110351-94-5

Basic information

• Product Name: (S)-4-ETHYL-4-HYDROXY-7,8-DIHYDRO-1H-PYRANO[3,4-F]INDOLIZINE-3,6,10(4H)-TRIONE
• Synonyms: (S)-4-ETHYL-4-HYDROXY-7,8-DIHYDRO-1H-PYRANO[3,4-F]INDOLIZINE-3,6,10(4H)-TRIONE;(s)-8-Ethyl-8-hydroxy-2,3,5,8-tetrahydro-6-oxa-3a-aza-cyclopenta[b]naphthalene-1,4,7-trione ;(S)-4-hydroxy-4-propyl-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione;(S)-4-hydroxy-4-propyl-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3;(S)-4-Ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione;1H-Pyrano[3,4-f]indolizine-3,6,10(4H)-trione, 4-ethyl-7,8-dihydro-4-hydroxy-, (4S)-;(4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10-trione;1H-Pyrano[3,4-f]indolizine-3,6,10(4H)-trione, 4-ethyl-7,8-dihydro-4-hydroxy-, (S)-
• CAS NO: 110351-94-5
• Molecular Formula: C₁₃H₁₃NO₅
• Molecular Weight: 263.24602
• Product Categories: Anti-cancer
• Mol File: 110351-94-5.mol
• Article Data: 17

Chemical Properties

• Melting Point: 183-185℃ (decomposition)
• Boiling Point: 666.634 °C at 760 mmHg
• Flash Point: 356.968 °C
• Appearance: /
• Density: 1.506 g/cm³
• Storage Temp.: 2-8°C
• PKA: 11.20±0.20(Predicted)
• CAS DataBase Reference: (S)-4-ETHYL-4-HYDROXY-7,8-DIHYDRO-1H-PYRANO[3,4-F]INDOLIZINE-3,6,10(4H)-TRIONE(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-4-ETHYL-4-HYDROXY-7,8-DIHYDRO-1H-PYRANO[3,4-F]INDOLIZINE-3,6,10(4H)-TRIONE(110351-94-5)
• EPA Substance Registry System: (S)-4-ETHYL-4-HYDROXY-7,8-DIHYDRO-1H-PYRANO[3,4-F]INDOLIZINE-3,6,10(4H)-TRIONE(110351-94-5)

Safety Data

• HazardClass: IRRITANT
• Hazardous Substances Data: 110351-94-5(Hazardous Substances Data)

Usage

Chemical Properties

Light yellow solid.

Uses

(4S)-4-Ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione is a key intermediate in the synthesis of Irinotecan (I767500) and Camptothecin (C175150) analogs.

Preparation

Synthesis of (S)-4-Ethyl-4-hydroxy-7,8-dihydro-1h-pyrano[3,4-f]indolizine-3,6,10(4h)-trione: Compound (Formula 4) 4.3 g (100 mmol), 200 ml of dichloromethane, 200 ml of 2M sulfuric acid, stirred at room temperature for 2 h, separated the organic layer, washed with saturated brine, dried, recovered dichloromethane to dryness, and recrystallized from isopropanol to obtain S-tricyclic lactone (Formula 1) 1.5 g, mp 172-174°C, [α]D15+115.6° (C=0.5, chloroform), yield 57%.

Application

(S)-4-Ethyl-4-hydroxy-7,8-dihydro-1h-pyrano[3,4-f]indolizine-3,6,10(4h)-trione is the key intermediate for the synthesis of a series of (20S)-camptothecin analogues. Since its isolation from the Chinese plant Camptothecaacuminata by Wall et al. In 1966, (20S)-camptothecin, a pent acyclic natural alkaloid, has re-emerged as one of the most important lead compounds for the discovery of new and selective anticancer drugs because of the disclosure of its unique mechanism of action as a selective inhibitor DNA topoisomerase Ⅰ, a process causing irreversible DNA damage and subsequent cell death. Three camptothecin derivatives with high antitumor activity, topotecan, belotecan, and irinotecan, have been launched as anticancer drugs in clinical practice, and many other analogues are at various stages of clinical development.

Clinical claims and research

Camptothecin is a pentacyclic alkaloid extracted from Camptotheca by Wall et al. in the early 1960s. As an anticancer chemical, the compound has quickly attracted people's attention due to its strong inhibitory activity against leukemia and various other malignant tumors in animal experiments. In the total synthesis of camptothecin, The total synthesis of (S)-4-Ethyl-4-hydroxy-7,8-dihydro-1h-pyrano[3,4-f]indolizine-3,6,10(4h)-trione is research focus.

Synthetic route

(S)-4′-ethyl-4′-hydroxy-7′,8′-dihydrospiro[[1,3]dioxolane-2,6′-pyrano[3,4-f]indolizine]-3′,10′(1′H,4′H)-dione (110351-93-4) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 60℃; for 3h;	100%
With trifluoroacetic acid at 20℃; for 6h;	93%
With trifluoroacetic acid for 3h; Ambient temperature;	88.9%

C17H21NO7 (165674-36-2) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 60℃; for 3h;	100%

(S,E)-6-benzylidene-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,10(4H,6H)-dione → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Stage #1: (S,E)-6-benzylidene-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,10(4H,6H)-dione With oxygen; ozone In dichloromethane at -40℃; for 0.75h; Stage #2: With dimethylsulfide In dichloromethane at -40 - 20℃; for 2h;	96%

(S)-4′-ethyl-4′-hydroxy-7′,8′-dihydrospiro[[1,3]dioxolane-2,6′-pyrano[3,4-f]indolizine]-3′,10′(1′H,4′H)-dione (110351-93-4) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 60℃; for 3h;	100%
With trifluoroacetic acid at 20℃; for 6h;	93%
With trifluoroacetic acid for 3h; Ambient temperature;	88.9%

C17H21NO7 (165674-36-2) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 60℃; for 3h;	100%

(S,E)-6-benzylidene-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,10(4H,6H)-dione → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Stage #1: (S,E)-6-benzylidene-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,10(4H,6H)-dione With oxygen; ozone In dichloromethane at -40℃; for 0.75h; Stage #2: With dimethylsulfide In dichloromethane at -40 - 20℃; for 2h;	96%

1,1-dimethylethyl (S)-4-ethyl-3,4,8,10-tetrahydro-4,6-dihydroxy-3,10-dioxo-1H-pyrano[3,4 - f] indolidin-7-carboxylate (183434-04-0) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
In toluene; trifluoroacetic acid at 110℃; for 2h;	93.4%
With trifluoroacetic acid In toluene at 110℃; for 1.66667h;	77%

(S)-α-ethyl-α-hydroxy-1,1-(ethylenedioxy)-6-hydroxymethyl-5-oxo-1,2,3,5-tetrahydroindolizine-7-acetamide (110314-10-8) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
With trifluoroacetic acid for 3h; Ambient temperature;	93%
With sulfuric acid In 1,2-dimethoxyethane
Multi-step reaction with 2 steps 1: acetic acid / 2 h / 70 °C 2: 2N aq. sulfuric acid / 1,2-dimethoxy-ethane / 8 h / 50 °C View Scheme

4'-ethyl-1',4',7',8'-tetrahydro-4'-hydroxy-3'H,10'H-spiro[1,3-dioxolane-2,6'-pyrano[3,4-f]indolizine]-3',10'-dione (102978-41-6) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 98.1 percent / DMAP / CH2Cl2 / 4 h / 40 °C 2: aq. K2CO3 / methanol / Ambient temperature 3: 88.9 percent / 80percent aq. CF3COOH / 3 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: 20 h / 75 °C 2: sulfuric acid / 1,2-dimethoxy-ethane View Scheme
Multi-step reaction with 3 steps 1: 20 h / 75 °C 2: acetic acid / 2 h / 70 °C 3: 2N aq. sulfuric acid / 1,2-dimethoxy-ethane / 8 h / 50 °C View Scheme
Multi-step reaction with 3 steps 1: 20 h / 70 °C 2: p-toluenesulfonica acid / acetic acid / 7 h / 70 °C 3: 2N aq. sulfuric acid / 1,2-dimethoxy-ethane / 8 h / 50 °C View Scheme
Multi-step reaction with 3 steps 1.1: copper(l) chloride / dichloromethane / 8 h / 20 °C 2.1: potassium hydroxide / methanol / 5 h / 67 °C 2.2: pH 2-3 3.1: trifluoroacetic acid / 6 h / 20 °C View Scheme

1,1-ethylenedioxy-5-oxo-(5'-ethyl-2'H,5'H,6'H-6-oxopyran)-[3',4',f]-Δ6(8)-tetrahydroindolizine (127318-97-2) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: O2, (EtO)3P, tBuONa / dimethylformamide / 2 h / -40 °C 2: 98.1 percent / DMAP / CH2Cl2 / 4 h / 40 °C 3: aq. K2CO3 / methanol / Ambient temperature 4: 88.9 percent / 80percent aq. CF3COOH / 3 h / Ambient temperature View Scheme
Multi-step reaction with 8 steps 1: 94 percent / DIBAL-H / tetrahydrofuran / 2 h / -78 °C 2: 96 percent / MsCl, TEA / tetrahydrofuran / 24 h / Ambient temperature 3: (DHQD)2-PHAL, K3Fe(CN)6, K2CO3, K2OsO2, CH3SO2NH2 / 2-methyl-propan-2-ol; H2O / 96 h / Ambient temperature 4: pyridine / 3 h / Ambient temperature 5: 93 percent / i-PrNEt / CH2Cl2 / 3 h / Ambient temperature 6: 92 percent / aq. K2CO3 / methanol / 2 h / Ambient temperature 7: 84 percent / pyridinium chlorochromate, AcONa, molecular sieves 4 Angstroem / 24 h / Ambient temperature 8: 100 percent / aq. HCl / tetrahydrofuran; H2O / 3 h / 60 °C View Scheme
Multi-step reaction with 5 steps 1: 94 percent / DIBAL-H / tetrahydrofuran / 2 h / -78 °C 2: 96 percent / MsCl, TEA / tetrahydrofuran / 24 h / Ambient temperature 3: (DHQD)2-PHAL, K3Fe(CN)6, K2CO3, K2OsO2, CH3SO2NH2 / 2-methyl-propan-2-ol; H2O / 96 h / Ambient temperature 4: I2, CaCO3 / methanol; H2O / 24 h / Ambient temperature 5: 100 percent / aq. HCl / tetrahydrofuran; H2O / 3 h / 60 °C View Scheme

4-acetoxy-4-ethyl-6,6-(ethylenedioxy)-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,10(4H)-dione (144788-94-3) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: aq. K2CO3 / methanol / Ambient temperature 2: 88.9 percent / 80percent aq. CF3COOH / 3 h / Ambient temperature View Scheme

citrazinic acid (99-11-6) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 17 steps 1: 78 percent / POPCl3, Me4NCl / 2 h / 130 - 142 °C 2: 84 percent / tetrahydrofuran / 1 h / 0 °C 3: 100 percent / TMSCl / 12 h / Ambient temperature 4: 89 percent / methanol / 20 h / Heating 5: 1.) n-BuLi / 1.) heptane, hexane, 0 deg C, 30 min, 2.) hexane, heptane, -30 deg C - 0 deg C, 1 h 6: 71 percent / NaBH4, n-Bu4NCl / H2O / 18 h 7: 99.3 percent / t-BuOK / tetrahydrofuran / 1 h / 20 - 30 °C 8: 89 percent / Pd(OAc)2, K2CO3, DPP / dimethylformamide / 16 h / 90 °C / 775.7 Torr 10: 92 percent / OsO4, Me3NO*2H2O / 2-methyl-propan-2-ol / 24 h / 40 °C 11: 76 percent / PS-30 catalyst / various solvent(s) / 48 h 12: 100 percent / NaOCl, 4-acetoxy-TEMPO, KBr, NaHCO3 / CH2Cl2; H2O / 0.67 h 13: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 14: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 15: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 16: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 17: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

2,6-dichloropyridine-4-carboxylic acid (5398-44-7) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 16 steps 1: 84 percent / tetrahydrofuran / 1 h / 0 °C 2: 100 percent / TMSCl / 12 h / Ambient temperature 3: 89 percent / methanol / 20 h / Heating 4: 1.) n-BuLi / 1.) heptane, hexane, 0 deg C, 30 min, 2.) hexane, heptane, -30 deg C - 0 deg C, 1 h 5: 71 percent / NaBH4, n-Bu4NCl / H2O / 18 h 6: 99.3 percent / t-BuOK / tetrahydrofuran / 1 h / 20 - 30 °C 7: 89 percent / Pd(OAc)2, K2CO3, DPP / dimethylformamide / 16 h / 90 °C / 775.7 Torr 9: 92 percent / OsO4, Me3NO*2H2O / 2-methyl-propan-2-ol / 24 h / 40 °C 10: 76 percent / PS-30 catalyst / various solvent(s) / 48 h 11: 100 percent / NaOCl, 4-acetoxy-TEMPO, KBr, NaHCO3 / CH2Cl2; H2O / 0.67 h 12: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 13: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 14: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 15: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 16: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

1-(2,6-dichloropyridin-4-yl)propan-1-one (183433-62-7) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 15 steps 1: 100 percent / TMSCl / 12 h / Ambient temperature 2: 89 percent / methanol / 20 h / Heating 3: 1.) n-BuLi / 1.) heptane, hexane, 0 deg C, 30 min, 2.) hexane, heptane, -30 deg C - 0 deg C, 1 h 4: 71 percent / NaBH4, n-Bu4NCl / H2O / 18 h 5: 99.3 percent / t-BuOK / tetrahydrofuran / 1 h / 20 - 30 °C 6: 89 percent / Pd(OAc)2, K2CO3, DPP / dimethylformamide / 16 h / 90 °C / 775.7 Torr 8: 92 percent / OsO4, Me3NO*2H2O / 2-methyl-propan-2-ol / 24 h / 40 °C 9: 76 percent / PS-30 catalyst / various solvent(s) / 48 h 10: 100 percent / NaOCl, 4-acetoxy-TEMPO, KBr, NaHCO3 / CH2Cl2; H2O / 0.67 h 11: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 12: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 13: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 14: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 15: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

5-Benzyloxymethyl-4-(1-hydroxy-1-hydroxymethyl-propyl)-6-methoxy-pyridine-2-carboxylic acid propyl ester (183433-74-1) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 7 steps 1: 76 percent / PS-30 catalyst / various solvent(s) / 48 h 2: 100 percent / NaOCl, 4-acetoxy-TEMPO, KBr, NaHCO3 / CH2Cl2; H2O / 0.67 h 3: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 4: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 5: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 6: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 7: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

5-Benzyloxymethyl-4-((S)-1-hydroxy-1-hydroxymethyl-propyl)-6-methoxy-pyridine-2-carboxylic acid propyl ester (183433-75-2) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 6 steps 1: 100 percent / NaOCl, 4-acetoxy-TEMPO, KBr, NaHCO3 / CH2Cl2; H2O / 0.67 h 2: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 3: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 4: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 5: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 6: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

2,6-dichloro-4-(2-ethyl-1,3-dioxolan-2-yl)pyridine (183433-63-8) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 14 steps 1: 89 percent / methanol / 20 h / Heating 2: 1.) n-BuLi / 1.) heptane, hexane, 0 deg C, 30 min, 2.) hexane, heptane, -30 deg C - 0 deg C, 1 h 3: 71 percent / NaBH4, n-Bu4NCl / H2O / 18 h 4: 99.3 percent / t-BuOK / tetrahydrofuran / 1 h / 20 - 30 °C 5: 89 percent / Pd(OAc)2, K2CO3, DPP / dimethylformamide / 16 h / 90 °C / 775.7 Torr 7: 92 percent / OsO4, Me3NO*2H2O / 2-methyl-propan-2-ol / 24 h / 40 °C 8: 76 percent / PS-30 catalyst / various solvent(s) / 48 h 9: 100 percent / NaOCl, 4-acetoxy-TEMPO, KBr, NaHCO3 / CH2Cl2; H2O / 0.67 h 10: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 11: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 12: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 13: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 14: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

6-chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine (183433-64-9) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 13 steps 1: 1.) n-BuLi / 1.) heptane, hexane, 0 deg C, 30 min, 2.) hexane, heptane, -30 deg C - 0 deg C, 1 h 2: 71 percent / NaBH4, n-Bu4NCl / H2O / 18 h 3: 99.3 percent / t-BuOK / tetrahydrofuran / 1 h / 20 - 30 °C 4: 89 percent / Pd(OAc)2, K2CO3, DPP / dimethylformamide / 16 h / 90 °C / 775.7 Torr 6: 92 percent / OsO4, Me3NO*2H2O / 2-methyl-propan-2-ol / 24 h / 40 °C 7: 76 percent / PS-30 catalyst / various solvent(s) / 48 h 8: 100 percent / NaOCl, 4-acetoxy-TEMPO, KBr, NaHCO3 / CH2Cl2; H2O / 0.67 h 9: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 10: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 11: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 12: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 13: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

6-Chloro-4-(2-ethyl-[1,3]dioxolan-2-yl)-2-methoxy-pyridine-3-carbaldehyde (183433-65-0) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 12 steps 1: 71 percent / NaBH4, n-Bu4NCl / H2O / 18 h 2: 99.3 percent / t-BuOK / tetrahydrofuran / 1 h / 20 - 30 °C 3: 89 percent / Pd(OAc)2, K2CO3, DPP / dimethylformamide / 16 h / 90 °C / 775.7 Torr 5: 92 percent / OsO4, Me3NO*2H2O / 2-methyl-propan-2-ol / 24 h / 40 °C 6: 76 percent / PS-30 catalyst / various solvent(s) / 48 h 7: 100 percent / NaOCl, 4-acetoxy-TEMPO, KBr, NaHCO3 / CH2Cl2; H2O / 0.67 h 8: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 9: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 10: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 11: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 12: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

[6-Chloro-4-(2-ethyl-[1,3]dioxolan-2-yl)-2-methoxy-pyridin-3-yl]-methanol (183433-66-1) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 11 steps 1: 99.3 percent / t-BuOK / tetrahydrofuran / 1 h / 20 - 30 °C 2: 89 percent / Pd(OAc)2, K2CO3, DPP / dimethylformamide / 16 h / 90 °C / 775.7 Torr 4: 92 percent / OsO4, Me3NO*2H2O / 2-methyl-propan-2-ol / 24 h / 40 °C 5: 76 percent / PS-30 catalyst / various solvent(s) / 48 h 6: 100 percent / NaOCl, 4-acetoxy-TEMPO, KBr, NaHCO3 / CH2Cl2; H2O / 0.67 h 7: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 8: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 9: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 10: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 11: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

(S)-4-Ethyl-3,4-dihydroxy-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-6-carboxylic acid propyl ester (194999-55-8) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 2: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 3: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 4: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

propyl (S)-4-ethyl-3,4,7,8-tetrahydro-4-hydroxy-3,8-dioxo-1H-pyrano[3,4-c] pyridine-6-carboxylate (183434-02-8) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 2: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

propyl (S)-4-ethyl-3,4-dihydro-4-hydroxy-8-methoxy-3-oxo-1H-pyrano[3,4-c]pyridine-6-carboxylate (183434-00-6) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 2: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 3: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

3-Benzyloxymethyl-6-chloro-4-(2-ethyl-[1,3]dioxolan-2-yl)-2-methoxy-pyridine (183433-67-2) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 10 steps 1: 89 percent / Pd(OAc)2, K2CO3, DPP / dimethylformamide / 16 h / 90 °C / 775.7 Torr 3: 92 percent / OsO4, Me3NO*2H2O / 2-methyl-propan-2-ol / 24 h / 40 °C 4: 76 percent / PS-30 catalyst / various solvent(s) / 48 h 5: 100 percent / NaOCl, 4-acetoxy-TEMPO, KBr, NaHCO3 / CH2Cl2; H2O / 0.67 h 6: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 7: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 8: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 9: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 10: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

5-Benzyloxymethyl-6-methoxy-4-(1-methylene-propyl)-pyridine-2-carboxylic acid propyl ester (183433-72-9) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 8 steps 1: 92 percent / OsO4, Me3NO*2H2O / 2-methyl-propan-2-ol / 24 h / 40 °C 2: 76 percent / PS-30 catalyst / various solvent(s) / 48 h 3: 100 percent / NaOCl, 4-acetoxy-TEMPO, KBr, NaHCO3 / CH2Cl2; H2O / 0.67 h 4: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 5: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 6: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 7: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 8: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

5-Benzyloxymethyl-4-((S)-1-formyl-1-hydroxy-propyl)-6-methoxy-pyridine-2-carboxylic acid propyl ester (183433-96-7) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 5 steps 1: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 2: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 3: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 4: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 5: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

5-Benzyloxymethyl-4-(2-ethyl-[1,3]dioxolan-2-yl)-6-methoxy-pyridine-2-carboxylic acid propyl ester (183433-68-3) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions

Yield

Multi-step reaction with 9 steps 2: 92 percent / OsO4, Me3NO*2H2O / 2-methyl-propan-2-ol / 24 h / 40 °C 3: 76 percent / PS-30 catalyst / various solvent(s) / 48 h 4: 100 percent / NaOCl, 4-acetoxy-TEMPO, KBr, NaHCO3 / CH2Cl2; H2O / 0.67 h 5: 96 percent / H2 / Pd/C / methanol / 96 h / 775.7 Torr / Ambient temperature; other catalyst, reaction time, temperature 6: 99 percent / TEMPO, KBr, NaHCO3, NaOCl / CH2Cl2; H2O / 0.5 h 7: 89 percent / TMSCl, NaI / acetonitrile / 6 h / 0 - 20 °C 8: 74 percent / Cs2CO3 / dimethylsulfoxide / 21 h / 47 - 50 °C 9: 93.4 percent / trifluoroacetic acid; toluene / 2 h / 110 °C View Scheme

C15H17NO4 (165674-31-7) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Multi-step reaction with 6 steps 1: (DHQD)2-PHAL, K3Fe(CN)6, K2CO3, K2OsO2, CH3SO2NH2 / 2-methyl-propan-2-ol; H2O / 96 h / Ambient temperature 2: pyridine / 3 h / Ambient temperature 3: 93 percent / i-PrNEt / CH2Cl2 / 3 h / Ambient temperature 4: 92 percent / aq. K2CO3 / methanol / 2 h / Ambient temperature 5: 84 percent / pyridinium chlorochromate, AcONa, molecular sieves 4 Angstroem / 24 h / Ambient temperature 6: 100 percent / aq. HCl / tetrahydrofuran; H2O / 3 h / 60 °C View Scheme
Multi-step reaction with 3 steps 1: (DHQD)2-PHAL, K3Fe(CN)6, K2CO3, K2OsO2, CH3SO2NH2 / 2-methyl-propan-2-ol; H2O / 96 h / Ambient temperature 2: I2, CaCO3 / methanol; H2O / 24 h / Ambient temperature 3: 100 percent / aq. HCl / tetrahydrofuran; H2O / 3 h / 60 °C View Scheme

C15H19NO5 (165674-30-6) → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Multi-step reaction with 7 steps 1: 96 percent / MsCl, TEA / tetrahydrofuran / 24 h / Ambient temperature 2: (DHQD)2-PHAL, K3Fe(CN)6, K2CO3, K2OsO2, CH3SO2NH2 / 2-methyl-propan-2-ol; H2O / 96 h / Ambient temperature 3: pyridine / 3 h / Ambient temperature 4: 93 percent / i-PrNEt / CH2Cl2 / 3 h / Ambient temperature 5: 92 percent / aq. K2CO3 / methanol / 2 h / Ambient temperature 6: 84 percent / pyridinium chlorochromate, AcONa, molecular sieves 4 Angstroem / 24 h / Ambient temperature 7: 100 percent / aq. HCl / tetrahydrofuran; H2O / 3 h / 60 °C View Scheme
Multi-step reaction with 4 steps 1: 96 percent / MsCl, TEA / tetrahydrofuran / 24 h / Ambient temperature 2: (DHQD)2-PHAL, K3Fe(CN)6, K2CO3, K2OsO2, CH3SO2NH2 / 2-methyl-propan-2-ol; H2O / 96 h / Ambient temperature 3: I2, CaCO3 / methanol; H2O / 24 h / Ambient temperature 4: 100 percent / aq. HCl / tetrahydrofuran; H2O / 3 h / 60 °C View Scheme

C17H23NO7 → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 84 percent / pyridinium chlorochromate, AcONa, molecular sieves 4 Angstroem / 24 h / Ambient temperature 2: 100 percent / aq. HCl / tetrahydrofuran; H2O / 3 h / 60 °C View Scheme

C17H21NO7 → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 93 percent / i-PrNEt / CH2Cl2 / 3 h / Ambient temperature 2: 92 percent / aq. K2CO3 / methanol / 2 h / Ambient temperature 3: 84 percent / pyridinium chlorochromate, AcONa, molecular sieves 4 Angstroem / 24 h / Ambient temperature 4: 100 percent / aq. HCl / tetrahydrofuran; H2O / 3 h / 60 °C View Scheme

C19H25NO8 → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 92 percent / aq. K2CO3 / methanol / 2 h / Ambient temperature 2: 84 percent / pyridinium chlorochromate, AcONa, molecular sieves 4 Angstroem / 24 h / Ambient temperature 3: 100 percent / aq. HCl / tetrahydrofuran; H2O / 3 h / 60 °C View Scheme

C15H19NO6 → (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5)

Conditions	Yield
Multi-step reaction with 5 steps 1: pyridine / 3 h / Ambient temperature 2: 93 percent / i-PrNEt / CH2Cl2 / 3 h / Ambient temperature 3: 92 percent / aq. K2CO3 / methanol / 2 h / Ambient temperature 4: 84 percent / pyridinium chlorochromate, AcONa, molecular sieves 4 Angstroem / 24 h / Ambient temperature 5: 100 percent / aq. HCl / tetrahydrofuran; H2O / 3 h / 60 °C View Scheme
Multi-step reaction with 2 steps 1: I2, CaCO3 / methanol; H2O / 24 h / Ambient temperature 2: 100 percent / aq. HCl / tetrahydrofuran; H2O / 3 h / 60 °C View Scheme

(4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5) + 2-amino-5-methylthiopropiophenone (124623-17-2) → (S)-4,11-Diethyl-4-hydroxy-9-methylsulfanyl-1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]fluorene-3,13-dione

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 24h; Heating;	99%

1-(2-amino-phenyl)-3-trimethylsilanyl-propan-1-one (1609324-12-0) + (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5) → (4S)-4-ethyl-4-hydroxy-11-[2-(trimethylsilyl)ethyl]-1H-pyrano[3':4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione

Conditions	Yield
With toluene-4-sulfonic acid; acetic acid In toluene at 100℃; for 20h;	98%

2-(3'-trimethylsilylpropionyl)-N-Boc-aniline (1609257-42-2) + (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (110351-94-5) → (4S)-4-ethyl-4-hydroxy-11-[2-(trimethylsilyl)ethyl]-1H-pyrano[3':4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione

Conditions	Yield
With toluene-4-sulfonic acid; acetic acid In toluene at 100℃; for 24h;	96%

Upstream product

• 110314-10-8 (S)-α-ethyl-α-hydroxy-1,1-(ethylenedioxy)-6-hydroxymethyl-5-oxo-1,2,3,5-tetrahydroindolizine-7-acetamide 
• 183434-04-0 1,1-dimethylethyl (S)-4-ethyl-3,4,8,10-tetrahydro-4,6-dihydroxy-3,10-dioxo-1H-pyrano[3,4 - f] indolidin-7-carboxylate 
• 99-11-6 citrazinic acid 
• 5398-44-7 2,6-dichloropyridine-4-carboxylic acid 
• 73427-97-1 6-(acetoxymethyl)-1,1'-(ethylenedioxy)-7-<1'-(ethoxycarbonyl)propyl>-5-oxo-Δ⁶⁽⁸⁾-tetrahydroindolizine 
• 58610-66-5 6'-cyano-α-ethyl-2',3'-dihydro-5'-oxospiro<1,3-dioxolane-2,1'(5'H)-indolizine>-7'-acetic acid, ethyl ester 
• 58610-64-3 7’-methyl-5’-oxo-3’,5’-dihydro-2’H-spiro[[1,3]dioxolane-2,1‘-indolizine]-6’-carbonitrile 
• 183433-64-9 6-chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine 
• 183433-63-8 2,6-dichloro-4-(2-ethyl-1,3-dioxolan-2-yl)pyridine 
• 183433-62-7 1-(2,6-dichloropyridin-4-yl)propan-1-one 
• 144788-94-3 4-acetoxy-4-ethyl-6,6-(ethylenedioxy)-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,10(4H)-dione 
• 102978-41-6 4'-ethyl-1',4',7',8'-tetrahydro-4'-hydroxy-3'H,10'H-spiro[1,3-dioxolane-2,6'-pyrano[3,4-f]indolizine]-3',10'-dione 
• 165674-36-2 C₁₇H₂₁NO₇ 
• 110351-93-4 (S)-4′-ethyl-4′-hydroxy-7′,8′-dihydrospiro[[1,3]dioxolane-2,6′-pyrano[3,4-f]indolizine]-3′,10′(1′H,4′H)-dione 

Downstream Products

• 7689-03-4 camptothecin 
• 149882-15-5 7-(chloromethyl)-10,11-(ethylenedioxy)-(20S)-camptothecin 
• 86639-52-3 7-ethyl-10-hydroxycamptothecin 
• 97682-44-5 irinotecan 
• 220913-32-6 DB-67 
• 100286-90-6 irinotecan hydrochloirde 
• 86639-63-6 10-amino-20(S)-camptothecin 

Relevant articles and documents

Synthetic studies on camptothecins. Part 3

A concise and efficient asymmetric process for the total synthesis of (20S)-7-ethyl-10-hydroxycamptothecin (=SN-38; 1f), an active metabolic form of the prodrug irinotecan, is described. This approach features the enantioselective cyanosilylation of indolizinone 4 into the corresponding cyanohydrin 5, mediated by a bifunctional thiourea-based cinchona alkaloid under mild conditions, and I2-catalyzed Friedlnder condensation of the tricyclic lactone 6 and 2-amino-5-hydroxy propiophenone (=1-(2-amino-5- hydroxyphenyl)propan-1-one). Copyright

Enantioselective synthesis of 20(S)-camptothecin using an enzyme- catalyzed resolution

The important key intermediate of a 20(S)-camptothecin synthesis was prepared enantioselectively using an enzyme-catalyzed resolution. A commercially available papain was found to exhibit the highest enantioselectivity with moderate activity, and the (S)-enantiomer of 99% ee was obtained as the remaining substrate.

Camptothecin derivative and preparation method and application thereof

The invention relates to a compound with a structure shown in a formula (I), a stereoisomer of the compound and a pharmaceutically acceptable salt form of the compound, and further relates to a preparation method of the compound, a pharmaceutical composition containing therapeutically effective dose of the compound, and application of the pharmaceutical composition in the preparation for the prevention and/or treatment of cancer. The compound is a camptothecin derivative with a novel structure with 10 site and 11 site of a stem nucleus introduced with methylene dioxy groups and 7-site introduced with different substituted groups. The raw materials of the preparation method can be obtained easily, a synthetic method is simple, a purification method is simple and fast, the compound has excellent cytotoxic activity in vitro and excellent antitumor effect in vivo, and the compound has broad medicinal prospects.(Please see the specification for the formula).

COMPOUND OF CAMPTOTHECIN AND PREPARATION AND USE THEREOF

The present disclosure relates to a compound of formula I, a pharmaceutical composition thereof and the use thereof as an anti-tumor drug.