171596-29-5

Usage

InChI:InChI=1/C22H23N3O3/c1-24-8-9-25-17(22(24)26)11-15-14-4-2-3-5-16(14)23-20(15)21(25)13-6-7-18-19(10-13)28-12-27-18/h2-7,10,15,17,20-21,23H,8-9,11-12H2,1H3/t15?,17-,20?,21-/m1/s1

Synthetic route

C22H19ClN2O5*(x)ClH + methylamine (74-89-5) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
In dichloromethane at 0 - 5℃; for 3h; Temperature; Solvent;	99.3%

methylamine (74-89-5) + methyl (1R,3R)-1-(3,4-methylenedioxyphenyl)-2-chloroacetyl-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indol-3-carboxylate (171489-59-1) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
In water; N,N-dimethyl-formamide at 20℃;	95%
In N,N-dimethyl-formamide at 20℃; for 10h;	95%
In methanol for 3h; Reflux; Large scale;	95.3%

(6R,12aR)-6-(3,4-dihydroxyphenyl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione + 1,2-dibromomethane (74-95-3) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
With sodium hydroxide In N,N-dimethyl-formamide at 60℃; for 6h;	95%
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 8h;	93%
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 8h;	93%
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 8h;	93%

(1R,3R)-methyl-1,2,3,4-tetrahydro-2-(2-(benzyl(methyl)amino)acetyl)-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (1224724-00-8) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
With hydrogen; Raney Ni In ISOPROPYLAMIDE at 80℃; under 2280.15 Torr; for 22h; Product distribution / selectivity;	94%

methyl (1R,3R)-1-(3,4-methylenedioxyphenyl)-2-chloroacetyl-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indol-3-carboxylate (171489-59-1) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
With methylamine In dichloromethane for 2h;	93.5%
With methylamine In water for 20h; Ionic liquid;	355 mg

sarcosine ethyl ester hydrochloride (52605-49-9) + (1R,3R)-1-benzo[1,3]dioxol-5-yl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester hydrochloride → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
With potassium carbonate In ethylene glycol at 110℃; Solvent; Reagent/catalyst; Temperature; Green chemistry;	92.7%

1-benzo[1,3]dioxol-5-yl-2-{[(9H-fluoren-9-ylmethoxycarbonyl)-methyl-amino]-acetyl}-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester (749864-18-4) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
With piperidine In N,N-dimethyl-formamide at 20℃; for 1h;	92%

C22H20N4O3 → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Stage #1: C22H20N4O3 With sulfuric acid In isopropyl alcohol for 12h; Reflux; Stage #2: With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 8h; Temperature;	91.2%

(1R,3R)-1-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid + methylamine (74-89-5) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
In tetrahydrofuran; water at 50℃; Solvent; Temperature;	91%

sarcosine (107-97-1) + (1R,3R)-1-benzo[1,3]dioxol-5-yl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester hydrochloride → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Stage #1: sarcosine; (1R,3R)-1-benzo[1,3]dioxol-5-yl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester hydrochloride With triethylamine In tetrahydrofuran at 30℃; for 0.333333h; Stage #2: With dicyclohexyl-carbodiimide In tetrahydrofuran for 0.5h; Solvent; Reagent/catalyst; Temperature; Further stages;	90.54%

piperonal (120-57-0) + C15H19N3O3*ClH → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
In isopropyl alcohol at 80℃; for 16h; Solvent; Temperature;	58.2%

methylamine (74-89-5) + methyl (1R,3R)-1-(3,4-methylenedioxyphenyl)-2-chloroacetyl-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indol-3-carboxylate (171489-59-1) → (6R,12aS)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-27-3) + (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
In methanol at 50℃; for 16h;	A 1.1% B 54%

(1R,3R)-1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid hydrochloride (474668-76-3) + sarcosine ethyl ester hydrochloride (52605-49-9) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 50 - 55℃; for 10h; Large scale reaction;	52.6%

(1R,3R)-1-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroacetyl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide (951661-81-7) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Stage #1: (1R,3R)-1-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroacetyl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -50 - -35℃; for 2 - 6h; Stage #2: With ammonium chloride In tetrahydrofuran; hexane; water; ethyl acetate at -40 - 30℃; Product distribution / selectivity;	48%
Stage #1: (1R,3R)-1-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroacetyl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide With n-butyllithium In tetrahydrofuran; hexane at -40 - -35℃; for 2.5h; Stage #2: With ammonium chloride In tetrahydrofuran; hexane; water; ethyl acetate at -40 - 30℃; Product distribution / selectivity;

piperonal (120-57-0) + Boc-D-Trp-OH (5241-64-5) + chloroacetyl chloride (79-04-9) + methylamine (74-89-5) → (6S,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,12,12a tetrahydropyrazino [1',2':1,6] pyrido[3,4b] indole1,4(6H,7H)-dione (171596-28-4) + (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Stage #1: Boc-D-Trp-OH With dmap; dicyclohexyl-carbodiimide In dichloromethane for 0.166667h; Microwave irradiation; Stage #2: piperonal With trifluoroacetic acid In chloroform for 0.5h; Pictet-Spengler cyclisation; Microwave irradiation; Stage #3: chloroacetyl chloride; methylamine Further stages;	A 45% B 32%

piperonal (120-57-0) + rhodaninoic acid → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 25 percent / TFA / methanol; CH2Cl2 / 60 h / 20 °C 2: 91 percent / sodium bicarbonate / CH2Cl2 / 1 h / 0 °C 3: 54 percent / methanol / 16 h / 50 °C View Scheme
Multi-step reaction with 3 steps 1: 85 percent / aq.HCl / methanol / 36 h / Heating 2: 78 percent / NaHCO3 / CH2Cl2; H2O 3: 88 percent / CHCl3; ethanol / 7 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 95 percent / Et3N; MgSO4 / CH2Cl2 / 24 h 2: 43 percent / DMAP / CH2Cl2 / 2 h / 20 °C 3: 92 percent / methanol / 16 h / 50 °C View Scheme
Multi-step reaction with 3 steps 1: 95 percent / Et3N; MgSO4 / CH2Cl2 / 24 h 2: DMAP; basic alumina / CH2Cl2 / 2 h / -25 - 20 °C 3: 92 percent / piperidine / dimethylformamide / 1 h / 20 °C View Scheme

(R)-(+)-tryptophan methyl ester hydrochloride (14907-27-8, 5619-09-0, 7524-52-9, 26988-71-6, 41222-70-2, 67557-19-1, 109492-62-8) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 25 percent / TFA / methanol; CH2Cl2 / 60 h / 20 °C 2: 91 percent / sodium bicarbonate / CH2Cl2 / 1 h / 0 °C 3: 54 percent / methanol / 16 h / 50 °C View Scheme
Multi-step reaction with 3 steps 1: 85 percent / aq.HCl / methanol / 36 h / Heating 2: 78 percent / NaHCO3 / CH2Cl2; H2O 3: 88 percent / CHCl3; ethanol / 7 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 95 percent / Et3N; MgSO4 / CH2Cl2 / 24 h 2: 43 percent / DMAP / CH2Cl2 / 2 h / 20 °C 3: 92 percent / methanol / 16 h / 50 °C View Scheme

(1R,3R)-methyl 1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (171596-41-1) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 91 percent / sodium bicarbonate / CH2Cl2 / 1 h / 0 °C 2: 54 percent / methanol / 16 h / 50 °C View Scheme
Multi-step reaction with 2 steps 1: 93 percent / NaHCO3 / CHCl3 / 20 °C 2: 77 percent / ethanol / Heating View Scheme

(1R,3R)-1-benzo[1,3]dioxol-5-yl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester hydrochloride → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 78 percent / NaHCO3 / CH2Cl2; H2O 2: 88 percent / CHCl3; ethanol / 7 h / Heating View Scheme

(R)-2-{[1-Benzo[1,3]dioxol-5-yl-meth-(E)-ylidene]-amino}-3-(1H-indol-3-yl)-propionic acid methyl ester → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 43 percent / DMAP / CH2Cl2 / 2 h / 20 °C 2: 92 percent / methanol / 16 h / 50 °C View Scheme
Multi-step reaction with 2 steps 1: DMAP; basic alumina / CH2Cl2 / 2 h / -25 - 20 °C 2: 92 percent / piperidine / dimethylformamide / 1 h / 20 °C View Scheme

piperonal (120-57-0) + glycocoll ester → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 42 percent / TFA / CH2Cl2 / 20 °C 2: 93 percent / NaHCO3 / CHCl3 / 20 °C 3: 77 percent / ethanol / Heating View Scheme

D-Tryptophan methyl ester (4299-70-1, 7303-49-3, 22032-65-1) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 42 percent / TFA / CH2Cl2 / 20 °C 2: 93 percent / NaHCO3 / CHCl3 / 20 °C 3: 77 percent / ethanol / Heating View Scheme
Multi-step reaction with 3 steps 1.1: hydrogenchloride / water; toluene / 15 h / Reflux; Large scale 2.1: triethylamine / dichloromethane / 0.17 h / 20 °C / Large scale 2.2: 1 h / 20 °C / Large scale 3.1: methanol / 3 h / Reflux; Large scale View Scheme
Multi-step reaction with 3 steps 1: isopropyl alcohol / 10 h / 70 - 80 °C / Large scale 2: triethylamine / chloroform / 2 h / 20 - 30 °C 3: methylamine / dichloromethane / 2 h View Scheme

methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (1321600-91-2) + methylamine hydrochloride (593-51-1) → (6S,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,12,12a tetrahydropyrazino [1',2':1,6] pyrido[3,4b] indole1,4(6H,7H)-dione (171596-28-4) + (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
With triethylamine In methanol Reflux;

piperonal (120-57-0) + (R)-(+)-tryptophan methyl ester hydrochloride (14907-27-8, 5619-09-0, 7524-52-9, 26988-71-6, 41222-70-2, 67557-19-1, 109492-62-8) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 3 h / 85 °C 1.2: 1 h / 0 - 10 °C 2.1: water; tetrahydrofuran / 1 h / 55 °C / Inert atmosphere View Scheme

piperonal (120-57-0) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 0.25 h / 110 °C 2: triethylamine / water; tetrahydrofuran / 2 h / 0 - 10 °C / Inert atmosphere 3: water; tetrahydrofuran / 1 h / 55 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: 0.25 h / 110 °C 2: triethylamine / tetrahydrofuran; water / 2 h / 0 - 10 °C / Inert atmosphere 3: tetrahydrofuran; water / 1 h / 55 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: acetonitrile / 105 °C / Autoclave 2: sodium carbonate / acetonitrile; water / 5 - 10 °C 3: water; isopropyl alcohol / 110 - 120 °C View Scheme

N-Boc-D-tryptophan → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / Inert atmosphere 1.2: 1 h / -20 - 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / toluene / 15 h / 45 - 50 °C 3.1: toluene / 8 h / 110 °C View Scheme

C24H25N3O5 → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
In toluene at 110℃; for 8h;	0.39 g

piperonal (120-57-0) + (R)-ethyl 2-(2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)-N-methylpropanamido)acetate (1422164-52-0) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: trifluoroacetic acid / toluene / 15 h / 45 - 50 °C 2: toluene / 8 h / 110 °C View Scheme

Boc-D-Trp-OH (5241-64-5) → (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 0.33 h / -20 °C / Inert atmosphere 1.2: 0.5 h / -20 °C / Inert atmosphere 2.1: 4-methyl-morpholine / tetrahydrofuran / Inert atmosphere 2.2: 1 h / -20 - 20 °C / Inert atmosphere 3.1: trifluoroacetic acid / toluene / 15 h / 45 - 50 °C 4.1: toluene / 8 h / 110 °C View Scheme

(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → (6R,12aS)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-27-3)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In dimethyl sulfoxide; isopropyl alcohol at 83℃; for 5h;	98%

naphthalene-1,5-disulfonate (81-04-9) + (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione naphthalene-1,5-disulfonic acid salt

Conditions	Yield
In Isopropyl acetate at 45℃; for 48h; pH=2 - 3; Solvent;	95.4%

salicylic acid (69-72-7) + (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione salicylic acid salt

Conditions	Yield
In Isopropyl acetate at 45℃; for 48h; pH=2 - 3; Solvent;	94.81%

(S)-Mandelic acid (17199-29-0) + (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione mandelic acid salt

Conditions	Yield
In Isopropyl acetate at 45℃; for 48h; pH=2 - 3; Solvent;	94.25%

(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → (6R,12aS)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-3,3,12a-trideuterio-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (1021702-43-1)

Conditions	Yield
With water-d2; potassium carbonate In tetrahydrofuran; dimethylsulfoxide-d6 at 65℃; for 16h;	94%

malonic acid (141-82-2) + (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → C3H4O4*C22H19N3O4 (1242099-10-0)

Conditions	Yield
In ethyl acetate for 5h;	85%
In acetonitrile Product distribution / selectivity;
In acetonitrile at 25℃; for 0.5h;

(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → 3-((2-(benzo[d][1,3]dioxole-5-carbonyl)-1H-indol-3-yl)methyl)-1-methylpiperazine-2,5-dione (1220393-12-3)

Conditions	Yield
With dipotassium peroxodisulfate; water; tetramethlyammonium chloride In dimethyl sulfoxide at 40℃; for 7h;	79%
With 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran; water at 20℃; for 8h; Product distribution / selectivity;

(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → C22H19N3O5

Conditions	Yield
With N-Bromosuccinimide; acetic acid at 50℃; for 5h; Reagent/catalyst;	78%

4-Methoxybenzenethiol (696-63-9) + (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → (6R)-6-(6-((4-methoxyphenyl)thio)benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione

Conditions	Yield
With tetrabutylammonium tetrafluoroborate for 4.5h; Electrolysis; Inert atmosphere; Sealed tube; regioselective reaction;	65%

2-Fluoro-5-nitropyridine (456-24-6) + (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → (6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-7-(5-nitropyridin-2-yl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 23℃; for 40h; Inert atmosphere;	61%

(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → C22H15(2)H4N3O4

Conditions	Yield
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; deuterium In tetrahydrofuran at 55℃; under 750.075 Torr; for 22h; Inert atmosphere;	46%

2,8-difluoro-5-(trifluoromethyl)-5Hdibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate + (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → C23H18F3N3O4

Conditions	Yield
With [(Tp)NiIV(CF3)3] In dimethyl sulfoxide at 25℃; for 24h; Inert atmosphere; Sealed tube; Glovebox;	43%

(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → C22H19N3O5

Conditions	Yield
With tert.-butylnitrite; 2,3-dicyano-5,6-dichloro-p-benzoquinone In acetonitrile at 20℃; for 15h; Irradiation;	42%

(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → 11-benzo[1,3]dioxol-5-yl-3-methyl-2,3,4a,11-tetrahydro-10H-3,10,11a-triaza-benzo[b]fluorene-1,4,5-trione

Conditions	Yield
With potassium superoxide; 18-crown-6 ether In N,N-dimethyl-formamide at 25℃; for 6h; Winterfeldt oxidation;	38%
Multi-step reaction with 2 steps 1: O2; KOtBu / dimethylformamide; tetrahydrofuran / 4 h 2: 16.2 mg / PyBrOP; di-isopropylethylamine / dimethylformamide; tetrahydrofuran / 16 h / 25 °C View Scheme

(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (171596-29-5) → (6R,12aR)-6-benzo[1,3]dioxol-5-yl-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6] pyrido[3,4-b]indole-1,4-dithione (422311-80-6)

Conditions	Yield
With Lawessons reagent In tetrahydrofuran at 20℃; for 72h;	25%

Upstream product

• 74-89-5 methylamine 
• 171489-59-1 methyl (1R,3R)-1-(3,4-methylenedioxyphenyl)-2-chloroacetyl-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indol-3-carboxylate 
• 951661-81-7 (1R,3R)-1-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroacetyl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide 
• 474668-76-3 (1R,3R)-1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid hydrochloride 
• 52605-49-9 sarcosine ethyl ester hydrochloride 
• 120-57-0 piperonal 
• 5241-64-5 Boc-D-Trp-OH 
• 79-04-9 chloroacetyl chloride 
• 153-94-6 D-tryptophan 
• 171489-03-5 (6R,12aR)-6-(3,4-dihydroxyphenyl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione 
• 74-95-3 1,1-dibromomethane 
• 139-85-5 3,4-dihydroxybenzaldehyde 
• 54-12-6 Trp 
• 5241-64-5 BOC-tryptophane 

Downstream Products

• 171596-27-3 (6R,12aS)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione 
• 1220393-12-3 3-((2-(benzo[d][1,3]dioxole-5-carbonyl)-1H-indol-3-yl)methyl)-1-methylpiperazine-2,5-dione 
• 1242099-13-3 C₁₀H₁₂O₃*C₂₂H₁₉N₃O₄ 
• 1242099-11-1 C₈H₈O₃*C₂₂H₁₉N₃O₄ 
• 1242099-09-7 C₉H₁₀O₂*C₂₂H₁₉N₃O₄ 
• 1370438-57-5 (1R,3R)-1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide 
• 477970-21-1 (6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2,7-dimethyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione 
• 531500-48-8 11-benzo[1,3]dioxol-5-yl-3-methyl-2,3,4a,11-tetrahydro-10H-3,10,11a-triaza-benzo[b]fluorene-1,4,5-trione 

Relevant academic research and scientific papers

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Preparation method of phosphodiesterase inhibitor

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Method for preparing Tadalafil by one-pot method

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Tadalafil preparation method

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