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CAS No. : | 58581-89-8 | MDL No. : | MFCD00242781 |
Formula : | C22H24ClN3O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 381.90 | Pubchem ID : | - |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P270-P301+P312-P330-P501 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: CH3COONa / 3 h / 245 - 250 °C 2: aq. NaOH / 2 h / Heating 3: 1.) 23percent aq. HCl, 2.) KOH / 1.) reflux, 3 h, 2.) methanol, reflux, 2 h | ||
Multi-step reaction with 4 steps 1: CH3COONa / 3 h / 245 - 250 °C 2: aq. NaOH / 2 h / Heating 3: 90 percent / hydrazine sulfate, aq. NaOH / 2 h / Heating 4: aq. NaOH / 1 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 2.) NaBH4 / 1.) CH3OH, room temp. 2: 1.) 23percent aq. HCl, 2.) KOH / 1.) reflux, 3 h, 2.) methanol, reflux, 2 h | ||
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water / 1 h / 25 - 35 °C 1.2: 2 h / 0 - 10 °C 2.1: tetrahydrofuran / 1 h / 0 - 10 °C / Reflux 3.1: hydrogenchloride / 2 h / 20 °C / Reflux 3.2: 2 h / Reflux | ||
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water / 1 h / 25 - 35 °C 1.2: 2 h / 0 - 10 °C 2.1: tetrahydrofuran / 1 h / 0 - 10 °C / Reflux 3.1: hydrogenchloride / 2 h / 20 °C / Reflux 3.2: 2 h / Reflux |
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water / 1 h / 25 - 35 °C 1.2: 2 h / 0 - 10 °C 2.1: acetonitrile / 1 h / 0 - 10 °C / Reflux 3.1: hydrogenchloride / 2 h / 20 °C / Reflux 3.2: 2 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: CH3COONa / 3 h / 245 - 250 °C 2: aq. NaOH / 2 h / Heating 3: 1.) 23percent aq. HCl, 2.) KOH / 1.) reflux, 3 h, 2.) methanol, reflux, 2 h | ||
Multi-step reaction with 4 steps 1: CH3COONa / 3 h / 245 - 250 °C 2: aq. NaOH / 2 h / Heating 3: 90 percent / hydrazine sulfate, aq. NaOH / 2 h / Heating 4: aq. NaOH / 1 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: aq. NaOH / 2 h / Heating 2: 1.) 23percent aq. HCl, 2.) KOH / 1.) reflux, 3 h, 2.) methanol, reflux, 2 h | ||
Multi-step reaction with 3 steps 1: aq. NaOH / 2 h / Heating 2: 90 percent / hydrazine sulfate, aq. NaOH / 2 h / Heating 3: aq. NaOH / 1 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The aqueous solution of 1H-azepine, 4-hydrazinohexahydro-1-methyl dihydrochloride of the previous step, was cooled down to a temperature below 10 C and 420 g of sodium hydroxide 50% (3.35 eq) were added. 420 g of benzoic acid, 2-[(4-chlorophenyl)acetyl] (1.0 eq.) and 1664 ml methanol were also added. The mixture was refluxed during 4 hours. Subsequently, it was cooled to 60 C and 143 g of sodium hydroxide 50% (1.14 eq) were added. The reaction was heated and distilled until a temperature of 100 C to remove the methanol. The mixture was cooled down to 60 C and 2050 ml of isobutylmethylketone (MIBK) and 500 ml of water were added. The aqueous layer was separated. 1750 ml of water and 172 g HCI (36%)(1.1 eq.) were added to the organic layer. The aqueous layer was separated. The organic layer was extracted at the same temperature with 525 ml of water. Some impurities of the process were dissolved in the organic layer. The aqueous layers were combined and 1880 ml of MIBK and 151 g of sodium hydroxide 50% (1.2 eq.) were added. The mixture was maintained 15 min. under stirring and the aqueous layer was separated. The organic layer was treated with charcoal. The treated solution was cooled down to 0-5 C crystallizing a solid. After two hours at 0-5 C, an off solid was filtered-off and washed with MIBK. The wet product was dried under vacuum to yield anhydrous azelastine. Purity by HPLC: 99.8% 1H-RMN (dmso-6d, 400 MHz): 1.59-1.65 (1 H, m), 1.76-2.05 (5H, m), 2.24 (3H, s), 2.44-2.60 (5H, m), 4.32 (2H, s), 5.13-5.21 (1 H, m), 7.35 (4H, s), 7.80 (1 H, td, 7.2 Hz, 1.2 Hz), 7.86 (1 H, td, 8.0 Hz, 1.6 Hz), 7.95 (1 H, d, 8.0 Hz), 8.27 (1 H, dd, /.2 Hz, 1.2 Hz). 13C-RMN (dmso-6d, 100 MHz): 24.8 (t), 32.0 (t), 33.0 (t), 37.1 (t), 46.8 (q), 53.6 (t), 55.3 (d), 58.3 (t), 125.2 (d), 126.6 (d), 127.3 (s), 128.0 (s), 128.4 (d), 130.6 (d), 131.1 (s), 133.2 (d), 137.0 (s), 144.5 (s), 157.2 (s). IR (KBr): 3441, 2962, 2931, 2846, 2789, 1636, 1588, 1493, 1350, 1334, 775. mp: 113.0-114.1C. KF: <0.1 %. The X-ray diffraction analysis gave the diffractogram shown in FIG. 1. The Differential Scanning Calorimetry analysis gave the curve shown in FIG. 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water In ethanol Heating / reflux; | A three-neck flask was charged with 25 g of anhydrous azelastine and 150 ml of a mixture of ethanol/water (1/1) were added. The reaction mixture was stirred for 10 minutes at room temperature, and then heated until dissolution (Ta 76 °C). The solution was slowly cooled and the product crystallized at 54 °C. The suspension was cooled at 0-5 °C and maintained for over 2 hours at this temperature. The solid product was isolated by filtration and washed with 5 ml of ethanol/water (1/1). The solid was dried at room temperature under vacuum to obtain 24 g of azelastine monohydrate as a white product. IR (KBr): 3526, 3396, 2929, 2792, 1635, 1586, 1490, 1340, 1324, 1015, 772. KF: 3.8% (theoretic for the monohydrate 4.5%). The X-ray diffraction analysis gave the diffractogram shown in FIG. 3. The Differential Scanning Calorimetry analysis gave the curve shown in FIG. 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Stage #1: azelastine With 1,4-diaza-bicyclo[2.2.2]octane; tri(4-tolyl)aminium hexafluorophosphate In acetonitrile at -5℃; Inert atmosphere; Stage #2: phenylmagnesium bromide In tetrahydrofuran; acetonitrile at 0℃; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With mixed selector chiral stationary phase prepared with co-immobilized human serum albumin and cellulase on a poly(glycidylmethacrylate-co-ethylene glycol dimethacrylate) monolith In aq. phosphate buffer; isopropyl alcohol at 20℃; Resolution of racemate; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With C17H24N5Ru(1+)*F6P(1-); potassium acetate; potassium carbonate In 1-methyl-pyrrolidin-2-one at 35℃; for 72h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With pentamethylcyclopentadienyl(benzene)cobalt(III) hexafluorophosphate; potassium carbonate; silver carbonate In 2-methyltetrahydrofuran at 100℃; for 16h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.1 g | Stage #1: C14H23N3O(2+)*C4H2O4(2-) With hydrogenchloride at 20℃; for 2h; Reflux; Stage #2: 2‐(4-chlorophenylacetyl)benzoic acid for 2h; Reflux; | 2.3 3) Put 8.0g of compound 2 and 44mL of 36% hydrochloric acid into the reaction flask at room temperature, stir, heat to reflux, and reflux for 2h. After the reaction is completed, it is cooled to room temperature. Sodium carbonate is added to adjust the pH to 7, and the adjustment is complete.Add 6.0g of compound 3, heat to reflux, reflux for 2h, after the reaction is complete, cool to room temperature,Add 50% potassium carbonate to adjust the pH, add 100 mL of dichloromethane, separate the liquids to take the organic phase,The aqueous phase was extracted once more with 50 mL of dichloromethane, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure 8.1 g of brown oily liquid compound 4 was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.5 g | Stage #1: C14H23N3O(2+)*C4H2O4(2-) With hydrogenchloride at 20℃; for 2h; Reflux; Stage #2: 2‐(4-chlorophenylacetyl)benzoic acid for 2h; Reflux; | 4.3 3) Put 7.5g compound 2 and 41mL 36% hydrochloric acid into the reaction flask at room temperature, stir,The temperature is raised to reflux, and the reaction is refluxed for 2h. After the reaction is completed, it is cooled to room temperature. Add sodium carbonate to adjust the pH to 7,After adjusting, add 5.6g compound 3, heat to reflux, reflux for 2h,After the reaction is complete, cool down to room temperature, add 50% potassium carbonate to adjust the pH, Add 100mL of dichloromethane, separate the liquids and take the organic phase,The aqueous phase was extracted once more with 50 mL of dichloromethane, and the organic phases were combined and washed once with water.Wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure 7.5 g of brown oily liquid compound 4 was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 1 h / 0 - 10 °C / Reflux 2.1: hydrogenchloride / 2 h / 20 °C / Reflux 2.2: 2 h / Reflux | ||
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 1 h / 0 - 10 °C / Reflux 2.1: hydrogenchloride / 2 h / 20 °C / Reflux 2.2: 2 h / Reflux | ||
Multi-step reaction with 2 steps 1.1: acetonitrile / 1 h / 0 - 10 °C / Reflux 2.1: hydrogenchloride / 2 h / 20 °C / Reflux 2.2: 2 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8 g | Stage #1: C14H23N3O(2+)*C4H4O4(2-) With hydrogenchloride at 20℃; for 2h; Reflux; Stage #2: 2‐(4-chlorophenylacetyl)benzoic acid for 2h; Reflux; | 1.3; 3.3; 5.3-6.3 3) Put 8.0g compound 2 and 44mL 36% hydrochloric acid into the reaction flask at room temperature, stir,The temperature is raised to reflux, and the reaction is refluxed for 2h. After the reaction is completed, it is cooled to room temperature.Add sodium carbonate to adjust the pH to 7, after adjustment, add 6.0g of compound 3, and heat to reflux.Reflux for 2h,After the reaction is complete, cool to room temperature,Add 50% potassium carbonate to adjust the pH to 7, add 100 mL of dichloromethane, separate and take the organic phase, extract the aqueous phase again with 50 mL of dichloromethane, combine the organic phases, and wash once with water.Wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure 8.0 g of brown oily liquid compound 4 was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With hydrogenchloride In toluene Reflux; | 1.4-6.4 4) Pour 8.2g of compound 4 and 164mL of toluene into the reaction flask, add 4.3g of 36% hydrochloric acid under stirring, heat to reflux, connect to a water separator, reflux and separate water, and complete the separation.Cool down to 010, stir and crystallize for 1h, filter with suction, discharge, vacuum dryObtain 8.0 g of azelastine hydrochloride as a white solid product,Yield: 87.0%, HPLC purity 99.88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water / 1 h / 25 - 35 °C 1.2: 2 h / 0 - 10 °C 2.1: tetrahydrofuran / 1 h / 0 - 10 °C / Reflux 3.1: hydrogenchloride / 2 h / 20 °C / Reflux 3.2: 2 h / Reflux | ||
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water / 1 h / 25 - 35 °C 1.2: 2 h / 0 - 10 °C 2.1: tetrahydrofuran / 1 h / 0 - 10 °C / Reflux 3.1: hydrogenchloride / 2 h / 20 °C / Reflux 3.2: 2 h / Reflux | ||
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water / 1 h / 25 - 35 °C 1.2: 2 h / 0 - 10 °C 2.1: acetonitrile / 1 h / 0 - 10 °C / Reflux 3.1: hydrogenchloride / 2 h / 20 °C / Reflux 3.2: 2 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With 1,1'-bis-(diphenylphosphino)ferrocene; nickel(II) chloride hexahydrate; 1,8-diazabicyclo[5.4.0]undec-7-ene In methanol; N,N-dimethyl acetamide at 80℃; for 21h; Inert atmosphere; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 100% 2: 100% | With dihydrogen peroxide In water at 50℃; for 4.33333h; | 4.3. Synthesis of azelastine N -oxides (3, 4) To a suspension of azelastine hydrochloride ( 1 , 55.0 g, 0.14 mol) in ammonium hydroxide solution (25% in H2O, 100 mL) was added DCM (100 mL), and the mixture was stirred for 10 min. The or- ganic phase was separated, and the aqueous phase was extracted with DCM (3 ×100 mL). The combined organic phases were evaporated to dryness to yield azelastine base ( 2 , 53.77 g, 0.14 mol) as a white amorphous powder. Compound 2 (53.77 g, 0.14 mol) was dissolved in methanol (200 mL) at 50 °C, and an aqueous solution of hydrogen peroxide (35%, 35.4 g, 0.36 mol) was added over a period of 20 min under stirring. The reaction was stirred for another 4 h at 50 °C, and to the resulting clear solution water (150 mL) was added. The methanol was removed under diminished pressure, and the resulting aqueous phase was saturated with sodium chloride. After extraction with DCM (2 ×300 mL), the combined organic phases were washed with water (150 mL), dried over MgSO 4 , and evaporated to dryness. After column chromatography (1.5 kg, SiO 2 , DCM:MeOH:NH4OH (25% in H2O), 80:10:1), 3 (26.0 g, 65 mmol), and 4 (16.6 g, 42 mmol), as well as mixture (9.0 g) of both were obtained each as a white powder. Re -chromatography of the mix- ture yielded both diastereomers in almost quantitative yields. Data for ( SS / RR ) azelastine N -oxide ( 3 , rac (SS/RR) 4-(4- (4-chlorobenzyl) -1-oxophthalazin-2(1 H )-yl) -1-methylazepane 1-oxide): m.p. 154.2 °C; R F = 0.41 (DCM:MeOH:NH 4 OH, 80:10:1); IR (ATR): = 3037 w , 2955 w , 2937 w , 2864 w , 2768 w , 2598 w , 1634 vs , 1610 w , 1588 s , 1557 vw , 1491 m, 1464 m , 1443 w , 1427 w , 1407 w, 1387 w , 1353 m , 1344 m , 1334 m , 1299 vw , 1284 w , 1268 w , 1233 vw , 1183 w , 1173 w , 1148 w , 1104 w , 1092 w ,1083 w , 1048 m , 1032 w , 1012 w , 998 w , 976 vw , 961 w , 939 w , 926 w , 911 m , 875 m , 846 w , 828 w , 814 m , 799 w , 792 w , 782 vs , 736 m , 721 w , 693 s , 677 w , 639 w , 615 w , 592 m , 581 w , 547 vw , 515 w , 504 w , 486 m cm -1 ; UV/Vis (MeOH): max (log ) = 211 (4.42) nm, 290 (3.6) nm, 246 (3.59) nm, 256 (3.55) nm; 1 H NMR (400 MHz, CDCl 3 ): = 8.48-8.42 (m, 1H, 13-H), 7.81-7.72 (m, 3H, 10- H + 11- H + 12-H), 7.35-7.30 (m, 2H, 3- H + 5-H), 7.21-7.16 (m, 2H, 2- H + 6-H), 5.39 (dddd, J = 10.5, 7.0, 7.0, 3.4 Hz, 1H, 16-H), 4.27f (d, J = 1.5 Hz, 2H, 7-H 2 ), 3.48-3.43 (m, 1H, 19-H a ), 3.43-3.35 (m, 1H, 18-H a ), 3.18 (s, 3H, 23-H 3 ), 3.18-3.13 (m, 1H, 21-H a ), 3.13-3.08 (m, 1H, 19-H b ), 3.08-2.98 (m, 1H, 18-H b ), 2.36-2.20 (m, 2H, 17-H a + 20-H b ), 1.80-1.62 (m, 3H, 17-H b + 20-H b + 21-H b ) ppm; 13 C NMR (101 MHz, CDCl 3 ): = 158.3 (C-15), 145.0 (C-8), 135.8 (C-1), 133.1 (C-11), 132.6 (C-4), 131.6 (C-10), 130.9 (C-2 + C-6), 128.7 (C-3 + C-5), 128.7 (C-9), 127.8 (C-13), 127.6 (C-14), 124.0 (C-12), 73.2 (C-19), 65.6 (C-18), 61.8 (C-22f), 53.7 (C-16), 38.0 (C-7), 31.5 (C-17), 26.3 (C-21), 19.5 (C-20) ppm; MS (ESI, MeOH): m/z = 398.20 ([ M + H ] + , 100%), 795.20 ([2M + H ] + , 30%); analysis calcd for C 22 H 24 ClN 3 O 2 . H 2 O (415.91): C 63.53, H 6.30, N 10.10; found: C 63.29, H 6.57, N 9.94. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-methylazepan-4-one hydrochloride; benzoic acid hydrazide at 20℃; Stage #2: With potassium hydroxide In methanol at 0 - 20℃; for 5h; Stage #3: 2-(p-chlorophenylacetyl)benzoic acid Further stages; | 7 Example 7: Preparation of Azelastine Hydrochloride Add 1 mol of N-methylhexahydroazepin-4-one hydrochloride and 1.1 mol of benzoic hydrazide to the reaction kettle, and stir the reaction at room temperature for 1-5 h.Then cool with ice-salt water or ice-salt bath until0-20; add 500mL of methanol solution of 2mol/L KOH dropwise for 5h,Add 1.30 mol of potassium borohydride, continue to cool and stir for 30 min, and then stir for 6 h at 40-50 °C;Then use DCM (extraction (10ml×3), after drying with 0.50kg MgSO4, then add HCl-containing ether solution to form salt, and precipitation;Then add 10kg pure water and 1 mol of 2-(p-chlorophenylacetyl) benzoic acid, adjust the pH to 7 with 20% NaOH solution, stir and reflux, and cool under stirring to make the oily matter become solid particles, use 20% The pH of the NaOH was adjusted to 9, so that the azelastine free base was fully separated out, left standing, filtered, washed with water and dried;The dried 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-IH-azepin-4-yl)-1-(2H)-phthalazine was first dissolved by heating with acetone, added Activated carbon, stirred and refluxed for 60min, filtered while hot, the filter residue was washed with hot acetone, the filtrate was salted with HCl-containing isopropanol solution under cooling and stirring, frozen, filtered, washed with cold acetone, drained, and dried at 100°C Dry, and recrystallize once more from acetone and ethanol to give 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-IH-azepin-4-yl)-1-(2H)- Phthalazine hydrochloride (99.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sodium methoxide / ethanol / 48.5 h / 20 °C 2.1: hydrogen / methanol / 20 h / 20 °C 3.1: glacial acetic acid; NaNO2 / lithium hydroxide monohydrate / 0 °C / Green chemistry 3.2: pH < 6 / Green chemistry 4.1: 20 °C 4.2: 5 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydrogen / methanol / 20 h / 20 °C 2.1: glacial acetic acid; NaNO2 / lithium hydroxide monohydrate / 0 °C / Green chemistry 2.2: pH < 6 / Green chemistry 3.1: 20 °C 3.2: 5 h / 0 - 20 °C |
A341055[ 79307-93-0 ]
4-(4-Chlorobenzyl)-2-(1-methylazepan-4-yl)phthalazin-1(2H)-one hydrochloride
Reason: Free-salt