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Chemical Structure| 219735-99-6 Chemical Structure| 219735-99-6

Structure of 219735-99-6

Chemical Structure| 219735-99-6

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Product Details of [ 219735-99-6 ]

CAS No. :219735-99-6
Formula : C7H8BClO3
M.W : 186.40
SMILES Code : C1=C(C(=CC=C1OC)B(O)O)Cl
MDL No. :MFCD03411935

Safety of [ 219735-99-6 ]

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

Computational Chemistry of [ 219735-99-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 2
Num. H-bond acceptors 3.0
Num. H-bond donors 2.0
Molar Refractivity 47.77
TPSA ?

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

49.69 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

1.43
Log Po/w (WLOGP)?

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

0.03
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.

0.6
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

-0.1
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.39

Water Solubility

Log S (ESOL):?

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

-2.13
Solubility 1.37 mg/ml ; 0.00734 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.

-2.08
Solubility 1.56 mg/ml ; 0.00834 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

-2.03
Solubility 1.73 mg/ml ; 0.00927 mol/l
Class?

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

Soluble

Pharmacokinetics

GI absorption?

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

High
BBB permeant?

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

No
P-gp substrate?

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

No
CYP1A2 inhibitor?

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

No
CYP2C19 inhibitor?

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

No
CYP2C9 inhibitor?

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

No
CYP2D6 inhibitor?

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

No
CYP3A4 inhibitor?

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

No
Log Kp (skin permeation)?

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

-6.42 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)

1.98

Application In Synthesis of [ 219735-99-6 ]

* 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 [ 219735-99-6 ]

[ 219735-99-6 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 41252-98-6 ]
  • [ 219735-99-6 ]
  • 2'-chloro-4'-methoxy-2-methyl-3-nitro-biphenyl [ No CAS ]
  • 2
  • [ 219735-99-6 ]
  • [ 550377-08-7 ]
  • 4-[1-<i>tert</i>-butoxycarbonyl-5-(2-chloro-4-methoxy-phenyl)-1<i>H</i>-pyrazol-3-yl]-piperidine-1-carboxylic acid <i>tert</i>-butyl ester [ No CAS ]
  • 3
  • [ 866141-75-5 ]
  • [ 219735-99-6 ]
  • 2-(2-chloro-4-methoxy-phenyl)-6-cyclopropylmethyl-7-ethyl-4-methyl-7,8-dihydro-6<i>H</i>-1,3,6,8a-tetraaza-acenaphthylene [ No CAS ]
  • 4
  • [ 960605-15-6 ]
  • [ 219735-99-6 ]
  • [ 960605-16-7 ]
  • 5
  • [ 900027-23-8 ]
  • [ 219735-99-6 ]
  • C14H13ClO3S [ No CAS ]
  • 6
  • [ 464192-28-7 ]
  • [ 219735-99-6 ]
  • [ 960605-20-3 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 47; The mixture of <strong>[219735-99-6]2-chloro-4-methoxyphenyl boronic acid</strong> (372 mg), 2-bromo-5- formylthiazole(576 mg), sodium bicarbonate (6 mL, 1 M), dioxane (6 mL) and palladium tetrakistriphenylphosphine (30 mg) was heated at 1000C for 4 hours. The mixture was filtered through celite and diluted with ethyl acetate (100 mL) and washed with water (100 mL) followed by brine (50 mL). The organic fraction was dried with sodium sulfate and concentrated in vacuo to give the coupled product as a brown solid. To a solution of trimethyl phosphonoacetate (146 mg) in 5 mL of THF was added n-butyllithium (0.59 mL, 1.6 M in hexane) at O0C. The resulting solution was stirred at this temperature for 30 min. To this solution was added a THF solution (5 mL) of the above intermediate aldehyde (170 mg). The mixture was slowly warmed to rt and stirred for 2 hours. After quenching the mixture was water, the mixture was extracted with ethyl acetate, dried with sodium sulfate and concentrated in vacuo to give the enoate as a brown oily solid. To this enoate (83 mg) was added 5 mL of EPO <DP n="53"/>THF:MeOH:water (3:1:1) followed by LiOH (2 mL, 1 M). The mixture was stirred at rt for 5 hours. After acidified with concentrated HCl until pH = 4, the slurry was extracted with 30% isopropanol in chloroform, dried with sodium sulfate and concentrated in vacuo to give the enoic acid as a yellow solid. To this enoic acid (100 mg) was added toluene (5 mL) and thionyl chloride (2 mL). The mixture was heated to reflux for 1 hour and the solvent was distilled off under reduced pressure. The residue was taken up with toluene (5 mL) and to it was added anthranilic acid methyl ester (74 mg). The resulting mixture was heated to reflux for additional 1 hour. The solvent was removed and the residue was taken up with DMSO (6 mL). Only part of solid dissolved, the remaining solid was filtered and LC-MS showed it was mainly the desired compound, which was taken up with methanol (18 mL). To this mixture was added tosyl hydrazide (500 mg). The mixture was heated at reflux. After one day, an additional 300 mg of tosyl hydrazide was added. After two and a half days, the resulting mixture was concentrated and dissolved in acetone. The solution was directly purified by biotage (5%-25% ethyl acetate in petroleum ether) to give the anthranilide methyl ester as an oily solid. This methyl ester was dissolved in 5 mL of THF:MeOH: water (3:1:1) followed by LiOH (3 mL, 1 M). The mixture was stirred at rt for 4 hours. After Gilson purification, the acid was obtained as a white solid. To this methyl ether derivative was added 5 mL of dichloromethane and 0.23 mL of borontribromide (0.23 mL, IN in dichloromefhane) at O0C. After stirring at RT for 2h, the reaction was quenched by water at O0C. The mixture was concentrated in vacuo and then dissolved by DMSO. The DMSO solution was purified by Gilson to give Example 47 as a white solid. IH NMR (acetone-d6, 500 MHz) delta 11.42 (s, IH), 8.56 (d, IH), 8.07 (d, IH), 7.77 (d, IH), 7.70 (s, IH), 7.56 (t, IH), 7.15 (t, IH), 6.95 (d, IH), 6.84 (dd, IH), 3.34 (t, 2H), 2.88 (t, 2H); LCMS m/z 401 (M-I), 403 (M++l).
  • 7
  • [ 219735-99-6 ]
  • 2'-chloro-4'-methoxy-2-methyl-biphenyl-3-ylamine [ No CAS ]
  • 8
  • [ 219735-99-6 ]
  • 2'-chloro-3-iodo-4'-methoxy-2-methyl-6-methylsulfanyl-biphenyl [ No CAS ]
  • 9
  • [ 219735-99-6 ]
  • 2'-chloro-4'-methoxy-2-methyl-6-thiocyanato-biphenyl-3-ylamine [ No CAS ]
  • 10
  • [ 219735-99-6 ]
  • 2'-chloro-3-iodo-4'-methoxy-2-methyl-6-thiocyanato-biphenyl [ No CAS ]
  • 11
  • [ 219735-99-6 ]
  • 2'-chloro-3-iodo-6-methanesulfonyl-4'-methoxy-2-methyl-biphenyl [ No CAS ]
  • 12
  • [ 219735-99-6 ]
  • (2'-chloro-6-methanesulfonyl-4'-methoxy-2-methyl-biphenyl-3-yl)-(1-ethyl-5-hydroxy-1<i>H</i>-pyrazol-4-yl)-methanone [ No CAS ]
  • 13
  • [ 219735-97-4 ]
  • [ 219735-99-6 ]
  • 6-(2-chloro-4-methoxyphenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine [ No CAS ]
  • 14
  • [ 219735-98-5 ]
  • [ 219735-99-6 ]
  • 15
  • [ 219735-84-9 ]
  • [ 219735-99-6 ]
  • [ 677742-36-8 ]
YieldReaction ConditionsOperation in experiment
36% With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In ethanol; toluene; for 5h;Heating / reflux; To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (3.0 g, 11.3 mmol) in ethanol (10 mL) and toluene (40 mL), was added [NA2C03] (14.17 [ML,] 2 M), 2-chloro-4- methoxyphenylboronic acid (3.17 g, 17.0 mmol), and Pd (PPh3) 2Cl2 (0.48 g, 0.68 mmol) and the mixture was heated at reflux for 5h. The reaction was cooled and poured into EtOAc and H20 (500 mL). The EtOAc layer was washed with H20, brine, dried [(NA2SO4),] filtered and concentrated in vacuo. Purification using flash chromatography (10% EtOAc-Hexane) gave 1.51 g (36 %) of 2-benzyloxy-4- (2-chloro-4-methoxy-phenyl)-3-nitro-pyridine as a viscous oil: MS (AP) m/z 370.8 [[(M+H) +, 100].]
  • 16
  • [ 4316-93-2 ]
  • [ 219735-99-6 ]
  • [ 677743-93-0 ]
YieldReaction ConditionsOperation in experiment
73% [[00313]] 4, 6-Dichloro-5-aminopyrimidine (5.8 g, 0.036 mol) was diluted in [ETOH] (25 ml) and toluene (100 ml). A 2M [NA2CO3] (45.0 ml) was added followed by Pd (PPh3) 2Cl2 (1.5 g, 0.0021 mol), and <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (0.035 mol). The reaction was warmed to reflux under an inert atmosphere for 5 hours. The reaction was then allowed to cool to room temperature and poured over [ETOAC/H2O.] The organic layer was separated and washed with sat'd sodium chloride, dried [(MGS04),] filtered and concentrated. The material was flushed through a plug of silica using [50%] EtOAc/hexane as an eluting solvent. The crude material was concentrated in vacuo and diluted in 5 ml butanol. [4-HEPTYAMINE] was added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 80% EtOAc/hexane as the eluting solvent the desired intermediate [6- (2-CHLORO-4-METHOXY-PHENYL)-N4- (1-PROPYL-BUTYL)-] pyrimidine-4, 5-diamine was isolated (0.29 g, 73%). MS (AP) 349.3 [[(M+H) +,] 100].
  • 17
  • [ 475174-71-1 ]
  • [ 219735-99-6 ]
  • [ 475174-72-2 ]
YieldReaction ConditionsOperation in experiment
With barium dihydroxide;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; nitrogen; water; at 80℃; for 3h; Production Example 7 7-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine After dissolving 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (100 mg) in 1,2-dimethoxyethane (6 ML) and water (1 ML), 2-chloro-4-methoxyphenylboric acid (138 mg), tetrakis(triphenylphosphine)palladium (0) complex(0) complex (86 mg) and barium hydroxide octahydrate (233 mg) were added and the mixture was heated and stirred at 80C for 3 hours under a nitrogen stream.. water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine, in that order.. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated. under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (90 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as yellow crystals.1H NMR (400MHz, CDCl3) delta 1.30 (t, J = 7.6 Hz, 3H), 3.15 (q, J = 7.6 Hz, 2H), 3.90 (s, 3H), 6.96 (dd, J = 2.4, 8.4 Hz, 1H), 7.07 (dd, J = 1.6, 7.2 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 7.2, 8.8 Hz, 1H), 8.40 (dd, J = 1.6, 8.8 Hz, 1H).
  • 18
  • [ 219735-99-6 ]
  • [ 7064-38-2 ]
  • 4-(2-chloro-4-methoxyphenyl)-5-methylisoxazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 16h; Reference example 4 4-(2-chloro-4-methoxyphenyl)-5-methylisoxazole To a suspension of the compound prepared in reference example 3 (644 mg), 4-iodo-5-methylisoxazole (658 mg) and sodium bicarbonate (791 mg) in dimethoxyethane (2.5 ml) / water (2.5 ml), tetrakis (triphenylphosphine) palladium (36 mg) was added. The mixture was stirred for 16 hours at 80§C. To the reaction mixture that was cooled to room temperature, water and ethyl acetate were added. An insoluble matter was removed by filtration. An organic layer was separated from filtrate, it was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane: ethyl acetate = 19: 1 ? 15: 1) to give the title compound (637 m g) having the following physical data. TLC: Rf 0.44 (n-hexane: ethyl acetate = 3: 1); NMR (300MHz, CDCl3): delta 8.29 (brs, 1H), 7.16 (d, J = 8.4Hz, 1H), 7.04 (d, J = 2.4Hz, 1H), 6.87 (dd, J = 8.4, 2.4Hz, 1H), 3.84 (s, 3H), 2.41 (brs, 3H).
  • 19
  • tert-butyl (6AS,10AR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6AH)-carboxylate [ No CAS ]
  • [ 219735-99-6 ]
  • [ 313668-71-2 ]
YieldReaction ConditionsOperation in experiment
68% Example 94 tert-butyl (+-)-cis-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate The title compound was prepared by the method of Example 90 from tert-butyl (+-)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (121 mg, 0.27 mmol) and corresponding <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (100 mg, 0.54 mmol), to afford after chromatographic purification the title compound (141 mg, 68%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) delta7.21 (d, 1H, J=8.4 Hz), 6.94-6.99 (m, 3H), 6.82 (dd, 1H, J=2.9 Hz, 8.8 Hz), 3.75-4.00 (m, 7H), 3.60-3.70 (m, 1H), 3.10-3.50 (m, 7H), 2.80-3.00 (m, 1H), 1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (CI, NH3): 441 (base, M+H).
68% Example 94 tert-butyl (+-)-cis-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate The title compound was prepared by the method of Example 90 from tert-butyl (+-)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (121 mg, 0.27 mmol) and corresponding <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (100 mg, 0.54 mmol), to afford after chromatographic purification the title compound (141 mg, 68%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) delta 7.21 (d, 1H, J=8.4 Hz), 6.94-6.99 (m, 3H), 6.82 (dd, 1H, J=2.9 Hz, 8.8 Hz), 3.75-4.00 (m, 7H), 3.60-3.70 (m, 1H), 3.10-3.50 (m, 7H), 2.80-3.00 (m, 1H), 1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (C1, NH3): 441 (base, M+H).
60% tert-butyl (6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (187 mg, 1.0 mmol) to afford after chromatographic purification the title compound (133 mg, 60%). 1H NMR (CDCl3, 300 MHz) delta7.23 (d, 1H, J=8.8 Hz), 7.01 (s, 2H), 6.97 (s, 1H), 6.84 (dd, 1H, J=8.5, 2.6 Hz), 3.84-4.24 (m, 2H), 3.84 (s, 3H), 3.68-3.74 (m, 1H), 3.24-3.54 (m, 4H), 2.86-3.26 (m, 3H), 1.84-1.8 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 441 [M+H+].
  • 20
  • [ 313688-72-1 ]
  • [ 219735-99-6 ]
  • [ 313671-64-6 ]
YieldReaction ConditionsOperation in experiment
64% With sodium carbonate;Pd(PPh3)2Cl2; Step A Tert-butyl (8aS,12aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.15 g, 64%) was prepared by the general method of Example 89, step C from tert-butyl (8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50 mmol), <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (0.19 g, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.025 mmol), Na2CO3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam.
64% With sodium carbonate;Pd(PPh3)2Cl2; Step A Tert-butyl (8aS,12aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.15 g, 64%) was prepared by the general method of Example 89, step C from tert-butyl (8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50 mmol), <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (0.19 g, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.025 mmol), Na2CO3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam.
  • 21
  • [ 313669-58-8 ]
  • [ 219735-99-6 ]
  • [ 313671-91-9 ]
YieldReaction ConditionsOperation in experiment
23% With sodium carbonate;Pd(PPh3)2Cl2; Step A Tert-butyl (7aS,11aR)-2-[2-chloro-4-methoxyphenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.053 g, 23%) was prepared by the general method of Example 89, step C from tert-butyl (7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.20 g, 0.50 mmol), <strong>[219735-99-6]2-chloro-4-methoxyphenyl boronic acid</strong> (0.19 g, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.025 mmol), Na2CO3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam.
  • 22
  • [ 5419-55-6 ]
  • [ 219735-98-5 ]
  • sodium hydrogensulfite [ No CAS ]
  • [ 219735-99-6 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane; water; Part I. A solution of the iodide compound from Part H (7.00 g, 26.1 mmol) in anhydrous tetrahydrofuran (50 mL) was cooled to 90 C., and treated with a hexane solution of n-butyllithium (16.5 mL, 1.6 M, 26.4 mmol). After 15 minutes, the solution was treated with triisopropylborate (6.10 mL, 26.4 mmol) and was allowed to warm to ambient temperature over 6 hours. The resulting mixture was treated with 6 N aqueous HCl (5 mL) and water (5 mL), which was stirred for 1 hour, then poured into water (100 mL) and extracted with ethyl acetate (2*100 mL). The extracts were washed in sequence with 1 N aqueous sodium bisulfite and brine (80 mL each), combined, dried over sodium sulfate, filtered and evaporated. The residual solid was triturated with 1:1 ether-hexane, collected by filtration and dried under vacuum to afford pure product, 2-chloro-4-methoxybenzeneboronic acid (3.05 g, 16.4 mmol, 63%). m.p. 191-195 C.
  • 23
  • [ 885220-90-6 ]
  • [ 219735-99-6 ]
  • [ 885221-14-7 ]
YieldReaction ConditionsOperation in experiment
26% With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 85℃; for 16h; EXAMPLE 24; SYNTHESIS OF [3-(2-CHLORO-4-METHOXY-PHENYL)-2,5-DIMETHYL-PYRAZOLO[l,5- A]PYRIMIDIN-7-YL] - [ 1 -(3 -METHYL- [ 1 ,2,4] OXADIAZOL-5 - YL)-PROPYL] -AMINE; Step 24A; To Cmpd 5d (100 mgl) was added <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (70 mg) followed by potassium carbonate (80 mg) and a solution of dioxane/water (0.9 mL/0.2 mL). The reaction mixture was sparged with nitrogen for 5 min, then tetrakis(triphenyphosphine)palladium(0) (80 mg) was added, and the reaction vessel was sealed and heated at 850C for 16 hr. The solvent was evaporated, and the residue was purified directly by preparative thin-layer silica gel chromatography using 30% ethyl acetate in hexanes as eluant, providing Cmpd 24a as a solid (31 mg, 26%). LC/MS: 403.0 (MH+)
  • 24
  • [ 917910-71-5 ]
  • [ 219735-99-6 ]
  • [ 917910-72-6 ]
YieldReaction ConditionsOperation in experiment
The mixture of this bromoacid intermediate (0.71 g), the aryl boronic acid (0.67 g), Pd(PPh3)4 (323 mg), NaHCO3 solution (11.2 mL, 1 N) and dioxane (40 mL) was heated at 100 C. under nitrogen overnight in a sealed tube. The mixture was then partitioned between ethyl acetate and 1 N NaOH solution. The organic layer was washed with 1 N NaOH solution. The combined aqueous layers were acidified with concentrated HCl until pH=4-5. The resulting mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine and dried with sodium sulfate. The removal of solvent afforded the biaryl product.
  • 25
  • C13H19BrN2O4S [ No CAS ]
  • [ 219735-99-6 ]
  • C20H25ClN2O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 12h; EXAMPLE 4; Commercially available 2-bromo-5-formylthiazole (5 g, 26 mmol) in tetrahydrofuran (50 mL) was cooled to 0 0C. To this solution was added portionwise, sodium <n="39"/>borohydride (1.23 g, 32 mmol), and the reaction mixture was stirred for 1 h at 0 0C, and then allowed to warm to room temperature and stirred for another hour. Upon reaction completion, water (100 ml) was added and the mixture was allowed to stir for 30 minutes. The reaction mixture was concentrated in vacuo and purified via flash chromatography (Biotage 40M). To the corresponding thiazole-alcohol (3.87 g, 20 mmol) in CH2Cl2 (10OmL) at 0 0C was added carbon tetrabromide (13.2 g, 40 mmol) and triphenylphosphine (10 g, 40 mmol). The reaction mixture was allowed to stir at room temperature for 1 h. The mixture was concentrated in vacuo and purified via flash chromatography (Biotage 40 M). To a pre-cooled (0 0C) solution containing commercially available ethyl N-(diphenylmethylene) glycinate (2.87 g, 10.7 mmol) in tetrahydrofuran (18 mL), was added potassium tert-butoxide (1.2 g, 10.7 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at this temperature for 30 minutes and cooled to -78 0C. To this pre-cooled (-780C ) solution was added the thiazolyl bromide (1.83g, 7.1 mmol) in tetrahydrofuran (8 mL). The reaction mixture was stirred at this temperature for 30 minutes, and then allowed to stir at room temperature for 1 h. A saturated solution of ammonium chloride (40 mL) was then added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (Biotage 40M). To the corresponding Schiff base (3.17 g, 7.1 mmol) was added concentrated hydrochloric acid (9 mL), and the reaction mixture was allowed to stir for 1 h at room temperature. Following the completion of the reaction, the aqueous layer was washed 3 times with ethyl acetate (2OmL), and the aqueous layer was concentrated in vacuo. Without further purification, the amine (1.99g, 7.16 mmol) in CH2Cl2 (100 mL) was treated with triethylamine ( 2.89g, 29 mmol) and di- tert-butyl dicarbonate (3.1g, 14.3 mmol). The reaction mixture was stirred for 12 h at room temperature. Upon reaction completion, a saturated solution of sodium bicarbonate (100 mL) was added, and the mixture was allowed to stir for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (Biotage 40 M). To the amino acid (0.82g, 2.1 mmol) in toluene (20 mL) was added (2- chloro-4-methoxyphenyl)boronic acid ( 0.81 g, 4.3 mmol), tetrakis-triphenylphosphine palladium (0.12 g, 0.1 mmol), and potassium carbonate (0.89 g, 6.4 mmol). The reaction mixture was heated to 100 0C for 12 h. Following the reaction completion, the mixture was concentrated in vacuo and purified via flash chromatography (Biotage 40M). To the desired amino acid (0.57g, 1.3 mmol) in tetrahydrofuran (6 mL) was added water (6 mL), methanol (1 mL), and lithium hydroxide (0.12 g, 5.2 mmol). The biphasic reaction mixture was allowed to stir at room temperature for 12 h. The mixture was concentrated in vacuo, diluted with 10 mL of water, cooled to 0 0C and acidified with concentrated HCl to a pH of 3. The acidic solution was extracted three times with ethyl acetate (10 mL), and the organic extracts were dried with sodium sulfate and concentrated in vacuo. Without further purification, the carboxylic acid (0.14 g, 0.33 mmol) in tetrahydrofuran (5 mL) at -20 0C was treated with 4-methylmorpholine (0.067 g, 0.67 mmol), followed by the dropwise addition of isobutyl chloroformate (0.045 g, 0.33 mol). The reaction mixture was stirred for 10 minutes, followed by the <n="40"/>addition of ethyl-2-aminobenzoate (0.11 g, 0.67 mmol). The mixture was stirred at -20 0C for 2 h and then room temperature for 12 h. Following the reaction completion, the precipitate was filtered off and the filtrate was concentrated in vacuo and purified via flash chromatography (Biotage 40S). To the purified anthranilic acid derivative (18 mg, 33 mmol) in CH2Cl2 (3 xnL) at 0 0C, was added borontribromide (IM, 0.33 mmol). The mixture was allowed to stir at 0 0C for 10 minutes and then room temperature for 1 h. Following the reaction completion, water (10 mL) was added, and the Triphasic mixture was stirred for 10 minutes. The reaction mixture was then concentrated in vacuo, diluted with 10 mL of water, cooled to 0 0C and basified with sodium hydroxide to a pH of 14. The basic reaction mixture was allowed to stir for 12 h at room temperature. The mixture was concentrated in vacuo and then diluted with water (2 mL). The aqueous solution was acidified with concentrated hydrochloric acid (pH= 3) and then purified by reverse phase HPLC (Gilson) to provide the de...
  • 26
  • [ 1070892-04-4 ]
  • [ 219735-99-6 ]
  • [ 1070973-29-3 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 85℃; for 6h; To a mixture of delta-bromo^-trifluoromethyl-isonicotinonitrile 1-1 (2.51 g, 10 mmol) in dioxane (3.3 mL) and water (3.3 ml_), were added 2-chloro-4- methoxyphenylboronic acid (2.3 g, 12.5 mmol) and Na2CO3 (6.3 g). The mixture was purged with nitrogen gas for 10 min, then Pd(PPh3)4 (1.2 g, 1.0 mmol) was added. The mixture was stirred in a sealed vessel at 85 0C for 6 hrs, then extracted by ethyl acetate. The organic layer was washed with water, dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (10/1 ) yielded 5-(2-chloro-4-methoxy-phenyl)-2-trifluoromethylisonicotinonitrile (1.31 g). tR = 2.96 min (method 1).
  • 27
  • [ 5419-55-6 ]
  • [ 50638-46-5 ]
  • [ 219735-99-6 ]
YieldReaction ConditionsOperation in experiment
Reference example 3 2-chloro-4-methoxyboronic acid A solution of 3-chloro-4-bromoanisole (2.14 g) in anhydrous tetrahydrofuran (10 ml) was cooled at -78§C. 1.56 M n-butyl lithium / hexane (6.5 ml) was dropped into the solution, and the mixture was stirred for 30 minutes. Triisopropyl borate (2.3 ml) was dropped into the reaction mixture, and the mixture was stirred for 2 hours at -78§C. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. A obtained solid was washed with t-butyl methyl ether (4 ml), filtered and dried over to give the title compound (681 mg) having the following physical data. TLC: Rf 0.55 (methylene chloride: methanol = 19: 1); NMR (300MHz, CDCl3): delta 7.22 (d, J = 8.4Hz, 1H), 6.93 (d, J = 2.4Hz, 1H), 6.86 (dd, J = 8.4, 2.4Hz, 1H), 3.79 (s, 3H).
  • 28
  • [ 56-05-3 ]
  • [ 219735-99-6 ]
  • [ 915070-39-2 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In ethanol; water; toluene; at 90℃; Method 1G; Method 1A was used with the following exceptions: K2CO3 as the base, EtOH (0.15 M):water:toluene (2:1:1) as the solvent. The reaction was heated in the microwave at 50 C. for 2 hours.
  • 29
  • [ 1186482-08-5 ]
  • [ 219735-99-6 ]
  • [ 1186483-43-1 ]
YieldReaction ConditionsOperation in experiment
Example 37 5-[6-(2-Chloro-4-methoxy-phenyl)-pyridazin-3-ylmethyl]-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine (Compound 228) From 5-(6-chloro-pyridazin-3-ylmethyl)-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine and 2-chloro-4-methoxy-phenyl boronic acid following general procedure A. MS 465.0 (M+H+); H1 NMR (DMSO-d6): delta(ppm) 10.63 (s, 1H), 9.81 (s, 1H), 7.98-8.20 (m, 3H), 7.74-7.80 (m, 1H), 7.56-7.58 (m, 1H), 7.47-7.54 (m, 1H), 7.22-7.23 (m, 1H), 7.07-7.12 (m, 1H), 6.48 (s, 2H), 3.84 (s, 3H).
  • 30
  • [ 881658-92-0 ]
  • [ 219735-99-6 ]
  • [ 1217296-45-1 ]
  • 31
  • [ 1211579-32-6 ]
  • [ 219735-99-6 ]
  • [ 1217296-52-0 ]
  • 32
  • [ 1039826-64-6 ]
  • [ 219735-99-6 ]
  • [ 1108185-05-2 ]
  • 33
  • [ 583-69-7 ]
  • [ 219735-99-6 ]
  • 2-(2-chloro-4-methoxyphenyl)-1,4-benzoquinone [ No CAS ]
  • [ 858218-68-5 ]
  • 34
  • [ 1279107-01-5 ]
  • [ 219735-99-6 ]
  • [ 1279107-02-6 ]
YieldReaction ConditionsOperation in experiment
98% With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 20 - 80℃; Step 3 4-[2-(2-Chloro-4-methoxy-phenyl)-1-trifluoromethanesulfonyl-1H-indol-5-yl]-3-methyl-benzonitrile Trifluoro-methanesulfonic acid 5-(4-cyano-2-methyl-phenyl)-1-trifluoromethanesulfonyl-1-indol-2-yl ester (31 mg, 0.06 mmol) and 2-Chloro-4-Methoxyphenylboronic acid (13.5 mg, 0.073 mmol) were mixed with toluene (0.5 ml), EtOH (0.3 ml) and NaHCO3 (19.2 mg, 0.018 mmol) aqueous solution (0.2 ml), while the mixture was degassed with N2, a catalytic amount of Pd(Ph3P)4 was added, the reaction mixture was heated to 80 C. for 3 hours, stirred overnight at room temperature; partitioned between EtOAc and water, the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by the filtering through a pad of silica gel (5% EtOAc/hexanes) to give 4-[2-(2-chloro-4-methoxy-phenyl)-1-trifluoromethanesulfonyl-1H-indol-5-yl]-3-methyl-benzonitrile as a white solid (30 mg, 98%).
  • 35
  • [ 1285505-77-2 ]
  • [ 219735-99-6 ]
  • [ 1285506-55-9 ]
YieldReaction ConditionsOperation in experiment
67.6% With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 2h; Example 60Synthesis of N-[(E)-3-(2'-chloro-4'-hydroxy-biphenyl-2-yl)-2-methyl-acryloyl]-guanidine<Step 1>Intermediate 1 (50 mg, 0.126 mmol) and <strong>[219735-99-6]2-chloro-4-methoxyphenyl boronic acid</strong> (25.9 mg, 0.139 mmol) were dissolved in a mixed solution of dioxane and water (v/v=3/1, 2.0 mL). Pd(PPh3)4 (8.04 mg, 6.95 mumol) and Na2CO3 (41.6 mg, 0.378 mmol) were added to the solution and then stirred at 90 C. for 2 hours. After cooling it to room temperature, the solvent was eliminated in vacuo and then purified by reversed phase HPLC (0.1% TFA in water/CH3CN) to obtain the objective coupling product (38.9 mg, 67.6%).MS: 345
 

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