[ CAS No. 20090-58-8 ] {[proInfo.proName]}

Name: 20090-58-8|4-Chloro-5-methylpyrimidin-2-amine|98%
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Quality Control of [ 20090-58-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 20090-58-8 ]

CAS No. :	20090-58-8	MDL No. :	MFCD00725898
Formula :	C₅H₆ClN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UDBZUFZWXJJBAL-UHFFFAOYSA-N
M.W :	143.57	Pubchem ID :	588628
Synonyms :

Calculated chemistry of [ 20090-58-8 ] Expand+

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.2
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	36.41
TPSA :	51.8 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) :	-6.34 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.43
Log Po/w (XLOGP3) :	1.18
Log Po/w (WLOGP) :	1.03
Log Po/w (MLOGP) :	0.33
Log Po/w (SILICOS-IT) :	1.31
Consensus Log Po/w :	1.06

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.97
Solubility :	1.55 mg/ml ; 0.0108 mol/l
Class :	Very soluble
Log S (Ali) :	-1.86
Solubility :	1.97 mg/ml ; 0.0137 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.27
Solubility :	0.766 mg/ml ; 0.00533 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.58

Safety of [ 20090-58-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 20090-58-8 ]

* 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 [ 20090-58-8 ]
Downstream synthetic route of [ 20090-58-8 ]

[ 20090-58-8 ] Synthesis Path-Upstream 1~3

1
[ 15981-91-6 ]
[ 20090-58-8 ]

Yield	Reaction Conditions	Operation in experiment
29%	Stage #1: for 0.75 h; Reflux Stage #2: With ammonia In water at 10℃;	Step b: 4-Chloro-2-amino-5-methylpyrimidineA mixture of 5-methylisocytosine (3 g, 24.0 mmol) and POCl₃(20 mL) was refluxed for 45 minutes. Excess of POCl₃was removed under reduced pressure and the residue was poured over ice. The resulting mixture was made basic with ammonia at 10° C. The precipitate was filtrated and crystallized from ethanol to give 4-chloro-2-amino-5-methylpyrimidine (1 g 29.0percent yield). ¹H NMR (400 MHz, DMSO): δ 8.11 (s, 1 H), 6.81 (br s, 2 H), 2.04 (s, 3 H).

Reference： [1] Patent: US2009/221597, 2009, A1, . Location in patent: Page/Page column 41
[2] Journal of the Chemical Society, 1947, p. 41,45

2
[ 1780-31-0 ]
[ 20090-58-8 ]
[ 14394-70-8 ]

Reference： [1] Patent: WO2004/74278, 2004, A1, . Location in patent: Page 31-33

3
[ 1780-31-0 ]
[ 20090-58-8 ]
[ 14394-70-8 ]

Reference： [1] Patent: WO2004/74278, 2004, A1, . Location in patent: Page 31-33

[ 20090-58-8 ] Synthesis Path-Downstream 1~36

1
[ 20090-58-8 ]
[ 100-36-7 ]
N⁴-(2-diethylamino-ethyl)-5-methyl-pyrimidine-2,4-diyldiamine [ No CAS ]

Reference： [1]Journal of the Chemical Society,1947,p. 41,45

2
[ 15981-91-6 ]
[ 20090-58-8 ]

Yield	Reaction Conditions	Operation in experiment
29%		Step b: 4-Chloro-2-amino-5-methylpyrimidineA mixture of 5-methylisocytosine (3 g, 24.0 mmol) and POCl3 (20 mL) was refluxed for 45 minutes. Excess of POCl3 was removed under reduced pressure and the residue was poured over ice. The resulting mixture was made basic with ammonia at 10 C. The precipitate was filtrated and crystallized from ethanol to give 4-chloro-2-amino-5-methylpyrimidine (1 g 29.0% yield). 1H NMR (400 MHz, DMSO): delta 8.11 (s, 1 H), 6.81 (br s, 2 H), 2.04 (s, 3 H).

Reference： [1]Patent: US2009/221597,2009,A1 .Location in patent: Page/Page column 41
[2]Journal of the Chemical Society,1947,p. 41,45

4
[ 20090-58-8 ]
N,N-diethyl-propanediylamine [ No CAS ]
N⁴-(3-diethylamino-propyl)-5-methyl-pyrimidine-2,4-diyldiamine [ No CAS ]

Reference： [1]Journal of the Chemical Society,1947,p. 41,45

5
[ 20090-58-8 ]
[ 749898-76-8 ]
[ 14394-70-8 ]
[ 749898-14-4 ]
[ 749898-17-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In 1-methyl-pyrrolidin-2-one; at 70℃; for 20h;	Potassium t-butoxide (0. 41G) was added to the product of example 1 step b) (0. 5G) and the mixture of products of example 20 & 21 step a) (0.26g) in NMP (5ml). The mixture was stirred at 70 C for 20h. The resulting mixture was cooled, acidified with acetic acid (2ml) and purified by reverse phase HPLC (Symmetry gradient 90-50% aqueous, ammonium acetate (0.2% aq. ) in acetonitrile) to give the title compounds as a solids (15mg each). 1- [ [6- [4- [ (4-AMINO-5-METHYL-2-PYRIMIDINYL) OXY]-L-PIPERIDINYL]-3- pyridinyl] carbonyl] pyrrolidine. MS (APCI+) 383 [M+H] + H NMR 8 (DMSO) 8.34 (d, lH), 7.71 (dd, lH), 7.70 (s, lH), 6.86 (d, lH), 6.64 (s, 2H), 5.08 (heptet, lH), 4.03-3. 97 (m, 2H), 3.55-3. 35 (m, 6H), 2.03-1. 93 (m, 2H), 1.90 (s, 3H), 1.83 (s, 4H), 1.65-1. 55 (m, 2H) 1- [ [6- [4- [ (2-AMINO-5-METHYL-4-PYRIMIDINYL) OXY]-L-PIPERIDINYL]-3- pyridinyl] carbonyl]pyrrolidine MS (APCI+) 383 [M+H] + 'H NMR No.(DMSO) 8.34 (d, lH), 7.80 (dd, LH), 7.72 (s, lH), 6. 88 (d, lH), 6.23 (s, 2H), 5.31 (heptet, LH), 3.97-3. 87 (m, 2H), 3.58-3. 40 (m, 6H), 2.03-1. 94 (m, 2H), 1.89 (d, 3H), 1. 83 (s, 4H), 1.72-1. 62 (m, 2H)

Reference： [1]Patent: WO2004/74278,2004,A1 .Location in patent: Page 31-33

6
[ 1780-31-0 ]
[ 20090-58-8 ]
[ 14394-70-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; water; at 100℃; for 0.25h;Irradiation; CEM discover microwave at 100W;	2,4-dichloro-5-methylpyrimidine (2.6g), Hunigs base (2. 8ML) and aqueous ammonia (4ml) in dioxane (4ml) were irradiated in a CEM discover microwave at 100 C/100W for 15MIN. The resultant mixture was shaken between isohexane and sat. aq. sodium hydrogen carbonate. The insoluble white solid was filtered off and dried in vacuo to give a mixture of the sub-title compounds (2g). 2-chloro-5-methyl-4-pyrimidinamine: Major (85%) LH NMR 6 (DMSO) 7.82 (s, LH), 7.21 (s, 2H), 1.94 (s, 3H) 4-CHLORO-5-METHYL-2-PYRIMIDINAMINE : Minor (15%) H NMR 8 (DMSO) 8.13 (s, lH), 6.83 (s, 2H), 2.07 (s, 3H)

Reference： [1]Patent: WO2004/74278,2004,A1 .Location in patent: Page 31-33

7
[ 20090-58-8 ]
[ 163105-89-3 ]
[ 1185856-33-0 ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 120℃; for 0.5h;Microwave irradiation;	Preparation of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-(6-methoxypyridin-3-yl)-5-methylpyrimidin-2-yl)cyclopropanecarboxamide Step a: 4-(6-Methoxypyridin-3-yl)-5-methylpyrimidin-2-amineTo <strong>[20090-58-8]4-chloro-5-methylpyrimidin-2-amine</strong> (250 mg, 1.74 mmol), tetrakistriphenylphosphine palladium (0) (100 mg, 0.087 mmol) and 6-methoxypyridin-3-ylboronic acid (398 mg, 2.60 mmol), 1,2-DME (6 mL) and Na2CO3 (1.74 mL, 2 M, 3.47 mmol) were added and heated to 120 C. in a microwave reactor for 30 minutes. The reaction mixture was filtered using acetonitrile and the filtrate was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield 4-(6-methoxypyridin-3-yl)-5-methylpyrimidin-2-amine (160 mg, 43%). ESI-MS m/z calc. 216.10, found 217.5 (M+1)+. Retention time 0.52 minutes.

Reference： [1]Patent: US2009/221597,2009,A1 .Location in patent: Page/Page column 42

8
[ 20090-58-8 ]
[ 220210-56-0 ]
[ 1185856-26-1 ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 120℃; for 0.5h;Microwave irradiation;	Step c: tert-Butyl 3-(2-amino-5-methylpyrimidin-4-yl)benzoateTo 4-chloro-5-methylpyrimidin-2-amine (150 mg, 1.04 mmol), tetrakistriphenylphosphine Palladium (0) (60 mg, 0.052 mmol) and <strong>[220210-56-0]3-(tert-butoxycarbonyl)phenylboronic acid</strong> (347 mg, 1.56 mmol), 1,2-DME (3 mL) and Na2CO3 (1.04 mL, 2 M, 2.08 mmol) were added and heated to 120 C. in a microwave reactor for 30 minutes. The reaction mixture was filtered using EtOAc and the filtrate was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield tert-butyl 3-(2-amino-5-methylpyrimidin-4-yl)benzoate (148 mg, 50%). ESI-MS m/z calc. 285.1, found 286.5 (M+1)+. Retention time 1.33 minutes.

Reference： [1]Patent: US2009/221597,2009,A1 .Location in patent: Page/Page column 41

9
[ 850568-54-6 ]
[ 20090-58-8 ]
[ 1185856-30-7 ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 120℃; for 0.5h;Microwave irradiation;	Preparation of 4-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)benzoic acid Step a: tert-Butyl 4-(2-amino-5-methylpyrimidin-4-yl)benzoateTo 4-chloro-5-methylpyrimidin-2-amine (150 mg, 1.04 mmol), tetrakistriphenylphosphine Palladium (0) (60 mg, 0.052 mmol) and <strong>[850568-54-6]4-(tert-butoxycarbonyl)phenylboronic acid</strong> (347 mg, 1.56 mmol), 1,2-DME (3 mL) and Na2CO3 (1.04 mL, 2 M, 2.08 mmol) were added and heated to 120° C. in a microwave reactor for 30 minutes. The reaction mixture was filtered using EtOAc and the filtrate was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield tert-butyl 4-(2-amino-5-methylpyrimidin-4-yl)benzoate (149 mg, 50percent). ESI-MS m/z calc. 285.1, found 286.3 (M+1)+. Retention time 1.36 minutes.

Reference： [1]Patent: US2009/221597,2009,A1 .Location in patent: Page/Page column 41; 42

10
[ 20090-58-8 ]
[ 1097180-24-9 ]
[ 1227858-11-8 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 80℃; for 3.5h;	To a solution of 1,1-dimethylethyl (25)-2-(3-bromo-2-oxopropyl)-l-piperidinecarboxylate D2 (0.100 g, 0.31 mmol) in DMF (1 ml) was added 4-chloro-5-methyl-2-pyrimidinamine (0.067 g, 0.47 mmol) and the mixture was stirred at 80 0C for 3.5 h. The reaction mixture was charged into a SCX column and was eluted with methanol and ammonia 2 M in methanol. Collected fractions gave 0.086 g of a crude containing the desired product iV-Boc protected. MS: (ES/+) m/z: 366 [M+l]. C18H25ClN4O2 requires 365. To a solution of this material (0.086 g) in DCM (4 ml), TFA (1 ml) was added dropwise at 0 0C and the solution was stirred for 1 h at rt. The solvent was removed and the residue charged into a SCX column and eluted with methanol and ammonia 2 M in methanol. Collected fractions gave a crude (0.072 g) containing the free amine 7-chloro-6-methyl-2-[(25)-2- piperidinylmethyl]imidazo[l,2-alpha]pyrimidine. UPLC: rt = 0.41, peak observed: 265 (M+l, 100%) and 267 (M+l, 33%). C13H17ClN4 requires 265. Into a 7 ml screw capped vial 2- methyl-5-phenyl-l,3-thiazole-4-carboxylic acid (0.071 g, 0.33 mmol) was dissolved in DCM (1 ml), Oxalyl chloride (0.057 ml, 0.65 mmol) then DMF (one drop) were added and the resulting mixture was stirred for 30 min at rt. The solvent was removed under reduced pressure and the resulting yellow solid dissolved in DCM (1 ml) and added dropwise to the solution containing the crude (0.072 g) 7-chloro-6-methyl-2-[(25)-2- piperidinylmethyl]imidazo[l,2-alpha]pyrimidine and TEA (0.113 ml, 0.81 mmol) in DCM (1 ml) cooled at 0 0C. The ice-bath was removed and the reaction mixture left under stirring at rt for 2 h. DCM (1 ml) was added and the mixture washed with NaHCO3 (2 ml); the organic phase was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by Fraction Lynx (two runs) and the free base of the title compound was obtained (0.004 g, 0.001 mmol, 3% yield from D2, three steps). UPLC: rt = 0.64, peak observed: 466 (M+l, 100%) and 468 (M+l, 33%). C24H24ClN5OS requires 466. 1H NMR [the product is present as a mixture of conformers (ratio c.ca 60/40)] (500 MHz, DMSO-d6). The free base (0.003 g, 0.0006 mmol) was transferred into a 7 ml screw capped vial with anhydrous Et2O (0.2 ml) and the solution cooled to 0 0C. HCl (0.14 ml of a 1 M solution in Et2O, 0.14 mmol) was added dropwise and the mixture stirred for 15 min. The solvent was removed under reduced pressure and the resulting solid triturated with anhydrous Et2O. The title compound was obtained (0.003 g, 0.006 mmol, 93% yield).
	In N,N-dimethyl-formamide; at 80℃; for 3.5h;	Example 37-chloro-6-methyl-2-({(2S)-1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]-2-piperidinyl}methyl)imidazo[1,2-a]pyrimidine (HCl salt) (E3) To a solution of 1,1-dimethylethyl (2S)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate D2 (0.100 g, 0.31 mmol) in DMF (1 ml) was added 4-chloro-5-methyl-2-pyrimidinamine (0.067 g, 0.47 mmol) and the mixture was stirred at 80 C. for 3.5 h. The reaction mixture was charged into a SCX column and was eluted with methanol and ammonia 2 M in methanol. Collected fractions gave 0.086 g of a crude containing the desired product N-Boc protected. MS: (ES/+) m/z: 366 [M+1]. C18H25ClN4O2 requires 365. To a solution o material (0.086 g) in DCM (4 ml), TFA (1 ml) was added dropwise at 0 C. and the solution was stirred for 1 h at it The solvent was removed and the residue charged into a SCX column and eluted with methanol and ammonia 2 M in methanol. Collected fractions gave a crude (0.072 g) containing the free amine 7-chloro-6-methyl-2-[(2S)-2-piperidinylmethyl]imidazo[1,2-a]pyrimidine. UPLC: rt=0.41, peak observed: 265 (M+1, 100%) and 267 (M+1, 33%). C13H17ClN4 requires 265. Into a 7 ml screw capped vial 2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (0.071 g, 0.33 mmol) was dissolved in DCM (1 ml), Oxalyl chloride (0.057 ml, 0.65 mmol) then DMF (one drop) were added and the resulting mixture was stirred for 30 min at rt. The solvent was removed under reduced pressure and the resulting yellow solid dissolved in DCM (1 ml) and added dropwise to the solution containing the crude (0.072 g) 7-chloro-6-methyl-2-[(2S)-2-piperidinylmethyl]imidazo[1,2-a]pyrimidine and TEA (0.113 ml, 0.81 mmol) in DCM (1 ml) cooled at 0 C. The ice-bath was removed and the reaction mixture left under stirring at rt for 2 h. DCM (1 ml) was added and the mixture washed with NaHCO3 (2 ml); the organic phase was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by Fraction Lynx (two runs) and the free base of the title compound was obtained (0.004 g, 0.001 mmol, 3% yield from D2, three steps). UPLC: rt=0.64, peak observed: 466 (M+1, 100%) and 468 (M+1, 33%). C24H24ClN5OS requires 466. 1H NMR [the product is present as a mixture of conformers (ratio c.ca 60/40)] (500 MHz, DMSO-d6). The free base (0.003 g, 0.0006 mmol) was transferred into a 7 ml screw capped vial with anhydrous Et2O (0.2 ml) and the solution cooled to 0 C. HCl (0.14 ml of a 1 M solution in Et2O, 0.14 mmol) was added dropwise and the mixture stirred for 15 min. The solvent was removed under reduced pressure and the resulting solid triturated with anhydrous Et2O. The title compound was obtained (0.003 g, 0.006 mmol, 93% yield).

Reference： [1]Patent: WO2010/60471,2010,A1 .Location in patent: Page/Page column 20-21
[2]Patent: US2010/160344,2010,A1 .Location in patent: Page/Page column 9-10

11
[ 20090-58-8 ]
C₁₉H₂₇BN₂O₅ [ No CAS ]
C₁₈H₂₁N₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In methanol; toluene; at 85℃; for 4h;Inert atmosphere;	General procedure: A mixture of intermediate 56 (0.36 g, 0.84 mmol), 4-chloro-5-fluoropyrimidin-2-amine (0.10 g, 0.67 mmol), tetrakis(triphenylphosphine)palladium (0.08 g, 0.07 mmol), sodium carbonate (1.01 ml, 2.02 mmol), toluene (12.5 ml) and MeOH (1.5 ml) was stirred under an argon atmosphere at 85 C for 4 hours. The mixture was cooled to ambient temperature and purified by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (0: 1 to 1 :0 by volume), to afford the desired product as a yellow solid (0.09 g, 36%). LCMS (Method C): Rt = 2.26 min, m/z [M+H]+ = 308/310 Intermediates 63 to 71, 183 and 184 were prepared according to the reaction protocol of intermediate 62 using the appropriate starting materials (Table 9).

Reference： [1]Patent: WO2014/174021,2014,A1 .Location in patent: Page/Page column 131

12
[ 20090-58-8 ]
C₁₂H₁₁N₅O [ No CAS ]

Reference： [1]Patent: WO2014/174021,2014,A1

13
[ 20090-58-8 ]
C₁₄H₉F₆N₅O₅S₂ [ No CAS ]

Reference： [1]Patent: WO2014/174021,2014,A1

14
[ 20090-58-8 ]
N-methyl-1-[trans-4-(methylamino)cyclohexyl]methanesulfonamide hydrochloride [ No CAS ]
1-[4-[(2-amino-5-methyl-pyrimidin-4-yl)-methyl-amino]cyclohexyl]-N-methyl-methanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; caesium carbonate; ruphos; In tert-butyl alcohol; at 85℃;	Step A: N-methyl-1-[trans-4-(methylamino)cyclohexyl]methanesulfonamide hydrochloride (example 3, step F, 129 mg), <strong>[20090-58-8]4-chloro-5-methyl-pyrimidin-2-amine</strong> (72 mg), Cs2CO3 (390mg), Pd(OAc)2 (11 mg) and RuPhos (47mg) were dissolved in tert-butanol (1 ml) in a schlenk tube. The reaction mixture was heated to 85C, stirred at 85C overnight. The reaction mixture was taken up in THF (10 ml) and filtered over celite. The filtrate was concentrated in vacuo. The residue was purified on a semi-preparative HPLC to yield 1-[4-[(2-amino-5-methyl-pyrimidin-4-yl)-methyl-amino]cyclohexyl]-N-methyl-methanesulfonamide (Compound 29 in Table 1). MS (HPLC/MS): 328 (MH+). Retention time: 1.82min.

Reference： [1]Patent: EP2924026,2015,A1 .Location in patent: Paragraph 0074

15
[ 20090-58-8 ]
[ 214614-61-6 ]
5-methyl-4-(4-(methylsulfonyl)phenethoxy)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3%	With sodium hydride; In 1,4-dioxane; mineral oil; at 80℃;	To a solution of <strong>[20090-58-8]4-chloro-5-methylpyrimidin-2-amine</strong> (25 mg, 0.17 mmol) in Dioxane (0.5 ml) were added 2,2-dimethylpropane-l,3-diol (19.95 mg, 0.19 mmol) and NaH 60% dispersion in mineral oil (13.93 mg, 0.34 mmol) and the resulting mixture was stirred at 60 C overnight. The mixture was quenched with 6N HCl (0.058 ml, 0.34 mmol) and the volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 10 - 50%; 12 min; Column: C18) to give 3-((2-amino-5-methylpyrimidin-4-yl)oxy)-2,2-dimethylpropan-l-ol (5.2 mg, 0.025 mmol, 14% yield) as a white solid. MS (ES+) C10H17N3O2 requires: 211, found: 212 [M+H]+. NMR (600 MHz, de-DMSO) delta: 8.04 (brs, 2H), 7.95 (s, 1H), 4.68 (brs, 1H), 4.13 (brs, 2H), 3.26 (s, 2H), 1.97 (s, 3H), 0.92 (s, 6H). The compound was prepared by the same procedure as Example 43 with a different temperature (80 C) till the completion of the reaction. The residue was purified by mass- triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 10 - 30%; 12 min; Column: C18) to give 5-methyl-4-(4- (methylsulfonyl)phenethoxy)pyrimidin-2-amine (1.5 mg, 0.174 mmol, 3% yield) as a white solid. MS (ES+) C14H17N3O3S requires: 307, found: 308 [M+H]+. NMR (500 MHz, de- DMSO) delta: 7.94 (s, 1H), 7.90 (brs, 2H), 7.87 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 4.59 (t, J= 6.3 Hz, 2H), 3.19 (s, 3H), 3.21-3.16 (m, 2H), 1.89 (s, 3H).

Reference： [1]Patent: WO2016/145383,2016,A1 .Location in patent: Paragraph 0181

16
[ 20090-58-8 ]
[ 16047-86-2 ]
[ 76-05-1 ]
3-((2-amino-5-methylpyrimidin-4-yl)(methyl)amino)-2,2-dimethylpropan-1-ol-2,2,2-trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%		A solution of <strong>[20090-58-8]4-chloro-5-methylpyrimidin-2-amine</strong> (30 mg, 0.20 mmol) in ethanol (0.5 ml) was treated with triethylamine (0.058 ml, 0.41 mmol) and 2,2-dimethyl-3- (methylamino)propan-l-ol (36.7 mg, 0.31 mmol) and the mixture was irradiated in a microwave reactor at 150C for 3.5 h, then quenched with 6N HCl (0.070 ml, 0.41 mmol) and the residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 0 - 30%; 12 min; Column: CI 8) to give 3-((2-amino-5- methylpyrimidin-4-yl)(methyl)amino)-2,2-dimethylpropan-l-ol 2,2,2-trifluoroacetate (6 mg, 0.018 mmol, 8% yield) as a white solid. MS (ES+) C11H20N4O requires: 224, found: 225 [M+H]+. NMR (600 MHz, de-DMSO) delta: 11.95 (brs, 1H), 7.57 (s, 1H), 7.47 (brs, 2H), 4.65 (brs, 1H), 3.71 (brs, 2H), 3.35 (s, 3H), 3.16 (s, 2H), 2.22 (s, 3H), 0.83 (s, 6H).

Reference： [1]Patent: WO2016/145383,2016,A1 .Location in patent: Paragraph 0183

17
[ 20090-58-8 ]
(1-(methyl sulfonyl)piperidine-4,4-diyl)dimethanol [ No CAS ]
(4-[(2-amino-5-methylpyrimidin-4-yl)oxy]methyl}-1-methanesulfonylpiperidin-4-yl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4%	With triethylamine; at 150℃; for 3.5h;Microwave irradiation;	A solution of <strong>[20090-58-8]4-chloro-5-methylpyrimidin-2-amine</strong> (30 mg, 0.20 mmol) in ethanol (0.5 ml) was treated with triethylamine (0.058 ml, 0.41 mmol) and 2,2-dimethyl-3- (methylamino)propan-l-ol (36.7 mg, 0.31 mmol) and the mixture was irradiated in a microwave reactor at 150C for 3.5 h, then quenched with 6N HCl (0.070 ml, 0.41 mmol) and the residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 0 - 30%; 12 min; Column: CI 8) to give 3-((2-amino-5- methylpyrimidin-4-yl)(methyl)amino)-2,2-dimethylpropan-l-ol 2,2,2-trifluoroacetate (6 mg, 0.018 mmol, 8% yield) as a white solid. MS (ES+) C11H20N4O requires: 224, found: 225 [M+H]+. NMR (600 MHz, de-DMSO) delta: 11.95 (brs, 1H), 7.57 (s, 1H), 7.47 (brs, 2H), 4.65 (brs, 1H), 3.71 (brs, 2H), 3.35 (s, 3H), 3.16 (s, 2H), 2.22 (s, 3H), 0.83 (s, 6H). The compound was prepared by the same procedure as Example 72. The required alcohol (l-(methylsulfonyl)piperidine-4,4-diyl)dimethanol) was prepared as described below. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 10 - 50%; 12 min; Column: C18) to give (4- [(2-amino-5-methylpyrimidin-4-yl)oxy]methyl}-l-methanesulfonylpiperidin-4-yl)methanol (1.33 mg, 4.03 mupiiotaomicron, 4 % yield) as a pale yellow solid. MS (ES+) C13H22N4O4S requires: 330, found: 331 [M+H]+. NMR (600 MHz, de-DMSO) delta: 8.03 (brs, 2H), 7.90 (s, 1H), 4.71 (brs, 1H), 4.21 (s, 2H), 3.38 (s, 2H), 3.15-3.00 (m, 4H), 2.80 (s, 3H), 1.91 (s, 3H), 1.58-1.47 (m, 4H)

Reference： [1]Patent: WO2016/145383,2016,A1 .Location in patent: Paragraph 0185

18
[ 20090-58-8 ]
[ 917-92-0 ]
4-(3,3-dimethylbut-1-yn-1-yl)-5-methylpyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%		To a vial (20 ml) was added <strong>[20090-58-8]4-chloro-5-methylpyrimidin-2-amine</strong> (50 mg, 0.34 mmol), THF (1 ml), 3, 3 -dimethylbut- 1-yne (57.2 mg, 0.69 mmol), and TEA (1 ml, 7.17 mmol). The mixture was stirred and purged with N2 for 5 min. To this was added copper(I) iodide (6.63 mg, 0.03 mmol) and PdCh(PPh3)2 (12.22 mg, 0.017 mmol), the vial sealed and stirred at room temperature 18h. The reaction was then heated in a dry block at 60C for 5h. To the reaction was added more 3,3-dimethylbut-l-yne (114 mg, 1.4 mmol), copper(I) iodide (6.63 mg, 0.03 mmol) and PdCh(PPh3)2 (12.22 mg, 0.017 mmol) and the reaction was heated in a dry block at 60C for 16 h. The volatiles were removed under reduced pressure. The residue was dissolved in DCM and purified via silica gel chromatography (0 - 100 % of a 20 % of IPA/EtOAc solution in Hexanes, 4 g Redisep, 10 ml/min, 20 min) to give 4-(3,3-Dimethylbut-l-yn-l-yl)-5- methylpyrimidin-2-amine_(63 mg, 0.333 mmol, 96 % yield) as a yellow solid that was used as is for further derivatization. The crude product (10 mg) was dissolved in MeOH/DMSO and purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 30 - 70%; 12 min; Column: C18) to give 4-(3,3-dimethylbut-l-yn-l- yl)-5-methylpyrimidin-2-amine as a white solid. MS (ES+) C11H15N3 requires: 189, found: 190 [M+H]+. NMR (de-DMSO) delta: 8.13 (s, 1H), 6.43 (brs, 2H), 2.08 (s, 3H), 1.31 (s, 9H).

Reference： [1]Patent: WO2016/145383,2016,A1 .Location in patent: Paragraph 0191

19
[ 20090-58-8 ]
[ 917-92-0 ]
4-(3,3-dimethylbutyl)-5-methylpyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: WO2016/145383,2016,A1

20
[ 20090-58-8 ]
[ 126-30-7 ]
3-((2-amino-5-methylpyrimidin-4-yl)oxy)-2,2-dimethylpropan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%	With sodium hydride; In 1,4-dioxane; mineral oil; at 60℃;	To a solution of <strong>[20090-58-8]4-chloro-5-methylpyrimidin-2-amine</strong> (25 mg, 0.17 mmol) in Dioxane (0.5 ml) were added 2,2-dimethylpropane-l,3-diol (19.95 mg, 0.19 mmol) and NaH 60% dispersion in mineral oil (13.93 mg, 0.34 mmol) and the resulting mixture was stirred at 60 C overnight. The mixture was quenched with 6N HCl (0.058 ml, 0.34 mmol) and the volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 10 - 50%; 12 min; Column: C18) to give 3-((2-amino-5-methylpyrimidin-4-yl)oxy)-2,2-dimethylpropan-l-ol (5.2 mg, 0.025 mmol, 14% yield) as a white solid. MS (ES+) C10H17N3O2 requires: 211, found: 212 [M+H]+. NMR (600 MHz, de-DMSO) delta: 8.04 (brs, 2H), 7.95 (s, 1H), 4.68 (brs, 1H), 4.13 (brs, 2H), 3.26 (s, 2H), 1.97 (s, 3H), 0.92 (s, 6H).

Reference： [1]Patent: WO2016/145383,2016,A1 .Location in patent: Paragraph 0176
[2]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 1503 - 1507

21
[ 20090-58-8 ]
3-((2-amino-5-methylpyrimidin-4-yl)oxy)-2,2-dimethylpropan-1-ol [ No CAS ]