[ CAS No. 108381-28-8 ] {[proInfo.proName]}

Name: 108381-28-8|4-(Benzyloxy)-2-chloropyrimidine|97%
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Quality Control of [ 108381-28-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 108381-28-8 ]

CAS No. :	108381-28-8	MDL No. :	MFCD06798233
Formula :	C₁₁H₉ClN₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SNCGVIVLUWJDQN-UHFFFAOYSA-N
M.W :	220.66	Pubchem ID :	15133237
Synonyms :

Calculated chemistry of [ 108381-28-8 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.09
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	58.02
TPSA :	35.01 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.54 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.65
Log Po/w (XLOGP3) :	2.96
Log Po/w (WLOGP) :	2.56
Log Po/w (MLOGP) :	1.95
Log Po/w (SILICOS-IT) :	2.95
Consensus Log Po/w :	2.61

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.47
Solubility :	0.0753 mg/ml ; 0.000341 mol/l
Class :	Soluble
Log S (Ali) :	-3.36
Solubility :	0.0968 mg/ml ; 0.000439 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.94
Solubility :	0.00255 mg/ml ; 0.0000115 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.02

Safety of [ 108381-28-8 ]

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

Application In Synthesis of [ 108381-28-8 ]

* 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 [ 108381-28-8 ]
Downstream synthetic route of [ 108381-28-8 ]

[ 108381-28-8 ] Synthesis Path-Upstream 1~2

1
[ 3934-20-1 ]
[ 100-51-6 ]
[ 108381-28-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran for 0.5 h; Reflux Stage #2: at -78℃; for 1 h;	Step 1. A mixture formed by 2.26 g (20.1 mmol, 1 equiv.) of potass tert-butoxide and 4.3 g (40.2 mmol, 2 equiv.) of compound phenylmethanol in 10 ml of THF was heated under reflux temperature for half an hour. The reaction mixture was cooled down to 0 ⁰C and slowly added drop-wise to 3 g (20.1 mmol, 1 equiv.) of 2,4-dichloropyrimidine dissolved in 15 ml of N,N- dimethyl formamide, maintaining the temperature below -78 ⁰C. After stirring for one hour, it was left to reach room temperature. The mixture was added drop-wise to 100 ml of cold water, obtaining white solid 4-(benzyloxy)-2-chloropyrimidine (3.3 g, 75percent). The compound was determination by LC-MS (LC-MS (m/z) =222.0 [M+H]⁺)
24%	Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 1 - 2℃; for 0.5 h; Stage #2: at 1 - 2℃; for 3.5 h;	To a cooled (1-2° C.) suspension of sodium hydride (60percent in mineral oil) (1.5 equiv) in 250 ml THF, benzyl alcohol (1.0 equiv.) was added dropwise and the mixture stirred 30 min under N₂. This suspension was then added in small portions (via syringe, over 1 hr) to a solution of 2,4-dichloropyrimidine (1.5 equiv.) in THF also at 1-2° C. (internal thermometer). The resulting mixture (0.06 M) was stirred at temp <2° C. for 2.5 hrs, then quenched with NH₄Cl_(sat.) and extracted with EtOAc. Upon separation, the organic layer was washed with NaCl_(sat.), dried over Na₂SO₄, concentrated and purified by silica gel chromatography (hexanes/DCM eluant) to yield 4-(benzyloxy)-2-chloropyrimidine (24percent). LC/MS=221.0 (M+H), LC=3.93 min.

Reference： [1] Organic Letters, 2017, vol. 19, # 7, p. 1854 - 1857
[2] Chemistry - A European Journal, 2017, vol. 23, # 58, p. 14563 - 14575
[3] Patent: WO2011/19405, 2011, A1, . Location in patent: Page/Page column 107
[4] Patent: US2011/195980, 2011, A1, . Location in patent: Page/Page column 28
[5] Patent: EP1564212, 2005, A1, . Location in patent: Page 13

2
[ 3934-20-1 ]
[ 108381-28-8 ]

Reference： [1] Tetrahedron, 1992, vol. 48, # 37, p. 8117 - 8126
[2] Patent: WO2011/22440, 2011, A2, . Location in patent: Page/Page column 169
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1208 - 1224

[ 108381-28-8 ] Synthesis Path-Downstream 1~37

1
[ 3934-20-1 ]
[ 100-51-6 ]
[ 108381-28-8 ]
2-(benzyloxy)-4-chloropyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide;18-crown-6 ether; In toluene; at 20℃; for 1h;Inert atmosphere;	To a solution of 2,4-dichloropyrimidine (90) (2.0 g, 0.0134 mmol) in toluene (20 mL) was added benzyl alcohol (1.53 ml, 1.59 g, 0.0147 mol), KOH (0.82 g, 0.0147 mol) and 18-crown-6 (0.177 g, 0.00067 mol) and stirred at rt for Ih. The reaction mixture was diluted with EtOAc (400 mL) and washed with water (3 x 50 mL), dried over MgSO4, filtered and concentrated to give a white solid that was chromatographed (hexane:CH2Cl2, 1 :1 to 3:7) to afford 2.09 g (71%) of a mixture of 96 with regioisomeric 2-(benzyloxy)-4-chloropyrimidine (relative ratio 75:25 by 1H-NMR, respectively); MS (m/z): [M+Na]+ 243.1

Reference： [1]Tetrahedron,1992,vol. 48,p. 8117 - 8126
[2]Patent: WO2011/22440,2011,A2 .Location in patent: Page/Page column 169
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 1208 - 1224

2
[ 108381-28-8 ]
[ 134896-34-7 ]
[ 134896-37-0 ]

Reference： [1]Tetrahedron Letters,1991,vol. 32,p. 2273 - 2276
[2]Tetrahedron,1992,vol. 48,p. 8117 - 8126

4
[ 108381-28-8 ]
(4-benzyloxy-pyrimidin-2-yl)-hydrazine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3191 - 3193

5
[ 108381-28-8 ]
[ 2393-23-9 ]
(4-benzyloxy-pyrimidin-2-yl)-(4-methoxy-benzyl)-amine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3191 - 3193

6
[ 108381-28-8 ]
[ 516471-21-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3191 - 3193

7
[ 108381-28-8 ]
4-Benzyloxy-2-(4-{(E)-3-[4-(3,5-difluoro-phenyl)-piperazin-1-yl]-propenyl}-5-methyl-pyrazol-1-yl)-pyrimidine; hydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3191 - 3193

8
[ 108381-28-8 ]
1-[1-(4-benzyloxy-pyrimidin-2-yl)-5-methyl-1<i>H</i>-pyrazol-4-yl]-3-[4-(3,5-difluoro-phenyl)-piperazin-1-yl]-propan-1-ol; hydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3191 - 3193

9
[ 108381-28-8 ]
1-[1-(4-benzyloxy-pyrimidin-2-yl)-5-methyl-1<i>H</i>-pyrazol-4-yl]-3-[4-(3,5-difluoro-phenyl)-piperazin-1-yl]-propan-1-one; hydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3191 - 3193

10
[ 108635-83-2 ]
[ 108381-28-8 ]
2-({1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-piperidin-4-yl}-aminomethyl)-4-benzyloxypyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In triethylamine; for 62h;Heating / reflux;	EXAMPLE 10 2-({1-[1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl]-piperidin-4-yl}-aminomethyl)-4-benzyloxypyrimidine (7) A mixture formed by 6.4 g of 1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-N-methyl-4-aminopiperidine (9), 5 g of <strong>[108381-28-8]4-benzyloxy-2-chloropyrimidine</strong> and 5.2 g of potassium carbonate in 64 mL of triethylamine is heated under reflux temperature for 62 hours. Once the reaction is finished, it is processed by removing the solvent under reduced pressure to obtain a residue, which is dissolved in 64 mL of methylene chloride and 62 mL of water. The mixture formed is neutralized with hydrochloric acid, the organic phase is separated and the aqueous phase is again extracted with 32 mL of methylene chloride. The organic phases are brought together, washed with 60 mL of water and the solvent is removed. The residue obtained is recrystallized in 64 mL of acetonitrile, obtaining 5.6 g of 2-({1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-piperidin-4-yl}-aminomethyl)-4-benzyloxy-pyrimidine (7). 13C-NMR (CDCl3, delta in ppm): 28.87 (CH2), 29.03 (CH3), 47.09 (CH2), 67.04 (CH2), 122.02 (CH), 141.61 (C), 169.04 (C).

Reference： [1]Patent: EP1564212,2005,A1 .Location in patent: Page 13

11
[ 114136-60-6 ]
[ 108381-28-8 ]
[ 353293-62-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide;	First Step 2.6 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 1.7 g of <strong>[108381-28-8]4-benzyloxy-2-chloropyrimidine</strong> were dissolved in 20 ml of N,N-dimethylformamide, to this solution was added 1.07 g of potassium carbonate, and the mixture was stirred for 2 hours at 80 C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 1.6 g of 4-benzyloxy-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine.

Reference： [1]Patent: US6537948,2003,B1

12
[ 3934-20-1 ]
[ 100-51-6 ]
[ 108381-28-8 ]

Yield	Reaction Conditions	Operation in experiment
75%		Step 1. A mixture formed by 2.26 g (20.1 mmol, 1 equiv.) of potass tert-butoxide and 4.3 g (40.2 mmol, 2 equiv.) of compound phenylmethanol in 10 ml of THF was heated under reflux temperature for half an hour. The reaction mixture was cooled down to 0 0C and slowly added drop-wise to 3 g (20.1 mmol, 1 equiv.) of 2,4-dichloropyrimidine dissolved in 15 ml of N,N- dimethyl formamide, maintaining the temperature below -78 0C. After stirring for one hour, it was left to reach room temperature. The mixture was added drop-wise to 100 ml of cold water, obtaining white solid 4-(benzyloxy)-2-chloropyrimidine (3.3 g, 75%). The compound was determination by LC-MS (LC-MS (m/z) =222.0 [M+H]+)
24%		To a cooled (1-2 C.) suspension of sodium hydride (60% in mineral oil) (1.5 equiv) in 250 ml THF, benzyl alcohol (1.0 equiv.) was added dropwise and the mixture stirred 30 min under N2. This suspension was then added in small portions (via syringe, over 1 hr) to a solution of 2,4-dichloropyrimidine (1.5 equiv.) in THF also at 1-2 C. (internal thermometer). The resulting mixture (0.06 M) was stirred at temp <2 C. for 2.5 hrs, then quenched with NH4Cl(sat.) and extracted with EtOAc. Upon separation, the organic layer was washed with NaCl(sat.), dried over Na2SO4, concentrated and purified by silica gel chromatography (hexanes/DCM eluant) to yield 4-(benzyloxy)-2-chloropyrimidine (24%). LC/MS=221.0 (M+H), LC=3.93 min.
		EXAMPLE 9 4-Benzyloxy-2-chloropyrimidine A mixture formed by 18.9 g of sodium tert-butoxide and 40.6 g of benzyl alcohol in 80 mL of THF, is heated under reflux temperature for half an hour, is subsequently cooled to 0C and slowly added drop-wise to 26.6 g of 2,4-dichloropyrimidine dissolved in 133 mL of N,N-dimethylformamide, maintaining the temperature below -50C. After stirring for one hour, it is left to reach room temperature, the tetrahydrofuran is removed under reduced pressure and the obtained residue is added drop-wise to 800 mL of cold water, obtaining a precipitate which is dried in an oven with forced air circulation at a temperature of 60C, once dried, it is resuspended for two hours in 78 mL of methanol, filtered and again dried in an oven with forced air circulation at a temperature of 60C. 24 g of impurity free 4-benzyloxy-2-chloropyrimidine are obtained. 13C-NMR (CDCl3, delta in ppm): 69.13 (CH2), 107.31 (CH), 128.50 (CH), 135.11 (C), 160.11 (C).

Reference： [1]Organic Letters,2017,vol. 19,p. 1854 - 1857
[2]Chemistry - A European Journal,2017,vol. 23,p. 14563 - 14575
[3]Patent: WO2011/19405,2011,A1 .Location in patent: Page/Page column 107
[4]Patent: US2011/195980,2011,A1 .Location in patent: Page/Page column 28
[5]Patent: EP1564212,2005,A1 .Location in patent: Page 13

13
[ 108381-28-8 ]
[ 1260088-93-4 ]
[ 1260089-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate;bis(dibenzylideneacetone)-palladium(0); DavePhos; In toluene; at 120℃; for 0.333333h;Inert atmosphere; Microwave irradiation; Sealed tube;	Step 1-Synthesis of 4-(benzyloxy)-N-(4-(4'-morpholino-5',6'-dihydrospiro[cyclopropane-1,7'-pyrano[2,3-d]pyrimidine]-2'-yl)phenyl)pyrimidin-2-amine (cq): 4-(4'-morpholino-5',6'-dihydrospiro[cyclopropane-1,7'-pyrano[2,3-d]pyrimidine]-2'-yl)aniline (co) (79.5 mg, 0.235 mmol), <strong>[108381-28-8]4-(benzyloxy)-2-chloropyrimidine</strong> (63.4 mg, 0.287 mmol), bis(dibenzylideneacetone)palladium(0) (8.2 mg, 0.014 mmol), sodium tert-butoxide (35.8 mg, 0.372 mmol), and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (9.8 mg, 0.025 mmol) were weighed into a microwave vial. The vial was evacuated and purged 3× with N2, then degassed toluene (2.1 mL, 2.0E1 mmol) was added and the vial sealed. The reaction was microwaved at 120 C. for 20 min. The reaction mixture was filtered through Celite, washing extensively with CH2Cl2. This was then concentrated onto silica gel and subjected to column chromatography using a 12 g column, with a gradient of 0% to 100% ethyl acetate in hexanes. The product containing fractions were combined and evaporated under reduced pressure to give 4-(benzyloxy)-N-(4-(4'-morpholino-5',6'-dihydrospiro[cyclopropane-1,7'-pyrano[2,3-d]pyrimidine]-2'-yl)phenyl)pyrimidin-2-amine: 1H NMR (400 MHz, DMSO) delta 8.75 (s, 1H), 8.12 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 6.98 (d, J=6.5 Hz, 1H), 4.81-4.67 (m, 3H), 4.44 (t, J=5.7 Hz, 2H), 3.79-3.69 (m, 4H), 3.48-3.40 (m, 4H), 2.71 (t, J=5.9 Hz, 2H), 1.86 (t, J=5.9 Hz, 2H), 1.01 (t, J=6.0 Hz, 2H), 0.73 (t, J=6.3 Hz, 2H).

Reference： [1]Patent: US2010/331305,2010,A1 .Location in patent: Page/Page column 51-52

14
[ 108381-28-8 ]
[ 1260089-19-7 ]
[ 1260089-30-2 ]

Yield	Reaction Conditions	Operation in experiment
71.75%	With sodium t-butanolate;bis(dibenzylideneacetone)-palladium(0); DavePhos; In toluene; at 120℃; for 0.666667h;Inert atmosphere; Microwave irradiation;	Step 1-Synthesis of (S)-4-(benzyloxy)-N-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)phenyl)pyrimidin-2-amine (cb): (S)-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)aniline (ca) (68.6 mg1.00 equiv, 210.17 mumoles) was weighed into a microwave vial with a stirbar. <strong>[108381-28-8]4-(benzyloxy)-2-chloropyrimidine</strong> (57.4 mg, 1.24 equiv, 260.13 mumoles), sodium t-butoxide (31.4 mg, 326.73 mmoles), bis(dibenzylideneacetone)palladium (8.6 mg14.96 mumoles) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (7.3 mg18.55 mumoles) were added, then the reaction vial was evacuated and purged with N2 3 times. Toluene (2 mL) was added, and the reaction was heated in a CEM microwave at 120 C. for 40 minutes with PowerMax off. The reaction was then filtered through Celite, washing with CH2Cl2. The crude material was concentrated under reduced pressure onto silica gel, and was then purified using flash chromatography on a 4 g column using a gradient of 0% to 100% EtOAc in heptane. The product containing fractions were concentrated to give (S)-4-(benzyloxy)-N-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)phenyl)pyrimidin-2-amine (cb) (77 mg0.72 equiv150.80 mumoles71.75% yield) as an oil. 1H NMR (400 MHz, CDCl3) delta 8.40-8.33 (m, 2H), 8.18 (d, J=5.7, 1H), 7.66 (d, J=8.8, 2H), 7.49-7.30 (m, 5H), 6.28 (d, J=5.7, 1H), 5.44 (s, 2H), 4.48-4.29 (m, 2H), 4.09-3.45 (m, 6H), 2.72-2.49 (m, 2H), 2.03-1.91 (m, 2H), 1.72-1.50 (m, 2H), 1.34 (d, J=6.7, 3H).

Reference： [1]Patent: US2010/331305,2010,A1 .Location in patent: Page/Page column 47

15
[ 108381-28-8 ]
[ 138500-86-4 ]
[ 1266479-93-9 ]

Yield	Reaction Conditions	Operation in experiment
31%	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 15h;Inert atmosphere;	Step 2. A mixture of <strong>[108381-28-8]4-(benzyloxy)-2-chloropyrimidine</strong> (3.2 g, 14.5 mmol, 1.0 equiv.), 2-(4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (4.2 g, 17.4 mmol, 1.2 equiv.), Pd(dippf)Cl2 (1.18 g, 1.45 mmol, 0.1 equiv.), Na2CO3 (6.1 g, 58 mmol, 4.0 equiv.), dioxane (5 ml) and water (1 ml) was added to the filtrate. The reaction mixture was heated to 1000C for 15 h under nitrogen atmosphere. The residue was purified by silica gel chromatography (CH2Cl2/ methanol 500:1 to 200:1) to afford 2-(4-(4-(benzyloxy)pyrimidin-2-yl)phenyl)acetonitrile (1.3 g, 31%) as white solid. The title compound was determination by LC-MS (LC-MS (m/z) =302.1 [M+H]+).

Reference： [1]Patent: WO2011/19405,2011,A1 .Location in patent: Page/Page column 107

16
[ 109-01-3 ]
[ 108381-28-8 ]
[ 1268273-86-4 ]