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Chemical Structure| 55512-82-8 Chemical Structure| 55512-82-8

Structure of 3-Bromoisothiazole
CAS No.: 55512-82-8

Chemical Structure| 55512-82-8

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Product Details of [ 55512-82-8 ]

CAS No. :55512-82-8
Formula : C3H2BrNS
M.W : 164.02
SMILES Code : BrC1=NSC=C1
MDL No. :MFCD07778378
InChI Key :OTNWEAKNUYQUKP-UHFFFAOYSA-N
Pubchem ID :15323364

Safety of [ 55512-82-8 ]

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

Computational Chemistry of [ 55512-82-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 6
Num. arom. heavy atoms 5
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 0.0
Molar Refractivity 29.81
TPSA ?

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

41.13 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.69
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

2.01
Log Po/w (WLOGP)?

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

1.91
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.

0.53
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

3.07
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.84

Water Solubility

Log S (ESOL):?

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

-2.74
Solubility 0.299 mg/ml ; 0.00182 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-2.5
Solubility 0.518 mg/ml ; 0.00316 mol/l
Class?

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

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

-2.14
Solubility 1.2 mg/ml ; 0.00729 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

Yes
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.

-5.87 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

2.0
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)

2.62

Application In Synthesis of [ 55512-82-8 ]

* 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.

  • Downstream synthetic route of [ 55512-82-8 ]

[ 55512-82-8 ] Synthesis Path-Downstream   1~16

  • 4
  • [ 55512-82-8 ]
  • N-(4-bromo-3-[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide [ No CAS ]
  • 2-(2-chlorophenyl)-N-[3-sulfamoyl-4-(1,2-thiazol-3-yl)phenyl]acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
1% General procedure: N-(4-Bromo-3-[(d imethylam ino)methylene]su lfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (amount as indicated in examples) was dissolved in methanol (3 mL in case of 0.59 mmol scale) and degassed with nitrogen. Bis(pinacolato)diboron (2.5 eq), mesylate[(di(1 -adamantyl)-n-butylphosphine)-2-(2?-amino-1 ,1 ?-biphenyl)]palladium(l I) (cataCXium A Pd G3, 0.05 eq) and N,N-diisoproyplethylamine (2.5 eq) were added andit was stirred for 1 hour at 50C. The catalyst was removed by filtration and the filtrate was reduced in vacuo.The crude was redissolved in n-propanol (3 mL in case of 0.59 mmol scale), followed by degassing with nitrogen. The corresponding hetarylbromide (2 eq), potassium fluoride (0.23 eq), bis(tri-tert-butylphosphine)palladium(0) (0.05 eq) and triphenylphosphine (0.05 eq) were added. It was again degassed with nitrogen and potassium phosphate (2.5 eq) was added, followed by irradiating for 1 hour at 10000 in the microwave.Any precipitate was removed by filtration and the filtrate was concentrated in vacuo andredissolved in methanol (2 mL in case of 0.59 mmol scale). Aqueous ammoniumhydroxide solution (33%, 2 mL) was added. It was stirred until UPLC-MS showed completion of deprotection. In most cases stirring overnight was sufficient, in certain cases longer stirring and addition of further aqueous ammonium hydroxide solution was necessary. The reaction mixture was then concentrated in vacuo and purified as indicatedintheexamples.
  • 5
  • [ 55512-82-8 ]
  • 2-(difluoromethoxy)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline [ No CAS ]
  • 3-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)isothiazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
37.2% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 90℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation; Intermediate I-1 (15 mg, 0.045 mmol) and <strong>[55512-82-8]3-bromoisothiazole</strong> (10.98 mg, 0.067 mmol) were dissolved in DMF (446 muL). PdCl2(dppf)-CH2Cl2 (2.187 mg, 2.68 mumol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 26.8 muL, 0.054 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90 °C in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 35 to 80percent B in 10 minutes) to give Example 5 (5.0 mg, 0.017 mmol, 37.2percent): 1H NMR (500MHz, METHANOL-d4) delta 8.89 (d, J=4.7 Hz, 1H), 8.59 (s, 1H), 8.13 (d, J=1.9 Hz, 1H), 8.10 (d, J=4.7 Hz, 1H), 7.84-7.52 (m, 2H), 2.64 (s, 3H); LC^MS: Method H, RT = 1.08 min, MS (ESI) m/z: 293.9 (M+H)+; Analytical HPLC Method B: 97.4percent purity
  • 6
  • [ 55512-82-8 ]
  • 2-butyl-3-((5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one [ No CAS ]
  • 2-butyl-3-((5'-(isothiazol-3-yl)-2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% Intermediate 123d was reacted with <strong>[55512-82-8]3-bromoisothiazole</strong> in a method analogous to Example 122 to give Example 123 (5.9 mg, 11.5 muiotaetaomicron, 46percent). LC-MS (Method Al) RT = 1.39 min, MS (ESI) m/z: 512.4 (M+H)+. H NMR (500 MHz, DMSO-cfe) delta 9.18 (d, 7=4.6 Hz, 1H), 8.12 (br d, 7=7.9 Hz, 1H), 8.09 - 8.01 (m, 2H), 7.75 (br d, 7=7.9 Hz, 1H), 7.17 (br d, 7=7.9 Hz, 2H), 7.07 (br d, 7=7.9 Hz, 2H), 4.68 (s, 2H), 2.32 (t, 7=7.6 Hz, 2H), 1.90 - 1.77 (m, 6H), 1.67 (br d, 7=6.7 Hz, 2H), 1.49 (quin, 7=7.5 Hz, 2H), 1.27 (dq, 7=14.9, 7.4 Hz, 2H), 0.81 (t, 7=7.3 Hz, 3H) (1 exchangeable proton not observed).
  • 7
  • [ 55512-82-8 ]
  • [4-[3-(benzyloxy)propyl]quinolin-7-yl]boronic acid [ No CAS ]
  • 4-[3-(benzyloxy)propyl]-7-(1,2-thiazol-3-yl)quinolone [ No CAS ]
YieldReaction ConditionsOperation in experiment
49.28% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 4h;Inert atmosphere; In a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [4-[3-(benzyloxy)propyljquinolin-7-yljboronic acid (904 mg, 2.81 mmol, 1 equiv), Na2CO3 (596.6 mg, 5.63 mmol, 2 equiv), <strong>[55512-82-8]3-bromo-1,2-thiazole</strong> (923.3 mg, 5.63 mmol, 2 equiv), and Pd(PPh3)4 (325.2 mg, 0.28 mmol, 0.1 equiv) in dioxane (20 mL) and H20 (5 mL). The resulting solution was stirred for 4 hours at 80 °C in an oil bath. The resulting mixture was cooled to room temperature and concentrated. Theresidue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 500 mg (49.28percent) of 4- [3 -(benzyloxy)propylj -7-( 1 ,2-thiazol-3-yl)quinoline as a light brow solid. LC-MS: (ES, m/z): [M+Hj = 361.1.
  • 8
  • [ 55512-82-8 ]
  • (R)-6-(3-hydroxypyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(chloro difluoromethoxy)phenyl)nicotinamide [ No CAS ]
  • (R)-6-(3-hydroxypyrrolidin-1-yl)-5-(isothiazol-3-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; To a reaction flask were added compound 5 (200 mg, 0.392 mmol), <strong>[55512-82-8]3-bromoisothiazole</strong> (96 mg, 0.588 mmol), Pd(dppf)Cl2 (32 mg, 0.02 mmol) and sodium carbonate (126 mg, 1.18 mmol), 2 mL glycol dimethyl ether and 0.4 mL water were added, bubbled with nitrogen gas for 10 minutes, heated to 120 C in microwave and reacted for 0.5 hour. After TLC detected the reaction was complete, the reaction was concentrated, purified by silica gel column chromatography to afford 84 mg of a product, yield: 46%. LC-MS(APCI): m/z = 467.3(M+1)+; 1H NMR (400 MHz, DMSO) delta 10.17 (s, 1H), 9.04 (s, 1H), 8.90 (s, 1H),8.76 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 9.1 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 4.86 (d, J = 3.4 Hz, 1H), 4.21 (s, 1H), 3.41 (dd, J = 17.0, 9.3 Hz, 1H), 3.29 - 3.18 (m, 2H), 2.90 (d, J = 11.1 Hz, 1H), 1.89 - 1.80 (m, 1H), 1.75 (s, 1H).
  • 9
  • [ 55512-82-8 ]
  • [ 183723-09-3 ]
  • 3-bromo-N-(isothiazol-3-yl)-4-methylbenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% With copper(l) iodide; (1R,2R)-1,2-diaminocyclohexane; potassium carbonate; In 1,4-dioxane; at 120℃; for 12h; To a solution of 3-bromo-4-methylbenzamide (78.30 mg, 365.80 pmol) in dioxane (2 mL) were added <strong>[55512-82-8]3-bromoisothiazole</strong> (50 mg, 304.83 pmol), Cul (11.61 mg, 60.97 pmol), (li?,2i?)-cyclohexane-l,2-diamine (6.96 mg, 60.97 pmol) and K2CO3 (84.26 mg, 609.67 pmol). The reaction mixture was stirred at 120C for 12 hours, then poured into water extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, and concentrated under reduce pressure. The crude product was purified by column chromatography (S1O2) eluting with a gradient of 5-10% EtOAc in petroleum ether to give the title compound as a yellow solid (40 mg, 44%). NMR (400 MHz, DMSO-Tis) d ppm 2.43 (s, 3 H) 7.51 (d, 7=8.0 Hz, 1 H) 7.87 (d, 7=4.8 Hz, 1 H) 7.96 (dd, Ji = 8.0, J2 = 2.0 Hz, 1 H) 8.18 - 8.38 (m, 1 H) 9.07 (d, 7=4.8 Hz, 1 H) 11.55 (s, 1 H); ESI-MS m/z [M+H]+ =297.0.
  • 10
  • [ 55512-82-8 ]
  • 5-bromo-2-fluoro-4-methylbenzamide [ No CAS ]
  • 5-bromo-2-fluoro-N-(isothiazol-3-yl)-4-methylbenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% With copper(l) iodide; (1R,2R)-1,2-diaminocyclohexane; potassium carbonate; In 1,4-dioxane; at 120℃; under 760.051 Torr; for 16h;Inert atmosphere; A mixture of 5-bromo-2-fluoro-4-methylbenzamide (300 mg, 1.29 mmol), 3- bromoisothiazole (212.05 mg, 1.29 mmol), Cul (49.24 mg, 258.57 pmol), K2CO3 (357.35 mg, 2.59 mmol) and ( 17?, 2i?)-cyclohexane- 1,2-diamine (29.53 mg, 258.57 pmol) in dioxane (4 mL) was degassed and purged with N2 (3 x). The reaction mixture was stirred at 120C for 16 hours under N2 atmosphere and then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2S04 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (S1O2) eluting with a gradient of 0-20% EtOAc in petroleum ether to give the title compound as a white solid (150 mg, 37%). NMR (400 MHz, DMSO-r/e) d ppm 2.47 (s, 3 H) 7.12 (d, =12.4 Hz, 1 H) 8.03 (d, J= 4.8 Hz, 1 H) 8.34 (d, =7.6 Hz, 1 H) 8.67 (d, =4.8 Hz, 1 H) 9.32 (d, .7=13.6 Hz, 1 H); ESI-MS m/z [M+H]+ = 314.8.
  • 11
  • [ 55512-82-8 ]
  • tert-butyl (R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate [ No CAS ]
  • tert-butyl (R)-3-((5-(isothiazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 16h; To a stirred solution of tert-butyl (R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1- carboxylate (0.72 g, 1.25 mmol) and <strong>[55512-82-8]3-bromoisothiazole</strong> (0.3 g, 1.63 mmol) in 1,4-dioxane (20 mL) was added tetrakis(triphenyl phosphine)palladium(0) (0.18 g, 0.25 mmol) followed by 2M aqueous solution of sodium carbonate (0.4 g, 3.77 mmol) and the reaction mixture heated at 100 C for16 hours. After cooling the reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (25% ethyl acetate/hexane) to provide tert-butyl (R)-3-((5- (isothiazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidine-1-carboxylate as a pale yellow liquid (0.23 g, 35% yield): MS (ES) m/z 529.9 (M+H).
  • 12
  • [ 55512-82-8 ]
  • 5-(trifluoromethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine [ No CAS ]
  • 2-(isothiazol-3-yl)-5-(trifluoromethyl)aniline [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate; methanesulfonic acid(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); In 1,4-dioxane; water; at 80℃; for 1h;Inert atmosphere; To a reaction vessel containing 3- bromoisothiazole (114 mg, 0.697 mmol), the product from Example 128 Step 1 (250 mg, 0.697 mmol), 1 M KsP04(aq) (1.20 ml, 1.20 mmol) and dioxane (4.80 ml) was added XPhos Pd G3 (29.5 mg, 0.035 mmol). The resultant reaction mixture was degassed with N2 for 10 min and then heated to 80 C for 1 h. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-15%EtOAc/isohexane) to afford the title compound (154 mg, 0.580 mmol, 83% yield, 92% purity) as a light brown solid. UPLC-MS (Method 1): m/z 245.2 (M+H)+(ES+), at 1.57 min.1H NMR (500 MHz, DMSO-cfe) d 9.16 (d, J = 4.8 Hz, 1 H), 8.00 (d, = 4.9 Hz, 1 H), 7.95 (d, J = 8.2 Hz, 1 H), 7.16 (d, J = 1.9 Hz, 1 H), 7.12 (br s, 2H), 6.86 (dd, J = 8.4, 1.9 Hz, 1 H).
  • 13
  • [ 55512-82-8 ]
  • 3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile [ No CAS ]
  • 3-amino-4-(isothiazol-3-yl)benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With potassium phosphate; methanesulfonic acid(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere; To a reaction vessel containing the product from Example 152 Step 1 (236 mg, 0.706 mmol), <strong>[55512-82-8]3-bromoisothiazole</strong> (127 mg, 0.776 mmol), 1 M KsP04(aq) (1.24 ml, 1.24 mmol) and dioxane (4.96 ml) was added XPhos Pd G3 (30 mg, 0.035 mmol). The resultant reaction mixture was degassed with N2 for 10 min and then heated to 80 C for 2 h. The reaction mixture was allowed to cool to RT, filtered through Celite, washed with MeOH (10 ml) and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-25% EtOAc/isohexane) to afford the title compound (104 mg, 0.511 mmol, 72% yield, 99% purity) as a yellow solid. UPLC- MS (Method 1): m/z 202.2 (M+H)+(ES+), at 1.26 min.1H NMR (500 MHz, DMSO-cfe) d 9.17 (d, J = 4.8 Hz, 1 H), 8.02 (d, = 4.8 Hz, 1 H), 7.94 (d, = 8.1 Hz, 1 H), 7.19 (d, = 1.7 Hz,1 H), 7.14 (br s, 2H), 6.97 (dd, J = 8.1 , 1.7 Hz, 1 H).
  • 14
  • [ 55512-82-8 ]
  • 5-amino-2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile [ No CAS ]
  • 5-amino-2-chloro-4-(isothiazol-3-yl)benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 1h;Inert atmosphere; A mixture of the product from Example 178 Step 1 (100 mg, 322 pmol, 90% purity), <strong>[55512-82-8]3-bromoisothiazole</strong> (31 pi, 352 pmol), 1 M K3PC>4(aq) (550 mI, 550 pmol) and dioxane (3 ml) was treated with Pd(dppf)Cl2- DCM complex (13 mg, 15.9 pmol). The resultant solution was degassed with N2 for 10 min, then heated at 80 C for 1 h. The reaction mixture was concentrated onto silica and purified by chromatography on silica gel (24 g cartridge, 0-40% EtOAc/isohexane) to afford the title compound (57 mg, 227 pmol, 70% yield, 94% purity) as a yellow solid. UPLC-MS (Method 1) m/z 236.1 (M+H)+at 1.43 min
  • 15
  • [ 55512-82-8 ]
  • 5-amino-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile [ No CAS ]
  • 5-amino-2-fluoro-4-(isothiazol-3-yl)benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 1h;Inert atmosphere; A mixture of the product from Step 1 above (200 mg, 736 pmol, 96% purity), <strong>[55512-82-8]3-bromoisothiazole</strong> (65 pi, 0.74 mmol), 1M K3PC>4(aq) (1.30 ml, 1.30 mmol) and dioxane (6 ml) was treated with Pd(dppf)CI2-DCM complex (30 mg, 37 pmol). The resultant solution was degassed with N2for 10 min, then heated at 80 C for 1 h. The reaction mixture was concentrated onto silica and purified by chromatography on silica gel (40 g cartridge, 0-40% EtOAc/isohexane) to afford the title compound (81 mg, 364 pmol, 50% yield, 99% purity) as a yellow solid. UPLC-MS (Method 1) m/z 220.2 (M+H)+at 1.32 min.
  • 16
  • [ 55512-82-8 ]
  • [ 5419-55-6 ]
  • C9H16BNO2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium; In tetrahydrofuran; at -70℃; for 1h;Inert atmosphere; To a mixture of 88a (0.30 g, 1.83 mmol, 1.00 eq) and triisopropyl borate (482 mg, 2.56 mmol, 589 uL, 1.40 eq) in THF (4 mL) n-BuLi (2.5 M, 1.02 mL, 1.40 eq) was added drop- wise at -70C under N2. The reaction mixture was stirred at -70C for 1 hr. LCMS showed the starting material was consumed completely. Water (8 mL) was added to the reaction mixture at 0C, and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give 88b (0.34 g, crude) as a brown oil.
 

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