[ CAS No. 84539-22-0 ]

Name: 84539-22-0|4-(5-Bromopyrimidin-2-yl)morpholine|98%
Brand: Ambeed
SKU: A674602
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Quality Control of [ 84539-22-0 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 84539-22-0 ]

CAS No. :	84539-22-0	MDL No. :	MFCD00483251
Formula :	C₈H₁₀BrN₃O	Boiling Point :	382.8°C at 760 mmHg
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	244.09 g/mol	Pubchem ID :	-
Synonyms :

Calculated chemistry of of [ 84539-22-0 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.5
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	55.46
TPSA :	38.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.09 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.26
Log Po/w (XLOGP3) :	0.98
Log Po/w (WLOGP) :	0.69
Log Po/w (MLOGP) :	0.64
Log Po/w (SILICOS-IT) :	1.62
Consensus Log Po/w :	1.24

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.25
Solubility :	1.38 mg/ml ; 0.00567 mol/l
Class :	Soluble
Log S (Ali) :	-1.37
Solubility :	10.4 mg/ml ; 0.0425 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.7
Solubility :	0.49 mg/ml ; 0.00201 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.04

Safety of [ 84539-22-0 ]

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

Application In Synthesis of [ 84539-22-0 ]

* 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 [ 84539-22-0 ]
Downstream synthetic route of [ 84539-22-0 ]

[ 84539-22-0 ] Synthesis Path-Upstream 1~2

1
[ 84539-22-0 ]
[ 870521-33-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 77 - 105

2
[ 84539-22-0 ]
[ 73183-34-3 ]
[ 957198-30-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 90℃; Inert atmosphere	A mixture of 4- (5-bromopyrimidin-2-yl) morpholine (2.01 g, 8.23 mmol) , bis (pinacolato) diboron (3.8 g, 15 mmol) , potassium acetate (2.5 g, 25 mmol) and Pd (dppf) Cl₂(0.61 g, 0.83 mmol) in 1, 4-dioxane (30 mL) was stirred at 90 under N₂overnight. The reaction mixture was cooled to rt and diluted with water (20 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 7/3 to give a white solid product (0.4 g, 88) .[1817]MS (ESI, pos. ion) m/z: 292.0 [M+1]⁺

Reference： [1] Patent: WO2016/615, 2016, A1, . Location in patent: Paragraph 00730

[ 84539-22-0 ] Synthesis Path-Downstream 1~31

1
[ 57356-66-8 ]
[ 84539-22-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With bromine; In dichloromethane; at 20℃; for 1h;	General procedure: To a solution of compound 6a (0.36 mmol) in CH2Cl2 (25 mL), Br2 (22 muL, 0.43 mmol) was added, the reaction mixture was stirred at room temperature for 1 h and then treated with aqueous Na2CO3 for 2 h. The organic layer was separated, the solvent was removed in vacuo and the residue was recrystallizes from hexane.

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 1064 - 1069
[2]Russian Chemical Bulletin,2014,vol. 63,p. 1350 - 1358
Izv. Akad. Nauk, Ser. Khim.,2014,p. 1350 - 1358
[3]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1586 - 1605

2
[ 4318-42-7 ]
[ 84539-22-0 ]
Mo(CO)6 [ No CAS ]
(4-isopropyl-piperazin-1-yl)-(2-morpholin-4-yl-pyrimidin-5-yl)-methanone [ No CAS ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 2339 - 2343

3
[ 87120-72-7 ]
[ 84539-22-0 ]
[ 1010827-24-3 ]

Yield	Reaction Conditions	Operation in experiment
2%	With potassium tert-butylate;tetrakis(triphenylphosphine) palladium(0); XPhos; In toluene; at 100℃; for 16h;	Step 1: 4-(2-Morpholin-4-yl-pyrimidin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester To a degassed solution of 4-(5-bromo-pyrimidin-2-yl)-morpholine (4.70 g, 19.26 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.63 g, 23.11 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (5.40 g, 48.15 mmol, 2.5 equiv), dicyclohexyl-(2',4',6'-triisopropyl-biphenyl-2-yl)-phosphane (0.18 g, 0.39 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone)dipalladium(0) (1.60 g, 1.54 mmol, 0.08 equiv). The reaction mixture was stirred under nitrogen at 100 C. for 16 h, cooled to rt, filtered and the filtrate concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluding with a gradient of heptane/ethyl acetate (3:2→2:3) to provide 0.14 g (2%) of the title compound in 90% purity according to 1H NMR. 1H NMR (360 MHz, DMSO): δ 1.11-1.25 (m, 2H), 1.39 (s, 9H), 1.84 (d, J=14.1 Hz, 2H), 2.88 (br s, 2H), 3.30 (br s, 1H), 3.46 (t, J=5.0 Hz, 4H), 3.64 (t, J=4.1 Hz, 4H), 3.84 (d, J=12.7 Hz, 2H), 5.03 (d, J=8.6 Hz, 1H), 7.96 (s, 2H). MS (ESI): 364.3 [M+H]+.

Reference： [1]Patent: US2008/64697,2008,A1 .Location in patent: Page/Page column 27

4
[ 84539-22-0 ]
[ 1066-54-2 ]
[ 926009-59-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1586 - 1605

5
[ 84539-22-0 ]
[ 926009-60-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1586 - 1605

6
[ 84539-22-0 ]
[ 926009-39-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1586 - 1605

7
[ 84539-22-0 ]
C₂₀H₁₇N₆ClO [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1586 - 1605

8
[ 110-91-8 ]
[ 84539-22-0 ]

Yield	Reaction Conditions	Operation in experiment
		Potassium carbonate (0.34g) was added to a solution of 2-chloro-5-bromo-pyrimidine (0.5g) in DMF (20MOI). The reaction mixture was stirred at RT FOR 15min. Morpholine (0.2g) was added and the reaction mixture was stirred at rt for 2h. The excess DMF was removed by evaporation and the residue was partitioned between H20/ETOAC (30: 30ML) The EtOAc layer was dried (MgSO4) and evaporated to dryness to give the sub-title compound as a cream solid (0.2g). LCMS electrospray (+ve) 246 (MH+).

Reference： [1]Patent: WO2004/101546,2004,A1 .Location in patent: Page 34

9
[ 110-91-8 ]
[ 32779-36-5 ]
[ 84539-22-0 ]

Yield	Reaction Conditions	Operation in experiment
100%		To a solution of morpholine (1.44 g, 16.5 mmol) in MeCN (70 mL) at room temperature was added K2C03 (2.28 g, 16.5 mmol). After 1 hr at room temperature, 5-bromo-2-chIoro-pyrimidine (2.90 g, 15 mmol) was added and the reaction mixture was stirred for 18 hr at reflux. The reaction was stopped by the addition of water (50 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 x 50 mL) and the combined organic phases were dried over Na2S04, filtered and concentrated under reduced pressure to give 4-(5-bromopyrimidin-2- yl)morpholine in quantitative yield.
95%	With potassium carbonate; In acetonitrile; at 85℃; for 10h;	To a solution of 5-bromo-2-chloropyrimidine (3 g, 15.50 mmol) in acetonitrile (40 mL) was added morpholine (4.1 mL, 47 mmol) and potassium carbonate (11 g, 78.80 mmol) . The mixture was heated at 85 and stirred for 10 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was diluted with water (30 mL) . The resulting mixture was extracted with DCM (40 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo to give a white solid product (3.6 g, 95) .[1814]MS (ESI, pos. ion) m/z: 245.9 [M+1]+.
85%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h;	Step 1: DIPEA (640 pL, 3.87 mmol) was added to 5-bromo-2-chloropyrimidine (500 mg, 2.58 mmol) in CH3CN (11 mL). Then, morpholine (220 mg, 2.58 mmol) was added to the mixture. The reaction mixture was stirred at rt for 1 6h. The solvent was evaporated to dryness and water followed by CH2CI2 were added to the crude material. The organic layer was separated and concentrated to dryness. The residue was purified by column chromatography eluting with CH2CI2 and a gradient of CH2CI2/MeOH from [100:0] to [9:1]. The product fractions were combined and concentrated to dryness to afford 5-bromo-2- morpholinopyrimidine Ex.23a (535 mg, 85%) as white solid.

71%		[0325] K2C03 (14.2g, lO3mmol) was added to the solution of morpholine (9.0 g, 103 mmol) in acetonitrile (900 mL) and the resulting suspension was stirred at RT for 1 h. 5-Bromo-2-chloropyrimidine (20 g, 103 mmol) was added portionwise. The reaction mixture was stirred for 16h at 80C, then cooled down to RT and diluted with EtOAc (100 mL) and water (50 mL). The organic product was extracted with EtOAc (2x100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (100-200 mesh) (20% EtOAc in petroleum ether) to afford 18.0 g (71%) of 4-(5-bromopyrimidin-2-yl)morpholine as an off white solid (TLC system: 30% EtOAc in pet ether, Rf: 0.6).
	With potassium carbonate; In water; acetonitrile;	Example III-5 Morpholine (1.44 g, 16.5 mmol) is initially charged in acetonitrile (70 ml). Potassium carbonate (2.30 g, 16.5 mmol) is added, and the reaction mixture is stirred at room temperature for another hour. 5-Bromo-2-chloropyrimidine (2.90 g, 15.0 mmol) is added, and the reaction mixture is stirred at reflux for another 16 hours. After cooling, the reaction mixture is stirred into water (100 ml) and then extracted with ethyl acetate (2*50 ml). The organic phase is dried over sodium sulphate, filtered and concentrated. This gives 2.95 g (81% of theory) of 4-(5-bromo-2-pyrimidinyl)morpholine. HPLC: log P (pH 2.3)=2.15 (purity: 92%) m.p. 90 C.

Reference： [1]Patent: WO2018/211277,2018,A1 .Location in patent: Page/Page column 71-72
[2]Patent: WO2016/615,2016,A1 .Location in patent: Paragraph 00729
[3]Patent: WO2018/138359,2018,A1 .Location in patent: Page/Page column 41; 48
[4]Journal of Organic Chemistry,2021,vol. 86,p. 8900 - 8925
[5]Journal of Medicinal Chemistry,2010,vol. 53,p. 77 - 105
[6]Patent: WO2017/121647,2017,A1 .Location in patent: Paragraph 0323; 0324; 0325
[7]Patent: US2004/82586,2004,A1

10
[ 37828-58-3 ]
[ 183438-24-6 ]
[ 84539-22-0 ]

Reference： [1]Organic Letters,2008,vol. 10,p. 1715 - 1718

11
[ 84539-22-0 ]
[ 870521-33-8 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 77 - 105

12
C₁₄H₁₅BClNO₃ [ No CAS ]
[ 84539-22-0 ]
[ 1467061-22-8 ]

Yield	Reaction Conditions	Operation in experiment
159 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 0.5h;Inert atmosphere;	To a solution of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (154 mg, 0.584 mmol) in anhydrous 1,4-dioxane (5 mL) and DMF (1 mL) was added N,N-dimethylformiminium chloride (150 mg, 1.17 mmol). The reaction mixture was stirred at room temperature for 20 minutes, then treated with 2 M aqueous potassium carbonate (400 mg, 2.90 mmol), <strong>[84539-22-0]4-(5-bromopyrimidin-2-yl)morpholine</strong> (145 mg, 0.594 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.068 mmol). The reaction was degassed with nitrogen for 2 minutes and heated to 90 C. for 30 minutes. The cooled reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (petroleum ether/EtOAc=1:4) to afford 6-chloro-5-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-indole-3-carbaldehyde (159 mg, 79.4% yield) as an yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 10.01 (s, 1H), 8.55 (s, 2H), 8.46 (s, 1H), 8.12 (s, 1H), 7.79 (s, 1H), 3.84 (m, 4H), 3.77 (m, 4H).

Reference： [1]Patent: US2013/267493,2013,A1 .Location in patent: Paragraph 1052

13
[ 1449248-93-4 ]
[ 84539-22-0 ]
C₂₉H₂₈N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 75℃; for 7h;Inert atmosphere;	General procedure: To a solution of the aryl bromide and corresponding aryl boronic acid or aryl boronic acid pinacol ester in the listed solvent mixture were added the listed palladium catalyst and aqueous solution of base (See Table S1). The mixtures were stirred under Ar at 70-90 C for the stated time. The reaction mixtures were then cooled to room temperature. The products were purified by flash chromatography or by crystallization using the stated solvents.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3366 - 3372

14
[ 98437-23-1 ]
[ 84539-22-0 ]
[ 887413-59-4 ]