[ CAS No. 89402-43-7 ] {[proInfo.proName]}

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Quality Control of [ 89402-43-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 89402-43-7 ]

SDS Specification

Alternatived Products of [ 89402-43-7 ]

Product Details of [ 89402-43-7 ]

CAS No. :	89402-43-7	MDL No. :	MFCD04039314
Formula :	C₅H₂ClF₂N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PERMDYZFNQIKBL-UHFFFAOYSA-N
M.W :	149.53	Pubchem ID :	2783248
Synonyms :

Calculated chemistry of [ 89402-43-7 ] Expand+

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	29.16
TPSA :	12.89 ?2

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.79 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.68
Log Po/w (XLOGP3) :	2.01
Log Po/w (WLOGP) :	2.85
Log Po/w (MLOGP) :	1.95
Log Po/w (SILICOS-IT) :	2.91
Consensus Log Po/w :	2.28

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.53
Solubility :	0.445 mg/ml ; 0.00297 mol/l
Class :	Soluble
Log S (Ali) :	-1.91
Solubility :	1.85 mg/ml ; 0.0124 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.18
Solubility :	0.0988 mg/ml ; 0.000661 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.77

Safety of [ 89402-43-7 ]

Signal Word:	Danger	Class:	3
Precautionary Statements:	P273	UN#:	1993
Hazard Statements:	H225-H302-H412	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 89402-43-7 ]

* 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 [ 89402-43-7 ]
Downstream synthetic route of [ 89402-43-7 ]

[ 89402-43-7 ] Synthesis Path-Upstream 1~1

1
[ 89402-43-7 ]
[ 514797-99-0 ]

Reference： [1] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1903 - 1910
[2] European Journal of Organic Chemistry, 2002, # 24, p. 4174 - 4180

[ 89402-43-7 ] Synthesis Path-Downstream 1~10

1
[ 89402-43-7 ]
[ 246847-98-3 ]

Yield	Reaction Conditions	Operation in experiment
85.94%	With ammonia; at 120℃; for 24h;Autoclave;	5-chloro-2,3-difluoro-pyridine (100g, 0.669mol) and ammonia (1.125L, 8.025mol) added to the autoclave.After the reaction 120 sealed 24h, the reaction was complete, the cooling pale yellow solid precipitation, filtration, the filter cake was washed with water, and the filtrate was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, the organic phase was distilled off under reduced pressure, with beating a small amount of petroleum ether, filtration, and precipitation cake cake obtained will be collected at the same time to give the compound 2-amino-3-fluoro-5-chloropyridine 84.22g, yield 85.94%.
76%	With ammonia; In water; at 150℃; for 1h;Microwave irradiation;Product distribution / selectivity;	Example 4Preparation of 6-chloro-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol; Example 4(a) 5-chloro-3-fluoropyridin-2-amine: To a 20 mL microwave vial equipped with a stir bar was added 5-chloro-2,3-difluoropyridine (2.0 g, 41 mmol). Ammonium hydroxide (ca 12 mL) was then added and the mixture was stirred until homogeneous. The solution was capped and heated in the microwave reactor at 150 C. for three 20 minute increments until a white solid precipitated out of solution. The white solid was filtered, washed with water, and dried to afford 2-amino-5-chloro-3-fluoropyridine (1.5 g, 76% yield), characterized by 1H NMR (d6-DMSO).
73%	With ammonia; In water; at 165℃; for 3h;Product distribution / selectivity;	Example 5(a) 5-Chloro-3-fluoropyridin-2-amine.; To a stainless steel high pressure reactor was added 5-chloro-2,3-difluoropyridine (18.0 g) and ammonium hydroxide (65 mL). The reaction was heated to 165 C. for three hours. The reaction mixture was then cooled to room temperature and diluted with water (100 mL). The resultant solid was filtered, dried, re-dissolved in CH2Cl2, and passed through a silica gel plug to afford 12.8 g (73%) of the title compound as an off-white solid.

Reference： [1]Patent: CN105669539,2016,A .Location in patent: Paragraph 0058; 0059; 0060
[2]Patent: US2008/242695,2008,A1 .Location in patent: Page/Page column 34
[3]Patent: US2008/242695,2008,A1 .Location in patent: Page/Page column 34

2
[ 89402-43-7 ]
[ 105-56-6 ]
[ 1227572-25-9 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of ethyl cyanoacetate (Aldrich) (4 g, 35.4 mmol) in anhydrous DMSO (30 mL) at 0 C. was added slowly NaH (60%, 1.42 g, 35.6 mmol). The mixture was stirred at 0 C. for 0.5 h, then 5-chloro-2,3-difluoropyridine (Combi-Blocks) (5.3 g, 35.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4, 1:1) to give (5-chloro-3-fluoro-pyridin-2-yl)-acetonitrile as a yellow gum (3.2 g, 37%).Step BTo the solution of (5-chloro-3-fluoro-pyridin-2-yl)-acetonitrile (2.8 g, 11.5 mmol) in DMSO (30 mL) was added NaCl (2 g, 34 mmol). The reaction mixture was heated at 170 C. for 2 h. The mixture was partitioned between ethyl acetate and water. Organic layer was separated, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4, 1:3) to give (5-chloro-3-fluoro-pyridin-2-yl)-acetonitrile as a brown oil (0.85 g, 43%).

Reference： [1]Patent: US2011/118283,2011,A1 .Location in patent: Page/Page column 12

3
[ 89402-43-7 ]
[ 94050-90-5 ]
[ 114420-56-3 ]

Yield	Reaction Conditions	Operation in experiment
97.1%		Adding water separately in the reaction kettle 20L, dimethyl sulfoxide 40L, sodium hydroxide to 9.5 kg (237mol), stirring, add R-2 - (P-hydroxy-phenoxy) propionic acid (optical purity 99.5%, content 99%) 18 kg (99mol), heating under stirring to the 45 C reaction 1 hour. By adding 17 kg (113.7mol) of 5-chloro -2,3-difluoro-pyridine, heating to 95 C reaction 6 hours, HPLC tracking of the reaction, when the raw material R-2 - (P-hydroxy-phenoxy) propionic acid is less than 1% of the, stop the reaction. Pressure reducing and recovering the solvent, adding residues 40L water to stir and dissolve, using 15% hydrochloric acid to adjust PH=3, separating solid under stirring, filtering, alkyne grass ester acid drying to 30 kg. Yield 97.1%, content of 99.1%, optical purity 99.2%.
91.3%		Add 15 mL of DMF to a 50 mL three-necked flask equipped with a constant pressure dropping funnel, a condenser and a thermometer.6.37g (0.035mol) R-HPPA, to be completely dissolved, add 7.26g (0.0525mol) K2CO3 particles, heat to 70-80 C stirMix for 2h, the system turns pink,4.76g (0.032mol) was then kept under constant temperature with a constant pressure dropping funnel.2,3-Difluoro-5-chloropyridine was slowly added dropwise to the reaction system, and it was dropped in about 30 minutes. Then, the temperature was raised to 90 C to keep the reaction, and the experiment was followed up by TLC, and the reaction was finished for about 8 hours. After the reaction solution is cooled to room temperature, adjust the pH of the system to 2-3 under ice bath conditions, and adjustDuring the process, a beige solid appeared and disappeared with the stirring. The ice bath was stirred for 1 hour, and there was a constant beige.The solid was precipitated, washed with water, suction filtered, dried to give 9.10 g of a beige solid, yield: 91.3%, and the purity was 97.5% by HPLC.
62%		N, N - dimethyl formamide (40 ml), (R)-2 - (4 - hydroxy-phenoxy) propionic acid (0.02 muM, 3 . 64g), potassium carbonate (0.02 muM, 2 . 76g), 75 C under stirring 0.5h after, then adding an equivalent amount of potassium carbonate, to continue stirring 0.5h. Slowly dropping 2,3-difluoro -5 - chloro pyridine (0.02 muM, 3 . 00g), after the completion of the dropping, the reaction temperature to maintain 75 C, 12h. Stop heating, cooling to room temperature, the reaction solution is poured into 100 ml ice water, dilute hydrochloric acid to adjust the pH 4 - 5, filter, a small amount of ice water washing three times, vacuum drying, be (R)-2-[4-(3-fluoro-5-chloro pyridine-2-yloxy) phenoxy] propionic acid white solid 3.86g, yield 62.0%.

62%		N, N-dimethylformamide (40 mL),(R) - (+) - 2- (4-hydroxyphenoxy) propionic acid (0.02 mol, 3.64 g)Potassium carbonate (0.02 mol, 2.76 g),After stirring at 75 C for 0.5 h,Then add the same amount of potassium carbonate,Continue stirring for 0.5 h.Slowly dropping 2,3-difluoro-5-chloropyridine (0.02 mol, 3.00 g)After dripping,The reaction temperature was maintained at 75 C,overnight.Stop heating,Cooled to room temperature,The reaction solution was poured into 200 mL of ice water,Dilute hydrochloric acid to adjust pH 4-5, filter,Washed with a small amount of ice water three times,Vacuum drying,(R) -2- [4- (3-fluoro-5-chloropyridin-2-oxy) phenoxy] propionic acid as a white solid, 3.86 g,Yield 62.0%.
62.0%		N, N-dimethylformamide (40 mL), (R) - (+) - 2- (4-hydroxyphenoxy) propionic acid (0.02 mol, 3.64 g) Potassium carbonate (0.02 mol, 2.76 g), After stirring at 75 C for 0.5 h, Then add the same amount of potassium carbonate, Continue stirring for 0.5 h. A solution of 2,3-difluoro-5-chloropyridine (0.02 mol, 3.00 g) After dripping, The reaction temperature was maintained at 75 C, overnight. Stop heating, Cooled to room temperature, The reaction solution was poured into 200 mL of ice water, Dilute hydrochloric acid to adjust pH 4-5, filter, Washed with a small amount of ice water three times, Vacuum drying, (R) -2- [4- (3-fluoro-5-chloropyridin-2-yloxy) phenoxy] propionic acid as a white solid, 3.86 g, Yield 62.0%.
62%		N, N-dimethylformamide (40 mL),(R) - (+) - 2- (4-hydroxyphenoxy) propionic acid(0.02 mol, 3.64 g),Potassium carbonate (0.02 mol, 2.76 g),Stirring at 0.5 C for 0.5 h, then add the same amount of potassium carbonate, continue stirring 0.5h.A solution of 2,3-difluoro-5-chloropyridine (0.02 mol, 3.00 g)After completion of the dropwise addition, the reaction temperature was maintained at 75 C overnight.The heating was stopped, the mixture was cooled to room temperature, and the reaction solution was poured into 200 mL of ice water,Dilute hydrochloric acid to adjust the pH 4-5, filter, washed with a small amount of ice water three times,Vacuum drying, too(R) -2- [4- (3-fluoro-5-chloropyridin-2-yloxy) phenoxy] propionic acidWhite solid 3.86 g,Yield 62.0%.
62%		N, N-dimethylformamide (40 mL),(R) - (+) - 2- (4-hydroxyphenoxy) propionic acid (0.02 mol, 3.64 g)Potassium carbonate (0.02 mol, 2.76 g),After stirring at 75 C for 0.5 h,Then add the same amount of potassium carbonate,Continue stirring for 0.5 h.A solution of 2,3-difluoro-5-chloropyridine (0.02 mol, 3.00 g)After dripping,The reaction temperature was maintained at 75 C,overnight.Stop heating,Cooled to room temperature,The reaction solution was poured into 200 mL of ice water,Dilute hydrochloric acid to adjust pH 4-5,filter,Washed with a small amount of ice water three times,Vacuum drying,(R) -2- [4- (3-fluoro-5-chloropyridin-2-yloxy) phenoxy] propionic acid as a white solid, 3.86 g,Yield 62.0%.
62%		N,N-dimethylformamide (40 mL),<strong>[94050-90-5](R)-(+)-2-(4-hydroxyphenoxy)propionic acid</strong> (0.02 mol, 3.64 g),Potassium carbonate (0.02 mol, 2.76 g),After stirring at 75 C for 0.5 h,Add the same amount of potassium carbonate,Stirring was continued for 0.5 h. Slowly add 2,3-difluoro-5-chloropyridine (0.02 mol, 3.00 g),After the completion of the dropwise addition, the reaction temperature was maintained at 75 C overnight. Stop heating and cool to room temperature. Pour the reaction solution into 200 mL of ice water.Dilute hydrochloric acid to adjust pH 4-5, filter,Wash three times with a small amount of ice water,Vacuum drying,(R)-2-[4-(3-Fluoro-5-chloropyridin-2-oxy)phenoxy]propionic acidWhite solid 3.86g,The yield was 62.0%.
62%		N, N - dimethyl formamide (40 ml), (R)-2 - (4 - hydroxy-phenoxy) propionic acid (0.02 muM, 3 . 64 g), potassium carbonate (0.02 muM, 2 . 76 g), 75 C under stirring 0.5 h after, then adding an equivalent amount of potassium carbonate, to continue stirring 0.5 h. Slowly dropping 2, 3 - difluoro -5 - chloro pyridine (0.02 muM, 3 . 00 g), after the completion of the dropping, the reaction temperature to maintain 75 C, 12 h. Stop heating, cooling to room temperature, the reaction solution is poured into 100 ml ice water, dilute hydrochloric acid to adjust the pH 4 - 5, filter, a small amount of ice water washing three times, vacuum drying, be (R)-2 - [4 - (3 - fluoro -5 - chloro pyridine -2 - yloxy) phenoxy] propionic acid white solid 3.86 g, yield 62.0%.
	With tetrabutylammomium bromide; potassium carbonate; In N,N-dimethyl-formamide; at 60 - 70℃; for 2h;	500 g of DMF was added to a 1000 mL four-necked flask, 100 g of compound A was charged,113.6 g of potassium carbonate and 5 g of tetrabutylammonium bromide, the temperature was raised to 60 C, and 120.31 g of the product was added dropwise2,3-difluoro-5-chloropyridine in 50 g of DMF in a mixed solution at a controlled temperature of 65 to 70 C,After completion of the dropwise addition, the reaction was allowed to proceed for about 2 hours, the reaction was completed,The pH was adjusted to 7 to 8 with hydrochloric acid, stirred for 1 hour, filtered, and the solid was the ether compound (Compound H) and dried.
5.92 g		(R) -2- (4- (5-chloro-3-fluoropyridin-2-yloxy)Phenoxy) propanoic acid In a reactor equipped with a magnetic stirrer,Thermometer and condenser 100mL three-necked flask was added N, N- dimethylformamide (DMF) (40mL),(R) 2- (4-hydroxyphenoxy) propionic acid (0.02 mol),After stirring to dissolve,Potassium carbonate (0.04 mol) was added portionwiseHeating to 60 ~ 80 stirring 0.5 ~ 1.0hr.2,3-Difluoro-5-chloropyridine (0.02 mol) was added dropwise,Continue stirring reaction 6 ~ 8hr.The reaction was cooled to room temperature,Poured into ice water (250 mL)To the mixture was slowly added dilute hydrochloric acid,Adjusted to pH = 4 ~ 5,filter,Washed,The title compound (5.92 g) was dried to give a white solid.
	With tetrabutylammomium bromide; potassium carbonate; In N,N-dimethyl-formamide; at 55 - 60℃; for 2h;	500 g of DMF was placed in a 1000 mL four-necked flask, and 100 g of Compound A, 113. 6 g of potassium carbonate and 5 g of tetrabutylammonium bromide were added, and the temperature was raised to 60 C. 90.3 g of Compound B was added dropwise, and the temperature was controlled at 60 to 55 C. At the end of the addition, the reaction was about 2 hours and the reaction was completed.Add to 1000g water,Adjust the pH to 7~8 with hydrochloric acid and stir for 1 hour.Filtered, the solid is etherified and dried.

Reference： [1]Patent: CN105418494,2016,A .Location in patent: Paragraph 0039; 0040; 0041; 0042; 0043
[2]Patent: CN108752269,2018,A .Location in patent: Paragraph 0024; 0025
[3]Patent: CN106632258,2017,A .Location in patent: Paragraph 0025; 0026
[4]Patent: CN106699649,2017,A .Location in patent: Paragraph 0024; 0025; 0026
[5]Patent: CN106632007,2017,A .Location in patent: Paragraph 0024; 0025; 0026
[6]Patent: CN106699648,2017,A .Location in patent: Paragraph 0024; 0025; 0026
[7]Patent: CN106632293,2017,A .Location in patent: Paragraph 0024; 0025; 0026
[8]Patent: CN108218847,2018,A .Location in patent: Paragraph 0014-0016
[9]Patent: CN108409654,2018,A .Location in patent: Paragraph 0014-0016
[10]Chinese Chemical Letters,2011,vol. 22,p. 535 - 538
[11]Patent: CN106632045,2017,A .Location in patent: Paragraph 0079; 0080
[12]Patent: CN104277034,2017,B .Location in patent: Paragraph 0098; 0099
[13]Patent: CN106632005,2019,B .Location in patent: Paragraph 0041; 0043; 0047; 0048

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[ 67-56-1 ]
[ 89402-43-7 ]
[ 94050-90-5 ]
[ 89402-41-5 ]