[ CAS No. 663194-10-3 ]

Name: 663194-10-3|4-(4-Bromopyrimidin-2-yl)morpholine|97%
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Quality Control of [ 663194-10-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 663194-10-3 ]

SDS Specification

Alternatived Products of [ 663194-10-3 ]

Product Details of [ 663194-10-3 ]

CAS No. :	663194-10-3	MDL No. :	MFCD03861153
Formula :	C₈H₁₀BrN₃O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AVLAJWPBZJNJDQ-UHFFFAOYSA-N
M.W :	244.09	Pubchem ID :	45787495
Synonyms :

Calculated chemistry of [ 663194-10-3 ]

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) :	-6.48 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.19
Log Po/w (XLOGP3) :	1.84
Log Po/w (WLOGP) :	0.69
Log Po/w (MLOGP) :	0.64
Log Po/w (SILICOS-IT) :	1.62
Consensus Log Po/w :	1.4

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.79
Solubility :	0.398 mg/ml ; 0.00163 mol/l
Class :	Soluble
Log S (Ali) :	-2.26
Solubility :	1.33 mg/ml ; 0.00545 mol/l
Class :	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 :	2.31

Safety of [ 663194-10-3 ]

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 [ 663194-10-3 ]

* 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 [ 663194-10-3 ]
Downstream synthetic route of [ 663194-10-3 ]

[ 663194-10-3 ] Synthesis Path-Upstream 1~2

1
[ 19810-79-8 ]
[ 663194-10-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	With phosphorus(V) oxybromide In acetonitrile for 1 h; Heating / reflux	2c) 4- (4-BROMO-PVRIMIDIN-2-VL)-MORPHOLINE A mixture of 2-morpholin-4-yl-pyrimidin-4-ol (6.08 g, 33.6 MMOL) and phosphorus OXYBROMIDE (12.5 g, 43.7 MMOL) in 330 mL MECN is heated to reflux for 1 hour. The reaction is cooled to room temperature, concentrated to half volume, and poured over ice. The resulting mixture is neutralized with a saturated solution of NaHCOs, and then extracted with methylene chloride. The organic phase is washed with saturated NACI (aqueous), dried over ANHYDROUS MGS04, FILTERED, concentrated and dried to an off-white solid (7.11 g, 87percent). M+H'= 245.97. H NMR (CDC13) ; a 8.05 (d, 1H), 6.70 (d, 1H), 3.75 (m, 8H).

Reference： [1] Patent: WO2005/28444, 2005, A1, . Location in patent: Page/Page column 50-51

2
[ 110-91-8 ]
[ 3921-01-5 ]
[ 663194-10-3 ]
[ 1209459-32-4 ]

Yield	Reaction Conditions	Operation in experiment
19%	Stage #1: With potassium carbonate In tetrahydrofuran at 20℃; for 0.0833333 h; Stage #2: at 20℃;	2,4-dibromopyrimidine (438.4mg, 1.84mmol) and potassium carbonate (1.27g, 9.21mmol) in tetrahydrofuran (10mL) were added together and stirred at room temperature for 5min. Morpholine (174.8μL, 2.03mmol) was then added dropwise and the solution continued to stir at room temperature for 5h. The reaction mixture was filtered and the filtrate was collected and then concentrated under reduced pressure. The products were purified by silica column chromatography in hexanes and ethyl acetate to afford 28a and 28b in 19percent and 66percent yields, respectively. (0070) 4-(4-bromopyrimidin-2-yl)morpholine (28a). (White solid, Yield: 19percent). ¹H NMR (500MHz, CDCl₃) δ ppm 3.74–3.77 (m, 4H) 3.79–3.83 (m, 4H) 6.70 (d, J=4.88Hz, 1H) 8.05 (d, J=4.88Hz, 1H). LCMS found 246.0, [M+H]⁺. (0071) 4-(2-bromopyrimidin-4-yl)morpholine (28b). (White solid, Yield: 66percent) ¹H NMR (500MHz, CDCl₃) δ ppm 3.66 (br. s., 4H) 3.76–3.83 (m, 4H) 6.43 (d, J=6.35Hz, 1H) 8.02 (d, J=6.35Hz, 1H). LCMS found 246.0, [M+H]⁺.

Reference： [1] European Journal of Medicinal Chemistry, 2017, vol. 141, p. 446 - 459

[ 663194-10-3 ] Synthesis Path-Downstream 1~13

1
[ 19810-79-8 ]
[ 663194-10-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	With phosphorus(V) oxybromide; In acetonitrile; for 1.0h;Heating / reflux;	2c) 4- (4-BROMO-PVRIMIDIN-2-VL)-MORPHOLINE A mixture of <strong>[19810-79-8]2-morpholin-4-yl-pyrimidin-4-ol</strong> (6.08 g, 33.6 MMOL) and phosphorus OXYBROMIDE (12.5 g, 43.7 MMOL) in 330 mL MECN is heated to reflux for 1 hour. The reaction is cooled to room temperature, concentrated to half volume, and poured over ice. The resulting mixture is neutralized with a saturated solution of NaHCOs, and then extracted with methylene chloride. The organic phase is washed with saturated NACI (aqueous), dried over ANHYDROUS MGS04, FILTERED, concentrated and dried to an off-white solid (7.11 g, 87percent). M+H'= 245.97. H NMR (CDC13) ; a 8.05 (d, 1H), 6.70 (d, 1H), 3.75 (m, 8H).

Reference： [1]Patent: WO2005/28444,2005,A1 .Location in patent: Page/Page column 50-51

2
4-boronic acid-1-chloro-isoquinoline [ No CAS ]
[ 663194-10-3 ]
[ 848841-49-6 ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 95℃; for 4.5h;	2F) 1-CHLORO-4- (2-MORPHOLIN-4-VL-PVRIMIDIN-4-VL)-ISOQUINOLINE 4-(4-BROMO-PYRIMIDIN-2-YL)-MORPHOLINE (3.7 g, 15.0 MMOL) (see Example 2c) and 4-boronic ACID-1-CHLORO-ISOQUINOLINE (6.2 g, 29.9 MMOL) are dissolved in 60 mL ethylene glycol dimethyl ether (DME) with 3 mL ETOH in a large sealed tube. A solution of NA2CO3 (6.1 g, 57.8 MMOL) in 20 mL water is added and N2 is bubbled through the red solution for 5 minutes. The PDC12 (PPh3) 2 catalyst (2.1 g, 3.0 MMOL) is added, and the mixture is heated to 95°C for 4.5 hours. Upon cooling, water is added, and the product is extracted with CH2CI2. The organic layer is washed with saturated NACI (aqeuous), dried over NA2SO4, filtered and concentrated. The white solid product (1.8 g, 37percent) is obtained using Biotage flash column chromatography silica gel, eluting with 10-20percent ethyl acetate in hexane, m. p. 180.5-180. 6°C. M+H = 327.1. H NMR (CDC13) 8 8.48 (t, 2H), 8.43 (s, 1H), 8.36 (d, 1H), 7. 77 (m ; 2H), 6.83 (d, 1H), 3.89 (t, 4H), 3.80 (t, 4H). CHN analysis CAIC. : percent C: 62.48, percent H: 4.63, percent N: 17.15, percent CI : 10.85. Found: percent C : 62.32, percent H: 4.58, percent N: 16.99, percent CI : 10. 81. The solid is used to prepare Example 2.

Reference： [1]Patent: WO2005/28444,2005,A1 .Location in patent: Page/Page column 52

3
(4-boronic acid-[2,6]naphthyridin-1-yl)-(4-isopropyl-phenyl)-amine [ No CAS ]
[ 663194-10-3 ]
(4-isopropyl-phenyl)-[4-(2-morpholin-4-yl-pyrimidin-4-yl)-[2,6]naphthyridin-1-yl]-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; for 1.5h;Heating / reflux;	Example 29 (4-ISOPROPYL-PHENYL)- [4- (2-MORPHOLIN-4-YL-PYRIMIDIN-4-YL)- [2, 6] NAPHTHYRIDIN-1-YL]-AMINE A degassed solution of (4-boronic ACID- [2, 6] NAPHTHYRIDIN-1-YL)- (4-ISOPROPYL-PHENYL)- amine (400 mg, 1 eq), 4- (4-BROMO-PYRIMIDIN-2-YL)-MORPHOLINE (300 mg, 1.2 eq), PdCl2(PPh3)2 (0.1 eq) in DME (5 mL) and Na2CO3 (2M, 5 mL) is heated at reflux for 1.5 h. DME is removed in vacuo and residue is dissolved in CH2CI2 (20 mL). After washing with H20 and brine, this organic solution is dried (MgS04) and concentrated to an oil. Chromatography (SiO2, 40percent EtOAc-hexane) provided (4-ISOPROPYL-PHENYL)- [4- (2-MORPHOLIN-4-YL-PYRIMIDIN-4- YL)-[2, 6] NAPHTHYRIDIN-1-YL]-AMINE (200 mg, 47percent) as light yellow solid. HRMS ESI M/Z 427.2275 (M+H, C25H27ON6 requires 427. 2246). 1H NMR (300 MHz, CDCI3) o 10.06 (s, 1 H), 8.75 (d, J = 6.0 Hz, 1 H), 8.48 (t, J = 3.0 Hz 1 H), 7.75 (d, J = 6. 0 HZ, 1 H), 7.64 (d, J = 9. 0 HZ, 2H), 7.31 (d, J = 9. 0 HZ, 2H), 6.90 (d, J = 3. 0 Hz 1 H), 3.92 (m, 4H), 3.94 (m, 4H), 2.96 (m, 1H), 1.30 (d, J= 6.. 0 Hz, 6H).

Reference： [1]Patent: WO2005/28444,2005,A1 .Location in patent: Page/Page column 75-76

4
[ 557-21-1 ]
[ 663194-10-3 ]
[ 75825-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 2.08333h;Inert atmosphere;	In a sealed tube a mixture of <strong>[663194-10-3]4-(4-bromopyrimidin-2-yl)morpholine</strong> (0.40 g, 1.64 mmol), Zn(CN)2 (0.35 g, 3.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol) in anhydrous DMF was degassed with argon for 10 minutes and then warmed at 12O0C. After 2 hours, the mixture was cooled and diluted with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20percent ethyl acetate in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford 2-morpholin-4-yl- pyrimidine-4-carbonitrile.

Reference： [1]Patent: WO2010/36632,2010,A1 .Location in patent: Page/Page column 222

5
[ 110-91-8 ]
[ 3921-01-5 ]
[ 663194-10-3 ]
[ 1209459-32-4 ]

Yield	Reaction Conditions	Operation in experiment
19%; 66%		<strong>[3921-01-5]2,4-dibromopyrimidine</strong> (438.4mg, 1.84mmol) and potassium carbonate (1.27g, 9.21mmol) in tetrahydrofuran (10mL) were added together and stirred at room temperature for 5min. Morpholine (174.8muL, 2.03mmol) was then added dropwise and the solution continued to stir at room temperature for 5h. The reaction mixture was filtered and the filtrate was collected and then concentrated under reduced pressure. The products were purified by silica column chromatography in hexanes and ethyl acetate to afford 28a and 28b in 19percent and 66percent yields, respectively. (0070) 4-(4-bromopyrimidin-2-yl)morpholine (28a). (White solid, Yield: 19percent). 1H NMR (500MHz, CDCl3) delta ppm 3.74?3.77 (m, 4H) 3.79?3.83 (m, 4H) 6.70 (d, J=4.88Hz, 1H) 8.05 (d, J=4.88Hz, 1H). LCMS found 246.0, [M+H]+. (0071) 4-(2-bromopyrimidin-4-yl)morpholine (28b). (White solid, Yield: 66percent) 1H NMR (500MHz, CDCl3) delta ppm 3.66 (br. s., 4H) 3.76?3.83 (m, 4H) 6.43 (d, J=6.35Hz, 1H) 8.02 (d, J=6.35Hz, 1H). LCMS found 246.0, [M+H]+.