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Imidazoles
3-(1H-Imidazol-2-yl)propan-1-amine dihydrochloride
Imidazoles
Amines

[ CAS No. 33544-86-4 ] {[proInfo.proName]}

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Chemical Structure| 33544-86-4
Chemical Structure| 33544-86-4
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Product Details of [ 33544-86-4 ]

CAS No. :33544-86-4 MDL No. :MFCD08668395
Formula : C6H13Cl2N3 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 198.09 Pubchem ID :-
Synonyms :

Safety of [ 33544-86-4 ]

Signal Word:Warning Class:
Precautionary Statements:P264-P280-P302+P352-P305+P351+P338-P332+P313-P337+P313-P362 UN#:
Hazard Statements:H315-H319 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 33544-86-4 ]

* 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 [ 33544-86-4 ]

[ 33544-86-4 ] Synthesis Path-Downstream   1~23

  • 1
  • [ 79463-77-7 ]
  • [ 33544-86-4 ]
  • [ 92742-02-4 ]
YieldReaction ConditionsOperation in experiment
With sodium 1.) ethanol; 2.) ether, room temp., 5 h; Yield given. Multistep reaction;
Reference： [1]Buschauer, A.; Schunack, W. [Journal of Heterocyclic Chemistry, 1984, vol. 21, p. 753 - 757]
  • 2
  • [ 92741-92-9 ]
  • [ 33544-86-4 ]
  • [ 88-99-3 ]
YieldReaction ConditionsOperation in experiment
63% With hydrogenchloride for 8h; Heating;
Reference： [1]Buschauer, A.; Schunack, W. [Journal of Heterocyclic Chemistry, 1984, vol. 21, p. 753 - 757]
YieldReaction ConditionsOperation in experiment
9 Preparation of 3-(2-imidazolyl)propylguanidine sulphate Treatment of the picrate with hydrochloric acid in the normal way, followed by recrystallization of the product from isopropyl alcohol-ethanol-ether affords 2-(3-aminopropyl)imidazole dihydrochloride as a hygroscopic solid, m.p. 148°-150°C.
  • 4
  • 2-[4-(morpholin-4-yl)piperidin-1-yl]-3-phenylquinoxaline-6-carboxylic acid [ No CAS ]
  • [ 33544-86-4 ]
  • N-[3-(1H-imidazol-2-yl)propyl]-2-[4-(morpholin-4-yl)piperidin-1-yl]-3-phenylquinoxaline-6-carboxamide dihydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl acetamide at 20℃; for 2h; 7.4 N-[3-(lH-imidazoI-2-yl)propyl]-2-[4-(morpholin-4-yl)piperidin-l-yl]-3-phenyIquinoxaline- 6-carboxamide dihydrochloride 2-[4-(Mo holin-4-yl)piperidin-l-yl]-3-phenylquinoxaline-6-carboxylic acid (108.0 mg, 0.26 mmol) was dissolved in DMA (5 ml). To this solution was added 3-(lH-imidazol-2-yl)propan-l-amine dihydrochloride (94.2 mg, 0.48 mmol), TEA (200 μ, 1.43 mmol) and HATU (116 mg, 0.31 mmol). The mixture was stirred for 2 h at rt. The mixture was diluted with toluene (10 mL) and then concentrated under reduced pressure. The residue was diluted with toluene (10 mL) and then concentrated under reduced pressure again to remove DMA. The residue was purified by NH silica gel chromatography to give a yellow syrup. The residue was was dissolved in MeOH (10 mL) and then treated with a 4 N HC1 (5 mL). The resulting solution was stirred for 30 min at rt. The solution was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and then diluted with THF (5 mL) and diisopropyl ether (30 mL). The resulting suspension was sonicated and then concentrated under reduced pressure to obtain N-[3 -( 1 H-imidazol-2-yl)propyl]-2-[4-(morpholin-4-yl)piperidin- 1 -yl]-3 -phenylquinoxaline-6- carboxamide dihydrochloride (144 mg, 93%). H NMR (300 MHz, DMSO-i/6) δ 1.63 - 1.84 (m, 2 H), 2.03 (m, J= 7.1 Hz, 4 H), 2.79 (t, J= 12.5 Hz, 2 H), 3.01 (t, J= 7.6 Hz, 2 H), 3.22 - 3.42 (m, 7 H), 3.77 - 3.97 (m, 6 H), 6.55 (s, 1 H), 7.48 - 7.65 (m, 5 H), 7.82 (d, J= 8.7 Hz, 1 H), 7.97 (dd, J= 7.8, 1.7 Hz, 2 H), 8.14 (dd, J= 8.7, 2.0 Hz, 1 H), 8.49 (d, J= 1.9 Hz, 1 H), 8.89 (t, J= 5.6 Hz, 1 H), 14.16 (br s, 1 H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2015/161142, 2015, A1 Location in patent: Paragraph 00281
  • 5
  • 2-chloro-3-(4-fluorophenyl)quinoxaline-6-carbonyl chloride [ No CAS ]
  • [ 33544-86-4 ]
  • 2-chloro-3-(4-fluorophenyl)-N-[3-(1H-imidazol-2-yl)propyl]quinoxaline-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% With triethylamine In N,N-dimethyl acetamide at 20℃; for 16h; 29.1 2-Chloro-3-(4-fluorophenyl)-iV-[3-(lH-imidazol-2-yl)propyl]quinoxaline-6- carboxamide 2-Chloro-3-(4-fluorophenyl)quinoxaline-6-carbonyl chloride (1.35 g, 4.21 mmol) (prepared similarly to Example 3, step 6, or Example 27, step 6) was dissolved in DMA (91.5 mL). To the solution was added 3-(lH-imidazol-2-yl)-l-propanamine dihydrochloride (1.00 g, 5.05 mmol) and triethylamine (2.93 mL, 21.0 mmol), and the mixture was stirred at rt for 16 hours. To the mixture was added saturated aqueous NaHCC>3 (100 mL) and the mixture was stirred at rt for 30 minutes. Filtered and washed the solid with water and dried. Purified by silica gel chromatography to give 2-chloro-3-(4-fluorophenyl)-N- [3-(lH-imidazol-2-yl)propyl]quinoxaline-6-carboxamide (620 mg, 36%) as a pale yellow solid. LCMS (ESI+): m/z = 410.1 (Μ+Η). NMR (400 MHz, DMSO-c) δ 11.70 (s, 1 H), 9.09 (t, J= 5.3 Hz, 1 H), 8.68 (d, 7= 1.6 Hz, 1 H), 8.34 (dd, J= 8.8, 1.9 Hz, 1 H), 8.18 (d, 7= 8.7 Hz, 1 H), 8.02 - 7.88 (m, 2 H), 7.44 (t, 7= 8.9 Hz, 2 H), 6.88 (s, 2 H), 3.40 (dd, 7= 12.6, 6.7 Hz, 2 H), 2.72 (t, 7= 7.5 Hz, 2 H), 2.02 - 1.89 (m, 2 H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2015/161142, 2015, A1 Location in patent: Paragraph 00343
  • 6
  • 2-chloro-3-(4-fluorophenyl)quinoxaline-6-carbonyl chloride [ No CAS ]
  • [ 33544-86-4 ]
  • N-(3-(1H-imidazol-2-yl)propyl)-3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine In N,N-dimethyl acetamide at 20℃; for 72h; 43.1 N-(3-(lH-imidazol-2-yl)propyl)-3-chIoro-2-(4-fluorophenyl)quinoxaline-6-carboxamide To a mixture of 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carbonyl chloride (28.2 g, 87.8 mmol, prepared according to Example 44, Route 1, Step 3) in N,N-dimethylacetamide (650 mL) was added 3-(lH-imidazol-2-yl)propan-l-amine dihydrochloride (20.9 g, 106 mmol) and TEA (61 mL, 440 mmol) and the resulting mixture was stirred at room temperature for 3 days. The reaction was then pured into saturated sodium bicarbonate (500 mL) and stirred for 90 minutes. The solids were filtered and washed with water (400 mL) and ether (400 mL). The solids were then added to water (500 mL) and sonicated for 10 minutes. The solids were filtered to give N-(3-(lH-imidazol-2-yl)propyl)-3-chloro-2-(4- fluorophenyl)quinoxaline-6-carboxamide (29 g, 80%). LCMS (ESI+): m/z = 410.1 (M+H). 'HNMR (400 MHz, DMSO-i δ 11.73 (bs, 1 H), 9.11 (bs, 1 H), 8.59 (d, J= 1.6 Hz, 1 H), 8. 32 (dd, J= 8.8, 1.6 Hz, 1 H), 8.23 (d, J= 8.8 Hz, 1 H), 7.96-7.93 (m, 2 H), 7.45-7.40 (m, 2 H), 6.98 (bs, 1 H), 6.82 (bs, 1 H), 3.42- 3.38 (m, 2 H), 2.74-2.70 (m, 2 H), 2.00-1.93 (m, 2 H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2015/161142, 2015, A1 Location in patent: Paragraph 00384
  • 7
  • 3-(5-fluoro-2-methoxypyridin-4-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid [ No CAS ]
  • [ 33544-86-4 ]
  • 3-(5-fluoro-2-methoxypyridin-4-yl)-2-(4-fluorophenyl)-N-[3-(1H-imidazol-2-yl)propyl]quinoxaline-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
76.5% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In ethyl acetate; N,N-dimethyl-formamide at 20℃; 44.6 3-(5-Fluoro-2-methoxy-4-pyridyl)-2-(4-fluorophenyl)-N-[3-(lH-imidazol-2- yl)propyl]quinoxaline-6-carboxamide (1-466) To a solution of 3-(5-fluoro-2-methoxy-4-pyridyl)-2-(4-fluorophenyl)quinoxaline-6- carboxylic acid (150 mg, 0.381 mmol) and 3-(lH-imidazol-2-yl)-l-propanamine 2HC1 (113 mg, 0.572 mmol) in DMF (2.4 mL) and TEA (0.532 mL, 3.81 mmol) was added 2,4,6-tripropyl-l,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide (1.67 mol/L) in EtOAc (0.457 mL, 0.763 mmol, 1.67 mol/L). The solution was stirred at rt overnight. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with 10% LiCl, then water 2x then brine, dried over anhydrous Na2S04, and filtered. The filtrate was concentrated in vacuo to give a crude residue and then purfied in a silica column using 0- 8% MeOH in DCM to afford a white solid product (146 mg, 76.5%). LCMS (ESI+): m/z = 501.2. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (d, J= 1.6 Hz, 1H), 8.33 (dd, J= 8.8, 1.9 Hz, 1H), 8.27 (d, J= 8.7 Hz, 1H), 7.95 (s, 1H), 7.63 (dd, J= 8.8, 5.3 Hz, 2H), 7.20 - 7.09 (m, 3H), 6.95 (s, 2H), 3.95 (s, 3H), 3.51 (t, J= 6.9 Hz, 2H), 2.85 (t, J= 7.5 Hz, 2H), 2.07 (m, 2H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2015/161142, 2015, A1 Location in patent: Paragraph 00392
  • 8
  • 3-(5-chloro-2-fluorophenyl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid [ No CAS ]
  • [ 33544-86-4 ]
  • 3-(5-chloro-2-fluorophenyl)-2-(4-fluorophenyl)-N-[3-(1H-imidazol-2-yl)propyl]quinoxaline-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In ethyl acetate; N,N-dimethyl-formamide at 20℃; 45.3 3-(5-Chloro-2-fluoro-phenyl)-2-(4-fluorophenyI)-N-[3-(lH-imidazol-2- yl)propyl]quinoxaline-6-carboxamide (1-480) To a solution of 3-(5-chloro-2-fluoro-phenyl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid (2.85 g, 7.18 mmol) and 3-(lH-imidazol-2-yl)-l-propanamine 2HC1 (2.13 g, 10.8 mmol) in DMF (45 mL) and TEA (5.01 mL, 35.9 mmol) was added 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane- 2,4,6-trioxide (1.67 mol/L) in EtOAc (8.60 mL, 14.4 mmol). The solution was stirred at rt overnight. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with 10% LiCl, then water twice then brine, dried over anhydrous Na2S04, filtered. The filtrate was concentrated in vacuo to give a crude residue. Purification by silica gel chromatography afforded a white solid product (2.90 g, 80%). LCMS (ESI+): m/z = 504.1. 1HNMR (400 MHz, Methanol-d4) δ 8.66 (s, 1H), 8.38 - 8.23 (m, 2H), 7.82 (d, J = 3.5 Hz, 1H), 7.61 (d, J = 6.9 Hz, 2H), 7.52 (s, 1H), 7.14 (t, J = 8.6 Hz, 2H), 7.08 (t, J = 9.0 Hz, 1H), 6.96 (s, 2H), 3.53 (t, J = 6.8 Hz, 2H), 2.87 (t, J = 7.5 Hz, 2H), 2.16 - 2.05 (m, 2H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2015/161142, 2015, A1 Location in patent: Paragraph 00400
  • 9
  • 2-chloro-7-fluoro-3-(4-fluorophenyl)quinoxaline-6-carbonyl chloride [ No CAS ]
  • [ 33544-86-4 ]
  • N-(3-(1H-imidazol-2-yl)propyl)-2-chloro-7-fluoro-3-(4-fluorophenyl)quinoxaline-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% With triethylamine In N,N-dimethyl acetamide at 20℃; 50.7 N-(3-(lH-imidazoI-2-yl)propyl)-2-chloro-7-fluoro-3-(4-fluorophenyl)quinoxaIine-6- carboxamide To a suspension of 2-chloro-7-fluoro-3-(4-fluorophenyl)quinoxaline-6-carbonyl chloride (102 mg, 0.301 mmol) in DMA (4.3 mL)) was added 3-(lH-imidazol-2-yl)-l-propanamine 2HCl (72 mg, 0.36 mmol) and TEA (0.210 mL, 1.50 mmol). The resulting mixture was stirred at rt overnight. The mixture was distributed between aqueous saturated sodium bicarbonate and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water five times, dried, and concentrated. Purification by silica gel chromatography provided N-(3-(lH-imidazol-2-yl)propyl)-2- chloro-7-fluoro-3-(4-fluorophenyl)quinoxaline-6-carboxamide (46 mg, 36%). LCMS (ESI+): m/z = 428.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 8.43 (d, J = 7.2 Hz, 1 H), 7.97-7.92 (m, 2 H), 7.84 (d, J = 10.8 Hz, 1 H), 7.34-7.28 (m, 2 H), 6.95 (s, 2 H), 3.52-3.48 (m, 2 H), 2.88-2.84 (m, 2 H), 2.10-2.03 (m, 2 H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2015/161142, 2015, A1 Location in patent: Paragraph 00422
  • 10
  • C20H18FN3O3 [ No CAS ]
  • [ 33544-86-4 ]
  • 3-(4-fluorophenyl)-N-[3-(1H-imidazol-2-yl)propyl]-2-(morpholin-4-ylmethyl)quinoxaline-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
26% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In tetrahydrofuran at 20℃; 64.6 3-(4-Fluorophenyl)-N-[3-(lH-imidazol-2-yl)propyl]-2-(morpholin-4- ylmethyl)quinoxaline- 6-carboxamide (1-405) A mixture of 3-(4-fluorophenyl)-2-(morpholin-4-ylmethyl)quinoxaline-6-carboxylic acid (93 mg,0.25 mmol), and 3-(lH-imidazol-2-yl)-l-propanamine 2HC1 (60.2 mg, 0.304 mmol) and Ν,Ν,Ν',Ν'- Tetramethyl-0-(7-azabenzotriazol-l-yl)uronium Hexafluorophosphate (116 mg, 0.304 mmol) in THF (1 mL) was added TEA (176 uL, 1.26 mmol). The solution was stirred at rt overnight. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with 10% LiCl, then water 2x then brine, dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo to give a crude residue. The crude residue was purified by HPLC to give 3-(4-fluorophenyl)-N-[3-(lH-imidazol-2- yl)propyl]-2-(morpholin-4-ylmethyl)quinoxaline-6-carboxamide as a formic acid salt (35 mg, 26 %). (ESI+): m/z = 475.2 (M+H). 1H NMR (400 MHz, Chloroform-d) δ 8.57 - 8.51 (m, 1H), 8.42 (s, 1H), 8.28 - 8.15 (m, 2H), 7.92 (dd, J = 8.6, 5.4 Hz, 2H), 7.36 (s, 2H), 7.31 (t, J = 8.7 Hz, 2H), 3.89 (s, 2H), 3.68 - 3.60 (m, 4H), 3.55 (s, 2H), 3.09 (s, 2H), 2.59 (d, J = 4.1 Hz, 4H), 2.22 - 2.09 (m, 2H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2015/161142, 2015, A1 Location in patent: Paragraph 00456
  • 11
  • 2-(4-chlorophenyl)-4-ethoxyquinoline-7-carboxylic acid [ No CAS ]
  • [ 33544-86-4 ]
  • N-(3-(1H-imidazol-2-yl)propyl)-2-(4-chlorophenyl)-4-ethoxyquinoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In tetrahydrofuran at 20℃; 11.7 N-(3-(lH-Imidazol-2-yl)propyl)-2-(4-chlorophenyl)-4-ethoxyquinoline-7-carboxamide To a solution of 2-(4-chlorophenyl)-4-ethoxyquinoline-7-carboxylic acid (88.0 mg, 0.27 mmol) in THF (1.3 mL) was added 3-(lH-imidazol-2-yl)propan-l-amine,2[HCl](79.8 mg, 0.40 mmol), TBTU (112 mg, 0.30 mmol) , TEA (190 uL, 1.3 mmol) at rt. The reaction mixture was stirred at rt overnight. To the mixture was added 2 mL IN NaOH and 10 ml of water. The resulting precipitate was filtered and purified by HPLC to yield N-(3-(lH-imidazol-2-yl)propyl)-2-(4-chlorophenyl)-4- ethoxyquinoline-7-carboxamide (75mg, 58%) LCMS: (FA) ES+ 435.1; lH NMR (400 MHz, DMSO-dg) δ 8.99 (m, 1H), 8.54 (d, J = 1.4 Hz, 1H), 8.36 (d, J = 8.7 Hz, 2H), 8.20 (d, J = 8.6 Hz, 1H), 8.18 (s, 1H), 7.98 (dd, J = 8.6, 1.7 Hz, 1H), 7.64 (m, 2H), 6.92 (s, 2H), 4.49 (q, J = 7.0 Hz, 2H), 3.39 (q, J = 6.7 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 1.96 (m, 2H), 1.54 (t, J = 7.0 Hz, 3H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 00285
  • 12
  • 4-ethoxy-2-(4-fluorophenyl)quinazoline-7-carboxylic acid [ No CAS ]
  • [ 33544-86-4 ]
  • 4-ethoxy-2-(4-fluorophenyl)-N-[3-(1H-imidazol-2-yl)propyl]quinazoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 1.08333h; 1.4 4-Ethoxy-2-(4-fluorophenyl)-N-[3-(lH-imidazol-2-yl)propyl]quinazoline-7-carboxamide To a mixture at rt of 4-ethoxy-2-(4-fluorophenyl)quinazoline-7-carboxylic acid (166 mg, 0.532 mmol) and TBTU (205 mg, 0.638 mmol) in dimethyl sulfoxide (3.0 mL, 42 mmol) was added DIPEA (139 uL, 0.797 mmol). The mixture became homogeneous and was stirred at rt for 5 min. 3-(lH- imidazol-2-yl)-l-propanamine 2HC1 (137 mg, 0.691 mmol ) and DIPEA (278 uL, 1.59 mmol) were added. The mixture was stirred at rt for 1 h. This reaction mixture was partitioned between EtOAc and 1M K2CO3 (stirred for 2 h). Separated organics was washed with brine X2, dried over Na2SC>4 and concentrated. The product was purified on ISCO (12 g silica) using 0-8% MeOH/DCM. Pertinent fractions were concentrated to give 4-ethoxy-2-(4-fluorophenyl)-N-[3-(lH-imidazol-2- yl)propyl]quinazoline-7-carboxamide (158 mg, 71%) as an off white solid. LC-MS: (FA) ES+ 420.2; 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 9.08 (t, J = 5.2 Hz, 1H), 8.62-8.56 (m, 2H), 8.46 (d, J = 1.5 Hz 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.05 (dd, J = 8.5, 1.5 Hz, 1H), 7.45-7.38 (m, 2H), 6.99 (s, 1H), 6.79 (s, 1H), 4.79 (q, J = 7.1 Hz, 2H), 3.43-3.35 (m, 2H), 2.79-2.75 (m, 2H), 2.01-1.91 (m, 2H), 1.54 (t, J = 7.1 Hz, 3H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 00239
  • 13
  • C19H15FN2O3 [ No CAS ]
  • [ 33544-86-4 ]
  • 4-(cyclopropylmethoxy)-2-(4-fluorophenyl)-N-[3-(1H-imidazol-2-yl)propyl]quinazoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU In dimethyl sulfoxide at 20℃; for 1.08333h; The compounds listed in the table below were prepared in an analogous fashion to that described in Example 3 starting from the appropriate starting materials:
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 00240
  • 14
  • C16H11ClN2O3 [ No CAS ]
  • [ 33544-86-4 ]
  • 2-(4-chlorophenyl)-N-[3-(1H-imidazol-2-yl)propyl]-4-methoxyquinazoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 1.08333h; The compounds listed in the table below were prepared in an analogous fashion to that described in Example 3 starting from the appropriate starting materials:
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 00240
  • 15
  • 2-(4-chlorophenyl)-4-(4-fluorophenyl)quinazoline-7-carboxylic acid [ No CAS ]
  • [ 33544-86-4 ]
  • 2-(4-chlorophenyl)-4-(4-fluorophenyl)-N-[3-(1H-imidazol-2-yl)propyl]quinazoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 20℃; for 1h; 14.3 2-(4-Chlorophenyl)-4-(4-fluorophenyl)-N-[3-(lH-imidazol-2-yl)propyl]quinazoline-7- carboxamide (1-57) A mixture of 2-(4-chlorophenyl)-4-(4-fluorophenyl)quinazoline-7-carboxylic acid (149 mg, 0.374 mmol) and 3-(lH-imidazol-2-yl)-l-propanamine 2HC1 (135 mg, 0.682 mmol) in pyridine (3.44 ml) was stirred at rt for 5 min. To the resulting heterogeneous mixture was added T3P (1.68 mol/1) in EtOAc (620 μ, 1.04 mmol). The reaction mixture was stirred at rt for 1 h. 500 ul of water were added to quench the reaction mixture. After stirring for 15 min, the mixture was concentrated on the rotovap, (bath temperature at 40 °C). The residue was mixed with 20 ml of water and the resulting suspension was made basic to pH 10 with 1 M aqueous K2CO3. The suspension was extracted with EtOAc x2. The combined organic layer was dried over Na2SC>4 and concentrated. The crude product was purified on ISCO (12 silica, dryload) using 0-8% DCM/MeOH over 25 min to give 2-(4-chlorophenyl)-4-(4-fluorophenyl)-N- [3-(lH-imidazol-2-yl)propyl]quinazoline-7-carboxamide (159 mg, 83%) as a white solid. LCMS: (FA) ES+ 486.1; 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 9.19 (t, J= 5.5 Hz, 1H), 8.65 - 8.60 (m, 3H), 8.21-8.17 (m, 1H), 8.14-8.09 (m,lH), 8.04-7.98 (m, 2H), 7.71-7.65 (m, 2H), 7.56-7.49 (m, 2H), 6.99 (s, 1H), 6.79 (s, 1H), 3.44-3.37 (m, 2H), 2.75-2.69 (m,2H), 2.02-1.92 (m, 2H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 00304
  • 16
  • 2-chloro-4-ethoxyquinoline-7-carboxylic acid [ No CAS ]
  • [ 33544-86-4 ]
  • N-(3-(1H-imidazol-2-yl)propyl)-2-chloro-4-ethoxyquinoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; HATU In tetrahydrofuran at 20℃; for 2h; 15.2 Step 2: N-(3-(lH-Imidazol-2-yl)propyl)-2-chloro-4-ethoxyquinoline-7-carboxamide (INT-8) THF (37 ml) and TEA (5. lmL, 36.4 mmol) were added into a flask with 2-chloro-4-ethoxy- quinoline-7-carboxylic acid (1.83g, 7.3 mmol), 3-(lH-imidazol-2-yl)propan-l-amine dihydrochloride (1.58g, 8.0 mmol) and HATU (2.84 g, 7.47 mmol). The reaction mixture was stirred at rt for 2 h. After adding ice/water, the reaction mixture was extracted with EtOAc twice. The combined organic layers were washed with brine then dried to afford crude N-(3-(lH-imidazol-2-yl)propyl)-2-chloro-4- ethoxyquinoline-7-carboxamide (2.61g, 100%). The crude material was used without purification in the next step. LCMS: (FA) ES+ 359.2
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 00307
  • 17
  • 4-(ethylamino)-2-(4-fluorophenyl)quinazoline-7-carboxylic acid [ No CAS ]
  • [ 33544-86-4 ]
  • 4-(ethylamino)-2-(4-fluorophenyl)-N-[3-(1H-imidazol-2-yl)propyl]quinazoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With N-ethyl-N,N-diisopropylamine; HATU In dimethyl sulfoxide for 2h; 2.4 4-(Ethylamino)-2-(4-fluorophenyl)-N-[3-(lH-imidazol-2-yl)propyl]quinazoline-7- carboxamide To a mixture of 4-(ethylamino)-2-(4-fluorophenyl)quinazoline-7-carboxylic acid (83 mg, 0.27 mmol), 3-(lH-Imidazol-2-yl)propan-l-amine FontWeight="Bold" FontSize="10" 2[HCl](68.6 mg, 0.346 mmol) and DIPEA (209 uL, 1.20 mmol) in dimethyl sulfoxide (0.99 mL, 14 mmol) was added HATU (112 mg, 0.293 mmol). The mixture was stirred for 2 h. The reaction mixture was quenched with 50 uL of water and stirred for 15min. The mixture was then partitioned between 25 ml of diluted ammonia and 25 ml of EtOAc. The separated aqueous layer (some brine was added to help separation) was extracted with EtOAc (25 ml). Combined organic layers were washed with diluted ammonia (X2) and brine (X2), dried over Na2SC>4 and concentrated. The product was purified on ISCO (12 g silica) using 0-10% MeOH/DCM over 25 min. Pure fractions were combined, concentrated and dried under vacuum to give 4-(ethylamino)-2-(4- fluorophenyl)-N-[3-(lH-imidazol-2-yl)propyl]quinazoline-7-carboxamide (77.5 mg, 69%) as a white solid. LC-MS: (FA) ES+ 419.2; 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.95 (t, J = 5.5 Hz, 1H), 8.58 - 8.51 (m, 2H), 8.48 (t, J = 5.4 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 1.7 Hz, 1H), 7.88 (dd, J = 8.5, 1.7 Hz, 1H), 7.38-7.31 (m, 2H), 6.99 (s, 1H), 6.78 (s, 1H), 3.76 - 3.67 (m, 2H), 3.40 - 3.33 (m, 2H), 2.70 (t, J = 7.6 Hz, 2H), 1.98 - 1.89 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 0244
  • 18
  • C18H16FN3O2 [ No CAS ]
  • [ 33544-86-4 ]
  • 4-[ethyl(methyl)amino]-2-(4-fluorophenyl)-N-[3-(1H-imidazol-2-yl)propyl]quinazoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide for 2h; The compounds listed in the table below were prepared in an analogous fashion to that described in Example 3 starting from the appropriate starting materials:
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 0245
  • 19
  • 2-(5-chloro-2-thienyl)-4-ethoxyquinazoline-7-carboxylic acid [ No CAS ]
  • [ 33544-86-4 ]
  • 2-(5-chloro-2-thienyl)-4-ethoxy-N-[3-(1H-imidazol-2-yl)propyl]quinazoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
61% Stage #1: 2-(5-chloro-2-thienyl)-4-ethoxyquinazoline-7-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3-(1H-imidazol-2-yl)propan-1-amine dihydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; 4.5 2-(5-Chloro-2-thienyl)-4-ethoxy-N-[3-(lH-imidazol-2-yl)propyl]quinazoline-7-carboxamide (1-35) 2-(5-Chloro-2-thienyl)-4-ethoxyquinazoline-7-carboxylic acid (0.108 g, 0.323 mmol) was partially dissolved in DCM (8.0 mL). 2.0 M of oxalyl chloride in DCM (0.210 mL, 0.419 mmol) was added, followed by DMF (2.50 uL, 0.0323 mmol). The mixture was stirred at rt under nitrogen atmosphere for 30 min. To the resulting pale orange solution 3-(lH-imidazol-2-yl)-l-propanamine.2HCl (95.8 mg, 0.484 mmol ) was added, followed by addition of DIPEA (0.350 mL, 2.01 mmol) dropwise. The resulted brown solution was stirred at rt under a nitrogen atmosphere overnight. The mixture was quenched with 15 mL of water, extracted with 5% MeOH/DCM (50 mL, 10 mL x 2). The combined DCM solution was washed with brine, dried over anhydrous Na2S04, filtered. The filtrate was evaporated in vacuo to give a crude product. The crude product was chromatographed on a 24 g silica column using MeOH/DCM (0/100 to 10/90) to afford 2-(5-chloro-2-thienyl)-4-ethoxy-N-[3-(lH-imidazol-2- yl)propyl]quinazoline-7-carboxamide as an off-white solid product (88.1 mg, 61%). UPLC-MS/5 min: (FA) ES+ 442.1. lH NMR (400 MHz, Methanol-d4) δ 8.26 (d, J = 1.2 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.92 (dd, J = 8.5, 1.7 Hz, 1H), 7.88 (d, J = 4.0 Hz, 1H), 7.07 (d, J = 4.0 Hz, 1H), 6.95 (s, 2H), 4.74 (q, J = 7.1 Hz, 2H), 3.47 (t, J = 6.8 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.05 (p, J = 7.1 Hz, 2H), 1.57 (t, J = 7.1 Hz, 3H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 00252
  • 20
  • 4-(ethylthio)-2-(4-fluorophenyl)quinazoline-7-carboxylic acid [ No CAS ]
  • [ 33544-86-4 ]
  • N-(3-(1H-imidazol-2-yl)propyl)-4-(ethylthio)-2-(4-fluorophenyl)quinazoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In tetrahydrofuran at 20℃; for 1h; 5.3 N-(3-(lH-imidazol-2-yl)propyl)-4-(ethylthio)-2-(4-fluorophenyl)quinazoline-7-carboxamide To a solution of 4-(ethylthio)-2-(4-fluorophenyl)quinazoline-7-carboxylic acid (57.0 mg, 0.174 mmol) in THF (0.634 mL), 3-(lH-Imidazol-2-yl)propan-l-amine2[HCl] (51.6 mg, 0.260 mmol), TBTU (72.6 mg, 0.191 mmol) and TEA (121 uL, 0.868 mmol) was added at rt. The reaction mixture was stirred at rt for about 1 h. The mixture was added to 10 ml of water and a solid precipitated out of solution, filtered and collected. The crude solid was purified by HPLC to afford N-(3-(lH-imidazol-2- yl)propyl)-4-(ethylthio)-2-(4-fluorophenyl)quinazoline-7-carboxamide (39 mg, 52%) was obtained. LC- MS: (FA) ES+ 436.1 1H NMR (400 MHz, DMSO-d6) 5 9.11 (br s, 1 H) 8.63 (br dd, J=8.22, 5.96 Hz, 2 H) 8.48 (s, 1 H) 8.17 (br d, J=8.16 Hz, 1 H) 8.07 (br d, J=8.28 Hz, 1 H) 7.44 (br t, J=8.72 Hz, 2 H) 6.90 (s, 2 H) 3.53 (m, 2 H) 3.34 - 3.44 (m, 2 H) 2.73 (m, 2 H) 1.90 - 2.02 (m, 2 H) 1.50 (t, J=7.22 Hz, 3 H)
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 00256
  • 21
  • 4-chloro-2-(4-chlorophenyl)quinazoline-7-carbonyl chloride [ No CAS ]
  • [ 33544-86-4 ]
  • 4-chloro-2-(4-chlorophenyl)-N-[3-(1H-imidazol-2-yl)propyl]quinazoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; 7.2 4-Chloro-2-(4-chlorophenyl)-N-[3-(lH-imidazol-2-yl)propyl]quinazoline-7-carboxamide (INT-5) To a suspension of 2-(4-chlorophenyl)-4-hydroxy-quinazoline-7-carboxylic acid (1.90 g, 6.32 mmol) in thionyl chloride (4.61 mL, 63.2 mmol) was added ~5 drops of DMF. The mixture was then stirred at reflux for 1 h, cooled to rt, and evaporated solvent, and dried on hi-vacuum for 2 h to afford crude 4-chloro-2-(4-chlorophenyl)quinazoline-7-carbonyl chloride as yellow solid. The solid was dissolved in the mixture of THF (51.2 mL, 632 mmol) and DMF (7.34 mL, 94.8 mmol), followed by the solution of TEA (2.64 mL, 19.0 mmol), and 3-(lH-imidazol-2-yl)-l-propanamine 2HC1 (1.44 g, 7.27 mmol) in DMF (9.78 mL, 126 mmol). The mixture was stirred at rt for overnight. Half of the volume of solvent was removed by rotovap, and the remaining solvent was diluted with water, and a precipitate formed. The resulting slurry was filtered and the collected solid was washed with a little water and dried under vacuum to give 4-chloro-2-(4-chlorophenyl)-N-[3-(lH-imidazol-2-yl)propyl]quinazoline-7- carboxamide (2.30 g; 85%) as yellow solid. LCMS (ESI+): m/z = 426.3 (M+H). NMR (400 MHz, DMSO- g) δ 9.21 (s, 1H), 8.62 (s, 1H), 8.52 (d, J = 8.7 Hz, 2H), 8.39 (d, J= 8.6 Hz, 1H), 8.24 (d, J= 8.6 Hz, 1H), 8.15 (s, 1H), 7.70 (d, J = 8.6 Hz, 2H), 6.91 (s, 2H), 3.41 (q, J = 6.5 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 2.07 - 1.82 (m, 2H)
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 0263
  • 22
  • 4-chloro-2-(5-chloro-2-thienyl)quinazoline-7-carbonyl chloride [ No CAS ]
  • [ 33544-86-4 ]
  • 4-chloro-2-(5-chloro-2-thienyl)-N-[3-(1H-imidazol-2-yl)propyl]quinazoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.134 g With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; 9.2 4-Chloro-2-(5-chloro-2-thienyl)-N-[3-(lH-imidazol-2-yl)propyl]quinazoline-7-carboxamide A mixture of 2-(5-chloro-2-thienyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylic acid (1.00 g, 3.26 mmol), thionyl chloride (8.0 mL, 110 mmol), DMF (0.050 mL, 0.64 mmol) in DCM (5.0 mL) was heated to reflux (95°C, heating block) for 1 h, cooled to rt overnight. The mixture became a yellow suspension. The suspension was rotavaped and azeotroped with anhydrous DCM to give a yellow solid intermediate 4-chloro-2-(5-chloro-2-thienyl)quinazoline-7-carbonyl chloride (1.09 g, crude 97%). [00270] A mixture of the intermediate 4-chloro-2-(5-chloro-2-thienyl)quinazoline-7-carbonyl chloride (0.802 g, 3.17 mmol) and 3-(lH-imidazol-2-yl)-l-propanamine 2HC1 (0.465 g, 2.35 mmol) were suspended in anhydrous DCM (10 mL, 200 mmol). DIPEA (1.70 mL, 9.78 mmol) was added and the resulted pale brown solution was stirred at rt for 1 h and the mixture turned into a pale orange suspension. The suspension was filtered and the solid was washed with DCM (3 mL x 4), dried in vacuum pump to give the first crop of 4-chloro-2-(5-chloro-2-thienyl)-N-[3-(lH-imidazol-2-yl)propyl]quinazoline-7- carboxamide (0.633 g). The filtrate was diluted with DCM (30 mL) and water (70 mL) to give a bilayer suspension, filtered and washed with DCM, dried in vacuo to give the second crop of product (0.134 g, combined yield from both crops was 52%). UPLC-MS/5 min: (FA) ES+ 432.1. lH NMR (400 MHz, DMSO-d6) δ 9.19 (t, J = 5.3 Hz, 1H), 8.51 (s, 1H), 8.32 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 3.9 Hz, 1H), 7.32 (d, J = 4.0 Hz, 1H), 6.91 (d, J = 4.8 Hz, 2H), 3.38 (d, J = 6.2 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.00 - 1.92 (m, 2H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 00269-00270
  • 23
  • 2-(4-chlorophenyl)-4-propyl-quinazoline-7-carboxylic acid [ No CAS ]
  • [ 33544-86-4 ]
  • 2-(4-chlorophenyl)-N-[3-(1H-imidazol-2-yl)propyl]-4-propylquinazoline-7-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 20℃; for 1.08333h; 10.4 2-(4-Chlorophenyl)-N-[3-(lH-imidazol-2-yl)propyl]-4-propylquinazoline-7-carboxamide (I- 4) A mixture of 2-(4-chlorophenyl)-4-propyl-quinazoline-7-carboxylic acid (545 mg, 1.67 mmol) and 3-(lH-imidazol-2-yl)-l-propanamine 2HC1 (513 mg, 2.59 mmol) in pyridine (8.62 mL) was stirred at rt for 5 min. To the resulting thick mixture was added T3P (1.68 M in EtOAc, 2.44 mL, 4.11 mmol ). The mixture was then stirred for 1 h. 1.5 mL of water was added and the mixture was concentrated in vacuo (at 40 °C). The thick liquid residue that remained was diluted with 20 mL of water under stirring. The light suspension mixture was slowly made basic by addition of 4 M aqueous K2CO3 to pH 10-11. The resulting suspension was stirred for 1 h. The solid was filtered off, washed with water and was dried under vacuum to give 750 mg of light purple solid. Purification on ISCO (24g silica; dry load) using 0-8%) MeOH in DCM gave 2-(4-chlorophenyl)-N-[3-(lH-imidazol-2-yl)propyl]-4-propyl- quinazoline-7-carboxamide as an off white solid (605 mg, 1.47 mmol, 83%). LC-MS: (FA) ES+ 434.1; 'HNMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 9.12 (t, J = 5.4 Hz, 1H), 8.61 - 8.57 (m, 2H), 8.53 (d, J = 1.5 Hz, 1H), 8.44 (d, J = 8.7 Hz, 1H), 8.10 (dd, J = 8.7, 1.7 Hz, 1H), 7.69 - 7.64 (m, 2H), 6.89 (s, 2H), 3.43 - 3.34 (m, 4H), 2.72 (t, J = 7.5 Hz, 2H), 2.03 - 1.89 (m, 4H), 1.06 (t, J = 7.4 Hz, 3H).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/118565, 2016, A1 Location in patent: Paragraph 00276

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