Home Cart 0 Sign in  
X

[ CAS No. 13425-93-9 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
3d Animation Molecule Structure of 13425-93-9
Chemical Structure| 13425-93-9
Chemical Structure| 13425-93-9
Structure of 13425-93-9 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 13425-93-9 ]

Related Doc. of [ 13425-93-9 ]

Alternatived Products of [ 13425-93-9 ]

Product Details of [ 13425-93-9 ]

CAS No. :13425-93-9 MDL No. :MFCD09031937
Formula : C11H11NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :QOGPNCUTXVZQSL-UHFFFAOYSA-N
M.W : 205.21 Pubchem ID :459611
Synonyms :

Calculated chemistry of [ 13425-93-9 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.18
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 56.75
TPSA : 51.58 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.29 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.93
Log Po/w (XLOGP3) : 1.78
Log Po/w (WLOGP) : 1.96
Log Po/w (MLOGP) : 0.59
Log Po/w (SILICOS-IT) : 1.93
Consensus Log Po/w : 1.64

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.6
Solubility : 0.521 mg/ml ; 0.00254 mol/l
Class : Soluble
Log S (Ali) : -2.48
Solubility : 0.677 mg/ml ; 0.0033 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.39
Solubility : 0.0842 mg/ml ; 0.00041 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.67

Safety of [ 13425-93-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 13425-93-9 ]

* 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.

  • Upstream synthesis route of [ 13425-93-9 ]
  • Downstream synthetic route of [ 13425-93-9 ]

[ 13425-93-9 ] Synthesis Path-Upstream   1~18

  • 1
  • [ 13425-93-9 ]
  • [ 35654-56-9 ]
YieldReaction ConditionsOperation in experiment
82.7% With trichlorophosphate In toluene at 115℃; for 1 h; To a suspension of 6,7-dimethoxyquinolin-4-ol (45 g, 0.22 mol) in toluene (100 mL) was added phosphoryl trichloride (60 mL, 0.66 mol, Tianjin FuChen Chem. Co. Ltd.). The reaction was heated to 115 °C for 1 hour and then cooled down to rt. The mixture was diluted with EtOAc (400 mL), and the pH of the solution was adjusted to 7-8 with 3 M NaOH aqueous solution. The resulted mixture was extracted with EtOAc (150 mL x 2). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as a pale yellow solid (40.5 g, 82.7percent). MS (ESI, pos. ion) m/z: 224.0 [M+H]+; *H NMR (400 MHz, CDC13): δ 4.05 (s, 3H), 4.06 (s, 3H), 7.27 (s, 1H), 7.35 (d, J= 4.8 Hz, 1H), 7.41 (s, 1H), 7.42 (s, 1H), 8.57 (d, J= 4.8 Hz, 1H)
78% at 100℃; for 6 h; A solution of 6 (50 g, 0.24 mol) in POCl3 (400 mL) was stirred at 100°C for 6 h. Most of the solvent was recovered under vacuum. The residue was added slowly to cooled water 500 mL and adjusted with 10percent K2CO3 to pH ~ 9, and stirred for another 1 h. The resulting solid was filtrated, washed with H2O (50 mL × 2), and dried at 55°C for 4 h to give 7 (41.8 g, 78percent) as a light brown solid; mp 130.2-131.4° C (Lit.13 130−131 C). 1H NMR (400 MHz, DMSO-d6): δ 3.96 (s, 3H),3.97 (s, 3H), 7.35 (s, 1H), 7.44(s, 1H), 7.54 (d, J = 5.2 Hz, 1H), 8.61 (d, J = 5.2 Hz, 1H). MS (ESI): m/z =223.2 [M + H]+, 245.2 [M + Na]+.
55% at 125℃; for 2 h; 6,7-Dimethoxyquinolin-4-ol (0.64g) was dissolved in net POCI3 (3 mL). The solution was heated to 125°C for 2 h. The excess amount of POCI3 was removed by evaporation under vacuum. The residue was basified with sat. NaHC03 (aq) and then extracted with EtOAc. The organic layer was dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography using 10No.20percent methanol/EtOAc to give 4-chloro-6,7-dimethoxyquinoline (0.38 g, 55percent yield) ; 1H NMR (400 MHz, CHCI3- d) 6 ppm 4.04 (s, 3 H) 4.06 (s, 3 H) 7.35 (d, J=5.1 Hz, 1 H) 7.40 (s, 1 H) 7.42 (s, 1 H) 8.57 (d, J=4.8 Hz, 1 H).
43.4% With trichlorophosphate In N,N-dimethyl-formamide for 4 h; Heating / reflux To a mixture 6,7-dimethoxyquinolin-4-ol (Intermediate A, Step 2, 245 mg, 1.2 mmol) in phosphorus oxychloride (10 ml_) was added DMF (0.1 ml_). The reaction was heated at reflux for 4 h, then cooled to rt and concentrated under reduced pressure. The residue was dissolved with ethyl acetate, and the organic solution was washed successively with NaHCψ3 (saturated aqueous solution) and water, dried (Na2SO4), filtered and concentrated under reduced pressure to give 116 mg (43.4percent) of title compound, which was taken onto next step without further purification.
35.6 kg With trichlorophosphate In acetonitrile at 60 - 70℃; Large scale Preparation of 4-Chloro-6,7-dimethoxy-quinoline[0059] A reactor was charged sequentially with 6,7-dhnethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77°C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent ??,?? (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent(approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to - 20 to - 25 °C and held for 2.5 hours resulting in solid precipitate, which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound (35.6 kg).
8.0 kg With trichlorophosphate In acetonitrile at 80℃; for 9 h; Large scale A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65 °C and phosphorus oxychloride (POCb, 50.0 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 80 °C. The reaction was deemed complete (approximately 9.0 hours) when less than 2 percent of the starting material remained (in process high-performance liquid chromotography [HPLC] analysis). The reaction mixture was cooled to approximately 10 °C and then quenched into a chilled solution of dichloromethane (DCM, 238.0 kg), 30percent ΝΗ,ΟΗ (135.0 kg), and ice (440.0 kg). The resulting mixture was warmed to approximately 14 °C, and phases were separated. The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation to remove the solvent (approximately 190.0 kg). Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and the mixture was cooled to approximately 10 °C, during which time the product crystallized out. The solids were recovered by centrifugation, washed with n heptane (20.0 kg), and dried at approximately 40 °C to afford the title compound (8.0 kg).
35.6 kg With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale [00119] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77°C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent ΝΟΗ (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to - 20 to - 25 °C and held for 2.5 hours resulting in solid precipitate, which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound (35.6 kg).
35.6 kg With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale Preparation of 4-Chloro-6,7-dimethoxy-quinoline [00114] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POCI3, 130.6 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent ΝΟΗ (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg) and the filter bed was washed with DCM (1 18.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound. (35.6 kg).
35.6 kg With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale A reactor was charged sequentially with 6,7-dimemoxy-quinoline-4— ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POCI3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent ΝΟΗ (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to - 20 to - 25 °C and held for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound (35.6 kg).
35.6 kg With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale A reactor was charged sequentially with 6,7—dimethoxy—quinoline—4—ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POCi3, 130.6 kg) was added. After the addition of POCi3, the temperature of the reaction mixture was raised to approximatey 77 °C. The reaction was deemed compiete (approximatey 13 hours) when less than 3percent of the starting materia remained, as measured by in-process bigh-performance liquid cbromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a cbilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resultmg mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyfio super-cel NF (Celite; 5.4 kg), and the futer bed was washed with DCM (118.9 kg). The combined organic phase was washed with brnie (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by yacuum distillation with the remoyal of solyent (approximately 95 L residual yolume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by yacuum distiliation with the remoyal of soiyent (approximateiy 90 L residual yolume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to —20 to —25 °C and heid for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a futer at approximately 25 °C under rtrogen to afford the title compound (35.6 kg).
35.6 kg With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale [00264] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphonas oxychioride (POd3, 130.6 kg) was added. After the addition of POC13, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-2 5 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NP (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase wasconcentrated by vacuum distillation with the removal of solvent (approximateLy 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound. (35.6 kg).
35.6 kg With trichlorophosphate In acetonitrile at 77℃; for 13 h; Large scale Fool 13] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POC13, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLCJ analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichioromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound (35.6 kg).
35.6 kg
Stage #1: at 60℃; Large scale
Stage #2: at 77℃; for 13 h; Large scale
A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 - 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 - 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-eel NF (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent
35.6 kg With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale 10096] A reactor was charged sequentially with 6,7- dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60° C. and phosphorus oxychloride (POC13, 130.6kg) was added. After the addition of POC13, the temperature of the reaction mixture was raised to approximately 77° C. The reaction was deemed complete (approximately 13 hours) when <3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7° C. and then quenched into a chilled solution of dichioromethane (DCM, 482.8 kg), 26percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-25° C., and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cd NF (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to —20 to —25° C. and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25° C. under nitrogen to afford the title compound. (35.6 kg).
35.6 kg With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale The 6,7-dimethoxy-quinolin-4-ol (47.0 kg) and acetonitrile (318.8 kg) are sequentially added into the reactor. The resulting mixture is heated to about 60 °C, and add phosphorus acyl chlorine (POCl3, 130.6 kg). Adding POCl3the rear, the temperature of the reaction mixture the climbs to approximately 77 °C. When there is less than 3percent of the starting material (in the process for preparing the high performance liquid chromatography [HPLC] analysis), then the reaction as complete (about 13 hours). Cooling the reaction mixture to about 2-7°C, then the dichloromethane (DCM, 482.8 kg), 26percent NH4OH (251.3 kg) and water (900 L) quenching of the frozen solution. The resulting mixture is heated to about 20-25°C, and separation phase. Silicon, organic AW is passes through NF (CeliteTM; 5.4 kg) bed filter, and the filter bed in a DCM (118.9 kg) washing. Combined organic phase with the saline (282.9 kg) washing with water (120 L) mixing. Separation-phase, and the vacuum distilling to concentrate the organic phase in order to remove the solvent (about 95 L of the residual volume). The DCM (686.5 kg) is added in the reactor containing organic phase and carry out vacuum distillation and condensation in order to remove the solvent (about 90 L of the residual volume). Furthermore, by adding methyl 3rd-butyl ether (MTBE, 226.0 kg), and the mixture temperature is adjusted to -20 to -25 ° C and keep 2.5 hours, form a solid precipitate, then filtered and with n-heptane (92.0 kg) washing and about 25 °C lower, in the nitrogen, is dried in the filter in order to obtain the title compound (35.6 kg).
8.0 kg With trichlorophosphate In acetonitrile at 65 - 80℃; for 0.9 h; Large scale Preparation of 4-Chloro-6,7-dimethoxy-quinoline
A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (10.0 kg) and acetonitrile (64.0 L).
The resulting mixture was heated to approximately 65 °C and phosphorus oxychloride (POCl3, 50.0 kg) was added.
After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 80 °C.
The reaction was deemed complete (approximately 9.0 hours) when less than 2 percent of the starting material remained (in process high-performance liquid chromotography [HPLC] analysis).
The reaction mixture was cooled to approximately 10 °C and then quenched into a chilled solution of dichloromethane (DCM, 238.0 kg), 30percent NH4OH (135.0 kg), and ice (440.0 kg).
The resulting mixture was warmed to approximately 14 °C, and phases were separated.
The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation to remove the solvent (approximately 190.0 kg). Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and the mixture was cooled to approximately 10 °C, during which time the product crystallized out.
The solids were recovered by centrifugation, washed with n heptane (20.0 kg), and dried at approximately 40 °C to afford the title compound (8.0 kg).
1775.9 g With thionyl chloride In N,N-dimethyl acetamide at 100 - 120℃; Large scale 1.65 kg (13.9 mol) of thionyl chloride was added dropwise to a solution containing 2.2 kg (10.72 mol)4-hydroxy-6,7-dimethoxyquinoline in 5.3 L (57 mol) solution of N, N-dimethylacetamide was added and heated to 100 to 120 ° C for 4 to 7 hours (when HPLC Indicating that the feed is less than 3percent unreacted as the reaction is complete). After the reaction was cooled to room temperature, was added 2.2L of ice water, with 30percent sodium hydroxide solution to PH = 7 ~ 8, and a temperature controlled at 25 . And after completion, stirring was continued for 1 hour, sufficiently precipitate solid particles, was filtered; the cake was washed twice with 1L of water, and dried at 60 ~ 70 , to give a yellowish white powder of 4-chloro-6,7-dimethoxy-quinoline 1775.9 g, molar yield 74.2percent
35.6 kg With trichlorophosphate In acetonitrile at 77℃; for 13 h; Large scale A reactor was charged sequentially with 6,7-dimethoxyquinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POd3, 130.6 kg) was added. After the addition of P0db, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removaL of soLvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by [00841 A reactor was charged sequentially with 6,7—dimethoxy—quinoline—4—oI (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POd3, 130.6 kg) was added. After the addition of P0db, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removaL of soLvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by
35.6 kg With trichlorophosphate In acetonitrile at 0.6 - 0.77℃; for 13 h; Large scale [00166] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxy chloride (POCb, 130.6 kg) was added. After the addition of POCb, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to - 20 to - 25 °C and held for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound (35.6 kg).

Reference: [1] Patent: WO2013/180949, 2013, A1, . Location in patent: Paragraph 0170
[2] Heterocycles, 2016, vol. 92, # 10, p. 1882 - 1887
[3] Patent: WO2005/121125, 2005, A1, . Location in patent: Page/Page column 41-42
[4] Patent: WO2008/48375, 2008, A1, . Location in patent: Page/Page column 49
[5] Journal of the American Chemical Society, 1946, vol. 68, p. 1264
[6] Journal of Medicinal Chemistry, 2003, vol. 46, # 23, p. 4910 - 4925
[7] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 1015 - 1018
[8] Patent: WO2004/85425, 2004, A1, . Location in patent: Page 172
[9] Journal of Medicinal Chemistry, 2010, vol. 53, # 7, p. 2892 - 2901
[10] Patent: WO2010/83414, 2010, A1, . Location in patent: Page/Page column 24 - 25
[11] Patent: WO2012/109510, 2012, A1, . Location in patent: Page/Page column 27-28
[12] Patent: WO2013/59788, 2013, A1, . Location in patent: Paragraph 0059
[13] Patent: WO2013/43840, 2013, A1, . Location in patent: Paragraph 00111-00112
[14] Patent: WO2013/70890, 2013, A1, . Location in patent: Paragraph 00118-00119
[15] Patent: WO2013/166296, 2013, A1, . Location in patent: Paragraph 00114
[16] Patent: WO2014/165786, 2014, A1, . Location in patent: Paragraph 00196
[17] Patent: WO2014/165779, 2014, A1, . Location in patent: Paragraph 0077; 0078; 0079
[18] Patent: WO2015/164869, 2015, A1, . Location in patent: Paragraph 00263; 00264
[19] Patent: WO2016/22697, 2016, A1, . Location in patent: Paragraph 00111; 00112; 00113
[20] Patent: WO2016/19285, 2016, A1, . Location in patent: Paragraph 0095; 0096
[21] Patent: US2016/772, 2016, A1, . Location in patent: Paragraph 0095; 0096
[22] Patent: TWI516477, 2016, B, . Location in patent: Page/Page column 31; 32
[23] Patent: EP2758057, 2017, B1, . Location in patent: Paragraph 0107
[24] Patent: CN103664778, 2017, B, . Location in patent: Paragraph 0054-0058
[25] Patent: WO2018/136796, 2018, A1, . Location in patent: Paragraph 0081; 0082; 0083; 0084
[26] Patent: WO2018/227119, 2018, A1, . Location in patent: Paragraph 00163; 00164; 00165-00166
  • 2
  • [ 13425-93-9 ]
  • [ 67000-01-5 ]
  • [ 35654-56-9 ]
Reference: [1] Patent: US2012/252840, 2012, A1,
  • 3
  • [ 13425-93-9 ]
  • [ 1634-04-4 ]
  • [ 96042-30-7 ]
  • [ 35654-56-9 ]
Reference: [1] Patent: US2012/252840, 2012, A1,
  • 4
  • [ 13425-93-9 ]
  • [ 666734-51-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 6082 - 6093
  • 5
  • [ 13436-14-1 ]
  • [ 13425-93-9 ]
YieldReaction ConditionsOperation in experiment
90% With potassium hydroxide In ethanol; water at 180℃; for 0.833333 h; Microwave Ethyl 4-hydroxy-6,7-dimethoxyquinoline-3-carboxylate (700 mg, 2.53 mmol) was added into a solution of potassium hydroxide (450 mg, 7.6 mmol) in 20 mL of H20/EtOH (1: 1; v: v). This mixture was placed in a sealed vessel (XP-500 Plus vessel) and heated by microwave (MARS 5 Microwave System) at 180°C, under 260-280 psi pressure for 50 minutes. The reaction mixture was cooled to room temperature and transferred into a flask. The solution was then acidified with HOAc (about 2 mL) to pH about 6, saturated with NaCl and extracted with THF (3 x 100 mL). The combined oil layers were washed with brine and concentrated to give 6,7-dimethoxyquinolin-4-ol (90percent yield); (at) H NMR (400 MHz, DMSO-a\\3) 6 ppm 3.81 (s, 3 H) 3.84 (s, 3 H) 5.93 (d, J--7.3 Hz, 1 H) 7.05 (s, 1 H) 7.42 (s, 1 H) 7.76 (d, (at)=7.3 Hz, 1 H).
Reference: [1] Patent: WO2005/121125, 2005, A1, . Location in patent: Page/Page column 41-42
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 1264
  • 6
  • [ 4101-30-8 ]
  • [ 109-94-4 ]
  • [ 13425-93-9 ]
YieldReaction ConditionsOperation in experiment
55%
Stage #1: With sodium methylate In 1,2-dimethoxyethane at 20℃; for 16.5 h;
Stage #2: With sodium ethanolate In 1,2-dimethoxyethane at 20℃; for 24 h;
To a solution of 2-amino-4,5-dimethoxylacetophenone (4.5 g, 23 mmol) in DME (100 ml_) was added NaOMe (5.0 g, 92 mmol). The reaction was stirred for 30 min after which ethyl formate (8.5 g, 115 mmol) was added and the reaction mixture was stirred for 16 h at rt. Then NaOEt (21percent dispersion in oil, 22 g, 69.1 mmol) was <n="48"/>added and the reaction mixture was stirred for an additional 24 h at it Water (1OmL) was then added, and the mixture was stirred for 1 h, then concentrated under reduced pressure. The pH of the resulting aqueous mixture was adjusted to pH 7 using HCI (2N aqueous solution). The resulting precipitated was collected by filtration, and then successively washed with water, ethyl acetate and ethyl ether. The solid was dried under mechanical vacuum give 2.6 g (yield 55 percent) of the title compound.1H NMR (400 MHz, DMSO-cfe) δ 10.97 (bs, 1 H), 7.79 (d, 1 H), 7.42 (s, 1 H), 6.96 (s, 1 H), 5.96 (d, 1 H), 3.84 (s, 3 H), 3.81 (s, 3 H); ES-MS m/z 206.2 [M+H]+, LCMS RT (min) 1.21.
Reference: [1] Patent: WO2008/48375, 2008, A1, . Location in patent: Page/Page column 46-47
  • 7
  • [ 101-84-8 ]
  • [ 213699-53-7 ]
  • [ 13425-93-9 ]
YieldReaction ConditionsOperation in experiment
95% at 120 - 230℃; for 0.0833333 h; 5-((3,4-Dimethoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (16.1 g, 52 mmol) was added to a pre-heated 1000 mL round-bottom flask containing 1-phenoxy benzene (100 mL) at 230 °C.
The reaction was stirred for 5 min, and then cooled to 120°C. n-Hexane (100 mL) was added to the solution to allow the product to precipitate out from the reaction solution.
The mixture was further stirred at rt overnight.
The solid was collected and crystallized in a solution of EtOAc/ n-hexane (50 mL, v/v = 10/1) to afford the title compound as a brown solid (10.2 g, 95percent).
Reference: [1] Patent: US2010/239576, 2010, A1,
[2] Patent: EP2408300, 2016, B1, . Location in patent: Paragraph 0354
  • 8
  • [ 213699-53-7 ]
  • [ 13425-93-9 ]
YieldReaction ConditionsOperation in experiment
68.6% at -20℃; Reflux [0169] A solution of 5-(((3,4-dimethoxyphenyl)amino)methylene)-2,2-dimethyl- l,3-dioxane-4,6-dione (100 g, 0.33 mol) in 1,2-dichlorobenzene (1.2 L, Aladdin) was heated to reflux for 5 hours, then cooled down to -20 °C and stirred further for 2 hours. The mixture was filtered to give the title compound as a pale solid (45.8 g, 68.6percent). MS (ESI, pos. ion) m/z: 206.1 [M+H]+; *H NMR (400 MHz, CDC13): δ 3.88 (s, 3H), 3.92 (s, 3H), 6.26 (d, J= 7.2 Hz, 1H), 6.99 (s, 1H), 7.64 (d, J= 7.2 Hz, 1H), 7.70 (s, 1H), 11.86 (s, 1H).
Reference: [1] Patent: WO2013/180949, 2013, A1, . Location in patent: Paragraph 0169
  • 9
  • [ 122-51-0 ]
  • [ 13425-93-9 ]
Reference: [1] Patent: WO2004/85425, 2004, A1, . Location in patent: Page 171-172
  • 10
  • [ 26893-22-1 ]
  • [ 13425-93-9 ]
Reference: [1] Journal of the American Chemical Society, 1946, vol. 68, p. 1264
[2] Patent: US2002/111492, 2002, A1,
  • 11
  • [ 6315-89-5 ]
  • [ 13425-93-9 ]
Reference: [1] Journal of the American Chemical Society, 1946, vol. 68, p. 1264
[2] Patent: WO2013/180949, 2013, A1,
[3] Patent: EP2408300, 2016, B1,
[4] Patent: WO2005/121125, 2005, A1,
  • 12
  • [ 213699-53-7 ]
  • [ 13425-93-9 ]
  • [ 848128-82-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 1015 - 1018
  • 13
  • [ 1131-62-0 ]
  • [ 13425-93-9 ]
Reference: [1] Heterocycles, 2016, vol. 92, # 10, p. 1882 - 1887
  • 14
  • [ 4101-32-0 ]
  • [ 13425-93-9 ]
Reference: [1] Heterocycles, 2016, vol. 92, # 10, p. 1882 - 1887
  • 15
  • [ 26717-39-5 ]
  • [ 13425-93-9 ]
Reference: [1] Patent: WO2005/121125, 2005, A1,
  • 16
  • [ 13425-93-9 ]
  • [ 190728-25-7 ]
Reference: [1] Patent: WO2012/109510, 2012, A1,
[2] Patent: US2012/252840, 2012, A1,
[3] Patent: US2012/252840, 2012, A1,
[4] Patent: US2012/252840, 2012, A1,
[5] Patent: US2012/252840, 2012, A1,
[6] Patent: WO2013/59788, 2013, A1,
[7] Patent: WO2013/43840, 2013, A1,
[8] Patent: WO2013/43840, 2013, A1,
[9] Patent: WO2013/70890, 2013, A1,
[10] Patent: WO2014/165786, 2014, A1,
[11] Patent: WO2013/166296, 2013, A1,
[12] Patent: US2016/772, 2016, A1,
[13] Patent: WO2013/166296, 2013, A1,
[14] Patent: WO2013/180949, 2013, A1,
[15] Patent: WO2014/165779, 2014, A1,
[16] Patent: WO2015/164869, 2015, A1,
[17] Patent: WO2015/164869, 2015, A1,
[18] Patent: WO2016/22697, 2016, A1,
[19] Patent: WO2016/19285, 2016, A1,
[20] Patent: US2016/772, 2016, A1,
[21] Patent: TWI516477, 2016, B,
[22] Patent: EP2758057, 2017, B1,
[23] Patent: EP2758057, 2017, B1,
[24] Patent: CN103664778, 2017, B,
[25] Patent: CN103664778, 2017, B,
[26] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 1, p. 11 - 17
[27] Patent: CN108264482, 2018, A,
[28] Patent: WO2018/136796, 2018, A1,
[29] Patent: WO2018/227119, 2018, A1,
  • 17
  • [ 13425-93-9 ]
  • [ 475108-18-0 ]
Reference: [1] Heterocycles, 2016, vol. 92, # 10, p. 1882 - 1887
  • 18
  • [ 13425-93-9 ]
  • [ 1140909-48-3 ]
Reference: [1] Patent: WO2012/109510, 2012, A1,
[2] Patent: WO2013/59788, 2013, A1,
[3] Patent: WO2013/43840, 2013, A1,
[4] Patent: WO2013/43840, 2013, A1,
[5] Patent: WO2013/166296, 2013, A1,
[6] Patent: US2016/772, 2016, A1,
[7] Patent: WO2013/166296, 2013, A1,
[8] Patent: WO2014/165786, 2014, A1,
[9] Patent: WO2015/164869, 2015, A1,
[10] Patent: WO2015/164869, 2015, A1,
[11] Patent: WO2016/22697, 2016, A1,
[12] Patent: US2016/772, 2016, A1,
[13] Patent: TWI516477, 2016, B,
Same Skeleton Products
Historical Records

Pharmaceutical Intermediates of
[ 13425-93-9 ]

Cabozantinib Intermediates

Chemical Structure| 849217-60-3

[ 849217-60-3 ]

N-(4-Fluorophenyl)-N'-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide

Chemical Structure| 1131-62-0

[ 1131-62-0 ]

1-(3,4-Dimethoxyphenyl)ethanone

Chemical Structure| 4101-32-0

[ 4101-32-0 ]

4',5'-Dimethoxy-2'-nitroacetophenone

Chemical Structure| 849217-48-7

[ 849217-48-7 ]

1-((4-Fluorophenyl)carbamoyl)cyclopropanecarboxylic acid

Chemical Structure| 35654-56-9

[ 35654-56-9 ]

4-Chloro-6,7-dimethoxyquinoline

Related Functional Groups of
[ 13425-93-9 ]

Ethers

Chemical Structure| 23432-39-5

[ 23432-39-5 ]

6-Methoxyquinolin-4-ol

Similarity: 0.97

Chemical Structure| 190728-25-7

[ 190728-25-7 ]

4-((6,7-Dimethoxyquinolin-4-yl)oxy)aniline

Similarity: 0.94

Chemical Structure| 749922-34-7

[ 749922-34-7 ]

7-(Benzyloxy)quinolin-4-ol

Similarity: 0.93

Chemical Structure| 4964-76-5

[ 4964-76-5 ]

7-Methoxyquinoline

Similarity: 0.91

Chemical Structure| 131802-60-3

[ 131802-60-3 ]

7-(Benzyloxy)quinoline

Similarity: 0.90

Alcohols

Chemical Structure| 23432-39-5

[ 23432-39-5 ]

6-Methoxyquinolin-4-ol

Similarity: 0.97

Chemical Structure| 749922-34-7

[ 749922-34-7 ]

7-(Benzyloxy)quinolin-4-ol

Similarity: 0.93

Chemical Structure| 611-36-9

[ 611-36-9 ]

4-Hydroxyquinoline

Similarity: 0.89

Chemical Structure| 14300-45-9

[ 14300-45-9 ]

2,4-Dihydroxy-6-methoxyquinoline

Similarity: 0.88

Chemical Structure| 580-20-1

[ 580-20-1 ]

Quinolin-7-ol

Similarity: 0.86

Related Parent Nucleus of
[ 13425-93-9 ]

Quinolines

Chemical Structure| 23432-39-5

[ 23432-39-5 ]

6-Methoxyquinolin-4-ol

Similarity: 0.97

Chemical Structure| 190728-25-7

[ 190728-25-7 ]

4-((6,7-Dimethoxyquinolin-4-yl)oxy)aniline

Similarity: 0.94

Chemical Structure| 749922-34-7

[ 749922-34-7 ]

7-(Benzyloxy)quinolin-4-ol

Similarity: 0.93

Chemical Structure| 4964-76-5

[ 4964-76-5 ]

7-Methoxyquinoline

Similarity: 0.91

Chemical Structure| 131802-60-3

[ 131802-60-3 ]

7-(Benzyloxy)quinoline

Similarity: 0.90