27773-65-5

Usage

Uses

The main metabolite

Synthetic route

Vinpocetine (42971-09-5) → Apovincaminic acid (27773-65-5)

Conditions	Yield
With sodium hydroxide In 1,4-dioxane at 80℃; for 2h;	98%
With sodium hydroxide In ethanol for 5h; Reflux;	92.4%
With sodium hydroxide In methanol at 40℃; for 1h; Kinetics; Further Variations:; Reagents; Solvents; Temperatures; pH-values;

apovincamine (4880-92-6) → Apovincaminic acid (27773-65-5)

Conditions	Yield
With sodium hydroxide In ethanol for 3h; Reflux;	96%
With sodium hydroxide In ethanol at 20℃; for 2h; Reflux;	96%
With sodium hydroxide In tetrahydrofuran; methanol for 12h;
With hydrogenchloride at 20 - 37℃; for 2h; object of study: degree of hydrolysis;
With sodium hydroxide at 65℃; for 2h;

MR-711 (78101-34-5) → Apovincaminic acid (27773-65-5)

Conditions	Yield
With hydrogenchloride at 20 - 37℃; for 2h; object of study: degree of hydrolysis;
With esterases of rat plasma; water at 37℃; object of study: rate of hydrolysis;

Vinpocetine (42971-09-5) → Apovincaminic acid (27773-65-5) + 14,15-dihydro-14β-hydroxy-(3α,16α)-eburnamenine-14-carboxylic acid ethyl ester (40163-56-2) + 3α-epivincaminic acid ethyl ester + 14-epivincaminic acid + vinburnine (4880-88-0) + (3α,14β,16α)-14,15-dihydro-14-hydroxyeburnamenine-14-carboxylic acid (28152-73-0)

Conditions	Yield
With hydrogenchloride at 80℃; for 336h; Product distribution; Rate constant; Thermodynamic data; ln A, Ea, ΔS<*>; degradation of vinpocetine in aqueous solutions, degradation products equilibria in solutions, effect of various pH, temperature and ionic strength, buffer catalysis, metal ion catalysis, oxygen effect, mechanism;

3-(2-bromoethyl)-1H-indole (3389-21-7) → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 9 steps 1: 80 percent / NaHCO3 / acetonitrile / 24 h / Heating 2: H2 / 10percent Pd/C / methanol; ethyl acetate / 4 h / 2585.7 Torr 3: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 4: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 5: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 6: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 7: Et3N / CH2Cl2 / 0.5 h / 0 °C 8: 55 percent / DBU / 1 h / 100 °C 9: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme
Multi-step reaction with 10 steps 1: 80 percent / NaHCO3 / acetonitrile / 24 h / Heating 2: H2 / 10percent Pd/C / methanol; ethyl acetate / 4 h / 2585.7 Torr 3: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 4: 46 percent / TFA / 24 h / Heating 5: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 6: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 7: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 8: Et3N / CH2Cl2 / 0.5 h / 0 °C 9: 55 percent / DBU / 1 h / 100 °C 10: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

1-phenylpropyl (2S,3R)-3-cyano-3-ethylpipecolate (95407-25-3, 95407-56-0) → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 9 steps 1: 80 percent / NaHCO3 / acetonitrile / 24 h / Heating 2: H2 / 10percent Pd/C / methanol; ethyl acetate / 4 h / 2585.7 Torr 3: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 4: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 5: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 6: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 7: Et3N / CH2Cl2 / 0.5 h / 0 °C 8: 55 percent / DBU / 1 h / 100 °C 9: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme
Multi-step reaction with 10 steps 1: 80 percent / NaHCO3 / acetonitrile / 24 h / Heating 2: H2 / 10percent Pd/C / methanol; ethyl acetate / 4 h / 2585.7 Torr 3: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 4: 46 percent / TFA / 24 h / Heating 5: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 6: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 7: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 8: Et3N / CH2Cl2 / 0.5 h / 0 °C 9: 55 percent / DBU / 1 h / 100 °C 10: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

(2S,3R)-3-Cyano-3-ethyl-1-[2-(1H-indol-3-yl)-ethyl]-piperidine-2-carboxylic acid (95407-55-9) → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 7 steps 1: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 2: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 3: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 4: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 5: Et3N / CH2Cl2 / 0.5 h / 0 °C 6: 55 percent / DBU / 1 h / 100 °C 7: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme
Multi-step reaction with 8 steps 1: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 2: 46 percent / TFA / 24 h / Heating 3: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 4: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 5: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 6: Et3N / CH2Cl2 / 0.5 h / 0 °C 7: 55 percent / DBU / 1 h / 100 °C 8: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

(3R*,4S*,14R*,15R*,16S*)-14,15-dihydro-15-hydroxy-14-methoxycarbonyleburnamenine (95464-02-1) → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: Et3N / CH2Cl2 / 0.5 h / 0 °C 2: 55 percent / DBU / 1 h / 100 °C 3: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

1-cyano-1-ethyl-12-<(methoxycarbonyl)methyl>-1,2,3,4,6,7,12,12b-octahydroindolo<2,3-a>quinolizine (95407-51-5) → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 5 steps 1: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 2: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 3: Et3N / CH2Cl2 / 0.5 h / 0 °C 4: 55 percent / DBU / 1 h / 100 °C 5: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

1-phenylpropyl (2S,3R)-3-cyano-3-ethyl-N-<2-(3-indolyl)ethyl>pipecolate (95407-50-4, 95407-59-3) → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 8 steps 1: H2 / 10percent Pd/C / methanol; ethyl acetate / 4 h / 2585.7 Torr 2: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 3: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 4: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 5: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 6: Et3N / CH2Cl2 / 0.5 h / 0 °C 7: 55 percent / DBU / 1 h / 100 °C 8: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme
Multi-step reaction with 9 steps 1: H2 / 10percent Pd/C / methanol; ethyl acetate / 4 h / 2585.7 Torr 2: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 3: 46 percent / TFA / 24 h / Heating 4: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 5: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 6: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 7: Et3N / CH2Cl2 / 0.5 h / 0 °C 8: 55 percent / DBU / 1 h / 100 °C 9: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

(10S,11S,11aR,11bS)-11a-Ethyl-11-methanesulfonyloxy-2,3,4,5,10,11,11a,11b-octahydro-1H-3a,9b-diaza-benzo[cd]fluoranthene-10-carboxylic acid methyl ester → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 55 percent / DBU / 1 h / 100 °C 2: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

N-(3-chloropropyl)-N-(9-phenylfluorenyl)-3-cyanoalanine benzyl ester (95407-43-5) → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 11 steps 1: NaI / acetonitrile / 22 h / Heating 3: 80 percent / NaHCO3 / acetonitrile / 24 h / Heating 4: H2 / 10percent Pd/C / methanol; ethyl acetate / 4 h / 2585.7 Torr 5: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 6: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 7: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 8: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 9: Et3N / CH2Cl2 / 0.5 h / 0 °C 10: 55 percent / DBU / 1 h / 100 °C 11: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme
Multi-step reaction with 12 steps 1: NaI / acetonitrile / 22 h / Heating 3: 80 percent / NaHCO3 / acetonitrile / 24 h / Heating 4: H2 / 10percent Pd/C / methanol; ethyl acetate / 4 h / 2585.7 Torr 5: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 6: 46 percent / TFA / 24 h / Heating 7: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 8: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 9: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 10: Et3N / CH2Cl2 / 0.5 h / 0 °C 11: 55 percent / DBU / 1 h / 100 °C 12: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

(S)-3-Cyano-2-[(3-iodo-propyl)-(9-phenyl-9H-fluoren-9-yl)-amino]-propionic acid benzyl ester → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 10 steps 2: 80 percent / NaHCO3 / acetonitrile / 24 h / Heating 3: H2 / 10percent Pd/C / methanol; ethyl acetate / 4 h / 2585.7 Torr 4: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 5: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 6: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 7: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 8: Et3N / CH2Cl2 / 0.5 h / 0 °C 9: 55 percent / DBU / 1 h / 100 °C 10: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme
Multi-step reaction with 11 steps 2: 80 percent / NaHCO3 / acetonitrile / 24 h / Heating 3: H2 / 10percent Pd/C / methanol; ethyl acetate / 4 h / 2585.7 Torr 4: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 5: 46 percent / TFA / 24 h / Heating 6: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 7: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 8: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 9: Et3N / CH2Cl2 / 0.5 h / 0 °C 10: 55 percent / DBU / 1 h / 100 °C 11: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

N-(3-chloropropyl)-3-cyanoalanine benzyl ester (95407-42-4) → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 12 steps 1: K3PO4, Pb(NO3)2 / acetonitrile / 24 h 2: NaI / acetonitrile / 22 h / Heating 4: 80 percent / NaHCO3 / acetonitrile / 24 h / Heating 5: H2 / 10percent Pd/C / methanol; ethyl acetate / 4 h / 2585.7 Torr 6: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 7: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 8: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 9: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 10: Et3N / CH2Cl2 / 0.5 h / 0 °C 11: 55 percent / DBU / 1 h / 100 °C 12: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme
Multi-step reaction with 13 steps 1: K3PO4, Pb(NO3)2 / acetonitrile / 24 h 2: NaI / acetonitrile / 22 h / Heating 4: 80 percent / NaHCO3 / acetonitrile / 24 h / Heating 5: H2 / 10percent Pd/C / methanol; ethyl acetate / 4 h / 2585.7 Torr 6: 1.) pyridine, TsCl, 2.) NaHCO3 / 1.) CH2Cl2, 1 h, 2.) 1 h 7: 46 percent / TFA / 24 h / Heating 8: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 9: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 10: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 11: Et3N / CH2Cl2 / 0.5 h / 0 °C 12: 55 percent / DBU / 1 h / 100 °C 13: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

1-cyano-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo<2,3-a>quinolizine (70672-30-9, 70702-10-2, 95463-99-3, 95464-00-9) → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 6 steps 1: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 2: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 3: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 4: Et3N / CH2Cl2 / 0.5 h / 0 °C 5: 55 percent / DBU / 1 h / 100 °C 6: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

1-cyano-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo<2,3-a>quinolizine (70672-30-9, 70702-10-2, 95463-99-3, 95464-00-9) → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 7 steps 1: 46 percent / TFA / 24 h / Heating 2: 1.) NaH / 1.) DMF, 0 deg C, 1 h, 2.) - 30 deg C, 1 h 3: 56 percent / LDA / tetrahydrofuran; hexane / 1.0 -78 deg C, 15 min, 2.) 0 deg C, 9 h 4: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 5: Et3N / CH2Cl2 / 0.5 h / 0 °C 6: 55 percent / DBU / 1 h / 100 °C 7: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

(3S,16R)-14-(methoxycarbonyl)-15-oxoeburnane (95464-01-0) → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 90 percent / NaBH4 / methanol / 0.05 h / -25 °C 2: Et3N / CH2Cl2 / 0.5 h / 0 °C 3: 55 percent / DBU / 1 h / 100 °C 4: aq. NaOH / methanol; tetrahydrofuran / 12 h View Scheme

vincamin (1617-90-9) → Apovincaminic acid (27773-65-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / toluene; water / 2 h 2: sodium hydroxide / 2 h / 65 °C View Scheme
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / toluene / 2 h / Reflux 2: sodium hydroxide / ethanol / 3 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / toluene / 2 h / Reflux 2: sodium hydroxide / ethanol / 2 h / 20 °C / Reflux View Scheme

Apovincaminic acid (27773-65-5) + (S)-aminopropan-1-ol → (41S,13aS)-13a-ethyl-N-((S)-1-hydroxypropan-2-yl)-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridin-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With 2-(7-azobenzotriazole)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 1h; Stage #2: (S)-aminopropan-1-ol In dichloromethane for 4h;	96%

Apovincaminic acid (27773-65-5) → (41S,13aS)-13a-ethyl-2,3,41,5,6,13a-hexahydro-H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxamide (27773-67-7)

Conditions	Yield
Stage #1: Apovincaminic acid With thionyl chloride In chloroform; N,N-dimethyl-formamide for 3h; Reflux; Stage #2: With ammonium hydroxide In chloroform; N,N-dimethyl-formamide at 20℃; for 2h;	95%
Stage #1: Apovincaminic acid With toluene-4-sulfonic acid In dichloromethane at 20℃; for 4h; Stage #2: With ammonia In dichloromethane at 20℃; for 3h;	83%
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: With ammonia In dichloromethane at 20℃; for 3h;	83%
Stage #1: Apovincaminic acid With thionyl chloride; N,N-dimethyl-formamide In chloroform for 4h; Reflux; Stage #2: With ammonium hydroxide In chloroform; water for 2h; Cooling with ice;

L-alanine methyl ester hydrochloride (2491-20-5) + Apovincaminic acid (27773-65-5) → ethyl (S)-methyl-2-((4S,13aS)-13a-ethyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridin-12-formylamino)propionate

Conditions	Yield
Stage #1: Apovincaminic acid With 2-(7-azobenzotriazole)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 1h; Stage #2: L-alanine methyl ester hydrochloride In dichloromethane for 4h;	95%

ethylamine (75-04-7) + Apovincaminic acid (27773-65-5) → (41S,13aS)-N,13a-diethyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: ethylamine In dichloromethane at 20℃; for 3h;	92%

Apovincaminic acid (27773-65-5) + (S)-2-amino-N-methoxy-N-methylpropanamide hydrochloride → (41S,13aS)-13a-ethyl-N-((S)-1-(methoxyl(methyl)amino)-1-oxopropan-2-yl)-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridin-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With 2-(7-azobenzotriazole)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; Stage #2: (S)-2-amino-N-methoxy-N-methylpropanamide hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane for 14h;	90.58%

N,O-dimethylhydroxylamine*hydrochloride (6638-79-5) + Apovincaminic acid (27773-65-5) → (41S,13aS)-13a-ethyl-N-methoxy-N-methyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridin-12-carboxamide

Conditions	Yield
With 2-(7-azobenzotriazole)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃;	90%

Apovincaminic acid (27773-65-5) + diethylamine (109-89-7) → (41S,13aS)-N,N,13a-triethyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: diethylamine In dichloromethane at 20℃; for 3h;	90%

1-aminopropan-2-one hydrochloride (7737-17-9) + Apovincaminic acid (27773-65-5) → (41S,13aS)-13a-ethyl-N-(2-oxopropyl)-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrid o[3,2,1-ij][1,5]naphthyridin-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With 2-(7-azobenzotriazole)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 1h; Stage #2: 1-aminopropan-2-one hydrochloride In dichloromethane for 4h;	89%

Apovincaminic acid (27773-65-5) → (41S,13aS)-13a-ethyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-hydrazide

Conditions	Yield
Stage #1: Apovincaminic acid With thionyl chloride In chloroform; N,N-dimethyl-formamide at 0℃; for 3h; Reflux; Stage #2: With hydrazine hydrate In chloroform; N,N-dimethyl-formamide at 20℃; for 2h;	89%

propylamine (107-10-8) + Apovincaminic acid (27773-65-5) → (41S,13aS)-13a-ethyl-N-propyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: propylamine In dichloromethane at 20℃; for 3h;	89%

1-pentanamine (110-58-7) + Apovincaminic acid (27773-65-5) → (41S,13aS)-13a-ethyl-N-pentyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: n-Pentylamine In dichloromethane at 20℃; for 3h;	88%

Apovincaminic acid (27773-65-5) + N-butylamine (109-73-9) → (41S,13aS)-N-butyl-13a-ethyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: N-butylamine In dichloromethane at 20℃; for 3h;	86%

di-n-propylamine (142-84-7) + Apovincaminic acid (27773-65-5) → (41S,13aS)-13a-ethyl-N,N-dipropyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5] naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: di-n-propylamine In dichloromethane at 20℃; for 3h;	86%

Apovincaminic acid (27773-65-5) + isopropylamine (75-31-0) → (41S,13aS)-13a-ethyl-N-isopropyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]-naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: isopropylamine In dichloromethane at 20℃; for 3h;	85%

Apovincaminic acid (27773-65-5) + dimethyl amine (124-40-3) → (41S,13aS)-13a-ethyl-N,N-dimethyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5] naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: dimethyl amine In dichloromethane at 20℃; for 3h;	85%

dibutylamine (111-92-2) + Apovincaminic acid (27773-65-5) → (41S,13aS)-N,N-dibutyl-13a-ethyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5] naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: dibutylamine In dichloromethane at 20℃; for 3h;	85%

piperidine (110-89-4) + Apovincaminic acid (27773-65-5) → ((41S,13aS)-13a-ethyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridin-12-yl)(piperidin-1-yl)methanone

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: piperidine In dichloromethane at 20℃; for 3h;	85%

Apovincaminic acid (27773-65-5) + methylamine (74-89-5) → (41S,13aS)-13a-ethyl-N-methyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With toluene-4-sulfonic acid In dichloromethane at 20℃; for 4h; Stage #2: methylamine With triethylamine In dichloromethane at 20℃; for 3h;	83%
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: methylamine In dichloromethane at 20℃; for 3h;	82%

Apovincaminic acid (27773-65-5) + Cyclopentamine (1003-03-8) → (41S,13aS)-N-cyclopentyl-13a-ethyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]-naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: Cyclopentamine In dichloromethane at 20℃; for 3h;	81%

4-methoxy-aniline (104-94-9) + Apovincaminic acid (27773-65-5) → C27H29N3O2

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: 4-methoxy-aniline In dichloromethane at 20℃; for 3h;	81%

pyrrolidine (123-75-1) + Apovincaminic acid (27773-65-5) → ((41S,13aS)-13a-ethyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridin-12-yl)(pyrrolidin-1-yl)methanone

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: pyrrolidine In dichloromethane at 20℃; for 3h;	81%

ethanolamine (141-43-5) + Apovincaminic acid (27773-65-5) → (41S,13aS)-13a-ethyl-N-(2-hydroxyethyl)-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]-naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: ethanolamine In dichloromethane at 20℃; for 3h;	79%

morpholine (110-91-8) + Apovincaminic acid (27773-65-5) → ((41S,13aS)-13a-ethyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridin-12-yl)(morpholino)methanone

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: morpholine In dichloromethane at 20℃; for 3h;	78%

Apovincaminic acid (27773-65-5) + propan-1-ol-3-amine (156-87-6) → (41S,13aS)-13a-ethyl-N-(3-hydroxypropyl)-2,3,41,5,6,13ahexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: propan-1-ol-3-amine In dichloromethane at 20℃; for 3h;	75%

Apovincaminic acid (27773-65-5) + aniline (62-53-3) → (41S,13aS)-13a-ethyl-N-phenyl-2,3,41,5,6,13a-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxamide

Conditions	Yield
Stage #1: Apovincaminic acid With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Stage #2: aniline In dichloromethane at 20℃; for 3h;	72%

Apovincaminic acid (27773-65-5) + 4-(nitrooxy)butyl bromide (146563-40-8) → (11aS,11bS)-11a-Ethyl-2,3,4,5,11a,11b-hexahydro-1H-3a,9b-diaza-benzo[cd]fluoranthene-10-carboxylic acid 4-nitrooxy-butyl ester

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 3h; Ambient temperature;	46.9%

Apovincaminic acid (27773-65-5) + 10-(nitrooxy)decyl bromide → (11aS,11bS)-11a-Ethyl-2,3,4,5,11a,11b-hexahydro-1H-3a,9b-diaza-benzo[cd]fluoranthene-10-carboxylic acid 10-nitrooxy-decyl ester

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 3h; Ambient temperature;	44.8%

Apovincaminic acid (27773-65-5) + 7-(nitrooxy)heptyl bromide → (11aS,11bS)-11a-Ethyl-2,3,4,5,11a,11b-hexahydro-1H-3a,9b-diaza-benzo[cd]fluoranthene-10-carboxylic acid 7-nitrooxy-heptyl ester

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 3h; Ambient temperature;	43%

Upstream product

• 42971-09-5 Vinpocetine 
• 1617-90-9 vincamin 
• 4880-92-6 apovincamine 
• 95464-01-0 (3S,16R)-14-(methoxycarbonyl)-15-oxoeburnane 
• 70672-30-9 1-cyano-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo<2,3-a>quinolizine 
• 70672-30-9 1-cyano-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo<2,3-a>quinolizine 
• 95407-42-4 N-(3-chloropropyl)-3-cyanoalanine benzyl ester 
• 95407-43-5 N-(3-chloropropyl)-N-(9-phenylfluorenyl)-3-cyanoalanine benzyl ester 
• 95407-50-4 1-phenylpropyl (2S,3R)-3-cyano-3-ethyl-N-<2-(3-indolyl)ethyl>pipecolate 
• 95407-51-5 1-cyano-1-ethyl-12-<(methoxycarbonyl)methyl>-1,2,3,4,6,7,12,12b-octahydroindolo<2,3-a>quinolizine 
• 95464-02-1 (3R*,4S*,14R*,15R*,16S*)-14,15-dihydro-15-hydroxy-14-methoxycarbonyleburnamenine 
• 95407-55-9 (2S,3R)-3-Cyano-3-ethyl-1-[2-(1H-indol-3-yl)-ethyl]-piperidine-2-carboxylic acid 
• 95407-25-3 1-phenylpropyl (2S,3R)-3-cyano-3-ethylpipecolate 
• 3389-21-7 3-(2-bromoethyl)-1H-indole 

Downstream Products

• 128759-76-2 VA-045 
• 4880-88-0 vinburnine 
• 95407-52-6 apovincaminic acid methyl mandelate ester 

Relevant academic research and scientific papers

Studies on the synthesis, structural characterization, Hirshfeld analysis and stability of apovincamine (API) and its co-crystal (terephthalic acid: Apovincamine = 1:2)

Apovincamine and the corresponding co-crystal have been synthesized and characterized by single crystal XRD, FT-IR, UV, TGA/DSG. Components of the crystalline phase have also been investigated in terms of their corresponding Hirshfeld surface. In the crystal lattice, a three-dimensional hydrogen-bonded network is observed in the co-crystal, including the formation of a two-dimensional molecular scaffold. Hirshfeld surfaces and fingerprint plots indicate that the structures are stabilized by H???H, C-H???π, C-H???O and O-H???N intermolecular interactions. In this work, the co-crystal strategy has been applied successfully to apovincamine. One important parameter, i.e. solubility in water, has also been significantly improved, which proves to be an important factor for bioavailability. Furthermore, DSC/TGA analysis indicates that the co-crystal maintains its crystallinity up to 200 °C, suggesting a higher stability of the co-crystal compared to apovincamine.

Spectrophotometric and liquid chromatographic determination of fenofibrate and vinpocetine and their hydrolysis products

Several spectrophotometric and HPLC methods are presented for the determination of fenofibrate, vinpocetine and their hydrolysis products. The resolution of either fenofibrate or vinpocetine and their hydrolysis products has been accomplished by using numerical spectrophotometric methods as partial least squares (PLS-1) and principal component regression (PCR) applied to UV spectra; and graphical spectrophotometric methods as first derivative of ratio spectra (1DD) or first (1D) and second (2D) derivative spectrophotometry for vinpocetine and fenofibrate, respectively. In addition HPLC methods were developed using ODS column with mobile phase consisting of acetonitrile-water (80:20, v/v, pH 4) with UV detection at 287:nm for fenofibrate and a mobile phase consisting of acetonitrile-10:mM KH 2PO4, containing 0.1% diethylamine (60:40, v/v, pH:4.6) with UV detection at 270:nm for vinpocetine. The proposed methods were successfully applied for the determination of each drug and its hydrolysis product in laboratory-prepared mixture and pharmaceutical preparation. The proposed HPLC and derivative spectrophotometric methods were used to investigate the kinetics of acidic and alkaline hydrolytic processes of each drug. The pH-rate profile of hydrolysis of each drug in Britton-Robinson buffer solutions was studied.

Kinetics and mechanisms of vinpocetine degradation in aqueous solutions

Under stressed conditions, vinpocetine (1; ethyl apovincamin-22-oate) equilibrates with vincaminic acid ethyl ester (2) and 14-epivincaminic acid ethyl ester (3), and hydrolyzes to apovincaminic acid (4). Sequentially, 2 is equilibrated with 14-epivincaminic acid ethyl ester (3) and hydrolyzes to vincaminic acid (5), which equilibrates with 4 and 14-epivincaminic acid (6). At acidic pH, the major route of degradation is 1?2→5. However, at neutral pH, the major route of degradation is 1→4?5. The kinetics for the degradation of 1 in the pH 1-3 region is represented by a consecutive reaction with a reversible step (second-order), but the degradation of 1 in the pH 3.5-6.0 region follows pseudo first-order kinetics. Significant buffer catalysis is observed with acetate and phosphate buffers. Reactions are dependent on the ionic strength, pH, and temperature. No oxygen effect on the degradation of vinpocetine is found.

Design, synthesis and biological evaluation of vincamine derivatives as potential pancreatic β-cells protective agents for the treatment of type 2 diabetes mellitus

A series of vincamine derivatives were designed, synthesized and evaluated as pancreatic β-cells protective agents for type 2 diabetes mellitus. Most of the compounds displayed potent pancreatic β-cells protective activities and five derivatives were found to exhibit 20–50-fold higher activities than vincamine. Especially for compounds Vin-C01 and Vin-F03, exhibited a remarkable EC50 value of 0.22 μM and 0.27 μM, respectively. Their pancreatic β-cells protective activities increased approximately 2 times than vincamine. In cell viability assay, compounds Vin-C01 and Vin-F03 could effectively promote β-cell survival and protect β-cells from STZ-induced apoptosis. Further cellular mechanism of action studies demonstrated that their potent β-cells protective activities were achieved by regulating IRS2/PI3K/Akt signaling pathway. The present study evidently showed that compounds Vin-C01 and Vin-F03 were two more potent pancreatic β-cells protective agents compared to vincamine and might serve as promising lead candidates for the treatment of type 2 diabetes mellitus.

DIAZA-BENZOFLUORANTHRENE COMPOUNDS

Disclosed are a series of diaza-benzofluoranthrene compounds. The present invention particularly relates to a compound represented by formula (I), pharmaceutically acceptable salts or tautomers thereof.

Pervone derivative and purpose thereof to treatment of diabetes B

The invention relates to the field of medicinal chemistry, in particular to a derivative shown as a general formula (I) and a purpose of a medicine composition containing the derivative to preparationof medicine for treating diabetes B. The compound has the effect of preventing pancreatic island beta cell apoptosis and can be used for treating the diabetes B. The general formula (I) is shown in the description.

A NEW DIAZA-BENZOFLUORANTHENE DERIVATIVE AS DRUG

The present invention relates to a new 16-tetrazolyl-eburnamenine of formula (I) or pharmaceutically acceptable salt thereof and/or hydrates and/or solvates thereof. The invention also relates to the pharmaceutical compositions containing the compound of formula (I) or hydrates or solvates thereof as active ingredient. The invention also relates to the synthesis of compounds of formula (I), and the chemical and pharmaceutical manufacture of medicaments containing these compounds, as well as the methods of treatment of mammals - including human - with these compounds. There is still further provided methods for the treatment of neurological, neurodegenerative and psychiatric diseases or conditions as well as comprising the step of administering to human, in need of such treatment and/or prophylaxis a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) or pharmaceutically acceptable salts thereof alone or together with at least one and a pharmaceutically acceptable carrier and/or diluent

Simultaneous evaluation of apovincaminic acid esters and their metabolite apovincaminic acid by solvent partition and GLC in biological samples. Preliminary data with MR 711

Apovincaminic acid (AVA) esters are eburnamenine derivatives with a vasodilating action that are mainly metabolized to AVA by enzymatic hydrolysis, in the rat in particular. In an organic solvent/water partition, AVA and AVA ester were quantitatively separated. AVA ester was then chemically hydrolysed into AVA. Unchanged AVA and AVA hydrolysed from its ester were separately methylated and quantitatively analysed by GLC. Using a flame ionisation detector, this method has a sensitivity of 20 ng making possible metabolic investigations to be carried out in vitro and in the urine and can be applied to any AVA ester. The method was applied in a preliminary investigation to MR 711, a methylene-methoxy-apovincaminic acid ester. When incubated in vitro with rat plasma, MR 711 was enzymatically converted into AVA. The urine of rats p.o. treated with 10 mg/kg of MR 711 contained AVA as the main metabolite.