[ CAS No. 361437-00-5 ] {[proInfo.proName]}

Name: 361437-00-5|(4-(4-Fluorophenoxy)phenyl)boronic acid|95%
Brand: Ambeed
SKU: A409889
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Quality Control of [ 361437-00-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 361437-00-5 ]

Product Details of [ 361437-00-5 ]

CAS No. :	361437-00-5	MDL No. :	MFCD13182406
Formula :	C₁₂H₁₀BFO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BXLDWIUCAAJXIZ-UHFFFAOYSA-N
M.W :	232.02	Pubchem ID :	21957375
Synonyms :

Calculated chemistry of [ 361437-00-5 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.0
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	62.74
TPSA :	49.69 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.97 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.46
Log Po/w (WLOGP) :	1.72
Log Po/w (MLOGP) :	1.94
Log Po/w (SILICOS-IT) :	0.83
Consensus Log Po/w :	1.39

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.15
Solubility :	0.163 mg/ml ; 0.000704 mol/l
Class :	Soluble
Log S (Ali) :	-3.15
Solubility :	0.165 mg/ml ; 0.000712 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.83
Solubility :	0.0342 mg/ml ; 0.000147 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.25

Safety of [ 361437-00-5 ]

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 [ 361437-00-5 ]

* 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.

Downstream synthetic route of [ 361437-00-5 ]

[ 361437-00-5 ] Synthesis Path-Downstream 1~40

1
[ 361437-00-5 ]
[ 287476-37-3 ]
[ 1027188-57-3 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In toluene for 1h; Heating;

Reference： [1]Robinson, Ralph P.; Laird, Ellen R.; Blake, James F.; Bordner, Jon; Donahue, Kathleen M.; Lopresti-Morrow, Lori L.; Mitchell, Peter G.; Reese, Matthew R.; Reeves, Lisa M.; Stam, Ethan J.; Yocum, Sue A. [Journal of Medicinal Chemistry, 2000, vol. 43, # 12, p. 2293 - 2296]

2
[ 100859-84-5 ]
[ 361437-00-5 ]
2-[4-(4-fluorophenoxy)phenyl]pyridine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,2-dimethoxyethane at 85℃;

Reference： [1]Shao, Bin; Victory, Sam; Ilyin, Victor I.; Goehring, R. Richard; Sun, Qun; Hogenkamp, Derk; Hodges, Diane D.; Islam, Khondaker; Sha, Deyou; Zhang, Chongwu; Nguyen, Phong; Robledo, Silvia; Sakellaropoulos, George; Carter, Richard B. [Journal of Medicinal Chemistry, 2004, vol. 47, # 17, p. 4277 - 4285]

3
[ 6271-78-9 ]
[ 361437-00-5 ]
6-[4-(4-fluoro-phenoxy)-phenyl]-nicotinamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 4277 - 4285

4
[ 10366-35-5 ]
[ 361437-00-5 ]
2-[4-(4-fluorophenoxy)phenyl]pyridine-3-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 4277 - 4285

5
[ 361437-00-5 ]
[ 25194-52-9 ]
6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 4277 - 4285

6
[ 361437-00-5 ]
[ 501690-40-0 ]
2-[4-(4-fluorophenoxy)phenyl]pyridine 5-carboxylic acid 2-(N-piperidinyl)ethylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With bis(triphenylphosphine)palladium⁽⁰⁾; potassium carbonate In 1,2-dimethoxyethane at 85℃;
	With potassium carbonate In 1,2-dimethoxyethane; water	1.b 2-[4-(4-Fluorophenoxy)phenyl]pyridine 5-carboxylic acid 2-(N-piperidinyl)ethylamide (3) b) 2-[4-(4-Fluorophenoxy)phenyl]pyridine 5-carboxylic acid 2-(N-piperidinyl)ethylamide (3): To a solution of compound 2 (536 mg, 2.0 mmol) in 1,2-dimethoxyethane (6 mL) was added 4-(4-fluorophenoxy)phenyl boronic acid (557 mg, 2.4 mmol), followed by water (2 mL) and potassium carbonate (746 mg, 5.4 mmol). Pd(PPh3)4 (92 mg, 0.08 mmol) was added to this mixture and the reaction mixture was heated at 85° C. for 16 hours under an argon atmosphere. The reaction mixture was allowed to return to ambient temperature, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate. The solution was filtered, concentrated, and then filtered over a bed of florisil to give crude compound 3.

7
[ 361437-00-5 ]
5-bromo-N-(2-piperidin-1-yl-ethyl)nicotinamide [ No CAS ]
5-[4-(4-fluorophenoxy)phenyl]pyridine 3-carboxylic acid 2-(N-piperidinyl)ethylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With bis(triphenylphosphine)palladium⁽⁰⁾; potassium carbonate In 1,2-dimethoxyethane at 85℃;

8
[ 361437-00-5 ]
6-bromo-pyridine-2-carboxylic acid (2-piperidin-1-yl-ethyl)amide [ No CAS ]
6-(4-(4-fluorophenoxy)phenyl)-N-(2-(piperidin-1-yl)ethyl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With bis(triphenylphosphine)palladium⁽⁰⁾; potassium carbonate In 1,2-dimethoxyethane at 85℃;

9
[ 361437-00-5 ]
2-[4-(4-fluorophenoxy)phenyl]pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		3 2-[4-(4-Fluorophenoxy)phenyl]pyridine-3-carboxamide (10) EXAMPLE 3 2-[4-(4-Fluorophenoxy)phenyl]pyridine-3-carboxamide (10) Compound 10 was prepared in a manner similar to the procedure described for compounds 8a-8h in Example 2 using compound 9 and 4-(4-fluorophenoxy)phenyl boronic acid. 1H NMR (400 MHz, CD3OD): δ 7.02-7.42 (m, 5H), 7.65 (d, 2H, J=8.8 Hz), 7.97-8.02 (m, 2H), 8.45 (d, 1H, J=4.9 Hz), 8.68 (d, 1H, J=4.9 Hz). 2-[4-(4-Fluorophenoxy)phenyl]pyridine-4-carboxamide was prepared similarly using compound 7 and 4-(4-fluorophenoxy)phenyl boronic acid. 1H NMR (400 MHz, CDCl3): δ 6.05 (bs, 1H), 6.31 (bs, 1H), 7.04-7.11 (m, 6H), 7.51 (d, 1H, J=5.0 Hz), 8.03 (d, 2H, J=8.8 Hz), 8.10 (s, IH), 8.81 (d, 1H, J=5.0 Hz).

Reference： [1]Current Patent Assignee: PURDUE PHARMA L.P. - US2003/55088, 2003, A1

10
6-Bromopyridine-2-carboxylic acid N-piperidinylethylamide [ No CAS ]
[ 361437-00-5 ]
6-(4-(4-fluorophenoxy)phenyl)-N-(2-(piperidin-1-yl)ethyl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1,2-dimethoxyethane (DME); water	16.b 6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid N-piperidinylethylamide (3) b) 6-[4-(fluorophenoxy)phenyl]pyridine carboxylic acid N-piperidinylethylamide (3): 4-(4-fluorophenoxy)phenyl boronic acid (557 mg, 2.4 mmol) was added to a solution of compound 2 (624 mg, 2.0 mmol) in 1,2-dimethoxyethane (DME) (6 mL), followed by water (2 mL) and potassium carbonate (746 mg, 5.4 mmol). Pd(PPh3)4 (92 mg, 0.08 mmol) was added to this mixture, and the reaction was heated at 85° C. for 16 hours under an argon atmosphere. The reaction was allowed to cool to ambient temperature, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate. The solution was filtered, concentrated, and then filtered over a bed of florisil to give crude compound 3.

Reference： [1]Current Patent Assignee: PURDUE PHARMA L.P. - US2002/40025, 2002, A1

12
[ 607-68-1 ]
[ 361437-00-5 ]
[ 1371596-31-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate In water; toluene at 95℃; for 18h; Inert atmosphere;	2.a EXAMPLE 2; (S)-l-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)ethane-l,2-diol (10)6 7 8 9 10; (a) Water (3 mL) was added to a mixture of compound 6 (0.5 g, 1.0 eq., AstaTech, Inc.), compound 7 (0.7 g), Pd(Ph3P)4 (0.3 g), K2C03 (0.4 g) and toluene (10 mL) under nitrogen, and the resulting mixture was shaken at 95 °C for 18 hours. Toluene (100 mL) and water (40 mL) were added to the reaction mixture. The organic layer was separated and purified by column (TCM/Hexanes 7/4) to obtain compound 8 as a yellow solid (0.5 g, yield 86%): 1H-NMR (400 MHz, CDC13): δ 8.09 (d, 1H, 8.9Hz), 7.97 (d, 1H, 8.6Hz), 7.84 - 7.88 (m, 1H), 7.71 (d, 2H, 8.1Hz), 7.53 - 7.57 (m, 1H), 7.01 - 7.09 (m, 6H).

Reference： [1]Current Patent Assignee: PURDUE PHARMA L.P. - WO2012/46132, 2012, A1 Location in patent: Page/Page column 100

13
[ 361437-00-5 ]
[ 1371596-32-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / toluene; water / 18 h / 95 °C / Inert atmosphere 2: tetrabutyl ammonium fluoride / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / N,N-dimethyl-formamide; tetrahydrofuran / 2 h / 90 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: PURDUE PHARMA L.P. - WO2012/46132, 2012, A1

14
[ 361437-00-5 ]
(S)-1-(4-(4-(4-fluorophenoxy)phenyl)quinazolin-2-yl)ethane-1,2-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / toluene; water / 18 h / 95 °C / Inert atmosphere 2: tetrabutyl ammonium fluoride / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / N,N-dimethyl-formamide; tetrahydrofuran / 2 h / 90 °C / Inert atmosphere 3: potassium carbonate; potassium hexacyanoferrate(III) / hydroquinidein 1,4-phthalazinediyl diether; potassium osmate(VI) dihydrate / water; <i>tert</i>-butyl alcohol / 24 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: PURDUE PHARMA L.P. - WO2012/46132, 2012, A1

15
[ 361437-00-5 ]
[ 1371595-84-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / toluene; water / 18 h / 95 °C / Inert atmosphere 2: potassium carbonate; triethylamine / N,N-dimethyl-formamide / 24 h / 100 °C

Reference： [1]Current Patent Assignee: PURDUE PHARMA L.P. - WO2012/46132, 2012, A1

16
[ 7379-35-3 ]
[ 361437-00-5 ]
[ 1578241-99-2 ]
[ 1578242-00-8 ]

Yield	Reaction Conditions	Operation in experiment
1: 66% 2: 7%	Stage #1: 4-chlorpyridine hydrochloride; (4-(4-fluorophenoxy)phenyl)boronic acid With ferrous(II) sulfate heptahydrate; dipotassium peroxodisulfate In dichloromethane; water at 20℃; for 5h; Stage #2: With sodium hydroxide In water

Reference： [1]Komeyama, Kimihiro; Nagao, Yuya; Abe, Manabu; Takaki, Ken [Bulletin of the Chemical Society of Japan, 2014, vol. 87, # 2, p. 301 - 313]

17
[ 361437-00-5 ]
[ 1127563-71-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: dipotassium peroxodisulfate; ferrous(II) sulfate heptahydrate / dichloromethane; water / 5 h / 20 °C 2: 3-chloro-benzenecarboperoxoic acid / 1,2-dichloro-ethane / 24 h / 20 °C 3: N,N-Dimethylcarbamoyl chloride / dichloromethane / 24 h / 0 - 20 °C

Reference： [1]Komeyama, Kimihiro; Nagao, Yuya; Abe, Manabu; Takaki, Ken [Bulletin of the Chemical Society of Japan, 2014, vol. 87, # 2, p. 301 - 313]

18
[ 3934-20-1 ]
[ 361437-00-5 ]
C₁₆H₁₀ClFN₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In acetonitrile at 90℃; for 4h;

Reference： [1]Park, Hwangseo; Shin, Yongje; Choe, Hyeonjeong; Hong, Sungwoo [Journal of the American Chemical Society, 2015, vol. 137, # 1, p. 337 - 348]

19
[ 361437-00-5 ]
4-((4-(4-(4-fluorophenoxy)phenyl)pyrimidin-2-yl)amino)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / acetonitrile / 4 h / 90 °C 2: hydrogenchloride / ethanol / 2 h / 160 °C / Microwave irradiation

Reference： [1]Park, Hwangseo; Shin, Yongje; Choe, Hyeonjeong; Hong, Sungwoo [Journal of the American Chemical Society, 2015, vol. 137, # 1, p. 337 - 348]

20
6-bromo-[1,2,4]triazole[4,3-a]pyridine-3(2H)-one [ No CAS ]
[ 361437-00-5 ]
[ 1354200-00-2 ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; isopropyl alcohol; toluene at 95℃;

Reference： [1]Koltun, Dmitry O.; Parkhill, Eric Q.; Elzein, Elfatih; Kobayashi, Tetsuya; Jiang, Robert H.; Li, Xiaofen; Perry, Thao D.; Avila, Belem; Wang, Wei-Qun; Hirakawa, Ryoko; Smith-Maxwell, Catherine; Wu, Lin; Dhalla, Arvinder K.; Rajamani, Sridharan; Mollova, Nevena; Stafford, Brian; Tang, Jennifer; Belardinelli, Luiz; Zablocki, Jeff A. [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 13, p. 3207 - 3211]

21
[ 371-41-5 ]
[ 361437-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: glycine-N',N'-dimethylamide hydrochloride; copper (I) iodide; Cs₂CO₃ / 1,4-dioxane / 48 h / 90 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran / -78 °C / Inert atmosphere 2.2: -78 °C / Inert atmosphere 3.1: hydrogenchloride / water monomer / Inert atmosphere
	Multi-step reaction with 2 steps 1: Cs₂CO₃; dimethylaminoacetic acid; copper (I) iodide / 1,4-dioxane / 8 h / 90 °C / Inert atmosphere 2: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / Cooling with ethanol-dry ice

Reference： [1]Tan, Guiping; Chen, Shuming; Siu, Chi-Ho; Langlois, Adam; Qiu, Yongfu; Fan, Hongbo; Ho, Cheuk-Lam; Harvey, Pierre D.; Lo, Yih Hsing; Liu, Li; Wong, Wai-Yeung [Journal of Materials Chemistry C, 2016, vol. 4, # 25, p. 6016 - 6026]
[2]Current Patent Assignee: GHUI PHARMACEUTICAL HANGZHOU; MINGHUI PHARMACEUTICAL SHANGHAI; MINGHUI PHARMACEUTICAL HANGZHOU; MINGHUI MEDICINE SHANGHAI - EP3912980, 2021, A1

22
[ 589-87-7 ]
[ 361437-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: glycine-N',N'-dimethylamide hydrochloride; copper (I) iodide; Cs₂CO₃ / 1,4-dioxane / 48 h / 90 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran / -78 °C / Inert atmosphere 2.2: -78 °C / Inert atmosphere 3.1: hydrogenchloride / water monomer / Inert atmosphere
	Multi-step reaction with 2 steps 1: Cs₂CO₃; dimethylaminoacetic acid; copper (I) iodide / 1,4-dioxane / 8 h / 90 °C / Inert atmosphere 2: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / Cooling with ethanol-dry ice

23
[ 55102-99-3 ]
[ 361437-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / -78 °C / Inert atmosphere 1.2: -78 °C / Inert atmosphere 2.1: hydrogenchloride / water / Inert atmosphere

24
C₁₄H₁₄BFO₃ [ No CAS ]
[ 361437-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In water Inert atmosphere;

25
[ 361437-00-5 ]
C₃₄H₂₂Cl₂F₂N₂O₂Pt₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / water; toluene / 48 h / 110 °C / Inert atmosphere 2: water; 2-ethoxy-ethanol / 16 h / 80 °C / Inert atmosphere

26
[ 361437-00-5 ]
C₂₂H₁₈FNO₃Pt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / water; toluene / 48 h / 110 °C / Inert atmosphere 2: water; 2-ethoxy-ethanol / 16 h / 80 °C / Inert atmosphere 3: sodium carbonate / 2-ethoxy-ethanol / 18 h / 80 °C / Inert atmosphere

27
[ 109-04-6 ]
[ 361437-00-5 ]
C₁₇H₁₂FNO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.3%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In water; toluene at 110℃; for 48h; Inert atmosphere;

28
[ 330-84-7 ]
[ 361437-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: bromine; iodine / carbon disulfide / 20 °C / Cooling with ice 2.1: n-butyllithium / tetrahydrofuran / 1 h / -78 - -65 °C / Inert atmosphere 2.2: 3 h / -60 - 0 °C / Cooling with ice

Reference： [1]Current Patent Assignee: ARROMAX PHARMATECH SUZHOU CO LTD - CN106146511, 2016, A

29
[ 55102-99-3 ]
[ 73183-34-3 ]
[ 361437-00-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 1-(4-fluorophenoxy)-4-bromobenzene With n-butyllithium In tetrahydrofuran at -78 - -65℃; for 1h; Inert atmosphere; Stage #2: bis(pinacol)diborane In tetrahydrofuran at -60 - 0℃; for 3h; Cooling with ice;	34.b Synthesis of 4- (4-fluorophenoxy) phenylboronic acid A solution of 1- (4-bromophenoxy) -4-fluorobenzene (10 g, 37 mmol)Was dissolved in anhydrous THF (80 mL)Under nitrogen protection,Cooled to -78 ° C,N-BuLi (16.4 mL, 41 mmol) was added dropwise, the temperature was maintained below -65 ° C,After stirring for 1 h,Continue to maintain the temperature -60 ,Triisopropyl borate (8.3 g, 44.4 mmol) was added dropwise,Slowly rose to 0 ° C, stir for 3 h.Water was added to the ice bath (30 mL) and stirred overnight. The reaction solution was concentrated to remove the organic phase,With 12N concentrated hydrochloric acid pH adjusted to 1 ~ 2, precipitation of solid,Filtration and drying gave the product (6.4 g, 75% yield).

Reference： [1]Current Patent Assignee: ARROMAX PHARMATECH SUZHOU CO LTD - CN106146511, 2016, A Location in patent: Paragraph 0339; 0340; 0341

30
[ 151266-23-8 ]
[ 361437-00-5 ]
3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With tripotassium phosphate tribasic; tetrakis-(triphenylphosphine)-palladium In 1,4-dioxane; water monomer for 3h; Inert atmosphere; Reflux;	11.3 Step 3: 3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine To a dried 25 mL two-necked-flask was added 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.00 g, 19.16mmol), intermediate (4-(4-fluorophenoxy)phenyl)boric acid (8.89 g, 38.31 mmol), and potassium phosphate (12.20 g, 57.47 mmol), 150 mL 1,4-dioxane and 50 mL H2O, and exchanged with Ar for 3 times, tetratriphenylphosphine palladium(3.32 g, 2.87 mmol) was added. The reacting solution was further exchanged with Ar for 3 times, and heated and refluxedfor three hours. TLC showed that the reaction was completed. The reaction system was added with 150 mL H2O, stirredfor 10min and filtered. The crude product was pulped with MeOH and EtOAc (MeOH: EtOAc = 1:5, 10mL) to afford 4.31g product, yield 70%.1H NMR (400 MHz, DMSO-d6): δ 13.45(s, 1H), 8.21(s, 1H), 7.66(d, J = 8.5 Hz, 2H), 7.27 (t, J = 8.7 Hz, 2H), 7.21-7.16(m,2H), 7.13(d, J = 8.5 Hz, 2H), 6.74(brs, 2H).MS ESI: m/z =322, [M+H]+.
70%	With tripotassium phosphate tribasic; tetrakis-(triphenylphosphine)-palladium In 1,4-dioxane; water monomer for 3h; Inert atmosphere; Reflux;	11.3 Step 3: 3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine To a dried 25 mL two-necked-flask was added 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.00 g, 19.16mmol), intermediate (4-(4-fluorophenoxy)phenyl)boric acid (8.89 g, 38.31 mmol), and potassium phosphate (12.20 g, 57.47 mmol), 150 mL 1,4-dioxane and 50 mL H2O, and exchanged with Ar for 3 times, tetratriphenylphosphine palladium(3.32 g, 2.87 mmol) was added. The reacting solution was further exchanged with Ar for 3 times, and heated and refluxedfor three hours. TLC showed that the reaction was completed. The reaction system was added with 150 mL H2O, stirredfor 10min and filtered. The crude product was pulped with MeOH and EtOAc (MeOH: EtOAc = 1:5, 10mL) to afford 4.31g product, yield 70%.1H NMR (400 MHz, DMSO-d6): δ 13.45(s, 1H), 8.21(s, 1H), 7.66(d, J = 8.5 Hz, 2H), 7.27 (t, J = 8.7 Hz, 2H), 7.21-7.16(m,2H), 7.13(d, J = 8.5 Hz, 2H), 6.74(brs, 2H).MS ESI: m/z =322, [M+H]+.
4.5 g	With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In 1,4-dioxane at 90℃; Inert atmosphere;	6.7.A Step A: 3- (4-p-Fluorophenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine A 100 mL reaction flask was charged with 5 g of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine, 50 mL of dioxane,4.8 g of 4-p-fluorophenylbenzeneboronic acid, 2 g of potassium carbonate and 0.5 g of tetrakistriphenylphosphine palladium were charged, and the reaction system was evacuated and protected by nitrogen. The reaction was then heated to 90 ° C. overnight. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated Silica gel column chromatography gave 4.5 g of a brown solid,

Reference： [1]Current Patent Assignee: GHUI PHARMACEUTICAL HANGZHOU; MINGHUI PHARMACEUTICAL SHANGHAI; MINGHUI PHARMACEUTICAL HANGZHOU; MINGHUI MEDICINE SHANGHAI - EP3912980, 2021, A1 Location in patent: Paragraph 0172; 0177-0178
[2]Current Patent Assignee: GHUI PHARMACEUTICAL HANGZHOU; MINGHUI PHARMACEUTICAL SHANGHAI; MINGHUI PHARMACEUTICAL HANGZHOU; MINGHUI MEDICINE SHANGHAI - EP3912980, 2021, A1 Location in patent: Paragraph 0172; 0177-0178
[3]Current Patent Assignee: NANJING HONGTENG CONSTRUCTION ENG - CN107501270, 2017, A Location in patent: Paragraph 0166; 0167; 0168; 0169

31
[ 1415824-86-0 ]
[ 361437-00-5 ]
tert‐butyl 4‐[({6‐amino‐5‐[4‐(4‐fluorophenoxy)phenyl]pyrimidin‐4‐yl}amino)methyl]piperidine‐1‐carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium carbonate In 1,4-dioxane; water at 150℃; for 3h;

Reference： [1]Askew, Ben C.; Bender, Andrew T.; Brugger, Nadia; Caldwell, Richard D.; Camps, Montserrat; Dhanabal, Mohanraj; Dutt, Vikram; Eichhorn, Thomas; Follis, Ariele Viacava; Gardberg, Anna S.; Goutopoulos, Andreas; Grenningloh, Roland; Head, Jared; Healey, Brian; Hodous, Brian L.; Huck, Bayard R.; Johnson, Theresa L.; Jones, Christopher; Jones, Reinaldo C.; Liu-Bujalski, Lesley; Meyring, Michael; Mochalkin, Igor; Morandi, Federica; Nguyen, Ngan; Potnick, Justin R.; Qiu, Hui; Santos, Dusica Cvetinovic; Schmidt, Ralf; Sherer, Brian; Shutes, Adam; Urbahns, Klaus; Wegener, Ansgar A.; Zimmerli, Simone C. [Journal of Medicinal Chemistry, 2019]

32
[ 55102-99-3 ]
[ 5419-55-6 ]
[ 361437-00-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 1-bromo-4-(4-fluorophenoxy) benzene With n-butyllithium In tetrahydrofuran; hexane for 0.666667h; Cooling with ethanol-dry ice; Stage #2: Triisopropyl borate In tetrahydrofuran; hexane	11.2 Step 2: (4-(4-fluorophenoxy)phenyl)boric acid To a dried 250 mL two-necked-flask was added intermediate1-bromo-4-(4-fluorophenoxy)benzene (2.00 g,7.49 mmol) and 100 mL anhydrous THF, and cooled in dry ice-ethanol bath. The reaction system was mixed slowly with2.4M n-butyl lithium in n-hexane (4.06 ml, 9.73 mmol) and continued to stir for 40min. Triisopropoxyboron was addeddropwise into the system. TLC showed that the reaction was completed. The reacting solution was slowly poured into100 mL saturated ammonium chloride solution and extracted with EtOAc(50 mL 3 3). The combined organic phase andwashed with saturated brine(100 mL 3 1) and dried with anhydrous sodium sulfate. After filtration and concentration,the residue was purified with silica gel column(petroleum ether: ethyl acetate = 97:3 ~ 55:45) to afford 1.5 g product,yield 86%.1H NMR (400 MHz, CDCl3): δ 8.16(d, J = 8.6 Hz, 2H), 7.10-6.94(m, 8H).
86%	Stage #1: 1-bromo-4-(4-fluorophenoxy) benzene With n-butyllithium In tetrahydrofuran; hexane for 0.666667h; Cooling with ethanol-dry ice; Stage #2: Triisopropyl borate In tetrahydrofuran; hexane	11.2 Step 2: (4-(4-fluorophenoxy)phenyl)boric acid To a dried 250 mL two-necked-flask was added intermediate1-bromo-4-(4-fluorophenoxy)benzene (2.00 g,7.49 mmol) and 100 mL anhydrous THF, and cooled in dry ice-ethanol bath. The reaction system was mixed slowly with2.4M n-butyl lithium in n-hexane (4.06 ml, 9.73 mmol) and continued to stir for 40min. Triisopropoxyboron was addeddropwise into the system. TLC showed that the reaction was completed. The reacting solution was slowly poured into100 mL saturated ammonium chloride solution and extracted with EtOAc(50 mL 3 3). The combined organic phase andwashed with saturated brine(100 mL 3 1) and dried with anhydrous sodium sulfate. After filtration and concentration,the residue was purified with silica gel column(petroleum ether: ethyl acetate = 97:3 ~ 55:45) to afford 1.5 g product,yield 86%.1H NMR (400 MHz, CDCl3): δ 8.16(d, J = 8.6 Hz, 2H), 7.10-6.94(m, 8H).

Reference： [1]Current Patent Assignee: GHUI PHARMACEUTICAL HANGZHOU; MINGHUI PHARMACEUTICAL SHANGHAI; MINGHUI PHARMACEUTICAL HANGZHOU; MINGHUI MEDICINE SHANGHAI - EP3912980, 2021, A1 Location in patent: Paragraph 0172; 0175-0176
[2]Current Patent Assignee: GHUI PHARMACEUTICAL HANGZHOU; MINGHUI PHARMACEUTICAL SHANGHAI; MINGHUI PHARMACEUTICAL HANGZHOU; MINGHUI MEDICINE SHANGHAI - EP3912980, 2021, A1 Location in patent: Paragraph 0172; 0175-0176

33
[ 361437-00-5 ]
3-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentane-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: tripotassium phosphate tribasic; tetrakis-(triphenylphosphine)-palladium / water monomer; 1,4-dioxane / 3 h / Inert atmosphere; Reflux 2: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / Inert atmosphere; Cooling with ethanol-dry ice 3: Dess-Martin periodane / dichloromethane / Inert atmosphere; Cooling with ethanol-dry ice