27773-65-5

Basic information

• Product Name: (3alpha,16alpha)-eburnamenine-14-carboxylic acid
• Synonyms: (3alpha,16alpha)-eburnamenine-14-carboxylic acid;apovincaminic acid;(13aS)-13aβ-Ethyl-2,3,5,6,13a,13bβ-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxylic acid;(13aS,13bS)-13a-Ethyl-2,3,5,6,13a,13b-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxylic acid;(3S,16S)-Eburnamenine-14-carboxylic acid;Apovinacaminic acid;cis-Apovincaminic acid;(+)-cis-ApovincaMinic A
• CAS NO: 27773-65-5
• Molecular Formula: C₂₀H₂₂N₂O₂
• Molecular Weight: 322.40088
• EINECS: 248-651-1
• Product Categories: Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals
• Mol File: 27773-65-5.mol
• Article Data: 9

Chemical Properties

• Melting Point: 126-129 °C
• Boiling Point: 429.9±45.0 °C(Predicted)
• Appearance: /
• Density: 1.38±0.1 g/cm3(Predicted)
• PKA: 3.36±0.40(Predicted)
• CAS DataBase Reference: (3alpha,16alpha)-eburnamenine-14-carboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: (3alpha,16alpha)-eburnamenine-14-carboxylic acid(27773-65-5)
• EPA Substance Registry System: (3alpha,16alpha)-eburnamenine-14-carboxylic acid(27773-65-5)

Safety Data

• Hazardous Substances Data: 27773-65-5(Hazardous Substances Data)

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

• 1617-90-9 vincamin 
• 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 
• 42971-09-5 Vinpocetine 
• 78101-34-5 MR-711 

Downstream Products

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

Relevant articles and documents

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.

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.

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