[ CAS No. 31402-54-7 ] {[proInfo.proName]}

Name: 31402-54-7|5-Bromo-N-methylpyrimidin-2-amine|98%
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Quality Control of [ 31402-54-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 31402-54-7 ]

CAS No. :	31402-54-7	MDL No. :	MFCD07368227
Formula :	C₅H₆BrN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UDQGIOYIJKRLFH-UHFFFAOYSA-N
M.W :	188.03	Pubchem ID :	13098184
Synonyms :

Calculated chemistry of [ 31402-54-7 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.2
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	39.04
TPSA :	37.81 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) :	-6.59 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.65
Log Po/w (XLOGP3) :	1.21
Log Po/w (WLOGP) :	1.09
Log Po/w (MLOGP) :	0.51
Log Po/w (SILICOS-IT) :	1.28
Consensus Log Po/w :	1.15

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.2
Solubility :	1.2 mg/ml ; 0.00638 mol/l
Class :	Soluble
Log S (Ali) :	-1.6
Solubility :	4.71 mg/ml ; 0.0251 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.94
Solubility :	0.213 mg/ml ; 0.00114 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.74

Safety of [ 31402-54-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 31402-54-7 ]

* 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 [ 31402-54-7 ]
Downstream synthetic route of [ 31402-54-7 ]

[ 31402-54-7 ] Synthesis Path-Upstream 1~6

1
[ 32779-36-5 ]
[ 74-89-5 ]
[ 31402-54-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	for 72 h; Reflux	40percent Aqueous methylamine solution (35 ml) and methanol (20 ml) were added to 5-bromo-2-chloropyrimidine (3 g, 15.5 mmol) and the resulting mixture was heated to reflux for 3 days. The mixture was cooled, then the solvent was evaporated under reduced pressure, the residue was partitioned with methylene chloride and 1 M sodium hydroxide, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.0 g, 100percent) as a white solid.¹H-NMR (CDCl₃) δ: 2.98 (3H, d, J=5.12 Hz), 5.16 (1H, brs), 8.29 (2H, s).
98%	With potassium carbonate In tetrahydrofuran; water; <i>tert</i>-butyl alcohol at 150℃; for 0.25 h; microwave	5-bromo-2-chloropyrimidine (2.00 g, 10.34 mmol), methylamine (41 percent in water, 2.00 mL, 23.78 mmol) and potassium carbonate (1.43 g, 10.34 mmol) in tert-butanol (4 mL)/THF (4 mL) are stirred for 15 min at 150⁰C in a microwave reactor. The crude mixture is diluted with DCM, the organic phase is washed with semi-saturated potassium carbonate solution and water, dried, filtered and evaporated down. Yield: 1.90 g (98 percent).
93%	Stage #1: at 115℃; for 48 h; Sealed vessel Stage #2: With sodium hydroxide In dichloromethane; water	[0238] Methylamine (2.0 M in methanol, 4O mL, 80 mmol) was added to 5- bromo-2-chloropyrirnidine (5.6 g, 29.0 mmol) in a sealable reaction vessel. After allowing to vent for a few minutes, the vessel was sealed, placed behind a safety shield and heated in a 115 ⁰C oil bath for 48 hours. Upon cooling the volatiles were removed in vacuo. The material was dissolved in CH₂Cl₂ (200 mL) and washed with IM NaOH (4O mL). The aqueous layer was extracted further with CH₂Cb (2x50 mL). The combined organics were dried over MgSO₄, filtered and concentrated yielding an off white solid (5.1 g, 93percent). LCMS (m/z): 188.0/190.0 (MH⁺).

93%	Stage #1: at 115℃; for 48 h; Sealed tube Stage #2: With sodium hydroxide In dichloromethane; water	Synthesis -Aminomethyl-5-bromopyrimidine[0083] Methylamine (2.0 M in methanol, 40 mL, 80 mmol) was added to 5-bromo-2- chloropyrimidine (5.6 g, 29.0 mmol) in a sealable reaction vessel. After allowing to vent for a few minutes, the vessel was sealed, placed behind a safety shield and heated in a 115 °C oil bath for 48 hours. Upon cooling the volatiles were removed in vacuo. The material was dissolved in CH₂C1₂ (200 mL) and washed with 1M NaOH (40 mL). The aqueous layer was extracted further with CH₂C1₂ (2x50 mL). The combined organics were dried over MgSC>4, filtered and concentrated yielding an off white solid (5.1 g, 93percent). LCMS (m/z):188.0/190.0 (MH ).
90%	at 60℃; for 6 h;	To 5-bromo-2-chloropyrimidine (2g, 10.34mmol) was added 1 M methylamine solution in THF (20ml). The contents were stirred at 6O⁰C for 6h after which TLC confirmed the absence of the reactant. The contents were allowed to cool down. The volatiles were evaporated under reduced pressure and the residue was subjected to flash chromatography (hexane/ethyl acetate) to get (5-bromo-pyrimidin- 2-yl)-methyl-amine (1.75g, 90percent). This material was taken through Stage C (as described above) to get methyl-[5-(4,4,5,5,-tetramethyl-[1 ,3,2]dioxaborolan-2- yl]amine.

Reference： [1] Patent: US2010/130492, 2010, A1, . Location in patent: Page/Page column 93
[2] Patent: WO2010/12747, 2010, A1, . Location in patent: Page/Page column 16-17
[3] Patent: WO2007/84786, 2007, A1, . Location in patent: Page/Page column 90
[4] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 1, p. 34 - 38
[5] Patent: WO2012/109423, 2012, A1, . Location in patent: Page/Page column 18
[6] Patent: WO2009/93981, 2009, A1, . Location in patent: Page/Page column 105
[7] Patent: WO2006/79791, 2006, A1, . Location in patent: Page/Page column 42
[8] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10033 - 10046

2
[ 7752-82-1 ]
[ 74-88-4 ]
[ 31402-54-7 ]
[ 38696-21-8 ]

Yield	Reaction Conditions	Operation in experiment
20%	Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25 h; Stage #2: at 0 - 20℃; for 4.5 h;	Step 39a: 5-Bromo-N-methylpyrimidin-2-amine (compound 0601-116) and 5-bromo-N,N- dimethylpyrimidin-2-amine (compound 0601-117)A mixture of 5-bromopyrimidin-2-amine (3.48 g, 20 mmol) and DMF (20 mL) was cooled to 0°C. To the mixture NaH (60percent, 1.44 g, 36 mmol) was added. After 15 minutes, iodomethane (5 mL, 80 mmol) was added and stirred at 0°C for 0.5 h and the mixture was warmed to room temperature for additional 4 hours. Water (30 mL) was added and extracted with ethyl acetate (3 x 30 mL). The combined organic layers was washed with brine, dried over Na2S04, concentrated and purified by column chromatograph on silica gel (ethyl acetate in petroleum ether, 10percent v/v) to give two compounds: compound 0601-116 (0.76 g, 20percent) as a white solid, LCMS: 190 [M+2]⁺; ¹HNMR (400 MHz, DMSO-<3/4) δ 2.75 (d, J= 4.8 Hz, 3H), 7.35 (d, J= 4.0 Hz, 1H), 8.34 (s, 2H); compound 0601-117 (1.96 g, 49percent) as a yellow solid, LCMS: 202 [M+l]⁺; ¹HNMR (400 MHz, DMSO-<3/4) δ 3.12 (s, 6H), 8.43 (s, 2H).
20%	Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25 h; Stage #2: at 0 - 20℃; for 4.5 h;	Step 39a: 5-Bromo-N-methylpyrimidin-2-amine (compound 0601-116) and 5-bromo-N,N-dimethylpyrimidin-2-amine (compound 0601-117)[0353]A mixture of 5-bromopyrimidin-2-amine (3.48 g, 20 mmol) and DMF (20 mL) was cooled to 0° C. To the mixture NaH (60percent, 1.44 g, 36 mmol) was added. After 15 minutes, iodomethane (5 mL, 80 mmol) was added and stirred at 0° C. for 0.5 h and the mixture was warmed to room temperature for additional 4 hours. Water (30 mL) was added and extracted with ethyl acetate (3×30 mL). The combined organic layers was washed with brine, dried over Na2SO4, concentrated and purified by column chromatograph on silica gel (ethyl acetate in petroleum ether, 10percent v/v) to give two compounds: compound 0601-116 (0.76 g, 20percent) as a white solid, LCMS: 190 [M+2]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 2.75 (d, J=4.8 Hz, 3H), 7.35 (d, J=4.0 Hz, 1H), 8.34 (s, 2H); compound 0601-117 (1.96 g, 49percent) as a yellow solid, LCMS: 202 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 3.12 (s, 6H), 8.43 (s, 2H).
20%	Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25 h; Stage #2: at 0 - 20℃; for 4.5 h;	5-bromo-pyrimidine-2-amine (3.48g, 20mmol) and a mixture of DMF (20mL) was cooled to 0 . NaH (60percent, 1.44g, 36mmol) to the mixture was added. After 15 minutes, then 0.5 hours with stirring at O ° C. was added iodoethane (5 mL, 80 mmol), the mixture was further warmed to room temperature for 4 hours. With the addition of water (30mL) and extracted with ethyl acetate (3x30mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated and purified by column chromatography (petroleum ether in ethyl acetate, 10percent v / v) on silica gel to give the two compounds: Compound 0601 the -116 as a white solid (0.76g, 20percent)

Reference： [1] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 173
[2] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0352; 0353
[3] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0310

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[ 931-61-3 ]
[ 31402-54-7 ]

Reference： [1] Journal of Organic Chemistry, 1983, vol. 48, # 7, p. 1064 - 1069

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[ 593-51-1 ]
[ 32779-36-5 ]
[ 31402-54-7 ]

Reference： [1] Patent: WO2006/44823, 2006, A2, . Location in patent: Page/Page column 197

5
[ 31402-54-7 ]
[ 5388-21-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2692 - 2703

6
[ 7752-82-1 ]
[ 74-88-4 ]
[ 31402-54-7 ]
[ 38696-21-8 ]

Yield	Reaction Conditions	Operation in experiment
20%	Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25 h; Stage #2: at 0 - 20℃; for 4.5 h;	Step 39a: 5-Bromo-N-methylpyrimidin-2-amine (compound 0601-116) and 5-bromo-N,N- dimethylpyrimidin-2-amine (compound 0601-117)A mixture of 5-bromopyrimidin-2-amine (3.48 g, 20 mmol) and DMF (20 mL) was cooled to 0°C. To the mixture NaH (60percent, 1.44 g, 36 mmol) was added. After 15 minutes, iodomethane (5 mL, 80 mmol) was added and stirred at 0°C for 0.5 h and the mixture was warmed to room temperature for additional 4 hours. Water (30 mL) was added and extracted with ethyl acetate (3 x 30 mL). The combined organic layers was washed with brine, dried over Na2S04, concentrated and purified by column chromatograph on silica gel (ethyl acetate in petroleum ether, 10percent v/v) to give two compounds: compound 0601-116 (0.76 g, 20percent) as a white solid, LCMS: 190 [M+2]⁺; ¹HNMR (400 MHz, DMSO-<3/4) δ 2.75 (d, J= 4.8 Hz, 3H), 7.35 (d, J= 4.0 Hz, 1H), 8.34 (s, 2H); compound 0601-117 (1.96 g, 49percent) as a yellow solid, LCMS: 202 [M+l]⁺; ¹HNMR (400 MHz, DMSO-<3/4) δ 3.12 (s, 6H), 8.43 (s, 2H).
20%	Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25 h; Stage #2: at 0 - 20℃; for 4.5 h;	Step 39a: 5-Bromo-N-methylpyrimidin-2-amine (compound 0601-116) and 5-bromo-N,N-dimethylpyrimidin-2-amine (compound 0601-117)[0353]A mixture of 5-bromopyrimidin-2-amine (3.48 g, 20 mmol) and DMF (20 mL) was cooled to 0° C. To the mixture NaH (60percent, 1.44 g, 36 mmol) was added. After 15 minutes, iodomethane (5 mL, 80 mmol) was added and stirred at 0° C. for 0.5 h and the mixture was warmed to room temperature for additional 4 hours. Water (30 mL) was added and extracted with ethyl acetate (3×30 mL). The combined organic layers was washed with brine, dried over Na2SO4, concentrated and purified by column chromatograph on silica gel (ethyl acetate in petroleum ether, 10percent v/v) to give two compounds: compound 0601-116 (0.76 g, 20percent) as a white solid, LCMS: 190 [M+2]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 2.75 (d, J=4.8 Hz, 3H), 7.35 (d, J=4.0 Hz, 1H), 8.34 (s, 2H); compound 0601-117 (1.96 g, 49percent) as a yellow solid, LCMS: 202 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 3.12 (s, 6H), 8.43 (s, 2H).
20%	Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25 h; Stage #2: at 0 - 20℃; for 4.5 h;	5-bromo-pyrimidine-2-amine (3.48g, 20mmol) and a mixture of DMF (20mL) was cooled to 0 . NaH (60percent, 1.44g, 36mmol) to the mixture was added. After 15 minutes, then 0.5 hours with stirring at O ° C. was added iodoethane (5 mL, 80 mmol), the mixture was further warmed to room temperature for 4 hours. With the addition of water (30mL) and extracted with ethyl acetate (3x30mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated and purified by column chromatography (petroleum ether in ethyl acetate, 10percent v / v) on silica gel to give the two compounds: Compound 0601 the -116 as a white solid (0.76g, 20percent)

[ 31402-54-7 ] Synthesis Path-Downstream 1~6

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[ 931-61-3 ]
[ 31402-54-7 ]

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 1064 - 1069

2
[ 31402-54-7 ]
[ 73183-34-3 ]
[ 904326-88-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium acetate In N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere;	18.2 N,N-Dimethylformamide (20 ml) was added to 5-bromo-N-methylpyrimidin-2-amine (3.0 g, 16.0 mmol), bispinacolatodiboron (4.86 g, 19.2 mmol), and potassium acetate (4.7 g, 47.9 mmol) and the atmosphere in the reaction vessel was substituted with nitrogen. A 1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (650 mg, 0.80 mmol) was added, the atmosphere in the reaction vessel was substituted with nitrogen again, and the resulting mixture was stirred at 80° C. for 2 hours. The reaction mixture was partitioned with ethyl acetate and saturated brine and filtrated through celite and the organic layer was washed twice with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=8:2 to 6:4) to give the title compound (3.8 g, 100%) as a white solid.1H-NMR (CDCl3) δ: 1.32 (12H, s), 3.03 (3H, d, J=5.12 Hz), 5.66 (1H, brs), 8.58 (2H, brs).
82%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 115℃; for 5h; Inert atmosphere;	20 /V-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (i 12): /V-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (i 12): To a stirred solution of 5-bromo-/V-methylpyrimidin-2-amine (0.5 g, 2.65 mmol) in dioxane (10 ml_), bispinacolatodiboron (0.81 g, 3.19 mmol) and KOAc (0.39 g, 3.97 mmol) were added and the reaction was degassed with argon for 20 min. PdCI2(dppf) (0.19 g, 0.26 mmol) was then added and the reaction mixture was purged with argon for another 10 min. The reaction was heated at 1 15°C for 5h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ethyl acetate, filtered and filtrate was concentrated under reduced pressure to afford /V-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidin-2- amine (i12) (0.5 g, 82%). MS (ESI) m/e (M+1 )+: 236
64%	With potassium acetate In 1,4-dioxane at 115℃; for 4.25h; Heating / reflux;	2 [0240] To a dry 50O mL flask was added 2-methylamino-5-bromopyrimidlne(9.5 g, 50.5 mmol), potassium acetate (15.1 g, 154.4 mmol), 4,4,5,5,-tetramethyl-2- (4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (14.1 g, 55.5 mmol) and dioxane (280 mL). Argon was bubbled through the solution for 15 minutes, at which time l,l'-bis(diphenylphosphino)ferrocene palladium(H) chloride dichloromethane adduct (2.05 g, 2.51 mmol) was added. The reaction was refluxed in a 115 0C oil bath for 4 hours under argon. After cooling to room temperature, EtOAc (500 mL) was added and the resulting slurry was sonicated and filtered. Additional EtOAc (500 mL) was used to wash the solid. The combined organics were washed with H2O (2x300 mL), NaCl(Saq, (300 mL), dried over Na2SO4, filtered and the solvents were removed in vacuo. Purification by SiO2 chromatography (50% EtOAc/hexanes) yielded an off white solid (7.66 g, 64%). LCMS (m/z): 154 (MH+ of boronic acid, deriving from in situ product hydrolysis on LC). 1H NMR (CDCl3): δ 8.58 (s, 2H), 5.56 (s, IH), 3.02 (d, 3H), 1.32 (s, 12H).

64%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 115℃; for 4h; Inert atmosphere;
64%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 115℃; for 4h; Inert atmosphere;	2 Synthesis of methyl[5-(4,4,5,5-tetramethyl(l ,3,2-dioxaborolan-2-yl))pyrimidin-2- yl] amine[0085] To a dry 500 mL flask was added 2-methylamino-5-bromopyrimidine (9.5 g, 50.5 mmol), potassium acetate (15.1 g, 154.4 mmol), 4,4,5,5, -tetramethyl-2-(4,4,5, 5,- tetramethyl-l ,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (14.1 g, 55.5 mmol) and dioxane (280 mL). Argon was bubbled through the solution for 15 minutes, at which time l,l'-bis(diphenylphosphino)ferrocene palladium(II) chloride dichloromethane adduct (2.05 g, 2.51 mmol) was added. The reaction was refluxed in a 1 15 °C oil bath for 4 hours under argon. After cooling to room temperature, EtOAc (500 mL) was added and the resulting slurry was sonicated and filtered. Additional EtOAc (500 mL) was used to wash the solid. The combined organics were washed with H20 (2x300 mL), NaCl(sat ), (300 mL), dried over Na2S04, filtered and the solvents were removed in vacuo. Purification by Si02 chromatography (50% EtOAc/hexanes) yielded an off white solid (7.66 g, 64%).LCMS (m/z): 154 (MH+ of boronic acid, deriving from in situ product hydrolysis on LC). ¾ NMR (CDCls): δ 8.58 (s, 2H), 5.56 (s, 1H), 3.02 (d, 3H), 1.32 (s, 12H).

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2010/130492, 2010, A1 Location in patent: Page/Page column 93
[2]Current Patent Assignee: UCB - WO2016/124508, 2016, A1 Location in patent: Page/Page column 43
[3]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2007/84786, 2007, A1 Location in patent: Page/Page column 90-91
[4]Burger, Matthew T.; Knapp, Mark; Wagman, Allan; Ni, Zhi-Jie; Hendrickson, Thomas; Atallah, Gordana; Zhang, Yanchen; Frazier, Kelly; Verhagen, Joelle; Pfister, Keith; Ng, Simon; Smith, Aaron; Bartulis, Sarah; Merrit, Hanne; Weismann, Marion; Xin, Xiaohua; Haznedar, Joshua; Voliva, Charles F.; Iwanowicz, Ed; Pecchi, Sabina [ACS Medicinal Chemistry Letters, 2011, vol. 2, # 1, p. 34 - 38]
[5]Current Patent Assignee: DANA-FARBER CANCER INSTITUTE - WO2012/109423, 2012, A1 Location in patent: Page/Page column 19

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[ 2942-13-4 ]
[ 31402-54-7 ]
5-(6-methoxy-1,3-benzothiazol-2-yl)-N-methylpyrimidin-2-amine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1976 - 1980

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[ 74-88-4 ]
[ 31402-54-7 ]
[ 38696-21-8 ]

Yield	Reaction Conditions	Operation in experiment
20%; 49%		Step 39a: 5-Bromo-N-methylpyrimidin-2-amine (compound 0601-116) and 5-bromo-N,N- dimethylpyrimidin-2-amine (compound 0601-117)A mixture of 5-bromopyrimidin-2-amine (3.48 g, 20 mmol) and DMF (20 mL) was cooled to 0C. To the mixture NaH (60%, 1.44 g, 36 mmol) was added. After 15 minutes, iodomethane (5 mL, 80 mmol) was added and stirred at 0C for 0.5 h and the mixture was warmed to room temperature for additional 4 hours. Water (30 mL) was added and extracted with ethyl acetate (3 x 30 mL). The combined organic layers was washed with brine, dried over Na2S04, concentrated and purified by column chromatograph on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give two compounds: compound 0601-116 (0.76 g, 20%) as a white solid, LCMS: 190 [M+2]+; 1HNMR (400 MHz, DMSO-<¾) delta 2.75 (d, J= 4.8 Hz, 3H), 7.35 (d, J= 4.0 Hz, 1H), 8.34 (s, 2H); compound 0601-117 (1.96 g, 49%) as a yellow solid, LCMS: 202 [M+l]+; 1HNMR (400 MHz, DMSO-<¾) delta 3.12 (s, 6H), 8.43 (s, 2H).
20%; 49%		Step 39a: 5-Bromo-N-methylpyrimidin-2-amine (compound 0601-116) and 5-bromo-N,N-dimethylpyrimidin-2-amine (compound 0601-117)[0353]A mixture of 5-bromopyrimidin-2-amine (3.48 g, 20 mmol) and DMF (20 mL) was cooled to 0 C. To the mixture NaH (60%, 1.44 g, 36 mmol) was added. After 15 minutes, iodomethane (5 mL, 80 mmol) was added and stirred at 0 C. for 0.5 h and the mixture was warmed to room temperature for additional 4 hours. Water (30 mL) was added and extracted with ethyl acetate (3×30 mL). The combined organic layers was washed with brine, dried over Na2SO4, concentrated and purified by column chromatograph on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give two compounds: compound 0601-116 (0.76 g, 20%) as a white solid, LCMS: 190 [M+2]+; 1HNMR (400 MHz, DMSO-d6) delta 2.75 (d, J=4.8 Hz, 3H), 7.35 (d, J=4.0 Hz, 1H), 8.34 (s, 2H); compound 0601-117 (1.96 g, 49%) as a yellow solid, LCMS: 202 [M+1]+; 1HNMR (400 MHz, DMSO-d6) delta 3.12 (s, 6H), 8.43 (s, 2H).
20%; 49%		5-bromo-pyrimidine-2-amine (3.48g, 20mmol) and a mixture of DMF (20mL) was cooled to 0 . NaH (60%, 1.44g, 36mmol) to the mixture was added. After 15 minutes, then 0.5 hours with stirring at O C. was added iodoethane (5 mL, 80 mmol), the mixture was further warmed to room temperature for 4 hours. With the addition of water (30mL) and extracted with ethyl acetate (3x30mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated and purified by column chromatography (petroleum ether in ethyl acetate, 10% v / v) on silica gel to give the two compounds: Compound 0601 the -116 as a white solid (0.76g, 20%)

Reference： [1]Patent: WO2011/130628,2011,A1 .Location in patent: Page/Page column 173
[2]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0352; 0353
[3]Patent: JP2015/187145,2015,A .Location in patent: Paragraph 0310

5
[ 31402-54-7 ]
[ 5388-21-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2692 - 2703

6
[ 1255099-13-8 ]
[ 31402-54-7 ]
[ 2784626-53-3 ]

Yield	Reaction Conditions	Operation in experiment
62%	With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 1h; Microwave irradiation; Inert atmosphere;	Methyl 4-methyl-3-[2-[2-(methylamino)pyrimidin-5-yl]ethynyl]benzoate To a MW vial was added methyl 3-ethynyl-4-methyl-benzoate (300mg, 1.72mmol), 5-bromo-N-methylpyrimidin-2-amine (389mg, 2.07mmol), MeCN (5.0mL) and DIPEA (0.90mL, 5.17mmol). The reaction mixture was degassed using nitrogen, Cui (16.4mg, 0.09mmol) and PdCl2(PPhs)2 (60.6mg, 0.09mmol) were added and the reaction was heated under MW irradiation for 60min at 100°C. The reaction was concentrated in vacuo. The residue was purified on silica (EtOAc:heptane, 1 :9 to 1 :1) to provide the title compound (302mg, 62%) as a beige solid. UPLC (Method A) 3.33 min, 100 %, [M+H]+ = 282.2.
62%	With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 1h; Microwave irradiation; Inert atmosphere;	Methyl 4-methyl-3-[2-[2-(methylamino)pyrimidin-5-yl]ethynyl]benzoate To a MW vial was added methyl 3-ethynyl-4-methyl-benzoate (300mg, 1.72mmol), 5-bromo-N-methylpyrimidin-2-amine (389mg, 2.07mmol), MeCN (5.0mL) and DIPEA (0.90mL, 5.17mmol). The reaction mixture was degassed using nitrogen, Cui (16.4mg, 0.09mmol) and PdCl2(PPhs)2 (60.6mg, 0.09mmol) were added and the reaction was heated under MW irradiation for 60min at 100°C. The reaction was concentrated in vacuo. The residue was purified on silica (EtOAc:heptane, 1 :9 to 1 :1) to provide the title compound (302mg, 62%) as a beige solid. UPLC (Method A) 3.33 min, 100 %, [M+H]+ = 282.2.

Reference： [1]Current Patent Assignee: BENEVOLENTAI LIMITED - WO2022/129913, 2022, A1 Location in patent: Page/Page column 37
[2]Current Patent Assignee: BENEVOLENTAI LIMITED - WO2022/129913, 2022, A1 Location in patent: Page/Page column 37

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Ghs Precautionary Statements

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.
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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.
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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.
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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

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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

[ CAS No. 31402-54-7 ] {[proInfo.proName]}

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Medicinal Chemistry

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[ 31402-54-7 ] Synthesis Path-Upstream 1~6

[ 31402-54-7 ] Synthesis Path-Downstream 1~6

Related Functional Groups of [ 31402-54-7 ]

Bromides

Amines

Related Parent Nucleus of [ 31402-54-7 ]

Pyrimidines

Precautionary Statements-General

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Storage

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Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 31402-54-7 ]

Related Parent Nucleus of
[ 31402-54-7 ]