Structure of 14927-64-1
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| CAS No. : | 14927-64-1 |
| Formula : | C12H12O |
| M.W : | 172.22 |
| SMILES Code : | O=C1CCC2=C1C=C3CCCC3=C2 |
| English Name : | 2,3,6,7-Tetrahydro-s-indacen-1(5H)-one |
| MDL No. : | MFCD09866841 |
| InChI Key : | LXDKNEXOGZDIAC-UHFFFAOYSA-N |
| Pubchem ID : | 10931891 |
* 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 |
|---|---|---|
| 96% | With hydrogen In isopropyl alcohol for 18h; | |
| 85% | With methanesulfonic acid; Pd(OH)2/C; hydrogen In methanol at 25℃; for 12h; | C Step C: 1,2,3,5,6,7-Hexahydro-s-indacene To a solution of 2,3,6,7-tetrahydro-s-indacen-1(5H)-one (15 g, 87.10 mmol, 1 eq) in MeOH (200 mL) was added with MeSO3H (16.94 g, 176.22 mmol, 2.02 eq) and Pd(OH)2/C (3.2 g, 20 wt % loading on activated carbon). The reaction mixture was degassed and purged with H2 three times. The resulting mixture was stirred at 25 °C for 12 hours under H2 (15 psi). The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, only eluting with petroleum ether) to give the title compound (12 g, 85 %) as a white solid. 1H NMR (400 MHz, CDCl3) d 7.14 (s, 2 H), 3.00-2.85 (m, 8 H) and 2.16-2.09 (m, 4 H). |
| 84.65% | With methanesulfonic acid; Pd(OH)2/C; hydrogen In methanol at 25℃; for 12h; | C Step C: 1,2,3,5,6,7-hexahydro-s-indacene To a solution of 2,3,6,7-tetrahydro-s-indacen-1(5H)-one (15 g, 87.10 mmol, 1 eq) in MeOH (200 mL) was added with CH3SO3H (16.94 g, 176.22 mmol, 2.02 eq) and Pd(OH)2/C (3.2 g, 20 wt.% loading on activated carbon). The reaction mixture was degassed and purged with H2three times. The resulting mixture was stirred at 25 °C for 12 hours under H2(15 psi). The reaction mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO2, only eluting with petroleum ether) to give the title compound (12 g, 84.65% yield) as a white solid.1H NMR (400 MHz, CDCl3): d 7.14 (s, 2 H), 3.00-2.85 (m, 8 H) and 2.16-2.09 (m, 4 H). |
| 79% | With methanesulfonic acid; Pd(OH)2/C; hydrogen In methanol at 20℃; for 16h; | 3 Step 3: 1,2,3,5,6,7-Hexahydros-indacene Into a 1000-mL round-bottom flask, was placed a solution of 1,2,3,5,6,7-hexahydros-indacen-1- one (37.2 g, 216.00 mmol), MeOH (300 mL), and CH3SO3H (42 g). Then Pd(OH)2/C (20% wt, 8 g) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 16 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:150 to 1:100). This resulted in 27.1 g (79%) of the title compound as a white solid. |
| 79% | With methanesulfonic acid; Pd(OH)2/C; hydrogen In methanol at 20℃; for 16h; | 1 Step 1: 1,2,3,5,6,7-Hexahydro-s-indacene Into a 1-L round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-l-one (37.2 g, 216 mmol) and MSA (42 g, 437.5 mmol) in MeOH (300 mL). Then Pd(OH)2/C (20% wt, 8 g) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred for 16 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1 : 150 to 1 : 100). This resulted in 27.1 g (79%) of the title compound as a white solid. |
| 79% | With methanesulfonic acid; Pd(OH)2/C; hydrogen In methanol at 20℃; for 16h; | 3 Step 3: 1,2,3,5,6,7-Hexahydro-s-indacene Into a 1000-mL round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydros-indacen-1-one (37.2 g, 216 mmol), MeOH (300 mL), and CH3SO3H (42 g, 437.5 mmol). Then Pd(OH)2/C(20% wt., 8 g) was added. The flask was evacuated and flushed three times with hydrogen. Theresulting solution was stirred for 16 h at RT under an atmosphere of hydrogen. The solids werefiltered out. The resulting mixture was concentrated under vacuum. The residue was applied ontoa silica gel column and eluted with ethyl acetate/petroleum ether (1:150 to 1:100). This resulted in27.1 g (79%) of the title compound as a white solid. |
| 79% | With methanesulfonic acid; Pd(OH)2/C; hydrogen In methanol at 20℃; for 16h; | 3 Step 3: l,2,3,5,6,7-Hexahydros-indacene Into a lOOO-mL round-bottom flask, was placed a solution of 1,2, 3,5,6, 7-hexahydros-indacen-l- one (37.2 g, 216.00 mmol), MeOH (300 mL), CH3SO3H (42 g). Then Pd(OH)2/C (20% wt, 8 g) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 16 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1 : 150 to 1 : 100). This resulted in 27.1 g (79%) of the title compound as a white solid. |
| 73% | With methanesulfonic acid; Pd(OH)2/C; hydrogen In methanol; water at 25℃; for 48h; | 2 Step 2. 1,2,3,5,6,7-Hexahydro-s-indacene. To a solution of 3,5,6,7-tetrahydro-2H-s-indacen-1- one (27 g, 156.77 mmol) in MeOH (400 ml) was added MsOH (22.32 ml, 314 mmol) and 10 % Pd(OH)2 /C (50 % in water, 12 g). The RM was stirred at 25° C for 48 h under H2 (50 psi). The suspension was filtered through a pad of siliceous earth and the filtrate concentrated in vacuo. FCC (SiO2, 0- 100 % EtOAc in Pet. ether) gave 1,2,3,5,6,7-hexahydro-s-indacene. Y = 73 % yield) as a white solid. NMR (400 MHz, MeOD) d 7.00 (s, 2H), 2.83 - 2.79 (m, 8H), 2.05 - 2.02 (m, 4H). |
| 44% | With hydrogenchloride; zinc amalgam | |
| With potassium hydroxide; hydrazine hydrate | ||
| With methanesulfonic acid; hydrogen; palladium(II) hydroxide In methanol at 20℃; for 16h; | ||
| 27.1 g | With methanesulfonic acid; Pd(OH)2/C; hydrogen In methanol at 20℃; for 16h; | 3 Step 3: 1,2,3,5,6,7-Hexahydro-s-indacene Into a 1000 mL round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydros-indacen-1-one (37.20 g, 216.0 mmol, 1.0 equiv.) and CH3SO3H (42.00 g, 437.5 mmol, 2.0 equiv.) in MeOH (300 mL). Then Pd(OH)2/C (20% wt., 8 g) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 16 h at ambient temperature under an atmosphere of hydrogen. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel column, eluting with ethyl acetate/petroleum ether (1:150 to 1:100) to give 27.1 g of 1,2,3,5,6,7-Hexahydro-s-indacene as a white solid. |
| 61 g | With hydrogenchloride; 10% Pd/C In ethanol at 20℃; | RR 1,2,3,5,6,7-Hexahydro-s-indacene 1,2,3,5,6,7-Hexahydro-s-indacene A mixture of 3,5,6,7-tetrahydro-2H-s-indacen-1-one (90 grams), ethanol (1L), 10% palladium on carbon (1-2 grams) and concentrated hydrochloric acid (50 mL) was hydrogenated on a Parr shaker at room temperature until hydrogen uptake ceased. The mixture was filtered through a Celite pad. The pad was washed with 1L diethyl ether. The filtrate was diluted with water and the organic phase was separated. The aqueous phase was extracted with 1L of ether, and the combined ether extracts were washed with water, saturated sodium bicarbonate solution and brine. The ether extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting pale yellow solid was recrystallized from methanol to afford 61 grams of the title compound as colorless crystals, m.p. 56.6-58.5°C. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 94% | With sodium tetrahydroborate In methanol for 4h; Ambient temperature; | |
| With lithium aluminium tetrahydride In diethyl ether; benzene Heating; | ||
| 53.48 g | With methanol; sodium tetrahydroborate In methanol at 40 - 60℃; for 3h; | 4 3,5,6,7-tetrahydro-2H-s-indacen-1-one was synthesized according to the literature (Synth. Commun. 2003, 33, 2029-2043).52.56 g (305 mmol) of 3,5,6,7-tetrahydro-2H-s-indacen-1-one was charged into a 1 L three-necked flask and 450 mL of dried methanol was added. To this mixture was added 11.5 g (305 mmol) of sodium borohydride at 40 ° C. over 1 hour, then warmed to 60 ° C. and stirred for 2 hours. The mixture was then cooled, quenched with 750 mL of 5% dilute hydrochloric acid, and extracted with 750 mL of diethyl ether. The organic layer was separated, washed three times with 500 mL of water,After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure,53.48 g (307 mmol) of 1,2,3,5,6,7-hexahydro-s-indacen-1-ol was obtained as a white solid. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | With sulfuric acid at 55℃; for 16h; | 2 Step 2: 1,2,3,5,6,7-Hexahydro-s-indacen-1-one Into a 1,000 mL round-bottom flask was placed a solution of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (53.50 g, 253.0 mmol, 1.0 equiv.) in conc. H2SO4 (300 mL). The resulting solution was stirred for 16 h at 55 °C and then was quenched by adding the reaction mixture carefully to 1,500 mL of water/ice. The solids were collected by filtration and then dried under an infrared lamp for 24 h. This resulted in 37.4 g (85%) of 1,2,3,5,6,7-Hexahydro-s-indacen-1-one as a yellow solid. |
| 82% | With sulfuric acid at 55℃; for 24h; | 1 Step 1. 1,2,3,5,6,7-Hexahydro-s-indacen-1-one. A solution of 3-chloro-1-indan-5-yl-propan-1- one (40 g, 191.68 mmol) in c. H2SO4 (260 ml) was stirred at 55° C for 24 h. The RM was added dropwise to ice - water (2 l) and the resulting mixture was extracted (EtOAc, 500 ml x 3). The organic phase was washed (brine, 200 ml x 3), dried (Na2SO4) and concentrated in vacuo to give 3,5,6,7-tetrahydro-2H-s-indacen-1-one as a white solid. Y = 82 %.1H NMR (400 MHz, MeOD) d 7.50 (s, 1H), 7.36 (s, 1H), 3.11 - 3.09 (m, 2H), 2.99 - 2.93 (m, 4H), 2.69 - 2.66 (m, 2H), 2.16 - 2.11 (m, 2H). |
| 69.17% | With sulfuric acid In water at 70℃; for 12h; | B Step B: 2,3,6,7-tetrahydro-s-indacen-1(5H)-one To concentrated H2SO4 (1.84 kg, 18.39 mol, 98 wt.% in aqueous solution, 37.25 eq) was added 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (103 g, 493.57 mmol, 1 eq). Then the reaction mixture was stirred at 70 °C for 12 hours. The reaction mixture was poured into ice-water (4.5 L) and the resulting suspension was filtered. The filter cake was dissolved in EtOAc (500 mL) and washed with saturated aqueous Na2CO3 solution (500 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic layers were concentrated in vacuum to give the title compound (60 g, 69.17% yield, 98% purity on LCMS) as a yellow solid.1H NMR (400 MHz, CDCl3): d 7.58 (s, 1 H), 7.30 (s, 1 H), 3.08-2.96 (m, 2 H), 2.95-2.91 (m, 4 H), 2.70 (t, 2 H) and 2.15-2.05 (m, 2 H).LCMS: m/z 173.2 (M+H)+(ES+). |
| 69% | With sulfuric acid In water at 70℃; for 12h; | B Step B: 2,3,6,7-Tetrahydro-s-indacen-1(5H)-one To a concentrated H2SO4 solution (1.84 kg, 18.39 mol, 98 wt % in aqueous solution, 37.25 eq) was added to 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (103 g, 493.57 mmol, 1 eq). The reaction mixture was stirred at 70 °C for 12 hours, poured into ice-water (4.5 L) and filtered. The filter cake was dissolved in EtOAc (500 mL) and saturated aqueous Na2CO3 solution (500 mL) was added. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic layers were concentrated in vacuo to give the title compound (60 g, 69 % yield, 98 % purity on LCMS) as a yellow solid. 1H NMR (400 MHz, CDCl3) d 7.58 (s, 1 H), 7.30 (s, 1 H), 3.08-2.96 (m, 2 H), 2.95-2.91 (m, 4 H), 2.70 (t, 2 H) and 2.15-2.05 (m, 2 H). LCMS: m/z 173.2 (M+H)+ (ES+). |
| 69.17% | With sulfuric acid In water at 70℃; for 12h; | Step B: 2,3,6,7-tetrahydro-s-indacen-1(5H)-one To conc. H2SO4 (1.84 kg, 18.39 mol, 98 wt.% in aq solution, 37.25 eq) was added 3- chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (103 g, 493.57 mmol, 1 eq). Then the reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was poured into ice-water (4.5 L) and the resulting suspension was filtered. The filter cake was dissolved in EtOAc (500 mL) and washed with sat aq Na2CO3 solution (500 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic layers were concentrated in vacuum to give the title compound (60 g, 69.17% yield, 98% purity on LCMS) as a yellow solid. LCMS: m/z 173.2 (M+H)+ (ES+). 1H NMR (CDd3): d 7.58 (s, 1H), 7.30 (s, 1H), 3.08-2.96 (m, 2H), 2.95-2.91 (m, 4H), 2.70 (t, 2H), 2.15-2.05 (m, 2H). |
| 62% | With sulfuric acid at 55℃; for 40h; | 61.2; 62.2 A mixture of 3-chloro-l-(2,3-dihydro-l//-inden-5-yl)propan-l-one (35.0 g, 167.72 mmol) in concentrated H2SO4 (210 mL) was stirred at 55°C for 40 h. After cooling to room temperature, the mixture was quenched with ice water (300 ml,) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were dried over anhydrous NazSCL, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (10% EtOAc in petroleum ether) to give the title compound (18 g, 62% yield) as a yellow solid. NMR (400 MHz, CDCI3) d = 7.57 (s, 1H), 7.30 (s, 1H), 3.08 (t, ./= 6.0 Hz, 2H), 2.98 - 2.91 (m, 4H), 2.69 (t J= 5.6 Hz, 2H), 2.17 - 2.10 (m, 2EI). MS: m/z 172.8 (M H ). |
| 43% | With sulfuric acid | |
| With sulfuric acid | ||
| With sulfuric acid at 90℃; for 4h; | ||
| 37.4 g | With sulfuric acid at 55℃; for 16h; | 2 Step 2: 1,2,3,5,6,7-Hexahydros-indacen-1-one Into a 1000-mL round-bottom flask, was placed a solution of 3-chloro-1-(2,3-dihydro-1H-inden- 5-yl)propan-1-one (53.5 g, 253 mmol) in cc. H2SO4 (300 mL). The resulting solution was stirred for 16 h at 55oC and then was quenched by the addition of 1500 mL of water/ice. The solids were collected by filtration and then was dried over infrared lamp for 24 h. This resulted in 37.4 g (85%) of the title compound as a yellow solid |
| 37.4 g | With sulfuric acid at 55℃; for 16h; | 2 Step 2: 1,2,3,5,6,7-Hexahydro-s-indacen-1-one Into a 1000-mL round-bottom flask was placed a solution of 3-chloro-1-(2,3-dihydro-1H-inden-5- yl)propan-1-one (53.5 g, 253 mmol) in conc. H2S04 (300 mL). The resulting solution was stirred for 16 h at 55°C and was then quenched by adding the reaction mixture carefully to 1500 mL of water/ice. The solids were collected by filtration and then was dried over infrared lamp for 24 h.This resulted in 37.4 g (85%) of the title compound as a yellow solid. |
| With sulfuric acid at 60℃; for 24h; | ||
| 112.2 g | With sulfuric acid at 55℃; for 16h; | A.2 Into a 1000-mL round-bottom flask was placed a solution of 3-chloro-l-(2,3-dihydro-l i7- inden-5-yl)propan-l-one (160.5 g, 759.0 mmol) in cone. H2SO4 (900 mL). The resulting solution w'as stirred for 16 h at 55°C and was then quenched by adding the reaction mixture carefully to 4500 mL of water/ice. The solids were collected by filtration and dried over infrared lamp for 24 h. This resulted in 1 12 2 g (85%) of the title compound as a yellow solid. |
| 37.4 g | With sulfuric acid at 55℃; for 16h; | 2 Step 2: l,2,3,5,6,7-Hexahydros-indacen-l-one Into a lOOO-mL round-bottom flask, was placed a solution of 3-chloro-l-(2,3-dihydro-lH-inden- 5-yl)propan-l-one (53.5 g, 253 mmol) in cc. H2SO4 (300 mL). The resulting solution was stirred for 16 h at 55°C and then was quenched by the addition of 1500 mL of water/ice. The solids were collected by filtration and then was dried over infrared lamp for 24 h. This resulted in 37.4 g (85%) of the title compound as a yellow solid. |
| With sulfuric acid at 20 - 70℃; | ii; ii Reaction Scheme 2 - Steps ii and iii (Method B) 3-Chloro-i-(2,3-dihydro-ifT-inden-5-yl)propan-i-one (12) (350 g) and cone sulfuric acid (5 vol, 3185 g) were charged into a round bottom flask at 25 ± 5 °C. The reaction mixture was heated to 70 ± 2°C and stirred for 8-10 hours. The absence of 3-chloro-i- (2,3-dihydro-ifT-inden-5-yl)propan-i-one (12) was confirmed by HPLC (Limit: < 2.0 %)· The reaction mixture was cooled to 0-5 °C. A nitration mixture was prepared from cone sulfuric acid (0.33 vol, 210.2 g) and cone. HN03 (0.5 vol, 248.5 g) at 10-15 °C. The nitration mixture was added to the above reaction mixture at 0-5 °C over a period of 45-60 minutes. The reaction mixture was maintained at 0-5 °C for 2 hours. The absence of 1,2,3,5,6,7-hexahydro-s-indacen-i-one (13) was confirmed by HPLC (Limit: < 2.0 %). After completion of the reaction, the reaction mixture was added into ice cold water (25 vol, 8.75 L) and maintained at 15 ± 10 °C for 1 hour. The product was extracted into ethyl acetate (1 x 10 vol: 3.5 L, 2 x 5 vol: 1.75 L). The combined organic layers were washed with 10% NaHC03 solution (10 vol, 3.5 L) at 25 ± 5 °C and dried over Na2S04 (175 g). The solvent was distilled off (up to 1 vol, 350 mL) under vacuum at below 45 °C and then co-distilled with n-heptane (2 vol, 700 mL) completely. n-Heptane (2 vol, 700 mL) was added and the reaction mixture was stirred for 1 hour at 25 ± 5 °C. The solid product was filtered, washed with n-heptane (0.5 vol, 175 mL) and dried under vacuum for 2 hours at 45-50 °C. The crude product was dissolved in methanol (2.0 vol, 700 mL) at 55-60 °C. Charcoal 5% was added and the reaction mixture was refluxed for 1 hour and then cooled to 45 °C. The reaction mixture was filtered through a hyflow bed and washed twice with methanol (2x (0.5 vol, 175 mL)). The filtrate was cooled to 0-5 °C and maintained for 2-3 hours at 0-5 °C. The solid product was filtered, washed with cold methanol (0.25 vol, 87.5 mL) and dried under vacuum for 3 hours at 45-50 °C. Final Product: 8-nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (14) and 4- nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (15) Brown solid Weight ratio of 14:15 was 7:1. Combined Output (14+15): 217 g Combined Yield (14+15): 60 % lH NMR (DMSO-d6; 400 MHz): 7.66 (s, lH), 3.08 (t, 2H), 2.98 (t, 2H) 2.88 (t, 2H), 2.72 (t, 2H) and 2.12 (m, 2H). Moisture content (by Karl Fischer titration): 0.72 HPLC purity: 96.44 % | |
| With sulfuric acid at 65 - 70℃; Large scale; | 2.ii Reaction scheme 2 - step (ii) and step (iii) Sulfuric acid (300.0 L) was charged at 25 to 30 °C into a 2.0 KL clean and dry glass- lined reactor. 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (9) (60.0 Kg) was charged lot wise at 25 to 30 °C and the reaction mixture was maintained for 30 minutes at 25 to 30 °C. The reaction mixture was slowly heated to 65 to 70 °C and maintained at 65 to 70 °C for 24 hours. The absence of 3-chloro-1-(2,3-dihydro-1H-inden-5- yl)propan-1-one (9) was confirmed by HPLC (Limit: Then the reaction mixture was cooled to o to 5 °C. A nitration mixture*1 was added slowly at o to 5 °C and the reaction mixture was maintained at o to 5 °C for 1 hour. The absence of 1,2,3,5,6,7-hexahydro-s-indacen-1-one (10) was confirmed by HPLC (Limit: ≤ 1.0 %). | |
| With sulfuric acid at 25 - 70℃; Large scale; | 2.b Sulfuric acid (300.0 L) was charged at 25 to 30°C into a 2.0 KL clean and dry glass- lined reactor.3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (9) (60.0 Kg) was charged lot wise at 25 to 30°C and the reaction mixture was maintained for 30 minutes at 25 to 30°C. The reaction mixture was slowly heated to 65 to 70°C and maintained at 65 to 70°C for 24 hours. The absence of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan- 1-one (9) was confirmed by HPLC (Limit: ≤ 1.0 %). | |
| 65.4 % | With sulfuric acid In dichloromethane Reflux; | Synthesis of tert-butyl 3-methylpiperazine-1-carboxylate (9) H2SO4 was added to DCM (15 mL, 0.28 mmol). And PTC (330 mg, 0.97 mmol) was added to DCM. The mixture was stirred at 0 °C for 3 min. 8 (2.0 g, 9.58 mmol) was added portionwise at 0 °C. The mixture was stirred at reflux overnight. The mixture was added into ice then extracted with DCM, the DCM layer was dried over Na2SO4. Purified by flash column chromatography (Hexane: Ethyl acetate = 20:1) as a brown solid (9, 1.68 g, 65.4%). |
| 65.4 % | With sulfuric acid In dichloromethane Reflux; | Synthesis of tert-butyl 3-methylpiperazine-1-carboxylate (9) H2SO4 was added to DCM (15 mL, 0.28 mmol). And PTC (330 mg, 0.97 mmol) was added to DCM. The mixture was stirred at 0 °C for 3 min. 8 (2.0 g, 9.58 mmol) was added portionwise at 0 °C. The mixture was stirred at reflux overnight. The mixture was added into ice then extracted with DCM, the DCM layer was dried over Na2SO4. Purified by flash column chromatography (Hexane: Ethyl acetate = 20:1) as a brown solid (9, 1.68 g, 65.4%). |
| 49 % | With sulfuric acid at 60℃; | Preparation of 3,5,6,7-tetrahydro-s-indacen-1(2H)-one(M2) M1 (3.00 g, 14.4 mmol) was added in portions to concentrated sulfuric acid (30 mL) and stirred at 60 for 48 hours. Upon completion of the reaction, the mixture was slowly diluted with ice water at 0 . Subsequently, the pH was adjusted to 7 using a saturated NaOH aqueous solution. Following ethyl acetate (EA) extraction, the resulting product was further purified through column chromatography on silica gel, affording compound M2 (1.21 g, 49%). ESI-MS calculated for [M+H]+: 173.1, found: 173.1. |
| 49 % | With sulfuric acid at 60℃; | Preparation of 3,5,6,7-tetrahydro-s-indacen-1(2H)-one(M2) M1 (3.00 g, 14.4 mmol) was added in portions to concentrated sulfuric acid (30 mL) and stirred at 60 for 48 hours. Upon completion of the reaction, the mixture was slowly diluted with ice water at 0 . Subsequently, the pH was adjusted to 7 using a saturated NaOH aqueous solution. Following ethyl acetate (EA) extraction, the resulting product was further purified through column chromatography on silica gel, affording compound M2 (1.21 g, 49%). ESI-MS calculated for [M+H]+: 173.1, found: 173.1. |
| With sulfuric acid at 25 - 70℃; | Sulfuric acid (300.0 L) was charged at 25 to 30 °C into a 2.0 KL clean and dry glass- lined reactor. 3-chloro-i-(2,3-dihydro-iH-inden-5-yl)propan-i-one (9) (60.0 Kg) was charged lot wise at 25 to 30 °C and the reaction mixture was maintained for 30 minutes at 25 to 30 °C. The reaction mixture was slowly heated to 65 to 70 °C and maintained at 65 to 70 °C for 24 hours. The absence of 3-chloro-i-(2,3-dihydro-iW-inden-5-yl)- propan-i-one (9) was confirmed by HPLC (Limit: Then the reaction mixture was cooled to o to 5 °C. A nitration mixture*1was added slowly at o to 5 °C and the reaction mixture was maintained at o to 5 °C for 1 hour. The absence of 1,2,3,5,6,7-hexahydro-s-indacen-i-one (10) was confirmed by HPLC (Limit: Demineralised water (900.0 L) was charged at 25 to 30 °C into a 2.0 KL clean and dry glass-lined reactor. The water was cooled to o to 5 °C. The reaction mixture was added slowly added to the reactor at o to 5 °C. Toluene (480.0 L) was added and the temperature was raised to 30 to 35 °C. The reaction mixture was maintained at 30 to 35 °C for 30 minutes and allowed to settle at 30 to 35 °C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (6.0 Kg) and toluene (30.0 L)). The Celite bed was washed with toluene (60.0 L). The solid was filtered and sucked dry for 30 min. The reaction mixture was charged to a 2.0 KL clean and dry glass-lined reactor. The reaction mixture was allowed to settle at 30 to 35 °C for 30 minutes. The layers were separated (aqueous layer (AL-i) and organic layer (OL-i)) and OL-i was kept aside. Toluene (60.0 L) was charged to AL-i. The reaction mixture was stirred at 35 to 40 °C for 30 minutes and allowed to settle at 35 to 40 °C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and OL-2 was kept aside. OL-i and OL-2 were combined to form OL-3.A 5 % saturated sodium bicarbonate solution (prepared from demineralised water (300.0 L) and sodium bicarbonate (15.0 Kg)) was slowly charged to OL-3 at 30 to 35 °C. The reaction mixture was stirred at 35 to 40 °C for 30 minutes and allowed to settle at 35 to 40 °C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (6.0 Kg) and demineralised water (60.0 L)). The Celite bed was washed with toluene (60.0 L). The reaction mixture was charged to a 3.0 KL clean and dry glass-lined reactor. The reaction mixture was allowed to settle at 30 to 35 °C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-4)) and OL-4 was kept aside.Toluene (60.0 L) was charged to AL-3. The layers were separated (aqueous layer (AL-4) and organic layer (OL-5)) and OL-5 was kept aside. OL-4 and OL-5 were combined to form OL-6. Brine solution (prepared from demineralised water (300.0 L) and sodium chloride (12.0 Kg) at 25 to 30 °C. The reaction mixture was stirred at 30 to 35 °C for 30 minutes and allowed to settle at 30 to 35 °C for 30 minutes. The layers were separated (aqueous layer (AL-5) and organic layer (OL-7)) and OL-7 was kept aside. OL-7 was dried over anhydrous Na2SO4(9.0 Kg) and the anhydrous Na2SO4was washed with toluene (30.0 L) at 25 to 30 °C. The solvent was distilled under vacuum at below 40 to 45 °C until 5 % remained. Methanol (60.0 L) was charged to the reaction mixture at 40 to 45 °C and down to 60 L of reaction mass. Methanol (120.0 L) was charged to the reaction mixture at 40 to 45 °C and the reaction mixture was cooled to 5 to 10 °C and maintained at 5 to 10 °C for 30 minutes. The solid product was filtered, washed with cooled methanol (30.0 L), and dried in a hot air oven at 40 to 45 °C for 6 hours to afford 38.87 Kg of a mixture of 8-nitro-i,2,3,5,6,7- hexahydro-s-indacen-i-one (11a) and 4-nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (nb)Combined Yield (na+nb): 62.24 %Weight ratio (na:iib): 9:1HPLC purity: 95.9 %Moisture content: 0.19 % ‘H NMR: (500 MHz, CDC13): 8 7.44(8, 1H), 2.21(m, 2H), 2.78 (t, 2H), 3.02 (m, 4H), 3.13 Ct, 2H)*1: To prepare the nitration mixture, sulfuric acid (27.0 L) was charged at 25 to 30 °C into a 160 L clean and dry glass-lined reactor. The reaction mixture was cooled to o to 5 °C. Nitric acid (27.0 L) at o to 5 °C was added slowly and the reaction mixture was maintained for 30 minutes at o to 5 °C to afford the nitration mixture. | |
| 90 g | With sulfuric acid at 20 - 90℃; | QQ 3,5,6,7-Tetrahydro-2H-s-indacen-1-one 3,5,6,7-Tetrahydro-2H-s-indacen-1-one Concentrated sulfuric acid (550 mL) was added dropwise, with stirring over a time period of 2 hours to 137 grams of 3-chloro-1-indan-5-yl-propan-1-one. The resulting thick black solution was heated to 90°C until hydrogen chloride evolution ceased (usually 1-4 hours). The mixture was then cooled to room temperature and poured onto 5 kg of ice. The resulting slurry was stirred overnight and filtered. The solid was washed with water until the water ran clear through the filter. The tan solid was then dried in vacuo and recrystallized from hexane to afford 90 grams of the title compound, m.p. 72.4-74.8°C. |
| With sulfuric acid at 70℃; for 12h; | ||
| 1.21 g | With sulfuric acid In water at 60℃; for 48h; | 1.2 Step 2: Synthesis of 3,5,6,7-tetrahydro-2H-S-inda-1-one M1 (3.00g, 14.4mmol) was added to concentrated sulfuric acid (30mL) in batches and stirred at 60°C for 48h. After the end of the reaction, ice water was slowly added to dilute at 0°C, then pH=7 was adjusted with saturated NaOH aqueous solution, and the compound M2 (1.21g, 49%) was purified by silica gel column chromatography. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | With sodium hydroxide In ethanol at 0℃; for 4h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 70% | With phosphorus pentachloride In benzene for 4h; cooling; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sulfuric acid at 70℃; for 3.5h; Yield given. Yields of byproduct given; | ||
| With sulfuric acid at 55 - 60℃; for 48h; | ||
| With sulfuric acid at 80 - 90℃; for 1h; regioselective reaction; |
| With sulfuric acid at 55 - 60℃; for 48h; | ||
| 1: 112.2 g 2: 10 g | With sulfuric acid at 55℃; for 16h; | 2 Step 2: 1,2,3,5,6,7-Hexahydro-s-indacen-l-one Into a 1-L round-bottom flask was placed a solution of 3-chloro-l-(2,3-dihydro-lH-inden-5- yl)propan-l-one (160.5 g, 759 mmol) in cone. H2S04(900 mL). The resulting solution was stirred for 16 h at 55°C and then was quenched by adding the reaction mixture carefully to 4500 mL of water/ice. The solids were collected by filtration and dried over infrared lamp for 24 h. The crude mixture was purified by chromatography and eluted with ethyl acetate/petroleum ether (1 : 100). This resulted in 10 g (7.6%) of l,6,7,8-tetrahydro-as-indacen-3(2H)-one (compound 113"a) and 112.2 g (85%) of the title compound (compound 113") as a yellow solid. NMR (400 MHz, DMSO-i) δ 7.44 (s, 1H), 7.39 (s, 1H), 3.13 - 2.79 (m, 8H), 2.70 - 2.55 (m, 2H), 2.20 - 1.90 (m, 2H).1H MR (400 MHz, DMSO-d) δ 7.49 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 3.19 - 2.98 (m, 4H), 2.93 - 2.80 (m, 3H), 2.68 - 2.54 (m, 2H), 2.15 - 1.95 (m, 2H). |
| 1: 112.2 g 2: 10 g | With sulfuric acid at 55℃; for 16h; | 2 Step 2: 3,5,6,7-tetrahydro-s-indacen-1(2H)-one and 1,6,7,8-tetrahydro-as-indacen-3(2H)-one Into a 1,000 mL round-bottom flask was placed a solution of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (160.50 g, 759.0 mmol, 1.0 equiv.) in conc. H2SO4 (900 mL). The resulting solution was stirred for 16 h at 55 °C and then was quenched by adding the reaction mixture carefully to 4,500 mL of water/ice. The solids were collected by filtration and dried under an infrared lamp for 24 h. The solids were purified by flash column chromatography, eluting with ethyl acetate/petroleum ether (1:100) to give 112.2 g of 3,5,6,7-tetrahydro-s-indacen-1(2H)-one and 10 g of 1,6,7,8-tetrahydro-as-indacen-3(2H)-one as a yellow solid.Major: 1H NMR (400 MHz, DMSO-d6) d 7.44 (s, 1H), 7.39 (s, 1H), 3.13-2.79 (m, 6H), 2.70-2.55 (m, 2H), 2.20-1.90 (m, 2H).Minor: 1H NMR (400 MHz, DMSO-d6) d 7.49 (d, 1H), 7.31 (d, 1H), 3.19-2.98 (m, 4H), 2.93-2.80 (m, 2H), 2.68-2.54 (m, 2H), 2.15-1.95 (m, 2H). |
| 1: 112.2 g 2: 10 g | With sulfuric acid at 55℃; for 16h; | 2 Step 2: 1,2,3,5,6,7-Hexahydro-s-indacen-1-one The solution of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (160.5 g, 759 mmol) in conc. H2SO4 (900 mL) in a 1000-mL round-bottom flask was stirred for 16 h at 55 °C. The reaction was quenched by adding the reaction mixture carefully to 4500 mL of water/ice. The solids were collected by filtration and dried over infrared lamp for 24 h. The crude mixture was purified by chromatography and eluted with EtOAc/ PE (1:100). This resulted in 10 g (7.6%) of 1,6,7,8- tetrahydro-as-indacen-3(2H)-one (Cpd 46A) and 112.2 g (85%) of the title compound as a yellow solid. Compound 46:1H NMR (400 MHz, DMSO-d6) d 7.44 (s, 1H), 7.39 (s, 1H), 3.20-2.75 (m, 6H), 2.70-2.60 (m, 2H), 2.20-1.90 (m, 2H). Compound 46A:1H NMR (400 MHz, DMSO-d6) d 7.49 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 3.20-2.90 (m, 4H), 2.90-2.75 (m, 2H), 2.70-2.60 (m, 2H), 2.20-1.90 (m, 2H) |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With sodium hydride In benzene for 15h; Heating; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95% | With sodium hydroxide In ethanol for 3h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With sodium hydride In benzene for 15h; Heating; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium <i>tert</i>-butylate In benzene |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium <i>tert</i>-butylate In diethyl ether; dichloromethane at 20℃; for 1h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 79% | Stage #1: 3,5,6,7-tetrahydro-2H-s-indacen-1-one With sulfuric acid; nitric acid at 0℃; for 2h; Stage #2: With methanesulfonic acid; Pd(OH)2/C; hydrogen In methanol at 25℃; for 16h; | A.3; A.4 Synthesis of l,2,3,5,6,7-hexahydros-indacen-4-amine Into a 1000-mL round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s- indacen-l -one (80.0 g, 464.5 mmol ) in H2SO4 (500 mL). Then HNO3 (58.5 g, 929.0 mmol) was added dropwise over 1 h at 0°C. The resulting solution was stirred for 1 h at 0°C. The reaction mixture was slowly added to a mixture of v ater/ice (1000 mL) and DCM (500 mL) with ice bath cooling. The organic layer was collected, dried over Na?.S04 and concentrated under (2403) vacuum. This resulted in 90 0 g (90%) of the mixture of 4-nitro-l,2,3,5,6,7-hexahydro-s-indacen- 1-one and 8-nitro-2,3,6,7-tetrahydros-indacen-l(5H)-one as a yellow solid. Into a lOOO-mL round-bottom flask was placed a solution of the mixture of 4-nitro- 1 ,2,3,5,6,7-hexahydro-s-indacen-l -one and 8-nitro-2,3,6,7-tetrahydros-indacen-l(5H)-one (21.7 g, 100.0 mmol) in MeOH (300 mL). To the solution was added MSA (11.5 g, 120.0 mmol). Then Pd(OH)2/C (20% wt., 5.5 g) w'as added. The flask was evacuated and filled three times with hydrogen. The resulting mixture was stirred for 16 h at 25°C under hydrogen (50 psi). The solids were filtered out and washed with methanol. The methanol filtrate and w'ash was diluted with water (500 mL) and the pH was adjusted to 10.6 with 2N NaOH. The resulting slurry was filtered and the crude solids were recrystallized from methanol/water (9: 1) with heating. This resulted in 13.7 g (79%) of the title compound as an off-white solid. MS-ESI: 174 (M+l). |
| 79% | Stage #1: 3,5,6,7-tetrahydro-2H-s-indacen-1-one With sulfuric acid; nitric acid at 0 - 20℃; for 2h; Stage #2: With methanesulfonic acid; Pd(OH)2/C; hydrogen In methanol at 20℃; for 16h; | 4 Step 4: 1,2,3,5,6,7-hexahydros-indacen-4-amine To a stirred solution of the mixture of 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one and 8-nitro- 2,3,6,7-tetrahydro-s-indacen-1(5H)-one (21.7 g, 100 mmol) in MeOH (300 mL) was added MSA (11.5 g, 120 mmol) at RT. Then Pd(OH)2/C (20% wt, 5.5 g) was added under nitrogen. The flask was evacuated and refilled three times with hydrogen. The resulting mixture was stirred for 16 h at RT under hydrogen with a ballon. The solids were filtered out and washed with MeOH (3x50 mL). The MeOH filtrate and wash was diluted with water (500 mL) and the pH was adjusted to 11 with 2N NaOH. The resulting slurry was filtered and the crude solids were recrystallized from MeOH/water (9:1) with heating. This resulted in 13.7 g (79%) of the title compound as an off- white solid. MS-ESI: 174 (M+1). |
| 8.8 kg | Stage #1: 3,5,6,7-tetrahydro-2H-s-indacen-1-one With sulfuric acid; nitric acid at 0 - 5℃; for 2h; Stage #2: With methanesulfonic acid; hydrogen In methanol; water for 9h; |
| 13.7 g | Stage #1: 3,5,6,7-tetrahydro-2H-s-indacen-1-one With sulfuric acid; nitric acid at 0℃; for 2h; Stage #2: With methanesulfonic acid; Pd(OH)2/C; hydrogen In methanol at 20℃; for 16h; | 3; 4 Step 3: 4-nitro-2,3,6,7-tetrahydro-s-indacen-l(5H)-one (114) (Major) and 8-nitro-2,3,6,7- tetrahydro-s-indacen-l(5H)-one (115) (Minor) Into a 1-L round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-l-one (80 g, 464.5 mmol) in H2S04(500 mL). Then HNO3 (58.5 g, 929 mmol) was added dropwise over lh at 0°C. The resulting solution was stirred for 1 hr at 0°C. The reaction mixture was slowly added to a mixture of water/ice (1000 mL) and DCM (500 mL) with ice bath cooling. The organic layer was collected, dried over Na2S04and concentrated under vacuum. This resulted in 90 g (90%) of the mixture of 4-nitro-2,3,6,7-hexahydro-s-indacen-l-one and 8-nitro-2,3,6,7-tetrahydro-5- indacen-l(5H)-one as a yellow solid. Step 4: l,2,3,5,6,7-hexahydro-s-indacen-4-amine Into a 1-L round-bottom flask was placed a solution of the mixture of 4-nitro-l,2,3,5,6,7- hexahydro-s-indacen-l-one and 8-nitro-2,3,6,7-tetrahydro-s-indacen-l(5H)-one (21.7 g, 100 mmol) in MeOH (300 mL). To the solution was added MSA (11.5 g, 120 mmol). Then Pd(OH)2/C (20%) wt, 5.5 g) was added. The flask was evacuated and filled three times with hydrogen. The resulting mixture was stirred for 16 h at RT under hydrogen (50 psi). The solids were filtered out and washed with methanol. The methanol filtrate and wash was diluted with water (500 mL) and the pH was adjusted to 10.6 with 2N NaOH. The resulting slurry was filtered and the crude solids were recrystallized from methanol/water (9: 1) with heating. This resulted in 13.7 g (79%>) of the title compound as an off-white solid. |
| 41.85 % | Stage #1: 3,5,6,7-tetrahydro-2H-s-indacen-1-one With sulfuric acid; nitric acid In methanol at 0 - 5℃; Large scale; Stage #2: With methanesulfonic acid; hydrogen; palladium(II) hydroxide In methanol at 20℃; Large scale; | 2.iv Reaction scheme 2 - step (iv) A mixture of 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11a) and 4-nitro- 1,2,3,5,6,7-hexahydro-s-indacen-1-one (11b) (9:1 ratio; 27.0 Kg) at 25 to 30 °C was charged into a 600 L clean and dry pressure reactor. Methanol (270 L) was charged at 25 to 30 °C. Methane sulfonic acid (14.3 Kg) was slowly charged at 25 to 30 °C and the reaction mixture was maintained for 30 minutes. 15 % Pd(OH)2 slurry (60 % wet)*2 was added. The reaction mixture was degassed under vacuum and filled with an argon atmosphere (0.5 Kg) three times. The reaction mixture was degassed under vacuum and filled with a hydrogen atmosphere (0.5 Kg) three times. Then the reaction mixture was stirred under hydrogen pressure (too Psi) at room temperature for 32 hours. The temperature was gradually raised up to 55 °C. The absence of 8-nitro-1,2,3,5,6,7- hexahydro-s-indacen-1-one (11a) and 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11b) was confirmed by HPLC (Limit: After completion of the reaction, the reaction mixture was cooled to 25 to 30 °C. The reaction mixture was degassed under vacuum and filled with nitrogen atmosphere (0.5 Kg) three times. The reaction mixture was filtered through a candy filter to remove Pd(OH)2, followed by a micro filter and the bed was washed with methanol (54 L). 95 % of the solvent was distilled off under vacuum at below 45 to 50 °C. Demineralised water (135 L) was charged into the reaction mixture at 25 to 30 °C and maintained for 30 minutes. The reaction mixture was cooled to 5-10 °C. The pH was adjusted to about 9-10 with 2 N aqueous NaOH solution (prepared from NaOH (6.48 Kg) and demineralised water (81 L)) and the reaction mixture was stirred for 30 minutes. Then toluene (135 L) was charged to the reaction mixture and the reaction mixture was stirred for 30 minutes. The reaction mixture was stirred for a further 30 minutes, whilst bringing the temperature up to 25 to 30 °C. The reaction mixture was allowed to settle for 30 minutes, whilst the temperature was maintained at 25 to 30 °C. The reaction mixture was filtered through a Celite bed (prepared with Celite (5.4 Kg) and toluene (13.5 L). The Celite bed was washed with toluene (54 L). The layers were separated (aqueous layer (AL-1) and organic layer (OL-1)) and OL-1 was kept aside. Toluene (54 L) was added to AL-1 at 25 to 30 °C. The reaction mixture was stirred at 25 to 30 °C for 30 minutes and allowed to settle at 25 to 30 °C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and AL-2 was kept aside. Toluene (54 L) was added to AL-1 at 25 to 30 °C. A brine solution (prepared with demineralised water (135 L) and sodium chloride (54 Kg)) was charged to the combined organic layers (OL-1 and OL-2) at 25 to 30 °C. The reaction mixture was stirred at 25 to 30 °C for 30 minutes and allowed to settle at 25 to 30 °C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-3)) and AL-3 was kept aside. Charcoal (1.3 Kg) was added to OL-3 and the temperature was raised to 35-40 °C and maintained at 35 to 40 °C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (5.4 Kg) and toluene (54 L)) at 35 to 40 °C. The Celite bed was washed with toluene (54 L). The organic layer was dried over anhydrous Na2SO4 (13.5 Kg). The Na2SO4 was washed with toluene (27 L). The solvent was distilled under vacuum at below 35 to 40 °C until 5 % remained. Methanol (40.5 L) was charged to the reaction mixture at 35 to 40 °C and distilled until 5 % remained. Methanol (97.2 L) and water (10.8 L) were charged to the reaction mixture at 35 to 40 °C. The reaction mixture was heated to 50 to 55 °C, stirred for 1 hour at 50 to 55 °C, slowly cooled to o to 5 °C and maintained at o to 5 °C for 30 minutes. The solid product was filtered and washed with cold methanol (13.5 L), and dried in a hot air oven at 40 to 45 °C for 6 hours to afford the product. *2: To prepare the 15 % Pd(OH)2 slurry, 20 % Pd(OH)2 on carbon (60 % wet; 4.05 Kg) was added to methanol (27 L). Final product: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) Output: 11.3 Kg Yield: 41.85 % HPLC purity: 98.1 % Moisture content: 0.10 1H NMR: (400 MHz, DMSO-d6): d 6.38 (S, 1H), 4.45 (S, 2H), 2.75 (t, 4H), 2.58 (t, 4H), 1.98 (t, 4H). Purification (A) of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) 1,2,3,5,6,7-Hexahydro-s-indacen-4-amine (12) (54.5 Kg) was charged at 25 to 30 °C into a 250 L clean and dry reactor. Toluene (27.2 L) was charged at 25 to 30 °C and the reaction mixture was stirred at 25 to 30 °C for 30 minutes. Methanol (163 L) was charged to the reaction mixture at 25 to 30 °C. The reaction mixture was stirred at 25 to 30 °C for 30 minutes, cooled to -5 to o °C, and stirred at -5 to o °C for 30 minutes. The solid product was filtered, washed with cold methanol (54.5 L), and dried at 40 to 45 °C for 6 hours. Final Product: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) Output: 40.5 Kg Yield: 74.31 % HPLC purity: 99.5 % Moisture content: 0.3 % 1H NMR: (400 MHz, DMSO-d6): d 6.33 (s, 1H), 4-53 (s, 2H), 2.72 (t, 4H), 2.57 ft, 4H), 1.98 (t, 4H). Crop Purification (B) of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) The filtered mother liquors from five batches of reaction scheme 2, step (iv) were combined and concentrated to afford crude 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (25 Kg) and purified through a 100-200 mesh silica gel column. The column was eluted with 5 to 10 % ethyl acetate (42 L) in hexane (658 L). The pure fractions were concentrated under reduced pressure (600 mm of Hg) at 40 to 45 °C to afford crude 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (15 Kg). Toluene (7.5 L) was added at 25 to 30 °C and the reaction mixture was stirred for 30 minutes at 25 to 30 °C. Methanol (45 L) was added at 25 to 30 °C and the reaction mixture was stirred for 30 minutes at 25 to 30 °C. The reaction mixture was cooled to -5 to 10 °C and stirred for 30 minutes. Purity was checked using HPLC (Limit 98 %, Single max purity: NMT: 1%). The solid was filtered, washed with cold methanol (15 L) and dried at 40 to 45 °C in vacuum tray drier for 6 hours. Final Product: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) Output: 10.2 Kg Yield: 9.36% HPLC purity: 99.3% Moisture content: 0.12% 1H NMR: (400 MHz, DMSO-d6): d 6.33 (S, 1H), 4.51 (S, 2H), 2.72 (t, 4H), 2.59 (t, 4H),1.99 (t, 4H). Combined yield of five batches of reaction scheme 2, step iv including purification (A) and crop purification (B): 46.56 % |
| 41.85 % | Stage #1: 3,5,6,7-tetrahydro-2H-s-indacen-1-one With sulfuric acid; nitric acid at 0 - 5℃; Large scale; Stage #2: With methanesulfonic acid; hydrogen; palladium(II) hydroxide In methanol at 20℃; Large scale; | 2.d Reaction scheme 2 - step (d) A mixture of 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11a) and 4-nitro- 1,2,3,5,6,7-hexahydro-s-indacen-1-one (11b) (9:1 ratio; 27.0 Kg) at 25 to 30°C was charged into a 600 L clean and dry pressure reactor. Methanol (270 L) was charged at 25 to 30°C. Methane sulfonic acid (14.3 Kg) was slowly charged at 25 to 30°C and the reaction mixture was maintained for 30 minutes. 15 % Pd(OH)2 slurry (60 % wet)*2 was added. The reaction mixture was degassed under vacuum and filled with an argon atmosphere (0.5 Kg) three times. The reaction mixture was degassed under vacuum and filled with a hydrogen atmosphere (0.5 Kg) three times. Then the reaction mixture was stirred under hydrogen pressure (100 Psi) at room temperature for 32 hours. After completion of the reaction, the reaction mixture was cooled to 25 to 30°C. The reaction mixture was degassed under vacuum and filled with nitrogen atmosphere (0.5 Kg) three times. The reaction mixture was filtered through a candy filter to remove Pd(OH)2, followed by a micro filter and the bed was washed with methanol (54 L).95 % of the solvent was distilled off under vacuum at below 45 to 50°C. Demineralised water (135 L) was charged into the reaction mixture at 25 to 30°C and maintained for 30 minutes. The reaction mixture was cooled to 5-10°C. The pH was adjusted to about 9-10 with 2 N aqueous NaOH solution (prepared from NaOH (6.48 Kg) and demineralised water (81 L)) and the reaction mixture was stirred for 30 minutes. Then toluene (135 L) was charged to the reaction mixture and the reaction mixture was stirred for 30 minutes. The reaction mixture was stirred for a further 30 minutes, whilst bringing the temperature up to 25 to 30°C. The reaction mixture was allowed to settle for 30 minutes, whilst the temperature was maintained at 25 to 30°C. The reaction mixture was filtered through a Celite bed (prepared with Celite (5.4 Kg) and toluene (13.5 L). The Celite bed was washed with toluene (54 L). The layers were separated (aqueous layer (AL-1) and organic layer (OL-1)) and OL-1 was kept aside. Toluene (54 L) was added to AL-1 at 25 to 30°C. The reaction mixture was stirred at 25 to 30°C for 30 minutes and allowed to settle at 25 to 30°C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and AL-2 was kept aside. Toluene (54 L) was added to AL-1 at 25 to 30°C. A brine solution (prepared with demineralised water (135 L) and sodium chloride (54 Kg)) was charged to the combined organic layers (OL-1 and OL-2) at 25 to 30°C. The reaction mixture was stirred at 25 to 30°C for 30 minutes and allowed to settle at 25 to 30°C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-3)) and AL-3 was kept aside. Charcoal (1.3 Kg) was added to OL-3 and the temperature was raised to 35-40°C and maintained at 35 to 40°C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (5.4 Kg) and toluene (54 L)) at 35 to 40°C. The Celite bed was washed with toluene (54 L). The organic layer was dried over anhydrous Na2SO4 (13.5 Kg). The Na2SO4 was washed with toluene (27 L). The solvent was distilled under vacuum at below 35 to 40°C until 5 % remained. Methanol (40.5 L) was charged to the reaction mixture at 35 to 40°C and distilled until 5 % remained. Methanol (97.2 L) and water (10.8 L) were charged to the reaction mixture at 35 to 40°C. The reaction mixture was heated to 50 to 55°C, stirred for 1 hour at 50 to 55°C, slowly cooled to 0 to 5°C and maintained at 0 to 5°C for 30 minutes. The solid product was filtered and washed with cold methanol (13.5 L), and dried in a hot air oven at 40 to 45°C for 6 hours to afford the product. *2: To prepare the 15 % Pd(OH)2 slurry, 20 % Pd(OH)2 on carbon (60 % wet; 4.05 Kg) was added to methanol (27 L). Final product: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) Output: 11.3 Kg Yield: 41.85 % HPLC purity: 98.1 % Moisture content: 0.10 1H NMR: (400 MHz, DMSO-d6): δ 6.38 (S, 1H), 4.45 (S, 2H), 2.75 (t, 4H), 2.58 (t, 4H), 1.98 (t, 4H). Purification (A) of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) 1,2,3,5,6,7-Hexahydro-s-indacen-4-amine (12) (54.5 Kg) was charged at 25 to 30°C into a 250 L clean and dry reactor. Toluene (27.2 L) was charged at 25 to 30°C and the reaction mixture was stirred at 25 to 30°C for 30 minutes. Methanol (163 L) was charged to the reaction mixture at 25 to 30°C. The reaction mixture was stirred at 25 to 30°C for 30 minutes, cooled to -5 to 0°C, and stirred at -5 to 0°C for 30 minutes. The solid product was filtered, washed with cold methanol (54.5 L), and dried at 40 to 45°C for 6 hours. Final Product: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) Output: 40.5 Kg Yield: 74.31 % HPLC purity: 99.5 % Moisture content: 0.3 % 1H NMR: (400 MHz, DMSO-d6): δ 6.33 (s, 1H), 4.53 (s, 2H), 2.72 (t, 4H), 2.57 (t, 4H), 1.98 (t, 4H). |
| Multi-step reaction with 3 steps 1: sulfuric acid; nitric acid / dichloromethane / 3 h / 0 °C 2: trifluoroacetic acid / 20 °C / Inert atmosphere 3: 10% Pd/C; hydrogen / dichloromethane / 8 h / 0 - 20 °C | ||
| 45 % | Stage #1: 3,5,6,7-tetrahydro-2H-s-indacen-1-one With sulfuric acid; potassium nitrate at 0℃; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran at 66℃; Inert atmosphere; | Preparation of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine(M3) At 0 , compound M2 (1.00 g, 5.81 mmol) was dissolved in concentrated sulfuric acid, followed by the gradual addition, in portions, of solid KNO3 powder (882 mg, 8.72 mmol). The reaction proceeded at 0 for an additional 2 hours. Upon completion, the reaction mixture was slowly quenched with a 15% NaOH solution under ice-bath conditions. Ethyl acetate (EA) extraction followed, and the resulting black oily substance was rotary evaporated. The oily material was dissolved in anhydrous THF (15 mL), and under ice-bath conditions, a 1 M LiAlH4 THF suspension (15 mL) was slowly added in the presence of nitrogen protection. The reaction continued at 66 for 12 hours. After confirming the reaction completion via TLC, the reaction mixture was quenched with a saturated Na2SO4 solution containing 15% NaOH. The resulting mixture was filtered to remove solids, and EA extraction was performed. Further purification through silica gel column chromatography (PE:EA=3:1) yielded a brown solid, compound M3 (453 mg, 45%). 1H NMR (400 MHz, DMSO- d6) δ 6.33 (s, 1H), 4.51 (s, 2H), 2.70 (t, J = 7.4 Hz, 4H), 2.57 (t, J = 7.4 Hz, 4H), 1.95 (p, J = 7.4 Hz, 4H). ESI-MS calculated for [M+H]+: 174.1, found: 174.1. |
| 45 % | Stage #1: 3,5,6,7-tetrahydro-2H-s-indacen-1-one With sulfuric acid; potassium nitrate at 0℃; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran at 66℃; Inert atmosphere; | Preparation of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine(M3) At 0 , compound M2 (1.00 g, 5.81 mmol) was dissolved in concentrated sulfuric acid, followed by the gradual addition, in portions, of solid KNO3 powder (882 mg, 8.72 mmol). The reaction proceeded at 0 for an additional 2 hours. Upon completion, the reaction mixture was slowly quenched with a 15% NaOH solution under ice-bath conditions. Ethyl acetate (EA) extraction followed, and the resulting black oily substance was rotary evaporated. The oily material was dissolved in anhydrous THF (15 mL), and under ice-bath conditions, a 1 M LiAlH4 THF suspension (15 mL) was slowly added in the presence of nitrogen protection. The reaction continued at 66 for 12 hours. After confirming the reaction completion via TLC, the reaction mixture was quenched with a saturated Na2SO4 solution containing 15% NaOH. The resulting mixture was filtered to remove solids, and EA extraction was performed. Further purification through silica gel column chromatography (PE:EA=3:1) yielded a brown solid, compound M3 (453 mg, 45%). 1H NMR (400 MHz, DMSO- d6) δ 6.33 (s, 1H), 4.51 (s, 2H), 2.70 (t, J = 7.4 Hz, 4H), 2.57 (t, J = 7.4 Hz, 4H), 1.95 (p, J = 7.4 Hz, 4H). ESI-MS calculated for [M+H]+: 174.1, found: 174.1. |
| 74.31% | Stage #1: 3,5,6,7-tetrahydro-2H-s-indacen-1-one With sulfuric acid; nitric acid at 0 - 30℃; Large scale; Stage #2: With methanesulfonic acid In methanol at 25 - 30℃; Large scale; Stage #3: With Pd(OH)2/C; hydrogen In methanol at 20℃; Large scale; | A mixture of 8-nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (11a) and 4-nitro- 1,2,3,5,6,7-hexahydro-s-indacen-i-one (11b) (9:1 ratio; 27.0 Kg) at 25 to 30 °C was charged into a 600 L clean and dry pressure reactor. Methanol (270 L) was charged at 25 to 30 °C. Methane sulfonic acid (14.3 Kg) was slowly charged at 25 to 30 °C and the reaction mixture was maintained for 30 minutes. 15 % Pd(0H)2slurry (60 % wet)*2was added.The reaction mixture was degassed under vacuum and filled with an argon atmosphere (0.5 Kg) three times. The reaction mixture was degassed under vacuum and filled with a hydrogen atmosphere (0.5 Kg) three times. Then the reaction mixture was stirred under hydrogen pressure (100 Psi) at room temperature for 32 hours. The temperature was gradually raised up to 55 °C. The absence of 8-nitro-i,2,3,5,6,7- hexahydro-s-indacen-i-one (11a) and 4-nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (nb) was confirmed by HPLC (Limit: After completion of the reaction, the reaction mixture was cooled to 25 to 30 °C. The reaction mixture was degassed under vacuum and filled with nitrogen atmosphere (0.5 Kg) three times. The reaction mixture was filtered through a candy filter to remove Pd(0H)2, followed by a micro filter and the bed was washed with methanol (54 L). 95 % of the solvent was distilled off under vacuum at below 45 to 50 °C. Demineralised water (135 L) was charged into the reaction mixture at 25 to 30 °C and maintained for 30 minutes. The reaction mixture was cooled to 5-10 °C. The pH was adjusted to about 9-10 with 2 N aqueous NaOH solution (prepared from NaOH (6.48 Kg) and demineralised water (81 L)) and the reaction mixture was stirred for 30 minutes. Then toluene (135 L) was charged to the reaction mixture and the reaction mixture was stirred for 30 minutes. The reaction mixture was stirred for a further 30 minutes, whilst bringing the temperature up to 25 to 30 °C. The reaction mixture was allowed to settle for 30 minutes, whilst the temperature was maintained at 25 to 30 °C.The reaction mixture was filtered through a Celite bed (prepared with Celite (5.4 Kg) and toluene (13.5 L). The Celite bed was washed with toluene (54 L). The layers were separated (aqueous layer (AL-i) and organic layer (OL-i)) and OL-i was kept aside. Toluene (54 L) was added to AL-i at 25 to 30 °C. The reaction mixture was stirred at 25 to 30 °C for 30 minutes and allowed to settle at 25 to 30 °C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and AL-2 was kept aside. Toluene (54 L) was added to AL-i at 25 to 30 °C. A brine solution (prepared with demineralised water (135 L) and sodium chloride (54 Kg)) was charged to the combined organic layers (OL-i and OL-2) at 25 to 30 °C. The reaction mixture was stirred at 25 to 30 °C for 30 minutes and allowed to settle at 25 to 30 °C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-3)) and AL-3 was kept aside. Charcoal (1.3 Kg) was added to OL-3 and the temperature was raised to 35-40 °C and maintained at 35 to 40 °C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (5.4 Kg) and toluene (54 L)) at 35 to 40 °C. The Celite bed was washed with toluene (54 L). The organic layer was dried over anhydrous Na2SO4(13.5 Kg). The Na2SO4was washed with toluene (27 L).The solvent was distilled under vacuum at below 35 to 40 °C until 5 % remained.Methanol (40.5 L) was charged to the reaction mixture at 35 to 40 °C and distilled until 5 % remained. Methanol (97.2 L) and water (10.8 L) were charged to the reaction mixture at 35 to 40 °C. The reaction mixture was heated to 50 to 55 °C, stirred for 1 hour at 50 to 55 °C, slowly cooled to o to 5 °C and maintained at o to 5 °C for 30 minutes.The solid product was filtered and washed with cold methanol (13.5 L), and dried in a hot air oven at 40 to 45 °C for 6 hours to afford 11.3 Kg of crude 1,2, 3,5,6, 7-hexahydro- s-indacen-4-amine (12).Yield: 41.85 %HPLC purity: 98.1 %Moisture content: 0.10 *H NMR: (400 MHz, DMSO-d6): 8 6.38 (S, 1H), 4.45 (S, 2H), 2.75 (t, 4H), 2.58 (t, 4H), 1.98 (t, 4H).*2: To prepare the 15 % Pd(0H)2slurry, 20 % Pd(0H)2on carbon (60 % wet; 4.05 Kg) was added to methanol (27 L).Purification (A) ofi,2,3,5,6,7-hexahiidro-s-mdacen-4-amme (12)Crude i,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (54.5 Kg) was charged at 25 to 30 °C into a 250 L clean and dry reactor. Toluene (27.2 L) was charged at 25 to 30 °C and the reaction mixture was stirred at 25 to 30 °C for 30 minutes. Methanol (163 L) was charged to the reaction mixture at 25 to 30 °C. The reaction mixture was stirred at 25 to 30 °C for 30 minutes, cooled to -5 to o °C, and stirred at -5 to o °C for 30 minutes. The solid product was filtered, washed with cold methanol (54.5 L), and dried at 40 to 45 °C for 6 hours to afford 40.5 Kg of purified i,2,3,5,6,7-hexahydro-s-indacen-4-amine (12).Yield: 74-31 % HPLC purity: 99.5 %Moisture content: 0.3 %JH NMR: (400 MHz, DMSO-d6): 86.33 (s, 1H), 4-53 (s, 2H), 2.72 (t, 4H), 2.57 (t, 4H), 1.98 (t, 4H). |
| Multi-step reaction with 2 steps 1: sulfuric acid; nitric acid / 1 h / 0 °C 2: Pd(OH)2/C; hydrogen; methanesulfonic acid / methanol / 24 h / 20 °C / 760.05 Torr | ||
| 453 mg | Stage #1: 3,5,6,7-tetrahydro-2H-s-indacen-1-one With sulfuric acid; potassium nitrate In water at 0℃; for 2h; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran at 66℃; for 12h; Inert atmosphere; | 1.3 Step 3: Synthesis of 1,2,3,5,6,7-hexahydro-S-inda-4-amine The compound M2 (1.00g, 5.81mmol) was dissolved in concentrated sulfuric acid at 0°C, and KNO3solid powder (882mg, 8.72mmol) was slowly added in batches, and the reaction continued at 0°C for 2h. After the reaction is over, 15% NaOH solution is slowly added under ice bath conditions to quench, EA is extracted, and the black oil is spun dry. The oil was dissolved in anhydrous THF (15 mL), followed by 1 M THF suspension of LiAlH4 (15 mL) slowly dropwise under ice bath conditions, and the reaction was carried out at 66 °C under nitrogen protection for 12 h. After the TLC detection reaction, the reaction solution was quenched with a saturated Na2SO4 solution containing 15% NaOH, followed by filtration to remove the solids, EA extraction, and purified by silica gel column chromatography (PE:EA=3:1) to obtain brown solid M3 (453mg, 45%). |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 1: 64% 2: 10% | With sulfuric acid; nitric acid at 0℃; for 1h; | 61.3; 62.3 Step 3: Synthesis of 8-nitro-2, 3 6, 7-tetrahydro-s-indacen-l (5H)-one & 4-nitro-2, 3 6, 7-tetrahydro-s- indacen- 1 (5H) -one To a solution of 3,5,6, 7-†etrahydro-2//-s-indacen-l-one (15.0 g, 87.09 mmol) in concentrated H28Q4 (75 mL) was added concentrated HNO3 (5 mL) slowly at 0°C. The resulting mixture was stirred at 0°C for 1 h. The reaction mixture was slowly added to ice water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na^SCfi, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-15 % EtOAc in petroleum ether) to give 8-nitro-3 ,5 ,6,7 ~tetrahydro-2if-s-indacen- 1 - one (12 g, 64% yield) and 4~nitro-3,5,6,7~ietrahydro-2//-s-indacen-l~one (1.8 g, 10% yield) both as white solid. H NMR (400 MHz, CDCI3) d = 7.46 (s, i l l). 3.15 - 3.11 (m, 2H), 3.05 (L ,/ 7.6 I lx. 2H), 3.00 (t,J = 7.6 Hz, 2H), 2.81 - 2.76 (m, 211). 2.25 - 2.15 (m, 2H). H NMR (400 MHz, CDC13) d = 7.83 (s, 1H), 3.57 - 3 46 (m, 3H), 3.42 (t, .7=7.6 Hz, 2H), 3.05 (t, J = 7.6 Hz, 2H), 2.82 - 2.76 (m, 2H), 2 26 - 2.20 (m, 2H). |
| 1: 10% 2: 60% | With sulfuric acid; nitric acid at 0℃; for 2h; | 3; 1 Step 1: 4-nitro-2,3,6,7-tetrahydro-s-indacen-l(5H)-one Into a 1-L round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-l-one (40 g, 232 mmol) in H2SO4 (250 mL). Then HNO3 (29 g, 464 mmol) was added dropwise over 1 h at 0°C. The resulting solution was stirred for 1 hr at 0°C. The reaction mixture was slowly added to a mixture of water/ice (500 mL) and DCM (250 mL) with ice bath cooling. The organic layer was collected, dried over anhydrous Na2S04 and concentrated under vacuum. The crude product was purified by silica gel column with a gradient of ethyl acetate and petroleum ether (1 :50 to 1 : 1). This resulted in minor product 5 g (10%) of the title compound and major product 30 g (60%) of 8-nitro-2,3,6,7-tetrahydro-s-indacen-l(5H)-one both as a yellow solid. |
| With sulfuric acid; nitric acid at 0 - 5℃; for 2h; |
| With sulfuric acid; nitric acid at 0℃; for 2h; Overall yield = 90 percent; Overall yield = 90 g; | A.3 Into a 1000-mL round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s- indacen-l -one (80.0 g, 464.5 mmol ) in H2SO4 (500 mL). Then HNO3 (58.5 g, 929.0 mmol) was added dropwise over 1 h at 0°C. The resulting solution was stirred for 1 h at 0°C. The reaction mixture was slowly added to a mixture of v ater/ice (1000 mL) and DCM (500 mL) with ice bath cooling. The organic layer was collected, dried over Na?.S04 and concentrated under (2403) vacuum. This resulted in 90 0 g (90%) of the mixture of 4-nitro-l,2,3,5,6,7-hexahydro-s-indacen- 1-one and 8-nitro-2,3,6,7-tetrahydros-indacen-l(5H)-one as a yellow solid. | |
| With sulfuric acid; nitric acid at 0 - 5℃; | iii; iii Reaction Scheme 2 - Steps ii and iii (Method B) 3-Chloro-i-(2,3-dihydro-ifT-inden-5-yl)propan-i-one (12) (350 g) and cone sulfuric acid (5 vol, 3185 g) were charged into a round bottom flask at 25 ± 5 °C. The reaction mixture was heated to 70 ± 2°C and stirred for 8-10 hours. The absence of 3-chloro-i- (2,3-dihydro-ifT-inden-5-yl)propan-i-one (12) was confirmed by HPLC (Limit: < 2.0 %)· The reaction mixture was cooled to 0-5 °C. A nitration mixture was prepared from cone sulfuric acid (0.33 vol, 210.2 g) and cone. HN03 (0.5 vol, 248.5 g) at 10-15 °C. The nitration mixture was added to the above reaction mixture at 0-5 °C over a period of 45-60 minutes. The reaction mixture was maintained at 0-5 °C for 2 hours. The absence of 1,2,3,5,6,7-hexahydro-s-indacen-i-one (13) was confirmed by HPLC (Limit: < 2.0 %). After completion of the reaction, the reaction mixture was added into ice cold water (25 vol, 8.75 L) and maintained at 15 ± 10 °C for 1 hour. The product was extracted into ethyl acetate (1 x 10 vol: 3.5 L, 2 x 5 vol: 1.75 L). The combined organic layers were washed with 10% NaHC03 solution (10 vol, 3.5 L) at 25 ± 5 °C and dried over Na2S04 (175 g). The solvent was distilled off (up to 1 vol, 350 mL) under vacuum at below 45 °C and then co-distilled with n-heptane (2 vol, 700 mL) completely. n-Heptane (2 vol, 700 mL) was added and the reaction mixture was stirred for 1 hour at 25 ± 5 °C. The solid product was filtered, washed with n-heptane (0.5 vol, 175 mL) and dried under vacuum for 2 hours at 45-50 °C. The crude product was dissolved in methanol (2.0 vol, 700 mL) at 55-60 °C. Charcoal 5% was added and the reaction mixture was refluxed for 1 hour and then cooled to 45 °C. The reaction mixture was filtered through a hyflow bed and washed twice with methanol (2x (0.5 vol, 175 mL)). The filtrate was cooled to 0-5 °C and maintained for 2-3 hours at 0-5 °C. The solid product was filtered, washed with cold methanol (0.25 vol, 87.5 mL) and dried under vacuum for 3 hours at 45-50 °C. Final Product: 8-nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (14) and 4- nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (15) Brown solid Weight ratio of 14:15 was 7:1. Combined Output (14+15): 217 g Combined Yield (14+15): 60 % lH NMR (DMSO-d6; 400 MHz): 7.66 (s, lH), 3.08 (t, 2H), 2.98 (t, 2H) 2.88 (t, 2H), 2.72 (t, 2H) and 2.12 (m, 2H). Moisture content (by Karl Fischer titration): 0.72 HPLC purity: 96.44 % | |
| With sulfuric acid; nitric acid In methanol at 0 - 5℃; Large scale; Overall yield = 62.24 percent; Overall yield = 38.87 kg; | 2.iii Reaction scheme 2 - step (ii) and step (iii) The reaction mixture was maintained at o to 5 °C. Demineralised water (900.0 L) was charged at 25 to 30 °C into a 2.0 KL clean and dry glass-lined reactor. The water was cooled to o to 5 °C. The reaction mixture was added slowly added to the reactor at o to 5 °C. Toluene (480.0 L) was added and the temperature was raised to 30 to 35 °C. The reaction mixture was maintained at 30 to 35 °C for 30 minutes and allowed to settle at 30 to 35 °C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (6.0 Kg) and toluene (30.0 L)). The Celite bed was washed with toluene (60.0 L). The solid was filtered and sucked dry for 30 min. The reaction mixture was charged to a 2.0 KL clean and dry glass-lined reactor. The reaction mixture was allowed to settle at 30 to 35 °C for 30 minutes. The layers were separated (aqueous layer (AL-1) and organic layer (OL-1)) and OL-1 was kept aside. Toluene (60.0 L) was charged to AL-1. The reaction mixture was stirred at 35 to 40 °C for 30 minutes and allowed to settle at 35 to 40 °C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and OL-2 was kept aside. OL-1 and OL-2 were combined to form OL-3. A 5 % saturated sodium bicarbonate solution (prepared from demineralised water (300.0 L) and sodium bicarbonate (15.0 Kg)) was slowly charged to OL-3 at 30 to 35 °C. The reaction mixture was stirred at 35 to 40 °C for 30 minutes and allowed to settle at 35 to 40 °C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (6.0 Kg) and demineralised water (60.0 L)). The Celite bed was washed with toluene (60.0 L). The reaction mixture was charged to a 3.0 KL clean and dry glass-lined reactor. The reaction mixture was allowed to settle at 30 to 35 °C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-4)) and OL-4 was kept aside. Toluene (60.0 L) was charged to AL-3. The layers were separated (aqueous layer (AL-4) and organic layer (OL-5)) and OL-5 was kept aside. OL-4 and OL-5 were combined to form OL-6. Brine solution (prepared from demineralised water (300.0 L) and sodium chloride (12.0 Kg) at 25 to 30 °C. The reaction mixture was stirred at 30 to 35 °C for 30 minutes and allowed to settle at 30 to 35 °C for 30 minutes. The layers were separated (aqueous layer (AL-5) and organic layer (OL-7)) and OL-7 was kept aside. OL-7 was dried over anhydrous Na2SO4 (9.0 Kg) and the anhydrous Na2SO4 was washed with toluene (30.0 L) at 25 to 30 °C. The solvent was distilled under vacuum at below 40 to 45 °C until 5 % remained. Methanol (60.0 L) was charged to the reaction mixture at 40 to 45 °C and down to 60 L of reaction mass. Methanol (120.0 L) was charged to the reaction mixture at 40 to 45 °C and the reaction mixture was cooled to 5 to 10 °C and maintained at 5 to 10 °C for 30 minutes. The solid product was filtered, washed with cooled methanol (30.0 L), and dried in a hot air oven at 40 to 45 °C for 6 hours to afford the product. *1: To prepare the nitration mixture, sulfuric acid (27.0 L) was charged at 25 to 30 °C into a 160 L clean and dry glass-lined reactor. The reaction mixture was cooled to o to 5 °C. Nitric acid (27.0 L) at o to 5 °C was added slowly and the reaction mixture was maintained for 30 minutes at o to 5 °C to afford the nitration mixture. Final Product: 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11a) and 4- nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11b) Combined Output (11a+11b): 38.87 Kg Combined Yield (11a+11b): 62.24 % Weight ratio (11a:11b): 9:1 HPLC purity: 95.9% Moisture content: 0.19% 1H NMR: (500 MHz, CDCl3):h7.44(S, 1H), 2.2i(m, 2H), 2.78 (t, 2H), 3.02 (m, 4H), 3.13 (t, 2H) | |
| With sulfuric acid; nitric acid at 0 - 5℃; Large scale; Overall yield = 62.24 percent; Overall yield = 38.87 kg; | 2.c Reaction scheme 2 - step (b) and step (c) Then the reaction mixture was cooled to 0 to 5°C. A nitration mixture*1 was added slowly at 0 to 5°C and the reaction mixture was maintained at 0 to 5°C for 1 hour. The reaction mixture was maintained at 0 to 5°C. Demineralised water (900.0 L) was charged at 25 to 30°C into a 2.0 KL clean and dry glass-lined reactor. The water was cooled to 0 to 5°C. The reaction mixture was added slowly added to the reactor at 0 to 5°C. Toluene (480.0 L) was added and the temperature was raised to 30 to 35°C. The reaction mixture was maintained at 30 to 35°C for 30 minutes and allowed to settle at 30 to 35°C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (6.0 Kg) and toluene (30.0 L)). The Celite bed was washed with toluene (60.0 L). The solid was filtered and sucked dry for 30 min. The reaction mixture was charged to a 2.0 KL clean and dry glass-lined reactor. The reaction mixture was allowed to settle at 30 to 35°C for 30 minutes. The layers were separated (aqueous layer (AL-1) and organic layer (OL-1)) and OL-1 was kept aside. Toluene (60.0 L) was charged to AL-1. The reaction mixture was stirred at 35 to 40°C for 30 minutes and allowed to settle at 35 to 40°C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and OL-2 was kept aside. OL-1 and OL-2 were combined to form OL-3. A 5 % saturated sodium bicarbonate solution (prepared from demineralised water (300.0 L) and sodium bicarbonate (15.0 Kg)) was slowly charged to OL-3 at 30 to 35°C. The reaction mixture was stirred at 35 to 40°C for 30 minutes and allowed to settle at 35 to 40°C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (6.0 Kg) and demineralised water (60.0 L)). The Celite bed was washed with toluene (60.0 L). The reaction mixture was charged to a 3.0 KL clean and dry glass-lined reactor. The reaction mixture was allowed to settle at 30 to 35°C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-4)) and OL-4 was kept aside. Toluene (60.0 L) was charged to AL-3. The layers were separated (aqueous layer (AL-4) and organic layer (OL-5)) and OL-5 was kept aside. OL-4 and OL-5 were combined to form OL-6. Brine solution (prepared from demineralised water (300.0 L) and sodium chloride (12.0 Kg) at 25 to 30°C. The reaction mixture was stirred at 30 to 35°C for 30 minutes and allowed to settle at 30 to 35°C for 30 minutes. The layers were separated (aqueous layer (AL-5) and organic layer (OL-7)) and OL-7 was kept aside. OL-7 was dried over anhydrous Na2SO4 (9.0 Kg) and the anhydrous Na2SO4 was washed with toluene (30.0 L) at 25 to 30°C. The solvent was distilled under vacuum at below 40 to 45°C until 5 % remained. Methanol (60.0 L) was charged to the reaction mixture at 40 to 45°C and down to 60 L of reaction mass. Methanol (120.0 L) was charged to the reaction mixture at 40 to 45°C and the reaction mixture was cooled to 5 to 10°C and maintained at 5 to 10°C for 30 minutes. The solid product was filtered, washed with cooled methanol (30.0 L), and dried in a hot air oven at 40 to 45°C for 6 hours to afford the product. *1: To prepare the nitration mixture, sulfuric acid (27.0 L) was charged at 25 to 30°C into a 160 L clean and dry glass-lined reactor. The reaction mixture was cooled to 0 to 5°C. Nitric acid (27.0 L) at 0 to 5°C was added slowly and the reaction mixture was maintained for 30 minutes at 0 to 5°C to afford the nitration mixture. Final Product: 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11a) and 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11b) Combined Output (11a+11b): 38.87 Kg Combined Yield (11a+11b): 62.24 % Weight ratio (11a:11b): 9:1 HPLC purity: 95.9% Moisture content: 0.19% 1H NMR: (500 MHz, CDCl3):δ7.44(S, 1H), 2.21(m, 2H), 2.78 (t, 2H), 3.02 (m, 4H), 3.13 (t, 2H) | |
| With sulfuric acid; nitric acid at 0 - 30℃; | Sulfuric acid (300.0 L) was charged at 25 to 30 °C into a 2.0 KL clean and dry glass- lined reactor. 3-chloro-i-(2,3-dihydro-iH-inden-5-yl)propan-i-one (9) (60.0 Kg) was charged lot wise at 25 to 30 °C and the reaction mixture was maintained for 30 minutes at 25 to 30 °C. The reaction mixture was slowly heated to 65 to 70 °C and maintained at 65 to 70 °C for 24 hours. The absence of 3-chloro-i-(2,3-dihydro-iW-inden-5-yl)- propan-i-one (9) was confirmed by HPLC (Limit: Then the reaction mixture was cooled to o to 5 °C. A nitration mixture*1was added slowly at o to 5 °C and the reaction mixture was maintained at o to 5 °C for 1 hour. The absence of 1,2,3,5,6,7-hexahydro-s-indacen-i-one (10) was confirmed by HPLC (Limit: Demineralised water (900.0 L) was charged at 25 to 30 °C into a 2.0 KL clean and dry glass-lined reactor. The water was cooled to o to 5 °C. The reaction mixture was added slowly added to the reactor at o to 5 °C. Toluene (480.0 L) was added and the temperature was raised to 30 to 35 °C. The reaction mixture was maintained at 30 to 35 °C for 30 minutes and allowed to settle at 30 to 35 °C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (6.0 Kg) and toluene (30.0 L)). The Celite bed was washed with toluene (60.0 L). The solid was filtered and sucked dry for 30 min. The reaction mixture was charged to a 2.0 KL clean and dry glass-lined reactor. The reaction mixture was allowed to settle at 30 to 35 °C for 30 minutes. The layers were separated (aqueous layer (AL-i) and organic layer (OL-i)) and OL-i was kept aside. Toluene (60.0 L) was charged to AL-i. The reaction mixture was stirred at 35 to 40 °C for 30 minutes and allowed to settle at 35 to 40 °C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and OL-2 was kept aside. OL-i and OL-2 were combined to form OL-3.A 5 % saturated sodium bicarbonate solution (prepared from demineralised water (300.0 L) and sodium bicarbonate (15.0 Kg)) was slowly charged to OL-3 at 30 to 35 °C. The reaction mixture was stirred at 35 to 40 °C for 30 minutes and allowed to settle at 35 to 40 °C for 30 minutes. The reaction mixture was filtered through a Celite bed (prepared with Celite (6.0 Kg) and demineralised water (60.0 L)). The Celite bed was washed with toluene (60.0 L). The reaction mixture was charged to a 3.0 KL clean and dry glass-lined reactor. The reaction mixture was allowed to settle at 30 to 35 °C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-4)) and OL-4 was kept aside.Toluene (60.0 L) was charged to AL-3. The layers were separated (aqueous layer (AL-4) and organic layer (OL-5)) and OL-5 was kept aside. OL-4 and OL-5 were combined to form OL-6. Brine solution (prepared from demineralised water (300.0 L) and sodium chloride (12.0 Kg) at 25 to 30 °C. The reaction mixture was stirred at 30 to 35 °C for 30 minutes and allowed to settle at 30 to 35 °C for 30 minutes. The layers were separated (aqueous layer (AL-5) and organic layer (OL-7)) and OL-7 was kept aside. OL-7 was dried over anhydrous Na2SO4(9.0 Kg) and the anhydrous Na2SO4was washed with toluene (30.0 L) at 25 to 30 °C. The solvent was distilled under vacuum at below 40 to 45 °C until 5 % remained. Methanol (60.0 L) was charged to the reaction mixture at 40 to 45 °C and down to 60 L of reaction mass. Methanol (120.0 L) was charged to the reaction mixture at 40 to 45 °C and the reaction mixture was cooled to 5 to 10 °C and maintained at 5 to 10 °C for 30 minutes. The solid product was filtered, washed with cooled methanol (30.0 L), and dried in a hot air oven at 40 to 45 °C for 6 hours to afford 38.87 Kg of a mixture of 8-nitro-i,2,3,5,6,7- hexahydro-s-indacen-i-one (11a) and 4-nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (nb)Combined Yield (na+nb): 62.24 %Weight ratio (na:iib): 9:1HPLC purity: 95.9 %Moisture content: 0.19 % ‘H NMR: (500 MHz, CDC13): 8 7.44(8, 1H), 2.21(m, 2H), 2.78 (t, 2H), 3.02 (m, 4H), 3.13 Ct, 2H)*1: To prepare the nitration mixture, sulfuric acid (27.0 L) was charged at 25 to 30 °C into a 160 L clean and dry glass-lined reactor. The reaction mixture was cooled to o to 5 °C. Nitric acid (27.0 L) at o to 5 °C was added slowly and the reaction mixture was maintained for 30 minutes at o to 5 °C to afford the nitration mixture. | |
| With sulfuric acid; nitric acid at 0 - 20℃; for 2h; Overall yield = 90 percent; Overall yield = 90 g; | 3 Step 3: Mixture of 4-nitro-2,3,6,7-tetrahydros-indacen-1(5H)-one and 8-nitro-2,3,6,7- tetrahydros-indacen-1(5H)-one To a stirred solution of 1,2,3,5,6,7-hexahydro-s-indacen-1-one (80 g, 464.5 mmol) in H2SO4 (500 mL) was added HNO3(58.5 g, 929 mmol) dropwise over 1 h at 0 °C. The resulting solution was stirred for 1 h at RT. The reaction mixture was slowly added to a mixture of water/ice (1000 mL) and DCM (500 mL) with ice bath cooling. The organic layer was collected, dried over Na2SO4 and concentrated under vacuum. This resulted in 90 g (90%) of the mixture of 4-nitro-1,2,3,5,6,7- hexahydro-s-indacen-1-one and 8-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one as a yellow solid. MS-ESI: 218 (M+1). |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: 78 percent / AlCl3 / CH2Cl2 / -10 - 20 °C 2: H2SO4 / 48 h / 55 - 60 °C | ||
| Multi-step reaction with 8 steps 1: 93 percent / AlCl3 / CH2Cl2 / 4 h 2: 89 percent / NaOBr / 1.) 3 h, 0 deg C; 2.) r. t., overnight 3: 94 percent / conc. H2SO4 / Heating 4: 94 percent / LiAlH4 / diethyl ether / 12 h / Heating 5: 96 percent / PCC / CH2Cl2 / 2 h / Ambient temperature 6: 91 percent / pyridine, piperidine / 24 h / 80 °C 7: 95 percent / H2 / Pd/C / dioxane / 18 h / 3040 - 3800 Torr 8: PPS / 5 h / 80 °C | ||
| Multi-step reaction with 8 steps 1: 93 percent / AlCl3 / CH2Cl2 / 4 h 2: 89 percent / NaOBr / 1.) 3 h, 0 deg C; 2.) r. t., overnight 4: 94 percent / LiAlH4 / diethyl ether / 12 h / Heating 5: 96 percent / PCC / CH2Cl2 / 2 h / Ambient temperature 6: 91 percent / pyridine, piperidine / 24 h / 80 °C 7: 95 percent / H2 / Pd/C / dioxane / 18 h / 3040 - 3800 Torr 8: PPS / 5 h / 80 °C |
| Multi-step reaction with 2 steps 1: 77 percent / AlCl3 / CH2Cl2 / 1 h 2: conc. H2SO4 / 3.5 h / 70 °C | ||
| Multi-step reaction with 2 steps 1: 44 percent / AlCl3 2: 43 percent / H2SO4 | ||
| Multi-step reaction with 2 steps 1: aluminium chloride / nitromethane / 5 h / Ambient temperature 2: conc. sulfuric acid / 4 h / 90 °C | ||
| Multi-step reaction with 2 steps 1: AlCl3 / nitromethane 2: H2SO4 | ||
| Multi-step reaction with 2 steps 1: AlCl3 / benzene 2: H2SO4 | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 16.5 h / -10 - 20 °C 2: sulfuric acid / 16 h / 55 °C | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 16.5 h / -10 - 20 °C 2: sulfuric acid / 16 h / 55 °C | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 16.5 h / 10 - 20 °C 2: sulfuric acid / 16 h / 55 °C | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 2 h / -10 - 27 °C / Inert atmosphere 2: sulfuric acid / water / 12 h / 70 °C | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 16.5 h / -10 - 20 °C 2: sulfuric acid / 16 h / 55 °C | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 18 h / 20 °C 2: sulfuric acid / 24 h / 60 °C | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 2 h / -10 - 27 °C / Inert atmosphere 2: sulfuric acid / water / 12 h / 70 °C | ||
| Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 0.5 h / -10 - -8 °C 1.2: 12 h / -10 - 30 °C 2.1: sulfuric acid / 20 - 70 °C | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 2 h / -10 - 27 °C / Inert atmosphere 2: sulfuric acid / water / 12 h / 70 °C | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 8 h / 0 - 10 °C / Large scale 2: sulfuric acid / 40 h / 55 °C | ||
| Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 30 min / -10 - 19 °C / Inert atmosphere; Large scale 1.2: 2 h / -10 - 15 °C / Inert atmosphere; Large scale 2.1: sulfuric acid / 24 h / 25 - 70 °C / Large scale | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 2 h / 0 - 20 °C 2: sulfuric acid / dichloromethane / Reflux | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 8 h / 20 °C 2: sulfuric acid / 48 h / 60 °C | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 16.5 h / -10 - 20 °C / Inert atmosphere 2: sulfuric acid / 16 h / 55 °C | ||
| Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 30 min / -10 - -5 °C / Inert atmosphere; Large scale 1.2: 2 h / -10 - 15 °C / Inert atmosphere; Large scale 2.1: sulfuric acid / 24.5 h / 25 - 70 °C | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 3 h / 0 - 20 °C 2: sulfuric acid / 20 - 90 °C | ||
| Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 0.17 h / Inert atmosphere 1.2: 12.5 h / 20 °C / Inert atmosphere 2.1: sulfuric acid / 12 h / 70 °C | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 8 h / 0 - 20 °C 2: sulfuric acid / water / 48 h / 60 °C |
