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Chemical Structure| 327-78-6 Chemical Structure| 327-78-6

Structure of 327-78-6

Chemical Structure| 327-78-6

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Product Details of [ 327-78-6 ]

CAS No. :327-78-6
Formula : C8H3ClF3NO
M.W : 221.56
SMILES Code : FC(C1=CC(N=C=O)=CC=C1Cl)(F)F
MDL No. :MFCD00013874
InChI Key :NBJZEUQTGLSUOB-UHFFFAOYSA-N
Pubchem ID :2733265

Safety of [ 327-78-6 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H301+H331-H315-H319-H334-H335
Precautionary Statements:P501-P261-P270-P271-P264-P280-P284-P302+P352-P342+P311-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P310+P330-P304+P340+P311-P403+P233-P405
Class:6.1
UN#:2206
Packing Group:

Computational Chemistry of [ 327-78-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 14
Num. arom. heavy atoms 6
Fraction Csp3 0.12
Num. rotatable bonds 2
Num. H-bond acceptors 5.0
Num. H-bond donors 0.0
Molar Refractivity 44.24
TPSA ?

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

29.43 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.16
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

4.95
Log Po/w (WLOGP)?

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

4.48
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.

3.15
Log Po/w (SILICOS-IT)?

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

3.69
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.69

Water Solubility

Log S (ESOL):?

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

-4.52
Solubility 0.00673 mg/ml ; 0.0000304 mol/l
Class?

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

Moderately soluble
Log S (Ali)?

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

-5.31
Solubility 0.0011 mg/ml ; 0.00000494 mol/l
Class?

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

Moderately 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

-3.9
Solubility 0.0278 mg/ml ; 0.000126 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

Yes
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.

-4.14 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

0.0
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<2.0
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)

1.78

Application In Synthesis of [ 327-78-6 ]

* 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 [ 327-78-6 ]

[ 327-78-6 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 757251-39-1 ]
  • [ 327-78-6 ]
  • [ 755037-03-7 ]
YieldReaction ConditionsOperation in experiment
94.5% In ethyl acetate; at 20℃; for 1.5h; To a stirred solution of 7 (131 g, 0.5 mol) in EA (900 mL), 8 (153 g, 0.7 mol) was added in batches. The mixture was stirred at room temperature for 1.5 h, and filtered to afford the crude title product. Next, the precipitate was suspended in diethyl ether (2 L), and stirred for 2 h. Then, the mixture was filtered and dried to give the target compound 1 as a white crystal (229 g, 94.5 %) with 99.8 % HPLC purity.
90% In dichloromethane; at 0 - 20℃; for 16h;Inert atmosphere; To a solution of intermediate 13 (288 g, 1.1 mol) and dichloromethane (960 mL), isocyanate 4 (292 g, 1.3 mol) in dichloromethane (500 mL) was added dropwise at 0 C under argon. The mixture was stirred at room temperature, and a brown solid precipitated after 20 min. The mixture was stirred for 16 h and then filtered. The precipitate was suspended in diethyl ether (2 L) and stirred for 2 h. Then, the mixture was filtered and dried under vacuum for 4 h at 35 C to provide 1 (478 g, 90%) as a white solid with 99.96% HPLC purity. Mp: 206-207 C, ESI MS (m/z): 483.3 [M+H]+, 485.3 [M+H]+, 505.3 [M+Na]+, 507.3 [M+Na]+. HRMS (ESI): m/z calcd for C21H15ClF4N4O3 [M+Na]+ 505.0661, found 505.0667. 1H NMR (400 MHz, DMSO-d6): delta (ppm) 10.40 (s, 1H), 9.78 (s, 1H), 9.11 (s, 1H), 8.58 (d, J=6.0 Hz, 1H), 8.12-8.21 (m, 2 H), 7.64-7.69 (m, 2H), 7.60 (d, J=8.8 Hz, 1H), 7.34 (dd, J=2.8 Hz, 2.4 Hz, 1H), 7.30 (dd, J=2.4 Hz, 2.4 Hz, 1H), 7.08 (d, J=1.5 Hz, 1H), 2.81 (d, J=4.7 Hz, 3H).
87% In dichloromethane; for 24h; A solution of 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (384 mg, 1.73 mmol) and CH2C12 (2.5 mL) was added to a solution of HB/52 (450 mg, 1.72 mmol) and CH2C12 (2.5 mL) in an 8 mL vial. Stirred for 24 hours and isolated the product by vacuum filtration.Obtained 720 mg (87%) of the title compound as a white powder: ?H NIVIR (400 MHz, DMSOd 6) oe 9.52 (s, 1H), 8.78 (br q, J=4.8 Hz, 1H), 8.73 (d, J=i.0 Hz, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.10-8.20 (m, 2H), 7.63 (s, 2H), 7.42 (d, J=2.5 Hz, 1H), 7.34 (dd, J11.5, 2.7 Hz, 1H), 7.18 (dd,J=5.5, 2.6 Hz, 1H), 7.07 (dd, J=8.8, 1.5 Hz, 1H), 2.79 (d, J4.9 Hz, 3H); ?9F NMR (100 MHz, DMSO-d6) oe -61.1 (s, 3F), -124.0 (s, iF); LC-MS (ESI+) m/z: [M+H] Calcd for C2,H,6C1F4N403 483.1; Found 483.2 (FIGs. 7-8).
85% In acetone; at 40℃; for 5h; EXAMPLE 7 (0037) Under the protection of nitrogen, 171.5 g of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide and 1200 ml of acetone are added to a reaction vessel equipped with a stirrer, a thermometer and a dropping funnel, which is kept at 40 C., and then slowly add dropwise 159.5 g of 4-chloro-3-(trifluoromethyl) phenyl isocyanate in 600 ml of acetone solution (completed in about 2 hours), and then maintain the temperature and stir again for another 3 hours, filter to obtain a filter cake, which is then dried in vacuum to obtain 269 g of a white or off-white solid of Regorafenib. HPLC content is 99.4%, mp: 187 to 188 C., yield 85%.
74.9% In tetrahydrofuran; toluene; at 27℃; for 4.5h; 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (30 g) was dissolved in tetrahydrofuran (150 mL) at 27C and the solution containing 4-chloro-3 (trifluoromethyl) phenyl isocyanate (28 g) in toluene (36 mL) was added slowly at 27C in 90 minutes. The reaction mass was stirred for 3 hours at same temperature. After completion of reaction, tetrahydrofuran (51 mL) and methanol (15 mL) were added to the reaction mixture at 27C. Acetyl chloride (12 mL) was added drop wise to the reaction mixture at 27C for 10 minutes and stirred for 1 hour at same temperature. Compound was filtered and washed with tetrahydrofuran (30 mL) and then with acetone (140 mL). The obtained compound was dissolved in mixture of tetrahydrofuran (280 mL), 45% w/w aqueous sodium hydroxide solution (12 g) and water (80 mL) at 40C and stirred the reaction mass for 30 mm at 40C. The reaction mass was cooled to 20C and water (50 mL) was added. The reaction mass was further cooled to 0C and stirred at same temperature for 15 minutes. Reaction mass was distilled to completely evaporate the solvent at 35C and then the reaction mass was co-distilled with acetone (30 mL) at 35C. Acetone (280 mL) was added to the reaction mass at 27C and stirred for 15 minutes at same temperature. Reaction mass was cooled to 0C and stirred for 30 mm at same temperature. The solid was filtered and washed with chilled mixture of water (65 mL) and acetone (160 mL). The wet compound was dried for 2 hours at 25-30C to obtain the title compound. Yield: 41 .5 g (74.9 %); HPLC purity: 99.22%
73.46% In tetrahydrofuran; at 30℃; for 12h; 4-Chloro-3-(trifluoromethyl)phenylisocyanate (101.8 g) was dissolved in THF (200 ml) andadded to the solution of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide in THF (800 ml) at 30C and stirred for 12h.The reaction was monitored by LC-MS analysis and controlled 4-(4-amino-3 -fluorophenoxy)-N-methylpyridine-2-carboxamide content to NMT 50 ppm during reaction. The reaction mass was concentrated and co-distilled with acetone (2 x 200 ml). The concentrated mass was dissolved in acetone (4000 ml) at 55C,treated with activated carbon (15 g) for 30 mm and filtered through hyflo bed. The filtrate was partially concentrated, cooled to 20C, filtered and dried the product to yield crude Regorafenib anhydrous form 1(135.9 g, 73.46%). HPLC purity: 99.43 1%
47% In toluene; at 20℃; for 72h; To a solution of 4- (4-AMINO-3-FLUOROPHENOXY) pyridine-2-carboxylic acid methylamide (177 mg, 0.68 mmol) in toluene (3 mL) was added 4-chloro-3-(trifluoromethyl) phenyl isocyanate (150. MG, 0.68 mmol). The mixture was stirred at rt for 72 h. The reaction was concentrated under reduced pressure and the residue was triturated with diethylether. The resulting solid was collected by filtration and dried in vacuo for 4 h to afford the title compound (155 MG,. 0. 32 mmol; 47% yield) ; H-NMR (DMSO-d6) 2. 78 (d, J=4.9, 3H), 7.03-7. 08 (M, 1H), 7.16 (dd, J=2.6, 5.6, 1H), 7.32 (dd, J=2.7, 11.6, 1H), 7.39 (d, J=2.5, 1H), 7.60 (s, 2H), 8.07-8. 18 (M, 2H), 8. 50 (d, J=5. 7,1H), 8.72 (s, 1H), 8.74-8. 80 (M, 1H), 9.50 (s, 1H) ; MS (HPLC/ES) 483.06 m/z = (M + 1)
47% In toluene; at 20℃; for 72h; To a solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide (starting material 1, 177 mg, 0.68 mmol) in toluene (3 mL) was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (150 mg, 0.68 mmol). The mixture was stirred at room temperature for 72 h. The reaction was concentrated under reduced pressure and the residue was triturated with diethylether. The resulting solid was collected by filtration and dried in vacuo for 4 h to afford the title compound (155 mg, 0.32 mmol; 47% yield); 1H-NMR (DMSO-d6) 2.78 (d, J=4.9, 3H), 7.03-7.08 (m, 1H), 7.16 (dd, J=2.6, 5.6, 1H), 7.32 (dd, J=2.7, 11.6, 1H), 7.39 (d, J=2.5, 1H), 7.60 (s, 2H), 8.07-8.18 (m, 2H), 8.50 (d, J=5.7, 1H), 8.72 (s, 1H), 8.74-8.80 (m, 1H), 9.50 (s, 1H); MS (HPLC/ES) 483.06 m/z = (M + 1).
47% In toluene; at 20℃; for 72h; To a solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide (starting material 1 , 177 mg, 0.68 mmol) in toluene (3 ml_) was added 4-chloro-3- (trifluoromethyl)phenyl isocyanate (150 mg, 0.68 mmol). The mixture was stirred at room temperature for 72 h. The reaction was concentrated under reduced pressure and the residue was triturated with diethylether. The resulting solid was collected by filtration and dried in vacuo for 4 h to afford the title compound (155 mg, 0.32 mmol; 47% yield); 1H- NMR (DMSO-de) 2.78 (d, J=4.9, 3H), 7.03-7.08 (m, 1 H), 7.16 (dd, J=2.6, 5.6, 1 H), 7.32 (dd, J=2.7, 11.6, 1 H), 7.39 (d, J=2.5, 1 H), 7.60 (s, 2H), 8.07-8.18 (m, 2H), 8.50 (d, <n="16"/>J=5.7, 1 H), 8.72 (s, 1 H), 8.74-8.80 (m, 1 H), 9.50 (s, 1 H); MS (HPLC/ES) 483.06 m/z = (M + 1 ).
47% In toluene; at 20℃; for 72h; To a solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide (177 mg, 0.68 mmol) in toluene (3 mL) was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (150 mg, 0.68 mmol). The mixture was stirred at room temperature for 72 h. The reaction was concentrated under reduced pressure and the residue was triturated with diethylether. The resulting solid was collected by filtration and dried in vacuo for 4 h to afford the title compound (155 mg, 0.32 mmol; 47% yield); 1H-NMR (DMSO-d6) 2.78 (d, J=4.9, 3H), 7.03-7.08 (m, 1H), 7.16 (dd, J=2.6, 5.6, 1H), 7.32 (dd, J=2.7, 11.6, 1H), 7.39 (d, J=2.5, 1H), 7.60 (s, 2H), 8.07-8.18 (m, 2H), 8.50 (d, J=5.7, 1H), 8.72 (s, 1H), 8.74-8.80 (m, 1H), 9.50 (s, 1H); MS (HPLC/ES) 483.06 m/z=(M+1).
47% In toluene; at 20℃; for 72h; Example 1: Preparation of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3- fluorophenoxy}-pyridine-2-carboxylic acid methylamide; To a solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide (177 mg, 0.68 mmol) in toluene (3 mL) was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (150 mg, 0.68 mmol). The mixture was stirred at rt for 72 h. The reaction was concentrated under reduced pressure and the residue was triturated with diethylether. The resulting solid was collected by filtration and dried in vacuo for 4 h to afford the title compound (155 mg, 0.32 mmol; 47% yield); 1H-NMR (DMSO-d6) 2.78 (d, J=4.9, 3H), 7.03-7.08 (m, 1H), 7.16 (dd, J=2.6, 5.6, 1H), 7.32 (dd, J=2.7, 11.6, 1H), 7.39 (d, J=2.5, 1H), 7.60 (s, 2H), 8.07-8.18 (m, 2H), 8.50 (d, J=5.7, 1H), 8.72 (s, 1H), 8.74-8.80 (m, 1H), 9.50 (s, 1H); MS (HPLC/ES) 483.06 m/z = (M + 1).
In ethyl acetate; at 20 - 45℃; for 1.5h; Example 1: Preparation of 4- [4-([4-chloro-3-(trifluoromethyl)phenyll carbamoyl} amino)-3- fluorophenoxyl-N-methylpyridine-2-carboxamide in the polymorph IIExample 11O g 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide, obtained as described in WO 2005/009961 , are suspended in ethyl acetate at room temperature. The suspension is heated to 400C and 8,84 g of the commercially available 4-Chlor-3-(trifluormethyl)-phenylisocyanate solved in 10 g ethyl acetate are added within 45 min. at 40 - 45C. The suspension is cooled within 45 min. to room temperature. The crystals are sucked off, washed with ethyl acetate and dried 15 h at room temperature and 40 mbar. The product is tested thermoanalytically (DSC) and corresponds to the title compound of formula (I) in the polymorph ?.
350 g In dichloromethane; at 0 - 5℃; for 4h;Inert atmosphere; 4-chloro-3-(trifloromethyl)phenyl isocyanate (318.0) and 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (125 g) were added to a pre-cooled dichioromethane (2500 ml) at 0C to 5C under nitrogen atmosphere. Stirred the reaction mixture for 60 minutes at the same temperature. Another lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (125 g) was added to the reaction mixture at 0C to 5C and stirred the reaction mixture for 3 hours. Filtered the solid and washed with dichloromethane and dried the compound at 35C to 40C for 4 hours to get the title compound. Yield: 350 g;Content of 4-(4-amino-3 -fluorophenoxy)-N-methylpicolinamide: 704.13 ppm (0.070 % by HPLC)
5.5 g In acetone; at 25 - 30℃; 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (4g, 0.01 moles) was added in to a reaction flask containing acetone (20 ml) at 25-30C and stirred for 15 minutes. 4-chloro-3-trifluoromethylisocyanate (6.1g, 0.02 moles) was added slowly over a period of 5 to 10 minutes and stirred the reaction mixture 3 to 4 hours. Toluene (20 n L) was added to the reaction mass and stirred for 30 min at 25-30C.The obtained reaction mass was filtered and washed with toluene (8 mL). Dried the material still constant weight appears to yield title product a crystalline material. (0106) Yield: 5.5 gm (0107) Chromatographic Purity (By HPLC): 97%
In ethyl acetate; at 20℃; for 0.5h; the 3.0g (11mmol) of Intermediate 7 was dissolved in 20mL ethyl acetate was added 3.5g (16mmol)) 4- chloro-3-trifluoromethylphenyl isocyanate (8), at room temperature the reaction 30min, suction filtered, washed with 50mL diethyl ether cake filtration, dried to give a pale pink powder (1).Yield 94.5%, 99.8% purity
Join with stirringRegiofenib intermediate 1 and its weight 8.300 times the amount of tetrahydrofuran in the reaction vessel,Replace the nitrogen,Control temperature is 25 C,Intravenous addition of rigofene intermediate 1 within 25 min, 32% by weight of 2.948 times4-chloro-3-(trifluoromethyl)benzene isocyanate- tetrahydrofuran solution, reaction at 25 C for 3 h,Adding rigofene intermediate 1 weight 0.906 times the amount of methanol, reacting at 25 C for 1 h;Adding ryogofibine intermediate 1 by weight of 0.457 times of hydrochloric acid,Reacted at 25 C for 4 h,Filter by suction, wash, and dry.
Under the protection of nitrogen,RGFN 1 and dichloromethane were added to the reaction vessel, and the molar ratio of RGFN 1: dichloromethane was 1:12-18.Stir in the reactor at a temperature of 25 to 30 C for 15 to 20 minutes.Then open the circulating refrigeration oil bath valve of the reactor jacket or circulating chilled water (?-10 C) to cool the system temperature to 0 C.Further adding 4-chloro-3-(trifluoromethyl)benzene isocyanate (RGFN-C for short),The molar ratio of RGFN 1:RGFN-C is 1:1 to 1.2.Stir the reaction at 0 C or below for 15-20 min,The reaction kettle was closed and stirred for 30 min.Close the circulating refrigeration oil bath valve or turn off the circulating oil bath refrigeration to open the circulating oil bath heating switch or open the reactor jacket circulating cooling water, slowly heat up, control the temperature in the reactor system 25 ~ 30 C, continue to stir the reaction for 2h,Then open the reaction vessel jacketed circulating refrigeration oil bath valve or cycle refrigerationWater (?-10 C) is cooled to the temperature of the reactor. The temperature of the system is below 0 C. The mixture is stirred and decanted for 12 hours. The reactor is closed and stirred. The bottom of the reactor is opened, and the solid-liquid mixture in the reactor is centrifuged or filtered. The filter cake is washed 2 to 4 times with dichloromethane previously pre-frozen to a temperature of 0 C or below.Each time the amount of dichloromethane is 1 times the weight of RGFN 2, the cake is turnedMove to the drying tray in the vacuum drying box, crush the larger block, spread evenly, spread the thickness ? 30mm, 0.075MPa ~ 0.1MPa vacuum under vacuum and dry, the drying temperature is 25 ~ 30 C Dry under reduced pressure for 2h~4h,4-[4-([4-chloro-3-(trifluoromethyl)phenyl)carbamoyl}amino)-3-fluorophenylamino]-N-methylpyridine-2-carboxamide is obtained,That is, intermediate 2 (abbreviated as RGFN 2), the yield is 80-90%.
86.7 g In tetrahydrofuran; at 20℃; for 5h; In a 500 mL closed four-neck reaction flask, 31.4 g of 3-fluoro-4-nitrophenol (II), 34.1 g of N-methyl-4-chloro-2-pyridinecarboxamide, 27.8 g of potassium carbonate and 150 g were added. Diethylene glycol dimethyl ether, heating under reflux, stirring reaction for 6 hours, adding 200 g of water to precipitate a solid at the end of the reaction, and filtering to obtain 4-(4-nitro-3-fluorophenoxy)-2-(methylamine) 56.4 g of crude formyl)pyridine (III),Add 56.4 grams of III obtainedIn a 500 mL closed high pressure autoclave, 1.16 g of Raney nickel and 200 g of methanol were passed through 2 atm of hydrogen, and the temperature was controlled at 20 C. The reaction was stirred for 3 hours. The reaction was filtered to recover Raney nickel, and the methanol was distilled off under reduced pressure to obtain 50.2 g. IV,Then 50.2 g of IV was added to a 500 mL closed four-neck reaction flask, and 42.6 g of 4-chloro-3-(trifluoromethyl)phenylisocyanate and 200 g of tetrahydrofuran were added.The reaction was stirred at room temperature for 20 hours at 20 C, and 75 g of 10% dilute hydrochloric acid was added dropwise to the end of the reaction to precipitate a solid. The residue was filtered to obtain the hydrochloride salt of the product, the sodium carbonate aqueous solution was free and then extracted with ethyl acetate. The ester product was 83.7 g of regomafenib with a total yield of 86.4%.
31.5 g To a reaction flask with a stirrer was added 20.0 g of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide prepared by stage 2 method 2a (i.e. formula (IV) Compound), glacial acetic acid (molar ratio of the compound of formula (IV) to glacial acetic acid is 1: 0.15) and 180 g of tetrahydrofuran as a solvent. A solution of 18.7 g of (4-chloro-3-trifluoromethyl-phenyl) isocyanate (compound of formula (V)) and 21.1 g of toluene was added dropwise at room temperature over approximately 90 minutes. The resulting solution was stirred for 3 hours to complete the reaction.30 g of tetrahydrofuran and 7.8 g of methanol were then added to the reaction mixture. Then 9.0 g of acetyl chloride was added dropwise to the reaction mixture over 15 minutes. After stirring for an additional 2 hours, the suspension was filtered and the solid was washed with tetrahydrofuran (18.2 g) and acetone (136.4 g).The solid was added to a mixture of acetone (268.6 g), water (55.8 g) and aqueous sodium hydroxide solution (8.2 g, 45% w / w) at 40 C. The mixture was stirred for an additional 30 minutes. Then by using 4- {4-[([4-chloro-3- (trifluoromethyl) -phenyl] amino} carbonyl) amino] -3-fluorophenoxy} -N-methylpyridine-2 -Seeding of crystals of carboxamide monohydrate initiates crystallization. After cooling to 20 C, 31.6 g of water were added. The suspension was cooled to about 3 C and stirred for 30 minutes.The product was filtered off, washed with a cold mixture of acetone (106 g) and water (44 g) and dried under reduced pressure (30 C, 80 mbar).In this way, 31.3 g of the product 4- {4-[([4-chloro-3- (trifluoromethyl) -phenyl] amino} carbonyl) amino] -3-fluorophenoxy} -N -Methylpyridine-2-carboxamide monohydrate as white crystals.

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  • 2
  • [ 327-78-6 ]
  • [ 755037-03-7 ]
  • 3
  • [ 98-32-8 ]
  • [ 327-78-6 ]
  • 3-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-4-hydroxybenzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% at 20℃; General procedure: A solution of amine 1-10 (0.2 g, 1 equiv) was treated with 4-chloro-3-(trifluoromethyl)phenyl isocyanate 11 (1.0 equv) in dryacetonitrile (3-4 mL). The reaction mixture was stirred at rt untilthe consumption of starting materials (TLC monitoring). Reactionwas quenched with H2O to give a precipitate that was filtered-offand washed with diethyl ether (3 x 5 mL) and dried under vacuumto afford the products 12-21.
 

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