6559-91-7

Basic information

• Product Name: 4'-Demethylepipodophyllotoxin
• Synonyms: (5R)-5,8,8aβ,9-Tetrahydro-9α-hydroxy-5β-(4-hydroxy-3,5-dimethoxyphenyl)furo[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aαH)-one;(5R)-5β-(3,5-Dimethoxy-4-hydroxyphenyl)-7α-(hydroxymethyl)-8α-hydroxy-5,6,7,8-tetrahydronaphtho[2,3-d]-1,3-dioxole-6β-carboxylic acid 6,7-lactone;(5R)-5β-(3,5-Dimethoxy-4-hydroxyphenyl)-9α-hydroxy-5,5aα,6,8,8aβ,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d]-1,3-dioxole-6-one;(5R,5aα,8aβ)-5,8,8a,9-Tetrahydro-5β-(4-hydroxy-3,5-dimethoxyphenyl)-9α-hydroxyfuro[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one;4-Domethylpodophyllotoxin, 4'-demethyl-epi-Podophyllotoxin;4'-O-deMethylepipodophyllotoxin;4-DeMethyl Epipodophyllotoxin(DMEP);Furo[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one,5,8,8a,9-tetrahydro-9-hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-,(5R,5aR,8aR,9S)-
• CAS NO: 6559-91-7
• Molecular Formula: C₂₁H₂₀O₈
• Molecular Weight: 400.38
• EINECS: 2017-001-1
• Product Categories: chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;Miscellaneous Natural Products;Plant Oils, Toxins, Phenolic Acids & Derivatives;Inhibitors
• Mol File: 6559-91-7.mol
• Article Data: 34

Chemical Properties

• Melting Point: 246-248°C
• Boiling Point: 626.5 °C at 760 mmHg
• Flash Point: 224.4 °C
• Appearance: /
• Density: 1.446 g/cm³
• Storage Temp.: -20°C Freezer
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 9.94±0.40(Predicted)
• CAS DataBase Reference: 4'-Demethylepipodophyllotoxin(CAS DataBase Reference)
• NIST Chemistry Reference: 4'-Demethylepipodophyllotoxin(6559-91-7)
• EPA Substance Registry System: 4'-Demethylepipodophyllotoxin(6559-91-7)

Safety Data

• Hazardous Substances Data: 6559-91-7(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Solid

Uses

A potent inhibitor of microtubule assembly.

Definition

ChEBI: An organic heterotetracyclic compound that is the 9- epimer of 4'-demethylpodophyllotoxin.

Synthetic route

podofilox (518-28-5) → 4'-demethylepipodophyllotoxin (6559-91-7)

Conditions	Yield
With methanesulfonic acid; DL-methionine; trifluoroacetic acid at 40℃; for 0.75h;	93%
Stage #1: podofilox With methanesulfonic acid; sodium iodide In dichloromethane at 0 - 20℃; for 5h; Stage #2: With barium carbonate In water; acetone at 40℃; for 0.5h;	90%
Stage #1: podofilox With 1-(Trimethylsilyl)imidazole In dichloromethane at 0℃; Stage #2: With water; barium carbonate In acetone	79%

Carbonic acid benzyl ester 4-((5R,5aR,8aR)-6,9-dioxo-5,5a,6,8,8a,9-hexahydro-furo[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxy-phenyl ester (156350-44-6) → 4'-demethylepipodophyllotoxin (6559-91-7)

Conditions	Yield
With ruthenium(II) chloride; (S)-N2,N2'-bis(pyridin-2-ylmethyl-1,1'-binaphthyl-2,2'-diamine); hydrogen In isopropyl alcohol at 20 - 25℃; under 38002.6 Torr; for 18h;	89%

4'-O-demethyl-4β-bromo-4-desoxypodophyllotoxin (16477-16-0) → 4'-demethylepipodophyllotoxin (6559-91-7)

Conditions	Yield
With water; barium carbonate In acetone at 40℃; for 4h;	71%
With barium carbonate In water; acetone for 1h; Heating;	52%

acetic acid (64-19-7) + podofilox (518-28-5) → 4'-demethylepipodophyllotoxin (6559-91-7) + 4'-demethyl-β-apopicropodophyllotoxin (102306-96-7) + 4'-demethyl-1-O-ethyl-1-epipodophyllotoxin (102306-95-6) + epipodophyllotoxin (4375-07-9)

Conditions	Yield
With hydrogen bromide 1.) 15 min, 2.) RT, 20 h; Multistep reaction. Further byproducts given;

acetic acid (64-19-7) + podofilox (518-28-5) → 4'-demethylepipodophyllotoxin (6559-91-7) + 4'-demethyl-β-apopicropodophyllotoxin (102306-96-7) + 3',4'-didemethylepipodophyllotoxin (102306-97-8) + epipodophyllotoxin (4375-07-9)

Conditions	Yield
With hydrogen bromide 1.) 15 min, 2.) RT, 20 h; Multistep reaction. Further byproducts given;

etoposide (33419-42-0) → 4'-demethylepipodophyllotoxin (6559-91-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium iodide; chloro-trimethyl-silane / acetonitrile / 0 °C 2: water; barium carbonate / acetone / 20 °C View Scheme

syringic aldehyde (134-96-3) → 4'-demethylepipodophyllotoxin (6559-91-7)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: sodium hydroxide / tetrahydrofuran / 25 - 30 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 3 h / -20 - -15 °C / Inert atmosphere 3.1: iron(III) chloride / dichloromethane / 1 h / 18 - 22 °C 4.1: triethylamine / dichloromethane / 1 h / -2 - 2 °C 5.1: palladium diacetate; triphenylphosphine; potassium carbonate / acetonitrile / 20 h / 75 - 85 °C 6.1: pyridine; ozone / dichloromethane; methanol / 5 h / -25 - -15 °C 6.2: 4 h / 20 °C / Inert atmosphere 7.1: (S)-N2,N2'-bis(pyridin-2-ylmethyl-1,1'-binaphthyl-2,2'-diamine); ruthenium(II) chloride; hydrogen / isopropyl alcohol / 18 h / 20 - 25 °C / 38002.6 Torr View Scheme

C17H16O6 → 4'-demethylepipodophyllotoxin (6559-91-7)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 3 h / -20 - -15 °C / Inert atmosphere 2.1: iron(III) chloride / dichloromethane / 1 h / 18 - 22 °C 3.1: triethylamine / dichloromethane / 1 h / -2 - 2 °C 4.1: palladium diacetate; triphenylphosphine; potassium carbonate / acetonitrile / 20 h / 75 - 85 °C 5.1: pyridine; ozone / dichloromethane; methanol / 5 h / -25 - -15 °C 5.2: 4 h / 20 °C / Inert atmosphere 6.1: (S)-N2,N2'-bis(pyridin-2-ylmethyl-1,1'-binaphthyl-2,2'-diamine); ruthenium(II) chloride; hydrogen / isopropyl alcohol / 18 h / 20 - 25 °C / 38002.6 Torr View Scheme

C23H24O8 → 4'-demethylepipodophyllotoxin (6559-91-7)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: iron(III) chloride / dichloromethane / 1 h / 18 - 22 °C 2.1: triethylamine / dichloromethane / 1 h / -2 - 2 °C 3.1: palladium diacetate; triphenylphosphine; potassium carbonate / acetonitrile / 20 h / 75 - 85 °C 4.1: pyridine; ozone / dichloromethane; methanol / 5 h / -25 - -15 °C 4.2: 4 h / 20 °C / Inert atmosphere 5.1: (S)-N2,N2'-bis(pyridin-2-ylmethyl-1,1'-binaphthyl-2,2'-diamine); ruthenium(II) chloride; hydrogen / isopropyl alcohol / 18 h / 20 - 25 °C / 38002.6 Torr View Scheme

C30H28O10 → 4'-demethylepipodophyllotoxin (6559-91-7)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 1 h / -2 - 2 °C 2.1: palladium diacetate; triphenylphosphine; potassium carbonate / acetonitrile / 20 h / 75 - 85 °C 3.1: pyridine; ozone / dichloromethane; methanol / 5 h / -25 - -15 °C 3.2: 4 h / 20 °C / Inert atmosphere 4.1: (S)-N2,N2'-bis(pyridin-2-ylmethyl-1,1'-binaphthyl-2,2'-diamine); ruthenium(II) chloride; hydrogen / isopropyl alcohol / 18 h / 20 - 25 °C / 38002.6 Torr View Scheme

C31H27F3O12S → 4'-demethylepipodophyllotoxin (6559-91-7)

Conditions

Yield

Multi-step reaction with 3 steps 1.1: palladium diacetate; triphenylphosphine; potassium carbonate / acetonitrile / 20 h / 75 - 85 °C 2.1: pyridine; ozone / dichloromethane; methanol / 5 h / -25 - -15 °C 2.2: 4 h / 20 °C / Inert atmosphere 3.1: (S)-N2,N2'-bis(pyridin-2-ylmethyl-1,1'-binaphthyl-2,2'-diamine); ruthenium(II) chloride; hydrogen / isopropyl alcohol / 18 h / 20 - 25 °C / 38002.6 Torr View Scheme

4'-demethylepipodophyllotoxin (6559-91-7) → 4β-azido-4-deoxy-4′-demethylepipodophyllotoxin (117604-05-4)

Conditions	Yield
With sodium azide; trifluoroacetic acid In chloroform at 20℃;	100%
With sodium azide; trifluoroacetic acid In chloroform for 0.25h;	94%
With sodium azide; trifluoroacetic acid In chloroform at 20℃; Cooling with ice;	91.8%

4'-demethylepipodophyllotoxin (6559-91-7) + tert-butyldimethylsilyl chloride (18162-48-6) → 4,4'-bis-O-(dimethyl-tert-butylsilyl)-4'-O-demethylepipodophyllotoxin (153230-70-7)

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide for 20h;	98%
With 2,6-dimethylpyridine In dichloromethane at 0℃; for 1h;	81%

4'-demethylepipodophyllotoxin (6559-91-7) + acetic acid (64-19-7) → 4'-demethylepipodophyllotoxin diacetate (22823-30-9)

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	98%

4'-demethylepipodophyllotoxin (6559-91-7) + benzyl chloroformate (501-53-1) → 4'-demethyl-4'-O-(benzoyloxycarbonyl)epipodophyllotoxin (23363-33-9)

Conditions	Yield
With triethylamine In dichloromethane at 0℃; for 2h;	97%
With triethylamine In dichloromethane at 0 - 35℃; for 2h;	97%
With triethylamine In dichloromethane at 0 - 35℃; for 2h;	97%

4'-demethylepipodophyllotoxin (6559-91-7) + chloroacetonitrile (107-14-2) → 2-chloro-N-[9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]acetamide

Conditions	Yield
sulfuric acid at 20℃; for 3h; Ritter Reaction;	96%

4'-demethylepipodophyllotoxin (6559-91-7) + chloroacetonitrile (107-14-2) → 4-chloroacetamido-4-deoxy-4'-demethylepipodophyllotoxin (150059-96-4)

Conditions	Yield
With sulfuric acid In isopropyl alcohol at 20℃; for 1h; Inert atmosphere;	96%
With sulfuric acid at 20℃; for 1h; Ritter Reaction;	93%
sulfuric acid at 20℃;	93%
With sulfuric acid Ritter Amidation;
Ritter Amidation;

4'-demethylepipodophyllotoxin (6559-91-7) + propionic acid (802294-64-0) → C27H28O10

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	94%

4'-demethylepipodophyllotoxin (6559-91-7) + butyric acid (107-92-6) → C29H32O10

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	94%

4'-demethylepipodophyllotoxin (6559-91-7) + chloroacetonitrile (107-14-2) → 4-chloroacetamido-4-deoxy-4'-demethylepipodophyllotoxin

Conditions	Yield
With sulfuric acid at 20℃;	93%

nicotinic acid (59-67-6) + 4'-demethylepipodophyllotoxin (6559-91-7) → C33H26N2O10

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	92%

pyridine-4-carboxylic acid (55-22-1) + 4'-demethylepipodophyllotoxin (6559-91-7) → C33H26N2O10

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	92%

4'-demethylepipodophyllotoxin (6559-91-7) + 4-nitro-benzoic acid (62-23-7) → C35H26N2O14

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	92%

4'-demethylepipodophyllotoxin (6559-91-7) → 4β-azido-4-deoxy-4′-demethylepipodophyllotoxin (117604-05-4) + 4β-azido-4'-dimethyl-4-deoxy-epipodophyllotoxin (117507-85-4)

Conditions	Yield
With tris-(2-chloro-ethyl)-amine; boron trifluoride diethyl etherate In dichloromethane; benzene at -15℃; for 1h;	A 91% B n/a

4'-demethylepipodophyllotoxin (6559-91-7) + Dibenzyl phosphite (17176-77-1) → dibenzyl 4'-demethyl-4-epipodophyllotoxin-4'-phosphate

Conditions	Yield
With tetrachloromethane; dmap; N-ethyl-N,N-diisopropylamine In acetonitrile at -10℃;	90%
With dmap; N-ethyl-N,N-diisopropylamine In tetrachloromethane; acetonitrile at -10℃; Inert atmosphere;	90.1%

4'-demethylepipodophyllotoxin (6559-91-7) → 4'-demethyl-β-apopicropodophyllotoxin (102306-96-7)

Conditions	Yield
With sulfuric acid; acetic anhydride for 1h; Heating;	90%

4'-demethylepipodophyllotoxin (6559-91-7) + tert-butyldimethylsilyl chloride (18162-48-6) → 4'-O-tert-butyldimethylsilanyl-4'-O-demethyl-4-epipodophyllotoxin (118356-07-3)

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 1.5h;	89%
With 1H-imidazole In N,N-dimethyl-formamide for 4.5h;	86%
With 1H-imidazole In tetrahydrofuran	60%

nicotinic acid (59-67-6) + 4'-demethylepipodophyllotoxin (6559-91-7) → C27H23NO9 (888029-90-1)

Conditions	Yield
With dicyclohexyl-carbodiimide; dmap In dichloromethane at 20℃; for 2h;	89%

2-Picolinic acid (98-98-6) + 4'-demethylepipodophyllotoxin (6559-91-7) → C27H23NO9 (888029-91-2)

Conditions	Yield
With dicyclohexyl-carbodiimide; dmap In dichloromethane at 20℃; for 2h;	89%

5-bromo-3-pyridinecarboxylic acid (20826-04-4) + 4'-demethylepipodophyllotoxin (6559-91-7) → C27H22BrNO9 (888029-94-5)

Conditions	Yield
With dicyclohexyl-carbodiimide; dmap In dichloromethane at 20℃; for 2h;	87%

2-chloronicotinic acid (2942-59-8) + 4'-demethylepipodophyllotoxin (6559-91-7) → C27H22ClNO9 (888029-92-3)

Conditions	Yield
With dicyclohexyl-carbodiimide; dmap In dichloromethane at 20℃; for 2h;	87%

phenylacetic acid (103-82-2) + 4'-demethylepipodophyllotoxin (6559-91-7) → C37H32O10

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	87%

4'-demethylepipodophyllotoxin (6559-91-7) + benzyl chloroformate (501-53-1) → 4'-benzyloxycarbonyl-4'-demethylpodophyllotoxin (23412-22-8)

Conditions	Yield
With triethylamine In dichloromethane at 20℃;	85.65%

4'-demethylepipodophyllotoxin (6559-91-7) + C10H11N3O2S2 → C31H29N3O9S2

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24.25h; Cooling with ice;	85%

4'-demethylepipodophyllotoxin (6559-91-7) + 2-azido-2-deoxy-3,4,6-tri-O-acetyl-β-D-glucopyranose → 3″,4″,6″-tri-O-acetyl-2-azido-deoxy-4′-desmethylepipdophyllotoxin-β-D-glucopyranoside

Conditions	Yield
Stage #1: 4'-demethylepipodophyllotoxin With boron trifluoride diethyl etherate In dichloromethane at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 3,4,6-tri-O-acetyl-2-azido-2-deoxy-β-D-glucopyranose In dichloromethane at -20℃; for 2h; Inert atmosphere; Molecular sieve;	85%
Stage #1: 4'-demethylepipodophyllotoxin With boron trifluoride diethyl etherate In dichloromethane at 0℃; Inert atmosphere; Stage #2: 3,4,6-tri-O-acetyl-2-azido-2-deoxy-β-D-glucopyranose In dichloromethane at -5℃; for 4h; Inert atmosphere;

pyridine-4-carboxylic acid (55-22-1) + 4'-demethylepipodophyllotoxin (6559-91-7) → C27H23NO9 (888029-89-8)

Conditions	Yield
With dicyclohexyl-carbodiimide; dmap In dichloromethane at 20℃; for 2h;	83%

6-Chloro-3-pyridinecarboxylic acid (5326-23-8) + 4'-demethylepipodophyllotoxin (6559-91-7) → C27H22ClNO9 (888029-93-4)

Conditions	Yield
With dicyclohexyl-carbodiimide; dmap In dichloromethane at 20℃; for 2h;	83%

4'-demethylepipodophyllotoxin (6559-91-7) → 2'-chloro-4′-demethylepipodophyllotoxin (138261-31-1)

Conditions	Yield
With N-chloro-succinimide In N,N-dimethyl-formamide at 0 - 20℃; for 18h;	82%
With N-chloro-succinimide In N,N-dimethyl-formamide for 3.5h; Ambient temperature;	75%
With N-chloro-succinimide In chloroform at 20℃; for 4h; regioselective reaction;
With N-chloro-succinimide In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;

4'-demethylepipodophyllotoxin (6559-91-7) + 3-Phenylpropionic acid (501-52-0) → C39H36O10

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	82%

Upstream product

• 16477-16-0 4'-O-demethyl-4β-bromo-4-desoxypodophyllotoxin 
• 477-47-4 (+/-)-podophyllotoxin 
• 156350-44-6 Carbonic acid benzyl ester 4-((5R,5aR,8aR)-6,9-dioxo-5,5a,6,8,8a,9-hexahydro-furo[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxy-phenyl ester 
• 134-96-3 syringic aldehyde 
• 33419-42-0 etoposide 
• 518-28-5 podofilox 
• 1185862-69-4 7-chlorodeoxypodophyllotoxin 
• 106636-74-2 4β-bromo-4-desoxypodophyllotoxin 
• 153230-77-4 4,4'-bis(tert-butyldimethylsilyl)-4'-O-demethylepipodophyllol 
• 746639-24-7 4β-iodo-4-O-demethylpodophyllotoxin 
• 220995-81-3 4-bromo-4'-demethyl-epipodophyllotoxin 
• 106636-74-2 1α-bromo-desoxypodophyllotoxin 
• 64-19-7 acetic acid 

Downstream Products

• 22823-30-9 4'-demethylepipodophyllotoxin diacetate 
• 217475-21-3 2''-3''-di-O-benzyletoposide 
• 3590-93-0 4'-demethyl-4-deoxypodophyllotoxin 
• 290371-79-8 (5S,5aR,8aR,9R)-9-(4-Hydroxy-3,5-dimethoxy-phenyl)-8-oxo-5,5a,6,8,8a,9-hexahydro-furo[3',4':6,7]naphtho[2,3-d][1,3]dioxole-5-carbonitrile 
• 683805-45-0 [(4aR,5R,6R,11bS)-6-(4-Hydroxy-3,5-dimethoxy-phenyl)-2,2-dimethyl-4a,5,6,11b-tetrahydro-4H-1,3,8,10-tetraoxa-cyclopenta[b]phenanthren-5-yl]-acetonitrile 
• 683805-46-1 2-[(4aR,5R,6R,11bS)-6-(4-Hydroxy-3,5-dimethoxy-phenyl)-2,2-dimethyl-4a,5,6,11b-tetrahydro-4H-1,3,8,10-tetraoxa-cyclopenta[b]phenanthren-5-yl]-acetamide 
• 683805-43-8 8-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethoxy-phenyl]-6,7-bis-hydroxymethyl-5,6,7,8-tetrahydro-naphtho[2,3-d][1,3]dioxol-5-ol 
• 683805-44-9 {6-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethoxy-phenyl]-2,2-dimethyl-4a,5,6,11b-tetrahydro-4H-1,3,8,10-tetraoxa-cyclopenta[b]phenanthren-5-yl}-methanol 

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