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Chemical Structure| 350-30-1 Chemical Structure| 350-30-1

Structure of 3-Chloro-4-fluoronitrobenzene
CAS No.: 350-30-1

Chemical Structure| 350-30-1

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Product Details of [ 350-30-1 ]

CAS No. :350-30-1
Formula : C6H3ClFNO2
M.W : 175.54
SMILES Code : FC1=CC=C([N+]([O-])=O)C=C1Cl
MDL No. :MFCD00007206
InChI Key :DPHCXXYPSYMICK-UHFFFAOYSA-N
Pubchem ID :67688

Safety of [ 350-30-1 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H312-H332
Precautionary Statements:P280

Computational Chemistry of [ 350-30-1 ] 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 3.0
Num. H-bond donors 0.0
Molar Refractivity 40.23
TPSA ?

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

45.82 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.51
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

2.57
Log Po/w (WLOGP)?

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

2.81
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.

1.9
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

0.77
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.91

Water Solubility

Log S (ESOL):?

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

-2.89
Solubility 0.229 mg/ml ; 0.0013 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.

-3.18
Solubility 0.116 mg/ml ; 0.00066 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

-2.67
Solubility 0.375 mg/ml ; 0.00214 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.

-5.55 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

2.0 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)

1.87

Application In Synthesis of [ 350-30-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 350-30-1 ]
  • Downstream synthetic route of [ 350-30-1 ]

[ 350-30-1 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 350-30-1 ]
  • [ 179687-79-7 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.25 h;
Stage #2: for 36 h;
Sodium hydride (95percent, 0.935 g, 37 mmol) is suspended in dry DMF (20 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added dropwise over 15 minutes pyridin-2-yl-methanol (3.42 g, 31. 3 mmol) in dry DMF (20 mL). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2- CHLORO-L-FLUORO-4-NITRO-BENZENE (5 g, 28.5 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 36 HOURS. Water (80 mL) was added slowly to the reaction mixture, and a yellow precipitate resulted. The resultant solid is isolated by suction filtration, washed with water (80 ml), and air dried to yield 7. 52 g (28.5 mmol, 100percent) of the clean desired material as a yellow powder.
100%
Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.583333 h;
Stage #2: at 0℃; for 36 h;
Sodium hydride (95percent, 0.935 g, 37 mmol) is suspended in dry DMF (20 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added dropwise over 15 minutes pyridin-2-yl-methanol (3.42 g, 31.3 mmol) in dry DMF (20 mL). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2-Chloro-1-fluoro-4-nitro-benzene (5 g, 28.5 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 36 hours. Water (80 mL) was added slowly to the reaction mixture, and a yellow precipitate resulted. The resultant solid is isolated by suction filtration, washed with water (80 ml), and air dried to yield 7.52 g (28.5 mmol, 100percent) of the clean desired material as a yellow powder.
85%
Stage #1: With potassium hydroxide In acetonitrile for 0.333333 - 0.5 h;
Stage #2: at 40℃; for 18 h;
A mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes.
To this was added 400 g of 3-chloro-4-fluoronitrobenzene and the mixture was stirred at 40° C. for a minimum of 18 hours until the reaction was complete.
Water was added and the precipitated yellow solids were filtered and washed with water.
The product was dried (40-50° C., 10 mm Hg, 24 h) to the product in 85-95percent yield.
References: [1] Patent: WO2004/46101, 2004, A2, . Location in patent: Page 36.
[2] Patent: US2005/101617, 2005, A1, . Location in patent: Page/Page column 11.
[3] Patent: US2005/59678, 2005, A1, . Location in patent: Page 6.
  • 2
  • [ 586-98-1 ]
  • [ 350-30-1 ]
  • [ 179687-79-7 ]
YieldReaction ConditionsOperation in experiment
87.5% With potassium hydroxide In tetrahydrofuran at 20 - 25℃; for 20 h; Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3.x.100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.; Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.)
86% With potassium hydroxide In acetonitrile at 20 - 40℃; for 4 - 23 h; EXAMPLE 1
Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene
2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.).
The resulting suspension was warmed to 35° C.
A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C.
The mixture was held for 14 hours.
The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3*100 mL).
The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.
Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.)
85%
Stage #1: With potassium hydroxide In acetonitrile for 0.333333 - 0.5 h;
Stage #2: at 40℃; for 18 h;
A mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. To this was added 400 g of 3-chloro-4- fluoronitrobenzene and the mixture was stirred at 40 °C for a minimum of 18 hours until the reaction was complete. Water was added and the precipitated yellow solids were filtered and washed with water. The product was dried (40-50 °C, 10 mm Hg, 24 h) to the product in 85-95percent yield.
84% With potassium hydroxide In acetonitrile at 35 - 40℃; for 18 h; Example 3 Preparation of N-[3-Chloro-4-(2-pyridinylmethoxy)]phenyl-2-cyanoacetamide In a 12-L multi-necked flask, 2-pyridyl carbinol (0.13 kg, 1.19 mole, 1.05 eq) was dissolved in acetonitrile (0.88 L) and to it was added potassium hydroxide flakes (85percent) (80 g, 1.25 eq). The resulting suspension was warmed to 35° C. A solution of 3-chloro-4-fluoronitrobenzene (0.20 kg, 1.14 mol) in acetonitrile (1.0 L) was added at 35-40° C. The mixture was held for 18 h until reaction completion. The mixture was then cooled back to 20-25° C., quenched with water (4 L) and the resulting slurry was filtered and washed with water (3.x.200 mL). The resulting product was isolated as a tan solid (251 g, 84percent yield). A mixture of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene (0.149 kg, 0.56 mole) and 2percent (w/w) of 5percent Pt/C (6.0 g, 50percent water wet) in tetrahydrofuran (0.895 L) was hydrogenated in a 2-L stainless steel Parr reactor at 25 psi, 25° C. for a minimum of 8 h. The mixture was filtered through a celite pad (50 g, 15 cm diameter) and washed with tetrahydrofuran (0.45 L). The filtrate was distilled to a volume of 0.30 L and the concentrate was transferred to a 2-L multi-neck flask and used as is in the next step. To the 2-L flask equipped with mechanical stirrer, temperature probe, claisen head and condenser was added ethylcyanoacetate (0.421 kg, 3.72 mole, 6.6 eq.). The reaction mixture was heated to (100-115° C.) while removing tetrahydrofuran and ethanol. The temperature was raised to 125° C. and the mixture was held for a minimum of 24 h until the aniline starting material was consumed and no distillate was collected. The mixture was cooled to room temperature over 1 h. At 50-60° C., solids crystallized out and ethyl acetate (0.15 L) was added. The mixture was further cooled to 0-10° C. and held for 1 h. The mixture was filtered on a 15 cm diameter Buchner funnel and washed with 50 mL of the filtrate followed by pre-cooled (0-10° C.) ethyl acetate (0.15 L). The product was dried at 60° C. for a minimum of 16 h in a vacuum oven to give the titled compound (0.12 kg, 71percent) as a brown solid. The product was purified by slurrying in cold ethyl acetate (1-1.3 volumes) for 1 hr. 1H NMR: δ (DMSO-d6) 10.31 (s, 1H, NH), 8.58 (dd, 1H, Ar), 7.86 (dt, 1H, Ar), 7.75 (d, 1H, Ar), 7.55 (d, 1H, Ar), 7.39-7.32 (m, 2H, Ar), 7.21 (d, 1H, Ar), 5.25 (s, 2H, OCH2Pyr), 3.88 (s, 2H, NCCH2CO).
81.9% With potassium carbonate In N,N-dimethyl-formamide at 20 - 40℃; for 32 h; Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3.x.100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.; Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.)
76.5% With potassium hydroxide In N,N-dimethyl-formamide at 20 - 35℃; for 20 - 27 h; Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3.x.100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.; Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.)
48.7% With sodium hydride In 1-methyl-pyrrolidin-2-one at 20 - 25℃; for 20 h; Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3.x.100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.; Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.)

References: [1] Patent: US2006/270668, 2006, A1, . Location in patent: Page/Page column 16.
[2] Patent: US2006/270668, 2006, A1, . Location in patent: Page/Page column 16.
[3] Patent: WO2005/34955, 2005, A1, . Location in patent: Page/Page column 17-18.
[4] Patent: US2006/270669, 2006, A1, . Location in patent: Page/Page column 18.
[5] Patent: US2006/270668, 2006, A1, . Location in patent: Page/Page column 16.
[6] Patent: US2006/270668, 2006, A1, . Location in patent: Page/Page column 16.
[7] Patent: US2006/270668, 2006, A1, . Location in patent: Page/Page column 16.
[8] Patent: US2006/270668, 2006, A1, . Location in patent: Page/Page column 16.
[9] Patent: US2006/270668, 2006, A1, . Location in patent: Page/Page column 16.
[10] Patent: US2006/270668, 2006, A1, . Location in patent: Page/Page column 16.
[11] Patent: WO2010/151710, 2010, A2, . Location in patent: Page/Page column 32.
[12] Patent: WO2011/2523, 2011, A1, . Location in patent: Page/Page column 51.
  • 3
  • [ 55401-97-3 ]
  • [ 350-30-1 ]
  • [ 179687-79-7 ]
References: [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 22, p. 5147 - 5154.
  • 4
  • [ 586-98-1 ]
  • [ 350-30-1 ]
  • [ 524955-09-7 ]
  • [ 179687-79-7 ]
References: [1] Patent: US5821246, 1998, A, .
 

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Chemical Structure| 104222-34-6

A460327 [104222-34-6]

5-Chloro-4-fluoro-2-nitroaniline

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Chemical Structure| 3107-19-5

A155741 [3107-19-5]

1,3-Dichloro-2-fluoro-5-nitrobenzene

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Chemical Structure| 1481-68-1

A164209 [1481-68-1]

1-Chloro-2,4-difluoro-5-nitrobenzene

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Aryls

Chemical Structure| 4815-64-9

A125993 [4815-64-9]

1-Chloro-3-fluoro-5-nitrobenzene

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Chemical Structure| 21397-07-9

A121310 [21397-07-9]

2-Chloro-3-fluoronitrobenzene

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Chemical Structure| 104222-34-6

A460327 [104222-34-6]

5-Chloro-4-fluoro-2-nitroaniline

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Chemical Structure| 3107-19-5

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1,3-Dichloro-2-fluoro-5-nitrobenzene

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Chemical Structure| 1481-68-1

A164209 [1481-68-1]

1-Chloro-2,4-difluoro-5-nitrobenzene

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Chlorides

Chemical Structure| 4815-64-9

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1-Chloro-3-fluoro-5-nitrobenzene

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Chemical Structure| 21397-07-9

A121310 [21397-07-9]

2-Chloro-3-fluoronitrobenzene

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Chemical Structure| 104222-34-6

A460327 [104222-34-6]

5-Chloro-4-fluoro-2-nitroaniline

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A155741 [3107-19-5]

1,3-Dichloro-2-fluoro-5-nitrobenzene

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1-Chloro-2,4-difluoro-5-nitrobenzene

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Nitroes

Chemical Structure| 4815-64-9

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1-Chloro-3-fluoro-5-nitrobenzene

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2-Chloro-3-fluoronitrobenzene

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Chemical Structure| 104222-34-6

A460327 [104222-34-6]

5-Chloro-4-fluoro-2-nitroaniline

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Chemical Structure| 3107-19-5

A155741 [3107-19-5]

1,3-Dichloro-2-fluoro-5-nitrobenzene

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A164209 [1481-68-1]

1-Chloro-2,4-difluoro-5-nitrobenzene

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