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Chemical Structure| 151169-74-3 Chemical Structure| 151169-74-3

Structure of 2,3-Dichlorophenylboronic acid
CAS No.: 151169-74-3

Chemical Structure| 151169-74-3

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Product Details of [ 151169-74-3 ]

CAS No. :151169-74-3
Formula : C6H5BCl2O2
M.W : 190.82
SMILES Code : OB(C1=CC=CC(Cl)=C1Cl)O
MDL No. :MFCD01075703
InChI Key :TYIKXPOMOYDGCS-UHFFFAOYSA-N
Pubchem ID :2734661

Safety of [ 151169-74-3 ]

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

Computational Chemistry of [ 151169-74-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 2.0
Molar Refractivity 46.29
TPSA ?

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

40.46 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.0
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

2.08
Log Po/w (WLOGP)?

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

0.67
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.

1.48
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

0.57
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.96

Water Solubility

Log S (ESOL):?

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

-2.67
Solubility 0.407 mg/ml ; 0.00213 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.

-2.56
Solubility 0.526 mg/ml ; 0.00276 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

-2.52
Solubility 0.572 mg/ml ; 0.003 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.

-5.99 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

1.0 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)

1.97

Application In Synthesis of [ 151169-74-3 ]

* 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 [ 151169-74-3 ]

[ 151169-74-3 ] Synthesis Path-Downstream   1~54

  • 1
  • [ 10168-58-8 ]
  • [ 151169-74-3 ]
  • [ 847406-09-1 ]
YieldReaction ConditionsOperation in experiment
36% With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 90℃; for 48h; To a stirred solution of 4-BROMO-3-METHYL- pyridine N-oxide (0.985 G, 5.2 mmol) (prepared from 4-bromo-3-methyl-pyridine in the same manner as in Example 1B) and 2,3-dichloro PHENYLBORONIC acid (1-. 0 G, 5.2 mmol) in DME (5.8 mL) was added potassium carbonate (0.869 g, 6.3 mmol). The mixture was de- gassed by bubbling nitrogen with a syringe for 5 min through the mixture, followed by addition of Pd- (PPH3) 4 (0.606 g, 0.52 mmol). A reflux condenser was attached to the flask and the mixture heated to 90C for 48 h. The mixture was cooled to ambient temper- ature and partitioned between ethyl acetate and brine. The organic layer was washed with brine (3X20 ML) and dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel elut- ing with 4% 7 N methanolic ammonia/DCM to provide the title compound (0.483 g, 5.24 mmol, 36% yield) as a white SOLID. 1H NMR (CDC13, 400 MHz) 5-8. 18 (s, 1H), 8. 14 (m, 1H), 7.57 (m, 1H), 7.33 (t, J=8 Hz, 1H), 7.15 (m, 1H), 7. 08 (d, J=6., 64 Hz, 1H, 2. 10 (s, 3H).
  • 2
  • [ 847406-13-7 ]
  • [ 151169-74-3 ]
  • [ 847406-17-1 ]
YieldReaction ConditionsOperation in experiment
30.5% With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 85℃; for 18h; To a stirred solution of 7A (0.800 g, 2.55 mmol) in 10 mL toluene was added 2, 3-dichlorophenyl boronic acid (0.975 g, 5.11 mmol) and cesium car- bonate (1. 33 g, 5.62 mmol). The mixture was de- gassed with nitrogen for 10 MIN, THEN E>D (PPh3) 4 (0. 148 g, 0. 128 mmol) was added. The mixture was heated to 85C for 18 h then cooled to ambient tem- perature. The crude product was partitioned between toluene and brine. The organic layer was washed (2 X 30 ML) with brine and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel eluting with 2: 1 EtOAc/Hexane to pro- vide the title compound (0.295 g, 30. 5%) as a light oil which solidified upon standing to a white solid. 1H NMR (CDC13 400 MHz) 5 8.33 (d, J=2. 73 Hz, 1H), 8. 1 (d, J=1.56 Hz, 1H)., 7.51 (dd, J=1.95, 7.80 Hz, 1H), 7.27 (t, J=3.9 Hz, 1H), 7.23 (m, 2H), 4.2 (q, J=7. 02,14. 04 Hz, 2H), 3.71 (m, 2H), 2.91 (m, 2H), 2.49 (m, 1H), 2.05 (m, 2H), 1.9 (m, 2H), 1.28 (t, J=7.41 Hz, 3H).
  • 3
  • [ 3510-66-5 ]
  • [ 151169-74-3 ]
  • [ 847406-05-7 ]
YieldReaction ConditionsOperation in experiment
27% With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 90℃; for 48h; To a stirred solution of 2-bromo-5-methyl- pyridine (1.00 g, 5.81 mmol) and 2,3-dichloro phen- ylboronic acid (1.33 g, 6. 98 mmol) in DME (5.8 ML) was added potassium carbonate (1.21 g, 8.7 mmol). The mixture was degassed by bubbling nitrogen with a syringe for 5 min through the mixture, followed by addition of Pd (PPH3) 4 (0.672 g, 0.58 MMOL). A reflux condenser was attached to the flask and the mixture heated to 90C FOR 48 h. The mixture was cooled to ambient temperature and partitioned between. ethyl acetate and brine. The organic phase was washed with brine (3X20 mL) and dried over sodium sulfate, filtered, and concentrated IN VACUO. The resulting oil was purified by flash chromatography on silica gel ELUTING WITH 1 : 1 ethyl acetate: hexane to provide the title compound' (0. 380 g, 5. 81. MMOL, 27% yield) as A light yellow oil which ch solidified upon standing to an off with solid. 1H NMR (CDCl3, 400 MHz) 5 8. 54 (M, 1H), 7. 58 (m, 1H), 7.5 (s, 2H), 7.44 (DD, J=1.56, 7.42 Hz, 1H), 7.43 (m, 1H), 7. 27 (t, J=7.81 Hz, 1H), 2. 40 (s, 3H).
  • 4
  • [ 17973-86-3 ]
  • [ 151169-74-3 ]
  • 3-bromo-6-(2,3-dichlorophenyl)pyridazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In monoethylene glycol diethyl ether; water; at 80℃; for 17h; Intermediate 2: 3-Bromo-6-(2,3-dichlorophenyl)pyridazine.To a suspension of 3,6-dibromopyridazine (5g, 21mmol) in ethylene glycol dimethyl ether (100ml) was added 2,3-dichlorophenyl boronic acid (4.03g, 21mmol), tetrakis(triphenylphosphine)palladium(0) (1.2g, 1.05mmol) and sodium carbonate (2N, aqueous) (50ml), the mixture was then heated to 800C for 17 hours whilst under argon. The dark crude reaction mixture was then evaporated to dryness. The residue was partitioned between water (200ml) and dichloromethane (300ml). The aqueous layer was separated and further extracted with dichloromethane (200ml). The combined dichloromethane layers were evaporated and the residue was purified by chromatography (90g of silica) eluting with 75% dichloromethane/ petroleum ether 40:60. The title compound was obtained as a pink coloured solid (680mg). 1H-NMR (CDCl3) ? 7.38 (IH, X, J= 8), 7.58-7.63 (2H, m), 7.70-7.76 (2H, m) LC/MS m/z [MH+] 305 consistent with molecular formula C10H581Br35Cl2N2
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 17h; To a suspension of 3,6-dibromopyridazine (5g, 21mmol) in ethylene glycol dimethyl ether (100ml) was added 2,3-dichlorophenyl boronic acid (4.03g, 21mmol), tetrakis(triphenylphosphine)palladium(0) (1.2g, 1.05mmol) and sodium carbonate (2N, aqueous) (50ml), the mixture was then heated to 800C for 17 hours whilst under argon. The dark crude <n="169"/>reaction mixture was then evaporated to dryness. The residue was partitioned between water (200ml) and dichloromethane (300ml). The aqueous layer was separated and further extracted with dichloromethane (200ml). The combined dichloromethane layers were evaporated and the residue was purified by chromatography (9Og of silica) eluting with 75% dichloromethane/ petroleum ether 40:60. The title compound was obtained as a pink coloured solid (680mg). 1H-NMR (CDCl3) δ 7.38 (IH, t, /= 8), 7.58-7.63 (2H, m), 7.70-7.76 (2H, m) LC/MS m/z [MH+] 305 consistent with molecular formula Ci0H581Br35Cl2N2
  • 5
  • [ 135034-10-5 ]
  • [ 151169-74-3 ]
  • [ 927673-83-4 ]
YieldReaction ConditionsOperation in experiment
With potassium fluoride; triphenylphosphonium tetrafluoroborate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; at 100℃; for 1h; Intermediate 5: 3-Chloro-6-(2,3-dichlorophenyl)pyridazine.To a suspension of intermediate 4 (3.2g, 13.2mmol) in 1,4-dioxane (40ml) was added 2,3- dichlorophenyl boronic acid (2.5g, 13.2mmol), tris(dibenzylideneacetone)-di-palladium(0)- chloroform adduct (725mg, 0.79mmol), potassium fluoride (2.5g, 43.5mmol) and tri-tert- butylphosphine-tetra-fluoroborate (458mg, 1.58mmol), the mixture was then heated to 1000C for 1 hour whilst under argon. The dark crude reaction mixture was then evaporated to dryness. The solid was suspended in ethyl acetate (50ml) and poured through cellite and again evaporated to dryness. The sample was then purified by chromatography (9Og of silica) eluting with 10% ethyl acetate/ petroleum ether 40:60. The title compound was obtained as a white solid (2.2g). 1H-NMR (CDCl3) ? 7.38 (IH, t, J= 8), 7.59-7.63 (3H, m), 7.83 (IH, d, J= 9) LC/MS m/z [MH+] 259 consistent with molecular formula C10H535Cl3N2
With potassium fluoride; tri-tert-butylphosphine-tetrafluoroborate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; In 1,4-dioxane; at 100℃; for 1h; To a suspension of intermediate 4 (3.2g, 13.2mmol) in 1,4-dioxane (40ml) was added 2,3- dichlorophenyl boronic acid (2.5g, 13.2mmol), tris(dibenzyrideneacetone)-di-palladium(0)- chloroform adduct (725mg, 0.79mmol), potassium fluoride (2.5g, 43.5mmol) and tri-tert- butylphosphine-tetra-fluoroborate (458mg, 1.58mmol), the mixture was then heated to 1000C for 1 hour whilst under argon. The dark crude reaction mixture was then evaporated to dryness. The solid was suspended in ethyl acetate (50ml) and poured through cellite and again evaporated to dryness. The sample was then purified by chromatography (9Og of silica) eluting with 10% ethyl acetate/ petroleum ether 40:60. The title compound was obtained as a white solid (2.2g). 1H-NMR (CDCl3) δ 7.38 (IH, t, J= 8), 7.59-7.63 (3H, m), 7.83 (IH, d, J= 9) LC/MS m/z [MH+] 259 consistent with molecular formula Ci0H535Cl3N2
  • 6
  • [ 21075-83-2 ]
  • [ 151169-74-3 ]
  • N'-(2,3-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
39% With triethylamine;copper diacetate; In 1,2-dichloro-ethane; at 50℃; for 3h; Step 1: N'-(2,3-Dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), 2,3-dichlorophenylboronic acid (Lancaster; 1.29 g, 6.8 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (960 μL, 6.8 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50 C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluding with 10% ethyl acetate/hexanes, to give N'-(2,3-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (775 mg, 39%) as a solid.
  • 7
  • 4-(6-bromopyridazin-3-yl)morpholine [ No CAS ]
  • [ 151169-74-3 ]
  • 4-[6-(2,3-dichlorophenyl)-3-pyridazinyl]morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In monoethylene glycol diethyl ether; water; at 80℃; for 16h; Example 15: 4-[6-(2,3-Dichlorophenyl)-3-pyridazinyl]morpholine hydrochloride salt.To a suspension of intermediate 8 (500mg, 2.04mmol) in ethylene glycol dimethyl ether (10ml) was added 2,3-dichlorophenyl-boronic acid (428mg, 2.24mmol), tetrakis(triphenylphosphine)palladium(0) (120mg, 1 lOmu&;mol) and sodium carbonate (2N, aqueous) (5ml), the mixture was then heated to 800C for 16 hours whilst under argon. The dark crude reaction mixture was then evaporated to dryness. The residue was partitioned between water (200ml) and dichloromethane (300ml). The aqueous layer was separated and further extracted with dichloromethane (200ml). The combined dichloromethane layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (50g of silica) eluting with (30%) ethyl acetate/ petroleum ether 40:60 to give the free base of the title compound as an off white solid 1H- NMR (CDCl3.) ? 3.70-3.73 (4H, m), 3.87-3.89 (4H, m), 6.95 (IH, d, J= 9), 7.32 (IH, t, J= 8), 7.52- 7.54 (IH, m), 7.60-7.65 (2H, m). The sample was dissolved in 1,4-dioxane (5ml) and treated with hydrogen chloride (IM) solution in diethyl ether (ImI) which was then frozen and dried using freeze drying apparatus to obtain the title compound as an off white solid (160mg). LC retention time 2.47 mins, MS m/z 310 consistent with [MH+] for molecular formula C14H1335Cl2N3O
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 16h; To a suspension of intermediate 47 (500mg, 2.04mmol) in ethylene glycol dimethyl ether (10ml) was added 2,3-dichlorophenyl-boronic acid (428mg, 2.24mmol), tetrakis(triphenylphosphine)palladium(0) (120mg, l lOμmol) and sodium carbonate (2N, aqueous) (5ml), the mixture was then heated to 800C for 16 hours whilst under argon. The dark crude reaction mixture was then evaporated to dryness. The residue was partitioned between water (200ml) and dichloromethane (300ml). The aqueous layer was separated and further extracted with dichloromethane (200ml). The combined dichloromethane layers were dried (Na2SC>4), filtered and evaporated. The residue was purified by chromatography (5Og of silica) eluting with (30%) ethyl acetate/ petroleum ether 40:60 to give the free base of the title compound as an off white solid 1H- NMR (CDCl3) δ 3.70-3.73 (4H, m), 3.87-3.89 (4H, m), 6.95 (IH, d, J = 9), 7.32 (IH, t, J = 8), 7.52- 7.54 (IH, m), 7.60-7.65 (2H, m). The sample was dissolved in 1,4-dioxane (5ml) and treated with hydrogen chloride (IM) solution in diethyl ether (ImI) which was then frozen and dried using freeze drying apparatus to obtain the title compound as an off white solid (160mg). LC retention time 2.47 mins, MS m/z 310 consistent with [MH+] for molecular formula C14H1335Cl2N3O
  • 8
  • [ 54903-86-5 ]
  • [ 151169-74-3 ]
  • [ 1079402-04-2 ]
YieldReaction ConditionsOperation in experiment
35% With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 36h; To a suspension of 3-bromopyridine-2,6-diamine (0.376 g, 2.00 mmol) in 1 ,4-dioxane (12 ml) and water (6 ml) was added 2,3-dichlorophenyl boronic acid (0.573 g, 3.00 mmol), potassium carbonate (0.552 g, 4.00 mmol) and palladium tetrakis(triphenylphosphine) (0.115 g, 0.01 mmol). The reaction was purged with nitrogen and heated at 809C for 18 hours. Further palladium tetrakis(triphenylphosphine) (0.115 g, 0.01 mmol) and 2,3-dichlorophenyl boronic acid (0.573 g, 3.00 mmol) were added and the reaction heated at 8O0C for a further 18 hours before concentrating in vacuo. The residue was taken up in ethyl acetate (20 ml) and washed with a saturated aqueous solution of K2CO3 before drying over MgSO4 and concentrating in vacuo. The residue was purified by silica gel column chromatography, eluting with 99:1 dichloromethane:methanol, then recrystallised from toluene to afford the title compound (0.180 g, 35% yield). <n="149"/>MP 170-1720C LCMS Rt=0.97 minMS m/z 254 [MH]+1HNMR (Cl6-DMSO): 5.00 (br s, 2H), 5.60 (br s, 2H), 5.75 (d, 1 H), 6.90 (d, 1 H), 7.23 (d, 1 H), 7.35 (t, 1 H), 7.55 (d, 1 H)
  • 9
  • [ 17357-32-3 ]
  • [ 151169-74-3 ]
  • [ 657405-39-5 ]
YieldReaction ConditionsOperation in experiment
62% Example lb) (536mg, [2MMOL)] and Pd (PPh3) 4 (120mg, [0.] [LOMMOL)] in DME [(25ML)] were stirred at room temperature for [10MIN.] 2,3-Dichlorobenzene boronic acid [(L.] [OG,] 5.24mmol) was then added and the mixture heated to [80C] for 3h and for a further 18h at room temperature. The reaction was diluted with water [(50ML)] and ethyl acetate [(100ML),] the aqueous layer separated and washed with ethyl acetate [(50ML] x 2). The combined organics were washed with brine, dried [(MGS04)] and evaporated to give the title compound as a dark orange gum. The product was purified by flash chromatography (10% EtOAc/isohexane) to give a pale yellow solid (315mg, [62%).'H] NMR [(CDC13)] 8 2.56 (3H, s, CH3), 7.27- 7.33 (3H, [M,] ArH), 7.52 [(1H,] d, [ARH),] 7.90 [(1H,] d, ArH).
  • 10
  • [ 81067-38-1 ]
  • [ 151169-74-3 ]
  • [ 60145-20-2 ]
  • 11
  • [ 1161945-05-6 ]
  • [ 151169-74-3 ]
  • [ 1161943-60-7 ]
YieldReaction ConditionsOperation in experiment
53% Tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol), was added to a solution of 2,3-dichlorophenylboronic acid (57 mg, 0.30 mmol) and 2-[(3-bromophenyl)-sulfonylamino]benzenesulfonamide (97 mg, 0.25 mmol) in DMF (1 mL). The reaction mixture was stirred at RT under argon for 15 minutes before addition of 2M Na2CO3 (0.5 mL). The reaction was stirred overnight at 90 C., filtered and purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (61 mg, 53%) as a white solid.1H NMR (400 MHz, Acetone-d6) δ ppm 7.97-8.01 (m, 2H), 7.80-7.89 (m, 1H), 7.60-7.74 (m, 4H), 7.47-7.52 (m, 2H), 7.42 (d, 1H), 7.15 (t, 1H). MS m/z M-H 455/457/459
  • 12
  • [ 39619-90-4 ]
  • [ 151169-74-3 ]
  • [ 1255871-78-3 ]
YieldReaction ConditionsOperation in experiment
43% With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 100℃; for 0.666667h; A mixture of 3-<;5-bromo-pyridin-3-yl)~propionic acid methyl ester (155mg). 2,3- dichlorobeϖzeneboronic acid {142 mg, 0.744 mmol), PdCI2(OpPf) CH2CI2 addυct (48.6 mg. 0.069 mmol) and Na2CO3 (2 M, 0.929 ml, 1.859 mmol) in DMF (5 ml) was heated at 1009C. After 40 min, solvent was removed in vacuo. The residue was purified via flash column (EtOAc/Heptane«0-20-25%, v/v) to give 3-[5-(2,3-Dichloro-phenyl)-pyridirv3-ylJ- propionic acid methyl ester (101 mg, 0.326 mmol, 43 % yield). ESl-MS mlr. 310[M+1f; 1H NMR (CDCI3, 400 MHz) δ 2.71 (t, J - 7.6 Hz, 2H), 3.05 (t, J * 7.6 Hz, 2H)1 3.70 (s, 3H), 7.23 (dd, J « 7.6, 1.8 Hz, 1H), 7.30 (t. J » 7.6 Hz, 1H)1 7.53 (dd, J * 7.6, 1.6 Hz, 1H), 7.63 (s, 1H). 8.52 (S. 2H).
  • 13
  • [ 1255871-80-7 ]
  • [ 151169-74-3 ]
  • [ 1255871-86-3 ]
YieldReaction ConditionsOperation in experiment
74% With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; A mixture of 2,3-dichlorophenylboronic acid (279 mg, 1.464 mmol), methyl 2~(5- bromopyridin-3-yl)cyclopropanecarboxy»ate (357 mg, 1.394 mmol), PdCI2(dppf).CH?CI2 adduct (114 mg, 0.139 mmol) and Na2CO3 (2 M in water, 1.743 ml, 3.49 mmoi) in OMF (7 ml) was heated at 1OOCC under nitrogen atmosphere. After 1 h, the solvent was removed under vacuo. The residue was purified by flash column (EtOAc/Heptanes0- 25%, v/v) to give methyi 2-(5-(2,3-dichlorophenyl)pyridiϖ-3-yl)cyclopropanecarboxylate (335 mg, 1.040 mmol, 74 % yield). ESI-MS mlr. 322[M-H)*; 1H NMR (CDCI3, 400 MHz) 1.38-1.41 (m, 1H), 1.68-1.73 (m, 1H), 1.97-2.01 (m, 1H), 2.58-2.63 (m, 1H), 3.75 (s, 3H), 7.21 (dd, J = 7.6, 1.2 Hz, 1H), 7.30 (t, J * 7.6 Hz1 1H)1 7.43 (bs, 1H), 7.53 (, J * 7.6, 1.2 Hz, 1 H)1 848 (d, J = 1.6 Hz1 1 H), 8.50 (d, J * 1.6 Hz, 1 H),
  • 14
  • [ 1279106-70-5 ]
  • [ 151169-74-3 ]
  • [ 1279103-78-4 ]
YieldReaction ConditionsOperation in experiment
26% With potassium carbonate;palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere; To a solution of 2-Bromo-5-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-1H-indole (80 mg, 0.28 mmol) and 2,3-Dichlorobenzeneboronic acid (53 mg, 0.28 mmol) in 1,4-dioxane (2 mL) was degassed and purged with nitrogen (10 min) and then aqueous K2CO3 (2 M, 0.2 mL) was added and purged with nitrogen again (20 min). Pd(dppf)2Cl2 (10 mol %, 21 mg) was added to the above reaction mixture and stirred at 100 C. After 18 h the reaction mixture was filtered through Celite and the filtrate extracted with EtOAc (3*20 mL). The organic phase (EtOAc layer) was washed with brine, dried over Na2SO4 and concentrated to a residue which was purified by column chromatography (10-30% EtOAc-Hexane) to obtain 2-(2,3-Dichloro-phenyl)-5-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-1H-indole (25 mg, 26%), MS (M+H)=410.
  • 15
  • [ 1384958-64-8 ]
  • [ 151169-74-3 ]
  • [ 1386859-70-6 ]
YieldReaction ConditionsOperation in experiment
37% With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 72℃;Inert atmosphere; Synthesis of Compound 3155Ethyl 2-amino-7-(2,3-dichlorophenyl)-3H-l-benzazepine-4-carboxylate [000198] (2,3-Dichlorophenyl)boronic acid (764 mg, 4.00 mmol), ethyl 2-amino-7-bromo- 3H-l-benzazepine-4-carboxylate (399 mg, 1.29 mmol), toluene (15.0 mL), ethanol (1.5 mL), cesium carbonate (1.74 g, 5.34 mmol), and water (3.0 mL) were combined and the slurry was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (147 mg, 0.127 mmol) was added, the mixture degassed again, then heated in an oil bath at 72 C overnight. In the morning ethyl 2-amino-7-bromo-3H-l-benzazepine-4-carboxylate was consumed and the reaction was complete. The crude product was isolated using ethyl acetate and aq. NaHC03 washes. The crude product was dissolved in ethyl acetate and cooled to give a crop of crystals with sufficient purity. Final yield of desired product was 180 mg (37%). MS (ESI+) consistent forC19Hi6Cl2N202 (M+H)+: m/z 375.0.
  • 16
  • [ 630409-69-7 ]
  • [ 151169-74-3 ]
  • [ 1612886-63-1 ]
YieldReaction ConditionsOperation in experiment
80% With trans-bis(triphenylphosphine)palladium dichloride; sodium carbonate monohydrate; In 1,4-dioxane; water; at 60℃; for 1.5h; General procedure: A mixture of 46-triflate (485mg, 1.22mmol), 2,4-dichlorophenylboronic acid (279mg, 1.46mmol), trans-dichlorobis(triphenyl-phosphine)palladium (ii) (85.0mg, 0.122mmol), and sodium carbonate monohydrate (453mg, 3.65mmol) in 1,4-dioxane/ H2O (1:1, 2.4ml) was stirred at 60C for 1.5h. The mixture was partitioned between H2O (10ml) and CH2Cl2 (15ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×15ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting brown oil was absorbed onto silica gel and purified by flash chromatography (silica gel, 20%-60% EtOAc/hexanes) to deliver ethyl 2-(2-aminopyrimidin-4-yl)-4-(2,4-dichlorophenyl)thiazole-5-carboxylate (259mg, 0.655mmol, 54% yield) as a yellow solid.
  • 17
  • 6-iodo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-5(8H)-one [ No CAS ]
  • [ 151169-74-3 ]
  • 6-(2,3-dichlorophenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-5(8H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 90℃; for 16h;Sealed tube; Pd2(dba)3 (3.3 mg, 3.6 imol) was added to a pre-degassed solution of 6-iodo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-5(8H)-one (30.0mg, 0.O9Ommol), (2,3-dichlorophenyl)boronic acid (172 mg, 0.900 mmol), SPhos(3.0 mg, 7.2 imol) and potassium phosphate, tribasic (57.3 mg, 0.270 mmol) in toluene (1.0 mL) in a 4 mL vial. The vessel was sealed and the reaction mixture was heated to 90 C, with stirring. After 16 h, the reaction mixture was cooled and loaded directly onto a column andpurified by flash chromatography (0-100%, EtOAc incyclohexane) to give the title compound (20.8 mg, 66%) asa white solid. LCMS (Method A) : = 1.26 mi m/z = 352[M+H] .
  • 18
  • 2-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)propan-1-ol [ No CAS ]
  • [ 151169-74-3 ]
  • 2-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)propan-1-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 85℃; for 3h;Inert atmosphere; 2-(4-(5-amino-6-chloro-l,2,4-triazin-3-yl)piperazin-l-yl)propan-l-ol (80 mg, 0.293 mmol), 2,3-dichlorophenyl)boronic acid (84 mg, 0.44 mmol), cesium carbonate (191 mg, 0.587 mmol) were dissolved in 2 mL degassed /?-dioxane/H,20 (v/v 3:1) and tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at 85C for 3 hours. Solids were filtered off and filtrate was concentrated under reduced pressure. The residue was subject to flash column chromatography to give a product as yellow solid (52 mg, 96.5% purity, 45.0% yield). LC- MS [ESI-MH+]: mlz 383; -NMR (500MHz, DMSO-d6) δ 0.945 (3H, d, J = 6.5 Hz), 2.550 (4H, m), 2.610 (1H, m), 3.702 (4H, br), 4.026 (IH, m), 4.340 (1H, dd, Ji = 4.5 Hz, J2 = 6.5 Hz). 6.450 - 7.100 (IH, br), 7.358 (IH, dd, Ji = 1.5 Hz, J2 = 8.0 Hz), 7.448 (IH, t, J = 2.5 Hz), 7.710 (lH, dd, Ji = 1.5 Hz, J2 = 8.0 Hz).
  • 19
  • (S)-1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-ol [ No CAS ]
  • [ 151169-74-3 ]
  • (S)-1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 85℃; for 3h;Inert atmosphere; (5 -l-((5-Amino-6-chloro-l,2,4-triazin-3-yl)amino)-3- (2,2,2-trifluoroethoxy)propan-2-ol (67 mg, 0.222 mmol), (2,3-dichlorophenyl)boronic acid I (85 mg, 0.444 mmol), cesium carbonate (145 mg, 0.444 mmol) were dissolved in 2 mL degassed /^-dioxane/HsO (v/v 3:1) and tetrakis(triphenylphosphine)palladium (121 mg, 0.105 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at 85C for 3 hours. LC-MS analysis indicated the reaction was completed. Solids were filtered off and filtrate was concentrated under reduced pressure. The residue was subject to flash column chromatography to give a product as white solids (70 mg, 95.3%, 76% yield). LC-MS [ESI- MH+]: mlz 412; -NMR (500MHz, CDC13) δ 3.641 (IH, br), 3.709 (3H, m), 3.923 (2H, q, J = 8.0 Hz), 4.115 (1H, m), 5.3 - 6.2 (IH, br), 7.400 (2H, m), 7.650 (1H, m).
  • 20
  • 5-amino-6-chloro-3-N-(1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperidin-4-yl)amino-1,2,4-triazine [ No CAS ]
  • [ 151169-74-3 ]
  • 3-N-(1-N-mPEG3-piperidin-4-yl) lamotrigine [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 85℃; for 4.16667h;Inert atmosphere; 5-Amino-6-chloro-3-(l-N-mPEG3-piperidin-4-yl)amino-l,2,4-triazine (189.9 mg, 0.51 mmol) was dissolved in dioxane (10 mL). (2,3-Dichlorophenyl)boronic acid (262.6 mg, 1.38 mmol) and cesium carbonate (699.6 mg, 2.13 mmol) were added. And then water (2.5 mL) was added. Tetrakis(triphenylphosphine)palladium (160.6 mg, 0.14 mmol) was added. The mixture was purged with nitrogen for a few minutes, and then heated to 85 C during 40 min, and kept at 85 C for 3.5 h. The mixture was concentrated under reduced pressure to dryness. The residue was mixed with water, extracted with dichloromethane (4 x 20 mL). The organic solution was concentrated. The residue was purified with column chromatography on silica gel using 1-10% methanol/dichloromethane to afford product (166.2 mg, Yield: 68%). NMR (500 MHz, Chloroform- /) δ 7.551 (dd, J= 2.0 Hz and 7.5 Hz, 1H), 7.362-7.308 (m, 1H), 4.735 (br, 2H), 3.920 (br, 1H), 3.648-3.609 (m, 10H), 3.545-3.526 (m, 2H), 3.362 (s, 3H), 2.914 (br, 2H), 2.604 (br, 2H), 2.245 (br, 2H), 2.058 (br, 2H), 1.61 1 (m, 3H). LC-MS: 485.0 (MHVz).
  • 21
  • 5-amino-6-chloro-3-(4-(N,N-methyl (mPEG<SUB>3</SUB>)amino)piperidin-1-yl)-1,2,4-triazine [ No CAS ]
  • [ 151169-74-3 ]
  • 3-N-((4-N,N-methyl-mPEG<SUB>3</SUB>-amino)piperidin-1-yl)lamotrigine [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (476.8 mg, 2.499 mmol) and 5-amino-6-chloro-3- (4-(N,N-methyl (111PEG3) amino)piperidin-l-yl)-l,2,4-triazine (349.7 mg, 0.899 mmol) was dissolved in water/dioxane (5/15 mL). Cesium carbonate (1.0573 g, 3.21 mmol) was added. The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (99.7 mg, 0.086 mmol) was added. The mixture was purged with nitrogen for a few minutes, and then heated to 90 C during 15 min, and kept at 90 C for 4 h. The mixture was concentrated under reduced pressure to dryness. The residue was mixed with brine, extracted with dichloromethane (4 x 20 mL). The organic solution was concentrated. The residue was purified with column chromatography using 1-5% methanol in dichloromethane to afford product (244.6 mg) in 55% yield. NMR (500 MHz, Chloroform-;/) δ 7.54 (dd, J= 8.3, 1.8 Hz, 1H), 7.38 - 7.28 (m, 2H), 4.90 (d, J = 13.0 Hz, 2H), 4.67 (s, 2H), 3.62 (q, J = 3.4, 2.8 Hz, 8H), 3.53 (dd, J= 5.7, 3.7 Hz, 2H), 3.36 (s, 3H), 2.86 (t, J= 12.9 Hz, 2H), 2.71 (br, 3H), 2.33 (s, 3H), 1.87 (d, J= 12.5 Hz, 2H), 1.55 - 1.48 (m, 2H). MS for C22H32C12N603: 499.2 (MH+).
  • 22
  • tert-butyl 4-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate [ No CAS ]
  • [ 151169-74-3 ]
  • C19H24Cl2N6O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
49% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 85℃; for 3.91667h;Inert atmosphere; Tert-Butyl 4-((5-amino-6-chloro- 1 ,2,4-triazm-3-yl)amino)piperidine- 1 -carboxylate (250 mg, 0.76 mmol), (2,3-dichlorophenyl)boronic acid (392.9 mg, 2.06 mmol) and cesium carbonate (703.2 mg, 2.14 mmol) was dissolved in dioxane/water (10 mL/2.5 mL). Tetrakis(triphenyl phosphine)palladium (284.2 mg, 0.25 mmol) was added. The mixture was purged with nitrogen for a few minutes, and then heated to 85 C during 25 min, and kept at 85 C for 3.5 h. The mixture was concentrated under reduced pressure to dryness. The residue > was mixed with water, extracted with dichloromethane (4 x 20 mL). The organic solution was concentrated. The residue was purified with column chromatography on silica gel using 1- 10% methanol/dichloromethane to afford product (162.5 mg, Yield: 49%).
  • 23
  • 5-amino-6-chloro-3-(4-(1-Boc-piperidin-4-yl)piperazin-1-yl)-1,2,4-triazine [ No CAS ]
  • [ 151169-74-3 ]
  • 3-N-(1-Boc-(piperidin-4-yl)piperazin-1-yl) lamotrigine [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 3.41667h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (515.2 mg, 2.70 mmol) and 3-amino-6-chloro-3- (l-Boc-piperidin-4-yl) piperazin-l-yl)-l,2,4-triazine (326.4 mg, 0.820 mmol) was dissolved Hn water/dioxane (5/15 mL). Cesium carbonate (1.0435 g, 3.17 mmol) was added. The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (143.8 mg, 0.124 mmol) was added. The mixture was purged with nitrogen for a few minutes, and then heated to 90 C during 15 min, and kept at 90 <>C for 3 h. The mixture was concentrated under reduced pressure to dryness. The residue was mixed with brine, extracted with dichloromethane (2 x 20. mL). The organic solution was concentrated. The residue was purified with flash column chromatography on silica gel using 1-5% methanol/dichloromethane to afford 3-N-(l-Boc-(piperidin-4-yl)piperazin-l-yl) lamotrigine (320.8 mg) in 77% yield. NMR (500 MHz, Chloroforn /) δ 7.58 - 7.49 (m, 1H), 7.42 - 7.29 (m, 2H), 4.69 (s, 2H), 4.14 (br, 2H), 3.88 (s, 4H), 2.70 (s, 2H), 2.62 (t, J = 5.1 Hz, 4H), 2.42 (m, 1H), 1.81 (d, J = 1 1.0 Hz, 2H), 1.43 (s, 9H), 1.41 (m, 2H). MS for C23H31 CI2N7O2: 508.2 (MH+).
  • 24
  • (S)-5-amino-6-chloro-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl]-1,2,4-triazine [ No CAS ]
  • [ 151169-74-3 ]
  • (S)-5-amino-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl] lamotrigine [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (363. l mg, 1.903 mmol) and 5-amino-6-chloro-3- [4-Boc-3-(s)-(hydroxymethyl)piperazin-l -yl] 1 ,2,4-triazine (215.6 mg, 0.625 mmol) was dissolved in water/dioxane (5/15 mL). Cesium carbonate (733.6 mg, 2.229 mmol) were added. The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (139.6 mg, 0.121 mmol) was added. The mixture was purged with nitrogen for a few minutes, and then heated to 90 C during 10 min, and kept at 90 OC for 4 h. The mixture was concentrated under reduced pressure to dryness. The residue dissolved in dichloromethane, washed with brine, dried over anhydrous sodium sulfate, concentrated. The residue was dissolved in methanol (5 mL), ammonium hydroxide (20 mL) was added to afford a white suspension. The mixture was stirred at r. t. for 4 h. The mixture was concentrated to remove all of solvents. The residue was separated with NH-column using 0-10% methanol in dichloromethane to afford 5-amino-3-[4-Boc-3-(s)-(hydroxymethyl)piperazin-l-yl] lamotrigine (205.5 mg) in 72% yield. MS for C 19H24CI2N6O3: 455.0 (MH+).
  • 25
  • (R)-7-(5-amino-6-chloro-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one [ No CAS ]
  • [ 151169-74-3 ]
  • (R)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 5h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (285.2mg, 1.495 mmol) and (R)-7-(5-amino-6- chloro-l,2,4-triazin-3-yl)tetrahydro-lH-oxazolo[3,4-a]pyrazin-3(5H)-one(179.6 mg, 0.664 mmol) was dissolved in water/dioxane (5/15 mL). Cesium carbonate (722.5 mg, 2.195 mmol) were added. The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (120.2 mg, 0.104 mmol) was added. The mixture was purged with nitrogen for a few minutes, and stirred at 90 C for 5 h. The mixture was concentrated to remove organic solvents. The & residue was dissolved in dichloromethane (30 mL). Water (10 mL) was added and brine (40 mL) was added. The organic solution was separated and the aqueous solution was extracted with dichloromethane (2 x 50 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was purified with flash column chromatography on silica gel using 30-100% ethyl acetate /hexane to afford product as white solid (155.8 mg) in 62% yield. 1H NMR (500 MHz, Chloroform-i/) δ 7.60 - 7.53 (m, 1H), 7.37 - 7.29 (m, 2H), 5.07 (d, J = 12.7 Hz, 1H), 4.85 (d, J = 13.7 Hz, 1H), 4.77 (s, 2H), 4.45 (dd, J = 8.9, 8.2 Hz, 1H), 4.01 (dd, J= 9.0, 5.6 Hz, 1H), 3.95 - 3.84 (m, 2H), 3.1 1 (td, J= 12.8, 3.7 Hz, 1H), 2.96 (td, J = 12.8, 3.7 Hz, 1H), 2.84 (dd, J = 13.0, 11.0 Hz, 1H). MS for Ci5U{4C 602: 381.0 (MH+).
  • 26
  • (S)-7-(5-amino-6-chloro-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one [ No CAS ]
  • [ 151169-74-3 ]
  • (S)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (225.6mg, 1.182 mmol) and (S)-7-(5-amino-6- chloro-l ,2,4-triazin-3-yl)tetrahydro-lH-oxazolo[3,4-a]pyrazin-3(5H)-one (164.8 mg, 0.609 mmol) and cesium carbonate (701.2 mg, 2.131 mmol) were dissolved in water/dioxane (5/15 mL). The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (1 15.9 mg, 0.100 mmol) was added. The mixture was purged with nitrogen for a few minutes, and stirred at 90 OC for 4 h. The mixture was concentrated to remove organic solvents. The residue was dissolved in dichloromethane (30 mL). Water (10 mL) was added and brine (40 mL) was added. The organic solution was separated and the aqueous solution was extracted with dichloromethane (2 x 50 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was purified with flash column chromatography on silica gel to afford slight yellow solid (104.8 mg) as product in 45% yield. NMR (500 MHz, Chloroform-i/) δ 7.58 (dd, J = 5.7, 3.9 Hz, IH), 7.38 - 7.31 (m, 2H), 5.08 (d, J = 12.5 Hz, IH), 4.86 (d, J = 13.6 Hz, IH), 4.79 (s, 2H), 4.47 (t, J = 8.6 Hz, IH), 4.02 (dd, J = 9.0, 5.6 Hz, IH), 3.96 - 3.85 (m, 2H), 3.12 (td, J - 12.7, 3.7 Hz, IH), 2.98 (td, J = 12.8, 3.7 Hz, IH), 2.85 (dd, J= 13.0, 11.0 Hz, IH). MS for Ci5H14Cl2N602: 381.0 (MH+).
  • 27
  • 1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-ol [ No CAS ]
  • [ 151169-74-3 ]
  • 3-N-(3-hydroxyazetin-1-yl)lamotrigine [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 5h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (0.934 g, 4.89 mmol), l-(5-amino-6-chloro- 1 ,2,4- triazin-3-yl)azetidin-3-ol (457.7 mg, 2.27 mmol) and cesium carbonate (2.2244 g, 6.76 mmol) was dissolved in water/dioxane (5/15 mL). The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (315.1 mg, 0.273 mmol) was added. The mixture was purged with nitrogen for a few minutes, and stirred at 90 C for 5 h. The mixture was concentrated to remove organic solvents. The residue was mixed with a mixture of dichloromethane and water, sonicated for a few minutes. The mixture was filtered and the solid was washed with dichloromethane and dried under high vacuum to afford product (560.0 mg) in 79% yield. NMR (500 MHz, Methanol-^) δ 7.67 (dd, J= 8.1, 1.6 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.36 (dd, J = 7.7, 1.6 Hz, I H), 4.69 (tt, J = 6.6, 4.4 Hz, 1H), 4.37 (ddd, J = 9.5, 6.6, 1.2 Hz, 2H), 3.94 (ddd, J = 9.5, 4.4, 1.2 Hz, 2H). MS for C^HnC NsO: 312.0 (MH+).
  • 28
  • (R)-8-(5-amino-6-chloro-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one [ No CAS ]
  • [ 151169-74-3 ]
  • (R)-8-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 5h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (0.3392 g, 1.778 mmol), (R)-8-(5-amino-6-chloro- l,2,4-triazin-3-yl)hexahydropyrazino[2,l-c][l,4]oxazin-4(3H)-one (244.1 mg, 0.857 mmol) and cesium carbonate (0.8478 g, 2.58 mmol) was dissolved in water/dioxane (5/15 mL). The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (158.4 mg, 0.137 mmol) was added. The mixture was purged with nitrogen for a few minutes, and stirred at 90 C for 5 h. The mixture was concentrated to remove organic solvents. The residue was mixed with brine, extracted with dichloromethane (3 x 50 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was purified with flash column chromatography on silica gel using 30-100% ethyl acetate in hexane to afford yellow solid as product (290.1 mg) in 86% yield. 1H NMR (500 MHz, Chloroform-i/) δ 7.57 (dd, J= 6.3, 3.3 Hz, 1H), 7.35 (q, J = 3.8, 3.2 Hz, 2H), 4.90 - 4.82 (m, 2H), 4.79 (s, 2H), 4.71 - 4.64 (m, 1H), 4.24 - 4.16 (m, 2H), 4.12 - 4.02 (m, 2H), 3.70 - 3.58 (m, 2H), 3.01 (td, J = 12.9, 3.4 Hz, IH), 2.89 - 2.77 (m, 2H). MS for 395.0 (MH+).
  • 29
  • (S)-8-(5-amino-6-chloro-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1 ,4]oxazin-4(3H)-one [ No CAS ]
  • [ 151169-74-3 ]
  • (S)-6-(2,3-dichlorophenyl)-3-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-1,2,4-triazin-5-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 4.75h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (0.450.4 g, 2.360 mmol), (S)-6-chloro-3- (hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-l,2,4-triazin-5-amine (282.3 mg, 1.043 mmol) and cesium carbonate (1.1547 g, 3.51 mmol) was dissolved in water/dioxane (5/15 mL). The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (178.5 mg, 0.154 mmol) was added. The mixture was purged with nitrogen for a few minutes, and stirred at 90 C for 4 h 45 min. The mixture was concentrated to remove organic solvents. The residue was mixed with brine, extracted with dichloromethane (3 x 50 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was purified with flash column chromatography on silica gel using 30-100% ethyl acetate in hexane and 10% methanol in ethyl acetate to afford a yellow solid (376.8 mg) in 95% yield. NMR (500 MHz, Chloroform-;/) δ 7.55 (dd, J = 7.4, 2.3 Hz, IH), 7.38 - 7.29 (m, 2H), 4.77 (s, IH), 4.72 (s, 2H), 4.59 (d, J = 12.6 Hz, I H), 3.87 (dd, J= 11.4, 3.3 Hz, IH), 3.79 (dd, J = 1 1.1, 3.1 Hz, I H), 3.73 (td, J = 11.5, 2.4 Hz, IH), 3.32 (t, J = 11.1, 10.2 Hz, IH), 3.14 (td, J = 12.7, 3.2 Hz, IH), 2.87 - 2.80 (m, IH), 2.71 (d, J= 11.7 Hz, IH), 2.63 (dd, J= 12.8, 10.9 Hz, IH), 2.46 - 2.23 (m, 3H). MS for C^sC NeO: 381.0 (MH+).
  • 30
  • 1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-4-(trifluoromethyl)piperidin-4-ol [ No CAS ]
  • [ 151169-74-3 ]
  • 3-N-(4-hydroxy-4-trifluoromethyl)piperidinyl lamotrigine [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (228.6 mg, 1.198 fnmol), l-(5-amino-6-chloro- l,2,4-triazin-3-yl)-4-(trifluoromethyl)piperidin-4-ol (224 mg, 0.753 mmol) and cesium carbonate (725.3 mg, 2.204 mmol) was dissolved in water/dioxane (5/15 mL). The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (127.5 mg, 0.1 10 mmol) was added. The mixture was purged with nitrogen for a few minutes, and stirred at 90 oc for 2 h. The mixture was concentrated to remove organic solvents. The residue was mixed with brine, extracted with dichloromethane (3 x 50 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated, The residue was purified twice with flash column chromatography on silica gel using 30-100% ethyl acetate/hexane. The product was dissolved in warm dichloromethane, cooled, filtered. The white solid was collected to afford product (161.7 mg) in 53% yield. NMR (500 MHz, Chloroform-d) δ 7.55 (dd, J= 7.6, 2.0 Hz, 1H), 7.38 - 7.26 (m, 2H), 4.82 (d, J - 13.4 Hz, 2H), 4.71 (s, 2H), 3.24 (td, J = 13.1, 2.8 Hz, 2H), 1.96 (s, 1H), 1.89 (td, J = 13.1 , 4.6 Hz, 2H), 1 .80 (d, J = 2.5 Hz, 1H), 1.77 (s, 1H). MS for C15HHCI2F3N50: 408.1 (MH+).
  • 31
  • (S)-1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol [ No CAS ]
  • [ 151169-74-3 ]
  • (S)-1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 17.5h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (94.6 mg, 0.496 mmol), (S)-l-((S)-4-(5-amino-6- chloro-l,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-l-yl)-3-methoxypropan-2-ol (69 mg, 0.207 mmol) and cesium carbonate (231.1 mg, 0.702 mmol) was dissolved in water/dioxane (3/10 mL). The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (72.2 mg, 0.062 mmol) was added. The mixture was purged with nitrogen for a few minutes, and stirred at 90 oC for 17.5 h. The mixture was concentrated to remove organic solvents. The residue was mixed with brine, extracted with dichloromethane (3 x 50 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was purified with flash column chromatography on silica gel using methanol in dichloromethane to afford product (54.9 mg) in 60% yield. NMR (500 MHz, Chloroform- d) 8 7.53 (dd, J = 7.5, 2.1 Hz, IH), 7.36 - 7.26 (m, 2H), 4.94 (br, 2H), 4.17 (d, J = 1 1.4 Hz, 2H), 3.92 (ddt, J= 9.6, 6.7, 3.6 Hz, 1 H), 3.81 (dd, J= 11.9, 5.6 Hz, 1H), 3.69 - 3.50 (m, 3H), 3.41 (dd, J = 9.9, 4.1 Hz, 1H), 3.35 (s, 3H), 3.34 - 3.31 (m, 1H), 3.05 - 2.97 (m, 1H), 2.81 (dd, J= 13.5, 9.6 Hz, 1H), 2.62 (br, 1 H), 2.52 - 2.41 (m, 2H). MS for C,8H24C12N603: 443.0 (MH+)
  • 32
  • (S)-tert-butyl 4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazine-1-carboxylate [ No CAS ]
  • [ 151169-74-3 ]
  • (S)-5-N-(4-N-t-Boc-3-(hydroxymethyl)piperazinyl)lamotrigine [ No CAS ]
YieldReaction ConditionsOperation in experiment
61% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 3h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (187.1 mg, 0.981 mmol), (S)-tert-butyl 4-(5- amino-6-chloro-l,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazine-l-carboxylate(156 mg, 0.452 mmol) and cesium carbonate (485.3 mg, 1.475 mmol) was dissolved in water/dioxane (3/10 mL). The mixture was degassed with nitrogen, Tetrakis(triphenylphosphine)palladium (107.5 mg, 0.093 mmol) was added. The mixture was purged with nitrogen for a few minutes, and stirred at 90 C for 3 h. The mixture was concentrated to remove organic solvents. The residue was mixed with brine, extracted with dichloromethane (3 x 50 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was purified twice with flash column chromatography on silica gel using 1-10% methanol in dichloromethane to afford slight yellow solid as product (126.5 mg) in 61% yield. NMR (500 MHz, Chloroform-if) 5 7.56 (dd, J= 6.6, 3.1 Hz, lH), 7.37 - 7.29 (m, 2H), 4.90 (br, 1H), 4.79 (s, 2H), 4.57 (br, 1H), 4.23 - 3.98 (s, 2H), 3.73 (br, 2H), 3.24 (s, 2H), 3.09 (s, 2H), 1.48 (s, 9H). MS for C^C Wy. 455.0 (MH+).
  • 33
  • (S)-1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol [ No CAS ]
  • [ 151169-74-3 ]
  • (S)-1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 3h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (162.5 mg, 0.852 mmol), (S)-l-((S)-4-(5-amino-6- chloro-l,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-l-yl)-3-methoxypropan-2-ol (156.4 mg, 0.470 mmol) and cesium carbonate (485.4 mg, 1.475 mmol) was dissolved in water/dioxane (3/10 mL). The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (100.8 mg, 0.087 mmol) was added. The mixture was purged with nitrogen for a few minutes, and stirred at 90 C for 3 h. The mixture was concentrated to remove organic solvents. The residue was mixed with brine, extracted with dichloromethane (3 x 50 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was purified twice with flash column chromatography on silica gel using 30-100% ethyl acetate/hexane. The product was dissolved in warm dichloromethane, cooled, filtered. The solution was collect and purified with flash column chromatography on silica gel using 1-10% methanol in dichloromethane to afford the product (141.5 mg) in 68% yield. NMR (500 MHz, Chloroform-^/) δ 7.56 (dd, J= 7.3, 2.3 Hz, 1H), 7.39 - 7.29 (m, 2H), 4.91 (br, 1H), 4.75 (s, 2H), 4.63 (br, 1H), 4.04 - 3.92 (m, 3H), 3.47 - 3.42 (m, 3H), 3.39 (s, 3H), 3.40 - 3.36 (m, 1H), 3.19 (d, J = 11.7 Hz, 1H), 3.07 (br, 1H), 2.94 (d, J = 1 1.4 Hz, 1H), 2.52 (dd, J = 12.6, 9.0 Hz, 1H), 2.42 - 2.32 (m, 3H). MS for C|8H24C12N603: 443.0 (MH+).
  • 34
  • 1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol [ No CAS ]
  • [ 151169-74-3 ]
  • 1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 3.5h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (217.9 mg, 1 .142 mmol), l-((S)-4-(5-amino-6- chloro-l,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-l-yl)-3-(tert-butoxy)propan-2-ol (228 mg, 0.608 mmol) and cesium carbonate (626.7 mg, 1.904 mmol) was dissolved in water/dioxane (3.5/10 mL). The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (135.7 mg, 0.1 17 mmol) was added. The mixture was purged with nitrogen for a few minutes, and stirred at 90 C for 3.5 h using microwave. The mixture was concentrated to remove organic solvents. The residue was mixed with brine, extracted with dichloromethane (3 x 50 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was purified twice with flash column chromatography on silica gel using 1-10% methanol in dichloromethane to afford the product (223.1 mg) in 76% yield. NMR (500 MHz, Chloroform-;/) δ 7.56 (dd, J = 7.4, 2.1 Hz, 1H), 7.40 -7.28 (m, 2H), 4.90 (br, 1H), 4.75 (s, 2H), 4.63 (br, 1H), 4.05 - 3.95 (m, 2H), 3.90 (m, l H), 3.51 - 3.40 (m, 2H), 3.35 - 3.31 (m, l H), 3. 8 (dd, J= 27.4, 11 .7 Hz, lH), 3.00 (dd, J = 23.9, 11.5 Hz, 1H), 2.56 - 2.32 (m, 4H), 2.23 (td, J= 11.9, 3.7 Hz, 1H), 1.19 (d, 9H). MS for C2iH3oCl2N603: 485.2 (MH+).
  • 35
  • tert-butyl 4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate [ No CAS ]
  • [ 151169-74-3 ]
  • tert-butyl 4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 4.5h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (678 mg, 3.55 mmol), tert-butyl 4-(5-amino-6- chloro-l,2,4-triazin-3-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate (600 mg, 1.76 mmol) and cesium carbonate (1.8595 g, 6.56 mmol) was dissolved in water/dioxane (6/20 mL). The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (294 mg, 0.255 mmol) was added. The mixture was purged with nitrogen for a few minutes, and stirred at 90 C for 4.5 h. The mixture was concentrated to remove organic solvents. The residue was mixed with brine, extracted with dichloromethane (3 x 80 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was purified twice with flash column chromatography on silica gel using 1-10 methanol/dichloromethane, 30-100% ethyl acetate/hexane to afford product (61 1.5 mg) in 77% yield. NMR (500 MHz, Chloroform-i/) δ 7.56 (dd, J= 7.9, 1.7 Hz, 1H), 7.41 - 7.30 (m, 2H), 4.76 (s, 2H), 4.01 (s, 2H), 3.50 (s, 2H), 3.40 (s, 2H), 1.45 (s, 9H), 1H), 1.07 (s, 2H), 0.97 (s, 2H). MS for C2oH24Cl2N602: 451.0 (MH+).
  • 36
  • tert-butyl 4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3,3-dimethylpiperazine-1-carboxylate [ No CAS ]
  • [ 151169-74-3 ]
  • tert-butyl 4-(5-amino-6-(2,3-diehlorophenyl)-1,2,4-triazin-3-yl)-3,3-dimethylpiperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
67% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere; (2,3-dichlorophenyl)boronic acid (174.1 mg, 0.912 mmol), tert-butyl 4-(5-amino-6- chloro-l,2,4-triazin-3-yl)-3,3-dimethylpiperazine-l-carboxylate (179 mg, 0.522 mmol) and cesium carbonate (0.520 g, 1.58 mmol) was dissolved in water/dioxane (2/7 mL). The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (136.5mg, 0.1 18 mmol) was added. The mixture was purged with nitrogen for a few minutes, and stirred at 90 oC for 2 h. The mixture was concentrated to remove organic solvents. The residue was mixed with brine, extracted with dichloromethane (3 x 80 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was purified with flash column chromatography on silica gel using 1-10% methanol/dichloromethane, 30-70% ethyl acetate/hexane to afford product (158.3 mg) in 67% yield. lH NMR (500 MHz, Chloroform- d) δ 7.55 - 7.53 (m, 1H), 7.37 - 7.30 (m, 2H), 4.66 (s, 2H), 4.18 - 4.15 (m, 2H), 3.56 - 3.51 (m, 4H), 1.58 (d, J= 2.5 Hz, 6H), 1.46 (s, 9 H). MS for C20H26Q2N6O2: 453.2 (MH+).
  • 37
  • 2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethoxy)ethanol [ No CAS ]
  • [ 151169-74-3 ]
  • 2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane-d8; water; at 85℃;Inert atmosphere; 2-(2-((5-amino-6-chloro- 1 ,2,4-triazin-3-yl)amino)ethoxy)ethanol (196 mg, 0.837 mmol), 2,3-dichlorophenylboronic acid (200 mg, 1.05 mmol), cesium carbonate (496 mg, 1.51 mmol) were dissolved in a dioxane/water (3/1) mixture solution (20 mL). The solution was bubbled with N2 gas for 3 min before Pd(PPh.3)4 (203 mg, 0.176 mmol) was added and N2 bubbling another 2 min before the reaction was heated up to 85C. The reaction was monitored with HPLC and LC-MS to confirm the completeness in 2-3 hrs. The dioxane was then removed via rotary evaporation. The residue was dissolved in MeOH and loaded on Biotage samplet directly. The silicone gel column purification was using a program 2-10% MeOH/DCM in 20 CV. The product was well separated from other components and the fractions were confirmed with TLC, hplc, and LC-MS before the fractions were combined. A heavily oil-like product (152 mg, 53% yield) was obtained after high vauco drying. UPLC (Agilent extended C-18, 0.5 mL/min, 10-100% ACN in 5 min) 4.76 min; LC-MS (ESI, MH+) 344.0 + 346.0 (-70%); 1H NMR (500 MHz, CDCI3) δ 3.65- 3.66 (2H, m), 3.74-3.79 (6H, m), 7.34-7.39 (2H, m), 7.58-7.60 (1H, m).
  • 38
  • N-(2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)methanesulfonamide [ No CAS ]
  • [ 151169-74-3 ]
  • N-(2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)methanesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
69.2% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 85℃; for 2h;Inert atmosphere; (2,3-Dichlorophenyl)boronic acid (162 mg, 850 mmol), N-(2-(2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)ethoxy)ethyl)methane- sulfinamide(176 mg, 566 mmol), cesium carbonate (369 mg, 1.13 mmol) were dissolved in 20 ml degassed diaxane/H20 ( 3:1) and tetrakis(triphenylphosphine)palladium (164 mg, 142 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at 85C. Dioxane 3 mL was added after 15 min at 85C. A sample was checked by LC-MS after 2 hours reaction. Solvent was evaporated to dryness at 50C, reduced pressure. Residue was dried in high vacuum for 2 hours. Residue was mixed with DCM/MeOH and loaded on 25 samplet, dried in vacuum for overnight. Silica gel column purification gives the desired product 165 mg (69.2% yield). RP-HPLC (betasil CI 8, 0.5 mL/min, 10-100% ACN in 10 min) 4.72 min (with purity 97.7 %); LC-MS (ESI, MH+, free base) 421 ; 1H NMR (500 MHz,CDCl3) δ 3.01 ( 3H, s), 3.34-3.36 (2 H, t), 3.66-3.71( 6H, m),5.14(2H, br), 5.57( 1H, br), 6.20-6.27( 1H, br), 7.36-7.40 (2H, m), 7.58-7.61 (lH, m).
  • 39
  • 6-chloro-N3-(10-((2-(2-methoxyethoxy)ethoxy)methyl)-2,5,8,11-tetraoxatridecan-13-yl)-1,2,4-triazine-3,5-diamine [ No CAS ]
  • [ 151169-74-3 ]
  • 6-(2,3-dichlorophenyl)-N3-(10-((2-(2-methoxyethoxy)ethoxy)methyl)-2,5,8,11-tetraoxatridecan-13-yl)-1,2,4-triazine-3,5-diamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
65.5% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 85℃;Inert atmosphere; (2,3-dichlorophenyl)boronic acid (216 mg, 1.132 mmol), 6-chloro-N3-(10-((2-(2- methoxyethoxy)ethoxy)methyl)-2,5,8, 1 1 -tetraoxatridecan- 13-yl)-l ,2,4-triazine-3,5-diamine (353 mg, 0.754 mmol), cesium carbonate (492 mg, 1.51 mmol) were dissolved in 30 mL degassed mixture of diaxane/H20 (3:1) and tetrakis(triphenylphosphine)palladium (218 mg, 0.189 mmol) was added under nitrogen atmosphere . The reaction mixture was stirred at 85C. for overnight. Solvent was evaporated to dryness at 50C under the reduced pressure. Residue was purified on silica gel column to give the product 286 mg (65.5% yield). RP- HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 6.36 min (with purity 95.3%); LC-MS (ESI, MH+) 578; NMR (500 MHz,CDCl3) δ 3.36 (6H,s), 3.54-3.80 (22H, m), 3.80 (lH,br), 3.84-3.86 (2H, t), 5.10 (2H, br), 6.61(1H, br), 7.34-7.39 (2H, m), 7.56-7.60 (1H, m).
  • 40
  • 2-((5-amino-6-chloro-1,2,4-triazin-3-yl)(methyl)amino)ethanol [ No CAS ]
  • [ 151169-74-3 ]
  • 2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere; (2,3-dichlorophenyl)boronic acid (410 mg, 2.15 mmol), 2-((5- amino-6-chloro-l ,2,4-triazin-3-yl)(methyl)amino)ethanol (292 mg, 1.43 mmol), cesium carbonate (934 mg, 2.87 mmol) were dissolved in 30 mL degassed dioxane/tkO (3: 1) and tetrakis(triphenylphosphine)palladium (934 mg, 2.87 mmol) was added under nitrogen ) atmosphere. The reaction mixture was stirred at 90C for 2 hours. Solvent was evaporated to dryness and residue was purified on silica gel column to give the desired product 320 mg (71% yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 4.55 min (with purity 95.8%); LC-MS (ESI, MH+) 314; 1H NMR (500 MHz,DMSO-d6) δ 3.22 (3H, s), 3.66- 3.72 (4H, m), 7.53-7.57 (2H, m), 7.84-7.87 (IH, m), 8.25 (IH, br), 9.23 (IH, br).
  • 41
  • 6-chloro-N3-methyl-N3-(2-(methylamino)ethyl)-1,2,4-triazine-3,5-diamine [ No CAS ]
  • [ 151169-74-3 ]
  • 6-(2,3-dichlorophenyl)-N3-methyl-N3-(2-(methylamino)ethyl)-1,2,4-triazine-3,5-diamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
69.8% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 85℃; for 1.5h;Inert atmosphere; (2,3-dichlorophenyl)boronic acid (347 mg, 1.82 mmol), 6-chloro-N3- methyl-N3-(2-(methylamino)ethyl)-l ,2,4-triazine-3,5-diamine (1.212 mmol, 263 mmol), cesium carbonate (790 mg, 2.42 mmol) were dissolved in 30 mL degassed dioxane/H20 (3:1) and tetrakis(triphenylphosphine)palladium (350 mg, 0.303 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at 85C for 1.5 hour. Solvent was evaporated to dryness at 50C under the reduced pressure. Residue was mixed with DCM/MeOH and insoluble was filtered and concentrated. Reside was purified on silica gel column to give product 277 mg (69.8% yield). RP-HPLC (betasil CI 8, 0.5 mL/min, 10-100% ACN in 10 min) 3.97 min (with purity 98.0%); LC-MS (ESI, MH+) 327; 1H NMR (500 MHz, D20) δ 2.77 (3H,s), 3.26 (3H, s), 3.38-3.41 (2H, t), 4.00-4.09 (2H,m), 7.45-7.52 (2H, m), 7.78-7.80 (1H, m).
  • 42
  • tert-butyl (3-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-hydroxypropyl)carbamate [ No CAS ]
  • [ 151169-74-3 ]
  • C17H22Cl2N6O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
69.1% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 85℃; for 2h;Inert atmosphere; (2,3-dichlorophenyl)boronic acid (234 mg, 1.23 mmol), tert-butyl (3- ((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-2-hydroxypropyl)carbamate (261 mg, 0.819 mmol), cesium carbonate (534 mg, 1.64 mmol) were dissolved in 30 mL degassed dioxane/H20 ( 3:1) and tetrakis(triphenylphosphine)palladium (237 mg, 0.205 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at 85C for 2 hours. Solvent was evaporated to dryness at 50C under the reduced pressure. Residue was purified on silica gel column to give product 243 mg (69.1% yield). The product was mixed with 15 mL of 4.0N HC1 in dioxane and 5 ml of methanol, stirred at r.t. for 2 hour. Solvent was evaporated to dryness. Residue was dried in high vacuum overnight to give the final product as hydrochloride salt. RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 4.09 min (with purity 99.8%); LC-MS (ESI, MH+) 329; 1H NMR (500 MHz, D20) δ 2.87-2.93 (lH,m), 2.92-3.15 (1H, d), 3.52-3.70 (2H, m), 4.13 (1H, br), 7.45-7.52 (2H, m), 7.78-7.80 (lH, m).
  • 43
  • 2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropan-1-ol [ No CAS ]
  • [ 151169-74-3 ]
  • 2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropan-1-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
66.3% With dipotassium hydrogenphosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 85 - 90℃; 2-((5-Amino-6-chloro-l,2,4-triazin-3-yl)amino)-2-methylpropan-l-ol (Compound 3) (1.00 g, 4.59 mmol) and (2,3-dichlorophenyl)boronic acid (1.753 g, 9.19 mmol) were dissolved in 20 mL of 1,4-dioxane. Pd(PPh3)4 (531 mg, 0.459 mmol), K2HP04 (1.761 g, 10.1 1 mmol) and 5 mL of DI water were added to the above reaction mixture. The reaction mixture was degassed for 10-15 minutes and then stirred under heating (at 85-90 C) for 4-6 hours. The reaction mixture was concentrated, and to it, 5 mL of DI water and 10 mL of ethyl acetate, were added. The pH was adjusted to ~l-2 with aqueous HC1. The reaction mixture was then filtered through celite bed. The organic layer was separated and the aqueous layer was again washed with EtOAc (2 x 10 mL). The pH of the aqueous layer was adjusted to ~ 9-10 using aqueous KOH and the compound was extracted into dichloromethane ("DCM") (2 x 25 mL). The DCM solution was concentrated and the crude product thus obtained was purified by column chromatography, giving 2-((5-amino-6-(2,3- dichlorophenyl)-l,2,4-triazin-3-yl)amino)-2-methylpropan-l-ol (Compound 1). (1.00 g, 66.3% yield). NMR (500 MHz, DMSO-d6): δ 7.70 (d, 1H), 7.45 (t, IH), 7.35 (d, 1H), 6.30-7.20 (br s, 2H), 6.1-6.30 (br s, IH), 5.1 -5.3 (br s, IH), 3.45-3.55 (d, 2H), 1.25-1.50 (s, 6H); MS (ESI) for C13H15C12N50: 328.05 (MH+).
  • 44
  • 5-amino-6-chloro-3-N-(4-N-boc-piperazinyl)amino-1,2,4-triazine [ No CAS ]
  • [ 151169-74-3 ]
  • C18H22Cl2N6O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 6h;Inert atmosphere; A mixture of (2,3-dichlorophenyl)boronic acid (355.4 g, 1.86 mmol), 5-amino-6- chloro-3-(4-N-BOC-piperazin-l-yl)amino-l,2,4-triazine (302.4 mg, 0.96 mmol) and cesium carbonate (1.0591 g, 3.22 mmol) was dissolved in dioxane/water (10 mL/2 mL), followed by addition of tetrakis(triphenylphosphine)palladium (112.6 mg, 0.097 mmol). The mixture was purged with nitrogen for a few minutes. The mixture was heated to 90 C over 30 minutes, and kept at 90 C for 5.5 hours. The mixture was cooled to room temperature and concentrated to remove the organic solvent. The residue was dissolved in water and extracted with dichloromethane (3 x 40 mL). The combined organic solution was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified with flash column chromatography on silica gel using 1 -10% methanol/dichloromethane. The product was purified again with flash column chromatography on silica gel using 30- 55% ethyl acetate/hexane to afford intermediate (222.5 mg, 55%).
  • 45
  • [ 1013906-19-8 ]
  • [ 151169-74-3 ]
  • 3-(2,3-dichlorophenyl)-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
68.6% With palladium diacetate; potassium carbonate; In N,N-dimethyl-formamide; at 85℃; General procedure: To a solution of compound 6 or 7 (0.274 mmol) in DMF (4 mL)and water (1 mL) was added Pd(OAc)2 (6 mg, 0.027 mmol), then boronic acid 8 (0.548 mmol) and K2CO3 (75.6 mg, 0.548 mmol) andthe mixture was stirred under reflux at 85 C. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was allowed to cool at room temperature and the mixture was extracted with ethylacetate (3 30 mL). The organic layers were collected, combined, washed with saturated aq NaCl(2 25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purifiedby column chromatography on silica gel to afford the coupled product.
  • 46
  • tert-butyl (1-(4-amino-5-bromopyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate [ No CAS ]
  • [ 151169-74-3 ]
  • tert-butyl (1-(4-amino-5-(2,3-dichlorophenyl)-pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.07 g With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 110℃; for 3h;Inert atmosphere; Microwave irradiation; Step a: A suspension of fer?-butyl (l-(4-amino-5-bromopyrimidin-2-yl)-4- methylpiperidin-4-yl)carbamate (966 mg, 2.50 mmol), (2,3-dichlophenyl)boronic acid (596 mg, 3.13 mmol), potassium phosphate (1.59 g, 7.50 mmol), and PdCl2(dppf) DCM adduct (204 mg, 0.25 mmol) in MeCN:H20 (9: 1, 10 mL, degassed) was stirred in a microwave reactor for 3 h at 110 C. After cooling to RT, the reaction was filtered through a pad of Celite followed by EtOAc (50 mL) wash. The combined filtrates were concentrated and the resulting residue was purified by silica chromatography (0 to 5% gradient of MeOH DCM) to give fer?-butyl (l-(4-amino-5-(2,3- dichlorophenyl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate (1.07 g, 2.37 mmol). MS m/z 452.4 (M+H)+.
1.07 g With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 110℃; for 3h;Microwave irradiation; Step a: A suspension of tert-butyl (1-(4-amino-5-bromopyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate (966 mg, 2.50 mmol), (2,3-dichlophenyl)boronic acid (596 mg, 3.13 mmol), potassium phosphate (1.59 g, 7.50 mmol), and PdCl2(dppf).DCM adduct (204 mg, 0.25 mmol) in MeCN:H2O (9:1, 10 mL, degassed) was stirred in a microwave reactor for 3 h at 110 C. After cooling to RT, the reaction was filtered through a pad of Celite followed by EtOAc (50 mL) wash. The combined filtrates were concentrated and the resulting residue was purified by silica chromatography (0 to 5% gradient of MeOH/DCM) to give tert-butyl (1-(4-amino-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate (1.07 g, 2.37 mmol). MS m/z 452.4 (M+H)+.
  • 47
  • 2-amino-3-bromo-6-chloropyrazine [ No CAS ]
  • [ 151169-74-3 ]
  • [ 212779-33-4 ]
YieldReaction ConditionsOperation in experiment
91% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 120℃;Inert atmosphere; Compound B1-1 (5.00g, 24.0mmol, 1.0eq.),2,3-Dichlorophenylboronic acid (5.04g, 26.4mmol, 1.1eq.), Pd(dppf)Cl2 (350.1mg, 2mol%) and K3PO4(10.18g, 48.0mmol, 2.0eq.) was placed in a 200mL single-neck flask, and the system was evacuated to replace nitrogen.Add 1,4-dioxane (54 mL) and water (6 mL) to react overnight in an oil bath at 120C, and monitor until the conversion of the raw materials is complete. Diatomite filtration,The filtrate was concentrated, and 30mL ethyl acetate was added for extraction,Wash with saturated sodium chloride aqueous solution 3 times, concentrate, and purify by column chromatography.Compound B1-2 (5.94 g, yield 91%) was obtained.
80% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 70℃; for 12h;Inert atmosphere; The mixture of 3-bromo-6-chloropyrazin-2-amine (600 mg, 2.87 mmol, 1.0 eq, CAS 212779-21-0), (2,3-dichlorophenyl)boronic acid (547 mg, 2.87 mmol, 1.0 eq), Pd(dppf)Cl2 (210 mg, 287 pmol, 0.1 eq) and K3PO4 (1.82 g, 8.61 mmol, 3.0 eq) in dioxane (15 mL) and H20 (3 mL) was evacuated and refilled 3 times with N2 gas, then stirred at 70 C for 12 hours. The mixture was concentrated under reduced pressure to afford a residue, which was purified by column chromatography (petroleum ether / ethyl acetate = 1 : 0 ~ 10 : 1) to afford 6-chloro-3-(2,3-dichlorophenyl)pyrazin-2-amine (630 mg, 80% yield) as a yellow solid. LCMS m/z [M+H]+ = 273.9/275.9.
74% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; for 4h;Inert atmosphere; Reflux; General procedure: To a clean dry round-bottom flask, which was purged with nitrogen to remove water traces and other particles, 3-bromo-6-chloropyrazin-2-amine (1.0 eq) was added and dissolved in dry THF (10 volumes). Then, (2,3-dichlorophenyl) boronic acid (1.3 to 1.5 eq) was added and stirred for 10 min under inert atmosphere. The reaction mass was degassed using a nitrogen inlet and vacuum outlet for 15 min. Tetrakis (triphenylphosphine) palladium (0) (0.1 eq) was added and stirred for 15 min. After the addition of a solution of 2 M Na2CO3, the reaction mixture was slowly heated to reflux. The process of the reaction was evaluated by TLC and LCMS. After the solution was stirred for 4 h, it was cooled to RT. Ethyl acetate and water were added, and the reaction mixture was stirred for another10 min. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by ash chromatography (0% to 50% gradient of ethyl acetate/n-hexane) to get 6-chloro-3-(2,3-dichlorophenyl)pyrazin-2-amine (3) as a yellow crystalline solid. MS m/z 274.10/276.11 (M + H)+.
70% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 6h;Inert atmosphere; [00693] 3-Bromo-6-chloropyrazine-2-amine (5.00 g, 24.0 mmol) and Na2C03 10H2O (20.6 g, 72.0 mmol) were suspended in mixture dioxane: water, 4: 1. The solvent was degassed by passing argon through it and Pd(dppf)Ch (0.88 g, 1.20 mmol) was added. The reaction was carried out 6 hrs at 110 C. The reaction mixture was filtered through celite pad (AcOEt). The residue was purified by column chromatography (hexane: AcOEt, 9: 1 -> 4: 1) to give 4.63 g (70%) of 6-chloro-3-(2,3-dichlorophenyl)pyrazin-2-amine . NMR (400 MHz, DMSO- d6) δ 7.85 (s, 1H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.39 (dd, J = 7.6, 1.6 Hz, 1H), 6.70 (s, 2H). LC-MS (ESI) m/z: [M + H] found 275.7.
63% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 80℃; for 16h; To a solution of 3-bromo-6-chloropyrazin-2-amine (30 g, 144 mmol, 1 equiv) in dioxane (360 mL) was added (2,3-dichlorophenyl)boronic acid (33 g, 173 mmol, 1.2 equiv), a solution of K3PO4 (92 g, 432 mmol, 3.0 equiv) in H20 (36 mL), and Pd(dppf)Cl2 (11 g, 14.4 mmol, 0.1 equiv). The reaction mixture was warmed to 80 C and stirred for 16 hours, after which the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 6-chloro-3-(2,3-dichlorophenyl)pyrazin-2-amine (25 g, 91 mmol, 63% yield) as a yellow solid. 1H MR (400 MHz, DMSO-d6) δ 7.87 - 7.82 (m, 1 H), 7.73 (dd, J = 7.94, 1.54 Hz, 1H), 7.50 - 7.44 (m, 1H), 7.41 - 7.36 (m, 1H), 6.69 (br s, 2 H).
47% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere; A 500 mL single-necked eggplant flask was charged with 3-bromo-6-chloropyrazin-2-amine (14.0 g, 67.3 mmol, 1 eq) and2,3-Dichlorobenzeneboronic acid (19.3 g, 101 mmol, 1.5 eq),Then add 188mL of dioxane and47mL water mixed solvent,Cesium carbonate (54.8 g, 168 mmol, 2.5 eq) was addedPd (dppf) Cl2 (5.5 g, 6.7 mmol, 0.1 eq),Under nitrogen protection,Then warmed to 90 reaction 2h, poured into water,The mixture was extracted with ethyl acetate. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1/10) as developing solvent. The developing solvent was spin-dried and dried in vacuo to give 8.7 g of a green solid,Chloro-3- (2,3-dichlorophenyl) pyrazin-2-amine (47% yield, HPLC purity 98%).
38% With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 130℃; for 18h;Inert atmosphere; To a stirred solution of 3-bromo-6-chloropyrazin-2-amine (2 g, 9.61 mmol) in ACN: H2O (20 ml, 9:1), (2,3-dichlorophenyl)boronic acid (2, 2.7 g, 14.2 mmol), potassium phosphate tribasic (6.10 g, 28.8 mmol) were added. The reaction mixture was degassed with argon for a 10 min and Pd(dppf)Cl2CH2Cl2(0.78 g, 0.96 mmol) was added. The reaction mixture was degassed again with argon and heated at 130 C. with stirring for 18 h. Progress of the reaction was monitored by TLC, which showed complete consumption of starting material. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was diluted with water (100 mL) and the extracted with EtOAc (3*200 mL). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography [silica gel (100-200 mesh), gradient 10-12% ethyl acetate in hexane] to give 6-chloro-3-(2,3-dichlorophenyl)pyrazin-2-amine (1.0 g, 38%) as a yellow solid. MS (ESI+ve): 274.12 1H-NMR (400 MHz; CDCl3): δ 8.02 (s, 1H), 7.58-7.60 (d, J=8.02 Hz, 1H), 7.32-7.36 (m, 2H), 4.63 (bs, 2H).
633 mg With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 120℃; for 4h;Microwave irradiation; Intermediate 6 6-(4-amino-4-methylpiperidin-l-yl)-3-(2.3-dichlorophenyl)pyrazin-2-amine [00240] A suspension of 3-bromo-6-chloropyrazin-2-amine (1.2 g, 5.76 mmol), (2,3- dichlophenyl)boronic acid (1.1 g, 5.76 mmol), potassium phosphate (3.67 g, 17.27 mmol), and PdCl2(dppf) DCM adduct (235 mg, 0.288 mmol) in MeCN:H20 (9: 1, 15 mL, degassed) was stirred in a microwave reactor for 4 h at 120 C. After cooling to RT, the reaction was filtered through a pad of Celite followed by EtOAc (25 mL) wash. The combined filtrates were concentrated and the resulting residue was purified by silica chromatography (0 to 30% gradient of EtO Ac/heptane) to give 6-(4-amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin-2- amine (633 mg, 2.306 mmol). MS m/z 276.4 (M+H)+.
633 mg With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In water; acetonitrile; at 120℃; for 4h;Microwave irradiation; A suspension of 3-bromo-6-chloropyrazin-2-amine (1.2 g, 5.76 mmol), (2,3- dichlophenyl)boronic acid (1.1 g, 5.76 mmol), potassium phosphate (3.67 g, 17.27 mmol), and PdCl2(dppf) DCM adduct (235 mg, 0.288 mmol) in MeCN:H20 (9: 1, 15 mL, degassed) was stirred in a microwave reactor for 4 h at 120 C. After cooling to RT, the reaction was filtered through a pad of Celite followed by EtO Ac (25 mL) wash. The combined filtrates were concentrated and the resulting residue was purified by silica chromatography (0 to 30% gradient of EtO Ac/heptane) to give 6-(4-amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin-2- amine (633 mg, 2.306 mmol). MS m/z 276.4 (M+H)+.
633 mg With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 120℃; for 4h;Microwave irradiation; A suspension of 3-bromo-6-chloropyrazin-2-amine (1.2 g, 5.76 mmol), (2,3-dichlophenyl)boronic acid (1.1 g, 5.76 mmol), potassium phosphate (3.67 g, 17.27 mmol), and PdCl2(dppf).DCM adduct (235 mg, 0.288 mmol) in MeCN:H20 (9:1, 15 mE, degassed) was stirred in a microwave reactor for 4 h at 120 C. After cooling to RT, the reaction was filtered through a pad of Celite followed by EtOAc (25 mE) wash. The combined filtrates were concentrated and the resulting residue was purified by silica chromatography (0 to 30% gradient of EtOAc/heptane) to give 6-(4-amino-4- methylpiperidin-1 -yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (633 mg, 2.306 mmol). MS mlz 276.4 (M+H).
633 mg With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 120℃; for 4h;Microwave irradiation; 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine A suspension of 3-bromo-6-chloropyrazin-2-amine (1.2 g, 5.76 mmol), (2,3-dichlophenyl)boronic acid (1.1 g, 5.76 mmol), potassium phosphate (3.67 g, 17.27 mmol), and PdCl2(dppf).DCM adduct (235 mg, 0.288 mmol) in MeCN:H2O (9:1, 15 mL, degassed) was stirred in a microwave reactor for 4 h at 120 C. After cooling to RT, the reaction was filtered through a pad of Celite followed by EtOAc (25 mL) wash. The combined filtrates were concentrated and the resulting residue was purified by silica chromatography (0 to 30% gradient of EtOAc/heptane) to give 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (633 mg, 2.306 mmol). MS m/z 276.4 (M+H)+.

  • 48
  • [ 56-05-3 ]
  • [ 151169-74-3 ]
  • [ 1604677-77-1 ]
YieldReaction ConditionsOperation in experiment
46% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 90℃; for 2h; 2-Amino-4,6-dichloropyrimidine (1 g, 6.1 mmol)And <strong>[151169-74-3]2,3-dichlorobenzeneboronic acid</strong> (1.39 g, 6.7 mmol)Was dissolved in 1,4-dioxane (24 ml) and water (6 ml)Sodium carbonate (1.3 g, 12.2 mmol) and tetraphenylphenylphosphine palladium (176 mg, 0.15 mmol) were added,Reacted at 90 C for 2 hours,The solvent was evaporated under reduced pressure, ethyl acetate (30 ml) and water (30 ml) were added, followed by extractionThe organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give Compound 19-1 (0.78 g, yield 46%).
31% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 95℃; for 2h;Sealed tube; A mixture of 4,6-dichloropyrimidin-2-amine (0.50 g, 3.05 mmol), (2,3-dichlorophenyl)boronic acid (0.64 g, 3.35 mmol), sodium carbonate (0.65 g, 6.10 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (0.088 g, 0.076 mmol) in 1,4-dioxane/water (30 mL; 4:1) was heated in a sealed tube at 95 00 for 2 h. The reaction mixture was run through a plug of silica (EtOAc) and then concentrated. Purification by column chromatography (1 :4-*1 :3 EtOAc/hexane)afforded the desired product as a white solid (0.26 g, 31%). LCMS [M+H] 274; 1H NMR (400 MHz, DMSO-d6) ö ppm 6.89 (1 H, 5) 7.33 (2H, br 5) 7.44 - 7.52 (2H, m) 7.71 -7.81 (1H, m).
31% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 95℃; for 2h;Sealed tube; Intermediate 21 -chloro-4-N-methylpyrimidine-2,4-diamine. A mixture of 4,6-dichloropyrimidin-2-amine (0.50 g, 3.05 mmol), (2,3- dichlorophenyl)boronic acid (0.64 g, 3.35 mmol), sodium carbonate (0.65 g, 6.10 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (0.088 g, 0.076 mmol) in 1 ,4-dioxane/water (30 mL; 4: 1 ) was heated in a sealed tube at 95C for 2 h. The reaction mixture was run through a plug of silica (EtOAc) and then concentrated. Purification by column chromatography (1 :4→1 :3 EtOAc/hexane) afforded the desired product as a white solid (0.26 g, 31 %). LCMS [M+H]+ 274; 1 H NMR (400 MHz, DMSO-d6) 56.89 (1 H, s) 7.33 (2H, br s) 7.44 - 7.52 (2H, m) 7.71 - 7.81 (1 H, m).
  • 49
  • [ 19745-07-4 ]
  • [ 151169-74-3 ]
  • 2-chloro-5-(2,3-dichlorophenyl)pyrazine [ No CAS ]
  • 50
  • tert-butyl ((1-(5-bromo-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate [ No CAS ]
  • [ 151169-74-3 ]
  • tert-butyl ((1-(5-(2,3-dichlorophenyl)-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With potassium phosphate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); In tetrahydrofuran; water; at 100℃; for 1h;Microwave irradiation; Inert atmosphere; To a mixture of teri-butyl ((l-(5-bromo-3-methyl-4-oxo-7-((2- (trimethylsilyl)emoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-(i]pyrimidin-2-yl)-4- methylpiperidin-4-yl)methyl)carbamate (200 mg, 0.342 mmol) in 9: 1 THF:H20 (3 mL) was added (2,3-dichlorophenyl)boronic acid (82 mg, 0.428 mmol), potassium phosphate (218 mg, 1.026 mmol), and chloro(2-dicyclohexylphosphino-2 4',6'-triisopropyl-l, -biphenyl)[2-(2'- amino-l, -biphenyl)]palladium(II) (13.5 mg, 0.017 mmol) under nitrogen. The mixture was microwave heated to 100 C for 60 min. At completion, the reaction was concentrated and the resulting residue was purified by flash chromatograpy over silica gel (0-50% EtOAc/heptane) to provide semi-pure teri-butyl ((l-(5-(2,3-dichlorophenyl)-3-methyl-4-oxo-7-((2- (trimethylsilyl)emoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-(i]pyrimidin-2-yl)-4- methylpiperidin-4-yl)methyl)carbamate (138 mg, 55% yield). LCMS: m/z 650 (M+H)+, Rt=1.73 min.
  • 51
  • 1,4-dihydroquinazoline-2-thiol [ No CAS ]
  • [ 151169-74-3 ]
  • 2-((2,3-dichlorophenyl)thio)quinazoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% General procedure: Compounds a to r were prepared by following a generalsynthetic procedure in which the solution of 1,4-dihydroquinazoline-2-thiol (100 mg, 0.609 mmol) indichloromethane (4 mL) was added the Cu(OAc)2 (166 mg,0.913 mmol), Et3N (0.43 mL, 3.045 mmol) and stirredfor 10-15 min at RT, followed by addition of substitutedboronic acid (1.219 mmol). The reaction mixture was stirredat RT for 12 h. After completion of the reaction, as indicatedby TLC, the reaction mixture was quenched with water(10 mL) and extracted with dichloromethane (2×15 mL).The organic layer was washed with water, brine solutionand dried over anhydrous Na2SO4, filtered the solvent,and concentrated under reduced pressure to give the crudecompound. The crude compound was purified by flash columnchromatography (100-200 mesh silica gel), eluted at10-20% ethyl acetate/pet ether to afford the S-substitutedquinazoline derivative. The characterization data for thecompounds are given below.
  • 52
  • [ 106-37-6 ]
  • [ 151169-74-3 ]
  • C12H7BrCl2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 3h;Inert atmosphere; 2,3-Dichlorobenzeneboronic acid (572.4.0 mg, 3.0 mmol),Dibromobenzene (0.43 mL, 3.6 mmol) and sodium carbonate (795.0 mg, 7.5 mmol) were added to a dry 25 mL egg-shaped flask, the nitrogen was evacuated three times,Additional Pd [P (ph) 3] 4 (346.7 mg, 0.3 mmol) was added,Nitrogen exchange three times, into the bubble oxygenated ethylene glycol dimethyl ether solution 8mLAnd distilled water 1mL, heated to 90 C for 3 hours.TLC tracking until the conversion of raw materials is completed, stop heating,After cooling to room temperature, add water to quench the reaction. Extraction with ethyl acetate,The organic phase is washed three times with anhydrous sodium sulfate.After concentration under reduced pressure, the crude product was purified by column chromatography(Petroleum ether: dichloromethane = 20: 1 → petroleum ether: dichloromethane = 8: 1)S16 was obtained as a white solid (634 mg, 70% yield).
  • 53
  • [ 5332-24-1 ]
  • [ 151169-74-3 ]
  • 3-(2,3-dichlorophenyl)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90 - 100℃; for 8h;Inert atmosphere; General procedure: Compounds 3a-h were prepared according to the followinggeneral procedure [2,3]: To a 3-bromoquinoline (100 mg,0.48 mmol) suspension in dioxane (3.0 mL), placed in ascrew capped reaction tube, was added Pd(PPh3)4 (1.5 mol%, 2 mmol), aryl boronic acid (1.2 mmol), and K3PO4 (153mg, 1.5 mmole), and the mixture was flushed with dry nitrogengas for few minutes. The reaction mixture was thenheated at 90-100 C for 8 h. After completion of reaction, 20mL of water was added and the mixture was cooled to roomtemperature. The organic and aqueous layers were separatedand the latter was extracted three times with ethyl acetate (3 15 mL). Solvent was removed under reduced pressure by meansof rotary evaporation and the residue obtained was purifiedthrough column chromatography. Using the aforementionedprocedure, the following compounds were prepared:
  • 54
  • [ 1010120-55-4 ]
  • [ 151169-74-3 ]
  • 5-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ No CAS ]
 

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[ 151169-74-3 ]

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