* 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.
Stage #1: With acetic acid In water at 4.5 - 15℃; for 2.66667 h; Inert atmosphere Stage #2: at 0 - 10℃; for 0.333333 h; Inert atmosphere
Procedure Using Formaldehyde in Place of Diethoxymethane:To a 250 L reactor, under N2 atmosphere, was charged with about 40percent aqueous dimethylamine (35.68 kg, 1.0 eqv.) at about 17° C. The mixture was cooled to about 4.5° C. and glacial acetic acid (43.4 kg, 2.5 eq.) was added dropwise over 140 min while maintaining the temperature using below about 15° C. After stirring for 20 min at about 3° C., 37percent aqueous formaldehyde (25.9 kg, 1.1 eq.) was slowly added over about 20 min while keeping the temperature between about 0° C. to about 10° C. 6-Fluoroindole (39.2 kg) was added. The reaction was exothermic and reached a final temperature of about 40° C., which was then cooled down to about 20° C. The reaction solution was slowly added in a 650 L reactor charged with aqueous 3M NaOH over a period of about 40 min. The suspension was stirred for about 40 min while keeping the temperature between about 5 and 20° C. The product was filtered, rinsed with DI water (120 kg) and dried at about 50° C. to afford the compound of Formula II (45.4 kg). Yield: 85percent.
81%
Stage #1: With acetic acid In water at 3 - 17℃; for 2.66667 h; Inert atmosphere; Large scale Stage #2: at 0 - 40℃; Inert atmosphere; Large scale Stage #3: With sodium hydroxide In water at 5 - 20℃; for 1.33333 h; Inert atmosphere; Large scale
A 250 L reactor was charged with approx. 40percent aq. dimethylamine (35.7 kg, 317 mol) at approx. 17°C. under an inert atmosphere. The mixture was cooled to approx. 4.5° C. and glacial acetic acid (43.4kg, 723 mol) was added dropwise over 140 mm while maintaining the temperature at approx. 15° C. Afier stirring for 20 mm at about 3° C., 37percent aqueous formaldehyde (25.9 kg, 319 mol) was slowly added over about 20 mm while keeping the temperature between approx. 0°C. to approx. 10°C. 6-Fluoroindole (39.2kg, 290 mol) was added. The reaction was exothermic and reached a final temperature of approx. 40° C., and it was then cooled down to approx. 20° C. The reaction solution was slowly added to a 650 L reactor previously charged with aq. NaOH (3 M) over a period of approx. 40 mm. The formed suspension was stirred for approx. 40 mm while keeping the temperature between 5 to 20°C. The precipitate was filtered from solution, washed with water on the filter, and dried at approx. 50° C. to afford Compound (II) (45.4 kg, 8 1percent).
Reference：
[1] Patent: US2011/152539, 2011, A1, . Location in patent: Page/Page column 4
[2] Patent: US2016/168089, 2016, A1, . Location in patent: Page/Page column 0081; 0082
[3] Chemical Communications, 2016, vol. 52, # 34, p. 5868 - 5871
[4] Journal of Organic Chemistry, 2018, vol. 83, # 17, p. 9902 - 9913
[5] Patent: WO2010/36362, 2010, A1, . Location in patent: Page/Page column 44
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Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With formic acid In water at 80℃; for 2 h; Reflux Stage #2: With acetic acid In water at 2 - 40℃; Stage #3: With sodium hydroxide In water at 5 - 20℃;
Synthesis of the Compound of Formula IIDetailed syntheses of the compound of Formula II from commercially available 6-fluoroindole are provided below. Scheme II uses diethoxymethane and dimethylamine to generate the "iminium ion species". An alternative procedure using formaldehyde in place of diethoxymethane is also provided below. Synthetic Procedure:Preparation of formaldehyde was carried out in reactor A. The synthesis of the compound of Formula II was carried out in reactor B. Precipitation of the final product was carried out in reactor C.Procedure:To reactor A were charged diethoxymethane (65 ml/54 g), water (50 ml) and formic acid (39 ml/47 g). The mixture was heated to about 80° C./reflux for about 2 hours and then cooled to about 20° C. To reactor B were charged 6-fluoroindole (50 g) and 80percent acetic acid (66 ml/70 g, 2.5 eq. to 6-fluoroindole). The suspension was cooled to 2-5° C. 40percent Dimethylamine (aq) (103 ml/92 g, 2.2 eq. to 6-fluoroindole) was added drop-wise to reactor B keeping the temperature below about 15° C. The reaction mixture was stirred for about 20 minutes and at the same time the temperature was adjusted to 2-4° C.The mixture from reactor A (DEM, water, formic acid, formaldehyde and ethanol at about 20° C.) was added drop-wise to reactor B while keeping the temperature at 2-8° C. The reaction mixture was stirred for additional 10 minutes at 2-8° C. The reaction mixture was slowly warmed to about 40° C. over a 1 hour period. The reaction mixture was stirred at about 40° C. for an additional 1 hour. The reaction mixture was cooled to about 20° C.To reactor C was charged 3M NaOH (800 ml, 1.24 eq. to the acetic acid+the formic acid) and the solution was cooled to about 10° C. The reaction mixture from reactor B was added drop-wise to the NaOH solution in reactor C while keeping the temperature at 10-15° C. (pH>14). The suspension was stirred for 40 minutes at 5-20° C. (pH>14). The product was collected by filtration and the filter-cake was washed twice with water (2.x.250 ml). The product was dried at about 60° C. under vacuum for 16 hours. Yield: 95percent. Purity by HPLC (280 nm): 98 area percent.
95%
Stage #1: With acetic acid In water at 2 - 15℃; for 0.333333 h; Inert atmosphere Stage #2: With formaldehyd; formic acid In ethanol; water at 2 - 40℃; for 2.16667 h; Inert atmosphere Stage #3: With sodium hydroxide In ethanol; water at 5 - 20℃; for 0.666667 h; Inert atmosphere
To reactor A were charged diethoxymethane (DEM)(65 mE, 0.52 mol), water (50 mE) and formic acid (39 mE, 1.02 mol)). The mixture was heated at approx. 80° C. (reflux) for approx. 2 h and then cooled to approx. 20° C. To reactor B were charged 6-fluoroindole (50 g, 0.37 mol) and 80percent acetic acid (66 mE, 1.17 mol). The suspension was cooled to 2-5° C. 40percent Aq. dimethylamine (103 mE, 2.04 mol) was added drop- wise to reactor B keeping the temperature below approx. 15° C. The reaction mixture was stirred for approx. 20 mm and at the same time the temperature was adjusted to 2-4° C. The mixture from reactor A (DEM, water, formic acid, formaldehyde and ethanol at about 20° C.) was added drop-wise to reactor B while keeping the temperature at 2-8° C. The reaction mixture was stirred for additional 10 mm at 2-8° C. The reaction mixture was slowly warmed to approx.40° C. over a 1 h period. The reaction mixture was stirred at approx. 40°C. for an additional 1 h. The reaction mixture was cooled to about 20° C. To reactor C was charged aq. NaOH (800 mE, 2.40 mol, 3 M) and the solution was cooled to about 10° C. The reaction mixture from reactor B was added dropwise to the NaOH solution in reactor C while keeping the temperature at 10-15°C. (pH>14). The suspension was stirred for 40 mm at 5-20°C. (pH>1 4). The product was collected by filtration and the filter-cake was washed twice with water (2x250 mE). The product was dried at approx. 60° C. under vacuum for 16 h to yield Compound (II) (67.6 g, 95percent) with 98percent UV purity in HPLC analysis.
Procedure Using Formaldehyde in Place of Diethoxymethane:To a 250 L reactor, under N2 atmosphere, was charged with about 40% aqueous dimethylamine (35.68 kg, 1.0 eqv.) at about 17 C. The mixture was cooled to about 4.5 C. and glacial acetic acid (43.4 kg, 2.5 eq.) was added dropwise over 140 min while maintaining the temperature using below about 15 C. After stirring for 20 min at about 3 C., 37% aqueous formaldehyde (25.9 kg, 1.1 eq.) was slowly added over about 20 min while keeping the temperature between about 0 C. to about 10 C. 6-Fluoroindole (39.2 kg) was added. The reaction was exothermic and reached a final temperature of about 40 C., which was then cooled down to about 20 C. The reaction solution was slowly added in a 650 L reactor charged with aqueous 3M NaOH over a period of about 40 min. The suspension was stirred for about 40 min while keeping the temperature between about 5 and 20 C. The product was filtered, rinsed with DI water (120 kg) and dried at about 50 C. to afford the compound of Formula II (45.4 kg). Yield: 85%.
81%
A 250 L reactor was charged with approx. 40% aq. dimethylamine (35.7 kg, 317 mol) at approx. 17C. under an inert atmosphere. The mixture was cooled to approx. 4.5 C. and glacial acetic acid (43.4kg, 723 mol) was added dropwise over 140 mm while maintaining the temperature at approx. 15 C. Afier stirring for 20 mm at about 3 C., 37% aqueous formaldehyde (25.9 kg, 319 mol) was slowly added over about 20 mm while keeping the temperature between approx. 0C. to approx. 10C. 6-Fluoroindole (39.2kg, 290 mol) was added. The reaction was exothermic and reached a final temperature of approx. 40 C., and it was then cooled down to approx. 20 C. The reaction solution was slowly added to a 650 L reactor previously charged with aq. NaOH (3 M) over a period of approx. 40 mm. The formed suspension was stirred for approx. 40 mm while keeping the temperature between 5 to 20C. The precipitate was filtered from solution, washed with water on the filter, and dried at approx. 50 C. to afford Compound (II) (45.4 kg, 8 1%).
With acetic acid; In water; at 0 - 20℃;
Example 2: Isopropyl 8-fluoro-1 ,1-dimethyl-3-[4-(morpholin-4-ylmethyl)benzoyl]-1, 2,3,6- tetrahydroazepino[4,5-b]indole-5-carboxylate[00164] Step 1: In a round bottom flask with stir bar were combined acetic acid (40 ml_), formaldehyde (9.3 ml_, 114 mmol, 37% soln in water), and dimethylamine (20.0 ml_, 178 mmol, 40% soln in water). The solution was cooled to 0 0C in an ice water bath and 6-fluoroindole (15 g, 111 mmol) was added in portions over one hour. After complete addition the ice bath was removed and the reaction warmed gradually to room temperature overnight, after which time the reaction mixture was poured into ice water. The pH was adjusted to 12 with an aqueous solution of sodium hydroxide. The resulting mixture was extracted with diethyl ether (2x). The combined extracts were dried over sodium sulfate and concentrated to dryness. Further drying under vacuum provided 1-(6-fluoro-1 H-indol-3-yl)-N,N-dimethylmethanamine as a white solid, which was used without further purification in the next step. MS (ES) m/z 191.0 ([M-H] ).
Step 2: In a round bottom flask with stir bar under nitrogen was placed 1 -(6-fluoro- 1 H-indol-3-yl)-N,N-dimethylmethanamine (21.03 g, 109.4 mmol). THF (200 rnl_) was added with stirring until all solid was in solution. In one portion iodomethane (17 ml_, 273.5 mmol) was added. Almost immediately a yellow precipitate formed. Stirring was continued overnight, after which time the solution was concentrated to dryness to provide 1-(6-fluoro-1 H-indol-3-yl)-N,N,N- trimethylmethanaminium iodide, which was used in the next step without further purification.
In water; N,N-dimethyl-formamide; at 100 - 105℃; for 8h;
Synthesis of the Compound of Formula IIIA detailed synthesis of the compound of Formula III from the compound of Formula II is provided below in Scheme III. Step-Wise Procedure:(6-Fluoro-1H-indol-3-ylmethyl)-dimethylamine (65 g), KCN (31 g), DMF (195 ml) and water (104 ml) were charged to the reactor. The reaction mixture was heated to about 100-105 C. (strong reflux) for about 5-8 hours. The reaction mixture was cooled to 20-25 C. Water (780 ml) and toluene (435 ml) were charged to the reactor and the mixture was stirred vigorously for >2 hours. The organic and aqueous layers were separated. The organic layer was washed with 5% NaHCO3 (6×260 ml), 2M HCl (260 ml), 5% NaHCO3 (260 ml) and 5% NaCl (260 ml), respectively. The organic layer was filtered and concentrated to dryness. MeOH (260 ml) was added and the solution was concentrated to dryness. The compound of Formula III was isolated as a brown oil. Yield: 90%. Purity by HPLC (280 nm): 95%. MS m/z: 193 (M+H)+.
90%
In water; N,N-dimethyl-formamide; at 100 - 105℃;Inert atmosphere;
(6-Fluoro-1 H-indol-3-ylmethyl)-dimethylamine (II) (65 g, 0.338 mol), KCN (31 g, 0.476 mol), DMF (195 mE) and water (104 mE) were charged to the reactot The reaction mixture was heated to about 100-105 C. (strong reflux) for about 5-8 h. The reaction mixture was cooled to 20-25 C. Water (780 mE) and toluene (435 mE) were charged to the reactor and the mixture was stirred vigorously for >2 h. The organic and aqueous layers were separated. The organic layer waswashedwith5%NaHCO3 (6x260mL), aq. HC1 (260 mE, 2 M), 5% NaHCO3 (260 mE) and 5% NaC1 (260 mE), respectively. The organic layer was filtered and concentrated to dryness. MeOR (260 mE) was added and the solution was concentrated to dryness to yield Compound (III) as a brown oil (53.0 g, 90%) with 95% UV purity according to HPLC analysis.
Synthesis of the Compound of Formula IIDetailed syntheses of the compound of Formula II from commercially available 6-fluoroindole are provided below. Scheme II uses diethoxymethane and dimethylamine to generate the ?iminium ion species?. An alternative procedure using formaldehyde in place of diethoxymethane is also provided below. Synthetic Procedure:Preparation of formaldehyde was carried out in reactor A. The synthesis of the compound of Formula II was carried out in reactor B. Precipitation of the final product was carried out in reactor C.Procedure:To reactor A were charged diethoxymethane (65 ml/54 g), water (50 ml) and formic acid (39 ml/47 g). The mixture was heated to about 80 C./reflux for about 2 hours and then cooled to about 20 C. To reactor B were charged 6-fluoroindole (50 g) and 80% acetic acid (66 ml/70 g, 2.5 eq. to 6-fluoroindole). The suspension was cooled to 2-5 C. 40% Dimethylamine (aq) (103 ml/92 g, 2.2 eq. to 6-fluoroindole) was added drop-wise to reactor B keeping the temperature below about 15 C. The reaction mixture was stirred for about 20 minutes and at the same time the temperature was adjusted to 2-4 C.The mixture from reactor A (DEM, water, formic acid, formaldehyde and ethanol at about 20 C.) was added drop-wise to reactor B while keeping the temperature at 2-8 C. The reaction mixture was stirred for additional 10 minutes at 2-8 C. The reaction mixture was slowly warmed to about 40 C. over a 1 hour period. The reaction mixture was stirred at about 40 C. for an additional 1 hour. The reaction mixture was cooled to about 20 C.To reactor C was charged 3M NaOH (800 ml, 1.24 eq. to the acetic acid+the formic acid) and the solution was cooled to about 10 C. The reaction mixture from reactor B was added drop-wise to the NaOH solution in reactor C while keeping the temperature at 10-15 C. (pH>14). The suspension was stirred for 40 minutes at 5-20 C. (pH>14). The product was collected by filtration and the filter-cake was washed twice with water (2×250 ml). The product was dried at about 60 C. under vacuum for 16 hours. Yield: 95%. Purity by HPLC (280 nm): 98 area %.
95%
To reactor A were charged diethoxymethane (DEM)(65 mE, 0.52 mol), water (50 mE) and formic acid (39 mE, 1.02 mol)). The mixture was heated at approx. 80 C. (reflux) for approx. 2 h and then cooled to approx. 20 C. To reactor B were charged 6-fluoroindole (50 g, 0.37 mol) and 80% acetic acid (66 mE, 1.17 mol). The suspension was cooled to 2-5 C. 40% Aq. dimethylamine (103 mE, 2.04 mol) was added drop- wise to reactor B keeping the temperature below approx. 15 C. The reaction mixture was stirred for approx. 20 mm and at the same time the temperature was adjusted to 2-4 C. The mixture from reactor A (DEM, water, formic acid, formaldehyde and ethanol at about 20 C.) was added drop-wise to reactor B while keeping the temperature at 2-8 C. The reaction mixture was stirred for additional 10 mm at 2-8 C. The reaction mixture was slowly warmed to approx.40 C. over a 1 h period. The reaction mixture was stirred at approx. 40C. for an additional 1 h. The reaction mixture was cooled to about 20 C. To reactor C was charged aq. NaOH (800 mE, 2.40 mol, 3 M) and the solution was cooled to about 10 C. The reaction mixture from reactor B was added dropwise to the NaOH solution in reactor C while keeping the temperature at 10-15C. (pH>14). The suspension was stirred for 40 mm at 5-20C. (pH>1 4). The product was collected by filtration and the filter-cake was washed twice with water (2x250 mE). The product was dried at approx. 60 C. under vacuum for 16 h to yield Compound (II) (67.6 g, 95%) with 98% UV purity in HPLC analysis.
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