[ CAS No. 849934-95-8 ] {[proInfo.proName]}

Name: 849934-95-8|Methyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate|97%
Brand: Ambeed
SKU: A705757
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Quality Control of [ 849934-95-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 849934-95-8 ]

CAS No. :	849934-95-8	MDL No. :	MFCD18760351
Formula :	C₁₅H₂₀BClO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SGIQMJIVHOIJJX-UHFFFAOYSA-N
M.W :	310.58	Pubchem ID :	67389783
Synonyms :

Calculated chemistry of [ 849934-95-8 ]

Physicochemical Properties

Num. heavy atoms :	21
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.53
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	83.79
TPSA :	44.76 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.83 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	3.33
Log Po/w (WLOGP) :	2.35
Log Po/w (MLOGP) :	2.04
Log Po/w (SILICOS-IT) :	2.81
Consensus Log Po/w :	2.11

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.81
Solubility :	0.048 mg/ml ; 0.000155 mol/l
Class :	Soluble
Log S (Ali) :	-3.95
Solubility :	0.0351 mg/ml ; 0.000113 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.08
Solubility :	0.0026 mg/ml ; 0.00000836 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.07

Safety of [ 849934-95-8 ]

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 [ 849934-95-8 ]

* 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 [ 849934-95-8 ]
Downstream synthetic route of [ 849934-95-8 ]

[ 849934-95-8 ] Synthesis Path-Upstream 1~1

1
[ 849934-95-8 ]
[ 1432908-05-8 ]

Reference： [1] Tetrahedron Letters, 2016, vol. 57, # 3, p. 449 - 451

[ 849934-95-8 ] Synthesis Path-Downstream 1~24

1
[ 849934-94-7 ]
[ 96042-30-7 ]
[ 849934-95-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium acetate; In water; dimethyl sulfoxide; bis(pinacol)diborane;	Preparation 17 Compounds of Formula (CB) (4-Bromo-2-chloro-phenyl)-acetic acid methyl ester (705 mg, 2.68 mmoles) was place into a 25 mL pear-shaped flask and was sealed under nitrogen. The material was then solubilized with 20 mL of anhydrous DMSO, and the resulting solution was degassed by passing a steady stream of nitrogen through the solution for 10 min. In a separate round-bottom flask were combined bis(pinacolato)diboron (0.82 g, 3.2 mmoles), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with DCM (1:1) (66 mg, 0.081 mmoles) and potassium acetate (0.79 g, 8.05 mmoles) with a stirring bar under nitrogen. Following degassification the bromide solution was transferred to the "catalytic" mixture and the resulting mix was stirred at 90 C. for 16 hours. After this period the reaction mix was combined with 60 mL of water and was extracted with benzene (41 5 mL). The combined benzene layer was washed with water (425 mL) and was dried over anhydrous Na2SO4. Following evaporation in vacuo the crude product was purified using flash silica chromatography (0-10% EtOAc/Hexane) to yield [2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]acetic acid methyl ester (502 mg, 83% yield) as a thick, clear residue. Note: TLC visualization accomplished using ceric ammonium molybdate stain. 1H-NMR (CDCl3): delta 7.83-7.81 (br s, 1H), 7.65 (br d, J=7.6 Hz, 1H), 7.29 (d, J=7.3 Hz, 1H), 3.80 (s, 2H), 3.70 (s, 3H), 1.34 (s, 12H).

Reference： [1]Patent: US2005/80111,2005,A1

2
[ 67197-54-0 ]
[ 849934-95-8 ]

Yield	Reaction Conditions	Operation in experiment
		(Example 86) [4-(5-[2-(tert-Butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-2-pyridinyl)-2-chlorophenyl]acetic acid (Exemplification Compound No.: 2-168) According to a method similar to Example (84-2) and Example (84-3), from (4-bromo-2-chlorophenyl)acetonitrile (205 mg, 0.89 mmol) obtained in Example (18-1), methyl [2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate was obtained.

Reference： [1]Patent: US2015/31674,2015,A1
[2]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1241 - 1246
[3]Tetrahedron Letters,2016,vol. 57,p. 449 - 451
[4]Patent: EP1806332,2007,A1

3
[ 849934-95-8 ]
[ 1209459-88-0 ]
[ 1428760-95-5 ]

Yield	Reaction Conditions	Operation in experiment
47%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran; water; toluene; for 18h;Inert atmosphere; Reflux;	KOAc (19 g, 194 mmol) and Pd(dppf)Cl2 (5% mol.) were added successively under vigorous stirring to a solution of <strong>[1209459-88-0]4-bromo-N-methylpicolinamide</strong> (16 g, 75 mmol) and methyl 2- (2-chloro-4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenyl)acetate (25 g, 82 mmol) in toluene (200 ml), THF (200 ml) and water (50 ml) under N2. The reaction mixture was heated to reflux for 18h. The resulting mixture was evaporated to dryness and the solid was extracted with DCM (3x50ml). The combined organic layers were dried by Na2S04, concentrated in vacuo and chromatographed on silica gel eluting with PE:ethyl acetate (1 : 1) to afford 75 (1 1 g, 47%) as pale white solid. LCMS: m/z 319 (M+l)+.

Reference： [1]Patent: WO2013/43232,2013,A2 .Location in patent: Paragraph 00563

4
[ 849934-95-8 ]
[ 1428760-94-4 ]

Reference： [1]Patent: WO2013/43232,2013,A2

5
[ 849934-95-8 ]
[ 1428759-62-9 ]

Reference： [1]Patent: WO2013/43232,2013,A2

6
[ 89794-02-5 ]
[ 849934-95-8 ]

Reference： [1]Patent: US2015/31674,2015,A1
[2]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1241 - 1246

7
[ 89720-77-4 ]
[ 849934-95-8 ]

Reference： [1]Patent: US2015/31674,2015,A1
[2]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1241 - 1246
[3]Tetrahedron Letters,2016,vol. 57,p. 449 - 451

8
[ 89283-31-8 ]
[ 849934-95-8 ]
methyl-2-(2-chloro-4-(5-methylpyridazin-3-yl)phenyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; water; at 90.0℃;Inert atmosphere;	A mixture of <strong>[849934-95-8]methyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate</strong> (682 mg, 2.2 mmol), 3-chloro-5-methylpyridazine (297 mg in 1.188 g dioxane, 2.3 mmol), KOAc (431 mg, 4.4 mmol), Pd(dppf)Cl2(II) (160 mg, 0.22 mmol) in dioxane (22 mL) and water (16 mL) was heated at 90 C. under N2 overnight. The reaction mixture was then diluted with EtOAc (100 mL) and washed with water (50 mL). The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was then purified by SiO2 chromatography eluting PE/EtOAc (55-60%) to give the target compound (186 mg, 30%) as a yellow solid. LCMS (ESI): m/z=277.0 [M+1]+.

Reference： [1]Patent: US2015/31674,2015,A1 .Location in patent: Paragraph 0346; 0347; 0715

9
[ 3430-17-9 ]
[ 849934-95-8 ]
methyl-2-(2-chloro-4-(3-methylpyridin-2-yl)phenyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; at 100.0℃;	Methyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate was coupled with 2-bromo-3-methylpyridine (Pd(dppf)Cl2, K2CO3, 100 C.) to afford methyl 2-(2-chloro-4-(3-methylpyridin-2-yl)phenyl)acetate which was condensed with 4-(((2r,5r)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde and cyclized to afford 2-((2r,5r)-2-((6-(2-chloro-4-(3-methylpyridin-2-yl)phenyl)(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)-1,3-dioxan-5-yl)isoindoline-1,3-dione. Introduction of the methylamine and deprotection were accomplished with standard protocols to afford I-200. 1H NMR (400 MHz, CDCl3) delta 8.47 (d, J=4.0 Hz, 1H), 7.59 (s, 1H), 7.54-7.52 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.44-7.39 (m, 2H), 7.19 (s, 1H), 7.15-7.12 (m, 1H), 5.49 (d, J=4.4 Hz, 1H), 4.98 (s, 1H), 4.62 (d, J=2.4 Hz, 2H), 4.07-4.03 (m, 2H), 3.15-3.10 (m, 2H), 3.04 (d, J=5.2 Hz, 3H), 2.33 (s, 3H; MS [M+H]+=493.1

Reference： [1]Patent: US2015/31674,2015,A1 .Location in patent: Paragraph 0622

10
[ 849934-94-7 ]
[ 73183-34-3 ]
[ 849934-95-8 ]

Yield	Reaction Conditions	Operation in experiment
> 99%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; for 18.0h;Inert atmosphere; Reflux;	In a flame-dried flask under inert atmosphere, 3 (18.3 g, 70.0 mmol, 1.0 equiv.), was diluted in 1,4-dioxane (278 mL) then bis(pinacolato)diboron (23.0 g, 90.5 mmol, 1.3 equiv.), KOAc (20.5 g, 209 mmol, 3.0 equiv.), and Pd(dppf)Cl2-DCM (2.8 g, 3.5 mmol, 0.05 equiv.) were all added. The mixture was heated at reflux for 18 h, reduced, dissolved in EtOAc, passed through a plug of silica gel, and then reduced to yield the white solid 4 (22.0 g, >99 %). Characterization data was identical to previous reports.[21]
97%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 18.0h;Inert atmosphere; Reflux;	step 1: A mixture of methyl 2-(4-bromo-2-chlorophenyl)acetate (13 g, 49.3 mmol), (PinB)2 (16.3 g, 64.1 mmol), KOAc (9.7 g, 98.7 mmol) and Pd(dppf)Cl2 (1.8 g, 2.47 mmol) was refluxed in dioxane (250 mL) under N2 for 18 h. After cooling to RT, the mixture was partitioned between EtOAc (600 mL) and H2O. The organic layer was separated and dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a PE/EtOAc gradient (15:1 to 5:1) as eluting solvents to give methyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (15 g, 97% yield). LCMS (ESI): m/z=311.0 [M+H]+.

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 449 - 451
[2]Patent: US2015/31674,2015,A1 .Location in patent: Paragraph 0357
[3]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1241 - 1246

11
[ 5315-25-3 ]
[ 849934-95-8 ]
methyl-2-[2-chloro-4-(6-methylpyridin-2-yl)phenyl]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
252 g	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; at 85.0℃;Inert atmosphere;	step 5: A 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with the solution from Step 4, sodium carbonate (2N, 1178 mL), 2-bromo-6-methylpyridine (202 g, 1.17 mol, 1.00 equiv), and Pd(PPh3)4 (15 g, 12.98 mmol, 0.01 equiv). The resulting solution was stirred at 85 C. overnight. The reaction was repeated. The combined reaction mixtures were cooled to RT, filtered, and diluted with water (5 L). The resulting solution was extracted with EtOAc (3×5 L). The combined organic layers were washed with brine (1×3 L), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified using by SiO2 chromatography eluting with EtOAc/PE (1:50) to afford 252 g (39%) of methyl 2-[2-chloro-4-(6-methylpyridin-2-yl)phenyl]acetate as yellow oil. (ES, m/z): [M+H+]=276. 1H-NMR (CDCl3): delta 8.08 (s, 1H), 7.87-7.84 (dd, J=6.0 Hz, 1H), 7.68-7.63 (t, J=7.8 Hz, 1H), 7.52-7.49 (d, J=1.8 Hz, 1H), 7.40-7.38 (d, J=7.8 Hz, 1H), 7.15-7.12 (d, J=7.5 Hz, 1H), 3.85 (s, 2H), 3.74 (s, 3H), 2.64 (s, 3H).

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1241 - 1246
[2]Patent: US2015/31674,2015,A1 .Location in patent: Paragraph 0345; 0340

12
[ 849934-95-8 ]
6-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)-8-(2-(piperazin-1-yl-sulfonyl)ethyl)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]

Reference： [1]Patent: US2015/31674,2015,A1

13
[ 849934-95-8 ]
methyl-2-(2-ethyl-4-(6-methylpyridin-2-yl)phenyl)acetate [ No CAS ]

Reference： [1]Patent: US2015/31674,2015,A1

14
[ 849934-95-8 ]
tert-butyl-(2s,5s)-2-(2-(6-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)-1,3-dioxan-5-yl-carbamate [ No CAS ]

Reference： [1]Patent: US2015/31674,2015,A1

15
[ 849934-95-8 ]
tert-butyl (1R,4R)-4-((6-(2-chloro-4-(5-methylpyridazin-3-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)cyclohexylcarbamate [ No CAS ]

Reference： [1]Patent: US2015/31674,2015,A1

16
[ 849934-95-8 ]
[ 298694-30-1 ]
methyl-2-(2-chloro-4-(2-methylthiazol-4-yl)phenyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; at 100℃;	Methyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzeneacetate [CASRN 849934-95-8] was coupled with <strong>[298694-30-1]4-bromo-2-methyl-thiazole</strong> (Pd(dppf)Cl2 K2CO3, 100 C.) to afford methyl 2-(2-chloro-4-(2-methylthiazol-4-yl)phenyl)acetate which was cyclized with 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde to afford 6-(2-chloro-4-(2-methylthiazol-4-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one. Alkylation of the lactam nitrogen with 2-(2-(bromomethyl)-1,3-dioxan-5-yl)isoindoline-1,3-dione afforded 2-((2r,5r)-2-((6-(2-chloro-4-(2-methylthiazol-4-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)-1,3-dioxan-5-yl)isoindoline-1,3-dione. Introduction of the methylamine and removal of the phthalimide group were accomplished by standard protocols. 1H NMR (400 MHz, DMSO-d6) delta 8.63 (s, 1H), 8.13 (s, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.95 (dd, J=1.6, 8.0 Hz, 1H), 7.83 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 4.99-4.90 (m, 1H), 4.47-4.42 (m, 2H), 3.93-3.89 (m, 2H), 3.31 (s, 3H), 3.11 (t, J=2.8 Hz, 2H), 2.91 (d, J=4.8 Hz, 3H), 2.81-2.76 (m, 1H), 2.74 (s, 3H); MS [M+H]+=499.1

Reference： [1]Patent: US2015/31674,2015,A1 .Location in patent: Paragraph 0603

17
[ 849934-95-8 ]
6-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1241 - 1246

18
[ 849934-95-8 ]
2-(2-((6-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)-1,3-dioxan-5-yl)isoindoline-1,3-dione [ No CAS ]
2-((2-((6-(2-chloro-4-(6-methylpyridin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)-1,3-dioxan-5-yl)carbamoyl)benzoic acid [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1241 - 1246

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[ 849934-95-8 ]
[ 1433193-87-3 ]