1421372-67-9|N1-(2-(Dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine| Ambeed

Structure of 1421372-67-9

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Quality Control of [ 1421372-67-9 ] Purity: 95% SDS Specification

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Product Details of [ 1421372-67-9 ]

CAS No. :	1421372-67-9
Formula :	C₂₅H₂₉N₇O₃
M.W :	475.54
SMILES Code :	O=[N+](C1=CC(NC2=NC=CC(C3=CN(C)C4=C3C=CC=C4)=N2)=C(OC)C=C1N(CCN(C)C)C)[O-]
MDL No. :	MFCD28167947
InChI Key :	PKEPAQKEINNCAB-UHFFFAOYSA-N
Pubchem ID :	71239349

Safety of [ 1421372-67-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1421372-67-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	35
Num. arom. heavy atoms	21
Fraction Csp3	0.28
Num. rotatable bonds	9
Num. H-bond acceptors	6.0
Num. H-bond donors	1.0
Molar Refractivity	140.61
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	104.27 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.64
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.78
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.29
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.1
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.69
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.9

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-5.02
Solubility	0.00454 mg/ml ; 0.00000956 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-5.66
Solubility	0.00103 mg/ml ; 0.00000217 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-7.19
Solubility	0.000031 mg/ml ; 0.0000000652 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	Yes
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	Yes
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	Yes
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.52 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<3.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.9

Application In Synthesis of [ 1421372-67-9 ]

* 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 [ 1421372-67-9 ]
Downstream synthetic route of [ 1421372-67-9 ]

[ 1421372-67-9 ] Synthesis Path-Upstream 1~4

1
[ 1421372-67-9 ]
[ 1421372-66-8 ]

Yield	Reaction Conditions	Operation 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

92.37%	With cobalt(II) sulphate heptahydrate; ammonium chloride; hydrazine hydrate In ethanol; water at 85℃; for 8 h;	Intermediate (VII) (15.3 g, 32.19 mmol, 1 eq) was dissolved in 50 mL of EtOH.3 ml of water, ammonium chloride (8 g, 0.15 mol), CoSO4.7H2O (0.9 g, 3.22 mmol, 0.1 eq) and 50 ml of hydrazine hydrate were added separately, and the reaction was stirred at 85 °C for 8 h, followed by TLC until the reaction was completed, and 100 ml of water was added to precipitate. Solid, stirred at room temperature for 1 hour, filtered, washed with water.The intermediate (VIII) was dried to 13.24 g, and the yield was 92.37percent.
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).
79.8%	With ammonium chloride; zinc In ethanol; water at 105℃; for 3 h;	60 g (126 mmol) of Intermediate 4 was dissolved in 500 mL of ethanol, and 4.7 g (88.2 mmol) of NH4CI, 49 · 4 g (756 mmol) of zinc powder were added to the above mixed solution, respectively.Finally, 150 mL of water was added to the mixed solution at once, and the mixture was heated to 105 ° C and stirred for 3 hours. After the reaction was completed, the mixture was filtered while hot, and the filter cake was washed with 150 mL of anhydrous ethanol. The filtrate was collected, and an appropriate amount of activated carbon was added thereto, heated to reflux at 80 ° C for 30 min, and filtered while hot, and the filter cake was washed with 300 mL of anhydrous ethanol. The filtrate was collected, and most of the solvent was evaporated under reduced pressure, and the residue was recrystallized from tetrahydrofuran.After suction filtration, the filter cake was dried to give 44.8 g of light gray solid.The yield is 79.8percent.
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).

References: [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] Patent: CN109134435, 2019, A, . Location in patent: Paragraph 0045-0053.
[5] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2898 - 2901.
[6] Patent: CN107793413, 2018, A, . Location in patent: Paragraph 0180; 0181; 0184; 0185.
[7] Patent: WO2013/14448, 2013, A1, . Location in patent: Page/Page column 124.
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[9] Patent: CN105348267, 2016, A, . Location in patent: Paragraph 0023; 0031; 0032; 0033.
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2
[ 1421372-67-9 ]
[ 79-10-7 ]
[ 1421373-65-0 ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: With 5%-palladium/activated carbon; hydrogen In tetrahydrofuran at 20℃; for 2 h; Stage #2: at 20℃; for 4 h; Inert atmosphere	To a 250 mL single-necked flask was added compound 5 (2.375 g, 5 mmol)And 5percent palladium-carbon (106 mg, 1 mmol)Treated with THF (60 mL) as solvent,Replace the gas three times,The reaction solution was allowed to stand in a hydrogen atmosphere (to ensure a sufficient amount of hydrogen)Stir at room temperature for 2 h,Rapid filtration of solid palladium-carbon,And acrylic acid (0.72 g, 10 mmol) was added to the filtrate,EDC · HCl (2.865 g, 15 mmol)And DIPEA (2.580 g, 20 mmol),And with nitrogen for protection, room temperature stirring 4h,TLC (CHCl3: MeOH = 8: 1, Rf = 0.8) After the reaction was complete,Concentrated under reduced pressure,Add chloroform and water extraction three times,The organic phase was taken, dried over anhydrous sodium sulfate,Filter, spin dry,A solution of AZD9291 as a yellowish solid, 1.521 g,Yield 61percent.

References: [1] Patent: CN106967050, 2017, A, . Location in patent: Paragraph 0020; 0023.

3
[ 1421372-67-9 ]
[ 79-10-7 ]
[ 814-68-6 ]
[ 1421373-65-0 ]

Yield	Reaction Conditions	Operation in experiment
72.1%	Stage #1: With palladium 10% on activated carbon; hydrogen In tetrahydrofuran at 20 - 50℃; Stage #2: at 20℃;	Will be 10 gramsN-(4-N,N,N'-trimethylethylenediamine-2-methoxy-5-Nitrophenyl)-4-(1-methyl-1H-indol-3-yl)Pyrimidin-2-amine is intermediate 3,Add 100ml of tetrahydrofuran solution,After heating to 50°C to dissolve it,Add 0.5 g of 10percent palladium metal on palladium carbon at room temperature.Vacuuming into the hydrogen,Response 10-12 hours (according to TLC dot board tracking)Withdrawal of hydrogen,Separately add 2.27 grams of acrylic acid,5.42 g of N,N-diisopropyl-ethylamineAnd 2.07 grams of acryloyl chloride continue stirring at room temperature for 1-2 hours (according to the TLC dot plate tracking),The reaction is completeDiluted with 100ml of water,Extract with dichloromethane,The resulting methylene chloride solution is dried over anhydrous sodium sulfate.Distilled under reduced pressure,Column purification 7.58g,Yield 72.1percent.

References: [1] Patent: CN107556293, 2018, A, . Location in patent: Paragraph 0026; 0027; 0028; 0029; 0030.

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[ 1421373-65-0 ]

References: [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] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 12 - 23.
[6] Patent: CN107188888, 2017, A, .
[7] Patent: CN107216313, 2017, A, .
[8] Patent: CN107793413, 2018, A, .
[9] Patent: CN108623567, 2018, A, .
[10] Patent: CN109134435, 2019, A, .

Historical Records

Technical Information

• Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Chan-Lam Coupling Reaction • Hydride Reductions • Leuckart-Wallach Reaction • Mannich Reaction • Nomenclature of Ethers • Petasis Reaction • Preparation of Amines • Preparation of Ethers • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reactions of Ethers • Specialized Acylation Reagents-Vilsmeier Reagent • Ugi Reaction

Related Functional Groups of
[ 1421372-67-9 ]

Aryls

A170176 [1421372-94-2]

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

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A134137 [152460-09-8]

N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyrimidin-2-amine

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A127173 [152460-10-1]

N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine

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6,7-Dimethoxy-N-(4-phenoxyphenyl)quinazolin-4-amine

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A141916 [240136-69-0]

4-(3-Nitrophenyl)pyrimidin-2-amine

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Ethers

A170176 [1421372-94-2]

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

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A523201 [179248-59-0]

6,7-Dimethoxy-N-(4-phenoxyphenyl)quinazolin-4-amine

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A137387 [175913-27-6]

4-Methoxy-7-nitro-1H-indole

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A322576 [179552-74-0]

N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine

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A127196 [99844-02-7]

4-(4-Methoxyphenyl)pyrimidin-2-amine

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Amines

A170176 [1421372-94-2]

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

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A134137 [152460-09-8]

N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyrimidin-2-amine

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A127173 [152460-10-1]

N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine

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A523201 [179248-59-0]

6,7-Dimethoxy-N-(4-phenoxyphenyl)quinazolin-4-amine

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A141916 [240136-69-0]

4-(3-Nitrophenyl)pyrimidin-2-amine

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Nitroes

A170176 [1421372-94-2]

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

Similarity: 0.78

A134137 [152460-09-8]

N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyrimidin-2-amine

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A141916 [240136-69-0]

4-(3-Nitrophenyl)pyrimidin-2-amine

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A137387 [175913-27-6]

4-Methoxy-7-nitro-1H-indole

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A322576 [179552-74-0]

N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine

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Related Parent Nucleus of
[ 1421372-67-9 ]

Indoles

A170176 [1421372-94-2]

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

Similarity: 0.78

A137387 [175913-27-6]

4-Methoxy-7-nitro-1H-indole

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A189267 [135531-92-9]

5-Methoxy-4-nitro-1H-indole

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A126477 [175913-29-8]

5-Methoxy-6-nitro-1H-indole

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A287603 [1308672-74-3]

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Similarity: 0.56

Pyrimidines

A170176 [1421372-94-2]

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

Similarity: 0.78

A134137 [152460-09-8]

N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyrimidin-2-amine

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A127173 [152460-10-1]

N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine

Similarity: 0.65

A141916 [240136-69-0]

4-(3-Nitrophenyl)pyrimidin-2-amine

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A230580 [641569-97-3]

Ethyl 4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzoate

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CAS No.: 1421372-67-9

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CAS No.: 1421372-67-9

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