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Chemical Structure| 98139-15-2 Chemical Structure| 98139-15-2

Structure of 4-Aminopyridine-2-carbonitrile
CAS No.: 98139-15-2

Chemical Structure| 98139-15-2

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Product Details of [ 98139-15-2 ]

CAS No. :98139-15-2
Formula : C6H5N3
M.W : 119.12
SMILES Code : N#CC1=NC=CC(N)=C1
MDL No. :MFCD07374351
InChI Key :GMKRESMCPMIWGU-UHFFFAOYSA-N
Pubchem ID :23131454

Safety of [ 98139-15-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 98139-15-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 33.36
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

62.7 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.85
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.22
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.54
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

-0.84
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

0.62
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.28

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.21
Solubility 7.34 mg/ml ; 0.0616 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.1
Solubility 9.55 mg/ml ; 0.0801 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-1.7
Solubility 2.37 mg/ml ; 0.0199 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

No
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.87 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.58

Application In Synthesis of [ 98139-15-2 ]

* 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 [ 98139-15-2 ]

[ 98139-15-2 ] Synthesis Path-Downstream   1~20

  • 2
  • [ 557-21-1 ]
  • [ 14432-12-3 ]
  • [ 98139-15-2 ]
YieldReaction ConditionsOperation in experiment
20% tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); at 145℃; for 20h; A mixture of 2-chloro-pyridin-4-ylamine (0.642 g, 5 mmol), Zn (CN) 2 (0.323 g, 2.75 mmol) and Pd (PPh3) 4 (0.288 g, 0.025 mmol) in 5 mL of DMF was heated at 145 C for 20 hours. After the reaction mixture cooled to room temperature, it was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried (MGS04), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 9: 1 HEXANES/ETHYL acetate to provide 0.29 g (20%) of the desired product. MS (DCI) m/e 120 (M+H) + ; IH NMR (300 MHz, DMSO-D6) 8 8.08 (d, J=5.76 Hz, 1H), 6.94 (d, J=2.34 Hz, 1H), 6.68 (dd, J=5. 76,2. 37 Hz, 1H), 6.59 (s, 2H).
  • 3
  • [ 98139-15-2 ]
  • [ 530-62-1 ]
  • C7H3N3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dimethyl sulfoxide; at 20℃; for 1.5h;Inert atmosphere; Step One & Two. N-(2-Cyanopyridin-4-yl)-6-hydroxy-2,4-dioxo- 1,2,3,4- tetrahydropyrimidine-5-carboxamide (H3)L_TO a solution of compound C2 (0.713 g, 4.40 mmol) in anhydrous DMSO (2 mL) was added compound HI (0.476 g, 4.00 mmol) at ambient temperature under nitrogen. The reaction mixture was then stirred for 1.5 h to provide a solution of compound H2 in DMSO which was used directly in the subsequent step.
  • 4
  • [ 98139-15-2 ]
  • N-(2-cyanopyridin-4-yl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [ No CAS ]
  • 5
  • methyl 4-(tert-butylsulfamoyl)-3-chloro-1-methyl-pyrrole-2-carboxylate [ No CAS ]
  • [ 98139-15-2 ]
  • 4-(tert-butylsulfamoyl)-3-chloro-N-(2-cyanopyridin-4-yl)-1-methyl-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
10 mg With lithium hexamethyldisilazane; In tetrahydrofuran; toluene; at 20℃; for 3h;Cooling with ice; Methyl 4-(tert-butylsulfamoyl)-3-chloro-l -methyl -pyrrole-2-carboxylate (50 mg, 0.16 mmol) and <strong>[98139-15-2]4-aminopyridine-2-carbonitrile</strong> (0.021 g, 0.18 mmol) were dissolved in THF (5 mL) and cooled in an ice bath. To this was added dropwise lithium bis(trimethylsilyl)amide in toluene (0.32 mL, 1 M, 0.32 mmol) over a period of 5 minutes. The resulting mixture was allowed to reach room temperature and was stirred for 3 hours. The resulting mixture was quenched using ammonium chloride (10 mL / aq. sat.). This was extracted using ethylacetate (3 X 20 mL). The combined extracts were washed with brine (20 mL), dried on Na2S04, filtered and concentrated in vacuo. The obtained crude was purified by silica gel column chromatography using gradient elution from heptane to iPrOH. (100:0 to 70:30). The desired fractions were concentrated in vacuo and dried in a vacuum oven at 55 C for 24 hours yielding compound 6 (10 mg) as a bright white powder. Method B; Rt: 0.91 min. m/z : 394.0 (M-H)~ Exact mass: 395.1. 1H NMR (0198) (400 MHz, DMSO-d6) delta ppm 1.18 (s, 9 H), 3.79 (s, 3 H), 7.38 (s, 1 H), 7.65 (s, 1 H), 7.90 (dd, J=5.6, 2.1 Hz, 1 H), 8.20 (d, J=2.0 Hz, 1 H), 8.63 (d, J=5.5 Hz, 1 H), 10.97 (br. s., 1 H).
  • 6
  • ethyl 3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate [ No CAS ]
  • [ 98139-15-2 ]
  • N-(2-cyanopyridin-4-yl)-3-fluoro-1-methyl-4-[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
47 mg With lithium hexamethyldisilazane; In tetrahydrofuran; toluene; at 0 - 20℃;Inert atmosphere; To ethyl 3-fluoro-l -methyl -4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxylate (128 mg, 0.37 mmol)and <strong>[98139-15-2]4-aminopyridine-2-carbonitrile</strong> (57.2 mg, 0.48 mmol) dissolved in dry THF (20 mL) at 0C under nitrogen atmosphere, lithium (0240) bis(trimethylsilyl)amide in toluene (1.5 mL, 1 M, 1.478 mmol) was added. The mixture was stirred 1 hour at 0C and further overnight at room temperature. The reaction mixture was quenched with NH4C1 solution (30 mL) and extracted with EtOAc (50 mL), diluted with brine (50 mL) and extracted again with EtOAc (50 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue (dissolved in 1 mL DMF) was purified by column chromatography on silica gel using a 120g Reveleris cartridge with a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated and the solid residue was crystallised from warm methanol (20 mL) upon addition of water. The light yellow crystals were filtered off and dried in vacuo at 50C overnight, resulting in compound 18 (47 mg). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.18 (d, J=6.8 Hz, 3 H), 3.82 (s, 3 H), 3.93 - 4.04 (m, 1 H), 7.62 (d, J=4.4 Hz, 1 H), 7.91 (dd, J=5.7, 2.2 Hz, 1 H), 8.21 (d, J=1.8 Hz, 1 H), 8.60 - 8.69 (m, 2 H), 10.72 (s, 1 H). Method D: Rt: 1.70 min. m/z: 418.0 (M-H)~ Exact mass: 419.1.
  • 7
  • ethyl 3-chloro-1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate [ No CAS ]
  • [ 98139-15-2 ]
  • 3-chloro-N-(2-cyano-4-pyridyl)-1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl]pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
29 mg With lithium hexamethyldisilazane; In tetrahydrofuran; at 20℃; Ethyl 1,5 -dimethyl- lH-pyrrole-2-carboxylate (2.5g, 15 mmol) was added drop wise to chlorosulfonic acid (10 mL, 150 mmol) at 0C under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was slowly added to ice-water (200 mL), followed by extraction with DCM (3 x 100 mL). The combined organic extracts were dried (Na2S04) and concentrated to give a light purple powder which decomposed over time to a dark sticky powder. This was dissolved in SOCl2 (8 mL, 110 mmol) and stirred 1 hour at 80C. The reaction mixture was concentrated and the residue was subjected to column chromatography on a Reveleris 120g cartridge using a gradient from 10 till 50 % EtOAc in heptane. The product fractions were concentrated to dryness yielding ethyl 4-chlorosulfonyl-l,5-dimethyl-pyrrole-2-carboxylate (600 mg) as white powder. Ethyl 4- chlorosulfonyl-l,5-dimethyl-pyrrole-2-carboxylate (600 mg, 2.26 mmol) was dissolved in ACN (4 mL) and dried on molecular sieves and NaHC03 (1.39 g, 16.5 mmol) was added. (R)-l,l,l- trifluoro-2-propylamine (766 mg, 6.77 mmol) was dissolved in ACN (1 mL) and dried on molecular sieves. The two suspensions were combined and heated at 80C for 4 hours. The reaction mixture was filtered and the filter cake was washed with acetonitrile. The combined filtrates were evaporated to dryness and the residue was purified using silica gel column chromatography to afford ethyl l,5-dimethyl-4-[[(lR)-2,2,2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxylate (600 mg) as co lories sticky powder. (0292) Ethyl l,5-dimethyl-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate (400 mg, 1.17 mmol) was dissolved in HO Ac (10 mL) and NCS (156 mg, 1.17 mmol) was added. The reaction mixture was heated at 40C over weekend. The reaction mixture was evaporated to dryness and the residue was purified using silica gel column chromatography (0293) (EtOAc in heptane from 0 to 100% to afford crude product which was purified again using silica gel column chromatography using methanol in DCM from 0.1 to 0.5 % to afford ethyl 3-chloro- l,5-dimethyl-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate (177 mg). Method D: Rt: 1.89 min. m/z: 375 (M-H)~ Exact mass: 376.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.12 (d, J=7.0 Hz, 3 H), 1.30 (t, J=7.2 Hz, 3 H), 2.48 (s, 3 H), 3.75 (s, 3 H), 3.82 - 3.94 (m, 1 H), 4.29 (q, J=7.0 Hz, 2 H), 8.42 (br. s., 1 H). Ethyl 3-chloro-l,5-dimethyl-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxylate (88 mg , 0.23 mmol) and <strong>[98139-15-2]4-aminopyridine-2-carbonitrile</strong> (33.4 mg, 0.28 mmol) were dissolved in THF (10 mL). Lithium bis(trimethylsilyl)amide (0.7 mL, 1 M, 0.7 mmol) was added drop wise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with sat. NH4C1 (5 mL). The organic layer was removed and the aqueous layer extracted with DCM (2 X 5 mL). The combined organic layers were evaporated to dryness and the residue was purified on silica (EtOAc in heptane from 0 to 100%) to afford a white powder. A second purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OmicronBeta-10muiotaeta,30chi150iotaetaiotaeta, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH) yielding compound 32 (29 mg) as a white powder. Method B: Rt: 0.93 min. m/z: 448 (M-H)~ Exact mass: 449.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.17 (d, J=6.8 Hz, 3 H), 2.48 - 2.52 (m, 3 H), 3.65 (s, 3 H), 3.94 (spt, J=7.2 Hz, 1 H), 7.91 (dd, J=5.6, 2.1 Hz, 1 H), 8.21 (d, J=1.8 Hz, 1 H), 8.45 (br. s., 1 H), 8.65 (d, J=5.7 Hz, 1 H), 11.05 (br. s., 1 H).
  • 8
  • ethyl 3-fluoro-1-methyl-4-[[1-(trifluoromethyl)cyclopropyl]sulfamoyl]pyrrole-2-carboxylate [ No CAS ]
  • [ 98139-15-2 ]
  • N-(2-cyano-4-pyridyl)-3-fluoro-1-methyl-4-[[1-(trifluoromethyl)cyclopropyl]sulfamoyl]pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
51 mg With lithium hexamethyldisilazane; In tetrahydrofuran; at 20℃; for 3h;Inert atmosphere; Ethyl 4-chlorosulfonyl-3-fluoro-l-methyl-pyrrole-2-carboxylate (1500 mg, 5.56 mmol) was dissolved in dry pyridine (26.25 mL, 325.2 mmol). l-(trifluoromethyl)cyclopropan-l -amine (1392 mg, 11.1 mmol) was added and the mixture was stirred at 70C for 6 hours. The mixture was concentrated in vacuo. The obtained residue was purified by silica gel column (0877) chromatography using gradient elution from heptane to EtOAc (100:0 to 0: 100) yielding ethyl 3-fluoro- 1 -methyl-4-[[ 1 -(trifluoromethyl)cyclopropyl]sulfamoyl]pyrrole-2-carboxylate (1.21 g) as a beige powder. Ethyl 3-fluoro-l-methyl-4-[[l- (0878) (trifluoromethyl)cyclopropyl]sulfamoyl]pyrrole-2-carboxylate (0.15 g, 0.31 mmol) and (0879) <strong>[98139-15-2]4-aminopyridine-2-carbonitrile</strong> (40.05 mg, 0.34 mmol) were dissolved in THF (3 mL) in a tube. The tube was flushed with nitrogen, capped with a septum and stirred at room temperature. To this was added lithium bis(trimethylsilyl)amide (0.76 mL, 1 M, 0.76 mmol) at once using a syringe. The obtained solution was stirred for 3 hours. Then ammonium chloride (aq. / sat. / 10 mL) was added and the layers where separated. Then it was extracted once using ethyl acetate (10 mL). The combined extracts were concentrated in vacuo and purified by silica gel column chromatography using gradient elution from heptane to EtOAc. (100:0 to 0:100). The obtained fractions were concentrated in vacuo and repurified by Prep HPLC on (RP SunFire Prep CI 8 OmicronBeta-10muetaiota,30chi150etaiotaetaiota). Mobile phase (0.25% NH4HCO3 solution in water, MeOH). The desired fractions were concentrated under reduced pressure and co-evaporated twice with methanol (2 X 20 mL) and dried in a vacuum oven at 55C for 18 hours resulting in compound 192 (51 mg) as a white powder. Method B: Rt: 0.90 min. m/z: 430.1 (M-H)" Exact mass: 431.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.14 - 1.30 (m, 4 H), 3.75 - 3.89 (m, 3 H), 7.57 (d, J=4.6 Hz, 1 H), 7.90 (dd, J=5.6, 2.1 Hz, 1 H), 8.21 (d, J=2.0 Hz, 1 H), 8.63 (d, J=5.7 Hz, 1 H), 9.15 (br. s., 1 H), 10.67 (br. s., 1 H).
  • 9
  • ethyl 3-fluoro-1-methyl-4-[(2,2,2-trifluoro-1,1-dimethylethyl)sulfamoyl]pyrrole-2-carboxylate [ No CAS ]
  • [ 98139-15-2 ]
  • N-(2-cyano-4-pyridyl)-3-fluoro-1-methyl-4-[(2,2,2-trifluoro-1,1-dimethylethyl)sulfamoyl]pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
45 mg With lithium hexamethyldisilazane; In tetrahydrofuran; at 20℃; for 3h;Inert atmosphere; Ethyl 4-chlorosulfonyl-3-fluoro-l-methyl-pyrrole-2-carboxylate (1200 mg, 4.45 mmol) was dissolved in dry pyridine (21 mL, 0.98 g/mL, 260.17 mmol). l,l,l-trifluoro-2-methylpropan-2- amine (1131.2 mg, 8.9 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution from heptane to EtOAc (100:0 to 0: 100) yielding ethyl 3- fluoro-l-methyl-4-[(2,2,2-trifluoro-l,l-dimethyl-ethyl)sulfamoyl]pyrrole-2-carboxylate (1.15 g) as a beige powder which was used as such in the next step. Ethyl 3-fluoro-l-methyl-4-[(2,2,2- trifluoro- l,l-dimethyl-ethyl)sulfamoyl]pyrrole-2-carboxylate (0.15 g, 0.42 mmol) and (0863) <strong>[98139-15-2]4-aminopyridine-2-carbonitrile</strong> (54.55 mg, 0.46 mmol) were dissolved in THF (4.1 mL) in a tube. The tube was flushed with nitrogen, capped with a septum and stirred at room temperature. To this was added lithium bis(trimethylsilyl)amide (1.04 mL, 1 M, 1.04 mmol) at once using a syringe. The obtained solution was stirred for 3 hours. Then ammonium chloride (aq. / sat. / 10 mL) was added and the layers where separated. Then it was extracted once using ethyl acetate (10 mL). The combined extracts were concentrated in vacuo and purified by silica gel column chromatography using gradient elution from heptane to EtOAc. (100:0 to 0:100). The obtained fractions were concentrated in vacuo and repurified by Prep HPLC (RP SunFire Prep CI 8 OmicronBeta-10muiotaeta,30chi150 mm), mobile phase (0.25% NH4HCO3 solution in water, MeOH). The desired fractions were concentrated under reduced pressure and co-evaporated twice with methanol (2 X 20 mL) and dried in a vacuum oven at 55C for 18 hours yielding compound 188 (45 mg) as a white powder. Method B: Rt: 0.94 min. m/z: 432.1 (M-H)" Exact mass: 433.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.39 (s, 6 H), 3.83 (s, 3 H), 7.58 (d, J=4.4 Hz, 1 H), 7.91 (dd, J=5.6, 1.9 Hz, 1 H), 8.21 (d, J=1.8 Hz, 1 H), 8.47 (br. s., 1 H), 8.63 (d, J=5.7 Hz, 1 H), 10.67 (br. s., 1 H)
  • 10
  • 1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxylic acid [ No CAS ]
  • [ 98139-15-2 ]
  • N-(2-cyanopyridin-4-yl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
4.6 g l-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-lH-pyrrole-2-carboxylic acid (200 mg, (0182) 0.729 mmol) was dissolved in DMF (1.7 mL) and triethylamine (0.41 mL, 2.9 mmol) and HATU (360 mg, 0.95 mmol) were added. After 10 minutes <strong>[98139-15-2]4-aminopyridine-2-carbonitrile</strong> (174 mg, 1.46 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and heated at 65C for 42 hours. The mixture was poured into water (50 mL) and the organics were extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried (Na2S04) and concentrated to dryness. The residue was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 100%) followed by prep. HPLC (Stationary phase: RP SunFire Prep C18 OBD-IotaOmicronmuiotaeta, 30 x 150mm), Mobile phase: 0.5% NH4OAc solution in water + 10% CH3CN, MeOH), resulting in compound 1 (4.6 mg). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.54 (s, 3 H), 3.94 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.43 (s, 1 H), 7.66 (d, J=1.3 Hz, 1 H), 7.86 - 8.12 (m, 2 H), 8.26 (d, J=2.0 Hz, 1 H), 8.60 (d, J=5.7 Hz, 1 H), 10.68 (br. s., 1 H). Method A; Rt: 1.22 min. m/z : 374.0 (M-H)~ Exact mass: 375.1.
  • 11
  • (3R*,4R*)-2-isobutyl-1-oxo-3-(thiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid [ No CAS ]
  • [ 98139-15-2 ]
  • C24H22N4O2S [ No CAS ]
  • 12
  • C17H13Cl2NO3S [ No CAS ]
  • [ 98139-15-2 ]
  • 5-chloro-N-(2-cyanopyridin-4-yl)-3-((3,5-dimethylphenyl)-sulfonyl)-1H-indole-2-carboxamide [ No CAS ]
  • 13
  • [ 19235-89-3 ]
  • [ 98139-15-2 ]
  • 14
  • 4-((diphenylmethylene)amino)picolinonitrile [ No CAS ]
  • [ 98139-15-2 ]
YieldReaction ConditionsOperation in experiment
81% With hydrogenchloride; In methanol; at 20℃; for 2h; Into a 50-mL round-bottom flask, was placed 4-[(diphenylmethylidene)amino] pyridine-2-carbonitrile (1.23 g, 2.17 mmol, 1.00 equiv., 50%), hydrogen chloride(2M) (8 mL, 2.00 equiv.), methanol (24 mL). The resulting solution was stirred for 120 min at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 2x10 mL of dichloromethane and the water phase combined. The pH value of the water phase was adjusted to 8 with sodium bicarbonate (sat. solution). The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x20 mL of brine, dried over Na2SC the solids were filtered out. The residue was evaporated and the result solid was dried in an oven under reduced pressure. This resulted in 0.28 g (81%) of 4-aminopyridine-2-carbonitrile as a yellow solid.
  • 15
  • [ 98139-15-2 ]
  • N-(2-(aminomethyl)pyridin-4-yl)-5-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)pyridin-2-amine [ No CAS ]
  • 16
  • [ 98139-15-2 ]
  • 5-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)-N-(2-(((tetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-4-yl)pyridin-2-amine hydrochloride [ No CAS ]
  • 17
  • 2-bromo-5-methoxy-4-[3-(pyrrolidin-1-yl)propoxy]pyridine [ No CAS ]
  • [ 98139-15-2 ]
  • 4-((5-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)pyridin-2-yl)amino)picolinonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
20% With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; caesium carbonate; tert-butyl XPhos; In 1,4-dioxane; at 110℃; for 16h;Sealed tube; Into a 30-mL sealed tube, was placed 2-bromo-5-methoxy-4-[3-(pyrrolidin-l- yl)propoxy]pyridine (314 mg, 1.00 mmol, 1.00 equiv.), <strong>[98139-15-2]4-aminopyridine-2-carbonitrile</strong> (240 mg, 2.01 mmol, 2.00 equiv.), Pd2(dba)3-chloroform (0.1 g, 0.10 equiv.), t-BuXPhos (0.085 g, 0.20 equiv.), Cs2C03 (970 mg, 2.97 mmol, 3.00 equiv.), dioxane (10 mL). The resulting solution was stirred for 16 h at 110 C in an oil bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined. The organic layer was washed with 1x50 mL of brine, dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (3 mL) was purified by Flash- Prep-HPLC with the following conditions (CombiFlash-1): Column, C18 silica gel; mobile phase, MeCN:Water=l :5 increasing to MeCN:Water=10: l within 120 min; Detector, UV 254 nm. 70 mg product was obtained. This resulted in 70 mg (20%) of 4-([5-methoxy-4-[3- (pyrrolidin-l-yl)propoxy]pyridin-2-yl]amino)pyridine-2-carbonitrile as an off-white solid.
  • 18
  • [ 98139-15-2 ]
  • 4-(4-(12-β-dihydroartemisinoxymethyl)-1H-1,2,3-triazol-1-yl)-picolinonitrile [ No CAS ]
  • 19
  • [ 98139-15-2 ]
  • C6H3N5 [ No CAS ]
  • 20
  • 1-(naphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [ No CAS ]
  • [ 98139-15-2 ]
  • N-(2-cyanopyridin-4-yl)-1-(naphthalen1-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With pyridine; trichlorophosphate; at 0℃; for 1h; P0C13 (0.3 mE) was added dropwise to a solution consisting of 1 -(naphthalen- 1 -yl)-5-(trifluoromethyl)-i Hpyrazole-4-carboxylic acid 2b (150 mg, 0.490 mmol), <strong>[98139-15-2]4-aminopicolinonitrile</strong> (64.2 mg, 0.53 9 mmol) and pyridine (5 mE). The mixture was stirred at 0 C. for 1 h. The resulting mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative HPEC (40% to 70% (v/v) ACN and H20 with 0.05% NH3) to afford compound 1. Compound 1 was concentrated to dryness under reduced pressure (101.30 mg, 5 1%). ECMS (ESI): RT=5.45 mm, mass calcd. for C2,H,2F3N50 407.348, mlz found 408.0 [M+H]. ?H NMR (400 MHz, DMSO-d5) oe ppm 11.31 (s, 1H), 8.71 (d, J=5.2 Hz, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H),8.00 (d, J=4.0 Hz, 1H), 7.83-7.77 (m, 1H), 7.76-7.62 (m, 3H), 7.14 (d, J=8.0 Hz, 1H).
 

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