dissolved, and the pH of the system is adjusted to 9.0 by a NaOH solution having a mass fraction of 20percent. 10.0, then join500ml of ethyl acetate was extracted and separated, the organic phase was discarded, the aqueous phase was stirred and crystallized at 10 ° C for 1 hour, filtered, and the product was washed with a small amount of ethanol, and vacuum dried at 50 ° C for 8 hours to obtain an oxetinib intermediate. Target product 160.65g, yield85.73percent, purity 99.68percent.
85.6% With palladium on activated charcoal; hydrogen In ethanol at 80℃; Autoclave; Inert atmosphere; Large scale The above obtainedN-[(4-Dimethylaminoethylamino-2-methoxy-5-nitrophenyl)]-4-(1-methyl-1H-indol-3-yl)-2-pyrimidinamine 3.8kg (7.99mol)It was added to an autoclave containing 38 L of ethanol, and then 380 g of palladium carbon was added to the system, replaced with nitrogen three times, and then hydrogen was replaced twice.The hydrogen pressure was set to 2 MPa, and the reaction was heated to 80 degrees overnight.After the end of the reaction, the autoclave was cooled, the reaction solution was withdrawn, filtered through a celite cake, and the filter cake was rinsed with ethanol.After concentrating to 15 kg, it was cooled, stirred and crystallized, returned to room temperature for 2 hours, filtered, and the filter cake was rinsed with ethanol.Drying gave 3.05 kg of silver-gray powder with a yield of 85.6percent (HPLC purity >99percent).
78% With hydrogen In tetrahydrofuran at 20℃; for 12 h; A solution of N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (1-methylindol-3-yl) 2-nitrophenyl-1,4-diamine (30.0 g, 0.063 mol) was added to a 1 L vial,Adding 600 mL of tetrahydrofuran and 10 g of Raney nickel,Hydrogen gas at a pressure of 3 atm was introduced at room temperature,Reaction for 12 h.After the reaction is complete,The reaction solution was filtered through celite,To obtain a brown solution,Concentrated under reduced pressure to give crude brown solid,The crude product was purified by recrystallization from 250 mL of a mixture of ethyl acetate and n-heptane (1: 1 by volume of ethyl acetate and n-heptane in the mixture)To give a light brown solid N1- (2- (dimethylamino) ethyl) -5-methoxy -N1- methyl -N4- (4- (1- methyl-indol-3-yl) pyrimidine-2 - yl) phenyl-1,2,4-triamine 21.9g, yield 78percent.
78% With hydrogen In tetrahydrofuran at 25℃; for 12 h; A solution of N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (1-methylindol-3-yl)Yl) -2-nitrophenyl-1,4-diamine (30.0 g, 0.063 mol) was added to a 1 L single-Then 600 mL of tetrahydrofuran and 10 g of Raney nickel were added and the pressure was 3 atm of hydrogen and reacted at 25 ° C for 12 h.After completion of the reaction, the reaction solution was filtered through celite and concentrated to give a crude product of brown solid which was recrystallized from 250 mL of a mixture of ethyl acetate and n-heptane (1: 1 by volume of ethyl acetate and n-heptane in the mixture) purification,A light brown solid product was obtainedMethyl-N4- (4- (1-methylindol-3-yl) pyrimidin-2-yl) phenyl -1,2,4-triamine 21.9 g, yield 78percent.
75% With palladium 10% on activated carbon; hydrogen In methanol for 24 h; N′-(2-(dimethylamino)ethyl)-5-methoxy-N′-methyl-N-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine (32) (5.00 g, 10.53 mmol) and Pd/C (10percent by weight) (250 mg, 2.10 mmol) were suspended in a mixture of MeOH (100 mL) and stirred under a hydrogen atmosphere for 24 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (DCM: MeOH: NH3·H2O=25:1:0.1) to afford the title compound (3.51 g, 75.0percent yield) : 1H NMR (400 MHz, DMSO-d6) δ8.43 (d, J = 7.9 Hz, 1H), 8.31 (s, 1H), 8.28 (d, J = 5.3 Hz, 1H), 7.79 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.49 (s, 1H), 7.28-7.23 (m, 1H),7.20-7.13 (m, 2H), 4.63 (s, 2H), 3.89 (s, 3H), 3.75 (s, 3H), 2.90 (t, J = 6.7 Hz, 2H), 2.64 (s, 3H), 2.38 (t, J = 6.6 Hz, 2H), 2.19 (s, 6H). MS (ESI) m/z 446.4 [M+H]+.
75% With methanesulfonic acid; platinum on carbon; hydrogen In water at 50℃; for 4 h; Autoclave; Inert atmosphere Example 1 (0622) AZD9291 Nitrodiamine (10.0 g), 5percent platinum-on-activated carbon (0.001 molar equivalents, 50percent water wet, 0.2 g, 0.02 relative weight), methanesulfonic acid (3.23 g, 1.6 molar equivalents) and water (100 mL, 10 relative volume) were mixed in a sealed autoclave. The headspace was inerted by 5 cycles of nitrogen pressurisation. The mixture was warmed to 50°C, and the headspace was purged by 3 cycles of pressurisation with hydrogen. The mixture was stirred for 4 hours at 50°C, dosing hydrogen gas to maintain a headspace pressure of 2 barg. The vessel was inerted by nitrogen purge cycles, and the mixture was filtered to remove catalyst particles. The clear filtrates were mixed with 2- methyltetrahydrofuran (60 mL, 6 relative volumes) and 2 M sodium hydroxide solution in water (19 mL, 1.8 mol eq). After a period of mixing, the mixture was settled and the lower aqueous layer was discarded. The organic layer was washed once with water (80 mL, 8 relative volumes) and then diluted with 2-methyltetrahydrofuran (80 mL, 8 relative volumes). The product solution in 2-methyltetrahydrofuran was distilled at 50°C under reduced pressure, to a residual volume of 60 mL. AZD9291 Aniline (seed) was added, and the mixture was cooled to 0°C over 4 hours. The resulting slurry was filtered, and the solids collected were washed with 2-methyltetrahydrofuran (20 mL, 2 relative volumes) to yield AZD9291 Aniline as an off-white powder (7.0 g, 75 percent> yield) after drying under vacuum. No detectable levels of AZD9291 Aniline Hydroxy were detected in the resulting AZD9291 Aniline by UPLC. (0623) UPLC methodology (0624) Apparatus An ultra performance liquid chromatograph fitted with a UV (0625) detector. The system should be capable of delivering a linear gradient. (0626) Column UPLC BEH Phenyl 1.7um, 2.1 x 100mm, or equivalent Phase A 0.06percent v/v trifluoroacetic acid in water (0627) Phase B 0.06percent v/v trifluoroacetic acid in acetonitrile (0628) Gradient profile1 Time Phase A Phase B (0629) (minutes) (0630) 0.0 90 10 (0631) 13 85 15 (0632) 20 30 70 (0633) 22 90 10 (0634) Flow rate 0.6 mL min"1 (0635) Injection volume 1 μ (0636) Column temperature 45°C (0637) Sample temperature 5°C (0638) Wavelength 245 nm (0639) Sample 1.0 mg/mL (approximately) (0640) concentration (0641) Diluent 40/60/0.1 v/v MeCN/ water/ trifluoroacetic acid
12 g With aluminum (III) chloride; iron In ethanol; water for 1.5 h; Reflux Compound 7 from the previous step, iron (12.8 g), and ammonium chloride (1.42 g) were heated in ethanol (100 mL) and water (30 mL) at reflux for 1.5 h. The mixture was cooled and filtered. The solids were rinsed with DCM. The filtrate was concentrated to approximately 20 mL and NaOH (1 N, 50 mL) was added. The gray precipitates were filtered off and rinsed with DCM. The mixture was partitioned and the organic layer was washed with NH4OH (50 mL), brine (100 mL) and concentrated to a brown foam (compound 8, 12 g).

Reference: [1] Patent: CN107216313, 2017, A, . Location in patent: Paragraph 0058; 0059; 0071; 0072
[2] Patent: CN108129342, 2018, A, . Location in patent: Paragraph 0054; 0055; 0056
[3] Patent: CN107188888, 2017, A, . Location in patent: Paragraph 0067-0069; 0070-0072
[4] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2898 - 2901
[5] Patent: CN107793413, 2018, A, . Location in patent: Paragraph 0180; 0181; 0184; 0185
[6] Patent: WO2013/14448, 2013, A1, . Location in patent: Page/Page column 124
[7] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8249 - 8267
[8] Patent: CN105348267, 2016, A, . Location in patent: Paragraph 0023; 0031; 0032; 0033
[9] Patent: CN108484579, 2018, A, . Location in patent: Paragraph 0039; 0040; 0042; 0043; 0045; 0046; 0048; 0049
[10] Patent: CN108623567, 2018, A, . Location in patent: Paragraph 0062; 0063; 0064
[11] Patent: CN106366072, 2017, A, . Location in patent: Paragraph 0076; 0077; 0078; 0108; 0109; 0110
[12] Patent: CN106366022, 2017, A, . Location in patent: Paragraph 0078; 0079; 0080; 0081; 0082; 0083
[13] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 12 - 23
[14] Patent: WO2017/134051, 2017, A1, . Location in patent: Page/Page column 62; 63
[15] Patent: WO2017/117070, 2017, A1, . Location in patent: Paragraph 00105
[16] Patent: EP3216786, 2017, A1, . Location in patent: Paragraph 0058-0059; 0313-0314
[17] European Journal of Medicinal Chemistry, 2019, p. 367 - 380
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YieldReaction ConditionsOperation in experiment
90.2% With potassium hydride In 1,2-dichloro-ethane at 50℃; for 8 h; 2-(4-(N-(2-(dimethylamino)ethyl)-N-methylamino)-2-methoxy-5-amino)-4-chloropyrimidine (5.4g, 15 . 4mmol) and 1 - methyl - 1H - indole (2.6g, 20 . 0mmol) dissolved in 1,2-dichloroethane (100 ml), by adding potassium hydride (1.0g, 24 . 6mmol), the reaction mixture 50 °C stirring reaction for 8 hours, TLC board determine the completion of the reaction, the reaction solution under reduced pressure to dry and concentration, adding ethyl acetate extraction, magnesium sulfate drying, and concentration to dry, ethanol and isopropanol mixed solvent crystallization, 2-(4-(N-(2-(dimethylamino)ethyl)-N-methylamino)-2-methoxy-5-aminophenylamino)-4-(1-methyl-1H-indole-3-yl)pyrimidine, pale yellow solid (6.2g), yield 90.2percent,
Reference: [1] Patent: CN106543060, 2017, A, . Location in patent: Paragraph 0069; 0070
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Reference: [1] Patent: WO2013/14448, 2013, A1,
[2] Patent: CN106366072, 2017, A,
[3] Patent: CN106366022, 2017, A,
[4] Patent: CN106543060, 2017, A,
[5] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 12 - 23
[6] Patent: EP3216786, 2017, A1,
[7] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2898 - 2901
[8] Patent: CN107188888, 2017, A,
[9] Patent: CN107216313, 2017, A,
[10] Patent: CN107793413, 2018, A,
[11] Patent: CN108129342, 2018, A,
[12] Patent: CN108129342, 2018, A,
[13] Patent: CN108623567, 2018, A,
  • 4
  • [ 1421372-94-2 ]
  • [ 1421372-66-8 ]
Reference: [1] Patent: WO2013/14448, 2013, A1,
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8249 - 8267
[3] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 12 - 23
[4] Patent: WO2017/117070, 2017, A1,
[5] Patent: EP3216786, 2017, A1,
[6] Patent: CN107188888, 2017, A,
[7] Patent: CN107216313, 2017, A,
[8] Patent: CN107793413, 2018, A,
[9] Patent: CN108623567, 2018, A,
[10] European Journal of Medicinal Chemistry, 2019, p. 367 - 380
  • 5
  • [ 1032452-86-0 ]
  • [ 1421372-66-8 ]
Reference: [1] Patent: WO2013/14448, 2013, A1,
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8249 - 8267
[3] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 12 - 23
[4] Patent: WO2017/117070, 2017, A1,
[5] Patent: EP3216786, 2017, A1,
[6] Patent: CN107188888, 2017, A,
[7] Patent: CN107216313, 2017, A,
[8] Patent: CN108129342, 2018, A,
[9] Patent: CN108623567, 2018, A,
[10] European Journal of Medicinal Chemistry, 2019, p. 367 - 380
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  • [ 450-91-9 ]
  • [ 1421372-66-8 ]
Reference: [1] Patent: WO2013/14448, 2013, A1,
[2] Patent: CN106366072, 2017, A,
[3] Patent: CN106366022, 2017, A,
[4] Patent: EP3216786, 2017, A1,
[5] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2898 - 2901
  • 7
  • [ 120-72-9 ]
  • [ 1421372-66-8 ]
Reference: [1] Patent: WO2013/14448, 2013, A1,
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8249 - 8267
[3] Patent: WO2017/117070, 2017, A1,
[4] European Journal of Medicinal Chemistry, 2019, p. 367 - 380
  • 8
  • [ 603-76-9 ]
  • [ 1421372-66-8 ]
Reference: [1] Patent: WO2013/14448, 2013, A1,
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8249 - 8267
[3] Patent: EP3216786, 2017, A1,
[4] European Journal of Medicinal Chemistry, 2019, p. 367 - 380
  • 9
  • [ 945016-63-7 ]
  • [ 1421372-66-8 ]
Reference: [1] Patent: WO2013/14448, 2013, A1,
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8249 - 8267
[3] Patent: WO2017/117070, 2017, A1,
  • 10
  • [ 448-19-1 ]
  • [ 1421372-66-8 ]
Reference: [1] Patent: CN106366072, 2017, A,
[2] Patent: CN106366022, 2017, A,
  • 11
  • [ 703-80-0 ]
  • [ 1421372-66-8 ]
Reference: [1] Patent: CN106366072, 2017, A,
[2] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2898 - 2901
  • 12
  • [ 19012-02-3 ]
  • [ 1421372-66-8 ]
Reference: [1] Patent: CN106366072, 2017, A,
[2] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2898 - 2901
  • 13
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  • [ 1421372-66-8 ]
Reference: [1] Patent: CN106366072, 2017, A,
[2] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2898 - 2901
  • 14
  • [ 123344-02-5 ]
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Reference: [1] Patent: CN107793413, 2018, A,
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  • [ 367-25-9 ]
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Reference: [1] Patent: CN107793413, 2018, A,
  • 16
  • [ 142-25-6 ]
  • [ 1421372-66-8 ]
Reference: [1] Patent: CN108129342, 2018, A,
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  • [ 1421372-66-8 ]
  • [ 814-68-6 ]
  • [ 1421373-65-0 ]
YieldReaction ConditionsOperation in experiment
95.5% With sodium carbonate In N,N-dimethyl-formamide at -5℃; for 2 h; The intermediate (VIII) (13.24 g, 29.74 mmol, 1 eq) was dissolved in 30 ml of N,N-dimethylformamide (DMF), and the mixture was stirred and cooled to -5 °, and acryloyl chloride (3.23 g, 35.69 mmol, 1.2) was added dropwise. Eq), the reaction was stirred at this temperature for 2 h, TLC was followed until the reaction was completed, 100 ml of water was added dropwise, and the mixture was stirred for 1 hour, filtered, and washed with water to give intermediate (X) 14.19 g, yield 95.5percent.
88% With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 40℃; for 12 h; 2-(4-(N-(2-(dimethylamino)ethyl)-N-methylamino)-2-methoxy-5-amino)-4-(1-methyl-1H-indole-3-yl) pyrimidine (4.0g, 9 . 0mmol) dissolved in tetrahydrofuran (10 ml), stirring, by adding acryloyl chloride (0.9g, 9 . 9mmol), dropping N,N-diisopropylethylamine (4.1g, 31.4 µM), the reaction mixture 40 °C stirring for 12 hours, TLC board determine the completion of the reaction, the reaction solution and concentration to dry, adding dilute hydrochloric acid is adjusted to neutral, adding the ethyl acetate extraction, magnesium sulfate drying, and concentration to dry, methanol is recrystallized, osimertinib, white solid (4.0g), yield 88.0percent, the step reaction equation is as follows:
86.37% With triethylamine In ethyl acetate at 5 - 10℃; Inert atmosphere A 250 ml four-necked flask was taken and Compound G (2.56 g, 5.75 mmol) was added.Triethylamine (1.08 g, 10.67 mmol) was dissolved in ethyl acetate (110 ml), and the mixture was stirred and cooled to 5 ° C under nitrogen.A mixed solution of acryloyl chloride (0.98 g, 10.83 mmol) / ethyl acetate (20 ml) was added dropwise at 5 to 10 °C.After the completion of the dropwise addition, the reaction was stirred, and water (100 ml) was added and stirred for 30 min, and then the organic phase was separated, and the aqueous phase was added to ethyl acetate (100 ml), and the organic phase was combined.The organic phase was washed once with (200 ml) saturated brine, and the organic phase was concentrated to dryness.Purification by column chromatography gave a pale yellow foamy solid 2.48 g.The molar yield was 86.37percent.
83% With N-ethyl-N,N-diisopropylamine In dichloromethane for 1.5 h; Cooling with ice Intermediate 3 prepared in Comparative Example 1 in which 3.45 g (38 mmol) of acryloyl chloride in 100 ml of dichloromethane was added dropwise to an ice-cooled water bath was charged with 17 g (38 mmol) and 7.2 ml of N, N-diisopropylethylamine ) In 250 ml of dichloromethane, In, stirring 1.5h. The mixture was then diluted with 250 ml of dichloromethane, washed with 2 × 250 ml of saturated sodium bicarbonate solution and the aqueous layer extracted twice with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo at 40 ° C. The crude product was purified by column chromatography to afford 16.01 g of a brown solid in 83.0percent yield with 99.3percent purity
72% With N-ethyl-N,N-diisopropylamine In chloroform at 5 - 15℃; for 2 h; A solution of N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (1-methylindol-3-yl) pyrimidin- Yl-1,2,4-triamine (8.9 g, 0.02 mol) was added to a 500 mL one-Add 250 mL of chloroform,Was added diisopropylethylamine (3.2g, 0.025mol) at 5 ,Then, acryloyl chloride (2.0 g, 0.022 mol) was added dropwise,Then reacted at 15 ° C for 2 h.After the reaction,The reaction solution was washed successively with 200 mL of water and 200 mL of saturated aqueous NaCl. The organic phase was dried over Na2SO4 and concentrated to give the crude product.The crude product was purified by recrystallization from 90 mL mixture of ethyl acetate and n-heptane (1: 1 by volume of ethyl acetate and n-heptane in the mixture)The resulting white solid product, Osimertinib, 7.2 g, yield 72percent.
72% With N-ethyl-N,N-diisopropylamine In chloroform at 5 - 15℃; for 2 h; A solution of N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (1-methylindol-3-yl)2-yl) phenyl-1,2,4-triamine (8.9 g, 0.02 mol) was added to 500 mLSingle mouth bottle,A mixture of 250 mL of chloroform was added to dissolve the solid, and then cooled to 5 to 10 ° C by adding diisopropylethylamine (3.2 g, .025 mol)Acryloyl chloride (2.0 g, 0.022 mol) was added and the reaction was carried out at 15 ° C for 2 h after completion of the dropwise addition.After completion of the reaction, the reaction solution was washed successively with 200 mL of water and 200 mL of saturated aqueous NaCl solution,The organic phase was dried with Na2SO4 and concentrated to give a crude product which was mixed with 90 mL of a mixture of ethyl acetate and n-heptaneLiquid in ethyl acetate and n-heptane in a volume ratio of 1: 1) to give the solid product Osimertinib 7.2 g, The yield was 72percent.
57.97% With N-ethyl-N,N-diisopropylamine In dichloromethane for 1.5 h; Cooling with ice A solution of acryloyl chloride (41 mg, 0.45 mmol) in methylene chloride was added dropwise to the cooled in an ice water bath.N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)Benzene-1,2,4-triamine (200 mg, 0.45 mmol) and DIPEA (70 mg, 0.54 mmol)Stir the mixture in dichloromethane (5 mL).After 1.5 hours of reaction,Diluted with dichloromethane,Wash with saturated sodium bicarbonate,The aqueous phase is extracted twice with dichloromethane,Combine the organic phase,Drying with anhydrous sodium sulfateconcentrate,Column chromatography afforded the title compound (130 mg, yield:57.97percent).
47% With N-ethyl-N,N-diisopropylamine In dichloromethane at -10℃; for 1 h; Acryloyl chloride (710 mg, 7.86 mmol) in DCM (5 mL) was added dropwise to a stirred solution of N′-(2-(dimethylamino)ethyl)-5-methoxy-N′-methyl-N-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (33) (3.50 g, 7.86 mmol) and DIPEA (2.03 g, 15.73 mmol) in DCM (30 mL) at -10 °C. The resulting solution was maintained at -10 °C for 1 h and then washed with brine, dried with Na2SO4, and concentrated. The resulting residue was purified by silica gel chromatography (DCM: MeOH: NH3·H2O=50:1:0.1) to afford N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (AZD9291) (1.80 g, 47.0percent yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ10.18 (s, 1H), 9.85 (s, 1H), 9.10 (s, 1H), 8.38 (d, J = 5.3 Hz, 1H), 8.07 (dd, J = 6.1, 2.5 Hz, 1H), 7.73 (s, 1H), 7.39 (dd, J = 6.3, 2.5 Hz, 1H), 7.27 (dt, J = 6.0, 2.4 Hz, 2H), 7.20 (d, J = 5.3 Hz, 1H), 6.80 (s, 1H), 6.46 (dd, J = 16.9, 2.2 Hz, 1H), 6.37 (dd, J = 16.9, 9.7 Hz, 1H), 5.71 (dd, J = 9.7, 2.2 Hz, 1H), 4.00 (s, 3H), 3.88 (s, 3H), 2.94 – 2.84 (m, 2H), 2.70 (s, 3H), 2.32 – 2.21 (m, 8H). 13C NMR (100 MHz, CDCl3) δ162.78, 162.10, 159.58, 157.90, 144.27, 138.25, 135.23, 134.61, 132.89, 129.64, 127.70, 125.99, 125.31, 121.72, 120.87, 120.23, 113.65, 110.03, 109.87, 107.90, 104.64, 88.28, 57.39, 56.42, 56.10, 45.42, 43.84, 33.06. MS (ESI) m/z 500.4 [M+H]+.
39% With N-ethyl-N,N-diisopropylamine In dichloromethane for 1.5 h; Cooling with ice A solution of acryloyl chloride (34.5 mg, 0.38 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred mixture of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100, 170 mg, 0.38 mmol) and DIPEA (0.073 mL, 0.42 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5h and then diluted with CH2Cl2 (25 mL) and washed with sat.NaHCO3 (50 mL). The aqueous washes were extracted with CH2Cl2 (2 x 25 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-4percent 7N methanolic ammonia in CH2Cl2 gave the title compound (75 mg, 39percent) as a cream solid after trituration with diethyl ether; 1H NMR: 2.21 (6H, s), 2.29 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd), 6.27 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.20-7.27 (2H, m), 7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s), 9.14 (1H, s), 10.22 (1H, s); m/z: ES+ MH+ 500.42.

Reference: [1] Patent: CN109134435, 2019, A, . Location in patent: Paragraph 0056-0074
[2] Patent: CN106543060, 2017, A, . Location in patent: Paragraph 0053-0055
[3] Patent: CN108129342, 2018, A, . Location in patent: Paragraph 0057; 0058; 0059
[4] Patent: CN107216313, 2017, A, . Location in patent: Paragraph 0074; 0074
[5] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2898 - 2901
[6] Patent: CN106366072, 2017, A, . Location in patent: Paragraph 0079; 0080; 0081; 0082; 0111-0115
[7] Patent: CN106366022, 2017, A, . Location in patent: Paragraph 0084; 0085; 0086; 0087; 0088; 0089; 0090
[8] Patent: CN107793413, 2018, A, . Location in patent: Paragraph 0191-0194
[9] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 12 - 23
[10] Patent: WO2013/14448, 2013, A1, . Location in patent: Page/Page column 65
[11] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8249 - 8267
  • 18
  • [ 1421372-66-8 ]
  • [ 625-36-5 ]
  • [ 1421373-65-0 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; water at 0 - 20℃; for 0.25 h;
Stage #2: With sodium hydroxide In tetrahydrofuran; water at 65℃; for 10 h;
To a stirred solution of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100, 10 g, 21.32 mmol) in THF (95 mL) and water (9.5 mL) at 0°C was added the 3-chloropropanoyl chloride (3.28 g, 25.59 mmol). The mixture was stirred at r.t. for 15 minutes then NaOH (3.48 g, 85.28 mmol) was added. The resulting mixture was heated to 65°C for 10h. The mixture was then cooled to r.t. and CH3OH (40 mL) and water (70 mL) were added. The resulting mixture was stirred overnight. The resulting solid was collected by filtration, washed with water (25 mL) and dried at 50°C for 12h to give the title compound (7.0 g, 94percent) as a solid form identified herein as polymorphic Form D. 1H NMR: 2.69 (3H, s) 2.83 (6H, d) 3.35 (4H, s) 3.84 (3H, s) 3.91 (3H, s) 5.75 (1H, d) 6.28 (1H, d) 6.67 (1H, dd) 7.05-7.23 (2H, m) 7.29 (1H, t) 7.43 (1H, d) 7.56 (1H, d) 8.21 (2H, s) 8.81 (1H, s) 9.47 (1H, s) 9.52 (1H, s) ES+ MH+ 500.26.
94%
Stage #1: at 20℃; for 0.25 h;
Stage #2: With sodium hydroxide In tetrahydrofuran; water at 65℃; for 10 h;
To a solution of N1- (2-dimethylaminoethyl) -5-methoxy-N1-methyl-N4- [4- (1-methylindol-3-yl) pyrimidin-2-yl ] Benzene-1,2,4-triamine(Intermediate 100, 10 g, 21.32 mmol) in THF (95 mL) and water (9.5 mL)To the stirred solution was added 3-chloropropionyl chloride (3.28 g, 25.59 mmol). The mixture was stirred at room temperature for 15 minutes and then addedNaOH (3.48 g, 85.28 mmol). The resulting mixture was heated to 65 & lt; 0 & gt; C for 10 hours. The mixture was then cooledTo room temperature, CH3OH (40 mL) and water (70 mL) were added. The resulting mixture was stirred overnight. The resulting solid was collected by filtrationWater (25 mL) and dried at 50 ° C for 12 hours to give the title compound as a solid (7.0 g, 94percent).
79.6%
Stage #1: at 0 - 28℃; for 1 h;
Stage #2: With sodium hydroxide In tetrahydrofuran; water for 8 h; Reflux
In room temperature,THF-H2O (825 ml -82.5 ml) was added to a 2 liter four-necked flask,Then, 82.5 g of the compound represented by the formula (IV)The mixture was cooled to 0 ° C.At 0 ° C to 5 ° C,23.55 g 3-chloropropionyl chloride was added dropwise.After the dropwise addition,The temperature was raised to 25 ° C to 28 ° C, stirring was continued for 1 hour,A mixture of 22.3 grams of sodium hydroxide was added in one portion.Heated to reflux for 8 hours. Cooling to 25 ~ 28 ,825 ml of ethyl acetate was added,410 ml of water and stir for 15 minutes.Standing,Dispensing. Separate organic Phase, washed with 410 ml of saturated sodium chloride once.The organic phase was separated and dried over anhydrous sodium sulfate for 1 hour.Filter, filter cake ethyl acetate 82 ml wash once,The filtrate was spin-dried to give the crude compound of formula (V).To the crude product was added 300 ml of isopropyl alcohol and 8.26 g of activated carbon,Heated to reflux for 1 hour,Hot filter.The filtrate was stirred under conditions,Down to 25 ° C,Precipitate solid.Filter, The filter cake was washed with isopropanol (2 x 40 ml)To give 74 g of an off-white solid, yield: 79.6percent.
Reference: [1] Patent: WO2013/14448, 2013, A1, . Location in patent: Page/Page column 66
[2] Patent: CN106699736, 2017, A, . Location in patent: Paragraph 0045; 0046; 0047; 0048; 0049
[3] Patent: CN107188888, 2017, A, . Location in patent: Paragraph 0073-0075
  • 19
  • [ 1421372-66-8 ]
  • [ 79-10-7 ]
  • [ 1421373-65-0 ]
YieldReaction ConditionsOperation in experiment
92.2%
Stage #1: With lithium carbonate; methanesulfonyl chloride In acetonitrile at 10℃; for 1.5 h;
Stage #2: at 0℃;
Methanesulfonyl chloride3.2 g (28 mmol) of lithium carbonate and 2.22 g (30 mmol) of lithium carbonate were added to 100 ml of acetonitrile,After stirring at 10 ° C, 2.02 g (28 mmol) of acrylic acid was added to the above solution and stirred for 1.5 h. 6.17 g (13.8 mmol) of Intermediate 3 prepared in Example 1 was added to the mixed anhydride solution at 0 ° C and monitored by TLC Raw materials disappear. The mixture was stirred for 1 h, extracted with ethyl acetate (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum at 45 ° C to give crude AZD9291. Recrystallization from 50 ml of acetonitrile gave 6.35 g of a brown solid with a yield of 92.2percent and a purity of 99.8percent. The HPLC profile is shown in FIG. 5.
Reference: [1] Patent: CN107216313, 2017, A, . Location in patent: Paragraph 0060; 0061; 0063; 0064
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  • [ 1421372-66-8 ]
  • [ 1421373-65-0 ]
Reference: [1] Patent: WO2013/14448, 2013, A1,
[2] Patent: CN106674202, 2017, A,
[3] Patent: CN108623567, 2018, A,
  • 21
  • [ 1421372-66-8 ]
  • [ 1421373-66-1 ]
Reference: [1] Patent: WO2013/14448, 2013, A1,
[2] Patent: WO2013/14448, 2013, A1,
[3] Patent: WO2013/14448, 2013, A1,
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8249 - 8267
[5] Patent: CN106674202, 2017, A,
[6] Patent: CN108623567, 2018, A,
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