[ CAS No. 91591-63-8 ] {[proInfo.proName]}

Name: 91591-63-8|2,5-Dichloro-4,6-dimethylnicotinonitrile|98%
Brand: Ambeed
SKU: A153281
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Quality Control of [ 91591-63-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 91591-63-8 ]

SDS Specification

Alternatived Products of [ 91591-63-8 ]

Product Details of [ 91591-63-8 ]

CAS No. :	91591-63-8	MDL No. :	MFCD00052631
Formula :	C₈H₆Cl₂N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UCGWYTUBYASPFG-UHFFFAOYSA-N
M.W :	201.05	Pubchem ID :	334852
Synonyms :

Calculated chemistry of [ 91591-63-8 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	48.9
TPSA :	36.68 Å²

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) :	-5.45 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.12
Log Po/w (XLOGP3) :	2.92
Log Po/w (WLOGP) :	2.88
Log Po/w (MLOGP) :	1.62
Log Po/w (SILICOS-IT) :	3.5
Consensus Log Po/w :	2.61

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.3
Solubility :	0.102 mg/ml ; 0.000506 mol/l
Class :	Soluble
Log S (Ali) :	-3.35
Solubility :	0.0895 mg/ml ; 0.000445 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.12
Solubility :	0.0151 mg/ml ; 0.0000753 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.02

Safety of [ 91591-63-8 ]

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 [ 91591-63-8 ]

* 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 [ 91591-63-8 ]
Downstream synthetic route of [ 91591-63-8 ]

[ 91591-63-8 ] Synthesis Path-Upstream 1~3

1
[ 23819-92-3 ]
[ 91591-63-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With tetramethlyammonium chloride; trichlorophosphate In dichloromethane at 85℃; for 5 h;	Phosphoryl chloride (973.2g), tetramethylammonium chloride (67.3g) and compound of Preparation 2 (227.1g) were added to dichloromethane (500g). The suspension was heated to 85°C and stirred for 5 hours. Excess of phosphoryl chloride was removed by distillation in vacuo. The reaction mixture was cooled below 30 °C and diluted with dichloromethane. The resulting solution was added to water (1350g) at room temperature and stirred for 30 minutes. The lower organic phase was separate and the aqueous phase extracted with dichloromethane. The organic phases were combined, washed with water and then treated with charcoal. The charcoal was filtered and a solvent swap to heptane was performed by distillation at atmospheric pressure. The solution was filtered at 50 °C and then cooled to 30 °C. On further cooling to 0°C crystals were obtained. These were isolated by filtration, washed twice with heptane. After drying at 50°C the desired product was obtained typically at 88-91 percent . The above process was repeated with a reduction in dichloromethane during crystallisation and adding some methanol. The resulting plate-like crystals were more easily transferred for subsequent use.

Reference： [1] Patent: WO2013/89573, 2013, A1, . Location in patent: Page/Page column 15-16
[2] MedChemComm, 2015, vol. 6, # 11, p. 1998 - 2003
[3] Chemistry of Heterocyclic Compounds, 2004, vol. 40, # 3, p. 308 - 314
[4] Patent: EP1845097, 2007, A1, . Location in patent: Page/Page column 6-7

2
[ 769-28-8 ]
[ 91591-63-8 ]

Reference： [1] Chemistry of Heterocyclic Compounds, 2004, vol. 40, # 3, p. 308 - 314
[2] Patent: WO2013/89573, 2013, A1,
[3] MedChemComm, 2015, vol. 6, # 11, p. 1998 - 2003

3
[ 123-54-6 ]
[ 91591-63-8 ]

Reference： [1] Patent: WO2013/89573, 2013, A1,

[ 91591-63-8 ] Synthesis Path-Downstream 1~64

1
[ 23819-92-3 ]
[ 91591-63-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With tetramethlyammonium chloride; trichlorophosphate; In dichloromethane; at 85℃; for 5.0h;	Phosphoryl chloride (973.2g), tetramethylammonium chloride (67.3g) and compound of Preparation 2 (227.1g) were added to dichloromethane (500g). The suspension was heated to 85C and stirred for 5 hours. Excess of phosphoryl chloride was removed by distillation in vacuo. The reaction mixture was cooled below 30 C and diluted with dichloromethane. The resulting solution was added to water (1350g) at room temperature and stirred for 30 minutes. The lower organic phase was separate and the aqueous phase extracted with dichloromethane. The organic phases were combined, washed with water and then treated with charcoal. The charcoal was filtered and a solvent swap to heptane was performed by distillation at atmospheric pressure. The solution was filtered at 50 C and then cooled to 30 C. On further cooling to 0C crystals were obtained. These were isolated by filtration, washed twice with heptane. After drying at 50C the desired product was obtained typically at 88-91 % . The above process was repeated with a reduction in dichloromethane during crystallisation and adding some methanol. The resulting plate-like crystals were more easily transferred for subsequent use.

Reference： [1]Patent: WO2013/89573,2013,A1 .Location in patent: Page/Page column 15-16
[2]MedChemComm,2015,vol. 6,p. 1998 - 2003
[3]Chemistry of Heterocyclic Compounds,2004,vol. 40,p. 308 - 314
[4]Patent: EP1845097,2007,A1 .Location in patent: Page/Page column 6-7

2
[ 91591-63-8 ]
[ 175204-44-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dihydrogen peroxide; potassium carbonate; In dimethyl sulfoxide; at 20℃; for 2.0h;	To a mixture of 2,5-dichloro-4,6- dimethylnicotinonitrile (1.0 g, 5.0 mmol) and K2CO3 (1.4 g, 10 mmol) in DMSO (10 mL) was added H2O2 (0.87 mL, 10 mmol). The mixture was stirred at 20C for 2 h. Then the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated to give a residue that was purified by silica gel chromatography (petroleum ether/ethyl acetate 1 :2) to give the title compound.

Reference： [1]Chemistry of Heterocyclic Compounds,2004,vol. 40,p. 308 - 314
[2]Patent: WO2020/92667,2020,A1 .Location in patent: Page/Page column 110

3
[ 52744-72-6 ]
[ 91591-63-8 ]
2-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-4,4-diphenyl-3,4-dihydro-quinazoline; compound with perchloric acid [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2005,vol. 41,p. 1045 - 1052

4
[ 91591-63-8 ]
2-mercapto-3-cyano-4,6-dimethyl-5-chloropyridine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2898 - 2908

5
[ 91591-63-8 ]
[ 923288-59-9 ]

Yield	Reaction Conditions	Operation in experiment
87.9%	With 1,10-Phenanthroline; hydroxylamine; In methanol; water; at 70 - 80℃;	Product of Preparation 3 (68.6g) and 1,10-phenanthroline monohydrate (0.9g) were suspended in methanol (240g) at room temperature. Water (518g) and a hydroxy lamine solution (50% in water, 80.9g), were added and the mixture heated to 70-80C and stirred for 5-6 hours. Water was added at 70-80 C and the solution held for 1 hour to induce crystallization. Crystallization was completed by cooling to 15C over 8 hours. The product was filtered off and washed twice with water and dried at 50C under vacuum. The product was an off white to light yellow and the yield was 87.9% .
70%	With 2-Methylpyrazine; hydroxylamine; In methanol; water; at 70 - 80℃;	To a suspension of <strong>[91591-63-8]2,5-dichloro-4,6-dimethylnicotinonitrile</strong> of formula (VIII) (lOOg, 0.497 mole) in methanol (600 ml) and water (800 ml) was added 50% aqueous solution of hydroxyl amine (l30g) and 2-methylpyrazine (7.02g, 0.0746) at room temperature. The reaction mixture was then stirred at 70-80C for 6-8 hours. After completion, water (800 ml) was added to the reaction mixture at 70- 80C and allowed to cool to room temperature. After stirring for 2 hours the reaction mixture was filtered, solid was washed with water (200ml x 3) and dried at 50C under vacuum to obtain 2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide of formula (IV) (82 g, 70%).

Reference： [1]Patent: WO2013/89573,2013,A1 .Location in patent: Page/Page column 16
[2]Patent: WO2019/123066,2019,A1 .Location in patent: Page/Page column 20; 21
[3]Journal of Medicinal Chemistry,2010,vol. 53,p. 3396 - 3411
[4]Patent: EP1845097,2007,A1 .Location in patent: Page/Page column 7

6
[ 91591-63-8 ]
3-amino-5-chloro-4,6-dimethyl-thieno[2,3-<i>b</i>]pyridine-2-carboxylic acid amide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2898 - 2908

7
[ 769-28-8 ]
[ 91591-63-8 ]

Reference： [1]Chemistry of Heterocyclic Compounds,2004,vol. 40,p. 308 - 314
[2]Patent: WO2013/89573,2013,A1
[3]MedChemComm,2015,vol. 6,p. 1998 - 2003

8
[ 91591-63-8 ]
2,5-dichloro-4,6-dimethylnicotinic acid [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2004,vol. 40,p. 308 - 314

9
thioglycolic acid methyl ester [ No CAS ]
[ 91591-63-8 ]
[ 1422287-26-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 346 - 350

10
[ 123-54-6 ]
[ 91591-63-8 ]

Reference： [1]Patent: WO2013/89573,2013,A1

11
[ 91591-63-8 ]
[ 1402714-41-3 ]

Reference： [1]Patent: WO2013/89573,2013,A1
[2]Patent: WO2013/89573,2013,A1

12
[ 91591-63-8 ]
2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide [ No CAS ]

Reference： [1]Patent: WO2013/89573,2013,A1
[2]Patent: WO2013/89573,2013,A1
[3]Patent: WO2019/123066,2019,A1
[4]Patent: WO2019/123066,2019,A1

13
[ 91591-63-8 ]
[ 896125-90-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,10-Phenanthroline; hydroxylamine; In methanol; water; at 70 - 80℃;Large scale;	A suspension of 2,5-Dichloro-4,6-dimethyl-nicotinonitrile (45.0 kg) and 50% hydroxy lamine (59.2 kg) in the presence of catalytic amount of 1,10-phenanthroline monohydrate (0.680 kg) in methanol / water (214 kg/362 kg) is heated to 70-80C. The mixture is agitated at 70-80C. Water (353 kg) is added slowly into the resulting solution while the temperature is maintained at > 79C. The solution is cooled to 75 C with stirring resulting in crystallization of (Z)-2,5-dichloro-N'-hydroxy-4,6-dimethylriicotinirnidamide. The suspension is further cooled to 20 C, the solid is filtered off and the wet cake is washed with water (160 kg). (Z)-2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide is dried under vacuum at max. 60C until residual water level is max 0.15% (KF).

Reference： [1]Patent: WO2013/89573,2013,A1 .Location in patent: Page/Page column 16-17

14
[ 91591-63-8 ]
[ 1391712-50-7 ]

Reference： [1]Patent: WO2013/89573,2013,A1
[2]Patent: WO2013/89573,2013,A1
[3]Patent: US2018/370958,2018,A1

15
[ 91591-63-8 ]
[ 1462832-92-3 ]

Reference： [1]Patent: WO2013/144180,2013,A1

16
[ 110-85-0 ]
[ 91591-63-8 ]
[ 1462849-59-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; at 120℃; for 0.25h;Microwave irradiation;	A mixture of <strong>[91591-63-8]2,5-dichloro-4,6-dimethylnicotinonitrile</strong> (200 mg, 0.995 mmol), K2C03 (275 mg, 1 .990 mmol) and piperazine (5141 mg, 59.7 mmol) was heated under microwave heating at 120C for 15 minutes. After cooling to room temperature the mixture was partitioned between 1 N HCI and DCM. The layers were separated and the aqueous layer was extracted once with DCM, basified with NaOH (4N) and extracted with DCM (4x). The combined organic layers were dried (sodium sulfate) and concentrated under reduced pressure to give 231 mg of a solid (0.922 mmol, yield 93%) MS(multi-mode) m/z = 251 .2 [M+1]+.

Reference： [1]Patent: WO2013/144180,2013,A1 .Location in patent: Page/Page column 74

17
[ 91591-63-8 ]
5-chloro-4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile [ No CAS ]

Reference： [1]MedChemComm,2015,vol. 6,p. 1998 - 2003

18
[ 91591-63-8 ]
[ 1417616-41-1 ]

Reference： [1]MedChemComm,2015,vol. 6,p. 1998 - 2003

19
[ 91591-63-8 ]
3-amino-5-chloro-N-cyclopropyl-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide hydrochloride [ No CAS ]

Reference： [1]MedChemComm,2015,vol. 6,p. 1998 - 2003

20
[ 91591-63-8 ]
N-(5-chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-2-phenylacetamide [ No CAS ]

Reference： [1]Patent: WO2017/34420,2017,A1

21
[ 91591-63-8 ]
5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With acetylhydroxamic acid; potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 7.0h;Inert atmosphere;	To a solution of acetohydroxamic acid (0.22 g, 2.98 mmol) in dry DMF (5 ml) under nitrogen was added potassium tertr-butoxide (0.33 g, 2.98 mmol). The reaction mixture was stirred at 20 C for 2 hr. 2,5-Dichloro-4,6-dimethylnicotinonitrile (0.50 g, 2.49 mmol) was then added and the resulting mixture was stirred at 20C for 5 hr, then diluted with H2O (150 ml) and stirred for 1 hr. The resulting white precipitate was filtered and washed with water. The filtrate was extracted with EtOAc (30 ml x 3). Combined organic fractions were dried (Na2S04), and the solvent was evaporated under vacuum to give further material. Both the isolated solid and the extracted material were combined and chromatographed on S1O2 eluting with a 0-50 % gradient of petroleum ether/EtOAc. The column purified product was recrystallized from DCM/petroleum ether to give (1) (0.22 g, 45% ) as a white solid, mp (DCM/petroleum ether) 214-216 C, *H NMR [(CD3)2SO] delta 6.25 (bs, 2H, N H2), 2.64 (s, 3H, CH3), 2.61 (s, 3H, CH3); LCMS [M + H] = 198; HPLC 99.8%; Anal calcd. for CsHsCI NsO : C, 48.6; H, 4.1; N, 21.4; found C, 48.8; H, 3.9, N, 21.4%.

Reference： [1]Patent: WO2017/34420,2017,A1 .Location in patent: Page/Page column 38; 39

22
[ 91591-63-8 ]
N-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2017/34420,2017,A1

23
[ 91591-63-8 ]
1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2017/34420,2017,A1

24
[ 91591-63-8 ]
phenyl (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)carbamate [ No CAS ]

Reference： [1]Patent: WO2017/34420,2017,A1

25
[ 91591-63-8 ]
1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-chlorophenyl)urea [ No CAS ]

Reference： [1]Patent: WO2017/34420,2017,A1

26
[ 91591-63-8 ]
8-chloro-7,9-dimethylpyrido[3',2': 4,5]furo[3,2-d]pyrimidin-4-ol [ No CAS ]

Reference： [1]Patent: US2017/369505,2017,A1

27
[ 91591-63-8 ]
4,8-dichloro-7,9-dimethylpyrido[3',2':4,5]furo[3,2-d]pyrimidine [ No CAS ]

Reference： [1]Patent: US2017/369505,2017,A1

28
[ 623-50-7 ]
[ 91591-63-8 ]
ethyl 3-amino-5-chloro-4,6-dimethylfuro[2,3-b]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15.5%	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 75℃;	Ethyl 3-amino-5-chloro-4,6-dimethylfuro[2,3-b]pyridine-2-carboxylate (D) 2,5-chloro-4,6-dimethylnicotinolnitrile (1.0 g, 6.0 mmol, 1.0 eq.), ethyl glycolate (0.6 mL, 6.6 mmol, 1.1 eq.) and Cs2CO3 (5.9 g, 18 mmol, 3.0 eq.) were added to a 100 mL RBF with NMP (9.23 mL) and allowed to stir at 75 C. overnight. The reaction mixture was filtered through a pad of Celite which was rinsed with DCM and EtOAc. The filtrate was concentrated and purified using reverse phase HPLC to provide the title compound (250 mg, 0.930 mmol, 15.5% yield). 1H NMR (400 MHz, DMSO-d6): delta 6.09 (s, 2H), 4.34 (q, J=7.0 Hz, 2H), 2.72 (s, 3H), 2.61 (s, 3H), 1.34 (t, J=7.0 Hz, 3H); ES-MS [M+1]+: 269.2.

Reference： [1]Patent: US2017/369505,2017,A1 .Location in patent: Paragraph 0753; 0754

29
[ 67-56-1 ]
[ 201230-82-2 ]
[ 91591-63-8 ]
methyl 5-chloro-3-cyano-4,6-dimethylpyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; triethylamine; at 70℃; under 2585.81 Torr; for 24.0h;	Triethylamine (20.4 mL, 146 mmol), palladium(ll) acetate (837 mg, 3.73 mmol), and 1 , 1 '-bis(diphenylphosphino)ferrocene (dppf; 4.14 g, 7.47 mmol) were added to a solution of <strong>[91591-63-8]2,5-dichloro-4,6-dimethylpyridine-3-carbonitrile</strong> (15.0 g, 74.6 mmol) in methanol (600 mL). Carbon monoxide was bubbled in, and the reaction mixture was heated at 70 C for 24 hours under 50 psi of carbon monoxide. After the reaction mixture had cooled to room temperature, it was filtered, and the filtrate was (0493) concentrated under reduced pressure. Silica gel chromatography (Eluent: 5:1 petroleum ether / ethyl acetate) afforded the product as a white solid. Yield: 15.3 g, 68.1 mmol, 91 %. 1 H NMR (400 MHz, CDCI3) delta 4.06 (s, 3H), 2.78 (s, 3H), 2.71 (s, 3H).

Reference： [1]Patent: WO2018/2760,2018,A1 .Location in patent: Page/Page column 85

30
[ 91591-63-8 ]
ethyl 3-bromo-5-chloro-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/85803,2018,A1
[2]Patent: WO2018/85813,2018,A1

31
[ 91591-63-8 ]
ethyl 5-chloro-4,6-dimethyl-3-vinylthieno[2,3-b]pyridine-2-carboxylate [ No CAS ]