17321-93-6|2-Amino-5-bromo-4-methylpyrimidine| Ambeed

Structure of 17321-93-6

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Quality Control of [ 17321-93-6 ] Purity: 97% SDS Specification

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Product Details of [ 17321-93-6 ]

CAS No. :	17321-93-6
Formula :	C₅H₆BrN₃
M.W :	188.03
SMILES Code :	NC1=NC=C(C(=N1)C)Br
MDL No. :	MFCD00094469
InChI Key :	LPQVTZJEIXYDQA-UHFFFAOYSA-N
Pubchem ID :	18616196

Safety of [ 17321-93-6 ]

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

Computational Chemistry of [ 17321-93-6 ] Show Less

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	39.1
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	51.8 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.51
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	0.95
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.14
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.	0.51
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	1.34
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.09

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.1
Solubility	1.5 mg/ml ; 0.00799 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.62
Solubility	4.46 mg/ml ; 0.0237 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	-2.54
Solubility	0.549 mg/ml ; 0.00292 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	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	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.	-6.77 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	0.0 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)	1.62

Application In Synthesis of [ 17321-93-6 ]

* 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 [ 17321-93-6 ]
Downstream synthetic route of [ 17321-93-6 ]

[ 17321-93-6 ] Synthesis Path-Upstream 1~3

1
[ 108-52-1 ]
[ 17321-93-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: With N-Bromosuccinimide In chloroform for 15 h; Stage #2: With sodium hydroxide In dichloromethane; chloroform; water	[0242] To a solution of 4-methylpyrimidine-2-ylamine (10.9 g, lOO mmol) in chloroform (400 mL) was added N-bromosuccinimide (17.8 g, 100 mmol). The solution was stirred in the dark for 15 hours, at which time it was added to CH₂Cl₂ (140O mL), washed with IN NaOH (3x200 mL) and NaCl_(sat.) (100 mL), dried over Na₂SO₄, filtered and concentrated, yielding 5-bromo-4-methylpyrimidine-2-ylamine (18.8 g, 99percent). LCMS (m/z): 188.0/190.0 (MH⁺). ¹H NMR (CDCl₃): δ 8.22 (s, IH), 5.02 (bs, 2H), 2.44 (s, 3H).
91%	With N-Bromosuccinimide In chloroform at 20℃; for 2 h;	Step 44a: 5-Bromo-4-methylpyrimidin-2-amine (Compound 0601-125)A mixture of 2-amino-4-methylpyrimidine (4.0 g, 36.7 mmol), NBS (7.18 g, 40.3 mmol) in chloroform (100 mL) was stirred for 2 h at room temperature, then the solvent was removed in vacuum. Water (100 mL) was added and stirred for 30 min at room temperature, filtered. The solid was washed with water and dried to get compound 0601- 125 (6.3 g, 91percent) as a white solid. LCMS: 188 [M+l]⁺, 1H NMR (400 MHz, DMSO-d₆) δ 2.32 (s, 3H), 6.79 (s, 2H), 8.21 (s, 1H).
91%	With N-Bromosuccinimide In chloroform at 20℃; for 2 h;	Step 44a: 5-Bromo-4-methylpyrimidin-2-amine (Compound 0601-125)[0378]A mixture of 2-amino-4-methylpyrimidine (4.0 g, 36.7 mmol), NBS (7.18 g, 40.3 mmol) in chloroform (100 mL) was stirred for 2 h at room temperature, then the solvent was removed in vacuum. Water (100 mL) was added and stirred for 30 min at room temperature, filtered. The solid was washed with water and dried to get compound 0601-125 (6.3 g, 91percent) as a white solid. LCMS: 188 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 2.32 (s, 3H), 6.79 (s, 2H), 8.21 (s, 1H).

91%	With N-Bromosuccinimide In chloroform at 20℃; for 2 h;	Chloroform (100 mL) solution of 2-amino-4-methylpyrimidine (4.0 g, 36.7 mmol), a mixture of NBS (7.18g, 40.3mmol) was stirred at room temperature for 2 hours, then the solvent was removed under vacuum. Water (100 mL) was added and stirred for 30 min at room temperature and filtered. The solid was washed with water, to give the compound 0601-125 and dried as a white solid (6.3g, 91percent).
86%	With N-Bromosuccinimide In chloroform for 18 h; Darkness	To a solution of 4-methylpyrimidine-2-ylamine (8.0 g, 0.073 mol) in chloroform (320 mL) was added N-bromosuccinimide (13.7 g, 0.077 mol). The reaction mixture was stirred in the dark for 18 hrs. LC/MS indicated the reaction was completed. The mixture was diluted with DCM, then washed with IN NaOH aq solution and brine, dried over MgS0₄, filtered and concentrated to yield 5-bromo-4-methylpyrimidine-2-ylamin (12 g, Yield: 86percent).
86%	With N-Bromosuccinimide In chloroform for 18 h; Darkness	To a solution of 4-methylpyrimidine-2-ylamine (8.0 g, 0.073 mol) in chloroform (320 mL) was added N-bromosuccinimide (13.7 g, 0.077 mol). The reaction mixture was stirred in the dark for 18 hrs. LC/MS indicated the reaction was completed. The mixture was diluted with DCM, then washed with 1N NaOH aq solution and brine, dried over MgSO₄, filtered and concentrated to yield 5-bromo-4-methylpyrimidine-2-ylamin (12 g, Yield: 86percent).
86%	With N-Bromosuccinimide In chloroform for 18 h; Darkness	Example 6 4-methyl-5-(4, 4, 5, 5-tetramethyl (1, 3, 2-dioxaborolan-2-yl)) pyrimidine-2-ylamine 42 [0204] To a solution of 4-methylpyrimidine-2-ylamine (8.0 g, 0.073 mol) in chloroform (320 mL) was added N-bromosuccinimide (13.7 g, 0.077 mol). The reaction mixture was stirred in the dark for 18 hrs. LC/MS indicated the reaction was completed. The mixture was diluted with DCM, then washed with IN NaOH aq solution and brine, dried over MgSO₄, filtered and concentrated to yield 5-bromo-4-methylpyrimidine-2-ylamin (12 g, Yield: 86percent).
81%	With N-Bromosuccinimide In dichloromethane at 25℃; for 16 h; Darkness	To a solution of compound 22 (500mg, 4.6 mmol) in DCM (50 mL) was added NBS (820mg, 4.6 mmol). The mixture was stirred in the dark for 16 hours at room temperature. The reaction was quenched with DCM (50 mL) and iN NaOH (50 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound 23 as a white solid (700 mg, 81percent yield), which was used directly in the next step without further purification.

References: [1] Patent: WO2007/84786, 2007, A1, . Location in patent: Page/Page column 91-92.
[2] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 10, p. 774 - 779.
[3] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 180.
[4] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0377; 0378.
[5] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0330.
[6] Patent: WO2012/82997, 2012, A1, . Location in patent: Page/Page column 82.
[7] Patent: US2014/65136, 2014, A1, . Location in patent: Paragraph 0197; 0198.
[8] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 4, p. 351 - 356.
[9] Patent: WO2009/146406, 2009, A1, . Location in patent: Page/Page column 69.
[10] Patent: WO2017/219800, 2017, A1, . Location in patent: Paragraph 00184; 00185; 00186.
[11] Chemische Berichte, 1930, vol. 63, p. 2601,2607.
[12] Patent: US2609372, 1950, , .
[13] Patent: US2609372, 1950, , .
[14] Patent: US2609372, 1950, , .
[15] Patent: US2609372, 1950, , .
[16] Patent: WO2009/13348, 2009, A2, . Location in patent: Page/Page column 64-65.

2
[ 17321-93-6 ]
[ 73183-34-3 ]
[ 944401-55-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium acetate In 1,4-dioxane for 8.33333 h; Inert atmosphere	A mixture of 5-bromo-4-methylpyrimidine-2-ylamine (5.0g, 26 mmol), potassium acetate (7.83g, 79.8 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,3,2- dioxaborolane (7.43 g, 29.2 mmol) in dioxane (140 mL) was stirred for 20 min under nitrogen. 1, 1 '-bis (diphenylphosphino) ferrocene palladium (II) chloride dichloromethane adduct (1.08 g, 1.33 mmol) was added to the reaction mixture. The reaction mixture was heated to 115 °C for 18 h under nitrogen. Upon completion, the mixture was cooled and EtOAc was added. The resulting mixture was sonicated and filtered. Additional EtOAc was used to wash the solid. The combined organic extracts were washed with water, dried over MgS0₄, filtered and concentrated. The crude was purified by chromatography eluting with 20-100percent EtO Ac/hex ane to yield 4.5 g of 4-methyl-5-(4,4,5,5-tetramethyl (l,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine (yield: 74percent). 1H-NMR (DMSO, 400 MHz): δ 8.28 (s, 1H), 6.86 (br s, 2H), 2.35 (s, 3 H), 1.25 (s, 12 H). MS (ESI) m/e (M+H⁺) 236.15, 154.07.
74%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 115℃; for 18 h; Inert atmosphere	A mixture of 5-bromo-4-methylpyrimidine-2-ylamine (5.0 g, 26 mmol), potassium acetate (7.83 g, 79.8mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (7.43 g,29.2 mmol) in dioxane (140 mL) was stirred for 20 min under nitrogen. 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane adduct (1.08 g, 1.33 mmol) was added to the reaction mixture. The reaction mixture was heated to 115° C. for 18 h under nitrogen. Upon completion, the mixture was cooled and EtOAc was added. The resulting mixture was sonicated and filtered. Additional EtOAc was used to wash the solid. The combined organic extracts were washed with water, dried over MgSO4, filtered and concentrated. The crude was purified by chromatography eluting with 20~100percent EtOAc/hexane to yield 4.5 g of 4-methyl-5-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine 26 (yield: 74percent). 1H-NMR (DMSO, 400 MHz): δ 8.28 (s, 1H), 6.86 (br s, 2H), 2.35 (s, 3H), 1.25 (s, 12H). MS (ESI) m/e (M+H+) 236.15, 154.07.
74%	With potassium acetate In 1,4-dioxane at 115℃; for 18 h; Inert atmosphere	A mixture of 5-bromo-4-methylpyrimidine-2-ylamine (5.Og, 26 mmol ), potassium acetate (7.83g, 79.8 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- 1,3,2-dioxaborolane (7.43 g, 29.2 mmol) in dioxane (140 mL) was stirred for 20 min under nitrogen. 1, l'-bis (diphenylphosphino) ferrocene palladium (II) chloride dichloromethane adduct (1.08 g, 1.33 mmol) was added to the reaction mixture. The reaction mixture was heated to 115 ° C for 18 h under nitrogen. Upon completion, the mixture was cooled and EtOAc was added. The resulting mixture was sonicated and filtered. Additional EtOAc was used to wash the solid. The combined organic extracts were washed with water, dried over MgSO₄, filtered and concentrated. The crude was purified by chromatography eluting with 20-100percent EtOAc/hexane to yield 4.5 g of 42 (yield: 74percent). ¹H-NMR (DMSO, <n="71"/>400 MHz): δ 8.28 (s, IH), 6.86 (br s, 2H), 2.35 (s, 3 H), 1.25 (s, 12 H). MS (ESI) m/e (M+H⁺) 236.15, 154.07.

References: [1] Patent: WO2012/82997, 2012, A1, . Location in patent: Page/Page column 83.
[2] Patent: US2014/65136, 2014, A1, . Location in patent: Paragraph 0198; 0199.
[3] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 4, p. 351 - 356.
[4] Patent: WO2009/146406, 2009, A1, . Location in patent: Page/Page column 69-70.
[5] Patent: WO2009/13348, 2009, A2, . Location in patent: Page/Page column 67.

3
[ 17321-93-6 ]
[ 73183-34-3 ]
[ 108-52-1 ]
[ 944401-55-2 ]

References: [1] Patent: WO2007/84786, 2007, A1, . Location in patent: Page/Page column 92-93.
[2] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 10, p. 774 - 779.
[3] Patent: WO2017/219800, 2017, A1, . Location in patent: Paragraph 00187; 00188.