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[ CAS No. 124668-49-1 ] {[proInfo.proName]}

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Chemical Structure| 124668-49-1
Chemical Structure| 124668-49-1
Structure of 124668-49-1 * Storage: {[proInfo.prStorage]}
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Product Details of [ 124668-49-1 ]

CAS No. :124668-49-1 MDL No. :MFCD09264378
Formula : C5H14Cl2N2 Boiling Point : -
Linear Structure Formula :- InChI Key :DHXXDTCOJUYKOQ-UHFFFAOYSA-N
M.W : 173.08 Pubchem ID :22121220
Synonyms :

Calculated chemistry of [ 124668-49-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 47.58
TPSA : 15.27 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.45 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 1.28
Log Po/w (WLOGP) : 0.74
Log Po/w (MLOGP) : 0.57
Log Po/w (SILICOS-IT) : 0.05
Consensus Log Po/w : 0.53

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.65
Solubility : 3.84 mg/ml ; 0.0222 mol/l
Class : Very soluble
Log S (Ali) : -1.2
Solubility : 10.9 mg/ml ; 0.0631 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.56
Solubility : 47.3 mg/ml ; 0.274 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 124668-49-1 ]

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 [ 124668-49-1 ]

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

  • Downstream synthetic route of [ 124668-49-1 ]

[ 124668-49-1 ] Synthesis Path-Downstream   1~50

  • 1
  • [ 55438-79-4 ]
  • [ 124668-49-1 ]
YieldReaction ConditionsOperation in experiment
87% Stage #1: 3-(dimethylamino)-1-(diphenylmethyl)azetidine With hydrogen In ethanol for 18h; Stage #2: With hydrogenchloride In ethanol 34.3 20% Palladium hydroxide-carbon (533 mg) was added to a solution of the above (1-benzhydrylazetidin-3-yl)dimethylamine (533 mg) in ethanol (15 mL), and the mixture was stirred for 18 hours in a hydrogen atmosphere. The catalyst was removed from the reaction mixture through filtration. 1N HCl in ethanol (4 mL) was added to the solvent of the filtrate, and the solvent was removed under reduced pressure. Ether was added to the residue, and the solid that precipitated was collected through filtration, to thereby give the title compound (300 mg, 87%). 1H-NMR (400MHz, DMSO-d6) δ:2.70 (6H, m), 4.05-4.10 (2H, m), 4.25-4.31 (1H, m), 4.38-4.43 (2H, m). LC-MSm/z:101 (M+H)+.
87% Stage #1: 3-(dimethylamino)-1-(diphenylmethyl)azetidine With hydrogen; dimethyl amine In ethanol for 18h; Stage #2: With hydrogenchloride In ethanol 18.3 3) Title Compound 20% Palladium hydroxide-carbon (533 mg) was added to the above-obtained (1-benzhydrylazetidin-3-yl)dimethylamine (533 mg) in ethanol (15 mL), followed by stirring in a hydrogen atmosphere for 18 hours. The catalyst was removed from the reaction mixture by filtration. 1N HCl-ethanol (4 mL) was added to the solvent of the filtrate. The solvent of the reaction mixture was evaporated, and then diethyl ether was added to the residue. The solid that precipitated was collected by filtration, to thereby give the title compound (300 mg, 87%). 1H-NMR(400MHz,DMSO-d6)δ:2.70(6H,m), 4.05-4.10(2H,m), 4.25-4.31(1H,m), 4.38-4.43(2H,m). LC-MS m/z:101(M+H)+.
87% With hydrogenchloride; hydrogen In ethanol for 18h; 102 [Referential Example 102]; Azetidin-3-yldimethylamine hydrochloride ; [] 20% Palladium hydroxide-carbon (533 mg) was added to (1-benzhydrylazetidin-3-yl)dimethylamine (533 mg) obtained from Referential Example 101 in ethanol (15 mL), and the resultant mixture was subjected to catalytic reduction in a hydrogen reduction for 18 hours. The catalyst was filtered off, and then 1N HCl-ethanol (4 mL) was added to the filtrate. The solvent was evaporated under reduced pressure. Ether was added to the residue, and the precipitated solid was recovered by filtration, to thereby give the title compound (300 mg, 87%).1H-NMR(400MHz,DMSO-d6)δ: 2.70 (6H,m), 4.05-4.10 (2H,m), 4.25-4.31(1H,m), 4.38-4.43(2H,m). LC-MSm/z: 101(M+H)+.
With hydrogenchloride; hydrogen In methanol
With hydrogenchloride; palladium dihydroxide; hydrogen 1) Et2O, 0 deg C; 2) EtOH, 60psi, r.t.; Multistep reaction;

  • 2
  • [ 577775-44-1 ]
  • [ 124668-49-1 ]
  • [ 577773-87-6 ]
YieldReaction ConditionsOperation in experiment
43% With triethylamine In DMF (N,N-dimethyl-formamide) at 80℃; for 10h; 10 Example 10; 2-n-Hexyl-1-(3-dimethylaminoazetidin-1-yl)-3-methylpyrido[1,2-a]benzimidazole-4-carbonitrile To N,N-dimethylformamide (2.5 ml) suspension of 163 mg (0.50 mmol) of 1-chloro-2-n-hexyl-3-methylpyrido[1,2-a]benzimidazole-4-carbonitrile were added 95.2 mg (0.55 mmol) of 3-dimethylaminoazetidine dihydrochloride and 349 µl (2.50 mol) of triethylamine, and the resultng mixture was heated at 80°C for 10 hours. After cooling, the solvent was evaporated under reduced pressure, and the residue was applied to a silica gel column chromatography. This was eluted with ethyl acetate to obtain the entitled compound. This compound was recrystallized from isopropyl ether and taken out through filtration to obtain 84 mg (43 %) of the entitled compound as a yellow crystal. MS(EI)m/z:390(M+H)+.1H-NMR(400MHz, CDCl3)δ: 0.94(3H, t, J=7.09Hz), 1.33-1.44(4H, m), 1.47-1.57 (4H, m) , 2.24 (6H, s) , 2.66(3H, s) , 2.83-2.87(2H, m), 3.36(1H, m), 4.14(2H, t, J=6.11Hz), 4.31(2H, t, J=6.85Hz), 7.35(1H, t, J=8.31Hz), 7.51(1H, t, J=8.31Hz), 7.95(1H, d, J=8.31Hz), 8.30(1H, d, J=8.31Hz). IR(ATR): 2929, 2817, 2221, 1625, 1590, 1467, 1442 cm-1.
  • 3
  • [ 1421372-34-0 ]
  • [ 124668-49-1 ]
  • [ 1421373-30-9 ]
YieldReaction ConditionsOperation in experiment
72% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 140℃; for 0.5h; Microwave irradiation; 167 Intermediate 167: N-[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amine N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 140 mg, 0.81 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 68, 406 mg, 0.74 mmol) and DIPEA (0.514 mL, 2.94 mmol) in DMA (3mL). The mixture was heated in a microwave at 140°C for 0.5h. The mixture was then part-purified by ion exchange chromatography, using an SCX column (20 g) and eluting with 0.35M methanolic ammonia. Appropriate fractions were combined nad concentrated in vacuo to provide an orange/brown gum. This gum was triturated with ethanol (15 mL) to give a solid which was collected by filtration and dried under vacuum to give the title compound (245 mg, 72%) as an orange solid; 1H NMR: 2.15 (6H, s), 3.17 (1H, dd), 3.76 (2H, dd), 3.97 (3H, s), 4.03-4.10 (2H, m), 6.29 (1H, s), 7.08 (1H, t), 7.14-7.21 (1H, m), 7.27 (1H, d), 7.45 (1H, d), 8.01 (1H, s), 8.28-8.37 (3H, m), 8.64 (1H, s), 11.79 (1H, s); m/z: ES+ MH+ 460.32.
  • 4
  • [ 1421372-44-2 ]
  • [ 124668-49-1 ]
  • [ 1421372-84-0 ]
YieldReaction ConditionsOperation in experiment
93% With N-ethyl-N,N-diisopropylamine In 2,2,2-trifluoroethanol at 140℃; for 1h; Microwave irradiation; 119 Intermediate 119: 5-Chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amine N,N-Dimethylazetidin-3-amine (Intermediate 26, 144 mg, 0.83 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 76, 312 mg, 0.75 mmol) and DIPEA (0.460 mL, 2.64 mmol) in 2,2,2-trifiuoroethanol (5 mL). The mixture was heated in a microwave at 140°C for1h. The cooled mixture was purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (347 mg, 93%) as an orange solid after trituration with diethyl ether; 1H NMR: 2.14 (6H, s), 3.09-3.18 (1H, m), 3.76 (2H, dd), 3.89 (3H, s), 4.01-4.11 (2H, m), 6.28 (1H, s), 6.98 (1H, t), 7.13-7.20 (1H, m), 7.46 (1H, d), 8.15 (1H, s), 8.23 (1H, d), 8.37 (1H, s), 8.47 (1H, s), 8.49 (1H, s), 11.84 (1H, s); m/z: ES+ MH+ 494.16.
  • 5
  • [ 1421372-47-5 ]
  • [ 124668-49-1 ]
  • [ 1421372-80-6 ]
YieldReaction ConditionsOperation in experiment
71% With N-ethyl-N,N-diisopropylamine In 2,2,2-trifluoroethanol at 140℃; for 1h; Microwave irradiation; 115 Intermediate 115: N-[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine N,N-dimethylazetidin-3-amine (Intermediate 26, 113 mg, 0.65 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)-pyrimidin-2-amine (Intermediate 79, 250 mg, 0.61 mmol) and DIPEA (0.374 mL, 2.15 mmol) in 2,2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at 140°C for1h. The cooled mixture was purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (213 mg, 71%) as an orange foam; 1H NMR: 2.13 (6H, s), 2.37 (3H, s), 3.09-3.16 (1H, m), 3.72 (2H, dd), 3.89 (3H, s), 3.93 (3H, s), 4-4.08 (2H, m), 6.27 (1H, s), 7.04 (1H, t), 7.20-7.26 (1H, m), 7.49 (1H, d), 7.90 (1H, s), 8.03 (1H, s), 8.23 (1H, s), 8.35 (1H, d), 8.46 (1H, s); m/z: ES+ MH+ 488.63.
  • 6
  • [ 1421372-92-0 ]
  • [ 124668-49-1 ]
  • [ 1421373-03-6 ]
YieldReaction ConditionsOperation in experiment
50% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 140℃; for 1h; Sealed tube; Microwave irradiation; 140 Intermediate 140: N-[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 109 mg, 0.63 mmol), N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 300 mg, 0.60 mmol), DIPEA (0.386 mL, 2.22 mmol) and DMA (4 mL) was sealed into a microwave tube and heated to 140°C for1h in the microwave reactor. After cooling, to r.t, the mixture was part-purified by ion exchange chromatography, using an SCX column. The column was first washed with CH3OH and then the desired product was eluted from the column using 0.7M methanolic ammonia. Clean fractions were concentrated in vacuo to give an orange gum. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (140 mg, 50%) as an orange solid; 1H NMR (CDCl3): 1.90-1.98 (2H, m), 2.05-2.12 (2H, m), 2.20 (6H, s), 3.15-3.23 (1H, m), 3.28 (2H, t), 3.69 (2H, dd), 3.96 (3H, s), 4.18 (4H, dt), 6.03 (1H, s), 6.87 (1H, d), 7.35 (1H, s), 7.97 (1H, s), 8.31 (1H, d), 9.02 (1H, s); m/z: ES+ MH+ 465.61.
  • 7
  • [ 1421372-94-2 ]
  • 3-(dimethylamino)azetidine dihydrochloride [ No CAS ]
  • [ 1421372-82-8 ]
YieldReaction ConditionsOperation in experiment
89% With N-ethyl-N,N-diisopropylamine; In 2,2,2-trifluoroethanol; at 140℃; for 1h;Microwave irradiation; N,N-dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 79 mg, 0.46 mmol) was added to a suspension of <strong>[1421372-94-2]N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine</strong> (Intermediate 129 (which may be prepared by the method described for Intermediate 87), 150 mg, 0.38 mmol) and DIPEA (0.264 mL, 1.53 mmol) in 2,2,2-trifluoroethanol (3 mL). The mixture was heated at 140C in a microwave for1h. The mixture was then purified directly by ion exchange chromatography, using an SCX column (50 g) and eluting with 1:1 7M methanolic ammonia in CH2Cl2. Concentration of appropriate fractions in vacuo gave a brick red solid. This solid was suspended in CH3OH and the solid was collected by filtration, washed with CH3OH (10 mL) and dried in vacuo to give the title compound (160 mg, 89%) as a red solid; m/z: ES+ MH+ 474.61.
  • 8
  • [ 1421373-18-3 ]
  • [ 124668-49-1 ]
  • [ 1421373-20-7 ]
YieldReaction ConditionsOperation in experiment
72% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 85℃; for 1h; 157 Intermediate 157: N-[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine N,N-dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 227 mg, 1.31 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]-pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 415 mg, 1.09 mmol) and DIPEA (0.755 mL, 4.36 mmol) in DMA (3.2 mL) and the mixture was heated at 85°C for1h. The mixture was part-purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 0-7% CH3OH in CH2Cl2 gave the title compound (360 mg, 72%) as an orange solid; 1H NMR: 2.15 (6H, s), 3.12-3.19 (1H, m), 3.74-3.78 (2H, m), 3.95 (3H, s), 4.04-4.09 (2H, m), 6.29 (1H, s), 7.08 (1H, td), 7.28 (1H, d), 7.36-7.41 (1H, m), 8.26 (1H, s), 8.35 (1H, d), 8.45-8.49 (2H, m), 8.78 (1H, s), 8.80 (1H, d); m/z: ES+ MH+ 461.33.
  • 9
  • [ CAS Unavailable ]
  • [ 124668-49-1 ]
  • [ 1421372-78-2 ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 100℃; for 0.5h; Microwave irradiation; 113 Intermediate 113: 5-Chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine DIPEA (0.408 mL, 2.33 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine . 0.8 toluene-4-sulfonic acid salt (Intermediate 87, 330 mg, 0.58 mmol) in DMA (3 mL). N,N-dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 121 mg, 0.70 mmol) was then added in one portion. The mixture was heated in a microwave at 100°C for 0.5h then the mixture was cooled and diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Appropriate fractions were concentrated in vacuo. Further purification by FCC, eluting with 1-10% CH3OH in CH2Cl2 gave the title compound (295 mg, 100%) as a brown gum; 1H NMR: (CDCl3) 2.18 (6H, s), 3.13-3.24 (1H, m), 3.67-3.75 (2H, m), 3.89 (3H, s), 3.96 (3H, s), 4.13 (2H, t), 6.04 (1H, s), 7.21-7.29 (1H, m, partially obscured by chloroform signal), 7.29-7.41 (3H, m), 8.22 (1H, s), 8.37 (1H, s), 8.46 (1H, d), 9.05 (1H, s); m/z: ES+ MH+ 508.
  • 10
  • [ 1442471-00-2 ]
  • [ 124668-49-1 ]
  • [ 1442474-34-1 ]
YieldReaction ConditionsOperation in experiment
57% Stage #1: 3-(dimethylamino)azetidine dihydrochloride With 1-Methylpyrrolidine In 1,4-dioxane at 55℃; for 0.166667h; Stage #2: prop-1-en-2-yl (3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate In 1,4-dioxane at 55℃; for 16h; 102 Example 102 Example 102 A suspension of N,N-dimethylazetidin-3-amine dihydrochloride (0.071 g, 0.410 mmol) and N-methylpyrrolidine (0.070 g, 0.821 mmol) in dioxane (4 mL) was heated at 55° C. for 10 minutes, treated with Example A50 (0.11 g, 0.205 mmol) and heated at 55° C. for 16 h. The mixture was concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)azetidine-1-carboxamide (68 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 9.09 (s, 1H), 8.71 (d, J=2.6 Hz, 1H), 8.65 (s, 1H), 8.21 (d, J=8.6 Hz, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.57 (d, J=11.0 Hz, 1H), 7.41 (dd, J=8.2, 1.2 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.3 Hz, 1H), 4.17 (q, J=7.3 Hz, 2H), 4.06-4.01 (m, 2 H), 3.86-3.77 (m, 2H), 3.04 (m, 1H), 2.09 (s, 6H), 1.24 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 578.2 [M+H]+.
57% Stage #1: 3-(dimethylamino)azetidine dihydrochloride With 1-Methylpyrrolidine In 1,4-dioxane at 55℃; for 0.166667h; Stage #2: prop-1-en-2-yl (3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate In 1,4-dioxane at 55℃; for 16h; 102 Example 102: A suspension of N,N-dimethylazetidin-3-amine dihydrochloride(0.071 g, 0.410 mmol) and N-methyl pyrrolidine (0.070 g, 0.821 mmol) in dioxane (4 mL)was heated at 55°C for 10 minutes, treated with Example ASO (0.11 g, 0.205 mmol) andheated at 55°C for 16 h. The mixture was concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to afford N -(3 -(2-chloro-4-fluoro-5 -(3-phenylureido )phenyl)-1-ethyl-2-oxo-1 ,2-dihydro-1 ,6-naphthyridin-7 -yl)-3-(dimethylamino)azetidine-1-carboxamide (68 mg, 57% yield). 1H NMR (400 MHz, DMSOd6):8 9.49 (s, 1 H), 9.09 (s, 1 H), 8.71 (d, J = 2.6 Hz, 1 H), 8.65 (s, 1 H), 8.21 (d, J = 8.6 Hz,1 H), 8.09 (s, 1 H), 7.94 (s, 1 H), 7.57 (d, J = 11.0 Hz, 1 H), 7.41 (dd, J = 8.2, 1.2 Hz, 2 H),7.26 (t, J = 7.8 Hz, 2 H), 6.97 (t, J = 7.3 Hz, 1 H), 4.17 (q, J = 7.3 Hz, 2 H), 4.06-4.01 (m, 2143wo 2013/184119 PCT/US2012/041378H), 3.86-3.77 (m, 2 H), 3.04 (m, 1 H), 2.09 (s, 6 H), 1.24 (t, J = 7.0 Hz, 3 H); MS (ESI) m/z:578.2 [M+Ht.
  • 11
  • [ 1442471-20-6 ]
  • [ 124668-49-1 ]
  • [ 1442474-61-4 ]
YieldReaction ConditionsOperation in experiment
70% With 1-Methylpyrrolidine In acetonitrile at 70℃; for 3h; 113 Example 113 A suspension of Example A57 (0.210 g, 0.407 mmol) in MeCN (8 mL) was treated with N,N-dimethylazetidin-3-amine dihydrochloride (0.300 g, 1.733 mmol) followed by 1-methylpyrrolidine (0.150 g, 1.762 mmol) and heated at 70° C. for 3 h. The mixture was cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 3-(dimethylamino)-N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide (160 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.56 (s, 1H), 9.48 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 8.08 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.42 (dd, J=8.2, 1.2 Hz, 2H), 7.24 (t, J=7.8 Hz, 2H), 7.14 (d, J=12.2 Hz, 1H), 6.93 (t, J=7.4 Hz, 1H), 4.21-3.91 (m, 6H), 3.32 (m, 1H), 2.73 (s, 6H), 2.07 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 558.3 [M+H]+.
70% With 1-Methylpyrrolidine In acetonitrile at 70℃; for 3h; 113 Example 113: A suspension of Example A57 (0.210 g, 0.407 mmol) in MeCN (8mL) was treated with N,N-dimethylazetidin-3-amine dihydrochloride (0.300 g, 1.733 mmol)followed by 1-methylpyrrolidine (0.150 g, 1.762 mmol) and heated at 70°C for 3 h. Themixture was cooled toRT, concentrated to dryness and purified via silica gel chromatography(MeO H/DCM) to afford 3-( dimethylamino )-N-(1-ethyl-3-( 4-fluoro-2-methyl-5-(3-phenylureido )phenyl)-2-oxo-1 ,2-dihydro-1 ,6-naphthyridin-7 -yl)azetidine-1-carboxamide(160 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6): 8 9.56 (s, 1 H), 9.48 (s, 1 H), 8.72 (s,1 H), 8.64 (s, 1 H), 8.08 (s, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.86 (s, 1 H), 7.42 (dd, J = 8.2, 1.2Hz, 2 H), 7.24 (t, J = 7.8 Hz, 2 H), 7.14 (d, J = 12.2 Hz, 1 H), 6.93 (t, J = 7.4 Hz, 1 H), 4.21-3.91 (m, 6 H), 3.32 (m, 1 H), 2.73 (s, 6 H), 2.07 (s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H); MS (ESI)m/z: 558.3 [M+H(
  • 12
  • [ 1951428-39-9 ]
  • [ 124668-49-1 ]
  • [ 1951426-76-8 ]
YieldReaction ConditionsOperation in experiment
70% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide; N,N-dimethyl-formamide at 23℃; for 5h; 54 Example 43 (7S)-4-[(6-Chloropyrazolo[1 ,5-a]pyridin-5-yl)amino]-N-(3,3,3-trifluoropropyl)-5,6,7,8- tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide Example 43 (7S)-4-[(6-Chloropyrazolo[1 ,5-a]pyridin-5-yl)amino]-N-(3,3,3-trifluoropropyl)-5,6,7,8- tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide A mixture comprising 75 mg (188 μηηοΙ) (7S)-4-[(6-chloropyrazolo[1 ,5-a]pyridin-5-yl)amino]- 5,6,7,8-tetrahydro[1 ]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to example 43a), 3.65 mL N,N-dimethylacetamide, 294 μΙ_ N-ethyl-N-isopropylpropan-2-amine, 140 mg 3,3,3-trifluoropropan-1 -aminium chloride and 335 μΙ_ 2,4,6-tripropyl-1 ,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide solution (50% in Ν,Ν-dimethylformamide) was stirred at 23°C for 5 hours. The crude mixture was concentrated and the residue crystallized from diethyl ether and ethanol to give 46.9 mg (48%) of the title compound. 1 H-NMR (DMSO-d6): δ= 1.87 (1 H), 2.16 (1 H), 2.40-2.53 (2H), 2.69 (1 H), 2.97 (2H), 3.16 (1 H), 3.26-3.43 (3H), 6.66 (1 H), 8.03 (1 H), 8.28 (1 H), 8.33 (1 H), 8.50 (1 H), 8.52 (1 H), 9.15 (1 H) ppm.
  • 13
  • [ 2022976-03-8 ]
  • [ 124668-49-1 ]
  • [ 2022976-05-0 ]
YieldReaction ConditionsOperation in experiment
62% With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 120℃; for 1h; 17 tert-Butyl 4-(7-bromo-6-chloro-3-cyano-2-(3-(dimethylamino)azetidin-1-yl)-8- fluoroquinolin-4-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(7-bromo-2,6-dichloro-3-cyano-8- fluoroquinolin-4-yl)piperazine-1-carboxylate (268 mg, 0.53 mmol), N,N- dimethylazetidin-3-amine dihydrochloride (368 mg, 2.12 mmol) and DIEA (549 mg, 4.25 mmol) in i-PrOH (20 mL) was stirred at 120oC for 1 h and then was allowed to cool to RT. The mixture was quenched with saturated NaHCO3 solution and partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (MeOH/dichloromethane = 1:40) to afford the desired product (189 mg, 62%yield) as a yellow solid. ESI-MS m/z: 569.3[M+H]+
  • 14
  • [ 792970-55-9 ]
  • [ 124668-49-1 ]
YieldReaction ConditionsOperation in experiment
82% With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 3h; 2 Step 2: At 0° C., into a solution of compound 47a-2 (5.0 g, 0.025 mmol) in dichloromethane (100 ml) was added a solution of HCl/1,4-dioxane(4M). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated to obtain the title compound 47-a(3.5 g, 82%). MS m/z(ESI): 173 [M+H]+.
82% With hydrogenchloride In 1,4-dioxane at 0 - 20℃; for 3h; 2 Preparation of compound n To a solution of compound n-2 (5.0 g, 0.025 mmol) in dichloromethane (100 ml) was added a hydrochloric acid/1,4-dioxane solution (4 M) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated to give the object N,N-dimethylazetidin-3-amine dihydrochloride n (3.5 g, 82%). MS m/z(ESI): 173 [M+H]+.
  • 15
  • [ 1446333-93-2 ]
  • [ 124668-49-1 ]
  • [ 1446314-70-0 ]
YieldReaction ConditionsOperation in experiment
76% With dicyclohexyl[3,6-dimethoxy-2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine; caesium carbonate; bis(dibenzylideneacetone)-palladium(0); ruphos In toluene; <i>tert</i>-butyl alcohol at 100℃; for 5h; 82 Example 82 Preparation of Cpd 943 A mixture of 7-bromo-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one (74.4 mg, 0.2 mmol, prepared in Example 48, Step A), 3-(dimethylamino)azetidine dihydrochloride (69.2 mg, 0.4 mmol), bis(dibenzylideneacetone)palladium(0) (11.5 mg, 0.02 mmol), RuPhos (9.3 mg, 0.02 mmol), BrettPhos (10.7 mg, 0.02 mmol) and Cs2CO3 (228.1 mg, 0.7 mmol) in toluene (0.2 mL) and t-butanol (0.2 mL) was heated at 100° C. for 5 h. The solvent was removed by rotary evaporation, then the residue was suspended in diethyl ether and filtered. The solid was washed thoroughly with water and dried to afford the title compound (59.5 mg, 76%) as a yellow solid: m.p. 246-250° C.; MS m/z 390.3 [M+H]+; 1H NMR (500 MHz, DMSO-d6): δ 8.72 (1H, s), 8.50 (1H, s), 8.32 (1H, s), 7.74 (1H, d, J=8.6 Hz), 6.47 (1H, dd, J=8.6 Hz, 2.2 Hz), 6.35 (1H, d, J=1.9 Hz), 4.05 (2H, m), 3.78 (2H, m), 3.27 (1H, m), 2.75 (3H, s), 2.37 (3H, s), 2.15 (6H, s).
  • 16
  • [ 1698028-12-4 ]
  • [ 124668-49-1 ]
  • [ 2135895-40-6 ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 100℃; 4.A Step A: Preparation of tert-Butyl 4-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-l- yl)-8-fluoroquinazolin-4-yl)piperazine-l-carboxylate (Compound 4-1). To a solution of tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-l-carboxylate (1.0 g, 2.08 mmol) and DIPEA (1.34 g, 10.4 mmol) in z'-PrOH (100 mL) at room temperature, N,N- dimethylazetidin-3-amine dihydrochloride (4.29 g, 2.49 mmol) was added and the resulting mixture was stirred at 100 °C overnight. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product (1.12 g, 100% yield). 1H-NMR (400 MHz, CDC13) δ: 7.76 (d, / = 1.8 Hz, 1H), 3.90-3.87 (m, 4H), 3.67- 3.64 (m, 4H), 1.49 (s, 9H).
  • 17
  • [ 2195426-93-6 ]
  • [ 124668-49-1 ]
  • [ 2195422-20-7 ]
YieldReaction ConditionsOperation in experiment
74% With N-ethyl-N,N-diisopropylamine In methanol at 65℃; Inert atmosphere; 2002 Example 2002: (R)-1-(3-((3'-(3-(3-(dimethylamino)azetidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol To a reaction vial containing 3-(dimethylamino)azetidine dihydrochloride (60 mg, 0.347 mmol) was added a solution of (R)-1-(3-((3'-(3-bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) dissolved in methanol (1.0 mL) and N,N-diisopropylethylamine (150 µL, 0.859 mmol). The reaction mixture was briefly flushed with N2, securely capped, sonicated for 10 sec, and placed in a 65 °C sand bath with shaking for 18-36h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10- 50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (15.5 mg, 74%). LC/MS Condition E: ret time 1.23 min; m/e = 482 (M+H)+; LC/MS Condition F: ret time 1.1 min; m/e = 482 (M+H)+.
  • 18
  • [ 2195426-94-7 ]
  • [ 124668-49-1 ]
  • [ 2195423-27-7 ]
YieldReaction ConditionsOperation in experiment
77% With N-ethyl-N,N-diisopropylamine In methanol at 65℃; for 48h; Inert atmosphere; 2087 Example 2087: 1,1'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(oxy))bis(propane-3,1-diyl))bis(N,N-dimethylazetidin-3-amine) A mixture of N,N-dimethylazetidin-3-amine, 2 HCl (110 mg, 0.636 mmol) and 3,3'-bis(3-bromopropoxy)-2,2'-dimethyl-1,1'-biphenyl (20 mg, 0.044 mmol) in methanol (3 mL) and N,N-diisopropylethylamine (220 µL, 1.26 mmol) was heated at 65 °C for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10- mM ammonium acetate; Gradient: 15-55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (16.6 mg, 77%). LC/MS Condition E: ret time 1.59 min; m/e = 495 (M+H)+. LC/MS Condition F: ret time 1.68 min; m/e = 495 (M+H)+.
  • 19
  • [ 2243987-20-2 ]
  • [ 124668-49-1 ]
  • [ 76-05-1 ]
  • [ 2244074-26-6 ]
YieldReaction ConditionsOperation in experiment
74% Stage #1: (S)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-5-propyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid trifluoroacetic acid salt; 3-(dimethylamino)azetidine dihydrochloride With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; Stage #2: With hydrazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #3: trifluoroacetic acid With acetic acid In water; acetonitrile at 20℃; 4 Example 4: (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-5-fluoro-4- hydroxyphenyl)-1H-indazol-3-yl)-5-propyl-4,5,6,7-tetrahydro-3H-imidazo[4,5- c] pyridin-6-yl)methanone To a solution of (5 -2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-5- propyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid, TFA (30 mg, 0.052 mmol), N,N-dimethylazetidin-3 -amine, 2HCl (27.0 mg, 0.156 mmol), and DIPEA (0.064 mL, 0.364 mmol) in DMF (1.5 mL), was added HATU (29.6 mg, 0.078 mmol) and the reaction mixture was stirred at RT overnight. Hydrazine (5 eq) was added, the reaction mixture was stirred at RT for 10 min, concentrated and purified by preparative HPLC to provide the TFA salt of the title compound (29.6 mg, 74 % yield).(m/z): [M+H]+calcd for C30H36FN7O2 546.29 found 546.6.
  • 20
  • [ 2244906-16-7 ]
  • [ 124668-49-1 ]
  • [ 2244904-62-7 ]
YieldReaction ConditionsOperation in experiment
36% With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; 319 Example 319 N-{1 -[5-(2-[3-(dimethylamino)azetidin-1 -yl]methyl}phenyl)thiophen-2-yl]ethyl}-6,7- dimethoxy-2-methylquinazolin-4-amine To 2-(5-{1 -[(6,7-dimethoxy-2-methylquinazolin-4-yl)amino]ethyl}thiophen-2-yl)benzaldehyde (described in example 179a; 50.0 mg, 1 15 μηηοΙ), N,N-dimethylazetidin-3-amine dihydrochloride (39.9 mg, 231 μηηοΙ) and acetic acid (13 μ, 230 μηηοΙ) in 1,2-dichloroethane (1.0 mL) was added NaBH(OAc)3 (48.9 mg, 231 μηιοΙ) and the solution stirred at room temperature overnight. The reaction was quenched with aqueous NaOH (1.0 M, 1.0 mL), the mixture extracted with DCM and the solvent removed in vacuo. Purification by preparative HPLC (basic conditions) gave the title compound as a white solid (22.3 mg, 36%). 1H-NMR (400 MHz, DMSO-de): δ [ppm] = 8.15 (d, 1H), 7.65 (s, 1H), 7.41 -7.37 (m, 1H), 7.37-7.33 (m, 1H), 7.31 -7.24 (m, 2H), 7.15 (d, 1H), 7.08 (dd, 1H), 7.05 (s, 1H), 5.97 (quin, 1H), 3.88-3.87 (m, 3H), 3.87-3.85 (m, 3H), 3.55 (s, 2H), 3.30-3.25 (m, 2H), 2.77-2.70 (m, 2H), 2.70-2.67 (m, 1H), 2.43 (s, 3H), 1.95 (s, 6H), 1.72 (d, 3H). LC-MS (method 7): m/z: [M+H]+ = 518, Rt = 0.57 min.
  • 21
  • [ 2250340-41-9 ]
  • [ 124668-49-1 ]
  • [ 2250340-47-5 ]
YieldReaction ConditionsOperation in experiment
67% With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 95℃; for 1h; Teri-butyl (S)-3-(((7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-l-yl)-4-oxo-3,4- -l-carboxylate To a suspension of te/t-butyl (5)-3-(((7-bromo-2,6-dichloro-4-oxo-3,4-dihydroquinazolin-5- yl)oxy)methyl)piperazine-l-carboxylate (500 mg, 0.98 mmol) in i-PrOH (20 ml) was added A/-ethyl-/V- isopropylpropan-2-amine (1.37 ml, 7.87 mmol) and A/,A/-dimethyl-azetidin-3-amine dihydrochloride (511 mg, 2.95 mmol) and the reaction mixture stirred at 95°C for 1 hour and allowed to cool. The reaction mixture was evaporated to dryness. The residue was purified by flash silica chromatography, elution 20% 2N methanolic ammonia in DCM. Pure fractions were evaporated to dryness then triturated with diethyl ether to afford te/t-butyl (5)-3-(((7-bromo-6-chloro-2-(3- (dimethylamino)azetidin-l-yl)-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)methyl)piperazine-l-carboxylate (377 mg, 67%) as a pale yellow solid. 1H NM (400 MHz, DMSO) 1.43 (s, 9H), 2.20 (s, 6H), 2.85 - 3.05 (m, 1H), 3.06 - 3.27 (m, 4H), 3.42 - 3.58 (m, 1H), 3.82 - 4.05 (m, 3H), 4.05 - 4.32 (m, 5H), 7.47 (s, m/z: ES+ [M+H]+ 571 / 573.
  • 22
  • [ 2409543-82-2 ]
  • [ 124668-49-1 ]
  • [ 2368910-10-3 ]
YieldReaction ConditionsOperation in experiment
77% With potassium fluoride; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 115℃; for 5h; 4 Step 4 A mixture of tert-butyl 4-{2-chloro-8-[(5-chloro-6-methyl-1H-indazol-4-yl)oxy]-6-methylpyrido[3,4-d]pyrimidin-4-yl}piperazine-1-carboxylate (136) (57 mg, 0.10 mmol), N,N-dimethylazetidin-3-amine dihydrochloride (109 mg, 0.63 mmol), DIEA (0.13 mL, 0.73 mmol) and KF (12 mg, 0.21 mmol) in DMSO (2 mL) was stirred at 115° C. for 5 hours. The crude reaction mixture was cooled to room temperature and diluted with EtOAc and wash with water (2*) and brine. The organic layer was dried over sodium sulfate and concentrate which gave tert-butyl 4-{8-[(5-chloro-6-methyl-1H-indazol-4-yl)oxy]-2-[3-(dimethylamino)azetidin-1-yl]-6-methylpyrido[3,4-d]pyrimidin-4-yl}piperazine-1-carboxylate (137) as brown foam (49 mg, 77% yield). LCMS (ESI) m/z 608 (M+H).
  • 23
  • [ 73576-33-7 ]
  • 3-(dimethylamino)azetidine dihydrochloride [ No CAS ]
  • 4‐(3‐(dimethylamino)azetidin‐1‐yl)‐6‐isopropylpyrimidin‐2‐amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 150℃; for 0.5h;Inert atmosphere; Microwave irradiation; A preparation for thiscompound was previously published by us [46]. A microwave vial charged with chloride 5 (248 mg, 1.44mmol), N,N-dimethylazetidin-3-amine dihydrochloride (250 mg, 1.44 mmol), DIPEA (0.76 mL, 4.33 mmol)and dioxane (10 mL) was heated for 30 min at 150 C under microwave irradiation. The reaction mixturewas diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers weredried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography(DCM:MeOH:TEA 100:0:0 to 90:9:1) gave the title compound as a white solid (220 mg, 65 %). Mp: 123.6-123.8 . 1H NMR (500 MHz, CDCl3) delta 5.49 (s, 1H), 4.87 (br, 2H), 4.04 (t, J = 7.8 Hz, 2H), 3.94 - 3.81 (m, 2H),3.21 (p, J = 5.6 Hz, 1H), 2.65 (hept, J = 6.8 Hz, 1H), 2.20 (s, 6H), 1.20 (d, J = 6.8 Hz, 6H). 13C NMR (126 MHz, CDCl3) delta 174.0, 164.6, 162.1, 89.1, 56.2, 53.9, 41.8, 35.5, 21.7. HPLC-MS (basic mode): tR = 3.4 min, purity: 97.8%, [M + H]+: 236. HR-MS [M + H]+ calcd for C12H22N5+: 236.1870, found 236.1878.
  • 24
  • [ 2412506-19-3 ]
  • [ 124668-49-1 ]
  • [ 2244074-18-6 ]
YieldReaction ConditionsOperation in experiment
53% With sodium hydrogencarbonate; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In 2-methyltetrahydrofuran; N,N-dimethyl acetamide at -20 - 20℃; 8 Example 8
(S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone
To a stirred solution of (S)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid, 2HCl (470 g, 876 mmol) and N,N-dimethylazetidin-3-amine, 2HCl (197 g, 1,139 mmol) in N,N-dimethylacetamide (2,436 mL) cooled to -20° C., was added DIPEA (413 mL, 2,366 mmol) over not less than 15 minutes (the exothermic addition caused batch temperature to raise to -9.1° C.). The batch was cooled back down to -15° C. and HCTU (453 g, 1095 mmol) was added. The mixture was warmed to 20° C. over 1 hour and held for an additional hour. Into the completed reaction mixture was added isopropyl acetate (5.0 L) and 1M HCl (2.0 L) and the mixture was stirred over 15 minutes, the layers were separated to extract impurities into the isopropyl acetate layer. The aqueous layer which contained the product was extracted three additional times with isopropyl acetate (5.0 L each). After the 4th extraction the aqueous layer was added to 2-methyltetrahydrofuran followed by saturated sodium bicarbonate solution (˜2.2 L, to adjust pH=8) stirred 15 minutes, the layers were separated, and the aqueous layer discarded. The organic layer was solvent swapped to acetonitrile and stirred at a final volume of 2.35 L at which time the product precipitated out of solution as amorphous filterable solids. The slurry was then filtered under nitrogen pressure to afford 345 grams of crude product. The crude product (345 g) was dissolved in methanol (1.035 L) with stirring at 55° C. was held over 15 hours to crystallize the product out of solution. The slurry was cooled to 10° C. and held at that temperature with stirring over 2 hours. The thickened slurry was filtered under nitrogen pressure over 2 hours at 20° C. followed by further drying under high vacuum with nitrogen bleed at 65° C. over 18 hours to afford the title compound as an off white to white free flowing solid (253 g, 53% yield). (m/z): [M+H]+ calculated for C30H36FN7O2 546.66 found 546.73.
  • 25
  • [ 2412812-46-3 ]
  • [ 124668-49-1 ]
  • [ 76-05-1 ]
  • [ 2412496-45-6 ]
YieldReaction ConditionsOperation in experiment
37% Stage #1: (S)-2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid trifluoroacetic acid salt; 3-(dimethylamino)azetidine dihydrochloride With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 3h; Stage #2: trifluoroacetic acid In water; acetonitrile 7 Example 7: (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone (S)-2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid, TFA (I-19) (50 mg, 0.089 mmol), 3-(Dimethylamino)azetidine dihydrochloride (23.20 mg, 0.134 mmol), and DIPEA (0.078 mL, 0.447 mmol) were dissolved in DMF (1.5 mL), then HATU (51.0 mg, 0.134 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours (reaction progress was monitored by LCMS). Hydrazine (0.014 mL, 0.447 mmol) was added to cleave undesired byproducts, and the solution was stirred at room temperature for 10 minutes. The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (5-70% ACN/Water gradient, C18 column) to provide the TFA salt of the title compound (25 mg, 37% yield). (m/z): [M+H]+ calcd for C30H37N7O2 528.30 found 528.3. 1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.40 (s, 1H), 8.27 (d, J=8.31, 1H), 7.30 (s, 1H), 7.04 (m, 2H), 6.71 (d, J=2.54, 1H), 6.64 (dd, J=2.53, 8.26, 1H), 4.26 (m, 1H), 4.06 (m, 2H), 3.82 (m, 2H), 3.64 (m, 2H), 3.03 (m, 2H), 2.74 (m, 2H), 2.47 (q, J=7.56, 2H), 2.07 (d, J=3.69, 6H), 1.07 (m, 6H), 1.00 (t, J=7.50, 3H).
37% Stage #1: (S)-2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid trifluoroacetic acid salt; 3-(dimethylamino)azetidine dihydrochloride With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 3h; Stage #2: trifluoroacetic acid 1 Example 1: (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone (S)-2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid, TFA (1-19) (50 mg, 0.089 mmol), 3-(Dimethylamino)azetidine dihydrochloride (23.20 mg, 0.134 mmol), and DIPEA (0.078 mL, 0.447 mmol) were dissolved in DMF (1.5 mL), then HATU (51.0 mg, 0.134 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours (reaction progress was monitored by LCMS). Hydrazine (0.014 mL, 0.447 mmol) was added to cleave undesired byproducts, and the solution was stirred at room temperature for 10 minutes. The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (5-70% ACN/Water gradient, C18 column) to provide the TFA salt of the title compound (25 mg, 37% yield). (m/z): [M+H]+ calcd for C30H37N7O2 528.30 found 528.3. 1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.40 (s, 1H), 8.27 (d, J=8.31, 1H), 7.30 (s, 1H), 7.04 (m, 2H), 6.71 (d, J=2.54, 1H), 6.64 (dd, J=2.53, 8.26, 1H), 4.26 (m, 1H), 4.06 (m, 2H), 3.82 (m, 2H), 3.64 (m, 2H), 3.03 (m, 2H), 2.74 (m, 2H), 2.47 (q, J=7.56, 2H), 2.07 (d, J=3.69, 6H), 1.07 (m, 6H), 1.00 (t, J=7.50, 3H).
  • 26
  • [ 2412496-41-2 ]
  • [ 124668-49-1 ]
  • [ 76-05-1 ]
  • [ 2412496-62-7 ]
YieldReaction ConditionsOperation in experiment
63% Stage #1: (S)-5-ethyl-2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid trifluoroacetate; 3-(dimethylamino)azetidine dihydrochloride With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: trifluoroacetic acid 2 Example 2: (S)-(3-(dimethylamino)azetidin-1-yl)(5-ethyl-2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone (S)-5-ethyl-2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid, TFA (30 mg, 0.055 mmol), 3-(dimethylamino)azetidine dihydrochloride (14.28 mg, 0.082 mmol), and DIPEA (0.048 mL, 0.275 mmol) were dissolved in DMF (1.50 mL), then HATU (31.4 mg, 0.082 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour (reaction progress was monitored by LCMS). Hydrazine (5.18 μl, 0.165 mmol) was added to cleave undesired byproducts, then the solution was stirred at room temperature for 10 minutes. The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (5-60% ACN/Water gradient, C18 column) to provide the TFA salt of the title compound (25 mg, 63% yield). (m/z): [M+H]+ calcd for C29H35N7O2 514.29 found 514.2.
  • 27
  • [ 2412812-47-4 ]
  • [ 124668-49-1 ]
  • [ 76-05-1 ]
  • [ 2412496-48-9 ]
YieldReaction ConditionsOperation in experiment
63% Stage #1: (S)-2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-propyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid trifluoroacetic acid salt; 3-(dimethylamino)azetidine dihydrochloride With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: trifluoroacetic acid 5 Example 5: (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-propyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone (0170) (S)-2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-propyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid, TFA (30 mg, 0.054 mmol), (I-20) 3-(dimethylamino)azetidine dihydrochloride (13.92 mg, 0.080 mmol), and DIPEA (0.047 mL, 0.268 mmol) were dissolved in DMF (1.50 mL), then HATU (30.6 mg, 0.080 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour (reaction progress was monitored by LCMS). Hydrazine (5.05 μl, 0.161 mmol) was added to cleave undesired byproducts, then the solution was stirred at room temperature for 10 minutes. The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (5-60% ACN/Water gradient, C18 column) to provide the TFA salt of the title compound (26 mg, 63% yield). (m/z): [M+H]+ calcd for C30H37N7O2528.30 found 528.2.
  • 28
  • [ 2243987-26-8 ]
  • [ 124668-49-1 ]
  • [ 76-05-1 ]
  • [ 2244074-28-8 ]
YieldReaction ConditionsOperation in experiment
67% Stage #1: (S)-5-ethyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid trifluoroacetate; 3-(dimethylamino)azetidine dihydrochloride With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 6h; Stage #2: trifluoroacetic acid 9 Example 9: (S)-(3-(dimethylamino)azetidin-1-yl)(5-ethyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone (S)-5-ethyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid, TFA (30 mg, 0.053 mmol) and HATU (30.4 mg, 0.080 mmol) were combined in DMF (1.0 mL). To the solution, N,N-dimethylazetidin-3-amine (16 mg, 0.160 mmol) and DIPEA (0.037 mL, 0.213 mmol) were added and the reaction mixture was stirred at room temperature for 6 hours (reaction progress was monitored by LCMS). Hydrazine (4.92 μl, 0.160 mmol) was added to cleave undesired byproducts, then the solution was stirred at room temperature for 10 minutes. The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (10-70% ACN/Water gradient, Zorbax Bonus-RP column) to provide the TFA salt of the title compound (27 mg, 67% yield). (m/z): [M+H]+ calcd for C29H34FN7O2 532.28 found 532.2.
  • 29
  • [ 2243987-20-2 ]
  • [ 124668-49-1 ]
  • [ 76-05-1 ]
  • [ 2244074-26-6 ]
YieldReaction ConditionsOperation in experiment
67% Stage #1: (S)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-5-propyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid trifluoroacetate; 3-(dimethylamino)azetidine dihydrochloride With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 18h; Stage #2: trifluoroacetic acid 11 Example 11: (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-5-propyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone S)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-5-propyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid, TFA (33 mg, 0.057 mmol), N,N-dimethylazetidin-3-amine, 2HCl (29.7 mg, 0.171 mmol), and DIPEA (0.060 mL, 0.343 mmol) were dissolved in DMF (2.0 mL), then HATU (28.2 mg, 0.074 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours (reaction progress was monitored by LCMS). Hydrazine (8.97 μl, 0.286 mmol) was added to cleave undesired byproducts, then the solution was stirred at room temperature for 10 minutes. The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (2-70% ACN/Water gradient, C18 column) to provide the TFA salt of the title compound (27 mg, 61% yield). (m/z): [M+H]+ calcd for C30H36FN7O2 546.29 found 546.5.
  • 30
  • [ 5866-98-8 ]
  • 3-(dimethylamino)azetidine dihydrochloride [ No CAS ]
  • 6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-3-nitrobenzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 4.33333h; To a solution of 2, 6-dichloro-3-nitrobenzonitrile (5.0 g, 23.0 mmol) in MeCN (40 mL) was stirred at 0, was added a solution of N, N-dimethylazetidin-3-amine dihydrochloride (2.1 g, 21.0 mmol) and DIPEA (7.8 g, 63.0 mmol) in MeCN (40 mL) dropwise in 20 min. The resulting mixture was then stirred at room temperature for 4 h and then poured into ice water. The precipitate was collected by filtration. The solid was washed with water and dried in vacuum to give the desired product (5 g, 98%yield) as a yellow solid. MS: m/z 281 (M+H) +.
  • 31
  • [ 2414057-09-1 ]
  • [ 124668-49-1 ]
  • [ 2414057-10-4 ]
YieldReaction ConditionsOperation in experiment
45% With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 16h; 1.11 Step 11: 5- (3- (dimethylamino) azetidin-1-yl) -6-methoxy-3- ( (2- (trimethylsilyl) ethoxy) methyl) quinazolin-4 (3H) -one To a solution of 5-fluoro-6-methoxy-3- ( (2- (trimethylsilyl) ethoxy) methyl) quinazolin-4 (3H) -one (3.2 g, 10 mmol) and Cs 2CO 3 (9.8 g, 30 mmol) in DMF (200 mL) stirred at room temperature, was added N, N-dimethylazetidin-3-aminedihydrochloride (2g, 12 mmol) . The resulting mixture was stirred at 90 for 16 hrs. The crude mixture was filtered and washed with EtOAc (100 mL) . The filtrate was poured into ice water and extracted with EtOAc (300 mL) . The organic phase was separated, washed with water and brine, dried over anhydrous Na 2SO 4, filtered and concentrated. The residue was purified by column chromatography on silica gel to give the desired product (1.8g, 45%yield) as oil. MS (ESI) m/z: 405 (M+H) +.
  • 32
  • [ 2414057-17-1 ]
  • [ 124668-49-1 ]
  • [ 2414057-18-2 ]
YieldReaction ConditionsOperation in experiment
61% With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 16h; 11.6 Step 6: 5- (3- (dimethylamino) azetidin-1-yl) -6-ethoxy-3- ( (2- (trimethylsilyl) ethoxy) methyl) quinazolin-4 (3H) -one o a mixture of N, N-dimethylazetidin-3-amine dihydrochloride (264 mg, 1.53 mmol) and Cs 2CO 3 (1.54 g, 4.72 mmol) in DMF (5 mL) stirred at room temperature, was added 6-ethoxy-5-fluoro-3- ( (2- (trimethylsilyl) ethoxy) methyl) quinazolin-4 (3H) -one (400 mg, 1.18 mmol) . The resulting mixture was stirred at 90 for 16 hrs. The crude mixture was filtered, washed with EtOAc (10 mL) . The filtrate was poured into ice water and extracted with EtOAc (30 mL) . The organic phase was separated, washed with water and brine, dried over anhydrous Na 2SO 4, filtered and concentrated. The residue was purified by column chromatography on silica gel to give the desired product (300 mg, 61%yield) as oil. MS: 419 (M+H) +.
  • 33
  • [ 2414057-21-7 ]
  • [ 124668-49-1 ]
  • [ 2414057-22-8 ]
YieldReaction ConditionsOperation in experiment
58% With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 16h; 12.2 Step 2: 5- (3- (dimethylamino) azetidin-1-yl) -6- (2-fluoroethoxy) -3- ( (2- (trimethylsilyl) ethoxy) methyl) quinazolin-4 (3H) -one To a solution of 5-fluoro-6- (2-fluoroethoxy) -3- ( (2- (trimethylsilyl) ethoxy) methyl) quinazolin-4 (3H) -one (140 mg, 0.39 mmol) and N, N-dimethylazetidin-3-amine dihydrochloride (88 mg, 0.51 mmol) in DMF (5 mL) stirred at room temperature, was added Cs 2CO 3 (512 mg, 2.16 mmol) . The resulting mixture was stirred at 90 for 16 hrs. The crude mixture was then filtered and washed with EtOAc. The filtrate was poured into ice water and extracted with EtOAc (20 mL) . The organic phase was separated, washed with brine, dried over anhydrous Na 2SO 4, filtered and concentrated. The residue was purified by column chromatography on silica gel to give the desired product (100 mg, 58%yield) as an oil. MS: 437 (M+H) +.
  • 34
  • [ 2640364-23-2 ]
  • [ 124668-49-1 ]
  • [ 2640364-24-3 ]
YieldReaction ConditionsOperation in experiment
66% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 120℃; for 3h; Inert atmosphere; 2B.2 Step 2: ethyl 2-(5-(3-(dimethylamino)azetidin-1-yl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoate To a solution of ethyl 2-(5-bromo-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (2.0g, 6.06 mmol, 1.0 eq), N,N-dimethylazetidin-3-amine dihydrochloride (1.57 g, 9.07 mmol, 1.5 eq), and CsCO3(8.0 g, 24.5 mmol, 4.0 eq) in toluene (50 mL) was added BINAP (376 mg, 0.606 mmol, 0.1 eq) and Pd2dba3 (250 mg, 0.27 mmol, 0.05 eq) under N2 and then heated to 120oC for 3h. LCMS showed the reaction was completed. The mixture was filtered and washed with both EtOAc (20 mL) and EtOH (20 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide ethyl 2- (5-(3-(dimethylamino)azetidin-1-yl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1.4 g). Yield 66% (ESI 350 (M+H)+).
  • 35
  • [ 2699667-78-0 ]
  • [ 124668-49-1 ]
  • [ 2412496-23-0 ]
YieldReaction ConditionsOperation in experiment
92% Stage #1: 3-(dimethylamino)azetidine dihydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20℃; for 0.333333h; Stage #2: (S)-2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid dihydrochloride With HATU In N,N-dimethyl acetamide at 10 - 25℃; for 2h; 7.2 Preparation 7 Sodium bicarbonate (1238 g, 1.47E+04 mmol) was added and the mixture was agitated until full dissolution was achieved. Agitation was stopped, and the solution held at 20° C. overnight. With stirring 10 volumes of 2-methyltetrahydrofuran (12,500 mL) was added to the aqueous solution. An exothermic event was observed. The internal temperature was adjusted to 20+-5° C. The aqueous acidic layer was added to a reactor over about 10 mins. A mild exotherm of 1° C. was observed. The mixture was agitated at 20° C. for about 15 min then allowed to settle at 20° C. The bottom aqueous layer was removed and added to the reactor. The organic layer was removed and extracted by charging 5 volumes of 2-methyltetrahydrofuran (6,250 mL) and mixing for about 15 min at 20° C. The combined organic layers were concentrated to 3 volumes (3.75 L) with a rotovap with a bath temperature at 50° C. 10 volumes of 2-methyltetrahydrofuran (12,500 mL) were added and the mixture was concentrated to 3 volumes (3.75 L) with a rotovap with a bath temperature at 50° C. Acetonitrile (2.00E+04 mL) was added to a 25 L jacketed reactor and its internal temperature was adjusted to 0-5° C. with mixing at 215 rpm. The concentrated batch (about 3.75 L) was added into the cooled acetonitrile over about 1 hr at 0-5° C. The mixture was allowed to age overnight at 0° C. while mixing at 215 rpm. It was filtered and the cake was washed with 4 volumes of pre-cooled acetonitrile (5,000 mL) at 0° C. The cake was dried on a filter under N2 gas pressure over 2 hours. The wet cake was further dried under high vacuum (with slight N2 purge) at 50° C. overnight to afford (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone (1150 g, 2179 mmol, 92% yield) as an amorphous solid.
  • 36
  • [ 2702333-21-7 ]
  • [ 124668-49-1 ]
  • [ 2702333-22-8 ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate In dimethyl sulfoxide at 90℃; for 8h; 78.2 tep 2 :Synthesis of ethyl 6-chloro-7-[(2R)-2-[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1- yl]-1-{6-[3-(dimethylamino)azetidin-1-yl]pyridin-3-yl}-4-oxo-1,4-dihydroquinoline-3- carboxylate To a stirred solution of N,N-dimethylazetidin-3-amine dihydrochloride (2.87 g, 16.6 mmol) in DMSO (50 mL ), was added potassium carbonate (2.87 g, 20.8 mmol) at 0 °C and stirred for 5 min, followed by addition of ethyl 6-chloro-7-[(2R)-2-[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-1-(6- chloropyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (8 g, 13.9 mmol) .The reaction was then heated to 90°C and stirred for 8 h. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 x 150 mL). The combined organic layer was washed with water (80 mL), brine solution (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was washed with 20% acetone in MTBE (3 X 50 mL) and dried under vacuum to afford ethyl 6-chloro-7-[(2R)-2-[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-1-{6-[3- (dimethylamino)azetidin-1-yl]pyridin-3-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylate (6.97 g, 78%) as pale brown solid. MS (ESI): m/z 637.1 [M+H]+
  • 37
  • [ 2728716-58-1 ]
  • [ 124668-49-1 ]
  • [ 2728716-59-2 ]
YieldReaction ConditionsOperation in experiment
77% Stage #1: tert-butyl (2S,4S)-4-(8-chloro-7-(6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo(4,3-c)quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; for 0.333333h; Stage #2: 3-(dimethylamino)azetidine dihydrochloride With triethylamine In acetonitrile at 70℃; for 2h; 3a.19; 3b.19 Step 19. tert-butyl (2S, 4S) -4-(8-chloro-7-(6-chloro-5-methyl- 1-(tetrahydro-2H-pyran-2-yI)-1H-indazol-4-yI)-4-(3-(dimethylamino)azetidin-1-yI)-6-fluoro-1H-pyrazolo[4, 3-c]quinolin-1-yI)-2-(cyanomethyl)piperidine-1-carboxylate To a solution of tert-butyl (2S,4S)-4-(8-chloro-7-(6-chloro-5-methyl- 1 -(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1 -yl)-2- (cyanomethyl)piperidine-1-carboxylate (0.73 g, 0.988 mmol) in DCM (10 ml) at 0°C was added m-CPBA (0.196 g, 1.136 mmol). The reaction mixture was stirred at this temperature for 20 mm. The reaction was quenched by adding sat’d Na2S2O3, diluted with ethyl acetateand washed with saturated NaHCO3, brine, filtered, dried and concentrated. The crude was dissolve in acetonitrile (8 ml) and triethylamine (0.561 ml, 4.03 mmol) and N,Ndimethylazetidin-3-amine dihydrochloride (0.261 g, 1.511 mmol) was added to reaction vial and the resulting mixture was stirred at 70 °C for 2 h. The crude was concentrated and the residue was purified by silica gel column (eluting with a gradient of 0-20% DCM in MeOH) togive the desired product (0.61 g, 77 %). LC-MS calculated for C40H47C12FN903 (M-’-H): m/z =790.3; found 790.3.
77% Stage #1: tert-butyl (2S,4S)-4-(8-chloro-7-(6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo(4,3-c)quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; for 0.333333h; Stage #2: 3-(dimethylamino)azetidine dihydrochloride With triethylamine In acetonitrile at 70℃; for 2h; 3a.19; 3b.19 Step 19. tert-butyl (2S, 4S) -4-(8-chloro-7-(6-chloro-5-methyl- 1-(tetrahydro-2H-pyran-2-yI)-1H-indazol-4-yI)-4-(3-(dimethylamino)azetidin-1-yI)-6-fluoro-1H-pyrazolo[4, 3-c]quinolin-1-yI)-2-(cyanomethyl)piperidine-1-carboxylate To a solution of tert-butyl (2S,4S)-4-(8-chloro-7-(6-chloro-5-methyl- 1 -(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1 -yl)-2- (cyanomethyl)piperidine-1-carboxylate (0.73 g, 0.988 mmol) in DCM (10 ml) at 0°C was added m-CPBA (0.196 g, 1.136 mmol). The reaction mixture was stirred at this temperature for 20 mm. The reaction was quenched by adding sat’d Na2S2O3, diluted with ethyl acetateand washed with saturated NaHCO3, brine, filtered, dried and concentrated. The crude was dissolve in acetonitrile (8 ml) and triethylamine (0.561 ml, 4.03 mmol) and N,Ndimethylazetidin-3-amine dihydrochloride (0.261 g, 1.511 mmol) was added to reaction vial and the resulting mixture was stirred at 70 °C for 2 h. The crude was concentrated and the residue was purified by silica gel column (eluting with a gradient of 0-20% DCM in MeOH) togive the desired product (0.61 g, 77 %). LC-MS calculated for C40H47C12FN903 (M-’-H): m/z =790.3; found 790.3.
  • 38
  • [ 2493-02-9 ]
  • [ 124668-49-1 ]
  • [ 2769141-05-9 ]
YieldReaction ConditionsOperation in experiment
79% With triethylamine In N,N-dimethyl-formamide at 20℃; for 2h; 1-(4-Bromophenyl)-3-(1-methylpiperidin-3-yl)urea (52e). General procedure: To a suspension of 206 mg 3-amino-1-methylpiperidine dihydrochloride (1.1 mmol) in 4 ml DMF were added 256 mg Et3N (2.5 mmol). Subsequently, 198 mg 4-bromophenylisocyanate (1 mmol) was added as solution in DMF and the reaction was stirred at ambient temperature until TLC indicated complete consumption of starting material (about 2 hours). The mixture was diluted with water and basified with NaOH. The resulting white suspension was stirred for about 30 min under ice cooling, before the solids were isolated by filtration. The filter cake was washed with water and dried in a convection oven at 60°C to yield 282 mg (90%) of the title substance as white solid.
79% With triethylamine In N,N-dimethyl-formamide at 20℃; for 2h; 1-(4-Bromophenyl)-3-(1-methylpiperidin-3-yl)urea (52e). General procedure: To a suspension of 206 mg 3-amino-1-methylpiperidine dihydrochloride (1.1 mmol) in 4 ml DMF were added 256 mg Et3N (2.5 mmol). Subsequently, 198 mg 4-bromophenylisocyanate (1 mmol) was added as solution in DMF and the reaction was stirred at ambient temperature until TLC indicated complete consumption of starting material (about 2 hours). The mixture was diluted with water and basified with NaOH. The resulting white suspension was stirred for about 30 min under ice cooling, before the solids were isolated by filtration. The filter cake was washed with water and dried in a convection oven at 60°C to yield 282 mg (90%) of the title substance as white solid.
9 N-(4-Bromophenyl)-3-(dimethylamino)azetidine-1-carboxamide (48) N-(4-Bromophenyl)-3-(dimethylamino)azetidine-1-carboxamide (48) The same method was applied as described above for the preparation of (37) using 140 mg N,N-dimethylazetidin-3-amine dihydrochloride (0,788 mmol) and 149 mg 4-bromophenylisocyanate (0,750 mmol) as starting materials. Yield: 176 mg (79%) as white solid. 1H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H),3.99 - 3.91 (m, 2H), 3.77 - 3.68 (m, 2H), 3.05 - 2.96 (m, 1H), 2.07 (s, 6H). 13C NMR (101 MHz, DMSO) δ 156.4, 139.7, 131.1, 120.5, 113.0, 54.5, 53.4, 41.4. ESI-MS m/z: 398.2 [M+H]+ HPLC tret = 3.12 min.
  • 39
  • [ 2768686-58-2 ]
  • [ 124668-49-1 ]
  • [ 2768686-67-3 ]
YieldReaction ConditionsOperation in experiment
76% With tris-(dibenzylideneacetone)dipalladium(0); Cs2CO3; dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine In toluene at 100℃; for 16h; Inert atmosphere; Step A. The mixture of benzyl (S)-4-((R)-2-chloro-7-(7-fluoro-3,4-dihydroquinolin-1(2H)- yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (2 g, 3.48 mmol), 3-(dimethylamino)azetidine dihydrochloride ( 903 mg, 5.22 mmol), Pd2(dba)3 (320 mg, 0.35 mmol), caesium carbonate (6806 mg, 20.88 mmol) and Ruphos (324 mg, 0.69 mmol) in dry toluene (50 mL) was degassed and purged with N2 three times and the mixture was stirred at 100 °C for 16 hrs. The solution was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting MeOH/DCM = 1:20) to give benzyl (S)-2-(cyanomethyl)-4-((R)-2-(3-(dimethylamino)azetidin-1-yl)-7-(7-fluoro-3,4- dihydroquinolin-1(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-1-carboxylate (1.7 g, 76% yield) as yellow solid. Mass Spectrum (ESI) m/z = 639 (M+1).
76% With tris-(dibenzylideneacetone)dipalladium(0); Cs2CO3; dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine In toluene at 100℃; for 16h; Inert atmosphere; Step A. The mixture of benzyl (S)-4-((R)-2-chloro-7-(7-fluoro-3,4-dihydroquinolin-1(2H)- yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (2 g, 3.48 mmol), 3-(dimethylamino)azetidine dihydrochloride ( 903 mg, 5.22 mmol), Pd2(dba)3 (320 mg, 0.35 mmol), caesium carbonate (6806 mg, 20.88 mmol) and Ruphos (324 mg, 0.69 mmol) in dry toluene (50 mL) was degassed and purged with N2 three times and the mixture was stirred at 100 °C for 16 hrs. The solution was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting MeOH/DCM = 1:20) to give benzyl (S)-2-(cyanomethyl)-4-((R)-2-(3-(dimethylamino)azetidin-1-yl)-7-(7-fluoro-3,4- dihydroquinolin-1(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-1-carboxylate (1.7 g, 76% yield) as yellow solid. Mass Spectrum (ESI) m/z = 639 (M+1).
76% With tris-(dibenzylideneacetone)dipalladium(0); Cs2CO3; dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine In toluene at 100℃; for 16h; Inert atmosphere; Step A. The mixture of benzyl (S)-4-((R)-2-chloro-7-(7-fluoro-3,4-dihydroquinolin-1(2H)- yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (2 g, 3.48 mmol), 3-(dimethylamino)azetidine dihydrochloride ( 903 mg, 5.22 mmol), Pd2(dba)3 (320 mg, 0.35 mmol), caesium carbonate (6806 mg, 20.88 mmol) and Ruphos (324 mg, 0.69 mmol) in dry toluene (50 mL) was degassed and purged with N2 three times and the mixture was stirred at 100 °C for 16 hrs. The solution was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting MeOH/DCM = 1:20) to give benzyl (S)-2-(cyanomethyl)-4-((R)-2-(3-(dimethylamino)azetidin-1-yl)-7-(7-fluoro-3,4- dihydroquinolin-1(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-1-carboxylate (1.7 g, 76% yield) as yellow solid. Mass Spectrum (ESI) m/z = 639 (M+1).
  • 40
  • [ CAS Unavailable ]
  • [ 124668-49-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
51% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 60℃; for 2h; 4.2 Step 2 Under stirring conditions at 25 degrees Celsius,To a solution of compound 22-1 (1.85 g, 3.63 mmol, 1.0 equiv) in N-methylpyrrolidone (18.0 mL) was added N,N-diisopropylethylamine (4.7 g, 36.36 mmol, 10.0 equiv) and 3-(dimethylamino)azetidine dihydrochloride (940 mg, 5.43 mmol, 1.5 equiv). The mixture was reacted at 60 degrees Celsius for 2 hours, and the reaction process was monitored by liquid quality. After the reaction was completed, the reaction solution was cooled to 25 degrees Celsius. The reaction solution was directly purified by reverse-phase flash chromatography (C18 column), and eluted with 50%→95% acetonitrile/water (0.1% ammonium bicarbonate) within 20 minutes; detector: UV254 nm; Compound 22 was obtained -2 (yellow solid, 450 mg, 51% yield).
  • 41
  • [ 2766623-78-1 ]
  • [ 124668-49-1 ]
  • [ 2766623-79-2 ]
YieldReaction ConditionsOperation in experiment
95% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 60℃; for 2h; Inert atmosphere; 5.2 Step 2 Under the stirring condition of nitrogen protection at 25 degrees Celsius, to 23-1 (4.3 g, 13.19 mmol,1.00 equiv) in N-methylpyrrolidone (43.0 mL) was added 3-(dimethylamino)azetidine dihydrochloride (3.42 g, 19.76 mmol,1.5 equiv) and N,N-diisopropylethylamine (8.53 g, 66.00 mmol, 5.0 equiv). The mixture was reacted at 60°C for 2 hours under nitrogen atmosphere. The reaction process was monitored by liquid quality. After the reaction, the reaction solution was cooled to 25 degrees Celsius. The reaction solution was directly purified by reversed-phase chromatography column (C18 column), and eluted with 5%→95% acetonitrile/water mobile phase (0.1% ammonia water) within 25 minutes; detector: UV254/220 nm, the compound was obtained 23-2 (white solid, 4.9 g, 95% yield).
  • 42
  • [ 2766623-89-4 ]
  • [ 124668-49-1 ]
  • [ 2766623-90-7 ]
YieldReaction ConditionsOperation in experiment
67% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 60℃; for 2h; Schlenk technique; Inert atmosphere; 8.2 Step 2 Under nitrogen protection and stirring at 25 degrees Celsius, compound 71-1 (460 mg, 0.83 mmol, 1.0 equiv), N-methylpyrrolidone (12.0 mL), 3-(dimethylamino)azetidine dihydrochloride were added to a 25 mL Schlenk tube in sequence. ) (131 mg, 1.24 mmol, 1.5 equiv) and N,N-diisopropylethylamine (1.12 g, 8.27 mmol, 10.0 equiv). The mixture was reacted at 60°C for 2 hours under nitrogen atmosphere. The reaction process was monitored by liquid quality. After the reaction, the reaction solution was cooled to 25 degrees Celsius. The reaction solution was directly purified by reversed-phase chromatography column (C18 column), and eluted with 10%→95% acetonitrile/water (0.1% ammonium bicarbonate) mobile phase within 35 minutes; detector: UV254/220 nm Compound 71-2 (yellow solid, 350 mg, 67% yield).
  • 43
  • [ CAS Unavailable ]
  • [ 124668-49-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
55% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 60℃; for 2h; 12.5 Step 5 To a solution of compound 75-4 (4 g, 6.94 mmol, 1.0 equiv) in N-methylpyrrolidone (40 mL) was added N,N-diisopropylethylamine (4.72 g) under stirring in air at 25°C g, 34.72 mmol, 5.0 equiv) and 3-(dimethylamino)azetidine dihydrochloride (1.9 g, 10.42 mmol, 1.5 equiv). The mixture was further stirred and reacted at 60 degrees Celsius for 2 hours, and the reaction process was monitored by liquid quality. After the reaction was completed, the reaction solution was cooled to 25 degrees Celsius. The reaction solution was directly purified by reverse-phase flash chromatography column (C18 column), and eluted with 35%→85% acetonitrile/water mobile phase (0.1% ammonium bicarbonate) within 25 minutes; detector: UV254 nanometer; obtained Compound 75-5 (yellow solid, 2.4 g, 55% yield).
  • 44
  • [ CAS Unavailable ]
  • [ 124668-49-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
93% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 60℃; for 3h; Inert atmosphere; 15.7 Step 7 Under nitrogen protection and stirring at 25 degrees Celsius, compound 78-6 (700 mg,1.55 mmol, 1.0 equiv) in N-methylpyrrolidone (7 mL) was added 3-(dimethylamino)azetidine dihydrochloride (311 mg, 1.71 mmol,1.1 equiv) and N,N-diisopropylethylamine (1.06 g, 7.76 mmol, 5.0 equiv).The mixture was reacted at 60 degrees Celsius for 3 hours, and the reaction process was monitored by liquid quality. After the reaction, the reaction solution was concentrated to obtain a crude product. The obtained crude product was purified by reversed-phase chromatography column (C18 column), and eluted with 5%→90% methanol/water (0.1% ammonia water) mobile phase within 20 minutes; detector: UV254/220 nm; the compound was obtained 78-7 (yellow solid, 754 mg, 93% yield).
  • 45
  • [ CAS Unavailable ]
  • [ 124668-49-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
82% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 60℃; for 2h; Inert atmosphere; Schlenk technique; 16.9 Step 9 Under nitrogen protection at 25°C, compound 79-8 (350 mg, 0.83 mmol, 1.0 equiv) was added to a 25 mL Schlenk tube,N-Methylpyrrolidone (4 mL), 3-(dimethylamino)azetidine bishydrochloride (96 mg, 0.96 mmol, 1.5 equiv) and N,N-diisopropylethylamine (822 mg, 6.36 mmol, 10.0 equiv). The mixture was reacted at 60 degrees Celsius for 2 hours under a nitrogen atmosphere, and the reaction process was monitored by liquid quality. After the reaction was completed, the mixture was cooled to 25°C and concentrated to obtain the crude product. The obtained crude product was purified by reversed-phase chromatography column (C18 column), and eluted with 10%→95% acetonitrile/water mobile phase (0.5% ammonium bicarbonate) within 20 minutes; detector: UV254/220 nm; Compound 79-9 was obtained (yellow solid, 320 mg, 82% yield).
  • 46
  • [ CAS Unavailable ]
  • [ 124668-49-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
98% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 60℃; for 16h; Inert atmosphere; 17.8 Step 8 Under the stirring condition of nitrogen protection at 25 degrees Celsius,To a solution of compound 80-7 (2.0 g, 4.16 mmol, 1.0 equiv) in N-methylpyrrolidone (20 mL) was added 3-(dimethylamino)azetidine bishydrochloride (660 mg,6.57 mmol, 1.5 equiv) and N,N-diisopropylethylamine (2.27 g, 17.56 mmol,4.0 equiv). The mixture was reacted at 60 degrees Celsius for 16 hours,The reaction process was monitored by liquid quality. After the reaction was completed, the reaction solution was cooled to 25 degrees Celsius, and the reaction solution was purified by reverse-phase chromatography (C18 column) with 5%→95% acetonitrile/water (10 mmol/L ammonium bicarbonate) within 50 minutes. The mobile phase was eluted; detector: UV254/220 nm; compound 80-8 was obtained (white solid, 2.20 g, yield 98%).
  • 47
  • [ CAS Unavailable ]
  • [ 124668-49-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
60% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 60℃; for 12h; Inert atmosphere; 20.6 Step 6 Under the stirring condition of nitrogen protection at 25 degrees Celsius,To compound 83-5 (340 mg, 0.64 mmol,1.0 equiv) in N-methylpyrrolidone (3 mL) was added 3-dimethylaminoazetidine dihydrochloride (175 mg, 0.96 mmol, 1.5 equiv) and N,N-diisopropyl Ethylamine (435 mg, 3.20 mmol, 5.0 equiv). The mixture was reacted at 60 degrees Celsius for 12 hours, and the reaction process was monitored by liquid quality. After the reaction, the reaction solution was cooled to 25 degrees Celsius, directly purified by a reversed-phase chromatographic column (C18 column), and eluted with 5%→95% methanol/water (0.1% ammonium bicarbonate) within 30 minutes; detection device: UV254/220 nanometer; the crude product of compound 83-6 was obtained, and the obtained crude product was purified by preparative silica gel thin layer chromatography (developing solvent system: dichloromethane/methanol=19/1) to obtain compound 83- 6 (white solid, 230 mg, 60% yield).
  • 48
  • [ CAS Unavailable ]
  • [ 124668-49-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
78% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 60℃; for 2h; 1.4 Step 4 Under stirring at room temperatureTo a solution of compound 1-3 (550 mg, 1.1 mmol, 1 equiv) in N-methylpyrrolidone (5.0 mL) was added N,N-diisopropylethylamine (1.9 mL, 10.9 mL) under stirring at room temperature mmol, 10 equiv) and 3-(dimethylamino)azetidine dihydrochloride (282.1 mg, 1.6 mmol, 1.5 equiv). The resulting mixture was stirred for 2 hours at 60 degrees Celsius, and the progress of the reaction was monitored by liquid mass and thin layer chromatography. After the reaction was completed, the reaction solution was cooled to 25 degrees Celsius. The reaction solution was directly purified by reversed-phase flash chromatography column (C18 column), and eluted with 50%→95% acetonitrile/water mobile phase (0.1% ammonium bicarbonate) within 20 minutes; detector, UV254 nanometer; obtained Compound 1-4 (pale yellow solid, 480 mg, 78% yield).
  • 49
  • [ 2766623-69-0 ]
  • [ 124668-49-1 ]
  • [ 2766623-70-3 ]
YieldReaction ConditionsOperation in experiment
51% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 60℃; for 2h; 2.2 Step 2 Under stirring at room temperature,To a solution of compound 20-1 (790 mg, 1.5 mmol, 1 equiv) in N-methylpyrrolidone (8.0 mL) was added N,N-diisopropylethylamine (2.5 mL, 14.7 mL) under stirring at room temperature mmol, 10 equiv) and 3-(dimethylamino)azetidine dihydrochloride (381.8 mg, 2.2 mmol, 1.5 equiv). The resulting mixture was stirred for 2 hours at 60 degrees Celsius, and the progress of the reaction was monitored by liquid mass and thin layer chromatography. After the reaction was completed, the reaction solution was cooled to 25 degrees Celsius. The reaction solution was directly purified by reversed-phase flash chromatography column (C18 column), and eluted with 50%→95% acetonitrile/water mobile phase (0.1% ammonium bicarbonate) within 20 minutes; detector, UV254 nanometer; obtained Compound 20-2 (pale yellow oily liquid, 450 mg, yield 51%).
  • 50
  • [ 2823477-41-2 ]
  • [ 124668-49-1 ]
  • [ 2823477-42-3 ]
YieldReaction ConditionsOperation in experiment
99% With N-ethyl-N,N-diisopropylamine In isopropanol at 95℃; for 16h; 5.B Step B: Preparation of tert-butyl (2-((7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1- yl)-8-fluoroquinazolin-4-yl)amino)ethyl)carbamate: To a suspension of tert-butyl (2-((7-bromo-2,6- dichloro-8-fluoroquinazolin-4-yl) amino)ethyl)carbamate (110 mg, 0.24 mmol) in isopropyl alcohol (6 mL) was added DIPEA (155 mg, 1.2 mmol) and N,N-dimethylazetidin-3-amine dihydrochloride (50 mg, 0.29 mmol). The resulting solution was stirred at 95 °C for 16 hours. After cooling to ambient temperature, solvent was removed under reduced pressure. Water was added and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl (2-((7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8- fluoroquinazolin-4-yl)amino)ethyl)carbamate (125 mg, 99%) as a solid. LCMS ESI (+) m/z 517 (M+H).
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