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Chemical Structure| 848942-61-0
Chemical Structure| 848942-61-0
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Product Details of [ 848942-61-0 ]

CAS No. :848942-61-0 MDL No. :MFCD18385011
Formula : C23H25ClFN5O3 Boiling Point : -
Linear Structure Formula :- InChI Key :DFJSJLGUIXFDJP-UHFFFAOYSA-N
M.W : 473.93 Pubchem ID :11488320
Synonyms :
AZD8931

Calculated chemistry of [ 848942-61-0 ]

Physicochemical Properties

Num. heavy atoms : 33
Num. arom. heavy atoms : 16
Fraction Csp3 : 0.35
Num. rotatable bonds : 8
Num. H-bond acceptors : 7.0
Num. H-bond donors : 2.0
Molar Refractivity : 128.38
TPSA : 88.61 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.34 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.65
Log Po/w (XLOGP3) : 4.02
Log Po/w (WLOGP) : 3.8
Log Po/w (MLOGP) : 2.57
Log Po/w (SILICOS-IT) : 3.44
Consensus Log Po/w : 3.5

Druglikeness

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

Water Solubility

Log S (ESOL) : -5.14
Solubility : 0.00342 mg/ml ; 0.00000722 mol/l
Class : Moderately soluble
Log S (Ali) : -5.58
Solubility : 0.00124 mg/ml ; 0.00000261 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -7.8
Solubility : 0.00000756 mg/ml ; 0.000000016 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 3.35

Safety of [ 848942-61-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 848942-61-0 ]

* 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 [ 848942-61-0 ]

[ 848942-61-0 ] Synthesis Path-Downstream   1~31

  • 1
  • [ 612500-78-4 ]
  • [ 96-30-0 ]
  • Sapitinib [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With potassium carbonate; potassium iodide; In acetonitrile; for 2h;Reflux; To a stirred mixture of compound 10 (480 mg, 1.19 mmol), KI (68.8 mg, 0.41 mmol) and K2CO3 (206.1 mg, 1.49 mmol) in CH3CN (15 mL) was added a solution of 2-chloro-N-methylacetamide (128.5 mg, 1.19 mmol) in CH3CN (3 mL) dropwise. Thereaction mixture was heated to reflux for 2 h. The solvent was removed under vacuum, and the residual was partitioned between CHCl3 and water. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography with concentrated ammonia in MeOH (1:7)/CH2Cl2 (1:10) to afford 11a (397 mg, 70%) as a white solid, mp 106-107 C. 1H NMR (CDCl3): d 8.69 (s, 1H), 8.41-8.37 (m, 3H), 7.54 (s, 1H), 7.29 (s,1H), 7.26 (s, 1H), 7.17-7.16 (m, 2H), 7.13 (s, 1H), 4.50-4.45 (m, 1H), 4.00 (s,3H), 3.04 (s, 2H), 2.86-2.81 (d+m, J = 5.0 Hz, 5H), 2.44-2.40 (m, 2H), 2.10-2.06 (m, 2H), 1.98-1.91 (m, 2H). LC-MS (ESI, m/z): calcd for C23H26ClFN5O3 ([M+H]+) 474.2, found 474.2. HRMS (ESI-TOF, m/z): calcd for C23H26ClFN5O3 ([M+H]+) 474.1708, found 474.1696.
60% With potassium carbonate; potassium iodide; In acetonitrile; for 1h;Heating / reflux; 2-Chloro-N-methylacetamide (32 mg, 0.3 mmol) was added dropwise to a mixture of 4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXY-6- [ (PIPERIDIN-4-YL) oxy] quinazoline (120 mg, 0.3 mmol), potassium iodide (16 mg, 0.1 mmol), and potassium carbonate (50 mg, 0.36 mmol) in acetonitrile (5 ml). The mixture was heated at reflux for one hour. After evaporation of the solvents under vacuum, the residue was taken up in dichloromethane. The organic solution was washed with water and brine, dried over magnesium sulfate. After evaporation of the solvents under vacuum, the residue was purified by chromatography on silica gel (eluant: 1% to 2% 7N methanolic ammonia in dichloromethane) to give the title compound as a white solid (85 mg, 60%). 'H NMR Spectrum: (CDC13) 1.98 (m, 2H), 2.08 (m, 2H), 2.46 (m, 2H), 2.85 (m, 2H), 2.87 (d, 3H), 3.07 (s, 2H), 4.02 (s, 3H), 4.49 (m, 1H), 7.16 (m, 4H), 7.31 (m, 2H), 8.49 (m, 1H), 8.71 (s, 1H) ; Mass spectrum : MH+ 474
  • 2
  • [ 612501-46-9 ]
  • [ 96-30-0 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
60% With triethylamine In acetonitrile at 20 - 75℃; B Example B; Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline (Compound (I))2-Chloro-N-methylacetamide (24.22 g, 223.1 mmol) and 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline dihydrochloride (86.00 g, 160.9 mmol), were slurried in acetonitrile (537 ml). To the stirred suspension, at ambient temperature, was added triethylamine (101 ml, 723.9 mmol). The reaction was heated to 75° C. held for 5 hours. The solution was cooled to 70° C. and ethanol (268 ml) added. The reaction was cooled to 45° C. and water (9.6 ml) added. Compound (I) (0.42 g) was added to establish crystallisation and then the slurry cooled to 20° C. over 2 hours. After stirring for a further 12 hours the product was isolated by filtration. The filter cake was washed twice with acetonitrile (102 ml): ethanol (51 ml): water (1.8 ml) and then with water (153 ml). The product was dried in vacuo at 60° C. to give the title compound as a white solid (45.9 g, 60%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.76-1.87 (m, 2H) 2.01-2.11 (m, 2H) 2.35-2.44 (m, 2H) 2.64 (d, J=4.74 Hz, 3H) 2.72-2.80 (m, 2H) 2.95 (s, 2H) 3.95 (s, 3H) 4.51-4.63 (m, 1H) 7.23 (s, 1H) 7.29 (td, J=8.08, 1.29 Hz, 1H) 7.46-7.58 (m, 2H) 7.75 (q, J=4.60 Hz, 1H) 7.83 (s, 1H) 8.38 (s, 1H) 9.59 (s, 1H) Mass spectrum: MH+ 474.
  • 3
  • [ 848942-61-0 ]
  • [ 110-17-8 ]
  • [ 1196531-39-1 ]
YieldReaction ConditionsOperation in experiment
98% In methanol; isopropyl alcohol at 0 - 65℃; Reflux; 2 Example 2; Preparation of Compound (I) Difumarate Form A: 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]-N-methylacetamide di-[(2E)-but-2-enedioate] Form AA solution of fumaric acid (1.4 kg, 12.1 mol) in methanol (26.6 kg) was added to a mixture of 2-[4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]-N-methylacetamide (2.93 kg, 84.8% w/w, 5.24 mol) in isopropanol (39 kg) maintaining the temperature >65° C. A line wash of methanol (3.6 kg) was charged. The mixture was heated at reflux for one hour before clarification, followed by a line wash of methanol (7 kg). The reaction mixture was distilled at atmospheric pressure to remove 47 kg of distillates. Isopropanol (15.8 kg was added and the reaction mixture distilled to remove 15.6 kg of distillates. Crystallisation occurred during the distillation. Isopropanol (21 kg) was added and the reaction cooled to 0° C. over 8 hours and held for 1 hour before isolation by filtration. The filter cake was washed with cold 50:50 isopropanol:MeOH (4 kg) followed by cold isopropanol (4 kg) and dried in vacuo at 50° C. to give the title compound as a white solid (3.64 kg, 98%); 1H NMR Spectrum: (DMSO) 1.85 (m, 1H), 2.08 (m, 1H), 2.50 (m, 1H), 2.66 (d, 3H), 2.83 (m, 1H), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, 1H), 6.64 (s, 4H), 7.23 (s, 1H), 7.28 (m, 1H), 7.46 (ddd, 1H), 7.55 (m, 1H), 7.70 (broad q, 1H), 7.85 (s, 1H), 8.38 (s, 1H).
98% In methanol at 65℃; for 1h; Industry scale; Reflux; 7 Example 6.; Preparation of compound (I) difumarate Form A:; 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. A solution of fumaric acid (1.4 kg, 12.1 mol) in methanol (26.6 kg) was added to a mixture of 2-[4-({4-[(3-chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (2.93 kg, 84.8% w/w, 5.24 mol) in isopropanol (39 kg) maintaining the temperature >;65°C. A line wash of methanol (3.6 kg) was charged. The mixture was heated at reflux for one hour before clarification, followed by a line wash of methanol (7 kg). The reaction mixture was distilled at atmospheric pressure to remove 47 kg of distillates. Isopropanol (15.8 kg was added and the reaction mixture distilled to remove 15.6 kg of distillates. Crystallisation occurred during the distillation. Isopropanol (21 kg) was added and the reaction cooled to 00C over 8 hours and held for 1 hour before isolation by filtration. The filter cake was washed with cold 50:50 isopropanol:MeOH (4 kg) followed by cold isopropanol (4 kg) and dried in vacuo at 500C to give the title compound as a white solid (3.64 kg, 98%); 1H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH).
  • 4
  • [ 1196531-32-4 ]
  • [ 2106-04-9 ]
  • Sapitinib [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With acetic acid In toluene Inert atmosphere;
55% With acetic acid In methoxybenzene at 90℃; for 20h; C Example C; Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline (Compound (I))Compound (I) was prepared according to the scheme shown below: 2-[4-(5-cyano-4-[(dimethylamino)methylene]amino }-2-methoxyphenoxy)piperidin-1-yl]-N-methylacetamide (7, 7.00 g, 17.71 mmoles), was suspended in methoxybenzene (35.8 g). Acetic acid (16.6 g) was charged and to the resulting solution was added 3-chloro-2-fluoroaniline (2.71 g, 18.07 mmoles). The reaction mixture was heated at 90° C. for 20 hours then cooled to 20° C. Water (37.04 g) was charged to the reaction mixture, and the organic layer discarded. To the resulting aqueous mixture was charged isopropanol (39.00 g), followed by aqueous ammonia (20.79 g, 25%). The reaction mixture was heated to 30° C. and seeded with Compound (I), which induced crystallisation. The reaction was then cooled to 0° C and the product isolated by filtration. The filter cake was washed twice with a mixture of water (7.28 g) and isopropanol (4.68 g), then dried to afford the Compound (I) (5.65 g, 55% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (m, 2H) 2.04 (m, 2H) 2.38 (m, 2H) 2.62 (d, J=4.5 Hz, 3H) 2.74 (m, 2H) 2.94 (s, 2H) 3.93 (s, 3H) 4.56 (tt, J=8.1, 3.8 Hz, 1H) 7.21 (s, 1H) 7.28 (m, 1H) 7.50 (m, 2H) 7.73 (q, J=4.5 Hz, 1H) 7.81 (s, 1H) 8.36 (s, 1H) 9.56 (br.s, 1H); Mass Spectrum: m/z (M+H)+ 474.2, 476.2.
55% With acetic acid In methoxybenzene at 90℃; for 20h; 1.7 Step 7. Preparation of compound (I). 2-[4-(5-cyano-4-{ [(dimethylamino)methylene] amino } -2-methoxyphenoxy)piperidin- 1 -yl] -JV-methylacetamide (compound (II),; 7.00 g, 17.71 mmoles), was suspended in methoxybenzene (35.8 g). Acetic acid (16.6 g) was charged and to the resulting solution was added 3-chloro-2-fluoroaniline (2.71 g, 18.07 mmoles). The reaction mixture was heated at 90 0C for 20 hours then cooled to 200C. Water (37.04 g) was charged to the reaction mixture, and the organic layer discarded. To the resulting aqueous mixture was charged isopropanol (39.00 g), followed by aqueous ammonia (20.79 g, 25%). The reaction mixture was heated to 30 0C and seeded with compound (I), which induced crystallisation. The reaction was then cooled to 00C and the product isolated by filtration. The filter cake was washed twice with a mixture of water (7.28 g) and isopropanol (4.68 g), then dried to afford the compound (I) (5.65 g, 55% yield); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.79 (m, 2 H) 2.04 (m, 2 H) 2.38 (m, 2 H) 2.62 (d, J=4.5 Hz, 3 H) 2.74 (m, 2 H) 2.94 (s, 2 H) 3.93 (s, 3 H) 4.56 (tt, J=8.1, 3.8 Hz, 1 H) 7.21 (s, 1 H) 7.28 (m, 1 H) 7.50 (m, 2 H) 7.73 (q, J=4.5 Hz, 1 H) 7.81 (s, 1 H) 8.36 (s, 1 H) 9.56 (br.s, 1 H); Mass Spectrum: m/z (M + H)+ 474.2, 476.2.
  • 5
  • [ 1196531-38-0 ]
  • [ 1252041-51-2 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
95% Stage #1: 2-[4-(4-amino-5-cyano-2-methoxy-phenoxy)-1-piperidyl]-N-methylacetamide; N,N'-bis(3-chloro-2-fluoro-phenyl)formamidine With acetic acid In 2-methyltetrahydrofuran at 80 - 92℃; for 6h; Stage #2: With sodium hydroxide In 2-methyltetrahydrofuran; water at 55 - 63℃; 2.7 Step 7, alternate 1 :; Preparation of compound (I).; 2-[4-(4-Amino-5-cyano-2- methoxyphenoxy)piperidin-l-yl]-N-methylacetamide (compound (III)) (10 g, 29.84 mmol) and TV, ΛT-bis(3-chloro-2-fluorophenyl)imidoformamide (compound (XI)) (11.46 g, 37.3 mmol) were suspended in 2-methyltetrahydrofuran (30.4 ml) and heated to 800C. To this yellow suspension was added acetic acid (7.6 ml, 127.33 mmol) and the resulting solution was heated to 92°C for 6 hours. 2-methyltetrahydrofuran (66.5 ml) and water (28.5 ml) were added and mixture was cooled to 550C before adding 50%w/w sodium hydroxide (7 ml, 131.29 mmol) resulting in a temperature rise to 63°C. The temperature was raised further to 69°C and after settling the aqueous phase was discarded. The organic phase was washed with water (3 x 20 ml) and each aqueous phase was discarded after settling. 2- methyltetrahydrofuran (100 ml, 997 mmol) was added and the volume reduced by distillation. Seed was added to induce crystallisation and the resulting mixture was cooled to 15°C. The crystalline form was initially obtained following a spontaneous crystallisation from the experiment as described. The resulting solid was isolated by filtration, washed twice with 2- methyltetrahydrofuran (19 ml) and dried under vacuum at 400C to yield compound (I) as a white solid (12.14 g, 95%). 1H NMR (400 MHz, DMSO-J6) δ ppm 1.12 (d, J= 6Hz, 1.3H), 1.26 -1.36 (m, 0.4H), 1.75-1.97 (m, 3.3H), 2.02-2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.7Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.52-3.59 (m, 0.4H), 3.72-3.87 (m, 0.86H), 3.95 (s, 3H), 4.53-4.63 (m, IH), 7.22 (s, IH), 7.29 (dt J= IHz J= 8Hz, IH), 7.51 (dt J= 7.4Hz, J= 18Hz, 2H), 7.71-7.77 (m, IH), 7.82 (s, IH), 8.37 (s, IH), 9.57 (s, IH). Mass Spectrum: m/z (M+H)+ 474.0. The NMR data above includes signals for the 2-methyltetrahydrofuran solvent which is present in a 0.43 molar equivalence. The signals pertaining to the solvent are at δ ppm shifts of 1.12, 1.26-1.36, 3.52-3.59 and 3.72-3.87. The cluster at 1.75-1.93 contains signals for the solvent and the parent compound. The XRPD for this compound is shown in Figure 2.
84.2% In 2-methyltetrahydrofuran; acetic acid at 79 - 90℃; for 8h; Inert atmosphere; Industrial scale;
  • 6
  • [ 1196531-38-0 ]
  • [ 1252041-52-3 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
73% Stage #1: 2-[4-(4-amino-5-cyano-2-methoxy-phenoxy)-1-piperidyl]-N-methylacetamide; N'-(3-chloro-2-fluoro-phenyl)-N,N-dimethyl-formamidine With acetic acid In 2-methyltetrahydrofuran at 90℃; for 14h; Stage #2: With sodium hydroxide In 2-methyltetrahydrofuran; water at 55 - 63℃; 4.7 Step 7: Preparation of compound (I).; 2-[4-(4-Amino-5-cyano-2- methoxyphenoxy)piperidin-l-yl]-N-methylacetamide (compound (III)) (0.50 g, 1.45 mmol) and N'-(3-chloro-2-fluoro-phenyl)-N,N-dimethyl-formamidine (compound (XII)) (0.32 g, 1.52 mmol) were suspended in methoxybenzene (3.1 ml). To this yellow suspension was added acetic acid (1.52 ml, 25.51 mmol) and the resulting solution was heated to 90 0C for 14 hours. The reaction mixture was cooled to 20 0C and water (2.58 mL) was added. The organic layer was removed and the aqueous layer washed with methoxybenzene (1.4 mL). Ethanol (2.45 mL) and ammonia (1.94 ml, 25.55 mmoles) were added to the aqueous layer. The solution was heated to 900C resulting in the loss of some ethanol by evaporation. The solution was cooled to 40 0C. Seed was added to induce crystallisation and the resulting mixture was cooled to 20 0C. The solid was isolated by filtration to yield compound (I) as a white solid (0.61 g, 73% yield). IH NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.87 (m, 2H), 2.02-2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.8Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.35 (s, 5.4H), 3.75 (s, 1.3H), 3.95 (s, 3H), 4.58 (hept., J=4.0Hz, IH), 6.90-6.95 (m, 1.3H), 7.23 (s, 1.8H), 7.26-7.34 (m, IH), 7.45-7.58 (m 2H), 7.72-7.78 (m, IH), 7.83 (s, IH), 8.38 (s, IH), 9.58 (s, IH). The NMR data above includes signals for the methoxybenzene solvent which is present in a 0.40 molar equivalence. The signals pertaining to the solvent are at δ ppm shifts of 3.75, and 6.90-6.95. The cluster at 7.26-7.34 contains signals for the solvent and the parent compound. The signal at δ ppm 3.35 is due to residual water. Mass Spectrum: m/z (M + H)+ 474.0, 476.0.
Inert atmosphere;
  • 8
  • [ 612501-80-1 ]
  • Sapitinib [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: potassium iodide; potassium carbonate / acetonitrile / 1 h / Reflux; Inert atmosphere
  • 10
  • [ 612501-81-2 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 2: potassium iodide; potassium carbonate / acetonitrile / 1 h / Reflux; Inert atmosphere
Multi-step reaction with 3 steps 1: 2 h / 20 °C 2: sodium hydroxide / water / 0 °C / pH Ca.9 3: potassium iodide; potassium carbonate / acetonitrile / 2 h / Reflux
Multi-step reaction with 2 steps 1: dichloromethane / 2 h / 25 °C 2: triethylamine / N,N-dimethyl-formamide / 16 h / 25 °C
  • 11
  • [ 2106-04-9 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: isopropyl alcohol / 3 h / 80 °C / Inert atmosphere 2: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 3: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 4: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 5: potassium iodide; potassium carbonate / acetonitrile / 1 h / Reflux; Inert atmosphere
  • 12
  • [ 848942-61-0 ]
  • [ 1623028-15-8 ]
YieldReaction ConditionsOperation in experiment
With lithium chloride In N,N-dimethyl-formamide
  • 13
  • [ 26791-93-5 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 11 steps 1: tin(II) chloride dihdyrate; hydrogenchloride / water / 3 h / 0 - 20 °C 2: 168 - 170 °C / Inert atmosphere 3: L-methionine; methanesulfonic acid / 18 h / 120 °C 4: pyridine; dmap / 6 h / 100 °C / Inert atmosphere 5: trichlorophosphate / 1 h / 80 - 100 °C 6: isopropyl alcohol / 3 h / Reflux 7: ammonia; N,N-diethylaniline / methanol / 18 h / 20 °C 8: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C 9: 2 h / 20 °C 10: sodium hydroxide / water / 0 °C / pH Ca.9 11: potassium iodide; potassium carbonate / acetonitrile / 2 h / Reflux
  • 14
  • [ 100905-33-7 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 11 steps 1: tin(II) chloride dihdyrate; hydrogenchloride / water / 2 h / 0 - 20 °C 2: 168 - 170 °C / Inert atmosphere 3: L-methionine; methanesulfonic acid / 18 h / 120 °C 4: pyridine; dmap / 6 h / 100 °C / Inert atmosphere 5: trichlorophosphate / 1 h / 80 - 100 °C 6: isopropyl alcohol / 3 h / Reflux 7: ammonia; N,N-diethylaniline / methanol / 18 h / 20 °C 8: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C 9: 2 h / 20 °C 10: sodium hydroxide / water / 0 °C / pH Ca.9 11: potassium iodide; potassium carbonate / acetonitrile / 2 h / Reflux
  • 15
  • [ 26759-46-6 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 10 steps 1: 168 - 170 °C / Inert atmosphere 2: L-methionine; methanesulfonic acid / 18 h / 120 °C 3: pyridine; dmap / 6 h / 100 °C / Inert atmosphere 4: trichlorophosphate / 1 h / 80 - 100 °C 5: isopropyl alcohol / 3 h / Reflux 6: ammonia; N,N-diethylaniline / methanol / 18 h / 20 °C 7: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C 8: 2 h / 20 °C 9: sodium hydroxide / water / 0 °C / pH Ca.9 10: potassium iodide; potassium carbonate / acetonitrile / 2 h / Reflux
  • 16
  • [ 5382-16-1 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: dichloromethane; 1,4-dioxane / 2 h / 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C 4: 2 h / 20 °C 5: sodium hydroxide / water / 0 °C / pH Ca.9 6: potassium iodide; potassium carbonate / acetonitrile / 2 h / Reflux
  • 17
  • [ 20323-74-4 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 10 steps 1: 168 - 170 °C / Inert atmosphere 2: L-methionine; methanesulfonic acid / 18 h / 120 °C 3: pyridine; dmap / 6 h / 100 °C / Inert atmosphere 4: trichlorophosphate / 1 h / 80 - 100 °C 5: isopropyl alcohol / 3 h / Reflux 6: ammonia; N,N-diethylaniline / methanol / 18 h / 20 °C 7: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C 8: 2 h / 20 °C 9: sodium hydroxide / water / 0 °C / pH Ca.9 10: potassium iodide; potassium carbonate / acetonitrile / 2 h / Reflux
  • 18
  • [ 109384-19-2 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C 3: 2 h / 20 °C 4: sodium hydroxide / water / 0 °C / pH Ca.9 5: potassium iodide; potassium carbonate / acetonitrile / 2 h / Reflux
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 16 h / 25 °C 2: caesium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C 3: dichloromethane / 2 h / 25 °C 4: triethylamine / N,N-dimethyl-formamide / 16 h / 25 °C
  • 19
  • [ 13794-72-4 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1: L-methionine; methanesulfonic acid / 18 h / 120 °C 2: pyridine; dmap / 6 h / 100 °C / Inert atmosphere 3: trichlorophosphate / 1 h / 80 - 100 °C 4: isopropyl alcohol / 3 h / Reflux 5: ammonia; N,N-diethylaniline / methanol / 18 h / 20 °C 6: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C 7: 2 h / 20 °C 8: sodium hydroxide / water / 0 °C / pH Ca.9 9: potassium iodide; potassium carbonate / acetonitrile / 2 h / Reflux
  • 20
  • [ 2815289-14-4 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 0 °C / pH Ca.9 2: potassium iodide; potassium carbonate / acetonitrile / 2 h / Reflux
  • 21
  • [ 179688-52-9 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1: pyridine; dmap / 6 h / 100 °C / Inert atmosphere 2: trichlorophosphate / 1 h / 80 - 100 °C 3: isopropyl alcohol / 3 h / Reflux 4: ammonia; N,N-diethylaniline / methanol / 18 h / 20 °C 5: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C 6: 2 h / 20 °C 7: sodium hydroxide / water / 0 °C / pH Ca.9 8: potassium iodide; potassium carbonate / acetonitrile / 2 h / Reflux
  • 22
  • [ 179688-53-0 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: trichlorophosphate / 1 h / 80 - 100 °C 2: isopropyl alcohol / 3 h / Reflux 3: ammonia; N,N-diethylaniline / methanol / 18 h / 20 °C 4: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C 5: 2 h / 20 °C 6: sodium hydroxide / water / 0 °C / pH Ca.9 7: potassium iodide; potassium carbonate / acetonitrile / 2 h / Reflux
  • 23
  • [ 740081-22-5 ]
  • Sapitinib [ No CAS ]
  • 24
  • [ 141699-59-4 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C 2: 2 h / 20 °C 3: sodium hydroxide / water / 0 °C / pH Ca.9 4: potassium iodide; potassium carbonate / acetonitrile / 2 h / Reflux
Multi-step reaction with 6 steps 1.1: potassium carbonate / water / 60 - 100 °C / Inert atmosphere; Industrial scale 1.2: 97 - 103 °C / Inert atmosphere; Industrial scale 2.1: hydrogenchloride / isopropyl alcohol / 75 - 85 °C / Inert atmosphere; Industrial scale 3.1: triethanolamine / ethanol / 12 h / 80 - 81 °C / Inert atmosphere; Industrial scale 4.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 5.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 5.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 6.1: 2-methyltetrahydrofuran; acetic acid / 8 h / 79 - 90 °C / Inert atmosphere; Industrial scale
Multi-step reaction with 6 steps 1.1: potassium carbonate / water / 60 - 100 °C / Inert atmosphere; Industrial scale 1.2: 97 - 103 °C / Inert atmosphere; Industrial scale 2.1: hydrogenchloride / isopropyl alcohol / 75 - 85 °C / Inert atmosphere; Industrial scale 3.1: triethanolamine / ethanol / 12 h / 80 - 81 °C / Inert atmosphere; Industrial scale 4.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 5.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 5.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 6.1: Inert atmosphere
Multi-step reaction with 6 steps 1.1: potassium carbonate / water / 60 - 100 °C / Inert atmosphere; Industrial scale 1.2: 97 - 103 °C / Inert atmosphere; Industrial scale 2.1: hydrogenchloride / isopropyl alcohol / 75 - 85 °C / Inert atmosphere; Industrial scale 3.1: bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate / toluene / 21 h / 125 °C / Inert atmosphere 4.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 5.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 5.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 6.1: Inert atmosphere
Multi-step reaction with 6 steps 1.1: potassium carbonate / water / 60 - 100 °C / Inert atmosphere; Industrial scale 1.2: 97 - 103 °C / Inert atmosphere; Industrial scale 2.1: hydrogenchloride / isopropyl alcohol / 75 - 85 °C / Inert atmosphere; Industrial scale 3.1: bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate / toluene / 21 h / 125 °C / Inert atmosphere 4.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 5.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 5.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 6.1: 2-methyltetrahydrofuran; acetic acid / 8 h / 79 - 90 °C / Inert atmosphere; Industrial scale
Multi-step reaction with 7 steps 1.1: potassium carbonate / water / 60 - 100 °C / Inert atmosphere; Industrial scale 1.2: 97 - 103 °C / Inert atmosphere; Industrial scale 2.1: hydrogenchloride / isopropyl alcohol / 75 - 85 °C / Inert atmosphere; Industrial scale 3.1: triethanolamine / ethanol / 12 h / 80 - 81 °C / Inert atmosphere; Industrial scale 4.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 5.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 5.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 6.1: toluene / Inert atmosphere 7.1: acetic acid / toluene / Inert atmosphere
Multi-step reaction with 7 steps 1.1: potassium carbonate / water / 60 - 100 °C / Inert atmosphere; Industrial scale 1.2: 97 - 103 °C / Inert atmosphere; Industrial scale 2.1: hydrogenchloride / isopropyl alcohol / 75 - 85 °C / Inert atmosphere; Industrial scale 3.1: bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate / toluene / 21 h / 125 °C / Inert atmosphere 4.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 5.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 5.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 6.1: toluene / Inert atmosphere 7.1: acetic acid / toluene / Inert atmosphere

Reference: [1]Wang, Min; Gao, Mingzhang; Zheng, Qi-Huang [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4455 - 4459]
[2]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[3]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[4]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[5]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[6]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[7]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
  • 26
  • [ 1196531-35-7 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 2.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 2.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 3.1: 2-methyltetrahydrofuran; acetic acid / 8 h / 79 - 90 °C / Inert atmosphere; Industrial scale
Multi-step reaction with 3 steps 1.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 2.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 2.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 3.1: Inert atmosphere
Multi-step reaction with 4 steps 1.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 2.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 2.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 3.1: toluene / Inert atmosphere 4.1: acetic acid / toluene / Inert atmosphere
  • 27
  • [ 1196531-33-5 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: hydrogenchloride / isopropyl alcohol / 75 - 85 °C / Inert atmosphere; Industrial scale 2.1: triethanolamine / ethanol / 12 h / 80 - 81 °C / Inert atmosphere; Industrial scale 3.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 4.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 4.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 5.1: 2-methyltetrahydrofuran; acetic acid / 8 h / 79 - 90 °C / Inert atmosphere; Industrial scale
Multi-step reaction with 5 steps 1.1: hydrogenchloride / isopropyl alcohol / 75 - 85 °C / Inert atmosphere; Industrial scale 2.1: triethanolamine / ethanol / 12 h / 80 - 81 °C / Inert atmosphere; Industrial scale 3.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 4.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 4.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 5.1: Inert atmosphere
Multi-step reaction with 5 steps 1.1: hydrogenchloride / isopropyl alcohol / 75 - 85 °C / Inert atmosphere; Industrial scale 2.1: bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate / toluene / 21 h / 125 °C / Inert atmosphere 3.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 4.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 4.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 5.1: Inert atmosphere
Multi-step reaction with 5 steps 1.1: hydrogenchloride / isopropyl alcohol / 75 - 85 °C / Inert atmosphere; Industrial scale 2.1: bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate / toluene / 21 h / 125 °C / Inert atmosphere 3.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 4.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 4.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 5.1: 2-methyltetrahydrofuran; acetic acid / 8 h / 79 - 90 °C / Inert atmosphere; Industrial scale
Multi-step reaction with 6 steps 1.1: hydrogenchloride / isopropyl alcohol / 75 - 85 °C / Inert atmosphere; Industrial scale 2.1: triethanolamine / ethanol / 12 h / 80 - 81 °C / Inert atmosphere; Industrial scale 3.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 4.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 4.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 5.1: toluene / Inert atmosphere 6.1: acetic acid / toluene / Inert atmosphere
Multi-step reaction with 6 steps 1.1: hydrogenchloride / isopropyl alcohol / 75 - 85 °C / Inert atmosphere; Industrial scale 2.1: bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate / toluene / 21 h / 125 °C / Inert atmosphere 3.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 4.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 4.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 5.1: toluene / Inert atmosphere 6.1: acetic acid / toluene / Inert atmosphere

Reference: [1]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[2]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[3]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[4]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[5]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[6]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
  • 28
  • [ 1196531-36-8 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: triethanolamine / ethanol / 12 h / 80 - 81 °C / Inert atmosphere; Industrial scale 2.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 3.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 3.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 4.1: 2-methyltetrahydrofuran; acetic acid / 8 h / 79 - 90 °C / Inert atmosphere; Industrial scale
Multi-step reaction with 4 steps 1.1: triethanolamine / ethanol / 12 h / 80 - 81 °C / Inert atmosphere; Industrial scale 2.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 3.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 3.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 4.1: Inert atmosphere
Multi-step reaction with 4 steps 1.1: bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate / toluene / 21 h / 125 °C / Inert atmosphere 2.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 3.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 3.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 4.1: Inert atmosphere
Multi-step reaction with 4 steps 1.1: bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate / toluene / 21 h / 125 °C / Inert atmosphere 2.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 3.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 3.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 4.1: 2-methyltetrahydrofuran; acetic acid / 8 h / 79 - 90 °C / Inert atmosphere; Industrial scale
Multi-step reaction with 5 steps 1.1: triethanolamine / ethanol / 12 h / 80 - 81 °C / Inert atmosphere; Industrial scale 2.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 3.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 3.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 4.1: toluene / Inert atmosphere 5.1: acetic acid / toluene / Inert atmosphere
Multi-step reaction with 5 steps 1.1: bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate / toluene / 21 h / 125 °C / Inert atmosphere 2.1: acetic acid; sulfuric acid; nitric acid / 42 - 48 °C / Inert atmosphere; Industrial scale 3.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 3.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 4.1: toluene / Inert atmosphere 5.1: acetic acid / toluene / Inert atmosphere

Reference: [1]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[2]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[3]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[4]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[5]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
[6]Goundry, William R. F.; Boardman, Kay; Cunningham, Oliver; Evans, Matthew; Jones, Martin F.; Millard, Kirsty; Rozada-Sanchez, Raquel; Sawyer, Yvonne; Siedlecki, Paul; Whitlock, Brian [Organic Process Research and Development, 2017, vol. 21, # 3, p. 336 - 345]
  • 29
  • [ 1196531-37-9 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 1.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 2.1: Inert atmosphere
Multi-step reaction with 2 steps 1.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 1.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 2.1: 2-methyltetrahydrofuran; acetic acid / 8 h / 79 - 90 °C / Inert atmosphere; Industrial scale
Multi-step reaction with 3 steps 1.1: 1 % platinum and 2% vanadium on carbon / acetonitrile / 40 °C / Inert atmosphere; Industrial scale 1.2: 6 h / 40 °C / 2250.23 Torr / Industrial scale 2.1: toluene / Inert atmosphere 3.1: acetic acid / toluene / Inert atmosphere
  • 30
  • [ 118811-07-7 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C 2: dichloromethane / 2 h / 25 °C 3: triethylamine / N,N-dimethyl-formamide / 16 h / 25 °C
  • 31
  • [ 96-30-0 ]
  • [ 2815289-14-4 ]
  • [ 848942-61-0 ]
YieldReaction ConditionsOperation in experiment
46.3 mg With triethylamine In N,N-dimethyl-formamide at 25℃; 1 Preparation of Compound 1 To a solution of 7V-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine (560 mg, 1.08 mmol, 1.00 eq, trifluoroacetic acid) (crude) in dimethyl formamide (5.00 mL) was added tri ethylamine (548 mg, 5.42 mmol, 754 pL, 5.00 eq) and 2-chloro-7V-m ethylacetamide (140 mg, 1.30 mmol, 1.20 eq) in portions. The mixture was stirred at 25 °C for 16 h. The mixture was diluted with ethyl acetate (50.0 mL) and water (30.0 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give a residue which was purified by p/cp-HPLC (column: Xtimate Cl 8 150*25mm*5pm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 22%-52%, 10 min). The desired fraction was collected and lyophilized to give 2-(4-((4-((3 -chi oro-2- fluoro-phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-l-yl)-A-methylacetamide (46.3 mg, 96.8 pmol, 9% yield, 99% purity) as a white solid. ’H NMR (400 MHz, DMSO-tL) 6 = 9.57 (s, 1H), 8.37 (s, 1H), 7.82 (s, 1H), 7.74 (br d, J= 4.4 Hz, 1H), 7.51 (td, J= 6.8, 13.7 Hz, 2H), 7.29 (dt, J= 1.0, 8.1 Hz, 1H), 7.22 (s, 1H), 4.57 (td, J = 4.0, 8.1 Hz, 1H), 3.94 (s, 3H), 2.95 (s, 2H), 2.79 - 2.72 (m, 2H), 2.63 (d, J= 4.8 Hz, 3H), 2.43 - 2.35 (m, 2H), 2.10 - 2.02 (m, 2H), 1.86 - 1.75 (m, 2H).
46.3 mg With triethylamine In N,N-dimethyl-formamide at 25℃; 1 Preparation of Compound 1 To a solution of 7V-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine (560 mg, 1.08 mmol, 1.00 eq, trifluoroacetic acid) (crude) in dimethyl formamide (5.00 mL) was added tri ethylamine (548 mg, 5.42 mmol, 754 pL, 5.00 eq) and 2-chloro-7V-m ethylacetamide (140 mg, 1.30 mmol, 1.20 eq) in portions. The mixture was stirred at 25 °C for 16 h. The mixture was diluted with ethyl acetate (50.0 mL) and water (30.0 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give a residue which was purified by p/cp-HPLC (column: Xtimate Cl 8 150*25mm*5pm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 22%-52%, 10 min). The desired fraction was collected and lyophilized to give 2-(4-((4-((3 -chi oro-2- fluoro-phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-l-yl)-A-methylacetamide (46.3 mg, 96.8 pmol, 9% yield, 99% purity) as a white solid. ’H NMR (400 MHz, DMSO-tL) 6 = 9.57 (s, 1H), 8.37 (s, 1H), 7.82 (s, 1H), 7.74 (br d, J= 4.4 Hz, 1H), 7.51 (td, J= 6.8, 13.7 Hz, 2H), 7.29 (dt, J= 1.0, 8.1 Hz, 1H), 7.22 (s, 1H), 4.57 (td, J = 4.0, 8.1 Hz, 1H), 3.94 (s, 3H), 2.95 (s, 2H), 2.79 - 2.72 (m, 2H), 2.63 (d, J= 4.8 Hz, 3H), 2.43 - 2.35 (m, 2H), 2.10 - 2.02 (m, 2H), 1.86 - 1.75 (m, 2H).
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