1197953-47-1|(2-Aminophenyl)dimethylphosphine oxide| Ambeed

CAS No. :	1197953-47-1
Formula :	C₈H₁₂NOP
M.W :	169.16
SMILES Code :	CP(C)(=O)C1=C(N)C=CC=C1
MDL No. :	MFCD23135529
InChI Key :	DHHGHQKIKXKQGJ-UHFFFAOYSA-N
Pubchem ID :	67052743

Safety of [ 1197953-47-1 ]

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

Computational Chemistry of [ 1197953-47-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	1
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	49.81
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	52.9 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.5
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	0.81
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.52
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.	1.12
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	1.06
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.2

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.74
Solubility	3.1 mg/ml ; 0.0183 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.5
Solubility	5.32 mg/ml ; 0.0314 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-2.82
Solubility	0.254 mg/ml ; 0.0015 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	Yes
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	Yes
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	No
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	No
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	No
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	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.76 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	1.0
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<1.0
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)	3.02

Application In Synthesis of [ 1197953-47-1 ]

* 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.

Downstream synthetic route of [ 1197953-47-1 ]

[ 1197953-47-1 ] Synthesis Path-Downstream 1~30

1
[ 615-43-0 ]
[ 7211-39-4 ]
[ 1197953-47-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium phosphate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 150℃; for 3.0h;	Step 1 : synthesis of compound 1To a solution of 2-iodoaniline ( 1.0 eq) and dimethylphosphine oxide (1.1 eq) in DMF were added potassium phosphate ( 1.1 eq) and palladium acetate/Xantphos (catalytic). The reaction was stirred at 150 °C for 3 hours and cooled to room temperature. The solvent was evaporated and the residue was worked up with DCM/water. The crude product was purified with a column(EtOAc/MeOH 10: 1 ) to give 1 as a brown solid (80percent yield).
80%	With potassium phosphate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 150℃; for 3.0h;	To a solution of 2-iodoaniline (1.0 eq) and dimethylphosphine oxide (1.1 eq) in DMF were added potassium phosphate (1.1 eq) and palladium acetate/Xantphos (catalytic). The reaction was stirred at 150 °C for 3 hours and cooled to room temperature. The solvent was evaporated and the residue was worked up with DCM/water. The crude product was purified with a column (EtOAc/MeOH 10:1) to give 1 as a brown solid (80percent yield).
80%	With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 150℃; for 3.0h;	Synthesis of 1 (0791) (0792) To a solution of 2-iodoaniline (1.0 eq) and dimethylphosphine oxide (1.1 eq) in DMF were added potassium phosphate (1.1 eq), palladium acetate/Xantphos (catalytic). The reaction was stirred at 150° C. for 3 hours and cooled to room temperature. The solvent was evaporated and the residue was worked up with DCM/water. The crude product was purified with a column (EtOAc/MeOH 10:1) to give 1 as a brown solid (80percent yield).

79.96%	With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In water; N,N-dimethyl-formamide; at 110 - 125℃; for 3.0h;Inert atmosphere;	The 2 - iodo aniline (990.01 g, 4. 52 muM, 1 equivalent) and dimethyl phosphine oxide (690 g, 5.2 muM, 1.15 equiv), K3PO4(0.594 g, 0.226 muM, 0.05 wt) in DMF (5.5 L, ) and water (0.55 L) in, the reaction mixture is under the protection of nitrogen, heated to 110 - 125 ° C and stirring 3 hours. LCMS and TLC (PE: EA = 10: 1, DCM: MeOH = 10: 1 ) Display the completion of reaction. The mixture is filtered and concentrated, wherein the DMF is removed, the resulting residues of ethyl acetate (2 L) dilution. Then adding HC / EA (4 M, 2 L) make the product into a salt , There are a large quantity of solid precipitate, stirring to make it uniform dispersion, the concrete filtering, the filter cake is used which acetone (0.4 L x 3) washing, and drying solid, to obtain the target compound (817 g, yield 79.96percent IS) AS Yellow Solid
62.15%	With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 100℃; for 16.0h;Inert atmosphere;	2-iodoaniline solution (12.50 g, 57.07 mmol) and Example 1J (5.35 g, 68.49 mmol), K3PO4 (14.54 g, 68.49 mmol), Xantphos (660.44 mg, 1.14 mmol) and palladium acetate ( 256.26 mg, 1.14 mmol) in DMF (80mL), the reaction mixture was stirred under nitrogen and heated to 100 deg. C and stirred for 16 hours. LCMS (DCM: methanol = 10: 1) showed the reaction was complete. The mixture was filtered and concentrated and the resulting residue was diluted with aqueous HCl (1N, 80mL), the pH is adjusted to about 2, and the resulting mixture was filtered. The filtrate (100mL × 2) and extracted with the DCM, the aqueous layer was separated, and washed with aqueous sodium bicarbonate to adjust the pH to about 9, and (200mL × 2) and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by recrystallization (the PE: ethyl acetate = 5: 1) to give the title compound (6.00 g, 35.47 mmol, 62.15percent yield) as a white solid.
62.15%	With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 120℃; for 6.0h;Inert atmosphere;	To a solution of 2-iodoaniline (1.0g, 4.57mmol, 1.Oeq) in dimethylformamide (lOmL) were added compound 128.1 (0.463g, 5.94mmol, Oeq) and potassium phosphate (1.937g, 9.14mmol, 2. Oeq). The reaction mixture was degassed for 10 min under argon atmosphere, and palladium acetate (0.103g, 0.457mmol, O. leq) and 4,5-Bis(Diphenylphosphino)-9,9-dimethylxanthene (0.529g, 0.914mmol, 0.2eq) were added. Reaction mixture was again degassed for 10 min and stirred at 120°C for 6h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 3percent methanol in dichloromethane as eluent to obtain 128.2. (0.48g, 62.15percent). MS(ES): m/z 170.16 [M+H]+
	With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 0.12℃;	[00366] A mMure of 2iodoaniHne (66 g, 0.393 moL 1.0 eq.), dimethyl phosphine oxide (36.4 g, 0466 meL 1.19 eq.), potasshim phosphate (92.4 g. 0.423 mol, 1.1 eq.), paNadk1m(H) acetate (4.56 g, 002 mol, 005 eq), and Xantphos (11.6g, 0.02 mel. 0.05 eq.) in DMF (700 mL) was stirred at ?120° C for ?6 h. The color of the mixture turned dark brown. Upon cooling to rt, celite (30 g) was added to the mixture. The mixture was then filtered and the filter cake was rinsed with EtOAc (2 x 250 mL). The filtrate was then concentrated in vacuo to afford a residue. [00367] Another batch of (2..aminophenyl)dimethylphosphine oxide was synthesized at the same scale as performed above, and the residue obtained from both batches were combined and purified as discussed below.[00368] To the combined residues was added EtOAc (1 L), and the resulting mixture was stirred at rt for ?1 h. The mixture was filtered, and the collected residue was washed with EtCAc (2 x 250 mL), The combined filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to afford an oil. The resulting oil was dissolved in a mixture of water / concentrated hydrochloric acid (1 .2 L / 300 mL) with agitation at rt, and stirred for 30 mm. The resulting mixture was filtered, and the collected residue was washed with aqueous hydrochloric acid (10percent, 300 mL). The combined aqueous filtrate was washed with EtOAc (2 x I L washes, followed by a 500 mL wash). The aqueous layer was cooled in an ice bath (less than 10° C internal mixture temperature) and the pH of the solution was adjusted to?12 (as determined by pH paper) by adding aqueous sodium hydroxide (30percent w/w), while maintaining an internal solution temperature of less than 20° C throughout the addition. The resulting solution was extracted with IPA?DCM (1/3 v/v, 4 x I L), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a viscous oil, which crystallized upon standing at rt. The resulting solids were triturated with EtOAc/heptane (1/10 v/v, 2 x 150 mL) to afford (2aminophenyl)dimethylphosphine oxide as a light brown solid.
	With palladium diacetate; N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 100℃; for 6.0h;Inert atmosphere;	2-iodoaniline (17.5 g, 79.9 mmol) and dimethyl phosphine oxide (6.9 g, 88.5 mmol) were added,Palladium acetate (0.3 g, 1.3 mmol), Xantphos (0.77 g, 1.3 mmol),N,N-diisopropylethylamine (22.7 g, 175.8 mmol), DMF (50 mL),Magnetic stirring. Under nitrogen protection, heat to 100°C for 6 hours,The 2-iodoaniline consumption was monitored by thin layer chromatography. Cool to room temperature2,4,5-trichloropyrimidine (17.5 g, 95.9 mmol) was added and the reaction was heated to 75°C for 6 hours.The reaction was complete by thin layer chromatography. Cool to room temperature, add water 300mL,Adjust pH to 5 with 5percent hydrochloric acid and extract with ethyl acetate (100 mL x 3).Wash with sodium bicarbonate solution (100 mL), wash with saturated sodium chloride solution (100 mL × 2),Dry over anhydrous sodium sulfate. It is filtered with suction and concentrated to give a crude brown solid.Recrystallization with ethyl acetate/petroleum ether (volume ratio 1:2) gave an almost white solid 17g.Yield 67.3percent.

2
[ 1197953-47-1 ]
[ 5750-76-5 ]
[ 1197953-49-3 ]

Yield	Reaction Conditions	Operation in experiment
84.6%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4.0h;	25 mL of a one-necked flask was added DMF (3 mL),2,5,6-trichloropyrimidine (0.72 g, 3.9 mmol) was added successively with stirring,2- (dimethylphosphonino) aniline (0.5 g, 3 mmol)Anhydrous potassium carbonate (0.62 g, 4.5 mmol), heated to 60 ° C and stirred for 4 h.(30 mL x 2), the organic phase was combined, washed with water (60 mL x 2), and the organic layer was dried over anhydrous sodium sulfate, and the organic layer was washed with ethyl acetate (30 mL) and water (30 mL) Filtered and concentrated, and the residue was passed through a silica gel column to give 0.8 g of a pale yellow solid in 84.6percent yield.
69%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5.0h;	(2-aminophenyl)dimethyl phosphorus oxide (8.76 g, 51.81 mmol), 2,4,5-trichloropyrimidine (14.92 g, 81.35 mmol), anhydrouspotassium carbonate (22.49 g, 162.29 mmol) and N,N-dimethylformamide (50 mL) were added in a 100 mLsingle-necked flask, and the mixture was heated to 60°C and reacted for 5 hours. After the reaction was completed, thereaction solution was cooled down to room temperature, added with water (30mL) and extracted with dichloromethane(100 mL 3 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered by suction, andevaporated under reduced pressure to remove the solvent. The resulting crude product was subjected to silica gelcolumn chromatography (mobile phase, dichloromethane : methanol = 40 : 1) to give (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethyl phosphorus oxide (11.3 g, 69.0percent yield).1H-NMR (300 MHz, CDCl3) : delta = 11.55 (s, 2H), 8.67 (dd, J = 4.4, 8.5 Hz, 1H), 8.22 (s, 1H), 7.59 (dd, J = 7.7, 8.1 Hz,1H), 1.86 (s, 3H), 1.82 (s, 3H). 13C-NMR (75 MHz, CDCl3) : delta = 156.85, 155.10, 133.05, 133.03, 129.77, 129.63, 123.56,123.40, 122.18, 122.09, 19.28, 18.33.HRMS (ESI, [M+H]+) m/z: 316.0175.
68.4%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 16 - 70℃; for 16.0h;	At 16 deg.C , Example 1K (2.50 g, 14.8 mmol) and 2,4,5-trichloropyrimidine (2.85 g, 15.5 mmol) in DMF (20mL) mixture was added DIPEA (3.82 g, 29.6 mmol). The reaction mixture was heated to 70 deg. C and stirred for 16 hours. TLC showed the reaction was complete. The reaction mixture was washed with water (50 mL) diluted (40mL × 3) and extracted with EtOAc. The combined organic phases were washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was recrystallized from ethanol to give the title compound (3.20 g, 10.1 mmol, 68.4percent yield) as a white solid.

61%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5.0h;	Step 2: Synthesis of 2:2,4,5-Trichloropyrimidine (1.57 eq), 1 (1.0 eq), and potassium carbonate (3.14 eq) in DMF were stirred at 60 °C for 5 hours and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (ISCO machine) (DCM/MeOH 20: 1 ) to give 2 as a yellow solid (61 percent yield).
61%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5.0h;	2,4,5-Trichloropyrimidine (1.57 eq), 1 (1.0 eq), and potassium carbonate (3.14 eq) in DMF were stirred at 60 °C for 5 hours and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (ISCO machine) (DCM/MeOH 20:1) to give 2 as a yellow solid (61 percent yield).
50%	With N-ethyl-N,N-diisopropylamine; for 12.0h;Reflux;	A solution of 2,4,5-trichloropyrimidine(1.82 g, 10 mmol), (2-aminophenyl)dimethylphosphine oxide(1.69 g, 10 mmol) and N,N-diisopropylethylamine (1.94 g, 15 mmol)in propan-2-ol (25 mL) was heated under reflux for 12 h. The solvent was removed by evaporation and the residue was dissolvedin CH2Cl2 (100 mL). The solution was washed with water andsaturated sodium chloride solution and dried, filtered andconcentrated. The residuewas purified by flash chromatography onsilica gel (0e2percent MeOH in DCM) to afford compound 51l (1.60 g,50percent). 1H NMR (400 MHz, DMSO-d6) delta 11.84 (s, 1H), 8.43 (s, 2H), 7.62(s, 2H), 7.25 (s, 1H), 1.83 (s, 3H), 1.80 (s, 3H); 13C NMR (100 MHz,DMSO-d6) d 157.01, 155.99, 142.48, 132.73, 131.47 (d, J 10 Hz),124.17 (d, J 6.0 Hz), 122.64, 122.06 (d, J 3.0 Hz), 121.73, 115.30,18.98, 18.28. HRMS (ESI, m/z) [M+H]+ calcd for C12H13Cl2N3OP:316.0173, found: 316.0175.
	With tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate; In N,N-dimethyl-formamide; at 65℃;	[00369] 245-trichloropyrimidine (54.2 g, 0296 mol, 1.0 eq.), (2arninophenyl)dimethyl..phosphine oxide (50.Og, 0.296 mole, 1.0 eq.), potassium carbonate (49.lg, 0355 mol, 1.2 eq.) and tetrabutylammonium bisuifate (10.2 g. 0.03 mole, 0.1 eq.) were combined in DMF (1050 mL), and heated at 65° C for -8.0-8.5 h. During the course of heating, an offwhite suspension formed. Upon coong, the mixture was cooled to rt and filtered. The coHected solids were rinsed with DMF (2 x 50 mL), and the combined filtrates were concentrated in vacuo. The resulting residue was dissolved in EtOAc (1 .3 L) and water (350 mL). The aqueous layer was isolated and extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine (20percent w/w, 500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford (2..((25dichloropyriniidin4 yl)amino)phenyl)dimethylphosphine oxide as an offwhite solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃;	General procedure: To a solution of 2,4-dichloro-5-fluoropyrimidine (0.5 g, 2.99 mmol) and (2-aminophenyl)dimethylphosphineoxide (0.323 g, 1.907 mmol) in DMF (6.36 mL) wasadded potassium carbonate (0.828 g, 5.99 mmol). The reactionmixture was stirred at 70 °C for overnight. After completion of thereaction, the resulting mixture was cooled to room temperature,quenched with water, extracted with DCM and washed with brine.The combined organic layer was dried over Na2SO4, filtered andconcentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (0-20percent MeOH in DCM)to give 3f as a yellowish solid (0.178 g, 31percent).
17 g	at 75℃; for 6.0h;	2-iodoaniline (17.5 g, 79.9 mmol) and dimethyl phosphine oxide (6.9 g, 88.5 mmol) were added,Palladium acetate (0.3 g, 1.3 mmol), Xantphos (0.77 g, 1.3 mmol),N,N-diisopropylethylamine (22.7 g, 175.8 mmol), DMF (50 mL),Magnetic stirring. Under nitrogen protection, heat to 100°C for 6 hours,The 2-iodoaniline consumption was monitored by thin layer chromatography. Cool to room temperature2,4,5-trichloropyrimidine (17.5 g, 95.9 mmol) was added and the reaction was heated to 75°C for 6 hours.The reaction was complete by thin layer chromatography. Cool to room temperature, add water 300mL,Adjust pH to 5 with 5percent hydrochloric acid and extract with ethyl acetate (100 mL x 3).Wash with sodium bicarbonate solution (100 mL), wash with saturated sodium chloride solution (100 mL × 2),Dry over anhydrous sodium sulfate. It is filtered with suction and concentrated to give a crude brown solid.Recrystallization with ethyl acetate/petroleum ether (volume ratio 1:2) gave an almost white solid 17g.Yield 67.3percent.
0.7 g	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;	Compound b1-1 (0.5 g, 3 mmol) was placed in a 100 mL three-necked flask, and DMF (30 mL) was added.Then, compound b2 (0.86 g, 4.7 mmol), anhydrous potassium carbonate (1.23 g, 9.5 mmol) was added, and stirred at 60 ° C overnight.TLC showed the reaction was almost complete, cooled to room temperature, and then water (100 mL)The organic phase was washed with brine and dried over anhydrous magnesium sulfate.Concentrated through the column to give 0.7 g of a yellow solid.

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3
[ 36082-50-5 ]
[ 1197953-47-1 ]
[ 1407520-11-9 ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate;tetra(n-butyl)ammonium hydrogensulfate; In N,N-dimethyl-formamide; at 65℃; for 7.0h;	Step 1 : Synthesis of 26A suspension of 5-bromo- 2,4-dichloropyrimidine (2.8 g, 12.3 mmol, 1.0 eq), 2- dimethylphosphonylbenzeneamine (2.08 g, 12.3 mmol, 1.0 eq), K2C03 (2.04 g, 14.8 mmol, 1 .2 eq), and nBu4HS04 (417 mg, 1 .23 mmol, 0.1 eq) in 50 mL of DMF was stirred at 65 °C for 7 hours and cooled to room temperature. After a filtration, the filtrate was evaporated to an oil, which was chromatographed (DCM/MeOH 20: 1 ) to give a yellow solid, 2.9 g, in 66percent yield.
66%	With tetrabutylammonium hydrogensulfate; potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 7.0h;	A suspension of 5-bromo- 2,4-dichloropyrimidine (2.8 g, 12.3 mmol, 1.0 eq), 2- dimethylphosphonylbenzeneamine (2.08 g, 12.3 mmol, 1.0 eq), K2CO3 (2.04 g, 14.8 mmol, 1.2 eq), and nBu4HS04 (417 mg, 1.23 mmol, 0.1 eq) in 50 mL of DMF was stirred at 65 °C for 7 hours and cooled to room temperature. After a filtration, the filtrate was evaporated to an oil, which was chromatographed (DCM/MeOH 20:1 ) to give a yellow solid, 2.9 g, in 66percent yield.

References: [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 4948 - 4964.
[2]Patent: WO2012/151561,2012,A1 .Location in patent: Page/Page column 48.
[3]Patent: WO2013/169401,2013,A1 .Location in patent: Page/Page column 50-51.

4
[ 1197953-47-1 ]
[ 1116239-79-2 ]
[ 1407520-38-0 ]

Yield	Reaction Conditions	Operation in experiment
54%	With hydrogenchloride; In isopropyl alcohol; at 150℃; for 2.0h;Microwave irradiation;	In a microwave vessel (20 mL) were placed 65 (600 mg, 1.7 mmol), 1 (282 mg, 1.7 mmol) and isopropanol (10 mL). After HCI (1.3 mL, 4 M in dioxane) was added, the resulting mixture was stirred in the microwave reactor at 150 °C for 2 hrs. The solvents were evaporated and the residue was purified via silica column chromatography (ISCO machine, EtOAc/Heptane, 0-100percent EtOAc to elute impurities and then MeOH/DCM, 0-20percent MeOH) to give pure 66 (900 mg, 54percent).
	With hydrogenchloride; In 1,4-dioxane; isopropyl alcohol; at 150℃; for 2.0h;Microwave irradiation;	Step 3 : In a microwave vessel (20 mL) were placed 65 (600 mg, 1.7 mmol), 1 (282 mg, 1.7 mmol) and isopropanol ( 10 mL). After HC1 (1.3 mL, 4 M in dioxane) was added, the resulting mixture was stirred in the microwave reactor at 150 °C for 2 hrs. The solvents were evaporated and the residue was purified via silica column chromatography (ISCO machine, EtOAc/Heptane, 0- 100percent EtOAc to elute impurities and then MeOH DCM, 0-20percent MeOH) to give pure 66 (900 mg, 54percent).

References: [1]Patent: WO2013/169401,2013,A1 .Location in patent: Page/Page column 59-60.
[2]Patent: WO2012/151561,2012,A1 .Location in patent: Page/Page column 59.

5
[ 1197953-47-1 ]
[ 1116239-79-2 ]
[ 1407520-39-1 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

6
[ 1197953-47-1 ]
[ 1407520-03-9 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

7
[ 1197953-47-1 ]
[ 1407520-08-4 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

8
[ 1197953-47-1 ]
cis-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)cyclohexyl)acrylamide [ No CAS ]
trans-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)cyclohexyl)acrylamide [ No CAS ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

9
[ 1197953-47-1 ]
[ 1407520-12-0 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

10
[ 1197953-47-1 ]
[ 1407520-13-1 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

11
[ 1197953-47-1 ]
[ 1407519-16-7 ]

References: [1]Patent: WO2012/151561,2012,A1 .

12
[ 1197953-47-1 ]
[ 1407519-17-8 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

13
[ 1197953-47-1 ]
[ 1407520-42-6 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .
[3]European Journal of Medicinal Chemistry,2017,vol. 136,p. 497 - 510.
[4]European Journal of Medicinal Chemistry,2017,vol. 139,p. 674 - 697.

14
[ 1197953-47-1 ]
[ 1407520-43-7 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

15
[ 1197953-47-1 ]
[ 1407520-44-8 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

16
[ 1197953-47-1 ]
[ 1407519-22-5 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

17
[ 1197953-47-1 ]
C₂₆H₃₅ClN₇O₅P [ No CAS ]

References: [1]Patent: WO2012/151561,2012,A1 .

18
[ 1197953-47-1 ]
[ 1407520-49-3 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

19
[ 1197953-47-1 ]
[ 1407519-23-6 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

20
[ 1197953-47-1 ]
[ 1407520-52-8 ]

References: [1]Patent: WO2012/151561,2012,A1 .

21
[ 1197953-47-1 ]
[ 1407520-53-9 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

22
[ 1197953-47-1 ]
[ 1407520-54-0 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

23
[ 1197953-47-1 ]
[ 1407520-55-1 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

24
[ 1197953-47-1 ]
[ 1407519-26-9 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

25
[ 1197953-47-1 ]
[ 1407519-27-0 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

26
[ 1197953-47-1 ]
[ 1407519-11-2 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

27
[ 1197953-47-1 ]
[ 1407519-12-3 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

28
[ 1197953-47-1 ]
[ 1407519-99-6 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

29
[ 1197953-47-1 ]
[ 1407520-00-6 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

30
[ 1197953-47-1 ]
[ 1407520-01-7 ]

References: [1]Patent: WO2012/151561,2012,A1 .
[2]Patent: WO2013/169401,2013,A1 .

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
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P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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