[ CAS No. 226419-21-2 ]

Name: 226419-21-2|4-Chloro-3,5-dimethoxyaniline|97%
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SKU: A192765
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Quality Control of [ 226419-21-2 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 226419-21-2 ]

CAS No. :	226419-21-2	MDL No. :	MFCD01321026
Formula :	C₈H₁₀ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	187.62 g/mol	Pubchem ID :	-
Synonyms :

Calculated chemistry of of [ 226419-21-2 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.84
TPSA :	44.48 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.16 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.86
Log Po/w (XLOGP3) :	1.81
Log Po/w (WLOGP) :	1.95
Log Po/w (MLOGP) :	1.45
Log Po/w (SILICOS-IT) :	1.74
Consensus Log Po/w :	1.76

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.38
Solubility :	0.779 mg/ml ; 0.00415 mol/l
Class :	Soluble
Log S (Ali) :	-2.36
Solubility :	0.812 mg/ml ; 0.00433 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.91
Solubility :	0.23 mg/ml ; 0.00123 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.68

Safety of [ 226419-21-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P264-P270-P301+P312-P330-P501	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 226419-21-2 ]

* 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 [ 226419-21-2 ]

[ 226419-21-2 ] Synthesis Path-Downstream 1~32

1
[ 10272-07-8 ]
[ 226419-21-2 ]

Yield	Reaction Conditions	Operation in experiment
64%	With copper(II) choride dihydrate; lithium chloride hydrate; In ethanol; for 3h;Reflux;	General procedure: A round-bottomed flask (25 mL) was charged with substrate (2 mmol), CuCl2·2H2O (6 mmol), LiCl·H2O (2 mmol) and EtOH (4 mL). The resulting reaction mixture was stirred at reflux. After the completion of the reaction monitored by TLC, EtOH was removed under reduced pressure. Then ammonium hydroxide (4 mL, 25%) and water (10 mL) were added and the aqueous phase was extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with brine (8 mL×3) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude mixture was purified by chromatography on silica gel to obtain the desired products.
26%	With N-chloro-succinimide; acetic acid; at 20℃; for 3h;	Svnthesis 1 16-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)ben2oic acid (AAA-114)/V-Chlorosuccinimide (15.7 g, 1 18 mmol) was added to a solution of 3,5-dimethoxyaniline (1) (20.0 g, 131 mmol) in AcOH (150 mL) and the reaction mixture was left to stir at RT for 3 h. The reaction mixture was diluted with water (200 mL) and EtOAc (200 mL). The phases were separated and the organic solution was washed with brine (200 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (120 g, 0-70% EtOAc in isohexanes) to afford 4-chloro-3,5-dimethoxyaniline (2) (6.61 g, 26%) as a colourless solid: m/z 188 [M+H]+ (ES+).
26%	With N-chloro-succinimide; In acetic acid; at 20℃; for 3h;	N-Chlorosuccinimide (15.7 g, 118 mmol) was added to a solution of 3,5-dimethoxyaniline (1) (20.0 g, 131 mmol) in AcOH (150 mL) and the reaction mixture was left to stir at RT for 3 h. The reaction mixture was diluted with water (200 mL) and EtOAc (200 mL). The phases were separated and the organic solution was washed with brine (200 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (120 g, 0-70% EtOAc in isohexanes) to afford 4-chloro-3,5-dimethoxyaniline (2) (6.61 g, 26%) as a colourless solid: m/z 188 [M+H]+ (ES+).

16%	With N-chloro-succinimide; acetic acid; at 20℃; for 4.5h;	4-Chloro-3,5-dimethoxyaniline (SG2-062-01): This was prepared using the previously reported method (US 2012/0149737). A mixture of 3,5-dimethoxyaniline (2.67 g, 20 mmol), acetic acid (25 mL), and N-chlorosuccinimide (3.37 g, 22 mmol) was stirred at room temperature for 4.5 h. Water (50 mL) and EtOAc (50 mL) were added. The organic layer was washed with brine (1 x 50 mL), dried (Na2S04), and concentrated under reduced pressure. The resulting residue was purified via column chromatography (S1O2) eluting with hexanes/EtOAc (gradient: 100% hexanes to 30% ethyl acetate in hexanes) to give the title compound as a brown solid (0.594 g, 16%). Mp: 153 C (dec). NMR (400 MHz, DMSO-) delta: 5.94 (s, 2H), 5.28 (s, 2H, disappeared on D2O shake), 3.69 (s, 6H). HPLC-MS (ESI+): m/z 190.1 [30%, (M37C1+H)+], 188.1 [100%, (M35C1+H)+].
16%	With N-chloro-succinimide; acetic acid; at 20℃; for 4.5h;	This was prepared using the previously reported method.7 A mixture of 3,5-dimethoxyaniline (2.67 g, 20 mmol), acetic acid (25 mL), and N-chlorosuccinimide (3.37 g, 22 mmol) was stirred at room temperature for 4.5 h. Water (50 mL) and EtOAc (50 mL) were added. The organic layer was washed with brine (1 x 50 mL), dried (Na2S04), and concentrated under reduced pressure. The resulting residue was purified via column chromatography (S1O2) eluting with hexanes/EtOAc (gradient: 100% hexanes to 30% ethyl acetate in hexanes) to give the title compound as a brown solid (0.594 g, 16%). Mp: 153 C (dec). lH NMR (400 MHz, DMSO-ifc) delta: 5.94 (s, 2H), 5.28 (s, 2H, disappeared on D20 shake), 3.69 (s, 6H). HPLC-MS (ESI+): m/z 190.1 [30%, (M37C1+H)+], 188.1 [100%, (M35C1+H)+].
13.1%	With N-chloro-succinimide; acetic acid; In dichloromethane; water; at 20℃; for 0.166667h;	To a solution of 3,5-dimethoxyaniline (20.0 g, 130 mmol) in AcOH (50 mL) was added NCS (17.0 g, 130 mmol) in portions over 10 mm. The mixture was stirred at RT for 16 h. The reaction was poured into DCM (200 mL) and H20 (200 mL), the organic phase was washed with Sat. NaC1 (100 mL), dried over anhydrous Na2504, filtered and evaporated to give a crude product which was purified by column chromatography on silica gel (PE: EA= 12: 1)to give desired product as a white solid (3.2 g, 13.1%). ?H NIVIR (400 IVIFIz, DMSO-d6) 5.96 (s, 2H), 5.28 (s, 2H), 3.71 (s, 6H), MS (ESI, m/e) [M+1] 188.1.

Reference： [1]Synthetic Communications,2018,vol. 48,p. 2708 - 2714
[2]Journal of Natural Products,2017,vol. 80,p. 2716 - 2722
[3]Patent: WO2011/27106,2011,A1 .Location in patent: Page/Page column 156-157
[4]Patent: US2012/149737,2012,A1 .Location in patent: Page/Page column 92
[5]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 127
[6]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 238-239
[7]Patent: WO2019/34009,2019,A1 .Location in patent: Paragraph 0180-0182

2
[ 226419-21-2 ]
[ 1272528-60-5 ]

Yield	Reaction Conditions	Operation in experiment
67%		Step (ii): 2-Chloro-5-iodo-1 ,3-dimethoxybenzene (3)4-Chloro-3,5-dimethoxyaniline (2) (6.61 g, 35.2 mmol) was added to a mixture of sulfuric acid (9.39 mL, 176 mmol) and H20 (100 mL) at 0C. Sodium nitrite (3.16 g, 45.8 mmol) was added and the reaction mixture was stirred at 0C for 30 min. The mixture was added to a pre-warmed mixture of sodium iodide (21.1 g, 141 mmol), iodine (4.47 g, 17.6 mmol), sulphuric acid (8 mL) and H20 (100 mL) at 80C and the resulting mixture was heated at reflux for 30 min. The mixture was allowed to cool to RT and then 40% sodium thiosulfate solution (200 mL) was added. The product was extracted with EtOAc (300 mL), the solvent was removed in vacuo and the residue was purified by silica gel chromatography (120 g, 0-50% EtOAc in isohexanes) to afford 2-chloro-5-iodo-1 ,3-dimethoxybenzene (3) (7.16 g, 67 % yield).
67%		4-Chloro-3,5-dimethoxyaniline (2) (6.61 g, 35.2 mmol) was added to a mixture of sulfuric acid (9.39 mL, 176 mmol) and H2O (100 mL) at 0 C. Sodium nitrite (3.16 g, 45.8 mmol) was added and the reaction mixture was stirred at 0 C. for 30 min. The mixture was added to a pre-warmed mixture of sodium iodide (21.1 g, 141 mmol), iodine (4.47 g, 17.6 mmol), sulphuric acid (8 mL) and H2O (100 mL) at 80 C. and the resulting mixture was heated at reflux for 30 min. The mixture was allowed to cool to RT and then 40% sodium thiosulfate solution (200 mL) was added. The product was extracted with EtOAc (300 mL), the solvent was removed in vacuo and the residue was purified by silica gel chromatography (120 g, 0-50% EtOAc in isohexanes) to afford 2-chloro-5-iodo-1,3-dimethoxybenzene (3) (7.16 g, 67% yield).
		To a solution of <strong>[226419-21-2]4-chloro-3,5-dimethoxyaniline</strong> (2.0 g, 10.70 mmol) in H20 (30 mL) and con. H2504 (3.0 mL)was added the solution of NaNO2 (1.11 g, 16.04 mmol) in water (6.0 mL) at 0-5C, the reaction was stirred at 0-5C for about 30 mm, the solution was added to the pre-warmed mixture of KI (7.11 g, 42.80 mmol) and 12 (1.36 g, 5.35 mmol) in H20 (30 mL) and con. H2504 (3.0 mL) at 80 C, the resulting mixture was stirred at 80 C for about 30 mm. The reaction was allowed to cool to ambient temperature, sat. Na25203 (100 mL) was added to quench the reaction. The mixture was extracted with EA (30 mL x 3), the combined organic phases were washed with sat. NaC1 (20 mL), dried over anhydrous Na2504, filtered, concentrated and purified by column chromatography on silica gel (200-300 mesh, eluent: PE:EA= 10: 1)to give the product as a white solid (2.1 g, 65.9%). ?H NMR (400 IVIFIz, DMSOd6) 7.09 (s, 2H), 3.84 (s, 6H). MS (ESI) m/e [M+1] 298.9.

Reference： [1]Journal of Natural Products,2017,vol. 80,p. 2716 - 2722
[2]Patent: WO2011/27106,2011,A1 .Location in patent: Page/Page column 157
[3]Patent: US2012/149737,2012,A1 .Location in patent: Page/Page column 92
[4]Patent: WO2019/34009,2019,A1 .Location in patent: Paragraph 0180; 0183-0184

3
[ 226419-21-2 ]
[ 1272528-62-7 ]

Reference： [1]Patent: WO2011/27106,2011,A1
[2]Patent: US2012/149737,2012,A1
[3]Journal of Natural Products,2017,vol. 80,p. 2716 - 2722

4
[ 226419-21-2 ]
[ 1272528-64-9 ]

Reference： [1]Patent: WO2011/27106,2011,A1
[2]Patent: US2012/149737,2012,A1

5
[ 226419-21-2 ]
[ 1272528-66-1 ]

Reference： [1]Patent: WO2011/27106,2011,A1
[2]Patent: US2012/149737,2012,A1

6
[ 226419-21-2 ]
C₁₀H₁₀ClIO₃ [ No CAS ]

Reference： [1]Patent: WO2011/27106,2011,A1

7
[ 226419-21-2 ]
[ 1272528-67-2 ]

Reference： [1]Patent: WO2011/27106,2011,A1
[2]Patent: US2012/149737,2012,A1

8
[ 226419-21-2 ]
[ 56518-51-5 ]

Reference： [1]Patent: WO2011/27106,2011,A1
[2]Patent: US2012/149737,2012,A1

9
[ 226419-21-2 ]
[ 102338-87-4 ]

Reference： [1]Patent: WO2011/27106,2011,A1
[2]Patent: US2012/149737,2012,A1

10
[ 226419-21-2 ]
[ 1272528-73-0 ]

Reference： [1]Patent: WO2011/27106,2011,A1
[2]Patent: US2012/149737,2012,A1

11
[ 226419-21-2 ]
[ 1610450-75-3 ]

Reference： [1]Patent: US2014/296208,2014,A1
[2]Patent: WO2014/162126,2014,A1
[3]Patent: WO2014/76484,2014,A1

12
[ 226419-21-2 ]
[ 1610450-02-6 ]

Reference： [1]Patent: WO2014/76484,2014,A1

13
[ 226419-21-2 ]
[ 1610450-74-2 ]

Yield	Reaction Conditions	Operation in experiment
640 mg	With boron tribromide; In dichloromethane;Reflux;	(i) 5-Amino-2-chloro-3-methoxyphenol BBr3 (1.1 ml, 11.64 mmol) was added dropwise to a solution of 4-chloro-3,5- dimethoxyaniline (2.19 g, 1 1.67 mmol) in DCM at rt. (precipitate formed). The mixture was stirred for 18h then heated under reflux for 6 h. A further 1 mL of BBr3 was added and the mixture stirred for 24h then quenched carefully with MeOH (10 mL). Water (100 mL) was added and the aqueous layer separated then basified with sat aq Na2C03 to pH 6. The mixture was extracted with DCM (2 x 100 mL), the organic layers combined, dried (MgS04), filtered and evaporated under reduced pressure. The residue was triturated with ether/isohexane to afford the sub-title compound (640 mg). 1 H NMR (400MHz; DMSO-d6) delta 9.44 (s, 1 H), 5.84 (s, 1 H), 5.82 (s, 1 H), 5.09 (s, 2H), 3.69 (s, 3H). LCMS m/z 174/6 (M+H)+ (ES+)
640 mg	With boron tribromide; In N,N-dimethyl-formamide; at 20℃; for 48h;	BBr3 (1.1 mL, 11.64 mmol) was added dropwise to a solution of <strong>[226419-21-2]4-chloro-3,5-dimethoxyaniline</strong> (2.19 g, 11.67 mmol) in DCM at rt. (ppte formed). The mixture was stirred for 18 h then heated under reflux for 6 h. A further 1 ml of BBr3 was added and the mixture stirred for 24 h then quenched carefully with MeOH (10 mL). Water (100 mL) was added and the aqueous layer separated then basified with sat aq Na2CO3 to pH 6. The mixture was extracted with DCM (2*100 mL), the organic layers combined, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was triturated with etherisohexane to afford the sub-title compound (640 mg). 1H NMR (400 MHz; DMSO-d6) delta 9.44 (s, 1H), 5.84 (s, 1H), 5.82 (s, 1H), 5.09 (s, 2H), 3.69 (s, 3H). LCMS m/z 174/6 (M+H)+ (ES+)
	With boron tribromide; In dichloromethane; at 20℃; for 48h;Reflux;	BBr3 (1.1 mL, 11.64 mmol) was added dropwise to a solution of <strong>[226419-21-2]4-chloro-3,5-dimethoxyaniline</strong> (2.19 g, 11.67 mmol) in DCM at rt. (ppte formed). The mixture was stirred for 18h then heated under reflux for 6h. A further imI of BBr3 was added and the mixture stirred for 24h then quenched carefully with MeOH (lOmL). Water (lOOmL) was added and the aqueous layer separated then basified with sat aq Na2003 to pH 6. The mixture was extracted withDCM (2xlOOmL), the organic layers combined, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was triturated with ether/isohexane to afford the sub-title compound (640 mg).1H NMR (400MHz; DMSO-d6) O 9.44 (5, 1H), 5.84 (5, 1H), 5.82 (5, 1H), 5.09 (5, 2H), 3.69 (5, 3H).LCMS m/z 174/6 (M+H) (ES)

Reference： [1]Patent: WO2014/76484,2014,A1 .Location in patent: Page/Page column 122; 123
[2]Patent: US2014/296208,2014,A1 .Location in patent: Paragraph 1105 - 1107
[3]Patent: WO2014/162126,2014,A1 .Location in patent: Page/Page column 121

14
[ 226419-21-2 ]
N-(5-(tert-butyl)-3-(3-(4-((2-((4-chloro-3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide [ No CAS ]

Reference： [1]Patent: US2014/296208,2014,A1
[2]Patent: WO2014/162126,2014,A1

15
[ 226419-21-2 ]
5-iodo-2-methylbenzene-1,3-diol [ No CAS ]

Reference： [1]Patent: WO2015/39172,2015,A1

16
[ 226419-21-2 ]
5-iodo-1,3-dimethoxy-2-methylbenzene [ No CAS ]

Reference： [1]Patent: WO2015/39172,2015,A1

17
[ 226419-21-2 ]
3-(3.5-dihydroxy-4-methyl-1,1':4',1''-terphenyl-2'-yl)propanamide [ No CAS ]

Reference： [1]Patent: WO2015/39172,2015,A1

18
[ 13061-96-6 ]
[ 226419-21-2 ]
[ 78025-93-1 ]

Yield	Reaction Conditions	Operation in experiment
27%	With palladium diacetate; potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 21h;Inert atmosphere; Reflux;	A mixture of 4-chloro-3,5-dimethoxyani1ine (3.0 g, 16.0 mmol), paliadium(II)acetate(180 rug 0 80 rnmol) 2-didohcxvlphosphino-2 4 6 -tiusoptopylhiphenyl (XPhos) (381 mg, 0.80 mmol), potassium carbonate (6.73 g, 48.7 mmol) and methylboronic acid (1.15 g, 19.2 mmol) in water (100 mL) and dioxane (100 mL) was heated to 100C (oil bath temperature) under nitrogen for 18 h. The reaction was not complete and heated to reflux for an additional 3 h, cooled to room temperature, diluted with water (200 mL) andextracted with ethyl acetate (3 x 150 mL), dried over magnesium sulfate, concentrated and purified by flash chromatography (ethyl acetate/hexanes) to give 3,5- dimethoxy-4- methylaniline (720 mg, 27%). 1H NMR (400 MHz, CDC13) 5.93 (s, 2H), 3.77 (s, 6H), 3.58 (bs, 2H), 1.98 (s, 3H). Sodium nitrite (340 mg, 4.93 mmol) was added to a mixture of 3,5-dimethoxy-4-methylaniline (720 mg, 4.31 mmol) in sulfuric acid (1.1 mL) andwater (13 mL) at 0C and stirred for 30 mm. The ensuing mixture was added to a preheated mixture of sodium iodide (2.58 g, 17.2 mmol) and iodine (555 mg, 2.19 mmol) in sulfuric acid (1.1 mL) and water (13 mL) at 80C, and the mixture heated to reflux for 30 mm. The reaction mixture was cooled to room temperature and diluted with a solution of sodium sulfite (20% w/w, 100 mL) and water (100 mL), and extracted with ethylacetate (3 x 100 mL). The organics were combined, dried over magnesium sulfate, concentrated and purified by flash chromatography (ethyl acetate/hexanes) to give 5-iodo- 1,3-dimethoxy-2- methylbenzene as a white powder (388 mg, 32%). 1H NMR (400 MHz, CDC13) 6.84 (s, 2H), 3.79 (s, 6H), 2.02 (s, 3H). 5-Iodo-1,3-dimethoxy-2-methylbenzene (388 mg, 1.39 mmol) in dichloromethane (8 mL) was cooled to 0C before adding neatboron tribromide (0.8 mL, 8 mmol) slowly over 1 mm under nitrogen. The reaction mixture was allowed to warm to room temperature slowly over 3 h and stirred for 18 h. The reaction mixture was slowly and cautiously poured onto ice water (100 mL) and extracted with ethyl acetate (3 x 60 mL) and the combined organics washed with brine (1 x 50 mL), dried over magnesium sulfate, concentrated and purified by flashchromatography (ethyl acetate/hexanes) to give 5-iodo-2-methylbenzene-1,3-diol as a white powder (260 mg, 74%). 1H NMR (400 MHz, d6-DMSO) 9.44 (s, 2H), 6.63 (s, 2H), 1.87 (s, 3H).

Reference： [1]Patent: WO2015/39172,2015,A1 .Location in patent: Page/Page column 55; 56

19
[ 226419-21-2 ]
[ 5750-76-5 ]
2,5-dichloro-N<SUP>4</SUP>-(4-chloro-3,5-dimethoxyphenyl)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 14.5h;Reflux;	General procedure: Procedure B: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.
94%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 14.5h;Reflux;	A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below. 2,5-Dichloro-/Y4-(4-chloro-3,5-dimethoxyphenyl)pyrimidin-4-amine (SG2-066): This was prepared from 2,4,5-trichloropyrimidine (0.183 g), SG2-062-01 (0.197 g), and DIPEA (0.210 mL) using procedure B (reaction time, 14.5 h). The precipitate was filtered, washed with isopropanol (1 x 10 mL), water (2 x 10 mL), isopropanol (1 x 10 mL), hexanes (1 x 10 mL), and dried to give the title compound as an off-white solid (0.315 g, 94%). Mp: 252 C (dec). NMR (400 MHz, DMSO-ifc) : delta 9.55 (s, 1H, disappeared on D20 shake), 8.42 (s, 1H), 7.23 (s, 2H), 3.81 (s, 6H). HPLC-MS (ESI+): m/z 356.0 [40%, (M35Cl35Cl35Cl+Na)+], 338.0 [30%, (MC135C137C137+H)+], 336.0 [95%, (M35C135C137C1+H)+], 334.1 [100%, (M35C135C135C1+H)+].

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 84
[2]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 186; 193

20
[ 1780-31-0 ]
[ 226419-21-2 ]
2-chloro-N<SUP>4</SUP>-(4-chloro-3,5-dimethoxyphenyl)-5-methylpyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 36h;Reflux;	General procedure: Procedure B: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.
55%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 36h;Reflux;	A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below. 2,5-Dichloro-/Y4-(4-chloro-3,5-dimethoxyphenyl)pyrimidin-4-amine (SG2-066): This was prepared from 2,4,5-trichloropyrimidine (0.183 g), SG2-062-01 (0.197 g), and DIPEA (0.210 mL) using procedure B (reaction time, 14.5 h). The precipitate was filtered, washed with isopropanol (1 x 10 mL), water (2 x 10 mL), isopropanol (1 x 10 mL), hexanes (1 x 10 mL), and dried to give the title compound as an off-white solid (0.315 g, 94%). Mp: 252 C (dec). NMR (400 MHz, DMSO-ifc) : delta 9.55 (s, 1H, disappeared on D20 shake), 8.42 (s, 1H), 7.23 (s, 2H), 3.81 (s, 6H). HPLC-MS (ESI+): m/z 356.0 [40%, (M35Cl35Cl35Cl+Na)+], 338.0 [30%, (MC135C137C137+H)+], 336.0 [95%, (M35C135C137C1+H)+], 334.1 [100%, (M35C135C135C1+H)+].

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 84
[2]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 186; 193-194

21
[ 1780-31-0 ]
[ 226419-21-2 ]
5-methyl-N⁴-(4-chloro-3,5-dimethoxyphenyl)-N²-[4-(1-methylpiperidin-4-ylcarbamoyl)-2-methoxyphenyl]pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Patent: WO2016/22460,2016,A1
[2]Patent: WO2017/66428,2017,A1

22
[ 226419-21-2 ]
monochasiol A [ No CAS ]