[ CAS No. 736990-02-6 ] {[proInfo.proName]}

Name: 736990-02-6|Ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate|97%
Brand: Ambeed
SKU: A297577
Price: 15.0 USD
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Quality Control of [ 736990-02-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 736990-02-6 ]

SDS Specification

Alternatived Products of [ 736990-02-6 ]

Product Details of [ 736990-02-6 ]

CAS No. :	736990-02-6	MDL No. :	MFCD11894323
Formula :	C₁₇H₂₂BNO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BFNARGGMOBETDJ-UHFFFAOYSA-N
M.W :	315.17	Pubchem ID :	21111505
Synonyms :

Calculated chemistry of [ 736990-02-6 ]

Physicochemical Properties

Num. heavy atoms :	23
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.47
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	90.86
TPSA :	60.55 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.67 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	3.59
Log Po/w (WLOGP) :	2.64
Log Po/w (MLOGP) :	1.56
Log Po/w (SILICOS-IT) :	2.75
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) :	-4.08
Solubility :	0.0261 mg/ml ; 0.0000829 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.55
Solubility :	0.00892 mg/ml ; 0.0000283 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.34
Solubility :	0.00142 mg/ml ; 0.00000452 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.05

Safety of [ 736990-02-6 ]

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 [ 736990-02-6 ]

* 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 [ 736990-02-6 ]
Downstream synthetic route of [ 736990-02-6 ]

[ 736990-02-6 ] Synthesis Path-Upstream 1~3

1
[ 16732-70-0 ]
[ 73183-34-3 ]
[ 736990-02-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium acetate In 1,4-dioxane at 80℃; for 3 h;	PdaCdba)^ (275 mg, 0.30 mmol) and tricyclohexylphosphine (504 mg, 1.80 mmol) in dioxane (30 roL) were added under argon to a stirred mixture of 5-bromoindole- 2-carboxylic acid ethyl ester (6.0 g, 22.4 mmol), KOAc (3.3 g, 33.6 mmol), bis(pinacolato)diboron (6.3 g, 24.6 mmol) and dioxane (20 mL) at 80 ⁰C. The mixture was stirred at 80 ⁰C for 3 h, cooled to rt and filtered through Celite^.(R).. The solids were washed with EtOAc and the combined filtrates were concentrated and purified by chromatography to yield the sub-title compound (6.8 g, 97percent).
97%	With potassium acetate In 1,4-dioxane at 80℃; for 3 h;	Pd(at) (dba)3 (275 mg, 0.30 mmol) and tricyclohexylphospliine (504 mg, 1.80 mmol) in dioxane (30 mL) were added under argon to a stirred mixture of 5- bromo-lH-indole-2-carboxylic acid ethyl ester (6.0 g, 22.4 mmol), KOAc (3.3 g, 33.6 mmol), bis(pinacolato)diboron (6.3 g, 24.6 mmol) and dioxane (20 mL) at 80°C. The resulting mixture was stirred at 80°C for 3 h, cooled to room temperature and filtered through a Celite pad. The filter cake was washed with EtOAc and the combined filtrates were concentrated and purified by chromatography to yield the sub-title compound (6.8 g, 97percent).
46%	With potassium acetate In 1,4-dioxane at 80℃; for 18 h;	A mixture prepared from Pd2(dba)3 (0.229 g, 0.25 mmol), tricyclohexylphosphine (0.421 g, 1.5 mmol) and dioxane (25 mL) was added under argon to a stirred mixture of 5-bromoindole-2-carboxylic acid ethyl ester (1.94 g, 7.2 mmol), KOAc (1.10 g, 11 mmol), bis (pinacolato)diboron (2.00 g, 7.9 mmol) and dioxane (25 mL) at 80 °C. After 2 h at 80°C another portion (16 mL) of the mixture prepared from Pd2 (dba)3, tricyclohexylphosphine and dioxane, as described herein, was added and the resulting mixture stirred at 80 °C for 16 h. The mixture was allowed to cool and filtered through Celite°. The filter cake was washed with EtOAc and the combined filtrates were concentrated and purified by. chromatography to yield the sub-title compound (1.10 g, 46percent).

Reference： [1] Patent: WO2006/77367, 2006, A1, . Location in patent: Page/Page column 101
[2] Patent: WO2005/123674, 2005, A1, . Location in patent: Page/Page column 58
[3] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8267 - 8276
[4] Patent: WO2005/123673, 2005, A1, . Location in patent: Page/Page column 50
[5] Patent: WO2004/76412, 2004, A2, . Location in patent: Page 101-102
[6] Journal of Medicinal Chemistry, 2011, vol. 54, # 23, p. 8174 - 8187
[7] Patent: EP2722329, 2014, A1, . Location in patent: Paragraph 0170

2
[ 7254-19-5 ]
[ 73183-34-3 ]
[ 736990-02-6 ]

Reference： [1] Patent: WO2014/60386, 2014, A1, . Location in patent: Page/Page column 44

3
[ 7254-19-5 ]
[ 736990-02-6 ]

Reference： [1] Patent: EP2722329, 2014, A1,

[ 736990-02-6 ] Synthesis Path-Downstream 1~36

1
[ 16732-70-0 ]
[ 73183-34-3 ]
[ 736990-02-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; at 80.0℃; for 3.0h;	PdaCdba)^ (275 mg, 0.30 mmol) and tricyclohexylphosphine (504 mg, 1.80 mmol) in dioxane (30 roL) were added under argon to a stirred mixture of 5-bromoindole- 2-carboxylic acid ethyl ester (6.0 g, 22.4 mmol), KOAc (3.3 g, 33.6 mmol), bis(pinacolato)diboron (6.3 g, 24.6 mmol) and dioxane (20 mL) at 80 0C. The mixture was stirred at 80 0C for 3 h, cooled to rt and filtered through Celite. The solids were washed with EtOAc and the combined filtrates were concentrated and purified by chromatography to yield the sub-title compound (6.8 g, 97%).
97%	With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; at 80.0℃; for 3.0h;	Pd(at) (dba)3 (275 mg, 0.30 mmol) and tricyclohexylphospliine (504 mg, 1.80 mmol) in dioxane (30 mL) were added under argon to a stirred mixture of 5- bromo-lH-indole-2-carboxylic acid ethyl ester (6.0 g, 22.4 mmol), KOAc (3.3 g, 33.6 mmol), bis(pinacolato)diboron (6.3 g, 24.6 mmol) and dioxane (20 mL) at 80C. The resulting mixture was stirred at 80C for 3 h, cooled to room temperature and filtered through a Celite pad. The filter cake was washed with EtOAc and the combined filtrates were concentrated and purified by chromatography to yield the sub-title compound (6.8 g, 97%).
46%	With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; at 80.0℃; for 18.0h;	A mixture prepared from Pd2(dba)3 (0.229 g, 0.25 mmol), tricyclohexylphosphine (0.421 g, 1.5 mmol) and dioxane (25 mL) was added under argon to a stirred mixture of 5-bromoindole-2-carboxylic acid ethyl ester (1.94 g, 7.2 mmol), KOAc (1.10 g, 11 mmol), bis (pinacolato)diboron (2.00 g, 7.9 mmol) and dioxane (25 mL) at 80 C. After 2 h at 80C another portion (16 mL) of the mixture prepared from Pd2 (dba)3, tricyclohexylphosphine and dioxane, as described herein, was added and the resulting mixture stirred at 80 C for 16 h. The mixture was allowed to cool and filtered through Celite. The filter cake was washed with EtOAc and the combined filtrates were concentrated and purified by. chromatography to yield the sub-title compound (1.10 g, 46%).

	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80.0℃;	To a stirred solution of ethyl 5-bromo-1H-indole-2-carboxylate (5g, 18. 6MMOL) in DMSO (75mL, 0. 25M), 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi-1, 3, 2-dioxaborolane (11.2g, 44. 3MMOL), potassium acetate (5. 5G, 56. 0 MMOL), and [bis (diphenylphosphino) ferrocene] dichloropalladium 11 (1. 23MMOL) were added. The mixture was de-gassed and charged with nitrogen for three times, and then heated at 80 C under nitrogen for overnight. The reaction was cooled to ambient temperature and diluted with ethyl acetate (2X100ML). The mixture was washed with water (1X50 mL), brine (1X50ML), dried over MGS04, and purified on a silica gel column to afford ethyl 5- (4, 4, 5, 5-TETRAMETHYL-1, 3, 2-dioxaborolan-2-yl)-1H- indole-2-carboxylate as an off-white SOLID. 1H NMR (400 MHz, DMSO-D6) 6 1. 31 (t, 3H), 4. 32 (m, 2H), 7. 18 (s, 1H), 7. 42 (d, 1H), 7. 54 (d, 1H), 8. 05 (s, 1H), 11. 96 (s, 1H) ; MS m/z 315 (M+1).
	With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In 1,4-dioxane; ethyl acetate; for 17.0h;Reflux; Inert atmosphere;	Potassium acetate (2.57 g; 26.2 mmol) was dried under high vacuum at 50C in the reaction flask over 2 hours. 5-Bromo-1H-indole-2-carboxylic acid ethyl ester (2.34 g; 8.75 mmol) was dissolved in degassed dioxane (100 mL) and added to the reaction flask, followed by bis(pinacolato)diboron and bis(triphenylphosphine)palladium (II) chloride, (0.30 g; 0.44 mmol). The reaction mixture was heated to reflux under a nitrogen atmosphere and stirred for 17 hours. The reaction mixture was cooled to 50C. 4-Iodopyridine (3.58 g; 1.75 mmol) was added to the reaction portion wise, followed by bis(triphenylphosphine)palladium (II) chloride (0.30 g; 0.44 mmol) and 2 M aqueous sodium carbonate solution (23 mL). The reaction was returned to reflux and stirred for 24 hours. Following complete consumption of the intermediate, the reaction was cooled to room temperature and the solvent was removed in vacuo. The crude reaction mixture was re-dissolved in ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration with ethyl acetate / heptane afforded the title compound (1.35 g, 59 %). 1H NMR (400MHz, DMSO): delta (ppm) = 1.35 (3H, t, J = 7.09 Hz), 4.36 (2H, q, J = 7.09 MHz), 7.24 (1H, s), 7.58 (1H, d, J= 8.56 Hz), 7.70-7.73 (3H, m), 8.14 (1H, s), 8.60 (2H, d, J= 5.87 Hz), 12.08 (1H, s). HPLC-MS (purity); retention time = 89%; 1.28min. MS ISP (m/e): 267.2 (100) [(M+H)+].

Reference： [1]Patent: WO2006/77367,2006,A1 .Location in patent: Page/Page column 101
[2]Patent: WO2005/123674,2005,A1 .Location in patent: Page/Page column 58
[3]Journal of the American Chemical Society,2017,vol. 139,p. 8267 - 8276
[4]Patent: WO2005/123673,2005,A1 .Location in patent: Page/Page column 50
[5]Patent: WO2004/76412,2004,A2 .Location in patent: Page 101-102
[6]Journal of Medicinal Chemistry,2011,vol. 54,p. 8174 - 8187
[7]Patent: EP2722329,2014,A1 .Location in patent: Paragraph 0170

2
[ 736990-02-6 ]
[ 50488-42-1 ]
[ 871829-38-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80.0℃; for 24.0h;	A stirred mixture of 5-(4,4,5,5-tetramethyl-[l,3,2]dioxaboiOlan-2-yl)rndole-2- carboxylic acid ethyl ester (3.00 g, 9.52 mmol; see step (a) above), 2-bromo-5- trifluoromethylpyridine (3.23 g5 14.28 mmol), Na2CO3 (aq, 2 M, 14.3 mL, 28.6 mmol), Pd(PPh3)4 (540 mg, 0.50 mmol), EtOH (10 mL) and toluene (40 mL) was heated at 80 C for 24 h. The mixture was cooled to rt, poured into water and extracted with EtOAc. The combined extracts were washed with water, brine, dried (Na2SO4), concentrated and purified by chromatography yielding the subtitle compound (3.0 g, 94%).
94%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80.0℃; for 24.0h;	A stirred mixture of 5-(4,4,5,5-tetramethyl[1,3,2]dloxaborolan-2-yl)-lH- indole-2-carboxylic acid ethyl ester (3.00 g, 9.52 mmol; see step (a) above), 2-bromo-5-(trifluoromethyl)pyridine (3.23 g, 14.28 mmol), sodium carbonate (2M, 14.30 mL, 28.56 mmol); Pd(PPh3)4 (540 mg, 0.50 mmol), EtOH (10 mL) and toluene (40 mL) were heated at 80C for 24 h. The mixture was cooled to room temperature, poured into water and extracted with EtOAc. The combined extracts were washed with water, brine and dried (Na(at)S04). Solvent removal and purification by chromatography gave the sub-title compound (3.0 g, 94%).
77%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80.0℃; for 18.0h;	A stirred mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indole- 2-carboxylic acid ethyl ester (300 mg, 0.95 mmol; see step (a) ), 2-bromo-5- (trifluoromethyl) pyridine (323 mg, 1.43 mmol), sodium carbonate (2M, 1.43 mL, 2.85 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol), EtOH (5 mL) and toluene(20 mL) was heated at 80C for 2 h. Another portion of Pd(PPh3)4 (54 mg, 0.05 mmol) was added and the heating continued for 16 h. The mixture was diluted with EtOAc, washed with brine, dried over MgS04, concentrated and purified by chromatography to give the sub-title compound (247 mg, 77%).

Reference： [1]Patent: WO2006/77367,2006,A1 .Location in patent: Page/Page column 101
[2]Patent: WO2005/123674,2005,A1 .Location in patent: Page/Page column 58-59
[3]Patent: WO2005/123673,2005,A1 .Location in patent: Page/Page column 50-51

Yield	Reaction Conditions	Operation in experiment
		Step 1 Preparation of 5-(4,4,5,5,-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (Intermediate BB) To a 50 mL round bottom flask, (500 mg 1.86 mmol) of AA, (567 mg 2.232 mmol) of the boronic ester, and (68.8 mg, 0.093 mmol) of (dppf)PdCl2 and (275 mg, 2.79 mmol) of potassium acetate were added. DMF (25 mL) was then added followed by DMSO (1 mL) and the solution was then flushed with nitrogen and heated at 80 C. for 24 h. The crude mixture was then concentrated under vacuum to provide a brown residue. The resulting residue was then purified by column chromatography (silica gel, 95:5 hexanes/EtOAc) and isolated as a white solid BB (304 mg, 0.967 mmol, 52%).

4
[ 109-04-6 ]
[ 736990-02-6 ]
[ 121217-69-4 ]