[ CAS No. 852227-90-8 ] {[proInfo.proName]}

Name: 852227-90-8|1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine|95%
Brand: Ambeed
SKU: A195241
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Quality Control of [ 852227-90-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 852227-90-8 ]

SDS Specification

Alternatived Products of [ 852227-90-8 ]

Product Details of [ 852227-90-8 ]

CAS No. :	852227-90-8	MDL No. :	MFCD08060504
Formula :	C₁₆H₂₄BNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DWJNNJSONWFVBT-UHFFFAOYSA-N
M.W :	273.18	Pubchem ID :	18525715
Synonyms :

Calculated chemistry of [ 852227-90-8 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.62
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	87.56
TPSA :	21.7 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.47 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	3.52
Log Po/w (WLOGP) :	2.21
Log Po/w (MLOGP) :	2.17
Log Po/w (SILICOS-IT) :	2.21
Consensus Log Po/w :	2.02

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.84
Solubility :	0.0394 mg/ml ; 0.000144 mol/l
Class :	Soluble
Log S (Ali) :	-3.66
Solubility :	0.0598 mg/ml ; 0.000219 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.44
Solubility :	0.0099 mg/ml ; 0.0000362 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.87

Safety of [ 852227-90-8 ]

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

Application In Synthesis of [ 852227-90-8 ]

* 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 [ 852227-90-8 ]
Downstream synthetic route of [ 852227-90-8 ]

[ 852227-90-8 ] Synthesis Path-Upstream 1~6

1
[ 22090-26-2 ]
[ 73183-34-3 ]
[ 852227-90-8 ]

Yield	Reaction Conditions	Operation in experiment
66%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxaneReflux; Inert atmosphere	An argon-purged 1,4-dioxane (30 mL) wasadded to a flask containing bromophenylpyrrolidine 5b (722mg, 3.19mmol), (BPin)2 (= bis(pinacolato)diboron (1.21 g,4.78mmol), AcOK (939 mg, 9.56mmol), and PdCl2(dppf )(dppf = 1,1-bis(diphenylphosphino)ferrocene, 79 mg, 0.097mmol) and the mixture was refluxed under argon for 14 h.The reaction mixture was extracted with hexane, which wasdried over Na2SO4 and evaporated. The obtained residuewas chromatographed (SiO2, hexane/AcOEt = 17:3) to affordblack-red needles (575 mg, 2.10mmol, 66percent). TLC (SiO2,CHCl3): R_f = 0.60. ¹H NMR (CDCl3): δ (ppm) = 1.32 (12H,s), 1.92.1(4H, m), 3.23.4(4H, m), 6.53 (2H, dd, J = 6.5,1.8 Hz), 7.67 (2H, dd, J = 6.5, 1.8 Hz). APCI-MS (CHCl3):m/z calcd for C16H25BNO2 ([MH]⁺), 274.1973; found,274.2256

Reference： [1] Bulletin of the Chemical Society of Japan, 2018, vol. 91, # 10, p. 1506 - 1514

2
[ 76-09-5 ]
[ 852227-90-8 ]

Reference： [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 13, p. 3712 - 3717[2] Angew. Chem., 2017, vol. 129, p. 3766 - 3771,6
[3] Heterocycles, 2017, vol. 95, # 1, p. 158 - 166

3
[ 4280-34-6 ]
[ 25015-63-8 ]
[ 852227-90-8 ]

Reference： [1] Organic Letters, 2018,

4
[ 123-75-1 ]
[ 73852-88-7 ]
[ 852227-90-8 ]

Reference： [1] ChemCatChem, 2016, vol. 8, # 7, p. 1319 - 1328

5
[ 54660-08-1 ]
[ 25015-63-8 ]
[ 852227-90-8 ]

Reference： [1] Organic Letters, 2018,

6
[ 4096-21-3 ]
[ 852227-90-8 ]

[ 852227-90-8 ] Synthesis Path-Downstream 1~28

1
[ 852227-90-8 ]
[ 1219741-39-5 ]
[ 1219741-74-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; N,N-dimethyl-formamide;tetrakis(triphenylphosphine) palladium(0); In water; at 150℃; for 0.166667h;Microwave irradiarion;	Step A 5-[(6-chloro-5-(4-pyrrolidin-1-ylphenyl)-1-[2-trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoic acid. K2CO3 (2 M in water) (0.215 mL, 0.429 mmol) followed by Pd(PPh3)4 (4.96 mg, 4.29 mumol) were added to a solution of <strong>[852227-90-8]1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine</strong> (45.0 mg, 0.165 mmol, Maybridge) and Intermediate 11A (80 mg, 0.143 mmol) in DMF (2 mL). The reaction was heated at 150 C. under microwave irradiation for 10 min. Volatiles were removed to afford the desired product which was used in the next step without further purification. LC-MS: calculated for C29H34ClN5O4Si 577.22, observed m/e 578.06 (M+H)+ (Rt 2.41 min).

Reference： [1]Patent: US2010/81643,2010,A1 .Location in patent: Page/Page column 101-102

Yield	Reaction Conditions	Operation in experiment
57%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;	General procedure: Step 34b: N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (Compound 0602-107)[0334]To a solution of compound 0601-107 (2.5 g, 11.6 mmol) and bis(pinacolato)diboron (4.4 g, 17.5 mmol) in dioxane (100 mL) was added potassium acetate (3.4 g, 35 mmol) and PdCl2(dppf)2 (0.95 g, 1.1 mmol). The mixture was degassed with nitrogen and heated at 85 C. for overnight. The reaction mixture was concentrated under reduced pressure to afford the crude product, which purified by column chromatography (ethyl acetate in petroleum ether, 15% v/v) to give the compound 0602-107 (1.55 g, 51%) as a pink solid. LCMS: 262 [M+1]+. 1H NMR (400 MHz, DMSO-d6) delta 1.29 (s, 12H), 2.03 (s, 3H), 7.30 (s, 1H), 7.31 (d, J=2.0 Hz 1H), 7.73 (d, J=2.0 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 9.93 (s, 1H).
57%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;	General procedure: Compound in dioxane (100mL) 0601-107 (2.5g, 11.6mmol) and a solution of bis (pinacolato) diboron (4.4 g, 17.5 mmol), potassium acetate (3.4 g, 35 mmol) and and PdCl2 (dppf) 2 ( 0.95g, 1.1mmol) was added. The mixture was degassed with nitrogen and heated overnight at 85 C.. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether in ethyl acetate, 15% v / v) to give the compound 0602-107 as a pink solid obtained (1.55 g, 51%).

3
[ 852227-90-8 ]
[ 1364719-83-4 ]
[ 1364719-91-4 ]

Yield	Reaction Conditions	Operation in experiment
44%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In ethanol; water; at 130℃; for 0.5h;Microwave irradiation;	Example 13 To a solution of Compound 41 (400 mg, 1.72 mmol) in ethanol (3 ml) were added <strong>[852227-90-8]1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine</strong> (565 mg, 2.07 mmol), PdCl2(PPh3)2 (85 mg, 0.121 mmol) and 2 M K2CO3 aq. (2.15 ml, 4.31 mmol), and the reaction mixture was stirred under microwave irradiation at 130 C. for 30 minutes. The reaction solution was diluted in ethyl acetate (300 ml), and the mixture was then stirred at 40 C. for one hour. Insoluble matter was filtered with Celite, followed by washing with brine and drying over sodium sulfate. The solvent was removed under reduced pressure. The concentrated residue was stirred in a mixed solvent of ethyl acetate (10 ml) and chloroform (10 ml) for 30 minutes, and then filtered to obtain Compound 42 (225 mg, 44%) as a brown solid. [0722] Compound 42; 1H-NMR (DMSO-d6) delta: 1.97 (t, J=6.34 Hz, 4H), 3.28 (t, J=6.34 Hz, 4H), 6.61 (d, J=9.12 Hz, 2H), 7.24 (d, J=11.66 Hz, 1H), 7.68 (d, J=7.60 Hz, 2H), 10.94 (s, 1H), 11.33 (s, 1H).

Reference： [1]Patent: US2013/184240,2013,A1 .Location in patent: Paragraph 0710; 0721; 0722

4
[ 852227-90-8 ]
[ 1364719-99-2 ]

Reference： [1]Patent: US2013/184240,2013,A1

5
[ 852227-90-8 ]
[ 1364720-08-0 ]
[ 1364720-16-0 ]

Reference： [1]Patent: US2013/184240,2013,A1

6
[ 852227-90-8 ]
[ 1364720-30-8 ]

Reference： [1]Patent: US2013/184240,2013,A1

7
[ 852227-90-8 ]
[ 1364680-69-2 ]

Reference： [1]Patent: US2013/184240,2013,A1

8
[ 852227-90-8 ]
[ 1569805-77-1 ]
[ 1569803-64-0 ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; at 80℃; for 3h;Inert atmosphere;	1-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyrrolidine (48.3 mg, 0.177 mmol) and (2R,3S,5R)-5-((6-chloro-5-iodo-lH- benzo[d]imidazol-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol (75 mg, 0.177 mmol) were dissolved in dioxane (600 mu) and water (600 mu) and sparged with 2 for 15 min. Then [l, -Bis(Diphenylphosphino)Ferrocene]Dichloropalladium (II) (25.8 mg, 0.035 mmol) was added and the reaction was stirred 3h at 80 C, followed by dilution with water and EtOAc. The aqueous phase was separate, extracted with EtOAc (x2) and the combined extracts were washed with brine, dried over Na2S04, filtered and concentrated. The resulting residue was purified by mass directed reverse phase HPLC eluted with acetonitrile in water containing 0.05% TFA. The desired fractions were combined, diluted with EtOAc and washed with aHC03. The aqueous phase was extracted with EtOAc (x2) and the combined extracts were washed with brine, dried over Na2S04, filtered and concentrated. The resulting residue was lyophilized from MeCN/water to give the title compound as a white solid. LC-MS: calculated for C23H26C1 304 443.16 observed m/e: 443.89 (M+H)+ (Rt 1.52 / 4 min); 'H NMR delta (ppm) (CD3OD): 7.39 (s, 1H), 7.25-7.22 (m, 3H), 6.61 (d, 2H), 5.00 (septet, 1H), 4.32-4.29 (m, 1H), 3.88 (dd, 1H), 3.66- 3.58 (m, 2H), 3.36-3.30 (m, 5H), 3.17-3.14 (m, 1H), 2.73-2.70 (m, 1H), 2.07-2.01 (m, 4H), 1.65 (q, 1H).

Reference： [1]Patent: WO2014/31445,2014,A1 .Location in patent: Page/Page column 82; 83

9
[ 852227-90-8 ]
methyl 5-((5-bromo-6-chloro-1H-indol-2-yl)methyl)-2-methylbenzoate [ No CAS ]
methyl 5-((6-chloro-5-(4-(pyrrolidin-1-yl)phenyl)-1H-indol-2-yl)methyl)-2-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; at 80℃;Inert atmosphere;	Methyl 5 -((5 -bromo-6-chloro- 1 H-indol-2-yl)methyl)-2-methylbenzoate (95 mg, 0.242 mmol), 1- [4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenyl]pyrrolidine (72.7 mg, 0.266 mmol) and Pd(Ph3P)4 (7.0 mg, 6.05 jimol) were mixed in a microwave vial, which was evacuated and charged with nitrogen. Then DME (1.9 mL) and 2N Na2CO3 (272 tl, 0.544 mmol) were added. The reaction was stirred at 80C in an oil bath for 3.5 hours.Then additional Pd(PPh3)4 (7 mg) was added and the reaction was stirred overnight. The reaction mixture was then partitioned between ethyl acetate and water. The aqueous layer was separated and extracted again with ethyl acetate. The organic layers were combined, and washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified on a Biotage 25S silica gel column, eluting with a gradient of 40-90%dichloromethane in hexanes to give the title compound. LC-MS: calculated for C28H27C1N202 458.18, observed mle: 459.31 (M+H) (Rt 2.45/4 mm).

Reference： [1]Patent: WO2014/139388,2014,A1 .Location in patent: Page/Page column 127; 128

10
[ 852227-90-8 ]
methyl 5-((5-bromo-6-chloro-1H-indol-2-yl)methoxy)-2-methylbenzoate [ No CAS ]
methyl 5-((6-chloro-5-(4-(pyrrolidin-1-yl)phenyl)-1H-indol-2-yl)methoxy)-2-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80 - 90℃; for 6h;Inert atmosphere;	Intermediate 7 (98 mg, 0.240 mmol) and 1-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine (79 mg, 0.288 mmol) were dissolved in DME (1.2 mL), and the reaction vessel was evacuated and charged with nitrogen. Then Pd(Ph3P)4 (13.9 mg, 0.0 12 mmol) and 2N aqueous Na2CO3 (264 tl, 0.528 mmol) were added. The reaction was stirred at 80 C for 4 hours, then additional Pd(PPh3)4 (13.8 mg) was added and the reaction was stirred at 90C for 2 hours. Once the reaction was complete it was cooled toroom temperature and partitoned between water and ethyl acetate. The organic layer wasseparated, washed with water, and brine, dried over sodium sulfate, filtered and evaporated.The crude product was purified on a Biotage 25 S silica gel column, eluting with a gradient of40-90% dichloromethane in hexanes to give the title compound. NMR oe (ppm)(CDC13):8.31 (br s, 1H), 7.57 (d, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.34 (d, 2H), 7.16 (d, 1H), 7.04 (dd,1H), 6.62 (d, 2H), 6.51 (s, 1H), 5.22 (s, 2H), 3.90 (s, 3H), 3.34 (m, 4H), 2.52 (s, 3H), 2.02 (m, 4H).

Reference： [1]Patent: WO2014/139388,2014,A1 .Location in patent: Page/Page column 138; 139; 140

11
[ 852227-90-8 ]
[(3R,3aR,6R,6aS)-3-(1-allyl-6-chloro-5-iodoimidazo[4,5-b]pyridin-2-yl)oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethylsilane [ No CAS ]
[(3R,3aR,6R,6aS)-3-[1-allyl-6-chloro-5-(4-pyrrolidin-1-ylphenyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethylsilane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 15h;Inert atmosphere;	1,1?-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichlormethane complex (17.1 mg, 0.021 mmol) was added to a stirred suspension of [(3R,3aR,6R,6aS)-3-(1-allyl-6-chloro-5-iodo-imidazo[4,5-b]pyridin-2-yl)oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (99.8 mg, 0.173 mmol), <strong>[852227-90-8]1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine</strong> (59.6 mg, 0.218 mmol), and tripotassium phosphate (225.0 mg, 1.060 mmol) in dioxane (1.38 ml) and water (0.35 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80 C. After 15 hours, the reaction mixture was cooled to room temperature. The reaction mixture was partitioned between EtOAc (40 ml) and water (40 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure to give an amber residue. This residue was dissolved in DCM, loaded onto a 5 g silica solid load cartridge and purified using an ISCO Rf and a 4 g silica column (CV=4.8 ml). The column was eluted as follows: 100% hexane (5 CV), 0-30% EtOAc/hexane gradient (70 CV), 30% EtOAc/hexane (21 CV) at 18 ml/min. The product fractions were combined and evaporated under reduced pressure to give the title compound as a yellow residue. LC-MS: calculated for C31H41ClN4O4Si 596.26 observed m/e: 597.39 (M+H)+ (Rt 1.34/2 min).

Reference： [1]Patent: US2015/284411,2015,A1 .Location in patent: Paragraph 0636; 0637

12
[ 123-75-1 ]
[ 73852-88-7 ]
[ 852227-90-8 ]

Reference： [1]ChemCatChem,2016,vol. 8,p. 1319 - 1328

13
[ 852227-90-8 ]
3-(5-[6-(4-pyrrolidin-1-yl-phenyl)-9-(2-ethylhexyl)-9H-carbazol-3-yl]-thiophene-2-yl)-2-cyano-acrylic acid [ No CAS ]