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Structure of 231278-20-9

Chemical Structure| 231278-20-9

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Product Details of [ 231278-20-9 ]

CAS No. :231278-20-9
Formula : C21H14ClFIN3O
M.W : 505.71
SMILES Code : IC1=CC2=C(NC3=CC=C(OCC4=CC=CC(F)=C4)C(Cl)=C3)N=CN=C2C=C1
MDL No. :MFCD09998827
InChI Key :UHFPFDMMKYQMLC-UHFFFAOYSA-N
Pubchem ID :10174519

Safety of [ 231278-20-9 ]

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

Computational Chemistry of [ 231278-20-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 28
Num. arom. heavy atoms 22
Fraction Csp3 0.05
Num. rotatable bonds 5
Num. H-bond acceptors 4.0
Num. H-bond donors 1.0
Molar Refractivity 117.75
TPSA ?

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

47.04 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.84
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

6.26
Log Po/w (WLOGP)?

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

6.62
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.

5.25
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

6.09
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

5.61

Water Solubility

Log S (ESOL):?

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

-7.17
Solubility 0.0000341 mg/ml ; 0.0000000675 mol/l
Class?

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

Poorly soluble
Log S (Ali)?

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

-7.04
Solubility 0.0000467 mg/ml ; 0.0000000922 mol/l
Class?

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

Poorly 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

-10.22
Solubility 0.0000000305 mg/ml ; 0.0000000001 mol/l
Class?

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

Insoluble

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

Yes
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

Yes
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

Yes
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

Yes
Log Kp (skin permeation)?

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

-4.94 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

2.0
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

1.0
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.

0.17

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<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)

2.94

Application In Synthesis of [ 231278-20-9 ]

* 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 [ 231278-20-9 ]

[ 231278-20-9 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 98556-31-1 ]
  • [ 202197-26-0 ]
  • [ 231278-20-9 ]
YieldReaction ConditionsOperation in experiment
96% In isopropyl alcohol; at 70℃; for 3.5h; 4-(3-fluorobenzyloxy)-3-chlorophenyl)-amine (12.3 g, 49 mmol), <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> 14.2 g, 49 mmol) and isopropanol (250 mL) were combined and the reaction mixture was heated to 70 C. for 3.5 hours. The resultant bright yellow solid product was collected by filtration (25.5 g, 96% yield). 1H NMR (DMSO-d6) δ 9.83 (s, 1H); 8.92 (s, 1H); 8.58 (s, 1H); 8.09 (d, 1H); 8.00 (d, 1H); 7.61 (d, 1H); 7.52 (d, 1H); 7.44 (m, 1H); 7.20-7.33 (m, 3H); 7.15 (m, 1H); 5.21 (s, 2H); MS m/z 506 (M+1)
95% In isopropyl alcohol; at 80℃; for 2h; General procedure: To a solution of compound 12 (5.8 g, 20 mmol) in i-PrOH was added anilines (22 mmol) at room temperature (RT). Then the reaction mixture was heated to 80 C for 2 h. After the start material was completed, the mixture was filtered through celite, and the cake was washed by i-PrOH, then dried to obtain the desired compound 13a-f.
95% With triethylamine; In isopropyl alcohol; at 20℃; for 9h;Reflux; To a round bottle, isopropanol (20 mL), 3-bromoaniline (0.62 g, 3.6 mmol), 4-cholo-6-iodo-quinazoline 15 (0.87 g, 3 mmol) andtriethylamine (0.36 g, 3.6 mmol) was added. The resulting reactionmixture was stirred at room temperature for 6 h and then at refluxfor another 3 h. After cooling to room temperature, the yellow solidwas collected by suck filtration, wash with isopropanol, water andether sequentially, and dried at 50 C to afford compound 12a as ayellow solid (0.74 g, 69% yield)
90 - 95% Example 1; Preparation of GW572016F; STAGE 1; A stirred suspension of 3H-6-iodoquinazolin-4-one (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq.) at 20 to 25C, then heated to 900C. Phosphorous oxychloride (1.1 eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 500C and toluene (5vols) added. Compound C (1.03 eq.) was added as a solid, the slurry was warmed back to 900C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 700C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-700C for 1 hour and then cooled to 200C over 1 hour. The suspension was stirred at 200C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-600C. <n="25"/>Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
90.72% In isopropyl alcohol;Reflux; Compound B2 (5.70 g, 19.70 mmol) and compound B4 (4.90 g, 19.70 mmol) were added to a jar, while isopropanol 150 mm was added and the mixture was heated under reflux overnight. After the reaction is completed, the temperature of the reaction system is lowered to room temperature.The solid product precipitated, was decompressed and filtered to obtain a filter cake. The cake was dried to obtain 9.10 g of a product (a yield of 90.72%). The product was of high purity without purification.
74.2% In isopropyl alcohol;Heating / reflux; 4-Chloro-6-iodoquinazoline (5.7g, 19.7 mmol) and 3-chloro-4-(3- fluorobenzyloxy)aniline (4.9g, 19.7 mmol) was refluxed in isopropanol (15OmL) overnight. The mixture was cooled to room temperature. The solid product was precipitated, filtrated and dried in vacuum. The product 1405-174 was pure enough and used without further purifcation.(7.4 g, 74.2%): LC-MS: 506 [M+l]+, 1U NMR (DMSO-J6): δ 5.29 (s, 2 H), 7.18 (m, IH), 7.33 (m, 3H), 7.48 (m, IH), 7.66 (m, IH), 7.74 (d, J= 9.0 Hz, 1 H), 7.90 (d, J= 2.2 Hz, 1 H), 8.37 (d, J= 9.0 Hz, 1 H), 8.94 (s, 1 H), 9.29 (s, 1 H).
Roschangar et al. ,Use of lithium N,O-dimethylhydroxylamide as an efficient in situ protecting agent for aromatic aldehydes. Tertrahedron 2002, 58, 1657-1666). Preparation analogous (Nishino et al.; Process for producing 4-aminoquinazoline compound by chlorination of quinazolin-4-one or its derivative and animation. 2003) as follows: To a mixture of 6-iodo-lH-quinazolin-4-one (10) (6.8Og; 25.0 mmol), toluene (5.0 mL) and POCl3 (27.5 mmol; 2.60 mL) carefully triethylamine (27.5 mmol; 3.81 mL) was added. The mixture was heated to 80 0C for 2 h, cooled to room temperature, a solution of 3-chloro~4-(3- fluorobenzyloxy)phenylamine (15) (27.50 mmol; 6.92 g) in 2~butanone (20.0 mL) added and the mixture stirred at 80 0C for another hour. The mixture was cooled to 00C, the yellow precipitate was filtered off and added to a NaOH solution (IN; 150 mL) by stirring. After 30 min the yellow solid was filtered off, washed with water and a small amount of acetone and dried in vacuo. Yield (8.38 g; 66%) analytical pure sample. 1H-NMR (DMSO-[D6]): δ (ppm) = 5.26 (s, 2H), 7.15-7.22 (m, IH), 7.27 (d, IH, J = 9.1 Hz), 7.29-7.35 (m, 2H), 7.43-7.51 (m, IH), 7.56 (d, IH, J = 8.8 Hz), 7.74 (dd, IH, J = 9.1 Hz, 4J = 2.5 Hz), 8.02 (d, IH5 4J = 2.5 Hz), 8.12 (dd; IH, J = 8.8 Hz, 4J = 1.7 Hz)5 8.62 (s, IH), 8.96 (d, 4J = 1.7 Hz), 9.90 (s, IH, exchangeable).
4-Chloro-6-iodoquinazoline (1wt) was added to a solution of fluorobenzyloxyaniline (0.894wt, 1.03equiv) in N-methylpyrrolidinone (8.26wt, 8vol) at ca 20C, and after the initial exotherm had subsided, the resulting solution was stirred at 20-25C for at least 30 minutes. The dark solution was treated with triethylamine (0. 58vol, 1.2equiv) and the mixture was stirred for 20-30 minutes. Isopropanol (2. 5vol) was added and the mixture was heated to ca 50C. Water (up to 3vol) was added slowly to the vessel over 10-15 minutes, while keeping the temperature at ca 50C. Once crystallisation had commenced the addition was stopped and the resulting slurry was aged for 30-45 minutes at ca 50C. Any residual water (from the 3vol) was added, then further water (5vol) was added to the vessel over ca 30 minutes while maintaining the temperature at ca 50C. The resulting slurry was cooled to ca 20C over ca 30 minutes and aged at ca 20C for at least 30 minutes. The solid was collected by filtration and washed sequentially with water (2 x 5vol), then isopropanol (5vol). The product was dried in vacuo at ca 60C to give the title compound as a cream crystalline solid.
at 90℃; for 1h; A stirred suspension of 3H-6-iodoquinazolin-4-one (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq.) at 20 to 25C, then heated to 900C. Phosphorous oxychloride (1.1eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 500C and toluene (5vols) added. Compound C (1.03 eq.) was added as a solid, the slurry was warmed back to 900C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 7O0C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-700C for 1 hour and then cooled to 200C over 1 hour. The suspension was stirred at 200C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-600C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
A stirred suspension of 3W-6-iodoquinazolin-4-one in toluene (5 vols) is treated with tri-n-butylamine (1.2 equiv.), and then heated to 70-800C. Phosphorous oxychloride (1.1 equiv.) is added and the reaction mixture is then heated to reflux and stirred at this temperature for at least 2 hours. The reaction mixture is then cooled to 55C and toluene (5vol) added followed by 3-chloro-4-[(3-fluorophenyl)rnethyl]oxy}aniline (1.03 equiv.). The reaction mixture is then warmed to 70-900C and stirred for at least 2 hours. The resultant slurry is transferred to a second vessel. The temperature is adjusted to 70-750C and 8 molar aqueous sodium hydroxide solution (2 vols) added over 1 hour, followed by water (6vol.) maintaining the contents at 70-850C. The mixture is stirred at 70-850C for ca. 1 hour and then cooled to 20-250C. The suspension is stirred for ca. 2 hours and the product collected by filtration, and washed successively with water, 0.1 molar aqueous sodium hydroxide, water, and IMS, then dried in vacuo. EPO <DP n="48"/>
A stirred suspension of 3H-6-iodoquinazolin-4-one (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq. ) at 20 to 25C, then heated to 90C. Phosphorous oxychloride (1.1eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 50C and toluene (5vols) added. Compound C (1.03 eq. ) was added as a solid, the slurry was warmed back to 90C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 70C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-70C for 1 hour and then cooled to 20C over 1 hour. The suspension was stirred at 20C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-60C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
The reaction mixture was cooled to 50C and toluene (5vols) added. Compound C (1.03 eq. ) was added as a solid and the slurry was warmed back to 90C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 70C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-70C for 1 hour and then cooled to 20C over 1 hour. The suspension was stirred at 20C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-60C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
4-Chloro-6-iodoquinazoline (1wt) was added to a solution of fluorobenzyloxyaniline (0.894wt, 1.03equiv) in N-methylpyrrolidinone (8.26wt, 8vol) at ca 200C, and after the initial exotherm had subsided, the resulting solution was stirred at 20-25C for at least 30 minutes. The dark solution was treated with triethylamine (0.58vol, 1.2equiv) and the mixture was stirred for 20-30 minutes. lsopropanol (2.5vol) was added and the mixture was heated to ca 500C. Water (up to 3vol) was added slowly to the vessel over 10-15 minutes, while keeping the temperature at ca 500C. Once crystallisation had commenced the addition was stopped and the resulting slurry was aged for 30-45 minutes at ca 500C. Any residual water (from the 3vol) was added, then further water (5vol) was added to the vessel over ca 30 minutes while maintaining the temperature at ca 500C. The resulting slurry was cooled to ca 200C over ca 30 minutes and aged at ca 200C for at least 30 minutes. The solid was collected by filtration and washed sequentially with <n="43"/>water (2 x 5vol), then isopropanol (5vol). The product was dried in vacuo at ca 600C to give the title compound as a cream crystalline solid.

  • 2
  • [ 98556-31-1 ]
  • [ 202197-25-9 ]
  • [ 231278-20-9 ]
YieldReaction ConditionsOperation in experiment
Stage 1: Preparation of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6- iodo-4-quinazolinamine 4-Chloro-6-iodoquinazoline (1wt) was added to a solution of fluorobenzyloxyaniline (0.894wt, 1.03equiv) in N-methylpyrrolidinone (8.26wt, 8vol) at ca 20C, and after the initial exotherm had subsided, the resulting solution was stirred at 20-25C for at least 30 minutes. The dark solution was treated with triethylamine (0.58vol, 1.2equiv) and the mixture was stirred for 20-30 minutes. Isopropanol (2.5vol) was added and the mixture was heated to ca 50C. Water (up to 3vol) was added slowly to the vessel over 10-15 minutes, while keeping the temperature at ca 50C. Once crystallisation had commenced the addition was stopped and the resulting slurry was aged for 30-45 minutes at ca 50C. Any residual water (from the 3vol) was added, then further water (5vol) was added to the vessel over ca 30 minutes while maintaining the temperature at ca 50C. The resulting slurry was cooled to ca 20C over ca 30 minutes and aged at ca 20C for at least 30 minutes. The solid was collected by filtration and washed sequentially with water (2 x 5vol), then isopropanol (5vol). The product was dried in vacuo at ca 60C to give the title compound as a cream crystalline solid.
  • 3
  • [ 443882-99-3 ]
  • [ 98556-31-1 ]
  • [ 231278-20-9 ]
YieldReaction ConditionsOperation in experiment
Example 6: N-r3-Chloro-4-(3-Fluorobenzyloxy)-Phenyll-6-Iodoquinazolin-4-amine preparation (one-pot process)[00088] 30.0 g of "Intermediate-A" (compound of Formula A), 17.8 g of iron powder (70 mesh), 51.3 g of ammonium chloride, 432 ml of ethanol and 108 ml of water were refluxed for 5 hours in IL reactor equipped with mechanical stirrer and condenser. The reaction mixture was then cooled to 20-250C and separated from insoluble iron oxide by vacuum filtration. The filtered solids were washed with ethanol (4 x 100 ml). The resulting filtrate was evaporated from reactor under reduced pressure to resulting in a wet orange residue. The residue was dissolved in 350 ml of dichloromethane and 300 ml water. The separated organic phase was washed with water (2 x 300 ml). The obtained organic solution was concentrated to about 150 ml followed by addition of 300 ml iso- propanol. The mixture was concentrated to 300 ml followed by addition 150 ml iso- propanol. The resulting mixture was concentrated to 300 ml. Then iso-propanol was added to obtain a final volume of about 570 ml (purity determined by HPLC: 98.5%).[00089] 23.8 g of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> were added to the organic solution, heated to reflux, stirred for 30 minutes and then cooled to 20-250C. The slurry was filtered and washed with 110 ml iso-propanol to obtain 53.5 g of wet crude product. Then it was triturated in 830 ml of boiling acetone for an hour, cooled and filtered. The product was triturated twice again each time in 655 ml of boiling acetone for an hour, cooled and filtered. Finally it was dried at 250C in vacuum oven to afford 32.2 g of "Intermediate-C" (Yield: 60%, Purity: 92.62%).
  • 4
  • [ 1227853-05-5 ]
  • [ 132131-24-9 ]
  • [ 231278-20-9 ]
YieldReaction ConditionsOperation in experiment
(ii) Preparation of N-[3-chloro-4-[(3-fluorobenzyloxy)phenyl]-6-iodo-quinazolin amine (3)Into a one liter four-necked round bottomed flask, 50OmL of xylene, 50.0 g of N'-^-chloro- 4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine obtained by the process given in example-(l), 40 g of <strong>[132131-24-9]2-amino-5-iodobenzonitrile</strong> obtained by the process given in above step (i) and 25 mL of acetic acid were charged under stirring. The reaction was maintained at reflux condition for 10 hours and the completion of the reaction was monitored by TLC. The solvent was distilled off completely under vacuum and cooled to room temperature. 100 mL of isopropylalcohol was added and adjusted the pH to basic (about 10) with aqueous ammonia solution. The mass was maintained at that temperature for about lhr. The mass was cooled to room temperature and filtered and dried to get 70.0 g of N-[3-chloro-4-[(3- fluorobenzyloxy)phenyl]-6-iodo-quinazolinamine as a pale yellow coloured crystalline powder.Purity: 99.43% by HPLC Melting point range: 222-225 C
With acetic acid; In xylene; for 10h;Reflux; (ii) Preparation of N-[3-chloro-4-[(3-fluorobenzyloxy)phenyl]-6-iodo-quinazolin amine (3)Into a one liter four-necked round bottomed flask, 500 mL of xylene, 50.0 g of N1-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine obtained by the process given in example-(1), 40 g of <strong>[132131-24-9]2-amino-5-iodobenzonitrile</strong> obtained by the process given in above step (i) and 25 mL of acetic acid were charged under stirring. The reaction was maintained at reflux condition for 10 hours and the completion of the reaction was monitored by TLC. The solvent was distilled off completely under vacuum and cooled to room temperature. 100 mL of isopropylalcohol was added and adjusted the pH to basic (about 10) with aqueous ammonia solution. The mass was maintained at that temperature for about 1 hr. The mass was cooled to room temperature and filtered and dried to get 70.0 g of N-[3-chloro-4-[(3-fluorobenzyloxy)phenyl]-6-iodo-quinazolinamine as a pale yellow coloured crystalline powder.Purity: 99.43% by HPLCMelting point range: 222-225 C.
  • 6
  • [ 98556-31-1 ]
  • [ 944483-37-8 ]
  • [ 231278-20-9 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide;Reflux; Example 1 Preparation of N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodine-quinazolin-4-amine 6-Iodine-3H-quinazolin-4-ketone (100 g) was added into a 2000 mL flask, dissolved in a mixed solvent of thionyl chloride (1000 mL) and N,N-dimethylformamide (20 mL), heated to reflux until the reaction solution is clear and transparent. After thionyl chloride was removed, anhydrous toluene was added to the residues and removed under reduced pressure, and the process of the adding and removing of toluene was repeated again to removed the remained thionyl chloride residues. The intermediate was dissolved in isopropyl alcohol (2000 mL), 3-chloro-4-(3-fluoro-benzyloxy)-aniline hydrochloride was added, and anhydrous K2CO3 (150 g) was added with mechanical stirring before the mixture was heated to reflux over night. The reaction solution was cooled to room temperature overnight, the precipitation was filtered and washed with water for multi-times until the pH of washing solution reached neutral. After drying under vacuum, 95 g of the title product was collected in a pale white solid. m/z M+1+: 506
  • 7
  • [ 13529-27-6 ]
  • [ 104-15-4 ]
  • [ 231278-20-9 ]
  • 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde tosylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 1 :Preparation of lapatinib2-Fluraldehyde diethyl acetal (40 gm) was dissolved in dimethoxy ethane (270 ml) at room temperature under nitrogen atmosphere and then cooled to -40C. N-Butyl lithium (180 ml) was added to the solution for 45 minutes and stirred for 2 hours at -40 to -35C. To the reaction mass was added triisopropyl borate (53 gm) for 30 minutes and stirred for 2 hours at -40 to -35C. The temperature of the reaction mass was raised to 0C and then added acetic acid (12 ml), stirred for 30 minutes at 0C. To the reaction mass was added water (15 ml) and stirred for 15 minutes. A mixture of ethanol (200 ml), triethylamine (41 ml) and N-{3-chloro-4-[(3-fluorobenzyl)oxy}phenyl}-6-iodo-4- quinazolinamine (59 gm) was added to the above reaction mass at 20 to 25C and then added palladium carbon (5%, 3.5 gm). The contents were heated to 60 to 65 C and maintained for 4 hours 60 to 65C. The reaction mass was cooled to room temperature and maintained for 30 minutes at room temperature. The reaction mass was filtered through hi-flo bed and the filtrate was cooled to 20 to 25C. To the reaction mass was added p-toluenesulfonic acid (91 gm) and stirred for 1 hour at room temperature. The separated solid was filtered and dried under vacuum at 50 to 55C for 5 hours to obtain 60 gm of 5-[4-({3-chloro-4-{(3-fluorophenyl)methoxy]phenyl)amino)quinazolin-6- yl]furan-2-carbaldehyde p-toluenesulfonic acid.5-[4-({3-Chloro-4-{(3-fluorophenyl)methoxy]phenyl)amino)quinazolin-6- yl]furan-2-carbaldehyde p-toluenesulfonic acidt as obtained above, tetrhydrofuran (1000 ml), 2-(methanesulphonyl)ethylamine (40 gm) and acetic acid (35 ml) were added at room temperature. Diisopropylethylamine (108 ml) was added to the reaction mass and stirred for 2 hours at 30 to 35C, and then cooled to 20C. To the reaction mass was added sodium triacetoxy borohydride (66 gm) and maintained for 3 hours at 20 to 25C, and then added a mixture of sodium hydroxide solution (25%, 310 ml) and water (200 ml). The layers were separated and aqueous layer was extracted with tetrahydrofuran. The combined organic layer was dried over sodium sulfate and the solvent was distilled off under vacuum at below 50C to obtain residual mass. To the residual mass was added isopropyl acetate (300 ml) and stirred for 30 minutes at 55 to 60C. The reaction mass was cooled to room temperature and stirred for 30 minutes at room temperature, filtered. The solid obtained was dried under vacuum at 50 to 55C for 6 hours to obtain 78 gm of crude lapatinib.Crude lapatinib as obtained above was dissolved in methanol (390 ml) and dichloromethane (780 ml) and then treated with carbon (7 gm) at room temperature. The reaction mass was stirred for 20 minutes and filtered through hi-flo bed. The solvent was distilled off under vacuum at 45 to 50C to obtain residual mass. To the residual mass was added methanol (50 ml) and stirred for 1 hour at room temperature. The separated solid was filtered and dried under vacuum at 50 to 55C for 6 hours to obtain 66 gm of lapatinib
  • 8
  • (E)-N'-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)formamidine [ No CAS ]
  • [ 132131-24-9 ]
  • [ 231278-20-9 ]
YieldReaction ConditionsOperation in experiment
92.2% With toluene-4-sulfonic acid; In toluene; at 110℃; for 5h; (8.69 g, 16.2 mmol) (E)-N'-(3-chloro-4-((3-chlorobenzyl)oxy)phenyl)-N-(3-chloro-4-((3-fluoro) Benzyl)oxy)phenyl)formamidine and (3.72g, 15.23mmol) <strong>[132131-24-9]2-amino-5-iodobenzonitrile</strong>, 0.2g 4-toluenesulfonic acid were added toIn 50 mL of toluene, it was heated in an oil bath to 110 C for 5 h.After TLC monitors the reaction, it is cooled to room temperature and then steamed to a small volume.The ice water was poured into the reaction mixture, and the mixture was stirred and filtered, and then filtered and washed with EtOAc (EtOAc) 7.1 g yield 92.2 %The HPLC purity was 99.6%.
 

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